INTRODUCTION:

Oral drug delivery has been known for decades as the most widely utilized route of administration among all the routes. All the pharmaceutical products formulated for systemic delivery via the oral route of administration, irrespective of the mode of delivery (Immediate, Extended or Controlled release) and the design of dosage forms (either solid, dispersion, or liquid), must be developed within the intrinsic characteristics of GI physiology.

A drug delivery system is defined as a formulation or a device that enables the introduction of a therapeutic substance in the body and improves its efficacy and safety by controlling the rate, time, and place of release of drugs in the body. This process includes the administration of the therapeutic product, the release of the active ingredients by the product, and the subsequent transport of the active ingredients across the biological membranes to the site of action. The term therapeutic substance also applies to an agent such as gene therapy that will induce in vivo production of the active therapeutic agent. Drug delivery system is an interface between the patient and the drug. It may be a formulation of the drug to administer it for a therapeutic purpose or a device used to deliver the drug. This distinction between the drug and the device is important, as it is the criterion for regulatory control of the delivery The advantage of administering a single dose of a drug that is released over an extended period of time to maintain a near–constant or uniform blood level of a drug often translates in to better patient compliance, as wellas enhanced clinical efficacy of the drug for its intended use.

System by the drug or medicine control agency. If a device is introduced into the human body for purposes other than drug administration, such as therapeutic effect by a physical modality or a drug may be incorporated into the device for preventing complications resulting from the device, it is regulated strictly as a device. Traditional drug delivery system has been characterized by immediate release and repeated dosing of the drug which might lead to the risk of dose fluctuation, this arises the need of a formulation with control release that maintain a near-constant or uniform blood level. The desire to maintain a near-constant or uniform blood level of a drug often translates into better patient compliance, as well as enhanced clinical efficacy of the drug for its intended use. 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.

Some drugs are inherently long lasting and require only once a day oral dosing to sustain adequate drug blood levels and the desired therapeutic effect. These drugs are formulated in the conventional manner in the form of immediate release dosage forms. However, many other drugs are not inherently long lasting and require multiple daily dosing to achieve the desired therapeutic results. Multiple daily dosing is inconvenient for the patient and can result in missed doses, made up doses and non compliance with the regimen. When conventional immediate-release dosage forms are taken on schedule and more than once daily, they cause sequential therapeutic blood level peaks and valleys (troughs) associated with the administration of each dose. However, when doses are not administered on schedule, the resulting peaks and valleys reflect less than optimum drug therapy. For example, if doses are administered too frequently, minimum toxic concentrations of drug may be reached, resulting in toxic side effects. If doses are missed, periods of sub therapeutic drug blood levels or those below the minimum effective concentration may result, with no benefit to the patient. Extended-release tablets and capsules are commonly taken only once or twice daily, compared to their counterpart conventional forms which may have to be taken three or four times daily to achieve the same therapeutic effect. Typically, extended 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. The sustained plasma drug levels provided by extended release products often at times eliminate the need for night dosing which benefits not only the patient but also the caregiver.³It form produces wide range of fluctuation in drug concentration in the blood stream and tissues with consequent undesirable toxicity and poor efficiency. The maintenance of concentration of drug in plasma within therapeutic index is very critical for effective treatment.

ORAL DRUG DELIVERY SYSTEM:

Oral drug delivery is the most preferred and convenient option as the oral route provides maximum active surface area among all the drug delivery systems for administration of various drugs. The attractiveness of these dosage forms is due to awareness to toxicity and ineffectiveness of drugs when administered by oral conventional method in the form of tablets and capsules. Usually conventional dosage.

Sustained release, prolonged release, modified release, extended release or depot formulations are terms used to identify drug delivery systems that are designed to achieve or extend therapeutic effect by continuously releasing medication over an extended period of time after administration of single dose. The goal in designing sustained delivery system is to reduce the frequency of dosing or to increase effectiveness of the drug by localization at the site of action, reducing the dose required or providing uniform drug delivery. So, sustained release dosage form is a dosage form that release one or more drugs continuously in a predetermined pattern for a fixed period of time, either systemically or to a specified target organ.³

The scientific framework required for the successful development of an oral drug delivery system consists of a basic understanding of the following three aspects:

1. The anatomic and physiologic characteristics of the gastrointestinal tract.

2. Physicochemical, pharmacokinetic and pharmacodynamic characteristics of the drug.

3. Physicomechanical characteristics and the drug delivery mode of the dosage form to be designed.

Table 1: Anatomic and physiologic characteristics of the GI track⁵

Region	Surface Area(m²)	pH of The Region	Transit Time
Region	Surface Area(m²)	pH of The Region	Fluid	Solid
GIT	200	-	-	-
Stomach	0.1-0.2	1-3.5	50 min.	8 hrs.
Small intestine	4500	5-7.5	2-6 hrs.	4-9 hrs.
Large intestine	0.5-0.1	6.8	2-6 hrs.	3 hrs. to 3 days

Fig 1: Gastrointestinal anatomy and dynamics

Stomach:

The stomach is an organ with a capacity for storage and mixing. Under fasting conditions the stomach is a collapsed bag with a residual volume of 50 mL and contains a small amount of gastric fluid (pH 1-3) and air. The stomach has four main areas: cardia, fundus, body, and pylorus. Within 2-4 hrs after eating a meal the stomach has emptied its contents into the duodenum.

Intestine:

The small intestine is a tubular viscous organ and has enormous number of villi on its mucosal surface that create a huge surface area. The surface of the mucous membrane of the small intestine possesses about 5 million villi, each about 0.5 to 1 mm long. These villi are minute fingerlike projections of the mucosa and have a length of 0.5-1.5 mm. Absorption of material occurs by facilitate diffusion, osmosis, and active transport.

The small intestine is the largest section of the digestive tube and it is arbitrarily divided in three parts. Duodenum (20-30 cm), Jejunum (2-5 m) and ileum (3-5 m). The duodenum has a pH of 5 to 6 and the lower ileum approaches a pH of 8.

· Conventional drug therapy requires periodic doses of therapeutic agents. These agents are formulated to produce maximum stability, activity and bioavailability. For most drugs, conventional methods of drug administration are effective, but some drugs are unstable or toxic and have narrow therapeutic ranges. Some drugs also possess solubility problems.

· In such cases, a method of continuous administration of therapeutic agent is desirable to maintain fixed plasma levels as shown in Figure.

Drug levels in the blood with Conventional drug delivery system ⁶

Drug levels in the blood with Controlled drug delivery system

Drug levels in the blood with

a) Traditional drug delivery systems and

b) Controlled drug delivery systems.

· To overcome these problems, controlled drug delivery systems were introduced three decades ago. These delivery systems have a number of advantages over traditional systems such as improved efficiency, reduced toxicity, and improved patient convenience. The main goal of controlled drug delivery systems is to improve the effectiveness of drug therapies.

· Ideally a sustained release oral dosage form is designed to release rapidly some pre determined fraction of the total dose in to GI tract. This fraction (loading dose) is an amount of drug, which will produce the desired pharmacological response as promptly as possible and the remaining fraction of the total dose (maintenance dose) is then release at a constant rate. The rate of the drug absorption from the entire maintenance dose into the body should equal to the rate of the drug removal from the body by all the processes over the time.

· In this system, drug concentration is maintained in the therapeutic window for a prolonged period of time, thereby ensuring extended therapeutic action. Ideally two main objectives exist for these systems. These are spatial delivery, which is related to the control over the location of drug release and temporal drug delivery, in which the drug is delivered over an extended period of time during treatment.

The conventional dosage forms are immediate release type. Non-immediate release delivery systems may be divided conveniently into following categories:⁷

1) Delayed Release

2) Sustained Release

3) Controlled Release

4) Prolonged Release

5) Site-specific and Receptor release

1. Delayed Release:

Delayed release systems are those systems that use repetitive, intermittent dosing of a drug from one or more immediate release units incorporated into a single dosage form. Delayed release dosage form does not produce or maintain uniform drug blood levels within the therapeutic range.

2. Sustained Release system:

It includes any drug delivery system that achieves slow release of drug over an extended period of time.

3. Controlled Release system:

If the system is successful at maintaining constant drug level in the blood or target tissues, it is considered as a controlled release system. Drug delivery systems from which therapeutic agents may be automatically delivered at predetermined rates over a long period of time are called as controlled drug delivery systems.

4. Prolonged Release system:

In this system, without maintaining constant level, the duration of action is extended over that achieved by conventional delivery, it is considered as a prolonged release system. This is illustrated in Fig.1.2.1.4

Fig. 2: Drug levels in the blood with prolonged release drug delivery system

5. Site-Specific and Receptor Release:

In the case of site-specific release, the target is a certain organ or tissue, while for receptor release, the target is the particular receptor for a drug within an organ or tissue. Both of these systems satisfy the spatial aspects of drug delivery.

Extended Release:^9-11

Extended release drug delivery system is designed to achieve a prolonged therapeutic effect by continuously releasing medication over an extended period of time after administration of a single dose.

The smaller doses which are given after loading dose are called maintenance dose. Maintainance dose is achived by extended release of the drug.

Advantages:

· The frequency of drug administration is reduced.

· Patient compliance can be improved, and drug administration can be made more convenient as well.

· The blood level oscillation occurs by multiple dosing of conventional dosage forms is reduced, because a more even blood level is maintained.

· Minimizing drug accumulation with chronic dosing.

· Total amount of drug administered can be reduced, thus maximizing availability with a minimum dose.

· In addition, better control of drug absorption can be attained, since the high blood level peaks that may be observed after administration of a dose.

· The safety margin of high-potency drugs can be increased, and the incidence of both local and systemic adverse side effects can be reduced in sensitive patient.

Limitations:

· Administration of extended release medication does not permit the prompt termination of therapy.

· The physician has less flexibility in adjusting dosage regimens. This is fixed by the dosage form design.

· Extended release forms are designed for the normal population i.e., on the basis of average drug biological half-life. Consequently, disease states that alter drug disposition, significant patient variation.

· Economic factors must also be assessed, since more costly processes.

Table: 2 Types of Matrix for Extended Release

Sr. No.	Matrix Characteristic	Material
1	Insoluble, erodible	Carnauba wax, Castor wax
2	Insoluble, inert	Polyethylene, Polyvinyl chloride Ethylcellulose
3	Hydrophilic	Methylcellulose, Hydroxyethylcellulose Hydroxypropylmethylcellulose
4	Hydrophobic	Ethyl cellulose, Glyceryl Behenate

Insoluble, inert material containing matrix tablets are not useful for high milligram potency formulations in which the polymer content would be sufficient to form a matrix, or for highly water-insoluble drugs in which dissolution in the matrix would become rate-limiting.

Hydrophilic matrix former represents non-digestible materials that form gels in situ. Drug release is controlled by penetration of water through a gel layer produced by hydration of the polymer and diffusion of drug through the swollen, hydrated matrix, in addition to erosion of the gelled layer.

The hydrophilic polymers can be arranged into three broad categories:

1. Non-cellulose natural or semi synthetic polymer

These are products of vegetable origin and are generally used as such agar, alginate, guar gum, chitosan and modified starches are commonly used polymer.

2. Polymers of acrylic acid

These are arranged in carbomer group and commercialized under the name of carbopol. The major disadvantage of this type of polymer is its pH dependent gelling characteristics.

3. Cellulose ether

This group of semi-synthetic cellulose derivatives is the most widely used group of polymer. Non-ionic such as HPMC of different viscosity grades are widely used group of polymers.

Advantages of matrix system:

· Easy to manufacture

· Versatile, effective, low cost

· Can be made to release high molecular weight compounds

· This device can offer zero-order release of the drug.

· Kinetics of a particular drug can be controlled by changing the characteristics of the polymer to meet the particular therapeutic conditions.

Disadvantages of matrix system:

· Difficult to deliver high molecular weight compounds.

· Generally increased cost per dosage unit.

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

· The drug release rate varies with the square root of time.

· Release rate continuously diminishes due to an increase in diffusion resistance and/ or a decrease in effective area at the diffusion front.

Mechanism of drug release from ER Tablet:^{12, 13}

Extended release tablets are often classified according to the mechanism of drug release. The following are the most common means used to achieve a slow controlled release of the drug from tablets,

A. Dissolution control

B. Drug transport control by diffusion

C. Erosion control

D. Combination of Diffusion & Dissolution System

E. Drug transport control by convective flow (accomplished by, for example, osmotic pumping)

A) Dissolution controlled release systems:

In dissolution controlled extended release systems the rate of dissolution of drug in the GI juices or another ingredients is the release controlling process. Sparingly water-soluble drug can form a preparation of a dissolution controlled extended release type.

Dissolution controlled extended release systems can also obtained by covering drug particles with a slowly dissolving coating. The release of the drug from such units occurs in two steps.

1- The liquid that surrounds the release unit dissolves the coating (rate limiting dissolution step).

2- The solid drug is exposed to the liquid and subsequently dissolves.

Extended release oral products employing dissolution as the rate-limiting step. A drug with a slow dissolution rate is inherently extended. Some example of these drugs includes digoxin, griseofulvin, and salicylamide.

For those drugs with high water solubility and therefore high dissolution rate, one can decrease solubility through appropriate salt of derivative formation. Unfortunately, forms such as these do not meet the criterion of constant availability rate because their surface area decreases with time. Nevertheless, extended drug release can be achieved by coating drug particles or granules with materials of varying thickness or by dispersing them in a polymeric matrix.

Fig. 3: Dissolution control of drug release via thickness and dissolution rate of the membrane barrier coat

Release depends on drug solubility and pore structure membrane. Constant release resulted when GI fluid passes through barrier to dissolve drug.

B) Diffusion Controlled Release:

There are basically two types of diffusion controlled systems which have been developed over the past two decades:

· Reservoir devices and

· Matrix devices systems (monolithic systems).

In diffusion controlled extended release systems the transport by diffusion of dissolved drug in pores filled with gastric or intestinal juice or in a solid (normally polymer) phase is the release controlling process.

The release unit can be tablet or a nearly spherical particle of about 1 mm in diameter (a granule or a milisphere). In both cases the release unit should stay more or less intact during course of the release process.

In Matrix Systems diffusion occurs in pores located within the bulk of the release unit, and in Reservoir Systems diffusion takes place in a thin water-insoluble film or membrane, often about 5-20 µm thick, which surrounds the release unit.

Drug is release from a diffusion controlled release unit in two steps-

1. The Liquid that surrounds the dosage from penetrates in release unit and dissolves the drug. A concentration gradient of dissolved drug is thus established between the interior and the exterior of the release unit.

2. The dissolved drug will diffuse in the pores of the release unit or the surrounding membrane and thus, dissolved drug will partition into the membrane surrounding the dose unit and diffuse in the membrane.

A dissolution step is normally involved in the release process but the diffusion step is the rate controlling step. The rate at which diffusion will occur depends on four variables:

· concentration gradients over the diffusion distance.

· area

· distance over which diffusion occurs

· diffusion co-efficient of the drug in the diffusion medium

a) Reservoir system:

In a reservoir system the diffusion occurs in a thin film surrounding the release unit.

Fig. 4: Schematic illustration of the mechanism of drug release from a diffusion based reservoir tablet (t = time)

This film is normally formed from a high molecular weight polymer. The diffusion distance will be constant during the course of the release and, as long as a constant drug concentration gradient is maintained, the release rate will be constant, i.e. a zero order release. One possible process for the release of the drug from a reservoir system involves partition of the drug dissolved inside the release unit to the solid membrane, followed by transport by diffusion of the drug within the membrane. Finally, the drug will partition to the solution surrounding the release unit. The driving force for the release is the concentration gradient of dissolved drug over the membrane.

In this 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 membrane, diffuse to the periphery, and exchange with the surrounding media.

Coefficient is defined as the concentration of drug in the membrane over the concentration of drug in the core. If the partition coefficient is high, the core will be depleted of drug in a short time so that zero order release will be observed only over a short segment of the time course of drug release.

b) Matrix Devices:

In a matrix system the drug is dispersed as solid particles within a porous matrix formed of a water insoluble polymer, such as polyvinyl chloride. Initially, drug particles located at the surface of the release unit will be dissolved and the drug released rapidly. Thereafter, drug particles at successively increasingly distances from the surface of the release unit will be dissolved and released by diffusion in the pores to the exterior of the release unit. Thus, the diffusion distance of dissolved drug will increase as the release process proceeds. The drug release, in terms of the cumulative amount of drug (M) release from a matrix in which drug particles are suspended is proportional to the square root of time i.e.

M=kt1/2

The main formulation factors by which the release rate from a matrix system can be controlled are

· The amount of drug in the matrix,

· The porosity of the release unit, The length of the pores in the release unit

· The solubility of the drug (which regulates the concentration gradient). The

characteristics of the pore system can be affected by,

For example: - The addition of soluble excipients and by the compaction pressure during tabletting.

Fig. 5: Schematic illustration of the mechanism of drug release from a diffusion based matrix tablet (t = time)

In a hydrophilic matrix, there are two competing mechanisms involved in the drug release: Fickian diffusional release and relaxation release. Diffusion is not the only pathway by which a drug is released from the matrix; the erosion of the matrix following polymer relaxation contributes to the overall release. The relative contribution of each component to the total release is primarily dependent on the properties of a given drug.

For example, the release of a sparingly soluble drug from hydrophilic matrix involves the simultaneous absorption of water and desorption of drug via a swelling-controlled diffusion mechanism. As water penetrates into a glassy polymeric matrix, the polymer swells and its glass transition temperature is lowered. At the same time, the dissolved drug diffuses through this swollen rubbery region into the external releasing medium.

C) Erosion controlled release systems

In erosion controlled extended release systems that rate of drug release is controlled by the erosion of a matrix in which drug is dispersed.

The matrix is normally a tablet, i.e. the matrix is formed by a tabletting operation and the system can be described as a continuous liberation of matrix material (both drug and excipients) from the surface of the tablet, i.e. surface erosion.

The consequence will be a continuous reduction in tablet weight during the course of the release process.

Fig. 7: Schematic illustration of the mechanism of drug release from erosion based matrix tablet (t=time)

Drug release from an erosion system can thus be described in two steps.

1. Matrix material, in which the drug is dissolved or dispersed, it is liberated from the surface of the tablet.

2. The drug is subsequently exposed to the GI fluids and mixed with or dissolved in the fluid.

One example is lipids or waxes, in which the drug is dispersed. Another example is polymers that gel in contact with water (Hydroxy ethyl cellulose), the gel will subsequently erode and release the drug dissolved. Diffusion of the drug in the gel may occur in parallel.

D) Combination of Diffusion & Dissolution System:

Strictly speaking, therapeutic system will never be dependent on dissolution or diffusion only. In practice, the dominant mechanism for release as either dissolution rate-limited or diffusion controlled release.

This type of drug delivery system combines diffusion & dissolution of both drugs as well as matrix material. Drug can not only diffuses out of dosage form; as described in previous matrix system, but matrix itself also under goes dissolution process. The complexity of the system arises from the fact that as the polymer dissolves the diffusional path length for the drug may change. This usually results in a moving boundary diffusion system. Zero-order release is possible only if surface erosion occurs and surface area does not change with time.

Swelling-controlled matrixes exhibit a combination of diffusion & dissolution mechanisms. Here the drug is dispersed in a polymer, but instead of an insoluble or non-erodable polymer, swelling of the polymer occurs. This allows for the entrance of the water, which causes dissolution of the drug & diffusion out of the swollen matrix. In these type of systems the release rate is highly dependant on the polymer swelling-rate and drug solubility. Mainly used excipients for these type of drug delivery systems are HPMC, Xanthan Gum etc.

The swelling behavior of heterogeneous swellable matrixs is described by front positions, where ‘front’ indicates the position in the matrix where the physical conditions sharply change. Three fronts are present, as shown in Fig.1.3.2.6

The ‘swelling front’ clearly separates the rubbery region from the glassy region.

The ‘erosion front’, separates the matrix from the solvent. The gel-layer thickness as a function of time is determined by the relative position of the swelling and erosion moving fronts.

The ‘diffusion front’ located between the swelling and erosion fronts, and constituting the boundary that separates solid from dissolved drug, has been identified.

During drug release, the diffusion front position in the gel phase is dependent on drug solubility and loading. The diffusion front movement is also related to drug dissolution rate in the gel.

Fig. 8: Fronts in a swellable HPMC matrix

Drug release is controlled by the interaction between water, polymer and drug. The delivery kinetics depends on the drug gradient in the gel layer. Therefore, drug concentration and thickness of the gel layer governs the drug flux. Drug concentration in the gel depends on drug loading and solubility. Gel-layer thickness depends on the relative contributions of solvent penetration, chain disentanglement and mass (polymer and drug) transfer in the solvent. Initially solvent penetration is more rapid than chain disentanglement, and a rapid build- up of gel-layer thickness occurs. However, when the solvent penetrates slowly, owing to an increase in the diffusional distance, little change in gel thickness is observed since penetration and disentanglement rates are similar. Thus gel-layer thickness dynamics in swellable matrix tablets exhibit three distinct patterns. The thickness increases when solvent penetration is the fastest mechanism, and it remains constant when the disentanglement and water penetration occur at a similar rate. Finally, the gel-layer thickness decreases when the entire polymer has undergone the glassy–rubbery transition. In conclusion, the central element of the release mechanism is a gel-layer forming around the matrix in response to water penetration. Phenomena that govern gel-layer formation, and consequently drug-release rate, are water penetration, polymer swelling, drug dissolution and diffusion, and matrix erosion. Drug release is controlled by drug diffusion through the gel layer, which can dissolve and/or erode.

E) Osmotic controlled release systems:

Drug delivery from these systems to a large extent is independent of the physiological factors of the GI tract and it can be utilized for systemic as well as targeted delivery of drugs.

The osmotic pump is similar to a reservoir device but contains an osmotic agent (e.g., the active agent in salt form) which acts to imbibe water from the surrounding medium via a semi-permeable membrane. Such a device, called the 'elementary osmotic pump', has been described by Theeuwes. Pressure is generated within the device which forces the active agent out of the device via an orifice. The internal volume of the device remains constant, and there is an excess of solid (saturated solution) in the device, then the release rate remains constant delivering a volume equal to the volume of solvent uptake.

The release of drug(s) from osmotic systems is governed by various formulation factors such as solubility and osmotic pressure of the core component(s), size of the delivery orifice and nature of the rate controlling membrane.

Fig. 9: Osmosis Pump

Drug selection for oral controlled release drug delivery systems

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, solubility at different pH and apparent partition coefficient.^{14, 15}

Table: 3 Physicochemical Parameters for drug selection

Parameter	Preferred value
Molecular weight/ size	< 1000 daltons
Solubility	> 0.1 mg/ml for pH 1 to pH 7.8
Apparent partition coefficient	High
Absorption mechanism	Diffusion
General absorbability	From all GI segments
Release	Should not be influenced by pH and enzymes

The pharmacokinetic evaluation requires knowledge on a drug’s elimination half-life, total clearance, absolute bioavailability, possible first- pass effect, and the desired steady concentrations for peak.

Table: 4. Pharmacokinetic parameters for drug selection

Parameter	Comment
Elimination half life	Preferably between 0.5 and 8 h
Total clearance	Should not be dose dependent
Apparent volume of distribution V_d	The larger V_d and MEC, the larger will be the required dose size.
Absolute bioavailability	Should be 75% or more
Intrinsic absorption rate	Must be greater than release rate
Therapeutic concentration Css av	The lower Css av and smaller V_d, the loss among of drug required
Toxic concentration	Apart the values of MTC and MEC, safer the dosage form. Also suitable for drugs with very short half-life.

Basic kinetics of controlled drug delivery:

To influence of drug properties and the route of administration on controlled drug delivery, following mechanisms need a fair mention,

1. Behavior of drug within its delivery systems

2. Behavior of the drug and its delivery system jointly in the body.

For conventional systems, the rate-limiting step in drug availability is usually absorption of drug across a biological membrane such as the gastro intestinal wall. However, in sustained/controlled release product, the release of drug from the dosage form is the rate limiting step, thus, drug availability is controlled by the kinetics of drug release than absorption.²³

Bilayer Tablet^16-19

Bi-layer tablets are tablets made by compressing several different granules fed into a die in succession, one on top of another, in layers. Each drug blend comes from a separate feed frame with individual weight control. Rotary tablet presses can be set up for two or three layers. More are possible but the design becomes very special. Ideally, a slight compression of each layer and individual layer ejection permits weight checking for control purposes. They have the appearance of a sandwich because the edges of each layer are exposed.

Fig. 10: General Concept of Bilayer Tablets

Advantages:

· Physical/chemical separation :

It is possible to avoid the incompatibility in between active-excipients and excipient-excipient by mean of physical separation.

· Multiple release profile:

Bilayer tablets are able to provide multiple release kinetics of same/different Drugs of same or different physico-chemical property by application of multiple tablets. Each layer was formulated in order to parcel out the delivery of drug dose by means of different release control mechanism.

· Immediate release ( disintegrating monolith):

Bilayer tablet can deliver the initial fast release required to achieve peak plasma concentration.

· Delay release ( Erodible and swelling monolith):

Delay release can also be achived by bilayer tablet by applying either erodible or swelling mechanism from which the drug were continuously released throughout

the GIT.

For synergetic therapeutic effect:

In the management of disease condition where synergetic therapeutic effect from two or more drugs is essential and that are not compatible with each other in such condition bilayer tablet is the only option.

· Layers may be colored differently to identify the product.

· Monograms and other distinctive markings may be impressed on the surfaces of the multi-layer tablets.

· Analytical work may be simplified by separating of the layers prior to assay.

Quality and GMP-requirements for bilayer tablet:

To produce a quality bi-layer tablet, in a validated and GMP-way, it is important that the selected press is capable of

· Preventing capping and separation of the two individual layers that constitute the bi-layer tablet.

· Providing sufficient tablet hardness.

· Preventing cross-contamination between the two layers.

· Producing a clear visual separation between the two layers.

· High yield.

· Accurate and individual weight control of the two layers.

For good-quality tablets with sharp definition between the layers, special care must be taken as follows:

· Dusty fines must be limited. Fines smaller than 100 meshes should be kept at a minimum.

· Maximum granule size should be less than 16 meshes for a smooth, uniform scrape-off at the die.

· Low moisture is essential if incompatibles are used.

· Weak granules that break down easily must be avoided. Excessive amounts of lubrication, especially metallic stearates, should be avoided for better adhesion of the layers.

· Formulation of multilayer tablets is more demanding than that of single-layer tablets. For this reason, selection of additives is critical.

Tablet Layer Press:

· A tablet multilayer press is simply a tablet press that has been modified so that it has two die-filling and compression cycles for each revolution of the press. In short, each punch compresses twice, once for the first layer of a two-layer tablet and a second time for the second layer.

· There are two types of layer presses presently in use-one in which each layer can be ejected from the press separately for the purpose of weight checking, and the second in which the first layer is compressed so hard that the second layer will not bond to it, or will bond so poorly that upon ejection the layers are easily separated for weighing. Once the proper weight adjustments have been made by adjusting the die fill, the pressure is adjust to the proper tablet hardness and bonding of the layers.

· Once hazard of layer tablet production is the lack of proper bonding of layers. This can result in a lot of 100,000 tablets ending up as 200,000 layers after several days if the layers are not sufficiently bonded.

· In a two layer tablet press, two hoppers above the rotary die table feed granulated material to two separate feed frames without intermixing. Continues, gentle circulation of the material through the hoppers and feed frames assures uniform filling without segregation of particle sizes that would otherwise carry over to the second layer and affect layer weight, tablet hardness, and, in the case of differently colored granulations, the press with three hoppers for the tree granulations instead of two.

Limitations of the single-sided press:

· The simplest design is a single-sided press with both chambers of the double feeder separated from each other. Each chamber is gravity or forced-fed with a different powder, thus producing the two individual layers of the tablet. When the die passes under the feeder, it is at first loaded with the first-layer powder followed by the second-layer powder. Then the entire tablet is compressed in one or two steps (two=pre- and main compression).

· The two layers in the die mix slightly at their interface and in most cases bond sufficiently so that no layer-separation occurs when the tablet is produced. This is the simplest way of producing a bi-layer tablet. The limitations of such single-sided press are:

· No weight monitoring/control of the individual layers

· No distinct visual separation between the two layers

· The fact that it is not possible to monitor and control the weight of the individual layers raises the question whether we can consider this production GMP? Individual layer-weight control on a single-sided press requires some form of measurement of the first layer. The first control loop indirectly monitors weight and controls the fill depth of the first layer. The second loop indirectly monitors the total tablet weight, but adjust only second-layer fill depth. In general, compression force is used to monitor tablet-or layer-weight. But to do so it is necessary to apply a compression force to the first layer before adding the second layer-powder. To apply a compression force to the first layer prior to adding the second layer, it is necessary to use two separate powder feeders with a compression station in- between. This can be achieved on a single-sided press by installing an additional feeder between the pre- and main- compression station. Very often the precompression roller must be reduced to a much smaller size in order to create the pace required for the second feeder. Additional limitations of such single-sided press are:

· Very short first layer dwell time due to the small compression roller, possibly resulting in poor de-aeration, capping and hardness problems. This may be corrected by reducing the turret-rotation speed (to extend the dwell time) but with the consequence of lower tablet output.

· Very difficult first-layer tablet sampling and sample transport to a test unit for in-line quality control and weight recalibration.

· To eliminate these limitations, a double-sided tablet press is preferred over a single-sided press. A double-sided press offers an individual fill station, precompression and main compression for each layer. In fact, the bi-layer tablet will go through 4 compression stages before being ejected from the press.

Limitations of “compression force” - controlled tablet presses

· Separation of the two individual layers is the consequence of insufficient bonding between the two layers during final compression of the bi-layer tablet. Correct bonding is only obtained when the first layer is compressed at a low compression force so that this layer can still interact with the second layer during final compression of the tablet. Bonding is severely restricted if the first layer is compressed at a too-high compression force. The low compression force required when compressing the first layer unfortunately reduces the accuracy of the weight monitoring/control of the first layer in the case of tablet presses with “compression force measurement”.

· Most double-sided tablet presses with automated production control use compression force to monitor and control tablet weight. The effective peak compression force exerted on each individual tablet or layer is measured by the control system at main-compression of that layer.

Release Patten of bilayer tablets having immediately release part and extended release part.

Fig. 11: Release pattern of bilayer Tablet

Fig. 12: Compression cycle of bi-layer tablet

Steps of compression of bi-layer tablet:

1. Filling of first layer.

2. Compression of first layer.

3. Ejection of upper punch.

4. Filling of second layer.

5. Compression of both layer together.

6. Ejection of bi-layer tablet.

Fig. 13: Bilayer Rotary Machine

CONCLUSION:

The most widely used measure of the margin of a drug’s safety is its therapeutic index, that is, the median toxic dose divided by the median effective dose. For very potent drugs, the therapeutic index may be narrow or very small. They are used in the treatment of chronic rather than acute conditions. Drugs for acute conditions require greater adjustment of the dosage by the physician than that provided by extended-release products. Modified-release products including extended-release, prolonged-release, controlled-release, controlled-delivery, slow-release and sustained-release. These preparations, by definition, have a reduced rate of release of active substance. In general, these terms are interchangeable. Extended release tablet are Designed to release their medication in controlled manner, at pre-determined rate, duration and location in the body to achieve and maintain optimum therapeutic blood levels of drug. Among the various routes of drug delivery oral route is most preferred route. But conventional dosage form offers few limitations which could be resolved by modifying the existing dosage form. Sustained and controlled drug delivery system helps in maintaince of constant plasma drug concentration and retards the release rate of drug therby extending the duration of action. There are various formulation strategies for sustained release tablets among which matrix tablet serves as an important tool. Hence the problem like poor patient compliance, multiple dosing, see-saw fluctuations can be easily minimized.

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Received on 30.06.2018 Modified on 18.08.2018

Res. J. Pharm. Dosage Form. & Tech. 2018; 10(4): 233-244.

DOI: 10.5958/0975-4377.2018.00035.6

Mechanism of drug release from ER Tablet: 12, 13

Preferred value

Comment

Quality and GMP-requirements for bilayer tablet:

REFERENCES:

Mechanism of drug release from ER Tablet:^{12, 13}