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Journal of Pharmaceutical Investigation

, Volume 45, Issue 1, pp 79–89 | Cite as

Terbinafine hydrochloride loaded nanoemulsion based gel for topical application

  • V. V. S. Narayana Reddy KarriEmail author
  • Suresh Kumar Raman
  • Gowthamarajan Kuppusamy
  • Shashank Mulukutla
  • Shanmugam Ramaswamy
  • Rajkumar Malayandi
Research Article

Abstract

The objective of the present study was to design and develop topical nanoemulsion based Terbinafine HCl (TBH) gel to increase its permeability and efficacy using rat as an animal model. Nanoemulsions were prepared by two different techniques viz. high pressure homogenization and high speed homogenization, the prepared nanoemulsions were incorporated into carbomer gel to obtain nanoemulsion based gel, which designated as Gel-P and Gel-S respectively. The developed gels were evaluated for drug content, stability, spreadability, and in vitro permeation using pork skin. The in vivo antifungal efficacy of the developed gels was assessed in albino Wistar rats. The globule size obtained by high pressure homogenization was less than 2 nm in radius (r.nm) and that by high speed homogenization was less than 10 r.nm. In vitro permeation studies revealed that Gel-P (51.19 ± 0.81 %) had higher permeation when compared to Gel-S (31.72 ± 1.12 %) and marketed cream (19.78 ± 1.01 %) which is essential to treat topical fungal diseases. In vivo antifungal studies in Wistar rats infected with Trichophyton mentagrophytes revealed that topical application of Gel-P and Gel-S cured the infection within 3 days compared to 14 days for Marketed Cream (M.C). This study confirms that the nanoemulsion gels provided greater permeation followed by cure rates of poorly soluble TBH in animal model and hence these systems could be the preferred drug carriers for drugs intended for topical use to overcome the permeability and efficacy problems.

Keywords

Terbinafine HCl Nanoemulsion gel Permeability Poorly soluble drug Topical antifungal Trichophyton mentagrophytes 

Notes

Acknowledgments

The authors (V. V. S. Narayana Reddy Karri, R. Suresh Kumar, K. Gowthamarajan, M. Shashank, R. Shanmugam, Rajkumar Malayandi) declare(s) that they have no conflicts of interest to disclose. The authors alone are responsible for the content and writing of the paper. The Author(s) confirm that the manuscript has not been previously published in any language anywhere and is also not in under simultaneous consideration by another journal. All institutional and national guidelines for the care and use of laboratory animals were followed. The author is grateful to IMTECH (Chandigarh, India) for providing the fungal species of Trichophyton mentagrophytes. The author would like to thank Ashish Wadhwani, Viral Patel, E Hemnath, Sumeet Sood, Chaithanya Chakravarthi, T Venkata Siddhartha and Y Karthik for their assistance in pharmacology and cell culture related work.

References

  1. Aggarwal AK, Jindal P (2013) Interaction of terbinafine hydrochloride with nicotinamide in solution and solid state. J Pharm Investig 44(1):23–32CrossRefGoogle Scholar
  2. Alberti I, Kalia YN, Naik A, Bonny J, Guy RH (2001) Effect of ethanol and isopropyl myristate on the availability of topical terbinafine in human stratum corneum in vivo. Int J Pharm 219:11–19CrossRefPubMedGoogle Scholar
  3. Anania FA, Rabin L (2002) Terbinafine hepatotoxicity resulting in chronic biliary ductopenia and portal fibrosis. Am J Med 112:741–742CrossRefPubMedGoogle Scholar
  4. Barbero AM, Frasch HF (2009) Pig and guinea pig skin as surrogates for human in vitro penetration studies: a quantitative review. Toxicol Vitro 23:1–13CrossRefGoogle Scholar
  5. Barot BS, Parejiya PB, Patel HK, Gohel MC, Shelat PK (2012) Microemulsion-based gel of terbinafine for the treatment of onychomycosis: optimization of formulation using D-optimal design. AAPS Pharm Sci Tech 13:184–192CrossRefGoogle Scholar
  6. Bhanu PV, Shanmugam V, Lakshmi PK (2011) Development and optimization of novel diclofenac emulgel for topical drug delivery. Int J Comp Pharm 02:2–5Google Scholar
  7. Burstein Z, Vildósola H, Lozano Z, Verona R, Vargas G (2004) Colestasic toxic hepatitis caused by terbinafine: case report. Rev Gastroenterol Peru 24:357–362PubMedGoogle Scholar
  8. Cardoso S, Schapoval E (1999) High-performance liquid chromatographic assay of terbinafine hydrochloride in tablets and creams. J Pharm Biomed Anal 19:809–812CrossRefPubMedGoogle Scholar
  9. Cevc G, Vierl U (2010) Nanotechnology and the transdermal route: a state of the art review and critical appraisal. J Control Release 141(3):277–299CrossRefPubMedGoogle Scholar
  10. Chambers WM, Millar A, Jain S, Burroughs AK (2001) Terbinafine-induced hepatic dysfunction. Eur J Gastroenterol Hepatol 13:1115–1118CrossRefPubMedGoogle Scholar
  11. Chen H, Khemtong C, Yang X, Chang X, Gao J (2011) Nanonization strategies for poorly water soluble drugs. Drug Discov Today 16(7–8):354–360CrossRefPubMedGoogle Scholar
  12. Dawson AL, Dellavalle RP, Elston DM (2012) Infectious skin diseases: a review and needs assessment. Dermatol Clin 30:141–151CrossRefPubMedGoogle Scholar
  13. Denouël J, Keller HP, Schaub P, Delaborde C, Humbert H (1995) Determination of terbinafine and its desmethyl metabolite in human plasma by high-performance liquid chromatography. J Chromatogr B 663:353–359CrossRefGoogle Scholar
  14. El Maghraby G (2008) Transdermal delivery of hydrocortisone from eucalyptus oil microemulsion: effects of cosurfactants. Int J Pharm 355(1–2):285–292CrossRefPubMedGoogle Scholar
  15. Fujita S (1992) Conditions required for successful experimental dermatophytosis and its histopathogenesis. Jap J Med Mycol 33:115–125CrossRefGoogle Scholar
  16. Fujita S (1997) Animal models of dermatomycoses in recent years. Jap J Med Mycol 38:33–37CrossRefGoogle Scholar
  17. Güngör S, Sedef Erdal M, Aksu (2013) New Formulation Strategies in Topical Antifungal Therapy. J Cosmet Dermatol Sci Appl 03:56–65Google Scholar
  18. Hinojosa JR, Hitchcock K (2007) Which oral antifungal is best for toenail onychomycosis? J Fam Pract 56:581–582PubMedGoogle Scholar
  19. Huang YB, Lin YH, Lu TM, Wang RJ, Tsai YH, Wu PC (2008) Transdermal delivery of capsaicin derivative-sodium nonivamide acetate using microemulsions as vehicles. Int J Pharm 349(1–2):206–211CrossRefPubMedGoogle Scholar
  20. International Conference on Harmonization (2003), Stability testing of new drug substances and products. ICH Q1A (R2)Google Scholar
  21. Jain J, Bhandari A, Shah D (2010) Novel Carriers For Transdermal Drug Delivery: a Review. Int J Pharm Appl Sci 1:62–69Google Scholar
  22. Kluge J, Muhrer G, Mazzotti M (2012) High pressure homogenization of pharmaceutical solids. J Supercrit Fluids 66:380–388CrossRefGoogle Scholar
  23. Lee SG, Jeong JH, Kim SR, Lee KM, Ahn BK, Kang MH, Choi YW (2012) Topical formulation of retinyl retinoate employing nanostructured lipid carriers. J Pharm Investig 42(5):243–250CrossRefGoogle Scholar
  24. Moser K, Kriwet K, Naik A, Kalia YN, Guy RH (2001) Passive skin penetration enhancement and its quantification in vitro. Eur J Pharm Biopharm 52:103–112CrossRefPubMedGoogle Scholar
  25. Newland JG, Abdel-Rahman SM (2009) Update on terbinafine with a focus on dermatophytoses. Clin Cosmet Investig Dermatol 2:49–63PubMedCentralPubMedGoogle Scholar
  26. Patel B, Banwait H, Parmar K, Patel M (2011) Formulation and evaluation of topical aceclofenac gel using different gelling agent. Int J Drug Dev Res 3:156–164Google Scholar
  27. Peltola S, Saarinen-Savolainen P, Kiesvaara J, Suhonen TM, Urtti A (2003) Microemulsions for topical delivery of estradiol. Int J Pharm 254:99–107CrossRefPubMedGoogle Scholar
  28. Prow TW, Grice JE, Lin LL, Faye R, Butler M, Becker W et al (2009) Nanoparticles and microparticles for skin drug delivery. Adv Drug Deliv Rev 63(6):470–491CrossRefGoogle Scholar
  29. Ramesh Raju R, Bujji Babu N (2011) Simultaneous analysis of RPHPLC method development and pharmaceutical dosage form. Pharmacophore 2:232–238Google Scholar
  30. Salunkhe SS, Bhatia NM, Pokharkar VB, Thorat JD, Bhatia MS (2013) Topical delivery of Idebenone using nanostructured lipid carriers: evaluations of sun-protection and anti-oxidant effects. J Pharm Investig 43(4):287–303CrossRefGoogle Scholar
  31. Shiloah E, Horowiz M, Zecler E (1997) Terbinafine-induced cholestatic liver injury. Harefuah 133:80–81Google Scholar
  32. Shivhare UD, Jain KB, Mathur VB, Bhusari KP, Roy AA (2009) Formulation development and evaluation of diclofenac sodium gel using water soluble polyacrylamide polymer. Dig J Nanomater Bios 4:285–290Google Scholar
  33. Silva AC, González-Mira E, García ML, Egea MA, Fonseca J, Silva R et al (2011) Preparation, characterization and biocompatibility studies on risperidone-loaded solid lipid nanoparticles (SLN): high pressure homogenization versus ultrasound. Colloids Surf B 86:158–165CrossRefGoogle Scholar
  34. Srpska M, Sad N, Serbia B, Johnson SE, Academy MM (2007) Experimentally induced dermatomycoses at rats and treatment with Lavandula angustifolia essential oil. Proc Nat Sci 113:249–254Google Scholar
  35. Stricker BH, Van Riemsdijk MM, Sturkenboom MC, Ottervanger JP (1996) Taste loss to terbinafine: a case-control study of potential risk factors. Br J Clin Pharmacol 42:313–318CrossRefPubMedCentralPubMedGoogle Scholar
  36. Thapa DM (2007) Current treatment of onychomycosis. Indian J Dermatol Venereol Leprol 73:373–376CrossRefGoogle Scholar
  37. The Fungal Research Trust (June 18th 2011) How common are fungal diseases? Fungal Research Trust 20th Anniversary meeting. LondonGoogle Scholar
  38. Trotta M (1999) Influence of phase transformation on indomethacin release from microemulsions. J Control Release 60:399–405CrossRefPubMedGoogle Scholar
  39. Van Cutsem J (1989) Animal models for dermatomycotic infections. Curr Top Med Mycol 3:1–35CrossRefPubMedGoogle Scholar
  40. Vincent AH, Jeffrey DC (2007) Measuring the size of nanoparticles in aqueous media using batch-mode dynamic light scattering. NCL Joint Assay Protocol PCC-1Google Scholar
  41. Zhu W, Guo C, Yu A, Gao Y, Cao F, Zhai G (2009) Microemulsion-based hydrogel formulation of penciclovir for topical delivery. Int J Pharm 378:152–158CrossRefPubMedGoogle Scholar

Copyright information

© The Korean Society of Pharmaceutical Sciences and Technology 2014

Authors and Affiliations

  • V. V. S. Narayana Reddy Karri
    • 1
    Email author
  • Suresh Kumar Raman
    • 1
  • Gowthamarajan Kuppusamy
    • 1
  • Shashank Mulukutla
    • 2
  • Shanmugam Ramaswamy
    • 1
  • Rajkumar Malayandi
    • 3
  1. 1.Department of PharmaceuticsJSS College of Pharmacy, Ootacamund, JSS UniversityMysoreIndia
  2. 2.Department of PharmacologyJSS College of Pharmacy, Ootacamund, JSS UniversityMysoreIndia
  3. 3.COE-BIO, Clinical Pharmacology and PharmacokineticsIPDO, Dr.Reddys LaboratoriesRanga Reddy DistrictIndia

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