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作者： Lígia Marquez Andradea. Luis Antônio Dantas Silvaa. Anna Paula Krawczyk-Santosa. Isabella Cristina de S.M.Amorima. Priscila Bianca Rodrigues da Rochaa. Eliana Martins Limab. Jorge Luiz V.Anjosc. Antonio Alonsod. Ricardo Neves Marretoa. Stephânia Fleury Taveiraa.

a

Laboratory of Nanosystems and Drug Delivery Devices (NanoSYS), School of Pharmacy - Universidade Federal de Goiás (UFG), Rua 240, Setor Leste Universitário, 74.605-170 Goiânia-GO, Brazil

b

Laboratory of Pharmaceutical Technology, School of Pharmacy - Universidade Federal de Goiás (UFG) – Praça Universitária, Setor Universitário, 74.605-220 Goiânia-GO, Brazil

c

Physics Department, Universidade Federal de Goiás (UFG), Campus Catalão - Av. Dr. Lamartine Pinto de Velar, 1120, St. Universitário, 74.704-020 Catalão-GO, Brazil

d

Biophysics Laboratory, Physics Institute - Universidade Federal de Goiás (UFG), Campus Samambaia - Caixa Postal 131, 74.0001-970 Goiânia-GO, Brazil

 

摘要：Combined therapy with corticosteroids and immunosuppressant-loaded nanostructured lipid carriers (NLC) could be useful in the treatment of skin diseases. To circumvent NLC loading capacity problems, loaded drugs should have different physicochemical characteristics, such as tacrolimus (TAC) and clobetasol (CLO). Therefore, in the present study, TAC and CLO were encapsulated in NLC (TAC-NLC, CLO-NLC and TAC+CLO-NLC), coated or otherwise with chitosan. Electron paramagnetic resonance (EPR) spectroscopy of different spin labels was used to investigate the impact of drug and oil incorporation on the lipid dynamic behavior of the lipid matrices. In addition, the impact of co-encapsulation on drug release and skin permeation was evaluated. Entrapment efficiency was greater than 90% for both drugs, even when the maximum drug loading achieved for TAC-NLC and CLO-NLC was kept at TAC+CLO-NLC, because TAC is more soluble in the solid lipid and CLO in the liquid lipid. EPR data indicated that both drugs reduced the lipid fluidity near the polar surface of the lipid matrix, which suggests their presence in this region. In addition, EPR data showed that liquid lipid is also present in more superficial regions of the nanoparticle matrix. CLO was released faster than TAC from TAC+CLO-NLC, probably because it is more soluble in the liquid lipid. TAC skin penetration was affected by CLO. A 5-fold increase in TAC penetration was observed from TAC+CLO-NLC when compared to TAC-NLC formulations. Coating also increased TAC and CLO permeation to deeper skin layers (1.8-fold and 1.6-fold, respectively). TAC+CLO-NLC seems to be an effective strategy for topical delivery of TAC and CLO, and thus constitutes promising formulations for the treatment of skin diseases.