Bilayer Tablets: An Emerging Trend
ABSTRACT
The interest in bilayer tablet as an oral immediate-release/controlled-release system has substantially increased in the past decade. Formulation of bi-layer or multi-layer tablets enables the combination of two or more drugs that may be incompatible or maybe intended for delivery at different rates. 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 provides 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.
INTRODUCTION
Oral drug delivery is most commonly route of administration, when compared to all other route of administration Bilayer tablet is new era for successful development of controlled release formulation along with various features to provide successful drug delivery system. It is well known that modified release dosage forms may offer one or more advantages over immediate release formulations of the same drug. A bilayer tablet involves the compression of two formulations into a single solid oral tablet, while maintaining a physical separation of the formulations by layering one on top of the other. It enables the controlled delivery of either a single or of multiple active pharmaceutical ingredients within a single tablet. This is particularly beneficial when, for example, one of the tablet layers provides an immediate release and the second layer a sustained release delivery. Bilayer is considerably more convenient for patients due to receive multiple medications or longer-lasting profiles in a single dosage form and has the added benefit of improved patient compliance.
Keywords: immediate-release, controlled-release, modified release, sustain release, bilayer, excipient.
TYPES OF LAYER TABLETS
1. Single-layer tablet.
2. Bi-layer tablet.
3. Multi-layer tablet.
PREPARATION OF BILAYER TABLET COMPACTION
Bilayer tablets are prepared with one layer of drug for immediate release and second layer designed to release drug either as a second dose or in an extended release form.
Manufacturing bilayer tablets has its own unique challenges mainly
for tablet delamination, cross-contamination layers, layer separation,
maintaining acceptable weight and depth control, and achieving acceptable
yields and throughput. In Practice, there are some manufacturing challenges.
Delamination
Tablet falls apart when the two halves of the tablet do not bond
completely. The two powders should adhere when compressed.
Cross-Contamination
When the powders of the first layer intermingle with the powders of
the second layer or vice versa, cross-contamination occurs. It may conquer the
very purpose of the bilayer tablet. Proper dust collection goes a long way
toward preventing cross contamination.
Production Yields
To prevent cross contamination, dust collection is required which
leads to losses. Thus, bilayer tablets have lower yields than single-layer
tablets.
Cost
Bilayer tableting is more expensive than single layer tableting for several reasons. First, the tablet press costs more. Second, the press generally runs more slowly in bilayer mode. Third, development of two compatible powders is must, which means more time spent on formulation development, analysis, and validation.
Traditional inert excipients with lack of desired functionalities have drawn the attention of pharmaceutical formulator in developing new co-processed excipient. It is predicted that the development of tailor-made designed excipients complying with safety, performance, and regulatory issues is a current and future trend in bilayer technology. With advantages offered by the upcoming newer combination of excipients and newer methods of co-processing, co-processed excipients are for sure going to gain attraction both from pharmaceutical excipient industry and pharmaceutical formulation industry. Furthermore, it opens the opportunity for development and use of single multifunctional excipients rather than multiple excipients in formulation. So, there is enough scope of development of new co-processed excipients to meet the demand of pharmaceutical industries for bilayer tablets.
SINGLE SIDED PRESS5
The simplest design is a single sided press with both chambers of
the doublet feeder separated from each other. Each chamber is gravity or forced
fed with different power, producing the two individual layers of tablets. When
die passes under the feeder, it is first loaded with the first layer powder
followed by the second layer powder. Then the entire tablet is compressed in
one or two steps.
·
Limitations of the single sided press
·
No
weight monitoring / control of the individual layers.
·
No
distinct visual separation between the two layers.
·
Capping
and hardness problems.
DOUBLE SIDED TABLET PRESS5
In 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 the layer. This measured peak compression force is the signal
used by the control system to reject out of tolerance and correct the die fill
depth when required.
BILAYER TABLET PRESS WITH
DISPLACEMENT MONITORING6
The displacement tablet
weight control principle is fundamentally different from the principle based
upon compression force. When measuring displacement, the control system
sensitivity does not depend on the tablet weight but depends on the applied
precompression force
Advantages
·
Weight
monitoring / control weight of the individual layers.
·
Avoid
capping and separation of the two individual layers.
·
Independence
from the machine stiffness.
·
Provide
sufficient hardness at maximum turret speed.
·
Maximum
prevention of cross-contamination between the two layers.
·
Clear
visual separation between the two layers and maximized yield.
NEED OF BILAYER TABLETS7,8,9
· Controlling the delivery rate of single or two different
active pharmaceutical ingredients.
· To separate incompatible Active pharmaceutical ingredient
(APIs) from each other.
· To control the release of API from one layer by utilizing the
functional property of the other layer.
· For the administration of fixed dose combinations of
different APIs.
ADVANTAFES OF BILAYER TABLETS
·
Maximum chemical and microbial stability over all oral dosage
form.
·
Offensive odour and bitter taste can be masked by coating
technique.
·
They offer greatest dose accuracy and least content
variability.
·
Easy to swallowing with least tendency for hang up.
·
Suitable for large scale production
DISADVANTAGES OF BILAYER TABLETS
·
Some drugs resist compression into dense compacts due to low
density character.
·
Bitter tasting drugs or drugs that are sensitive to oxygen
may require coating.
·
Difficult to swallow in case of children and unconscious
patients.
·
Drugs with poor wetting, slow dissolution properties may be
difficult to formulate.
VARIOUS APPROACHES USED IN THE BILAYER TABLET10,11
FLOATING DRUG DELIVARY SYSTEM
From the formulation and technological point of view, the floating drug delivery system considerably easy and logical approach in the development of Gastro retentive dosage forms (GRDFs).
The following approaches have been used for the design of flowing dosage forms of single and multiple-unit system.
Intra gastric bilayered floating tablets
These are also compressed tablet as and contain two layers i.e. Immediate and sustained release.
Multiple unit type
floating pills
These systems consist of sustained
release pills as ‘seeds’ surrounded by double layers. The inner layer consists
of effervescent agents while the outer layer is of swellable membrane layer.
When the system is immersed in dissolution medium at body temperature, it sinks
at once and then forms swollen pills like balloons, which float as they have
lower density
POLYMERIC BIO ADHESIVE SYSTEM12
These are designed to imbibe 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 bio adhesive property.
Disadvantages
The success is 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.
SWELLING SYSTEM13
These are designed to be sufficiently small on administration
so as not to make ingestion of the dosage form difficult. On ingestion they
rapidly swell or disintegrate and passage through the pylorus until after drug
release has progressed to a required degree. The simple bilayer tablet may
contain an immediate release layer with the other layer as extended release.
RECENT DEVELOPMENT IN FIELD OF BILAYER TABLETS
Large number of works has been done
in the pharmaceutical industries. Some of the recent findings are explained in
the below table.
|
DRUG(S) |
DOSAGE FORM |
RATIONALE |
|
Metformin
HCl, Glimipiride14 |
Bilayer
tablets |
Synergistic
effect in diabetes |
|
Metformin HCl, Atorvastatin Calcium15 |
Bilayer
tablets |
To
develop polytherapy for the treatment of NIDDS & hyperlipidemia |
|
Metformin HCl,
Pioglitazone HCl16 |
Bilayer tablets |
Synergistic
effect in diabetes mellitus |
|
Metformin,
Glipizide17 |
Bilayer tablets |
Synergistic
effect in diabetes mellitus |
|
Diclofenac
Potassium, Cyclobenzaprine HCl18 |
Bilayer tablets |
Synergistic
effect in pain. |
|
Diclofenac
Sodium, Paracetamol19 |
Bilayer tablets |
Synergistic
effect in pain. |
|
Ibuprofen,
Methocarbamol20 |
Bilayer tablets |
Synergistic
effect in back pain. |
|
Paracetamol,
Diclofenac Sodium21 |
Bilayer tablets |
Synergistic
effect of drugs in pain. |
|
Tramadol,
Acetaminophen22 |
Bilayer tablets |
Synergistic
effect of drugs in pain. |
|
Cefixime
Trihydrate, Dicloxacillin Sodium23 |
Bilayer tablets |
Synergistic
effect in bacterial infections |
|
Atorvastatin,
Calcium24 |
Bilayer buccal
tablets |
To overcome
bioavailability problem, reducing side effect and frequency of administration |
|
Atenolol,
Lovastatin25 |
Bilayer floating
tablets |
Synergistic
effect in hypertension and biphasic release profile |
CONCLUSION
Bi-layer tablets provide one of the important design approaches where incompatible drugs, with different indication, and same drug with different release rate can be incorporated in a single unit. Bi-layer tablets offer an excellent opportunity for manufacturers to separate themselves from their competitors, improve their products, efficacy, and protect against impersonator products. Bi-layer 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. When a quality bi-layer tablet needs to be produced in conjunction with accurate weight control of both layers, compression force-controlled presses are clearly limited because of their insufficient sensitivity and hence lack of accuracy at low compression forces required to secure interlayer bonding. Such problems become even more apparent when the tableting speed is high or increased. Accurate individual layer weight monitoring/control at high speed and in combination with reduced layer separation risk can be achieved with the displacement weight control system-based presses. It is a new technology of tablet formulation and dosage form and further improvement in this field is appreciable.
ACKNOWLEDGEMENT
The authors would like to acknowledge Dr. D.P. Singh, Ex-University Professor for support and discussion relating to this article and deep gratitude for their guidance, enthusiastic encouragement, support during my Ph.D. and grateful to our colleagues Mr. Gaurav Tripathi, Works Manager, Mr. Sanjay Chauhan, Sr. Manager, Supply Chain, and Ms. Monika Tomar, Manager-R&D, Sigachi Industries Private Limited, Telangana, India for support.
FUNDING:
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
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Abbreviations
Active Pharmaceutical Ingredients, NIDD: Non-Insulin-Dependent diabetic, HCl: Hydrochloric Acid, R&D: Research and Development
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