Abstract
Purpose. Homologous 3-alkyl-ester prodrugs (C2 to C4) of buprenorphine with decreased crystallinity have been synthesized and evaluated for transdermal delivery commensurate with opioid dependence treatment.
Methods. To assess the influence of derivatization on delivery, the permeation of the prodrugs through human skin was determined in vitro. Prodrug metabolism was measured in human blood and skin supernatant in vitro along with chemical hydrolysis controls. The pro-drugs' octanol/water partition coefficients were measured.
Results. Without exception, the prodrugs were completely hydrolyzed on passing through the skin and appeared as buprenorphine in the receptor compartment. However, using saturation conditions, in no instance did the buprenorphine flux through skin from a prodrug solution exceed the flux of buprenorphine base itself in vitro. Moreover, the flux of the acetyl ester, the least hydrophobic of the prodrugs, was not significantly elevated upon stripping the skin. Whether in blood or the skin supernatant, the prodrugs hydrolyzed in an apparent first-order fashion and rate constants and half-lives were calculated.
Conclusions. We conclude from the results that the prodrugs' very high octanol/water partition coefficients (hydrophobicity) placed them in viable tissue layer controlled diffusion. Consequently, one does not derive the potential flux-increasing benefit of reducing crystallinity that was expected.
Similar content being viewed by others
REFERENCES
C. R. Schuster. British Journal of Addiction. 84:19–28 (1989).
M. K. Lehman. Substance Abuse and Mental Health Services Administration News. 1:17–19 (1993).
R. E. Johnson, J. H. Jaffe, and P. J. Fudala. JAMA. 267:2750–5 (1992).
A. Goodman Gilman, L. S. Goodman, T. W. Rall, and F. Murad. Goodman and Gilman's The Pharmacological Basis of Therapeutics, Seventh Edition, Macmillan Publishing Company, New York, 1985, pp. 523–524.
S. D. Roy, E. Roos, and K. Sharma. J. Pharm. Sci. 83:126–130 (1994).
A. Stinchcomb, A. Paliwal, R. Dua, R. W. Woodard, and G. L. Flynn. Pharm. Res. 12:1526–1529 (1995).
G. L. Flynn, H. Durrheim, and W. I. Higuchi. J. Pharm. Sci. 70:52–56 (1981).
H. Imoto, Z. Zhou, A. L. Stinchcomb, and G. L. Flynn. Biol. Pharm. Bull. In press (1996).
S. W. Collier, N. M. Sheikh, A. Sakr, J. L. Lichtin, R. F. Stewart, and R. L. Bronaugh. Toxicol. Appl. Pharmacol. 99:522–533 (1989).
G. L. Flynn and S. H. Yalkowsky. J. Pharm. Sci. 61:838–852 (1972).
J. J. Fort, Z. Shao and A. K. Mitra. Int. J. Pharma. 100:233–239 (1993).
J. Drustrup, A. Fullerton, L. Christrup and H. Bundgaard. Int. J. Pharm. 71:105–116 (1991).
W. M. Smith. An Inquiry Into the Mechanism of Percutaneous Absorption of Hydrocortisone and Its 21-n-Alkyl Esters. Dissertation, The University of Michigan, 1982.
R. C. O'Neill and J. E. Carless. J. Pharmacol. 32 supp:10–11 (1980).
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Stinchcomb, A.L., Paliwal, A., Dua, R. et al. Permeation of Buprenorphine and Its 3-Alkyl-Ester Prodrugs Through Human Skin. Pharm Res 13, 1519–1523 (1996). https://doi.org/10.1023/A:1016079513007
Issue Date:
DOI: https://doi.org/10.1023/A:1016079513007