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Updated: May 10, 2026

Oromucosal as an Alternative Method for Administration of Cannabis Products in Rodents
Published on: August 22, 2025
An effective prodrug strategy to selectively enhance ocular exposure of a cannabinoid receptor (CB1/2) agonist
Nello Mainolfi1, James Powers, Jakal Amin
1Novartis Institutes for Biomedical Research , Global Discovery Chemistry, 100 Technology Square, Cambridge, Massachusetts 02139, United States.
Abstract:
Glaucoma is a leading cause of vision loss and blindness, with increased intraocular pressure (IOP) a prominent risk factor. IOP can be efficaciously reduced by administration of topical agents. However, the repertoire of approved IOP-lowering drug classes is limited, and effective new alternatives are needed. Agonism of the cannabinoid receptors CB1/2 significantly reduces IOP clinically and experimentally. However, development of CB1/2 agonists has been complicated by the need to avoid cardiovascular and psychotropic side effects. 1 is a potent CB1/2 agonist that is highly excluded from the brain. In a phase I study, compound 1 eyedrops were well tolerated and generated an IOP-lowering trend but were limited in dose and exposure due to poor solubility and ocular absorption. Here we present an innovative strategy to rapidly identify compound 1 prodrugs that are efficiently metabolized to the parent compound for improved solubility and ocular permeability while maintaining low systemic exposures.
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