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. 2003 Apr 21;4(3):124–135. doi: 10.1208/pt040345

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

Giridhar S Tirucherai 1,2, Ashim K Mitra 1,✉
PMCID: PMC2750638  PMID: 14621977

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.

Keywords: hydroxypropyl beta cyclodextrin, cornea, transport, prodrugs, aqueous diffusion layer

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References

  • 1.Snoeck R, Schols D, Andrei G, Neyts J, 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. doi: 10.1016/0166-3542(91)90053-T. [DOI] [PubMed] [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. doi: 10.1128/aac.23.5.676. [DOI] [PMC free article] [PubMed] [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;10:201–203. doi: 10.3109/02713689109020380. [DOI] [PubMed] [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. doi: 10.1136/bjo.80.2.140. [DOI] [PMC free article] [PubMed] [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. doi: 10.1056/NEJM199606063342302. [DOI] [PubMed] [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. doi: 10.1089/108076802321021081. [DOI] [PubMed] [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. doi: 10.1124/dmd.30.6.670. [DOI] [PubMed] [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. doi: 10.1016/0024-3205(91)90537-L. [DOI] [PubMed] [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. doi: 10.1023/A:1015838215268. [DOI] [PubMed] [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. doi: 10.1016/0928-0987(94)90001-9. [DOI] [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;58:181–185. doi: 10.1016/0024-3205(96)00024-0. [DOI] [PubMed] [Google Scholar]
  • 12.Loftsson T, Jarvinen T. Cyclodextrins in ophthalmic drug delivery. Adv Drug Deliv Res. 1993;36:59–79. doi: 10.1016/S0169-409X(98)00055-6. [DOI] [PubMed] [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. doi: 10.1016/S0040-4039(99)02280-7. [DOI] [Google Scholar]
  • 15.Higuchi T, Connors KA. Advances in Analytical Chemistry and Instrumentation. New York: Reilly CN; 1965. Phase-Solubility Techniques; pp. 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. doi: 10.1002/jps.1101. [DOI] [PubMed] [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. doi: 10.1023/A:1016258114283. [DOI] [PubMed] [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. doi: 10.1002/jps.2600810808. [DOI] [PubMed] [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. doi: 10.1002/jps.10072. [DOI] [PubMed] [Google Scholar]
  • 20.Loftsson T, Brewster ME. Pharmaceutical applications of cyclodextrins. 1. Drug solubilization and stabilization. J Pharm Sci. 1996;85:1017–1025. doi: 10.1021/js950534b. [DOI] [PubMed] [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. doi: 10.1016/S0731-7085(96)01900-0. [DOI] [PubMed] [Google Scholar]
  • 22.Narurkar MM, Mitra AK. Prodrugs of 5-iodo-2′-deoxyuridine for enhanced ocular transport. Pharm Res. 1989;6:887–891. doi: 10.1023/A:1015968724007. [DOI] [PubMed] [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. doi: 10.1111/j.2042-7158.1996.tb05914.x. [DOI] [PubMed] [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. doi: 10.1023/A:1016297728396. [DOI] [PubMed] [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. doi: 10.1023/A:1012091014242. [DOI] [PubMed] [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. doi: 10.1002/jps.2600840313. [DOI] [PubMed] [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. doi: 10.1016/S0168-3659(98)00182-5. [DOI] [PubMed] [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. [PubMed] [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. doi: 10.1023/A:1015848205447. [DOI] [PubMed] [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. doi: 10.1023/A:1018905109971. [DOI] [PubMed] [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. doi: 10.1021/bi9528816. [DOI] [PubMed] [Google Scholar]

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