INTRODUCTION:

The novel system of drug delivery offer a means of improving the therapeutic effectiveness of incorporated drugs by providing sustained, controlled delivery and / or targeting the drug to desired site. The goal of any drug delivery system is to provide a therapeutic amount of drug to the proper site in the body to achieve promptly and then maintain the desired drug concentration.

Controlled drug delivery systems, which release the drug in continuous manner by both dissolution controlled as well as diffusion controlled mechanisms. To control the release of the drugs, which are having different solubility properties, the drug is dispersed in swellable hydrophilic substances, an insoluble matrix of rigid non swellable hydrophobic materials or plastic materials. Most of drugs, conventional methods of drug administration are effective, but some drugs are unstable or poisonous and have narrow therapeutic ranges. Several drugs also possess solubility problems. In such cases, a technique of continuous administration of therapeutic agent is desirable to sustain fixed plasma levels as shown in Fig.

Sustained release tablets and capsules are commonly taken only once or twice daily, compared with counterpart conventional forms that may have to take three or four times daily to achieve the same therapeutic effect. Sustained release products provide an immediate release of drug that promptly produces the desired therapeutic effect, followed by gradual release of additional amounts of drug to maintain this effect over a predetermined period. Introduction of matrix tablet as sustained release (SR) has given a new break through for novel drug delivery system (NDDS) in the field of Pharmaceutical technology. It is usually supplied in micronized forms because small particle size is critical to the rapid formation of gelatinous layer on the tablet surface. It excludes complex production procedures such as coating and pelletization during manufacturing and drug release rate from the dosage form is controlled mainly by the type and proportion of polymer used in the preparations. Hydrophilic polymer matrix is widely used for formulating an SR dosage form. concentration of the drug in the body remains constant, two conditions must be fulfilled, namely 1) The zero order rate of drug release must determine the absorption rate of the drug, and 2) The rate at which the drug is released from maintenance dose (and subsequently the absorption rate) should be equal to the rate of drug elimination at the required steady-state concentration a list of important terms that describe different modified release dosage forms are defined below.

1. Modified release dosage forms:

Those dosage forms whose drug release characteristics of time course and/or location are chosen to accomplish therapeutic and/or convenience objectives not offered by conventional dosage forms.

2. Controlled release

The drug is released at a constant (zero order) rate and the drug concentration obtained after administration is invariant with time.

3. Delayed release:

The drug is released at a time other than immediately after administration.

4. Extended release:

Slow release of the drug so that plasma concentrations are maintained at a therapeutic level for a prolonged period of time usually between 8 and 12 hours.

5. Prolonged release:

The drug is provided for absorption over a longer period of time than from a conventional dosage form. However, there is an implication that onset is delayed because of an overall slower release rate from the dosage form.

6. Repeat action:

Indicates that an individual dose is released fairly soon after administration, and second or third doses are subsequently release that intermittent intervals.

7. Sustained release:

The drug is released slowly at a rate governed by the delivery system.

Oral Sustained Release dosage form:

Sustained release, sustained action, prolong action, controlled release, extended action, depot are terms used to identify drug delivery systems that are designed to achieve prolong therapeutic effect by continuously releasing medication over an extended period of time after administration of single dose.

Advantages of Controlled Drug Delivery System:^[4,5]

1. Maintains therapeutic concentrations over prolonged periods.

2. Avoids the high blood concentration.

3. Reduction in toxicity by slowing drug absorption.

4. Minimize the local and systemic side effects.

5. Improvement in treatment efficacy.

6. Minimize drug accumulation with chronic dosing .

Disadvantages of Matrix Tablets:^[4,5]

1. The remaining matrix must be removed after the drug has been released.

2. Greater dependence on GI residence time of dosage form.

3. Increased potential for first-pass metabolism.

4. Delay in onset of drug action.

5. Release rates are affected by food and the rate transit through the gut.

Drug Selection for Oral Sustained Release Drug Delivery System:^[6,7,8]

The biopharmaceutical evaluation of a drug for potential use in controlled release drug delivery system requires knowledge on the absorption mechanism of the drug form the G. I. tract, the general absorbability, the drug’s molecular weight, pKa, solubility at different pH and apparent partition coefficient.

Table 1: Parameter for Drug Selection

Parameter

Preferred value

1 Molecular Weight / Size

2 Solubility

3 Pka

4 Apparent partition coefficient

5 Absorption Mechanism

6 Absorbability

7 Release

< 1000

>0.1um / ml for pH 1 to 7.8

Non ionized moiety > 0.1% at pH 1 to 7.8

High

Diffusion

From all G.I.Segments

Should not be influenced by pH and Enzyme

Table No 2:Pharmacokinetic Parameter for Drug Selection

parameter

Preferred Value

1 Elimination half life

2Total Clearance

3 Elimination rate constant

4 Apparent volume of distribution Vd

5 Absolute bioavailability

6 Intrinsic absorption rate

7 Therapeutic concentration

8 Toxic concentration

Preferably between 0.5 and 8 hrs

Should not be dose dependent

Required for design

The larger Vd and MEC, the larger will be the required dose size

Should not be 75% or more

Must be greater than release rate

The lower and smaller Vd, the loss among the drug required

Apart the values of MTC and MEC, safer the dosage form.

Polymers used in Matrix tablets:^[9,10,11]

a) Hydrogels:

Polyhydroxyethylemethylacrylate (PHEMA), Cross-linked polyvinyl alcohol (PVA), Cross linked polyvinyl pyrrolidone (PVP), Polyethylene oxide (PEO), Polyacrylamide (PA).

b) Soluble polymers:

Polyethylene glycol (PEG), polyvinyl alcohol (PVA), Polyvinylpyrrolidone (PVP), Hydroxypropyl methyl cellulose (HPMC).

c) Biodegradable polymers:

Polylactic acid (PLA), Polyglycolic acid (PGA), Polycaprolactone (PCL), Polyanhydrides, Polyorthoesters

d) Non-biodegradable polymers:

Polyethylene vinyl acetate (PVA), Polydimethylsiloxane (PDS), Polyether urethane (PEU), Polyvinyl chloride (PVC), Cellulose acetate (CA), Ethyl cellulose (EC)

e) Mucoadhesive polymers:

Polycarbophil, Sodium carboxymethyl cellulose, Polyacrylic acid, Tragacanth, Methyl cellulose, Pectin

f) Natural polymers in sustained release drug delivery

Xanthan Gum, Guar Gum, Sodium Alginate, Pectin, Chitosan

Table 3: Different Drug And Polymer Used In Sustained Release Matrix Tablet

Drug

Polymer

1 Metoclopramide Hydrochloride

2 Ibuprofen

3 Metoprolol Succinate

4 Amroxol Hydrochloride

5 Tramadol Hydrochloride

6 Aceclofenac

Hydroxy Propyl Methyl Cellulose (HPMC)

Carboxymethylcellulose (CMC)

Ethyl Cellulose(EC)

Ethyl Cellulose, Cellulose acetate pthallate

HPMCK100M, Xantham gum, HPMC

HPMC

Carrageenan gum, Karaya gum, HPMC15.

Carbopol 971P, Carbopol

Design And Formulation Of Oral Suatained Release Drug Delivery System:^[`11,12]

The oral route of administration is the most preferred route due to flexibility in dosage form, design and patient compliance. But here one has to take into consideration, the various pH that the dosage form would encounter during its transit, the gastrointestinal motility, the enzyme system and its influence on the drug and the dosage form. The majority of oral sustained release systems rely on dissolution, diffusion or a combination of both mechanisms, to generate slow release of drug to the gastrointestinal milieu. Theoretically and desirably a sustained release delivery device, should release the drug by a zero-order process which would result in a blood level time profile similar to that after intravenous constant rate infusion. Sustained (zero-order) drug release has been attempted to be achieved with various classes of sustained drug delivery system

1. Diffusion sustained system.

i) Reservoir type.

ii) Matrix type.

2. Dissolution sustained system.

i) Reservoir type.

ii) Matrix type.

3. Methods using Ion-exchange.

4. Methods using osmotic pressure.

5. pH independent formulations.

6. Altered density formulations.

1. Diffusion Sustained System:

Basically diffusion process shows the movement of drug molecules from a region of a higher concentration to one of lower concentration. The flux of the drug J (in amount / area -time), across a membrane in the direction of decreasing concentration is given by Fick‟s law.

J= - D dc/dx.

D = diffusion coefficient in area/ time

dc/dx = change of concentration 'c' with distance 'x'

In common form, when a water insoluble membrane encloses a core of drug, it must diffuse through the membrane. The drug release rate dm/ dt is given by.

dm/ dt= ADKΔ C/L

Where; A = Area.

K = Partition coefficient of drug between the membrane and drug core

L= Diffusion path length (i.e. thickness of coat)

Δc= Concentration difference across the membrane.

i) Reservoir Type:

In the system, a water insoluble polymeric material encases a core of drug. Drug will partition into the membrane and exchange with the fluid surrounding the particle or tablet. Additional drug will enter the polymer, diffuse to the periphery and exchange with the surrounding media.

Figure: Diffusion sustained drug release: reservoir system

Description:

Drug core surrounded by polymer membrane which controls release rate.

Advantages:

Zero order delivery is possible, release rates variable with polymer type.

Disadvantages:

System must be physically removed from implant sites. Difficult to deliver high molecular weight compound, generally increased cost per dosage unit, potential toxicity if system fails.

ii) Matrix Type:

A solid drug is dispersed in an insoluble matrix and the rate of release of drug is dependent on the rate of drug diffusion and not on the rate of solid dissolution.

Higuchi has derived the appropriate equation for drug release for this system

Q = Dε/ T [2 A –εCs] Cst½

Where; Q = Weight in gms of drug released per unit area of surface at time t.

D = Diffusion coefficient of drug in the release medium.

ε = Porosity of the matrix.

Cs = Solubility of drug in release medium.

T= Tortuosity of the matrix.

A = Concentration of drug in the tablet, as gm/ ml.

Description:

Homogenous dispersion of solid drug in a polymer mixture.

Advantages:

Easier to produce than reservoir or encapsulated devices, can deliver high molecular weight compounds.

Disadvantages:

Cannot provide zero order release, removal of remaining matrix is necessary for implanted system. Diffusional mechanism is the system where a partially soluble membrane encloses a drug core. Dissolution of part of membrane allows for diffusion of the constrained drug through pores in the polymer coat. The release rate can be given by following equation.

Release rate = AD / L = [C1- C2]

Where;

A = Area.

D = Diffusion coefficient.

C1 = Drug concentration in the core.

C2 = Drug concentration in the surrounding medium.

L = Diffusional path length.

Thus diffusion sustained products are based on two approaches the first approach entails placement of the drug in an insoluble matrix of some sort. The eluting medium penetrates the matrix and drug diffuses out of the matrix to the surrounding pool for ultimate absorption. The second approach involves enclosing the drug particle with a polymer coat. In this case the portion of the drug which has dissolved in the polymercoat diffuses through an unstirred film of liquid into the surrounding fluid.

2. Dissolution Sustained Systems:

A drug with a slow dissolution rate is inherently sustained and for those drugs with high water solubility, one can decrease dissolution through appropriate salt or derivative formation. These systems are most commonly employed in the production of enteric coated dosage forms. To protect the stomach from the effects of drugs such as Aspirin, a coating that dissolves in natural or alkaline media is used. This inhibits release of drug from the device until it reaches the higher pH of the intestine. In most cases, enteric coated dosage forms are not truly sustaining in nature, but serve as a useful function in directing release of the drug to a special site.

i) Reservoir Type:

Drug is coated with a given thickness coating, which is slowly dissolved in the contents of gastrointestinal tract. By alternating layers of drug with the rate controlling coats as shown in figure, a pulsed delivery can be achieved. If the outer layer is quickly releasing bolus dose of the drug, initial levels of the drug in the body can be quickly established with pulsed intervals. Although this is not a true sustained release system, the biological effects can be similar. An alternative method is to administer the drug as group of beads that have coating of different thickness. The maintenance of drug levels at late times will be achieved from those with thicker coating.

ii) Matrix Type:

These are common type of dissolution sustained dosage form. It can be either a drug impregnated sphere or a drug impregnated tablet, which will be subjected to slow erosion. Two types of dissolution sustained pulsed delivery systems.

· Single bead type device with alternating drug and rate-controlling layer.

· Beads containing drug with differing thickness of dissolving coats.

Amongst sustained release formulations, hydrophilic matrix technology is the most widely used drug delivery system due to following advantages.

· Provide desired release profiles for a wide therapeutic drug category, dose and solubility.

· Simple and cost effective manufacturing using existing tableting unit operation equipment.

· Broad regulatory and patient acceptance.

3. Methods Using Ion Exchange:

It is based on the formation of drug resin complex formed when aionic solution is kept in contact with ionicresins. The drug from these complexes gets exchanged in gastrointestinal tract and released with excess of Na+ and Cl- present in gastrointestinal tract.

Anion Exchangers:

Resin+ - Drug- + Cl- goes to Resin+- Cl-+ Drug-

Cation Exchangers:

Resin-- Drug+ + Na+ goes to Resin- - Na+ + Drug+

These systems generally utilize resin compounds of water insoluble cross linked polymer. They contain salt forming functional group in repeating positions on the polymer chain. The release rate can be further sustained by coating the drug resin complex by microencapsulation process.

4. Methods Using Osmotic Pressure:

A semi permeable membrane is placed around a tablet, particle or drug solution that allows transport of water into the tablet with eventual pumping of drug solution out of the tablet through a small delivery aperture in tablet coating.

Two types of osmotically sustained systems are:

Type A contains an osmotic core with drug.

Type B contains the drug in flexible bag with osmotic core surrounding.

5. pH– Independent Formulations:

The gastrointestinal tract present some unusual features for the oral route of drug administration with relatively brief transit time through the gastrointestinal tract. Since most drugs are either weak acids or weak bases, the release from sustained release formulations is pH dependent. A buffered sustained release formulation is prepared by mixing a basic or acidic drug with one or more buffering agent, granulating with appropriate pharmaceutical excipients and coating with gastrointestinal fluid permeable film forming polymer. When gastrointestinal fluid permeates through the membrane, the buffering agents adjust the fluid inside to suitable constant pH thereby rendering a constant rate of drug release.

CLASSIFICATION OF MATRIX TABLETS:

On the Basis of Retardant Material Used:

1. Hydrophobic Matrices (Plastic matrices):^[16]

In this method of obtaining sustained release from an oral dosage form, drug is mixed with an inert or hydrophobic polymer and then compressed in to a tablet. Sustained release is produced due to the fact that the dissolving drug has diffused through a network of channels that exist between compacted polymer particles. Examples of materials that have been used as inert or hydrophobic matrices include polyethylene, polyvinyl chloride, ethyl cellulose and acrylate polymers and their copolymers. The rate-controlling step in these formulations is liquid penetration into the matrix. The possible mechanism of release of drug in such type of tablets is diffusion. Such types of matrix tablets become inert in the presence of water and gastrointestinal fluid.

2. Lipid Matrices:

These matrices prepared by the lipid waxes and related materials. Drug release from such matrices occurs through both pore diffusion and erosion. Release characteristics are therefore more sensitive to digestive fluid composition than to totally insoluble polymer matrix. Carnauba wax in combination with stearyl alcohol or stearic acid has been utilized for retardant base for many sustained release formulation.

3. Hydrophilic Matrices:

Hydrophilic polymer matrix systems are widely used in oral controlled drug delivery because of their flexibility to obtain a desirable drug release profile, cost effectiveness, and broad regulatory acceptance. The formulation of the drugs in gelatinous capsules or more frequently, in tablets, using hydrophilic polymers with high gelling capacities as base excipients is of particular interest in the field of controlled release. Infect a matrix is defined as well mixed composite of one or more drugs with a gelling agent (hydrophilic polymer). These systems are called swellable controlled release systems.

4. Biodegradable Matrices:

These consist of the polymers which comprised of monomers linked to one another through functional groups and have unstable linkage in the backbone. They are biologically degraded or eroded by enzymes generated by surrounding living cells or by non enzymetic process in to oligomers and monomers that can be metabolized or excreted. Examples are natural polymers such as proteins and polysaccharides; modified natural polymers; synthetic polymers such as aliphatic poly (esters) and poly anhydrides.

5. Mineral Matrices:

These consist of polymers which are obtained from various species of seaweeds. Example is Alginic acid which is a hydrophilic carbohydrate obtained from species of brown seaweeds (Phaephyceae) by the use of dilute alkali.

Methods of preparation of Matrix Tablet:^[13]

1.Direct Compression:

In this process powdered materials are compressed directly without changing the properties of the drug like physical and chemical properties.

2.Wet Granulation:

In this method weighed quantities of drug and polymer are mixed with sufficient volume of granulating agent. After enough cohesiveness was obtained, then screening of wet mass. The granules are dried and screening of dry granules, then blending with lubricant and disintegrant to produce “running powder” tablets are compressed using a single-punch tablet compression machine.

3.Melt Granulation:

In this process use of a substance, which melts at relatively low temperature. This substance can be added in the molten form over the substrate, which is then heated above its melting point. Different lipophilic binders were tried by using melt granulation technique.

4.Hot-Melt Extrusion Process:

In the hot-melt extrusion process, a mixture of the active ingredients, the thermoplastic polymers and other processing aids is fed into the barrel of the extruder through the hopper. The materials are transferred inside the heated barrel by a rotating screw. The materials melt at elevated temperatures and the molten mass is continuously pumped through the die attached at the end of the barrel. Depending upon the dimensions of the die cylinders, films can also be produced from the extruder.

Evaluation of Sustained release Matrix tablets:^[14,15]

Before marketing a sustained release product, it is must to assure the strength, safety, stability and reliability of a product by forming in-vitro and in vivo analysis and correlation between the two. Various authors have discussed the evaluating parameters and procedures for sustained release formulations.

• Weight Variation:

Twenty tablets were weighed individually and then collectively, average weight of the tablets was calculated.

• Hardness:

Hardness test was conducted for tablets from each batch using Monsanto hardness tester and average values were calculated

• Friability:

The tablets were tested for friability testing using Roche friabilator, which revolves at 25rpm for 4min.

• Thickness:

The thicknesses of tablets were determined using micrometer screw gauge.

• Content Uniformity:

Using UV Visible spectrophotometer found the amount of the drug using the calibration curve method.

• Kinetic Studies:

• In Vitro Dissolution Study:

Drug release study is generally determined in Rotating Paddles apparatus. Mainly buffer is used as a dissolution medium. The temperature of the bath maintained at 37⁰C and required sample of the dissolution medium in which drug is release is taken at a regular interval and the same quantity of the medium is replace. The amounts of the drug released is determined using an UV spectrophotometer a Drug dissolved at specified time period is plot as percent release versus time.

• Stability Studies:

Short Term Stability Study: To determine change in vitro release profile on storage, a short term stability study of the optimal batch.

• In–Vivo Methods:

Once the satisfactory in-vitro profile is achieved, it becomes necessary to conduct in-vivo evaluation and establish in-vitro in-vivo correlation. The various in-vivo evaluation methods are:-

• a. Clinical response

• b. Blood level data

• c. Urinary excretion studies

• d. Nutritional studies.

• e. Toxicity studies

• f. Radioactive tracer techniques

CONCLUSION:

The aim of this review article has been on the formulation of sustained-release matrix tablet, advantages and disadvantages and various polymer used to design such dosage form. Above discussion concludes that many oral delivery problems like drug fluctuation in plasma levels, low bioavailability, patient compliance and more frequent dose administration. So matrix tablet can overcome the above problems of conventional oral drug delivery. It can easily concluded that sustained-release formulation are helpful in increasing the efficiency of the dose as well as they are also improving the patient’s compatibility matrix forming polymer can be successfully used to prepare Matrix tablet, releasing drug in a controlled manner.

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Received on 17.02.2016 Modified on 15.03.2016

Res. J. Pharm. Dosage Form. and Tech. 2016; 8(2):154-160.

DOI: 10.5958/0975-4377.2016.00020.3