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A Preformulation Strategy for the Selection of Penetration Enhancers for a Transungual Formulation

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Abstract

Onychomycosis is associated with the cutaneous fungal infection of the nail and the nail folds (skin surrounding the nail). It is therefore important to target drug delivery into the nail folds along with nail plate and the nail bed. Systematic and strategic selection of the penetration enhancers specific for the skin and the nail is discussed. Twelve penetration enhancers were screened for their ability to improve solubility, in vitro nail penetration, in vitro skin permeation, and in vitro skin penetration of the antifungal drug ciclopirox olamine. In contrast to transdermal drug delivery, the main selection criteria for skin penetration enhancer in topical drug delivery were increased drug accumulation in the epidermis and minimal permeation across the skin. Thiourea improved the solubility and nail penetration of ciclopirox olamine. It also showed enhancement in the transungual diffusion of the drug. Propylene glycol showed a 12-fold increase in solubility and 3-fold increase in epidermal accumulation of ciclopirox olamine, while minimizing the transdermal movement of the drug. Thiourea was the selected nail permeation enhancer and propylene glycol was the selected skin penetration enhancer of ciclopirox olamine. A combination of the selected enhancers was also explored for its effect on drug delivery to the nail and nail folds. The enhancer combination reduced the penetration of ciclopirox in the skin and also the permeation through the nail. The proposed preformulation strategy helps to select appropriate enhancers for optimum topical delivery and paves way towards an efficient topical formulation for passive transungual drug delivery.

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REFERENCES

  1. Baran R, Hay RJ, Tosti A, Haneke E. A new classification of onychomycosis. Br J Dermatol. 1998;139:567–71.

    Article  CAS  PubMed  Google Scholar 

  2. Drake LA. Impact of onychomycosis on quality of life. J Am Podiatr Med Assoc. 1997;87(11):507–11.

    CAS  PubMed  Google Scholar 

  3. Drake LA, Scher RK, Smith EB, Faich GA, Smith SL, Hong JJ, et al. Effect of onychomycosis on quality of life. J Am Acad Dermatol. 1998;38:702–4.

    Article  CAS  PubMed  Google Scholar 

  4. Lubeck DP. Measuring health-related quality of life in onychomycosis. J Am Acad Dermatol. 1998;38:S64–8.

    Article  CAS  PubMed  Google Scholar 

  5. Drake LA, Patrick DL, Fleckman P, André J, Baran R, Haneke E, et al. The impact of onychomycosis on quality of life: development of an international onychomycosis-specific questionnaire to measure patient quality of life. J Am Acad Dermatol. 1999;41(2 Part1):189–96.

    Article  CAS  PubMed  Google Scholar 

  6. Turner RR, Testa MA. Measuring the impact of onychomycosis on patient quality of life. Qual Life Res. 2000;9(1):39–53.

    Article  CAS  PubMed  Google Scholar 

  7. Gregory N. Special patient populations: onychomycosis in the HIV-positive patient. J Am Acad Dermatol. 1996;35(3 part 2):S13–6.

    Article  CAS  PubMed  Google Scholar 

  8. Moreno-Coutiño G, Arenas R, Reyes-Terán G. Clinical presentation of onychomycosis in HIV/AIDS: a review of 280 Mexican cases. Indian J Dermatol. 2011;56(1):120–1.

    Article  PubMed  Google Scholar 

  9. Gupta AK, Taborda P, Taborda V, Gilmour J, Rachlis A, Salit I, et al. Epidemiology and prevalence of onychomycosis in HIV-positive individuals. Int J Dermatol. 2000;39:749–53.

    Google Scholar 

  10. Levy LA. Epidemiology of onychomycosis in special-risk populations. J Am Podiatr Med Assoc. 1997;87(12):546–50.

    CAS  PubMed  Google Scholar 

  11. Gupta AK, Lynde CW, Jain, Sibbald RG, Elewski BE, Daniel CR, et al. A higher prevalence of onychomycosis in psoriatics compared with non-psoriatics: a multicentre study. Br J Dermatol. 1997;136:786–9.

    Article  CAS  PubMed  Google Scholar 

  12. Szepietowski JC, Salomon J. Do fungi play a role in psoriatic nails? Mycoses. 2007;50(6):437–42.

    Article  PubMed  Google Scholar 

  13. Winston JA, Miller JL. Treatment of onychomycosis in diabetic patients. Clin Diabetes. 2006;24(4):160–6.

    Article  Google Scholar 

  14. Gupta AK, Fleckman P, Baran R. Ciclopirox nail lacquer topical solution 8% in the treatment of toenail onychomycosis. J Am Acad Dermatol. 2000;43:S70–80.

    Article  CAS  PubMed  Google Scholar 

  15. Monti D, Saccomani L, Chetoni P, Burgalassi S, Saettone MF, Mailland F. In vitro transungual permeation of ciclopirox from a hydroxypropyl chitosan-based, water-soluble nail lacquer. Drug Dev Ind Pharm. 2005;31:11–7.

    CAS  PubMed  Google Scholar 

  16. Johnson L. Dermatophytes—the skin eater. Mycologist. 2003;17(4):147–9.

    Article  Google Scholar 

  17. Subissi A, Monti D, Togni G, Maillan F. Ciclopirox: recent nonclinical and clinical data relevant to its use as a topical antimycotic agent. Drugs. 2010;70(16):2133–52.

    Article  PubMed  Google Scholar 

  18. Khengar R, Jones S, Turner R, Forbes B, Brown M. Nail swelling as a pre-formulation screen for the selection and optimisation of ungual penetration enhancers. Pharm Res. 2007;24(12):2207–12.

    Article  CAS  PubMed  Google Scholar 

  19. Williams A, Barry B. Penetration enhancers. Adv Drug Deliv Rev. 2004;56:603–18.

    Article  CAS  PubMed  Google Scholar 

  20. Escarrone AL, Bittencourt C, Laporta L, dos Santos M, Primel E, Caldas S. LC–UV method with pre-column derivatization for the determination of ciclopirox olamine in raw material and topical solution. Chromatographia. 2008;67:967–71.

    Article  CAS  Google Scholar 

  21. Lehr K-H, Damm P. Quantification of ciclopirox by high-performance liquid chromatography after pre-column derivatization. J Chromatogr. 1985;339:451–6.

    CAS  PubMed  Google Scholar 

  22. Myoung Y, Choi H-K. Permeation of ciclopirox across porcine hoof membrane: effect of pressure sensitive adhesives and vehicles. Eur J Pharm Sci. 2003;20:319–25.

    Article  CAS  PubMed  Google Scholar 

  23. Frank JD, Manson JM, Cartwright ME. Separation of epidermis from dermis in the rhesus monkey. Exp Dermatol. 1995;4(2):89–92.

    Article  CAS  PubMed  Google Scholar 

  24. Kassis V, SØndergaard J. Heat separation of normal human skin for epidermal and dermal prostaglandin analysis. Arch Dermatol Res. 1982;273:301–6.

    Article  CAS  PubMed  Google Scholar 

  25. Murthy SN, Vaka SR, Sammeta SM, Nair AB. TranScreen-N: method for rapid screening of trans-ungual drug delivery enhancers. J Pharm Sci. 2009;98(11):4264–71.

    Article  CAS  PubMed  Google Scholar 

  26. Manda P, Sammeta SM, Repka MA, Murthy N. Iontophoresis across the proximal nail fold to target drugs to the nail matrix. J Pharm Sci. 2012;101(7):2392–7.

    Article  CAS  PubMed  Google Scholar 

  27. Kokjohn K, Bradley M, Griffiths B, Ghannoum M. Evaluation of in vitro activity of ciclopirox olamine, butenafine HCl and econazole nitrate against dermatophytes, yeasts and bacteria. Int J Dermatol. 2003;42(S1):11–7.

    Article  CAS  PubMed  Google Scholar 

  28. Chouhan P, Saini TR. Hydration of nail plate: a novel screening model for transungual drug permeation enhancers. Int J Pharm. 2012;436(1–2):179–82.

    Article  CAS  PubMed  Google Scholar 

  29. Traynor MJ, Turner RB, Evans CR, Khengar RH, Jones SA, Brown MB. Effect of a novel penetration enhancer on the ungual permeation of two antifungal agents. J Pharm Pharmacol. 2010;62(6):730–7.

    CAS  PubMed  Google Scholar 

  30. Gupta AK, Kohli Y. In vitro susceptibility testing of ciclopirox, terbinafine, ketoconazole and itraconazole against dermatophytes and nondermatophytes, and in vitro evaluation of combination antifungal activity. Br J Dermatol. 2003;149(2):296–305.

    Article  CAS  PubMed  Google Scholar 

  31. Shehata AS, Mukherjee PK, Ghannoum MA. Comparison between the standardized clinical and laboratory standards institute M38-A2 method and a 2,3-Bis(2-methoxy-4-nitro-5-[(sulphenylamino)carbonyl])-2H-tetrazolium hydroxide based method for testing antifungal susceptibility of dermatophytes. J Clin Microbiol. 2008;46(11):3668–71.

    Article  CAS  PubMed  Google Scholar 

  32. Singh J, Zaman M, Gupta AK. Evaluation of microdilution and disk diffusion methods for antifungal susceptibility testing of dermatophytes. Med Mycol. 2007;45(7):595–602.

    Article  CAS  PubMed  Google Scholar 

  33. Schaller M, Borelli C, Berger U, Walker B, Schmidt S, Weindl G, et al. Susceptibility testing of amorolfine, bifonazole and ciclopirox olamine against Trichophyton rubrum in an in vitro model of dermatophyte nail infection. Med Mycol. 2009;47:753–8.

    Article  CAS  PubMed  Google Scholar 

  34. Kumar S, Malick AW, Meleer NM, Mouskountakis JD, Behl CR. Studies of in vitro skin permeation and retention of a leukotriene antagonist from topical vehicles with a hairless guinea pig model. J Pharm Sci. 1992;81(7):631–4.

    Article  CAS  PubMed  Google Scholar 

  35. Thomas NS, Panchagnula R. Transdermal delivery of zidovudine: effect of vehicles on permeation across rat skin and their mechanism of action. Eur J Pharm Sci. 2003;18(1):71–9.

    Article  CAS  PubMed  Google Scholar 

  36. Touitou E, Abed L. Effect of propylene glycol, Azone and n-decylmethyl sulphoxide on skin permeation kinetics of 5-fluorouracil. Int J Pharm. 1985;27:89–98.

    Article  CAS  Google Scholar 

  37. Bonina FP, Montenegro L. Penetration enhancer effects on in vitro of heparin sodium percutaneous absorption salt. Int J Pharm. 1992;82:171–7.

    Article  CAS  Google Scholar 

  38. Lorenzetti OJ. Propylene glycol gel vehicles. Cutis. 1979;23:747–50.

    CAS  PubMed  Google Scholar 

  39. Ritschel W, Panchagnula R, Stemmer K, Ashraf M. Development of an intracutaneous depot of drugs. Skin Pharmacol. 1991;4:235–45.

    Article  CAS  PubMed  Google Scholar 

  40. Puglia C, Bonina F, Trapani G, Franco M, Ricci M. Evaluation of in vitro percutaneous absorption of lorazepam and clonazepam from hydro-alcoholic gel formulations. Int J Pharm. 2001;228(1–2):79–87.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Pharmaceutical Sciences, School of Pharmacy, Temple University, Philadelphia, Pennsylvania, 19140, USA

    Biji Palliyil & David B. Lebo

  2. cGMP Services, School of Pharmacy, Temple University, Philadelphia, Pennsylvania, USA

    David B. Lebo

  3. School of Pharmacy, Temple University, Philadelphia, Pennsylvania, 19140, USA

    Pankil R. Patel

  4. 3307 North Broad Street, Philadelphia, Pennsylvania, 19140, USA

    David B. Lebo

Authors
  1. Biji Palliyil
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  2. David B. Lebo
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  3. Pankil R. Patel
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Correspondence to David B. Lebo.

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Palliyil, B., Lebo, D.B. & Patel, P.R. A Preformulation Strategy for the Selection of Penetration Enhancers for a Transungual Formulation. AAPS PharmSciTech 14, 682–691 (2013). https://doi.org/10.1208/s12249-013-9954-0

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  • DOI: https://doi.org/10.1208/s12249-013-9954-0

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