推拉式渗透泵药物传递系统处方设计关键要素研究

Key Formulation Considerations of Push-Pull Osmotic Pump (PPOP) Drug Delivery System

目的推拉式渗透泵(push-pull osmotic pump,PPOP)是渗透泵药物传递系统中的一种剂型,被广泛应用于BCS II类药物的配方开发中。然而,对于PPOP的处方设计诸多关键要素仍然缺乏基于实验数据的讨论。因此,本实验通过研究PPOP关键制剂影响因素,希望为该制剂实践应用中的处方调整提供建议。方法以硝苯地平为模型药物,考察3种市售高相对分子质量聚氧乙烯(polyethylene oxide,PEO)的水合溶胀速率和溶胀后凝胶强度。研究半透膜包衣厚度变化,助推层中促渗剂的比例以及含药层与助推层比例(drug layer/push layer,DL/PL)对模型药物释放的影响。结果 3种高相对分子质量PEO(POLYOXTM301,POLYOXTMCoagulant和POLYOXTM303)的溶胀速率和凝胶强度随着相对分子质量的增加而增强,其中溶胀速率差异并不显著(P> 0. 05),而凝胶强度差异显著(P <0. 05)。在高相对分子质量PEO中添加促渗剂,例如氯化钠,可以明显提高PEO的溶胀率。较厚的半透膜包衣会延迟药物释放,当半透膜厚度高于180μm时,可能导致药物释放不完全(<90%)。当测试条件固定,助推层中氯化钠比例在10%和30%之间调整时,药物溶出曲线间没有显著差异。但当助推层中氯化钠含量比例高于50%时,PPOP的药物释放变慢且不完全。结论 DL/PL的比例对药物释放有显著影响。DL/PL比率越低,药物释放越快,越完全。对于模型药物硝苯地平PPOP,推荐使用DL/PL=2的比例。

OBJECTIVE Push-pull osmotic pump (PPOP) is one of conventional osmotic pump systems, which has been widely investigated for formulation development of BCS Ⅱ APIs. However, there is still a lack of experimental data based discussions for some key formulation factors of PPOP. Thus, to investigate some key formulation factors by designed experiments and tried to give some recommendations for those considerations in industrial formulation development. METHODS Nifedipine was selected as the model drug in this study. The hydration & swell rate and strength of three grades of commercialized high molecular weight polyethylene oxide (PEO) were evaluated via swelling volume change using a home-made apparatus and via compression force using texture analyzer, respectively. The effect of different film coating thickness, proportion of osmotic agent in push layer, and ratios of push layer to pull layer were investigated by drug dissolution using USP apparatus Ⅱ as well. RESULTS The swelling rate and strength of three grades of high molecular weight PEO (POLYOXTM 301, POLYOXTM Coagulant, and POLYOXTM 303) enhanced along with the molecular weight. The difference of swelling rate is not significant (P>0.05), but that of swelling gel strength is significant (P<0.05). Adding osmotic agent, e.g. NaCl, could significantly improve the swelling rate. Thicker coating membrane retarded drug release and as the coating thickness was higher than 180 μm, it caused incomplete drug release (<90%). When the NaCl proportion in push layer was between 10% and 30 %, there was no significant differences among drug dissolution profiles. However, when the percent of NaCl content in push layer was above 50%, the drug release from PPOP became slower and more incomplete (<90%). CONCLUSION The ratio of DL/PL has significant impact on drug release. The lower the ratio of DL/PL resulted in faster and more complete drug release. For nifedipine case, the ratio of 2 was recommended.