title: Microemulsion based gel for topical dermal delivery of pseudolaric acid B: In vitro and in vivo evaluation.
abstract: Pseudolaric acid B (PAB) possesses comparable fungicidal activity against Candida albicans to amphotericin B and antifungal activity against azole-resistant Candida species. However, its poor water solubility makes the formulation a considerable challenge for dermal permeation of PAB. The aim of this project was to improve the solubility and eventually the dermal permeability and bioavailability by developing a microemulsion based gel for PAB (PAB ME-gel). PAB ME-gel was formulated using isopropyl myristate as oil phase, cremphor EL as surfactant, transcutol P as cosurfactant, and carbopol as gel matrix, and characterized by droplet size, morphology, pH, and rheology. The 3 month storage test showed that PAB ME-gel possessed good physicochemical stability. In vitro permeation of PAB through rat skin from ME-gel was investigated in comparison with PAB microemulsion (PAB ME) and PAB hydrogel (PAB gel), and results showed that ME significantly enhanced PAB retention in the skin and permeation through the skin whether it was incorporated into the gel or not. In vivo dermatopharmacokinetics study using microdialysis further confirmed that ME-gel significantly increased PAB dermal bioavailability compared with the gel (41.95 ± 8.89 μg/ml vs. 13.90 ± 2.22 μg/ml). In vitro sensitivity against C. albicans test indicated that the antifungal activity of PAB ME-gel increased with the increase of PAB loading, and 8 mg/g of PAB ME-gel exhibited a higher antifungal activity than that of 20mg/g miconazole nitrate cream. In vivo antifungal activity evaluation in C. albicans infected guinea pigs showed that 8 mg/g of PAB ME-gel exhibited a higher efficacy than that of 20mg/g miconazole nitrate cream after 7 day treatment. Overall, the results indicated that the ME enhanced in vitro permeability, in vivo dermal bioavailability, and antifungal activity of PAB. Therefore, ME-gel may be a promising approach for topical dermal delivery of PAB to treat skin fungal infection.
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Wan
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China; Guangdong Provincial Hospital of Chinese Traditional Medicine, Guangzhou 510370, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Xu
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
authors.forename: Jingtong
authors.initials: J
authors.lastname: Pan
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
authors.forename: Mengyao
authors.initials: M
authors.lastname: Qin
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
authors.forename: Wenhui
authors.initials: W
authors.lastname: Pan
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
authors.forename: Guoguang
authors.initials: G
authors.lastname: Zhang
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
authors.forename: Zushuai
authors.initials: Z
authors.lastname: Wu
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
authors.forename: Chuanbin
authors.initials: C
authors.lastname: Wu
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China. Electronic address: lssxyh@mail.sysu.edu.cn.
authors.forename: Yuehong
authors.initials: Y
authors.lastname: Xu
mesh_terms: D000279:Administration, Cutaneous; D000818:Animals; D000935:Antifungal Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics*; D019540:Area Under Curve; D002176:Candida albicans / Q000187:drug effects*; D002626:Chemistry, Pharmaceutical; D002851:Chromatography, High Pressure Liquid; D004224:Diterpenes / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics*; D016503:Drug Delivery Systems; D004355:Drug Stability; D004655:Emulsions / Q000737:chemistry*; D005260:Female; D005782:Gels / Q000737:chemistry; D008828:Microbiological Techniques; D009226:Myristates / Q000737:chemistry; D051381:Rats; D017207:Rats, Sprague-Dawley; D012869:Skin Absorption; D012995:Solubility; D013501:Surface-Active Agents / Q000737:chemistry
chemical_list: D000935:Antifungal Agents; D004224:Diterpenes; D004655:Emulsions; D005782:Gels; D009226:Myristates; D013501:Surface-Active Agents; C008205:isopropyl myristate; C058391:pseudolaric acid B
keywords: Antifungal; Dermal delivery; Dermatopharmacokinetics; Microdialysis; Microemulsion; Pseudolaric acid B; Pseudolaric acid B (PubChem CID: 71307573); miconazole nitrate (PubChem CID: 68553)