SBIR-STTR Award

There is currently no reliable therapy and no cure for tinnitus. NeuroSystec, in collaboration with basic and clinical scientists at the Kresge Hearing Research Institute (KHRI) and the Medical University of Hannover (MHH), has: 1) confirmed that gacyclidine (NST-001) is effective in animal models for tinnitus and 2) suppresses human tinnitus through compassionate therapy. However, for effective and practical tinnitus control, NST-001 must be formulated for chronic and long-term administration. In this regard, NST-001 is not sufficiently stable; not sufficiently soluble; and suffers from problems of loss to catheters and other components of delivery systems during administration. In a breakthrough discovery, NeuroSystec has developed a solid drug-delivery device which solves the problems of sustained and long-term administration of NST-001. However, while this technology will allow therapy for many patients, it will still suffer from problems associated with drug loss in those patients who have been fitted with a cochlear implant (CI). The materials used to fabricate CIs will adsorb a substantial fraction of NST-001 from solutions, when these solutions are administered through or near the CI. To solve this drug delivery problem, NeuroSystec plans to employ a nanoparticle formulation of the drug to: 1) keep the drug in a stable suspension capable of passing through a proprietary antibacterial filter; and 2) avoid loss of drug to CI components during or after release into the cochlea. To achieve this end, NeuroSystec plans to meet the following goals during the period of the proposed project: Specific aim 1. Improve existing mixing technology to be used in the solvent-displacement method for nanoparticles fabricated from GMP materials that are approved for human implantation [e.g., poly(lactide-co-glycolide), PLGA or equivalent material] and to co-formulate nanoparticles with light oils (triglycerides) to adjust their densities, sedimentation times and drug-binding properties. Specific aim 2. Develop methodologies for loading nanoparticles with NST-001 after fabrication that would allow for use of the formulation in patients fitted with a CI. Specific aim 3. Develop methodologies for loading nanoparticles with NST-001 concurrently with nanoparticle fabrication (the conventional method).

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There is currently no reliable therapy and no cure for tinnitus. Scientists at INSERM in Montpellier, France demonstrated the effectiveness of gacyclidine in an animal model of tinnitus. Later, clinical scientists the Medical University of Hannover (MHH) confirmed that gacyclidine suppressed human tinnitus in compassionate use individual patient therapy. However, for effective and practical tinnitus control, NST-001 (gacyclidine) must be formulated for chronic and long-term administration. In this regard, NST-001 is not sufficiently stable; not sufficiently soluble in its stable free base form; and suffers from problems of loss to catheters and other components of delivery systems during administration. In Phase I and follow-up research, NeuroSystec has successfully developed a squalene-based nanoparticle formulation that addresses the problems with NST-001 formulation. In this Phase II proposal NeuroSystec will continue with this formulation; the ultimate goal is to produce a commercially viable product that can be safely used for long term administration via an osmotic pump in humans. To accomplish this goal the Company has the following Specific Aims 1) Finalize a squalene (or other pharmaceutically acceptable lipid)-based nanoparticle formulation with and without NST- 001 suitable for animal studies, a pilot sterile manufacturing procedure for drug product and a sterile filtration methodology with <5% drug loss. 2) Demonstrate that this formulation meets criteria for drug delivery and long term stability. Develop manufacturing and storage procedures for loading osmotic pumps with the sterile nanoparticles containing NST-001 formulation. 3) Establish the safety and efficacy of the NST-001 nanoparticle formulation in comparison to solution formulation in an animal model of tinnitus; compare the effectiveness of middle and inner ear delivery of the formulation. At the completion of Phase II NeuroSystec will be able to commence clinical testing of NST-001 to treat severe tinnitus.

Public Health Relevance:
There is currently no cure and no effective therapy for severe tinnitus, a disease that afflicts approximately 2 million Americans. NeuroSystec will develop and evaluate a novel lipid based nanoparticle formulation to deliver a promising new drug to the inner ear for the treatment of severe tinnitus.

Thesaurus Terms:
2,6,10,14,18,22-Tetracosahexaene, 2,6,10,15,19,23-Hexamethyl-, (All-E)-; Active Follow-Up; Address; Affect; American; Animal Model; Animal Models And Related Studies; Animals; Body Temperature; Catheters; Chronic; Clinical; Clinical Evaluation; Clinical Testing; Clinical Trials; Clinical Trials, Unspecified; Cochlea; Cochlear Organ; Cochlear Structure; Data; Dioxanedione Polymer With Dimethyldioxanedione Polymer; Disadvantaged; Disease; Disorder; Drug Delivery; Drug Delivery Systems; Drug Formulations; Drug Targeting; Drug Targetings; Drugs; Ear, Internal; Effectiveness; Filtration; Formulation; Formulations, Drug; Fractionation, Filtration; France; Glycolic-Lactic Acid Polyester; Goals; Human; Human, General; Implant; Individual; Labyrinth; Lipids; Man (Taxonomy); Man, Modern; Medical; Medication; Method Loinc Axis 6; Methodology; Methods; Patients; Pharmaceutic Preparations; Pharmaceutical Preparations; Phase; Physiologic; Physiological; Piperidine, 1-(2-Methyl-1-(2-Thienyl)Cyclohexyl)-, Cis-; Poly(Glycolide Lactide)Copolymer; Poly(Lactide-Co-Glycolide); Poly(Lactide-Co-Glycoside); Polyglactin; Preparation; Principal Investigator; Procedures; Programs (Pt); Programs [publication Type]; Pump; Research; Ringing-Buzzing-Tinnitus; Sbir; Sbirs (R43/44); Safety; Scientist; Small Business Innovation Research; Small Business Innovation Research Grant; Solutions; Squalene; Sterility; System; System, Loinc Axis 4; Testing; Tinnitus; Universities; Work; Animal Efficacy; Base; Clinical Investigation; Clinical Test; Commercialization; Compare Effectiveness; Design; Designing; Disease/Disorder; Drug/Agent; Effective Therapy; Falls; Follow-Up; Gacyclidine; Improved; Inner Ear; Meetings; Methyl-2-R-(Piperidine-1-)-1-(Thienyl-2)1-Cyclohexene; Model Organism; Nano Particle; Nanoparticle; Novel; Programs; Public Health Relevance; Research Clinical Testing; Sterile; Success