Formulation and Evaluation of Montelukast and Levocetirizine Bilayer Tablets

INTRODUCTION

Oral drug delivery has been known for decades as the most widely utilized route of administration among all the routes that have been explored for the systemic delivery of the drugs.1 In the past few decades, 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 for promoting patient convenience and compliance. Bilayer tablets can be a primary option to avoid chemical incompatibilities between APIs by physical separation, and to enable the development of different drug release profiles (immediate release with extended release).2,3

Asthma is a common chronic inflammatory disease of the airways characterized by variable symptoms, reversible airflow obstruction and bronchospasm. Asthma is thought to be caused by a combination of genetic and environmental factors.4

Allergic rhinitis is a symptomatic disorder of the nose induced by inflammation mediated by immunoglobin E in the membrane lining the nose after allergen exposure. These symptoms occur while breathing something allergic to, such as dust, animal dander.5

Combining montelukast with levocetirizine, gives additional benefits in comparison to either drug alone and could be considered for patients whose quality of life is impaired by persistent allergic rhinitis. Montelukast is stable in alkaline condition and levocetirizine is acid stable.6 Preparing a matrix tablet, both the drugs would be in contact and make it unstable during the shelf life of the formulation. Hence it is recommended to prepare bilayer tablet, as it improves and increases the stability of both the drugs in combinations.7 The main objective of this study is to formulate and evaluate the bilayer tablets of montelukast and levocetrizine to overcome limitations of either drug alone. In the present investigation bilayer tablets of montelukast and levocetrizine were prepared using croscarmellose sodium in immediate release layer and different grades of HPMC (K15M, K100M) for sustained release layer.8

MATERIALS AND METHODS

Montelukast and levocetrizine were obtained as gift samples from Micro Lab, Bangalore, India. HPMC K100M, HPMC K15M were obtained from Karnataka Fine Lab, Bangalore. All other materials and solvents used in this study were of analytical grade.

Formulation of Bilayer Tablets of Montelukast and Levocetrizine

Preformulation studies:

The drug and excipient compatibility studies were done using FTIR. The FTIR spectra for pure drugs are obtained using a FTIR spectrophotometer Bruker Optic, Tensor 27, USA with ATR (Attenuated total reflectance).

Dose calculation for sustained release part of double layered tablet:

Initial Dose (DI)= 10 mg

Half-life of montelukast (t1/2)= 5.5 h

Elimination rate constant (Ke) = 0.693/ t1/2

                                                = 0.693/5.5

                                                = 0.126 hr-1

Calculation of sustained dose

Sustained dose = Initial dose × Ke × Time

                         = 10 × 0.126 × 12

                         = 15.12 mg

Immediate release layer contains 5 mg of levocetrizine. Sustained release layer contains 15.12 mg of montelukast.

Preparation of immediate release layer:

Levocetrizine is the fast release layer. Croscarmellose sodium was used as a super disintegrant and starch paste was used as binder. Magnesium stearate was used for lubrication and talc was added as glidant. The formula is presented in table 1. All the ingredients were weighed accurately and mixed well for about 30 min.

Preparation of sustained release layer:

In the sustained release layer, montelukast was used as active ingredient along with two dif-ferent grades of HPMC (K15M, K100M) as hydrophilic polymer. All the ingredients were mixed and then microcrystalline cellulose was added as diluent, talc was added as a glidant and magnesium stearate as a lubricant. All the above mixtures were blended properly in mortar and pestle for about 15 minutes. Formulation chart is presented in table 2.

Characterization of prepared granules:

The granules of both the layers of IR/SR were evaluated for various pre-compression parameters. The angle of repose was measured by fixed funnel method. Bulk and tapped densities were determined by tapped density apparatus from which compressibility index and Hausner ratio were calculated.

Formulation of bilayered tablets:

Bilayered tablets were prepared by using single head rotary tablet compression machine (Rimek, Mumbai). Eight mm diameter punches (Mini Press I, RIMEK, India) were used for compression. The sustained release layer granuleswere placed in the die cavity and was pre-compressed. The immediate release layer granules were placed above the pre-compressed bed of sustained release layer and subjected to full compression to obtain an intact double layered tablet with optimum hardness of 3.7 – 5.2 kg/cm2 .

The total weight of each bilayer tablet was adjusted to 225mg, containing 5mg of levocertizine in fast release layer and 15.12mg of montelukast in sustained release layer. Prepared bi-layer tablets were evaluated for various post compression parameters and in vitro dissolution studies.

Evaluation of bilayer tablets:9–11

The prepared tablets were subjected to various evaluation tests like thickness, hardness, weight variation, friability, and drug content.

Dissolution study:

The release profile of bilayer tablets were determined using USP dissolution testing apparatus II (paddle type) at 50 rpm. The dissolution test was performed using pH1.2 HCl buffer for 2 h. After 2 h the pH was raised to 6.8 by using 0.2 M tri sodium phosphate solution. Dissolution test was carried out for a period of 12 h using phosphate buffer pH 6.8. The temperature of the dissolution medium was maintained at 37 ± 0.5°. Five ml sample was withdrawn at regular intervals and replaced with the same volume of fresh dissolution medium. After filtration, the amount of drug release was determined from the standard calibration curve of pure drug.13

The in vitro dissolution data was fitted into different kinetic models like zero and first order, Korsemeyer-peppas and Higuchi model to find out the drug release profile.

Stability studies:

To assess the drug and formulation stability, short term stability studies were carried out. Short term stability studies were carried out for most satisfactory formulation. Formulation was sealed in aluminium packaging and kept in humidity chamber maintained at 30 ±2°C/ 65± 5% RH for 2 months. After 30 and 60 days, samples were analyzed for drug content and in vitro release studies.

RESULT

In the present studies the possible interaction between the levocetrizine and montelukast and polymers was carried out. The result revealed no considerable changes in the FT-IR peaks of drugs when mixed with polymers compared to pure drugs. FTIR spectra are mentioned in figure 1-5.

Bilayer tablets were successfully prepared. Precompression parameters and postcompression parameters were evaluated. The results of all formulations were found to be within limits (weight variation 0.15 to 0.35%, hardness range 4.2- 4.5kg/ cm2, friability <1%, drug content 89.12 -99.31% for levocetrizine and 95.6 – 99.46 % for montelukast.

The pre-compression data are reported in Table 3 and the post compression data in table 4. In vitro drug release studies of immediate release layer were carried out using USP type II dissolution apparatus. From in vitro drug dissolution profile of the bilayer tablet, it was found that 99.8 ± 0.11% of the levocetrizine was released from immediate release layer in 7 min from formulation F 7; data is presented in figure 6.

In vitro drug release study of sustained release layer showed that up to 6 h the percentage re-lease of F 7 was found to be 36.23%±0.65. After 6 h the release rate decreased slightly and a sustained release pattern was observed for 12 h. It was observed that formulation F7 showed high drug release rate is 90.77% ± 0.31. Results are in figure 7.From the release kinetic data it was found that all the formulations revealed zero-order release kinetics. Korsmeyer- Peppas data reveals that the drug is released by non-Fickian diffusion mechanism.

DISCUSSION

A total number of nine formulations of bilayer tablets were prepared by direct compression method using HPMC (K100M, K15M) as a drug release retardant polymer and croscarmel-lose sodium as a super disintegrant. The preformulation studies such as bulk density, tapped density, angle of repose, Carr’s index and Hausner ratio were evaluated and found to be within prescribed limits and indicated good free flowing property. The average weight of tablets was 225 mg.

In vitro drug release study:

The release of drug from bilayer tablets varied according to the types and proportion of polymers. Ideally, a bilayer tablet should release the required quantity of drug in order to maintain an effective drug plasma concentration. From in vitro drug dissolution profile of the bilayer tablet, as presented in result section above it is found that hydrophilic matrix of HPMC controlled the montelukast release effectively for 12 h. It was observed that formulation F7 showed high drug release rate is 90.77% ± 0.31. The order of drug release from the selected polymers were found to decrease in the following order HPMC K15M > HPMC K100M. Among the two grades of polymer used in tablet preparation the lower viscosity grade i.e. HPMC K15M, showed more amount of drug release than higher viscosity grade polymers i.e. HPMC K100M. The short term stability study of F7 formulation did not show any major change in physicochemical parameters and drug release profile.

CONCLUSION

In the present study we successfully formulated and evaluated bilayer tablet of levocetrizine and montelukast as a single dosage form. On the basis of the results F7 was selected as best formulation and it sustained the drug release for longer period of time over 12 h. Thus, the objective of the present work to formulate bilayer tablet, using different proportions and grades of release rate controlling and gel forming polymers like HPMC has been successfully achieved.

CONFLICT OF INTEREST

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.