Probucol-Ursodeoxycholic Acid Otic Formulations: Stability and In Vitro Assessments for Hearing Loss Treatment

• Published in: Journal of pharmaceutical sciences 2024-08, Vol.113 (8), p.2595-2604
• Main Authors: Ionescu, Corina M., Kovacevic, Bozica, Jones, Melissa A., Wagle, Susbin R., Foster, Thomas, Mikov, Momir, Mooranian, Armin, Al-Salami, Hani
• Format: Article
• Language: English
• Subjects: Animals; Antioxidants - administration & dosage; Antioxidants - chemistry; Antioxidants - pharmacology; Cell Line; Cell Survival - drug effects; Cisplatin; Cisplatin - administration & dosage; Cisplatin - pharmacology; Cyclodextrin; Drug Carriers - chemistry; Drug Compounding - methods; Drug delivery; Drug Liberation; Drug Stability; Excipients - chemistry; Hair Cells, Auditory - drug effects; Hair Cells, Auditory - metabolism; Hearing loss; Hearing Loss - chemically induced; Hearing Loss - drug therapy; HEI-OC1; Mice; Particle Size; Probucol; Probucol - administration & dosage; Probucol - chemistry; Probucol - pharmacokinetics; Probucol - pharmacology; UDCA; Ursodeoxycholic Acid - administration & dosage; Ursodeoxycholic Acid - chemistry; Ursodeoxycholic Acid - pharmacology
• ISSN: 0022-3549; 1520-6017; 1520-6017
• DOI: 10.1016/j.xphs.2024.04.032

•Cyclodextrins, polyvinylpyrrolidone, polyvinyl acetate and polyethylene glycol increase probucol solubility.•Probucol based microparticles can be dispersed in aqueous solutions, allowing for slow probucol release from the particulate matrix.•Ursodeoxycholic acid stabilises probucol microparticles and delays probucol release.•Probucol based microparticles show no cytotoxicity in permissive HEI-OC1 cells.•Ursodeoxycholic acid in combination with probucol enhances probucol's protective effects in vitro against cisplatin. Targeted drug delivery is an ongoing aspect of scientific research that is expanding through the design of micro- and nanoparticles. In this paper, we focus on spray dried microparticles as carriers for a repurposed lipophilic antioxidant (probucol). We characterise the microparticles and quantify probucol prior to assessing cytotoxicity on both control and cisplatin treated hair cells (known as House Ear Institute-Organ of Corti 1; HEI-OC1). The addition of water-soluble polymers to 2% β-cyclodextrin resulted in a stable probucol formulation. Ursodeoxycholic acid (UDCA) used as formulation excipient increases probucol miscibility and microparticle drug content. Formulation characterisations reveals spray drying results in spherical UDCA-drug microparticles with a mean size distribution of ∼5–12 μm. Probucol microparticles show stable short-term storage conditions accounting for only ∼10% loss over seven days. By mimicking cell culture conditions, both UDCA-probucol (67%) and probucol only (82%) microparticles show drug release in the initial two hours. Furthermore, probucol formulations with or without UDCA preserve cell viability and reduce cisplatin-induced oxidative stress. Mitochondrial bioenergetics results in lower basal respiration and non-mitochondrial respiration, with higher maximal respiration, spare capacity, ATP production and proton leak within cisplatin challenged UDCA-probucol groups. Overall, we present a facile method for incorporating lipophilic antioxidant carriers in polymer-based particles that are tolerated by HEI-OC1 cells and show stable drug release, sufficient in reducing cisplatin-induced reactive oxygen species accumulation.