萘普生微乳经皮给药系统的处方前研究

Pre-formulation study of microemulsion transdermal delivery system of naproxen

目的：测定萘普生的表观溶解度和油水分配系数。研究溶解度、促渗剂、接受液对萘普生体外经皮渗透性能的影响。方法：采用高效液相色谱法（HPLC）测定萘普生在水、不同pH缓冲液、各种油相和表面活性剂中的溶解度。通过摇瓶法测定萘普生的表观油水分配系数。以累积渗透量、稳态渗透速率常数和渗透系数为评价指标研究5种促渗剂和5种接受液对萘普生体外经皮渗透行为的影响。结果：32℃时,萘普生在水中的平衡溶解度为25.7 mg·L^-1,在各种油相和表面活性剂中的溶解度约是水中的200-4 000倍。萘普生在正辛醇/水体系中的表观油水分配系数为2.5（logP）;在正辛醇/缓冲液体系中的表观油水分配系数随pH值的升高而减小。促渗剂的促渗效果不明显,有的还会抑制渗透;萘普生在以20%丙二醇-生理氯化钠溶液、pH 7.4缓冲液、20%乙醇-pH 7.4缓冲液、20%聚乙二醇400-pH 7.4缓冲液作为接受液时,均有良好的渗透效果,10 h累积透过量最小可达2.08 mg。结论：萘普生是一种优良的经皮给药模型药物,开发其经皮给药微乳制剂有望提高疗效、减少毒副作用。微乳可选择将萘普生溶解在油或表面活性剂中的方法制备,pH 7.4的缓冲液可作为其透皮制剂的接受液。

Objective：To determine the equilibrium solubility of naproxen and its partition coefficients,and study the effect of solubility,enhancer,receptor solution on penetrable performance of naproxen through skin.Methods：HPLC method was established and used to detect the solubility of naproxen in water,buffer solutions,oils and surfactants.The partition coefficients of naproxen in n-octanol-water/buffer solution system were determined by shaking flash method.The effect of all tested enhancers and receptors on in vitro penetrable performance of napro-xen was evaluated by cumulative permeated amount,stable state permeation rate and permeation coefficient.Results：The equilibrium solubility of naproxen in distilled water was 25.7 mg·L^-1 at 32 ℃.The solubility in various tested oils and surfactants was as 200-4 000 times as those in water.The apparent partition coefficient of naproxen in n-octanol-water system was 2.5（logP）,which gradually diminished with pH increasing of buffer in n-octanol-buffer solution systems.5 kinds of enhancers had no obvious effect on penetrable ability of naproxen,and some restrained permeation.The selected receptors except saline demonstrated good permeated efficacy.The cumulative permeated amount in 10 h was 2.08 mg at least.Conclusion：Naproxen would be a good transdermal delivery model drug,and the further research of naproxen microemulsion transdermal delivery system maybe useful for increasing therapeutic effect and reducing toxicity.The microemulsion of naproxen could be produced by dissolving the drug in surfactants or oils.The buffer of pH 7.4 was selected as receptor for microemulsion transdermal delivery system of naproxen.