氟非尼酮局部施用形式的探索及其干预大鼠皮肤瘢痕形成的实验研究
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摘要
一、目的
通过对氟非尼酮(fluorofenidone, AKF-PD)基本理化性质的研究,构建并初步评价AKF-PD凝胶、乳膏和SLN凝胶,探索AKF-PD局部施用的理想形式；研究AKF-PD在大鼠皮肤瘢痕形成中的作用及其可能的作用机制,为AKF-PD新适应症的研究开发提供实验依据。
二、方法与结果
1.AKF-PD基本性质处方前研究
建立AKF-PD含量测定方法,并测定AKF-PD的溶解度及油/水分配系数。结果表明AKF-PD在水中微溶,溶解度为2.5 mg-mL-1(25℃),pH对溶解度影响小；AKF-PD易溶于乙醇,可溶于PEG400、丙二醇和异丙醇,微溶于甘油。AKF-PD略有亲脂性,LogP值为1.182。
2.AKF-PD三种剂型的构建与评价
通过单因素实验筛选了溶剂、成胶基质种类和用量、pH调节剂、防腐剂、抑晶剂,确定凝胶剂处方并制备0.5% AKF-PD溶液型凝胶,该凝胶剂避光在高温和低温条件下均可保存10d。制备载药量为1%的混悬型凝胶,供后续比较不同载药量凝胶间的差异。
AKF-PD加入油相后,以Tween 80和单硬脂酸甘油酯为乳化剂,高温乳化后获得AKF-PD乳膏,乳膏中AKF-PD量为1%时为溶液型,载药量为2%时为混悬型。1%乳膏在高温和低温条件下均可保存10d。
采用超声乳化后低温固化法制备SLN,单因素考察后经正交实验优化处方与工艺条件,所得SLN粒径为179.3±4.8 nm,包封率较低,为19.08±0.68%。该SLN赋型于卡波姆中构建了AKF-PD SLN凝胶,载药量为0.36%；SLN与SLN凝胶均对温度敏感,可在4℃条件下保存10d。
3.三种AKF-PD外用形式的体外经皮渗透实验
考察AKF-PD0.5%与1%凝胶、1%与2%乳膏、0.36%凝胶与SLN凝胶在离体乳猪皮肤中体外经皮渗透行为。建立体外经皮渗透实验方法,于1、2、4、8、12、24h取样,考察t时间的单位面积累积渗透量Q。和24h的皮肤滞留量。
凝胶中AKF-PD透皮速度较快,且载药量在0.5%-1%范围内,24h的单位面积累积渗透量(Q24)和皮肤滞留量均存在剂量相关性；1%乳膏与2%乳膏Q24无显著差别,但Q24均较1%凝胶少,而皮肤滞留量与1%凝胶无显著差别；0.36%SLN凝胶与同浓度的普通凝胶经皮渗透行为无显著差别,未能较普通凝胶提高AKF-PD皮肤滞留量。选择0.5%凝胶、1%凝胶和1%乳膏进行药效学实验。
4.AKF-PD对大鼠皮肤瘢痕形成的干预及其机制研究
建立大鼠皮肤线性瘢痕模型,考察AKF-PD0.5%凝胶剂、1%凝胶和1%乳膏对大鼠皮肤瘢痕形成的干预及其作用机制。结果表明AKF-PD能抑制成纤维细胞的增殖和胶原纤维的沉积,但是会延缓切口愈合时间；其中对成纤维细胞的抑制作用具有剂量相关性,1%凝胶与1%乳膏的作用效果约为0.5%凝胶的2倍。实验组瘢痕组织中的TGF-β1的表达略高于其他对照组,可能与取样点不足以及取样点时间延后有关。
三、结论
AKF-PD具有较好的经皮渗透能力,凝胶及乳膏均为可选剂型；外用施予AKF-PD能抑制大鼠线性瘢痕中成纤维细胞的增殖和胶原的沉积,且对成纤维细胞的抑制作用具有剂量相关性,但AKF-PD抑制瘢痕形成的作用机制以及该作用与药物皮肤滞留和经皮渗透之间的关系仍有待进一步研究。
OBJECTIVES
To 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 RESULTS
The 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.
CONCLUSIONS
AKF-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.
通过对氟非尼酮(fluorofenidone, AKF-PD)基本理化性质的研究,构建并初步评价AKF-PD凝胶、乳膏和SLN凝胶,探索AKF-PD局部施用的理想形式；研究AKF-PD在大鼠皮肤瘢痕形成中的作用及其可能的作用机制,为AKF-PD新适应症的研究开发提供实验依据。
二、方法与结果
1.AKF-PD基本性质处方前研究
建立AKF-PD含量测定方法,并测定AKF-PD的溶解度及油/水分配系数。结果表明AKF-PD在水中微溶,溶解度为2.5 mg-mL-1(25℃),pH对溶解度影响小；AKF-PD易溶于乙醇,可溶于PEG400、丙二醇和异丙醇,微溶于甘油。AKF-PD略有亲脂性,LogP值为1.182。
2.AKF-PD三种剂型的构建与评价
通过单因素实验筛选了溶剂、成胶基质种类和用量、pH调节剂、防腐剂、抑晶剂,确定凝胶剂处方并制备0.5% AKF-PD溶液型凝胶,该凝胶剂避光在高温和低温条件下均可保存10d。制备载药量为1%的混悬型凝胶,供后续比较不同载药量凝胶间的差异。
AKF-PD加入油相后,以Tween 80和单硬脂酸甘油酯为乳化剂,高温乳化后获得AKF-PD乳膏,乳膏中AKF-PD量为1%时为溶液型,载药量为2%时为混悬型。1%乳膏在高温和低温条件下均可保存10d。
采用超声乳化后低温固化法制备SLN,单因素考察后经正交实验优化处方与工艺条件,所得SLN粒径为179.3±4.8 nm,包封率较低,为19.08±0.68%。该SLN赋型于卡波姆中构建了AKF-PD SLN凝胶,载药量为0.36%；SLN与SLN凝胶均对温度敏感,可在4℃条件下保存10d。
3.三种AKF-PD外用形式的体外经皮渗透实验
考察AKF-PD0.5%与1%凝胶、1%与2%乳膏、0.36%凝胶与SLN凝胶在离体乳猪皮肤中体外经皮渗透行为。建立体外经皮渗透实验方法,于1、2、4、8、12、24h取样,考察t时间的单位面积累积渗透量Q。和24h的皮肤滞留量。
凝胶中AKF-PD透皮速度较快,且载药量在0.5%-1%范围内,24h的单位面积累积渗透量(Q24)和皮肤滞留量均存在剂量相关性；1%乳膏与2%乳膏Q24无显著差别,但Q24均较1%凝胶少,而皮肤滞留量与1%凝胶无显著差别；0.36%SLN凝胶与同浓度的普通凝胶经皮渗透行为无显著差别,未能较普通凝胶提高AKF-PD皮肤滞留量。选择0.5%凝胶、1%凝胶和1%乳膏进行药效学实验。
4.AKF-PD对大鼠皮肤瘢痕形成的干预及其机制研究
建立大鼠皮肤线性瘢痕模型,考察AKF-PD0.5%凝胶剂、1%凝胶和1%乳膏对大鼠皮肤瘢痕形成的干预及其作用机制。结果表明AKF-PD能抑制成纤维细胞的增殖和胶原纤维的沉积,但是会延缓切口愈合时间；其中对成纤维细胞的抑制作用具有剂量相关性,1%凝胶与1%乳膏的作用效果约为0.5%凝胶的2倍。实验组瘢痕组织中的TGF-β1的表达略高于其他对照组,可能与取样点不足以及取样点时间延后有关。
三、结论
AKF-PD具有较好的经皮渗透能力,凝胶及乳膏均为可选剂型；外用施予AKF-PD能抑制大鼠线性瘢痕中成纤维细胞的增殖和胶原的沉积,且对成纤维细胞的抑制作用具有剂量相关性,但AKF-PD抑制瘢痕形成的作用机制以及该作用与药物皮肤滞留和经皮渗透之间的关系仍有待进一步研究。
OBJECTIVES
To 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 RESULTS
The 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.
CONCLUSIONS
AKF-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.
引文
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