INTRODUCTION:

Now a day’s various countries are developed a combination therapy such as hypertension of various disease and cardiovascular diseases. More than 90% of the formulations manufactured today are ingested orally. The system allows to inclusion of more than one drug into the dosage form¹². Formulation of bilayer tablets from different polymers allow manipulation over more than are different types of drug delivery of one or more drug, i.e., they may be drug released with a bolus and then at a controlled rate or by targeted drug delivery in the GIT using the pH development in the polymers. Number of issues of production of bilayer tablets^2,15.

Fig.1: Bilayer Tablet

Bilayer tablets are prepared by two layers. One layer of drug for immediate release while second layer designed to release drug, later, either as second dose or in a sustained release manner. Bilayer tablet is suitable for incidental release of two drugs in combination, separate two incompatible products and also for extended-release tablet in which one layer is immediate release as initial dose and second layer dose is maintenance. Bilayer tablet is a development technology to overcome the short coming of the single layered tablet. Player tablets contain sustained release layers, immediate and the immediate release layer delivers the initial dose, its addition of super disintegrates, which encourage the drug release rate and attains the onset of action quickly (loading dose) whereas sustained release (maintenance dose) layer release of drug in these layer is prolonged time period²⁵. The aim in designing sustained or controlled delivery systems is to decrease the repetition of the dosing or to increase effectiveness of the drug by localization at the site of action, lowering the dose required or provide uniform drug delivery. The main objective of sustained release drug delivery is to make sure safety and to improve patient compliance. Immediate release drug delivery system is intended to rapidly disintegrate²⁵. It is associate with variation in drug plasma levels, which leads to reduce or loss in drug effectiveness or increase incidence of side effects. The preparation of tablets in the forms of multi-layers is used to provide systems for the administration of drugs, which are opposite and to provide controlled release tablet preparations by surrounding or multiple swelling layers. Many bilayer tablets have both the layers as the sustain release layers examples, are a certain ant diabetic agent^14,23.

Advantages:

· The administration of sustained release preparation as one layer with the immediate release preparation as the second layer is extended release possible⁴.

· The thickness of each layer can be accurately controlled.

· Stopping of cross-contamination between two layers.

· Producing a clear visible separation between two layers.

· The separation of two opposite substance with addition of any barrier layer between them is possible.

· Individual and accurate weight control of two layers¹⁸.

· Large scale production.

· Flexible concept.

· Cost of the bilayer tablets is lower compared to another oral dosages form²².

Fig.2: Co-Morbid Condition

Disadvantages:

· Swallowing problems of the children and unconscious patients.

· Add complication and bilayer tablet presses are expensive.

· Intermediate hardness, layer is separation reduced yield⁹.

· Incorrect individual layer weight control.

· Some drugs counter compression into dense compacts, due to amorphous nature, low density¹³.

Limitation of bilayer tablet:

· Layer separation.

· Capping.

· Hardness problem²⁶.

Types of bilayer tablets:

The term bilayer tablets containing they may be either the same (homogeneous) or different (heterogeneous).

1) Homogenous type:

Bilayer tablets are release drug profile preferred is different from one another. Bilayer tablets are characterization of depending upon release pattern.

The bilayer tablets are prepared one layer of the immediate release and second layer is extended release manner³⁰.

2) Heterogeneous type:

Bilayer tablet is suitable for continuous release two drugs in combination, separate two incompatible substances¹³.

Bilayer Tablets: Quality and GMP Requirement:

To produce a quality bi-layered tablet, in a validated and GMP way, it is important to select a bi-layer tablet press capable of: ²⁰.

· High yield.

· Preventing capping and separation of the two individual layers that form the bilayer tablet.

· Preventing cross-contamination between the two layers.

· Producing a clear visible separation between the two layers.

· Accurate and individual weight control of the two layers.

Applications:

· Mostly bilayer tablets used in combination therapy.

· Bilayer tablets are used to transport the loading dose and maintenance dose of the same or different drug⁷.

· Bilayer tablets are used to provide the two different drugs having different release profile.

· Bilayer tablets are used for bilayer floating tablets in which one layer is floating layer another one is immediate drug release layer²¹.

Various techniques used in preparation of bilayer tablet:

1) OROS Push Pull Technology

2) L-OROS Technology

3) EN SO TROL Technology

4) DUROS TROL Technology

5) Elan Drug Technology’ Dual release Drug Delivery System

1) OROS Push Pull Technology:

This technique consists of mainly two or three layers among which the one or more layer is necessary of the drug and other layer are consist of push layer. Mainly consists of drug along with two or more different agents are used in drug layer. So, the drug layer contains of drug which is in poorly soluble form. There is more addition of suspending agent and osmotic agent. A semipermeable membrane surrounded to the tablet core³².

Fig. 3: Bilayer and Trilayer OROS Push Pull Technology

2) L-OROS Technology:

This system is used for the solubility problem also developed the L-OROS system a lipid soft gel product holding drug in a dissolved state is osmotic push layer and then a semi permeable membrane, drilled with an exit orifice²⁸.

Fig. 4: L-OROS^TM Technology

3) EN SO TROL Technology:

Solubility enhancement of an order of magnitude or to generate optimized dosage form shire laboratory use an integrated approach to drug delivery attracting on identification and incorporation of the identified enhancer into controlled release technologies³⁰.

Fig. 5: EN SO TROL Technology

4) DUROS Technology:

DUROS is based on implant technology, which provides a different wide range of therapeutic compounds, includes proteins, peptide and other bioactive macro-molecules. The DUROS system consists from an outer cylindrical titanium alloy reservoir. Reservoir are high impact strength and protects the drug molecules from enzymes¹⁶.

Fig. 6: DUROS Technology

5) Elan Drug Technologies Dual Release Drug Delivery System:

This system is a bilayer tablet which can provide immediate or sustained release of two drug or release rates are different in the same drug in on dosage form. In these punching of tablet. Process can provide an immediate release granulate and modified release hydrophilic matrix complex as separate layers within the one tablet⁵.

Benefits:

· Unit dose tablet presentation.

· Bilayer tableting technology.

· Similarity of two different CR formulations combined.

· Tailored release rate of two drug components¹¹.

· Similarity for immediate release and modified release components in one tablet.

Type of bilayer tablet press:

1. Single side tablet press.

2. Double sided tablet press or “compression force” controlled tablet press²⁴.

3. Bilayer tablet press with displacement monitoring.

4. Multilayer compression basics.

1) Single-sided tablet press:

The simplest design is a single sided press with both chambers of the doublet feeder separated from each other. Each chamber is gravity or force fed with different powers, thus producing the two separate layers of the tablets. When the die passes under the feeder it is at first loaded with the first layer powder followed by second layer of powder. Then after compression of tablet in one or two steps³⁹.

Limitations:

· No distinct visible separation between the two layers.

· No weight monitoring or individual layers are control.

· Very short first layer, possibly resulting in poor deaeration, capping and hardness problems²⁹.

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

2) Double sided tablet presses:

A double-sided press offers on individual fill station, pre-compression and main compression for each layer. In fact, the bi-layer tablet will go through four compression stages before being ejected from the press. Most double-sided tablet presses with computerized production control use compression force to monitor and tablet weight³¹.

Advantages:

· Maximized yield.

· Low compression force exerted on the first layer to EOA ignore capping and separation of the individual layer.[19]

· Maximum precaution of cross-contamination between two layers.

· Displacement weight monitoring for accurate and independent weight control of the separate layer.

3) Bilayer tablet press with displacement monitoring:

These technique displacement tablet weight control principles based upon compression force measuring displacement depends on the applied pre compression force not depend on tablet weight. In these techniques the lower the pre-compression force, the more the monitoring control system and this ideal for good inter-layer bonding of the bi-layer tablet³⁶.

Advantages:

· Weight monitoring.

· Maximum precaution of cross contamination between the two layers.

· Low compression force expands on the first layer to avoid capping and separation of the two individual layers⁷.

4) Multilayer compression basics:

Multilayer compression basics presses can be designed specifically for multilayer compression or a standard double press can be converted for multipliers. Multilayer tablet define has been long utilized to developed sustained release formulations such tablets have fast releasing layer and may contain players or triple layers to sustain the drug release from the tablet¹⁰.

Various approaches of bilayer tablet:

1) Floating drug delivery system.

2) Swelling system.

3) Polymeric bio adhesive.

Characterization of bilayer tablets:

1). Angle of repose:

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

Tan θ = -------

Where,

h = height

r = radius

2). Density:

The bulk density and tapped bulk density were determined and calculated using the following formulas²⁹.

Mass

Bulk density = --------

Volume

3). Particle size distribution:

The particle size distribution was measured using sieving method.

4). Photo-microscope study:

Photo-microscope image of TGG and GG was taken by photo-microscope.

5). Moisture sorption capacity:

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 investigated for the amount of moisture in the after weight²⁴.

6) Compressibility:

The compressibility index was calculated by using formulation,

7) Hausner’s Ratio:

It is calculated by the formula,

Evaluation of sustain release bilayer tablet:

1) General appearance:

The general appearance of a tablet its visual identity and overall “elegance” is essential for consumer acceptance. Includes tablet shape, size, color, presence or absence of an Odour, taste, surface texture, physical of any identifying marking.

2) Size and thickness:

Thickness and diameter was measured using vernier caliper. Thickness and diameter of tablets were important for uniformity of tablet size³².

3) Tablet hardness:

The hardness of tablet of each formulation was measured by Monsanto harness tester. The hardness was measured in kg/cm²_.

4) Friability:

Friability is the measure of tablet strength. 20 tablets were weighed accurately and placed in the tumbling apparatus that revolves at 255 pm dropping the tablets through a distance of six inches with each revolution. After 4 min, weighted of tablets and the percentage loss in tablet weight was determined¹⁸.

5) Weight variation:

Twenty tablets are selected randomly from each batch and weight individually to check weight variation. Calculate average weight and comparing the individual tablet weights the average¹⁶.A little variation is allowed in weight of tablet according to U.S. pharmacopoeia.

The following percentage deviation shown in tablet in weight variation is allowed. [48]

Table 1: Weight Variation Parameters

Average weight tablet	Percentage deviation
130 mg or less	± 10
>130 mg and < 324 mg	± 75
324 mg or more	± 5

6) Drug content and release:

To evaluate tablets possible for efficacy, the amount of drug per tablet needs be monitored from tablet to tablet and batch to batch and a measure of the tablet’s ability to release the drug needs to be ascertained¹².

7) In- vitro dissolution study:

Dissolution study is done in simulated gastric and intestinal fluids to assess their ability in providing the desired controlled drug delivery. In-vitro drug release studies are carried out using USP dissolution test apparatus at 37°C temperature at specific RPM or as in mentioned monograph^20,33.

CONCLUSION:

Bilayer tablet is suitable for sequential release of two sustained release tablet in one layer is immediate release and second layer is extended release. This technology, avoids daily administration of dosage form. Currently in this technology is used for administration of drugs like anti-diabetic, anti-hypertensive, anti-inflammatory, anti-pyretic, anti-asthmatic to the patients. Bilayer tablets are novel approaches. Bilayer tablets are used quality and GMP –requirement can vary widely. These articles are explained why many different types of presses are being used to produce bilayer tablet and ranging from simple single-sided presses. This technique is safe, cost effective and reproducible.

ACKNOWLEDGEMENT:

The authors are grateful to the authorities of Loknete Dr. J. D. Pawar College of Pharmacy, Manur for the facilities.

CONFLICT OF INTEREST:

The authors declare no conflict of interest.

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Received on 16.03.2021 Modified on 27.04.2021

Res. J. Pharma. Dosage Forms and Tech.2021; 13(3):253-258.

DOI: 10.52711/0975-4377.2021.00042