SBIR-STTR Award

Intermediate and posterior uveitis cause 10% of blindness in the U.S. The mainstay of therapy is to eradicate the infectious cause and to quell the inflammation with corticosteroids or immunosuppressants. Delivery of anti-inflammatory drugs to the posterior portion of the globe in therapeutic concentrations has proven difficult. There are four methods of delivering compounds to the posterior chamber: intravitreal injection, oral administration with subsequent distribution into the eye through optic blood flow, peribulbar injection, and passive diffusion through the sclera following topical application. Each method has its well-known drawbacks. This proposal will study non-invasive drug delivery to the posterior portion of the rabbit's eye. Specific aims include studying the passive permeability of a corticosteroid and mechanisms to enhance non-invasive transscleral delivery to the posterior retina. Included in these mechanisms are means to decrease conjunctival and choroidal pre-retinal clearance. Lastly, once we have determined the formulation and conditions that maximize corticosteroid delivery, we will study in vivo effectiveness of our technique in the treatment of endotoxin-induced uveitis in the rabbit model.

Thesaurus Terms:
drug delivery system, eye disorder chemotherapy, eye pharmacology, retina, therapy design /development, uveitis choroid uvea, conjunctiva, corticosteroid, dexamethasone, dosage, endotoxin, membrane permeability, nonhuman therapy evaluation, noninvasive diagnosis, pharmacokinetics, retina circulation, sclera laboratory rabbit

The overarching aim of this innovative proposal is to develop and then commercialize a non-invasive topical product which is safe and easy to administer that treats severe uveitis, including intermediate and posterior uveitis. Uveitis is the third leading cause of blindness in the United States. Heretofore, the primary treatments of intermediate and posterior uveitis are either oral medications (with significant systemic side effects) or invasive local methods, such as an intravitreal injection (IVT), periocular injection or implantation of a sustained release drug delivery device into the eye. Thus, there is a great need to develop a superior drug delivery system in terms of safety, patient acceptance and efficacy for severe uveitis. Our previous, successful SBIR phase I proposal (1 R43 EY014772-01) and subsequent studies gave us insights on the permeability of a water soluble corticosteroid to the eye globe; clearance effects of the conjunctiva and retina/choroid and the dosing requirements of dexamethasone sodium phosphate (DSP) to treat an in vivo IVT EIU rabbit model using a controlled release, passive diffusion-based methodology. The investigation of Aciont's vasoconstrictor technology, based on the principle of reducing the eye's blood flow clearance effects funded by that grant reached a successful endpoint. This proposal builds upon our prior SBIR work by advancing our technology closer toward commercialization into a viable product. The following main aims for this SBIR phase II proposal are closely related: 1) Complete Engineering of First Generation, Passive Diffusion Based Applicator/Device; 2) Complete Formulation Development for a Single Unit Dose Treatment Protocol under an Acute, Severe Uveitis Disease Condition Model; 3) Establish a Repeat Dose Treatment Protocol To Address a Chronic Uveitis Condition (i.e., Efficacy in Primate Model); and 4) Establish 28 Day Local Tolerance and Safety in a Chronic Uveitis Repeat Dose Treatment Protocol. Potentially, our approach can lead to a non-invasive delivery system that allows for a very simple treatment in the doctor's office which can be performed by a nurse or paraprofessional in a range of 5-10 minutes. Such a system has the potential to curtail a significant portion of the acute sight threatening condition of severe uveitis in a single treatment. A long term goal could be to train patients to administer our treatment system by themselves.

Public Health Relevance:
Our phase II SBIR proposes to develop a non-invasive ocular drug delivery system allowing for a simple, timely (potentially, 5 minutes or less) application procedure in the doctor's office of a device (resembling a scleral lens) which can be performed by a nurse or paraprofessional. Such a system could curtail a significant portion of an acute sight threatening condition of severe uveitis in a single treatment.

Thesaurus Terms:
(11beta,16alpha)-9-Fluoro-11,17,21-Trihydroxy-16-Methylpregna-1,4-Diene-3,20-Dione; 1-Dehydro-16alpha-Methyl-9alpha-Fluorohydrocortisone; 16alpha-Methyl-9alpha-Fluoro-1,4-Pregnadiene-11beta,17alpha,21-Triol-3,20-Dione; 16alpha-Methyl-9alpha-Fluoro-Delta1-Hydrocortisone; 16alpha-Methyl-9alpha-Fluoroprednisolone; 9alpha-Fluoro-11beta,17alpha,21-Trihydroxy-16alpha-Methylpregna-1,4-Diene-3,20-Dione; 9alpha-Fluoro-16alpha- Methylprednisolone; Aacidexam; Acute; Address; Adexone; Adherence; Adherence (Attribute); Adrenal Cortex Hormones; Adverse Effects; Affect; Aknichthol Dexa; Alba-Dex; Alin; Alin Depot; Alin Oftalmico; Ambene; Amplidermis; Anemul Mono; Animals; Anterior; Antimicotico; Application Procedure; Aquapred; Area; Auxiloson; Azona; Baycuten; Baycuten N; Blindness; Blood Flow; Body Tissues; Budgets; Cataract; Cells; Choroid; Chronic; Clinic; Clinical; Clinical Trials; Clinical Trials, Unspecified; Contractor; Contralateral; Corson; Corticoids; Corticosteroids; Cortidexason; Cortisumman; Data; Decacort; Decadrol; Decadron; Decalix; Decameth; Decasone R.P.; Dectancyl; Deenar; Dekacort; Deltafluorene; Deronil; Desamethasone; Desameton; Development; Device Designs; Device Or Instrument Development; Devices; Dex-4; Dexa-Mamallet; Dexa-Rhinosan; Dexa-Scheroson; Dexa-Sine; Dexace; Dexacortal; Dexacortin; Dexafarma; Dexafluorene; Dexalocal; Dexamecortin; Dexameth; Dexamethasone; Dexamethasonum; Dexamonozon; Dexapos; Dexinoral; Dexone; Diffusion; Dinormon; Disease; Disorder; Dose; Drug Administration, Topical; Drug Delivery; Drug Delivery Systems; Drug Formulations; Drug Targeting; Drug Targetings; Drugs; Effects, Longterm; Elements; Engineering; Engineerings; Evaluation; Exposure To; Eye; Eyeball; Fluoro-9alpha Methyl-16alpha Prednisolone; Fluorodelta; Formulation; Formulations, Drug; Fortecortin; Frequencies (Time Pattern); Frequency; Funding; Gammacorten; Gel; Generations; Goals; Grant; Hexadecadrol; Hexadrol; Hour; Human; Human, General; Hydrogen Oxide; Inflm; Infiltration; Inflammation; Injection Of Therapeutic Agent; Injections; Investigation; Laboratories; Lead; Location; Lokalison-F; Long-Term Effects; Loverine; Mammals, Primates; Mammals, Rabbits; Man (Taxonomy); Man, Modern; Maps; Measures; Medication; Method Loinc Axis 6; Methodology; Methods; Methylfluorprednisolone; Millicorten; Modeling; Mymethasone; Nurses; Ocasa; Ophthalmoscopy; Oral; Orgadrone; Oryctolagus Cuniculus; Outcome; Outer Pigmented Layer Of Retina; Patient Education; Patient Instruction; Patient Training; Patients; Pb Element; Performance; Permeability; Personnel, Nursing; Pharmaceutic Preparations; Pharmaceutical Preparations; Phase; Pigment Cell Layer Of Retina; Pigmented Layer Of Retina; Porifera; Position; Positioning Attribute; Posterior Uveitis; Predni-F; Pregna-1,4-Diene-3,20-Dione, 9-Fluoro-11,17,21-Trihydroxy-16-Methyl-, (11beta,16alpha)-; Preparation; Primates; Procedures; Proteins; Protocol; Protocols Documentation; Protocols, Treatment; Rgm; Rabbit, Domestic; Rabbits; Regimen; Reproducibility; Research Design; Retina; Retinal Pigment Epithelium; Retinal Pigment Epithelial Cells; Review Literature; Rivers; Sbir; Sbirs (R43/44); Safety; Sclera; Sight; Site; Small Business Innovation Research; Small Business Innovation Research Grant; Spersadex; Spersadox; Sponges; Sponges (Zoology); Structure; Structure Of Retinal Pigment Epithelium; Study Type; Surface; System; System, Loinc Axis 4; Technology; Testing; Therapeutic Corticosteroid; Time; Tissues; Topical Application; Toxic Effect; Toxicities; Training; Translating; Translatings; Treatment Protocols; Treatment Regimen; Treatment Schedule; Treatment Side Effects; United States; Uveitis; Uveitis, Posterior; Vasoactive Agonists; Vasoconstrictor Agents; Vasoconstrictor Drugs; Vasoconstrictors; Vasopressor Agents; Vision; Visumetazone; Water; White Of Eye; Work; Auricularum; Base; Cataractogenesis; Cataractous Lenses; Clinical Investigation; Commercialization; Conjunctiva; Controlled Release; Cost; Design; Designing; Device Development; Disease/Disorder; Drug/Agent; Experiment; Experimental Research; Experimental Study; Gene Product; Heavy Metal Pb; Heavy Metal Lead; Implantation; In Vitro Testing; In Vivo; Inflammatory Marker; Innovate; Innovation; Innovative; Insight; Instrument Development; Language Translation; Lens; Meetings; Migration; Non-Human Primate; Nonhuman Primate; Ophthalmic Drug; Patient Safety; Preclinical Study; Prototype; Public Health Relevance; Research Study; Residence; Safety Study; Side Effect; Sodium Phosphate; Study Design; Therapy Adverse Effect; Topical Administration; Topical Drug Application; Topically Applied; Treatment Adverse Effect; Uptake; Uveoretinitis; Vasopressor