盐酸米安色林鼻用制剂的处方前研究

Preformulation research on the nasal preparation of mianserin hydrochloride

目的研究盐酸米安色林(MIA)的平衡溶解度、表观油水分配系数(P_(app))及溶液化学稳定性,并筛选其经鼻黏膜吸收的理想促渗剂,为制备该药鼻腔给药新制剂提供理论依据。方法采用HPLC法测定MIA的含量及其在不同溶剂中的平衡溶解度;通过摇瓶法测定药物在正辛醇-水及正辛醇-不同pH缓冲液体系中的P_(app);在80℃高温下放置,测定MIA在不同pH缓冲液中的降解百分率;以离体羊鼻黏膜为模型,采用Franz扩散池法完成药物体外渗透试验。结果MIA在不同溶剂中平衡溶解度的大小顺序为:丙二醇>5%DM-β-CD>5%HP-β-CD>1%F68>PEG400>5%SBE-β-CD>水;药物在酸性与中性pH下其平衡溶解度较大,而在碱性pH下很低。在正辛醇-不同pH缓冲液体系中,MIA的P_(app)随介质pH升高,呈增大趋势;此外,当介质pH<6.0时,MIA溶液的化学稳定性较差,当pH≥6.0时,其稳定性较好。4种候选促渗剂对MIA经鼻黏膜吸收均有明显促进作用,以5%DM-β-CD的促渗效果最佳。结论3种β-CD水溶性衍生物均可增加MIA的溶解度;pH值对MIA的平衡溶解度、P_(app)及溶液化学稳定性均有明显影响;DM-β-CD可能是MIA鼻用制剂的理想增溶剂及促渗剂。

Objective To determine the equilibrium solubility,apparent oil-water partition coefficient(P_(app))and solution chemical stability of mianserin hydrochloride(MIA),and to screen the optimal permeation enhancer of the drug absorption via nasal mucosa to provide a theoretical basis for MIA nasal preparation.Methods The concentration of MIA and its equilibrium solubility in various solvents were determined by HPLC.The P_(app)values of MIA in the n-octanol-water and n-octanol different pH buffer systems were measured with the shaking bottle method.The degradation percentage of MIA aqueous solution was also determined under different pHs and at various time intervals after it was placed at 80℃.Finally,the ideal permeation enhancer of MIA absorption across the nasal mucosa was sieved by Franz diffusion cell method,with in vitro sheep nasal mucosa as the test model.Results The equilibrium solubility of MIA in different solvents followed the order below:propylene glycol>5%DM-β-CD>5%HP-β-CD>1%F68>PEG400>5%SBE-β-CD>purified water.Meantime,the equilibrium solubility of MIA was larger at acidic or neutral pH media,but quite low at alkaline pH environment.In n-octanol different pH buffer systems,the P_(app)values of MIA generally increased with pH.MIA aqueous solution was less stable in acidic pHs below 6.0,and most stable at pH≥6.0.The candidate permeation enhancers all exhibited an obvious permeation-improving effect on MIA absorption through the nasal mucosa,but 5%DM-β-CD proved to be the strongest.Conclusion The three water-solubleβ-CD derivatives all improve the solubility of MIA.The pH obviously affects the equilibrium solubility of the drug,its P_(app)and aqueous solution chemical stability.DM-β-CD may be an ideal solubilizing agent and permeation enhancer for MIA nasal preparation.