Division of Molecular Pharmaceutics and Drug Delivery, The University of Texas at Austin College of Pharmacy, Austin, Texas 78712, United States.
Mol Pharm. 2022 Jan 3;19(1):318-331. doi: 10.1021/acs.molpharmaceut.1c00805. Epub 2021 Nov 30.
Oral drug therapy requiring large quantities of active pharmaceutical ingredients (APIs) can cause a substantial pill burden, which can increase nonadherence and worsen healthcare outcomes. Maximizing the drug loading of APIs in oral dosage forms is essential to reduce pill burden. This can be challenging for poorly water-soluble APIs without compromising performance. We show a promising strategy for maximizing the drug loading of pH-dependent APIs in amorphous solid dispersions (ASDs) produced by hot-melt extrusion (HME) without compromising their dissolution performance. We examine potential increases in the drug loading (w/w) of telmisartan in ASDs by incorporating bases to modify pH during HME. Telmisartan is a weakly acidic, poorly water-soluble API with pH-dependent solubility. It is practically insoluble at physiological pH, but its solubility increases exponentially at pH values above 10. Telmisartan was extruded with the polymer Soluplus and various bases. With no base, the maximum drug loading achieved by extrusion was only 5% before crystalline telmisartan was detected. Including a strong, water-soluble base (NaOH or KOH) increased the maximum amorphous drug loading to 50%. These results indicate that telmisartan has pH-dependent solubility in a molten polymer, similar to that in an aqueous solution. We also examine the stability of Soluplus when extruded with a strong base, using solid-state nuclear magnetic resonance (ssNMR) to determine that NaOH (but not KOH) causes degradation by hydrolysis. Supersaturation was maintained for at least 20 h during dissolution testing of a 50% telmisartan ASD in biorelevant media.
口服药物疗法需要大量的活性药物成分 (API)，这可能会导致很大的药丸负担，从而增加不依从性并恶化医疗效果。最大限度地提高口服剂型中 API 的药物负载对于减轻药丸负担至关重要。对于水溶性差的 API 来说，如果不影响其性能，这可能是一个挑战。我们展示了一种有前途的策略，通过热熔挤出 (HME) 生产的无定形固体分散体 (ASD) 中添加碱性物质来调节 pH 值，从而最大限度地提高 pH 依赖性 API 的药物负载，而不会影响其溶解性能。我们研究了通过在 HME 过程中加入碱性物质来改变 pH 值，从而增加替米沙坦在 ASD 中的药物负载 (w/w) 的潜力。替米沙坦是一种弱酸性、水溶性差的 API，其溶解度随 pH 值而变化。在生理 pH 值下，它几乎不溶，但在 pH 值高于 10 时，其溶解度呈指数级增加。替米沙坦与聚合物 Soluplus 和各种碱性物质一起挤出。在没有碱性物质的情况下，挤出时达到的最大药物负载仅为 5%，然后就检测到结晶替米沙坦。加入强碱 (NaOH 或 KOH) 可将最大无定形药物负载增加到 50%。这些结果表明，替米沙坦在熔融聚合物中具有类似于水溶液中的 pH 依赖性溶解度。我们还使用固态核磁共振 (ssNMR) 研究了强碱挤出时 Soluplus 的稳定性，结果表明 NaOH（而不是 KOH）会因水解而导致降解。在生物相关介质中对 50%替米沙坦 ASD 进行溶解测试时，至少在 20 小时内保持了过饱和度。
