INTRODUCTION:
Pharmacological therapies either require or benefit from the administration of drugs in a sequential manner. These combined formulations function from a single dosage form, which simplifies the therapy and reduces or eliminates the chances of improper administration. [1] There are many routes to deliver drugs into the body, viz oral (through swallowing), sub mucosal (through buccal and sublingual mucosa), parenteral (through injection), transdermal (through skin), pulmonary (through inhalation) etc. Despite disadvantages, oral drug delivery remains the preferred route of drug delivery due to patient compliance. [2] It is well known that modified release dosage forms may offer one or more advantages over immediate release formulations of the same drug. The design of modified release drug product is usually intended to optimize a therapeutic regimen. Usually conventional dosage form produce wide ranging fluctuations 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.
Bilayer tablet is new era for the successful development of controlled release formulation along with various features to provide a way of successful drug delivery system. In the last decade, interest in developing a combination of two or more Active Pharmaceutical Ingredients (API) in a single dosage form (bi-layer tablet) has increased in the pharmaceutical industry.
Bilayer formulations carry more than one drug and deliver each of them without any pharmacokinetic or dynamic interactions, with their individual rate of delivery. 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. [3,4]
Fig.1: Bilayer Tablet[3,4]
Need of Bilayer Tablets: [5-8]
1 For the administration of fixed dose combinations of different APIs, prolong the drug product life cycle, buccal/mucoadhesive delivery systems; fabricate novel drug delivery systems such as chewing device and floating tablets for gastro-retentive drug delivery.
2 Controlling the delivery rate of either single or two different active pharmaceutical ingredients.
3 To modify the total surface area available for API layer either by sandwiching with one or two in active layers in order to achieve swellable/erodible barriers for modified release.
4 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 (such as, osmotic property).
Advantages of The Bilayer Tablet Dosage Form: [5-8]
1 Product identification is easy and rapid requiring no additional steps when employing an embossed and/or monogrammed punch face.
2 Cost is lower compared to all other oral dosage form.
3 Greatest chemical and microbial stability over all oral dosage form.
4 Objectionable odour and bitter taste can be masked by coating technique.
5 Flexible Concept.
6 They are unit dosage form and offer the greatest capabilities of all oral dosage form for the greatest dose precision and the least content variability.
7 Easy to swallowing with least tendency for hang up.
8 Suitable for large scale production.
Disadvantages of Bilayer Tablet Dosage Form: [5-8]
1 Some drugs resist compression into dense compacts, owing to amorphous nature, low density character.
2 Bitter tasting drugs, drugs with an objectionable odour or drugs that are sensitive to oxygen may require encapsulation or coating.
3 Difficult to swallow in case of children and unconscious patients.
4 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.
Ideal Characteristics of Bilayer Tablets: [5-9]
1 A bilayer tablet should have elegant product identity while free of defects like chips, cracks, discoloration and contamination.
2 It should have sufficient strength to withstand mechanical shock during its production packaging, shipping and dispensing.
3 It should have the chemical and physical stability to maintain its physical attributes over time. The bilayer tablet must be able to release the medicinal agents in a predictable and reproducible manner.
4 It must have a chemical stability shelf-life, so as not to follow alteration of the medicinal agents.
Preparation of Bilayer Tablets: [10-17]
Bilayer tablets are prepared with one layer of drug for immediate release with the second layer designed to release drug later, either as a second dose or in an extended release form. The bilayer tablets with two incompatible drugs can also be prepared by compressing separate layers of each drug so as to minimize area of contact between two layers. An additional intermediate layer of inert material may also be included.
Compaction:
To produce adequate tablet formulation, certain requirements such as sufficient mechanical strength and desired drug release profile must be met. At times, this may be difficult task for formulator to achieve these conditions especially in bilayer tablet formulation where double compression technique is involved, because of poor flow and compatibility characteristics of the drug which will result in capping and/or lamination. The compaction of a material involves both the compressibility and consolidation.
1.Compression:
It is defined as reduction in bulk volume by eliminating voids and bringing particles into closer contacts.
2.Consolidation:
It is the property of the material in which there is increased mechanical strength due to inter particulate interaction (bonding). The compression force on layer 1 was found to be major factor influencing tablet delamination.
Quality and GMP Requirements: [18-21]
To produce a quality bilayer tablet in a validated and GMP-way, it is important that the selected press is capable of :
1 Preventing capping and separation of the two individual layers that constitute the bilayer tablet.
2 Providing sufficient tablet hardness.
3 Preventing cross-contamination between the two layers.
4 Producing a clear visual separation between the two layers.
5. High yield Accurate and individual weight control of the two layers.
These requirements seem obvious but are not so easily accomplished
Types of Tablet Press:[6,22-24]
1. Single sided tablet press.
2. Double sided tablet press.
3. Bilayer tablet press with displacement monitoring.
Fig 2: Preparation of bilayer tablet Compaction[10]
1. Single Sided Press:
Fig.3: Single Sided 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 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:
1 No weight monitoring / control of the individual layers.
2 No distinct visual separation between the two layers.
3 Very short first layer dwell time due to the small compression roller, possibly resulting in poor deaeration, capping and hardness problems.
4 This may be corrected by reducing the turret rotation speed (to extend the dwell time) but with the consequence of lower tablet output.
2. Double Sided Tablet Press:
Fig.4: Double Sided Tablet Press
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.
3. Bilayer Tablet Press With Displacement Monitoring:
Fig.5: Tablet Press With Displacement Monitoring
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 pre-compression force.
Advantages:
1 Weight monitoring / control for accurate and independent weight control of the individual layers.
2. Low compression force exerted on the first layer to avoid capping and separation of the two individual layers.
3 Independence from the machine stiffness.
4 Increased dwell time at pre-compression of both first and second layer to provide sufficient hardness at maximum turret speed.
5 Maximum prevention of cross-contamination between the two layers.
6 Clear visual separation between the two layers and maximized yield.
4. Different Tablet Presses For Bilayer Tablets:[25-27]
The XM 12 Bi-Layer Tablet Press features a retractable second layer feeder that permits automated first layer sampling at production speeds. The first layer sampling capability also offers a hardening feature, in which the main compression station will automatically compress the first layer tablet for in-process measurement. The two feeders are zero clearance and are configured with an integrated dust extraction manifold which cleans the die table and completely eliminates any potential for cross-contamination. WipCon® solution available for potent for Small-Scale Bi-layer Applications. The KORSCH XM 12 Bi-Layer Tablet Press is a small-scale press which is ideal for product development scale-up, clinical trials and midrange production. The bi-layer execution, single-layer conversion kit and exchangeable turret offer unprecedented flexibility. The XM 12 Bi-Layer Tablet Press offers a new standard in GMP with extreme accessibility to the compression zone and a combination of quick disconnects and smooth surfaces that permit fast cleaning and changeover. The machine features are
Fig.6: XM 12 Bi-Layer Tablet Press
4.1) Small-Scale bi-Layer:
a) 5 KN First Layer Tamping Force.
b) 40 KN Pre-compression Force.
c) 80 KN Main Compression Force.
d) Single-Layer Conversion Capability.
4.2) Bi-layer application:
The XM 12 features an exchangeable turret capability to permit a single machine to run all press tool sizes to provide maximum flexibility and versatility. An internal lift arm eliminates the cost and space requirement of a large external turret removal device.
a) Single layer conversion kit adds yet another dimension of flexibility.
b) Single Layer Conversion.
c) 30 Minute Conversion Time.
d) High Speed Single-Layer Capability (120 RPM)
Advantages:
a) Flexible Concept.
b) Bi-Layer execution with optional single-layer conversion kit.
c) Exchangeable turret.
d) Turret sizes for product development, scale-up, and mid-range production.
e) Full production capability in a scale-up machine.
f) Self-contained, fully portable design.
g) Fast and Easy Changeover.
h) Internal turret lift device for extreme simplicity in turret removal and installation.
i) Clean compression zone with quick-disconnect design.
Various Techniques for Bilayer Tablet: [28-30]
1. OROS® Push Pull Technology:
This system consist of mainly two or three layers among which the one or more layers are essential of the drug and other layers are consist of push layer. The drug 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. 7: Bilayer and trilayer OROS Push pull technology.
2. L-OROS Tm Technology:
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. 8: L – OROS tm technology.
3. 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.
Fig.9: EN SO TROL technology.
4. DUROS Technology:
The system consists from an outer cylindrical titanium alloy reservoir. 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 release minute quantity of concentrated form in continues and consistent from over months or year.
Fig.10: DUROS Technology
5. 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 for 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 greater 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 bilayer effect to the final dosage form. 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.
Challenges In Bilayer Manufacturing:[31,32]
Conceptually, bilayer tablets can be seen as two single layer tablets compressed into one. In Practice, there are some manufacturing challenges.
1.Delamination: Tablet falls apart when the two halves of the tablet do not bond completely. The two granulations should adhere when compressed.
2.Cross-contamination: When the granulation of the first layer intermingles with the granulation 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.
3.Production yields: To prevent cross contamination, dust collection is required which leads to losses. Thus, bilayer tablets have lower yields than single layer tablets.
4.Cost: Bilayer tabletting is more expensive than single layer tabletting for several reasons. First, the tablet press costs more. Second, the press generally runs more slowly in bilayer mode. Third, development of two compatible granulations is must, which means more time spent on formulation development, analysis and validation. These factors, if not well controlled/optimized, in one way or another will impact the bilayer compression per se and the quality attributes of the bilayer tablets (sufficient mechanical strength to maintain its integrity and individual layer weight control). Therefore, it is critical to obtain an insight into the root causes to enable design of a robust product and process.
Various Approaches Used In The Bilayer Tablet: [33,34]
A) Floating Drug Delivery System:
From the formulation and technological point of view, the floating drug delivery systems are considerably easy and logical approach in the development of Gastro-retentive dosage forms (GRDFs).
Approaches To Design Floating Drug Delivery System:
The following approaches have been used for the design of floating dosage forms of single and multiple unit systems.
i) Intra Gastric Bilayered Floating Tablets:
Fig.11: Intra Gastric Bilayered Floating Tablets
Floating systems or hydro-dynamically controlled systems are low-density systems that have sufficient buoyancy to float over the 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. While the system is floating on the gastric contents, the drug is released slowly at the desired rate from the system. After release of drug, the residual system is emptied from the stomach. This results in an increased GRT and a better control of the fluctuations in plasma drug concentration. These are also compressed tablet and contain two layers i.e. immediate and sustained release.
ii) 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.
Fig. 12: Multiple units of oral FDDS
B) Polymeric Bioadhesive System:
Fig. 13: Polymeric Bioadhesive System
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 bioadhesive property for sustained release or with two drugs showing synergistic effect or which are incompatible.
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. 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.
Evaluation of Bilayer Tablet: [35-39 ]
a) Pre-Compression Evaluation Parameters:
1. Particle size distribution:
The particle size distribution can be measured using sieving method.
2. Angle of Repose:
The diameter of the powder cone was measured and the angle of repose was calculated using the following equation:
where h and r are the height and radius of the powder cone.
3. 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.
4. 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 ð2Þ
TBD ¼ weight of the powder = tapped volume of the packing ð3Þ
5. Compressibility:
The compressibility index of the disintegrate was determined by Carr’s compressibility index.
Where 
is the freely settled
bulk density of the powder and 
is the tapped density
of the powder.
6. Hausnser’s ratio:
It is calculated by the formula,
b) Post-Compression Evaluation of Bilayer Tablet:
1. General Appearance:
The general appearance of a tablet, its visual identity and overall elegance is essential for consumer acceptance. It includes tablet’s size, shape, color, presence or absence of an odor, taste, surface texture, physical flaws and consistency and legibility of any identifying marking.
2. Tablet Thickness and Size:
Thickness and diameter of tablets were important for uniformity of tablet size. Thickness and diameter was measured using vernier caliper.
3. 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.
4. Friability:
Friability is the measure of tablet strength. Electrolab 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
5. 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.
6. 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.
7. Stability Study (Temperature Dependent):
The bilayer tablets are packed in suitable packaging and stored under the following conditions for a period as prescribed by ICH guidelines for accelerated studies. The tablets were withdrawn after a period of 15 days and analyzed for physical characterization (Visual defects, Hardness, Friability and Dissolution etc.) and drug content. The data obtained is fitted into first order equations to determine the kinetics of degradation.
Commercially Available Bilayer Tablets: [40]
|
Product Name |
Chemical Name |
Developer |
|
ALPRAX PLUS |
Sertraline, Al70prazolam |
Torrent Pharmaceuticals Ltd |
|
Glycomet® GP2Forte |
Metformin hydrochloride, Glimepiride |
USV Limited |
|
Newcold Plus |
Levocetrizine hydrochloride, Phenyl propanolamine, Paracetamol |
Piramal Healthcare Ltd. |
|
DIUCONTIN-K®20/250 |
Furosemide, Potassium chloride |
T.C. Health Care Pvt. Ltd. |
|
DIAMICRON® XRMEX500 |
Gliclazide, Metformin hydrochloride |
Sedia® Pharmaceuticals (India) Pvt. Ltd. |
|
Revelol®- Am 25/5 |
Metoprolol succinate, Amlodipine besilate |
Ipca Laboratories Ltd. |
CONCLUSION:
Bilayer tablets offer an excellent opportunity for manufacturers to separate themselves from their competitors, improve their product efficacy and protect against impersonator products. Bilayer tablet quality and GMP requirements can vary widely. This explains why many different types of presses are being used to produce bilayer tablets, ranging from simple single sided presses to highly sophisticated machines. When a quality of bilayer 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 inter layer bonding. Such problems become even more apparent when the tabletting 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, the use of an ‘air compensator’ in combination with displacement control also appears to be the best solution.
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Received on 17.10.2013 Modified on 28.10.2013
Accepted on 01.11.2013 © RJPT All right reserved
Research J. Pharm. and Tech. 6(12): Dec. 2013; Page 1443-1451