BioTherapeutics Pharmaceutical Sciences, Pfizer Inc. 700 Chesterfield Parkway West, Chesterfield, MO 63017, United States; Wang Biologics, LLC, 907 Wellesley Place, Chesterfield, MO 63017, United States.
Int J Pharm. 2015 Jul 25;490(1-2):308-15. doi: 10.1016/j.ijpharm.2015.05.069. Epub 2015 May 29.
Injectable drug products are ideally developed as isotonic solutions. Often, hypertonic injectables may have to be marketed for a variety of reasons such as product solubilization and stabilization. A key concern during product formulation development is the local and systemic tolerability of hypertonic products upon injection. This report reviews and discusses the tolerability in terms of local discomfort, irritation, sensation of heat and pain, along with other observed side effects of hypertonicity in both in-vitro systems and in-vivo animal and human models. These side effects clearly depend on the degree of hypertonicity. The sensation of pain among different injection routes seems to follow this order: intramuscular>subcutaneous>intravenous or intravascular. It is recommended that the upper osmolality limit should be generally controlled under 600 mOsm/kg for drug products intended for intramuscular or subcutaneous injection. For drug products intended for intravenous or intravascular injection, the recommended upper limit should be generally controlled under 1,000 mOsm/kg for small-volume injections (≤ 100 mL) and 500 mOsm/kg for large-volume injections (>100mL). Several options are available for minimization of hypertonicity-induced pain upon product administration.
注射剂型药物理想情况下应开发为等渗溶液。由于各种原因，如产品溶解和稳定，高渗注射剂可能不得不上市。在产品配方开发过程中，关键关注的是注射后高渗产品的局部和全身耐受性。本报告综述并讨论了体外系统以及动物和人体模型中高渗性的局部不适、刺激、发热和疼痛感觉以及其他观察到的副作用的耐受性。这些副作用显然取决于高渗性的程度。不同注射途径的疼痛感觉似乎遵循以下顺序：肌肉内>皮下>静脉或血管内。建议对于肌肉内或皮下注射的药物产品，通常应将上渗透压限制控制在 600mOsm/kg 以下。对于用于静脉内或血管内注射的药物产品，对于小容量注射（≤100ml），建议的上限通常应控制在 1000mOsm/kg 以下，对于大容量注射（>100ml），建议上限通常应控制在 500mOsm/kg 以下。在产品给药时，可采用多种方法来减轻高渗性引起的疼痛。
