Low-melting mixture solvents as novel solubilizing agents: Improving tolvaptan formulation and therapeutic efficacy

Abstract

Presently, a significant number of pharmaceutical drugs exhibit poor solubility in water and fall within categories II and IV of the biopharmaceutical classification system. This predicament has prompted the exploration for novel solvents or excipients to enhance the solubility and bioavailability of the active compounds in aqueous environments. Low-melting mixture solvents (LoMMSs) have gained recognition as potential solvents for active pharmaceutical ingredients to improve therapeutic efficacy and delivery. This study focuses on the preparation of a eutectic mixture composed of betaine, malic acid, proline, and water (BE-MA-PR-WA) to enhance the formulation options for tolvaptan, an FDA-approved medication used to treat acute congestive heart failure, which has limited solubility in aqueous solutions. The findings presented in this article represent the first reported results on the administration of LoMMS-solubilized tolvaptan. Furthermore, an examination of the solubility and bioavailability of tolvaptan utilizing this mixture was conducted, alongside an assessment of its toxicity. The solubility of tolvaptan in BE-MA-PR-WA (1:1:1:7) increased 483 times compared to solubility in water. Toxicity studies indicated that the LoMMS formulation BE-MA-PR-WA was safe for oral administration. The oral bioavailability of tolvaptan was significantly increased by 1.9-fold in the BE-MA-PR-WA than that in water. In addition, the 5-hour urine volume of rats indicated that BE-MA-PR-WA also enhanced the diuretic effects of tolvaptan in rats. The findings suggest that BE-MA-PR-WA enhance the solubility and bioavailability of tolvaptan, and are deemed non-toxic. Consequently, LoMMS may be deemed promising solubilizing agents, potentially facilitating the absorption of poorly bioavailable medications.