Gastro retentive drug delivery system (GRDDS)

Oral route is the most acceptable route for drug administration. Apart from conventional dosage forms several other forms were developed in order to enhance the drug delivery for prolonged time period and for delivering drug to a particular target site. Gastro-retentive drug delivery system (GRDDS) has gainned immense popularity in the field of oral drug delivery recently. it is a widely employed approach to retain the dosage form in the stomach for an extended period of time and release the drug slowly that can address many challenges associated with conventional oral delivery, including poor bioavailability. different innovative approaches are being applied to fabricate GRDDS. Gastroretentive drug delivery is an approach to prolong gastric residence time, there by targeting site-specific drugs release in the upper gastrointestinal tract (GIT) for local or systemic effects. It is obtained by retaining dosage form into stomach and by releasing the in controlled manner.

1. GASTRO-RETENTIVE DRUG DELIVERY SYSTEM Submitted by: Shweta Nehate M. Pharm 1 st sem Guided by: Dr. Hitesh Jain Asso. Professor Forwarded by: Dr. D. B. Meshram Principal Pioneer Pharmacy Degree College, Vadodara

2. CONTENTS Introduction Gastrointestinal tract physiology Potential candidates for GRDDS Factors affecting GRDDS Merits and Demerits Approaches for GRDDS Methodology Evaluation parameters Applications Marketed formulations Conclusion Reference 2

3. INTRODUCTION Gastroretentive drug delivery is an approach to prolong gastric residence time, there by targeting site-specific drugs release in the upper gastrointestinal tract ( GIT) for local or systemic effects. It is obtained by retaining dosage form into stomach and by releasing the in controlled manner. 3

4. GASTROINTESTINAL TRACT PHYSIOLOGY 4 Migrating myoelectric cycle

5. POTENTIAL CANDIDATES FOR GRDDS Drugs acting locally in the stomach. E.g. Antacids and drugs for H. Pylori viz., Misoprolol. Drugs that are primarily absorbed in the stomach. E.g. Amoxicillin Drugs that is poorly soluble at alkaline pH. E.g. Furosemide , Diazepam, Verampil , etc. Drugs with a narrow absorption window. E.g. Cyclosporine, Levodopa , Methotrexate etc. 5

6. Drugs which are absorbed rapidly from the GI tract. E.g. Metronidazole , tetracycline. Drugs that degrade in the colon. E.g. Ranitidine, Metformin . Drugs that disturb normal colonic microbes. E.g. Antibiotics against H. Pylori. Drugs with less half life. 6

7. DRUG CANDIDATES NOT SUITABLE FOR GRDDS 7 Drugs that have very limited acid solubility. E.g. Phenytoin, etc. Drugs that suffer instability in the gastric environment. E.g. Erythromycin, etc. Drugs intended for selective release in the colon. E.g. 5-Amino salicylic acid and corticosteroids, etc. Drugs having extensive first pass metabolism.

8. FACTORS AFFECTING THE GRDDS Density Size and Shape of the dosage form Single or Multi unit formulation Age Gender Body posture Frequency of intake Diseased state of an individual 8

9. MERITS Improved drug absorption. Enhanced bioavailability. Reduced dose frequency. Controlled drug delivery of drugs. Minimized mucosal irritation. Local action. Better patient compliance. Site specific drug delivery. 9

10. DEMERITS Drugs that cause gastric lesions. E.g. NSAIDs. Drugs that undergo first pass metabolism. E.g. Nifedipine . Drugs that have very limited acid solubility and stability. E.g. Phenytoin. Drugs that degrade in acidic environment. Drugs which are well absorbed along the entire GIT. Requires high levels of fluids in stomach. Requires presence of food to delay gastric emptying. 10

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12. APPROACHES TO GASTRIC RETENSION High density system Low density system Mucoadhesive system Raft forming system Swellable system Superporous hydrogels Self unfolding systems 12

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14. FLOATING DRUG DELIVERY SYSTEMS Floating drug delivery systems have a bulk density lower than gastric fluids and thus remain buoyant in the stomach for prolonged period of time, without affecting the gastric emptying rate. While the system is floating on the gastric contents, the drug is released slowly at a desired rate from the system. This type is also called as hydro dynamically balanced system (HBS). 14

15. MECHANISM OF FDDS FDDS has a bulk density less than gastric fluids and soremain buoyant in the stomach without affecting the gastric emptying rate for a prolonged period of time. F= buoyancy- gravity = (D f -Ds) gv Where,F= total vertical force, Df= fluid density, Ds= object density, v = volume, g = acceleration due to gravity. 15

16. TYPES OF FLOATING SYSTEM 16

17. 17 Effervescent system: This are low density FDDS is based on the formation of CO 2 within the device following contact with the body.

18. Non effervescent system: 18 This system use a gel forming (or) swellable cellulose type of Hydrocolloids, polysaccharide, matrix forming polymer like polycarbonate, polystyrene and polymethacrylate. One of the formulation methods involves the mixing of the drug with gelforming hydrocolloids .

19. This hydrocolloids swell in contact with gastric fluid after oral administration and maintains integrity of shape and a bulk density barrier, the air trapped by swollen polymer confer buoyancy to the dosage forms. 19

20. RAFT FORMING SYSTEM 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, forming a continuous layer called raft. 20

21. MICROPOROUS COMPARTMENT SYSTEM This technology is based on the encapsulation of a drug reservoir inside a microporous compartment with pores along its top and bottom walls. The peripheral wall of the drug reservoir compartment is completely sealed to prevent any direct contact of gastric surface with the undissolved drug. 21

22. ALGINATE BEADS It is prepared by dropping sodium alginate solution into solution of calcium chloride, causing the precipitates of calcium alginate. Freeze dry in liquid nitrogen at -40ºc for 24 hrs. Formation of porous system which can maintain a floating force over 12 hrs. 22

23. MICROSPHERES Microballons/ hollow microspheres loaded with drugs prepared by solvent evaporation or solvent diffusion/ evaportaion methods. Buoyancy and drugs release depends on quality of polymers, plasticizer polymer and solvents used. 23

24. MAGNETIC SYSTEM This approach to enhance the GRT is based on the simple principle that the dosage form contains a small internal magnet, and a magnet placed on the abdomen over the position of the stomach. Although magnetic system seems to work, the external magent must be positioned with a degree of precision that might compromise patient compliance. 24

25. B. HIGH DENSITY SYSTEM Gastric contents have a density close to water. A density close to 2.5g/cm 3 is necessary for significant prolongation of gastric residence time. The commonly used excipients in high density system includes barium sulphate , zinc oxide, iron powder, and titanium dioxide . The major drawback 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. 25

26. C. BIOADHESIVE OR MUCOADHESIVE SYSTEM Bio/ muco-adhesive are those which bind to the gastric epithelial cell surface or mucin and serve as a potential means of extending the GRT of drug delivery system (DDS) in the stomach,by interesting the intimacy and duration of contact of drug with the biological membrance. The basis of adhesion in that a dosage form can stick to the mucosal surface by different mechanism. These mechanism are: 26

27. The wetting theory. The diffusion theory. The absorption theory. The electron theory. 27 POLYMER MUCUS MEMBRANE

28. D. SWELLABLE SYSTEMS These are dosage forms which after swallowing, swell to an extent that prevents their exit from the pylorus. As a result, the dosage form is retained in stomach for a long period of time. These systems may be named as “plug type system”, since they exhibit tendency to remain logged at the pyloric sphincter. 28

29. E. SUPERPOROUS HYDROGELS 29 Superporous hydrogel in dry state. Superporous hydrogel in water swollen state. On the right, schematic illustration of the transit or superporous hydrogels

30. Swellable agents with pore size ranging between 10nm and 10µm, absorption of water by conventional hydrogel is very slow process and several hours may be needed to reach as equilibrium state during which premature evacuation of the dosage form may occur. Superporous hydrogels swell to equilibrium size with in a minute, due to rapid water uptake by capillary wetting through numerous interconnected open pores. 30

31. F. SELF UNFOLDING SYSTEM These systems are made of biodegradable polymers and are capable of being mechanically increased in size relative to the initial dimensions. After being swallowed, these dosage forms swell to a size that prevents their passage though rough the pylorus and therefore, the dosage form is prone to be retained in the stomach for a long period of time. 31

32. METHODOLOGY Direct compression method Melt granulation technique Effervescent technique Spray drying technique Solvent evaporation technique Wet granulation technique Ionotropic gelation technique 32

33. EVALUATION PARAMETERS Pre- compression test: Size and shape Particle size Density Specific gravity Flow properties Post compression test: Thickness and diameter Hardness and friability Weight variation test floating time Content uniformity Dissolution test Mucoadhesive test 33

34. IN VITRO TEST: Floating lag time Floating time Dissolution study Swelling index Mucoadhesive test Density IN VIVO TEST: Radiology Scintigraphy Gastroscopy Magnetic marker monitoring Ultrasonography 34

35. APPLICATIONS Enhanced bioavailability Sustained drug delivery Site specific drug delivery system Absorption enhancement Minimized adverse activity at the colon Reduced fluctuation of drug concentration 35

36. MARKETED FORMULATIONS 36

37. CONCLUSION: FDDS promise to be potential approach for gastric retention. The goal of any drug delivery system is to provide a therapeutic amount of drug to the proper site in the body and also to achieve and maintain the desired plasma concentration of the drug for a particular period of time. However, incomplete release of the drug, shorter residence times of dosage forms in the upper GIT leads to lower oral bio-availability. Such limitations of the conventional dosage forms have paved way to an era of controlled and novel drug delivery system. 37

38. REFERNCE: Doshi S.M., Tank H.M., “Gastro Retention, An Innovation over Conventional poorly Soluble Drugs: A Review”, International Journal of Pharmaceutical and Chemical Science, 2012 ;1(2):859-866. S.P. Vyas, Roop K. Khar, CONTROLLED DRUG DELIVERY – Concepts & Advances, Vallabh Prakashan, pp- 196-217. N.K. Jain, Progress in controlled & Novel Drug Delivery System, 1 st edition 2004 CBS Publishers, pp- 76-97. 38

39. G. Chawla, P. Gupta, Pharmaceutical Technology, July 2003 , 50-68 39