PRESENTED BY:

Mr. SOMNATH A. PATIL

M. Pharm 2nd semester

MAEER’S MAHARASHTRA INSTITUTE OF

PHARMACY, PUNE

INTRODUCTION

APPROACHES

EVALUATION

CONCLUSION

REFERENCES

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.

These are drug delivery system which possesses the

ability of retaining drug in GIT particularly in the

stomach for prolonged period of time .

After the drug release for required period the dosage

form should get degraded without causing any gastric

disturbances.

NEED FOR GASTRORETENTIVE DRUG DELIVERY SYSTEM

A controlled drug delivery system with prolonged residence time in the stomach is of particular interest for drugs which……..

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, the feeding state results

in a lag time prior to onset of gastric emptying.

Size of dosage form-better GRT is possessed by

1)Tetrahydron shaped devices

2)Single or multicomponent dosage form : The

multicomponent dosage form shows more effect comparing to

single dosage form.

Density

Food intake and nature of food-high meal is responsible

for GRT disturbance.

Age –elder people have significant larger GRT.

High density system

Floating systems

Expandable systems

Superporous hydrogels

Bioadhesive systems

Magnetic systems

Gastric contents have a density close to water (~1.004).

A density close to 2.5g/cm3 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.

Single-unit floating dosage system

Non effervescent systems

Effervescent (gas-generating) systems

Multiple-unit floating dosage system

Hollow microspheres

Raft-forming systems

Single-Unit Floating Dosage System

Noneffervescent Systems :

These systems contain one or more hydrocolloids and aremade into a single unit along with drug and other additives.

When comes in contact with water, the hydrocolloids at thesurface of the system swell and facilitate floating.

The coating forms a viscous barrier, and the inner polymerslowly gets hydrated as well, facilitating the controlled drugrelease. Such systems are called “hydrodynamicallybalanced systems (HBS)”.

The polymers used in this system includeshydroxypropylmethylcellulose,hydroxyethylcellulose,hydroxypropylcellulose, sodium carboxymethylcellulose,agar, carrageenans, and alginic acid.

GAS GENERATING SYSTEM

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.

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 ofmultiple-unit systems and better floating properties as aresult of the central hollow space inside the microsphere.

The general techniques involved in their preparation includesimple solvent evaporation and solvent diffusion andevaporation.

The drug release and better floating properties mainlydepend on the type of polymer, plasticizer, and solventemployed for the preparation.

Polymers such as polycarbonate, Eudragit S, and celluloseacetate 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 to float on the gastric fluids.

EXPANDABLE SYSTEM

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 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 or

bioreosion of polymer layer, enabling its elimination.

SUPERPOROUS HYDROGELS:

Swellable agents with pore size ranging between 10nm and

10µm, 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.

MUCOADHESIVE 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.

Polymer

Mucus membrane

MAGNETIC SYSTEM :

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.

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 totalanatomical structure in relatively high resolution.

The visualization of GI tract by MRI has to be furtherimproved by the administration of contrast media.

For solid DFs, the incorporation of a superparamagneticcompound such as ferrous oxide enables their visualizationby MRI.

Radiology (X-Ray):

In this technique a radio-opaque material has to beincorporated in the DF, and its location is tracked by X-raypicture.

ɣ-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

The buoyancy time & duration of buoyancy is

performed in u.s.p dissolution apparatus 2 in simulated

fluid & 0.1N HCL maintained at 37˚C environment.

Time interval between the introduction of tablet in

dissolution media. It s buoyancy to the dissolution media

was taken as buoyancy lag time.

Brand Name Active Ingredient(s)

Cifran OD ®

Madopar ®

Valrelease ®

Topalkan ®

Almagate FlatCoat ®

Liquid Gavison ®

ConvironCytotec®

Microcapsulesdrug located centrally withinthe particle, where it isencased within a uniquepolymeric membrane as adrug located centrally withinthe particle, where it isencased within a uniquepolymeric membrane

Microsphere

has its drug dispersed throughout the particle i.e. the internal structure is a matrix of drug and polymeric excipients

Microspheres can be defined as solid, approximately

spherical particles ranging in size from 1 to 1000 µm.

They are made from polymeric, waxy, or other

protective materials such as starches, gums, proteins,

fats and waxes and used as drug carrier matrices for

drug delivery. Natural polymers as albumin and gelatin

are also used in preparation of microspheres.

Controlled release delivery Biodegradable microspheres

are used to control drug release rates thereby decreasing

toxic side effects, and eliminating the inconvenience of

repeated injections.

Biodegradable microspheres have the advantage over

large polymer implants in that they do not require

surgical procedures for implantation and removal.

PLGA copolymer is one of the synthetic biodegradable

and biocompatible polymers that has reproducible and

slow-release characteristics in vivo .

1-Chitosan

2-Gelatine

3-Polyadipic anhydride

4-Gellan- gum

5-Polypeptide

6-Albumin

7-Poly lactic acid (PLA)

8-Poly lactic - co- glycolic acid (PLGA)

Microspheres prepared by using Calcium chloride

solution

Microspheres delivery system for theophylline using

emulsification solvent diffusion system .

Chitosan microcapsule containing theophylline &sodium

carboxy methyl cellulose prepared by emulsion phase

separation method.

Clarithromycin floating beads prepared by emulsion

gelation methods .

Microspheres have been prepared by three basic

methods as well as other modified methods:

Solvent extraction / evaporation method (single and

double emulsification)

Co acervation or phase separation.

Spray drying.

Modified methods.

Oil phase (polymer + solvent) is injected into the

aqueous phase (water + surfactant), the solvent dissolves

into the aqueous phase and evaporates at the air-liquid

interface.

This method was successfully used for numerous of

water insoluble and slightly soluble drugs encapsulated

in microspheres such as lidocaine,lurbiprofen, all-trans

retinoic acid and testosterone.

The micro particulate carriers of natural polymers i.e.,

those of proteins and carbohydrates prepared by single

emulsion technique. The natural polymers are dissolved or

dispersed in aqueous medium followed by dispersion in

non-aqueous medium e.g.., oil.

In the second step of preparation cross-linking of the

dispersed globule is carried out. The cross linking can be

achieved either by means of heat or by using the chemical

crosslinkers.

Involves the formation of the multiple emulsions and is

best suited to the water-soluble drugs, peptides, proteins

and the vaccines. The aqueous protein solution is

dispersed in a lipophilic organic continuous phase. This

protein solution may contain the active constituents..

The primary emulsion is then subjected to the

homogenization or the sonication before addition to the

aqueous solution of the polyvinyl alcohol (PVA).

e.g. proteins/peptides are conventional molecule are

successfully incorporated in to the microspheres.

This method is based on dispersion of drug as solid or

organic solution in organic polymeric solution, then

addition of the second solvent in which the polymer is

insoluble where phase separation occurs and polymer

loaded with drug precipitate as microspheres.

BSA is an example prototype for this method.

In this technique the drug and polymer are mixed in a

solvent system, then the solvent is evaporated by

spraying the solution leaving the polymeric particles

loaded with the drug.

This method generates heat so it is not suitable for heat

sensitive drugs.

e.g. Fluconazole and tetracycline hydrochloride.

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.

Vyas SP Khar RK.gastroretentive system ,in; controlled drug

delivery Vallabh Prakashan ,Delhi India .2006 p.197-217

Chawla G, Gupta P, Bansal AK. Gastroretentive drug

delivery systems. In: Jain NK. editor. Progress in

controlled and novel drug delivery systems. CBS

Publishers and Distributors. New Delhi. 2004. p. 76-97.

Encyclopedia of Pharmaceutical Technology..

Julan UD. Floating Drug Delivery System: 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.

Bhaskara R.jasti ,design of controlled release drug

delivery system ,M graw hill chemical engineering page

number 173-223.

AV Mayavanshi &SS gajjar ,floating drug delivery

system to increase gastric retention time of drug ;A

Review 2008