4.Gastro-Retentive Drug Delivery System.pdf

GASTRO-RETENTIVE DRUG DELIVERY SYSTEM Dr. Muhammad Harris Shoaib  OBJECTIVES  Prolonging the residence time of an oral dosage form in the stomach from several hours to days.  Delivering drug locally in both stomach and the upper small intestinal tract  Ideal for deliv...

GASTRO-RETENTIVE DRUG DELIVERY SYSTEM Dr. Muhammad Harris Shoaib  OBJECTIVES  Prolonging the residence time of an oral dosage form in the stomach from several hours to days.  Delivering drug locally in both stomach and the upper small intestinal tract  Ideal for delivering drug for treating peptic ulcer  Improving patient compliance  STOMACH PHYSIOLOGY AND FUNCTION  Composed of three compartments ◼ Fundus ◼ Body ◼ Antrum  The Fundus and body act as a reservoir for the ingested material  The fundus generates a positive pressure (due to gas accumulation) that help the stomach content to move along  Distal stomach (antrum) is a mixing site and acts as a drain pump to the duodenum  Act as a food reservoir, food processor, food sterilizer and food delivery port to the intestine  Food enters through the cardiac end and exit through pyloric end  During food processing cardiac end is closed to prevent food from entering the oesophagus  Pylorus sieves the processed food to prevent the large objects and undigested food from entering into the upper intestine  Stomach size and volume varies, ranges from 50 ml fasted state to 1.5 L in fed state  After ingestion, the food and other ingested material mixed with the gastric juice containing water, HCl, electrolytes, pepsin, protein and mucus.  Absorption is poor due to less surface area.  GASTRIC MOTILITY  Divided into several phases collectively called the interdigestive myoelectric motor complex (IMMC)  Different motility in fasted and fed state  MOTILITY PHASES (Fasted/normal state) ◼ PHASE I ◼ Also called basal state lasted for about 45-60 min ◼ Characterized by the relative absence of contraction ◼ PHASE II ◼ Also called preburst state lasted for 30-45 min is characterized by increasing frequency and strength of contraction. ◼ PHASE III ◼ Also called the burst state ◼ Approx 5-15 min ◼ Characterized by strong contraction. ◼ This phase clears out the stomach of digested material and saliva ◼ Also called “Housekeeper waves” ◼ PHASE IV ◼ No contraction ◼ Short period ◼ Last for 5 min  MOTILITY PHASE (Fed state) ◼ Stomach handles liquids and solid materials differently ◼ Liquids are emptied first (usually within 30 min) by the slow and sustained contractions of the proximal stomach ◼ Gastric emptying depends on the type, nutrition density, quantity and particle size of the meal ◼ It can be extended upto 14 hrs ◼ Particle less than 5 mm in diameter are known to be emptied by the contraction of the distal stomach following the emptying of liquid ◼ Particle larger than 5 mm are retained in the stomach till digestion ◼ Gastric emptying time is usually within 2-6 hrs for a regular meal  LIMITATIONS AND PROBLEMS IN DEVELOPING GASTRO RETENTIVE DRUG DELIVERY SYSTEM  GR System should generally not be administered in the fasted state due to risk of emptying during the next house keeper wave  Release rate depends on IMMC phase  A single unit dosage form may be emptied out in the duodenum in “all or nothing” fashion. This makes retention time less predictable   If Gastric retention for long time is desired, small gastro-retentive system rely on continuous eating by the patient to avoid housekeeper wave  FACTOR CONTROLLING GASTRIC RETENTION OF DOSAGE FORM  Density of dosage form ◼ Dosage forms having a density lower than the gastric contents (< 1 g/cm3) can float to the surface. ◼ High density systems sink to bottom of the stomach ◼ Both situation isolates pylorus form the system  Shape and size of the delivery system ◼ Size greater the 7 mm had better residence time ◼ Irregular geometry increases the gastric residence time  Food intake and its nature ◼ Food intake, viscosity and volume of fluid, caloric value and frequency of feeding have a profound effect on the gastric retention of dosage form  Effect of gender, Age and posture ◼ Female have slower emptying rate than males ◼ Elderly person have slow emptying rate ◼ No significant change due to posture  POTENTIAL DRUG CANDIDAE FOR GASTRO RETENTIVE DRUG DELIVERY SYSTEM  Drugs those are locally active in the stomach e.g. misroprostol, antacids etc.  Drugs that have narrow absorption window in gastrointestinal tract (GIT) e.g. L-DOPA, para aminobenzoic acid, furosemide, riboflavin etc.  Drugs those are unstable in the intestinal or colonic environment e.g. captopril, ranitidine HCl, metronidazole.  Drugs that disturb normal colonic microbes e.g. antibiotics against Helicobacter pylori.  Drugs that exhibit low solubility at high pH values e.g. diazepam, chlordiazepoxide, verapamil HCl.  DRUGS UNSUITABLE FOR GASTRORETENTIVE DRUG DELIVERY SYSTEMS  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. TYPES OF GASTRO RETENTIVE DRUG DELIVERY SYSTEM Gastroretentive drug delivery systems: (a) floating (effervescent, hydrodynamically balanced system, porous foam powders), (b) expandable, (c) swelling (superporous hydrogels, swelling polymers), (d) bioadhesive, and (e) high density.  TYPES OF GASTRO RETENTIVE DRUG DELIVERY SYSTEM  FLOATING DRUG DELIVERY SYSTEM ◼ Having density less than gastric fluid and so remain buoyant in the stomach without affecting gastric emptying rate for a prolong period of time ◼ System is floating and the drug released slowly at a desired rate ◼ Non Effervescent System ◼ System swells unrestrained via imbibitions of gastric fluid to an extent that it prevents their exit from the stomach ◼ Swelling possible due to mixing of drug with gel former ◼ Having bulk density of less than one within the outer gelatinous barrier ◼ The air trapped by theswollen polymer confers buoyancy to these dosage forms. ◼ Excipients includes HPMC, polyacrylate polymers, polyvinyl acetate, Carbopol, agar, sodium alginate, calcium chloride, polyethylene oxide and polycarbonates ◼ Colloidal Gel Barrier system ◼ Also called Hydrodynamically balanced system ◼ Drug is enclosed in a hard gelatin capsule shell together with a gel forming hydrophilic polymer such as HPMC, Hydroxyethyl cellulose, Sodium carboxymethyl cellulose ◼ When capsule shell disintegrates, the polymer forms a hydrated boundary layer ◼ The hydrated boundary layer also entraps some air inside which lowers the overall density of the system as compared to GI fluids ◼ Drug releases as the polymer erodes ◼ Madopar (Levodopa + Banseracid hydrochloride) and Valrelease (Diazepam) are the common example Hydrodynamically balanced system ◼ Microporous Compartment system ◼ Based on the encapsulation of a drug reservoir inside a microporous compartment with pores along its top and bottom walls ◼ In the stomach, the floatation chamber containing entrapped air causes the delivery system to float over the gastric content ◼ Gastric fluid enters through the aperture, dissolves the drug and carries the dissolved drug for continuous transport across the intestine for absorption ◼ Alginate Beads ◼ Multi-unit floating dosage forms have been developed from freeze-dried calcium alginate ◼ Spherical beads of approximately 2.5 mm in diameter can be prepared by dropping sodium alginate solution into aqueous solution of calcium chloride, causing the precipitation of calcium alginate ◼ The beads are then separated, snap-frozen in liquid nitrogen, and freeze-dried at -40ºC for 24 hours, leading to the formation of a porous system, which can maintain a floating force for over 12 hours ◼ These floating beads gave a prolonged residence time of more than 5.5 hours ◼ Hollow microspheres/Micro ballons ◼ 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 ◼ 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 ◼ The microballoon floated continuously over the surface of an acidic dissolution media containing surfactant for more than 12 h  Chitosan Microspheres Prepared by the Water-in-Oil Emulsion Solvent floating microspheres of Diffusion Method levodopa/carbidopa ◼ Gas generating or Effervescent System ◼ These buoyant systems utilize matrices prepared with swellable polymers such as methocel, polysaccharides (e.g., chitosan), effervescent components (e.g., sodium bicarbonate, citric acid or tartaric acid) ◼ Upon arrival in the stomach, Bicarbonate component react with gastric acids and generate carbon dioxide, causing the formulation to float in the stomach ◼ Another type of system has beads of the ion exchange resin coated with semi permeable membrane and loaded with bicarbonate and the active drug ◼ The semi permeable membrane will act as a barrier and gases will entrap inside the beads  EXPANDABLE SYSTEM (Super porous hydrogels)  Expanding hydrogels have been used to resist transit through the pylorus in the fasted state and then gradually degrade to allow passage  Modified form is Superporous hydrogels  A superporous hydrogel is enclosed in a capsule so that the initial volume is small for easy swallowing  After oral administration, it swells quickly in the gastric juice to a large size, so that its emptying into the intestine is prevented  When the gastric contraction reaches the hydrogel, the gastric tissues slide over the hydrogel since it is elastic and slippery  While a drug is released from this dosage form, it slowly undergoes degradation in the stomach by either mechanical force or chemical/enzymatic ◼ Requirements for Superporous Hydrogels ◼ The size must be small enough for easy swallowing ◼ Hard gelatin capsules with size 000 were used to house the superporous hydrogel dosage form ◼ Swelling must be fast enough in stomach to overcome the gastric emptying by IMMC ◼ The size of the swollen gel must be large enough to be retained in the stomach ◼ The swollen gel should be strong enough to withstand the peristaltic contraction/stomach contraction pressure (50–70 cm water pressure) and abrasion and shear forces. ◼ A superporous hydrogel dosage form should be emptied from the stomach after drugs are released by mechanical/chemical/enzymatic degradation The pH of the monomer mixture is low due to the addition of acid (A), and this makes polymerization very slow. The addition of NaHCO3 results in foaming and at the same time the pH of the solution increases (B). The pH increase accelerates the polymerization process, which is completed before the foam subsides. This leads to the superporous hydrogel formation (C). A, acid; C, crosslinker; F, foaming agent; I, initiator; and M, monomer.  BIO/MUCOADHESIVE SYSTEM ◼ Based on the adhesive capacities of some polymers with mucins covering the surface epithelium of the stomach. ◼ Polycarbophil or crosslinked poly(acrylic acid) and a hydrophobic protein called zein were used to design formulations that can adhere to the stomach lining for the extended gastric retention. ◼ Adhesive capability can be loss due to contamination by the soluble mucin and other protein present in the gastric juice  HIGH DENSITY DOSAGE FORM ◼ Sedimentation has been employed as a retention mechanism for pellets ◼ Dense pellets (approximately 3g/cm3) 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 5.8–25 hours, depending more on density than on the diameter of the pellet ◼ Commonly used excipients are barium sulphate, zinc oxide, titanium dioxide and iron powder, etc for increasing the density Intragastric residence positions of floating and nonfloating units  DOSAGE FORM WITH SPECIAL SHAPES ◼ Elastomers or plastic made from polyethylene or nylon would increase the Gastric retention time ◼ Tetrahedron (each leg 2cm) and rings (3.6 cm in diameter) provide Gastric retention upto 24 hrs or more ◼ Neither easily digestible nor easy to load and release drug  MAGNETIC DOSAGE FORM ◼ Made by mixing ferrite powder with other excipient ◼ Retention possible by an externally applied strong magnetic field