Alginate coated chitosan core shell nanoparticles for oral delivery of enoxaparin: in vitro and in vivo assessment.

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.

Bagre AP ，Jain K ，Jain NK 《-》

Oral delivery of insulin from alginate/chitosan crosslinked by glutaraldehyde.

Insulin is mainly administered via subcutaneous route by injection which is the cause of painful and possible infections. Oral insulin administration would present a more convenient form of application because it is less invasive. Oral delivery of insulin to the gastrointestinal tract is one of the most challenging issues, because it numerous barriers to overcome in order to create an effective system for insulin delivery. In the present study, insulin-loaded alginate/chitosan blend gel beads were prepared with different mass ratios. Chitosan was depolymerized by gamma irradiation at a dose of 80 kGy reducing its molecular weight for ideal blend with sodium alginate. The homogeneous solution of alginate and chitosan was dripped into CaCl2 solution (2%), the resultant calcium crosslinked beads were dipped in glutaraldehyde (2%) solution sequentially to prepare dual crosslinked beads with improved mechanical properties so as to withstand the simulated gastric fluid (SGF) and simulated intestinal fluid (SIF). Morphological structure, FTIR analysis, thermogravimetry analysis, specific surface area, gel fraction, swelling kinetics in SGF and SIF, loading efficiency, insulin release behavior, mucoadhesivity of the alginate/chitosan beads were investigated. The cumulative insulin release of pure alginate beads (10:0) reached as maximum level 100% in 3h after they were dipped in SIF. Concerning the beads Alg/Chi (8:2), Alg/Chi (7:3) and Alg/Chi (6:4) the cumulative release of insulin reached 90.5%, 89.2% and 70.2%, respectively in 6h. The rate of 100% was reached after 24h for Alg/Chi (8:2), Alg/Chi (7:3) and after 73 h for Alg/Chi (6:4). The presence of chitosan in the blend beads decreased the cumulative insulin release in gastric media and enhanced behavior of alginate/chitosan beads in intestinal medium due to the crosslinking. The alginate/chitosan beads crosslinked by glutaraldehyde may be considered as potential insulin carriers for oral drug delivery system.

Tahtat D ，Mahlous M ，Benamer S ，Khodja AN ，Oussedik-Oumehdi H ，Laraba-Djebari F ... -  《-》

Chitosan nanoconstructs for improved oral delivery of low molecular weight heparin: In vitro and in vivo evaluation.

The aim of present study was to investigate the potential of mucoadhesive polymer chitosan (CS) and N-trimethyl chitosan (TMC) based nanoparticulate systems for oral bioavailability enhancement of low molecular weight heparin (LMWH). The TMC was synthesized by methylation of chitosan followed by characterization using infrared spectroscopy and (1)H-NMR spectroscopy. The IR and NMR spectra of TMC confirmed the presence of trimethyl groups and estimated the degree of quaternization for TMC about 46%. TMC nanoparticles were then prepared by ionic gelation method. The developed CS-NPs and TMC-NPs were characterized for various parameters including morphology, particle size, zeta potential, entrapment efficiency, in vitro release behavior and storage stability at different temperature and simulated gastrointestinal tract conditions. The fluorescent microscopy study confirmed the higher particle uptake of TMC-NPs by gastrointestinal epithelium in comparison to the CS-NPs. The concentration of LMWH in the systemic circulation followed by oral administration of formulations was estimated using FXa chromogenic assay. A significant increase (p<0.05) in the oral bioavailability of LMWH was observed with TMC-NPs than both CS-NPs as well as plain LMWH solution. These findings suggested that TMC nanoparicles hold promise for oral delivery of LMWH and clinical applicability for the treatment of vascular disorders like deep vein thrombosis and pulmonary embolism, etc.

Paliwal R ，Paliwal SR ，Agrawal GP ，Vyas SP ... -  《-》

pH-sensitive chitosan/alginate core-shell nanoparticles for efficient and safe oral insulin delivery.

Mukhopadhyay P ，Chakraborty S ，Bhattacharya S ，Mishra R ，Kundu PP ... -  《-》

Chitosan coated sodium alginate-chitosan nanoparticles loaded with 5-FU for ocular delivery: in vitro characterization and in vivo study in rabbit eye.

The objective of the study was to develop chitosan (CH) coated sodium alginate-chitosan (SA-CH) nanoparticles, i.e. CH-SA-CH NPs loaded with 5-FU for ophthalmic delivery. Drug loaded nanoparticles (DNPs) were prepared by ionic gelation technique using sodium alginate (SA) and chitosan (CH) and then suspended in chitosan solution. The mean size of nanoparticles and morphology were characterized by dynamic light scattering, scanning electron microscopy, atomic force microscopy and zeta potential. The in vitro release was studied by dialysis membrane technique. The size and drug encapsulation efficiency were dependent on molar ratio of SA and CH. The size of SA-CH nanoparticles was significantly increased with changed morphology after CH coating. SA-CH nanoparticles did not show any interaction with mucin while an enhanced viscosity was observed on coating of nanoparticles with CH. CH-SA-CH DNPs presented a sustained release of 5-FU compared to the 5-FU solution with high burst effect. In vivo study in rabbit eye showed significantly greater level of 5-FU in aqueous humor compared to 5-FU solution. The enhanced mucoadhesiveness of CH-SA-CH DNPs results in higher bioavailability as compared to the uncoated nanoparticles. Optimized formulation was found non-irritant and tolerable when tested by modified Draize test in rabbit eye.

Nagarwal RC ，Kumar R ，Pandit JK 《-》