AAPS PharmSciTech

, Volume 13, Issue 3, pp 883–889 | Cite as

Development and Clinical Evaluation of Clotrimazole–β-Cyclodextrin Eyedrops for the Treatment of Fungal Keratitis

Research Article


Fungal keratitis is a serious corneal disease that may result in loss of vision. There are limited treatment options available in Iraqi eye hospitals which might be the main reason behind the poor prognosis of many cases. The purpose of this study was to prepare and pharmaceutically evaluate clotrimazole–β-cyclodextrin (CTZ–β-CD) eyedrops then clinically assess its therapeutic efficacy on fungal keratitis compared with extemporaneous amphotericin B eyedrops (0.5% w/v). A CTZ–β-CD ophthalmic solution was prepared and evaluated by various physicochemical, microbiological, and biological tests. The prepared formula was stable in 0.05 M phosphate buffer pH 7.0 at 40 ± 2°C and 75 ± 5% RH for a period of 6 months. Light has no significant effect on the formula’s stability. The CTZ–β-CD eyedrops efficiently complied with the isotonicity, sterility, and antimicrobiological preservative effectiveness tests. Results of the clinical study revealed that 20 (80%) patients showed a favorable response to the CTZ–β-CD eyedrops, while 16 patients (64%) exhibited a favorable response to amphotericin B (P > 0.05). The mean course of treatment was significantly (P < 0.05) less in the CTZ treatment group than in the amphotericin group (21.5 ± 5.2 vs. 28.3 ± 6.4 days, respectively). The CTZ formulation was significantly (P < 0.05) more effective in the management of severe cases and also against Candida sp. than amphotericin B. There was no significant difference (P < 0.05) between both therapies against filamentous fungi. The CTZ–β-CD formulation can be used alternatively to other ophthalmic antimycotic treatment options in developing countries where stability, cost, or efficacy is a limiting factor.

Key words

clotrimazole β-cyclodextrin eyedrops fungal keratitis Iraq 



The authors are grateful to the College of Pharmacy/ Baghdad University for the financial support and to Dr. Faiz ALShakarchi (Ophthalmologist Consultant in Ibn Al-Haetham Teaching Eye Hospital, Baghdad, Iraq) for his kind help in the clinical study.


  1. 1.
    Whitcher JP, Srinivasan M, Upadhyay MP. Corneal blindness: a global perspective. Bull World Health Organ. 2001;79:214–21.PubMedGoogle Scholar
  2. 2.
    Ahmed E. A textbook of ophthalmology. India: Oxford University Press; 2008. p. 199–200.Google Scholar
  3. 3.
    Rose RH, Miller D, Alfonso FC. The changing spectrum of fungal keratitis in South Florida. Ophthalmology. 1994;101:1005–13.Google Scholar
  4. 4.
    Williams G, Cellank MC, Billson F. Suppurative keratitis in rural Bangladesh, the value of gram stain in planning management. Int Ophthalmol. 1991;15:131–5.PubMedCrossRefGoogle Scholar
  5. 5.
    Sharma S, Srinivason M, George C. The current status of Fusarium species in mycotic keratitis in South India. Indian J Med Microbiol. 1993;11:140–7.Google Scholar
  6. 6.
    Upadhyay MP, Karmacharya PC, Thuladhor NR, Bryan LE, Smolin G. The epidemiologic characteristics, predisposing factors and etiologic diagnosis of corneal ulceration in Nepal. Am J Ophthalmol. 1991;111:92–9.PubMedGoogle Scholar
  7. 7.
    Hagan M, Wright E, Newmen M, Dolin P. Causes of suppurative keratitis in Ghana. Br J Ophthalmol. 1995;79:1204–8. PMCID: PMC505322.CrossRefGoogle Scholar
  8. 8.
    Al-Shakarchi F. Initial therapy for suppurative microbial keratitis in Iraq. Br J Ophthalmol. 2007;91:1583–7.PubMedCrossRefGoogle Scholar
  9. 9.
    Al-Shakarchi F, Amin M, Hassen F, Al-Bakri F. Fungal keratitis in Iraq. Research presented in the third international congress of the Arab-Ophthalmic Association in Amman, Jordan, from 31 Oct 2002 to 2 Nov 2002.Google Scholar
  10. 10.
    Srinivasan M. Fungal keratitis. Curr Opin Ophthalmol. 2004;15:321–7.PubMedCrossRefGoogle Scholar
  11. 11.
    Antoine D, Nicolas T, Le Gwenae M, Nicolas V. Preparation and stability of voriconazole eye drop solution. Antimicrob Agents Chemother. 2009;53(2):798–9. doi: 10.1128/AAC.01126-08.CrossRefGoogle Scholar
  12. 12.
    Cohen T, Sauvageon-Martre H, Brossard D, D’Hermies F, Bardin C, Chast F, Chaumeil JC. Amphotericin B eye drops as a lipidic emulsion. Int J Pharm. 1996;137:249–54. doi: 10.1016/0378-5173(96)04473-0.CrossRefGoogle Scholar
  13. 13.
    Fromtling RA. Overview of medically important antifungal azole derivatives. Clin Microbiol Rev. 1988;1:187–217. PMCID: PMC358042.PubMedGoogle Scholar
  14. 14.
    Mselle J. Use of topical clotrimazole in human keratomycosis. Ophthalmologica. 2001;215(5):357–60.PubMedCrossRefGoogle Scholar
  15. 15.
    Delgado JN, Remers WA. Wilson and Gisvold’s text book of organic medicine and pharmaceutical chemistry. 10th ed. Philadelphia: Lippincott Williams and Wilkins; 1988. p. 185–7.Google Scholar
  16. 16.
    Loftsson T, Stefánsson E. Cyclodextrins in eye drop formulations: enhanced topical delivery of corticosteroids to the eye. Acta Ophthalmol. 2002;80:144–50.CrossRefGoogle Scholar
  17. 17.
    Abdul Rasool BK, Salmo HM, Al-Akayleh FT. Physicochemical characterization of clotrimazole-β-cyclodextrin inclusion complex. Al-Mustansiriya J Sci. 2006;17:28–41.Google Scholar
  18. 18.
    Draize J, Woodward G, Calvery O. Methods for the study of irritation and toxicity of substance applied topically to the skin and mucous membrane. J Pharmacol Exp Ther. 1994;82:377–90.Google Scholar
  19. 19.
    Ahmed MO, El-Gibaly I, Ahmed SM. Effect of cyclodextrins on the physicochemical properties and antimycotic activity of clotrimazole. Int J Pharm. 1998;171(1):111–21. doi: 10.1016/S0378-5173(98)00163-X.CrossRefGoogle Scholar
  20. 20.
    Sautou-Miranda V, Labret F, Grand-Boyer A, Gellis C, Chopineau J. Impact of deep-freezing on the stability of 25 mg/ml vancomycin ophthalmic solutions. Int J Pharm. 2002;234:205–7. doi: 10.1016/S0378-5173(01)00961-9.PubMedCrossRefGoogle Scholar
  21. 21.
    Loftsson T, Stefánsson E, Kristinsson JK, Fridriksdottir H, Sverrisson T, Gudmundsdottir G, Thorisdottir S. Topically effective acetazolamide eye-drop solution in man. Pharm Sci. 1996;6:277–9. doi: 10.1111/j.2042-7158.1996.tb00611.x.Google Scholar
  22. 22.
    Leck AK, Thomas PA, Hagan M, Kaliamurthy J, Ackuaku E, John M, et al. Aetiology of suppurative corneal ulcers in Ghana and South India, and epidemiology of fungal keratitis. Br J Ophthalmol. 2002;86:1211–5. doi: 10.1136/bjo.86.11.1211.PubMedCrossRefGoogle Scholar
  23. 23.
    Gopinathan U, Garg P, Fernandes M, Sharma S, Athmanathan S, Rao GN. The epidemiological features and laboratory results of fungal keratitis: a 10-year review at a referral eye care center in South India. Cornea. 2002;21:555–9.PubMedCrossRefGoogle Scholar
  24. 24.
    Leck A, Matheson M, Tuft S, Waheed K, Lagonowski H. Scedosporium apiospermum keratomycosis with secondary endophthalmitis. Eye. 2003;17:841–3. doi: 10.1038/sj.eye.6700477.PubMedCrossRefGoogle Scholar
  25. 25.
    Ahmed I, Gokhale RD, Shah M, Patton TF. Physicochemical determinants of drug diffusion across the conjunctiva, sclera, and cornea. J Pharm Sci. 1987;76:583–6. doi: 10.1002/jps.2600760802.PubMedCrossRefGoogle Scholar
  26. 26.
    Loftsson T, Masson M. Cyclodextrins in topical drug formulations: theory and practice. Int J Pharm. 2001;212:29–40.PubMedCrossRefGoogle Scholar
  27. 27.
    Lang JC, Stiemke MM. Biological barriers to ocular delivery. In: Reddy IW, editor. Ocular therapeutics and drug delivery, a multi-disciplinary approach. Lancaster: Technomic Publications; 1996. p. 51–132.Google Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2012

Authors and Affiliations

  1. 1.Department of Pharmaceutics and Pharmacy PracticeDubai Pharmacy CollegeDubaiUnited Arab Emirates
  2. 2.Department of Pharmaceutics, College of PharmacyBaghdad UniversityBaghdadIraq

Personalised recommendations