Abstract
Bexarotene (BEX), a specific retinoic acid X receptor (RXR) agonist granted by Food and Drug Administration (FDA) approval for the clinical treatment of T cell lymphoma, has now been found to exert pharmacological effects in the nervous system, with low bioavailability and poor cerebral distribution limiting its application in treatment on neurological disorders. Pharmaceutical co-crystal was a helpful method to improve the bioavailability and tissue distribution of active pharmaceutical ingredients (APIs). Here, 2bexarotene-ligustrazine (2BEX-LIG), a novel co-crystal system of BEX and ligustrazine (LIG) of which with BEX is an API, was constructed with satisfactory stability and enhanced solubility. The pharmacokinetics characteristics of BEX were detected, and the results showed that the absolute bioavailability and the cerebral concentration of BEX in rats administrated with 2BEX-LIG were enhanced from 22.89% to 42.86% and increased by 3.4-fold, respectively, compared with those in rats administrated an equivalent of BEX. Hence, our present study indicated that the novel co-crystal of 2BEX-LIG contributed to improving BEX oral bioavailability and cerebral distribution, thereby providing significant advantages for clinical application of brain tumors and other neurological diseases.
Highlights
Co-crystals have attracted increasing interest in a variety of fields because of their superior properties as multicomponent materials that are rationally designed through the crystal engineering principle [1,2,3]
BEX has been used for the treatment of non-small cell lung cancer (NSCLC) [15], triple negative breast cancer (TNBC) [16], glioblastoma multiforme (GBM) [17], and thyroid cancer [18]
A co-crystal of BEX and LIG, 2BEX-LIG, was generated and a rapid and sensitive LC-MS detecting method was applied to measure the concentration of BEX in plasma and tissues in order to assess whether oral administration with the novel co-crystal can enhance the bioavailability and the cerebral distribution of BEX
Summary
Co-crystals have attracted increasing interest in a variety of fields because of their superior properties as multicomponent materials that are rationally designed through the crystal engineering principle [1,2,3]. Pharmaceutical co-crystals are potentially attractive to improve physicochemical properties of active pharmaceutical ingredients (APIs), including stability [4,5,6], solubility [7,8,9,10], bioavailability [11,12,13], and tissue distribution. BEX was formulated into linoleic acid or sunflower oil [25] to improve the physicochemical properties, the oral bioavailability of BEX in rats was still quite low, at 31.5% and 31.4%, respectively. A co-crystal of BEX and LIG, 2BEX-LIG, was generated and a rapid and sensitive LC-MS detecting method was applied to measure the concentration of BEX in plasma and tissues in order to assess whether oral administration with the novel co-crystal can enhance the bioavailability and the cerebral distribution of BEX. The new co-crystal and the new finding of its pharmacokinetic characteristics may provide a new strategy to enlarge clinical usage of BEX, especially to those of the nerve system diseases and impulse dosage forms of marketed drugs
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