NOVEL APPROACH OF BILAYERED TABLETS: AN OVERVIEW

About Authors:
Patel Pinkesh*1, Patel Chirag J1, Prof. Satyanand Tyagi2, Umesh Kumar1, Patel Jaimin1, Chaudhari Bharat1
1Department of Pharmaceutics, Maharishi Arvind Institute of Pharmacy, Mansarovar, Jaipur, Rajasthan, India-302020.
2President & Founder, Tyagi Pharmacy Association (TPA) & Scientific Writer (Pharmacy), Chattarpur, New Delhi, India-110074.
*pinkesh.patan@yahoo.com, +91-8866436904

ABSTRACT:
In the last decade, interest in developing a combination of two or more Active Pharmaceutical Ingredients (API) in a single dosage form (bilayer tablet) has increased in the pharmaceutical industry. Pharmacokinetic profile relies on the fact that the fast release layer provide the loading dose of drug and the sustained release of drug maintain the drug concentration within therapeutic window for longer period of time. Bilayer tablets offer definite advantages over conventional release formulation of the same drug. Now a day, several pharmaceutical companies are developing bilayer tablet for co-administration of drugs to improve the therapeutic efficacy as well as to reduce the chances of drug-drug interaction.

Reference Id: PHARMATUTOR-ART-1566

INTRODUCTION
Oral ingestion has long been the most convenient and commonly employed route of drug delivery due to its ease of administration. It is well known that modified release dosage forms may offer one or more advantages over immediate release formulations of the same drug. There are many ways to design modified release dosage forms for oral administration; from film coated pellets, tablets or capsules to more sophisticated and complicated delivery systems such as osmotically driven systems, systems controlled by ion exchange mechanism, systems using three dimensional printing technology and systems using electrostatic deposition technology. The design of modified release drug product is usually intended to optimize a therapeutic regimen by providing slow and continuous delivery of drug over the entire dosing interval whilst also providing greater patient compliance and convenience [1, 2]. The most common controlled delivery system has been the matrix type such as tablets and granules where the drug is uniformly dissolved or dispersed throughout the polymer, because of its effectiveness, low cost, ease of manufacturing and prolonged delivery time period [3].

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 [4].

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. 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 [5].

ADVANTAGES OF BILAYER TABLET
The advantages of the bilayer tablet over the other conventional preparations of oral solid dosage forms include:
1.      When the two different layers of the tablet content two different drugs, then the tablet can be easily used in combination therapy.
2.      Frequency of the dose administration is reduced which ultimately improve the patient compliance.
3.      This formulation can be use to deliver separate two incompatible substance.
4.      In case of drugs having a low half life, each of the two layers of the tablet respectively content a loading dose and maintenance dose of the same and thus increase the bioavailability of the drug.
5.      In case of a conventional dosage form due to fluctuation of the dose interval the plasma drug concentration may differ (under medication or over medication), but in this dosage form the plasma drug concentration is always constant, which ultimately provide a more effective action of the drug.
6.      Greatest chemical and microbial stability over all oral dosage form.
7.      Better control of drug absorption can be attained, since the high blood level peaks that may be observed after administration of a dose of high availability drug can be       reduced by formulation in an extended action form. The safety margin of high        potency drugs can be increased and the local and systemic adverse effects can be   reduced in sensitive patients.
8.      Suitable for large scale production [6-8].

LIMITATIONS OF BILAYER TABLET
From the above mentioned advantage of bilayer tablets it is quite clear that in pharmaceutical industry it is a great revolution, but there are certain limitations in the formulation and use of bilayer tablets, such as:
1.      Drugs with poor wetting, slow dissolution properties, optimum absorption high in GIT may be difficult to formulate or manufacture as a tablet that will still provide adequate or full drug bioavailability.
2.      One of the major challenges in bilayer formulation is lack of sufficient bonding and adhesion at the interface between the adjacent compacted layers which is often the result of an interfacial crack and layer separation.
3.      Difficult to swallow in case of children and unconscious patients.
4.      If the compacted layers are too soft or too hard, they will not bind securely with each other which can lead to compromised mechanical integrity and also the separation of the layers.
5.      Other challenges during development include establishing the order of layer sequence, layer weight ratio, elastic mismatch of the adjacent layers, first layer tamping force, and cross contamination between layers.
6.      The adjacent layers of a bilayer tablet are bonded together by mechanical means, so the factors influences the stress state is very important. The mechanical properties of each layer and the tablet, and compression parameters along with specialized techniques and compression condition plays a very important role for the same.
7.      Administration of sustained release bilayer tablet does not permit the prompt termination of therapy.
8.      Bitter testing drugs, drugs with an objectionable odour or drugs that are sensitive to oxygen may require encapsulation or coating.
9.      The physician has a less flexibility on adjusting the dose regimens [6, 8, 9].

GENERAL PROPERTIES OF BI-LAYER TABLET DOSAGE FORMS
1.      A bi-layer tablet should have sufficient strength to withstand mechanical shock during its production packaging, shipping and dispensing.
2.      A bi-layer tablet should have elegant product identity while free of defects like chips, cracks, discoloration, and contamination.
3.      A bi-layer tablet should have the chemical and physical stability to maintain its physical attributes over time. The bi-layer tablet must be able to release the medicinal agents in a predictable and reproducible manner [6, 8].

GMP REQUIREMENTS FOR BILAYER TABLET
To produce a quality bi-layer tablet, in a validated and GMP-way, it is very important to follow the following criteria for the selection of bilayer press. These requirements seem obvious but are not so easily accomplish. The press should be capable of:
1.      Preventing capping and separation of the two individual layers that constitute the bi-layer tablet;
2.      Preventing cross-contamination between the two layers;
3.      Providing sufficient tablet hardness;
4.      Accurate and individual weight control of the two layers;
5.      Producing a clear visual separation between the two layers;
6.      Manufacturing products of high yield [6, 9].

VARIOUS APPROACHES USED IN THE BILAYER TABLET               

A.    Floating Drug Delivery System
These are designed to have a low density and thus float on gastric contents after administration until the system either disintegrates or the device absorbs fluid to the point where its density is such that it loses buoyancy and can pass more easily from the stomach with a wave of motility responsible for gastric emptying. The bilayer tablet is designed in such a manner that, one layer gives the immediate dosing of the drug which gives faster onset of action while other layer is designed as a floating layer which floats in the stomach (GI-fluid).

Disadvantages: It may not have the controlled loss of density alternatively required for it to eventually exit from the stomach. Floating tablets are not applicable to higher dose levels of highly water soluble drugs where large amounts of polymer are needed to retard drug release, as in case of water soluble drugs. The performance of floating formulation may also be posture dependant. A patient sitting upright may ensure prolonged gastric residence of a buoyant dosage form, whereas a supine patient might allow ready presentation of the floating dosage form to the pylorus and thus allow rapid exit of the dosage form from the stomach. Hence, floating dosage forms might be expected to only have limited applications.

B.     Polymeric Bioadhesive System
These are designed to imbide fluid following administration such that the outer layer becomes a viscous, tacky material that adheres to the gastric mucosa/mucus layer. This should encourage gastric retention until the adhesive forces are weakened. These are prepared as one layer with immediate dosing and other layer with bioadhesive property.

Disadvantages: The success seen in animal models with such system has not been translated to human subjects due to differences in mucous amounts, consistency between animals and humans.

The system adheres to mucous not mucosa. The mucous layer in humans would appear to slough off readily, carrying any dosage form with it. Therefore, bioadhesive dosage form would not appear to offer a solution for extended delivery of drug over a period of more than a few hours.

C.    Swelling System
These are designed to be sufficiently small on administration so as not to make ingestion of the dosage form difficult (e.g., less than approximately 23 mm long and less than 11 mm wide for an oval or capsule –shaped tablet whereas 10- 12mm in diameter for round tablets). On ingestion they rapidly swell or disintegrate or unfold to a size that precludes passage through the pylorus until after drug release has progressed to a required degree. Gradual erosion of the system or its breakdown into smaller particles enables it to leave stomach. The simple bilayer tablet may contain an immediate release layer with the other layer as extended release or conventional release [10].

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