Oral floating extended release stavudine hydrophilic matrix tablets: formulation design and in vitro investigations

Abstract

Stavudine (d4T) is a nucleoside analogue reverse transcriptase inhibitor commonly used as part of highly active antiretroviral therapy, which is administered twice a day. Formulation of extended-release (ER) d4T improves patient compliance and minimizes dose related side effects. This study, therefore, aims at formulating once-a-day floating d4T ER hydrophilic matrix tablets using hydroxypropyl methylcellulose (HPMC) as a release-modifying polymer. NaHCO3 and microcrystalline cellulose (MCC), grade Avicel® PH 101, were used as floating aid and release modifier, respectively. The effects of the levels of NaHCO₃ (5 -10%), MCC (25 - 40%) and compression force (CF) (10 - 20 KN) on floating lag time, friability (Fr), release, and other tablet characteristics were assessed. The release kinetics was determined by fitting the data into different models. Floating lag-time, Fr and d4T release were optimized using a 2-level 3-factor full factorial experimental design and the optimum regions obtained were validated and therapeutic levels of d4T release were obtained for a period of 24 h from all formulations. The results indicated that CF has considerable impact on floating lag time. The floating lag-time of the tablets, at a CF of 10 KN and concentrations of MCC and NaHCO₃ indicated above, was below 25 min. However, when the CF was raised to 20 KN, the minimum lag time was 75 min. The effect of NaHCO3 on floating lag time was dependent on the level of MCC, suggesting that its level should be increased with MCC level. For acceptable Fr, MCC should be increased at a lower level of NaHCO₃. CF significantly decreased Fr. Thus, Fr and floating lag time are absolutely competitive responses. Therefore, an optimum region for these responses was obtained. As evidenced by the similarity factor, the release rate was not significantly affected by the levels of NaHCO₃, MCC or CF. Nonetheless, optimum region for the desired drug release was obtained which followed first order at 25% MCC level, and Korsemeyer-Peppas model at 40%. Validation of the optimum formulation confirmed the results obtained. Thus, the in vitro results showed that the d4T regimen could be reduced from twice a day to once a day. .


Ethiopian Pharmaceutical Journal Vol. 25 (1) 2007: pp. 51-62