Skip to main content
SpringerLink
Log in

Development of nanovesicular systems for dermal imiquimod delivery: physicochemical characterization and in vitro/in vivo evaluation

  • Biocompatibility Studies
  • Published:
Journal of Materials Science: Materials in Medicine Aims and scope Submit manuscript

Abstract

The aim of the current investigation was to develop and statistically evaluate nanovesicular systems for dermal imiquimod delivery. To this purpose, transethosomes were prepared with phospholipid, ethanol and different permeation enhancers. Conventional ethosomes, with soy phospholipid and ethanol, were used as control. The prepared vesicles were characterized for size, zeta potential, stability and entrapment efficiency. The optimal transethosomal formulation with mean particle size of 82.3 ± 9.5 nm showed the higher entrapment efficiency (68.69 ± 1.7 %). In vitro studies, permeation results of accumulated drug and local accumulation efficiency were significantly higher for transethosomes (24.64 µg/cm2 and 6.70, respectively) than control (14.45 µg/cm2 and 3.93, respectively). Confocal laser scanning microscopy of rhodamine 6G-loaded transethosomes revealed an enhanced retention into the deeper skin layers as compared to conventional ethosomes. Besides, Fourier-transform infra-red spectroscopy studies were also performed to understand the mechanism of interaction between skin and carriers. What’s more, results of in vivo studies indicated the transethosomes of imiquimod providing the most effectiveness for dermal delivery among all of the formulations. These results suggested that transethosomes would be a promising dermal carrier for imiquimod in actinic keratose treatment.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Madan V, Lear JT, Szeimies RM. Non-melanoma skin cancer. Lancet. 2010;375(9715):673–85.

    Article  Google Scholar 

  2. Rogers HW, Weinstock MA, Harris AR, Hinckley MR, Feldman SR, Fleischer AB, Coldiron BM. Incidence estimate of nonmelanoma skin cancer in the United States. Arch Dermatol. 2006;146(3):283–7.

    Google Scholar 

  3. De Vries E, De Poll-Franse V, Louwman WJ, et al. Predictions of skin cancer incidence in the Netherlands up to 2015. Br J Dermatol. 2005;152(3):481–8.

    Article  Google Scholar 

  4. Criscione VD, Weinstock MA, Naylor MF, Luque C, Eide MJ, Bingham SF. Actinic keratoses: natural history and risk of malignant transformation in the Veterans Affairs Topical Tretinoin Chemoprevention Trial. Cancer. 2009;115(11):2523–30.

    Article  Google Scholar 

  5. Cohen JL. Actinic keratosis treatment as a key component of preventive strategies for nonmelanoma skin cancer. J Clin Aesthet Dermatol. 2010;3:39–44.

    Google Scholar 

  6. Stritt A, Merk HF, Braathen LR, von Felbert V. Photodynamic therapy in the treatment of actinic keratosis. Photochem Photobiol. 2008;84:388–98.

    Article  Google Scholar 

  7. Weinberg JM. Topical therapy for actinic keratoses: current and evolving therapies. Rev Recent Clin Trials. 2006;1:53–60.

    Article  Google Scholar 

  8. Li L, Shukla S, Lee A, Garfield SH, Maloney DJ, Ambudkar SV, Yuspa SH. The skin cancer chemotherapeutic agent ingenol-3-angelate (PEP005) is a substrate for the epidermal multidrug transporter (ABCB1) and targets tumor vasculature. Cancer Res. 2010;70:4509–19.

    Article  Google Scholar 

  9. Resnick L, Rabinovitz H, Binninger D, Marchetti M, Weissbach H. Topical sulindac combined with hydrogen peroxide in the treatment of actinic keratoses. J Drugs Dermatol. 2009;8:29–32.

    Google Scholar 

  10. Hadley G, Derry S, Moore RA. Imiquimod for actinic keratosis: systematic review and meta-analysis. J Invest Dermatol. 2006;126:1251–5.

    Article  Google Scholar 

  11. Swanson N, Abramovits W, Berman B, Kulp J, Rigel DS, Levy S. Imiquimod 2.5 % and 3.75 % for the treatment of actinic keratoses: results of two placebo-controlled studies of daily application to the face and balding scalp for two 2-week cycles. J Am Acad Dermatol. 2010;62:582–90.

    Article  Google Scholar 

  12. Lacarrubba F, Nasca MR, Micali G. Advances in the use of topical imiquimod to treat dermatologic disorders. Ther Clin Risk Manag. 2008;4:87–97.

    Google Scholar 

  13. Dos Anjos JL, Alonso A. Terpenes increase the portioning and molecular dynamics of an amphipathic spin label in stratum corneum membranes. Int J Pharm. 2008;350:103–12.

    Article  Google Scholar 

  14. Aqil M, Ahad A, Sultana Y, Ali A. Status of terpenes as skin penetration enhancers. Drug Discov Today. 2007;12:1061–7.

    Article  Google Scholar 

  15. Ahad A, Aqil M, Kohli K, Chaudhary H, Sultana Y, Mujeeb M, Talegaonkar S. Chemical penetration enhancers: a patent review. Exp Opin Ther Pat. 2009;19:969–88.

    Article  Google Scholar 

  16. Chourasia MK, Kang L, Chan SY. Nanosized ethosomes bearing ketoprofen for improved transdermal delivery. Results Pharm Sci. 2011;1:60–7.

    Article  Google Scholar 

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

    Article  Google Scholar 

  18. Sinico C, Fadda AM. Vesicular carriers for dermal drug delivery. Expert Opin Drug Deliv. 2009;6:813–25.

    Article  Google Scholar 

  19. Touitou E, Dayan N, Bergelson L, Godin B, Eliaz M. Ethosomes-novel vesicular carriers for enhanced delivery: characterization and skin penetration properties. J Control Release. 2000;65:403–18.

    Article  Google Scholar 

  20. Dragicevic-Curic N, Scheglmann D, Albrecht V, Fahr A. Temoporfin-loaded invasomes: development, characterization and in vitro skin penetration studies. J Control Release. 2008;127:59–69.

    Article  Google Scholar 

  21. Manconi M, Mura S, Sinico C, Fadda AM, Vila AO, Molina F. Development and characterization of liposomes containing glycols as carriers for diclofenac. Colloids Surf A. 2009;342:53–8.

    Article  Google Scholar 

  22. Song CK, Balakrishnan P, Shim CK, et al. A novel vesicular carrier, transethosome, for enhanced skin delivery of voriconazole: characterization and in vitro/in vivo evaluation. Colloids Surf B Biointerfaces. 2012;92:299–304.

    Article  Google Scholar 

  23. Duangjit S, Opanasopit P, Rojanarata T, Ngawhirunpat T. Characterization and in vitro skin permeation of meloxicam-loaded liposomes versus transfersomes. J Drug Deliv. 2010;2011.

  24. Caon T, Costa AC, de Oliveira MA, Micke GA, Simoes CM. Evaluation of the transdermal permeation of different paraben combinations through a pig ear skin model. Int J Pharm. 2010;391:1–6.

    Article  Google Scholar 

  25. Jain S, Tiwary AK, Sapra B, Jain NK. Formulation and evaluation of ethosomes for transdermal delivery of lamivudine. AAPS Pharm Sci Tech. 2007;8:111.

    Article  Google Scholar 

  26. Wang JP, Guo F, Ma M. 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. 2014;16:2505.

    Article  Google Scholar 

  27. Verma DD, Verma S, Blume G, Fahr A. Particle size of liposomes influences dermal delivery of substances into skin. Int J Pharm. 2003;258:141–51.

    Article  Google Scholar 

  28. Chen Y, Wu QQ, Zhang ZH, Yuan L, Liu X, Zhou L. Preparation of curcumin-loaded liposomes and evaluation of their skin permeation and pharmacodynamics. Molecules. 2012;17:5972–87.

    Article  Google Scholar 

  29. Balakrishnan P, Shanmugam S, Lee WS, et al. Formulation and in vitro assessment of minoxidil niosomes for enhanced skin delivery. Int J Pharm. 2009;377:1–8.

    Article  Google Scholar 

  30. Roy M, Gallardo M, Estelrich J. Influence of size on electrokinetics behavior of phosphatidylserine and phosphatidylehanolamine lipids vesicles. J Colloid Interface Sci. 1998;206:512–7.

    Article  Google Scholar 

  31. Mohammed AR, Weston N, Coombes AGA, Fitzgerald M, Perrie Y. Liposome: formulation of poorly water soluble drugs: optimisation of drug loading and ESEM analysis of stability. Int J Pharm. 2004;285(1–2):23–34.

    Article  Google Scholar 

  32. Cilurzo F, Minghetti P, Sinico C. New born pig skin as model membrane in in vitro drug permeation studies: a technical note. AAPS Pharm Sci Technol. 2007;8:E1–4.

    Article  Google Scholar 

  33. Manconi M, Caddeo C, Sinico C, et al. Ex vivo skin delivery of diclofenac by transcutol containing liposomes and suggested mechanism of vesicle–skin interaction. Eur J Pharm Biopharm. 2011;78(1):27–35.

    Article  Google Scholar 

  34. Honeywell-Nguyen PL, Groenink HW, Bouwstra JA. Elastic vesicles as a tool for dermal and transdermal delivery. J Liposome Res. 2006;16:273–80.

    Article  Google Scholar 

  35. Touitou E, Godin B, Weiss C. Enhanced delivery of drugs into and across the skin by ethosomal carriers. Drug Dev Res. 2000;50:406–15.

    Article  Google Scholar 

  36. Paolino D, Lucania G, Mardente D, Alhaique F, Fresta M. Ethosomes for skin delivery of ammonium glycyrrhizinate: in vitro percutaneous permeation through human skin and in vivo anti-inflammatory activity on human volunteers. J Control Release. 2005;106:99–110.

    Article  Google Scholar 

  37. Godin B, Touitou E. Erythromycin ethosomal systems: physicochemical characterization and enhanced antibacterial activity. Curr Drug Deliv. 2005;2:269–75.

    Article  Google Scholar 

  38. Müller RH, Radtke M, Wissing SA. Solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) in cosmetic and dermatological preparations. Adv Drug Deliv Rev. 2002;54:S131–55.

    Article  Google Scholar 

  39. Esposito E, Drechsler M, Mariani P, et al. Nanosystems for skin hydration: a comparative study. Int J Cosmetic Sci. 2007;29(1):39–47.

    Article  Google Scholar 

  40. Lampidis TJ, Castello C, Del Giglio A, Pressman BC, Viallet P, Trevrrow KW, Valet GK, Tapiero H, Savaraj N. Relevance of the chemical charge of rhodamine dyes to multiple drug resistance. Biochem Pharmacol. 1898;38:4267–71.

    Article  Google Scholar 

  41. Laugel C, Yagoubi N, Baillet A. ATR-FTIR spectroscopy: a chemometric approach for studying the lipid organisation of the stratum corneum. Chem Phys Lipids. 2005;135:55–68.

    Article  Google Scholar 

  42. Ibrahim SA, Li SK. Chemical enhancer solubility in human stratum corneum lipids and enhancer mechanism of action on stratum corneum lipid domain. Int J Pharm. 2010;383:89–98.

    Article  Google Scholar 

  43. Garidel P. Mid-FTIR-Microspectroscopy of stratum corneum single cells and stratum corneum tissue. Phys Chem Chem Phys. 2002;4(22):5671–7.

    Article  Google Scholar 

  44. Panchagnula R, Salve PS, Thomas NS, Jain AK, Ramarao P. Transdermal delivery of naloxone: effect of water, propylene glycol, ethanol and their binary combinations on permeation through rat skin. Int J Pharm. 2001;219(1–2):95–105.

    Article  Google Scholar 

  45. Mendelsohn R, Chen HC, Rerek ME, Moore DJ. Infrared microspectroscopic imaging maps the spatial distribution of exogenous molecules in skin. J Biomed Opt. 2003;8(2):185–90.

    Article  Google Scholar 

  46. Elsayed MA, Abdallah YO, Naggar FV, Khalafallah NM. Lipid vesicles for skin delivery of drugs: reviewing three decades of research. Int J Pharm. 2006;332:1–16.

    Article  Google Scholar 

  47. Zhang JP, Wei YH, Zhou Y, Li YQ, Wu XA. Ethosomes, binary ethosomes and transfersomes of terbinafine hydrochloride: a comparative study. Arch Pharm Res. 2012;35:109–17.

    Article  Google Scholar 

  48. Guo F, Wang JP, Ma M, Tan FP, Li N. Skin targeted lipid vesicles as novel nano-carrier of ketoconazole: characterization, in vitro and in vivo evaluation. J Mater Sci. 2015;26:175.

    Google Scholar 

  49. Abraham MH, Chdha HS, Mitchell RC. The factors that influence skin penetration of solutes. J Pharm Pharmacol. 1995;47:8–16.

    Article  Google Scholar 

  50. Roberts MS, Pugh WJ, Hadgraft J. Epidermal permeability-penetrant structure relationships: 2. The effect of H-bonding groups in penetrants on their diffusion through the stratum corneum. Int J Pharm. 1996;132:23–32.

    Article  Google Scholar 

  51. Wertz PW. Epidermal lipids. Semin Dermatol. 1992;11:106–13.

    Google Scholar 

  52. Hadgraft J, Peck J, Williams DG, Pugh WJ, Allan G. Mechanisms of action of skin penetration enhancers/retarders: azone and analogues. Int J Pharm. 1996;141:17–25.

    Article  Google Scholar 

Download references

Acknowledgments

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

Author information

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

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

Authors
  1. Man Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jinping Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Fang Guo
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mingzhu Lei
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Fengping Tan
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Nan Li
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Nan Li.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ma, M., Wang, J., Guo, F. et al. Development of nanovesicular systems for dermal imiquimod delivery: physicochemical characterization and in vitro/in vivo evaluation. J Mater Sci: Mater Med 26, 192 (2015). https://doi.org/10.1007/s10856-015-5524-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s10856-015-5524-1

Keywords

Search

Navigation