Abstract
LW6 (3-[2-(4-adamantan-1-yl-phenoxy)-acetylamino]-4-hydroxy-benzoic acid methyl ester) is a potent inhibitor of drug efflux by the breast cancer resistance protein (BCRP). However, its poor aqueous solubility leads to low bioavailability, which currently limits in vivo applications. Therefore, the present study aimed to develop ternary solid dispersion (SD) formulations in order to enhance the aqueous solubility and dissolution rate of LW6. Various SDs of LW6 were prepared using a solvent evaporation method with different drug/excipient ratios. The solubility and dissolution profiles of LW6 in different SDs were examined, and F8-SD which is composed of LW6, poloxamer 407, and povidone K30 at a weight ratio of 1:5:8 was selected as the optimal SD. The structural characteristics of F8-SD were also examined using Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD), and scanning electron microscopy (SEM). In the acidic to neutral pH range, F8-SD achieved rapid dissolution with a drug release of 76–81% within 20 min, while the dissolution of pure LW6 was negligible. The XRPD patterns indicated that F8-SD probably enhanced the solubility and dissolution of LW6 by changing the drug crystallinity to an amorphous state, in addition to the solubilizing effect of the hydrophilic carriers. Furthermore, F8-SD significantly improved the oral bioavailability of topotecan, which is a BCRP substrate, in rats. The systemic exposure of topotecan was enhanced approximately 10-fold by the concurrent use of F8-SD. In conclusion, the ternary SD formulation of LW6 with povidone K30 and poloxamer 407 appeared to be effective at improving the dissolution and in vivo effects of LW6 as a BCRP inhibitor.
Highlights
The breast cancer resistance protein (BCRP), designated as ABCG2, is the second member of the G subfamily of the ATP binding cassette (ABC) efflux transporters, which restricts the systemic exposure and organ distribution of various exogenous compounds, including drugs and toxins [1,2]
Given that BCRP plays a key role in reducing the bioavailability of various drugs and developing the multidrug resistance of anticancer drugs, a potent BCRP inhibitor may be valuable in improving the effectiveness of drug therapy
Since LW6 has the high melting point (279 ◦C), the solid dispersion (SD) of LW6 were prepared with various polymers at a weight ratio of 1:5 using the solvent evaporation method
Summary
The breast cancer resistance protein (BCRP), designated as ABCG2, is the second member of the G subfamily of the ATP binding cassette (ABC) efflux transporters, which restricts the systemic exposure and organ distribution of various exogenous compounds, including drugs and toxins [1,2]. It is ubiquitously expressed in normal tissues including the small intestine, liver, kidney, blood–brain barrier, testis, placenta, and mammary glands, in addition to cancer cells [1]. Tithserreesfuolrtein, tghleorwe ibsiaoasvtraoinlagbidlietmy lainmditfsotrhaeninefvfeivcotivaeppfolircmatuiolantsi.onThtheraetfiomrep, rtohverees itshae ssotrlounbgilditeymaannddinfovriavno eeffffeeccttivoef fLoWrm6u. lation that improves the solubility and in vivo effect of LW6
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