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4. Gastro Retentive Drug Delivery System: A Review

Patel Harshna*, Solanki N S
Bhupal Nobels’ Institute of Pharmaceutical Sciences, Udaipur, India
Corresponding Author: Patel Harshna, E-Mail : [email protected]
Received:17 July 2012 Accepted: 16 August 2012
Citation: Patel Harshna*, Solanki N S “Gastro Resistant Drug Delivery System: A Review” Int. J. Drug Dev. & Res., October-December 2012, 4(4): 1-8. doi: doi number
Copyright: © 2010 IJDDR, Patel Harshna et al. This is an open access paper distributed under the copyright agreement with Serials Publication, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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Abstract

IN recent years several advancement has been made in research and development of Oral Drug Delivery System. Concept of Novel Drug Delivery System arose to overcome the certain aspect related to physicochemical properties of drug molecule and the related formulations. Purpose of this review is to compile the recent literature with special focus on various gastro retentive approaches that have recently become leading methodologies in the field of site-specific orally administered controlled release drug delivery. Technological attempts have been made in the research and development of ratecontrolled oral drug delivery systems to overcome physiological adversities, such as short gastric residence times (GRT) and unpredictable gastric emptying times (GET). Therefore, gastro retentive drug delivery systems (GRDDS) have been developed, which prolong the gastric emptying time. Several techniques such as floating drug delivery system, low density systems, raft systems, mucoadhesive systems, high density systems, super porous hydro gels and magnetic systems, have been employed. This review on GRDDS attempts to compile the available information with all the possible mechanism used to achieve gastric retention.

Keywords

Delayed release tablet, Enteric coated, Ganscoater

INTRODUCTION

Tablets may be defined as a solid pharmaceutical dosage forms containing drug substances with or without suitable diluents and prepared either by compression or molding methods.
Controlled Release Tablets: Compressed tablets can be formulated to release the drug slowly over a prolonged period of time. Hence, these dosage forms have been referred to as prolonged release or sustained release dosage forms as well1. These tablets (as well as capsule version) can be categorized in to three types:
(1) Those that respond to some physiological condition to release the drug, such as enteric coatings;
(2) Those that release the drug in a relatively steady, controlled manner; and
(3) Those that combine combinations of mechanisms to release pulses of drug, such as repeat action tablets.
Enteric Coatings: Enteric coatings are those, which remain intact in the stomach, but will dissolve and release the contents once it reaches the small intestine2. Their prime intension is to delay the release of drugs, which are inactivated by the stomach contents or may cause nausea or bleeding by irritation of gastric mucosa. Cracking of the film either during application or on storage will result in a loss of enteric properties. Therefore, consideration must be given to the mechanical properties of the applied film. General rule to follow is to use 1 part plasticizer to 10 parts polymer. One should also consider viscosity of the plasticizer, its influence on the final coating solution, its effect on film permeability, tackiness, flexibility, solubility and taste and its toxicity, compatibility with other coating solution components and stability of the film and the final coated product3.

GASTRO-RESISTANT/DELAYED RELEASE DOSAGE FORMS

Gastro-resistant tablet dosage form is intended to release a drug after some time that is delay or after the tablet has passed through one part of the GI tract in to another. “Delayed-release dosage forms are modified-release dosage forms showing a release of the active substance(s) that is delayed4. Entericcoated dosage forms are designed to resist the acidic environment of the stomach and to disintegrate in the higher pH environment of the intestinal fluid. Proton pump inhibitors, H2 blockers, some NSAIDs, insulin delivery etc are suitable candidates for developing delayed release dosage forms.
· Products indicated for the treatment of GERD/PUD diseases dominate the global GI market, valued at $27.8bn in 2006 and it is expected to be the fastest growing therapeutic area within the GI market, with a forecast of 14.0% over the 2006-12 period5
· Reported revenue for GI disorders $49.9bn in 20076
· The global GI market is dominated by the proton pump inhibitor class (PPI), which accounted for $24,157m of sales in 2006 or 51.7% of the market5.
· Proton pump inhibitors ranked second in USA, with prescription sales of $14.1 billion and growth of 2.8 percent in 20077.

Advantages of DR formulation8

· Some drugs are irritating to gastric mucosa when directly exposed to gastric mucosa. (eg. Aspirin, NH4Cl)
· It minimizes nausea, bleeding associated with those drugs that irritates gastric mucosa.
· Deliver drug intended for local action in intestines.
· Deliver drugs that are optimally absorbed in small intestine to primary absorption site.
· Delayed release components for repeat action tablets.

INTRODUCTION TO GASTROESOPHAGEAL REFLUX DISEASE9, 10

Pathophysiology

GERD is caused by a failure of the cardia. In healthy patients, the “Angle of His”- the angle at which the esophagus enters the stomach—creates a valve that prevents duodenal bile, enzymes and stomach acid from traveling back into the esophagus where they
can cause burning and inflammation of sensitive esophageal tissue.
Another paradoxical cause of GERD-like symptoms is not enough stomach acid (hypochlorhydria). The valve that empties the stomach into the intestines is triggered by acidity. If there is not enough acid, this valve does not open and the stomach contents are churned up into the esophagus. However, there is still enough acidity to irritate the esophagus.

Factors that can contribute to GERD

· Hiatus hernia, which increases the likelihood of GERD due to mechanical and motility factors.
· Obesity: increasing body mass index is associated with more severe GERD.
· Zollinger-Ellison syndrome, which can be present with increased gastric acidity due to gastrin production.
· Hypercalcemia, which can increase gastrin production, leading to increased acidity.
Scleroderma and systemic sclerosis, which can feature esophageal dysmotility.
· Obstructive sleep apnea
· Gallstones, which can impede the flow of bile into the duodenum, which can affect the ability to neutralize gastric acid.

Drug treatment9, 10, 11

A number of drugs are prescribed for GERD treatment and they are among the most oftenprescribed forms of medication in most Western countries. They can be used in combination with other drugs, although some antacids can interfere with the function of other drugs:
· Proton pump inhibitors (such as omeprazole, pantoprazole, lansoprazole and rabeprazole) are the most effective in reducing gastric acid secretion. These drugs stop acid secretion at the source of acid production, i.e., the proton pump.
· Gastric H2 receptor blockers (such as ranitidine, famotidine and cimetidine) can reduce gastric secretion of acid. These drugs are technically antihistamines. They relieve complaints in about 50% of all GERD patients.
· Antacids before meals or symptomatically after symptoms begin can reduce gastric acidity (increase pH).
· Alginic acid (Gaviscon) may coat the mucosa as well as increase pH and decrease reflux. A metaanalysis of randomized controlled trials suggests alginic acid may be the most effective of nonprescription treatments.
· Prokinetics strengthen the lower esophageal sphincter (LES) and speed up gastric emptying. Cisapride, a member of this class, was withdrawn from the market for causing long QT syndrome.
· Sucralfate (Carafate) is also useful as an adjunct in helping to heal and prevent esophageal damage caused by GERD, however it must be taken several times daily and at least two (2) hours apart from meals and medications.
· Mosapride citrate is a 5-HT4 receptor agonist used outside the United States largely as a therapy for GERD and dyspepsia.

ENTERIC POLYMERS

There are considerable differences in polymers used in conventional (non-functional) coating and one intended to give a modified release performance on the dosage form. Enteric polymers are designed to resist the acidic nature of the stomach contents, yet dissolve readily in the duodenum. The mechanism by which enteric coating polymers function is by a variable pH solubility profile where the polymer remains intact at a low pH but at a higher pH will undergo dissolution to permit the release of the contents of the dosage form12.

Mechanism of drug release from enteric coating13

All enteric polymers posses ionizable acid groups, usually a free carboxylic acid from a phthalyl moiety. The equilibrium between unionized insoluble polymer and ionized soluble polymer will be determined by the pH of the medium and the pKa of the polymer. The Henderson-Hasselbach equation can be used to predict the ratio of ionized to unionized polymer based on these two parameters, i.e.
image

Factors to be considered while selecting enteric polymer14

1) Polymer backbone and pKa
2) Plasticizers and opacifiers
3) Quantity/thickness of the enteric coating
4) Effect of film stability on enteric behavior of formulation
5) Coating process.

Ideal requirements for enteric polymers15, 16

· Resistance to gastric fluids.
· Ready susceptibility to or permeable to intestinal fluid.
Compatibility with most coating solution components and drug substance.
· Stable alone and in coating solution. The film should not change on aging.
· Formation of a continuous film.
· Low cost and non toxicity.
· Ease of application without specialized equipment.
· Ability to be readily printed or to allow film to be applied to debossed tablet

Various enteric coating polymers17

1) Cellulose acetate phthalate
2) Polyvinyl acetate phthalate
3) Shellac
4) Methacrylic acid copolymers
5) Cellulose acetate trimellitate
6) Hydroxypropyl methylcellulose phthalate

Preformulation studies19

Angle of Repose

Angle of repose is the maximum angle that can be obtained between the free standing surfaces of the powder heap and the horizontal plane. It is a characteristic related to the interparticulate friction or resistance to movement between particles. The method used to find the angle of repose is to pour the powder in the form of a conical heap on a flat surface and measure the inclined angled with the horizontal pile20
Tan L = h/r
L = tan-1(h/r)
Where h = height of the heap
r = radius of the heap

Bulk density21

Bulk density is given by the mass “m” of the powder occupying a known volume “v” according to the relationship
Pb = (m/v) g/cc
It depends on particle size, shape, tendency of particle to adhere.
Tapped density
Weighed powder sample was transferred to a graduated cylinder and was placed on tapped density apparatus, was operated for a fixed number of taps (100). It is ratio of weight of sample to tapped volume22.
Tapped density = mass Tapped volume

Carr’s index

Based on the apparent bulk density and the tapped density, the percentage compressibility of the bulk drug was determined by using the following formula23.
Compressibility Index (%) = Tapped density – Bulk density X 100 Tapped density

Hausner’s ratio

The ratio of tapped density to bulk density of the powder is called the hausner ratio. Hausner ratio = Tapped density Bulk density

Drug/Excipient compatibility study25

The objective of drug/excipient compatibility considerations and practical studies is to delineate, as quick as possible, real and possible interactions between potential formulation excipients and the active pharmaceutical excipient26. Homogeneous mixtures of drug and excipients were prepared and filled in glass vials and self-seal LDPE (Low density Poly Ethylene) bags. The glass vials were maintained at 60± 2o C for 2 weeks. Those packed LDPE bags were maintained at 40±20 C/75± 5% RH for 1 month. Controlled conditions (2-80 C) maintained for comparison purpose.

Evaluation of core tablets

Hardness test

Hardness tester was used for the determination of hardness of the tablets

Thickness and diameter27

Thickness and diameter of the tablet were recorded during the process of compression using vernier calipers

Friability

10 tablets were accurately weighed and placed in the friabilator and operated for 100 revolutions. The tablet were dedusted and reweighed. The tablets that loose less than 1% weight were considered to compliant29.

Weight variation30

10 tablets were selected randomly from the 10% and weighed individually to check for weight variation.

Disintegration test31

Tablets were taken and introduced one tablet in each tube of disintegration apparatus and placed in 1 liter beaker and the time of disintegration was recorded. The study was done at room temperature.

Dissolution studies33

The in-vitro dissolution study was carried out in the USP dissolution (Electro lab) paddle type. 900ml of the dissolution medium was taken and the temperature was maintained at 37±0.5oc. The speed of paddle was set at 100rpm. Sampling was done at regular intervals. For each sample 10ml of the dissolution medium was withdrawn and same amount was replaced. The sample was filtered and diluted with dissolution medium and then analyzed in UV-spectrophotometer. The absorbance was measured at specified Smax and % drug release was calculated34

In-vitro drug release for enteric coated tablets35

Drug release studies were carried out using a USP type II dissolution test apparatus at 100rpm for 2hr in 0.1N HCL (900ml) maintained at 37±0.5oc. 10ml of sample was taken and sample was analyzed using UV-spectrophotometer at 260nm38. Then the dissolution medium was replaced with 0.6M tris buffer, pH 8.0 (900ml) and tested for drug release for 1 hr at same temperature and rotation speed. After 10, 20, 30, and 45mts, 10ml of the samples were taken out and 10ml volume of fresh tris buffer pH 8.0 was added to kept volume of dissolution medium constant and sample was analyzed using UV spectrophotometer at Smax 39.

Accelerated stability studies of the optimized batch40

In order to determine the change in evaluation parameters and in-vitro release profile on storage, stability study of optimized batch was carried out at accelerated storage condition at temperature 40oC 75% RH in a humidity chamber for 3 months. Sample were withdrawn after one week interval and evaluated for change in in-vitro drug release pattern, impurities.

Conflict of Interest

NIL

Source of Support

NONE

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