title: Enhanced bioavailability of nano-sized chitosan-atorvastatin conjugate after oral administration to rats.
abstract: A novel approach to improve the bioavailability and stability of atorvastatin (AT) was developed by constructing a nano-sized polymer-atorvastatin conjugate. Firstly, a novel chitosan-atorvastatin (CH-AT) conjugate was efficiently synthesized through amide coupling reaction. The formation of conjugate was confirmed by (1)H NMR and FT-IR spectrometry. Nano-sized conjugate with a mean size of 215.3±14.2 nm was prepared by the process of high pressure homogenization (HPH). Scanning electron microscopy (SEM) revealed that CH-AT nano-conjugate possess smooth surface whereas X-ray diffraction (XRD) spectra demonstrated amorphous nature of nano-conjugate. Further, CH-AT nano-conjugate showed solubility enhancement of nearly 4-fold and 100-fold compared to CH-AT conjugate and pure AT, respectively. In vitro drug release studies in simulated gastric fluid and simulated intestinal fluid suggested sustained release of AT from the conjugate. Additionally, the nano-conjugate significantly reduced the acidic degradation of AT. The plasma-concentration time profile of AT after oral administration of CH-AT nano-conjugate (2574±95.4 ng/mL) to rat exhibited nearly 5-fold increase in bioavailability compared with AT suspension (583±55.5 ng/mL). Finally, variable bioavailability, as observed for AT suspension was also reduced when AT was administered in form of CH-AT nano-conjugate. Taken together these data demonstrate that chitosan conjugate nano-prodrugs may be used as sustained polymeric prodrugs for enhancing bioavailability.
authors.affiliation: Department of Pharmaceutics, Faculty of Pharmacy, Hamdard University, New Delhi 110062, India.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Anwar
authors.forename: Musarrat H
authors.initials: MH
authors.lastname: Warsi
authors.forename: Neha
authors.initials: N
authors.lastname: Mallick
authors.forename: Sohail
authors.initials: S
authors.lastname: Akhter
authors.forename: Sachin
authors.initials: S
authors.lastname: Gahoi
authors.forename: Gaurav K
authors.initials: GK
authors.lastname: Jain
authors.forename: Sushma
authors.initials: S
authors.lastname: Talegaonkar
authors.forename: Farhan J
authors.initials: FJ
authors.lastname: Ahmad
authors.forename: Roop K
authors.initials: RK
authors.lastname: Khar
mesh_terms: D000268:Adhesiveness; D000284:Administration, Oral; D000818:Animals; D000069059:Atorvastatin; D001682:Biological Availability; D048271:Chitosan / Q000737:chemistry*; D002851:Chromatography, High Pressure Liquid; D004339:Drug Compounding; D004355:Drug Stability; D005260:Female; D006538:Heptanoic Acids / Q000008:administration & dosage / Q000493:pharmacokinetics*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics*; D007413:Intestinal Mucosa / Q000378:metabolism; D007421:Intestine, Small / Q000378:metabolism; D008855:Microscopy, Electron, Scanning; D015394:Molecular Structure; D058726:Nanoconjugates / Q000737:chemistry*; D010316:Particle Size; D011758:Pyrroles / Q000008:administration & dosage / Q000493:pharmacokinetics*; D051381:Rats; D012995:Solubility; D017550:Spectroscopy, Fourier Transform Infrared; D013499:Surface Properties
chemical_list: D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D058726:Nanoconjugates; D011758:Pyrroles; D048271:Chitosan; D000069059:Atorvastatin