In vitro and in vivo evaluation of a somatostatin analogue released from PLGA microspheres.
The purpose of this study was to design poly(lactide-co-glycolide) (PLGA) microspheres for the continuous delivery of the somatostatin analogue, vapreotide, over 2-4 weeks. The microspheres were produced by spray-drying and the desired characteristics, i.e. high encapsulation efficiency and controlled release over 2-4 weeks, achieved through optimizing the type of polymer, processing solvent, and co-encapsulated additive. The in vitro release was tested in fetal bovine serum preserved with 0.02% of thiomersal. Furthermore, formulations were injected intramuscularly into rats to obtain pharmacokinetic profiles. Encapsulation efficiency was between 34 and 91%, depending on the particular formulation. The initial peptide release (within 6 h) was lowest, i.e. <20%, when acetic acid was used as processing solvent and highest, i.e. 57%, with dichloromethane. The various co-encapsulated additives generally lowered the encapsulation efficiency by 15-30%. The best formulation in terms of low burst and effective drug serum levels (>1 ng/ml) over 21-28 days in rats was the one made with end-group uncapped PLGA 50:50, the solvent acetic acid and the additive polyethyleneglycol. In conclusion, the optimization of formulation parameters allowed us to produce vapreotide-loaded PLGA microspheres of suitable characteristics for therapeutic use.
Blanco-Príeto
M J
MJ
Institute of Pharmaceutical Sciences, ETH Zürich, Winterhurerstr. 190, 8057, Zürich, Switzerland.
Besseghir
K
K
Zerbe
O
O
Andris
D
D
Orsolini
P
P
Heimgartner
F
F
Merkle
H P
HP
Gander
B
B
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000032:analysis / Q000493:pharmacokinetics; D002151:Calorimetry; D002851:Chromatography, High Pressure Liquid; D003692:Delayed-Action Preparations; D004337:Drug Carriers; D004339:Drug Compounding; D005079:Excipients; D007273:Injections, Intramuscular; D019344:Lactic Acid; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008863:Microspheres; D010316:Particle Size; D011091:Polyesters; D011100:Polyglycolic Acid; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011108:Polymers; D051381:Rats; D017207:Rats, Sprague-Dawley; D013004:Somatostatin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000032:analysis / Q000493:pharmacokinetics
D000970:Antineoplastic Agents; D003692:Delayed-Action Preparations; D004337:Drug Carriers; D005079:Excipients; D011091:Polyesters; D011108:Polymers; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; C051458:vapreotide; D019344:Lactic Acid; C033616:poly(lactide); D013004:Somatostatin