INTRODUCTION:

Various developed and developing countries move towards a combination therapy for treatment of various diseases and disorders requiring long-term therapy¹. Bilayer tablet is a fixed-dose combination intended for oral application. It is an improved technique to overcome the limitations of the single-layered tablet². Bilayer tablets contain immediate and sustained release layers. The immediate release layer delivers the initial dose; it contains super disintegrants which promote the drug release rate and attain the onset of action quickly (loading dose). Whereas, sustained release (maintenance dose) layer releases the drug in a sustained manner for a prolonged period of time by using various polymers.

Diabetic, antihypertensive, antihistamines, analgesics, antipyretics, anti-allergic agents are mainly suitable for this type of drug delivery³. Bilayer tablets have certain key advantages and applications as compared to conventional monolayer tablets⁴.

Applications of bilayer tablets⁵:

Modify total surface area

Control the delivery rate

Provide synergic property

Provide the agonistic effect

Administer fixed dose combination

Modify the total surface area of apis:

Bilayer tablet is developed to modify the total surface area of active pharmaceutical ingredients either by sandwiching with one or two inactive layers in order to achieve swellable/ erodible barriers for modified release⁵.

Control the delivery rate:

The bilayer tablet is used to control the delivery rate of either single or two different active pharmaceutical ingredients. Various controlled release bilayer tablets are formulated. Table No. 1explains the functional ingredient, amount (mg) and release patterns of immediate and sustained release layer in the bilayer tablets.

Anupamsachan N et al, (2017) developed Nitazoxanide bilayer tablets for dual delivery of the drug. The first layer is immediate release and the second layer is controlled release. Sodium Starch Glycolate was used as the super disintegrant for an immediate release of one layer and HPMC 15 as the polymer for the controlled release layer. In in vitro release study, it shows maximum release in 2 hours (24%) due to increase in the number of super disintegrants and in controlled release, it was 95% at 12th hour⁶.

Jayaprakash S et al, (2011) developed bilayer tablets of Amlodipine Besylate and Metoprolol Succinate or the management of hypertension. The Amlodipine layer was formulated as immediate release using sodium starch Glycolate and pregelatinized starch as the super disintegrant, and Metoprolol Succinate formulated as sustained release using HPMC 100 and HPMC K4 M polymers. The IR layer showed initial release with 1 min.5 sec. and 99.24% of dissolution at the end of 30 min., and sustained release with 90.46% of dissolution at 20th hour. The kinetic studies of the formulations revealed, dissolution is the predominant mechanism of drug release⁷.

PamuSandhya et al, (2014) explained the formulation and evaluation of bilayer tablets of Glimepiride and Metformin Hydrochloride by direct compression method and wet granulation technology respectively. Sodium Starch Glycolate was used in immediate release layer and ethyl cellulose N 50, HPMC 100 M in the sustained release layer. The result showed 98.44% of dissolution at the end of the 15th min. in immediate release and 98.63% of dissolution at the 12th hour in sustained release⁸.

Dr. Vijayakuchana et al, (2017) discussed the formulation and characterization of bilayer tablets of Candesartan Cilexetil for treatment of hypertension. The immediate release Candesartan contains Crospovidone as the super disintegrant and sodium alginate, HPMC 100 M, Ethyl Cellulose used in the sustained release of Candesartan. The result showed a 99.85% drug release in 12 hours⁹.

Lokesh Kumar et al, (2016) discussed combinational therapy of extended-release Rosuvastatin calcium and Fenofibrate as bilayer tablet. Super disintegrants used in the immediate release are sodium starch Glycolate and Cross carmellose sodium. Microcrystalline cellulose and HPMC K4 M are used in the sustained release layer. The research concluded that the dissolution rate of Fenofibrate was 97.5% in 30 min. and that of Rosuvastatin was 12 hours, as sustained release layer¹⁰

Navesh Veer et al, (2018) formulated and evaluated bilayer tablets of sustained release Allopurinol and immediate release Telmisartan. The first layer is the immediate release layer, using sodium and sodium starch Glycolate and the second layer is the sustained release layer, using HPMC and microcrystalline cellulose. The result shows that the percentage cumulative release in in-vitro dissolution is 100.7% in 30 min. and, 99.4% at the 12th hour in sustained release ¹¹.

China Niranjanpantra et al, (2007) discussed the design and evaluation of bilayer tablets of Propranolol Hydrochloride. Super disintegrant sodium starch Glycolate was used in the immediate release layer and water immiscible polymers like ethyl cellulose, Eudragit RLPO, and Eudragit RSPO were used in the sustained release layer. The results showed that 30% of the Propranolol Hydrochloride was released within the first 15 min. of the dissolution study and within 12 hours for sustained release layer¹².

Metkar Vishal et al, (2012) formulated and evaluated bilayer tablets of Lornoxicam. The first layer is an immediate release layer using super disintegrant Ac - di sol and a second layer is a sustained release layer using HPMC k4 M and HPMC k 100 M. The IR layer showed 24.10% of dissolution in 1 hour and the SR layer showed 98% in 24 hours¹³.

Momin Shahanoor et al, (2017) discussed the formulation and evaluation of Propranolol Hydrochloride bilayer tablet. Super disintegrant Crosspovidone was used in IR layer and ethyl cellulose, in the SR layer. The SR layer showed 87.40% of dissolution at 12th hour¹⁴.

Provide synergic property:

Bilayer tablet can be formulated to produce the synergistic effect of drugs. Rajeev Sharma et al, (2014) developed and evaluated sustained release matrix bilayer matrix tablets of Glipizide and Metformin Hydrochloride. As both the drugs are used for the treatment of diabetes by providing the synergistic action by different mechanisms such as glipizide appears to lower blood glucose acutely, by stimulating the release of insulin from the pancreas, and metformin HCl, improves glucose tolerance in patients with Type II diabetes, by decreasing the hepatic glucose production, decreasing the intestinal absorption of glucose, and by improving the insulin sensitivity by increasing peripheral glucose uptake and utilization. Both drugs are sustained release. Because of Metformin Hydrochloride is a highly water-soluble drug with high dose (500 mg), there leads to difficulty in providing an extended release rate from formulation and there might be problems in controlling the initial burst of drug from such formulation. Thus, both the drugs show incompatibility with each other, and there arises a need to develop such a system to avoid intimate contact between the two drugs, i.e. sustained release bilayer tablet formulation of Glipizide& Metformin HCl using various polymers such as Hydroxyl Propyl Methyl Cellulose K15 M, Hydroxy Ethyl Cellulose and Ethylcellulose at different concentration¹⁵.

Provide agonistic effect:

Surendra G Gattaniet al, (2012) formulated the combination of diclofenac sodium and metoclopramide in a single tablet for the treatment of a migraine because the use of immediate-release metoclopramide enhances the absorption of sustained release diclofenacsodium. Whose absorption is slower due to gastric stasis especially in a migraine. This concluded that bilayer tablets of MTH and DS might be a suitable treatment for a migraine because they allow the sequential release of the two drugs¹⁶.

To administer fixed dose combination:

Combination products, also known as fixed-dose drug combinations, are combinations of two or more active drugs in a single dosage form. To administer fixed-dose combinations of different APIs, the drug product life cycle is prolonged and novel drug delivery systems such as chewing devices, buccal or mucoadhesive delivery systems, and floating tablets, gastro-retentive delivery, are fabricated. Table No 2 explains about immediate and floating layer of the bilayer tablets with Functional ingredient, release patterns.

R.P Swain et al, (2016) formulated and evaluated immediate release simvastatin and sustained release atenolol gastro – bilayer floating tablets. This tablet was prepared by direct compression method and optimized by using hydroxyl propyl methyl cellulose K100 (37.5%) as release retardant and sodium bicarbonate as a gas forming agent in sustained release layer and super disintegrant sodium starch glycollate was used in the immediate release layer. The result showed that the optimized formulations floated on the test medium for more than 12 hours with 9 min. of floating lag time. The release time for atenolol via diffusion mechanism was 12 hours and, more than 96% release of simvastatin was within 15 min¹⁷.

Nawar M Toma et al, (2013) discussed the formulation and evaluation of bilayer tablets containing 75 mg aspirin as immediate release using cross carmellose sodium and 75 mg clopidogrel as sustained release floating layer using polymer HPMC, ethyl cellulose, carbapol, and sodium bicarbonate. The result showed that the disintegration time of aspirin was 4 min using cross carmellose sodium and its release, within 30 min. The prolonged release of floating clopidogrel was 6 hours, with 60-second floating lag time¹⁸.

P.H. Wakde et al, (2013) designed and fabricated gastro-retentive bilayer floating tablet of propranolol hydrochloride using sodium starch glycolate –super disintegrant in immediate release and Gaur gum, Pectin was used as a gel-forming agent in sustained release (floating layer) and Sodium bicarbonate and citric acid as the gas generating agent. This study showed that the optimized formula gives 98.97±0.81% of drug release in 14 hours with a lag time 8 min¹⁹.

G.V. Wadageri et al, (2012) developed and evaluated Mucoadhesive Bilayer Buccal Tablets of Carvedilol. The optimized formula contains Hydroxypropyl Methylcellulose 15 cps, Carbopol 934p, and mannitol and ethyl cellulose as backing agents. This study concluded that the addition of Carbopol 934p increases the viscosity and swelling of tablets thereby controlling the release of the drug and improving the mucoadhesive properties with in vitro drug release 84.73%, in 8 h²⁰.

Shiv Kumar et al, (2018) formulated and evaluated bilayer floating tablets of Levocetirizine and Terbutaline. The immediate release Levocetirizine contains sodium starch glycollate as a super disintegrant and the floating layer Terbutaline contains polymers like HPMC and microcrystalline cellulose. This study concluded that the optimized formula gives 100.1% of drug release in Levocetirizine in 0.3 hours and 98.9% drug release in Terbutaline in 12 hours with 71-second lag time²¹.

The Bilayer Tablet is an improved beneficial technology to overcome the shortcomings of the single-layered tablet. This article explains the fundamentals of the Bilayer Tablet system, which includes application, advantages, disadvantages, various techniques of the system, etc.²²

Y. Indira Muzib et al, in their study, "Development and Characterization of Novel Trans Buccoadhesive Bilayer Tablets of Tapentadol Hydrochloride", formulated and evaluated Buccoadhesive bilayer tablets of Tapentadol Hydrochloride. Different polymers were used for the preparation and physicochemical characteristics were evaluated. Significant differences in the results were observed, which were dependent on the characteristics and composition of the bio-adhesive materials used.²³ In the study, "Formulation, development and evaluation of immediate and sustained release Bilayer Tablets containing Amitriptyline HCl and Pregabalin for the treatment of Neuropathic Pain", P. Purushothaman et al. prepared bilayer tablet comprising of Amitriptyline HCl (AMT) and Pregabalin (PGB), for effective treatment of neuropathic pain by sequential release of the drug. Disintegrant starch, at 14.70% concentration, produced excellent results by immediately releasing AMT to exert its anti-depression and other additional beneficial effects and K100M grade of HPMC produced excellent sustained release efficiency at 1:1 drug-polymer ratio. Bilayer tablet of AMT and PGB may prove to be very effective as a combination therapy for the treatment of neuropathic pain by sequential release of the drug.²⁴The bilayer tablets provide one of the important design approaches where incompatible drugs, with a different indication, and the same drug with different release rate can be incorporated in a single unit, or where, two incompatible drugs are needed to be provided in the single dosage form. The review highlights the material attributes, formulation design, process parameters that impact the performance, and manufacturability of the multi-layer tablets.²⁵

Table No: 1 Bi layer tablet with key ingredient

AUTHOR	IMMIATE RELEASE LAYER			SUSTAINED RELEASE LAYER
AUTHOR	Functional ingredient	Amount in mg	Release pattern	Functional ingredient	Amount in mg	Release pattern
Anupam et al.	Sodium starch glycolate	9 mg	25 % in 2 hour	HPMC HPMC E15	2.5 mg 170 mg	95 % in 12^th hour
Jayaprakash S et al.	Sodium starch glycolate	5 mg	99.24% in 30 min	HPMC100 HPMC K4 M	75 mg 15 mg	90.46 % in 12^th hour
Pamusandhya et al.	Sodium starch glycolate	9 mg	98.44 % in 15 min	HPMC 100 M	160 mg	98.63 % in 12^th hour
Dr.Vijayakuchana et al.	Cross povidone	8 mg	---	HPMC 100 M Ethyl cellulose	20 mg 20 mg	99.85 % in 12^th hour
Lokeshkumar et al.	Sodium starch glycolate Cross carmellose sodium	7.70 mg 15.60 mg	97.5 % in 30 min	HPMC K 4 M	90 mg	12 hour
Naveesh veer et al.	Sodium starch glycolate	25 mg	100.7 % in 30 min (% cumulative release)	HPMC	90 mg	99.4 % in 12^th hour
Chinamniranjanpathra et al.	Sodium starch glycolate	2.5 mg	30 % in 15 min	Ethyl cellulose eudragit RLPO eudragit RSPO	55 mg 82.5 % 82.5 %	12 hour
Metkarvishal et al.	Cross carmellose sodium	18 mg	24.10% in 1 hour	HPMC K 4 M HPMC 100 M	50 mg 25 mg	98 % in 24 hour
Momin Shahanoor	Cross carmellose sodium	1 mg	---	Ethyl cellulose	165 mg	87.40 % in 12^th hour

Table No: 2 Administer fixed dose combination

Author	Immediate release layer		Floating layer
Author	Functional ingredient	Release pattern	Functional ingredient	Release pattern	Lag time
R.P Swain et al.	Sodium starch Glycollate	96%within 15 min.	HPMCk 100	12 hour	9 min.
Nawar M Toma et al.	Cross Carmellose Sodium	Within30 min.	HPMC, Ethyl cellulose, Carbapol	6 hours	60 sec
P.H. Wakde et al.	Sodium starch Glycolate	---	Guar gum, Pectin	98.97% in 14 hour	8 min
Shiv Kumar et al.	Sodium starch Glycolate	100.1% in 0.3 hour	HPMC, Microcrystalline cellulose	98.9% in 12 hour	71 sec

In "Formulation and In-vitro Evaluation of Immediate Release Bilayer Tablets of Telmisartan and Amlodipine Besylate", Soham Shukla et al. developed a stable formulation of antihypertensive drugs of telmisartan and amlodipine besylate as an immediate release bilayer tablet and evaluated their pre-compression and post-compression parameters. Croscarmellose Sodium (CCS) was used as the super disintegrant and In vitro dissolution was carried out using USP dissolution apparatus type 2 (paddle) by using the HPLC method. The optimized formulation F-7 had 98.13% of drug release for telmisartan layer and 96.38% drug release for amlodipine besylate layer. The results suggest the feasibility of developing bilayer tablets with two drugs, Telmisartan and Amlodipine besylate, for the convenience of patients with severe hypertension, especially when monotherapy fails to control the blood pressure.²⁶ In the study, "Formulation Development and Evaluation of Bilayer Tablets of Telmisartan for Immediate Release and Metformin Hydrochloride for Sustained Release", Nishanth I. et al. developed bilayer tablets containing Telmisartan for immediate release and Metformin hydrochloride for sustained release. From the results, Bilayer tablet showed an initial burst effect to provide a dose of immediate release layer Telmisartan to control the blood pressure level and the sustained release of Metformin HCl, for 10 hours, to control the blood glucose level. The developed formulation provides an alternative to the conventional dosage form for the treatment of hypertension in patients with type II diabetes mellitus. Combination of Telmisartan as an immediate release layer and Metformin HCl as a sustained release layer reduces polytherapy to monotherapy and improves the patient compliance.²⁷Hamid Khan et al. formulated and evaluated in-lay tablets containing Telmisartan as a sustained release outer core and Hydrochlorothiazide as an immediate release inner core using HPMC and co-polymer Carbopol 71G. The tablets prepared, showed extended sustained release of Telmisartan over a period of 20 h and an immediate release of Hydrochlorothiazide within 30 min.²⁸

The study, "Formulation and Evaluation of Sustained Release Matrix Tablets Containing Aceclofenac and Paracetamol", by Hamid Khan et al, shows the formulation and evaluation of sustained release matrix tablets by Wet Granulation Method. Both the drugs are slightly soluble in water and have an almost similar half-life (3-4h). Hence they were formulated as sustained release matrix tablets. Sustained release matrix tablets containing Aceclofenac and Paracetamol were prepared and evaluated. HPMC K100 was used as matrix forming hydrophilic polymer along with PVP binder for both the drugs.²⁹ In "Design and Development of Sustained Release bilayered tablets of Glipizide" by Salma Banu S.K. and Venkateswara Rao T., they formulated and evaluated bilayer tablets of Glipizide. 30% of the drug present in the immediate release layer was released within the first 20 minutes and the remaining 70% of the drug's release was sustained based on the polymer selected. The formulation which comprised of HPC and HPMC as the polymers sustained the drug release for 12hrs and were found to be the best formulation.³⁰Prakash N Kendre et al., in the "Formulation and in vitro-in vivo Evaluation of Theophylline and Salbutamol Sulphate Sustained-Release Tablets", formulated and evaluated bilayer tablets of Theophylline and Salbutamol Sulphate, which indicated, for the management of asthma, their frequent dosing may reduce compliance, thus making prolonged release formulation necessary. The release rate could efficiently be modified by varying the matrix forming a polymer, the use of polymer blends and the addition of water soluble or water insoluble fillers (such as Dicalcium Phosphate, Lactose or Mannitol). The tablets swelled and eroded upon contact with release medium. Fitting the in-vitro drug release data to Korsmeyer Equation indicated that diffusion along with erosion could be the mechanism of drug release.³¹

CONCLUSION:

Bilayer Tablet is suitable for sequential release of two drugs. This technology avoids dose depended on side effects and also reduces the frequency of administration of the dosage form. Conventional solid oral dosage forms are traditional, but the Bilayer Tablet is a novel approach. Bilayer Tablets have various advantages such as increased synergic property, controllability of drug delivery for the administration of fixed-dose combinations and increased surface area of APIs.

ACKNOWLEDGEMENT:

The authors are grateful to the authorities of Nirmala College of Pharmacy, Muvattupuzha, Kerala.

CONFLICT OF INTEREST:

The authors declare no conflict of interest.

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Received on 04.09.2018 Modified on 17.11.2018

Research J. Pharm. and Tech. 2019; 12(5):2539-2544.

DOI: 10.5958/0974-360X.2019.00427.X