Development, in Vitro Characterization and Comparative Pharmacokinetic Evaluation of Novel Controlled Release Matrix Tablets vs. Conventional Tablets of Olanzapine in Healthy Human Volunteers

摘要

Antipsychotics (including Olanzapine) are frequently associated with some agonizing adverse effects that are based on their erratic bioavailability via conventional oral dosage form(s). This commonly leads to either non-compliance or complete withdrawal from medications by concerned patients. To optimize the release pattern of Olanzapine, it was formulated into controlled release (CR) matrix tablets by direct compression method using combinations of Methocel~R K.100 LV-CR and Ethocel~R standard 7 premiums as polymeric choices. These formulations were classified as F-A, F-B, and F-C based on combinations of Methocel~R and Ethocel~R in variable proportions. Physicochemical characterizations and drug release kinetics assessment of F-C (30% Methocel~R and 60% Ethocel~R) vs F-A and F-B in various dissolution media using paddle method at 50 rpm, depicted pH-independent zero-order release kinetics for twenty four hours. Pharmacokinetic profile comparison of selected formulation (E-C) with conventional reference tablets was conducted by utilizing randomized, open-labeled, 2-period, single-dose study protocol with 2-week washout period in healthy human volunteers, using HPLC-ECD method for quantification of Olanzapine. Estimation of comparative tolerability by the volunteers was also performed by clinical assessment of severity of associated adverse effects of Olanzapine. As compare to conventional tablets CR matrix tablets exhibited significantly protracted T_(max) and optimized C_(max) values (P<0.05). The manufacturing method employed was highly reproducible and the test tablets remained stable for six months at 40±2°C/75±5% relative humidity, it was finally concluded that the successfully developed CR lest tablets may provide better tolerability and acceptability to the concerned patients towards Olanzapine by lessening the severity of associated adverse effects.