Abstract：
OBJECTIVE: To improve the biological and toxicological properties of Mefenamic acid (MA), the galactosylated prodrug of MA named MefeGAL was included in polymeric solid dispersions (PSs) composed of poly(glycerol adipate) (PGA) and Pluronic® F68 (MefeGAL-PS). MefeGAL-PS was compared with polymeric solid formulations of MA (MA-PS) or a mixture of equal ratio of MefeGAL/MA (Mix-PS).
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.
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.
摘要：
目的：为了改善甲芬那酸（MA）的生物学和毒理学特性，名为MefeGAL的MA的半乳糖基化前药包含在由聚（己二酸甘油酯）（PGA）和Pluronic®F68（MefeGAL-PS）组成的聚合物固体分散体（PS）中。将MefeGAL-PS与MA的聚合物固体制剂(MA-PS)或等比例的MefeGAL/MA的混合物(Mix-PS)进行比较。
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。
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。
