Pulsatile Delivery of Methylphenidate Hydrochloride Pulsincap by Box-Behnken Design

Abstract

The objective of this study was to prepare and evaluate Methylphenidate hydrochloride pulsatile drug delivery system using pulsincap technique by applying Box-Behnken design. The drug is a central nervous system (CNS) stimulant used in the treatment of attention deficit hyperactivity disorder (ADHD). Pulsincap system was prepared by using formaldehyde cross linked capsules. Capsules were filled with methylphenidate hydrochloride granules and hydrogel plug made of HPMC K100M is placed over granules to achieve desired drug release after lag time. The untreated cap was then fitted and sealed using 5% ethyl cellulose ethanolic solution to the formaldehyde treated capsule body. Granules were prepared by wet granulation technique using two polymers Ethyl cellulose and Eudragit RS100. Box-Behnken design was applied for optimization in which three independent variables, X1 = Drug: polymer ratio, X2 = Polymer: polymer ratio (Ethyl cellulose: Eudragit RS 100) and X3 = Plug weight were selected. Two dependent variables Y1 = lag time and Y2 = percent release were selected. The empty formaldehyde treated capsules were evaluated for physical appearance, solubility, capsule dimensions and formaldehyde content. Hydrogel plugs were evaluated for hardness & thickness of the plug, lag time and swelling index. Granules were evaluated for percentage yield, assay and flow properties. The prepared pulsincap formulations were evaluated for weight variation, content uniformity, capsule lock length, in-vitro dissolutions studies, drug kinetics and stability studies. Contour plots and Response surface plots indicated that with the increase in X1 and X3 there is increase in Lag time and decrease in % drug release and whereas with the increase in X2 the lag time was at moderate level and % drug release was increased. From this observation, formulation F11 was optimized as it provided desired lag time of 4.2\(\pm\)0.27 hours and least drug release of 72\(\pm\)0.09% for 8 hrs. The formulations were found to be physically compatible with excipients and stable.