GASTRORETENTIVE DRUG DELIVERY SYSTEM

NADIA JAWAID

WHAT IS GRDDS??? Gastroretentive drug delivery is an approach to

prolong gastric residence time, thereby targeting site-specific drug release in the upper gastrointestinal tract (GIT) for local or systemic effects.

NEED FOR GRDDS…???Oral drug delivery system Sustained drug delivery systems

These drug delivery systems suffer from mainly two adversities: short gastric retention time(GRT) and unpredictable short gastric emptying time (GET)

which can result in incomplete drug release from the dosage form in the absorption zone (stomach or upper part of small intestine) leading to diminished efficacy of administered dose.

To formulate a site-specific orally administered controlled release dosage form, it is desirable to achieve a prolong gastric residence time by the drug delivery. Prolonged gastric retention time (GRT) in the stomach could be advantageous for local action e.g. treatment of peptic ulcer, etc.

POTENTIAL DRUG CANDIDATES FOR GASTRORETENTIVE DRUG DELIVERY

SYSTEMS1. Drugs acting locally in the stomach(active in stomach) e.g. Antacids and drugs for H. Pylori viz., Misoprostol2. Drugs that are primarily absorbed in the stomach e.g. Amoxicillin 3. Drugs that are poorly soluble at alkaline pH e.g. Furosemide, Diazepam, Verapamil, etc.4. Drugs with a narrow window of absorption e.g. Cyclosporine, Methotrexate, Levodopa, etc.5. Drugs which are absorbed rapidly from the GI tract. e.g. Metronidazole, tetracycline.6. Drugs that degrade in the colon. e.g. Ranitidine, Metformin HCl.7. Drugs that disturb normal colonic microbes e.g. antibiotics against Helicobacter pylori.

DRUGS UNSUITABLE FOR GRDDS1] DRUGS THAT HAVE VERY LIMITED ACID SOLUBILITY PHENYTOIN ETC.2) DRUGS THAT SUFFER INSTABILITY IN THE GASTRIC ENVIRONMENT E.G. ERYTHROMYCIN ETC.3) DRUGS INTENDED FOR SELECTIVE RELEASE IN THE COLON 5-AMINO SALICYLIC ACID AND CORTICOSTEROIDSETC.

FACTORS AFFECTING THE GASTRORETENTIVE SYSTEM.1. DENSITY.

2. SIZE.

3. SHAPE OF DOSAGE FORM.

4. SINGLE OR MULTIPLE UNIT FORMULATION.

5. FED OR UNFED STATE.

7. NATURE OF MEAL 8. FREQUENCY OF FEED 9. GENDER. 10. AGE.

11. POSTURE. 12.CONCOMITANT DRUG. 13. BIOLOGICAL FACTORS.

APPROACHES TO GASTRIC RETENTION

PHYSIOLOGY OF THE STOMACH The stomach is an organ with a capacity for storage and

mixing. The antrum region is responsible for the mixing and grinding of gastric contents.

Under fasting conditions, the stomach is a collapsed bag with a residual volume of approximately 50ml and contains a small amount of gastric fluid (pH 1–3) and air.

REQUIREMENTS FOR GASTRIC RETENTION

The dosage form must satisfy certain requirements:Able to withstand the forces caused by peristaltic waves in the stomach and the constant contractions and grinding and churning mechanisms.Resist premature gastric emptying.Device should be removed from the stomach with ease.

APPROACHES TO ACHIEVE GASTRIC RETENTION

Floating drug delivery systems

The major requirements for floating drug delivery system are:

• Release contents slowly to serve as a reservoir.• Maintain specific gravity lower than gastric contents (1.004 – 1.01 gm/cm3).• Form a cohesive gel barrier.

The inherent low density can be provided by theentrapment of air (e.g. hollow chambers) or by the incorporation of low density materials (e.g. fatty materials or oils, or foam powder.

Multiple-unit floating system preferred over Single-unit dosage because of dose dumping.

Multiple-unit floating system:

Air compartment multiple-unit system hollow microspheres (microballoons)

Microparticles.

Based on the mechanism of buoyancy two distinctly different technologies, i.e. non-effervescent and effervescent systems have been utilized in the development of floating drug delivery system.

Non-effervescent SystemsPrepared from gel-forming or highly swellable cellulose type hydrocolloids, polysaccharides or matrix forming polymers like polyacrylate, polycarbonate, polystyrene and polymethacrylate.

The air trapped by the swollen polymer confers buoyancy to these dosage forms.

Excipients used are HPMC, polyacrylates, polyvinyl acetate, carbopol, agar, sodium alginate, calcium chloride, polyethylene oxide and polycarbonates.

This system can be further divided into the sub-types:

Hydrodynamically balanced systems:Sheth and Tossounian

DRUG + GEL- FORMING HYDROCOLLOID= BUOYANT

Single-unit dosage for contains one or more gel-forming hydrophilic polymers.

Excipients:

HPMC HEC HPC NaCMC Polycarbophil, Polyacrylate, Polystyrene, agar, carrageenans or alginic acid.

POLYMER+DRUGS

The capsule shell dissolves in contact with water andmixture swells to form a gelatinous barrier, whichimparts buoyancy to dosage form in gastric juice fora long period. Incorporation of fatty excipientsgives low-density formulations reducing theerosion.

MICROBALLOONS / HOLLOW MICROSPHERES

Microballoons / Hollow microspheres loaded with drugs prepared by solvent evaporation or solvent diffusion / evaporation methods.

Polymers used polycarbonate, cellulose acetate, calcium alginate, agar, and low methoxylated pectin etc. Buoyancy and drug release depends on quantity of polymers, plasticizer polymer and solvents used.

The microballoons floated continuously over the surface of an acidic dissolution media containing surfactant for >12 hours.

Are the best because they combine the advantages of multiple-unit system and good floating.

ALGINATE BEADSTalukdar and Fassihi

Recently developed a multiple-unit floating system based oncross-linked beads. They were made by using Ca2+and low methoxylated pectin (anionicpolysaccharide) or Ca2+ low methoxylated pectinand sodium alginate. These beads system can maintain a floating force for over 12 hrs. These beads improve gastric retention time (GRT) more than 5.5 hours.

MICROPOROUS COMPARTMENT SYSTEMS

Based on the principle of the encapsulation of a drug reservoir inside a microporous compartment with pores along its top and bottom walls.

Gastric fluid enters through the aperture, dissolves the drug and causes the dissolved drug for continuous transport across the intestine for drug absorption.

EFFEREVESENT GAS GENERATIONG SYSTEM

Floatability can be achieved by generation of gas bubbles(Carbon dioxide) These buoyant systems utilize matrices prepared with swellable polymers such as polysaccharides (e.g. chitosan), effervescent components (e.g. sodium bicarbonate, citric acid or tartaric acid, sodium alginate and sodium bicarbonate.

Multiple unit floating dosage forms generate gas (carbon dioxide) when ingested, floating mini capsules with a core of sodium bicarbonate, lactose and polyvinyl pyrrolidone (PVP) coated with hydroxypropyl methylcellulose (HPMC), and floating system based on ion exchange resin technology etc.

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 theoryMaterials commonly used for bioadhesion are polyacrylic acid, chitosan, cholestyramine, sodiumalginate, hydroxypropyl methylcellulose (HPMC),sucralfate, tragacanth, dextrin, polyethylene glycol and polylactic acids etc.

EXPANDABLE OR UNFOLDABLE SYSTEMSA dosage form will withstand gastric transit

bigger than pyloric sphincterand must be small enough to be

swallowed, and must not cause gastric obstructionGastroretentivity is improved by:

combination of substantial dimension with high rigidity of dosage form to withstand peristalsis and mechanical contractility of the stomach.

SUPER POROUS HYDROGELSIn this approach to improve gastric retention time (GRT) super porous hydrogels of average pore size >100 micro meter, swell to equilibrium size within a minute due to rapid water uptake by capillary wetting through numerous interconnected open pores. They swell to a large size and are intended to have sufficient mechanical strength to withstand pressure by gastric contraction.

MAGNETIC SYSTEMSEnhances the gastric retention time (GRT) 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.

ADVANTAGES OF GASTRORETENTIVE DRUG DELIVERY SYSTEM.

Improves patient compliance e.g. Furosemide

Enhanced bioavailability.

Increased Gastric retention time.

Enhanced absorption of drugs which solubilise only in stomach.

Drug releases in controlled manner for prolonged period e.g. b-lactams.

Site-specific drug delivery to stomach can be achieved.

Superior to single unit floating dosage -- no risk of dose dumping.

Avoids gastric irritation.

Better therapeutic effect of short half-life drugs can be achieved.

IN-VIVO EVALUATIONa) Radiology

b) Scintigraphy

c) Gastroscopy

d) Magnetic Marker Monitoring

e) Ultrasonography

f) 13C Octanoic Acid Breath Test

COMMONLY USED DRUGS IN FORMULATION OF

GASTRORETENTIVE DOSAGES FORMS Floating tablets

Floating capsules

Floating microspheres

Floating granules

Powders Films

Acetaminophen, Acetylsalicylic acid, Ampicillin, Amoxicillin trihydrate, Atenolol, Captopril. Chlorpheniramine maleate, Cipro. Diltiazem, Fluorouracil, Isosorbide dinitrate and mononitrate, PABA, Prednisolone,

Theophylline, Verapamil Diazepam, Furosemide, L-DOPA Nicardipine, Misoprostol, Propranolol,

Aspirin, Griseofulvin, p-nitro aniline, Ibuprofen, Terfenadine Diclofenac sodium, Indomethacin, Prednisolone Several basic drugs Cinnerzine

GASTRORETENTIVE PRODUCTS AVAILABLE INTHE MARKET

Brand Name

Cifran OD ®Madopar ®

Valrelease ®Topalkan ®

Almagate FlatCoat ®

Liquid Gavison ®Conviron

Cytotec®

Active Ingredient(s)

CiprofloxacinL-DOPA and Benserazide

DiazepamAluminium-magnesium antacid

Aluminium-magnesium antacid

Aluminium hydroxide,Ferrous sulphate

Misoprostol

REFERENCES:http://www.pharmainfo.net/reviews/gastroretentive-drug-delivery-system-overview

http://www.pharmainfo.net/reviews/gastroretentive-drug-delivery-system-overview

http://www.touchbriefings.com/pdf/17/pt031_p_garg.pdf

http://iglobaljournal.com/wp-content/uploads/2011/12/4.-Santosh-Shep-et-al.pdf

THANK YOU