GASTRORETENTIVE DRUG DELIVERY SYSTEMS

CONTENTS
INTRODUCTION APPROACHES EVALUATION CONCLUSION REFERENCES

INTRODUCTION
The control of gastrointestinal transit of orally administered dosage forms using gastroretentive drug delivery systems (GRDDS) can improve the bioavailability of drugs that exhibit site-specific absorption. Prolonged gastric retention can be achieved by using floating, swelling, bioadhesive, or high-density systems.

 Need for gastroretentive drug delivery system

A controlled drug delivery system with prolonged residence time in the stomach is of particular interest for drugs Are locally active in the stomach (misoprostol, antacids antibiotics against H.pylori). Have an absorption window in stomach or in the upper small intestine (L-dopa, P-aminobenzoic acid, furosemide). Are unstable in the intestine or colonic environment (captopril). Exhibit low solubility at high pH values (diazepam, verapamil). Alter normal flora of the colon (antibiotics). Absorbed by transporter mechanism (paclitaxel).

 Advantages
Improved drug absorption, because of increased GRT and more time spent by the dosage form at its absorption site.
Controlled delivery of drugs. Delivery of drugs for local action in the stomach. Minimizing mucosal irritation by drugs, by drug releasing slowly at a controlled rate. Treatment of gastrointestinal disorders such as gastro-esophageal reflux. Ease of administration and better patient compliance.

 Limitations
They require a sufficiently high level of fluids in the stomach for the drug delivery buoyancy, to float therein and to work efficiently.
Floating systems are not feasible for those drugs that have solubility or stability problems in gastric fluid. Drugs which are well absorbed along the entire GI tract and which undergoes significant first- pass metabolism, may not be desirable candidates for GRDDS since the slow gastric emptying may lead to reduced systemic bioavailability. Drugs that are irritant to gastric mucosa are not suitable for GRDDS.

 Gastric emptying
The process of gastric emptying occurs both during fasting and fed state. In fasted state, the process of gastric emptying is characterized by an interdigestive motility pattern that is commonly called migrating motor complex (MMC). This is a series of events that cycle through the stomach and small intestine every 1.2 to 2hrs.

 In the fed state, the gastric emptying rate is slowed down because the onset of MMC is delayed, i.e., the feeding state results in a lag time prior to onset of gastric emptying. FACTORS CONTROLLING THE GASTRIC RETENTION TIME OF DOSAGE FORM

Density of dosage form. Size of dosage form. Food intake and nature of food. Effects of gender, posture, and age.

APPROACHES
High density system Floating systems Expandable systems Superporous hydrogels Mucoadhesive or bioadhesive systems Magnetic systems

High density systems

Gastric contents have a density close to water (~1.004). A density close to 2.5g cm-3 is necessary for significant prolongation of gastric residence time. The commonly used excipients in high density system includes barium sulphate, zinc oxide, iron powder, and titanium dioxide. The major drawback with such systems is that it is technically difficult to manufacture them with a large amount of drug (>50%) and to achieve the required density of 2.4-2.8g/cm3.

Floating Systems

1. 2.

Single-unit floating dosage system

Noneffervescent systems Effervescent (gas-generating) systems

1. 2. 3.

Multiple-unit floating dosage system

Noneffervescent systems Effervescent (gas-generating) systems Hollow microspheres

Raft-forming systems

 Single-Unit Floating Dosage System

Noneffervescent Systems
These systems contain one or more hydrocolloids and are made into a single unit along with drug and other additives. When coming in contact with water, the hydrocolloids at the surface of the system swell and facilitate floating. The coating forms a viscous barrier, and the inner polymer slowly gets hydrated as well, facilitating the controlled drug release. Such systems are called hydrodynamically balanced systems (HBS). the polymers used in this system includes hydroxypropylmethylcellulose,hydroxyethylcellulose, hydroxypropylcellulose, sodium carboxymethylcellulose, agar, carrageenans, and alginic acid.

Hydrodynamically balanced system

 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 on the media. An alternative is incorporation of matrix containing portions of liquid, which produce gas that evaporates at body temperature. The main drawback of single unit dosage systems are high variability of gastrointestinal transit time when orally administered because of all-or-nothing nature of their gastric emptying.

 Multiple-Unit Floating Systems

Hollow Microspheres
Hollow microspheres possess the unique advantages of multipleunit systems and better floating properties as a result of the central hollow space inside the microsphere. The general techniques involved in their preparation include simple solvent evaporation and solvent diffusion and evaporation. The drug release and better floating properties mainly depend on the type of polymer, plasticizer, and solvent employed for the preparation. Polymers such as polycarbonate, Eudragit S, and cellulose acetate were used in the preparation of hollow microspheres.

 Raft-Forming Systems

this system is used for delivery of antacids and drug delivery for treatment of gastrointestinal infections and disorders. The mechanism involved in this system includes the formation of a viscous cohesive gel in contact with gastric fluids, wherein each portion of the liquid swells, forming a continuous layer called raft. This raft floats in gastric fluids because of the 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 more apt to float on the gastric fluids.

 Expandable systems
These systems include Unfoldable and Swellable systems. Unfoldable systems are made of biodegradable polymers. The concept is to make a carrier, such as a capsule, incorporating a compressed system which extends in the stomach. Caldwell et al. proposed different geometric forms (tetrahedron, ring or planar membrane [4-lobed, disc or 4-limbed cross form] ) of bioerodible polymer compressed within a capsule. Swellable systems are retained because of their mechanical properties. The swelling is usually results from osmotic absorption of water. The dosage form is small enough to be swallowed, and swells in gastric liquids. The bulk enables gastric retention and maintain the stomach in fed state, suppressing housekeeper waves. The whole system is coated by an elastic outer polymeric membrane which was permeable to both drug and body fluids and could control the drug release.

The device gradually decreases in volume and rigidity as a result depletion of drug and expanding agent and/or bioreosion of polymer layer, enabling its elimination.

Different geometric forms of unfoldable systems

Prior to administration(A) Drug reservoir (B) Swellable expanding agent (C) and the whole enclosed by elastic outer polymeric envelope. Post administration Pressure of the expanding agent (B) swells the elastic polymer (C). Drug is released from the dosage form through the elastic polymeric envelope (C) as indicated by the arrow

 Superporous hydrogels
Swellable agents with pore size ranging between 10nm and 10m, absorption of water by conventional hydrogel is very slow process and several hours may be needed to reach as equilibrium state during which premature evacuation of the dosage form may occur.
Superporous hydrogels swell to equilibrium size with in a minute, due to rapid water uptake by capillary wetting through numerous interconnected open pores.

They swell to large size and are intended to have sufficient mechanical strength to withstand pressure by the gastric contraction. This is achieved by co-formulation of a hydrophilic particulate material, Ac-Di-Sol.

 Mucoadhesive or bioadhedive system

The technique involves coating of microcapsules with bioadhesive polymer, which enables them to adhere to intestinal mucosa and remain for longer time period in the GI while the active drug is released from the device matrix.

The cationic chitosan polymers are pharmaceutically acceptable to be used in the preparation of bioadhesive formulations owing to their known ability to bind well to gastric mucosa.

 Magnetic systems
This system is based on a simple idea: the dosage form contains a small internal magnet, and a magnet placed on the abdomen over the position of the stomach. Although these systems seem to work, the external magnet must be positioned with a degree of precision that might compromise patient compliance.

EVALUATION OF GRDDS
Various parameters that need to be evaluated in gastroretentive formulation include dissolution profiles, specific gravity, content uniformity, hardness, and friability in case of solid dosage forms. In case of multi particulate drug delivery systems, differential scanning calorimetry, particle size analysis, flow properties, surface morphology, and mechanical properties are also performed. The tests for floating ability and drug release are generally performed in simulated gastric fluids at 37 C.

 Methods to asses gastroretentivity of GRDFs

Magnetic Resonance Imaging
It is a noninvasive technique and allow observation of total anatomical structure in relatively high resolution. The visualization of GI tract by MRI has to be further improved by the administration of contrast media. For solid DFs, the incorporation of a superparamagnetic compound such as ferrous oxide enables their visualization by MRI.

Radiology (X-Ray)
In this technique a radio-opaque material has to be incorporated in the DF, and its location is tracked by X-ray picture.

 -Scintigraphy
Gamma scintigraphy relies on the administration of a DF containing a small amount of radioisotope, e.g.,152Sm,which is a gamma ray emitter with a relatively short half life.

Gastroscopy
Gastroscopy is commonly used for the diagnosis and monitoring of the GI tract. This technique utilizes a fiberoptic or video system and can be easily applied for monitoring and locating GRDFs in the stomach.

 Swelling studies
Tablets weighed individually (W1) and placed in Petri dishes containing 15ml of 0.1N HCl. At regular intervals they are removed from Petri dishes and excess surface water was removed using filter paper The swollen tablets were reweighed (W2). The swollen tablets are dried at 60 C at 24hrs in an oven and kept in desiccators for 24hrs and reweighed (W3). Degree of swelling = W2 - W1 W1 %Erosion = W1 - W3 X 100 W1

 Measurement of bioadhesion strength

Measurement of either tensile or shear strength is the most commonly used invitro method to measure the bioadhesion strength. Measurement of tensile strength involves quantitating the force required to break the adhesive bond between the test polymer and model membrane. The method typically uses modified balance or a tensile tester. A section of freshly excised rabbit stomach tissue with the mucosal side exposed is secured on a weighed glass vial and placed in a baker containing USP simulated gastric fluid. Another section of same tissue is secured of to a rubber stopper with a vial cap with the mucous side exposed. A small quantity of test polymer is placed between the two mucosal tissues. The force required to detach the polymer from the tissue is recorded.

CONCLUSION
The development of GRDDs can be advantageous for the administration of some important drugs and significantly improves their therapeutic outcome. Gastroretentivity of a DF can be achieved by the development of devices that can be significantly expand their volume by unfolding or swelling, adhering to gastric mucosa, or have the suitable density to sink or float over the gastric fluids.

REFERENCES
Bardonnet PL, Faivre V, Pugh WJ, Piffaretti JC, Falson F. Gatroretentive dosage forms: Overview and special case of Helicobacter pylori. J Control Release. 2006;111:1-18. Ecyclopedia of Pharmaceutical Technology. Hari Vardhan Reddy L and Murthy RSR. Floating Dosage Systems in Drug Delivery. Critical Revises in Therapeutic Drug Carrier Systems. 2002;19(6):553-585. Julan UD. Floating Drug Delivery Dystem: An Approach to Gastroretension. Latest Reviews. 2007;5(1). Shweta A, Javed A, Alka A, Roop K, and Sanjula B. Floating drug delivery systems: a review. AAPS PharmSciTech. 2005;6 (3) Article 47.