Abstract：
:Various novel diesters of pilocarpic acid were synthesized and evaluated as prodrug forms for pilocarpine with the aim of improving the ocular delivery characteristics of the drug. The pilocarpic acid monoesters previously studied cyclized spontaneously to pilocarpine in aqueous solution and although they showed enhanced corneal permeability when compared with pilocarpine these monoesters suffered from poor solution stability. The present study shows that this problem can be totally overcome by blocking the free hydroxyl group in the monoesters. Diesters of pilocarpic acid were obtained by esterification of this group. Such compounds were found to possess a high stability in aqueous solution (shelf lives of more than 5 years at 20 degrees C were estimated) but at the same time were readily converted to pilocarpine under conditions simulating those occurring in vivo through a sequential process involving enzymatic hydrolysis of the O-acyl bond followed by spontaneous lactonization of the intermediate pilocarpic acid monoester. Rate data are given for the conversion of the diesters in human plasma and in various rabbit eye homogenates. The pH-solubility profile was derived for a diester and lipophilicity parameters were determined for the compounds. All diesters were markedly more lipophilic than pilocarpine and the corresponding pilocarpic acid monoesters. The results suggest that pilocarpic acid diesters may be potentially useful pilocarpine prodrugs as they combine a high solution stability with an adequate rate of conversion to pilocarpine under in vivo conditions.
journal_name
J Pharm Scijournal_title
Journal of pharmaceutical sciencesauthors
Bundgaard H,Falch E,Larsen C,Mosher GL,Mikkelson TJdoi
10.1002/jps.2600750811subject
Has Abstractpub_date
1986-08-01 00:00:00pages
775-83issue
8eissn
0022-3549issn
1520-6017pii
S0022-3549(15)47211-9journal_volume
75pub_type
杂志文章abstract：:Topical lidocaine has been recently marketed as a new treatment for post-herpetic neuralgia. The aim of our study was to characterize the absorption profile of and systemic exposure to lidocaine from patch and gel formulations in normal volunteers, patients with post-herpetic neuralgia, and patients with acute herpes ...
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