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Microparticles containing heparin were prepared by a water-in-oil-in-water emulsification and evaporation process with pure or blends of biodegradable (poly-epsilon-caprolactone and poly(D,L-lactic-co-glycolic acid)) and of positively-charged non-biodegradable (Eudragit RS and RL) polymers. The influence of polymers and some excipients (gelatin A and B, NaCl) on the particle size, the morphology, the heparin encapsulation rate as well as the in vitro drug release was investigated. The diameter of the microparticles prepared with the various polymers ranged from 80 to 130 microns and was found to increase significantly with the addition of gelatin A into the internal aqueous phase. Microparticles prepared with Eudragit RS and RL exhibited higher drug entrapment efficiency (49 and 80% respectively) but lower drug release within 24 h (17 and 3.5% respectively) than those prepared with PCL and PLAGA. The use of blends of two polymers in the organic phase was found to modify the drug entrapment as well as the heparin release kinetics compared with microparticles prepared with a single polymer. In addition, microparticles prepared with gelatin A showed higher entrapment efficiency, but a significant initial burst effect was observed during the heparin release. The in vitro biological activity of heparin released from the formulations affording a suitable drug release has been tested by measuring the anti-Xa activity by a colorimetric assay with a chromogenic substrate. The results confirmed that heparin remained unaltered after the entrapment process.

Heparin-loaded microparticles, prepared according to the double emulsion method with biodegradable (PCL and PLGA) and nonbiodegradable (Eudragit RS and RL) polymers used alone or in combination, with or without gelatin, were characterized in vitro and in vivo after oral administration in rabbits. The entrapment efficiency and the release of heparin were determined by a colorimetric method with Azure II. The antifactor Xa activity of heparin released in vitro after 24 h was assessed. After oral administration of heparin-loaded microparticles in rabbits, the time course of modification of the clotting time estimated by the activated partial thromboplastin time (APTT) was followed over 24 h. Microparticles with a size ranging from 80 to 280 microm were obtained. Heparin entrapment efficiency as well as heparin release depended on both the nature of the polymers and the presence of gelatin. The Eudragit polymers increased the drug loading but slowed down the heparin release, whereas gelatin accelerated the release. No change in clotting time was observed after oral administration of gelatin microparticles. Heparin-loaded microparticles prepared with blends of PLGA and Eudragit displayed a prolonged duration of action characterized by a twofold increase in APTT and a enhancement of absorption. This study demonstrated the feasibility of encapsulating heparin within polymeric particles, and the significant increase in APTT confirmed the oral absorption of heparin released from polymeric microparticles., (Copyright 2002 Wiley-Liss, Inc. and the American Pharmaceutical Association.)

Background: Owing to its short half-life and lack of oral absorption, heparin has to be administered by the parenteral route. An oral heparin formulation, however, would avoid the disadvantages of parenteral injections and would consequently be highly desirable for patients. Polymeric nanoparticles (NPs) prepared with biodegradable poly-epsilon-caprolactone (PCL) and poly(lactic-co-glycolic acid) (PLGA) and nonbiodegradable positively charged polymers (Eudragit RS and RL), used alone or in combination, were evaluated in vitro and in vivo after a single oral administration of heparin-loaded NPs in rabbits., Methods and Results: After oral administration of heparin-loaded NPs in rabbits (600 IU/kg), increases in both anti-factor Xa activity and activated partial thromboplastin time (aPTT) were detected with each formulation. Moreover, the anti-Xa activity was detected for a longer period than when a heparin solution was administered intravenously. A peak concentration of 0.16+/-0.01 IU/mL and an average aPTT of 24 seconds (2-fold increase) were obtained 7 hours after oral dosing of Eudragit RL/PCL NPs containing heparin, exhibiting an absolute bioavailability of 23%., Conclusions: The significant increases in anti-factor Xa activity and aPTT confirmed the oral absorption in rabbits of heparin released from polymeric NPs.

Nanoparticles of a highly soluble macromolecular drug, heparin, were formulated with two biodegradable polymers (poly-E-caprolactone [PCL] and poly (D, L-lactic-co-glycolic-acid) 50/50 [PLAGA]) and two nonbiodegradable positively charged polymers (Eudragit RS and RL) by the double emulsion and solvent evaporation method, using a high-pressure homogenization device. The encapsulation efficiency and heparin release profiles were studied as a function of the type of polymers employed (alone or in combination) and the concentration of heparin. Optimal encapsulation efficiency was observed when 5000 IU of heparin were incorporated in the first emulsion. High drug entrapment efficiency 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 efficiency compared with these two biodegradable polymers used alone; however, the in vitro drug release was not modified and remained low. On the other hand, the addition of esterase to the dissolution medium resulted in a significant 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.

Chemoattractant properties of human thrombin have been studied, by polymorphonuclear leucocyte migration under agarose gel, in the presence of various sulphated macromolecules such as standard heparins, low molecular weight heparins, CY216, K2165, PK10169 and pentosane polysulphate. These compounds did not attract polymorphonuclear leucocytes within the range of concentrations used, whilst thrombin alone is a cytotaxin for these cells. Addition of heparins to thrombin led to an increase in the chemoattractant activity of this enzyme for at least one of the doses studied. Augmentation of the chemoattractant activity of thrombin by heparins was shown at concentrations equivalent to those found in-vivo after administration of therapeutic doses of heparin. Pentosane polysulphate, at the studied concentrations, did not lead to a significant rise in the chemoattractant activity of thrombin.

Discusses the microencapsulation of low molecular weight heparin into polymeric particles designed with biodegradable and nonbiodegradable polycationic polymers. Advantages of low molecular weight heparin over unfractionated heparin; Range of encapsulation efficiency; Dependence of the encapsulation efficiency on the presence of the positively charged polymers.

The aim of the present work was to investigate the preparation of low molecular weight heparin (LMWH) nanoparticles (NP) as potential oral heparin carriers. The NP were formulated using an ultrasound probe by water-in-oil-in-water (w/o/w) emulsification and solvent evaporation with two biodegradable polymers [poly-ε-caprolactone, PCL and poly(d,l-lactic-co-glycolic acid) 50/50, PLGA] and two non-biodegradable positively charged polymers (Eudragit RS and RL) used alone or in combination. The mean diameter of LMWH-loaded NP ranged from 240 to 490 nm and was dependent on the reduced viscosity of the polymeric organic solution. The surface potential of LMWH NP prepared with Eudragit polymers used alone or blended with PCL and PLGA was changed dramatically from strong positive values obtained with unloaded NP to negative values. The highest encapsulation efficiencies were observed when Eudragit polymers took part in the composition of the polymeric matrix, compared with PCL and PLGA NP exhibiting low LMWH entrapment. The in vitro LMWH release in phosphate buffer from all formulations ranged from 10 to 25% and was more important (two- to threefold) when esterase was added into the dissolution medium. The in vitro biological activity of released LMWH, determined by the anti-factor Xa activity with a chromogenic substrate, was preserved after the encapsulation process, making these NP good candidates for oral administration. [ABSTRACT FROM AUTHOR]