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 p-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 sightthreatening optic 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 directly within the eye. The research will involve the synthesis of three model compounds, analytical methods development, and determination of lipophilicity of the compounds. In vivo activity studies will 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.Awardee's statement of the potential commercial applications of the research:The ultimate goal of this research is the commercial development of a new pilocarpine prodrug that can reduce the elevated intraocular pressure associated with most glaucomas. This product will compete for a large share of the $250 million annual U.S. market for antiglaucoma drugs.National Eye Institute (NEI)
