Bioavailability of indomethacin-saccharin cocrystals
Bioavailability of indomethacin-saccharin cocrystals
复制标题
DOI：
10.1111/j.2042-7158.2010.01189.x
复制
发表时间：
2010-11-01
影响因子：
3.3
通讯作者：
Velaga, Sitaram P.
中科院分区：
文献类型：
--
作者：
Jung, Min-Sook;Kim, Jeong-Soo;Velaga, Sitaram P.
目的药物共晶是一种新型的固体剂型，具有良好的物理化学性质，有望用于药物开发。然而，共晶体的体内生物利用度很少得到解决。吲哚美辛（IND）（一种生物制药分类系统II类药物）与糖精（SAC）的共晶已被证明在所有pH值下都具有比IND更高的溶解度。在这项研究中，我们的目的是评价IND-SAC共晶体的体外溶出度和体内生物利用度，并与物理混合物中的IND和市售产品Indomee进行比较。使用冷却间歇结晶而不加晶种进行共晶的结晶。使用高效液相色谱法、差示扫描量热法和粉末X射线衍射法验证了放大材料的化学和物理纯度。将IND-SAC共晶和IND加SAC与乳糖混合，并将制剂置于明胶胶囊中。然后使用转篮溶出法进行体外溶出研究。还测定了IND和IND-SAC共晶的固有溶出速率。最后，在比格犬中进行制剂的生物利用度研究。血浆样品进行了分析，使用高效液相色谱法和药物动力学数据进行了分析，使用标准methods.Key findingsThe散装共晶体（即按比例放大的材料）的化学和物理纯。在pH 7.4和pH 1.2下，共晶体的体外溶出速率高于IND，与Indomee（R）相似。IND-SAC共晶体在犬中的体内生物利用度显著较高（ANOVA，P < 0.05），但与Indomee（R）无显著性差异结论共晶体的水溶性提高，可提高吲哚美辛的生物利用度，共晶是一种可行的替代固体形式，其可以提高难溶性药物的溶解速率和生物利用度。
ObjectivesPharmaceutical cocrystals are new solid forms with physicochemical properties that appear promising for drug product development. However, the in-vivo bioavailability of cocrystals has rarely been addressed. The cocrystal of indomethacin (IND), a Biopharmaceutical Classification System class II drug, with saccharin (SAC) has been shown to have higher solubility than IND at all pH. In this study, we aimed to evaluate the in-vitro dissolution and in-vivo bioavailability of IND-SAC cocrystals in comparison with IND in a physical mixture and the marketed product Indomee (R).MethodsScale-up of the cocrystals was undertaken using cooling batch crystallisation without seeding. The chemical and physical purity of the up-scaled material was verified using high-performance liquid chromatography, differential scanning calorimetry and powder X-ray diffraction. The IND-SAC cocrystals and IND plus SAC were mixed with lactose and the formulations were placed into gelatin capsules. In-vitro dissolution studies were then performed using the rotating basket dissolution method. The intrinsic dissolution rate of IND and IND-SAC cocrystals was also determined. Finally, a bioavailability study for the formulations was conducted in beagle dogs. The plasma samples were analysed using high-performance liquid chromatography and the pharmacokinetic data were analysed using standard methodologies.Key findingsThe bulk cocrystals (i.e. scaled-up material) were chemically and physically pure. The in-vitro dissolution rate of the cocrystals was higher than that of IND and similar to that of Indomee (R) at pH 7.4 and pH 1.2. The in-vivo bioavailability of the IND-SAC cocrystals in dogs was significantly higher (ANOVA, P < 0.05) than that of IND but not significantly different from Indomee (R) (ANOVA, P > 0.05).ConclusionsThe study indicates that the improved aqueous solubility of the cocrystals leads to improved bioavailability of IND. Thus, the cocrystals are a viable alternative solid form that can improve the dissolution rate and bioavailability of poorly soluble drugs.