Hartlieb Karel J, Ferris Daniel P, Holcroft James M, Kandela Irawati, Stern Charlotte L, Nassar Majed S, Botros Youssry Y, Stoddart J Fraser
Department of Chemistry, Northwestern University , 2145 Sheridan Road, Evanston, Illinois 60208, United States.
Chemistry of Life Processes Institute, Northwestern University , 2145 Sheridan Road, Evanston, Illinois 60208, United States.
Mol Pharm. 2017 May 1;14(5):1831-1839. doi: 10.1021/acs.molpharmaceut.7b00168. Epub 2017 Apr 12.
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 γ-cyclodextrin (γ-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 (γ-CD) 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 IC value determined up to a concentration of 100 μM. 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 γ-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.
尽管布洛芬是使用最广泛的非甾体抗炎药（NSAIDs）之一，但作为游离酸，它在水性和生理环境中的溶解度较差。为了提高其口服生物利用度和吸收速率，人们对布洛芬新制剂的开发进行了广泛研究，包括使用辅料以及布洛芬盐，如赖氨酸布洛芬盐和布洛芬钠盐。这些研究的最终目标是缩短布洛芬达到最大吸收所需的时间，因为这段时间与镇痛/抗炎作用的起效速率直接相关，同时增加药物在体内的半衰期，即药物作用的持续时间。在此，我们展示了一种布洛芬与生物相容性金属有机框架CD-MOF形成的药物共晶。这种金属有机框架（MOF）基于γ-环糊精（γ-CD）环面，其在主面和次面上以交替方式与碱金属阳离子（如钾离子）配位，形成由（γ-CD）立方体构成的多孔框架。我们表明，布洛芬可以通过以下两种方式纳入CD-MOF-1中：（i）使用布洛芬钾盐作为碱阳离子源生产MOF的结晶过程，或（ii）游离酸的吸收和去质子化，从而使CD-MOF中布洛芬的吸收量达到23 - 26 wt%。体外活力研究表明，CD-MOF本身不影响细胞活力，在浓度高达100 μM时未测定到IC值。对小鼠进行了生物利用度研究，并将布洛芬/CD-MOF药物共晶与存在和不存在γ-CD的布洛芬钾盐对照样品进行了比较。从这些动物研究中，我们观察到布洛芬/CD-MOF-1共晶与布洛芬钾盐对照样品一样，布洛芬吸收迅速，在20分钟内观察到血浆峰值浓度，并且该共晶还有一个额外的好处，即在血浆样品中的半衰期延长了100%，并且本质上比纯盐形式的吸湿性更低。
