Docusate-Based Ionic Liquids of Anthelmintic Benzimidazoles Show Improved Pharmaceutical Processability, Lipid Solubility, and in Vitro Activity against Cryptococcus neoformans

Abstract

As the existing therapeutic modalities for the treatment of cryptococcal meningitis (CM) have suboptimal efficacy, repurposing existing drugs for the treatment of CM is of great interest. The FDA-approved anthelmintic benzimidazoles, albendazole, mebendazole, and flubendazole, have demonstrated potent but variable in vitro activity against Cryptococcus neoformans, the predominant fungal species responsible for CM. We performed molecular docking studies to ascertain the interaction of albendazole, mebendazole, and flubendazole with a C. neoformans β-tubulin structure, which revealed differential binding interactions and explained the different in vitro efficacies reported previously and observed in this investigation. Despite their promising in vitro efficacy, the repurposing of anthelmintic benzimidazoles for oral CM therapy is significantly hampered due to their high crystallinity, poor pharmaceutical processability, low and pH-dependent solubility, and drug precipitation upon entering the intestine, all of which result in low and variable oral bioavailability. Here, we demonstrate that the anthelmintic benzimidazoles can be transformed into partially amorphous low-melting ionic liquids (ILs) with a simple metathesis reaction using amphiphilic sodium docusate as a counterion. In vitro efficacy studies on a laboratory reference and a clinical isolate of C. neoformans showed 2-to 4-fold lower IC 90 values for docusate-based ILs compared to the pure anthelmintic benzimidazoles. Furthermore, using a C. neoformans strain with green fluorescent protein (GFP)-tagged β-tubulin and albendazole and its docusate IL as model candidates, we showed that the benzimidazoles and their ILs reduce the viability of C. neoformans by interfering with its microtubule assembly. Unlike pure anthelmintic benzimidazoles, the docusate-based ILs showed excellent solubility in organic solvents and >30-fold higher solubility in bioavailability-enhancing lipid vehicles. Finally, the docusate ILs were successfully incorporated into SoluPlus, a self-assembling biodegradable polymer, which upon dilution with water formed polymeric micelles with a size of <100 nm. Thus, the development of docusate-based ILs represents an effective approach to improve the physicochemical properties and potency of anthelmintic benzimidazoles to facilitate their repurposing and preclinical development for CM therapy.

Micro-Injection Moulding of PEO/PCL Blend–Based Matrices for Extended Oral Delivery of Fenbendazole

“…Hence, it was expected that moulded tablets of PEO and FBZ would show extended drug release and longer breakdown rates. Moreover, due to FBZ’s basic nature (pKa 5.12), it was expected that the imidazole ring at acidic pH would ionise and improve substantially the drug solubility [ 59 ]. Therefore, the test was carried out at a prolonged time period for a better comprehension of FBZ dissolution properties, achieving a complete drug dissolution under the acidic environment in 11 days.…”

Oral Self-Nanoemulsifying System Containing Ionic Liquid of BX795 Is Effective against Genital HSV-2 Infection in Mice

“…We previously demonstrated that anthelmintic benzimidazoles, weakly basic and hydrophobic drugs with poor aqueous and lipid solubility, and metformin, a hydrophilic base with poor lipid solubility, can be efficiently transformed into amphiphilic IL using sodium docusate, a biocompatible fatty anion. 14,15 Furthermore, the docusate-based IL of anthelmintic benzimidazoles and metformin showed significantly higher lipid solubility compared to the parent drug. Hence, we decided to use a similar approach to improve the lipid solubility of BX795.…”

Recent developments in membrane targeting antifungal agents to mitigate antifungal resistance

“…9l). 178 The docusate-based ionic liquids were synthesized by treating these drugs with sodium docusate (Doc) in the presence of 1 M HCl and methanol. Antifungal studies showed that the developed ABZs were more potent than the parent drugs.…”

“…Notably, the docusate-based ionic liquids have greater organic solubility over the drugs, and incorporation of polymers provided a micelle-forming ability to the docusate-based ionic liquids. 178…”