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Determination of physicochemical properties, stability in aqueous solutions and serum hydrolysis of pilocarpic acid diesters.
J Pharm Biomed Anal 1991; 9(9):737-45JP

Abstract

New alkyl and aralkyl pilocarpic acid diesters, prodrugs of pilocarpine, were synthesized with the aim of improving the bioavailability of pilocarpine by increasing its corneal permeability. These esters were several orders of magnitude more lipophilic than pilocarpine as determined by their apparent partition coefficients between 1-octanol and phosphate buffer (pH 7.40) (log P). Good correlation between log P and HPLC capacity factors of the compounds was observed. All the compounds are stable in acidic aqueous solution; in serum, however, pilocarpic acid diesters are hydrolysed enzymatically to pilocarpic acid monoester, which undergoes spontaneous cyclization to active pilocarpine and inactive isopilocarpine. The half-lives of the diesters in serum varied from 6-232 min. In addition to the direct effects of the R2, R1 moiety had a remarkable effect on the rate of enzyme-catalysed hydrolysis taking place in moiety R2. The formed pilocarpine was analysed with a new HPLC method which allowed good resolution of pilocarpine, isopilocarpine, pilocarpic acid and isopilocarpic acid. Rates for pilocarpine formation were both determined by experiment and calculated using the STELLA simulation programme with known degradation rate constants of pilocarpic acid diesters and monoesters. Since the simulations were in good agreement with the experimental results, it is concluded that STELLA simulation programme is useful in predicting pilocarpine formation.

Authors+Show Affiliations

Department of Pharmaceutical Chemistry, University of Kuopio, Finland.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

1821151

Citation

Järvinen, T, et al. "Determination of Physicochemical Properties, Stability in Aqueous Solutions and Serum Hydrolysis of Pilocarpic Acid Diesters." Journal of Pharmaceutical and Biomedical Analysis, vol. 9, no. 9, 1991, pp. 737-45.
Järvinen T, Suhonen P, Naumanen H, et al. Determination of physicochemical properties, stability in aqueous solutions and serum hydrolysis of pilocarpic acid diesters. J Pharm Biomed Anal. 1991;9(9):737-45.
Järvinen, T., Suhonen, P., Naumanen, H., Urtti, A., & Peura, P. (1991). Determination of physicochemical properties, stability in aqueous solutions and serum hydrolysis of pilocarpic acid diesters. Journal of Pharmaceutical and Biomedical Analysis, 9(9), pp. 737-45.
Järvinen T, et al. Determination of Physicochemical Properties, Stability in Aqueous Solutions and Serum Hydrolysis of Pilocarpic Acid Diesters. J Pharm Biomed Anal. 1991;9(9):737-45. PubMed PMID: 1821151.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Determination of physicochemical properties, stability in aqueous solutions and serum hydrolysis of pilocarpic acid diesters. AU - Järvinen,T, AU - Suhonen,P, AU - Naumanen,H, AU - Urtti,A, AU - Peura,P, PY - 1991/1/1/pubmed PY - 1991/1/1/medline PY - 1991/1/1/entrez SP - 737 EP - 45 JF - Journal of pharmaceutical and biomedical analysis JO - J Pharm Biomed Anal VL - 9 IS - 9 N2 - New alkyl and aralkyl pilocarpic acid diesters, prodrugs of pilocarpine, were synthesized with the aim of improving the bioavailability of pilocarpine by increasing its corneal permeability. These esters were several orders of magnitude more lipophilic than pilocarpine as determined by their apparent partition coefficients between 1-octanol and phosphate buffer (pH 7.40) (log P). Good correlation between log P and HPLC capacity factors of the compounds was observed. All the compounds are stable in acidic aqueous solution; in serum, however, pilocarpic acid diesters are hydrolysed enzymatically to pilocarpic acid monoester, which undergoes spontaneous cyclization to active pilocarpine and inactive isopilocarpine. The half-lives of the diesters in serum varied from 6-232 min. In addition to the direct effects of the R2, R1 moiety had a remarkable effect on the rate of enzyme-catalysed hydrolysis taking place in moiety R2. The formed pilocarpine was analysed with a new HPLC method which allowed good resolution of pilocarpine, isopilocarpine, pilocarpic acid and isopilocarpic acid. Rates for pilocarpine formation were both determined by experiment and calculated using the STELLA simulation programme with known degradation rate constants of pilocarpic acid diesters and monoesters. Since the simulations were in good agreement with the experimental results, it is concluded that STELLA simulation programme is useful in predicting pilocarpine formation. SN - 0731-7085 UR - https://www.unboundmedicine.com/medline/citation/1821151/Determination_of_physicochemical_properties_stability_in_aqueous_solutions_and_serum_hydrolysis_of_pilocarpic_acid_diesters_ L2 - https://linkinghub.elsevier.com/retrieve/pii/0731-7085(91)80215-U DB - PRIME DP - Unbound Medicine ER -