Anticoagulant Activity of Heparin Following Oral Administration of Heparin‐Loaded Microparticles in Rabbits

• Published in: Journal of pharmaceutical sciences Vol. 91; no. 3; pp. 760 - 768
• Main Authors: Jiao, Yuyan, Ubrich, Nathalie, Hoffart, Valérie, Marchand‐Arvier, Monique, Vigneron, Claude, Hoffman, Maurice, Maincent, Philippe
• Format: Journal Article
• Language: English
• Published: New York Elsevier Inc 01.03.2002; Wiley Subscription Services, Inc., A Wiley Company; Wiley; American Pharmaceutical Association
• Subjects: Administration, Oral; Animals; Anticoagulants - administration & dosage; Anticoagulants - pharmacology; Area Under Curve; Biological and medical sciences; Biological Availability; Blood. Blood coagulation. Reticuloendothelial system; Chemical Phenomena; Chemistry, Physical; double emulsion; Eudragit; General pharmacology; heparin; Heparin - administration & dosage; Heparin - pharmacology; Male; Medical sciences; microparticles; Microscopy, Electron, Scanning; Microspheres; oral absorption; Partial Thromboplastin Time; Particle Size; Pharmaceutical technology. Pharmaceutical industry; Pharmacology. Drug treatments; PLGA; Polymers; Rabbits; Solubility; heparin; double emulsion; microparticles; PLGA; Eudragit; oral absorption; Encapsulation; Glycolic acid copolymer; Methacrylate polymer; Pharmaceutical technology; Control release polymer; Ester polymer; Oral administration; Rabbit; Drug carrier; Anticoagulant; Bioavailability; Lagomorpha; Biological activity; Vertebrata; Lactic acid polymer; Mammalia; Absorption; Animal; Water oil water emulsion; Dosage form; Heparin sodium; Microparticle; Pharmacokinetics; Polycaprolactone
• ISSN: 0022-3549; 1520-6017
• DOI: 10.1002/jps.10097

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 μm 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. © 2002 Wiley‐Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 91:760–768, 2002