A BRIEF REVIEW ON SUSTAINED RELEASE MATRIX TABLETS OF BACLOFEN

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MATRIX SYSTEM:5
The matrix system is most often used for a drug-controlled release from a pharmaceutical dosage form. Among the innumerable method used in controlled release drug from pharmaceutical dosage form, the matrix system is the most frequently applied; it is release system for delay and control of the release of the drug that is dissolved or dispersed in a resistant supports to disintegration. To define matrix, it is necessary to know the characters that differentiate it from other controlled release dossage forms. Hence the following must be considered:
- The chemical nature of support (generally, the support are formed by polymeric net)
- The physical state of drug (dispersed under molecular or particulate form or both)
- The matrix shape and alteration in volume as a function of time.
- The route of administration (oral administration remains the most widely used but other route are adaptable)
- The release kinetic model.

The classification of matrix system:
Mineral matrix:

Drug retained in the support.
Drug adsorbed on the support.

Lipidic matrix:
Delivery by diffusion.
Delivery by surface erosion.

Hydrophillic matrix:
Unlimited swelling, delivery by diffusion.
Limited swelling controlled delivery through swelling.

Inert matrix:
Controlled delivery by diffusion.

Biodegradable matrix:
Non-Lipidic.

ADVANTAGES OF MATRIX SYSTEM:
- The interest awakened by matrix system in last few years is completely justified in view of the major advantages. Among these, the following stand out.
- With proper control of manufacturing process, reproducible release profiles are possible.
- There is no risk of “dumping” of a large part of dose, through the structure makes the immediate release of a small amount of active principle unavoidable.
- Their capacity to incorporate active principle is large, which suits them to delivery of large dosage

PRINCIPAL OF MODIFIED DRUG RELEASE:
Following either of the two principles can modify drug release:

Barrier principal:                   
In this method the retardant material is imposed between the drug and elusion medium. Drug release is by diffusion of the drug through the barrier and /or erosion of the barrier or permeation of the barrier by moisture.

Figure1.1: Barrier mediated models of sustained release dosage form regimen

A. Barrier mediated models of sustained release dosage form regimen. Drug diffusion through the barrier, B.permeation of barrier by elution media followed by drug dissolution. C, Erosion of barrier releasing drug, D rupture of permeation of elution media.12

Embedded matrix:
In this drug is dispersed embedded in a matrix of retardant material that May be encapsulated in a particulate form or compressed into the tablet. Drug release occurs by permeation of water leaching extraction of diffusion of drug from the matrix and erosion of matrix material.

Figure1.2: Embedded matrix concept as a mechanism of controlled released in sustained release dosage form design network model

SWELLABLE MATRICES AS SYSTEM FOR ORAL DELIVERY:6
Monolithic devices or matrices represent a substantial part of drug delivery systems.

Matrices containing swellable polymers are referred to as-
- Hydrogel matrices
- Swellable control release systems.
- Hydrophillic matrix tablet

Swellable matrices for oral administration are commonly manufactured as tablet by compression of hydrophilic microparticulate polymers. Therefore, the most appropriate classification for these systems is swellable matrix tablets. They are constituted of a blend of drug and one or more hydrophilic polymers.

The release of drug from swellable matrix tablets is based on glassy-rubbery transition of polymer as a result of water penetration into the matrix. The interaction between water, polymer and drug are the primary factors for drug release.

However, various formulation variables such as polymer grade, drug –polymer ratio, drug solubility and drug and polymer particle size, can influence drug release rate to greater or lesser degree. The central element of the mechanism of drug release in the gel layer (rubbery polymer), which is formed around the matrix. The gel layer is capable of preventing matrix disintegration and further rapid water penetration.

Water penetration, polymer swelling, drug dissolution and diffusion and matrix erosion are phenomenon determining gel layer thickness. Finally drug release is controlled by drug diffusion through the gel layer and/or by erosion of the gel layer.

MECHANISM OF DRUG RELEASE FROM  MATRIX  DEVICES:
Dissolution controlled release:4

Sustained release oral products employing dissolution as the time limiting step are simplest to prepare. If a drug has a rapid rate of dissolution it is possible to incorporate it into a tablet with a carrier that has a slow rate of dissolution.

In the dissolution process if the dissolution process is diffusion layer control, the rate of diffusion of drug from the solid surface to the bulk solution through an unstirred liquid film, is the rate limiting step. In this case the dissolution process at steady state would be described by Noyes-Whitney equation

dc/dt = KDA (Cs-C)------------------(1)

Where,
dc/dtis dissolution rate.
KD dissolution rate constant.
Csis saturation solubility of drug.
C is the concentration of drug in bulk of the solution.

In relation to diffusion expression, that

KD = D/v*I  -----------------------(2)

Where,
D
is dissolution coefficient
V
volume of dissolution media
I
is the thickness of unstirred liquid film.

From the above expression it can be seen that the rate of dissolution i.e. availability is approx. proportional to the solubility of the drug in the dissolution media i.e. (Cs) provided a constant area and diffusional path length are maintained. This equation predicts constant dissolution rate as long as enough drug is present to maintain Cs constant, provided surface area does not change.

Dissolution control formulations are categories as
- Encapsulation dissolution control
- Matrix dissolution control

Figure1.3: Schematic representation of dissolution controlled release systems –(a) matrix system, and (b) coated/encapsulated system

Encapsulation dissolution control:
This method involves coating individual particles or granules of drug with slowly dissolving material. The coated particles can be compressed directly into tablet as in spacetabs or placed in capsule as in spansule products.

Matrix dissolution control:
This method involves compression pf the drug with a slowly dissolving carrier in a tablet form. Here the rate of drug availability is controlled by the rate of penetration of the dissolution fluid into the matrix. This in turn, can be controlled by porosity of the tablet matrix, the presence of hydrophilic and the wettability of the tablet and particle surface.

Diffusion controlled release:
These systems are of two types

Encapsulation diffusion control:
In this system water –insoluble polymeric material encases a core of drug. Drug will partition into the polymer membrane and exchange with the fluid surrounding the particle or tablet.

Figure1.4: Drug release of diffusion across the insoluble membrane of reservoir device

The rate of drug release is given by the equation.

dm/dt =Adkrc--------------------(3)

Where,

A is area

D is diffusion coefficient

K is the partition coefficient of the drug between the membrane and the drug core

I is the diffusional path length

Δc is the concentration difference across the membrane.

An important parameter in the above eq (3) is the partition coefficient, which is defined as the concentration of the drug in the membrane over the concentration if the drug in core.

Matrix diffusion control:

Figure1.5: Diffusion controlled devices – (a) rigid matrix, and (b) swellable matrix.

In this system, a solid drug is dispersed in lipophillic or a hydrophilic polymer matrix and the rate of release of drug depends on the rate of drug diffusion and not on the rate of solid dissolution.

MATERIAL USE AS RETARDANTS  IN MATRIX TABLET FORMULATION:7,8
These classes of retardant materials are used to prepare matrix tablet formulations.

Water insoluble inert materials:
e.g. polyethylene, polyvinyl chloride, methyl acrylate, methacrylate copolymer, ethyl cellulose.

Insoluble, erodable materials
e.g.Steryl alcohol, stearic acid, polyethylene glycol, carnauba wax, caster wax, polyethylene glycol monosterate, triglycerides.

Hydrophillic materials:
e.g. Hydroxy propyl methylcellulose, sodium CMC, methylcellulose, hydroxy ethyl cellulose.

Natural gums: Galactomannose (guargum), chitosan, gum acacia, locust bean gum, sodium alginate, karaya gum, pectins, xanthan gum.

Natural polymers:
e.g. Ispaghula husk, tamarind seed polymer.

ADVANTAGES OF HYDROPHILIC MATRIX TABLETS:
1. With proper control of the manufacturing process, reproducible release profiles are possible. The variability associated with them is slightly less than that characterizing coated release form
2. Structure allows an immediate release of small amount of active principle there is no risk of dose dumping.
3. Their capacity to incorporate active principle is large, which suits them to delivery of large doses.
4. The manufacturing processes are notably simple. Tablet formulation can be done via direct compression or by wet granulation techniques.
5. Large variety of nonexpensives gelling agents is approved for oral use by the competent official organization.
6. The safety margin of high-potency drugs can be increased.
7. The drug release from hydrophilic matrices show a typical time dependent profile i.e. decreased drug release with time because of increased diffusion path length.

FACTORS INFLUENCING THE DRUG RELEASE FROM MATRIX:
- Choice of matrix material.
- Amount of drug incorporated in the matrix.
- Viscosity of the hydrophilic material in aqueous system at a fixed concentration.
- Drug: matrix ratio
- Tablet hardness, porosity, and density variation.
- Entrapped air in tablets.
- Tablet shape and size.
- Drug particle size.
- Solubility of drug in aqueous phase
- Surfactants and other additives

TABLET MANUFACTURING METHODS:8
Tablets are manufactured by wet granulation, Dry granulation or direct compression method.

Wet Granulation
Wet granulation is the process in which a liquid is added to a powder in a vessel equipped with any type of agitation that will produce agglomeration or granules. These granules after drying are compressed to form tablets.

Dry Granulation
In this technique, there is no use of liquids. The process involves the formation of slugs. Then the slugs are screened or milled to produce granules. The granules formed are then compressed to form tablets.

Direct compression
The term direct compression is used to define the process by which tablets are compressed directly from powder blends of active ingredient and suitable excipients, which will flow uniformly in the die cavity & forms a firm compact.

DRUG PROPERTIES RELEVANT TO CONTROLLED RELEASE FORMULATION 9,10,11
The design of controlled - release delivery systems is subject to several variables of considerable importance. Among these are the route of drug delivery, the type of delivery system, the disease being treated, the patient, the length of therapy and the properties of the drug. Each of these variables are interrelated and this imposes certain constrains upon choices for the route of delivery, the design of the delivery system and the length of therapy. Properties of drugs are very important for designing a sustained release dosage form mainly physicochemical and biological properties of the drug are most important.

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