Gastroretentive drug delivery system

This presentation includes introduction, physiology of GIT, factors affecting GRDDS, Advantages and disadvantages, approaches to GRDDS and their mechanism, some of the marketed products using GRDDS mechanism.

1. Submitted to : Dr. B . Wilson Head of the Department , Department of Pharmaceutics, College of Pharmaceutical Sciences, DSU Dayananda sagar college of Pharmacy, Banglore . Presented by: Arpitha B M M Pharm (I SEM), Department of Pharmaceutics, College of Pharmaceutical Sciences, DSU Dayananda Sagar College of Pharmacy, Banglore . Gastro rententive drug delivery system

2. C ontents Introduction Appropriate drug candidate for GRDDS Factors affecting GRDDS Advantages and disadvantages Approaches to GRDDS References 2 COPS DSU Department of Pharmaceutics

3. Introduction Oral route is extensively used, but not all drugs are uniformly absorbed throughout GIT. Drugs released after absorption window has no or negligible absorption. This can be overcome by retaining drug in stomach. Gatro rententive drug delivery (GRDDS) is one of the site specific drug delivery for the delivery of drugs at stomach. It is obtained by retaining dosage form into stomach and drug is being released at controlled manner at specific site. GRDDS is an approach to prolong gastric residence time, there by targetting site specific drug release in the upper gastrointestinal tract (GIT) for local and systemic effect. 3 COPS DSU Department of Pharmaceutics

4. Appropriate candidate for GRDDS Drugs acting locally in the stomach. e.g. Antacids and drugs for H. Pylori viz., Misoprostol Drugs that are primarily absorbed in the stomach. e.g. Amoxicillin Drugs that is poorly soluble at alkaline pH e.g. Furosemide , Diazepam, Verapamil etc. Drugs with a narrow window of absorption e.g. Cycloserine , Methotrexate , Levodopa etc. Drugs which are absorbed rapidly from the GIT e.g. Metronidazole , tetracycline. Drugs that degrade in the colon. e.g. Rantidine , Metformin HCl . Drugs that disturb normal colonic microbes. e.g. antibiotics against H. Pylori. COPS DSU Department of Pharmaceutics 4

5. Drugs that are unsuitable for GRDDS Have that have very limited acid solubility. e.g. phenytoin etc Drugs not stable in the gastric region. e.g . Erythromycin etc. Drugs intended for selective release in the colon. e.g. 5- amino salicylic acid and corticosteroids. 5 COPS DSU Department of Pharmaceutics

6. Physiology of the GIT The GI tract is essentially a tube about  nine metres  long that runs through the middle of the body from the mouth to the anus and includes the  throat (pharynx), oesophagus , stomach, small intestine (consisting of the duodenum, jejunum and ileum) and large intestine (consisting of the cecum , appendix, colon and rectum) . 6 COPS DSU Department of Pharmaceutics

7. Drug absorption in the case of- (a) Conventional dosage forms, (b) Gastroretentive drug delivery systems . 7 COPS DSU Department of Pharmaceutics

8. Gastric Emptying Gastric emptying occurs during fasting as well as fed states. Gastric emptying occurs as a result of gastric contraction, the nature of which depends on the contents of the stomach. Thus gastric emptying can be conveniently classified into gastric emptying of liquid, digestible solids, and indigestible solids. Liquids empty from the stomach as a result of Intragastric pressure generated by slow muscular contractions occurring  mainly from the proximal stomach (i.e. the upper body of the stomach). The removal of liquid is First order, i.e., the volume of liquid emptied per unit time is directly proportional to the volume remaining in the stomach. Digestible solids are known to be emptied only when they have been changed to a thick , creamy substance called chyme . Indigestible solids including oral dosage forms are known to be emptied from the stomach in fasting state by a distinct cycle of Myoelectrical activity known as the  Interdigestive   Migrating myoelectric complex (IMMC). 8 COPS DSU Department of Pharmaceutics

9. Gastric motility : This is called the   interdigestive myloelectric cycle or migrating myloelectric cycle (MMC) , which is further divided into following 4 phases:- 1. Phase I (basal phase): lasts from 30 to 60 minutes with rare contractions. 2. Phase II ( preburst phase): lasts for 20 to 40 minutes with intermittent action potential and contractions. As the phase 9 COPS DSU Department of Pharmaceutics 3. Phase III (burst phase): lasts for 10 to 20minutes. It includes intense and regular contractions for short period. It is due to this wave that all the undigested material is swept out of the stomach down to the small intestine. It is also known has housekeeper phase . 4.   Phase IV:  lasts for 0 to 5 minutes and occurs between phases III and I of two consecutive cycles. progresses the intensity and frequency also increases gradually.

10. Gastrointestinal Transit Time The residence time of liquid & solid foods in each segment of the GI tract is different. Since most drugs are absorbed from the upper intestine (duodenum, jejunum, and ileum), the total effective time for drug absorption is  3-8 hrs . This is why one has to take most drugs 3-6 times a day. Segment Type of food   Solid   Liquid Stomach 10-30mins 1-3hrs Duodenum 60secs 60secs Jejunum & ileum 3hr±1.5hr 4hr±105hr Colon - 20-50hr 10 COPS DSU Department of Pharmaceutics

11. FACTORS CONTROLLING GASTRIC RETENTION OF DOSAGE FORMS Density of dosage forms A density of  <1.0 gm/cm3  is required to exhibit floating property. Shape and size of the dosage form Dosage forms having a diameter of more than 7.5 mm show a better gastric residence time compared with one having 9.9 mm. Ring-shaped and tetrahedron-shaped devices have a better gastric residence time as compared with other shapes. Food intake and its nature The presence or absence of food in the gastrointestinal tract (GIT) influences the gastric retention time (GRT) of the dosage form. Usually the presence of food in the gastrointestinal tract (GIT) improves the gastric retention time (GRT) of the dosage form and thus, the drugs absorption increases by allowing its stay at the absorption site for a longer period. Again , increase in acidity and caloric value shows down gastric emptying time (GET), which can improve the gastric retention of dosage forms. 11 COPS DSU Department of Pharmaceutics

12. Fed or unfed state Under fasting conditions : GI motility is characterized by periods of strong motor activity or the migrating myoelectric complex (MMC) that occurs every 2 to 3 hours. The MMC sweeps undigested material from the stomach and, if the timing of administration of the formulation coincides with that of the MMC, the GRT of the unit can be expected to be very short. However, in the  fed state , MMC is delayed and GRT is considerably longer. Nature of meal Feeding of indigestible polymers or fatty acid salts can change the motility pattern of the stomach to a fed state, thus decreasing the gastric emptying rate and prolonging drug release. Disease state Gastric ulcer, diabetes, hypothyroidism increase GRT. Hyperthyroidism, duodenal ulcers decrease GRT. 12 COPS DSU Department of Pharmaceutics

13. Advantages Improved drug absorption because of increased GRT. Enhanced bioavailability. Controlled drug delivery. Reduced dosing frequency. Ease of administration. Better patient compliance. Targeted therapy for local ailments in the upper GIT. Reduced fluctuations of drug concentration. Delivery of drugs with narrow absorption window in small intestine region. 13 COPS DSU Department of Pharmaceutics

14. Disadvantage Retention in stomach is not desirable for drugs that cause gastric lesions/irritations. e.g. NSAIDS. Drugs degraded in the acidic environment of stomach. e.g. insulin. Drugs undergo significant first- pass metabolism. e.g. nifedipine . Drugs have limited acid solubility. e.g.phenytoin . These systems require a high level of fluid in the stomach for drug delivery to float and work efficiently. These systems do not offer significant over the conventional dosage forms for drugs, which are absorbed throughout GIT. 14 COPS DSU Department of Pharmaceutics

15. APPROACHES FOR PROLONGING THE GASTRIC RESIDENCE TIME 1.High-density systems (HDS) 2.Floating systems. (FS ) 3 . Swelling and expanding systems(SS ) 4 . Mucoadhesive & Bioadhesive systems. 15 COPS DSU Department of Pharmaceutics

16. 1. High density system Gastric contents have a density close to water( 1.004 gm/ cm3 ). When the patient take high-density pellets , they 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 gm/cm3 seems necessary for significant prolongation of gastric residence time . Drawback is technically it is difficult to manufacture such systems with high amount of drug (>50%) and to achieve a density of about 2-8. Barium sulphate , zinc oxide, iron powder, and titanium dioxide are examples for excipients used. 16 COPS DSU Department of Pharmaceutics

17. 2. Floating system (low density) 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: a. Hydro dynamically balanced systems (HBS) b. Gas-generating systems c. Volatile liquid/ vacuum containing systems 17 COPS DSU Department of Pharmaceutics

18. a. HYDRODYNAMICALLY BALANCED SYSYTEMS HBS/Colloidal barrier systems contain drugs with gel forming hydrocolloids to float on stomach contents. This prolongs GI residence time and maximises drug reaching its absorption site. Prepared by incorporating a high level(20-75%w/w) gelforming hydrocolloids . E.g.:- Hydoxyethylcellulose , hydroxypropylcellulose , HPMC & Sod. CMC into the formulation and then compressing these granules into a tablets or capsules. maintains the bulk density less than 1. 18 COPS DSU Department of Pharmaceutics

19. b. 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 CO2 , are usually incorporated in the dosage form , thus reducing the density of the system and making it float over chyme . 19 COPS DSU Department of Pharmaceutics

20. c. Volatile liquid/ vaccum containing system These systems contain an inflatable chamber , which contains a liquid (ether, cyclopentane ), that gasifies at body temperature to cause inflatation of the chamber in stomach. These devices are osmotically controlled floating systems containing a hollow deformable unit that can convert from a collapsed to an expanded position, and returns to collapsed position after an extended period. 20 COPS DSU Department of Pharmaceutics

21. 3.Swelling system A dosage form in the stomach will withstand gastric transit if it bigger than pyloric sphincter , but should be small enough to be swallowed. These systems swells many times its original size. Cross linking should be optimum highly cross linked don’t swell. Sustained and controlled release is achieved by selection of proper molecular weight polymer, and swelling of polymer retards drug release. Chitosan , HPMC, sodium starch glycolate , Carbopol are used. Diclofenac , Ciprofloxacin, Furosemide are reported with these systems. 21 COPS DSU Department of Pharmaceutics

22. 4. BIOADHESIVE OR MUCOADHESIVE SYSTEMS Delivery device within the human to enhance drug absorption in a site-specific manner. Bio adhesive polymers used which adhere to the epithelial surface in the stomach & improves the prolongation of gastric retention. These mechanisms are: 1) The wetting theory 2) The diffusion theory 3) The absorption theory 4) The electron theory. Materials commonly used for bioadhesion are poly acrylic acid, chitosan , cholestyramine , sodium alginate, hydroxypropyl methylcellulose (HPMC), sucralfate , tragacanth , dextrin, polyethylene glycol and polylactic acids etc. 22 COPS DSU Department of Pharmaceutics

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24. COPS DSU Department of Pharmaceutics 24 GRDDS Marketed drugs .

25. References N. K. Jain, Progress in Controlled & Novel Drug Delivery Systems, 1st edition 2004, CBS Publishers, page no.76-86. International Journal of Pharma and Bio Sciences GASTRORETENTIVE DRUG DELIVERY SYSTEM - A REVIEW by RIZWANA KHAN* Institute of Pharmacy Bundelkhand University, Jhansi , U. P ., India. S. P. Vyas & R. K. Khar , Controlled drug delivery- concepts and advances, Vallabha Prakashan publishers, page no. 197- 217. 25 COPS DSU Department of Pharmaceutics

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