Ghent University, Laboratory of Medical Biochemistry and Clinical Analysis, Faculty of Pharmaceutical Sciences, Ottergemsesteenweg 460, B-9000, Ghent, Belgium.
Pharmaceutical Product Development & Supply, Janssen Pharmaceutica NV, Turnhoutseweg 30, B-2340, Beerse, Antwerp, Belgium.
AAPS J. 2022 Dec 1;25(1):4. doi: 10.1208/s12248-022-00771-5.
Formulating aqueous suspensions is an attractive strategy to incorporate poorly water-soluble drugs, where the drug release can be tailored to maintain desired release profiles of several weeks to months after parenteral (i.e., intramuscular or subcutaneous) administration. A sustained drug release can be desirable to combat chronic diseases by overcoming pill fatigue of a daily oral intake, hence, improving patient compliance. Although the marketed aqueous suspensions for intramuscular injection efficiently relieve the daily pill burden in chronic diseases, the exact drug release mechanisms remain to be fully unraveled. The in vivo drug release and subsequent absorption to the systemic circulation are influenced by a plethora of variables, resulting in a complex in vivo behavior of aqueous suspensions after intramuscular administration. A better understanding of the factors influencing the in vivo performance of aqueous suspensions could advance their drug development. An overview of the potential influential variables on the drug release after intramuscular injection of aqueous suspensions is provided with, where possible, available pharmacokinetic parameters in humans or other species derived from literature, patents, and clinical trials. These variables can be categorized into drug substance and formulation properties, administration site properties, and the host response towards drug particles. Based on the findings, the most critical factors are particle size, dose level, stabilizing excipient, drug lipophilicity, gender, body mass index, and host response.
配制水混悬剂是一种有吸引力的策略，可用于掺入难溶于水的药物，其中药物释放可以进行定制，以在注射（即肌内或皮下）给药后维持数周到数月的所需释放曲线。通过克服每日口服的药丸疲劳，持续释放药物可用于治疗慢性病，从而提高患者的顺应性。尽管市售的用于肌内注射的水混悬剂可有效减轻慢性病患者的每日药丸负担，但确切的药物释放机制仍有待充分阐明。体内药物释放以及随后向全身循环的吸收受到大量变量的影响，导致肌内给药后水混悬剂的体内行为非常复杂。更好地了解影响水混悬剂体内性能的因素可以推进其药物开发。本文概述了影响肌内注射水混悬剂药物释放的潜在影响因素，其中可能包括来自文献、专利和临床试验的人类或其他物种的可用药代动力学参数。这些变量可以分为药物物质和制剂特性、给药部位特性以及宿主对药物颗粒的反应。根据研究结果，最关键的因素是粒径、剂量水平、稳定赋形剂、药物亲脂性、性别、体重指数和宿主反应。
