title: Polymeric micelles of amphiphilic graft copolymer of α-tocopherol succinate-g-carboxymethyl chitosan for tamoxifen delivery: Synthesis, characterization and in vivo pharmacokinetic study.
abstract: Novel amphiphilic graft copolymers were prepared from low molecular weight carboxymethyl chitosan (LMW Cmc) and α-tocopherol succinate (TS) via an amidation reaction and confirmed by (1)H NMR and IR spectroscopy. These graft copolymers are self-assembled to nanosized core-shell-structural micelles in an aqueous milieu. The critical micelle concentration (CMC) decreased with an increasing substitution of TS on LMW Cmc, which ranged from 7.94×10(-8) to 1.58×10(-6)g/mL. Cmc-TS4.5 (Cmc-TS with a charged molar ratio of TS to glucosamine units of Cmc∼4.5) was shown maximum TMX loading up to 8.08±0.98%. Both blank and TMX-loaded PM's of Cmc-TS4.5 exhibit spherical shape with particle size below 200nm. An in vitro release study in simulated gastric and intestinal fluid demonstrated that TMX release from TMX-PM4.5 (TMX-PMs prepared with amphiphilic polymer Cmc-TS4.5, and the weight ratio of Cmc-TS4.5 to TMX was 8:1) was slow and pH dependent. In vivo oral absorption study revealed Cmc-TS4.5 based PM's permeated the epithelial barrier via the paracellular route without causing any intestinal damage. In vivo toxicity study demonstrated the safety of PM's after oral administration. Compared to tamoxifen control, TMX-PM4.5 dosed to fasted female Sprague Dawley rats showed a 1.9 fold increase in AUC0-72h. Thus, the results suggested that Cmc-TS micelles are a promising carrier for TMX delivery.
authors.affiliation: Department of Pharmaceutical Technology (Formulations), National Institute of Pharmaceutical Education and Research, Sector-67, S.A.S Nagar 160062, Punjab, India.
authors.forename: Sunil K
authors.initials: SK
authors.lastname: Jena
authors.affiliation: Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research, Sector-67, S.A.S Nagar 160062, Punjab, India. Electronic address: abhays@niper.ac.in.
authors.forename: Abhay T
authors.initials: AT
authors.lastname: Sangamwar
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D001826:Body Fluids / Q000378:metabolism; D060326:Chemistry Techniques, Synthetic; D048271:Chitosan / Q000031:analogs & derivatives* / Q000737:chemistry; D004337:Drug Carriers / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics* / Q000633:toxicity; D065546:Drug Liberation; D057927:Hydrophobic and Hydrophilic Interactions; D008823:Micelles; D008970:Molecular Weight; D058105:Polymerization; D051381:Rats; D017207:Rats, Sprague-Dawley; D012997:Solvents / Q000737:chemistry; D013629:Tamoxifen / Q000737:chemistry*; D024502:alpha-Tocopherol / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry
chemical_list: D004337:Drug Carriers; D008823:Micelles; D012997:Solvents; C514968:carboxymethyl-chitosan; D013629:Tamoxifen; D048271:Chitosan; D024502:alpha-Tocopherol
keywords: 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (PubChem CID: 2723939); Carboxymethyl chitosan; Clomiphene citrate (PubChem CID: 3033832); Coumarin-6 (PubChem CID: 100334); N-hydroxysuccinimide (PubChem CID: 80170); Pharmacokinetic; Phosphotungstic acid (PubChem CID: 16212977); Polymeric micelles; Sodium chloride (PubChem CID: 5234); Tamoxifen; Tamoxifen (PubChem CID: 2733526); Toxicity; d-α-tocopherol succinate; d-α-tocopherol succinate (PubChem CID: 20353)