AMPHOTERICIN B TOPICAL EXTEMPORANEOUS PREPARATIONS FOR THE TREATMENT OF NON-DERMATOPHYTIC ONYCHOMYCOSIS
Objective: At present, the nail preparation to cure onychomycosis, caused by non-dermatophyte molds, is not commercially available in Thailand. The physical and chemical stability of amphotericin B (AmB) extemporaneous preparations in the presence of 30% dimethyl sulfoxide (DMSO) and their in vitro nail permeation was evaluated.
Methods: AmB extemporaneous preparations in the presence of 30% DMSO were prepared from a commercial sterile injection product, and cream or hydrophilic ointment. Physical stability was tested at 30°C for 2 months, or using 6 heating-cooling cycles. The chemical stability and in vitro nail permeation of AmB content were analyzed using high-performance liquid chromatography (HPLC). In vitro nail permeation was performed by applying 3.5 mg/mm2 of the tested formulation on nail clippings for 5 consecutive days.
Results: The AmB cream and ointment extemporaneous preparations containing 30% DMSO, a permeation enhancer, were homogeneous and pale yellow to yellow cream or ointment. The AmB ointment was stable for up to 60 days. The ointment preparation allows in vitro penetration through nails up to 14.17 μg/cm2. The ointment preparation allows significantly better penetration through than the cream preparation due to the presence of DMSO, sodium lauryl sulfate (SLS), and water in the ointment preparation.
Conclusion: The AmB extemporaneous ointment was successfully compounded from a commercial sterile injection product with a beyond-use date of 60 days. The ointment preparation is currently under further investigation for in vivo efficacy.
2. Welsh O, Vera-Cabrera L, Welsh E. Onychomycosis. Clin Dermatol 2010;28:151-9.
3. Maddy AJ, Tosti A. Hair and nail diseases in the mature patient. Clin Dermatol 2018;36:159-66.
4. Rodgers P, Bassler M. Treating onychomycosis. Am Fam Physician 2001;63:663-73.
5. Tabara K, Szewczyk AE, Bienias W, Wojciechowska A, Pastuszka M, Oszukowska M, et al. Amorolfine vs. ciclopirox-lacquers for the treatment of onychomycosis. Postepy Dermatol Alergol 2015;32:40-5.
6. Ungpakorn R. Mycoses in Thailand: Current concerns. Nihon Ishinkin Gakkai Zasshi 2005;46:81-6.
7. Chaowattanapanit S, Pattanaprichakul P, Leeyaphan C, Chaiwanon O, Sitthinamsuwan P, Kobwanthanakun W, et al. Coexistence of fungal infections in psoriatic nails and their correlation with severity of nail psoriasis. Indian Dermatol Online J 2018;9:314-7.
8. Alastruey-Izquierdo A, Cuenca-Estrella M, Monzón A, Mellado E, Rodríguez-Tudela JL. Antifungal susceptibility profile of clinical Fusarium spp. isolates identified by molecular methods. J Antimicrob Chemother 2008;61:805-9.
9. Lacroix C, de Chauvin MF. In vitro activity of amphotericin B, itraconazole, voriconazole, posaconazole, caspofungin and terbinafine against Scytalidium dimidiatum and Scytalidium hyalinum clinical isolates. J Antimicrob Chemother 2008;61:835-7.
10. Lurati M, Baudraz-Rosselet F, Vernez M, Spring P, Bontems O, Fratti M, et al. Efficacious treatment of non-dermatophyte mould onychomycosis with topical amphotericin B. Dermatology 2011;223:289-92.
11. Wilkinson JM, McDonald C, Parkin JE, Sunderland VB. A high-performance liquid-chromatographic assay for amphotericin B in a hydrophilic colloidal paste base. J Pharm Biomed Anal 1998;17:751-5.
12. Komesmuneeborirak P, Werawatganone P, Muangsiri W. Formulation of topical preparations containing high concentration of permeation enhancer in a treatment of onychomycosis. Thai J Pharm Sci 2013;38:192-4.
13. Harmanization of Standard and Technical Requirements in ASEAN. ASEAN Guideline Onstability Study of Drug Product, R1; 2013. Available from: https://www.asean.org/wp-content/uploads/2012/10/ asean-guideline-on-stability-study-of-drug-product-r1-2013.pdf. [Last accessed on 2020 Jun 24].
14. Murdan S. Drug delivery to the nail following topical application. Int J Pharm 2002;236:1-26.
15. Fischer-Levancini C, Sanchez-Regana M, Llambi F, Collgros H, Exposito-Serrano V, Umbert-Millet P. Nail psoriasis: Treatment with tazarotene 0.1% hydrophilic ointment. Actas Dermosifiliogr 2012;103:725-8.
16. Valdes BS, Serro AP, Gordo PM, Silva A, Gonçalves L, Salgado A, et al. New polyurethane nail lacquers for the delivery of terbinafine: Formulation and antifungal activity evaluation. J Pharm Sci 2017;106:1570-7.
17. Walters KA, Abdalghafor HM, Lane ME. The human nail-barrier characterisation and permeation enhancement. Int J Pharm 2012;435:10-21.
18. Niazi S. Handbook of Pharmaceutical Manufacturing Formulations: Semisolid Products. New York: CRC Press; 2009. p. 184-327.
19. United States Pharmacopeia Commission. United States Pharmacopeia and National Formulary, USP41-NF36. Washington, DC: United States Pharmacopeia Commission; 2018.
20. Vejnovic I, Simmler L, Betz G. Investigation of different formulations for drug delivery through the nail plate. Int J Pharm 2010;386:185-94.
21. Swati H, Krishan K, Chandra NB, Richa S. Design, formulation and in vitro drug release from transdermal patches containing imipramine hydrochloride as model drug. Int J Pharm Pharm Sci 2017;6:220-5.
22. The United States Food and Drug Administration. Inactive Ingredient Search for Approved Drug Products; 2019. Available from: https:// www.accessdata.fda.gov/scripts/cder/iig/index.cfm. [Last accessed on 2019 Nov 15].
23. Putri MC, Harmita H, Iskandarsyah I. Improving transdermal drug delivery system for medroxyprogesterone acetate by olive oil and dimethylsulfoxide (DMSO) as penetration enhancers: In vitro penetration study. Int J Pharm Pharm Sci 2020;4:12-5.
24. Franz TJ. Absorption of amorolfine through human nail. Dermatology1992;184:18-20.
25. Myoung Y, Choi HK. Permeation of ciclopirox across porcine hoof membrane: Effect of pressure sensitive adhesives and vehicles. Eur J Pharm Sci 2003;20:319-25.
26. Sheskey PJ, Cook WG, Cable CG. Handbook of Pharmaceutical Excipients. 8th ed. London: Pharmaceutical Press; 2017. p. 331-3.
27. Asher IM, Schwartzman G. Amphotericin B. In: Florey K, editor. Analytical Profiles of Drug Substances. Vol. 6. New York: Academic Press; 1997. p. 1-42.
28. World Health Organization. Forty-third Report of the WHO Expert Committee on Specifications for Pharmaceutical Preparations. Geneva: World Health Organization; 2009. p. 99.
29. McAuley WJ, Jones SA, Traynor MJ, Guesné S, Murdan S, Brown MB. An investigation of how fungal infection influences drug penetration through onychomycosis patient’s nail plates. Eur J Pharm Biopharm 2016;102:178-84.
30. Gunt HB, Kasting GB. Effect of hydration on the permeation of ketoconazole through human nail plate in vitro. Eur J Pharm Sci 2007;32:254-60.
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