NOVEL SUBCUTANEOUS SUSTAINED RELEASE NANOPARTICLES ENCAPSULATING LOW MOLECULAR WEIGHT HEPARIN (LMWH): PREPARATION, CHARACTERIZATION AND EVALUATION Original Article (original) (raw)
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Asian Journal of Pharmaceutical and Clinical Research, 2017
Objective: The objective of the present study was to prepare and evaluate a novel oral formulation of nanoparticles for the systemic delivery of low molecular weight heparin (LMWH). Methods: Nanoparticles were prepared by polyelectrolyte complexation (PEC) method using polymers sodium alginate and chitosan. Entrapment efficiency of LMWH in nanoparticles was found to be ̴88%. Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), X‑ray diffraction (XRD), Scanning electron microscopy (SEM) studies carried for nanoparticles. In vitro release studies were performed for the formulations. Ex vivo permeation studies were performed optimized formulation by using small intestine of rat and in vivo studies were conducted on rat model.Results: In vitro release studies demonstrated that the release of LMWH was negligible in the stomach and high in the small intestine. FTIR has indicated that there is no interaction between the ingredients in nanoparticle. DSC...
Preparation and In Vitro Evaluation of Heparin-Loaded Polymeric Nanoparticles
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Nanoparticles of a highly soluble macromolecular drug, heparin, were formulated with two biodegradable polymers (poly-ecaprolactone [PCL] and poly (D, L-lactic-co-glycolic-acid) 50/50 [PLAGA]) and two nonbiodegradabl e positively charged polymers (Eudragit RS and RL) by the double emulsion and solvent evaporation method, using a high-pressure homogenization device. The encapsulation ef ciency and heparin release pro les were studied as a function of the type of polymers employed (alone or in combination) and the concentration of heparin. Optimal encapsulation ef ciency was observed when 5000 IU of heparin were incorporated in the rst emulsion. High drug entrapment ef ciency was observed in both Eudragit RS and RL nanoparticles (60% and 98%, respectively), compared with PLAGA and PCL nanoparticles (<14%). The use of the two types of Eudragit in combination with PCL and PLAGA increased the encapsulation ef ciency compared with these two biodegradable polymers used alone; however, the in vitro drug release was not modi ed and remained low. On the other hand, the addition of esterase to the dissolution medium resulted in a signi cant increase in heparin release. The in vitro biological activity of released heparin, evaluated by measuring the anti-Xa activity by a colorimetric assay, was conserved after the encapsulation process.
Oral bioavailability of a low molecular weight heparin using a polymeric delivery system
Journal of Controlled Release, 2006
Low molecular weight heparins (LMWHs) are the standards of anticoagulant for the prevention of deep vein thrombosis (DVT) in patients undergoing arthroplasty and abdominal surgery. However, LMWHs are so far only administered by parenteral route. Thus, they are usually replaced by oral warfarin for outpatient therapy. Since warfarin has a slow onset and high incidence of drug-drug interaction, there is a great need for the development of an oral LMWH formulation. LMWH (tinzaparin)-loaded nanoparticles prepared with a blend of a polyester and a polycationic polymethacrylate by the double emulsion method were administered orally in fasted rabbits. The plasma tinzaparin concentration was measured by a chromogenic anti-factor Xa assay. After oral administration of two doses of tinzaparin-loaded nanoparticles (200 and 600 anti-Xa U/kg), the oral absorption was observed between 4 and 10 or 12 h, with a delayed onset of action ranging from 3 to 4 h. Mean absolute bioavailabilities were 51% and 59% for the two tested doses. We now report that the encapsulation of tinzaparin into nanoparticles is likely to contribute to its oral efficacy with an anticoagulant effect prolonged up to 8 h.
Low molecular weight heparin gels, based on nanoparticles, for topical delivery
International Journal of Pharmaceutics, 2012
A commercial suspension of nanoparticles (Eudragit ® RS 30D) was used to manufacture a gel for topical application. Gels were prepared by mixing a polycationic polymer (Eudragit ® RS 30D) and a low molecular weight heparin (LMWH), an antithrombotic agent. Gels formed spontaneously at a ratio of 1:1 as a result of electrostatic interactions between the polyanionic drug and the polycationic polymer. Different types of heparin were used: Bemiparin, Enoxaparin (Lovenox ®), Nadroparin (Fraxiparin ®) and Tinzaparin (Innohep ®). Several LMWH concentrations were tested. Rheological measurements were performed to investigate the gel behavior. Gel formation was confirmed by dynamic rheological measurements as the elastic modulus (G) was higher than the viscous one (G). The amount of heparin incorporated into the gel matrix was determined. A maximum of incorporation (100%) was reached using a heparin solution of 600 IU/mL. The release kinetics of LMWH from the gel were also studied. Regardless of the LMWH used in the formulation, a biphasic release profile was observed. Accordingly, a burst effect was observed. Afterwards, the release rate became steady. The penetration of the LMWH through the dermal barrier was also investigated.
Development and characterization of polymer lipid hybrid nanoparticles for oral delivery of LMWH
Artificial cells, nanomedicine, and biotechnology, 2017
The present study aimed to develop an improved oral delivery system for low-molecular-weight heparin (LMWH), novel polymer lipid hybrid nanoparticles were developed. LMWH loaded chitosan polymer lipid hybrid nanoparticles (LMWH-CS-PLNs) were developed using double emulsification and solvent evaporation method. The performance of developed formulations was evaluated by using in vitro and in vivo behavior, such as drug release studies, in vitro permeation study, in vivo venous thrombolytic study, in vitro uptake studies by using intestinal epithelium resembling Caco-2 cell lines. The new CS-PLNs might provide an effective strategy for oral delivery of LMWH with improved encapsulation efficiency as compared to CS-NPs and SA-LNPs.
International Journal of Pharmaceutics, 2015
Low molecular weight heparins (LMWHs) have risen in popularity over the past decades. Owing to their appropriate pharmacokinetic profile, they enable long-term clinical applications, e.g. prophylaxis of deep vein thrombosis. Although the administration of LMWHs is not as frequent as of heparin, it still requires once daily injection at least. In order to prolong LMWH release, and thus provide less frequent subcutaneous administration, we designed and thoroughly evaluated thermoresponsive poloxamerbased systems combined with LMWH/chitosan pH-responsive nanocomplexes. A LMWH/chitosan mass ratio of 1:2 was the most appropriate for preparation of small, homogenous and stable nanocomplexes. Thermoresponsive hydrogels were examined by gelation temperature and time, thermal analysis, gel dissolution, LMWH release, and cytotoxicity in vitro. Hydrogels' behaviour was significantly shifted by gel composition e.g. the addition of hydroxypropylmethylcellulose to poloxamer-based systems decreased gelation temperature and time (from 28.6 C to 25.1 C and from 50 s to 44 s, respectively), but prolonged gel dissolution and LMWH release (7 and 4 days, respectively). Prolongation of drug release was additionally achieved with incorporation of LMWH/chitosan nanocomplexes into the gelling systems. As formulations demonstrated no cytotoxicity in vitro, it may be concluded that these double-responsive platforms are promising candidates for prolonged subcutaneous LMWH delivery during long-term treatment. 2015 Elsevier B.V. All rights reserved.
Increase in the Vascular Residence Time of Propranolol-Loaded Nanoparticles Coated with Heparin
Journal of Nanoscience and Nanotechnology, 2008
Propranolol-HCl incorporated nanoparticles prepared with a blend of a polyester and a polycationic polymer and coated or not with a low molecular weight heparin by electrostatic interactions were prepared by emulsification followed by solvent evaporation. The mean diameter was 388 and 357nm for coated and uncoated nanoparticles, respectively, and the entrapment efficiency ranged from 20 to 32%. Coated nanoparticles were negatively-charged, whereas uncoated nanoparticles displayed a positive zeta potential (+30 mV). After intravenous administration to rabbits of propranolol-HCl solution and propranolol-loaded nanoparticles coated or not with heparin, pharmacokinetic data revealed that coated nanoparticles exhibited a prolonged blood residence time. It can be concluded that the hydrophilic layer of heparin at the surface of nanoparticles conferred stealth properties which probably reduce the phagocytosis process and avoid immediate uptake by the mononuclear phagocytic system.
Development and in Vitro, in Vivo Evaluation of Controlled Release, Biocompatible Nanoparticles
2012
The intention of the study was to formulate poly (D, L-lactic-co-glycolic acid) PLGA nanoparticles containing glibenclamide and to characterize by both in vitro and in vivo method. Nanoparticles were prepared by emulsion solvent evaporation technique using methanol and dichloromethane in a ratio 2:1 as solvent with (PVA/polysorbate-80) in a fixed concentration as surfactant. The prepared nanoparticles were characterized by transmission electron microscopy (TEM), differential scanning calorimetry (DSC), stability and for in vitro drug release study. The in vivo antidiabetic study along with biochemical and haematological study was also carried out using streptozotacin induced female albino rats. Stable glibenclamide loaded PLGA nanoparticles were successfully prepared by solvent evaporation technique without any incompatibility as indicated by DSC study. The drug release from prepared nanoparticles continued for 3 days in a controlled zero order fashion. The optimised formulation was...
Journal of Pharmacy and Pharmacology, 2013
Objectives Management of blood coagulation-related diseases is currently limited by the inability to provide an adequate drug concentration in blood circulation for a long term. As a promising way to overcome this problem, the long-acting forms of these drugs have attracted many interests in recent years. Methods In this study, chitosan-heparin nanoparticles were prepared as a polymeric delivery system intended for the prolonged intravenous delivery of heparin where the drug was used as both the therapeutic agent and a gel-forming counter-ion. The nanoparticle preparation method was optimized using a Taguchi orthogonal array. Critical formulation variables were optimized in this study in terms of their corresponding effects on the target response of particle size. Nanoparticles were characterized by the Fourier transform infrared spectroscopy, transmission electron microscopy and zeta potential. Key findings The size, polydispersity index, zeta potential and encapsulation efficiency...