Tags

Type your tag names separated by a space and hit enter

Pilocarpine prodrugs. II. Synthesis, stability, bioconversion, and physicochemical properties of sequentially labile pilocarpine acid diesters.
J Pharm Sci 1986; 75(8):775-83JP

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.

Authors

No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

3772750

Citation

Bundgaard, H, et al. "Pilocarpine Prodrugs. II. Synthesis, Stability, Bioconversion, and Physicochemical Properties of Sequentially Labile Pilocarpine Acid Diesters." Journal of Pharmaceutical Sciences, vol. 75, no. 8, 1986, pp. 775-83.
Bundgaard H, Falch E, Larsen C, et al. Pilocarpine prodrugs. II. Synthesis, stability, bioconversion, and physicochemical properties of sequentially labile pilocarpine acid diesters. J Pharm Sci. 1986;75(8):775-83.
Bundgaard, H., Falch, E., Larsen, C., Mosher, G. L., & Mikkelson, T. J. (1986). Pilocarpine prodrugs. II. Synthesis, stability, bioconversion, and physicochemical properties of sequentially labile pilocarpine acid diesters. Journal of Pharmaceutical Sciences, 75(8), pp. 775-83.
Bundgaard H, et al. Pilocarpine Prodrugs. II. Synthesis, Stability, Bioconversion, and Physicochemical Properties of Sequentially Labile Pilocarpine Acid Diesters. J Pharm Sci. 1986;75(8):775-83. PubMed PMID: 3772750.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Pilocarpine prodrugs. II. Synthesis, stability, bioconversion, and physicochemical properties of sequentially labile pilocarpine acid diesters. AU - Bundgaard,H, AU - Falch,E, AU - Larsen,C, AU - Mosher,G L, AU - Mikkelson,T J, PY - 1986/8/1/pubmed PY - 1986/8/1/medline PY - 1986/8/1/entrez SP - 775 EP - 83 JF - Journal of pharmaceutical sciences JO - J Pharm Sci VL - 75 IS - 8 N2 - 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. SN - 0022-3549 UR - https://www.unboundmedicine.com/medline/citation/3772750/Pilocarpine_prodrugs__II__Synthesis_stability_bioconversion_and_physicochemical_properties_of_sequentially_labile_pilocarpine_acid_diesters_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0022-3549(15)47211-9 DB - PRIME DP - Unbound Medicine ER -