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.
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