PILOCARPINE PRODRUGS WITH IMPROVED BIOAVAILABILITY

INTRAOCULAR PRESSURE (IOP) IS NOT ADEQUATELY CONTROLLED BY SINGLE DRUG THERAPY IN MORE THAN 50 PERCENT OF GLAUCOMA PATIENTS. THE DEVELOPMENT OF ADDITIONAL DRUGS TO TREAT GLAUCOMA EITHER ALONE OR IN COMBINATION WITH ADRENERGIC BETA-ANTAGONISTS IS THEREFORE APPROPRIATE. THIS PROJECT SEEKS TO DEVELOP PRODRUGS OF PILOCARPINE. THESE PRODRUGS ARE EXPECTED TO REDUCE THE ELEVATED IOP THAT IS ASSOCIATED WITH MOST GLAUCOMAS AND IS RESPONSIBLE FOR SIGHT-THREATENINGOPTIC NERVE DAMAGE. SOFT QUATERNARY DERIVATIVES OF PILOCARPINE WILL BE USED. THESE PRODRUGS ARE DESIGNED TO BE MORE LIPOPHILIC THAN PILOCARPINE, PROVIDING IMPROVED CORNEAL PENETRATION. HOWEVER, AS QUATERNARY SALT DERIVATIVES, THEY ARE EXPECTED TO BE SUFFICIENTLY WATER SOLUBLE TO ALLOW FORMULATION IN AN AQUEOUS BUFFER VEHICLE. PREDICTABLE METABOLISM, SUCH AS ENZYMATIC HYDROLYSIS, WILL THEN RELEASE PILOCARPINE DIRECTLYWITHIN THE EYE. THE RESEARCH WILL INVOLVE THE SYNTHESIS OF THREE MODEL COMPOUNDS, ANALYTICAL METHODS DEVELOPMENT, AND DETERMINATIONOF LIPOPHILICITY OF THE COMPOUNDS. IN VIVO ACTIVITY STUDIESWILL EVALUATE MIOTIC AND OCULAR HYPOTENSIVE ACTIVITY IN A RABBIT MODEL. THE PHASE I STUDY WILL PROVIDE A STRONG FOUNDATION FOR FURTHER DEVELOPMENT IN PHASE II. BENEFITS OF THE PRODRUG WILL INCLUDE IMPROVED BIOAVAILABILITY, LOWER AND LESS FREQUENT DOSAGE, AND IMPROVED PATIENT COMPLIANCE.