Novel High-Drug-Loaded Amorphous Dispersion Tablets of Posaconazole; In Vivo and In Vitro Assessment.,Molecular Pharmaceutics

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Novel High-Drug-Loaded Amorphous Dispersion Tablets of Posaconazole; In Vivo and In Vitro Assessment.
Molecular Pharmaceutics ( IF 4.5 ) Pub Date : 2020-08-24 , DOI: 10.1021/acs.molpharmaceut.0c00471
Deanna M Mudie ₁ , Aaron M Stewart ₁ , Nishant Biswas ₁ , Timothy J Brodeur ₁ , Kimberly B Shepard ₁ , Adam Smith ₁ , Michael M Morgen ₁ , John M Baumann ₁ , David T Vodak ₁

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Amorphous solid dispersions (ASDs) can increase the bioavailability of drugs with poor aqueous solubility. However, concentration-sustaining dispersion polymers (CSPs) incorporated in ASDs can result in low drug loading and, therefore, a large dosage-form size or multiple units to meet dose requirements, potentially decreasing patient compliance. To address this challenge, a high-loaded dosage-form (HLDF) architecture for ASDs was developed, in which a drug is first spray-dried with a high glass-transition temperature (T_g) dispersion polymer to facilitate high drug loading while maintaining physical stability. The ASD is then granulated with a CSP designed to extend supersaturation in solution. The HLDF differs from traditional ASD architectures in which the dispersion polymer inside the ASD acts as the CSP. By strategically combining two different polymers, one “inside” and one “outside” the ASD, solubilization performance, physical stability, and overall drug loading are maximized. This study demonstrates in vivo performance of the HLDF architecture using posaconazole as a model drug. Two sizes of HLDF tablets were tested in beagle dogs, along with traditional ASD architecture (benchmark) tablets, ASD tablets without a CSP, and a commercial crystalline oral suspension (Noxafil OS). HLDF tablets performed equivalently to the benchmark tablets, the smaller HLDF tablet being 40% smaller (by mass) than the benchmark tablet. The HLDF tablets doubled the blood plasma AUC relative to Noxafil OS. In line with the in vivo outcome, in vitro results in a multicompartment dissolution apparatus demonstrated similar area under the curve (AUC) values in the intestinal compartment for ASD tablets. However, the in vitro data underpredicted the relative in vivo AUC of Noxafil OS compared to the ASD tablets. This study demonstrated that the HLDF approach can increase drug loadings while achieving good performance for ASD drug products.

中文翻译：

泊沙康唑新型高载药量无定形分散片；体内和体外评估。

无定形固体分散体 (ASD) 可以提高水溶性差的药物的生物利用度。然而，在 ASD 中加入的浓度维持分散聚合物 (CSP) 会导致低载药量，因此需要大剂型或多个单位才能满足剂量要求，这可能会降低患者的依从性。为了应对这一挑战，ASD 开发了一种高负载剂型 (HLDF) 架构，其中药物首先在高玻璃化转变温度 ( T _g) 分散聚合物以促进高载药量，同时保持物理稳定性。然后将 ASD 与旨在延长溶液中过饱和度的 CSP 一起造粒。HLDF 不同于传统的 ASD 架构，其中 ASD 内部的分散聚合物充当 CSP。通过战略性地结合两种不同的聚合物，一种在 ASD 的“内部”和一种“外部”，可最大限度地提高增溶性能、物理稳定性和整体载药量。该研究表明在体内使用泊沙康唑作为模型药物的 HLDF 结构的性能。在比格犬身上测试了两种尺寸的 HLDF 片剂，以及传统的 ASD 架构（基准）片剂、不含 CSP 的 ASD 片剂和商业结晶口服混悬液 (Noxafil OS)。HLDF 片的性能与基准片相当，较小的 HLDF 片比基准片小 40%（按质量计）。相对于 Noxafil OS，HLDF 片剂使血浆 AUC 增加了一倍。与体内结果一致，多隔室溶出度仪的体外结果表明 ASD 片剂在肠道隔室中的曲线下面积 (AUC) 值相似。然而，体外数据低估了相对的体内与 ASD 片剂相比，Noxafil OS 的 AUC。该研究表明，HLDF 方法可以增加载药量，同时实现 ASD 药品的良好性能。

更新日期：2020-08-24

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