The use of additives to modulate the release of a sparingly water soluble drug entrapped in PLA50 microparticles: in vivo investigation.
Sustained and total release of the sparingly water soluble compound, namely 1-[2-(4-fluorobenzoyl)aminoethyl]-4-(7-methoxynaphthyl) piperazine hydrochloride (FAM), from poly (DL-lactic acid) (PLA50) microparticles was previously shown to be feasible if the particles are obtained by grinding a solid mixture composed of the polymer and a percolating array of the compound mixed with an additive. Such microparticles, where the additive was poly (ethylene glycol) (PEG), dimyristoylphosphatidylcholine (DMPC), or Poloxamer 6800, were administrated subcutaneously to rats either as depot or using a liquid vehicle. The variations of the plasma concentration vs time determined by high pressure liquid chromatography and fluorometric detection, were plotted for the various microparticle systems, blood being taken twice from each animal and each measurement being triplicated. Data were analysed by non-compartmental analysis, in order to evaluate the elimination constant, the half-life, the area under the curve and the bioavailability for each system. Kinetics experiments were performed over 24h and also for 7 days. It was found that, for the selected formulations, the release of the sparingly water soluble compound depends on the dissolution rate in vivo and on the physicochemical characteristics of the additive, including solubility and micelle formation. Data correlated well with the results of previous in vitro investigation.
Mallard
C
C
Centre de Recherches sur les Biopolymères Artificiels, UPRESA CNRS 5473, University Montpellier, Faculty of Pharmacy, France.
Coudane
J
J
Rault
I
I
Vert
M
M
D000818:Animals; D019540:Area Under Curve; D001549:Benzamides / Q000008:administration & dosage* / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D001682:Biological Availability; D002214:Capsules / Q000737:chemistry; D002626:Chemistry, Pharmaceutical; D002851:Chromatography, High Pressure Liquid; D003692:Delayed-Action Preparations; D004134:Dimyristoylphosphatidylcholine; D007275:Injections, Intravenous; D007279:Injections, Subcutaneous; D019344:Lactic Acid / Q000737:chemistry; D008297:Male; D008823:Micelles; D008863:Microspheres; D010879:Piperazines / Q000008:administration & dosage* / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D020442:Poloxamer; D011091:Polyesters; D011092:Polyethylene Glycols; D011108:Polymers / Q000737:chemistry; D051381:Rats; D017208:Rats, Wistar; D012995:Solubility; D014867:Water
D001549:Benzamides; D002214:Capsules; D003692:Delayed-Action Preparations; D008823:Micelles; D010879:Piperazines; D011091:Polyesters; D011108:Polymers; D014867:Water; D020442:Poloxamer; C092824:1-((4-fluorobenzoylamino)ethyl)-4-(7-methoxy-1-naphthyl)piperazine hydrochloride; D019344:Lactic Acid; D011092:Polyethylene Glycols; C033616:poly(lactide); D004134:Dimyristoylphosphatidylcholine