Antagonists of cannabinoid receptor 1 (CB1) have the potential to treat several metabolic diseases including obesity and fatty liver disease. Recently, rimonabant and other developed CB1 antagonists were withdrawn from the market because of the observed adverse effects on the central nervous system (CNS).

Studies clearly showed that rimonabant is well absorbed and has a high BBB permeability. Thus, reduced BBB or decreased rimonabant penetration into the brain is a crucial issue to overcome the CNS side-effects. For such a purpose rimonabant was entrapped in polymeric nanoparticles (NPs), able to release such a lipophilic drug  in a controlled manner while circulating in the vasculature, prolong its apparent biological half–life and deliver the drug to a specifically targeted organ while minimizing the passage through the BBB.

The preliminary data of rimonabant encapsulation in polymeric nanoparticles showed encouraging results for the encapsulation of small amounts of rimonabant, but when we attempted to increase the drug content within the NPs the drug loading efficiency decreased. Thus, there is a clear need to modify the lipophilicity and solubility properties of the molecule. Modification of rimonabant into a higher lipophilic molecule was performed to facilitate incorporation into the polymeric nanoparticles.

It is believed that such an approach will improve rimonabant prodrug encapsulation within polymeric nanoparticles enabling efficient drug loading without escape or release of the prodrug into circulation, thus preventing its penetration into the brain. Once the prodrug-loaded NPs reach the target organ following controlled biodegradation of the NPs and progressive release of the prodrug, appropriate enzymatic cleavage of the ester bond will result in the formation of active rimonabant able to elicit an adequate local peripheral therapeutic activity and thus overcome the CNS side-effects.