Novel amorphous solid dispersion based on natural deep eutectic solvent for enhancing delivery of anti-tumor RA-XII by oral administration in rats.

Abstract At present, oral chemotherapy showing the advantages of non-invasiveness, convenience, and high patient compliance, is gradually replacing traditional intravenous chemotherapy to treat patients with cancer. RA-XII, a unique natural cyclopeptide, exhibits various biological activities, such as anti-tumor, anti-angiogenic, and anti-metastatic activities. Designing an orally available formulation of RA-XII is of great importance in the development of clinically useful anticancer agents. However, RA-XII shows low oral bioavailability in rats due to its poor solubility and low permeability. To overcome these limitations, in this work, a natural deep eutectic solvent (NADES) was designed to efficiently deliver RA-XII by oral administration. A novel NADES composed of betaine and mandelic acid in the molar ratio of 1:1 (Bet-Man NADES) was successfully prepared based on a binary phase diagram of Bet and Man. Acute toxicity studies indicated that Bet-Man NADES was well tolerated with acceptable toxicity. In Bet-Man NADES solutions, the solubility of RA-XII was increased by up to 17.54-fold, and the diffusion and permeability of RA-XII carried out in a Franz cell was also significantly improved 10.35 times. In terms of biopharmaceutical classification this is translated into a change for RA-XII from class IV to class II systems. More importantly, Bet-Man NADES was transferred into the solid formulation by the inclusion of a polymer, and amorphous solid dispersions based on Bet-Man NADES (PVP K30/NADES/RA-XII, ASDs) were successfully prepared to improve uniformity, apparent solubility, dissolution, and cytotoxicity in vitro. Consequently, the oral bioavailability of RA-XII in NADES solutions and ASDs was enhanced by approximately 11.58 and 7.56 times compared with that of pure RA-XII in 0.5% CMC Na. Thus, it can be seen that a natural deep eutectic solvent and its modified amorphous solid dispersions are appropriate novel strategies for improving dissolution rate and bioavailability of poor soluble natural products such as RA-XII.