Wednesday, August 15, 2007
Sunday, August 12, 2007
Floating DDS
Floating Microspheres: Development, Characterization and Applications
Despite tremendous advancement in drug delivery, oral route remains the preferred route for the administration of therapeutic agents, low cost of therapy and ease of administration leads to higher levels of patient compliance1.
Conventional oral dosage forms such as tablets, capsules provide specific drug concentration in systemic circulation without offering any control over drug delivery and also cause great fluctuations in plasma drug levels.
Although single unit floating dosage forms have been extensively studied, these single unit dosage forms have the disadvantage of a release all or nothing emptying process while the multiple unit particulate system pass through the GIT to avoid the vagaries of gastric emptying and thus release the drug more uniformly. The uniform distribution of these multiple unit dosage forms along the GIT could result in more reproducible drug absorption and reduced risk of local irritation; this gave birth to oral controlled drug delivery and led to development of Gastro-retentive floating microspheres2, 3.
Over the last three decades, various attempts have been done to retain the dosage form in the stomach as a way of increasing retention time. High-density systems having density of ~3 g/cm3, are retained in the rugae of the stomach. The only major drawbacks with such systems is that it is technically difficult to manufacture them with a large amount of drug (>50%) and to achieve the required density of 2.4–2.8 g/cm3. Swelling systems are capable of swelling to a size that prevents their passage through the pylorus; as a result, the dosage form is retained in the stomach for a longer period of time. Upon coming in contact with gastric fluid, the polymer imbibes water and swells4,5, 6. Bio/mucoadhesive systems bind to the gastric epithelial cell surface, or mucin, and extend the GRT by increasing the intimacy and duration of contact between the dosage form and the biological membrane. The epithelial adhesive properties of mucin have been applied in the development of Gastro retentive drug delivery systems. Floating systems first described by Davis (1968), are low-density systems that have sufficient buoyancy to float over the gastric contents and remain in the stomach for a prolonged period. While the system floats over the gastric contents, the drug is released slowly at the desired rate, which results in increased gastro-retention time and reduces fluctuation in plasma drug concentration1,7, 8.
The floating drug delivery system can be divided into gas generating and non-effervescent systems. Floatation of drug delivery system in stomach can be achieved by effervescent systems, incorporating a floating chamber filled with vacuum, air or carbon dioxide produced as a result of effervescent reaction between organic acids and carbonates incorporated. These buoyant systems utilize matrices prepared with swellable polymers (e.g. methocel), polysaccharides (e.g. chitosan), effervescent components containing sodium bicarbonate, citric acid and tartaric acid or chambers containing a liquid that gasifies at body temperature. Non-effervescent systems incorporate a high level (20–75% w/w) of one or more gel forming, cellulosic hydrocolloids (e.g., hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, sodium carboxymethyl cellulose), polysaccharides, or matrix-forming polymers (e.g., polycarbophil, polyacrylates, polystyrene) into hollow microspheres, tablets or capsules 5, 9.
Development of Floating Microspheres
Floating microspheres are gastro-retentive drug delivery systems based on non-effervescent approach. Hollow microspheres are in strict sense, spherical empty particles without core. These microspheres are characteristically free flowing powders consisting of proteins or synthetic polymers, ideally having a size less than 200 micrometer. Solid biodegradable microspheres incorporating a drug dispersed or dissolved throughout particle matrix have the potential for controlled release of drugs10,11.
Gastro-retentive floating microspheres are low-density systems that have sufficient buoyancy to float over gastric contents and remain in stomach for prolonged period. As the system floats over gastric contents, the drug is released slowly at desired rate resulting in increased gastric retention with reduced fluctuations in plasma drug concentration.
When microspheres come in contact with gastric fluid the gel formers, polysaccharides, and polymers hydrate to form a colloidal gel barrier that controls the rate of fluid penetration into the device and consequent drug release. As the exterior surface of the dosage form dissolves, the gel layer is maintained by the hydration of the adjacent hydrocolloid layer. The air trapped by the swollen polymer lowers the density and confers buoyancy to the microspheres. However a minimal gastric content needed to allow proper achievement of buoyancy1,7,11,12. Hollow microspheres of Acrylic resins, Eudragit, PMAA, Polyethylene oxide, and Cellulose acetate; Polystyrene floatable shells; Polycarbonate floating balloons and Gelucire floating granules are the recent developments.
The advantages of hollow microspheres include:
Improves patient compliance by decreasing dosing frequency.
Bioavailability enhances despite first pass effect because fluctuations in plasma drug concentration is avoided, a desirable plasma drug concentration is maintained by continuous drug release.
Better therapeutic effect of short half-life drugs can be achieved.
Gastric retention time is increased because of buoyancy.
Drug releases in controlled manner for prolonged period.
Site-specific drug delivery to stomach can be achieved.
Enhanced absorption of drugs which solubilise only in stomach.
Superior to single unit floating dosage forms as such microspheres releases drug uniformly and there is no risk of dose dumping.
Avoidance of gastric irritation, because of sustained release effect, floatability and uniform release of drug through multiparticulate system.
Hollow microspheres are prepared by solvent diffusion and evaporation methods to create the hollow inner core. The polymer is dissolved in an organic solvent and the drug is either dissolved or dispersed in the polymer solution. The solution containing the drug is then emulsified into an aqueous phase containing polyvinyl alcohol to form oil in water emulsion. After the formation of a stable emulsion, the organic solvent is evaporated either by increasing the temperature under pressure or by continuous stirring13,14. The solvent removal leads to polymer precipitation at the o/w interface of droplets, forming cavity and thus making them hollow to impart the floating properties15, 16,17. The polymers studied for the development of such systems include Cellulose acetate, Chitosan, Eudragit, Acrycoat, Methocil, Polyacrylates, Polyvinyl acetate, Carbopol, Agar, Polyethylene oxide and Polycarbonates.
Characterization of Floating Microspheres
Floating microspheres are characterized by their micromeritic properties such as particle size, tapped density, compressibility index, true density and flow properties including angle of repose. The particle size is determined by optical microscopy; true density is determined by liquid displacement method; tapped density and compressibility index are calculated by measuring the change in volume using a bulk density apparatus; angle of repose is determined by fixed funnel method. The hollow nature of microspheres is confirmed by scanning electron microscopy 18, 19,20.
Floating behavior of hollow microspheres is studied in a dissolution test apparatus by spreading the microspheres on a simulated gastric fluid (pH 1.2) containing tween 80 as a surfactant; the media is stirred and a temperature of 37◦C is maintained throughout the study. After specific intervals of time, both the fractions of the microspheres floating and settled are collected; the buoyancy of the floating microspheres can be calculated using the data.
The in-vivo floating behavior can be investigated by X-ray photography of hollow microspheres loaded with barium sulphate in the stomach of beagle dogs. The in-vitro drug release studies are performed in a dissolution test apparatus using 0.1N hydrochloric acid as dissolution media. The in-vivo plasma profile can be obtained by performing the study in suitable animal models (e.g. beagle dogs). The in-vitro and in-vivo data can be correlated.
Applications of Floating Microspheres
Floating microspheres are especially effective in delivery of sparingly soluble and insoluble drugs. It is known that as the solubility of a drug decreases, the time available for drug dissolution becomes less adequate and thus the transit time becomes a significant factor affecting drug absorption. For weakly basic drugs that are poorly soluble at an alkaline pH, hollow microspheres may avoid chance for solubility to become the rate-limiting step in release by restricting such drugs to the stomach. The positioned gastric release is useful for drugs efficiently absorbed through stomach such as Verapamil hydrochloride. The gastro-retentive floating microspheres will alter beneficially the absorption profile of the active agent, thus enhancing its bioavailability. Drugs that have poor bioavailability because of their limited absorption to the upper gastrointestinal tract can also be delivered efficiently thereby maximizing their absorption and improving the bioavailability12,13.
Hollow microspheres can greatly improve the pharmacotherapy of the stomach through local drug release, leading to high drug concentrations at the gastric mucosa, thus eradicating Helicobacter pylori from the sub-mucosal tissue of the stomach and making it possible to treat stomach and duodenal ulcers, gastritis and oesophagitis21. The development of such systems allow administration of non-systemic, controlled release antacid formulations containing calcium carbonate and also locally acting anti-ulcer drugs in the stomach; e.g. Lansoprazole17. Buoyant microspheres are considered as a beneficial strategy for the treatment of gastric and duodenal cancers.
The floating microspheres can be used as carriers for drugs with so-called absorption windows, these substances, for example antiviral, antifungal and antibiotic agents (Sulphonamides, Quinolones, Penicillins, Cephalosporins, Aminoglycosides and Tetracyclines) are taken up only from very specific sites of the GI mucosa. In addition, by continually supplying the drug to its most efficient site of absorption, the dosage forms may allow for more effective oral use of peptide and protein drugs such as Calcitonin, Erythropoietin, Vasopressin, Insulin, low-molecular-weight Heparin, and LHRH.
Hollow microspheres of non-steroidal anti inflammatory drugs are very effective for controlled release as well as it reduces the major side effect of gastric irritation; for example floating microspheres of Indomethacin are quiet beneficial for rheumatic patients.
The drugs recently reported to be entrapped in hollow microspheres include Aspirin, Griseofulvin, Ibuprofen, Terfenadine, Diclofenac sodium, Indomethacin, Prednisolone, Lansoprazole, Celecoxib, Piroxicam, Theophylline, Diltiazem hydrochloride, Verapamil hydrochloride and Riboflavin.
Summary
Gastro retentive floating microspheres have emerged as an efficient means of enhancing the bioavailability and controlled delivery of many drugs The increasing sophistication of delivery technology will ensure the development of increasing number of gastro-retentive drug delivery systems to optimize the delivery of molecules that exhibit absorption window, low bioavailability, and extensive first pass metabolism. The control of gastro intestinal transit could be the focus of the next decade and may result in new therapeutic possibilities with substantial benefits for patients.
Despite tremendous advancement in drug delivery, oral route remains the preferred route for the administration of therapeutic agents, low cost of therapy and ease of administration leads to higher levels of patient compliance1.
Conventional oral dosage forms such as tablets, capsules provide specific drug concentration in systemic circulation without offering any control over drug delivery and also cause great fluctuations in plasma drug levels.
Although single unit floating dosage forms have been extensively studied, these single unit dosage forms have the disadvantage of a release all or nothing emptying process while the multiple unit particulate system pass through the GIT to avoid the vagaries of gastric emptying and thus release the drug more uniformly. The uniform distribution of these multiple unit dosage forms along the GIT could result in more reproducible drug absorption and reduced risk of local irritation; this gave birth to oral controlled drug delivery and led to development of Gastro-retentive floating microspheres2, 3.
Over the last three decades, various attempts have been done to retain the dosage form in the stomach as a way of increasing retention time. High-density systems having density of ~3 g/cm3, are retained in the rugae of the stomach. The only major drawbacks with such systems is that it is technically difficult to manufacture them with a large amount of drug (>50%) and to achieve the required density of 2.4–2.8 g/cm3. Swelling systems are capable of swelling to a size that prevents their passage through the pylorus; as a result, the dosage form is retained in the stomach for a longer period of time. Upon coming in contact with gastric fluid, the polymer imbibes water and swells4,5, 6. Bio/mucoadhesive systems bind to the gastric epithelial cell surface, or mucin, and extend the GRT by increasing the intimacy and duration of contact between the dosage form and the biological membrane. The epithelial adhesive properties of mucin have been applied in the development of Gastro retentive drug delivery systems. Floating systems first described by Davis (1968), are low-density systems that have sufficient buoyancy to float over the gastric contents and remain in the stomach for a prolonged period. While the system floats over the gastric contents, the drug is released slowly at the desired rate, which results in increased gastro-retention time and reduces fluctuation in plasma drug concentration1,7, 8.
The floating drug delivery system can be divided into gas generating and non-effervescent systems. Floatation of drug delivery system in stomach can be achieved by effervescent systems, incorporating a floating chamber filled with vacuum, air or carbon dioxide produced as a result of effervescent reaction between organic acids and carbonates incorporated. These buoyant systems utilize matrices prepared with swellable polymers (e.g. methocel), polysaccharides (e.g. chitosan), effervescent components containing sodium bicarbonate, citric acid and tartaric acid or chambers containing a liquid that gasifies at body temperature. Non-effervescent systems incorporate a high level (20–75% w/w) of one or more gel forming, cellulosic hydrocolloids (e.g., hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, sodium carboxymethyl cellulose), polysaccharides, or matrix-forming polymers (e.g., polycarbophil, polyacrylates, polystyrene) into hollow microspheres, tablets or capsules 5, 9.
Development of Floating Microspheres
Floating microspheres are gastro-retentive drug delivery systems based on non-effervescent approach. Hollow microspheres are in strict sense, spherical empty particles without core. These microspheres are characteristically free flowing powders consisting of proteins or synthetic polymers, ideally having a size less than 200 micrometer. Solid biodegradable microspheres incorporating a drug dispersed or dissolved throughout particle matrix have the potential for controlled release of drugs10,11.
Gastro-retentive floating microspheres are low-density systems that have sufficient buoyancy to float over gastric contents and remain in stomach for prolonged period. As the system floats over gastric contents, the drug is released slowly at desired rate resulting in increased gastric retention with reduced fluctuations in plasma drug concentration.
When microspheres come in contact with gastric fluid the gel formers, polysaccharides, and polymers hydrate to form a colloidal gel barrier that controls the rate of fluid penetration into the device and consequent drug release. As the exterior surface of the dosage form dissolves, the gel layer is maintained by the hydration of the adjacent hydrocolloid layer. The air trapped by the swollen polymer lowers the density and confers buoyancy to the microspheres. However a minimal gastric content needed to allow proper achievement of buoyancy1,7,11,12. Hollow microspheres of Acrylic resins, Eudragit, PMAA, Polyethylene oxide, and Cellulose acetate; Polystyrene floatable shells; Polycarbonate floating balloons and Gelucire floating granules are the recent developments.
The advantages of hollow microspheres include:
Improves patient compliance by decreasing dosing frequency.
Bioavailability enhances despite first pass effect because fluctuations in plasma drug concentration is avoided, a desirable plasma drug concentration is maintained by continuous drug release.
Better therapeutic effect of short half-life drugs can be achieved.
Gastric retention time is increased because of buoyancy.
Drug releases in controlled manner for prolonged period.
Site-specific drug delivery to stomach can be achieved.
Enhanced absorption of drugs which solubilise only in stomach.
Superior to single unit floating dosage forms as such microspheres releases drug uniformly and there is no risk of dose dumping.
Avoidance of gastric irritation, because of sustained release effect, floatability and uniform release of drug through multiparticulate system.
Hollow microspheres are prepared by solvent diffusion and evaporation methods to create the hollow inner core. The polymer is dissolved in an organic solvent and the drug is either dissolved or dispersed in the polymer solution. The solution containing the drug is then emulsified into an aqueous phase containing polyvinyl alcohol to form oil in water emulsion. After the formation of a stable emulsion, the organic solvent is evaporated either by increasing the temperature under pressure or by continuous stirring13,14. The solvent removal leads to polymer precipitation at the o/w interface of droplets, forming cavity and thus making them hollow to impart the floating properties15, 16,17. The polymers studied for the development of such systems include Cellulose acetate, Chitosan, Eudragit, Acrycoat, Methocil, Polyacrylates, Polyvinyl acetate, Carbopol, Agar, Polyethylene oxide and Polycarbonates.
Characterization of Floating Microspheres
Floating microspheres are characterized by their micromeritic properties such as particle size, tapped density, compressibility index, true density and flow properties including angle of repose. The particle size is determined by optical microscopy; true density is determined by liquid displacement method; tapped density and compressibility index are calculated by measuring the change in volume using a bulk density apparatus; angle of repose is determined by fixed funnel method. The hollow nature of microspheres is confirmed by scanning electron microscopy 18, 19,20.
Floating behavior of hollow microspheres is studied in a dissolution test apparatus by spreading the microspheres on a simulated gastric fluid (pH 1.2) containing tween 80 as a surfactant; the media is stirred and a temperature of 37◦C is maintained throughout the study. After specific intervals of time, both the fractions of the microspheres floating and settled are collected; the buoyancy of the floating microspheres can be calculated using the data.
The in-vivo floating behavior can be investigated by X-ray photography of hollow microspheres loaded with barium sulphate in the stomach of beagle dogs. The in-vitro drug release studies are performed in a dissolution test apparatus using 0.1N hydrochloric acid as dissolution media. The in-vivo plasma profile can be obtained by performing the study in suitable animal models (e.g. beagle dogs). The in-vitro and in-vivo data can be correlated.
Applications of Floating Microspheres
Floating microspheres are especially effective in delivery of sparingly soluble and insoluble drugs. It is known that as the solubility of a drug decreases, the time available for drug dissolution becomes less adequate and thus the transit time becomes a significant factor affecting drug absorption. For weakly basic drugs that are poorly soluble at an alkaline pH, hollow microspheres may avoid chance for solubility to become the rate-limiting step in release by restricting such drugs to the stomach. The positioned gastric release is useful for drugs efficiently absorbed through stomach such as Verapamil hydrochloride. The gastro-retentive floating microspheres will alter beneficially the absorption profile of the active agent, thus enhancing its bioavailability. Drugs that have poor bioavailability because of their limited absorption to the upper gastrointestinal tract can also be delivered efficiently thereby maximizing their absorption and improving the bioavailability12,13.
Hollow microspheres can greatly improve the pharmacotherapy of the stomach through local drug release, leading to high drug concentrations at the gastric mucosa, thus eradicating Helicobacter pylori from the sub-mucosal tissue of the stomach and making it possible to treat stomach and duodenal ulcers, gastritis and oesophagitis21. The development of such systems allow administration of non-systemic, controlled release antacid formulations containing calcium carbonate and also locally acting anti-ulcer drugs in the stomach; e.g. Lansoprazole17. Buoyant microspheres are considered as a beneficial strategy for the treatment of gastric and duodenal cancers.
The floating microspheres can be used as carriers for drugs with so-called absorption windows, these substances, for example antiviral, antifungal and antibiotic agents (Sulphonamides, Quinolones, Penicillins, Cephalosporins, Aminoglycosides and Tetracyclines) are taken up only from very specific sites of the GI mucosa. In addition, by continually supplying the drug to its most efficient site of absorption, the dosage forms may allow for more effective oral use of peptide and protein drugs such as Calcitonin, Erythropoietin, Vasopressin, Insulin, low-molecular-weight Heparin, and LHRH.
Hollow microspheres of non-steroidal anti inflammatory drugs are very effective for controlled release as well as it reduces the major side effect of gastric irritation; for example floating microspheres of Indomethacin are quiet beneficial for rheumatic patients.
The drugs recently reported to be entrapped in hollow microspheres include Aspirin, Griseofulvin, Ibuprofen, Terfenadine, Diclofenac sodium, Indomethacin, Prednisolone, Lansoprazole, Celecoxib, Piroxicam, Theophylline, Diltiazem hydrochloride, Verapamil hydrochloride and Riboflavin.
Summary
Gastro retentive floating microspheres have emerged as an efficient means of enhancing the bioavailability and controlled delivery of many drugs The increasing sophistication of delivery technology will ensure the development of increasing number of gastro-retentive drug delivery systems to optimize the delivery of molecules that exhibit absorption window, low bioavailability, and extensive first pass metabolism. The control of gastro intestinal transit could be the focus of the next decade and may result in new therapeutic possibilities with substantial benefits for patients.
Insulin Inhalaing
Will Inhaled Insulin Really Take Your Breath Away?
by John Walsh, P.A., C.D.E.
The FDA approved the first inhaled version of insulin called Exubera from Pfizer Inc. in January 2006. It was available in September 2006, 84 years after the first insulin injections were given. It is approved for those over 18 years of age with diabetes, but realistically is only appropriate for those with Type 1 who are on larger doses of insulin, such as 60 or more units per day, or those with Type 2 who can tolerate larger doses of insulin.
Artist's Concept, 1996Background
Over the years, various attempts have been made to capture the $3 billion injected insulin market. Two alternative sites of delivery have fared well in the competition: into the lungs and through the stomach.
Delivery of an insulin pill through the stomach has two hurdles to overcome: getting intact insulin molecules past acidity and digestive enzymes in the stomach and intestines, and then opening the intestinal membranes to insulin transport. These problems have stymied researchers for at least 40 years, although a new novel approach discussed below offers some hope.
Delivery of insulin to the small bath towel size area of the upper nasal airways suffers from poor transport across the nasal membranes. This requires very large doses of insulin or use of a chemical to enhance insulin transport. Chemicals used to enhance insulin transport often cause nasal irritation and a runny nose. Even a mild cold or stuffiness could easily change the intended insulin dose. About 100 units of insulin must be deposited into the nose to deliver 10 units into the blood. Insulin production costs would seem prohibitive except that a similar ratio applies to lung delivery where insulin delivery is rapidly progressing.
Compared to nasal delivery, transport of insulin through the lungs allows transport across a surface area the size of a singles tennis court. Absorption into the bloodstream occurs through the thin alveolar walls of the lungs and this appears to be the most promising approach for delivery at this time. However, there is concern about the long-term effects of inhaling a growth protein into the lungs over time. It is hoped the large surface area over which it is spread will minimize negative effects, but small decreases in oxygen transport have already been noted in some research studies.
Exubera
Exubera is the first of the inhaled insulin to be released. It is a short-acting powder form of insulin that is inhaled before each meal. A long-acting insulin still needs to be given each day by injection. In developing Exubera, Pfizer and Aventis have collaborated with Nektar Therapeutics (formerly Inhale Therapeutics), a company that specializes in finding delivery solutions for oral, injectable and pulmonary drug administration to create an inhaler. The Exubera inhaler weighs about 4 ounces and is about the size of an eyeglass case when closed. It opens to about 12 inches for delivery. It is portable but not discreet.
Similar to other inhaled insulins, a number of side effects have been reported. These include coughing, shortness of breath, sore throat and dry mouth. Exubera is not approved for smokers or anyone who has smoked in the last six months because almost twice as much of the inhaled insulin can enter the bloodstream and increase the possibility of an overdose. It is also not improved for anyone with a lung disorder, such as asthma, emphysema, or chronic obstructive pulmonary disease. Exercise also increases transport and likelihood of lows.
A major problem with Exubera is the inability to deliver precise insulin doses. The smallest blister pack available contains the equivalent of 3 units of Regular insulin. A 3 unit dose would make it difficult for many people using insulin to achieve accurate control which is the real goal of any insulin therapy. Using the 1800 Rule for Regular insulin, someone on 60 units of insulin per day would lower their blood sugar about 90 mg/dl (5 mmol) per 3 unit pack, while someone on 30 units a day would drop 180 mg/dl (10 mmol) per pack. Precise control flies out the window with this sledge hammer approach, especially compared to an insulin pump that can deliver one twentieth of a unit with precision.
Pfizer hopes to make Exubera available in September of 2006. Although no price has been published, it will certainly be higher than bottled insulin. It is not clear how soon Medicare, Medicaid, and insurance policies will begin to cover inhaled insulin.
How Exubera Works
The most critical element in delivering a drug to the massive surface area of the lungs is to create a particle small enough to get past the back of the throat yet large enough so it is not breathed right back out of the lungs into the air.
Nektar, with experience in protein delivery, was able to create a particle containing 20% insulin with a micron size that is just right for deep lung delivery. They created two dry powder blister packs, one with 9 units of insulin per pack and a smaller one that has 3 units per pack. These can be combined for a variety of doses in any multiple of 3 units.
Once the blister packs are loaded into the device, a trigger is squeezed to disperse the insulin powder as a cloud into the clear chamber above. A slow, deep breath then brings the finely powdered air cloud into the lungs. Consistent, reproducible delivery is aided by having the insulin as only a tiny portion of the inhaled air and placing it near the front of the air being inhaled. Breathing technique is critical and two or more breaths are required for delivery, according to manufacturers. One problem seen with similarly inhaled asthma drugs has been poor consistency of technique by the same individual over time. This problem may be reduced with an inhaler that uses a more normal breathing approach. The insulin powder appears to be stable for 6 to 24 months at room temperature.
Other Players
Aradigm Corporation of Hayward, California, working with Novo Nordisk, is developing a similar approach with its patented AERxTM Diabetes Management System. They also report that inhaled U250 and U500 Regular insulins are absorbed more quickly than injected Regular using their controlled breathing device. Action times of the inhaled Regular aerosol appear to be between that of injected Humalog and Regular insulins. Novo is planning to offer 1 unit dose increments in its product.
Andaris, a privately-held company with about 70 employees in Nottingham, England, was purchased in 2003 by Cambridge-based Quadrant. Started in 1994, Andaris began developing injectable microscopic contrast agents for diagnostic tests with ultrasound. In the process, they also developed a 5 micron hollow microcapsule of insulin using a low temperature, spray drying technique that preserves the insulin structure. This insulin microcapsule can be inhaled directly into the lungs for absorption. Quadrant is now working with Innovata, MicroDose Technologies, and Bristol-Meyers Squibb to develop the QDose inhaled insulin product. They are planning a more discreet inhaler for delivery.
by John Walsh, P.A., C.D.E.
The FDA approved the first inhaled version of insulin called Exubera from Pfizer Inc. in January 2006. It was available in September 2006, 84 years after the first insulin injections were given. It is approved for those over 18 years of age with diabetes, but realistically is only appropriate for those with Type 1 who are on larger doses of insulin, such as 60 or more units per day, or those with Type 2 who can tolerate larger doses of insulin.
Artist's Concept, 1996Background
Over the years, various attempts have been made to capture the $3 billion injected insulin market. Two alternative sites of delivery have fared well in the competition: into the lungs and through the stomach.
Delivery of an insulin pill through the stomach has two hurdles to overcome: getting intact insulin molecules past acidity and digestive enzymes in the stomach and intestines, and then opening the intestinal membranes to insulin transport. These problems have stymied researchers for at least 40 years, although a new novel approach discussed below offers some hope.
Delivery of insulin to the small bath towel size area of the upper nasal airways suffers from poor transport across the nasal membranes. This requires very large doses of insulin or use of a chemical to enhance insulin transport. Chemicals used to enhance insulin transport often cause nasal irritation and a runny nose. Even a mild cold or stuffiness could easily change the intended insulin dose. About 100 units of insulin must be deposited into the nose to deliver 10 units into the blood. Insulin production costs would seem prohibitive except that a similar ratio applies to lung delivery where insulin delivery is rapidly progressing.
Compared to nasal delivery, transport of insulin through the lungs allows transport across a surface area the size of a singles tennis court. Absorption into the bloodstream occurs through the thin alveolar walls of the lungs and this appears to be the most promising approach for delivery at this time. However, there is concern about the long-term effects of inhaling a growth protein into the lungs over time. It is hoped the large surface area over which it is spread will minimize negative effects, but small decreases in oxygen transport have already been noted in some research studies.
Exubera
Exubera is the first of the inhaled insulin to be released. It is a short-acting powder form of insulin that is inhaled before each meal. A long-acting insulin still needs to be given each day by injection. In developing Exubera, Pfizer and Aventis have collaborated with Nektar Therapeutics (formerly Inhale Therapeutics), a company that specializes in finding delivery solutions for oral, injectable and pulmonary drug administration to create an inhaler. The Exubera inhaler weighs about 4 ounces and is about the size of an eyeglass case when closed. It opens to about 12 inches for delivery. It is portable but not discreet.
Similar to other inhaled insulins, a number of side effects have been reported. These include coughing, shortness of breath, sore throat and dry mouth. Exubera is not approved for smokers or anyone who has smoked in the last six months because almost twice as much of the inhaled insulin can enter the bloodstream and increase the possibility of an overdose. It is also not improved for anyone with a lung disorder, such as asthma, emphysema, or chronic obstructive pulmonary disease. Exercise also increases transport and likelihood of lows.
A major problem with Exubera is the inability to deliver precise insulin doses. The smallest blister pack available contains the equivalent of 3 units of Regular insulin. A 3 unit dose would make it difficult for many people using insulin to achieve accurate control which is the real goal of any insulin therapy. Using the 1800 Rule for Regular insulin, someone on 60 units of insulin per day would lower their blood sugar about 90 mg/dl (5 mmol) per 3 unit pack, while someone on 30 units a day would drop 180 mg/dl (10 mmol) per pack. Precise control flies out the window with this sledge hammer approach, especially compared to an insulin pump that can deliver one twentieth of a unit with precision.
Pfizer hopes to make Exubera available in September of 2006. Although no price has been published, it will certainly be higher than bottled insulin. It is not clear how soon Medicare, Medicaid, and insurance policies will begin to cover inhaled insulin.
How Exubera Works
The most critical element in delivering a drug to the massive surface area of the lungs is to create a particle small enough to get past the back of the throat yet large enough so it is not breathed right back out of the lungs into the air.
Nektar, with experience in protein delivery, was able to create a particle containing 20% insulin with a micron size that is just right for deep lung delivery. They created two dry powder blister packs, one with 9 units of insulin per pack and a smaller one that has 3 units per pack. These can be combined for a variety of doses in any multiple of 3 units.
Once the blister packs are loaded into the device, a trigger is squeezed to disperse the insulin powder as a cloud into the clear chamber above. A slow, deep breath then brings the finely powdered air cloud into the lungs. Consistent, reproducible delivery is aided by having the insulin as only a tiny portion of the inhaled air and placing it near the front of the air being inhaled. Breathing technique is critical and two or more breaths are required for delivery, according to manufacturers. One problem seen with similarly inhaled asthma drugs has been poor consistency of technique by the same individual over time. This problem may be reduced with an inhaler that uses a more normal breathing approach. The insulin powder appears to be stable for 6 to 24 months at room temperature.
Other Players
Aradigm Corporation of Hayward, California, working with Novo Nordisk, is developing a similar approach with its patented AERxTM Diabetes Management System. They also report that inhaled U250 and U500 Regular insulins are absorbed more quickly than injected Regular using their controlled breathing device. Action times of the inhaled Regular aerosol appear to be between that of injected Humalog and Regular insulins. Novo is planning to offer 1 unit dose increments in its product.
Andaris, a privately-held company with about 70 employees in Nottingham, England, was purchased in 2003 by Cambridge-based Quadrant. Started in 1994, Andaris began developing injectable microscopic contrast agents for diagnostic tests with ultrasound. In the process, they also developed a 5 micron hollow microcapsule of insulin using a low temperature, spray drying technique that preserves the insulin structure. This insulin microcapsule can be inhaled directly into the lungs for absorption. Quadrant is now working with Innovata, MicroDose Technologies, and Bristol-Meyers Squibb to develop the QDose inhaled insulin product. They are planning a more discreet inhaler for delivery.
Exubera
Exubera - Inhaled Insulin for Type 1 and Type 2 Diabetes
The product of a joint development programme between Aventis and Pfizer, Exubera is an inhaled short-acting insulin preparation indicated for the treatment of type 1 and type 2 diabetes. It is the most advanced inhaled insulin in development and, if approved, could eliminate the need for meal-time insulin injections in diabetic patients requiring insulin therapy.
Phase III development of Exubera has been completed. However, because of concerns about the drug's long-term pulmonary safety, filings for regulatory approval in Europe and the US have been put back several times to allow for more safety data. Exubera has now been filed for regulatory approval with the EMEA in Europe, although there are suggestions that it may not secure approval.
NON-INVASIVE INSULIN DELIVERY
At present, diabetics who require insulin to keep their blood sugar levels under tight control (target HbA1c levels of <7%) have to administer it by injection. The need for daily repeat injections is a major drawback for diabetics. It interferes with daily activities and can lead to patients developing needle phobia. Although special self-injection pens, which are easier to use and deliver an accurate dose of insulin, are available they do not remove the need for regular injections. However, injections are considered the most efficient and reliable way to deliver insulin to the bloodstream at present.
Various alternatives to injectable insulin have been investigated:
Insulin patches
Insulin pumps
Oral formulations designed to resist insulin digestion in the gastrointestinal tract
Inhaled insulin
Of all the alternative delivery routes, pulmonary delivery of insulin looks the most promising.
PULMONARY DELIVERY OF EXUBERA
The concept of delivering insulin directly to the lungs (pulmonary insulin) was first advanced in 1925. However, the technical hurdles are high. Most insulin sprayed or inhaled through the mouth tends to become deposited in the pharynx and never reaches the lungs.
In developing Exubera, Pfizer and Aventis have collaborated with Nektar Therapeutics (formerly Inhale Therapeutics), a company that specialises in finding delivery solutions for oral, injectable and pulmonary drug administration. Exubera is a rapid-acting, fine dry-powder insulin which was developed using Nektar Therapeutics proprietary inhalation technology. Apart from the benefit of needless administration, inhaled insulin enters the bloodstream more rapidly than by subcutaneous injection. This is likely to be especially beneficial when administering insulin just before meals and may aid treatment compliance.
CLINICAL TRIALS SUGGEST PULMONARY DELIVERY OF EXUBERA IS EFFECTIVE
Over 2,000 patients have so far received Exubera in clinical trials worldwide, some for as long as five years. Results from the phase III clinical trials suggest that Exubera may be as effective as injected insulin and superior to oral agents in lowering blood glucose in patients with diabetes.
A phase III study involving 328 patients with type 1 diabetes, for example, showed that patients using Exubera before meals plus two daily insulin injections had glycaemic control comparable to patients on four insulin injections. Compared with patients who received only insulin injections, patients receiving Exubera experienced significant reductions in both fasting plasma glucose levels (blood glucose measured before breakfast) and two-hour post-prandial glucose levels (blood glucose measured after meals). Patients also preferred using Exubera, were more satisfied with their overall treatment and showed greater improvements in symptoms and cognitive function (assessed by the Diabetes Quality of Life and Treatment Satisfaction questionnaire).
While Exubera appears efficacious, concerns have been raised about the safety of inhaled preparations and whether Exubera will compromise lung capacity or damage lung tissue in long-term use. In the clinical trials the frequency and nature of adverse events were similar in the Exubera and control groups. However, mild to moderate cough occurred more frequently in Exubera-treated patients, which disappeared with increased exposure. A small non-progressive difference in pulmonary function tests, but without clinical manifestation, was also observed between a limited group of Exubera and control patients. Additional studies are being conducted to address this safety concern and determine Exubera's long-term pulmonary safety profile.
MARKETING COMMENTARY
Diabetes is rapidly reaching epidemic proportions, affecting 150 million people worldwide and projected to double in prevalence by 2025. Since many cases go undiagnosed these figures are likely to be an underestimate of the true prevalence. Left uncontrolled, diabetes can lead to coronary heart disease, kidney failure, blindness, limb amputations and premature death. Compliance with insulin therapy is important in preventing the adverse clinical effects of the disease. Exubera has been described as a patient-friendly agent and, if approved, will certainly provide diabetic patients with a welcome relief from the need to give daily, meal-time insulin injections.
The product of a joint development programme between Aventis and Pfizer, Exubera is an inhaled short-acting insulin preparation indicated for the treatment of type 1 and type 2 diabetes. It is the most advanced inhaled insulin in development and, if approved, could eliminate the need for meal-time insulin injections in diabetic patients requiring insulin therapy.
Phase III development of Exubera has been completed. However, because of concerns about the drug's long-term pulmonary safety, filings for regulatory approval in Europe and the US have been put back several times to allow for more safety data. Exubera has now been filed for regulatory approval with the EMEA in Europe, although there are suggestions that it may not secure approval.
NON-INVASIVE INSULIN DELIVERY
At present, diabetics who require insulin to keep their blood sugar levels under tight control (target HbA1c levels of <7%) have to administer it by injection. The need for daily repeat injections is a major drawback for diabetics. It interferes with daily activities and can lead to patients developing needle phobia. Although special self-injection pens, which are easier to use and deliver an accurate dose of insulin, are available they do not remove the need for regular injections. However, injections are considered the most efficient and reliable way to deliver insulin to the bloodstream at present.
Various alternatives to injectable insulin have been investigated:
Insulin patches
Insulin pumps
Oral formulations designed to resist insulin digestion in the gastrointestinal tract
Inhaled insulin
Of all the alternative delivery routes, pulmonary delivery of insulin looks the most promising.
PULMONARY DELIVERY OF EXUBERA
The concept of delivering insulin directly to the lungs (pulmonary insulin) was first advanced in 1925. However, the technical hurdles are high. Most insulin sprayed or inhaled through the mouth tends to become deposited in the pharynx and never reaches the lungs.
In developing Exubera, Pfizer and Aventis have collaborated with Nektar Therapeutics (formerly Inhale Therapeutics), a company that specialises in finding delivery solutions for oral, injectable and pulmonary drug administration. Exubera is a rapid-acting, fine dry-powder insulin which was developed using Nektar Therapeutics proprietary inhalation technology. Apart from the benefit of needless administration, inhaled insulin enters the bloodstream more rapidly than by subcutaneous injection. This is likely to be especially beneficial when administering insulin just before meals and may aid treatment compliance.
CLINICAL TRIALS SUGGEST PULMONARY DELIVERY OF EXUBERA IS EFFECTIVE
Over 2,000 patients have so far received Exubera in clinical trials worldwide, some for as long as five years. Results from the phase III clinical trials suggest that Exubera may be as effective as injected insulin and superior to oral agents in lowering blood glucose in patients with diabetes.
A phase III study involving 328 patients with type 1 diabetes, for example, showed that patients using Exubera before meals plus two daily insulin injections had glycaemic control comparable to patients on four insulin injections. Compared with patients who received only insulin injections, patients receiving Exubera experienced significant reductions in both fasting plasma glucose levels (blood glucose measured before breakfast) and two-hour post-prandial glucose levels (blood glucose measured after meals). Patients also preferred using Exubera, were more satisfied with their overall treatment and showed greater improvements in symptoms and cognitive function (assessed by the Diabetes Quality of Life and Treatment Satisfaction questionnaire).
While Exubera appears efficacious, concerns have been raised about the safety of inhaled preparations and whether Exubera will compromise lung capacity or damage lung tissue in long-term use. In the clinical trials the frequency and nature of adverse events were similar in the Exubera and control groups. However, mild to moderate cough occurred more frequently in Exubera-treated patients, which disappeared with increased exposure. A small non-progressive difference in pulmonary function tests, but without clinical manifestation, was also observed between a limited group of Exubera and control patients. Additional studies are being conducted to address this safety concern and determine Exubera's long-term pulmonary safety profile.
MARKETING COMMENTARY
Diabetes is rapidly reaching epidemic proportions, affecting 150 million people worldwide and projected to double in prevalence by 2025. Since many cases go undiagnosed these figures are likely to be an underestimate of the true prevalence. Left uncontrolled, diabetes can lead to coronary heart disease, kidney failure, blindness, limb amputations and premature death. Compliance with insulin therapy is important in preventing the adverse clinical effects of the disease. Exubera has been described as a patient-friendly agent and, if approved, will certainly provide diabetic patients with a welcome relief from the need to give daily, meal-time insulin injections.
Inhaled Insulin
Inhaled insulin
May prove to be a panacea
For over 80 years exogenous insulin has been given by injection. The injection devices have improved—disposable syringes and pen injection devices are more convenient and less traumatic than the boil to sterilise, use until too blunt devices of yesteryear—but patients and healthcare professionals remain uneasy about the concept of injections. Yet the evidence based drive for increasingly tight glycaemic control means that more patients should be offered more injections. A recent attempt to circumvent the need for injection that may soon hit a clinic near you is the use of the lung as an absorption pathway, with the development of insulins to be taken by inhalation. Two versions, a powder and an aerosol, may be nearing launch.
Insulin can be effective given by inhalation. This was first shown in 1971, although the early work was not pursued, and it was not until 2000 that the modern era of inhaled insulin began.1 2 The bioavailability is 10-15% and the dose equivalent about three times that of injected insulin. The pharmacodynamics of inhaled insulin offer an action profile with a fast onset (although slightly longer run-off) akin to that of rapid acting insulin analogues given subcutaneously, which in studies have shown better postprandial glucose control and less tendency to nocturnal hypoglycaemia.2 3 A Cochrane review of randomised controlled trials comparing inhaled with injected short acting unmodified human insulin used for prandial insulin replacement, in conjunction with a basal injected insulin, concluded that inhaled insulin provided equivalent control to fully injected regimens.4 However, the injected regimens were not always optimised: analogue insulins were not included, and control groups often simply continued their pre-trial regimens of injection twice daily. An opportunity to improve control with injected insulin was missed. With either regimen, fewer than 25% patients achieved optimal control. The included trials were short and conducted in patients with type 1 or 2 diabetes already on insulin. The review did not examine trials of inhaled insulin added to oral agents, but the data would again imply bioequivalence. In patients with type 2 diabetes, adding inhaled insulin to oral hypoglycaemic regimens does improve control more than doing nothing.5
The advantages of inhaled over injected insulins to date relate to patients' preferences. This is important—apart from patients' comfort, an expensive new insulin could have huge potential advantage if it encouraged adherence and resulted in more patients with diabetes achieving treatment targets. Sadly, the published data on patients' satisfaction, superficially encouraging, are difficult to interpret, as invariably patients have been comparing a new treatment with an old one. When a specially designed questionnaire was used, treatment satisfaction improved significantly in patients with type 1 and type 2 diabetes on taking part in the trials, irrespective of whether the mealtime insulins they took were injected or inhaled.6-8 Although the improvement was greater with inhaled insulin the injected insulin treatment was identical to pre-trial treatment limiting the potential for improvement. Notably, improvement in treatment satisfaction correlated with improved glycaemic control. Might greater satisfaction have been obtained with injected regimens if these had been optimised effectively? Were the studies just too short to show the biomedical gains one might anticipate from a treatment expressly designed to support compliance, or do the problems of insulin therapy extend beyond a dislike of needles?
Inhaled insulin has potential problems. The bioavailability is affected by asthma (decreased) and smoking (increased).9 10 Of course, if patients really dislike injections so much inhaled insulin might make its biggest impact on complications of diabetes if it were to be available only to proved non-smokers. Formation of anti-insulin antibodies is higher with inhaled insulin, and although this is dismissed as not affecting insulin requirement over time, older diabetologists will remember the drive to reduce insulin antibody formation, with the fears that antibodies delay and render unpredictable insulin absorption and even that antibody-antigen complexes may increase risk of microvascular disease.11 Finally, there have been concerns about possible long term effects of insulin on lung structure and function, although current published trials report no deleterious effects over the short-term.
Few people like injections and some are so terrified they refuse appropriate treatment for diabetes. Many are discouraged by previous experience of injections—none of whom will have used current insulin injection devices—and by healthcare professionals using injection therapy as a threat in a (vain) attempt to improve adherence. For patients with established type 1 diabetes lack of freedom to eat or not eat and the demand for (painful) blood glucose testing may be much more of an issue than injection therapy itself.12 In one study only 14% of injections were missed because they were injections.13 In this group healthcare providers will need more robust evidence of patients' preference than is currently available. Where inhaled insulins could really have an impact (in the developed world) will be if healthcare professionals and patients start to use insulin much earlier and more aggressively in type 2 diabetes, affecting the progression of diabetic complications. In the developing world, where cultural taboos against injection treatments may be even more real than here, inhaled insulin may be expected to deliver more in terms of health benefit—but is not likely to be more affordable or available than the currently inadequate supplies of injected insulin. Meanwhile, all patients are waiting to see if the new inhalations are safe. If they are, and if they are cheap enough, at least one barrier to better diabetes treatment may fall.
Stephanie A Amiel, professor
May prove to be a panacea
For over 80 years exogenous insulin has been given by injection. The injection devices have improved—disposable syringes and pen injection devices are more convenient and less traumatic than the boil to sterilise, use until too blunt devices of yesteryear—but patients and healthcare professionals remain uneasy about the concept of injections. Yet the evidence based drive for increasingly tight glycaemic control means that more patients should be offered more injections. A recent attempt to circumvent the need for injection that may soon hit a clinic near you is the use of the lung as an absorption pathway, with the development of insulins to be taken by inhalation. Two versions, a powder and an aerosol, may be nearing launch.
Insulin can be effective given by inhalation. This was first shown in 1971, although the early work was not pursued, and it was not until 2000 that the modern era of inhaled insulin began.1 2 The bioavailability is 10-15% and the dose equivalent about three times that of injected insulin. The pharmacodynamics of inhaled insulin offer an action profile with a fast onset (although slightly longer run-off) akin to that of rapid acting insulin analogues given subcutaneously, which in studies have shown better postprandial glucose control and less tendency to nocturnal hypoglycaemia.2 3 A Cochrane review of randomised controlled trials comparing inhaled with injected short acting unmodified human insulin used for prandial insulin replacement, in conjunction with a basal injected insulin, concluded that inhaled insulin provided equivalent control to fully injected regimens.4 However, the injected regimens were not always optimised: analogue insulins were not included, and control groups often simply continued their pre-trial regimens of injection twice daily. An opportunity to improve control with injected insulin was missed. With either regimen, fewer than 25% patients achieved optimal control. The included trials were short and conducted in patients with type 1 or 2 diabetes already on insulin. The review did not examine trials of inhaled insulin added to oral agents, but the data would again imply bioequivalence. In patients with type 2 diabetes, adding inhaled insulin to oral hypoglycaemic regimens does improve control more than doing nothing.5
The advantages of inhaled over injected insulins to date relate to patients' preferences. This is important—apart from patients' comfort, an expensive new insulin could have huge potential advantage if it encouraged adherence and resulted in more patients with diabetes achieving treatment targets. Sadly, the published data on patients' satisfaction, superficially encouraging, are difficult to interpret, as invariably patients have been comparing a new treatment with an old one. When a specially designed questionnaire was used, treatment satisfaction improved significantly in patients with type 1 and type 2 diabetes on taking part in the trials, irrespective of whether the mealtime insulins they took were injected or inhaled.6-8 Although the improvement was greater with inhaled insulin the injected insulin treatment was identical to pre-trial treatment limiting the potential for improvement. Notably, improvement in treatment satisfaction correlated with improved glycaemic control. Might greater satisfaction have been obtained with injected regimens if these had been optimised effectively? Were the studies just too short to show the biomedical gains one might anticipate from a treatment expressly designed to support compliance, or do the problems of insulin therapy extend beyond a dislike of needles?
Inhaled insulin has potential problems. The bioavailability is affected by asthma (decreased) and smoking (increased).9 10 Of course, if patients really dislike injections so much inhaled insulin might make its biggest impact on complications of diabetes if it were to be available only to proved non-smokers. Formation of anti-insulin antibodies is higher with inhaled insulin, and although this is dismissed as not affecting insulin requirement over time, older diabetologists will remember the drive to reduce insulin antibody formation, with the fears that antibodies delay and render unpredictable insulin absorption and even that antibody-antigen complexes may increase risk of microvascular disease.11 Finally, there have been concerns about possible long term effects of insulin on lung structure and function, although current published trials report no deleterious effects over the short-term.
Few people like injections and some are so terrified they refuse appropriate treatment for diabetes. Many are discouraged by previous experience of injections—none of whom will have used current insulin injection devices—and by healthcare professionals using injection therapy as a threat in a (vain) attempt to improve adherence. For patients with established type 1 diabetes lack of freedom to eat or not eat and the demand for (painful) blood glucose testing may be much more of an issue than injection therapy itself.12 In one study only 14% of injections were missed because they were injections.13 In this group healthcare providers will need more robust evidence of patients' preference than is currently available. Where inhaled insulins could really have an impact (in the developed world) will be if healthcare professionals and patients start to use insulin much earlier and more aggressively in type 2 diabetes, affecting the progression of diabetic complications. In the developing world, where cultural taboos against injection treatments may be even more real than here, inhaled insulin may be expected to deliver more in terms of health benefit—but is not likely to be more affordable or available than the currently inadequate supplies of injected insulin. Meanwhile, all patients are waiting to see if the new inhalations are safe. If they are, and if they are cheap enough, at least one barrier to better diabetes treatment may fall.
Stephanie A Amiel, professor
Inhaled Insulin
Figure 1— A: HbA1c (mean ± SD) during treatment with inhaled () versus subcutaneous () insulin at screening (n = 141 and 145, respectively), baseline (n = 143 and 145), and weeks 6 (n = 137 and 130), 12 (n = 143 and 145), and 24 (n = 134 and 140). B: Percentage of patients achieving defined levels of HbA1c at week 24 (LOCF) with inhaled (, n = 143) versus subcutaneous (, n = 145) insulin.------------------------------------------------------------------------------------------------
Efficacy and Safety of Inhaled Insulin (Exubera) Compared With Subcutaneous Insulin Therapy in Patients With Type 2 Diabetes
Results of a 6-month, randomized, comparative trial Priscilla A. Hollander, MD1, Lawrence Blonde, MD2, Richard Rowe, MD3, Adi E. Mehta, MD4, Joseph L. Milburn, MD5, Kenneth S. Hershon, MD6, Jean-Louis Chiasson, MD7 and Seymour R. Levin, MD8 for the Exubera Phase III Study Group
1 Baylor University Medical Center, Dallas, Texas2 Ochsner Clinic, New Orleans, Louisiana3 Division of Endocrinology, Department of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada4 Cleveland Clinic Foundation, Cleveland, Ohio5 North Texas Health Care Associates, Irving, Texas6 North Shore Diabetes and Endocrine Associates, New Hyde Park, New York7 Research Center, Department of Medicine, Centre Hospitalier de l’Université de Montréal, Campus Hôtel-Dieu, University of Montreal, Montreal, Quebec, Canada8 West Los Angeles VA Medical Center, Los Angeles, California
ABSTRACT
TOPABSTRACTINTRODUCTIONRESEARCH DESIGN AND METHODSRESULTSCONCLUSIONSReferences OBJECTIVE— Glycemic control using inhaled, dry-powder insulin plus a single injection of long-acting insulin was compared with a conventional regimen in patients with type 2 diabetes, which was previously managed with at least two daily insulin injections.
RESEARCH DESIGN AND METHODS— Patients were randomized to 6 months’ treatment with either premeal inhaled insulin plus a bedtime dose of Ultralente (n = 149) or at least two daily injections of subcutaneous insulin (mixed regular/NPH insulin; n = 150). The primary efficacy end point was the change in HbA1c from baseline to the end of study.
RESULTS— HbA1c decreased similarly in the inhaled (–0.7%) and subcutaneous (–0.6%) insulin groups (adjusted treatment group difference: –0.07%, 95% CI –0.32 to 0.17). HbA1c <7.0% name="BDY">
INTRODUCTION
TOPABSTRACTINTRODUCTIONRESEARCH DESIGN AND METHODSRESULTSCONCLUSIONSReferences Although the long-term benefits of tight glycemic control have been shown in patients with both type 1 and type 2 diabetes (1–5), insulin therapy is often delayed or suboptimally implemented despite elevated HbA1c levels, and a substantial number of patients remain poorly controlled (6).
Several factors contribute to the poor implementation of insulin therapy in the patient with type 2 diabetes, but the inconvenience and poor patient acceptability of a multiple daily injection regimen may play a major role (7). Currently, the majority of patients treated with insulin do not achieve recommended HbA1c goals (8). Reliance on fixed-ratio premixed insulins for treatment of a significant proportion of the type 2 diabetic population may significantly constrain the ability to achieve target glycemia. More acceptable forms of insulin delivery are required to improve the implementation of insulin therapy aiming for recommended treatment goals.
A dry-powder insulin delivery system that permits noninvasive application of rapid-acting insulin via inhalation has been developed. The pulmonary route exploits the large vascular bed and permeability of the alveoli to deliver insulin directly into the bloodstream (9). Inhaled insulin provides a rapid-acting insulin for management of both type 1 and type 2 diabetes, and preliminary short-term studies have shown that inhaled insulin provides reproducible and effective control of meal-related glycemia (10–12).
The time-action profile of human regular insulin injected subcutaneously limits its ability to control postprandial glycemia. Its relatively slow onset of action does not reproduce the physiologic secretion profile of insulin in response to a meal (13), thus resulting in excessive postprandial hyperglycemia and increased risk of hypoglycemia before the next meal. A study (14) in healthy subjects showed inhaled insulin to have a rapid onset of action that was significantly faster than regular insulin and a duration of action between that of insulin lispro and regular insulin. It has also been shown (15) in patients with type 2 diabetes that inhaled insulin is rapidly and reproducibly absorbed. As such, inhaled insulin appears to match the physiologic needs for mealtime use.
The present study aimed to 1) assess whether an insulin regimen involving pulmonary delivery of rapid-acting, dry-powder insulin plus a single injection of basal long-acting, subcutaneous insulin can provide glycemic control comparable to a conventional subcutaneous insulin regimen in a large cohort of patients with type 2 diabetes previously managed with at least two daily subcutaneous injections of insulin and 2) assess the tolerability of inhaled insulin over a 6-month period.
RESEARCH DESIGN AND METHODS
TOPABSTRACTINTRODUCTIONRESEARCH DESIGN AND METHODSRESULTSCONCLUSIONSReferences Men and women (n = 520) diagnosed with type 2 diabetes for at least 1 year were screened at 39 centers in the U.S. and Canada. Inclusion criteria were age 35–80 years; stable subcutaneous insulin schedule involving two to three injections daily for at least 2 months before study entry and not receiving any oral antidiabetic agents; screening and prerandomization HbA1c values of 6–11% inclusive, fasting plasma C-peptide >0.2 pmol/ml, and BMI 35 kg/m2; willingness to perform self-monitoring of blood glucose (SMBG) and otherwise comply with the study protocol; and written informed consent.
Exclusion criteria included poorly controlled asthma, chronic obstructive pulmonary disease or other significant respiratory disease; smoking during the last 6 months; abnormal screening chest X-ray; abnormal pulmonary function at screening (carbon monoxide diffusing capacity [DLCO] <75%,>120%, and forced expiratory volume in 1 s [FEV1] <70%>150 units/day.
The study protocol was approved by the institutional review board at each center.
This was a phase 3, open-label, parallel-group, comparator study consisting of a screening visit, a 4-week baseline lead-in phase, and a 24-week randomized treatment phase. During the baseline period, patients received a subcutaneous insulin regimen consisting of two doses of mixed NPH/regular. If the patient had previously been treated with an insulin regimen consisting of mixed NPH/regular insulin before breakfast and supper, the patient continued with this regimen. Otherwise, the patient received an appropriate two-dose regimen based on insulin requirements and glycemic control before entering the study.
Three weeks before randomization, patients met a dietitian for instruction on a weight-maintaining diet, which they were to maintain for the study duration. Patients were also instructed to perform 30 min of moderate exercise at least three times each week. The importance of diet and exercise was reinforced at clinic visits. All patients received instruction in SMBG, which they were to perform four times daily: before breakfast, lunch, supper, and bedtime. Target glucose ranges were 80–140 mg/dl (4.4–7.8 mmol/l) before meals and 100–160 mg/dl (5.6–8.9 mmol/l) before bedtime.
Before randomization, patients received instruction regarding the use of the insulin inhalation device. Using a computer-generated randomization scheme, performed through interactive voice response technology, patients were randomized to receive an inhaled insulin regimen (n = 149) or continue receiving conventional subcutaneous therapy as described above for 24 weeks (n = 150). The inhaled insulin regimen consisted of premeal inhaled insulin plus a single bedtime dose of Ultralente insulin. Inhaled insulin was administered within 10 min of the start of each meal and given in one to two inhalations using a dry-powder aerosol delivery system (Nektar Therapeutics, San Carlos, CA). The insulin powder was packaged in foil blisters of 1- and 3-mg doses (1 mg is equivalent to 2–3 units of subcutaneous insulin) (11).
Initial recommended doses for inhaled insulin were based on the subject’s weight, baseline subcutaneous insulin dose, and previous response to insulin. Administration of insulin, inhaled or injection, was preceded by SMBG, and the dose was adjusted weekly at the discretion of the investigator, based on SMBG results, to achieve target premeal glucose. Patients were also allowed to adjust doses when preprandial glucose was outside the above ranges, in anticipation of a smaller- or larger-than-usual meal or on an "as-needed" basis.
AssessmentsThe primary efficacy end point was the change in HbA1c from baseline to week 24. HbA1c was measured before randomization (at weeks –4 and –1) and at weeks 0, 6, 12, and 24. Mean HbA1c from weeks –1 and 0 was taken as baseline. The percentage of patients achieving HbA1c <7% name="SEC2">
RESULTS
TOPABSTRACTINTRODUCTIONRESEARCH DESIGN AND METHODSRESULTSCONCLUSIONSReferences Characteristics of the study participants at study entry are given in Table 1. The groups were well matched for all baseline characteristics. Both groups used only subcutaneous insulin at baseline, and the use of short- and long/intermediate-acting insulins at baseline was similar between treatment groups (Table 1). Daily insulin use in both groups trended slightly higher from week 6 to week 24 (inhaled group: short acting, 15.0 and 16.6 mg at weeks 6 and 24, respectively, and long acting, 34.0 and 37.9 units, respectively; subcutaneous group: short acting, 24.0 and 25.5 units, respectively, and intermediate acting, 50.1 and 52.3 units, respectively). As the inhaled insulin regimen involved only one daily injection of long-acting Ultralente along with premeal short-acting insulin, the basal-to-bolus ratio was shifted (i.e., less basal and more bolus insulin) relative to the subcutaneous group, where two daily doses of both intermediate- and short-acting insulin were used.
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Table 1— Demographic and clinical characteristics at study entry
Of the 299 patients enrolled, 1 withdrew consent after randomization. In the inhaled group, 3 patients discontinued for reasons related to study treatment (two adverse events and one insufficient clinical response), and 12 subjects discontinued for administrative reasons (e.g., protocol violation or withdrawn consent). Two subjects in the inhaled group died of causes unrelated to treatment (one of metastatic esophageal cancer and one of esophageal bleeding of unknown etiology). In the subcutaneous insulin group, one subject discontinued for insufficient clinical response and two subjects discontinued due to adverse events not considered related to the study drug. Six subjects in the subcutaneous group discontinued for administrative reasons.
Mean change in HbA1cMean HbA1c decreased similarly in the two treatment groups (Fig. 1A). After 24 weeks of treatment, mean HbA1c levels decreased from 8.1% at baseline to 7.4% (–0.7%) at week 24 in patients receiving inhaled insulin. Patients receiving subcutaneous showed a decrease from 8.2 to 7.6% (–0.6%). The difference between the adjusted mean changes from baseline for the two treatments (inhaled-subcutaneous) was –0.07% (95% CI –0.32 to 0.17). Thus, the upper limit of the 95% CI was <0.5 name="F1">
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Figure 1— A: HbA1c (mean ± SD) during treatment with inhaled () versus subcutaneous () insulin at screening (n = 141 and 145, respectively), baseline (n = 143 and 145), and weeks 6 (n = 137 and 130), 12 (n = 143 and 145), and 24 (n = 134 and 140). B: Percentage of patients achieving defined levels of HbA1c at week 24 (LOCF) with inhaled (, n = 143) versus subcutaneous (, n = 145) insulin.
Sixty-seven patients (47%) receiving inhaled insulin achieved HbA1c <7% href="http://care.diabetesjournals.org/cgi/content/full/27/10/2356#F1">Fig. 1B.
FPG and PPGFPG decreased from 152 mg/dl (8.44 mmol/l) at baseline to 132 mg/dl (7.33 mmol/l) at week 24 in those receiving inhaled insulin compared with 158 mg/dl (8.77 mmol/l) to 149 mg/dl (8.27 mmol/l) in the subcutaneous group. The difference between the adjusted mean changes from baseline was –15.9 mg/dl in favor of inhaled insulin (95% CI –26.6 to –5.2).
The treatment groups were comparable in terms of change from baseline in the 2-h PPG concentration at week 24. In patients receiving inhaled insulin treatment, 2-h PPG decreased from 244 mg/dl (13.5 mmol/l) at baseline to 221 mg/dl (12.3 mmol/l) at week 24, compared with a reduction from 252 mg/dl (14.0 mmol/l) to 231 mg/dl (12.8 mmol/l) in patients receiving subcutaneous treatment. The difference between adjusted mean changes from baseline was –9.41 mg/dl (95% CI –26.9 to 8.0).
HypoglycemiaIn the inhaled insulin group, 109 (76.2%) patients experienced a total of 1,104 hypoglycemic events: a crude event rate of 1.40 events per subject-month. One hundred four patients (71.7%) in the subcutaneous insulin group experienced a total of 1,278 events: a crude event rate of 1.57 events per subject-month. This represents a risk ratio (inhaled/subcutaneous) for any hypoglycemic event of 0.89 (95% CI 0.82–0.97), indicating that there is a lower risk of hypoglycemia associated with inhaled insulin. There were very few severe hypoglycemic events in either treatment group. Only four events in the inhaled group were classed as severe (crude event rate 0.5/100 subject-months) and one event in the subcutaneous group (0.1/100 subject-months).
Body weight and lipid profileAfter 24 weeks, mean body weight in the inhaled insulin group remained stable at 90.5 kg. However, there was an increase in body weight in the subcutaneous treatment group (89.2 kg at baseline, 90.6 kg at week 24). The adjusted mean treatment group difference was –1.29 kg (95% CI –1.98 to –0.59).
No differences in serum lipid parameters were seen between the two groups. After 24 weeks of treatment, the median changes from baseline in lipid parameters in the inhaled and subcutaneous insulin groups, respectively, were total cholesterol, 0 and 3 mg/dl (0.0 and 0.08 mmol/l); HDL cholesterol, 0 and 1 mg/dl (0.0 and 0.03 mmol/l); LDL cholesterol, –3 and 0 mg/dl (–0.08 and 0.0 mmol/l); and triglycerides, 3.5 and 8.0 mg/dl (0.04 and 0.09 mmol/l).
Safety and tolerabilityThe frequency and nature of adverse events, with the exception of cough, were comparable between the two treatment groups. A total of 126 patients in the inhaled insulin group and 118 patients in the subcutaneous insulin group experienced adverse events (including the hypoglycemic events discussed above) that were possibly or probably related to the treatment regimen. The majority of these were mild or moderate. Treatment-related adverse events experienced by >10% of patients in the inhaled insulin group were tremor (43 patients, 29%), asthenia (27 patients, 18%), sweating (25 patients, 17%), and dizziness (23 patients, 15%). All of these adverse events are symptoms compatible with hypoglycemia. Treatment-related adverse events experienced by >10% of patients in the subcutaneous group were tremor (40 patients, 27%), sweating (29 patients, 20%), asthenia (21 patients, 14%), and dizziness (19 patients, 13%). All-cause cough was experienced by 21% (32 of 149) of patients in the inhaled insulin treatment group compared with 2% (3 of 149) in the subcutaneous group. Cough was judged as mild to moderate in the inhaled group and decreased in incidence over the study period; the median duration of the period of increased cough was 2.0 weeks. There were six treatment-related severe adverse events reported in the inhaled insulin group; three hypoglycemia, one hyperglycemia, one neuralgia, and one anxiety. There was one treatment-related severe adverse event in the subcutaneous group (unconsciousness associated with hypoglycemia).
The incidence of clinical laboratory abnormalities was similar between the two treatment groups. Forty-three of 135 patients (32%) in the inhaled group had at least one laboratory test abnormality compared with 56 of 142 patients (39%) in the subcutaneous group. The most frequent laboratory abnormalities were in urinalysis (increases in urine glucose, urine white blood cells, and hyaline casts).
Inhaled insulin-treated patients developed increased insulin antibody serum binding. Median percentage binding was 5.0 and 1.5% (below the level of quantitation) in the inhaled and subcutaneous groups, respectively. Levels of antibodies did not correlate to HbA1c, insulin dose, or incidence of hypoglycemia, and there was no association with adverse events or pulmonary function.
Mean changes in FVC, FEV1, TLC, and DLCO were small and comparable between the two treatment groups (Table 2).
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Table 2— PFT results in subjects with a baseline and at least one postbaseline PFT measurement
Treatment satisfaction and quality of lifeThe mean overall satisfaction score improved significantly for the inhaled group (P < name="SEC3">
CONCLUSIONS
TOPABSTRACTINTRODUCTIONRESEARCH DESIGN AND METHODSRESULTSCONCLUSIONSReferences The results of this study show that inhaled insulin provides glycemic control comparable to a conventional insulin regimen in patients with type 2 diabetes, as assessed by the changes in HbA1c from baseline to week 24. The actual decrease in HbA1c in both treatment groups at week 24 was modest; however, such a change would be expected to reduce the development and/or progression of diabetes complications, as shown in the U.K. Prospective Diabetes Study (3,4). Moreover, the study was designed to demonstrate equivalence and was not target driven. Nevertheless, a greater proportion of patients in the inhaled insulin group reached the American Diabetes Association goal of HbA1c <7% href="http://care.diabetesjournals.org/cgi/content/full/27/10/2356#R16">16). The addition of premeal inhaled insulin reduced both FPG and PPG levels. Although both basal and postprandial glucose contribute to glucose exposure, the relative importance of each has been debated (17) and may depend on the severity of diabetes (18). Interestingly, FPG decreased more in the inhaled group than in the subcutaneous group. The bedtime administration of Ultralente basal insulin in the inhaled insulin group may have contributed to lower FPG.
Overall, inhaled insulin was well tolerated. The risk of a hypoglycemic event was lower in the inhaled group compared with the subcutaneous group, which is consistent with results from a previous study (12). As inhaled insulin is delivered systemically via the lungs, it is important to assess possible pulmonary adverse events. Cough of mild-to-moderate severity was observed with a greater frequency in the inhaled insulin group, although its incidence decreased as the study progressed, and no patient withdrew due to cough. In the present study, inhaled insulin treatment was not associated with adverse effects on pulmonary function parameters of FEV1, FVC, TLC, or DLCO. Long-term studies are underway to assess any potential effect more conclusively. Changes in lung function initially observed in a long-term extension study of the Exubera Phase III program remained small and nonprogressive. Furthermore, controlled discontinuation of Exubera in a subset of those patients resulted in lung function gains of similar magnitude to the initial small decrease (19).
Insulin antibodies with both animal and human insulins have previously been reported (20). In the present study, inhaled insulin–treated patients developed increased insulin antibody serum binding, but there was no correlation with parameters of clinical efficacy such as HbA1c, FPG, or hypoglycemia. Further analyses of combined data from a number of 3- to 6-month and extension studies (21) with inhaled insulin showed that antibody levels plateau after 12 months and also demonstrated no relation to efficacy measures or to pulmonary or other adverse events.
Both physicians and patients are often hesitant to initiate insulin therapy for several reasons. Weight gain has been a major concern (22), as has injection-related anxiety and/or phobia, all of which impede the timely use of insulin in patients with type 2 diabetes (23). During the present study, a greater increase in body weight occurred in patients who received subcutaneous insulin (1.4 kg) compared with inhaled insulin (no change). In a previous shorter study (11) in type 2 diabetes, inhaled insulin was not associated with increases in body weight. Whether the more physiologic insulin profile associated with inhaled insulin may have prevented weight gain remains to be established. Although the majority of patients in the present study had a BMI <35 href="http://care.diabetesjournals.org/cgi/content/full/27/10/2356#R24">24,25).
Reluctance to taking insulin by patients and reluctance to prescribe insulin by physicians contribute to poor glycemic control in many patients with type 2 diabetes, resulting in poor quality of life, greater risk for micro- and macrovascular complications, and increased long-term economic costs. By allowing the implementation of intensive insulin therapy with a noninvasive delivery system, inhaled insulin may allow patients to regard insulin therapy as a more positive treatment option. Although this was an open-label study in which patients volunteered to receive a novel therapeutic agent, a significantly higher level of patient satisfaction was seen with inhaled insulin. Many factors are likely to influence satisfaction; however, in the present study, the overall score as well as that of all satisfaction subscales favored inhaled insulin. Any effect of novelty with a new delivery system on satisfaction is likely to have diminished by the end of the study, and other studies show that that improved satisfaction with inhaled insulin peaks after 6 weeks, remains constant to 24 weeks (26), and is maintained after 1 year of continuous therapy (27). Therefore, the availability of inhaled insulin might help improve acceptance of insulin therapy by both patients and physicians.
In conclusion, this study demonstrated that inhaled insulin treatment in type 2 diabetes was effective, well tolerated, and comparable in glycemic control to a conventional subcutaneous insulin regimen. Ongoing studies will establish the long-term safety of inhaled insulin, but results from this 6-month study, together with those of other clinical studies of inhaled insulin (10–12), suggest that it may prove a novel and well-accepted treatment approach for the management of many patients with diabetes.
Results of a 6-month, randomized, comparative trial Priscilla A. Hollander, MD1, Lawrence Blonde, MD2, Richard Rowe, MD3, Adi E. Mehta, MD4, Joseph L. Milburn, MD5, Kenneth S. Hershon, MD6, Jean-Louis Chiasson, MD7 and Seymour R. Levin, MD8 for the Exubera Phase III Study Group
1 Baylor University Medical Center, Dallas, Texas2 Ochsner Clinic, New Orleans, Louisiana3 Division of Endocrinology, Department of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada4 Cleveland Clinic Foundation, Cleveland, Ohio5 North Texas Health Care Associates, Irving, Texas6 North Shore Diabetes and Endocrine Associates, New Hyde Park, New York7 Research Center, Department of Medicine, Centre Hospitalier de l’Université de Montréal, Campus Hôtel-Dieu, University of Montreal, Montreal, Quebec, Canada8 West Los Angeles VA Medical Center, Los Angeles, California
ABSTRACT
TOPABSTRACTINTRODUCTIONRESEARCH DESIGN AND METHODSRESULTSCONCLUSIONSReferences OBJECTIVE— Glycemic control using inhaled, dry-powder insulin plus a single injection of long-acting insulin was compared with a conventional regimen in patients with type 2 diabetes, which was previously managed with at least two daily insulin injections.
RESEARCH DESIGN AND METHODS— Patients were randomized to 6 months’ treatment with either premeal inhaled insulin plus a bedtime dose of Ultralente (n = 149) or at least two daily injections of subcutaneous insulin (mixed regular/NPH insulin; n = 150). The primary efficacy end point was the change in HbA1c from baseline to the end of study.
RESULTS— HbA1c decreased similarly in the inhaled (–0.7%) and subcutaneous (–0.6%) insulin groups (adjusted treatment group difference: –0.07%, 95% CI –0.32 to 0.17). HbA1c <7.0% name="BDY">
INTRODUCTION
TOPABSTRACTINTRODUCTIONRESEARCH DESIGN AND METHODSRESULTSCONCLUSIONSReferences Although the long-term benefits of tight glycemic control have been shown in patients with both type 1 and type 2 diabetes (1–5), insulin therapy is often delayed or suboptimally implemented despite elevated HbA1c levels, and a substantial number of patients remain poorly controlled (6).
Several factors contribute to the poor implementation of insulin therapy in the patient with type 2 diabetes, but the inconvenience and poor patient acceptability of a multiple daily injection regimen may play a major role (7). Currently, the majority of patients treated with insulin do not achieve recommended HbA1c goals (8). Reliance on fixed-ratio premixed insulins for treatment of a significant proportion of the type 2 diabetic population may significantly constrain the ability to achieve target glycemia. More acceptable forms of insulin delivery are required to improve the implementation of insulin therapy aiming for recommended treatment goals.
A dry-powder insulin delivery system that permits noninvasive application of rapid-acting insulin via inhalation has been developed. The pulmonary route exploits the large vascular bed and permeability of the alveoli to deliver insulin directly into the bloodstream (9). Inhaled insulin provides a rapid-acting insulin for management of both type 1 and type 2 diabetes, and preliminary short-term studies have shown that inhaled insulin provides reproducible and effective control of meal-related glycemia (10–12).
The time-action profile of human regular insulin injected subcutaneously limits its ability to control postprandial glycemia. Its relatively slow onset of action does not reproduce the physiologic secretion profile of insulin in response to a meal (13), thus resulting in excessive postprandial hyperglycemia and increased risk of hypoglycemia before the next meal. A study (14) in healthy subjects showed inhaled insulin to have a rapid onset of action that was significantly faster than regular insulin and a duration of action between that of insulin lispro and regular insulin. It has also been shown (15) in patients with type 2 diabetes that inhaled insulin is rapidly and reproducibly absorbed. As such, inhaled insulin appears to match the physiologic needs for mealtime use.
The present study aimed to 1) assess whether an insulin regimen involving pulmonary delivery of rapid-acting, dry-powder insulin plus a single injection of basal long-acting, subcutaneous insulin can provide glycemic control comparable to a conventional subcutaneous insulin regimen in a large cohort of patients with type 2 diabetes previously managed with at least two daily subcutaneous injections of insulin and 2) assess the tolerability of inhaled insulin over a 6-month period.
RESEARCH DESIGN AND METHODS
TOPABSTRACTINTRODUCTIONRESEARCH DESIGN AND METHODSRESULTSCONCLUSIONSReferences Men and women (n = 520) diagnosed with type 2 diabetes for at least 1 year were screened at 39 centers in the U.S. and Canada. Inclusion criteria were age 35–80 years; stable subcutaneous insulin schedule involving two to three injections daily for at least 2 months before study entry and not receiving any oral antidiabetic agents; screening and prerandomization HbA1c values of 6–11% inclusive, fasting plasma C-peptide >0.2 pmol/ml, and BMI 35 kg/m2; willingness to perform self-monitoring of blood glucose (SMBG) and otherwise comply with the study protocol; and written informed consent.
Exclusion criteria included poorly controlled asthma, chronic obstructive pulmonary disease or other significant respiratory disease; smoking during the last 6 months; abnormal screening chest X-ray; abnormal pulmonary function at screening (carbon monoxide diffusing capacity [DLCO] <75%,>120%, and forced expiratory volume in 1 s [FEV1] <70%>150 units/day.
The study protocol was approved by the institutional review board at each center.
This was a phase 3, open-label, parallel-group, comparator study consisting of a screening visit, a 4-week baseline lead-in phase, and a 24-week randomized treatment phase. During the baseline period, patients received a subcutaneous insulin regimen consisting of two doses of mixed NPH/regular. If the patient had previously been treated with an insulin regimen consisting of mixed NPH/regular insulin before breakfast and supper, the patient continued with this regimen. Otherwise, the patient received an appropriate two-dose regimen based on insulin requirements and glycemic control before entering the study.
Three weeks before randomization, patients met a dietitian for instruction on a weight-maintaining diet, which they were to maintain for the study duration. Patients were also instructed to perform 30 min of moderate exercise at least three times each week. The importance of diet and exercise was reinforced at clinic visits. All patients received instruction in SMBG, which they were to perform four times daily: before breakfast, lunch, supper, and bedtime. Target glucose ranges were 80–140 mg/dl (4.4–7.8 mmol/l) before meals and 100–160 mg/dl (5.6–8.9 mmol/l) before bedtime.
Before randomization, patients received instruction regarding the use of the insulin inhalation device. Using a computer-generated randomization scheme, performed through interactive voice response technology, patients were randomized to receive an inhaled insulin regimen (n = 149) or continue receiving conventional subcutaneous therapy as described above for 24 weeks (n = 150). The inhaled insulin regimen consisted of premeal inhaled insulin plus a single bedtime dose of Ultralente insulin. Inhaled insulin was administered within 10 min of the start of each meal and given in one to two inhalations using a dry-powder aerosol delivery system (Nektar Therapeutics, San Carlos, CA). The insulin powder was packaged in foil blisters of 1- and 3-mg doses (1 mg is equivalent to 2–3 units of subcutaneous insulin) (11).
Initial recommended doses for inhaled insulin were based on the subject’s weight, baseline subcutaneous insulin dose, and previous response to insulin. Administration of insulin, inhaled or injection, was preceded by SMBG, and the dose was adjusted weekly at the discretion of the investigator, based on SMBG results, to achieve target premeal glucose. Patients were also allowed to adjust doses when preprandial glucose was outside the above ranges, in anticipation of a smaller- or larger-than-usual meal or on an "as-needed" basis.
AssessmentsThe primary efficacy end point was the change in HbA1c from baseline to week 24. HbA1c was measured before randomization (at weeks –4 and –1) and at weeks 0, 6, 12, and 24. Mean HbA1c from weeks –1 and 0 was taken as baseline. The percentage of patients achieving HbA1c <7% name="SEC2">
RESULTS
TOPABSTRACTINTRODUCTIONRESEARCH DESIGN AND METHODSRESULTSCONCLUSIONSReferences Characteristics of the study participants at study entry are given in Table 1. The groups were well matched for all baseline characteristics. Both groups used only subcutaneous insulin at baseline, and the use of short- and long/intermediate-acting insulins at baseline was similar between treatment groups (Table 1). Daily insulin use in both groups trended slightly higher from week 6 to week 24 (inhaled group: short acting, 15.0 and 16.6 mg at weeks 6 and 24, respectively, and long acting, 34.0 and 37.9 units, respectively; subcutaneous group: short acting, 24.0 and 25.5 units, respectively, and intermediate acting, 50.1 and 52.3 units, respectively). As the inhaled insulin regimen involved only one daily injection of long-acting Ultralente along with premeal short-acting insulin, the basal-to-bolus ratio was shifted (i.e., less basal and more bolus insulin) relative to the subcutaneous group, where two daily doses of both intermediate- and short-acting insulin were used.
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Table 1— Demographic and clinical characteristics at study entry
Of the 299 patients enrolled, 1 withdrew consent after randomization. In the inhaled group, 3 patients discontinued for reasons related to study treatment (two adverse events and one insufficient clinical response), and 12 subjects discontinued for administrative reasons (e.g., protocol violation or withdrawn consent). Two subjects in the inhaled group died of causes unrelated to treatment (one of metastatic esophageal cancer and one of esophageal bleeding of unknown etiology). In the subcutaneous insulin group, one subject discontinued for insufficient clinical response and two subjects discontinued due to adverse events not considered related to the study drug. Six subjects in the subcutaneous group discontinued for administrative reasons.
Mean change in HbA1cMean HbA1c decreased similarly in the two treatment groups (Fig. 1A). After 24 weeks of treatment, mean HbA1c levels decreased from 8.1% at baseline to 7.4% (–0.7%) at week 24 in patients receiving inhaled insulin. Patients receiving subcutaneous showed a decrease from 8.2 to 7.6% (–0.6%). The difference between the adjusted mean changes from baseline for the two treatments (inhaled-subcutaneous) was –0.07% (95% CI –0.32 to 0.17). Thus, the upper limit of the 95% CI was <0.5 name="F1">
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Figure 1— A: HbA1c (mean ± SD) during treatment with inhaled () versus subcutaneous () insulin at screening (n = 141 and 145, respectively), baseline (n = 143 and 145), and weeks 6 (n = 137 and 130), 12 (n = 143 and 145), and 24 (n = 134 and 140). B: Percentage of patients achieving defined levels of HbA1c at week 24 (LOCF) with inhaled (, n = 143) versus subcutaneous (, n = 145) insulin.
Sixty-seven patients (47%) receiving inhaled insulin achieved HbA1c <7% href="http://care.diabetesjournals.org/cgi/content/full/27/10/2356#F1">Fig. 1B.
FPG and PPGFPG decreased from 152 mg/dl (8.44 mmol/l) at baseline to 132 mg/dl (7.33 mmol/l) at week 24 in those receiving inhaled insulin compared with 158 mg/dl (8.77 mmol/l) to 149 mg/dl (8.27 mmol/l) in the subcutaneous group. The difference between the adjusted mean changes from baseline was –15.9 mg/dl in favor of inhaled insulin (95% CI –26.6 to –5.2).
The treatment groups were comparable in terms of change from baseline in the 2-h PPG concentration at week 24. In patients receiving inhaled insulin treatment, 2-h PPG decreased from 244 mg/dl (13.5 mmol/l) at baseline to 221 mg/dl (12.3 mmol/l) at week 24, compared with a reduction from 252 mg/dl (14.0 mmol/l) to 231 mg/dl (12.8 mmol/l) in patients receiving subcutaneous treatment. The difference between adjusted mean changes from baseline was –9.41 mg/dl (95% CI –26.9 to 8.0).
HypoglycemiaIn the inhaled insulin group, 109 (76.2%) patients experienced a total of 1,104 hypoglycemic events: a crude event rate of 1.40 events per subject-month. One hundred four patients (71.7%) in the subcutaneous insulin group experienced a total of 1,278 events: a crude event rate of 1.57 events per subject-month. This represents a risk ratio (inhaled/subcutaneous) for any hypoglycemic event of 0.89 (95% CI 0.82–0.97), indicating that there is a lower risk of hypoglycemia associated with inhaled insulin. There were very few severe hypoglycemic events in either treatment group. Only four events in the inhaled group were classed as severe (crude event rate 0.5/100 subject-months) and one event in the subcutaneous group (0.1/100 subject-months).
Body weight and lipid profileAfter 24 weeks, mean body weight in the inhaled insulin group remained stable at 90.5 kg. However, there was an increase in body weight in the subcutaneous treatment group (89.2 kg at baseline, 90.6 kg at week 24). The adjusted mean treatment group difference was –1.29 kg (95% CI –1.98 to –0.59).
No differences in serum lipid parameters were seen between the two groups. After 24 weeks of treatment, the median changes from baseline in lipid parameters in the inhaled and subcutaneous insulin groups, respectively, were total cholesterol, 0 and 3 mg/dl (0.0 and 0.08 mmol/l); HDL cholesterol, 0 and 1 mg/dl (0.0 and 0.03 mmol/l); LDL cholesterol, –3 and 0 mg/dl (–0.08 and 0.0 mmol/l); and triglycerides, 3.5 and 8.0 mg/dl (0.04 and 0.09 mmol/l).
Safety and tolerabilityThe frequency and nature of adverse events, with the exception of cough, were comparable between the two treatment groups. A total of 126 patients in the inhaled insulin group and 118 patients in the subcutaneous insulin group experienced adverse events (including the hypoglycemic events discussed above) that were possibly or probably related to the treatment regimen. The majority of these were mild or moderate. Treatment-related adverse events experienced by >10% of patients in the inhaled insulin group were tremor (43 patients, 29%), asthenia (27 patients, 18%), sweating (25 patients, 17%), and dizziness (23 patients, 15%). All of these adverse events are symptoms compatible with hypoglycemia. Treatment-related adverse events experienced by >10% of patients in the subcutaneous group were tremor (40 patients, 27%), sweating (29 patients, 20%), asthenia (21 patients, 14%), and dizziness (19 patients, 13%). All-cause cough was experienced by 21% (32 of 149) of patients in the inhaled insulin treatment group compared with 2% (3 of 149) in the subcutaneous group. Cough was judged as mild to moderate in the inhaled group and decreased in incidence over the study period; the median duration of the period of increased cough was 2.0 weeks. There were six treatment-related severe adverse events reported in the inhaled insulin group; three hypoglycemia, one hyperglycemia, one neuralgia, and one anxiety. There was one treatment-related severe adverse event in the subcutaneous group (unconsciousness associated with hypoglycemia).
The incidence of clinical laboratory abnormalities was similar between the two treatment groups. Forty-three of 135 patients (32%) in the inhaled group had at least one laboratory test abnormality compared with 56 of 142 patients (39%) in the subcutaneous group. The most frequent laboratory abnormalities were in urinalysis (increases in urine glucose, urine white blood cells, and hyaline casts).
Inhaled insulin-treated patients developed increased insulin antibody serum binding. Median percentage binding was 5.0 and 1.5% (below the level of quantitation) in the inhaled and subcutaneous groups, respectively. Levels of antibodies did not correlate to HbA1c, insulin dose, or incidence of hypoglycemia, and there was no association with adverse events or pulmonary function.
Mean changes in FVC, FEV1, TLC, and DLCO were small and comparable between the two treatment groups (Table 2).
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Table 2— PFT results in subjects with a baseline and at least one postbaseline PFT measurement
Treatment satisfaction and quality of lifeThe mean overall satisfaction score improved significantly for the inhaled group (P < name="SEC3">
CONCLUSIONS
TOPABSTRACTINTRODUCTIONRESEARCH DESIGN AND METHODSRESULTSCONCLUSIONSReferences The results of this study show that inhaled insulin provides glycemic control comparable to a conventional insulin regimen in patients with type 2 diabetes, as assessed by the changes in HbA1c from baseline to week 24. The actual decrease in HbA1c in both treatment groups at week 24 was modest; however, such a change would be expected to reduce the development and/or progression of diabetes complications, as shown in the U.K. Prospective Diabetes Study (3,4). Moreover, the study was designed to demonstrate equivalence and was not target driven. Nevertheless, a greater proportion of patients in the inhaled insulin group reached the American Diabetes Association goal of HbA1c <7% href="http://care.diabetesjournals.org/cgi/content/full/27/10/2356#R16">16). The addition of premeal inhaled insulin reduced both FPG and PPG levels. Although both basal and postprandial glucose contribute to glucose exposure, the relative importance of each has been debated (17) and may depend on the severity of diabetes (18). Interestingly, FPG decreased more in the inhaled group than in the subcutaneous group. The bedtime administration of Ultralente basal insulin in the inhaled insulin group may have contributed to lower FPG.
Overall, inhaled insulin was well tolerated. The risk of a hypoglycemic event was lower in the inhaled group compared with the subcutaneous group, which is consistent with results from a previous study (12). As inhaled insulin is delivered systemically via the lungs, it is important to assess possible pulmonary adverse events. Cough of mild-to-moderate severity was observed with a greater frequency in the inhaled insulin group, although its incidence decreased as the study progressed, and no patient withdrew due to cough. In the present study, inhaled insulin treatment was not associated with adverse effects on pulmonary function parameters of FEV1, FVC, TLC, or DLCO. Long-term studies are underway to assess any potential effect more conclusively. Changes in lung function initially observed in a long-term extension study of the Exubera Phase III program remained small and nonprogressive. Furthermore, controlled discontinuation of Exubera in a subset of those patients resulted in lung function gains of similar magnitude to the initial small decrease (19).
Insulin antibodies with both animal and human insulins have previously been reported (20). In the present study, inhaled insulin–treated patients developed increased insulin antibody serum binding, but there was no correlation with parameters of clinical efficacy such as HbA1c, FPG, or hypoglycemia. Further analyses of combined data from a number of 3- to 6-month and extension studies (21) with inhaled insulin showed that antibody levels plateau after 12 months and also demonstrated no relation to efficacy measures or to pulmonary or other adverse events.
Both physicians and patients are often hesitant to initiate insulin therapy for several reasons. Weight gain has been a major concern (22), as has injection-related anxiety and/or phobia, all of which impede the timely use of insulin in patients with type 2 diabetes (23). During the present study, a greater increase in body weight occurred in patients who received subcutaneous insulin (1.4 kg) compared with inhaled insulin (no change). In a previous shorter study (11) in type 2 diabetes, inhaled insulin was not associated with increases in body weight. Whether the more physiologic insulin profile associated with inhaled insulin may have prevented weight gain remains to be established. Although the majority of patients in the present study had a BMI <35 href="http://care.diabetesjournals.org/cgi/content/full/27/10/2356#R24">24,25).
Reluctance to taking insulin by patients and reluctance to prescribe insulin by physicians contribute to poor glycemic control in many patients with type 2 diabetes, resulting in poor quality of life, greater risk for micro- and macrovascular complications, and increased long-term economic costs. By allowing the implementation of intensive insulin therapy with a noninvasive delivery system, inhaled insulin may allow patients to regard insulin therapy as a more positive treatment option. Although this was an open-label study in which patients volunteered to receive a novel therapeutic agent, a significantly higher level of patient satisfaction was seen with inhaled insulin. Many factors are likely to influence satisfaction; however, in the present study, the overall score as well as that of all satisfaction subscales favored inhaled insulin. Any effect of novelty with a new delivery system on satisfaction is likely to have diminished by the end of the study, and other studies show that that improved satisfaction with inhaled insulin peaks after 6 weeks, remains constant to 24 weeks (26), and is maintained after 1 year of continuous therapy (27). Therefore, the availability of inhaled insulin might help improve acceptance of insulin therapy by both patients and physicians.
In conclusion, this study demonstrated that inhaled insulin treatment in type 2 diabetes was effective, well tolerated, and comparable in glycemic control to a conventional subcutaneous insulin regimen. Ongoing studies will establish the long-term safety of inhaled insulin, but results from this 6-month study, together with those of other clinical studies of inhaled insulin (10–12), suggest that it may prove a novel and well-accepted treatment approach for the management of many patients with diabetes.
Inhaled Insulin
What is the problem and what is known about it so far?
Because people with type 1 diabetes can't make insulin and need to take it, they usually need more than one type of manufactured insulin to control their diabetes. The different types of insulin work at different rates and for different amounts of time. Three commonly used types of insulin are "short-acting," "intermediate-acting," and "long-acting."
Short-acting insulin works much faster than intermediate- or long-acting insulin, and it is used around mealtime. Short-acting insulin should be taken about 30-45 minutes before eating, and it peaks at about 2-3 hours. It can keep working for as long as 6 hours.
Intermediate-acting insulin is insulin mixed with a substance that makes the body absorb the insulin more slowly. It takes longer to start to work, and it stays in your body for a longer time. NPH is a type of intermediate-acting insulin that usually begins to work about 2-4 hours after injected. It peaks 4-10 hours after injection, and it keeps working for 10-16 hours.
Long-acting insulin starts to work in 6-10 hours and can stay in the body for 20 hours or more. It has a peak, but its top speed looks a lot like its normal speed. Like intermediate-acting insulin, it is usually taken in the morning or before bed.
People with type 1 diabetes can often keep their glucose levels under control by taking shots of intermediate-acting or long-acting insulin in the morning or before bed, as well as taking shots of short-acting insulin before meals. However, even though this type of routine has been shown to work for people with type 1 diabetes, many patients often stray from this routine, probably because of the burden of taking so many shots.
Why did the researchers do this particular study?
The researchers wanted to see if there was an easier way for patients with type 1 diabetes to take intermediate- or long-acting insulin in addition to taking short-acting insulin. They looked at whether inhaling short-acting insulin, in addition to taking shots of intermediate-acting insulin, was as good at controlling diabetes as taking shots of both short-acting insulin and intermediate-acting insulin.
Who was studied?
Patients with type 1 diabetes who took part in the Inhaled Insulin Phase III Type 1 Diabetes Study. The patients were between 12 and 65 years of age and had been taking two or more shots of insulin each day for at least 2 months before the study began.
How was the study done?
All of the patients took shots of intermediate-acting NPH insulin twice a day. In addition to those shots, 165 patients took shots of short-acting insulin before meals, and the remaining 163 patients inhaled short-acting insulin before meals. The inhaled insulin was a dry-powder insulin delivered with a device that looks a bit like an asthma inhaler.
During each day of the study, the patients measured their blood glucose levels before each meal, 2 hours after a meal, and before they went to bed. The study lasted for 6 months.
What did the researchers find?
Both groups were able to lower their A1C (a measure of long-term blood glucose control) to similar levels, and almost the same number of patients in each group were able to lower their A1C to the ideal range (less than 7%).
The blood glucose measurements taken 2 hours after a meal were about the same in each group, but the group who took inhaled insulin had lower blood glucose levels at bedtime.
The patients who took the inhaled insulin had hypoglycemia (low blood glucose, also known as an “insulin reaction”) less often, but had severe hypoglycemia (dangerously low blood glucose) more often.
What were the limitations of the study?
The patients were responsible for giving themselves the insulin and taking their own blood glucose measurements. The size of insulin doses may have slightly varied among the patients, and the patients may have taken their measurements at different times. These types of differences could slightly affect the results.
This was a fairly short study, and the researchers are conducting more studies to look at how inhaled insulin affects the long-term health of the lungs.
What are the implications of the study?
For patients with type 1 diabetes who aren't able or don't want to take insulin shots before each meal, inhaling short-acting insulin may be a good alternative to help control their diabetes.
Because people with type 1 diabetes can't make insulin and need to take it, they usually need more than one type of manufactured insulin to control their diabetes. The different types of insulin work at different rates and for different amounts of time. Three commonly used types of insulin are "short-acting," "intermediate-acting," and "long-acting."
Short-acting insulin works much faster than intermediate- or long-acting insulin, and it is used around mealtime. Short-acting insulin should be taken about 30-45 minutes before eating, and it peaks at about 2-3 hours. It can keep working for as long as 6 hours.
Intermediate-acting insulin is insulin mixed with a substance that makes the body absorb the insulin more slowly. It takes longer to start to work, and it stays in your body for a longer time. NPH is a type of intermediate-acting insulin that usually begins to work about 2-4 hours after injected. It peaks 4-10 hours after injection, and it keeps working for 10-16 hours.
Long-acting insulin starts to work in 6-10 hours and can stay in the body for 20 hours or more. It has a peak, but its top speed looks a lot like its normal speed. Like intermediate-acting insulin, it is usually taken in the morning or before bed.
People with type 1 diabetes can often keep their glucose levels under control by taking shots of intermediate-acting or long-acting insulin in the morning or before bed, as well as taking shots of short-acting insulin before meals. However, even though this type of routine has been shown to work for people with type 1 diabetes, many patients often stray from this routine, probably because of the burden of taking so many shots.
Why did the researchers do this particular study?
The researchers wanted to see if there was an easier way for patients with type 1 diabetes to take intermediate- or long-acting insulin in addition to taking short-acting insulin. They looked at whether inhaling short-acting insulin, in addition to taking shots of intermediate-acting insulin, was as good at controlling diabetes as taking shots of both short-acting insulin and intermediate-acting insulin.
Who was studied?
Patients with type 1 diabetes who took part in the Inhaled Insulin Phase III Type 1 Diabetes Study. The patients were between 12 and 65 years of age and had been taking two or more shots of insulin each day for at least 2 months before the study began.
How was the study done?
All of the patients took shots of intermediate-acting NPH insulin twice a day. In addition to those shots, 165 patients took shots of short-acting insulin before meals, and the remaining 163 patients inhaled short-acting insulin before meals. The inhaled insulin was a dry-powder insulin delivered with a device that looks a bit like an asthma inhaler.
During each day of the study, the patients measured their blood glucose levels before each meal, 2 hours after a meal, and before they went to bed. The study lasted for 6 months.
What did the researchers find?
Both groups were able to lower their A1C (a measure of long-term blood glucose control) to similar levels, and almost the same number of patients in each group were able to lower their A1C to the ideal range (less than 7%).
The blood glucose measurements taken 2 hours after a meal were about the same in each group, but the group who took inhaled insulin had lower blood glucose levels at bedtime.
The patients who took the inhaled insulin had hypoglycemia (low blood glucose, also known as an “insulin reaction”) less often, but had severe hypoglycemia (dangerously low blood glucose) more often.
What were the limitations of the study?
The patients were responsible for giving themselves the insulin and taking their own blood glucose measurements. The size of insulin doses may have slightly varied among the patients, and the patients may have taken their measurements at different times. These types of differences could slightly affect the results.
This was a fairly short study, and the researchers are conducting more studies to look at how inhaled insulin affects the long-term health of the lungs.
What are the implications of the study?
For patients with type 1 diabetes who aren't able or don't want to take insulin shots before each meal, inhaling short-acting insulin may be a good alternative to help control their diabetes.
Inhaled insulin
Although inhaled insulin is comparable to injected insulin in controlling high blood sugar, its use should be reserved for diabetic patients who cannot or will not use needles, according to a new study.
That's because its long-term safety has yet to be established, says Lisa Ceglia, MD, of the Tufts-New England Medical Center in Boston, a researcher on the study.
"For the time being, the most worrisome concern is the effect inhaled insulin may have on lung function," Ceglia tells WebMD. The review article shows that one of the most common side effects of such therapy is increased coughing and a mild decrease in test scores that measure lung function.
"Are there other things to worry about? Possibly," Ceglia says. "But pulmonary toxicity is the issue we focused on because of the way the therapy is administered."
The findings are published in the November issue of the Annals of Internal Medicine.
Short-Term Trials
Ceglia's team reviewed 16 trials of inhaled insulin involving 4,023 patients with type 1 or type 2 diabetes.
Most of the trials lasted only 12-24 weeks. The longest trial lasted two years. It evaluated Exubera, Pfizer Inc.'s inhaled insulin delivery system. Pfizer is a WebMD sponsor.
In January 2006, Exubera became the first new insulin delivery option to be approved by the FDA since insulin was discovered in the 1920s. Pfizer launched the drug in the U.S. market in September 2006.
"All of the trials were open-label, meaning that the patients knew what they were getting," Ceglia says. None of the trials used the so-called "double-dummy" technique, in which patients receive an inhaler and injections without knowing which one contains insulin.
Although that other technique may have produced more definitive results, it was not used because the trial designers considered it "logistically difficult and cumbersome."
"What these trials were designed to do is prove non-inferiority," says Larry Deeb, MD, president of medicine and science at the American Diabetes Association in Alexandria, Va. Deed was not connected with the study. "All Pfizer had to do was prove that inhaled insulin was as good as subcutaneous insulin, not that it was superior."
Inhaled Insulin Worked
Ceglia's analysis showed that inhaled insulin was "comparable" to injected insulin in controlling blood sugar. Its effects were "just slightly less" than those of injected insulin, Ceglia says.
Though injected insulin had a small advantage over inhaled insulin in reducing blood sugar, the same number of patients on either therapy achieved a benchmark of diabetes control: a hemoglobin A1c level of less than 7%.
"Clearly, inhaled insulin is not an improvement over subcutaneous insulin, a drug [with] which we've had 80 years of experience," Deeb tells WebMD. "Doctors should tell patients who are already doing well on subcutaneous insulin that they shouldn't expect to do any better if they switch to inhaled insulin."
But Ceglia's analysis also showed high levels of patient satisfaction with inhaled insulin therapy.
She suggested this may be related to the "novelty of the new delivery method" and cautioned it remains to be seen if patients will be as enthusiastic and adherent to inhaled insulin therapy over the long term.
"It's exciting that this new therapy is out," Ceglia says. "It's been in development for a long time. We'll just have to wait and see how it goes."
Safety Concerns
Ceglia's analysis doesn't raise any immediate alarm. "Certainly there was nothing in the first two years that was frightening," she says.
But that doesn't mean there are no concerns. Leading the list is inhaled insulin's long-term effect on lung function.
Even in the short term, patients on inhaled insulin are more than three times as likely as those on injected insulin to develop a dry cough. "This appears to be an immediate reaction to the inhalation and doesn't seem to progress over time," Ceglia says.
That's because its long-term safety has yet to be established, says Lisa Ceglia, MD, of the Tufts-New England Medical Center in Boston, a researcher on the study.
"For the time being, the most worrisome concern is the effect inhaled insulin may have on lung function," Ceglia tells WebMD. The review article shows that one of the most common side effects of such therapy is increased coughing and a mild decrease in test scores that measure lung function.
"Are there other things to worry about? Possibly," Ceglia says. "But pulmonary toxicity is the issue we focused on because of the way the therapy is administered."
The findings are published in the November issue of the Annals of Internal Medicine.
Short-Term Trials
Ceglia's team reviewed 16 trials of inhaled insulin involving 4,023 patients with type 1 or type 2 diabetes.
Most of the trials lasted only 12-24 weeks. The longest trial lasted two years. It evaluated Exubera, Pfizer Inc.'s inhaled insulin delivery system. Pfizer is a WebMD sponsor.
In January 2006, Exubera became the first new insulin delivery option to be approved by the FDA since insulin was discovered in the 1920s. Pfizer launched the drug in the U.S. market in September 2006.
"All of the trials were open-label, meaning that the patients knew what they were getting," Ceglia says. None of the trials used the so-called "double-dummy" technique, in which patients receive an inhaler and injections without knowing which one contains insulin.
Although that other technique may have produced more definitive results, it was not used because the trial designers considered it "logistically difficult and cumbersome."
"What these trials were designed to do is prove non-inferiority," says Larry Deeb, MD, president of medicine and science at the American Diabetes Association in Alexandria, Va. Deed was not connected with the study. "All Pfizer had to do was prove that inhaled insulin was as good as subcutaneous insulin, not that it was superior."
Inhaled Insulin Worked
Ceglia's analysis showed that inhaled insulin was "comparable" to injected insulin in controlling blood sugar. Its effects were "just slightly less" than those of injected insulin, Ceglia says.
Though injected insulin had a small advantage over inhaled insulin in reducing blood sugar, the same number of patients on either therapy achieved a benchmark of diabetes control: a hemoglobin A1c level of less than 7%.
"Clearly, inhaled insulin is not an improvement over subcutaneous insulin, a drug [with] which we've had 80 years of experience," Deeb tells WebMD. "Doctors should tell patients who are already doing well on subcutaneous insulin that they shouldn't expect to do any better if they switch to inhaled insulin."
But Ceglia's analysis also showed high levels of patient satisfaction with inhaled insulin therapy.
She suggested this may be related to the "novelty of the new delivery method" and cautioned it remains to be seen if patients will be as enthusiastic and adherent to inhaled insulin therapy over the long term.
"It's exciting that this new therapy is out," Ceglia says. "It's been in development for a long time. We'll just have to wait and see how it goes."
Safety Concerns
Ceglia's analysis doesn't raise any immediate alarm. "Certainly there was nothing in the first two years that was frightening," she says.
But that doesn't mean there are no concerns. Leading the list is inhaled insulin's long-term effect on lung function.
Even in the short term, patients on inhaled insulin are more than three times as likely as those on injected insulin to develop a dry cough. "This appears to be an immediate reaction to the inhalation and doesn't seem to progress over time," Ceglia says.
Altrnative Insulin Delivery System
Alternative Insulin Delivery Systems
Ever since insulin was first identified as the key to restoring normal glucose levels in people with diabetes, doctors and patients have been hoping for an alternative to insulin injections. Don't get us wrong, injecting insulin works pretty well. Many people have been able to lead relatively normal lives because of it. We have pretty advanced syringe and needle technology and insulin pens and pumps have made getting insulin into the body even easier. Even so, the quest continues to find an alternative way of administering insulin.
Scientists have been working on a number of new advances in insulin administration.
Transdermal (through the skin)
Our skin is a remarkable organ. It's very good at letting almost nothing in, and letting just a few selected things out. Patches to help people quit smoking have made it seem almost easy to deliver a drug through the skin. In fact, nicotine is a small molecule that is readily absorbed into the skin. It only takes a tiny amount to have an effect on the body. Insulin on the other hand, is far too large to get through the skin without a lot of help. Trying to change that is tough.
Scientists have been working on patches using electrical currents, ultrasound waves, and chemicals to help transport insulin through the skin. Although some companies are hoping to develop products that could provide boluses of insulin through the skin for mealtime, any success for transdermal delivery is likely to come with basal delivery of relatively small amounts over time. Either way, we have a while to wait before insulin patches might be available in pharmacies.
Inhaled Insulin Is On The Way (PDF)The world's first inhalable insulin should be on pharmacy shelves sometime in the summer of 2006, offering people with diabetes a new way to take a treatment that for more than 80 years has been accessible only through needles.
Read this article which appears in the April 2006 issue of Diabetes Forecast magazine.
Inhaled Insulin
Inhaled insulin is probably what you've been hearing the most about lately. Several products are being created in laboratories and have shown success at controlling blood glucose levels. Some of these are in phase 3 clinical trials (the final phase of testing before you can submit a device for FDA approval), but only one has been approved for use. And that one is only approved for adults.
In clinical trials, the approved inhaled insulin, Exubera, managed blood glucose levels as well as injected fast-acting insulin. Inhaled insulin does not replace longer-acting insulins, so those would still need to be injected.
The new inhaled insulin does not come without limitations. First, you have to inhale a lot of insulin to get the amount your body needs. That's because only a small percentage of the inhaled insulin actually reaches the bloodstream and lowers blood glucose. So, a lot of it is "wasted." Because of that, the cost of inhaled insulin is fairly high -- you have to pay for all that waste.
There are also questions about the safety of delivering insulin to the lungs. After all, that's what you're doing when you inhale the insulin. You send it straight to the lungs. Many scientists think the lungs are a great place to deliver a drug because of the large surface area and ready absorption. The fact remains: that is not what lungs were designed to do. Although inhaling insulin has proven safe in short-term studies, the long-term safety remains a question. Exubera's manufacturer, Pfizer, will study the long-term effects of Exubera on the lungs, as well as its safety and effectiveness in patients with lung disease.
Buccal
Buccal (BUCK-el) insulin is similar to inhaled insulin in some ways. Buccal or delivery into the mouth, involves a device that delivers a spray of insulin like what you'd get out of a can of spray paint. Instead of going into the lungs, the insulin is absorbed in the lining at the back of the mouth and throat. The good part is that it avoids any problems from putting large amounts of insulin in the lungs. The problem is that even more of the insulin gets wasted.
Other than that, research shows that buccal insulin works about as well as inhaled insulin.
Oral
Okay, we've got shots, pumps, inhaled insulin, and insulin sprays. What's left? You probably already know that insulin taken as a pill is quickly broken down in the stomach, just like the food you eat. That makes it useless for lowering blood glucose levels.
So insulin can't be taken by itself in a pill form. Some scientists are trying to "package" insulin using special coatings, or by altering the insulin structure to get it through the stomach. Like inhaled insulin and insulin sprays, it's likely that a lot of the insulin will be wasted before it gets where it's going. It would probably also take a long time to start working after you swallowed the pill. Not much research has been done on insulin pills so far.
What does all this mean? The fact is that injected insulin (by syringe, pump, or pen) is a really effective way to lower blood glucose levels. Even if one of these insulin delivery methods does become available, its possible people with diabetes (particularly people with type 1) will still be better able to control blood glucose with injections or they may be able to use one of the other methods for their basal dose, but would still need injections for mealtimes and other bolus doses.
Ever since insulin was first identified as the key to restoring normal glucose levels in people with diabetes, doctors and patients have been hoping for an alternative to insulin injections. Don't get us wrong, injecting insulin works pretty well. Many people have been able to lead relatively normal lives because of it. We have pretty advanced syringe and needle technology and insulin pens and pumps have made getting insulin into the body even easier. Even so, the quest continues to find an alternative way of administering insulin.
Scientists have been working on a number of new advances in insulin administration.
Transdermal (through the skin)
Our skin is a remarkable organ. It's very good at letting almost nothing in, and letting just a few selected things out. Patches to help people quit smoking have made it seem almost easy to deliver a drug through the skin. In fact, nicotine is a small molecule that is readily absorbed into the skin. It only takes a tiny amount to have an effect on the body. Insulin on the other hand, is far too large to get through the skin without a lot of help. Trying to change that is tough.
Scientists have been working on patches using electrical currents, ultrasound waves, and chemicals to help transport insulin through the skin. Although some companies are hoping to develop products that could provide boluses of insulin through the skin for mealtime, any success for transdermal delivery is likely to come with basal delivery of relatively small amounts over time. Either way, we have a while to wait before insulin patches might be available in pharmacies.
Inhaled Insulin Is On The Way (PDF)The world's first inhalable insulin should be on pharmacy shelves sometime in the summer of 2006, offering people with diabetes a new way to take a treatment that for more than 80 years has been accessible only through needles.
Read this article which appears in the April 2006 issue of Diabetes Forecast magazine.
Inhaled Insulin
Inhaled insulin is probably what you've been hearing the most about lately. Several products are being created in laboratories and have shown success at controlling blood glucose levels. Some of these are in phase 3 clinical trials (the final phase of testing before you can submit a device for FDA approval), but only one has been approved for use. And that one is only approved for adults.
In clinical trials, the approved inhaled insulin, Exubera, managed blood glucose levels as well as injected fast-acting insulin. Inhaled insulin does not replace longer-acting insulins, so those would still need to be injected.
The new inhaled insulin does not come without limitations. First, you have to inhale a lot of insulin to get the amount your body needs. That's because only a small percentage of the inhaled insulin actually reaches the bloodstream and lowers blood glucose. So, a lot of it is "wasted." Because of that, the cost of inhaled insulin is fairly high -- you have to pay for all that waste.
There are also questions about the safety of delivering insulin to the lungs. After all, that's what you're doing when you inhale the insulin. You send it straight to the lungs. Many scientists think the lungs are a great place to deliver a drug because of the large surface area and ready absorption. The fact remains: that is not what lungs were designed to do. Although inhaling insulin has proven safe in short-term studies, the long-term safety remains a question. Exubera's manufacturer, Pfizer, will study the long-term effects of Exubera on the lungs, as well as its safety and effectiveness in patients with lung disease.
Buccal
Buccal (BUCK-el) insulin is similar to inhaled insulin in some ways. Buccal or delivery into the mouth, involves a device that delivers a spray of insulin like what you'd get out of a can of spray paint. Instead of going into the lungs, the insulin is absorbed in the lining at the back of the mouth and throat. The good part is that it avoids any problems from putting large amounts of insulin in the lungs. The problem is that even more of the insulin gets wasted.
Other than that, research shows that buccal insulin works about as well as inhaled insulin.
Oral
Okay, we've got shots, pumps, inhaled insulin, and insulin sprays. What's left? You probably already know that insulin taken as a pill is quickly broken down in the stomach, just like the food you eat. That makes it useless for lowering blood glucose levels.
So insulin can't be taken by itself in a pill form. Some scientists are trying to "package" insulin using special coatings, or by altering the insulin structure to get it through the stomach. Like inhaled insulin and insulin sprays, it's likely that a lot of the insulin will be wasted before it gets where it's going. It would probably also take a long time to start working after you swallowed the pill. Not much research has been done on insulin pills so far.
What does all this mean? The fact is that injected insulin (by syringe, pump, or pen) is a really effective way to lower blood glucose levels. Even if one of these insulin delivery methods does become available, its possible people with diabetes (particularly people with type 1) will still be better able to control blood glucose with injections or they may be able to use one of the other methods for their basal dose, but would still need injections for mealtimes and other bolus doses.
painless injections
PAINLESS INJECTIONSUltra-Fine Needle Makes the Impossible Possible (December 20, 2005)
The award-winning Nanopass 33 needle (photo supplied by Terumo Corp.) (jiji)
Though injections are vital for preventing and treating diseases, they are almost universally disliked by children and adults. The fear of injections, however, may soon be a thing of the past. In July 2005, a painless needle went on sale to hospitals and other medical facilities. The instrument was jointly developed by two Tokyo-based companies - Terumo Corporation, a medical equipment manufacturer, and Okano Industrial Corp., a firm with an international reputation for its metal-pressing technology - with the goal of reducing the pain of shots.
The World's Thinnest NeedleThe painless syringe is called Nanopass 33 and is sold under the brand name Microtaper Needle. According to Terumo, Nanopass 33's tip is just 0.20 millimeters in diameter, 20% thinner than conventional needles used to inject insulin. It is the thinnest needle in the world and reduces the discomfort of an injection to about the same level as a mosquito bite. The suggested retail price for a pack of 70 syringes is ¥2,100 ($17.50 at ¥120 to the dollar).
Terumo decided that it wanted to do something for diabetics, whose dependence on insulin means they must give themselves several injections a day and live with the pain and anxiety of daily shots. About 600,000 people in Japan alone are said to suffer from diabetes. In developing the needle, Terumo hoped to provide them with some physical and psychological relief.
Nanopass 33 won the Japan Industrial Design Promotion Organization's Good Design Grand Prize in 2005, with judges describing it as a product that raised awareness of the need to reduce the pain experienced by patients and "an example of a need making an impossible technology possible, and a product that caused a stir in Japan's manufacturing."
Small Is BeautifulThe development of Nanopass 33 was made possible by Okano Industrial Corp., a small factory with a handful of employees that, despite its size, boasts a high level of technology. This small firm is so skilled in metal pressing that it has even attracted the attention of major international corporations and NASA. The company's president, Okano Masayuki, is known as a world-class craftsman and has been called a "metalwork magician."
The traditional method of manufacturing needles is to hollow out a cylindrical piece of metal, but it is extremely difficult to make ultra-thin needles this way. Through a process of trial and error, Okano Industrial hit upon the new method of rolling up a very thin sheet of stainless steel and welding the seam tightly to make a leak-proof cylinder. Through this innovative technique requiring ultra-precision processing, Okano Kogyo was able to bring Terumo's plan to fruition.
To reduce resistance at the time of injection, the sheet of metal is rolled into a cone with a particular contour - an extraordinary achievement given the fineness of the needle's tip. Terumo devised a special process for tapering the tip and mass producing the needles.
In an interview made available over the Internet, Okano Masayuki said that Terumo approached a number of companies with the idea for the syringe and only came to Okano Industrial after everybody else turned it down. He also revealed that a physics professor had deemed the plan theoretically impossible, holding that a sheet of metal so thin could not be rolled up. Okano says he decided to give it a try anyway because he could not resist taking up the challenge of a project that nobody else would take on; hearing that it could not be done made him all the more determined. "I like doing things that other people can't do," he said.
The desire to reduce the discomfort of patients thus combined with the passion of an artisan devoted to his trade to create a new product that overturns conventional wisdom.
The award-winning Nanopass 33 needle (photo supplied by Terumo Corp.) (jiji)
Though injections are vital for preventing and treating diseases, they are almost universally disliked by children and adults. The fear of injections, however, may soon be a thing of the past. In July 2005, a painless needle went on sale to hospitals and other medical facilities. The instrument was jointly developed by two Tokyo-based companies - Terumo Corporation, a medical equipment manufacturer, and Okano Industrial Corp., a firm with an international reputation for its metal-pressing technology - with the goal of reducing the pain of shots.
The World's Thinnest NeedleThe painless syringe is called Nanopass 33 and is sold under the brand name Microtaper Needle. According to Terumo, Nanopass 33's tip is just 0.20 millimeters in diameter, 20% thinner than conventional needles used to inject insulin. It is the thinnest needle in the world and reduces the discomfort of an injection to about the same level as a mosquito bite. The suggested retail price for a pack of 70 syringes is ¥2,100 ($17.50 at ¥120 to the dollar).
Terumo decided that it wanted to do something for diabetics, whose dependence on insulin means they must give themselves several injections a day and live with the pain and anxiety of daily shots. About 600,000 people in Japan alone are said to suffer from diabetes. In developing the needle, Terumo hoped to provide them with some physical and psychological relief.
Nanopass 33 won the Japan Industrial Design Promotion Organization's Good Design Grand Prize in 2005, with judges describing it as a product that raised awareness of the need to reduce the pain experienced by patients and "an example of a need making an impossible technology possible, and a product that caused a stir in Japan's manufacturing."
Small Is BeautifulThe development of Nanopass 33 was made possible by Okano Industrial Corp., a small factory with a handful of employees that, despite its size, boasts a high level of technology. This small firm is so skilled in metal pressing that it has even attracted the attention of major international corporations and NASA. The company's president, Okano Masayuki, is known as a world-class craftsman and has been called a "metalwork magician."
The traditional method of manufacturing needles is to hollow out a cylindrical piece of metal, but it is extremely difficult to make ultra-thin needles this way. Through a process of trial and error, Okano Industrial hit upon the new method of rolling up a very thin sheet of stainless steel and welding the seam tightly to make a leak-proof cylinder. Through this innovative technique requiring ultra-precision processing, Okano Kogyo was able to bring Terumo's plan to fruition.
To reduce resistance at the time of injection, the sheet of metal is rolled into a cone with a particular contour - an extraordinary achievement given the fineness of the needle's tip. Terumo devised a special process for tapering the tip and mass producing the needles.
In an interview made available over the Internet, Okano Masayuki said that Terumo approached a number of companies with the idea for the syringe and only came to Okano Industrial after everybody else turned it down. He also revealed that a physics professor had deemed the plan theoretically impossible, holding that a sheet of metal so thin could not be rolled up. Okano says he decided to give it a try anyway because he could not resist taking up the challenge of a project that nobody else would take on; hearing that it could not be done made him all the more determined. "I like doing things that other people can't do," he said.
The desire to reduce the discomfort of patients thus combined with the passion of an artisan devoted to his trade to create a new product that overturns conventional wisdom.
microjet injector
MicroJet injector for painless injections
Devices/Technology
Published: Monday, 21-Mar-2005
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Email to a Friend
Parents know all too well the pain experienced by their children - and themselves - when the time comes for immunizations at the doctor's office.
But a new MicroJet injector being developed by bioengineering students at the University of California, Berkeley, may help ease some of that dread by taking the needle - and the pain - out of the equation. The MicroJet uses an electronic actuator that could one day propel vaccinations, insulin or other drugs through the skin of the patient - without the device even touching the skin - with far less pain than a hypodermic needle.
The MicroJet improves upon current jet injectors now on the market, which also forgo the conventional needle but have less control over the volume and speed of drug delivered. The UC Berkeley bioengineers were able to achieve liquid jet speeds as high as 140 meters per second, or about 315 miles per hour, with the MicroJet.
The researchers will demonstrate their prototype during the March 17-19 annual meeting of the National Collegiate Inventors and Innovators Alliance (NCIIA) in San Diego.
"The World Health Organization advocates developing needleless drug delivery technologies because of the problems of contamination and disposal that go along with hypodermic needles," said Laleh Jalilian, one of the three UC Berkeley bioengineering undergraduates on the project. "There are other jet injectors on the market, but they are plagued by variability in the percentage of liquid delivered, which means that it is difficult to know exactly how much of the drug actually gets into the patient. The MicroJet we are developing uses a tunable electronic circuit to offer a finer level of control than the air- and spring-powered models available now."
The researchers modified a traditional syringe by taking out the needle and adding a tiny piezoelectric actuator that propels the liquid out of the tube. The actuator expands or contracts in response to an applied voltage. Because the MicroJet's source of power is electrical rather than mechanical, its range of control is continuous, allowing a far higher level of customization than the jet injectors used today.
"Other jet injection systems have only three or four factory settings, but human skin is tremendously variable, with some skin being thicker and tougher than others," said Dan Fletcher, UC Berkeley assistant professor of bioengineering and faculty advisor to the undergraduates. "Not only are there differences from person to person, there are significant differences within a single individual."
The researchers pointed out that the palm of the hand, for example, is tougher than the back of the hand, and that the skin of an adult is likely to be tougher than that of a child. They said there is a need for an injector that can be tailored to these variations.
The students were able to control the jet velocity of the MicroJet from 33 meters per second up to 140 meters per second. The amount of liquid they were able to eject ranged from 45 nanoliters to 140 nanoliters. They tested the MicroJet on agarose gel to mimic human skin and found that they could vary the penetration depth of the liquid from 1 to 8 millimeters.
While they have not yet started tests on humans, the researchers said the range of the injector is well beyond what would be needed to deliver drugs through human skin.
"Another great feature of the MicroJet is that the diameter of the nozzle is only 70 microns, which is nearly three times smaller than the thinnest conventional hypodermic needles," said Marcio von Muhlen, another of the UC Berkeley undergraduate researchers. "Since the area of the jet stream decreases with the square of the diameter, that's at least a nine-fold reduction in the area of skin affected. With smaller nozzle diameters and without the need to jam a needle some substantial distance under your skin, you won't trigger as many nerve receptors in the surrounding tissue, which means a relatively pain-free experience."
While current jet injectors also promise a less painful injection, in reality, reports of pain can vary depending upon the patient and the location of the shot. The researchers acknowledge the real life reports, but noted that the level of pain experienced can be a function of the settings on the injector.
"The beauty of the MicroJet is that it has a wide range of settings that can be customized to the patient's comfort and needs," said Jalilian.
Fletcher said the inspiration for the project came from the ubiquitous inkjet printer. "The printer's ink cartridges essentially deliver a very controlled, repetitive shot of liquid onto the paper," he said. "The liquid in an inkjet cartridge is propelled at relatively low speeds, but the idea is the same."
So does this signal the end of scary needles and crying babies in doctors' offices?
"We don't think the MicroJet will ever replace needles entirely, but we see this as providing an innovative option for physicians and patients," said von Muhlen.
The researchers noted that the precision of the MicroJet could one day make it a good candidate for microsurgery as well as for delivering arthritis drugs into the joints of hands and knees, areas that are too shallow for hypodermic needles. They even joke that the MicroJet injector could be used to make getting tattoos much more bearable.
The MicroJet project began two years ago as part of the Berkeley Summer Bioengineering Research Program, sponsored by the Guidant Foundation. Through the program, UC Berkeley undergraduate students compete for the chance to participate in funded research projects with department faculty.
Jalilian, von Muhlen and Menzies Chen joined the MicroJet project as part of that program. Once the program ended, the students on the MicroJet project applied for and won a $20,000 grant from the NCIIA to continue their research. (Chen graduated in December 2004, but is still working on the project).
They have also been supported by UC Berkeley's College of Engineering's Undergraduate Research Opportunities program, which funds student research in a variety of campus engineering labs.
"It's not common for such innovative research projects to be entirely run by undergraduates," said Fletcher. "Not only have they done excellent work on the research, they have applied for and received grants to fund the project. This illustrates the importance of having university programs that provide students with initiative the opportunity to go beyond the typical undergraduate curricula."
The project is also part of the California Institute for Quantitative Biomedical Research (QB3), which integrates the fields of engineering, physics, mathematics, biology and medical sciences at three UC campuses to catalyze human health research.
Future tests are planned on animal models and cadaver skins to fine-tune the device.
Devices/Technology
Published: Monday, 21-Mar-2005
Printer Friendly
Email to a Friend
Parents know all too well the pain experienced by their children - and themselves - when the time comes for immunizations at the doctor's office.
But a new MicroJet injector being developed by bioengineering students at the University of California, Berkeley, may help ease some of that dread by taking the needle - and the pain - out of the equation. The MicroJet uses an electronic actuator that could one day propel vaccinations, insulin or other drugs through the skin of the patient - without the device even touching the skin - with far less pain than a hypodermic needle.
The MicroJet improves upon current jet injectors now on the market, which also forgo the conventional needle but have less control over the volume and speed of drug delivered. The UC Berkeley bioengineers were able to achieve liquid jet speeds as high as 140 meters per second, or about 315 miles per hour, with the MicroJet.
The researchers will demonstrate their prototype during the March 17-19 annual meeting of the National Collegiate Inventors and Innovators Alliance (NCIIA) in San Diego.
"The World Health Organization advocates developing needleless drug delivery technologies because of the problems of contamination and disposal that go along with hypodermic needles," said Laleh Jalilian, one of the three UC Berkeley bioengineering undergraduates on the project. "There are other jet injectors on the market, but they are plagued by variability in the percentage of liquid delivered, which means that it is difficult to know exactly how much of the drug actually gets into the patient. The MicroJet we are developing uses a tunable electronic circuit to offer a finer level of control than the air- and spring-powered models available now."
The researchers modified a traditional syringe by taking out the needle and adding a tiny piezoelectric actuator that propels the liquid out of the tube. The actuator expands or contracts in response to an applied voltage. Because the MicroJet's source of power is electrical rather than mechanical, its range of control is continuous, allowing a far higher level of customization than the jet injectors used today.
"Other jet injection systems have only three or four factory settings, but human skin is tremendously variable, with some skin being thicker and tougher than others," said Dan Fletcher, UC Berkeley assistant professor of bioengineering and faculty advisor to the undergraduates. "Not only are there differences from person to person, there are significant differences within a single individual."
The researchers pointed out that the palm of the hand, for example, is tougher than the back of the hand, and that the skin of an adult is likely to be tougher than that of a child. They said there is a need for an injector that can be tailored to these variations.
The students were able to control the jet velocity of the MicroJet from 33 meters per second up to 140 meters per second. The amount of liquid they were able to eject ranged from 45 nanoliters to 140 nanoliters. They tested the MicroJet on agarose gel to mimic human skin and found that they could vary the penetration depth of the liquid from 1 to 8 millimeters.
While they have not yet started tests on humans, the researchers said the range of the injector is well beyond what would be needed to deliver drugs through human skin.
"Another great feature of the MicroJet is that the diameter of the nozzle is only 70 microns, which is nearly three times smaller than the thinnest conventional hypodermic needles," said Marcio von Muhlen, another of the UC Berkeley undergraduate researchers. "Since the area of the jet stream decreases with the square of the diameter, that's at least a nine-fold reduction in the area of skin affected. With smaller nozzle diameters and without the need to jam a needle some substantial distance under your skin, you won't trigger as many nerve receptors in the surrounding tissue, which means a relatively pain-free experience."
While current jet injectors also promise a less painful injection, in reality, reports of pain can vary depending upon the patient and the location of the shot. The researchers acknowledge the real life reports, but noted that the level of pain experienced can be a function of the settings on the injector.
"The beauty of the MicroJet is that it has a wide range of settings that can be customized to the patient's comfort and needs," said Jalilian.
Fletcher said the inspiration for the project came from the ubiquitous inkjet printer. "The printer's ink cartridges essentially deliver a very controlled, repetitive shot of liquid onto the paper," he said. "The liquid in an inkjet cartridge is propelled at relatively low speeds, but the idea is the same."
So does this signal the end of scary needles and crying babies in doctors' offices?
"We don't think the MicroJet will ever replace needles entirely, but we see this as providing an innovative option for physicians and patients," said von Muhlen.
The researchers noted that the precision of the MicroJet could one day make it a good candidate for microsurgery as well as for delivering arthritis drugs into the joints of hands and knees, areas that are too shallow for hypodermic needles. They even joke that the MicroJet injector could be used to make getting tattoos much more bearable.
The MicroJet project began two years ago as part of the Berkeley Summer Bioengineering Research Program, sponsored by the Guidant Foundation. Through the program, UC Berkeley undergraduate students compete for the chance to participate in funded research projects with department faculty.
Jalilian, von Muhlen and Menzies Chen joined the MicroJet project as part of that program. Once the program ended, the students on the MicroJet project applied for and won a $20,000 grant from the NCIIA to continue their research. (Chen graduated in December 2004, but is still working on the project).
They have also been supported by UC Berkeley's College of Engineering's Undergraduate Research Opportunities program, which funds student research in a variety of campus engineering labs.
"It's not common for such innovative research projects to be entirely run by undergraduates," said Fletcher. "Not only have they done excellent work on the research, they have applied for and received grants to fund the project. This illustrates the importance of having university programs that provide students with initiative the opportunity to go beyond the typical undergraduate curricula."
The project is also part of the California Institute for Quantitative Biomedical Research (QB3), which integrates the fields of engineering, physics, mathematics, biology and medical sciences at three UC campuses to catalyze human health research.
Future tests are planned on animal models and cadaver skins to fine-tune the device.
Floating Drug Delivery System
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Figure 2. (A) Multiple-unit oral floating drug delivery system. (B) Working principle of effervescent floating drug delivery system.
Ichikawa et al29 developed floating capsules composed of a plurality of granules that have different residence times in the stomach and consist of an inner foamable layer of gas-generating agents. This layer was further divided into 2 sublayers, the outer containing sodium bicarbonate and the inner containing tartaric acid. This layer was surrounded by an expansive polymeric film (composed of poly vinyl acetate [PVA] and shellac), which allowed gastric juice to pass through, and was found to swell by foam produced by the action between the gastric juices and the gas-generating agents.29 It was shown that the swellable membrane layer played an important role in maintaining the buoyancy of the pills for an extended period of time. Two parameters were evaluated: the time for the pills to be floating (TPF) and rate of pills floating at 5 hours (FP5h). It was observed that both the TPF and FP5h increased as the percentage of swellable membrane layer coated on pills having a effervescent layer increased. As the percentage of swellable layer was increased from 13% to 25% (wt/wt), the release rate was decreased and the lag time for dissolution also increased. The percentage of swellable layer was fixed at 13% wt/wt and the optimized system showed excellent floating ability in vitro (TPF ~10 minutes and FP5h ~80%) independent of pH and viscosity of the medium.
Yang et al30 developed a swellable asymmetric triple-layer tablet with floating ability to prolong the gastric residence time of triple drug regimen (tetracycline, metronidazole, and clarithromycin) in Helicobacter pylori–associated peptic ulcers using hydroxy propyl methyl cellulose (HPMC) and poly (ethylene oxide) (PEO) as the rate-controlling polymeric membrane excipients. The design of the delivery system was based on the swellable asymmetric triple-layer tablet approach. Hydroxypropylmethylcellulose and poly(ethylene oxide) were the major rate-controlling polymeric excipients. Tetracycline and metronidazole were incorporated into the core layer of the triple-layer matrix for controlled delivery, while bismuth salt was included in one of the outer layers for instant release. The floatation was accomplished by incorporatinga gas-generating layer consisting of sodium bicarbonate: calcium carbonate (1:2 ratios) along with the polymers. The in vitro results revealed that the sustained delivery of tetracycline and metronidazole over 6 to 8 hours could be achieved while the tablet remained afloat. The floating feature aided in prolonging the gastric residence time of this system to maintain high-localized concentration of tetracycline and metronidazole (Figure 3).
Figure 3. Schematic presentation of working of a triple-layer system. (A) Initial configuration of triple-layer tablet. (B) On contact with the dissolution medium the bismuth layer rapidly dissolves and matrix starts swelling. (C) Tablet swells and erodes. (D) and (E) Tablet erodes completely.
Ozdemir et al31 developed floating bilayer tablets with controlled release for furosemide. The low solubility of the drug could be enhanced by using the kneading method, preparing a solid dispersion with β cyclodextrin mixed in a 1:1 ratio. One layer contained the polymers HPMC 4000, HPMC 100, and CMC (for the control of the drug delivery) and the drug. The second layer contained the effervescent mixture of sodium bicarbonate and citric acid. The in vitro floating studies revealed that the lesser the compression force the shorter is the time of onset of floating, ie, when the tablets were compressed at 15 MPa, these could begin to float at 20 minutes whereas at a force of 32 MPa the time was prolonged to 45 minutes. Radiographic studies on 6 healthy male volunteers revealed that floating tablets were retained in stomach for 6 hours and further blood analysis studies showed that bioavailability of these tablets was 1.8 times that of the conventional tablets. On measuring the volume of urine the peak diuretic effect seen in the conventional tablets was decreased and prolonged in the case of floating dosage form.
Choi et al32 prepared floating alginate beads using gas-forming agents (calcium carbonate and sodium bicarbonate) and studied the effect of CO2 generation on the physical properties, morphology, and release rates. The study revealed that the kind and amount of gas-forming agent had a profound effect on the size, floating ability, pore structure, morphology, release rate, and mechanical strength of the floating beads. It was concluded that calcium carbonate formed smaller but stronger beads than sodium bicarbonate. Calcium carbonate was shown to be a less-effective gas-forming agent than sodium bicarbonate but it produced superior floating beads with enhanced control of drug release rates. In vitro floating studies revealed that the beads free of gas-forming agents sank uniformly in the media while the beads containing gas-forming agents in proportions ranging from 5:1 to 1:1 demonstrated excellent floating (100%).
Li et al33,34 evaluated the contribution of formulation variables on the floating properties of a gastro floating drug delivery system using a continuous floating monitoring device and statistical experimental design. The formulation was conceived using taguchi design. HPMC was used as a low-density polymer and citric acid was incorporated for gas generation. Analysis of variance (ANOVA) test on the results from these experimental designs demonstrated that the hydrophobic agent magnesium stearate could significantly improve the floating capacity of the delivery system. High-viscosity polymers had good effect on floating properties. The residual floating force values of the different grades of HPMC were in the order K4 M~ E4 M~K100 LV> E5 LV but different polymers with same viscosity, ie, HPMC K4M, HPMC E4M did not show any significant effect on floating property. Better floating was achieved at a higher HPMC/carbopol ratio and this result demonstrated that carbopol has a negative effect on the floating behavior.
Penners et al35 developed an expandable tablet containing mixture of polyvinyl lactams and polyacrylates that swell rapidly in an aqueous environment and thus reside in stomach over an extended period of time. In addition to this, gas-forming agents were incorporated. As the gas formed, the density of the system was reduced and thus the system tended to float on the gastric contents.
Fassihi and Yang36 developed a zero-order controlled release multilayer tablet composed of at least 2 barrier layers and 1 drug layer. All the layers were made of swellable, erodible polymers and the tablet was found to swell on contact with aqueous medium. As the tablet dissolved, the barrier layers eroded away to expose more of the drug. Gas-evolving agent was added in either of the barrier layers, which caused the tablet to float and increased the retention of tablet in a patient’s stomach.
Talwar et al37 developed a once-daily formulation for oral administration of ciprofloxacin. The formulation was composed of 69.9% ciprofloxacin base, 0.34% sodium alginate, 1.03% xanthum gum, 13.7% sodium bicarbonate, and 12.1% cross-linked poly vinyl pyrrolidine. The viscolysing agent initially and the gel-forming polymer later formed a hydrated gel matrix that entrapped the gas, causing the tablet to float and be retained in the stomach or upper part of the small intestine (spatial control). The hydrated gel matrix created a tortuous diffusion path for the drug, resulting in sustained release of the drug (temporal delivery).
Two patents granted to Alza Corporation revealed a device having a hollow deformable unit that was convertible from a collapsed to expandable form and vice versa. The deformable unit was supported by a housing that was internally divided into 2 chambers separated by a pressure-sensitive movable bladder. The first chamber contained the therapeutic agent and the second contained a volatile liquid (cyclopentane, ether) that vaporized at body temperature and imparted buoyancy to the system. The system contained a bioerodible plug to aid in exit of the unit from the body.38,39
Baumgartner et al40 developed a matrix-floating tablet incorporating a high dose of freely soluble drug. The formulation containing 54.7% of drug, HPMC K4 M, Avicel PH 101, and a gas-generating agent gave the best results. It took 30 seconds to become buoyant. In vivo experiments with fasted state beagle dogs revealed prolonged gastric residence time. On radiographic images made after 30 minutes of administration, the tablet was observed in animal’s stomach and the next image taken at 1 hour showed that the tablet had altered its position and turned around. This was the evidence that the tablet did not adhere to the gastric mucosa. The MMC (phase during which large nondisintegrating particles or dosage forms are emptied from stomach to small intestine) of the gastric emptying cycle occurs approximately every 2 hours in humans and every 1 hour in dogs but the results showed that the mean gastric residence time of the tablets was 240 ± 60 minutes (n = 4) in dogs. The comparison of gastric motility and stomach emptying between humans and dogs showed no big difference and therefore it was speculated that the experimentally proven increased gastric residence time in beagle dogs could be compared with known literature for humans, where this time is less than 2 hours.
Moursy et al41 developed sustained release floating capsules of nicardipine HCl. For floating, hydrocolloids of high viscosity grades were used and to aid in buoyancy sodium bicarbonate was added to allow evolution of CO2. In vitro analysis of a commercially available 20-mg capsule of nicardipine HCl (MICARD) was performed for comparison. Results showed an increase in floating with increase in proportion of hydrocolloid. Inclusion of sodium bicarbonate increased buoyancy. The optimized sustained release floating capsule formulation was evaluated in vivo and compared with MICARD capsules using rabbits at a dose equivalent to a human dose of 40 mg. Drug duration after the administration of sustained release capsules significantly exceeded that of the MICARD capsules. In the latter case the drug was traced for 8 hours compared with 16 hours in former case.
Atyabi and coworkers42 developed a floating system using ion exchange resin that was loaded with bicarbonate by mixing the beads with 1 M sodium bicarbonate solution. The loaded beads were then surrounded by a semipermeable membrane to avoid sudden loss of CO2. Upon coming in contact with gastric contents an exchange of chloride and bicarbonate ions took place that resulted in CO2 generation thereby carrying beads toward the top of gastric contents and producing a floating layer of resin beads (Figure 4) .The in vivo behavior of the coated and uncoated beads was monitored using a single channel analyzing study in 12 healthy human volunteers by gamma radio scintigraphy. Studies showed that the gastric residence time was prolonged considerably (24 hours) compared with uncoated beads (1 to 3 hours).
Figure 4. Pictorial presentation of working of effervescent floating drug delivery system based on ion exchange resin.
Non-Effervescent Floating Dosage Forms
Non-effervescent floating dosage forms use a gel forming or swellable cellulose type of hydrocolloids, polysaccharides, and matrix-forming polymers like polycarbonate, polyacrylate, polymethacrylate, and polystyrene. The formulation method includes a simple approach of thoroughly mixing the drug and the gel-forming hydrocolloid. After oral administration this dosage form swells in contact with gastric fluids and attains a bulk density of < href="http://www.aapspharmscitech.org/view.asp?art=pt060347#B43">43 developed polycarbonate microspheres by solvent evaporation technique. Polycarbonate in dichloromethane was found to give hollow microspheres that floated on water and simulated biofluids as evidenced by scanning electron microscopy (SEM). High drug loading was achieved and drug-loaded microspheres were able to float on gastric and intestinal fluids. It was found that increasing the drug-to-polymer ratio increased both their mean particle size and release rate of drug.
Nur and Zhang44 developed floating tablets of captopril using HPMC (4000 and 15 000 cps) and carbopol 934P. In vitro buoyancy studies revealed that tablets of 2 kg/cm2 hardness after immersion into the floating media floated immediately and tablets with hardness 4 kg/cm2 sank for 3 to 4 minutes and then came to the surface. Tablets in both cases remained floating for 24 hours. The tablet with 8 kg/cm2 hardness showed no floating capability. It was concluded that the buoyancy of the tablet is governed by both the swelling of the hydrocolloid particles on the tablet surface when it contacts the gastric fluids and the presence of internal voids in the center of the tablet (porosity). A prolonged release from these floating tablets was observed as compared with the conventional tablets and a 24-hour controlled release from the dosage form of captopril was achieved.
Bulgarelli et al45 studied the effect of matrix composition and process conditions on casein gelatin beads prepared by emulsification extraction method. Casein by virtue of its emulsifying properties causes incorporation of air bubbles and formation of large holes in the beads that act as air reservoirs in floating systems and serve as a simple and inexpensive material used in controlled oral drug delivery systems. It was observed that the percentage of casein in matrix increases the drug loading of both low and high porous matrices, although the loading efficiency of high porous matrices is lower than that of low porous matrices.
Fell et al46 prepared floating alginate beads incorporating amoxycillin. The beads were produced by dropwise addition of alginate into calcium chloride solution, followed by removal of gel beads and freeze-drying. The beads containing the dissolved drug remained buoyant for 20 hours and high drug-loading levels were achieved.
Streubel et al47 prepared single-unit floating tablets based on polypropylene foam powder and matrix-forming polymer. Incorporation of highly porous foam powder in matrix tablets provided density much lower than the density of the release medium. A 17% wt/wt foam powder (based on mass of tablet) was achieved in vitro for at least 8 hours. It was concluded that varying the ratios of matrix-forming polymers and the foam powder could alter the drug release patterns effectively.
Asmussen et al48 invented a device for the controlled release of active compounds in the gastrointestinal tract with delayed pyloric passage, which expanded in contact with gastric fluids and the active agent was released from a multiparticulate preparation. It was claimed that the release of the active compound was better controlled when compared with conventional dosage forms with delayed pyloric passage.
El-Kamel et al49 prepared floating microparticles of ketoprofen, by emulsion solvent diffusion technique. Four different ratios of Eudragit S 100 with Eudragit RL were used. The formulation containing 1:1 ratio of the 2 above-mentioned polymers exhibited high percentage of floating particles in all the examined media as evidenced by the percentage of particles floated at different time intervals. This can be attributed to the low bulk density, high packing velocity, and high packing factor.
Illum and Ping50 developed microspheres that released the active agent in the stomach environment over a prolonged period of time. The active agent was encased in the inner core of microspheres along with the rate-controlling membrane of a water-insoluble polymer. The outer layer was composed of bioadhesive (chitosan). The microspheres were prepared by spray drying an oil/water or water/oil emulsion of the active agent, the water-insoluble polymer, and the cationic polymer.
Streubel et al51 developed floating microparticles composed of polypropylene foam, Eudragit S, ethyl cellulose (EC), and polymethyl metha acrylate (PMMA) and were prepared by solvent evaporation technique. High encapsulation efficiencies were observed and were independent of the theoretical drug loading. Good floating behavior was observed as more than 83% of microparticles were floating for at least 8 hours. The in vitro drug release was dependent upon the type of polymer used. At similar drug loading the release rates increased in the following order PMMA < href="http://www.aapspharmscitech.org/view.asp?art=pt060347#B26">26 developed an HBS system containing a homogeneous mixture of drug and the hydrocolloid in a capsule, which upon contact with gastric fluid acquired and maintained a bulk density of less than 1 thereby being buoyant on the gastric contents of stomach until all the drug was released (Figure 5).
Figure 5. Working principle of hydrodynamically balanced system.
Sheth and Tossounian52 developed hydrodynamically balanced sustained release tablets containing drug and hydrophilic hydrocolloids, which on contact with gastric fluids at body temperature formed a soft gelatinous mass on the surface of the tablet and provided a water-impermeable colloid gel barrier on the surface of the tablets. The drug slowly released from the surface of the gelatinous mass that remained buoyant on gastric fluids (Figure 6, A and B).
Figure 6. Intragastric floating tablets. (A) United States patent 4 167 558, September 11, 1979. (B) United States patent 4 140 755, February 20, 1979.
Ushomaru et al53 developed sustained release composition for a capsule containing mixture of cellulose derivative or a starch derivative that formed a gel in water and higher fatty acid glyceride and/or higher alcohol, which was solid at room temperature. The capsules were filled with the above mixture and heated to a temperature above the melting point of the fat components and then cooled and solidified.
Bolton and Desai54 developed a noncompressed sustained release tablet that remained afloat on gastric fluids. The tablet formulation comprised 75% of drug and 2% to 6.5% of gelling agent and water. The noncompressed tablet had a density of less than 1 and sufficient mechanical stability for production and handling.
Kawashima et al prepared multiple-unit hollow microspheres by emulsion solvent diffusion technique. Drug and acrylic polymer were dissolved in an ethanol-dichloromethane mixture, and poured into an aqueous solution of PVA with stirring to form emulsion droplets. The rate of drug release in micro balloons was controlled by changing the polymer-to-drug ratio. Microballoons were floatable in vitro for 12 hours when immersed in aqueous media. Radiographical studies proved that microballoons orally administered to humans were dispersed in the upper part of stomach and retained there for 3 hours against peristaltic movements.55
Dennis et al56 invented a buoyant controlled release pharmaceutical powder formulation filled into capsules. It released a drug of a basic character at a controlled rate regardless of the pH of the environment. PH-dependent polymer is a salt of a polyuronic acid such as alginic acid and a pH-independent hydrocarbon gelling agent, hydroxypropylmethyl cellulose.
Spickett et al57 invented an antacid preparation having a prolonged gastric residence time. It comprised 2 phases. The internal phase consisted of a solid antacid and the external phase consisted of hydrophobic organic compounds (mono-, di-, and triglycerides) for floating and a non-ionic emulsifier.
Franz and Oth58 described a sustained release dosage form adapted to release of the drug over an extended period of time. It comprised a bilayer formulation in which one layer consisted of drug misoprostal and the other had a floating layer. The uncompressed bilayer formulation was kept in a capsule and was shown to be buoyant in the stomach for 13 hours. The dosage form was designed in such a way that all the drug was released in the stomach itself.
Wu et al59 developed floating sustained release tablets of nimodipine by using HPMC and PEG 6000. Prior to formulation of floating tablets, nimodipine was incorporated into poloxamer-188 solid dispersion after which it was directly compressed into floating tablets. It was observed that by increasing the HPMC and decreasing the PEG 6000 content a decline in in vitro release of nimodipine occurred.
Wong et al60 developed a prolonged release dosage form adapted for gastric retention using swellable polymers. It consisted of a band of insoluble material that prevented the covered portion of the polymer matrix from swelling and provided a segment of a dosage form that was of sufficient rigidity to withstand the contractions of the stomach and delayed the expulsion of the dosage form from the stomach.
Mitra61 developed a sustained release multilayered sheet-like medicament device. It was buoyant on the gastric contents and consisted of at least 1 dry, self-supporting carrier film of water-insoluble polymer. The drug was dispersed or dissolved in this layer and a barrier film overlaid the carrier film. The barrier film was compsosed of 1 water-insoluble layer and another water-soluble and drug-permeable polymer or copolymer layer. The 2 layers were sealed together in such a way that plurality of small air pockets were entrapped that gave buoyancy to the formulation.
Harrigan62 developed an intragastric floating drug delivery system that was composed of a drug reservoir encapsulated in a microporous compartment having pores on top and bottom surfaces. However, the peripheral walls were sealed to prevent any physical contact of the drug in the reservoir with the stomach walls.
Joseph et al25 developed a floating dosage form of piroxicam based on hollow polycarbonate microspheres. The microspheres were prepared by the solvent evaporation technique. Encapsulation efficiency of ~95% was achieved. In vivo studies were performed in healthy male albino rabbits. Pharmacokinetic analysis was derived from plasma concentration vs time plot and revealed that the bioavailability from the piroxicam microspheres alone was 1.4 times that of the free drug and 4.8 times that of a dosage form consisting of microspheres plus the loading dose and was capable of sustained delivery of the drug over a prolonged period.
There are several commercial products available based on the research activity of floating drug delivery (Table 1).
Table 1. Marketed Preparations of Floating Drug Delivery Systems59
S. no
Product
Active Ingredient
Reference No.
1
Madopar
Levodopa and benserzide
63
2
Valrelease
Diazepam
64
3
Topalkan
Aluminum magnesium antacid
65
4
Almagate flatcoat
Antacid
66
5
Liquid gavison
Alginic acid and sodium bicarbonate
67
Evaluation of floating drug delivery systems
Various parameters17 that need to be evaluated in gastro-retentive formulations include floating duration, dissolution profiles, specific gravity, content uniformity, hardness, and friability in case of solid dosage forms. In the case of multiparticulate drug delivery systems, differential scanning calorimetry (DSC), particle size analysis, flow properties, surface morphology, and mechanical properties are also performed.
The tests for floating ability (Table 2) and drug release are generally performed in simulated gastric fluids at 37ºC.
Table 2. In Vitro Floating and Dissolution Performance
Drug (Polymer Used)
Floating Media/Dissolution Medium and Method
Ref
Pentoxyfillin(HPMC K4 M)
500 mL of artificial gastric fluid pH 1.2 (without pepsin) at 100 rpm using USP XXIII dissolution apparatus. The time taken by the tablet to emerge on the water surface (floating lag time) and time until it floats on water surface was measured.
40
Amoxicillin beads(Calcium alginate)
For dissolution: 900 mL of deaerated 0.1 M HCl (pH 1.2) at 37ºC ± 1ºC in USP XXII dissolution tester at 50 rpm.
46
Ketoprofen(Eudragit S100Eudragit RL)
20 mL of simulated gastric fluid without pepsin, 50 mg of floating microparticles in 50-mL beakers were shaken horizontally in a water bath.% age of floating micro particles was calculated.For dissolution: 900 mL of either 0.1 N HCl or the phosphate buffer (pH 6.8) at 37ºC ± 0.1ºC in USP dissolution apparatus (I) at 100 rpm.
49
Verapamil(Propylene foam, Eudragit RS,ethyl cellulose, poly methyl meth acrylate)
30 mL of 0.1 N HCl (containing 0.02% wt/wt Tween 20), pH 1.2. Floatation was studied by placing 60 particles into 30-mL glass flasks. Number of settled particles was counted.
51
Captopril(Methocel K4M)
900 mL of enzyme-free 0.1 N HCl (pH 1.2) in USP XXIII apparatus II (basket method) at 37ºC at 75 rpm.
44
Theophylline(HPMC K4M,Polyethylene oxide)
0.1 N HCl in USP XXIII Apparatus II at 50 rpm at 37°C.Its buoyancy to upper 1/3 of dissolution vessel was measured for each batch of tablet.
23
Furosemide(β Cyclodextrin, HPMC 4000, HPMC 100,CMC, Polyethylene glycol)
For dissolution: continuous flow through cell gastric fluid of pH 1.2, 45–50 m N/m by adding 0.02% Polysorbate 20 (to reduce the surface tension), the flow rate to provide the sink conditions was 9mL/min.
32
Aspirin, Griseofulvin,p-Nitro Aniline(polycarbonate, PVA)
For dissolution: 500 mL of simulated gastric and intestinal fluid in 1000-mL Erlenmeyer flask. Flasks were shaken in a bath incubator at 37ºC.
43
Piroxicam (microspheres)(Polycarbonate)
For dissolution: 900 mL dissolution medium in USP paddle type apparatus at 37ºC at 100 rpm.
61
Ampicillin(Sodium alginate)
For dissolution: 500 mL of distilled water, JP XII disintegration test medium No.1 (pH 1.2) and No.2 (pH 6.8) in JP XII dissolution apparatus with paddle stirrer at 50 rpm.
68
Diclofenac(HPC-L)
An aliquot of 0.1 g of granules was immersed in 40 mL of purified water in a vessel at 37°C. Dried granules were weighed and floating percentage of granules was calculated.For dissolution: flow sampling system (dissolution tester: DT-300, triple flow cell) followed by 900 mL of distilled water in JP XII with paddles at 37 ºC ± 0.5ºC at 100 rpm.
69
Sulphiride(CP 934P)
For dissolution: 500 mL of each JP XII disintegration test medium No. 1 (pH 1.2) and No. 2 (pH 6.8) in JP XII dissolution apparatus at 37º C at 100 rpm.
70
Amoxicillin trihydrate(HPC)
For dissolution: 500–1000 mL (adequate to ensure sink conditions) of citrate/phosphate buffer of variable pH or solution of HCl (pH 1.2) in Erweka DT 6 dissolution tester fitted with paddles.
71
Ibuprofen, Tranilast(Eudragit S)
For dissolution: 900 mL dissolution medium (disintegration test medium No. 1 (pH 1.2) and No. 2 (pH 6.8) as specified in JP XI and as corresponding to USP XXI, paddle method at 37ºC at 100 rpm.
72
Isardipine(HPMC)
For dissolution: Method 1:300 mL of artificial gastric fluid in a beaker, which was suspended in water bath at 37ºC agitated by magnetic stirrer and by bubbling CO2 free air.Method 2:500/1000 mL of 0.1 M HCl and surfactant lauryl sulfate dimethyl ammonium oxide with rotating paddle at 50 rpm.
73
Potassium chloride(Metolose S.M. 100, PVP)
For dissolution: tablet was mounted onto the perspex holder except one face of the matrix was set flush with one face of the holder at 37ºC and the other face of the tablet was prevented from the dissolution media by a rubber closure; good mixing was maintained in the receiver by a magnetic stirrer at 100 rpm.
74
Verapamil(HPC-H, HPC-M, HPMC K15)
For dissolution: water in USP XXIII dissolution apparatus (method II) at 50 rpm.
75
PABA(Ethyl celluloseHPC-L)
70 mL of 50 mM acetate buffer with various pH (1–5) or viscosity (25–115 cps) in a 100-mL beaker at 37°C, 100 rpm.% age of floating pills was calculated.For dissolution: 50 mM acetate buffer (pH 4) in JP XI dissolution tester with paddles at 37ºC at 100 rpm.
76
Tetracycline, metronidazole, bismuth salt(Polyox, HPMC K4)
900 mL of 0.1 M HCl (pH 1.8) in USP dissolution apparatus at 50 rpm. The duration of floatation was observed visually.
30
Tranilast(Acrylic polymer, Eudragit RS)
Microballoons were introduced into 900 mL of disintegrating fluid solution no 1 (pH 1.2) containing Tween 20 (0.02% wt/vol) in USP XXII apparatus at 100 rpm . Percentage buoyancy was calculated.
55
Sotalol
Lag time required for the tablet to start floating on the top of the basket in dissolution apparatus was measured
77
Furosemide
Tablet were placed in a 400-mL flask at pH 1.2 and both the time needed to go upward and float on surface of the fluid and floating duration were determined.
31
Calcium carbonate(HPMC K4M, E4 M and Carbopol)
A continuous floating monitoring system was conceived. The upward floating force could be measured by the balance and the data transmitted to an online computer.Test medium used was 900 mL simulated gastric fluid (pH 1.2) at 37ºC.
33
Timmermans and Andre18 characterized the buoyancy capability of floating forms and sinking of nonfloating dosage forms using an apparatus to quantitatively measure the total force acting vertically on the immersed object. It was given by the vectorial sum of buoyancy F(b) and gravitational forces F(g) acting on the test object.
F = F ( b ) - F ( g )
(1)
Equation 1 can be rewritten as,
F = ( d f - d s ) g V = ( d f - W / V ) g V
(2)
where F is the resultant weight of the object, df and ds represent the fluid density and solid object density, g is the acceleration due to gravity and W and V are the weight and volume of the test objects. It can be seen from Equation 2 that if the resultant weight is more positive, better floating is exhibited by the object.
Li et al33,34 invented an online continuous floating monitoring system that was a modification of the system described by Timmermans and Andre.18 It was used to provide quantitative measurement of resultant floating force. The set-up consisted of an analytical balance connected with a computer. A capsule was inserted into the sample holder basket and the holder was immersed into the test medium (900 mL of simulated gastric fluid). A typical floating kinetic curve was obtained by plotting floating force vs time and 4 parameters were used to describe the floating properties of the capsules from this graph: F max, T max, Fr, and AUC f . Similar to Equation 2 conceived by Timmermans and Andre18 the overall force that the capsule is subjected can be given by
F = ( ρ m - ρ c ) g V c
(3)
where ρm and ρc are the density of floating media and test object and Vc is the volume of the test object. In this equation, 2 parameters, ρc and Vc, are important for overall floating force. During the measurement of buoyancy, Vc increased due to swelling of polymer and ρc increased due to water uptake. This increase led to an upward rise in floating force curve, which reached a maximum (Fmax) and declined until an equilibrium was reached.
Table 2 gives dissolution tests generally performed using USP dissolution apparatus. USP 28 states “the dosage unit is allowed to sink to the bottom of the vessel before rotation of the blade is started. A small, loose piece of nonreactive material with not more than a few turns of a wire helix may be attached to the dosage units that would otherwise float.78 However standard USP or BP methods have not been shown to be reliable predictors of in vitro performance of floating dosage forms.24 Pillay and Fassihi79 applied a helical wire sinker to the swellable floating system of theophylline, which is sparingly soluble in water and concluded that the swelling of the system was inhibited by the wire helix and the drug release also slowed down. To overcome this limitation a method was developed in which the floating drug delivery system was fully submerged under a ring or mesh assembly and an increase in drug release was observed. Also, it was shown that the method was more reproducible and consistent. However no significant change in the drug release was observed when the proposed method was applied to a swellable floating system of diltiazem, which is a highly water-soluble drug. It was thus concluded that the drug release from swellable floating systems was dependent upon uninhibited swelling, surface exposure, and the solubility of the drug in water.
Surface morphology was observed by SEM, which serves to confirm qualitatively a physical observation relating to surface area. In preparation of SEM analysis, the sample was exposed to high vacuum during the gold-coating process, which was needed to make the sample conductive.
Kawashima et al80 estimated the hollow structure of microspheres made of acrylic resins by measuring particle density (Pp) by a photographic counting method and a liquid displacement method. An image analyzer was used to determine the volume (v) of particles (n) of weight (w):
P = w / v
(4)
Porosity was measured by € = (1 – Pp /Pt) × 100, where Pt is the true density.
Bulgarelli et al45 developed casein gelatin beads and determined their porosity by mercury intrusion technique. The principle of this technique is that pressure (P) required to drive mercury through a pore decreases as described by the Washburn equation: P = (– 4 σ cos θ) d, where d is the pore diameter, σ is mercury / air interfacial tension, and θ is the contact angle at mercury air pore wall interface.
Sakuma et al81 prepared radiolabeled anionic poly metha acrylic acid nanoparticles and the particle size of nonlabeleled nanoparticles was measured by dynamic spectrophotometry.
In vivo gastric residence time of a floating dosage form is determined by X-ray diffraction studies, gamma scintigraphy,22 or roentgenography82 (Table 3).
Table 3. In Vivo Evaluation
Drug (Polymer)
Method
Ref
Tranilast(Eudragit S (BaSo4))
Two healthy male volunteers administered hard gelatin capsules packed with microballons (1000 mg) with 100 mL water. X-ray photographs at suitable intervals were taken.
55
Isardipine(HPMC)
Two phases:Phase I (fasted conditions):Five healthy volunteers (3 males and 2 females) in an open randomized crossover design, capsules ingested in sitting position with 100 mL of tap water.Phase II (fed states):Four subjects received normal or MR capsules in a crossover design after standard breakfast.Venous blood samples were taken in heparinized tubes at predetermined time intervals after dosing.
73
PABA+ Isosorbide dinitrate
Six healthy beagle dogs fasted overnight, then administered with capsules with 50 mL of water at 30 minutes after the meal.Control study: same amount of control pills without the effervescent layer were administered in the same protocol.The experimental design:Crossover design, 1-week washout time, plasma samples were taken by repeated venipuncture at upper part of the leg.
76
Hydrogel composites
Dogs (50 lbs) kept fasted and fed conditions.In each experiment (fed or fasted) 300 mL of water was given before administration of the capsules; X-ray pictures were taken.
83
Amoxycillin trihydrate
Six healthy fasted male subjects were selected; serum drug levels were compared in a single-dose crossover study following administration of tablets/capsules.
46
Floating beads
Gamma scintigraphy:In vivo behavior of coated and uncoated beads was monitored using a single channel analyzing study in 12 healthy human volunteers of mean age 34 yrs (22–49).
42
Pentoxyfillin
Four healthy beagle dogs (fasted for 24 hours). Tablet was administered with 100 mL of water for radiographic imaging. The animal was positioned in a right lateral/ventrodorsal recumbency.
40
Furosemide
Six purebred young male beagle dogs (9.6 to 14.3 kg), a 4-period crossover study balanced by residual effects was employed.Dogs were fasted overnight (water ad libitum), a catheter was inserted into right and left cephalic vein with 0.3 mL heparin lock, blood sampling was done at appropriate intervals.
84
Polystyrene nanoparticles
Dosing solution was administered to male SD strain rats fasted overnightThe radioactivity was measured with a gamma counter or a β counter (small intestine was cut into 10-cm portions).
63
Piroxicam
Nine healthy male albino rabbits weighing 2.2–2.5 kg were divided into 3 groups and were fasted for 24 hours.First batch: fed with 20 mg of Piroxicam powder in a gelatin capsule.Second batch: 67% piroxicam loaded piroxicam microspheres (~20mg of drug).Third batch: 7 mg of piroxicam and 67% piroxicam-loaded piroxicam microspheres (~20 mg of drug).
61
Calcium alginate multiple units floating beads
Seven healthy males (21–55 years). After fasting from midnight the night before the subjects consumed cereal (30 g) with milk (150 ml) to which was added ~20 Ci .99 m Tc-DTPA.An anterior image of stomach was obtained with γ camera.Static 120-second anterior images were acquired at suitable intervals and subjects remained standing/sitting for the duration of the study.
85
Furosemide
Six healthy males (60–71 kg) aged between 25 and 32 years for X-ray detection. Labeled tablets were given to subjects with 200 mL of water after a light breakfast, following ingestion. Gastric radiography revealed the duration for which the tablet stayed in stomach was determined.
31
Sulphiride
Three 3.5-kg white male rabbits10 mg of the drug/kg body weight was administered in a crossover manner with a 14-day washout period between dosing.Both IV and oral dosage form were given.
69
Applications of Floating Drug Delivery Systems
Floating drug delivery offers several applications for drugs having poor bioavailability because of the narrow absorption window in the upper part of the gastrointestinal tract. It retains the dosage form at the site of absorption and thus enhances the bioavailability. These are summarized as follows.
Sustained Drug Delivery
HBS systems can remain in the stomach for long periods and hence can release the drug over a prolonged period of time. The problem of short gastric residence time encountered with an oral CR formulation hence can be overcome with these systems. These systems have a bulk density of <1 href="http://www.aapspharmscitech.org/view.asp?art=pt060347#B41">41
Similarly a comparative study63 between the Madopar HBS and Madopar standard formulation was done and it was shown that the drug was released up to 8 hours in vitro in the former case and the release was essentially complete in less than 30 minutes in the latter case.
Site-Specific Drug Delivery
These systems are particularly advantageous for drugs that are specifically absorbed from stomach or the proximal part of the small intestine, eg, riboflavin and furosemide.
Furosemide is primarily absorbed from the stomach followed by the duodenum. It has been reported that a monolithic floating dosage form with prolonged gastric residence time was developed and the bioavailability was increased. AUC obtained with the floating tablets was approximately 1.8 times those of conventional furosemide tablets.84
A bilayer-floating capsule was developed for local delivery of misoprostol, which is a synthetic analog of prostaglandin E1 used as a protectant of gastric ulcers caused by administration of NSAIDs. By targeting slow delivery of misoprostol to the stomach, desired therapeutic levels could be achieved and drug waste could be reduced.86
Absorption Enhancement
Drugs that have poor bioavailability because of site-specific absorption from the upper part of the gastrointestinal tract are potential candidates to be formulated as floating drug delivery systems, thereby maximizing their absorption.
A significant increase in the bioavailability of floating dosage forms (42.9%) could be achieved as compared with commercially available LASIX tablets (33.4%) and enteric-coated LASIX-long product (29.5%).84
Miyazaki et al87 conducted pharmacokinetic studies on floating granules of indomethacin prepared with chitosan and compared the peak plasma concentration and AUC with the conventional commercially available capsules. It was concluded that the floating granules prepared with chitosan were superior in terms of decrease in peak plasma concentration and maintenance of drug in plasma.
Ichikawa et al76 developed a multiparticulate system that consisted of floating pills of a drug (p- amino benzoic acid) having a limited absorption site in the gastrointestinal tract. It was found to have 1.61 times greater AUC than the control pills.
The absorption of bromocriptine is limited to 30% from the gastrointestinal tract, however an HBS of the same can enhance the absorption. It was also studied that if metoclopramide is co delivered with bromocriptine, the side effects associated with high doses of bromocriptine can be prevented and the dosage from becomes therapeutically more potential.88
In few cases the bioavailability of floating dosage form is reduced in comparison to the conventional dosage form. In a recent study 3 formulations containing 25 mg atenolol, a floating multiple-unit capsule, a high-density multiple-unit capsule, and an immediate-release tablet were compared with respect to estimated pharmacokinetic parameters. The bioavailability of the 2 gastroretentive preparations with sustained release characteristics was significantly decreased when compared with the immediate-release tablet. This study showed that it was not possible to increase the bioavailability of a poorly absorbed drug such as atenolol using gastroretentive formulations.89
In some cases the reduction in bioavailability is compensated by advantages offered by FDDS, for example a hydrodynamically balanced system of L-dopa provided better control over motor fluctuations in spite of reduced bioavailability of up to 50% to 60% in comparison with standard L-dopa treatment. This could be attributed to reduced fluctuations in plasma drug levels in case of FDDS.90,91
Cook et al92 concluded that iron salts, if formulated as an HBS, have better efficacy and lesser side effects.
FDDS also serves as an excellent drug delivery system for the eradication of Helicobacter pylori, which causes chronic gastritis and peptic ulcers. The treatment requires high drug concentrations to be maintained at the site of infection that is within the gastric mucosa. By virtue of its floating ability these dosage forms can be retained in the gastric region for a prolonged period so that the drug can be targeted.93
Katayama et al68 developed a sustained release (SR) liquid preparation of ampicillin containing sodium alginate, which spreads out and aids in adhering to the gastric mucosal surface. Thus, the drug is continuously released in the gastric region.
Yang et al30 developed a swellable asymmetric triple-layer tablet with floating ability to prolong the gastric residence time of triple drug regimen (tetracycline, metronidazole, clarithromycin) of Helicobacter pylori–associated peptic ulcers using HPMC and PEO as the rate-controlling polymeric membrane excipients. Results demonstrated that sustained delivery of tetracycline and metronidazole over 6 to 8 hours could be achieved while the tablets remained floating. It was concluded that the developed delivery system had the potential to increase the efficacy of the therapy and improve patient compliance.
Floating microcapsules of melatonin were prepared by ionic interaction of chitosan and a surfactant, sodium dioctyl sulfosuccinate that is negatively charged. The dissolution studies of the floating microcapsules showed zero-order release kinetics in simulated gastric fluid. The release of drug from the floating microcapsules was greatly retarded with release lasting for several hours as compared with nonfloating microspheres where drug release was almost instantaneous. Most of the hollow microcapsules developed showed floating over simulated gastric fluid for more than 12 hours.94
Sato and Kawashima95 developed microballoons of riboflavin, which could float in JP XIII no 1 solution (simulated gastric fluid). These were prepared by an emulsion solvent technique. To assess the usefulness of the intragastric floating property of the developed microballoons of riboflavin, riboflavin powder, nonfloating microspheres of riboflavin, and floating microballoons of riboflavin were administered to 3 volunteers. Riboflavin pharmacokinetics was assessed by urinary excretion data. It could be concluded that although excretion of riboflavin following administration of floating microballoons was not sustained in fasted state, it was significantly sustained in comparison to riboflavin powder and nonfloating microspheres in the fed state. This could be due to the reason that the nonfloating formulation passes through the proximal small intestine at once from where riboflavin is mostly absorbed, while the floating microballoons gradually sank in the stomach and then arrived in the proximal small intestine in a sustained manner. Total urinary excretion (%) of riboflavin from the floating microballoons was lower than that of riboflavin powder. This was attributed to incomplete release of riboflavin from microballoons at the site of absorption.
Shimpi et al96 studied the application of hydrophobic lipid, Gelucire 43/01 for the design of multi-unit floating systems of a highly water-soluble drug, diltiazem HCl. Diltiazem HCl-Gelucire 43/01 granules were prepared by the melt granulation technique. The granules were evaluated for in vitro and in vivo floating ability, surface topography, and in vitro drug release. In vivo floating ability was studied by γ-scintigraphy in 6 healthy human volunteers and the results showed that the formulation remained in the stomach for 6 hours. It could be concluded that Gelucire 43/01 can be considered as an effective carrier for design of a multi-unit FDDS of highly water-soluble drugs such as diltiazem HCl.
A gastroretentive drug delivery system of ranitidine hydrochloride was designed using guar gum, xanthan gum, and hydroxy propyl methyl cellulose. Sodium bicarbonate was incorporated as a gas-generating agent. The effect of citric acid and stearic acid on drug release profile and floating properties was investigated. The addition of stearic acid reduces the drug dissolution due to its hydrophobic nature. A 32 full factorial design was applied to systemically optimize the drug release profile and the results showed that a low amount of citric acid and a high amount of stearic acid favor sustained release of ranitidine hydrochloride from a gastroretentive formulation. Hence, it could be concluded that a proper balance between a release rate enhancer and a release rate retardant could produce a drug dissolution profile similar to a theoretical dissolution profile of ranitidine hydrochloride.97
In a recent work by Sriamornsak et al,98 a new emulsion-gelation method was used to prepare oil-entrapped calcium pectinate gel (CaPG) beads as a carrier for intragastric floating drug delivery. The gel beads containing edible oil were prepared by gently mixing or homogenizing an oil phase and a water phase containing pectin, and then extruded into calcium chloride solution with gentle agitation at room temperature. The oil-entrapped calcium pectinate gel beads floated if a sufficient amount of oil was used. Scanning electron photomicrographs demonstrated very small pores, ranging between 5 and 40 µm, dispersed all over the beads. The type and percentage of oil played an important role in controlling the floating of oil-entrapped CaPG beads. The oil-entrapped CaPG beads were a good choice as a carrier for intragastric floating drug delivery.
Reddy and Murthy99 have discussed advantages and various disadvantages of single- and multiple-unit hydrodynamic systems.
Floating drug delivery is associated with certain limitations. Drugs that irritate the mucosa, those that have multiple absorption sites in the gastrointestinal tract, and those that are not stable at gastric pH are not suitable candidates to be formulated as floating dosage forms.
Floatation as a retention mechanism requires the presence of liquid on which the dosage form can float on the gastric contents. To overcome this limitation, a bioadhesive polymer can be used to coat the dosage so that it adheres to gastric mucosa,100 or the dosage form can be administered with a full glass of water to provide the initial fluid for buoyancy. Also single unit floating capsules or tablets are associated with an “all or none concept,” but this can be overcome by formulating multiple unit systems like floating microspheres or microballoons.101
Table 4 enlists examples of various drugs formulated as different forms of FDDS.
Table 4. List of Drugs Formulated as Single and Multiple Unit Forms of Floating Drug Delivery Systems.
Tablets Chlorpheniramine maleate
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Abstract
The purpose of writing this review on floating drug delivery systems (FDDS) was to compile the recent literature with special focus on the principal mechanism of floatation to achieve gastric retention. The recent developments of FDDS including the physiological and formulation variables affecting gastric retention, approaches to design single-unit and multiple-unit floating systems, and their classification and formulation aspects are covered in detail. This review also summarizes the in vitro techniques, in vivo studies to evaluate the performance and application of floating systems, and applications of these systems. These systems are useful to several problems encountered during the development of a pharmaceutical dosage form.
Keywords: floating drug delivery systems, single unit, multiple units, evaluation in vitro and in vivo
Introduction
Gastric emptying of dosage forms is an extremely variable process and ability to prolong and control the emptying time is a valuable asset for dosage forms, which reside in the stomach for a longer period of time than conventional dosage forms. Several difficulties are faced in designing controlled release systems for better absorption and enhanced bioavailability. One of such difficulties is the inability to confine the dosage form in the desired area of the gastrointestinal tract. Drug absorption from the gastrointestinal tract is a complex procedure and is subject to many variables. It is widely acknowledged that the extent of gastrointestinal tract drug absorption is related to contact time with the small intestinal mucosa.1 Thus, small intestinal transit time is an important parameter for drugs that are incompletely absorbed. Basic human physiology with the details of gastric emptying, motility patterns, and physiological and formulation variables affecting the cosmic emptying are summarized.
Gastroretentive systems can remain in the gastric region for several hours and hence significantly prolong the gastric residence time of drugs. Prolonged gastric retention improves bioavailability, reduces drug waste, and improves solubility for drugs that are less soluble in a high pH environment. It has applications also for local drug delivery to the stomach and proximal small intestines. Gastro retention helps to provide better availability of new products with new therapeutic possibilities and substantial benefits for patients.
The controlled gastric retention of solid dosage forms may be achieved by the mechanisms of mucoadhesion,2,3 flotation,4 sedimentation,5,6 expansion,7,8 modified shape systems,9,10 or by the simultaneous administration of pharmacological agents11,12 that delay gastric emptying. Based on these approaches, classification of floating drug delivery systems (FDDS) has been described in detail. In vivo/in vitro evaluation of FDDS has been discussed by scientists to assess the efficiency and application of such systems. Several recent examples have been reported showing the efficiency of such systems for drugs with bioavailability problems.
Basic Gastrointestinal Tract Physiology
Anatomically the stomach is divided into 3 regions: fundus, body, and antrum (pylorus). The proximal part made of fundus and body acts as a reservoir for undigested material, whereas the antrum is the main site for mixing motions and act as a pump for gastric emptying by propelling actions.13
Gastric emptying occurs during fasting as well as fed states. The pattern of motility is however distinct in the 2 states. During the fasting state an interdigestive series of electrical events take place, which cycle both through stomach and intestine every 2 to 3 hours.14 This is called the interdigestive myloelectric cycle or migrating myloelectric cycle (MMC), which is further divided into following 4 phases as described by Wilson and Washington.15
Phase I (basal phase) lasts from 40 to 60 minutes with rare contractions.
Phase II (preburst phase) lasts for 40 to 60 minutes with intermittent action potential and contractions. As the phase progresses the intensity and frequency also increases gradually.
Phase III (burst phase) lasts for 4 to 6 minutes. It includes intense and regular contractions for short period. It is due to this wave that all the undigested material is swept out of the stomach down to the small intestine. It is also known as the housekeeper wave.
Phase IV lasts for 0 to 5 minutes and occurs between phases III and I of 2 consecutive cycles.
After the ingestion of a mixed meal, the pattern of contractions changes from fasted to that of fed state. This is also known as digestive motility pattern and comprises continuous contractions as in phase II of fasted state. These contractions result in reducing the size of food particles (to less than 1 mm), which are propelled toward the pylorus in a suspension form. During the fed state onset of MMC is delayed resulting in slowdown of gastric emptying rate.16
Scintigraphic studies determining gastric emptying rates revealed that orally administered controlled release dosage forms are subjected to basically 2 complications, that of short gastric residence time and unpredictable gastric emptying rate.
Factors Affecting Gastric Retention
Gastric residence time of an oral dosage form is affected by several factors. To pass through the pyloric valve into the small intestine the particle size should be in the range of 1 to 2 mm.15 The pH of the stomach in fasting state is ~1.5 to 2.0 and in fed state is 2.0 to 6.0. A large volume of water administered with an oral dosage form raises the pH of stomach contents to 6.0 to 9.0. Stomach doesn’t get time to produce sufficient acid when the liquid empties the stomach, hence generally basic drugs have a better chance of dissolving in fed state than in a fasting state.
The rate of gastric emptying depends mainly on viscosity, volume, and caloric content of meals. Nutritive density of meals helps determine gastric emptying time. It does not make any difference whether the meal has high protein, fat, or carbohydrate content as long as the caloric content is the same. However, increase in acidity and caloric value slows down gastric emptying time. Biological factors such as age, body mass index (BMI), gender, posture, and diseased states (diabetes, Chron’s disease) influence gastric emptying. In the case of elderly persons, gastric emptying is slowed down. Generally females have slower gastric emptying rates than males. Stress increases gastric emptying rates while depression slows it down.17
The resting volume of the stomach is 25 to 50 mL. Volume of liquids administered affects the gastric emptying time. When volume is large, the emptying is faster. Fluids taken at body temperature leave the stomach faster than colder or warmer fluids. Studies have revealed that gastric emptying of a dosage form in the fed state can also be influenced by its size. Small-size tablets leave the stomach during the digestive phase while the large-size tablets are emptied during the housekeeping waves.
Timmermans and Andre18 studied the effect of size of floating and nonfloating dosage forms on gastric emptying and concluded that the floating units remained buoyant on gastric fluids. These are less likely to be expelled from the stomach compared with the nonfloating units, which lie in the antrum region and are propelled by the peristaltic waves.
It has been demonstrated using radiolabeled technique that there is a difference between gastric emptying times of a liquid, digestible solid, and indigestible solid. It was suggested that the emptying of large (>1 mm) indigestible objects from stomach was dependent upon interdigestive migrating myoelectric complex. When liquid and digestible solids are present in the stomach, it contracts ~3 to 4 times per minute leading to the movement of the contents through partially opened pylorus. Indigestible solids larger than the pyloric opening are propelled back and several phases of myoelectric activity take place when the pyloric opening increases in size during the housekeeping wave and allows the sweeping of the indigestible solids. Studies have shown that the gastric residence time (GRT) can be significantly increased under the fed conditions since the MMC is delayed.19
Several formulation parameters can affect the gastric residence time. More reliable gastric emptying patterns are observed for multiparticulate formulations as compared with single unit formulations, which suffer from “all or none concept.” As the units of multiparticulate systems are distributed freely throughout the gastrointestinal tract, their transport is affected to a lesser extent by the transit time of food compared with single unit formulation.20
Size and shape of dosage unit also affect the gastric emptying. Garg and Sharma21 reported that tetrahedron- and ring-shaped devices have a better gastric residence time as compared with other shapes. The diameter of the dosage unit is also equally important as a formulation parameter. Dosage forms having a diameter of more than 7.5 mm show a better gastric residence time compared with one having 9.9 mm.
The density of a dosage form also affects the gastric emptying rate. A buoyant dosage form having a density of less than that of the gastric fluids floats. Since it is away from the pyloric sphincter, the dosage unit is retained in the stomach for a prolonged period.
Timmermans et al studied the effect of buoyancy, posture, and nature of meals on the gastric emptying process in vivo using gamma scintigraphy.22 To perform these studies, floating and nonfloating capsules of 3 different sizes having a diameter of 4.8 mm (small units), 7.5 mm (medium units), and 9.9 mm (large units), were formulated. On comparison of floating and nonfloating dosage units, it was concluded that regardless of their sizes the floating dosage units remained buoyant on the gastric contents throughout their residence in the gastrointestinal tract, while the nonfloating dosage units sank and remained in the lower part of the stomach. Floating units away from the gastro-duodenal junction were protected from the peristaltic waves during digestive phase while the nonfloating forms stayed close to the pylorus and were subjected to propelling and retropelling waves of the digestive phase
The purpose of writing this review on floating drug delivery systems (FDDS) was to compile the recent literature with special focus on the principal mechanism of floatation to achieve gastric retention. The recent developments of FDDS including the physiological and formulation variables affecting gastric retention, approaches to design single-unit and multiple-unit floating systems, and their classification and formulation aspects are covered in detail. This review also summarizes the in vitro techniques, in vivo studies to evaluate the performance and application of floating systems, and applications of these systems. These systems are useful to several problems encountered during the development of a pharmaceutical dosage form.
Keywords: floating drug delivery systems, single unit, multiple units, evaluation in vitro and in vivo
Introduction
Gastric emptying of dosage forms is an extremely variable process and ability to prolong and control the emptying time is a valuable asset for dosage forms, which reside in the stomach for a longer period of time than conventional dosage forms. Several difficulties are faced in designing controlled release systems for better absorption and enhanced bioavailability. One of such difficulties is the inability to confine the dosage form in the desired area of the gastrointestinal tract. Drug absorption from the gastrointestinal tract is a complex procedure and is subject to many variables. It is widely acknowledged that the extent of gastrointestinal tract drug absorption is related to contact time with the small intestinal mucosa.1 Thus, small intestinal transit time is an important parameter for drugs that are incompletely absorbed. Basic human physiology with the details of gastric emptying, motility patterns, and physiological and formulation variables affecting the cosmic emptying are summarized.
Gastroretentive systems can remain in the gastric region for several hours and hence significantly prolong the gastric residence time of drugs. Prolonged gastric retention improves bioavailability, reduces drug waste, and improves solubility for drugs that are less soluble in a high pH environment. It has applications also for local drug delivery to the stomach and proximal small intestines. Gastro retention helps to provide better availability of new products with new therapeutic possibilities and substantial benefits for patients.
The controlled gastric retention of solid dosage forms may be achieved by the mechanisms of mucoadhesion,2,3 flotation,4 sedimentation,5,6 expansion,7,8 modified shape systems,9,10 or by the simultaneous administration of pharmacological agents11,12 that delay gastric emptying. Based on these approaches, classification of floating drug delivery systems (FDDS) has been described in detail. In vivo/in vitro evaluation of FDDS has been discussed by scientists to assess the efficiency and application of such systems. Several recent examples have been reported showing the efficiency of such systems for drugs with bioavailability problems.
Basic Gastrointestinal Tract Physiology
Anatomically the stomach is divided into 3 regions: fundus, body, and antrum (pylorus). The proximal part made of fundus and body acts as a reservoir for undigested material, whereas the antrum is the main site for mixing motions and act as a pump for gastric emptying by propelling actions.13
Gastric emptying occurs during fasting as well as fed states. The pattern of motility is however distinct in the 2 states. During the fasting state an interdigestive series of electrical events take place, which cycle both through stomach and intestine every 2 to 3 hours.14 This is called the interdigestive myloelectric cycle or migrating myloelectric cycle (MMC), which is further divided into following 4 phases as described by Wilson and Washington.15
Phase I (basal phase) lasts from 40 to 60 minutes with rare contractions.
Phase II (preburst phase) lasts for 40 to 60 minutes with intermittent action potential and contractions. As the phase progresses the intensity and frequency also increases gradually.
Phase III (burst phase) lasts for 4 to 6 minutes. It includes intense and regular contractions for short period. It is due to this wave that all the undigested material is swept out of the stomach down to the small intestine. It is also known as the housekeeper wave.
Phase IV lasts for 0 to 5 minutes and occurs between phases III and I of 2 consecutive cycles.
After the ingestion of a mixed meal, the pattern of contractions changes from fasted to that of fed state. This is also known as digestive motility pattern and comprises continuous contractions as in phase II of fasted state. These contractions result in reducing the size of food particles (to less than 1 mm), which are propelled toward the pylorus in a suspension form. During the fed state onset of MMC is delayed resulting in slowdown of gastric emptying rate.16
Scintigraphic studies determining gastric emptying rates revealed that orally administered controlled release dosage forms are subjected to basically 2 complications, that of short gastric residence time and unpredictable gastric emptying rate.
Factors Affecting Gastric Retention
Gastric residence time of an oral dosage form is affected by several factors. To pass through the pyloric valve into the small intestine the particle size should be in the range of 1 to 2 mm.15 The pH of the stomach in fasting state is ~1.5 to 2.0 and in fed state is 2.0 to 6.0. A large volume of water administered with an oral dosage form raises the pH of stomach contents to 6.0 to 9.0. Stomach doesn’t get time to produce sufficient acid when the liquid empties the stomach, hence generally basic drugs have a better chance of dissolving in fed state than in a fasting state.
The rate of gastric emptying depends mainly on viscosity, volume, and caloric content of meals. Nutritive density of meals helps determine gastric emptying time. It does not make any difference whether the meal has high protein, fat, or carbohydrate content as long as the caloric content is the same. However, increase in acidity and caloric value slows down gastric emptying time. Biological factors such as age, body mass index (BMI), gender, posture, and diseased states (diabetes, Chron’s disease) influence gastric emptying. In the case of elderly persons, gastric emptying is slowed down. Generally females have slower gastric emptying rates than males. Stress increases gastric emptying rates while depression slows it down.17
The resting volume of the stomach is 25 to 50 mL. Volume of liquids administered affects the gastric emptying time. When volume is large, the emptying is faster. Fluids taken at body temperature leave the stomach faster than colder or warmer fluids. Studies have revealed that gastric emptying of a dosage form in the fed state can also be influenced by its size. Small-size tablets leave the stomach during the digestive phase while the large-size tablets are emptied during the housekeeping waves.
Timmermans and Andre18 studied the effect of size of floating and nonfloating dosage forms on gastric emptying and concluded that the floating units remained buoyant on gastric fluids. These are less likely to be expelled from the stomach compared with the nonfloating units, which lie in the antrum region and are propelled by the peristaltic waves.
It has been demonstrated using radiolabeled technique that there is a difference between gastric emptying times of a liquid, digestible solid, and indigestible solid. It was suggested that the emptying of large (>1 mm) indigestible objects from stomach was dependent upon interdigestive migrating myoelectric complex. When liquid and digestible solids are present in the stomach, it contracts ~3 to 4 times per minute leading to the movement of the contents through partially opened pylorus. Indigestible solids larger than the pyloric opening are propelled back and several phases of myoelectric activity take place when the pyloric opening increases in size during the housekeeping wave and allows the sweeping of the indigestible solids. Studies have shown that the gastric residence time (GRT) can be significantly increased under the fed conditions since the MMC is delayed.19
Several formulation parameters can affect the gastric residence time. More reliable gastric emptying patterns are observed for multiparticulate formulations as compared with single unit formulations, which suffer from “all or none concept.” As the units of multiparticulate systems are distributed freely throughout the gastrointestinal tract, their transport is affected to a lesser extent by the transit time of food compared with single unit formulation.20
Size and shape of dosage unit also affect the gastric emptying. Garg and Sharma21 reported that tetrahedron- and ring-shaped devices have a better gastric residence time as compared with other shapes. The diameter of the dosage unit is also equally important as a formulation parameter. Dosage forms having a diameter of more than 7.5 mm show a better gastric residence time compared with one having 9.9 mm.
The density of a dosage form also affects the gastric emptying rate. A buoyant dosage form having a density of less than that of the gastric fluids floats. Since it is away from the pyloric sphincter, the dosage unit is retained in the stomach for a prolonged period.
Timmermans et al studied the effect of buoyancy, posture, and nature of meals on the gastric emptying process in vivo using gamma scintigraphy.22 To perform these studies, floating and nonfloating capsules of 3 different sizes having a diameter of 4.8 mm (small units), 7.5 mm (medium units), and 9.9 mm (large units), were formulated. On comparison of floating and nonfloating dosage units, it was concluded that regardless of their sizes the floating dosage units remained buoyant on the gastric contents throughout their residence in the gastrointestinal tract, while the nonfloating dosage units sank and remained in the lower part of the stomach. Floating units away from the gastro-duodenal junction were protected from the peristaltic waves during digestive phase while the nonfloating forms stayed close to the pylorus and were subjected to propelling and retropelling waves of the digestive phase
(Figure 1). It was also observed that of the floating and nonfloating units, the floating units were had a longer gastric residence time for small and medium units while no significant difference was seen between the 2 types of large unit dosage forms.
Figure 1. Intragastric residence positions of floating and nonfloating units.
When subjects were kept in the supine position it was observed that the floating forms could only prolong their stay because of their size; otherwise the buoyancy remained no longer an advantage for gastric retention.
A comparison was made to study the affect of fed and nonfed stages on gastric emptying. For this study all subjects remaining in an upright position were given a light breakfast and another similar group was fed with a succession of meals given at normal time intervals. It was concluded that as meals were given at the time when the previous digestive phase had not completed, the floating form buoyant in the stomach could retain its position for another digestive phase as it was carried by the peristaltic waves in the upper part of the stomach.
Approaches to Design Floating Dosage Forms
The following approaches have been used for the design of floating dosage forms of single- and multiple-unit systems.23
Single-Unit Dosage Forms
In Low-density approach4 the globular shells apparently having lower density than that of gastric fluid can be used as a carrier for drug for its controlled release. A buoyant dosage form can also be obtained by using a fluid-filled system that floats in the stomach.In coated shells24 popcorn, poprice, and polystyrol have been exploited as drug carriers. Sugar polymeric materials such as methacrylic polymer and cellulose acetate phthalate have been used to undercoat these shells. These are further coated with a drug-polymer mixture. The polymer of choice can be either ethylcellulose or hydroxypropyl cellulose depending on the type of release desired. Finally, the product floats on the gastric fluid while releasing the drug gradually over a prolonged duration.
Fluid- filled floating chamber25 type of dosage forms includes incorporation of a gas-filled floatation chamber into a microporous component that houses a drug reservoir. Apertures or openings are present along the top and bottom walls through which the gastrointestinal tract fluid enters to dissolve the drug. The other two walls in contact with the fluid are sealed so that the undissolved drug remains therein. The fluid present could be air, under partial vacuum or any other suitable gas, liquid, or solid having an appropriate specific gravity and an inert behavior. The device is of swallowable size, remains afloat within the stomach for a prolonged time, and after the complete release the shell disintegrates, passes off to the intestine, and is eliminated. Hydrodynamically balanced systems (HBS) are designed to prolong the stay of the dosage form in the gastro intestinal tract and aid in enhancing the absorption. Such systems are best suited for drugs having a better solubility in acidic environment and also for the drugs having specific site of absorption in the upper part of the small intestine. To remain in the stomach for a prolonged period of time the dosage form must have a bulk density of less than 1. It should stay in the stomach, maintain its structural integrity, and release drug constantly from the dosage form. The success of HBS capsule as a better system is best exemplified with chlordiazeopoxide hydrochloride. The drug is a classical example of a solubility problem wherein it exhibits a 4000-fold difference in solubility going from pH 3 to 6 (the solubility of chlordiazepoxide hydrochloride is 150 mg/mL and is ~0.1 mg/mL at neutral pH).
HBS of chlordiazeopoxide hydrochloride26 had comparable blood level time profile as of three 10-mg commercial capsules. HBS can either be formulated as a floating tablet or capsule. Many polymers and polymer combinations with wet granulation as a manufacturing technique have been explored to yield floatable tablets.
Various types of tablets (bilayered and matrix) have been shown to have floatable characteristics. Some of the polymers used are hydroxypropyl cellulose, hydroxypropyl methylcellulose, crosspovidone, sodium carboxymethyl cellulose, and ethyl cellulose.Self-correcting floatable asymmetric configuration drug delivery system23employs a disproportionate 3-layer matrix technology to control drug release.
The 3-layer principle has been improved by development of an asymmetric configuration drug delivery system in order to modulate the release extent and achieve zero-order release kinetics by initially maintaining a constant area at the diffusing front with subsequent dissolution/erosion toward the completion of the release process. The system was designed in such a manner that it floated to prolong gastric residence time in vivo, resulting in longer total transit time within the gastrointestinal tract environment with maximum absorptive capacity and consequently greater bioavailability. This particular characteristic would be applicable to drugs that have pH-dependent solubility, a narrow window of absorption, and are absorbed by active transport from either the proximal or distal portion of the small intestine.
Single-unit formulations are associated with problems such as sticking together or being obstructed in the gastrointestinal tract, which may have a potential danger of producing irritation.
Multiple-Unit Dosage Forms
The purpose of designing multiple-unit dosage form is to develop a reliable formulation that has all the advantages of a single-unit form and also is devoid of any of the above mentioned disadvantages of single-unit formulations. In pursuit of this endeavor many multiple-unit floatable dosage forms have been designed. Microspheres have high loading capacity and many polymers have been used such as albumin, gelatin, starch, polymethacrylate, polyacrylamine, and polyalkylcyanoacrylate. Spherical polymeric microsponges, also referred to as “microballoons,” have been prepared. Microspheres have a characteristic internal hollow structure and show an excellent in vitro floatability.27 In Carbon dioxide–generating multiple-unit oral formulations28 several devices with features that extend, unfold, or are inflated by carbon dioxide generated in the devices after administration have been described in the recent patent literature. These dosage forms are excluded from the passage of the pyloric sphincter if a diameter of ~12 to 18 mm in their expanded state is exceeded.
Classification of Floating Drug Delivery Systems (FDDS)
Floating drug delivery systems are classified depending on the use of 2 formulation variables: effervescent and non-effervescent systems.
Effervescent Floating Dosage Forms
These are matrix types of systems prepared with the help of swellable polymers such as methylcellulose and chitosan and various effervescent compounds, eg, sodium bicarbonate, tartaric acid, and citric acid. They are formulated in such a way that when in contact with the acidic gastric contents, CO2 is liberated and gets entrapped in swollen hydrocolloids, which provides buoyancy to the dosage forms.
Ichikawa et al28 developed a new multiple type of floating dosage system composed of effervescent layers and swellable membrane layers coated on sustained release pills. The inner layer of effervescent agents containing sodium bicarbonate and tartaric acid was divided into 2 sublayers to avoid direct contact between the 2 agents. These sublayers were surrounded by a swellable polymer membrane containing polyvinyl acetate and purified shellac. When this system was immersed in the buffer at 37ºC, it settled down and the solution permeated into the effervescent layer through the outer swellable membrane. CO2 was generated by the neutralization reaction between the 2 effervescent agents, producing swollen pills (like balloons) with a density less than 1.0 g/mL. It was found that the system had good floating ability independent of pH and viscosity and the drug (para-amino benzoic acid) released in a sustained manner28 (Figure 2, A and B).
Figure 1. Intragastric residence positions of floating and nonfloating units.
When subjects were kept in the supine position it was observed that the floating forms could only prolong their stay because of their size; otherwise the buoyancy remained no longer an advantage for gastric retention.
A comparison was made to study the affect of fed and nonfed stages on gastric emptying. For this study all subjects remaining in an upright position were given a light breakfast and another similar group was fed with a succession of meals given at normal time intervals. It was concluded that as meals were given at the time when the previous digestive phase had not completed, the floating form buoyant in the stomach could retain its position for another digestive phase as it was carried by the peristaltic waves in the upper part of the stomach.
Approaches to Design Floating Dosage Forms
The following approaches have been used for the design of floating dosage forms of single- and multiple-unit systems.23
Single-Unit Dosage Forms
In Low-density approach4 the globular shells apparently having lower density than that of gastric fluid can be used as a carrier for drug for its controlled release. A buoyant dosage form can also be obtained by using a fluid-filled system that floats in the stomach.In coated shells24 popcorn, poprice, and polystyrol have been exploited as drug carriers. Sugar polymeric materials such as methacrylic polymer and cellulose acetate phthalate have been used to undercoat these shells. These are further coated with a drug-polymer mixture. The polymer of choice can be either ethylcellulose or hydroxypropyl cellulose depending on the type of release desired. Finally, the product floats on the gastric fluid while releasing the drug gradually over a prolonged duration.
Fluid- filled floating chamber25 type of dosage forms includes incorporation of a gas-filled floatation chamber into a microporous component that houses a drug reservoir. Apertures or openings are present along the top and bottom walls through which the gastrointestinal tract fluid enters to dissolve the drug. The other two walls in contact with the fluid are sealed so that the undissolved drug remains therein. The fluid present could be air, under partial vacuum or any other suitable gas, liquid, or solid having an appropriate specific gravity and an inert behavior. The device is of swallowable size, remains afloat within the stomach for a prolonged time, and after the complete release the shell disintegrates, passes off to the intestine, and is eliminated. Hydrodynamically balanced systems (HBS) are designed to prolong the stay of the dosage form in the gastro intestinal tract and aid in enhancing the absorption. Such systems are best suited for drugs having a better solubility in acidic environment and also for the drugs having specific site of absorption in the upper part of the small intestine. To remain in the stomach for a prolonged period of time the dosage form must have a bulk density of less than 1. It should stay in the stomach, maintain its structural integrity, and release drug constantly from the dosage form. The success of HBS capsule as a better system is best exemplified with chlordiazeopoxide hydrochloride. The drug is a classical example of a solubility problem wherein it exhibits a 4000-fold difference in solubility going from pH 3 to 6 (the solubility of chlordiazepoxide hydrochloride is 150 mg/mL and is ~0.1 mg/mL at neutral pH).
HBS of chlordiazeopoxide hydrochloride26 had comparable blood level time profile as of three 10-mg commercial capsules. HBS can either be formulated as a floating tablet or capsule. Many polymers and polymer combinations with wet granulation as a manufacturing technique have been explored to yield floatable tablets.
Various types of tablets (bilayered and matrix) have been shown to have floatable characteristics. Some of the polymers used are hydroxypropyl cellulose, hydroxypropyl methylcellulose, crosspovidone, sodium carboxymethyl cellulose, and ethyl cellulose.Self-correcting floatable asymmetric configuration drug delivery system23employs a disproportionate 3-layer matrix technology to control drug release.
The 3-layer principle has been improved by development of an asymmetric configuration drug delivery system in order to modulate the release extent and achieve zero-order release kinetics by initially maintaining a constant area at the diffusing front with subsequent dissolution/erosion toward the completion of the release process. The system was designed in such a manner that it floated to prolong gastric residence time in vivo, resulting in longer total transit time within the gastrointestinal tract environment with maximum absorptive capacity and consequently greater bioavailability. This particular characteristic would be applicable to drugs that have pH-dependent solubility, a narrow window of absorption, and are absorbed by active transport from either the proximal or distal portion of the small intestine.
Single-unit formulations are associated with problems such as sticking together or being obstructed in the gastrointestinal tract, which may have a potential danger of producing irritation.
Multiple-Unit Dosage Forms
The purpose of designing multiple-unit dosage form is to develop a reliable formulation that has all the advantages of a single-unit form and also is devoid of any of the above mentioned disadvantages of single-unit formulations. In pursuit of this endeavor many multiple-unit floatable dosage forms have been designed. Microspheres have high loading capacity and many polymers have been used such as albumin, gelatin, starch, polymethacrylate, polyacrylamine, and polyalkylcyanoacrylate. Spherical polymeric microsponges, also referred to as “microballoons,” have been prepared. Microspheres have a characteristic internal hollow structure and show an excellent in vitro floatability.27 In Carbon dioxide–generating multiple-unit oral formulations28 several devices with features that extend, unfold, or are inflated by carbon dioxide generated in the devices after administration have been described in the recent patent literature. These dosage forms are excluded from the passage of the pyloric sphincter if a diameter of ~12 to 18 mm in their expanded state is exceeded.
Classification of Floating Drug Delivery Systems (FDDS)
Floating drug delivery systems are classified depending on the use of 2 formulation variables: effervescent and non-effervescent systems.
Effervescent Floating Dosage Forms
These are matrix types of systems prepared with the help of swellable polymers such as methylcellulose and chitosan and various effervescent compounds, eg, sodium bicarbonate, tartaric acid, and citric acid. They are formulated in such a way that when in contact with the acidic gastric contents, CO2 is liberated and gets entrapped in swollen hydrocolloids, which provides buoyancy to the dosage forms.
Ichikawa et al28 developed a new multiple type of floating dosage system composed of effervescent layers and swellable membrane layers coated on sustained release pills. The inner layer of effervescent agents containing sodium bicarbonate and tartaric acid was divided into 2 sublayers to avoid direct contact between the 2 agents. These sublayers were surrounded by a swellable polymer membrane containing polyvinyl acetate and purified shellac. When this system was immersed in the buffer at 37ºC, it settled down and the solution permeated into the effervescent layer through the outer swellable membrane. CO2 was generated by the neutralization reaction between the 2 effervescent agents, producing swollen pills (like balloons) with a density less than 1.0 g/mL. It was found that the system had good floating ability independent of pH and viscosity and the drug (para-amino benzoic acid) released in a sustained manner28 (Figure 2, A and B).
Figure 2. (A) Multiple-unit oral floating drug delivery system. (B) Working principle of effervescent floating drug delivery system.
Ichikawa et al29 developed floating capsules composed of a plurality of granules that have different residence times in the stomach and consist of an inner foamable layer of gas-generating agents. This layer was further divided into 2 sublayers, the outer containing sodium bicarbonate and the inner containing tartaric acid. This layer was surrounded by an expansive polymeric film (composed of poly vinyl acetate [PVA] and shellac), which allowed gastric juice to pass through, and was found to swell by foam produced by the action between the gastric juices and the gas-generating agents.29 It was shown that the swellable membrane layer played an important role in maintaining the buoyancy of the pills for an extended period of time. Two parameters were evaluated: the time for the pills to be floating (TPF) and rate of pills floating at 5 hours (FP5h). It was observed that both the TPF and FP5h increased as the percentage of swellable membrane layer coated on pills having a effervescent layer increased. As the percentage of swellable layer was increased from 13% to 25% (wt/wt), the release rate was decreased and the lag time for dissolution also increased. The percentage of swellable layer was fixed at 13% wt/wt and the optimized system showed excellent floating ability in vitro (TPF ~10 minutes and FP5h ~80%) independent of pH and viscosity of the medium.
Yang et al30 developed a swellable asymmetric triple-layer tablet with floating ability to prolong the gastric residence time of triple drug regimen (tetracycline, metronidazole, and clarithromycin) in Helicobacter pylori–associated peptic ulcers using hydroxy propyl methyl cellulose (HPMC) and poly (ethylene oxide) (PEO) as the rate-controlling polymeric membrane excipients. The design of the delivery system was based on the swellable asymmetric triple-layer tablet approach. Hydroxypropylmethylcellulose and poly(ethylene oxide) were the major rate-controlling polymeric excipients. Tetracycline and metronidazole were incorporated into the core layer of the triple-layer matrix for controlled delivery, while bismuth salt was included in one of the outer layers for instant release. The floatation was accomplished by incorporatinga gas-generating layer consisting of sodium bicarbonate: calcium carbonate (1:2 ratios) along with the polymers. The in vitro results revealed that the sustained delivery of tetracycline and metronidazole over 6 to 8 hours could be achieved while the tablet remained afloat. The floating feature aided in prolonging the gastric residence time of this system to maintain high-localized concentration of tetracycline and metronidazole (Figure 3).
Figure 3. Schematic presentation of working of a triple-layer system. (A) Initial configuration of triple-layer tablet. (B) On contact with the dissolution medium the bismuth layer rapidly dissolves and matrix starts swelling. (C) Tablet swells and erodes. (D) and (E) Tablet erodes completely.
Ozdemir et al31 developed floating bilayer tablets with controlled release for furosemide. The low solubility of the drug could be enhanced by using the kneading method, preparing a solid dispersion with β cyclodextrin mixed in a 1:1 ratio. One layer contained the polymers HPMC 4000, HPMC 100, and CMC (for the control of the drug delivery) and the drug. The second layer contained the effervescent mixture of sodium bicarbonate and citric acid. The in vitro floating studies revealed that the lesser the compression force the shorter is the time of onset of floating, ie, when the tablets were compressed at 15 MPa, these could begin to float at 20 minutes whereas at a force of 32 MPa the time was prolonged to 45 minutes. Radiographic studies on 6 healthy male volunteers revealed that floating tablets were retained in stomach for 6 hours and further blood analysis studies showed that bioavailability of these tablets was 1.8 times that of the conventional tablets. On measuring the volume of urine the peak diuretic effect seen in the conventional tablets was decreased and prolonged in the case of floating dosage form.
Choi et al32 prepared floating alginate beads using gas-forming agents (calcium carbonate and sodium bicarbonate) and studied the effect of CO2 generation on the physical properties, morphology, and release rates. The study revealed that the kind and amount of gas-forming agent had a profound effect on the size, floating ability, pore structure, morphology, release rate, and mechanical strength of the floating beads. It was concluded that calcium carbonate formed smaller but stronger beads than sodium bicarbonate. Calcium carbonate was shown to be a less-effective gas-forming agent than sodium bicarbonate but it produced superior floating beads with enhanced control of drug release rates. In vitro floating studies revealed that the beads free of gas-forming agents sank uniformly in the media while the beads containing gas-forming agents in proportions ranging from 5:1 to 1:1 demonstrated excellent floating (100%).
Li et al33,34 evaluated the contribution of formulation variables on the floating properties of a gastro floating drug delivery system using a continuous floating monitoring device and statistical experimental design. The formulation was conceived using taguchi design. HPMC was used as a low-density polymer and citric acid was incorporated for gas generation. Analysis of variance (ANOVA) test on the results from these experimental designs demonstrated that the hydrophobic agent magnesium stearate could significantly improve the floating capacity of the delivery system. High-viscosity polymers had good effect on floating properties. The residual floating force values of the different grades of HPMC were in the order K4 M~ E4 M~K100 LV> E5 LV but different polymers with same viscosity, ie, HPMC K4M, HPMC E4M did not show any significant effect on floating property. Better floating was achieved at a higher HPMC/carbopol ratio and this result demonstrated that carbopol has a negative effect on the floating behavior.
Penners et al35 developed an expandable tablet containing mixture of polyvinyl lactams and polyacrylates that swell rapidly in an aqueous environment and thus reside in stomach over an extended period of time. In addition to this, gas-forming agents were incorporated. As the gas formed, the density of the system was reduced and thus the system tended to float on the gastric contents.
Fassihi and Yang36 developed a zero-order controlled release multilayer tablet composed of at least 2 barrier layers and 1 drug layer. All the layers were made of swellable, erodible polymers and the tablet was found to swell on contact with aqueous medium. As the tablet dissolved, the barrier layers eroded away to expose more of the drug. Gas-evolving agent was added in either of the barrier layers, which caused the tablet to float and increased the retention of tablet in a patient’s stomach.
Talwar et al37 developed a once-daily formulation for oral administration of ciprofloxacin. The formulation was composed of 69.9% ciprofloxacin base, 0.34% sodium alginate, 1.03% xanthum gum, 13.7% sodium bicarbonate, and 12.1% cross-linked poly vinyl pyrrolidine. The viscolysing agent initially and the gel-forming polymer later formed a hydrated gel matrix that entrapped the gas, causing the tablet to float and be retained in the stomach or upper part of the small intestine (spatial control). The hydrated gel matrix created a tortuous diffusion path for the drug, resulting in sustained release of the drug (temporal delivery).
Two patents granted to Alza Corporation revealed a device having a hollow deformable unit that was convertible from a collapsed to expandable form and vice versa. The deformable unit was supported by a housing that was internally divided into 2 chambers separated by a pressure-sensitive movable bladder. The first chamber contained the therapeutic agent and the second contained a volatile liquid (cyclopentane, ether) that vaporized at body temperature and imparted buoyancy to the system. The system contained a bioerodible plug to aid in exit of the unit from the body.38,39
Baumgartner et al40 developed a matrix-floating tablet incorporating a high dose of freely soluble drug. The formulation containing 54.7% of drug, HPMC K4 M, Avicel PH 101, and a gas-generating agent gave the best results. It took 30 seconds to become buoyant. In vivo experiments with fasted state beagle dogs revealed prolonged gastric residence time. On radiographic images made after 30 minutes of administration, the tablet was observed in animal’s stomach and the next image taken at 1 hour showed that the tablet had altered its position and turned around. This was the evidence that the tablet did not adhere to the gastric mucosa. The MMC (phase during which large nondisintegrating particles or dosage forms are emptied from stomach to small intestine) of the gastric emptying cycle occurs approximately every 2 hours in humans and every 1 hour in dogs but the results showed that the mean gastric residence time of the tablets was 240 ± 60 minutes (n = 4) in dogs. The comparison of gastric motility and stomach emptying between humans and dogs showed no big difference and therefore it was speculated that the experimentally proven increased gastric residence time in beagle dogs could be compared with known literature for humans, where this time is less than 2 hours.
Moursy et al41 developed sustained release floating capsules of nicardipine HCl. For floating, hydrocolloids of high viscosity grades were used and to aid in buoyancy sodium bicarbonate was added to allow evolution of CO2. In vitro analysis of a commercially available 20-mg capsule of nicardipine HCl (MICARD) was performed for comparison. Results showed an increase in floating with increase in proportion of hydrocolloid. Inclusion of sodium bicarbonate increased buoyancy. The optimized sustained release floating capsule formulation was evaluated in vivo and compared with MICARD capsules using rabbits at a dose equivalent to a human dose of 40 mg. Drug duration after the administration of sustained release capsules significantly exceeded that of the MICARD capsules. In the latter case the drug was traced for 8 hours compared with 16 hours in former case.
Atyabi and coworkers42 developed a floating system using ion exchange resin that was loaded with bicarbonate by mixing the beads with 1 M sodium bicarbonate solution. The loaded beads were then surrounded by a semipermeable membrane to avoid sudden loss of CO2. Upon coming in contact with gastric contents an exchange of chloride and bicarbonate ions took place that resulted in CO2 generation thereby carrying beads toward the top of gastric contents and producing a floating layer of resin beads (Figure 4) .The in vivo behavior of the coated and uncoated beads was monitored using a single channel analyzing study in 12 healthy human volunteers by gamma radio scintigraphy. Studies showed that the gastric residence time was prolonged considerably (24 hours) compared with uncoated beads (1 to 3 hours).
Figure 4. Pictorial presentation of working of effervescent floating drug delivery system based on ion exchange resin.
Non-Effervescent Floating Dosage Forms
Non-effervescent floating dosage forms use a gel forming or swellable cellulose type of hydrocolloids, polysaccharides, and matrix-forming polymers like polycarbonate, polyacrylate, polymethacrylate, and polystyrene. The formulation method includes a simple approach of thoroughly mixing the drug and the gel-forming hydrocolloid. After oral administration this dosage form swells in contact with gastric fluids and attains a bulk density of < href="http://www.aapspharmscitech.org/view.asp?art=pt060347#B43">43 developed polycarbonate microspheres by solvent evaporation technique. Polycarbonate in dichloromethane was found to give hollow microspheres that floated on water and simulated biofluids as evidenced by scanning electron microscopy (SEM). High drug loading was achieved and drug-loaded microspheres were able to float on gastric and intestinal fluids. It was found that increasing the drug-to-polymer ratio increased both their mean particle size and release rate of drug.
Nur and Zhang44 developed floating tablets of captopril using HPMC (4000 and 15 000 cps) and carbopol 934P. In vitro buoyancy studies revealed that tablets of 2 kg/cm2 hardness after immersion into the floating media floated immediately and tablets with hardness 4 kg/cm2 sank for 3 to 4 minutes and then came to the surface. Tablets in both cases remained floating for 24 hours. The tablet with 8 kg/cm2 hardness showed no floating capability. It was concluded that the buoyancy of the tablet is governed by both the swelling of the hydrocolloid particles on the tablet surface when it contacts the gastric fluids and the presence of internal voids in the center of the tablet (porosity). A prolonged release from these floating tablets was observed as compared with the conventional tablets and a 24-hour controlled release from the dosage form of captopril was achieved.
Bulgarelli et al45 studied the effect of matrix composition and process conditions on casein gelatin beads prepared by emulsification extraction method. Casein by virtue of its emulsifying properties causes incorporation of air bubbles and formation of large holes in the beads that act as air reservoirs in floating systems and serve as a simple and inexpensive material used in controlled oral drug delivery systems. It was observed that the percentage of casein in matrix increases the drug loading of both low and high porous matrices, although the loading efficiency of high porous matrices is lower than that of low porous matrices.
Fell et al46 prepared floating alginate beads incorporating amoxycillin. The beads were produced by dropwise addition of alginate into calcium chloride solution, followed by removal of gel beads and freeze-drying. The beads containing the dissolved drug remained buoyant for 20 hours and high drug-loading levels were achieved.
Streubel et al47 prepared single-unit floating tablets based on polypropylene foam powder and matrix-forming polymer. Incorporation of highly porous foam powder in matrix tablets provided density much lower than the density of the release medium. A 17% wt/wt foam powder (based on mass of tablet) was achieved in vitro for at least 8 hours. It was concluded that varying the ratios of matrix-forming polymers and the foam powder could alter the drug release patterns effectively.
Asmussen et al48 invented a device for the controlled release of active compounds in the gastrointestinal tract with delayed pyloric passage, which expanded in contact with gastric fluids and the active agent was released from a multiparticulate preparation. It was claimed that the release of the active compound was better controlled when compared with conventional dosage forms with delayed pyloric passage.
El-Kamel et al49 prepared floating microparticles of ketoprofen, by emulsion solvent diffusion technique. Four different ratios of Eudragit S 100 with Eudragit RL were used. The formulation containing 1:1 ratio of the 2 above-mentioned polymers exhibited high percentage of floating particles in all the examined media as evidenced by the percentage of particles floated at different time intervals. This can be attributed to the low bulk density, high packing velocity, and high packing factor.
Illum and Ping50 developed microspheres that released the active agent in the stomach environment over a prolonged period of time. The active agent was encased in the inner core of microspheres along with the rate-controlling membrane of a water-insoluble polymer. The outer layer was composed of bioadhesive (chitosan). The microspheres were prepared by spray drying an oil/water or water/oil emulsion of the active agent, the water-insoluble polymer, and the cationic polymer.
Streubel et al51 developed floating microparticles composed of polypropylene foam, Eudragit S, ethyl cellulose (EC), and polymethyl metha acrylate (PMMA) and were prepared by solvent evaporation technique. High encapsulation efficiencies were observed and were independent of the theoretical drug loading. Good floating behavior was observed as more than 83% of microparticles were floating for at least 8 hours. The in vitro drug release was dependent upon the type of polymer used. At similar drug loading the release rates increased in the following order PMMA < href="http://www.aapspharmscitech.org/view.asp?art=pt060347#B26">26 developed an HBS system containing a homogeneous mixture of drug and the hydrocolloid in a capsule, which upon contact with gastric fluid acquired and maintained a bulk density of less than 1 thereby being buoyant on the gastric contents of stomach until all the drug was released (Figure 5).
Figure 5. Working principle of hydrodynamically balanced system.
Sheth and Tossounian52 developed hydrodynamically balanced sustained release tablets containing drug and hydrophilic hydrocolloids, which on contact with gastric fluids at body temperature formed a soft gelatinous mass on the surface of the tablet and provided a water-impermeable colloid gel barrier on the surface of the tablets. The drug slowly released from the surface of the gelatinous mass that remained buoyant on gastric fluids (Figure 6, A and B).
Figure 6. Intragastric floating tablets. (A) United States patent 4 167 558, September 11, 1979. (B) United States patent 4 140 755, February 20, 1979.
Ushomaru et al53 developed sustained release composition for a capsule containing mixture of cellulose derivative or a starch derivative that formed a gel in water and higher fatty acid glyceride and/or higher alcohol, which was solid at room temperature. The capsules were filled with the above mixture and heated to a temperature above the melting point of the fat components and then cooled and solidified.
Bolton and Desai54 developed a noncompressed sustained release tablet that remained afloat on gastric fluids. The tablet formulation comprised 75% of drug and 2% to 6.5% of gelling agent and water. The noncompressed tablet had a density of less than 1 and sufficient mechanical stability for production and handling.
Kawashima et al prepared multiple-unit hollow microspheres by emulsion solvent diffusion technique. Drug and acrylic polymer were dissolved in an ethanol-dichloromethane mixture, and poured into an aqueous solution of PVA with stirring to form emulsion droplets. The rate of drug release in micro balloons was controlled by changing the polymer-to-drug ratio. Microballoons were floatable in vitro for 12 hours when immersed in aqueous media. Radiographical studies proved that microballoons orally administered to humans were dispersed in the upper part of stomach and retained there for 3 hours against peristaltic movements.55
Dennis et al56 invented a buoyant controlled release pharmaceutical powder formulation filled into capsules. It released a drug of a basic character at a controlled rate regardless of the pH of the environment. PH-dependent polymer is a salt of a polyuronic acid such as alginic acid and a pH-independent hydrocarbon gelling agent, hydroxypropylmethyl cellulose.
Spickett et al57 invented an antacid preparation having a prolonged gastric residence time. It comprised 2 phases. The internal phase consisted of a solid antacid and the external phase consisted of hydrophobic organic compounds (mono-, di-, and triglycerides) for floating and a non-ionic emulsifier.
Franz and Oth58 described a sustained release dosage form adapted to release of the drug over an extended period of time. It comprised a bilayer formulation in which one layer consisted of drug misoprostal and the other had a floating layer. The uncompressed bilayer formulation was kept in a capsule and was shown to be buoyant in the stomach for 13 hours. The dosage form was designed in such a way that all the drug was released in the stomach itself.
Wu et al59 developed floating sustained release tablets of nimodipine by using HPMC and PEG 6000. Prior to formulation of floating tablets, nimodipine was incorporated into poloxamer-188 solid dispersion after which it was directly compressed into floating tablets. It was observed that by increasing the HPMC and decreasing the PEG 6000 content a decline in in vitro release of nimodipine occurred.
Wong et al60 developed a prolonged release dosage form adapted for gastric retention using swellable polymers. It consisted of a band of insoluble material that prevented the covered portion of the polymer matrix from swelling and provided a segment of a dosage form that was of sufficient rigidity to withstand the contractions of the stomach and delayed the expulsion of the dosage form from the stomach.
Mitra61 developed a sustained release multilayered sheet-like medicament device. It was buoyant on the gastric contents and consisted of at least 1 dry, self-supporting carrier film of water-insoluble polymer. The drug was dispersed or dissolved in this layer and a barrier film overlaid the carrier film. The barrier film was compsosed of 1 water-insoluble layer and another water-soluble and drug-permeable polymer or copolymer layer. The 2 layers were sealed together in such a way that plurality of small air pockets were entrapped that gave buoyancy to the formulation.
Harrigan62 developed an intragastric floating drug delivery system that was composed of a drug reservoir encapsulated in a microporous compartment having pores on top and bottom surfaces. However, the peripheral walls were sealed to prevent any physical contact of the drug in the reservoir with the stomach walls.
Joseph et al25 developed a floating dosage form of piroxicam based on hollow polycarbonate microspheres. The microspheres were prepared by the solvent evaporation technique. Encapsulation efficiency of ~95% was achieved. In vivo studies were performed in healthy male albino rabbits. Pharmacokinetic analysis was derived from plasma concentration vs time plot and revealed that the bioavailability from the piroxicam microspheres alone was 1.4 times that of the free drug and 4.8 times that of a dosage form consisting of microspheres plus the loading dose and was capable of sustained delivery of the drug over a prolonged period.
There are several commercial products available based on the research activity of floating drug delivery (Table 1).
Table 1. Marketed Preparations of Floating Drug Delivery Systems59
S. no
Product
Active Ingredient
Reference No.
1
Madopar
Levodopa and benserzide
63
2
Valrelease
Diazepam
64
3
Topalkan
Aluminum magnesium antacid
65
4
Almagate flatcoat
Antacid
66
5
Liquid gavison
Alginic acid and sodium bicarbonate
67
Evaluation of floating drug delivery systems
Various parameters17 that need to be evaluated in gastro-retentive formulations include floating duration, dissolution profiles, specific gravity, content uniformity, hardness, and friability in case of solid dosage forms. In the case of multiparticulate drug delivery systems, differential scanning calorimetry (DSC), particle size analysis, flow properties, surface morphology, and mechanical properties are also performed.
The tests for floating ability (Table 2) and drug release are generally performed in simulated gastric fluids at 37ºC.
Table 2. In Vitro Floating and Dissolution Performance
Drug (Polymer Used)
Floating Media/Dissolution Medium and Method
Ref
Pentoxyfillin(HPMC K4 M)
500 mL of artificial gastric fluid pH 1.2 (without pepsin) at 100 rpm using USP XXIII dissolution apparatus. The time taken by the tablet to emerge on the water surface (floating lag time) and time until it floats on water surface was measured.
40
Amoxicillin beads(Calcium alginate)
For dissolution: 900 mL of deaerated 0.1 M HCl (pH 1.2) at 37ºC ± 1ºC in USP XXII dissolution tester at 50 rpm.
46
Ketoprofen(Eudragit S100Eudragit RL)
20 mL of simulated gastric fluid without pepsin, 50 mg of floating microparticles in 50-mL beakers were shaken horizontally in a water bath.% age of floating micro particles was calculated.For dissolution: 900 mL of either 0.1 N HCl or the phosphate buffer (pH 6.8) at 37ºC ± 0.1ºC in USP dissolution apparatus (I) at 100 rpm.
49
Verapamil(Propylene foam, Eudragit RS,ethyl cellulose, poly methyl meth acrylate)
30 mL of 0.1 N HCl (containing 0.02% wt/wt Tween 20), pH 1.2. Floatation was studied by placing 60 particles into 30-mL glass flasks. Number of settled particles was counted.
51
Captopril(Methocel K4M)
900 mL of enzyme-free 0.1 N HCl (pH 1.2) in USP XXIII apparatus II (basket method) at 37ºC at 75 rpm.
44
Theophylline(HPMC K4M,Polyethylene oxide)
0.1 N HCl in USP XXIII Apparatus II at 50 rpm at 37°C.Its buoyancy to upper 1/3 of dissolution vessel was measured for each batch of tablet.
23
Furosemide(β Cyclodextrin, HPMC 4000, HPMC 100,CMC, Polyethylene glycol)
For dissolution: continuous flow through cell gastric fluid of pH 1.2, 45–50 m N/m by adding 0.02% Polysorbate 20 (to reduce the surface tension), the flow rate to provide the sink conditions was 9mL/min.
32
Aspirin, Griseofulvin,p-Nitro Aniline(polycarbonate, PVA)
For dissolution: 500 mL of simulated gastric and intestinal fluid in 1000-mL Erlenmeyer flask. Flasks were shaken in a bath incubator at 37ºC.
43
Piroxicam (microspheres)(Polycarbonate)
For dissolution: 900 mL dissolution medium in USP paddle type apparatus at 37ºC at 100 rpm.
61
Ampicillin(Sodium alginate)
For dissolution: 500 mL of distilled water, JP XII disintegration test medium No.1 (pH 1.2) and No.2 (pH 6.8) in JP XII dissolution apparatus with paddle stirrer at 50 rpm.
68
Diclofenac(HPC-L)
An aliquot of 0.1 g of granules was immersed in 40 mL of purified water in a vessel at 37°C. Dried granules were weighed and floating percentage of granules was calculated.For dissolution: flow sampling system (dissolution tester: DT-300, triple flow cell) followed by 900 mL of distilled water in JP XII with paddles at 37 ºC ± 0.5ºC at 100 rpm.
69
Sulphiride(CP 934P)
For dissolution: 500 mL of each JP XII disintegration test medium No. 1 (pH 1.2) and No. 2 (pH 6.8) in JP XII dissolution apparatus at 37º C at 100 rpm.
70
Amoxicillin trihydrate(HPC)
For dissolution: 500–1000 mL (adequate to ensure sink conditions) of citrate/phosphate buffer of variable pH or solution of HCl (pH 1.2) in Erweka DT 6 dissolution tester fitted with paddles.
71
Ibuprofen, Tranilast(Eudragit S)
For dissolution: 900 mL dissolution medium (disintegration test medium No. 1 (pH 1.2) and No. 2 (pH 6.8) as specified in JP XI and as corresponding to USP XXI, paddle method at 37ºC at 100 rpm.
72
Isardipine(HPMC)
For dissolution: Method 1:300 mL of artificial gastric fluid in a beaker, which was suspended in water bath at 37ºC agitated by magnetic stirrer and by bubbling CO2 free air.Method 2:500/1000 mL of 0.1 M HCl and surfactant lauryl sulfate dimethyl ammonium oxide with rotating paddle at 50 rpm.
73
Potassium chloride(Metolose S.M. 100, PVP)
For dissolution: tablet was mounted onto the perspex holder except one face of the matrix was set flush with one face of the holder at 37ºC and the other face of the tablet was prevented from the dissolution media by a rubber closure; good mixing was maintained in the receiver by a magnetic stirrer at 100 rpm.
74
Verapamil(HPC-H, HPC-M, HPMC K15)
For dissolution: water in USP XXIII dissolution apparatus (method II) at 50 rpm.
75
PABA(Ethyl celluloseHPC-L)
70 mL of 50 mM acetate buffer with various pH (1–5) or viscosity (25–115 cps) in a 100-mL beaker at 37°C, 100 rpm.% age of floating pills was calculated.For dissolution: 50 mM acetate buffer (pH 4) in JP XI dissolution tester with paddles at 37ºC at 100 rpm.
76
Tetracycline, metronidazole, bismuth salt(Polyox, HPMC K4)
900 mL of 0.1 M HCl (pH 1.8) in USP dissolution apparatus at 50 rpm. The duration of floatation was observed visually.
30
Tranilast(Acrylic polymer, Eudragit RS)
Microballoons were introduced into 900 mL of disintegrating fluid solution no 1 (pH 1.2) containing Tween 20 (0.02% wt/vol) in USP XXII apparatus at 100 rpm . Percentage buoyancy was calculated.
55
Sotalol
Lag time required for the tablet to start floating on the top of the basket in dissolution apparatus was measured
77
Furosemide
Tablet were placed in a 400-mL flask at pH 1.2 and both the time needed to go upward and float on surface of the fluid and floating duration were determined.
31
Calcium carbonate(HPMC K4M, E4 M and Carbopol)
A continuous floating monitoring system was conceived. The upward floating force could be measured by the balance and the data transmitted to an online computer.Test medium used was 900 mL simulated gastric fluid (pH 1.2) at 37ºC.
33
Timmermans and Andre18 characterized the buoyancy capability of floating forms and sinking of nonfloating dosage forms using an apparatus to quantitatively measure the total force acting vertically on the immersed object. It was given by the vectorial sum of buoyancy F(b) and gravitational forces F(g) acting on the test object.
F = F ( b ) - F ( g )
(1)
Equation 1 can be rewritten as,
F = ( d f - d s ) g V = ( d f - W / V ) g V
(2)
where F is the resultant weight of the object, df and ds represent the fluid density and solid object density, g is the acceleration due to gravity and W and V are the weight and volume of the test objects. It can be seen from Equation 2 that if the resultant weight is more positive, better floating is exhibited by the object.
Li et al33,34 invented an online continuous floating monitoring system that was a modification of the system described by Timmermans and Andre.18 It was used to provide quantitative measurement of resultant floating force. The set-up consisted of an analytical balance connected with a computer. A capsule was inserted into the sample holder basket and the holder was immersed into the test medium (900 mL of simulated gastric fluid). A typical floating kinetic curve was obtained by plotting floating force vs time and 4 parameters were used to describe the floating properties of the capsules from this graph: F max, T max, Fr, and AUC f . Similar to Equation 2 conceived by Timmermans and Andre18 the overall force that the capsule is subjected can be given by
F = ( ρ m - ρ c ) g V c
(3)
where ρm and ρc are the density of floating media and test object and Vc is the volume of the test object. In this equation, 2 parameters, ρc and Vc, are important for overall floating force. During the measurement of buoyancy, Vc increased due to swelling of polymer and ρc increased due to water uptake. This increase led to an upward rise in floating force curve, which reached a maximum (Fmax) and declined until an equilibrium was reached.
Table 2 gives dissolution tests generally performed using USP dissolution apparatus. USP 28 states “the dosage unit is allowed to sink to the bottom of the vessel before rotation of the blade is started. A small, loose piece of nonreactive material with not more than a few turns of a wire helix may be attached to the dosage units that would otherwise float.78 However standard USP or BP methods have not been shown to be reliable predictors of in vitro performance of floating dosage forms.24 Pillay and Fassihi79 applied a helical wire sinker to the swellable floating system of theophylline, which is sparingly soluble in water and concluded that the swelling of the system was inhibited by the wire helix and the drug release also slowed down. To overcome this limitation a method was developed in which the floating drug delivery system was fully submerged under a ring or mesh assembly and an increase in drug release was observed. Also, it was shown that the method was more reproducible and consistent. However no significant change in the drug release was observed when the proposed method was applied to a swellable floating system of diltiazem, which is a highly water-soluble drug. It was thus concluded that the drug release from swellable floating systems was dependent upon uninhibited swelling, surface exposure, and the solubility of the drug in water.
Surface morphology was observed by SEM, which serves to confirm qualitatively a physical observation relating to surface area. In preparation of SEM analysis, the sample was exposed to high vacuum during the gold-coating process, which was needed to make the sample conductive.
Kawashima et al80 estimated the hollow structure of microspheres made of acrylic resins by measuring particle density (Pp) by a photographic counting method and a liquid displacement method. An image analyzer was used to determine the volume (v) of particles (n) of weight (w):
P = w / v
(4)
Porosity was measured by € = (1 – Pp /Pt) × 100, where Pt is the true density.
Bulgarelli et al45 developed casein gelatin beads and determined their porosity by mercury intrusion technique. The principle of this technique is that pressure (P) required to drive mercury through a pore decreases as described by the Washburn equation: P = (– 4 σ cos θ) d, where d is the pore diameter, σ is mercury / air interfacial tension, and θ is the contact angle at mercury air pore wall interface.
Sakuma et al81 prepared radiolabeled anionic poly metha acrylic acid nanoparticles and the particle size of nonlabeleled nanoparticles was measured by dynamic spectrophotometry.
In vivo gastric residence time of a floating dosage form is determined by X-ray diffraction studies, gamma scintigraphy,22 or roentgenography82 (Table 3).
Table 3. In Vivo Evaluation
Drug (Polymer)
Method
Ref
Tranilast(Eudragit S (BaSo4))
Two healthy male volunteers administered hard gelatin capsules packed with microballons (1000 mg) with 100 mL water. X-ray photographs at suitable intervals were taken.
55
Isardipine(HPMC)
Two phases:Phase I (fasted conditions):Five healthy volunteers (3 males and 2 females) in an open randomized crossover design, capsules ingested in sitting position with 100 mL of tap water.Phase II (fed states):Four subjects received normal or MR capsules in a crossover design after standard breakfast.Venous blood samples were taken in heparinized tubes at predetermined time intervals after dosing.
73
PABA+ Isosorbide dinitrate
Six healthy beagle dogs fasted overnight, then administered with capsules with 50 mL of water at 30 minutes after the meal.Control study: same amount of control pills without the effervescent layer were administered in the same protocol.The experimental design:Crossover design, 1-week washout time, plasma samples were taken by repeated venipuncture at upper part of the leg.
76
Hydrogel composites
Dogs (50 lbs) kept fasted and fed conditions.In each experiment (fed or fasted) 300 mL of water was given before administration of the capsules; X-ray pictures were taken.
83
Amoxycillin trihydrate
Six healthy fasted male subjects were selected; serum drug levels were compared in a single-dose crossover study following administration of tablets/capsules.
46
Floating beads
Gamma scintigraphy:In vivo behavior of coated and uncoated beads was monitored using a single channel analyzing study in 12 healthy human volunteers of mean age 34 yrs (22–49).
42
Pentoxyfillin
Four healthy beagle dogs (fasted for 24 hours). Tablet was administered with 100 mL of water for radiographic imaging. The animal was positioned in a right lateral/ventrodorsal recumbency.
40
Furosemide
Six purebred young male beagle dogs (9.6 to 14.3 kg), a 4-period crossover study balanced by residual effects was employed.Dogs were fasted overnight (water ad libitum), a catheter was inserted into right and left cephalic vein with 0.3 mL heparin lock, blood sampling was done at appropriate intervals.
84
Polystyrene nanoparticles
Dosing solution was administered to male SD strain rats fasted overnightThe radioactivity was measured with a gamma counter or a β counter (small intestine was cut into 10-cm portions).
63
Piroxicam
Nine healthy male albino rabbits weighing 2.2–2.5 kg were divided into 3 groups and were fasted for 24 hours.First batch: fed with 20 mg of Piroxicam powder in a gelatin capsule.Second batch: 67% piroxicam loaded piroxicam microspheres (~20mg of drug).Third batch: 7 mg of piroxicam and 67% piroxicam-loaded piroxicam microspheres (~20 mg of drug).
61
Calcium alginate multiple units floating beads
Seven healthy males (21–55 years). After fasting from midnight the night before the subjects consumed cereal (30 g) with milk (150 ml) to which was added ~20 Ci .99 m Tc-DTPA.An anterior image of stomach was obtained with γ camera.Static 120-second anterior images were acquired at suitable intervals and subjects remained standing/sitting for the duration of the study.
85
Furosemide
Six healthy males (60–71 kg) aged between 25 and 32 years for X-ray detection. Labeled tablets were given to subjects with 200 mL of water after a light breakfast, following ingestion. Gastric radiography revealed the duration for which the tablet stayed in stomach was determined.
31
Sulphiride
Three 3.5-kg white male rabbits10 mg of the drug/kg body weight was administered in a crossover manner with a 14-day washout period between dosing.Both IV and oral dosage form were given.
69
Applications of Floating Drug Delivery Systems
Floating drug delivery offers several applications for drugs having poor bioavailability because of the narrow absorption window in the upper part of the gastrointestinal tract. It retains the dosage form at the site of absorption and thus enhances the bioavailability. These are summarized as follows.
Sustained Drug Delivery
HBS systems can remain in the stomach for long periods and hence can release the drug over a prolonged period of time. The problem of short gastric residence time encountered with an oral CR formulation hence can be overcome with these systems. These systems have a bulk density of <1 href="http://www.aapspharmscitech.org/view.asp?art=pt060347#B41">41
Similarly a comparative study63 between the Madopar HBS and Madopar standard formulation was done and it was shown that the drug was released up to 8 hours in vitro in the former case and the release was essentially complete in less than 30 minutes in the latter case.
Site-Specific Drug Delivery
These systems are particularly advantageous for drugs that are specifically absorbed from stomach or the proximal part of the small intestine, eg, riboflavin and furosemide.
Furosemide is primarily absorbed from the stomach followed by the duodenum. It has been reported that a monolithic floating dosage form with prolonged gastric residence time was developed and the bioavailability was increased. AUC obtained with the floating tablets was approximately 1.8 times those of conventional furosemide tablets.84
A bilayer-floating capsule was developed for local delivery of misoprostol, which is a synthetic analog of prostaglandin E1 used as a protectant of gastric ulcers caused by administration of NSAIDs. By targeting slow delivery of misoprostol to the stomach, desired therapeutic levels could be achieved and drug waste could be reduced.86
Absorption Enhancement
Drugs that have poor bioavailability because of site-specific absorption from the upper part of the gastrointestinal tract are potential candidates to be formulated as floating drug delivery systems, thereby maximizing their absorption.
A significant increase in the bioavailability of floating dosage forms (42.9%) could be achieved as compared with commercially available LASIX tablets (33.4%) and enteric-coated LASIX-long product (29.5%).84
Miyazaki et al87 conducted pharmacokinetic studies on floating granules of indomethacin prepared with chitosan and compared the peak plasma concentration and AUC with the conventional commercially available capsules. It was concluded that the floating granules prepared with chitosan were superior in terms of decrease in peak plasma concentration and maintenance of drug in plasma.
Ichikawa et al76 developed a multiparticulate system that consisted of floating pills of a drug (p- amino benzoic acid) having a limited absorption site in the gastrointestinal tract. It was found to have 1.61 times greater AUC than the control pills.
The absorption of bromocriptine is limited to 30% from the gastrointestinal tract, however an HBS of the same can enhance the absorption. It was also studied that if metoclopramide is co delivered with bromocriptine, the side effects associated with high doses of bromocriptine can be prevented and the dosage from becomes therapeutically more potential.88
In few cases the bioavailability of floating dosage form is reduced in comparison to the conventional dosage form. In a recent study 3 formulations containing 25 mg atenolol, a floating multiple-unit capsule, a high-density multiple-unit capsule, and an immediate-release tablet were compared with respect to estimated pharmacokinetic parameters. The bioavailability of the 2 gastroretentive preparations with sustained release characteristics was significantly decreased when compared with the immediate-release tablet. This study showed that it was not possible to increase the bioavailability of a poorly absorbed drug such as atenolol using gastroretentive formulations.89
In some cases the reduction in bioavailability is compensated by advantages offered by FDDS, for example a hydrodynamically balanced system of L-dopa provided better control over motor fluctuations in spite of reduced bioavailability of up to 50% to 60% in comparison with standard L-dopa treatment. This could be attributed to reduced fluctuations in plasma drug levels in case of FDDS.90,91
Cook et al92 concluded that iron salts, if formulated as an HBS, have better efficacy and lesser side effects.
FDDS also serves as an excellent drug delivery system for the eradication of Helicobacter pylori, which causes chronic gastritis and peptic ulcers. The treatment requires high drug concentrations to be maintained at the site of infection that is within the gastric mucosa. By virtue of its floating ability these dosage forms can be retained in the gastric region for a prolonged period so that the drug can be targeted.93
Katayama et al68 developed a sustained release (SR) liquid preparation of ampicillin containing sodium alginate, which spreads out and aids in adhering to the gastric mucosal surface. Thus, the drug is continuously released in the gastric region.
Yang et al30 developed a swellable asymmetric triple-layer tablet with floating ability to prolong the gastric residence time of triple drug regimen (tetracycline, metronidazole, clarithromycin) of Helicobacter pylori–associated peptic ulcers using HPMC and PEO as the rate-controlling polymeric membrane excipients. Results demonstrated that sustained delivery of tetracycline and metronidazole over 6 to 8 hours could be achieved while the tablets remained floating. It was concluded that the developed delivery system had the potential to increase the efficacy of the therapy and improve patient compliance.
Floating microcapsules of melatonin were prepared by ionic interaction of chitosan and a surfactant, sodium dioctyl sulfosuccinate that is negatively charged. The dissolution studies of the floating microcapsules showed zero-order release kinetics in simulated gastric fluid. The release of drug from the floating microcapsules was greatly retarded with release lasting for several hours as compared with nonfloating microspheres where drug release was almost instantaneous. Most of the hollow microcapsules developed showed floating over simulated gastric fluid for more than 12 hours.94
Sato and Kawashima95 developed microballoons of riboflavin, which could float in JP XIII no 1 solution (simulated gastric fluid). These were prepared by an emulsion solvent technique. To assess the usefulness of the intragastric floating property of the developed microballoons of riboflavin, riboflavin powder, nonfloating microspheres of riboflavin, and floating microballoons of riboflavin were administered to 3 volunteers. Riboflavin pharmacokinetics was assessed by urinary excretion data. It could be concluded that although excretion of riboflavin following administration of floating microballoons was not sustained in fasted state, it was significantly sustained in comparison to riboflavin powder and nonfloating microspheres in the fed state. This could be due to the reason that the nonfloating formulation passes through the proximal small intestine at once from where riboflavin is mostly absorbed, while the floating microballoons gradually sank in the stomach and then arrived in the proximal small intestine in a sustained manner. Total urinary excretion (%) of riboflavin from the floating microballoons was lower than that of riboflavin powder. This was attributed to incomplete release of riboflavin from microballoons at the site of absorption.
Shimpi et al96 studied the application of hydrophobic lipid, Gelucire 43/01 for the design of multi-unit floating systems of a highly water-soluble drug, diltiazem HCl. Diltiazem HCl-Gelucire 43/01 granules were prepared by the melt granulation technique. The granules were evaluated for in vitro and in vivo floating ability, surface topography, and in vitro drug release. In vivo floating ability was studied by γ-scintigraphy in 6 healthy human volunteers and the results showed that the formulation remained in the stomach for 6 hours. It could be concluded that Gelucire 43/01 can be considered as an effective carrier for design of a multi-unit FDDS of highly water-soluble drugs such as diltiazem HCl.
A gastroretentive drug delivery system of ranitidine hydrochloride was designed using guar gum, xanthan gum, and hydroxy propyl methyl cellulose. Sodium bicarbonate was incorporated as a gas-generating agent. The effect of citric acid and stearic acid on drug release profile and floating properties was investigated. The addition of stearic acid reduces the drug dissolution due to its hydrophobic nature. A 32 full factorial design was applied to systemically optimize the drug release profile and the results showed that a low amount of citric acid and a high amount of stearic acid favor sustained release of ranitidine hydrochloride from a gastroretentive formulation. Hence, it could be concluded that a proper balance between a release rate enhancer and a release rate retardant could produce a drug dissolution profile similar to a theoretical dissolution profile of ranitidine hydrochloride.97
In a recent work by Sriamornsak et al,98 a new emulsion-gelation method was used to prepare oil-entrapped calcium pectinate gel (CaPG) beads as a carrier for intragastric floating drug delivery. The gel beads containing edible oil were prepared by gently mixing or homogenizing an oil phase and a water phase containing pectin, and then extruded into calcium chloride solution with gentle agitation at room temperature. The oil-entrapped calcium pectinate gel beads floated if a sufficient amount of oil was used. Scanning electron photomicrographs demonstrated very small pores, ranging between 5 and 40 µm, dispersed all over the beads. The type and percentage of oil played an important role in controlling the floating of oil-entrapped CaPG beads. The oil-entrapped CaPG beads were a good choice as a carrier for intragastric floating drug delivery.
Reddy and Murthy99 have discussed advantages and various disadvantages of single- and multiple-unit hydrodynamic systems.
Floating drug delivery is associated with certain limitations. Drugs that irritate the mucosa, those that have multiple absorption sites in the gastrointestinal tract, and those that are not stable at gastric pH are not suitable candidates to be formulated as floating dosage forms.
Floatation as a retention mechanism requires the presence of liquid on which the dosage form can float on the gastric contents. To overcome this limitation, a bioadhesive polymer can be used to coat the dosage so that it adheres to gastric mucosa,100 or the dosage form can be administered with a full glass of water to provide the initial fluid for buoyancy. Also single unit floating capsules or tablets are associated with an “all or none concept,” but this can be overcome by formulating multiple unit systems like floating microspheres or microballoons.101
Table 4 enlists examples of various drugs formulated as different forms of FDDS.
Table 4. List of Drugs Formulated as Single and Multiple Unit Forms of Floating Drug Delivery Systems.
Tablets Chlorpheniramine maleate
Riboflavin- 5′ Phosphate110
Theophylline23
Furosemide31
Ciprofolxacin37
Pentoxyfillin40
Captopril44
Acetylsalicylic acid52
Nimodipine59
Amoxycillin trihydrate71
Verapamil HCl75
Isosorbide di nitrate76
Sotalol77
Atenolol89
Isosorbide mono nitrate100
Acetaminophen102,103
Ampicillin104
Cinnarazine105
Diltiazem106
Florouracil107
Piretanide108
Prednisolone109
Capsules
Nicardipine41
Furosemide31
Ciprofolxacin37
Pentoxyfillin40
Captopril44
Acetylsalicylic acid52
Nimodipine59
Amoxycillin trihydrate71
Verapamil HCl75
Isosorbide di nitrate76
Sotalol77
Atenolol89
Isosorbide mono nitrate100
Acetaminophen102,103
Ampicillin104
Cinnarazine105
Diltiazem106
Florouracil107
Piretanide108
Prednisolone109
Capsules
Nicardipine41
L- Dopa and benserazide63
hlordiazepoxide HCl64
Furosemide84
Misoprostal86
Diazepam111
Propranlol112
Urodeoxycholic acid113
Microspheres Verapamil27
Microspheres Verapamil27
Aspirin,
griseofulvin,
and p-nitroaniline43
Ketoprofen49
Tranilast55
Iboprufen80
Diclofenac sodium88
------------------------------------------------------------------------------------------------
The use of large single-unit dosage forms sometimes poses a problem of permanent retention of rigid large-sized single-unit forms especially in patients with bowel obstruction, intestinal adhesion, gastropathy, or a narrow pyloric opening (mean resting pyloric diameter 12.8 ± 7.0 mm). Floating dosage form should not be given to a patient just before going to bed as the gastric emptying of such a dosage form occurs randomly when the subject is in supine posture. One drawback of hydrodynamically balanced systems is that this system, being a matrix formulation, consists of a blend of drug and low-density polymers. The release kinetics of drug cannot be changed without changing the floating properties of the dosage form and vice versa.18
Conclusion
Drug absorption in the gastrointestinal tract is a highly variable procedure and prolonging gastric retention of the dosage form extends the time for drug absorption. FDDS promises to be a potential approach for gastric retention. Although there are number of difficulties to be worked out to achieve prolonged gastric retention, a large number of companies are focusing toward commercializing this technique.
The use of large single-unit dosage forms sometimes poses a problem of permanent retention of rigid large-sized single-unit forms especially in patients with bowel obstruction, intestinal adhesion, gastropathy, or a narrow pyloric opening (mean resting pyloric diameter 12.8 ± 7.0 mm). Floating dosage form should not be given to a patient just before going to bed as the gastric emptying of such a dosage form occurs randomly when the subject is in supine posture. One drawback of hydrodynamically balanced systems is that this system, being a matrix formulation, consists of a blend of drug and low-density polymers. The release kinetics of drug cannot be changed without changing the floating properties of the dosage form and vice versa.18
Conclusion
Drug absorption in the gastrointestinal tract is a highly variable procedure and prolonging gastric retention of the dosage form extends the time for drug absorption. FDDS promises to be a potential approach for gastric retention. Although there are number of difficulties to be worked out to achieve prolonged gastric retention, a large number of companies are focusing toward commercializing this technique.
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