PMID: 3772750Aug 1, 1986Paper

Pilocarpine prodrugs. II. Synthesis, stability, bioconversion, and physicochemical properties of sequentially labile pilocarpine acid diesters

Journal of Pharmaceutical Sciences
H BundgaardT J Mikkelson

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 determine...Continue Reading

References

Oct 1, 1976·Journal of Pharmaceutical Sciences·A Hussain, J E Truelove
Aug 1, 1985·Journal of Medicinal Chemistry·H BundgaardT J Mikkelson
May 1, 1974·Journal of Pharmaceutical Sciences·M A Nunes, E Brochmann-Hanssen
Sep 1, 1970·Journal of Pharmaceutical Sciences·P H ChungJ L Lach
Mar 1, 1983·Journal of Pharmaceutical Sciences·V H Lee

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Citations

Apr 1, 1990·European Journal of Drug Metabolism and Pharmacokinetics·L P BalantP Buri
Jan 1, 1991·Journal of Pharmaceutical and Biomedical Analysis·T JärvinenJ Vepsäläinen
Feb 1, 1992·Journal of Pharmaceutical and Biomedical Analysis·T JärvinenP Peura
Jun 6, 2000·Advanced Drug Delivery Reviews·R GurnyV Baeyens
Jul 30, 1999·International Journal of Pharmaceutics·M SznitowskaT Järvinen
Oct 31, 1998·European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences·P SuhonenA Urtti
Jan 23, 2003·Journal of Ocular Pharmacology and Therapeutics : the Official Journal of the Association for Ocular Pharmacology and Therapeutics·Giridhar S TirucheraiAshim K Mitra
Dec 9, 1998·Drug Metabolism Reviews·B Testa, J M Mayer
Apr 3, 1999·Journal of Pharmaceutical Sciences·J RautioT Jarvinen
Mar 1, 1992·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·A DurrerB Testa
Nov 30, 2004·European Journal of Pharmaceutics and Biopharmaceutics : Official Journal of Arbeitsgemeinschaft Für Pharmazeutische Verfahrenstechnik E.V·F LallemandR Gurny
Sep 14, 2007·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Abeer M Al-Ghananeem, Peter A Crooks
Apr 26, 2017·Drug Metabolism Reviews·Upendra A ArgikarAndrea J Bushee
May 18, 2021·Asian Journal of Pharmaceutical Sciences·Jagpreet KourBharti Sapra
Jul 1, 1997·Journal of Pharmaceutical Sciences·D ShanB Wang

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