Encapsulation of Ibuprofen in CD-MOF and Related Bioavailability Studies
Encapsulation of Ibuprofen in CD-MOF and Related Bioavailability Studies
复制标题
DOI：
10.1021/acs.molpharmaceut.7b00168
复制
发表时间：
2017-05-01
影响因子：
4.9
通讯作者：
Stoddart, J. Fraser
中科院分区：
文献类型：
--
作者：
Hartlieb, Karel J.;Ferris, Daniel P.;Stoddart, J. Fraser
虽然布洛芬是最广泛使用的非甾体抗炎药（NSAID）之一，但其作为游离酸在水性和生理环境中表现出差的溶解度。为了改善其口服生物利用度和摄取速率，已经进行了对布洛芬新制剂的开发的广泛研究，包括使用赋形剂以及布洛芬盐，例如布洛芬赖氨酸盐和布洛芬钠盐。这些研究的最终目标是减少布洛芬最大吸收所需的时间，因为这段时间与镇痛/抗炎作用的发生率成正比，并增加药物在体内的半衰期;即药物作用的持续时间。在此，我们提出了一种药物共晶布洛芬和生物相容性金属有机框架称为CD-MOF。该金属有机骨架（MOF）基于与碱金属阳离子（例如，K+离子）以交替方式在它们的主面和次面上形成由（γ-CD）（6）立方体构建的多孔框架。我们表明，布洛芬可以通过（i）使用布洛芬的钾盐作为用于生产MOF的碱金属阳离子源的结晶过程或通过（ii）游离酸的吸收和去质子化而掺入CD-M0 F-1内，导致在CD-M0 F内吸收23-26重量%的布洛芬。体外生存力研究表明，CD-MOF本质上不影响细胞的生存力，在高达100 μ M的浓度下未测定IC 50值。对小鼠进行生物利用度研究，并将布洛芬/CD-MOF药物共晶体与存在和不存在γ-CD的布洛芬钾盐的对照样品进行比较。从这些动物研究中，我们观察到布洛芬/CD-M0 F-1共晶体表现出与布洛芬钾盐对照样品相同的布洛芬快速摄取，在20分钟内观察到峰值血浆浓度，并且共晶体具有在血浆样品中延长100%的半衰期的额外益处，并且与纯盐形式相比本质上吸湿性较小。
Although ibuprofen is one of the most widely used nonsteroidal anti-inflammatory drugs (NSAIDs), it exhibits poor solubility in aqueous and physiological environments as a free acid. In order to improve its oral bioavailability and rate of uptake, extensive research into the development of new formulations of ibuprofen has been undertaken, including the use of excipients as well as ibuprofen salts, such as ibuprofen lysinate and ibuprofen, sodium salt. The ultimate goals of these studies are to reduce the time required for maximum uptake of ibuprofen, as this period of time is directly proportional to the rate of onset of analgesic/anti-inflammatory effects, and to increase the half-life of the drug within the body; that is, the duration of action of the effects of the drug. Herein, we present a pharmaceutical cocrystal of ibuprofen and the biocompatible metal-organic framework called CD-MOF. This metal-organic framework (MOF) is based upon gamma-cyclodextrin (gamma-CD) tori that are coordinated to alkali metal cations (e.g., K+ ions) on both their primary and secondary faces in an alternating manner to form a porous framework built up from (gamma-CD)(6) cubes. We show that ibuprofen can be incorporated within CD-MOF-1 either by (i) a crystallization process using the potassium salt of ibuprofen as the alkali cation source for production of the MOF or by (ii) absorption and deprotonation of the free-acid, leading to an uptake of 23-26 wt % of ibuprofen within the CD-MOF. In vitro viability studies revealed that the CD-MOF is inherently not affecting the viability of the cells with no IC50 value determined up to a concentration of 100 mu M. Bioavailability investigations were conducted on mice, and the ibuprofen/CD-MOF pharmaceutical cocrystal was compared to control samples of the potassium salt of ibuprofen in the presence and absence of gamma-CD. From these animal studies, we observed that the ibuprofen/CD-MOF-1 cocrystal exhibits the same rapid uptake of ibuprofen as the ibuprofen potassium salt control sample with a peak plasma concentration observed within 20 min, and the cocrystal has the added benefit of a 100% longer half-life in blood plasma samples and is intrinsically less hygroscopic than the pure salt form.