Emami Shahram, Siahi-Shadbad Mohammadreza, Adibkia Khosro, Barzegar-Jalali Mohammad
Drug Applied Research Center and Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran.
Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran.
Bioimpacts. 2018;8(4):305-320. doi: 10.15171/bi.2018.33. Epub 2018 May 31.
: Oral drug delivery is the most favored route of drug administration. However, poor oral bioavailability is one of the leading reasons for insufficient clinical efficacy. Improving oral absorption of drugs with low water solubility and/or low intestinal membrane permeability is an active field of research. Cocrystallization of drugs with appropriate coformers is a promising approach for enhancing oral bioavailability. : In the present review, we have focused on recent advances that have been made in improving oral absorption through cocrystallization. The covered areas include supersaturation and its importance on oral absorption of cocrystals, permeability of cocrystals through membranes, drug-coformer pharmacokinetic (PK) interactions, conducting in vivo-in vitro correlations for cocrystals. Additionally, a discussion has been made on the integration of nanocrystal technology with supramolecular design. Marketed cocrystal products and PK studies in human subjects are also reported. : Considering supersaturation and consequent precipitation properties is necessary when evaluating dissolution and bioavailability of cocrystals. Appropriate excipients should be included to control precipitation kinetics and to capture solubility advantage of cocrystals. Beside to solubility, cocrystals may modify membrane permeability of drugs. Therefore, cocrystals can find applications in improving oral bioavailability of poorly permeable drugs. It has been shown that cocrystals may interrupt cellular integrity of cellular monolayers which can raise toxicity concerns. Some of coformers may interact with intestinal absorption of drugs through changing intestinal blood flow, metabolism and inhibiting efflux pumps. Therefore, caution should be taken into account when conducting bioavailability studies. Nanosized cocrystals have shown a high potential towards improving absorption of poorly soluble drugs. : Cocrystals have found their way from the proof-of-principle stage to the clinic. Up to now, at least two cocrystal products have gained approval from regulatory bodies. However, there are remaining challenges on safety, predicting in vivo behavior and revealing real potential of cocrystals in the human.
口服给药是最受青睐的给药途径。然而，口服生物利用度差是临床疗效不足的主要原因之一。提高低水溶性和/或低肠膜通透性药物的口服吸收是一个活跃的研究领域。药物与合适的共形成物共结晶是提高口服生物利用度的一种有前景的方法。
在本综述中，我们重点关注了通过共结晶改善口服吸收方面的最新进展。涵盖的领域包括过饱和及其对共晶体口服吸收的重要性、共晶体通过膜的通透性、药物 - 共形成物的药代动力学（PK）相互作用、进行共晶体的体内 - 体外相关性研究。此外，还讨论了纳米晶体技术与超分子设计的整合。还报道了上市的共晶体产品及在人体中的PK研究。
在评估共晶体的溶解和生物利用度时，考虑过饱和及随之而来的沉淀特性是必要的。应包含合适的辅料以控制沉淀动力学并利用共晶体的溶解度优势。除了溶解度外，共晶体还可能改变药物的膜通透性。因此，共晶体可用于改善低通透性药物的口服生物利用度。已表明共晶体可能破坏细胞单层的细胞完整性，这可能引发毒性问题。一些共形成物可能通过改变肠道血流、代谢和抑制外排泵来影响药物的肠道吸收。因此，进行生物利用度研究时应谨慎。纳米级共晶体在改善难溶性药物的吸收方面显示出巨大潜力。
共晶体已从原理验证阶段进入临床。到目前为止，至少有两种共晶体产品已获得监管机构的批准。然而，在安全性、预测体内行为以及揭示共晶体在人体中的真正潜力方面仍存在挑战。
