FORMULATION DEVELOPMENT AND STATISTICAL OPTIMIZATION OF A BILAYER TABLET OF BOSENTAN MONOHYDRATE AND SILDENAFIL CITRATE IN MANAGEMENT OF PULMONARY ARTERIAL HYPERTENSION

Abstract

Objective: The current study aims at fabrication of an oral bilayer matrix tablet of bosentan monohydrate and sildenafil citrate; the optimisation of their in vitro release and characterization, thereby reducing the side effects associated with bosentan, reducing dosing frequency and increasing patient compliance in the management of pulmonary arterial hypertension.

Methods: Methocel K4M Premium DC2, a directly compressible HPMC grade was used as the sustained release polymer. Pregelatinised starch is used as a diluent and release modifier and sodium lauryl sulphate (SLS) as a solubiliser. The blends of both layers were prepared, evaluated for precompression characteristics and compressed by direct compression. The compressed bilayer tablets were evaluated for their hardness, weight variation, friability, content uniformity and swelling index. The principle objective was to assess the influence of the above variables on in vitro drug release of Bosentan using a 2³ factorial design. Responses are measured as drug release at 2h (Q2), 6h (Q6) and 10h (Q10).

Results: HPMC and pregelatinized starch form a synergistic gel thereby controlling drug release of bosentan for a 12 hour period. Batch BS09 consisting of 40 mg HPMC, 30 mg Pregeletinized starch and 5 mg SLS showed adequate controlled release for a 12 h period. Immediate release layer of sildenafil citrate showed optimum drug release of 102.96% within 30 min.

Conclusion: Bilayer tablet of bosentan and sildenafil is an ideal combination for patients failing monotherapy in pulmonary arterial hypertension.