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Effect of hydroxypropyl beta cyclodextrin complexation on aqueous solubility, stability, and corneal permeation of acyl ester prodrugs of ganciclovir

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Abstract

The purpose of the study was to investigate the effect of hydroxypropyl beta cyclodextrin (HPβCD) on aqueous solubility, stability, and in vitro corneal permeation of acyl ester prodrugs of ganciclovir (GCV). Aqueous solubility and stability of acyl ester prodrugs of Ganciclovir (GCV) were evaluated in pH 7.4 isotonic phosphate buffer solution (IPBS) in the presence and absence of HPβCD. Butyryl cholinesterase-mediated enzymatic hydrolysis of the GCV prodrugs was studied using various percentage w/v HPβCD. In vitro corneal permeation of GCV and its prodrugs (with and without 5% HPβCD) across isolated rabbit cornea was studied using side-by-side diffusion cells. HPβCD-prodrug complexation was of the AL type with values for complexation constants ranging between 12 and 108 M−1. Considerable improvement in chemical and enzymatic stability of the GCV prodrugs was observed in the presence of HPβCD. The stabilizing effect of HPβCD was found to depend on the degree of complexation and the degradation rate of prodrug within the complex. Five percent w/v HPβCD was found to enhance the corneal permeation of only the most lipophilic prodrug GCV dibutyrate (2.5-fold compared with 0% HPβCD). All other prodrugs showed little or no difference in transport in the presence of 5% w/v HPβCD. Agitation in the donor chamber largely influenced the transport kinetics of GCV dibutyrate across cornea. Results indicate the presence of an unstirred aqueous diffusion layer at the corneal surface that restricts the transport of the highly lipophilic GCV dibutyrate prodrug. HPβCD improves corneal permeation by solubilizing the hydrophobic prodrug and delivering it across the mucin layer at the corneal surface.

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References

  1. Snoeck R, Schols D, Andrei G, Neyts J, De Clercq E. Antiviral activity of anti-cytomegalovirus agents (HPMPC, HPMPA) assessed by a flow cytometric method and DNA hydridization technique. Antiviral Res. 1991;16:1–9.

    Article  CAS  Google Scholar 

  2. Smee DF, Martin JC, Verheyden JP, Matthews TR. Antiherpesvirus activity of the acyclic nucleoside 9-(1,3-dihydroxy-2-propoxymethyl)guanine. Antimicrob Agents Chemother. 1983;23:676–682.

    CAS  Google Scholar 

  3. Naito T, Nitta K, Kinouchi Y, Shiota H, Mimura Y. Effects of 9-(1,3-dihydroxy-2-propoxymethyl)guanine (DHPG) eye drops and cyclosporine eye drops in the treatment of herpetic stromal keratitis in rabbits. Curr Eye Res. 1991;10(suppl):201–203.

    Article  Google Scholar 

  4. Hoh HB, Hurley C, Claoue C, Viswalingham M, Easty DL, Goldschmidt P, Collum LM. Randomised trial of ganciclovir and acyclovir in the treatment of herpes simplex dendritic keratitis: a multicentre study. Br J Ophthalmol. 1996;80:140–143.

    Article  CAS  Google Scholar 

  5. Spector SA, McKinley GF, Lalezari JP, Samo T, Andruczk R, Follansbee S, Sparti PD, Havlir DV, Simpson G, Buhles W, Wong R, Stempien M. Oral ganciclovir for the prevention of cytomegalovirus disease in persons with AIDS. Roche Cooperative Oral Ganciclovir Study Group. N Engl J Med. 1996;334:1491–1497.

    Article  CAS  Google Scholar 

  6. Tirucherai GS, Dias C, Mitra AK. Corneal Permeation of Ganciclovir: Mechanism of Ganciclovir Permeation Enhancement by Acyl Ester Prodrug Design. J Ocul Pharmacol Ther. 2002;18:535–548.

    Article  CAS  Google Scholar 

  7. Macha S, Mitra AK. Ocular disposition of ganciclovir and its monoester prodrugs following intravitreal administration using microdialysis. Drug Metab Dispos. 2002;30:670–675.

    Article  CAS  Google Scholar 

  8. Yaksh TL, Jang JD, Nishiuchi Y, Braun KP, Ro SG, Goodman M. The utility of 2-hydroxypropyl-beta-cyclodextrin as a vehicle for the intracerebral and intrathecal administration of drugs. Life Sci. 1991;48:623–633.

    Article  CAS  Google Scholar 

  9. Usayapant A, Karara AH, Narurkar MM. Effect of 2-hydroxypropyl-beta-cyclodextrin on the ocular absorption of dexamethasone and dexamethasone acetate. Pharm Res. 1991;8:1495–1499.

    Article  CAS  Google Scholar 

  10. Loftsson T, Frithriksdottir H, Thorisdottir S, Stefansson E, Sigurthardottir AM, Guthmundsson O, Sigthorsson T. 2-hydroxypropyl-beta-cyclodextrin in topical carbonic anhydrase inhibitor formulations. Eur J Pharm Sci. 1994;1:175–180.

    Article  CAS  Google Scholar 

  11. Jarho P, Urtti A, Jarvinen K, Pate DW, Jarvinen T. Hydroxypropyl-beta-cyclodextrin increases aqueous solubility and stability of anandamide. Life Sci. 1996;58: PL 181–185.

    Article  Google Scholar 

  12. Loftsson T, Jarvinen T. Cyclodextrins in ophthalmic drug delivery. Adv Drug Deliv Res. 1993;36:59–79.

    Article  Google Scholar 

  13. Loftsson T, Stefansson E, Kristensson JK, Fridriksdottir, H, Sverrisson T, Gudmondsdottir G, Thorisdottir S. Topically effective acetazolamide drop solution in man. Pharm Sci. 1996;6:277–279.

    Google Scholar 

  14. Gao H, Mitra AK. Regioselective synthesis of various prodrugs of ganciclovir. Tetrahedron Lett. 2000;41:1131–1136.

    Article  CAS  Google Scholar 

  15. Higuchi T, Connors KA. “Phase-Solubility Techniques” In Advances in Analytical Chemistry and Instrumentation. New York: Reilly CN; 1965:117–212.

    Google Scholar 

  16. Tak RV, Pal D, Gao H, Dey S, Mitra AK. Transport of acyclovir ester prodrugs through rabbit cornea and SIRC-rabbit corneal epithelial cell line. J Pharm Sci. 2001;90:1505–1515.

    Article  CAS  Google Scholar 

  17. Cho MJ, Chen FJ, Huczek DL. Effects of inclusion complexation on the transepithelial transport of a lipophilic substance in vitro. Pharm Res. 1995;12:560–564.

    Article  CAS  Google Scholar 

  18. Albers E, Muller BW. Complexation of steroid hormones with cyclodextrin derivatives: substituent effects of the guest molecule on solubility and stability in aqueous solution. J Pharm Sci. 1992;81:756–761.

    Article  CAS  Google Scholar 

  19. Dias CS, Anand BS, Mitra AK. Effect of mono- and diacylation on the ocular disposition of ganciclovir: physicochemical properties, ocular bioreversion, and antiviral activity of short chain ester prodrugs. J Pharm Sci. 2002;91:660–668.

    Article  CAS  Google Scholar 

  20. Loftsson T, Brewster ME. Pharmaceutical applications of cyclodextrins. 1. Drug solubilization and stabilization. J Pharm Sci. 1996;85:1017–1025.

    Article  CAS  Google Scholar 

  21. Mielcarek J. Photochemical stability of the inclusion complexes formed by modified 1,4-dihydropyridine derivatives with beta-cyclodextrin. J Pharm Biomed Anal. 1997;15:681–686.

    Article  CAS  Google Scholar 

  22. Narurkar MM, Mitra AK. Prodrugs of 5-iodo-2′-deoxyuridine for enhanced ocular transport. Pharm Res. 1989;6:887–891.

    Article  CAS  Google Scholar 

  23. Jarho P, Jarvinen K, Urtti A, Stella VJ, Jarvinen T. Modified beta-cyclodextrin (SBE7-beta-CyD) with viscous vehicle improves the ocular delivery and tolerability of pilocarpine prodrug in rabbits. J Pharm Pharmacol. 1996;48:263–269.

    CAS  Google Scholar 

  24. Suhonen P, Jarvinen T, Lehmussaari K, Reunamaki T, Urtti A. Ocular absorption and irritation of pilocarpine prodrug is modified with buffer, polymer, and cyclodextrin in the eyedrop. Pharm Res. 1995;12:529–533.

    Article  CAS  Google Scholar 

  25. Pauletti GM, Gangwar S, Wang B, Borchardt RT. Esterasesensitive cyclic prodrugs of peptides: evaluation of a phenylpropionic acid promoiety in a model hexapeptide. Pharm Res. 1997;14:11–17.

    Article  CAS  Google Scholar 

  26. Bodor NS, Huang MJ, Watts JD. Theoretical studies on the structures of natural and alkylated cyclodextrins. J Pharm Sci. 1995;84:330–336.

    Article  CAS  Google Scholar 

  27. Masson M, Loftsson T, Masson G, Stefansson E. Cyclodextrins as permeation enhancers: some theoretical evaluations and in vitro testing. J Control Release. 1999;59:107–118.

    Article  CAS  Google Scholar 

  28. Higuchi T. Physical chemical analysis of percutaneous absorption process from creams and ointments. J Soc Cosmet Chem. 1960;11:85–97.

    Google Scholar 

  29. Inatomi T, Spurr-Michaud S, Tisdale AS, Gipson IK. Human corneal and conjunctival epithelia express MUC1 mucin. Invest Ophthalmol Vis Sci. 1995;36:1818–1827.

    CAS  Google Scholar 

  30. Hidalgo IJ, Hillgren KM, Grass GM, Borchardt RT. Characterization of the unstirred water layer in Caco-2 cell monolayers using a novel diffusion apparatus. Pharm Res. 1991;8:222–227.

    Article  CAS  Google Scholar 

  31. Wikman A, Karlsson J, Carlstedt I, Artursson P. A drug absorption model based on the mucus layer producing human intestinal goblet cell line HT29-H. Pharm Res. 1993;10:843–852.

    Article  CAS  Google Scholar 

  32. Ohvo H, Slotte JP. Cyclodextrin-mediated removal of sterols from monolayers: effects of sterol structure and phospholipids on desorption rate. Biochemistry. 1996;35:8018–8024.

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, 5005 Rockhill Road, 64110, Kansas City, MO

    Giridhar S. Tirucherai & Ashim K. Mitra

  2. Department of Clinical Pharmacology, Quintiles Inc, 10245 Hickman Mills Drive, 64137, Kansas City, MO

    Giridhar S. Tirucherai

Authors
  1. Giridhar S. Tirucherai
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  2. Ashim K. Mitra
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Correspondence to Ashim K. Mitra.

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Tirucherai, G.S., Mitra, A.K. Effect of hydroxypropyl beta cyclodextrin complexation on aqueous solubility, stability, and corneal permeation of acyl ester prodrugs of ganciclovir. AAPS PharmSciTech 4, 45 (2003). https://doi.org/10.1208/pt040345

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