Evaluation of a transtympanic delivery system in Mus musculus for extended release steroids

• Published in: European journal of pharmaceutical sciences Vol. 126; pp. 3 - 10
• Main Authors: Dormer, Nathan H., Nelson-Brantley, Jennifer, Staecker, Hinrich, Berkland, Cory J.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.01.2019
• Subjects: Animals; Cellulose - analogs & derivatives; Cellulose - chemistry; Delayed-Action Preparations; Drug Carriers - chemistry; Drug Liberation; Fluorescent Dyes - chemistry; Humans; Injection, Intratympanic; Labyrinth Diseases - drug therapy; Membranes, Artificial; Mice, Inbred C57BL; Microspheres; Polylactic Acid-Polyglycolic Acid Copolymer - chemistry; Round window membrane; Round Window, Ear - metabolism; Steroid; Steroids - administration & dosage; Steroids - adverse effects; Sudden hearing loss; Transtympanic; Steroid; Round window membrane; Microspheres; Sudden hearing loss; Transtympanic
• DOI: 10.1016/j.ejps.2018.01.020
• ISSN: 0928-0987; 1879-0720

The current investigation evaluated a novel extended release delivery system for treating inner ear diseases. The platform technology consists of a film forming agent (FFA) and microsphere component to localize and extend drug delivery within the ear. Studies evaluated dissolution kinetics of microspheres with multiple encapsulates, testing of a variety of FFAs, and ability to localize to the round window membrane in mice in vivo. Studies were completed at Orbis Biosciences and The University of Kansas Medical Center. In conjunction with in vitro characterization, an infrared dye-containing microsphere formulation was evaluated for round window membrane (RWM) localization and general tolerability in C57/BL6 Mus musculus for 35 days. Methods: In vitro characterization was performed using upright diffusion cells on cellulose acetate membranes, with drug content quantified by high performance liquid chromatography. Mus musculus dosing of infrared dye-containing microspheres was performed under anesthesia with a 27 GA needle and 2.0 μL injection volume In vitro dissolution demonstrates the ability of the FFA with microsphere platform to release steroids, proteins, peptides, and nucleic acids for at least one month, while necroscopy shows the ability of the FFA with dye-loaded microspheres to remain localized to Mus musculus RWM for the same period of time, with favorable tolerability. Conclusions: Combining FFA and microsphere for localized drug delivery may enable cost-effective, extended release local delivery to the inner ear of new and existing small molecules, proteins, peptides, and nucleic acids. [Display omitted]