Project Grant R44AI179391

ORAL DISSOLVABLE STRIPS (ODS) AS NEW PEDIATRIC AND ADULT DELIVERY MODE OF THERAPY FOR LATENT TUBERCULOSIS - PROJECT SUMMARY LATENT TUBERCULOSIS INFECTION (LTBI) PRESENTS A CRITICAL GLOBAL AND DOMESTIC HEALTH CHALLENGE AS THE RESERVOIR FOR FUTURE TB CASES, AND APPROXIMATELY ONE-QUARTER OF THE WORLD'S POPULATION CARRIES LTBI. IT HAS BEEN ESTIMATED THAT 5-10% OF THESE INDIVIDUALS ARE AT RISK OF DEVELOPING ACTIVE TB DISEASE DURING THEIR LIFETIME. THE US HAS SEEN A REVERSAL IN ITS DECADES-LONG DECLINE IN TB CASES, WITH A 5% INCREASE IN 2021 AND AN ADDITIONAL 3.7% RISE IN 2022, HIGHLIGHTING THE URGENT NEED FOR IMPROVED LTBI PREVENTIVE TREATMENT STRATEGIES. HOWEVER, CURRENT PEDIATRIC MULTI-DRUG FORMULATIONS FOR TB POSE SIGNIFICANT INFANT-RELATED AND CAREGIVER BARRIERS TO TREATMENT ADHERENCE. CAREGIVER BARRIERS INCLUDE THE DOSING COMPLEXITIES, SUCH AS MULTI-DRUG DOSING DIFFICULTY IN MEASURING PRECISE AMOUNTS OF THE LIQUID FORMULATIONS AND A LOW SHELF-LIFE. WHILE EFFECTIVE, THE RECOMMENDED THERAPY FOR LTBI FACES SIGNIFICANT CHALLENGES THAT LIMIT ITS SUCCESS, SUCH AS THE AVAILABILITY OF MEDICATION LIMITED TO LARGE TABLET FORMS (SWALLOWING DIFFICULTY IN CHILDREN), UNPALATABLE TASTE (POOR ADHERENCE), WEIGHT-BASED DOSING REQUIREMENTS (DIFFICULTY IN PRECISE DOSING) AND SAFETY CONCERNS (DUE TO SIDE EFFECTS OF CURRENT THERAPEUTICS). THE PRIMARY MEDICATIONS FOR TB, RIFAPENTINE (RPT) AND ISONIAZID (INH) ARE AVAILABLE ONLY IN LARGE TABLET FORMS THAT MANY PATIENTS, ESPECIALLY CHILDREN AND THOSE WITH SWALLOWING DIFFICULTIES, STRUGGLE TO TAKE. OAK'S INH-ORAL DISPERSIBLE STRIP (ODS) AND RPT-ODS ARE FORMULATION OPTIONS IN WHICH INH AND RPT ARE ENCAPSULATED AND CAPTURED WITH A SUPPORT MATRIX, THAT WILL REVOLUTIONIZE THE MANAGEMENT OF TB. OAK'S ODS ARE DEVELOPED THROUGH A PROPRIETARY PLATFORM THAT IS A KEY-ENABLING TECHNOLOGY FOR THE DEVELOPMENT OF IMPROVED THERAPY AND DRUG DELIVERY FOR PATIENTS OF ALL AGES. THE PHASE I PROJECT FOCUSED ON THE PRELIMINARY OPTIMIZATION OF INH AND RPT ODS AND ON GENERATING A PROOF OF CONCEPT SUPPORTING THE USE OF INH AND RPT ODS THROUGH IN VIVO PK STUDIES AND DEMONSTRATING BETTER TASTE MASKING EFFECT. IN THIS SBIR PHASE II, OAK WILL FOCUS ON OPTIMIZING THE INH AND RPT ODS. INITIALLY OAK WILL EVALUATE AN EFFICIENT MANUFACTURING PROCESS FOR ODS (AIM 1), WHEREIN THE ODS WILL BE MANUFACTURED AND ANALYZED USING THREE DISTINCT APPROACHES FOR A DECREASE IN WASTE AND MANUFACTURING COST, INCLUDING KNIFE-OVER CASTING AS SHEETS, TWIN SCREW EXTRUSION AS CONTINUOUS RIBBONS, AND DOSE EXTRUSION AS DISCRETE ODS. FURTHER, THE ENCAPSULATED INH AND RPT WILL BE DEVELOPED USING OPTIMIZATION AND SPRAY DRYING METHODS (AIM 2). LASTLY, THE MANUFACTURED INH AND RPT ODS WILL BE EVALUATED FOR THEIR TOXICITY, PK, AND STABILITY PROFILES USING IN VIVO AND IN VITRO METHODS (AIM 3), AND PREPARE FOR AN ANDA SUBMISSION (AIM 4). THESE OBJECTIVES ENSURE THE FINAL PRODUCTS' THERAPEUTIC EFFICACY AND COMMERCIAL VIABILITY. THE SUCCESSFUL COMPLETION OF THIS SBIR PHASE II PROJECT WILL BE FOLLOWED BY PREPARATION OF CHEMISTRY, MANUFACTURING, AND CONTROLS (CMC) DOCUMENTATION AND CONDUCTING PROCESS AND PRODUCT AUDITS. THIS WILL PAVE WAY FOR INITIATION OF PHASE I CLINICAL TRIALS AFTER CLEARANCE BY FDA.