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.