Leicester School of Pharmacy, De Montfort University, Leicester LE1 9BH, U.K.
Department of Infection & Immunity, Faculty of Infectious & Tropical Diseases, London School of Hygiene and Tropical Medicine, London WC1E 7HT, U.K.
Mol Pharm. 2021 Dec 6;18(12):4256-4271. doi: 10.1021/acs.molpharmaceut.1c00384. Epub 2021 Nov 1.
Artemisinin (ART) is a most promising antimalarial agent, which is both effective and well tolerated in patients, though it has therapeutic limitations due to its low solubility, bioavailability, and short half-life. The objective of this work was to explore the possibility of formulating ART cocrystals, i.e., artemisinin-orcinol (ART-ORC) and artemisinin-resorcinol (ART-RES), as oral dosage forms to deliver ART molecules for bioavailability enhancement. This is the first part of the study, aiming to develop a simple and effective formulation, which can then be tested on an appropriate animal model (i.e., mouse selected for in vivo study) to evaluate their preclinical pharmacokinetics for further development. In the current work, the physicochemical properties (i.e., solubility and dissolution rate) of ART cocrystals were measured to collect information necessary for the formulation development strategy. It was found that the ART solubility can be increased significantly by its cocrystals, i.e., 26-fold by ART-ORC and 21-fold by ART-RES, respectively. Screening a set of polymers widely used in pharmaceutical products, including poly(vinylpyrrolidone), hydroxypropyl methylcellulose, and hydroxypropyl methylcellulose acetate succinate, based on the powder dissolution performance parameter analysis, revealed that poly(vinylpyrrolidone)/vinyl acetate (PVP-VA) was the most effective crystallization inhibitor. The optimal concentration of PVP-VA at 0.05 mg/mL for the formulation was then determined by a dissolution/permeability method, which represented a simplified permeation model to simultaneously evaluate the effects of a crystallization inhibitor on the dissolution and permeation performance of ART cocrystals. Furthermore, experiments, including surface dissolution of single ART cocrystals monitored by Raman spectroscopy, scanning electron microscopy and diffusion properties of ART in solution measured by H and diffusion-ordered spectroscopy nuclear magnetic resonance spectroscopy, provided insights into how the excipient affects the ART cocrystal dissolution performance and bioavailability.
青蒿素 (ART) 是一种最有前途的抗疟药物，对患者既有效又耐受良好，但其溶解度低、生物利用度低和半衰期短，因此存在治疗限制。本工作的目的是探索将青蒿素共晶（即青蒿素-间苯二酚（ART-ORC）和青蒿素-间苯三酚（ART-RES））制成口服剂型，以提供青蒿素分子以提高生物利用度。这是研究的第一部分，旨在开发一种简单有效的制剂，然后在适当的动物模型（即选择用于体内研究的小鼠）上进行测试，以评估其临床前药代动力学，从而进一步开发。在目前的工作中，测量了 ART 共晶的物理化学性质（即溶解度和溶解速率），以收集制剂开发策略所需的信息。结果发现，ART 共晶可显著提高 ART 的溶解度，ART-ORC 和 ART-RES 分别提高 26 倍和 21 倍。基于粉末溶解性能参数分析，筛选了一组广泛用于药物产品的聚合物，包括聚乙烯吡咯烷酮、羟丙基甲基纤维素和羟丙基甲基纤维素醋酸琥珀酸酯，发现聚乙烯吡咯烷酮/醋酸乙烯酯（PVP-VA）是最有效的结晶抑制剂。然后通过溶解/渗透法确定制剂中 PVP-VA 的最佳浓度为 0.05mg/mL，这代表了一种简化的渗透模型，可同时评估结晶抑制剂对 ART 共晶溶解和渗透性能的影响。此外，实验包括通过拉曼光谱监测单个 ART 共晶的表面溶解、扫描电子显微镜和通过氢和扩散有序光谱核磁共振波谱法测量的 ART 在溶液中的扩散性质，深入了解赋形剂如何影响 ART 共晶的溶解性能和生物利用度。
