INTRODUCTION:

With many drugs, the basic goal of therapy is to achieve a steady –state blood or tissue level that is therapeutically effective and non toxic for an extended interlude of time. The proper dosage regimen design is an imperative element in accomplishing this goal. A basic concept in dosage form design is to optimize the delivery of medication so as to achieve a measure control of the therapeutic effect in the face of tentative fluctuations in the in vivo environment in which drug release takes place.¹ Oral route is the oldest, predominant and expedient route for the administration of therapeutic agents because of low cost of therapy and ease of administration leads to higher level of patient compliance. Approximately 50% of the drug delivery systems available in the market are oral drug delivery systems and historically too.²

It does not pose the sterility problem and minimal risk of damage at the site of administration.^{3, 4} The oral controlled release formulation have been developed for those drug that are easily absorbed from the gastrointestinal tract and have a short half-life are eliminated quickly from the blood circulation.⁵

The sustained action, sustained release, controlled release, prolonged action extended action, timed release, depot and respiratory dosage forms are terms used to identify drug delivery system that are designed to achieve a prolonged therapeutic effect by continuously releasing medication over an extended period of time after administration of a single dose.⁶

Table 1: Frequency distribution of manufactured dosage form types.

Dosage form	Frequency (%)
Tablets	46
Liquid oral	16
Capsule	15
Injections	13
suppositories	3
Topical	3
Eye preparations	2
Aerosols	1
Others	1

The USP /NF presently recognize several type of modified-release dosage forms as:

1. Oral Dosage Forms – Modified release dosage forms, extended release e.g. sustained release, controlled release, and prolonged release, Delayed release e.g. enteric-coated tablets.

2. Intramuscular Dosage Forms - Depot injection

3. Subcutaneous Dosage Forms - Implants

4. Transdermal Drug Delivery Systems- Transdermal Patches, gels, ointments creams.

CONTROLLED-RELEASE DRUG DELIVERY SYSTEM

An ideal dosage regimen in the drug therapy of any disease is the one immediately attains the desired therapeutic concentration of drug in plasma and uphold it unvarying for the complete period of treatment. This is achievable through administration of a drug in a particular dose and at a particular frequency.^7,8 When a drug is delivered as a conventional dosage form such as a tablet, the dosing interval is much shorter than the half-life of the drug resulting in a number of limitations associated with such as a:⁹

1. Poor patient compliance - Increased chances of missing the dose of a drug with short half-life for which frequent administration is necessary.

2. The inescapable fluctuations of drug concentration may lead to below medication or over medication.

3. A characteristic peak-valley plasma concentration-time profile is obtained which makes ability of steady-state condition difficult.

4. The fluctuations in drug levels may lead to precipitation of adverse effects especially of a drug with small Therapeutic Index whenever over medication occur.

To overcome these circumstances there are two approaches:

1. Development of new, better and safer drug molecule with long half- lives and large therapeutic effects.

2. Effective and safer use of existing drugs through concept and techniques of controlled and targeted delivery systems.

The first approaches have many disadvantages which therefore resulted in increases interest in the second approaches. The second approaches, owning to several technical advancement, have resulted in the development of drug delivery system capable of controlling the rate of drug delivery and sustaining the duration of therapeutic action.

ADVANTAGES OF CONTROLLED RELEASE DRUG DELIVERY SYSTEMS.^{10, 11}

1. Therapeutic advantage - Decline in fluctuation in steady state of the drug over a prolonged point in time, perfectly simulating an intravenous infusion of a drug.

2. Reduction in adverse side effects and upgrading in tolerability

3. Patient relieves and compliance - Oral drug delivery is the most frequent and convenient for patients, and a lessening in dosing frequency enhances compliance.

4. Reduction in healthcare charge - The total cost of therapy of the controlled release product could be comparable or lower than the immediate release product.

5. Keep away from night time dosing: - It is also superior for patients to avoid the dosing at night time.

DISADVANTAGES OF CONTROLLED RELEASE DRUG DELIVERY SYSTEM ^{10, 11}

1. Toxicity due to dose dumping.

2. Increased potential for first pass clearance

3. Unpredictable and often deprived invitro and invivo correlation.

4. Reclamation of drug is complicated in case of over dose, toxicity, poisoning, antipathy or hypersensitivity reactions.

CLASSIFICATION OF CONTROLLED RELEASE DRUG DELIVERY SYSTEM ^{12, 13}

1. Diffusion-controlled drug delivery system

Hydrophobic matrix systems

Matrix-type systems

Subcutaneous implants

Hydrophilic matrix systems

Semisolid matrix systems

Reservoir matrix systems

Transdermal drug delivery system

Drug in adhesive systems

Monolithic adhesive systems

Multilaminate adhesive systems

Inert matrix systems

Intravaginal rings Intrauterine devices

Intraocular inserts

Other diffusion controlled systems

2. Dissolution-controlled drug delivery system

Dissolution-controlled release coated technologies

Dissolution-controlled release of solid particles

Dissolution-controlled release matrix system technologies

3. Osmotic controlled drug delivery system Osmotic delivery systems for solids

Type I: single compartment

Type II: multiple compartments

Osmotic delivery systems for liquids

4. Programmable drug delivery system

Pulsatile systems

Feedback-controlled systems

5. Stimulus responsive drug delivery system

Physically modulated: Temperature

Chemically modulated: pH dependent

6. Biodegradable polymeric drug delivery system

Micro particles

Nanoparticles

Implants

7. Ligand-based targeting drug delivery system

MATRIX TABLETS

Introduction of matrix tablet as controlled release has given a new breakthrough for novel drug delivery system in the field of Pharmaceutical technology.^14,15 These technologies have often proven popular among the oral controlled drug delivery technologies due to their simplicity, ease in mechanized, elevated level of reproducibility, stability of the raw materials and dosage form, and simplicity of scale-up and process validation.¹⁶

Matrix tablet is a promising approach for the establishment of extended-release drug therapy as tablets offer the lowest cost approach to controlled release oral solid dosage forms. Matrix tablets may be defined as the “oral solid dosage forms in which the drug or active ingredient is homogeneously dispersed throughout the hydrophilic or hydrophobic matrices which serves as release rate retardants”. In gastric pH environment, matrix tablet gradually erodes alternatively at a pH corresponding to the upper small intestine; the tablet disintegrates rapidly to reduce coated particles, which in turn slowly releases drug. Two different release mechanisms are operative, either of which is zero-order erosion and decreasing surface area, and dissolution of coated particles, but the overall tablet release profile comprising the two mechanisms in sequence is nearly linear for most of the dose in the tablet. The result in the ability to control active pharmaceutical ingredient’s blood level’s in a narrow range, above the minimum effective level and below toxic level. This type of sustained-release tablet has clearly shown the potential of the tablet as a reliable sustained release dosage form with good release profile precision.¹⁷

Formulation of matrix tablets –

Formulation of matrices consists of drug, polymer and excipients. These components can be compressed into tablets directly or after granulation by dry, wet or hot melt method depending on the nature of the drug, excipients and the preference for process. The various formulation and manufacturing considerations in the design of matrix tablet are listed in the table 2.¹⁸

Table 2: The formulation and manufacturing consideration in the design of matrix tables

S.no.	Material/process	Parameters for consideration
1	Drug	Permeability, pKa, dose, stability, particle size, Solubility
2	Polymers	Particle size, type, level
3	Excipients	Level/type (solubility), type (stearates, non stearates, fatty acid/oils)
4	Manufacturing methods a. Direct compression b. Dry granulation c. Wet granulation § solvents § binders § process	a. Particle size of polymer / drug, flow aid. b. Slugging/roller compaction. § Aqueous/non aqueous § Water-soluble/insoluble, enteric polymers, fatty acids/waxes. § Low shear § High shear § Fluidized bed/foam granulation
5	Characteristics of dosage forms a. Physical properties b. Presence of coating § Functional § Non-functional	a. Hardness, size, shape, volume, friability. § Water soluble/insoluble polymer, enteric polymers, and fatty acids/waxes. § Elegance/aesthetics

CLASSIFICATION OF MATRIX TABLET^{19, 20, 21}

1. Classification on the basis of release rate retardant material (polymer) used - Matrix tablets can be classified into 5 types.

[A] Hydrophilic matrices – These matrix systems are widely used in oral controlled drug delivery because of their flexibility to obtain a desirable drug release profile, cost efficiency, and wide regulatory acceptance. Polymers that swell in aqueous medium that swell but are insoluble in water, called hydrogels, and those that swell and are soluble in water, called hydrophilic polymers. The polymers used in the preparation of hydrophilic matrices are divided in to three broad groups.

[i] Cellulose derivatives - Methylcellulose 400 and 4000cPs, Hydroxypropylcellulose (HPC), Hydroxyethyl cellulose (HEC), Hydroxypropylmethylcellulose (Hypromellose, HPMC) 25, 100, 4000 and 15000cPs, Ethylhydroxycellulose (E-HEC), Sodium carboxymethyl cellulose (Na-CMC).

Among all the hydrophilic polysaccharides, HPMC is the one most widely used as a drug release retardant excipients in hydrophilic matrices. It’s soluble in water, non-ionic, and it gels when in contact with water. It is stable at a pH between 3.0 and 11.0 and resists enzyme attack.²²

[ii] Non cellulose natural or semi synthetic polymers - Agar-Agar, Carob gum, Sodium, Alginates, Xanthan gum, Carrageenan, Chitosan, Guar gum, Pectin, Cross-linked high amylase starch, Polyethylene oxide, Homopolymers and copolymers of acrylic acid, Molasses Polysaccharides of Chitosan, mannose, galactose, and Modified starches.

[iii] Polymers of acrylic acid: Carbopol-934, the mainly used poymer.

[B] Hydrophobic matrices (plastic matrices) – This is the only system where the use of polymer is not essential to provide controlled drug release. Eg. Glycerides, Polyethylene, Ethyl cellulose, Polyvinyl acetate, Polyvinyl chloride, Cellulose acetate, Cellulose acetate propionate, Methaacrylic acid copolymers, Hypromellose acetate succcinate, Acrylate polymers and their copolymers.

In general it is known that the release of drugs from matrices formulated with hydrophobic polymers is slower than from matrices formulated with hydrophilic polymers.²³

[C]Lipid Matrices - These matrices prepared by the lipid waxes and related materials. Release characteristics are therefore more sensitive to digestive fluid composition than to totally impossible to crack or solve polymer matrix. Carnauba wax in mixture with stearyl alcohol or stearic acid has been utilized for retardant base for many sustained release formulation.²⁴

[D]Biodegradable Matrices - These consist of the polymers that are biologically degraded or eroded by enzymes generated by surrounding living cells or by non enzymatic process in to oligomers and monomers that can be metabolized or excreted. These polymers comprised of monomers linked to one another through functional groups and have unstable linkage in the backbone.²⁵

Table 3: Biodegradable Polymers and their Degradation Products²⁶

Polymers	Degradation Products
Polyester	Hydroxyalkyl acids, lactic acid, glycolic acid.
Poly(orthoester)	Pentaerythitol, propionic acid, hydroxyl butyric acid
Poly(caprolactone	ε-Hydroxycaproic acid
Poly(α-amino acids)	Amino acids
Pseudo-poly(amino acids)	Amino acids with trifunctional groups
Polydepsipeptides	Amino acids and α-hydroxy carboxylic acids
Polyphosphazene	Ammonia, phosphate, water.
Polyphosphoester	Phosphate
Polyanhydrides	Diacids
Polycyanoacrylates	Formaldehyde, alkyl cyanoacetates

Biological-degradation of polymers is influenced by a variety of factors such as:

1. Chemical structure and composition

2. Molecular weight

3. Polymer concentration

4. Hydrophilicity/hydrophobicity

5. Carrier morphological properties for example porosity shape and size

6. Additives in the system (acidic, basic, monomers, drugs)

7. Microenvironmental climate such as pH

8. Method of preparation

9. Sterilization

[E] Mineral Matrices- These consist of polymers which are obtained from various weeds. Example are Alginic acid which is hydrophilic carbohydrate obtained from species of brown seaweeds (Phaephyceae) by the use of dilute alkali.

2. Classification on the basis of porosity of matrix

A. Macro porous Systems - In such systems, the diffusion of drug takes place through pores of matrix, which are of size range 0.1 to 1 μm. This pore size is larger than diffusant molecule dimension.

B. Micro porous System - For micro porous systems, pore size ranges between 50 – 200 A°, which is slightly larger than diffusant molecules dimension.

C. Non-porous System - In this system, only the polymeric phase exists and no pore phase is in attendance.

MECHANISM OF DRUG RELEASE FROM MATRIX TABLET.^{27- 29}

Drug in the external layer exposed to the bathing solution is dissolved first and then diffuses out of the matrix. This process continues between the bathing solution and the solid drug moving toward the interior.

The following mathematical models involve describing this system:

1. A pseudo-steady state is maintained during drug release

2. The diameter of the drug particles is less than the average distance of drug diffusion through the matrix

3. The bathing solution provides sink conditions at all times. The release behavior for the system can be mathematically described by the following equation:

dM/dh = C_o. dh - C_s/2 ………. (1)

Where, dM = Change in the amount of drug released per unit are

dh = Change in the thickness of the zone of matrix that has been depleted of drug

C_o = Total amount of drug in a unit volume of matrix

C_s = Saturated concentration of the drug within the matrix.

Additionally, according to diffusion theory:

dM = ( Dm. Cs / h) dt ……….(2)

Where, Dm = Diffusion coefficient in the matrix.

h = Thickness of the drug-depleted matrix.

dt = Change in time.

By integration of equation 1 and equation 2:

M = [Cs. Dm (2C_o −Cs) t] ^½ ……………… (3)

When the quantity of drug is in excess of the saturation concentration then:

M = [2Cs.Dm.Co.t] ^1/2 ……………………… (4)

Equation 3 and equation 4 relate the amount of drug release to the square-root of time.

During the drug release through a porous or granular matrix the length and volume of the openings must be accounted for:

M = [Ds. C_a. p/T. (2C_o– p.C_a) t] ^1/2 ……………. (5)

Where, p = Porosity of the matrix.

t = Tortuosity.

C_a = solubility of the drug in the release medium.

Ds = Diffusion coefficient in the release medium.

T = Diffusional path length for pseudo steady state.

The equation can be written as:

M = [2D.C_a.Co (p/T) t] ^½ ………….. (6)

The entire porosity of the matrix can be considered with the following equation:

p = pa + Ca/ ρ + C_ex / ρ_ex ……………………… (7)

Where, p = Porosity.

ρ = Drug density.

p_a = Porosity due to air pockets in the matrix.

ρ_ex= Density of the water soluble excipients.

C_ex = Concentration of water soluble excipients For the purpose of da treatment.

Equation 7 can be reduced to:

M = k. t ^1/2 ……………………….. (8)

Where, k is a constant.

So that the quantity of drug released in opposition to the square root of time will be linear, in the case of drug release from matrix is diffusion-controlled and drug release can be controlled by the following parameters:

1. Initial concentration of drug in the matrix

2. Porosity

3. Tortuosity

4. Polymer coordination in the forming of matrix

5. Drug solubility.

MECHANISTIC MODELS USED TO STUDY DRUG RELEASE IN CONTROLLED RELEASE FORMULATIONS AS A FUNCTION OF THE MECHANISM INVOLVED.^30-34

Depending on the processes that control release, the control release mechanisms have been classified in four types of transport

1. Fickian diffusion (type I) - The mechanism of diffusion is the process that controls the release of the active principal ingredient.

2. Polymer swelling (type II) - Drug release is controlled by the swelling of the polymer.

3. Polymer swelling and polymer and drug dissolution (Anomalous, or “non-Fickian diffusion”) – Drug release depends simultaneously on the matrix swelling and diffusion phenomena.

4. Polymer erosion/degradation (“Supra II” type) - This occurs in matrices in which after the matrix has entered into contact with the dissolution medium these form a completely hydrated layer at the surface that is subject to continuous erosion.

DRUG RELEASE LIMITING FACTORS.^{35, 36}

1. Polymer hydration: very imperative step in polymer dissolution include absorption/adsorption of water in more available places, burst of polymer-polymer linkage with the simultaneous forming of water-polymer linking, of polymeric chains, disjointing, swelling and finally dispersion of polymeric chain in dissolution medium.

2. Solution solubility: In this way an enhanced simulation and correlation of in vitro drug release profile with in vivo drug administration can be achieved.

3. Drug solubility: for drug with aqueous solubility, release of drugs takes place by dissolution in infiltrating medium and in the case of poor solubility, release occurs by both dissolution and erosion of drug particles.

4. Diffusivity of polymer : The diffusion of small molecules in polymer structure is energy activated process in which the diffusant molecules moves to a successive series of equilibrium position when a sufficient amount of energy of activation for diffusion has been acquired by the diffusant is dependent on length of polymer chain , crystalline nature and cross linkeging of polymer and. Drug may be attributed to the three following factors

[A] Particle size of polymer

[B] Viscosity of polymer

[C] Concentration of polymer

5. Thickness of polymer diffusional path: The controlled release of a drug from both capsule and matrix type polymeric drug delivery system is fundamentally governed by Fick’s law of diffusion.

6. Thickness of hydrodynamic diffusion layer: The magnitude of drug release value decreases on increasing the thickness of hydrodynamic diffusion layer.

7. Drug loading dose: loading dose has a important effect on the drug release kinetics. The effect is more complex in case of poorly water soluble drugs, with rising initial drug loading the release rate first decreases and then increases, while, absolute release rate increased monotonically.

8. Surface area and volume: Release rate depend upon surface area of dosage form. The release from small tablet is faster than large cylindrical tablets.

9. Effect of diluents The effect of additives depends upon the nature of diluent. Water soluble diluents similar to lactose cause raise in drug release rate and release mechanism is also shifted towards Fickian diffusion; while insoluble diluents like dicalcium phosphate decrease the Fickian diffusion and increase the erosion rate of matrix.

EFFECTS OF BIOLOGICAL FACTORS ON THE DRUG RELEASE FROM MATRIX TABLET.^{35, 36}

1. Biological half-life

Drugs with short half-lives are usually excellent candidates for sustained release formulation. Drugs with half-life shorter than 2 hours are pitiable candidates. Drugs with long half-lives, more than 8 hours are also normally not used in sustaining form, since their drug release pattern is already sustained.

2. Absorption

Since the purpose of designing a sustain release product, it is essential that the rate of release must be slower than the absorption rate. It assumes that the absorption of the drug should occur at a comparatively homogeneous rate over the whole length of small intestine. This is not exact for many drugs. If a drug is absorbed by active transport or transport is limited to a specific section of intestine, sustain release dosage form may be unfavorable to absorption. One technique to provide sustaining delivery for dugs tries to uphold them in the stomach. This allows slow release of the drug, travels to the absorptive site.

3. Distribution

High apparent volume of distribution of drug affect the release rate pattern of elimination of the drug, and such drugs are poor candidate for oral sustained release drug delivery system.

4. Protein Binding

Proteins binding of drug play a noteworthy position in its therapeutic effects regardless the type of dosage form as extensive binding to plasma increase biological half-life and thus sometimes sustained release drug delivery system is not required.

5. Metabolism:

Drugs those are significantly metabolized sooner than absorption, whichever in the tissue of the intestine or in the lumen, show decreased bioavailability. Hence criteria for the drug to be used for formulating Sustained-Release dosage form is,

§ Drug should be freely soluble in water.

§ Drug should have larger therapeutic window.

§ Drug should be absorbed throughout the gastro intestinal tract.

§ Drug should have half life less than 5 hrs.

EFFECTS OF PHYSICOCHEMICAL FACTORS ON THE RELEASE FROM MATRIX TABLET ^{35, 36}

Dose Size

For orally administered drug delivery systems, a solitary dose of 0.5-1.0g is considered maximum for a conventional dosage form. This also holds exact for sustained release dosage form.

Ionization, pka and aqueous solubility

The majority of drugs are weak acids or bases. The unchanged structure of a drug permeates across membranes of lipids. Presenting the drug in an unchanged form is beneficial for drug permeation. Regrettably, the condition is made additional complex by the fact that the drug’s aqueous solubility will generally be decreased by conversion to unchanged form. Compounds with extremely low solubility (<0.01mg/ml) are innately sustained, since their release in the GI tract will be restricted by drug dissolution. Consequently it is understandable that the solubility of the compound will be poor choices for slightly soluble drugs.

Partition Coefficient - Compounds which are lipophilic in nature having high partition coefficient are poorly aqueous soluble and it retain in the lipophilic tissue for the longer time. In case of drugs with extremely low partition coefficient, it is very complicated for them to enter the membrane, follow-on reduced bioavailability. Furthermore, partitioning effects property applies equally to diffusion throughout polymer membranes. The selection of diffusion-limiting membranes must principally depend on the partitioning characters of the drug

Stability - Orally administered drugs can be subject to both enzymatic degradation and acid-base hydrolysis. Degradation will continue at a condensed rate for drugs in solid state. So, this is the favored work of art of delivery for difficulty cases.

CONCLUSION:

By this review and discussion, it can be easily elaorated that the matrix tablets formulation are supportive in escalating the efficiency of the dose as well as improving the patient’s compatibility. Various rate limiting factors, mechanism of drug release from matrix tablets, mechanist models have been discussed and it is concluded that HPMC polymer is widely used among all polymers due to its specific characteristics .Matrix tablets are the economical dosage forms.

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Received on 05.12.2013 Accepted on 06.12.2013

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