Intraocular pressure (IOP) is not adequately controlled by single drug therapy in more than 50% of glaucoma patients. The development of additional drugs to treat glaucoma either alone or in combination with adrenergic beta-antagonists is therefore appropriate. This proposal suggests the development of prodrugs of pilocarpine. These prodrugs are expected to reduce the elevated IOP which is associated with glaucoma and responsible for sight-treatening optic nerve damage. The proposed approach will use """"""""soft"""""""" quaternary derivatives of pilocarpine. 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 proposed 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 2. Benefits of the prodrug will include improved bioavailability, lower and less frequent dosage and improved patient compliance.
| Druzgala, P; Winwood, D; Drewniak-Deyrup, M et al. (1992) New water-soluble pilocarpine derivatives with enhanced and sustained muscarinic activity. Pharm Res 9:372-7 |
