Sustained release of recombinant human insulin-like growth factor-I for treatment of diabetes.
Recombinant human insulin-like growth factor-I (rhIGF-I) was found to improve glycemic control and enhance insulin sensitivity in patients with a syndrome of severe insulin resistance. Therefore, the protein may be considered as an alternative therapy in the treatment of diabetes when the patients become insensitive to insulin treatment. Because the protein was administered twice per day in the clinical trials, a sustained release polylactic-co-glycolic acid (PLGA) formulation for rhIGF-I with low initial burst (<20%), maximum possible protein loading (15-20%) and a continuous release of 1-2 weeks may provide greater patient convenience and compliance. The protein was encapsulated in PLGA for sustained release using a spray freeze-drying technique. Formulation parameters such as protein loading, polymer end group, and the presence of zinc carbonate were studied for their effects on in vitro release of rhIGF-I from PLGA microspheres. As the protein loading was increased, the initial burst increased. Due to the hydrophilic properties of the polymers, rhIGF-I encapsulated in unblocked PLGA (free acid end groups) gave a lower initial burst and a more steady-state release profile than the blocked PLGA (hydrocarbon end groups) with the same protein loading and PLGA molecular weight. At 15% w/w protein loading, the addition of 6% w/w zinc carbonate as a protein release modifier to the unblocked PLGA (12 kDa) decreased the initial burst of rhIGF-I. Therefore, a formulation consisting of 15% rhIGF-I and 6% zinc carbonate in 12 kDa, unblocked 50:50 PLGA can provide the required release characteristics in vitro. Rat studies revealed that rhIGF-I in this formulation was released in vivo at a rate which was comparable to that observed in vitro. These studies demonstrate the potential for a sustained release, 14-day formulation for rhIGF-I.
Lam
X M
XM
Department of Pharmaceutical Research and Development, Genentech, Inc., South San Francisco, CA 94080, USA. lam.xanthe@gene.com
Duenas
E T
ET
Daugherty
A L
AL
Levin
N
N
Cleland
J L
JL
D000818:Animals; D002254:Carbonates / Q000737:chemistry; D003692:Delayed-Action Preparations; D003920:Diabetes Mellitus / Q000188:drug therapy* / Q000235:genetics; D004339:Drug Compounding; D005260:Female; D007334:Insulin-Like Growth Factor I / Q000008:administration & dosage* / Q000378:metabolism / Q000627:therapeutic use*; D019344:Lactic Acid; D008855:Microscopy, Electron, Scanning; D008863:Microspheres; D011100:Polyglycolic Acid; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011108:Polymers; D051381:Rats; D017207:Rats, Sprague-Dawley; D011924:Rats, Zucker; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000627:therapeutic use; D017967:Zinc Compounds / Q000737:chemistry
D002254:Carbonates; D003692:Delayed-Action Preparations; D011108:Polymers; D011994:Recombinant Proteins; D017967:Zinc Compounds; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D007334:Insulin-Like Growth Factor I; C036650:zinc carbonate