title: Alginate coated chitosan core shell nanoparticles for oral delivery of enoxaparin: in vitro and in vivo assessment.
abstract: The objective of present research work was to develop alginate coated chitosan core shell nanoparticles (Alg-CS-NPs) for oral delivery of low molecular weight heparin, enoxaparin. Chitosan nanoparticles (CS-NPs) were synthesized by ionic gelation of chitosan using sodium tripolyphosphate. Core shell nanoparticles were prepared by coating CS-NPs with alginate solution under mild agitation. The Alg-CS-NPs were characterized for surface morphology, surface coating, particle size, polydispersity index, zeta potential, drug loading and entrapment efficiency using SEM, Zeta-sizer, FTIR and DSC techniques. Alginate coating increased the size of optimized chitosan nanoparticles from around 213 nm to about 335 nm as measured by dynamic light scattering in zeta sizer and further confirmed by SEM analysis. The performance of optimized enoxaparin loaded Alg-CS-NPs was evaluated by in vitro drug release studies, in vitro permeation study across intestinal epithelium, in vivo venous thrombosis model, particulate uptake by intestinal epithelium using fluorescence microscopy and pharmacokinetic studies in rats. Coating of alginate over the CS-NPs improved the release profile of enoxaparin from the nanoparticles for successful oral delivery. In vitro permeation studies elucidated that more than 75% enoxaparin permeated across the intestinal epithelium with Alg-CS-NPs. The Alg-CS-NPs significantly increased (p<0.05) the oral bioavailability of enoxaparin in comparison to plain enoxaparin solution as revealed by threefold increase in AUC of plasma drug concentration time curve and around 60% reduction in thrombus formation in rat venous thrombosis model. The core shell Alg-CS-NPs showed promising potential for oral delivery and significantly enhanced the in vivo oral absorption of enoxaparin.
authors.affiliation: Pharmaceutics Research Laboratory, Department of Pharmaceutical Sciences, Dr. H. S. Gour Central University, Sagar (M.P.) 470003, India.
authors.forename: Archana Pataskar
authors.initials: AP
authors.lastname: Bagre
authors.forename: Keerti
authors.initials: K
authors.lastname: Jain
authors.forename: Narendra K
authors.initials: NK
authors.lastname: Jain
mesh_terms: D000284:Administration, Oral; D000464:Alginates / Q000737:chemistry*; D000818:Animals; D000925:Anticoagulants / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D001682:Biological Availability; D048271:Chitosan / Q000737:chemistry*; D004337:Drug Carriers / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D017984:Enoxaparin / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D020723:Glucuronic Acid / Q000737:chemistry; D006603:Hexuronic Acids / Q000737:chemistry; D007413:Intestinal Mucosa / Q000378:metabolism; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry; D051381:Rats; D017207:Rats, Sprague-Dawley; D020246:Venous Thrombosis / Q000188:drug therapy*
chemical_list: D000464:Alginates; D000925:Anticoagulants; D004337:Drug Carriers; D017984:Enoxaparin; D006603:Hexuronic Acids; D020723:Glucuronic Acid; D048271:Chitosan
keywords: ANOVA; AUC; Alg-CS-NPs; CS-NPs; Chitosan; Core shell nanoparticles; DSC; Enoxaparin; FTIR; Fourier transform infrared spectroscopy; GI; KRPB; Kreb's Ringer phosphate bicarbonate solution; LMWH; Oral bioavailability; PDI; SEM; SGF; SIF; STPP; Sodium alginate; TPP; alginate coated chitosan core shell nanoparticles; analysis of variance; area under the curve; chitosan nanoparticles; differential scanning calorimetry; gastrointestinal; low molecular weight heparin; polydispersity index; scanning electron microscopy; simulated gastric fluid; simulated intestinal fluid; sodium tripolyphosphate; tripolyphosphate ion