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Development of ketoconazole nanovesicular system using 1,2-hexanediol and 1,4-cyclohexanediol for dermal targeting delivery: physicochemical characterization and in vitro/in vivo evaluation

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Abstract

The present study was aimed at the encapsulation of ketoconazole (KCZ) in the novel modified nanovesicles for dermal targeting delivery. To this purpose, innovative modified vesicles were prepared with soy phospholipid and aqueous solutions containing different concentrations of two targeting modifiers, 1,2-hexanediol and 1,4-cyclohexanediol. Conventional liposomes, with soy phospholipid and cholesterol, were used as control. The prepared formulations were characterized in terms of entrapment efficiency, size distribution, morphology, and stability. Dermal KCZ targeting delivery from modified vesicles was investigated in vitro and in vivo through newborn pig and rat skin, respectively. All vesicles showed a mean size ranging from 58 to 147 nm with fairly narrow size distribution and drug entrapment efficiency between 20 and 75 %. Results of in vitro and in vivo studies indicated that modified vesicles provided an improved KCZ targeting delivery into skin layers. Images of the confocal laser scanning microscopy analyses supported the conclusion that modified vesicles could enhance the drug deposition into the skin strata and reduce the drug permeation into the blood, due to a synergic effect of phospholipid and modifiers. Finally, histological evaluation showed that KCZ-loaded modified vesicles caused no irritation to the skin. The results obtained encouraged the use of the KCZ-loaded modified vesicles as the formulation for the potential topical treatment of fungal infections.

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References

  • Aggarwal N, Goindi S (2012) Preparation and evaluation of antifungal efficacy of griseofulvin loaded deformable membrane vesicles in optimized guinea pig model of Microsporum canis—Dermatophytosis. Int J Pharm 437:277–287

    Article  Google Scholar 

  • Allen TM, Cleland LG (1980) Serum-induced leakage of liposome contents. Biochim Biophys Acta 597:418–426

    Article  Google Scholar 

  • Allen TM, Cullis PR (2013) Liposomal drug delivery systems: from concept to clinical applications. Adv Drug Deliv Rev 65:36–48

    Article  Google Scholar 

  • Betz G, Nowbakht P, Imboden R, Imanidis G (2001) Heparin penetration into and permeation through human skin from aqueous and liposomal formulations in vitro. Int J Pharm 228:147–159

    Article  Google Scholar 

  • Caddeo C, Sales OD, Valenti D, Sauri AR, Fadda AM, Manconi M (2013) Inhibition of skin inflammation in mice by diclofenac in vesicular carriers: liposomes, ethosomes and PEVs. Int J Pharm 443:128–136

    Article  Google Scholar 

  • Carrer DC, Vermehren C, Bagatolli LA (2008) Pig skin structure and transdermal delivery of liposomes: a two photon microscopy study. J Control Release 132:12–20

    Article  Google Scholar 

  • Cross SE, Roberts MS (2000) The effect of occlusion on the epidermal penetration of parabens from a commercial test ointment, acetone and ethanol vehicles. J Invest Dermatol 115:914–918

    Article  Google Scholar 

  • Dohta Y, Yamashita T, Horiike S, Nakamura T, Fukami T (2007) A system for LogD screening of 96-well plates using a water-plug aspiration/injection method combined with high-performance liquid chromatography-mass spectrometry. Anal Chem 79:8312–8315

    Article  Google Scholar 

  • Foldvari M, Badea I, Wetting S, Baboolal D, Kumar P, Creagh AL, Haynes CA (2010) Topical delivery of interferon alpha by biphasic vesicles: evidence for a novel nanopathway across the stratum corneum. Mol Pharm 7(3):751–762

    Article  Google Scholar 

  • Godin B, Touitou E (2007) Transdermal skin delivery: predictions for humans from in vivo, ex vivo and animal models. Adv Drug Del Rev 59:1152–1161

    Article  Google Scholar 

  • Hadgraft J (2001) Skin, the final frontier. Int J Pharm 224:1–18

    Article  Google Scholar 

  • Jain AK, Thomas NS, Panchagnula R (2002) Transdermal drug delivery of imipramine hydrochloride. I. Effect of terpenes. J Control Release 79:93–101

    Article  Google Scholar 

  • Jenning V, Gysler A, Schafer-Korting M, Gohla SH (2000) Vitamin A loaded solid lipid nanoparticles for topical use: occlusive properties and drug targeting to the upper skin. Eur J Pharm Biopharm 49:211–218

    Article  Google Scholar 

  • Laiho LH, Pelet S, Hancewicz TM, Kaplan PD, So PTC (2005) Two-photon 3-D mapping of ex vivo human skin endogenous fluorescence species based on fluorescence emission spectra. J Biomed Opt 10(2):024016

    Article  Google Scholar 

  • Lampidis TJ, Castello C, Del Giglio A, Pressman BC, Viallet P, Trevrrow KW, Valet GK, Tapiero H, Savaraj N (1989) Relevance of the chemical charge of rhodamine dyes to multiple drug resistance. Biochem Pharmacol 38:4267–4271

    Article  Google Scholar 

  • Levy SB, Dulichan AM, Helman M (2009) Safety of a preservative system containing 1,2-hexanediol and caprylyl glycol. Cutan Ocul Toxicol 28:23–24

    Article  Google Scholar 

  • Li N, Sun Q, Tan F, Zhang J (2010) Effect of 1,4-cyclohexanediol on percutaneous absorption and penetration of azelaic acid. Int J Pharm 387:167–171

    Article  Google Scholar 

  • Li N, Jia W, Zhang Y, Tan F, Zhang J (2011) Synergistic effect of 1,4-cyclohexanediol and 1,2-hexanediol on percutaneous absorption and penetration of metronidazole. Int J Pharm 415:169–174

    Article  Google Scholar 

  • Lopez-Pinto JM, Gonzalez-Rodrıguez ML, Rabasco AM (2005) Effect of cholesterol and ethanol on dermal delivery from DPPC liposomes. Int J Pharm 298:1–12

    Article  Google Scholar 

  • Mahale NB, Thakkar PD, Mali RG, Walunj DR, Chaudhari SR (2012) Niosomes: novel sustained release nonionic stable vesicular systems—An overview. Adv Colloid Interface Sci 183–184:46–54

    Article  Google Scholar 

  • Manconi M, Caddeo C, Sinico C, Valenti D, Mostallino MC, Biggio G, Fadda AM (2011) Ex vivo skin delivery of diclofenac by transcutol containing liposomes and suggested mechanism of vesicle–skin interaction. Eur J Pharm Biopharm 78:27–35

    Article  Google Scholar 

  • Manconi M, Caddeo C, Sinico C, Valenti D, Mostallino MC, Lampis S, Monduzzi M, Fadda AM (2012) Penetration enhancer-containing vesicles: composition dependence of structural features and skin penetration ability. Eur J Pharm Biopharm 82:352–359

    Article  Google Scholar 

  • Maria FRGD, Maria VPQ, Fred B, Regina CS, Adriana GFA, David RA (2013) Update on therapy for superficial mycoses: review article part I*. Ann Bras Dermatol 88(5):764–774

    Article  Google Scholar 

  • Mezei M, Gulasekharam V (1980) Liposomes-a selective drug delivery system for the topical route of administration. I. Lotion dosage form. Life Sci 26(18):1473–1477

    Article  Google Scholar 

  • Mezei M, Gulasekharam V (1982) Liposomes. A selective drug delivery system for the topical route of administration: gel dosage form. J Pharm Pharmacol 34(7):473–474

    Article  Google Scholar 

  • Müller RH, Radtke M, Wissing SA (2002) Solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) in cosmetic and dermatological preparations. Adv Drug Deliv Rev 54:S131–S155

    Article  Google Scholar 

  • Nail A, Kalia YN, Guy RH, Fessi H (2004) Enhancement of topical delivery from biodegradable nanoparticles. Pharm Res 21:1818–1825

    Article  Google Scholar 

  • Panchagnula R, Desu H, Jain A, Khandavilli S (2004) Effect of lipid bilayer alteration on transdermal delivery of a high-molecular-weight and lipophilic drug: studies with paclitaxel. J Pharm Sci 93:2177–2183

    Article  Google Scholar 

  • Prausnitz MR, Langer R (2008) Transdermal drug delivery. Nat Biotechnol 26:1261–1268

    Article  Google Scholar 

  • Song YK, Kim CK (2006) Topical delivery of low-molecular-weight heparin with surface-charged flexible liposomes. Biomaterials 27:271–280

    Article  Google Scholar 

  • Srisuk P, Thongnopnua P, Rakanonchai U, Kanokpanont K (2012) Physico-chemical characteristics of methotrexate-entrapped oleic acid-containing deformable liposomes for in vitro transepidermal delivery targeting psoriasis treatment. Int J Pharm 427:426–434

    Article  Google Scholar 

  • Touitou E, Dayan N, Bergelson L, Godin B, Eliaz M (2000) Ethosomes—novel vesicular carriers for enhanced delivery: characterization and skin penetration properties. J Control Release 65:403–418

    Article  Google Scholar 

  • Verma DD, Verma S, Blume G, Fahr A (2003) Particle size of liposomes influences dermal delivery of substances into skin. Int J Pharm 258:141–151

    Article  Google Scholar 

  • Wertz PW (1992) Epidermal lipids. Semin Dermatol 11:106–113

    Google Scholar 

  • Williams AC, Barry BW (1991) Terpenes and the lipid-protein-partitioning theory of skin penetration enhancement. Pharm Res 8:17–24

    Article  Google Scholar 

  • Williams AC, Barry BW (2012) Penetration enhancers. Adv Drug Deliv Rev 64:128–137

    Article  Google Scholar 

  • Zhang Z, Wo Y, Zhang Y, Wang D, He R, Chen H, Cui D (2012) In vitro study of ethosome penetration in human skin and hypertrophic scar tissue. Nanomed Nanotechnol Biol Med 8:1026–1033

    Article  Google Scholar 

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Acknowledgments

The National Basic Research Project (2014CB932200) of the MOST is acknowledged for financial support.

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Authors and Affiliations

  1. Tianjin Key Laboratory of Drug Delivery & High-Efficiency, School of Pharmaceutical Science and Technology, Tianjin University, Tianjin, 300072, People’s Republic of China

    Jinping Wang, Fang Guo, Man Ma, Nan Li & Fengping Tan

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  1. Jinping Wang
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  2. Fang Guo
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  3. Man Ma
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  4. Nan Li
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  5. Fengping Tan
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Correspondence to Nan Li or Fengping Tan.

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Wang, J., Guo, F., Ma, M. et al. Development of ketoconazole nanovesicular system using 1,2-hexanediol and 1,4-cyclohexanediol for dermal targeting delivery: physicochemical characterization and in vitro/in vivo evaluation. J Nanopart Res 16, 2505 (2014). https://doi.org/10.1007/s11051-014-2505-0

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  • DOI: https://doi.org/10.1007/s11051-014-2505-0

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