METHODS: The in vitro and in vivo pharmacological and toxicological profiles of PSs have been investigated. In detail, we evaluated the anti-inflammatory (carrageenan-induced paw edema test), analgesic (acetic acid-induced writhing test) and ulcerogenic activity in mice after oral treatment. Additionally, the antiproliferative activity of PSs was assessed on in vitro models of colorectal and non-small cell lung cancer.
RESULTS: When the PSs were resuspended in water, MefeGAL\'s, MA\'s and their mixture\'s apparent solubilities improved due to the interaction with the polymeric formulation. By comparing the in-vivo biological performance of MefeGAL-PS with that of MA, MefeGAL and MA-PS, it was seen that MefeGAL-PS exhibited the same sustained and delayed analgesic and anti-inflammatory profile as MefeGAL but did not cause gastrointestinal irritation. The pharmacological effect of Mix-PS was present from the first hours after administration, lasting about 44 hours with only slight gastric mucosa irritation. In-vitro evaluation indicated that Mix-PS had statistically significant higher cytotoxicity than MA-PS and MefeGAL-PS.
CONCLUSIONS: These preliminary data are promising evidence that the galactosylated prodrug approach in tandem with a polymer-drug solid dispersion formulation strategy could represent a new drug delivery route to improve the solubility and biological activity of NSAIDs.
方法:已经研究了PSs的体外和体内药理学和毒理学特征。详细来说,我们评估了抗炎(角叉菜胶诱导的爪水肿试验),口服治疗后小鼠的镇痛(乙酸诱导的扭体试验)和致溃疡活性。此外,在结直肠癌和非小细胞肺癌的体外模型上评估了PSs的抗增殖活性.
结果:当PS重新悬浮在水中时,MefeGAL\'s,由于与聚合物制剂的相互作用,MA和它们的混合物的表观溶解度得到改善。通过比较MefeGAL-PS与MA的体内生物学性能,MefeGAL和MA-PS,观察到MefeGAL-PS表现出与MefeGAL相同的持续和延迟镇痛和抗炎特性,但不引起胃肠道刺激.Mix-PS的药理作用从给药后的第一个小时就存在,持续约44小时,只有轻微的胃粘膜刺激。体外评价表明,Mix-PS比MA-PS和MefeGAL-PS具有统计学上显著更高的细胞毒性。
结论:这些初步数据是有希望的证据,表明半乳糖基化前药方法与聚合物-药物固体分散体制剂策略相结合可以代表一种新的药物递送途径,以改善NSAIDs的溶解度和生物活性。