School of Pharmacy, The University of Auckland, Auckland, New Zealand.
J Pharm Pharmacol. 2013 Oct;65(10):1429-39. doi: 10.1111/jphp.12114. Epub 2013 Jul 24.
To investigate the feasibility of using an in-vitro model to simulate the incidence of post-injection drug precipitation (PDP), and to identify the roles of drug properties and delivery systems in its occurrence.
A literature review on incomplete absorption following extravascular injection (subcutaneous and intramuscular) was conducted. Six model drugs in nine different formulations were studied for an in-vitro/in-vivo correlation. A rapid in-vitro dilution method using a 96-well plate was used for predicting PDP by dilution with a physiological buffer. New formulations based on hydroxypropyl-β-cyclodextrin (CD), with and without co-solvents or pH control, were developed and tested on the in-vitro model.
The occurrence of precipitation detected from the in-vitro dilution model appeared to be correlated with clinical reports and animal studies. The formulation components played an important role in determining the potential for drug precipitation on dilution or pH neutralization. CD was found to reduce the tendency for precipitation. The addition of co-solvents may reduce the effect of CD, depending on the solvent used.
The in-vitro model can be used as a cost-effective screening tool in injectable formulation development for safe and effective delivery of poorly soluble drugs. PDP can be circumvented with a well-designed formulation.
研究使用体外模型模拟注射后药物沉淀（PDP）发生率的可行性，并确定药物性质和给药系统在其发生中的作用。
对血管外注射（皮下和肌肉内）后不完全吸收的文献进行了综述。研究了 9 种不同配方的 6 种模型药物，以进行体外/体内相关性研究。使用 96 孔板的快速体外稀释方法，通过用生理缓冲液稀释来预测 PDP。基于羟丙基-β-环糊精（CD），开发了新的配方，有无共溶剂或 pH 控制，并在体外模型上进行了测试。
从体外稀释模型中检测到的沉淀发生似乎与临床报告和动物研究相关。配方成分在确定稀释或 pH 中和时药物沉淀的潜力方面起着重要作用。发现 CD 降低了沉淀的趋势。共溶剂的添加可能会降低 CD 的效果，具体取决于所用的溶剂。
该体外模型可用作注射制剂开发中的经济有效的筛选工具，以安全有效地输送难溶性药物。可以通过精心设计的配方来避免 PDP。
