Analytical Sciences, Merck & Co., Inc., Rahway, New Jersey 07065, United States.
Analytical Research and Development, Merck & Co., Inc., Rahway, New Jersey 07065, United States.
Mol Pharm. 2020 May 4;17(5):1734-1747. doi: 10.1021/acs.molpharmaceut.0c00208. Epub 2020 Apr 17.
Injectable sustained release dosage forms have emerged as desirable therapeutic routes for patients that require life-long treatments. The prevalence of drug molecules with low aqueous solubility and bioavailability has added momentum toward the development of suspension-based long-acting parenteral (LAP) formulations; the previously undesirable physicochemical properties of Biopharmaceutics Classification System (BCS) Class II/IV compounds are best suited for extended release applications. Effective release (IVR) testing of crystalline suspensions affirms product quality during early-stage development and provides connections with performance. However, before correlations (IVIVCs) can be established, it is necessary to evaluate formulation attributes that directly affect IVR properties. In this work, a series of crystalline LAP nanosuspensions were formulated with different stabilizing polymers and applied to a continuous flow-through (USP-4) dissolution method. This technique confirmed the role of salt effects on the stability of polymer-coated nanoparticles through the detection of disparate active pharmaceutical ingredient (API) release profiles. The polymer stabilizers with extended hydrophilic chains exhibited elevated intrapolymer activity from the loss of hydrogen-bond cushioning in dissolution media with heightened ionic strength, confirmed through one-dimensional (1D) H NMR and two-dimensional nuclear Overhauser effect spectroscopy (2D NOESY) experiments. Thus, steric repulsion within the affected nanosuspensions was limited and release rates decreased. Additionally, the strength of interaction between hydrophobic polymer components and the API crystalline surface contributed to suspension dissolution properties, confirmed through solution- and solid-state spectroscopic analyses. This study provides a unique perspective on the dynamic interface between the crystalline drug and aqueous microenvironment during dissolution.
可注射的缓释剂型已成为需要长期治疗的患者的理想治疗途径。具有低水溶性和生物利用度的药物分子的流行，为基于混悬液的长效注射（LAP）制剂的发展增添了动力；生物药剂学分类系统（BCS）II/IV 类化合物以前不理想的物理化学性质最适合延长释放应用。结晶混悬剂的有效释放（IVR）测试可在早期开发阶段确认产品质量，并与性能建立联系。然而，在建立相关性（IVIVC）之前，有必要评估直接影响 IVR 特性的配方属性。在这项工作中，用不同的稳定剂聚合物制备了一系列结晶 LAP 纳米混悬剂，并应用于连续流动（USP-4）溶出方法。该技术通过检测不同的活性药物成分（API）释放曲线，证实了盐效应对聚合物包覆纳米颗粒稳定性的影响。亲水链延长的聚合物稳定剂在离子强度增加的溶解介质中氢键缓冲作用丧失，从而表现出更高的聚合物内活性，这一现象通过一维（1D）H NMR 和二维核 Overhauser 效应光谱（2D NOESY）实验得到证实。因此，受影响的纳米混悬剂内的空间排斥作用受到限制，释放速率降低。此外，疏水性聚合物成分与 API 结晶表面之间的相互作用强度也影响了混悬液的溶解性质，这一点通过溶液和固态光谱分析得到了证实。本研究提供了一个独特的视角，从动态角度考察了药物结晶与溶解过程中水性微环境之间的相互作用。
