An Intravaginal Ring for the Simultaneous Delivery of an HIV-1 Maturation Inhibitor and Reverse-Transcriptase Inhibitor for Prophylaxis of HIV Transmission

Abstract

Nucleocapsid 7 (NCp7) inhibitors have been investigated extensively for their role in impeding the function of HIV-1 replication machinery and their ability to directly inactivate the virus. A class of NCp7 zinc finger inhibitors, S-acyl-2-mercaptobenzamide thioesters (SAMTs), was investigated for topical drug delivery. SAMTs are inherently unstable due to their hydrolytically labile thioester bond thus requiring formulation approaches that can lend stability. We describe the delivery of N-[2-(3,4,5-trimethoxybenzoylthio)benzoyl]-β-alanine amide (SAMT-10), as a single agent antiretroviral (ARV) therapeutic and in combination with the HIV-1 reverse transcriptase inhibitor pyrimidinedione IQP-0528, from a hydrophobic polyether urethane (PEU) intravaginal ring (IVR) for a month. The physicochemical stability of the ARV-loaded IVRs was confirmed after 3 months at 40°C/75% relative humidity (RH). In vitro, 25 ± 3 mg/IVR of SAMT-10 and 86 ± 13 mg/IVR of IQP-0528 were released. No degradation of the hydrolytically labile SAMT-10 was observed within the matrix. The combination of ARVs had synergistic antiviral activity when tested in in vitro cell based assays. Toxicological evaluations performed on an organotypic EpiVaginal™ tissue model demonstrated a lack of formulation toxicity. Overall, SAMT-10 and IQP-0528 were formulated in a stable PEU IVR for sustained release. Our findings support the need for further preclinical evaluation.

Microbicide vaginal rings: Technological challenges and clinical development

“…Alternative biocompatible thermoplastic materials, most notably thermoplastic polyurethanes (TPUs) [42,59,[61][62][63][64], are also being evaluated for fabrication of microbicide-releasing rings, in order to extend material choice beyond the relatively hydrophobic silicone elastomers and EVA polymers. TPUs are multi-phase block copolymers formed by a step-growth polymerization reaction between diisocyanates, a low molecular weight diol and a high molecular weight diol ( Figure 5B).…”

Sustained Release Drug Delivery Applications of Polyurethanes

“…In the case of a reservoir system where the initial drug concentration is below its solubility, those drug molecules that diffuse out of the system will not be replaced by undissolved drug and the drug activity at the rate controlling membrane’s surface decreases with time, resulting in first order release kinetics. Models have also been developed which describe first order release kinetics from a cylindrical intravaginal ring [ 54 , 55 ]. However, a reservoir system where the drug concentration exceeds its solubility will feature a saturated solution at the membrane surface, resulting in zero order release kinetics.…”

“…A stiffer material will have a higher Young’s modulus. Ugaonkar et al leveraged the Young’s modulus as a measure of flexibility by subjecting a 25 mm long cylindrical segment to a defined elongation at a specified rate and again compared the measured value for their experimental dosage form to that of the marketed product Nuvaring ® [ 55 ]. Clark et al developed a model to predict the force necessary to compress an intravaginal ring material a given distance based on the Young’s modulus [ 54 ].…”

Past, Present, and Future Drug Delivery Systems for Antiretrovirals

“…Extensive work in the Kiser Lab has evaluated the use of polyurethane for the formation of vaginal rings. [89][90][91][92] Gupta et al 83 constructed matrix-type vaginal rings consisting of polyurethane loaded with dapivirine. Dapivirine was released at a near-zero order rate and the rate of drug release depended on the initial drug loading.…”