INTRODUCTION:

Usually conventional dosage form produce wide ranging fluctuation in drug concentration in the blood stream and tissues with consequent undesirable toxicity and poor efficiency. This factor such as repetitive dosing and unpredictable absorption led to the concept of controlled drug delivery systems. The goal in designing sustained or controlled delivery systems is to reduce the frequency of the dosing or to increase effectiveness of the drug by localization at the site of action, reducing the dose required or providing uniform drug delivery. The primary objective of sustained release drug delivery is to ensure safety and to improve efficacy of drugs as well as patient compliance (Kumar et al., 2010). Bi-layer tablet is suitable for sequential release of two drugs in combination, separate two incompatible substances and also for sustained release tablet in which one layer is immediate release as initial dose and second layer is maintenance dose (Shiyani et al.,2008). There is various application of the bi-layer tablet it consist of monolithic partially coated or multilayered matrices. In the case of bi-layered tablets drug release can be rendered almost unidirectional if the drug can be incorporated in the upper non-adhesive layer its delivery occurs into the whole oral cavity.

Various techniques for bilayer tablet:

OROS® push pull technology:

This system consist of mainly two or three layer among which the one or more layer are essential of the drug and other layer are consist of push layer (Fig.1). The layer mainly consists of drug along with two or more different agents. So this drug layer comprises of drug which is in poorly soluble form. There is further addition of suspending agent and osmotic agent. A semi permeable membrane surrounds the tablet core.

Fig. 1: Bilayer and trilayer OROS Push pull technology.

L-OROS tm technology: (Fig.-2)

This system used for the solubility issue Alza developed the L-OROS system where a lipid soft gel Product containing drug in a dissolved state is initially manufactured and then coated with a barrier membrane, than osmotic push layer and than a semi permeable membrane, drilled with an exit orifice.

Fig. 2: L – OROS tm technology

EN SO TROL technology:

Solubility enhancement of an order of magnitude or to create optimized dosage form Shire laboratory use an integrated approach to drug delivery focusing on identification and incorporation of the identified enhancer into controlled release technologies (Kale et al.,2011).

DUROS technology

The system consists from an outer cylindrical titanium alloy reservoir (Fig. 3).This reservoir has high impact strength and protects the drug molecules from enzymes. The DUROS technology is the miniature drug dispensing system that opposes like a miniature syringe and reglious minute quantity of concentrated form in continues and consistent from over months or Year.

Fig. 3 DUROS Technology

Elan drug technologies’ Dual release drug delivery system:

(DUREDAS™ Technology) is a bilayer tablet which can provide immediate or sustained release of two drugs or different release rates of the same drug in one dosage form. The tab letting process can provide an immediate release granulate and a modified-release hydrophilic matrix complex as separate layers within the one tablet. The modified-release properties of the dosage form are provided by a combination of hydrophilic polymers.

Benefits offered by the DUREDAS™ technology include:

· Bilayer tabletting technology.

· Tailored release rate of two drug components.

· Capability of two different CR formulations combined.

· Capability of immediate release and modified release components in one tablet.

· Unit dose, tablet presentation.

The DUREDAS™ system can easily be manipulated to allow incorporation of two controlled release formulations in the bi-layer. Two different release rates can be achieved from each side. In this way grater prolongation of sustained release can be achieved. Typically an immediate release granulate is first compressed followed by the addition of a controlled release element which is compressed onto the initial tablet. This gives the characteristic bi-layer effect to the final dosage form. A further extension of the DUREDAS™ technology is the production of controlled release combination dosage forms whereby two different drugs are incorporated into the different layers and drug release of each is controlled to maximize the therapeutic effect of the combination. Again both immediate release and controlled release combinations of the two drugs are possible. A number of combination products utilizing this technology approach have been evaluated. The DUREDAS™ technology was initially employed in the development of a number of OTC controlled release analgesics. In this case a rapid release of analgesic is necessary for a fast onset of therapeutic effect. Hence one layer of the tablets is formulated as immediate releases granulate. By contrast, the second layer of the tablet, through use of hydrophilic polymers, releases drug in a controlled manner. The controlled release is due to a combination of diffusion and erosion through the hydrophilic polymer matrix (http://www.port/ technology.com).

Advantages:

1. Flexible Concept.

2. Bi-Layer execution with optional single-layer conversion kit.

3. Exchangeable turret.

4. Turret sizes for product development, scale-up, and mid-range production.

5. Full production capability in a scale-up machine.

6. Self-contained, fully portable design.

7. Fast and easy changeover.

8. Internal turret lift device for extreme simplicity in turret removal and installation.

9. Clean compression zone with quick-disconnect design.

10. This dosage form has the advantage of separating two incompatible substances.

11. It makes possible sustained-release preparations with the immediate release quantity in one layer and the slow-release portion in the second.

12. The weight of each layer can be accurately controlled, in contrast to putting one drug of a combination product in a sugar coating.

13. Two-layer tablets require fewer materials than compression coated tablets, weight less, and may be thinner.

14. Monograms and other distinctive markings may be impressed on the surfaces of the multi layer tablets. Coloring may possibilities for unique tablet identity.

15. Analytical work may be simplified by separating of the layers prior to assay. Since there is no transfer to second set of punches and dies, as with the dry-coating machines, add shapes (such as triangles, squares, and ovals) present no operating problems except for those common tolling.

Immediate Release Tablet:

Definition:

The term “immediate release” pharmaceutical formulation includes any formulation in which the rate of release of drug from the formulation and/or the absorption of drug, is neither appreciably, nor intentionally, retarded by galenic manipulations. In the present case, immediate release may be provided for by way of an appropriate pharmaceutically acceptable diluent or carrier, which diluent or carrier does not prolong, to an appreciable extent, the rate of drug release and/or absorption. formulations of the invention may release at least 70% (preferably 80%) of active ingredient within 4 hours, such as within 3 hours, preferably 2 hours, more preferably within 1.5 hours, and especially within an hour (such as within 30 minutes), of administration, whether this be oral or parenteral.

Desired criteria for immediate release drug delivery system:

Immediate release dosage form should In the case of solid dosage it should dissolve or disintegrate in the stomach within a short period.

1. In the case of liquid dosage form it should be compatible with taste masking.

2. Be portable without fragility concern.

3. Have a pleasing mouth feel.

4. It should not leave minimal or no residue in the mouth after oral administration.

5. Exhibit low sensivity to environmental condition as humidity and temperature.

6. Be manufactured using conventional processing and packaging equipment at low cost.

7. Rapid dissolution and absorption of drug, which may produce rapid onset of action.

Potential candidate for immediate release oral dosage form:

Anti-diabetics

Acetohexamide, Chlorpropamide, Glibenclamide, Gliclazide, Glipizide, Tolazamide, Tolbutamide

Analgesics and Anti-inflammatory Agents:

Aloxiprin, Auranofin, Azapropazone, Benorylate, Diflunisal, Etodolac, Fenbufen, Fenoprofen Calcim, Flurbiprofen, Ibuprofen, Indomethacin, Ketoprofen, Meclofenamic Acid.

Anthelmintics:

Albendazole, Bephenium, Hydroxynaphthoate, Cambendazole, Dichlorophen, Ivermectin, Mebendazole, Oxamniq.

Anti-Arrhythmic Agents:

Amiodarone Hcl, Disopyramide, Flecainide Acetate, Quinidine Sulphate.

Anti-hypertensive Agents:

Amlodipine, Carvedilol, Benidipine, Darodipine, Dilitazem Hcl, Diazoxide, Felodipine, Guanabenz Acetate, Indoramin, Isradipine, Minoxidil, Nicardipine Hcl, Nifedipine.

Anti-migraine Agents :

Dihydroergotamine Mesylate, Ergotamine Tartrate, Methysergidemaleate, Pizotifen Maleate, Sumatriptan Succinate.

Sustained Release Tablet :

"Sustained release" or "extended release" or "controlled release" is defined herein as release of a pharmaceutical agent in a continuous manner over a prolonged period of time.

Advantages:

1. Avoid patient compliance problems

2. Employ less total drug.

a. Minimize or eliminate local side effects.

b. Minimize or eliminate systemic side effects.

c. Obtain less potentiation or reduction in drug activity with chronic use.

d. Minimize drug accumulation with chronic dosing.

3. Improve efficiency in treatment.

a. Cures or controls condition more promptly.

b. Improves control of condition i.e., reduced fluctuation in drug level.

c. Improves bioavailability of some drugs.

d. Make use of special effects, E.g. Sustained-release aspirin for morning relief of arthritis by dosing before bed time.

4. Economy i.e. reduction in health care costs. The average cost of treatment over an extended time period may be less, with less frequency of dosing, enhanced therapeutic benefits and reduced side effects. The time required for health care personnel to dispense and administer drug and monitor patient is also reduced.

Disadvantages:

1. Decreased systemic availability in comparison to immediate release conventional dosage forms, which may be due to incomplete release, increased first-pass metabolism, increased instability, insufficient residence time for complete release, site specific absorption, pH dependent stability etc.

2. Poor in vitro – in vivo correlation.

3. Possibility of dose dumping due to food, physiologic or formulation variables or chewing or grinding of oral formulations by the patient and thus, increased risk of toxicity.

4. Retrieval of drug is difficult in case of toxicity, poisoning or hypersensitivity reactions.

5. Reduced potential for dosage adjustment of drugs normally administered in varying strengths

6. Stability problems

7. Increased cost

8. More rapid development of tolerance and counseling

9. Need for additional patient education and counseling

Characterization of bilayer tablet:

Particle size distribution:

The particle size distribution was measured using sieving method.

Photo-microscope Study:

Photo-microscope image of TGG and GG was taken (X450 magnifications) by photomicroscope

Angle of Repose:

The diameter of the powder cone was measured and the angle of repose was calculated using the following equation.

Tan Ø=h/r

Where, h and r are the height and radius of the powder cone.

Moisture Sorption Capacity:

All disintegrates have capacity to absorb moisture from atmosphere which affects moisture sensitive drugs. Moisture sorption capacity was performed by taking 1 g of disintegrate uniformly distributed in Petri-dish and kept in stability chamber at 37±1°C and 100% relative humidity for

2 days and investigated for the amount of moisture uptake by difference between weights.

Density :

The loose bulk density (LBD) and tapped bulk density (TBD) were determined and calculated using the following formulas.

LBD ¼ weight of the powder=volume of the packing

TBD ¼ weight of the powder=tapped volume of the packing

Compressibility:

The compressibility index of the disintigrate was determined by Carr’s compressibility index.

C = 100 x (1-ÞB/ÞT) (Indian Pharmacopoeia, 1996; United States Pharmacopoeia, 2000:1944).

Evaluation of sustain release bilayer tablet:

Tablet Thickness and Size:

Thickness and diameter of tablets were important for uniformity of tablet size. Thickness and diameter was measured using venire caliper.

Tablet Hardness:

The resistance of tablets to shipping or breakage under conditions of storage, transportation and handling before usage depends on its hardness. The hardness of tablet of each formulation was measured by Monsanto hardness tester. The hardness was measured in kg/cm2.

Friability:

Friability is the measure of tablet strength. Electro lab EF- 2 friabilator (USP) was used for testing the friability using the following procedure. Twenty tablets were weighed accurately and placed in the tumbling apparatus that revolves at 25 rpm dropping the tablets through a distance of six inches with each revolution. After 4 min, the tablets were weighed and the percentage loss in tablet weight was determined.

% loss = [(Initial wt. of tablets – Final wt. of tablets)/ Initial wt. of tablets] ×100

Uniformity of weight:

Twenty tablets were selected at random and the average weight was calculated. Weight Variation was calculated and was compared with I. P. standards (Singh and Kim.,2000).

Dissolution Studies:

Bilayer tablets were subjected to in vitro drug release studies in simulated gastric and intestinal fluids to assess their ability in providing the desired controlled drug delivery. Drug release studies were carried out using USP dissolution test apparatus I at 100 rpm, 37±0.5°C, and pH 1.2 buffer (900 ml) (i.e. 0.1 N HCl) for 2 hours, since the average gastric emptying time is about 2 hours. The dissolution medium was replaced with pH 6.8 phosphate buffer (900ml) and experiment continued for another 10 hours. At different time intervals, 5ml of the samples were withdrawn and replaced with 5ml of drug-free dissolution medium. The samples withdrawn were analyzed by UV spectrophotometer using multi component mode of analysis (Atram et al., 2009).

CONCLUSION:

Bilayer tablet is improved beneficial technology to overcome the shortcoming of the single layered tablet. There is various application of the bi-layer tablet it consist of monolithic partially coated or multilayered Matrices. Bilayer tablet is suitable for sequential release of two drugs in combination, separate two incompatible substances and also for sustained release tablet in which one Layer is immediate release as initial dose and second layer is maintenance dose. The preparation of tablets in the form of multi layers is used to provide systems for the administration of drugs, which are incompatible and to provide controlled release tablet preparations by providing surrounding or multiple swelling layers. Bilayer tablet quality and GMP-requirements can vary widely. This explains why many different types of presses are being used to produce bi-layer tablets, ranging from simple single sided presses to highly sophisticated machines such as the Courtoy-R292F. Whenever high quality bilayer tablets need to be produced at high speed, the use of an ‘air compensator’ in .combination with displacement control appears to be the best solution (Kale et al., 2011).

REFERENCES:

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22. Ramesh DS, Guruvaiah, Harani A. Formulation and evaluation of bilayer sustained release matrix tablets of Metformin HCl and Pioglitazone. Amer-Euras J Sci Res 2010;5(3):176-82.

23. Kulkarni AS, Manish S. Design and floating bilayer tablets of Diltiazen HCl and Lovastatin. PDA J Pharm Sci Technol 2008;62(5):344-52.

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26. Atram SC, Udavant YK, Salunke RJ, Neb GB, Shahi SR, Gulecha BS, Padalkar AN. Formulation and evaluation of bilayer tablet containing Metoprolol succinate and Amlodipine besylate as a model drug for anti hypertensive therapy. J Pharm Res 2009;2(8):1335-47.

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Received on 28.03.2012 Modified on 20.04.2012

Research J. Pharm. and Tech. 5(6): June 2012; Page 716-720

COMBINATION OF DRUGS	REASON
Metformin hydrochloride + Pioglitazone	Reduce frequency of administration and improve patient compliance ( Ramesh et al., 2010).
Diltiazem hydrochloride + Lovastatin	Improve patient compliance and better disease management ( Kulkarni et al.,2008).
Metformin hydrochloride + Glimepiride	Improve oral therapeutic efficacy with optimal control of plasma drug level (Pattanayak et al., 2011).
Atorvastatin calcium + Nicotinic acid	Develop potential dosage form (Nirmal et al., 2008).
Metoprolol succinate + Amlodipine besylate	Lower doses of drug to reduce patient blood pressure, minimize dose dependent side effects and adverse reactions (Atram et al., 2009).
Salbutamol + Theophylline	Enhance patient compliance and prolong bronchodilation (Nagaraju et al., 2009).
Paracetamol + Diclofenac sodium	Reduce dose frequency and decrease incidence of GI side effects (Gohel et al., 2010).
Tramadol + Acetaminophen	Prolonged release up to 12 hs and improve patient compliance (Naeem et al., 2010).
Metoclopramide hydrochloride + Ibuprofen	Effective treatment of migraine and avoid chemical incompatibility between drugs (Shiyani et al., 2008).