具有不同稳定赋形剂的5个长效药物纳米杆菌的局部耐受性
抽象的
To investigate the effects of common nanosuspension-stabilizing excipients on the nature and temporal evolution of histopathological changes at intramuscular (i.m.) administration sites, 5 groups of 39 male rats per group received a single injection of 1 of the 5 analogous crystalline drug nanosuspensions containing 200 mg/ml of an antiviral compound with particle sizes of ±200 nm and identical vehicle compositions, except for the type of nanosuspension stabilizer. The investigated stabilizers were poloxamer 338, poloxamer 407, d-α-tocopherol polyethylene glycol 1,000-succinate (TPGS), polysorbate 80, and polysorbate 80 combined with egg phosphatidylglycerol. Histopathology and immunohistochemistry revealed progressive inflammatory changes at the i.m. administration sites and the draining lymph nodes that differed according to the time point of sacrifice and the type of stabilizer. Although the overall time course of inflammatory changes was similar across the groups, differences in the nature, severity, and timing of the inflammatory response were observed between animals injected with poloxamer- or TPGS-containing nanosuspensions and those injected with formulations containing polysorbate 80. A more severe and prolonged active inflammatory phase, the presence of multinucleate giant cells, prolonged macrophage infiltration of the formulation depot, and more persistent histiocytic infiltrates in the lymph nodes were observed in the polysorbate 80–containing nanosuspension groups. Such vehicle-mediated effects could influence the overall tolerability profile of long-acting nanosuspensions.
结论
用聚山梨醇酯80含纳米杆菌治疗的给药位点显示出更严重的急性炎症反应，略微延迟和柔软的淋巴细胞反应，MNGC的发育，较高的总炎症等级，以及略微相关的炎症反应的分辨率较慢与用其他稳定赋形剂处理的管理位点相比，制剂仓库的敏感性增加。来自含TPGS-含有TPGS-制剂处理的组的给药位点似乎在2套（聚山梨醇酯和泊洛昔尔基团）之间的某个地方，并用两者分享某些特征。因此，可以通过稳定赋形剂的类型调节观察到长效纳米杆菌的局部炎症反应和临界时间点的局部炎症反应的性质和动态和临界时间点可以通过稳定赋形剂的类型调节。这反过来可以影响血浆药代动力学，这在该研究中表现出与上述组织病理聚类的良好相关性。