GASTRO RETENTIVE DRUG DELIVERY DIFFERENT APPROACHES

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GASTRORETENTIVE DRUG DELIVERY SYSTEM PRESENTED BY RAVIVARMA VINAYAK DAS 1 st M.PHARM DEPARTMENT OF PHARMACEUTICS

CONTENTS :

CONTENTS INTRODUCTION NEED FOR GRDDS POTENTIAL DRUG CANDIDATES FOR GRDD S ADVANTAGES & LIMITATIONS CONCLUSION REFERENCES APPROACHES UNSTABLE CANDIDATES FOR GRDDS

INTRODUCTION:

INTRODUCTION The control of gastrointestinal transit of orally administered dosage forms using gastroretentive drug delivery systems (GRDDS) can improve the bioavailability of drugs that exhibit site-specific absorption. Prolonged gastric retention can be achieved by using floating, swelling, bioadhesive, high-density systems etc.

NEED FOR GASTRORETENTIVE DRUG DELIVERY SYSTEM:

NEED FOR GASTRORETENTIVE DRUG DELIVERY SYSTEM

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Absorption window

ADVANTAGES:

ADVANTAGES

Limitations:

Limitations

GASTRIC EMPTYING:

The process of gastric emptying occurs both during fasting and fed state. In fasted state , the process of gastric emptying is characterized by an interdigestive motility pattern that is commonly called migrating motor complex (MMC). This is a series of events that cycle through the stomach every 1.2 to 2hrs. In the fed state , the gastric emptying rate is slowed down because the onset of MMC is delayed, i.e., the feeding state results in a lag time prior to onset of gastric emptying. GASTRIC EMPTYING

FACTORS AFFECTING GRDDS:

FACTORS AFFECTING GRDDS

POTENTIAL DRUG CANDIDATES FOR GRDDS:

POTENTIAL DRUG CANDIDATES FOR GRDDS

DRUGS THAT ARE UNSUITABLE FOR GRDDS:

DRUGS THAT ARE UNSUITABLE FOR GRDDS

APPROACHES FOR PROLONGING THE GASTRIC RESIDENCE TIME:

APPROACHES FOR PROLONGING THE GASTRIC RESIDENCE TIME High-density systems. (HDS) Floating systems . (FS) Swelling and expanding systems. (SS) Mucoadhesive & Bioadhesive systems . (AS) FS HDS AS SS

CLASSIFICATION:

CLASSIFICATION

High-density systems:

High-density systems Gastric contents have a density close to water (  1.004 g cm− 3). When the patient is upright small high-density pellets sink to the bottom of the stomach where they become entrapped in the folds of the antrum and withstand the peristaltic waves of the stomach wall. A density close to 2.5 g cm −3 seems necessary for significant prolongation of gastric residence time. Barium sulphate, zinc oxide, iron powder, and titanium dioxide are examples for excipients used.

FLOATING SYSTEMS :

FLOATING SYSTEMS These have a bulk density lower than the gastric content. They remain buoyant in the stomach for a prolonged period of time, with the potential for continuous release of drug. They Include: Hydrodynamically balanced systems HBS™ Gas-generating systems Raft-forming systems Low-density systems

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Schematic localization of an intragastric floating system and a high-density system in the stomach.

LIMITATIONS OF FLOATING SYSTEMS:

LIMITATIONS OF FLOATING SYSTEMS Requires sufficient high level of fluids in the stomach for the drug delivery to float. Floating system is not feasible for those drugs that have solubility or stability problem in gastric fluids. The dosage form should be administered with a minimum of glass full of water (200-250 ml). The drugs, which are absorbed throughout gastro-intestinal tract, which under go firstpass metabolism (nifedipine, propranolol etc.), are not desirable candidate. Some drugs present in the floating system causes irritation to gastric mucosa.

GAS-GENERATING SYSTEMS:

GAS-GENERATING SYSTEMS Carbonates or bicarbonates, which react with gastric acid or any other acid (e.g., citric or tartaric) present in the formulation to produce CO 2 , are usually incorporated in the dosage form, thus reducing the density of the system and making it float on the media. An alternative is incorporation of matrix containing portions of liquid, which produce gas that evaporates at body temperature.

GAS-GENERATING SYSTEMS :

GAS-GENERATING SYSTEMS

INFLATABLE GASTROINTESTINAL DELIVERY:

INFLATABLE GASTROINTESTINAL DELIVERY System is incorporated with an inflatable chamber which contains liquid ether - gasifies at body temperature to cause the chamber to inflate in stomach . Inflatable chamber is loaded with a drug reservoir which can be a drug, impregnated polymeric then encapsulated in a gelatin capsule.

INFLATABLE GASTROINTESTINAL DELIVERY:

INFLATABLE GASTROINTESTINAL DELIVERY

INTRAGASTRIC OSMOTICALLY CONTROLLED DDS:

INTRAGASTRIC OSMOTICALLY CONTROLLED DDS Comprised of both an osmotic pressure controlled drug delivery device and an inflatable floating support in a biodegradable capsule . In stomach, the capsule quickly disintegrates and release the intragastric osmotically controlled drug delivery device . Inflatable support forms a deformable hollow polymeric bag containing liquid that gasifies at body temperature to inflate the bag. Consists of 2 compartments : Drug reservoir Osmotically active compartment

INTRAGASTRIC OSMOTICALLY CONTROLLED DDS:

INTRAGASTRIC OSMOTICALLY CONTROLLED DDS

VOLATILE LIQUID/VACUUM CONTAINING SYSTEM:

System can be float-flotation chamber, which may be vacuum or filled with air or a harmless gas Drug reservoir is encapsulated inside a microporous compartment VOLATILE LIQUID/VACUUM CONTAINING SYSTEM

RAFT-FORMING SYSTEMS:

RAFT-FORMING SYSTEMS This system is used for delivery of antacids and drug delivery for treatment of gastrointestinal infections and disorders. The mechanism involved in this system includes the formation of a viscous cohesive gel in contact with gastric fluids, wherein each portion of the liquid swells, forming a continuous layer called raft. This raft floats in gastric fluids because of the low bulk density created by the formation of CO 2 . Usually the system contains a gel-forming agent and alkaline bicarbonates or carbonates responsible for the formation of CO 2 to make the system less dense and more apt to float on the gastric fluids.

RAFT-FORMING SYSTEMS :

RAFT-FORMING SYSTEMS Schematic illustration of the barrier formed by a raft-forming system.

HYDRODYNAMICALLY BALANCE SYSTEM:

HYDRODYNAMICALLY BALANCE SYSTEM Prepared by incorporating a high level(20-75%w/w) gel-forming hydrocolloids. E.g.:- Hydoxyethylcellulose, hydroxypropylcellulose, HPMC & Sod. CMC into the formulation and then compressing these granules into a tablets or (encapsulating into capsules.) This hydocolloids forms a colloidal gel barrier around its surface which controls the rate of solvent penetration into the device and drug release from the device. It maintains the bulk density less than 1.

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HYDRODYNAMICALLY BALANCED SYSTEMS: HBS Schematic diagram shows the mode of action for HBS

HOLLOW MICROSPHERES/MICROBALLOONS:

HOLLOW MICROSPHERES/MICROBALLOONS Microballoons loaded with drug in their other polymeric shelf are prepared by simple solvent evaporation or solvent diffusion . Polymers used commonly: Polycarbonates , Cellulose acetate, Calcium alginate, Eudragit S, agar and low methoxylated pectin etc. Buoyancy and drug release depends on: Quantity of polymer Plasticizer polymer ratio Solvent used

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HOLLOW MICROSPHERES/MICROBALLOONS

ALGINATE BEADS:

ALGINATE BEADS Prepared by dropping a sodium alginate solution into aqueous solution of calcium chloride-precipitation of calcium alginate and maintain a porous system. Freeze dry at -40 o c for 24h. Multi unit floating dosage forms-cross linked beads Prepared by using calcium and low methoxylated pectin and calcium low methoxylated pectin and sodium alginate. Beads-spherical and 2.5 mm in diameter

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ALGINATE BEADS

SUPERPOROUS HYDROGELS:

SUPERPOROUS HYDROGELS Swellable agents have pore size ranging between 10nm and 10µm. Superporous hydrogels swell to equilibrium size with in a minute, due to rapid water uptake by capillary wetting through numerous interconnected open pores. They swell to large size and are intended to have sufficient mechanical strength to withstand pressure by the gastric contraction. This is achieved by co-formulation of a hydrophilic particulate material, and Ac-Di-Sol (crosscarmellose).

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On the left, superporous hydrogel in its dry (a) and water-swollen (b) state. On the right, schematic illustration of the transit of superporous hydrogel. From Gutierrez-Rocca, (2003). SUPERPOROUS HYDROGELS

EXPANDABLE SYSTEMS:

EXPANDABLE SYSTEMS

UNFOLDABLE SYSTEMS:

UNFOLDABLE SYSTEMS These are made of biodegradable polymers. The concept is to make a carrier, such as a capsule, incorporating a compressed system which extends in the stomach. Caldwell et al. proposed different geometric forms (tetrahedron, ring or planar membrane [4-lobed, disc or 4-limbed cross form] ) of bio erodible polymer compressed within a capsule .

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Different geometric forms of Unfoldable systems proposed by Caldwell et al. From Caldwell et al. (1988). UNFOLDABLE SYSTEMS

SWELLABLE SYSTEMS:

SWELLABLE SYSTEMS They are retained because of their mechanical properties. The swelling is usually results from osmotic absorption of water. The device gradually decreases in volume and rigidity as a result depletion of drug and expanding agent and/or bioreosion of polymer layer, enabling its elimination.

MUCOADHESIVE SYSTEMS :

MUCOADHESIVE SYSTEMS The basis of mucoadhesion is that a dosage form can stick to the mucosal surface by different mechanisms. Binding of polymer to the epithelial surface divided into 3 categories: Hydration –mediated adhesion Bonding –mediated adhesion Receptor mediated adhesion Examples for Materials commonly used for bioadhesion are poly(acrylic acid) (Carbopol®, polycarbophil), chitosan, Gantrez® (Polymethyl vinyl ether/maleic anhydride copolymers), cholestyramine, tragacanth, sodium alginate.

MAGNETIC SYSTEM:

MAGNETIC SYSTEM Based upon the principle that dosage form contains a small internal magnet ,and a magnet placed on the abdomen over the position of stomach can enhance the GRT.

Future Potential:

Future Potential To reduce the fluctuations in the plasma level of drug results from delayed gastric emptying. Drugs whose absorption limited to the upper gastrointestinal tract can be delivered efficiently. Buoyant delivery system for the treatment of gastric and duodenal cancers. Floating concept can also be utilized in the development of various anti-reflux formulations. Developing a controlled release system for the drugs, which are potential to treat the Parkinson’s disease. To explore the eradication of Helicobacter pylori by using the narrow spectrum antibodies.

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Marketed Products of GRDDS Brand name Delivery system Drug (dose) Company name Valrelease® Floating capsule Diazepam (15mg) Hoffmann-LaRoche, USA Madopar® HBS (Prolopa® HBS) Floating, CR capsule Benserazide (25mg) and L-dopa (100mg ) Roche Products, USA Liquid Gaviscon® Effervescent Floating liquid alginate preparations Al hydroxide (95 mg), Mg Carbonate (358 mg) GlaxoSmithkline, India Topalkan® Floating liquid alginate Preparation Al – Mg antacid Pierre Fabre Drug, France Conviron® Colloidal gel forming FDDS Ferrous sulphate Ranbaxy, India Cytotech® Bilayer floating capsule Misoprostol (100μg/200μg) Pharmacia, USA Cifran OD® Gas-generating floating form Ciprofloxacin (1gm) Ranbaxy, India

CONCLUSION:

CONCLUSION

REFERENCES:

REFERENCES Chien Yie W. Novel drug delivery systems. Vol-50. 2 nd ed. New York: Marcel Dekker . Inc; p.164-177. N K J ain. Gastroretentive drug delivery systems: G arima Chawla, P iyush G upta and A ravind K. B ansal, editors. Progress in controlled and novel drug delivery systems. 1 st ed. New delhi: CBS publihers and distributor; 2004. p76-95. Anand S. Surana and Rakhee K. Kotecha. An overview on various approaches to Oral controlled drug delivery system via gastroretention. IJPSRR. 2010 May; 2(2): 68-72. Singh Sanjay1, Joshi Vaibhav, and Barpete Pravin Kumar. Gastroretentive Drug Delivery System: Current Approaches. JPR. 2009; 2(5): 881-886 . Amit Kumar Nayak, Ruma Maji, Biswarup Das. Gastroretentive drug delivery systems: a review. AJPCR. 2010 Jan; 3(1): 2-10 . Ramdas T. Dolas1, Dr. Avinash Hosmani. Novel sustained release gastroretentive drug delivery system: a review. IJPRD. 2011 Jan; 3(11): 26-41 . Saurabh Sharma1, Arun Nanda and Lalit Singh. Gastroretentive Drug Delivery System: An Overview. IJRPBS. 2011 Jul; 2(3): 954-8 .

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