Oral low molecular weight heparin delivery by microparticles from complex coacervation.
As low molecular weight heparins exhibit limited oral absorption they usually have to be administered parenterally. Their strong negative charge appears to be one of the biggest hurdles to overcome in order to increase oral absorption. Complex coacervation has been proposed as a microencapsulation technique for increased oral drug absorption on the basis of charge compensation. Optimized tinzaparin/acacia gum mixture were coacervated with either gelatin A or B leading to microparticles with monodispersed size distribution, good fluidity and high encapsulation rates (>90%), while mean particle size varied between 5 and 20 microm, respectively, depending on the gelatin type. Tinzaparin was homogeneously distributed throughout the particle matrix and anti-Xa activity was maintained during preparation and storage. Drug release occurred in dependency of the pH triggering the dissociation between tinzaparin/acacia and gelatin. Cell binding experiments on Caco-2 led to slightly increased adhesion of gelatin A microparticles compared to gelatin B (A: 3.5+/-0.3%; B: 2.5+/-0.3%; solution: 1.9+/-0.1%), while drug transport did not differ from free tinzaparin solution. In-vivo results demonstrated an oral bioavailability of about 4.2+/-2.9% with gelatin B particles while gelatin A led to no absorption of tinzaparin. In conclusion, tinzaparin microparticles exhibited excellent particle properties in vitro and demonstrate potential for a formulation increasing the oral bioavailability of low molecular weight heparins.
Lamprecht
Alf
A
Laboratory of Pharmaceutical Engineering, University of Franche-Comté, Besançon, France. alf.lamprecht@univ-fcomte.fr
Ubrich
Nathalie
N
Maincent
Philippe
P
D000818:Animals; D000925:Anticoagulants / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D018938:Caco-2 Cells; D002448:Cell Adhesion; D055598:Chemical Phenomena; D002626:Chemistry, Pharmaceutical; D002627:Chemistry, Physical; D016503:Drug Delivery Systems; D005079:Excipients; D005780:Gelatin; D006170:Gum Arabic; D006495:Heparin, Low-Molecular-Weight / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008297:Male; D018613:Microscopy, Confocal; D008855:Microscopy, Electron, Scanning; D053758:Nanoparticles; D010316:Particle Size; D011817:Rabbits; D013050:Spectrometry, Fluorescence; D000078222:Tinzaparin
D000925:Anticoagulants; D005079:Excipients; D006495:Heparin, Low-Molecular-Weight; D000078222:Tinzaparin; D006170:Gum Arabic; D005780:Gelatin