Joshi R, Arora V, Desjardins J P, Robinson D, Himmelstein K J, Iversen P L
Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, USA.
Pharm Res. 1998 Aug;15(8):1189-95. doi: 10.1023/a:1011979505697.
This study characterizes the in vivo properties of an in situ forming gel, comprising of IPC of water-soluble polymers, PMA and PEG, for sustained release of macromolecular drugs.
40, 50, or 60% w/v formulations were injected subcutaneously in a rat model either alone, or containing model macromolecules, 3A2-ATG-psODN or REV-psODN, to (i) determine the approximate gelling and residence time of the gel at the site of injection (ii) assess the biological efficacy of the formulation using a MZ sleep time model and (iii) demonstrate specificity of the sequence and selectivity of the psODNs by measuring changes in microsomal enzyme levels and urine volumes.
A sol to gel transition requires 15 min in vivo, and the 60% w/v IPC gel remains at the site of injection for up to 72 hr. The MZ sleep times and CYP3A2 expression due to 3A2-ATG-psODNs released from the gel are significantly different compared to that of REV-psODNs.
The IPC solutions exhibit phase transformation in vivo. and demonstrate no evidence of toxicity. The pharmacological effects observed from the of release of 3A2-ATG-psODNs suggest that the formulation can entrap, protect, and sustain the delivery of macromolecules. .
本研究对一种原位形成凝胶的体内特性进行了表征，该凝胶由水溶性聚合物的原位沉淀复合物（IPC）、聚甲基丙烯酸酯（PMA）和聚乙二醇（PEG）组成，用于大分子药物的缓释。
将40%、50%或60% w/v的制剂单独或含有模型大分子、3A2 - 抗胸腺细胞球蛋白 - 磷硫酰化寡脱氧核苷酸（3A2 - ATG - psODN）或REV - 磷硫酰化寡脱氧核苷酸（REV - psODN）皮下注射到大鼠模型中，以（i）确定凝胶在注射部位的大致胶凝和停留时间，（ii）使用MZ睡眠时间模型评估制剂的生物学功效，以及（iii）通过测量微粒体酶水平和尿量的变化来证明psODN序列的特异性和选择性。
溶胶到凝胶的转变在体内需要15分钟，60% w/v的IPC凝胶在注射部位可保留长达72小时。与REV - psODN相比，从凝胶中释放的3A2 - ATG - psODN导致的MZ睡眠时间和细胞色素P450 3A2（CYP3A2）表达有显著差异。
IPC溶液在体内表现出相变，且未显示出毒性证据。从3A2 - ATG - psODN释放观察到的药理作用表明该制剂能够包裹、保护并持续递送大分子。
