Gastroretentive Drug Delivery System
- 1. • APPROACHES • RELEASE KINETICS • EVALUATION GASTRORETENTIVE DRUG DELIVERY SYSTEM -MADHURA NEWREKAR M .Pharm (QA) 1
- 2. CONTENTS INTRODUCTION ANATOMY & PHYSIOLOGY OF STOMACH FACTORS AFFECTING GRT GASTRORETENTIVE Vs OTHER CONVENTIONAL DDS ADVANTAGES & DISADVANTAGES APPROCHES FOR GI MODULATION RELEASE KINETICS EVALUATION RECENT ADVANCES IN GASTRORETENTIVE DDS CONCLUSION 2
- 3. Oral DDS Advantages: patient compliance Disadvantages: Fluctuations in plasma concentration Controlled Release DDS Advantages: Predictable plasma concentration Disadvantages: • Unpredictable gastric emptying time • Short gastric retention time Site specific , orally administered , prolonged GRT Gastroretentive DDS • Improves bioavailability • Reduced drug waste • Increases duration of drug release • Local action 3
- 4. GASTRORETENTIVE DRUG DELIVERY SYSTEM • It is an approach to prolong gastric retention of drug. • To target site specific release in upper gastrointestinal tract. • For local and systemic effects. 4
- 5. 5 It is locally effective in treatment of: Heartburns Infections caused due to Helicobacter pyroli like peptic ulcer Chronic gastritis . It is systemically effective in treatment : Which requires longer duration of drug action. Which requires repeated administration of drug, so to reduce frequent dosing. e.g. any infection
- 6. ANATOMY AND PHYSIOLOGY OF STOMACH • 3 Parts : • Fundus, Body ,Antrum Pyrolus • Fundus and body acts as a reservoir for undigested food • Antrum is the main site for mixing It also acts as a pump by gastric emptying by propelling actions 6
- 7. GASTROINTESTINAL MOTILITY AND GASTRIC EMPTYING Gastric emptying occurs during fasting as well as fed states. During the fasting state an inter- digestive series of electrical events take place, which cycle both through stomach and intestine every 2 to 3 hours. They are called as migrating myoelectric complexes(MMC). In the fed state, this cycle is delayed and hence the gastric emptying rate is slowed. MOTILITY PATTERN 7
- 8. FACTORS AFFECTING GASTRIC RETENTION TIME • Density of dosage form : A density of <1.0 gm/cm3 is required to exhibit floating property. • Size of the dosage form: The larger size would not allow the dosage form to quickly pass through the pyloric antrum into the intestine. 8
- 9. • Food intake and nature of food: Feeding of polymers of fatty acid salts leads to decrease in the gastric emptying rate. • Caloric content: Gastric retention time can be increased between 4 to 10 hours with a meal that is high in proteins and fats. • Frequency of feed: The gastric retention time can increase by over 400 minutes when successive meals are given compared with a single meal . 9
- 10. • Gender: Generally females have slower gastric emptying rates than male. • Age: In case of elderly persons, gastric emptying is slowed down. • Concomitant drug administration: Anticholinergic like atropine and propentheline, opiates like codeine and prokinetic agents like metoclopramide and cisapride will increase gastric emptying rate. 10
- 11. GRDDS VS OTHER CONVENTIONAL DDS Sr. No. Parameters Conventional Drug Delivery System Gastroretentive Drug Delivery System 1. Toxicity High risk of toxicity Low risk of toxicity 2. Patient Compliance Less Improves patient compliance 3. Drug with narrow absorption window in GIT Not suitable Suitable 11
- 12. 4. Drugs having shorter half lives Not much advantageous Very much advantageous 5. Drugs which are poorly soluble at an alkaline pH Not much advantageous Very much advantageous 12
- 13. ADVANTAGES • Sustained drug delivery. • Enhanced bioavailability. • Reduced frequency of dosing. • Reduced fluctuations in drug concentration • Extended time over critical concentration • Improved selectivity in receptor activation • Targeted therapy for local ailments in upper GIT. • Site specific drug delivery. 13
- 14. DISADVANTAGES 14 • Floating drug delivery systems require high fluid level in stomach to float and work effectively. • In patients with achlorhydria can be questionable in case of swellable system. • The mucus on the walls of the stomach is in a state of constant renewal, resulting in unpredictable adherence. • Retention of high density systems in the antrum part under the migrating waves of the stomach is questionable.
- 15. 15 • Unsuitable for drugs with limited acid solubility. e.g. Phenytoin • Unsuitable for drugs that are unstable in acidic environment. e.g. Erythromycin • Unsuitable for drugs that irritates or causes gastric lesions on slow release. e.g. Aspirin & NSAID’s • Unsuitable for drugs that are absorbed selectively in colon. e.g. corticosteroids.
- 16. DRUGS SUITABLE FOR GI MODULATION Drugs those are locally active in the stomach. e.g. misroprostol, antacids etc. Drugs that have narrow absorption window in gastrointestinal tract. e.g. levodopa ,furosemide, riboflavin etc. Drugs that exhibit low solubility at high pH values. e.g. diazepam, chlordiazepoxide,verapamil HCl. 16
- 17. DRUGS UNSUITABLE FOR GI MODULATION Drugs that have very limited acid solubility. e.g. phenytoin . Drugs that suffer instability in the gastric environment. e.g. erythromycin . Drugs intended for selective release in the colon. e.g. 5- amino salicylic acid and corticosteroids etc. 17
- 18. APPROACHES TO GASTRIC RETENTION APPROACHES LOW DENSITY SYSTEMS NONEFFERVESCENT SYSTEMS COLLOIDAL GEL BARRIER GEL SYSTEM MICROPOROUS COMPARTMENT SYSTEM ALGINATE BEADS HOLLOW MICROSPHERES EFFERVESCENT SYSTEMS VOLATILE LIQUID CONTAINING SYSTES GAS GENERATING SYSTEMS RAFT FORMING SYSTEM HIGH DENSITY SYSTEMS MUCOADHESIVE SYSTEMS SWELLING SYSTEMS EXPANDABLE SYSTEM MAGNETIC SYSTEM 18
- 19. LOW DENSITY SYSTEMS (FLOATING SYSTEMS) • NONEFFERVESCENT SYSTEMS: • Colloidal gel barrier systems: • The air trapped in by the swollen polymer maintains a density less than unity. 19
- 20. 20 Polymers: Cellulose type , polysaccharides ,matrix forming polymers . On coming in contact with gastric fluid, the hydrocolloid in the system hydrates and forms a colloid gel barrier around its surface.
- 21. • Microporous compartment system: • The encapsulation of a drug reservoir inside a microporous compartment with pores along its top and bottom walls. • The peripheral walls of the drug reservoir compartment are completely sealed to prevent any direct contact of gastric surface with the undissolved drug. • Gastric fluid enters through the aperture, dissolves the drug and carries the dissolved drug for continuous transport across the intestine for absorption. 21
- 22. • Alginate beads: They are prepared by dropping sodium alginate solution into aqueous solution of calcium chloride, causing the precipitation of calcium alginate. Freeze dried in liquid nitrogen at -4 ͦ C for 24 hours. Beads are of spherical size and 2.5 mm in diameter. 22
- 23. • Hollow microspheres (microballoons): • Hollow microspheres loaded with drug in their outer polymer shelf were prepared by a novel emulsion solvent diffusion method. • The ethanol/dichloromethane solution of the drug and an enteric acrylic polymer was poured into an agitated solution of Poly Vinyl Alcohol (PVA) that was thermally controlled at 40ºC. 23
- 24. • The gas phase is generated in the dispersed polymer droplet by the evaporation of dichloromethane formed and internal cavity in the microsphere of the polymer with drug. 24
- 25. • EFFEREVESCENT SYSTEMS: • Volatile liquid containing system: • These type of systems consist of two chambers separated by an impermeable, pressure-responsive,movable bladder. • The first chamber contains the drug and the second chamber contains the volatile liquid. The device inflates, and the drug is continuously released from the reservoir into the gastric fluid . • An inflatable chamber ,which contains a liquid e.g. Ether, cyclopentane, that gasifies at body temperature to cause the inflatation of the chamber in the stomach 25
- 26. 26 • The device may also consist of bio erodible plug made up of PVA, polyethylene, etc. That gradually dissolve causing the inflatable chamber to release gas and collapse after a predetermine time to permit the spontaneous ejection of the inflatable system from the stomach.
- 27. • Gas generating systems: • These delivery systems utilize effervescent reaction between carbonate/bicarbonate salts and citric/tartaric acid to liberate CO2, which get s entrapped in the gellified hydrocolloid layer of the systems, thus decreasing its specific gravity and making it float over chyme . • The drug is dispersed in a matrix of swellable polymer. 27
- 28. HIGH DENSITY SYSTEMS • High density pellets are small enough to be retained in the rugae or folds of the stomach body near the pyloric region. Dense pellets trapped in rugae also tend to withstand the peristaltic movements of the stomach wall. • With pellets, the GI transit time can be extended from an average of 6–25 hours, depending more on density than on the diameter of the pellets. • Commonly used excipients are barium sulphate, zinc oxide, titanium dioxide and iron powder, etc. • These materials increase density by up to 1.5–2.4g/cm-3. 28
- 29. BIOADHESIVE / MUCOADHESIVE SYSTEMS . • Bioadhesive polymers : polycarbophil, carbopol, lectins, chitosan and gliadin, etc . • The mechanism: 1.Hydration mediated adhesion: Certain hydrophilic polymers have the tendency to imbibe large amount of water and become sticky. 2.Bonding mediated adhesion: Physical or mechanical bonds can result from deposition and inclusion of the adhesive material in the crevices of the mucusa. 29
- 30. • Secondary chemical bonds, contributing to bioadhesive properties, consist of dispersive interactions (i.e. van der Walls interactions) and stronger specific interaction, which include hydrogen bonding. • The hydrophilic functional groups responsible for forming hydrogen bonds are the hydroxyl (--OH) and the carboxylic groups (--COOH). 3.Receptor mediated adhesion: • Certain polymers have the ability to bind to specific receptor sites on the cell surface. The receptor mediated events serves as a potential approach in bio/muco- adhesion, hence enhancing the gastric retention of dosage forms. 30
- 31. 31 The wetting theory Intimate contact with the mucous layers. The diffusion theory Physical entanglement of mucin strands into the flexible polymer chains. The absorption theory Vander Waal forces and hydrogen bonding. The electron theory Attractive electrostatic forces.
- 32. SWELLING SYSTEMS • These are the dosage forms, which after swallowing, swells to an extent that prevents their exit from the pylorus. • These systems may be named as ‘plug type systems’, since they exhibit the tendency to remain logged at the pyloric sphincter if that exceed a diameter of approximately 12-18mm in their expanded state. 32
- 33. 33 • Chitosan, HPMC, sodium Starch glycolate, Carbapol are used. • The balance between the extent and duration of swelling is maintained by the degree of cross linking between the polymeric chains.
- 34. EXPANDABLE SYSTEMS • These GRDFs are easily swallowed and reach a significantly larger size in the stomach due to swelling or unfolding processes that prolong their GRT. • After drug release, their dimensions are minimized with subsequent evacuation from the stomach. • Gastroretention is enhanced by the combination of substantial dimensions with high rigidity of the dosage form to withstand the peristalsis and mechanical contractility of the stomach. 34
- 36. MAGNETIC SYSTEMS • This approach to enhance the gastric retention time (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 magnet must be positioned with a degree of precision that might compromise patient compliance. 36
- 37. COMMONLY USED DRUGS IN FORMULATION OF GRDDS 37
- 38. POLYMERS AND OTHER INGRIEDIENTS USED IN FORMULATION OF GRDDS 38
- 39. PRODUCTS AVAILABLE IN MARKET 39 Dosage form Drugs Brand name Company,Country Floating control release capsule Levodopa, Benseramide MADOPAR Roche products, USA Floating capsule Diazepam VALRELEASE Hoffmann Laroche, USA Effervescent floating liquid alginate preparation Aluminium hydroxide, Magnesium carbonate LIQUID GAVISCON Glaxo Smith Kline,India Floating liquid alginate preparation Aluminium Magnesium antacid TOPALKAN Pierre fibre drug,France Colloidal gel forming capsule Ferrous sulphate CONVIRON Ranbaxy,India Gas generating floating swelleble tablets Ciprofloxacin CIFRAN OD Ranbaxy,India Mucoadhesive system Furosemide LASIX RETARD Sanofi,India
- 40. RELEASE KINETICS OF GRDDS 40 1. SWELLING SYSTEM: • Swelling can be described as a second order reaction. • Considering that the swelling process is affected by specific relations between the molecules of the swelling medium and the polymer pendant groups (amines, amides, carboxy), one can expect many kinds of polymer-solution interactions, and probably a complex kinetics. 2. FLOATING SYSTEM: • The release kinetics will depend on the polymers used and it usually follows zero or first order kinetics. 3. MUCOADHESIVE SYSTEMS: • It follows first order kinetics as the rate of drug release is dependent on the concentration of the drug present.
- 41. EVALUATION • IN VITRO EVALUATION: i) Floating systems a) Buoyancy Lag Time It is determined in order to assess the time taken by the dosage form to float on the top of the dissolution medium, after it is placed in the medium. These parameters can be measured as a part of the dissolution test. b) Floating Time Test for buoyancy is usually performed in SGF Simulated Gastric Fluid maintained at 370C.The time for which the dosage form continuously floats on the dissolution media is termed as floating time. c) Specific Gravity / Density Density can be determined by the displacement method using Benzene as displacement medium. 41
- 42. ii) Swelling systems a) Swelling Index After immersion of swelling dosage form into SGF at 370C, dosage form is removed out at regular interval and dimensional changes are measured in terms of increase in tablet thickness / diameter with time. b) Water Uptake : It is an indirect measurement of swelling property of swellable matrix. Here dosage form is removed out at regular interval and weight changes are determined with respect to time. So it is also termed as Weight Gain. Water uptake = WU = (Wt – Wo) * 100 / Wo Where, Wt = weight of dosage form at time t Wo = initial weight of dosage form 42
- 43. • In vitro dissolution test: In vitro dissolution test is generally done by using USP apparatus with paddle and GRDDS is placed normally as for other conventional tablets. 43
- 44. IN VIVO EVALUATION RADIOLOGY SCINTIGRAPHY GASTROSCOPY MAGNETIC MARKERS ULTRASONO GRAPHY • 13 C OCTANOIC ACID BREATH TEST 44
- 45. RECENT ADVANCES IN GRDDS 45 • Floating Rafts have been used in the treatment of Gastric esophageal reflux disease (GERD).The mechanism involved in the raft formation includes the formation of viscous cohesive gel in contact with gastric fluids, wherein each portion of the liquid swells forming a continuous layer called a raft.This raft floats on gastric fluids because of low bulk density created by the formation of CO2. • Usually, the system contains a gel forming agent and alkaline bicarbonates or carbonates responsible for the formation of CO2 to make the system less dense and float on the gastric fluids
- 46. 46 • Novel adhesive material derived from fimbriae of bacteria or its synthetic analogues are also being tried for the better attachment to the gut.
- 47. CONCLUSION • To design a successful GRDF ,it is necessary to take into consideration 1.Physiochemical properties of the drug 2.Physiological events in GIT 3.Formulation strategies 4.Correct combination of drug and excipients. • GRDD offers various potential advantages for drugs with poor bioavailability. • GRDDs are the most preferable system in order to deliver the drugs which have a narrow absorption window near the gastric region.. • Now a lot of research program is going on to develop new concepts. • In future,the system will become more promising and popular. 47
- 48. REFERENCES 48 • Yie W Chien , Novel Drug Delivery Systems , 2 nd Edition , Revised and expanded ,Drugs and Pharmaceutical Sciences , Volume 50 , Page no:164-177. • N.K.Jain, Progress in Controlled & Novel Drug Delivery System, 1st edition 2004,CBS Publication, p.no 76-97. • Amit Kumar Nayak, Ruma Maji and Biswarup Das ,Gastroretentive Drug Delivery System: A Review ,Asian Journal of Pharmaceutical and Clinical Research,Vol.3, Issue 1, January- March 2010,1-8. • S.Gopalakrishnan et al ,Journal of Pharmaceutical Science and Technology ,Vol. 3 , 2011,548-554. • Sunil Kumar, Faraz Jamil, Meenu Rajput and Saurabh Sharma ,Gastro Retentive Drug Delivery System: Features and Facts ,International Journal of Research in Pharmaceutical and Biomedical Sciences ,Vol. 3 ,Jan – Mar 2012 ,126-135. • Chhetri et al.,An overview on gastroretention drug delivery system , Journal of science and technology ,kathmandu university, Vol.10, No.I, November 2014, 90-103.
- 49. 49 THANK YOU
Editor's Notes
- #9: However, the floating tendency of the dosage form usually decreases as a function of time, as the dosage form gets immersed into the fluid, as a result of the development of hydrodynamic equilibrium.
- #10: Due to low fre of mmc
- #22: THIS TECH IS BASD on In the stomach, the floatation chamber containing entrapped air causes the deliv.ery system to float over the gastric content
- #30: 1. acquiring bioadhesive properties. The prolongedgastroretention of the bio/muco-adhesive deliverysystem is further controlled by the dissolution rateof the polymer. This approach involves the use of bioadhesive polymers, which can adhere to the epithelial surface in the stomach
- #33: A high degree of cross – linking retards the swelling ability of the system maintaining its physical integrity for prolonged period