title: Novel double coated nanocapsules for intestinal delivery and enhanced oral bioavailability of tacrolimus, a P-gp substrate drug.
abstract: This study proposes a new concept of double coated nanocapsules to improve the oral bioavailability of a P-glycoprotein (P-gp) substrate drug, tacrolimus, without modulating the physiological activity of the P-gp pump. Tacrolimus was incorporated in nanocapsules with different ratios of two polymethacrylate polymers followed by microencapsulation of these nanocapsules within hydroxypropylmethylcellulose using a spray drying technique. The influence of different formulations of tacrolimus administered orally to rats and pigs on the drug's absorption was investigated. Histopathological studies were performed on rats to follow the nanocapsule path in enterocytes. The novel formulations that released mostly drug loaded nanocapsules in the intestine were shown to enhance markedly the oral absorption of tacrolimus. The relative oral bioavailability of tacrolimus was 4.9 and 2.45 fold compared to the commercial product in rats and pigs respectively. Although there is no direct evidence that intact nanocapsules internalized in the enterocytes, numerous small oil cores were detected within the enterocytes showing the potential of P-gp substrates incorporated in such nanocarriers to escape the efflux pump.
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, The Hebrew University of Jerusalem, P.O. Box 12065, Jerusalem, 91120, Israel.
authors.forename: Taher
authors.initials: T
authors.lastname: Nassar
authors.forename: Alona
authors.initials: A
authors.lastname: Rom
authors.forename: Abraham
authors.initials: A
authors.lastname: Nyska
authors.forename: Simon
authors.initials: S
authors.lastname: Benita
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000284:Administration, Oral; D000704:Analysis of Variance; D000818:Animals; D019540:Area Under Curve; D001682:Biological Availability; D016503:Drug Delivery Systems / Q000379:methods; D020895:Enterocytes / Q000378:metabolism / Q000473:pathology; D065347:Hypromellose Derivatives; D007166:Immunosuppressive Agents / Q000737:chemistry / Q000493:pharmacokinetics; D007408:Intestinal Absorption; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000473:pathology; D008747:Methylcellulose / Q000031:analogs & derivatives / Q000737:chemistry; D008855:Microscopy, Electron, Scanning; D008863:Microspheres; D053769:Nanocapsules / Q000737:chemistry* / Q000648:ultrastructure; D010316:Particle Size; D010938:Plant Oils / Q000737:chemistry; D011109:Polymethacrylic Acids / Q000737:chemistry; D051381:Rats; D017207:Rats, Sprague-Dawley; D013499:Surface Properties; D013552:Swine; D016559:Tacrolimus / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D007166:Immunosuppressive Agents; D053769:Nanocapsules; D010938:Plant Oils; D011109:Polymethacrylic Acids; C038300:methylmethacrylate-methacrylic acid copolymer; D065347:Hypromellose Derivatives; D008747:Methylcellulose; D016559:Tacrolimus