Transdermal delivery of antiparkinsonian agent, benztropine. I. Effect of vehicles on skin permeation

The influence of pH and various lipophilic and hydrophilic vehicles on the epidermal permeation of benztropine (BZ) free base and its mesylate salt we re studied in vitro using the hairless mouse (HLM) and human cadaver (HC) s kin membranes. The pH-partition behavior of BZ base (pK(a) = 10) was examin ed using n-octanol and Britton-Robinson buffers over the pH range of 5-12. Unexpectedly, the ionized species of BZ yielded a high partition coefficien t (log K-octanol/water = 2.14), which was reflected by its relatively high skin permeability (P = 1.6 x 10(-2) cm h(-1)). BZ base delivered from a lip ophilic vehicle with a solubility parameter range of 7.1-10.3 (cal cm(3))(1 /2) exhibited a significantly enhanced rate of permeation as compared to th at attained from a hydrophilic vehicle of solubility parameter range betwee n 12.5-23.4 (cal cm(3))(1/2). Among the neat solvents examined, a lipophili c carrier, isopropyl myristate (IPM) provided the most enhancing effect on the permeation of BZ base. In addition, the neat IPM carrier offered the ma ximum BZ base flux of 150 mu g per cm(2) h(-1) across HC skin, which was ap proximately 16 times greater than the target delivery rate of BZ from a 10- cm(2) device. In comparison, BZ base exhibited a 2-60 times greater flux th an BZ mesylate when delivered from the neat solvents. However, interestingl y enough, the binary cosolvents consisting of IPM and short-chain alkanols such as ethanol (EtOH), isopropanol (iPrOH), and tertiary butanol (tBtOH), in particular a 2:8 combination, produced a marked synergistic enhancement of BZ flux from the mesylate salt, whereas a retarding effect was noticed f or the permeation of BZ base. The enhancement potency for the BZ mesylate p ermeation increased linearly with the carbon number of the branched alcohol s present in the binary mixtures. A tBtOH-IPM (2:8) combination produced th e highest BZ flux from the mesylate salt, i.e., 2016 mg per cm(2) h(-1), wh ich was 100-fold greater than from water and 44-540-fold greater than the i ndividual neat solvents, respectively. The observed permeation enhancement of BZ mesylate by the alkanol-IPM mixtures was probably as a result of a co mbination of decreasing barrier ability of the stratum corneum by the binar y vehicles and moderately partitioning BZ mesylate through the viable epide rmis/dermis. (C) 1999 Elsevier Science B.V. All rights reserved.