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Different effects of pH on the permeation of pilocarpine and pilocarpine prodrugs across the isolated rabbit cornea.
Eur J Pharm Sci 1998; 6(3):169-76EJ

Abstract

Ocular absorption of pilocarpine and many other ophthalmic drugs can be improved by prodrug derivatization. For stability and solubility reasons basic prodrugs must be formulated at acidic pH, which may affect the corneal drug permeability. We studied the effects of pH on in vitro permeation of pilocarpine, pilocarpic acid benzyl diester prodrugs [O-propionyl (I) and O-valeryl (II)] and O,O'-(1, 4-xylylene) bispilocarpic acid diester prodrugs [O,O'-diacetyl (III), O,O'-dipropionyl (IV) and O,O'-divaleryl (V)] through albino rabbit cornea. Reversed-phase high-performance liquid chromatography was used to assay pilocarpine and its prodrugs. The permeability coefficient for pilocarpine decreased more than three times, from 2. 8x10-6 cm/s to 0.9x10-6 cm/s, when the pH was decreased from 7.65 to 5.5. At pH 7.65 permeability of pilocarpine improved several fold with delivery as prodrugs. Acidic pH (5.5, 6.0) affected to a different extent the corneal permeability of pilocarpine given as prodrugs. Consequently, the rank order of the corneal permeabilities among the compounds was different at various pH values. The effect of pH was greatest (an order of magnitude) for prodrugs with intermediate lipophilicity (I, III, IV), while pH had only minor or no effect on permeability of the most lipophilic prodrugs (II, V). In conclusion, the effect of pH on pilocarpine delivery as prodrug is dependent on prodrug structure and the advantage gained with prodrugs relative to pilocarpine is dependent on formulation pH.

Authors+Show Affiliations

Department of Pharmaceutics, University of Kuopio, P.O. Box 1627, FIN-70211, Kuopio, Finland. suhonen@messi.uku.fiNo 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

9795043

Citation

Suhonen, P, et al. "Different Effects of pH On the Permeation of Pilocarpine and Pilocarpine Prodrugs Across the Isolated Rabbit Cornea." European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences, vol. 6, no. 3, 1998, pp. 169-76.
Suhonen P, Järvinen T, Koivisto S, et al. Different effects of pH on the permeation of pilocarpine and pilocarpine prodrugs across the isolated rabbit cornea. Eur J Pharm Sci. 1998;6(3):169-76.
Suhonen, P., Järvinen, T., Koivisto, S., & Urtti, A. (1998). Different effects of pH on the permeation of pilocarpine and pilocarpine prodrugs across the isolated rabbit cornea. European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences, 6(3), pp. 169-76.
Suhonen P, et al. Different Effects of pH On the Permeation of Pilocarpine and Pilocarpine Prodrugs Across the Isolated Rabbit Cornea. Eur J Pharm Sci. 1998;6(3):169-76. PubMed PMID: 9795043.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Different effects of pH on the permeation of pilocarpine and pilocarpine prodrugs across the isolated rabbit cornea. AU - Suhonen,P, AU - Järvinen,T, AU - Koivisto,S, AU - Urtti,A, PY - 1998/10/31/pubmed PY - 1998/10/31/medline PY - 1998/10/31/entrez SP - 169 EP - 76 JF - European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences JO - Eur J Pharm Sci VL - 6 IS - 3 N2 - Ocular absorption of pilocarpine and many other ophthalmic drugs can be improved by prodrug derivatization. For stability and solubility reasons basic prodrugs must be formulated at acidic pH, which may affect the corneal drug permeability. We studied the effects of pH on in vitro permeation of pilocarpine, pilocarpic acid benzyl diester prodrugs [O-propionyl (I) and O-valeryl (II)] and O,O'-(1, 4-xylylene) bispilocarpic acid diester prodrugs [O,O'-diacetyl (III), O,O'-dipropionyl (IV) and O,O'-divaleryl (V)] through albino rabbit cornea. Reversed-phase high-performance liquid chromatography was used to assay pilocarpine and its prodrugs. The permeability coefficient for pilocarpine decreased more than three times, from 2. 8x10-6 cm/s to 0.9x10-6 cm/s, when the pH was decreased from 7.65 to 5.5. At pH 7.65 permeability of pilocarpine improved several fold with delivery as prodrugs. Acidic pH (5.5, 6.0) affected to a different extent the corneal permeability of pilocarpine given as prodrugs. Consequently, the rank order of the corneal permeabilities among the compounds was different at various pH values. The effect of pH was greatest (an order of magnitude) for prodrugs with intermediate lipophilicity (I, III, IV), while pH had only minor or no effect on permeability of the most lipophilic prodrugs (II, V). In conclusion, the effect of pH on pilocarpine delivery as prodrug is dependent on prodrug structure and the advantage gained with prodrugs relative to pilocarpine is dependent on formulation pH. SN - 0928-0987 UR - https://www.unboundmedicine.com/medline/citation/9795043/Different_effects_of_pH_on_the_permeation_of_pilocarpine_and_pilocarpine_prodrugs_across_the_isolated_rabbit_cornea_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0928-0987(97)10002-1 DB - PRIME DP - Unbound Medicine ER -