马来酸阿塞那平经皮给药贴剂的研究

发布时间：2018-01-22 06:07

本文关键词： 马来酸阿塞那平经皮给药贴剂　出处：《苏州大学》2014年硕士论文　论文类型：学位论文

【摘要】：目的：将马来酸阿塞那平制备成经皮给药贴剂，通过对其进行体外渗透研究、制剂学研究、制剂质量研究和体内药动学研究制备合格的贴剂，以达到缓控释药的目的。方法：（1）对马来酸阿塞那平进行处方前研究。建立马来酸阿塞那平含量分析方法，包括标准曲线的绘制，精密度、回收率和稳定性的考察；对马来酸阿塞那平的理化性质进行了考察，包括不同溶剂中的溶解度和油水分配系数测定；采用Franz扩散池法，对马来酸阿塞那平的体外渗透能力进行评价；（2）采用溶剂挥发法制备马来酸阿塞那平贴剂，以粘附力、释放度和渗透量为评价指标，考察交联剂和增塑剂对贴剂的影响，优选最终处方，并对固化时间进行考察；（3）对贴剂的质量进行评价，，包括粘附力、释放度、渗透性和含量均匀度；（4）通过给予大鼠自制贴剂，初步研究马来酸阿塞那平贴剂的体内药动学特征。结果：（1）建立的马来酸阿塞那平HPLC含量分析方法，标准曲线线性关系良好，精密度、回收率符合要求，样品溶液在12h内稳定。溶解度测定结果显示，马来酸阿塞那平在水中的溶解度为6.42±0.48mg/mL，在其它溶剂中溶解度最高的是甲醇，17.90±1.72mg/mL，因此最终处方中加入1mL甲醇来溶解药物。马来酸阿塞那平的溶解度还显示出一定的pH依赖性，pH1.2时，溶解度为9.33±1.22mg/mL，而pH8.0时，溶解度为2.54±0.26mg/mL；马来酸阿塞那平的油水分配系数LogP值为-0.95，有一定的亲水性。体外渗透结果表明，马来酸阿塞那平渗透速率随着浓度增大而增大，当浓度达到5mg/mL时，渗透系数达到49.55μg/cm2h，24h累积透过量达到1.3mg，透过百分率也达到了61.69%，说明马来酸阿塞那平具有良好的经皮渗透性能。（2）通过考察各种因素对贴剂的影响，确定贴剂载药量为15%，增塑剂TEC用量为9.5%，交联剂琥珀酸用量为0.5%，固化时间为1h。通过不同方程拟合，确定药物从该贴剂中的释放符合higuchi方程，其释放机制为扩散和溶蚀的双重作用。（3）三批贴剂进行质量评价结果显示，贴剂粘附力大于14，持粘力大于75h；24h累积释放量大于350μg/cm2，释放百分比大于14%；渗透量大于280μg/cm2，渗透百分比大于11%；贴剂含量均匀度符合《中国药典》相关要求。（4）大鼠体内药代动力学试验结果表明，自制马来酸阿塞那平贴剂具有明显的缓释效果。结论：成功制备了具有缓释效果的马来酸阿塞那平贴剂，该制剂未见国内外文献和专利报道，为的后续研究打下基础。
[Abstract]:Objective: to prepare a transdermal patch of Asenapine maleate, and to prepare a qualified patch through in vitro permeation study, preparation study, preparation quality study and in vivo pharmacokinetic study. In order to achieve the purpose of slow and controlled release of drugs. Methods the analepine maleate content analysis method was established, including the drawing of standard curve, precision, recovery and stability. The physicochemical properties of Asenapine maleate were investigated, including the determination of solubility and oil-water partition coefficient in different solvents. The in vitro osmotic capacity of azenapine maleate was evaluated by Franz diffusion cell method. (2) Asena maleate patch was prepared by solvent volatilization method. The influence of crosslinking agent and plasticizer on the patch was investigated with adhesion, release and permeation as the evaluation index, and the final prescription was selected. The curing time was investigated. Evaluation of the quality of the patch, including adhesion, release, permeability and content uniformity; (4) the pharmacokinetic characteristics of Asenapine maleate patch were studied. Results the standard curve was linear, the precision and the recovery rate were satisfied with the standard curve established for the determination of HPLC content of atenapine maleate. The sample solution was stable within 12 hours, and the solubility of azenapine maleate in water was 6.42 卤0.48 mg / mL, and the highest solubility in other solvents was methanol. 17. 90 卤1. 72 mg / mL, so 1 mL methanol was added to the final prescription to dissolve the drug. The solubility of Asenapine maleate also showed a certain pH dependence at pH 1.2. The solubility was 9.33 卤1.22 mg / mL, while in pH8.0, the solubility was 2.54 卤0.26 mg / mL; The oil and water partition coefficient (LogP) of Asenapine maleate was -0.95, and it had hydrophilicity. The osmotic rate of Asenapine maleate increased with the increase of concentration in vitro. When the concentration reached 5 mg / mL, the permeation coefficient reached 49.55 渭 g / cm ~ (-2) h ~ (-1) and the cumulative transmittance reached 1.3 mg / mL, and the permeation percentage reached 61.69%. The results showed that Asenapine maleate had good transdermal permeability. (2) by examining the effect of various factors on the patch, the dosage of the patch was 15 and the amount of plasticizer TEC was 9.5%. The dosage of crosslinking agent succinic acid was 0.5 and the curing time was 1 h. By different equation fitting, the release of the drug from the patch was confirmed to be in accordance with the higuchi equation. The mechanism of release is diffusion and dissolution. The quality evaluation of three batches of patch shows that the adhesive force of the patch is more than 14 and the adhesive force is more than 75 h. The cumulative release amount was more than 350 渭 g / cm ~ 2 and the release percentage was more than 14 渭 g / cm ~ 2. The osmotic capacity was more than 280 渭 g / cm ~ 2, and the osmotic percentage was more than 11 渭 g / cm ~ 2. The results of pharmacokinetic test in rats showed that the self-made Asenapine maleate patch had obvious sustained release effect. Conclusion: Asenapine maleate patch with sustained release effect has been successfully prepared, which has not been reported in domestic and foreign literatures and patents, which lays a foundation for further study.
【学位授予单位】：苏州大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R943

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