Biopharmaceutical characterization of praziquantel cocrystals and cyclodextrin complexes prepared by grinding
Biopharmaceutical characterization of praziquantel cocrystals and cyclodextrin complexes prepared by grinding
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DOI：
10.1016/j.jpba.2017.01.025
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发表时间：
2017-04-15
影响因子：
3.4
通讯作者：
Jug, Mario
中科院分区：
文献类型：
--
作者：
Cugovcan, Martina;Jablan, Jasna;Jug, Mario
采用机械力化学活化技术，采用多种共研磨添加剂对吡喹酮进行活化，以改善吡喹酮的理化性质和生物药剂学性质。采用等摩尔量的柠檬酸（CA）、苹果酸（MA）、水杨酸（SA）和酒石酸（TA）进行液体辅助研磨，可以形成共晶，这些物质的溶解度和溶解速率均表现出pH依赖性。然而，如在稳定性测试期间所见，PZQ与MA的最可溶共晶是化学不稳定的。通过与无定形羟丙基-β-环糊精（HP β CD）和随机甲基化β-环糊精（ME β CD）进行净研磨制备的等摩尔环糊精复合物显示出药物溶解度和溶出速率的最高改善，但只有PZQ/HP β CD产物呈现出可接受的化学和光稳定性特征。通过将药物与MA和HP β CD以等摩尔比共研磨的组合方法也得到高度可溶的无定形产物，其再次是化学不稳定的，因此不适合于药物用途。对Caco-2单层的研究证实了PZQ/HP β CD复合物的生物相容性，并表明复合不会对固有的高PZQ渗透性产生不利影响（P-app（PZQ）=（3.72 +/- 0.33）x 10（-5）cm s（-1）和P-app（PZQ/HP β CD）=（3.65 +/- 0.21）x 10（-5）cm s（-1）; p >0.05）。所有这些都证实了与适当的添加剂共研磨是一种有前途的策略，以改善药物的生物药剂学性质。(C)2017 Elsevier B. V.版权所有。
Mechanochemical activation using several different co-grinding additives was applied as a green chemistry approach to improve physiochemical and biopharmaceutical properties of praziquantel (PZQ). Liquid assisted grinding with an equimolar amount of citric acid (CA), malic acid (MA), salicylic acid (SA) and tartaric acid (TA) gained in cocrystal formation, which all showed pH-dependent solubility and dissolution rate. However, the most soluble cocrystal of PZQ with MA was chemically unstable, as seen during the stability testing. Equimolar cyclodextrin complexes prepared by neat grinding with amorphous hydroxypropyl-P-cyclodextrin (HP beta CD) and randomly methylated beta-cyclodextrin (ME beta CD) showed the highest improvement in drug solubility and the dissolution rate, but only PZQ/HP beta CD product presented an acceptable chemical and photostability profile. A combined approach, by co-grinding the drug with both MA and HP beta CD in equimolar ratio, also gave highly soluble amorphous product which again was chemical instable and therefore not suitable for the pharmaceutical use. Studies on Caco-2 monolayer confirmed the biocompatibility of PZQ/HP beta CD complex and showed that complexation did not adversely affect the intrinsically high PZQ permeability (P-app(PZQ) = (3.72 +/- 0.33) x 10(-5) cm s(-1) and P-app(PZQ/HP beta CD)= (3.65 +/- 0.21) x 10(-5) cm s(-1); p >0.05). All this confirmed that the co-grinding with the proper additive is as a promising strategy to improve biopharmaceutical properties of the drug. (C) 2017 Elsevier B.V. All rights reserved.