New grafted PLA-g-PEG polymeric nanoparticles used to improve bioavailability of oral drugs

Polymeric nanoparticles (NPs) have shown promising results to be used as drug delivery carriers for controlled drug release and for targeting. The bioavailability of orally administrated drugs might be limited by an intestinal absorbed secretion process, which could in turn be mediated by P-glycoprotein (P-gp). The dispersion of Famotidine (drug model) within PEGylated nanoparticles (NPs) was evaluated in order to enhance the bioavailability using polyethylene glycol (PEG), which is known as a P-gp inhibitor. The hypothesis of this study is that the encapsulation of Famotidine into NPs prepared from PEG-g-PLA could inhibit the P-gp function. The first part of the study aimed to synthesize four copolymers of PEG grafted on a polylactide acid (PLA) polymer backbone (PLA-g-PEG) with ratios of 1 % and 5 % (molar ratio of PEG vs lactic acid monomer) of either 750 or 2000 Da molecular weights. These polymers have been used to prepare NPs loaded with Famotidine, which has low permeability and relatively low aqueous solubility. Prepared NPs were analyzed for their main physicochemical parameters such as size and size distribution, surface charge, morphology, encapsulation efficiency, percentage of residual poly(vinyl alcohol) (PVA) adsorbed at the surface of the NPs, thermal properties, crystalline structure and drug release. Also, NP formulations were tested in vitro on CaCo-2 monolayer cells in order to assess the bidirectional permeability of Famotidine. Generally speaking, NPs prepared from PLA-g-5%PEG grafted polymers showed improved drug permeability by inhibiting the P-gp efflux of Famotidine in the CaCo-2 in vitro model. Results showed a very significant decrease in the secretion of Famotidine from basolateral to apical when Famotidine was encapsulated in NPs prepared from 5 % grafting of either 750 or 2000 Da PEG, as well as in other combinations of physical mixtures containing PEG5%. The second part of the study is about those loaded NPs which showed promising results in terms of permeability and inhibition of P-gp efflux and which were selected to develop a solid oral dosage form. Dry granulation was used to densify NPs in order to develop tablets of the two selected NP formulations. NP based tablets showed a fast disintegration time (less than one minute) and a similar release profile as marketed Famotidine. The transport study of NP based tablets showed consistent results with NP formulations in terms of P-gp inhibition, which explains why the tablet’s manufacturing process had no effect on NPs. Our results demonstrated that the presence of hydrophilic polymers (PEG) on the surface of NPs grafted at 5 % PEG, irrespective to molecular weights, provides an effective way to control the interface between NPs and the biological systems (P-gp in this case) as they are designed to interact with. Taken together, these results show that encapsulation in a PEGylated polymeric NP could be a promising strategy to improve the oral bioavailability of P-gp substrates.

Keyphrases: Poly(ethylene glycol), CaCo-2, Poly(ethylene glycol), P-glycoprotein, Nanoparticles, Permeability, Poly(lactic) acid