| OBJECTIVESTo prepare and evaluate fluorofenidone (AKF-PD) gel, cream and SLN-gel on the basis of physicochemical property of AKF-PD to explore the ideal topical preparation. To study the effect and machanism of AKF-PD in inhibiting scar formation in rat cutaneous wounds and provide experimental basis for a new indication of AKF-PD. METHODS AND RESULTSThe analytical method of AKF-PD was set up and the determination of its solubility and oil/water partition coefficient was performed. The results showed that AKF-PD was slightly soluable in water, and the solubility was 2.5 mg-mL-1 (25℃) which was not sensitive to pH; AKF-PD was freely soluble in ethanol, soluble in PEG400, propylene glycol and isopropanol, and slightly soluable in glycerin. AKF-PD was partial lipophilic and the value of LogP was 1.182.The optimal prescription of 0.5% AKF-PD gel was obtained by formulation screening of solvent, kind and amount of gel matrix, pH adjusting agent, preservative, inhibiting crystal agent. The gel away from light could be deposited for 10 d at high temperature and low temperature conditions. Preparation of 1% AKF-PD gel had crystallization suspended and could be offered to compare the difference between gels with different drug loading.The cream of AKF-PD was prepared by incorporating AKF-PD in oil phase, and emulsification by Tween80 and glyceryl monostearate at high temperature. AKF-PD in 1% cream was soluble, but 2% cream had crystallization suspended.1% AKF-PD cream could be deposited for 10 d at high temperature and low temperature conditions. SLN was prepared by ultrasound emulsification and solidification at low temperature and the prescription were optimized by orthogonal test. The size of optimal formulation was 179.3±4.8 nm, and its low encapsulation efficiency was 19.08±0.68%. Then SLN was loaded in gel matrix and the drug loading was 0.36%. SLN and SLN gel were both sensitive to temperature and could be deposited for 10 d at 4℃.The penetration behavior of AKF-PD through excised skin of piglet in vitro was studied among 0.5% and 1% gel,1% and 2% cream,0.36% SLN gel and general gel. The method of in vitro permeation of AKF-PD was established to study the amout of percutaneous penetration per unit area,Qt (1-24 h) and retention in the skin at 24 h.AKF-PD from gels penetrated fast through piglet skin, and Q24 and retention in the skin had dose-dependence between 0.5%-1% drug loading. Q24 of AKF-PD from 1% and 2% cream had no significant difference and were both lower than that of 1% gel, but skin retention of AKF-PD from creams had no significant difference with 1% gel. There was no significant difference of penetration behavior between SLN gel and general gel. Finally,0.5% gel,1% gel and 1% cream of AKF-PD were chosen to study pharmacodynamics.The model of scar in rat cutaneous wounds was established for the pharmacodynamics of AKF-PD of 0.5% gel,1% gel,1% cream. The results showed that AKF-PD could inhibit fibroblast (FB) proliferation and collagen deposition, but would delay the wound healing. The dose-dependence of inhibiting FB was significant and there was no difference between 1% gel and 1% cream. The study on mechanism of inhibiting scar formation in rat cutaneous wounds showed that the content of TGF-β1 in scar tissue of the experimental group was slightly higher than other control groups. CONCLUSIONSAKF-PD penetrated fast through piglet skin, and gel and cream were both optional preparation. Topical application of AKF-PD could inhibit the proliferation of FB and the deposition of collagen, and the dose-dependence of inhibiting FB of AKF-PD was significant. However, the mechanism of action in inhibiting scar formation and its relation with percutaneous penetration and retention in the skin need to be further clarified. |
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