In vitro and in vivo release of poly(DL-lactic acid) microspheres containing neurotensin analogue prepared by novel oil-in-water solvent evaporation method.
Poly(DL-lactic acid) (PLA) microspheres containing a neurotensin analogue [NA; H(CH3)-Arg-Lys-Pro-Trp-tert-Leu-Leu-OEt.3HCl] were prepared by a novel oil-in-water (o/w) solvent evaporation method, and the release behaviors were evaluated in vitro. About 20% of the loaded NA was released initially, and the subsequent release lasted for a month from microspheres prepared with PLA of molecular weight 2000 (PLA 2000). A smaller initial release from PLA 4000 and PLA 6000 microspheres was found, but a lag time of 2-3 weeks during which the drug was not released was observed with PLA 4000 and PLA 6000 microspheres. The addition of relatively hydrophilic monoglycerides decreased the lag time, and a fairly constant release of NA was achieved. The pharmacokinetic behavior of NA from PLA 2000 microspheres was studied in rats. The release of the drug after a subcutaneous injection exhibited pseudo-zero-order kinetics for 1 month. The initial release of the drug from the microspheres was reflected in a sharp increase of the plasma levels of the de-ester form of NA [H(CH3)-Arg-Lys-Pro-Trp-tert-Leu-Leu-OH], and the subsequent steady-state levels agreed well with the predicted levels obtained from analysis of constant-infusion kinetics.
Yamakawa
I
I
Tsukuba Research Laboratories, Eisai Company, Ltd., Ibaraki, Japan.
Tsushima
Y
Y
Machida
R
R
Watanabe
S
S
D000595:Amino Acid Sequence; D000818:Animals; D003692:Delayed-Action Preparations; D006863:Hydrogen-Ion Concentration; D007279:Injections, Subcutaneous; D007773:Lactates; D019344:Lactic Acid; D008297:Male; D008863:Microspheres; D008969:Molecular Sequence Data; D009479:Neuropeptides / Q000493:pharmacokinetics*; D009842:Oligopeptides / Q000493:pharmacokinetics*; D011091:Polyesters; D011108:Polymers; D051381:Rats; D017208:Rats, Wistar
D003692:Delayed-Action Preparations; D007773:Lactates; D009479:Neuropeptides; D009842:Oligopeptides; D011091:Polyesters; D011108:Polymers; C068195:methylarginyl-lysyl-prolyl-tryptophyl-tert-leucyl-leucyl-ethyl ester; D019344:Lactic Acid; C033616:poly(lactide)