Osmotically controlled pulsatile release capsule of montelukast sodium for chronotherapy: Statistical optimization, in vitro and in vivo evaluation

The purpose of present study was to design, optimize and evaluate osmotically controlled pulsatile release capsule (PRC) of montelukast sodium (MKS) for the prevention of episodic attack of asthma in early morning and associated allergic rhinitis. Assembly of the capsular systems consisted of push, active and plug tablet arranged from bottom to top in hard gelatin capsule. The capsule system was coated with a semi-permeable membrane of cellulose acetate and drilled towards plug side in cap. A three-factor, three-level central composite design (CCD) with α = 1 was introduced to execute the experiments and quadratic polynomial model was generated to predict and assess the independent variables with respect to the dependent variables. The composition of optimal formulation was determined as weight of push tablet 138 mg (coded value: +0.59), plug tablet 60 mg (coded value: +0.49) and coating weight gain of 8.4 mg (coded value: -0.82). The results showed that the optimal formulation of PRCs had lag time of 4.5 h, release at 6 and 12 h are 61.95% and 96.29%, respectively. The X-ray radiographic imaging study was carried out to monitor the in vivo behavior of developed barium sulfate-loaded PRCs in rabbits under fasting conditions. In vivo pharmacokinetic study revealed T_max of 2 h for marketed tablets; however 7 h for PRCs with initial lag time of 4 h. Thus designed capsular system may be helpful for patients with episodic attack of asthma in early morning and associated allergic rhinitis.