尼可地尔鼻腔给药制剂的处方前研究

Preformulation research on nicorandil nasal preparation

目的考察尼可地尔溶液化学稳定性、油水分配系数(P)及溶解度并对该药经鼻黏膜吸收促渗剂进行筛选,为研制尼可地尔鼻腔给药新剂型奠定实验基础。方法建立尼可地尔的HPLC含量测定方法,研究在不同pH值下该药物溶液的化学稳定性、P值及溶解度;以离体羊鼻黏膜为实验模型,以羟丙基-β-环糊精(HP-β-CD)、磺丁基-β-环糊精(SBE-β-CD)、二甲基-β环糊精(DM-β-CD)为候选促渗剂,采用Franz扩散池法,筛选尼可地尔经鼻黏膜吸收的理想促渗剂。结果尼可地尔溶液在强酸pH下化学稳定性最好,而在强碱性pH值下最差;尼可地尔的P值随着pH值的增大总体呈增大趋势;尼可地尔的溶解度随介质pH值的增大总体呈减小趋势;HP-β-CD与SBE-β-CD对尼可地尔经羊鼻黏膜吸收有明显促进作用,而DM-β-CD对药物的吸收呈抑制作用。结论尼可地尔溶液的化学稳定性、油水分配系数及溶解度均与介质pH值密切相关。SBE-β-CD可能是制备尼可地尔鼻腔给药制剂的最佳促渗剂。

Objective To determine the chemical stability of aqueous solution,oil-water partition coefficient(P)and solubility of nicorandil,and further sieve the ideal permeation enhancer of the drug via nasal mucosa to provide a theoretical foundation for developing nicorandil nasal preparation.Methods An HPLC method was firstly established for the determination of nicorandil,the aqueous solution stability of the drug,its P value and solubility were studied under various pH conditions.In vitro sheep nasal mucosa as the test model and with Franz diffusion cell method,the ideal absorption enhancer for nicorandil via nasal mucosa were determined among three commonly usedβ-CD watersoluble derivatives,including HP-β-CD,SBE-β-CD and DM-β-CD.Results Nicorandil solution was found to be most stable under strongly acidic pH conditions and most unstable in strongly alkaline pH media.The P values of nicorandil generally increased with the pH value of media.The solubility of nicorandil tended to reduce with the increase of media pHs.HP-β-CD and SBE-β-CD both exhibited obvious permeation enhancing effect on the nicorandil absorption via in vitro sheep nasal mucosa.DM-β-CD showed an inhibitive effect on the nasal mucosa absorption of nicorandil.Conclusion The solution stability,P value and solubility of nicorandil are all closely related to the media pH values.SBE-β-CD may be the ideal permeation enhancer for nicorandil nasal preparation.