Gastro-retentive drugs: A review

Several technical advancements have led to the development of NDDS that could revolutionise methods of medication and provide a number of therapeutic benefits, says Prahlad Tayade

Conventional drug delivery system achieves as well as maintains the drug concentration within the therapeutically effective range needed for treatment only when taken several times a day. This results in a significant fluctuation in drug levels. Recently, several technical advancements have led to the development of several novel drug delivery systems (NDDS) that could revolutionize method of medication and provide a number of therapeutic benefits.

The most important objective of these New Drug Delivery Systems are:

First, it would be single dose, the duration of treatment, which releases the active ingredient over an extended period of time. Second, it should deliver the active entity directly to the site of action, thus minimizing or eliminating side effects.

Sustained release through gastric retention

During the last decade many studies have been performed concerning the sustained release dosage form of drugs, which have aimed at the prolongation of gastric emptying time (GET). The GET has been reported to be from 2 to 6 hours in humans in the fed state. Accordingly when a sustained release dosage form is administered orally, sufficient bioavailability and prolongation of the effective plasma level occasionally can’t be obtained.

Controlled release drug delivery systems that can be retained in stomach for a long time are important for drug that are degraded in intestine or for drugs like antacids or certain enzymes that should act locally in the stomach. If the drugs are poorly soluble in intestine due to alkaline pH, gastric retention may increase solubility before they are emptied, resulting in improved gastrointestinal absorption of drugs with narrow absorption window as well as for controlling release of drugs having site-specific absorption limitation.

Approaches to gastric retention

Over the last three decades, various approaches have been pursued to increase the retention of an oral dosage form in the stomach.

• Incorporation of passage delaying food excipients, principally fatty acids, to decrease the gastric emptying rate.
• Bioadhesive research, based upon the adhesive capacity of some polymer with glycoprotein (Mucin) closely applied to the surface epithelium of the stomach and intestine.
• The other approach is to alter the formulation’s density by using either high or low-density pellets, so called altered density approach.

High-density approach: Here, the density of the pellets must exceed that of normal stomach and should be at least 1.40. In preparing such formulations, drug can be coated on a heavy core or mixed with heavy inert materials such as barium sulfate, titanium dioxide, iron powder and oxide. The weighed pellet can then be covered with a diffusion-controlled membrane.

Low-density approach: While the system is floating on the gastric contents the drug is slowly released from the low density pellets or floating drug delivery systems (FDDS) and are also called as hydrodynamically balanced systems (HBS). FDDS or HBS have a bulk density lower than gastric fluid, that is, bulk density of less than one. HBS remains buoyant in the stomach without affecting the gastric emptying rate for a prolonged period of time and the drug is released slowly at a desired rate from the system. After the release of the drug, the residual system is emptied from the stomach.

Shells of polymer with lower density than that of the gastrointestinal fluid, (ex Polystyrene) have been used for this purpose. Swelling type dosage forms are such that on swallowing these products swell to an extent that prevents their exit from the stomach through the pylorus. As a result, the dosage form is retained in the stomach for a long period of time. These systems may be referred as ‘plug type system’ since they exhibit tendency to remain lodged at the pyloric sphincter. Modified shape systems are nondisintegrating geometric shapes molded from silstic elastomer or extruded from polyethylene blends which extend the gastric retentio time depending on size, shape and flexural modulus of the drug delivery system.

Unfortunately, most of these systems have many drawbacks. Floating system requires presence of food to delay their gastric emptying. They do not always release the drug at the intended site. Bioadhesive system adheres to the mucus. This adhesion is a result of electrostatic and H-bond formation at the mucus-polymer boundary. The bond formation is prevented by acidic environment and thick mucus present in the stomach.

Factors affecting gastric retention

These factors include density, size and shape of dosage form, concomitant intake of food and drugs such as anticholinergic agents (eg. atropine, propantheline), opiates (eg. codeine) and prokinetic agents (eg. metoclopramide) and biological factors such as gender, posture, age, body mass index and disease state. (eg. diabetes)

In order for a HBS dosage form to float in the stomach the density of the dosage form should be less than the gastric contents. However, the floating force kinetics of such dosage forms has shown that the bulk density of a dosage form is not the most appropriate parameter for describing its buoyancy.

These are better represented and monitored by resultant weight measurements and swelling experiments. This is because the magnitude of floating strength may vary as a function of time and usually decreases after immersion of the dosage form into the fluid consequently to the evolution of its hydrodynamical equilibrium.

The prolongation of gastric residence time (GRT) by food is expected to maximize drug absorption from FDDS due to increased dissolution of drug and longer residence at the most favorable sites of absorption. GRT of a dosage form in the fed state can also be influenced by its size.

Technological developments in FDDS

Most of the floating systems reported in the literature are single unit systems, such as floating tablets. These systems are unreliable and irreproducible in prolonging residence time in the stomach when orally administered owing to their fortuitous (all-or-nothing) emptying process. On the other hand, multiple unit dose forms appear to be better suited since they are claimed to reduce the intersubject variability in absorption and lower the probability of dose-dumping.

It also eliminates the dependence of the drug effect on gastric emptying, the mini depots being sufficiently small to make possible their passage through pylorus even between its actual openings. As a result, the drug will reach the site of optimum absorption and a high local concentration will also be avoided.

Based on the mechanism of buoyancy two distinctly different technologies, i.e. noneffervescent and effervescent systems have been utilized in the development of FDDS.

Noneffervescent systems: Commonly used excipients, here are gel-forming or highly swellable cellulose type hydrocolloids, polysaccharides and matrix forming polymers such as polycarbonate, polyacrylate, polymethacrylate and polystyrene. One of the approaches to the formulation of such floating dosage forms involves intimate mixing of drug with a gel forming hydrocolloid, which swells in contact with gastric fluid after oral administration and maintains a relative integrity of shape and a bulk density of less than unity within the outer gelatinous barrier.

The air entrapped by the swollen polymer confers buoyancy to these dosage forms. The gel structure acts as a reservoir for sustained drug release since the drug is slowly released by a controlled diffusion through the gelatinous barrier.

Effervescent systems: These buoyant delivery systems are prepared with swellable polymers such as methocel or polysaccharides e.g. Chitosan and effervescent components, e.g. sodium bicarbonate and citric or tartaric acid or matrices containing chambers of liquid that gasify at body emperature.

The matrices are fabricated so that upon contact with gastric fluid, carbon dioxide is liberated by the acidity of gastric contents and is entrapped in the gelyfiedhydrocolloid. This produces an upward motion of the dosage form and maintains its buoyancy. The carbon dioxide generating components may be intimately mixed within the tablet matrix to produce a single-layered tablet or a bilayered tablet may be compressed which contains the gas generating mechanism in one hydrocolloid containing layer and the drug in the other layer formulated for the SR effect.

The writer is Lecturer, Bombay College of Pharmacy, Kalina, Mumbai