Transdermal controlled delivery of antiparkinsonian agent, benztropine: Formulation development and pharmacokinetic evaluations.

摘要

The development of systemically effective transdermal therapeutic systems (TTS) was pursued to deliver a potent anticholinergic agent, benztropine (BZ).; As a first step benztropine mesylate salt (BM) is converted to free base form (BZ), by titration with 2N KOH up to pH 12 followed by ether extraction. Based on the PK model approach, the transdermal target delivery rate of BZ was determined to be 3 to 20 μg/hr at 10 cm2 device.; The mechanism of percutaneous transport enhancement of 2 different chemical derivatives of BZ i.e. BZ and BM in various single and binary vehicles was investigated using hairless mouse (HLM) and human cadaver (HC) skin. Among the single vehicles examined, a lipophilic carrier, isopropyl myristate (IPM) provided the most enhancing effect on the permeation of BZ.; In vitro cytotoxic studies on keratolytic cell line (JB6) using MTT assay indicated no significant difference (P > 0.05) between BZ and BM cytotoxicities at various drug concentrations and the cytotoxic effect is concentration dependent.; Drug-in-adhesive matrix type of transdermal device was fabricated in a monolithic structure using polyacrylate pressure sensitive adhesives (PSA). However, these adhesive matrices showed a physical instability due to “cold flow” when stored at elevated storage temperatures, i.e., 35°C, 45°C and 55°C. As a result, various approaches were employed to increase the cohesive strength of the polymer and decrease the tackiness of the patch.; The approaches used in the current study include (i) Addition of cross linker to rigidify the matrix; (ii) Incorporation of BZ and BM in the matrix at various concentrations; (iii) Incorporation of syloid (SY) in the matrix. Results indicated that the utilization of colloidal silicone dioxide in the adhesive polymer matrix appears to be a promising approach to modulate drug release and to improve physical stability of the matrix.; The elimination kinetics of BZ from the live HLM skin followed first order kinetics with a clearance half-life of 7.4 hrs, suggested that nearly all of the drug molecules bound to the skin tissues are cleared within 72 hours. The results of the this investigation indicate that TTS formulated with BZ, IPM, SY74 and acrylate PSA (DT-2516) is capable of 3 days continuous delivery of BZ with a sufficient flux for the effective treatment of Parkinson's disease. (Abstract shortened by UMI.)