Design of PEG-grafted-PLA nanoparticles as oral permeability enhancer for P-gp substrate drug model Famotidine.
Bioavailability of oral drugs can be limited by an intestinal excretion process mediated by P-glycoprotein (P-gp). Polyethylene glycol (PEG) is a known P-gp inhibitor. Dispersion of Famotidine (a P-gp substrate) within PEGylated nanoparticles (NPs) was used to improve its oral bioavailability. In this work, we evaluated the potential impact of NPs prepared from a grafted copolymer of polylactic acid and PEG on P-gp function by studying in vitro permeability of Famotidine across Caco-2 cells. Copolymers of PEG grafted on polylactic acid (PLA) backbone (PLA-g-PEG) were synthesised with 1 mol% and 5 mol% PEG vs. lactic acid monomer using PEG 750 and 2000 Da. The polymers were used to prepare Famotidine-loaded NPs and tested in vitro on Caco-2 cells. Significant decrease in basolateral-to-apical transport of Famotidine was observed when Famotidine was encapsulated in NPs prepared from PLA-g-PEG5%. NPs prepared from PLA-g-PEG5% are promising to improve oral bioavailability of P-gp substrates.
a Faculty of Pharmacy , University of Montreal , Montreal , Quebec , Canada.
Mohamed
M
Mokhtar
b Corealis Pharma , Pharmaceutical R&D , Laval , Quebec , Canada.
Patrick
P
Gosselin
a Faculty of Pharmacy , University of Montreal , Montreal , Quebec , Canada.
François
F
Lacasse
c Faculty of Pharmacy , University of Montreal, Lab of Nanotech Pharmacy , Montreal , Quebec , Canada.
Patrice
P
Hildgen
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D018938:Caco-2 Cells; D004337:Drug Carriers / Q000737:chemistry*; D015738:Famotidine / Q000008:administration & dosage* / Q000378:metabolism / Q000493:pharmacokinetics*; D006635:Histamine H2 Antagonists / Q000008:administration & dosage* / Q000378:metabolism / Q000493:pharmacokinetics*; D006801:Humans; D053758:Nanoparticles / Q000737:chemistry*; D010539:Permeability; D011091:Polyesters / Q000737:chemistry*; D011092:Polyethylene Glycols / Q000737:chemistry*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D004337:Drug Carriers; D006635:Histamine H2 Antagonists; D011091:Polyesters; D011092:Polyethylene Glycols; C033616:poly(lactide); D015738:Famotidine
Caco-2; Famotidine; P-gp; PEG; PLA; nanoparticles; permeability