Poly(vinylpyridine-co-vinylpyridine N-oxide) Excipients Mediate Rapid Dissolution and Sustained Supersaturation of Posaconazole Amorphous Solid Dispersions,Molecular Pharmaceutics

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Poly(vinylpyridine-co-vinylpyridine N-oxide) Excipients Mediate Rapid Dissolution and Sustained Supersaturation of Posaconazole Amorphous Solid Dispersions
Molecular Pharmaceutics ( IF 4.5 ) Pub Date : 2024-02-07 , DOI: 10.1021/acs.molpharmaceut.3c00789
Yu-Sheng Liu ₁ , Joseph Della Rocca ₂ , Luke Schenck ₁ , Athanas Koynov ₁ , Renee J Sifri ₁ , Matthew S Winston ₁ , Derek S Frank ₁

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The chemical structure of excipients molecularly mixed in an amorphous solid dispersion (ASD) has a significant impact on properties of the ASD including dissolution behavior, physical stability, and bioavailability. Polymers used in ASDs require a balance between hydrophobic and hydrophilic functionalities to ensure rapid dissolution of the amorphous dispersion as well as sustained supersaturation of the drug in solution. This work demonstrates the use of postpolymerization functionalization of poly(vinylpyridine) excipients to elucidate the impact of polymer properties on the dissolution behavior of amorphous dispersions containing posaconazole. It was found that N-oxidation of pyridine functionalities increased the solubility of poly(vinylpyridine) derivatives in neutral aqueous conditions and allowed for nanoparticle formation which supplied posaconazole into solution at concentrations exceeding those achieved by more conventional excipients such as hydroxypropyl methylcellulose acetate succinate (HPMCAS) or Eudragit E PO. By leveraging these functional modifications of the parent poly(vinylpyridine) excipient to increase polymer hydrophilicity and minimize the effect of polymer on pH, a new polymeric excipient was optimized for rapid dissolution and supersaturation maintenance for a model compound.

中文翻译：

聚（乙烯基吡啶-共-乙烯基吡啶 N-氧化物）赋形剂介导泊沙康唑无定形固体分散体的快速溶解和持续过饱和

以分子方式混合在无定形固体分散体 (ASD) 中的赋形剂的化学结构对 ASD 的性质（包括溶出行为、物理稳定性和生物利用度）具有重大影响。 ASD 中使用的聚合物需要疏水性和亲水性官能团之间的平衡，以确保无定形分散体的快速溶解以及溶液中药物的持续过饱和。这项工作演示了使用聚（乙烯基吡啶）赋形剂的聚合后官能化来阐明聚合物特性对含有泊沙康唑的无定形分散体溶出行为的影响。研究发现，吡啶官能团的N-氧化增加了聚（乙烯基吡啶）衍生物在中性水性条件下的溶解度，并允许纳米颗粒的形成，从而将泊沙康唑提供到溶液中，其浓度超过了更传统的赋形剂如乙酸琥珀酸羟丙甲基纤维素（HPMCAS）所达到的浓度。 ) 或 Eudragit E PO。通过利用母体聚（乙烯基吡啶）赋形剂的这些功能修饰来增加聚合物亲水性并最大限度地减少聚合物对 pH 值的影响，优化了新型聚合物赋形剂，以实现模型化合物的快速溶解和过饱和度维持。

更新日期：2024-02-07

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