Improved dissolution of an enteric polymer and its amorphous solid dispersions by polymer salt formation
Improved dissolution of an enteric polymer and its amorphous solid dispersions by polymer salt formation
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DOI：
10.1016/j.ijpharm.2022.121886
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发表时间：
2022-06-12
影响因子：
5.8
通讯作者：
Taylor, Lynne S.
中科院分区：
文献类型：
--
作者：
Qi, Qingqing;Taylor, Lynne S.
历史上用作肠溶包衣的弱酸性聚合物越来越多地用于增溶无定形固体分散体（ASD）制剂中。然而，对于这些含羧酸的聚合物如何溶解缺乏基本的理解，特别是当与亲脂性药物分子混合时，如在ASD中。确定控制其溶出的关键因素对于合理设计具有增强释放特性的新聚合物以解决当代ASD递送挑战，特别是在较高载药量下实现良好释放至关重要。在此，在鉴定聚合物通过电离溶解作为溶解的速率限制步骤后，通过用不同碱中和邻苯二甲酸基团将羟丙基甲基纤维素邻苯二甲酸酯（HP-50）转化为盐。进行表面归一化溶解以评估通过聚合物预电离经由盐形成实现的溶解速率改善。在pH 6.8（50 mM磷酸钠缓冲液）下，聚合物盐显示出比HP-50快约3倍的释放。重要的是，聚合物盐能够保持快速的溶解速率，而不管介质的缓冲能力如何，而质子化聚合物显示出随着介质缓冲能力向生理胃肠道值降低而大大降低的溶解。将HP-50和两种聚合物盐与亲脂性弱碱性抗真菌药物咪康唑以20%的载药量配制成ASD。用聚合物盐ASD实现快速药物释放速率，其中药物释放比质子化HP-50 ASD快14倍。这项研究强调了聚合物电离和缓冲能力在HP-50系统溶解中的关键作用，以及如何通过聚合物盐形成预电离是设计新聚合物以改善ASD性能的成功策略。
Weakly acidic polymers, historically used as enteric coatings, are increasingly being employed in solubility-enhancing amorphous solid dispersion (ASD) formulations. However, there is a lack of fundamental under-standing around how these carboxylic acid-containing polymers dissolve, in particular when molecularly mixed with a lipophilic drug, as in an ASD. Identification of critical factors dominating their dissolution is vital for rational design of new polymers with enhanced release properties to address contemporary ASD delivery chal-lenges, notably achieving good release at higher drug loadings. Herein, after identification of polymer solubi-lization via ionization as the rate limiting step for dissolution, hydroxypropylmethyl cellulose phthalate (HP-50) was converted to a salt by neutralization of the phthalic acid groups with different bases. Surface normalized dissolution was performed to assess the dissolution rate improvement achieved by polymer pre-ionization via salt formation. Polymer salts showed ~ 3-fold faster release than HP-50 at pH 6.8 (50 mM sodium phosphate buffer). Importantly, a polymer salt was able to maintain a rapid dissolution rate, irrespective of the buffer capacity of the medium, whereas the protonated polymer showed greatly diminished dissolution as medium buffer capacity decreased toward physiological gastrointestinal tract values. HP-50 and two polymer salts were formulated into ASDs with miconazole, a lipophilic and weakly basic antifungal drug, at a 20% drug loading. Rapid drug release rates were achieved with polymer salt ASDs, whereby drug release was 14 times faster than from the protonated HP-50 ASD. This study highlights the critical role of polymer ionization and buffer capacity in the dissolution of HP-50-based systems and how pre-ionization via polymer salt formation is a successful strategy for the design of new polymers for improved ASD performance.