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Reverse Hexagonal Phase Nanodispersion of Monoolein and Oleic Acid for Topical Delivery of Peptides: in Vitro and in Vivo Skin Penetration of Cyclosporin A

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Purpose

To obtain and characterize reverse hexagonal phase nanodispersions of monoolein and oleic acid, and to evaluate the ability of such system to improve the skin penetration of a model peptide (cyclosporin A, CysA) without causing skin irritation.

Methods

The nanodispersion was prepared by mixing monoolein, oleic acid, poloxamer, and water. CysA was added to the lipid mixture to obtain a final concentration of 0.6% (w/w). The nanodispersion was characterized; the skin penetration of CysA was assessed in vitro (using porcine ear skin mounted in a Franz diffusion cell) and in vivo (using hairless mice).

Results

The obtainment of the hexagonal phase nanodispersion was demonstrated by polarized light microscopy, cryo-TEM and small angle X-ray diffraction. Particle diameter was 181.77 ± 1.08 nm. At 0.6%, CysA did not change the liquid crystalline structure of the particles. The nanodispersion promoted the skin penetration of CysA both in vitro and in vivo. In vitro, the maximal concentrations (after 12 h) of CysA obtained in the stratum corneum (SC) and in the epidermis without stratum corneum (E) + dermis (D) were ∼2 fold higher when CysA was incorporated in the nanodispersion than when it was incorporated in the control formulation (olive oil). In vivo, 1.5- and 2.8-times higher concentrations were achieved in the SC and [E+D], respectively, when the nanodispersion was employed. No histopathological alterations were observed in the skin of animals treated with the nanodispersion.

Conclusion

These results demonstrate that the hexagonal phase nanodispersion is effective in improving the topical delivery of peptides without causing skin irritation.

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Acknowledgments

We thank Dr. Alexandre A. Steiner (St. Joseph's Hospital, Phoenix, AZ, USA) for critical comments on the manuscript, Dr. M. Helena. A. Santana (UNICAMP, Campinas, Brazil) for the light scattering analysis, Dr. Katarina Edwards for Cryo-TEM analysis, Dr. Lia Queiroz do Amaral for helpful discussions, Dr. Colleen M. Brophy (ASU, Tempe, USA) for microscopic facilities, and LNLS (project D11A- SAXS-2461) for the SAXRD measurements. This work was supported by “Coordenação de Aperfeiçoamento de Pessoal de Nível Superior” (CAPES, Brazil), Conselho Nacional de Pesquisa (CNPq, Brazil) and “Fundação de Amparo à Pesquisa do Estado de São Paulo” (FAPESP, Brazil). L.B. Lopes was the recipient of a CNPq fellowship.

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  1. Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Av. do Café, s/n, Ribeirão Preto, SP 14040-903, Brazil

    Luciana B. Lopes, Denise A. Ferreira, Daniel de Paula, M. Tereza J. Garcia & M. Vitória L. B. Bentley

  2. Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, São Paulo, Brazil

    José A. Thomazini

  3. Instituto de Física, Universidade de São Paulo, São Paulo, Brazil

    Márcia C. A. Fantini

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  1. Luciana B. Lopes
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Correspondence to M. Vitória L. B. Bentley.

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Lopes, L.B., Ferreira, D.A., de Paula, D. et al. Reverse Hexagonal Phase Nanodispersion of Monoolein and Oleic Acid for Topical Delivery of Peptides: in Vitro and in Vivo Skin Penetration of Cyclosporin A. Pharm Res 23, 1332–1342 (2006). https://doi.org/10.1007/s11095-006-0143-7

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