Evaluation of in vivo release characteristics of protein-loaded biodegradable microspheres in rats and severe combined immunodeficiency disease mice.
The in vivo release characteristics of protein-loaded biodegradable microspheres were examined in normal rats and severe combined immunodeficiency disease (SCID) mice. Bovine-derived superoxide dismutase (bSOD), encapsulated into microspheres comprised of poly(D,L-lactic-co-glycolic acid) and poly(D,L-lactic acid), was used as a model protein. Three types of bSOD-loaded microspheres with different release profiles were subcutaneously administered to normal rats. Anti-bSOD antibodies were first detected at day 9 after the administration of these microspheres, which was independent of their release profiles in vitro. A typical formulation with a sigmoidal release profile was subcutaneously administered to SCID mice. No immunoreaction was observed. The plasma bSOD concentration-time profile, determined by an enzyme-linked immunosorbent assay, well reflected the in vitro release profile of the formulation. The disappearance profile of active bSOD from the administration site also partly corresponded to both profiles. However, the relative bioavailability calculated with a profile on the subcutaneous injection of bSOD solution was 40.7%. These results indicated possible instability of bSOD released gradually at the administration site. The results of the present study using SCID mice would be suitable for discussing the in vitro-in vivo correlation of protein release from microspheres, and useful for designing long-term release formulations of protein drugs.
Morita
T
T
DDS Research Department, Discovery Research Laboratory, Tanabe Seiyaku Co., Ltd., 3-16-89 Kashima, Yodogawa-ku, 532-8505, Osaka, Japan. t-morita@tanabe.co.jp
Sakamura
Y
Y
Horikiri
Y
Y
Suzuki
T
T
Yoshino
H
H
D000818:Animals; D001673:Biodegradation, Environmental; D001682:Biological Availability; D002417:Cattle; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D016513:Mice, SCID; D008863:Microspheres; D051381:Rats; D017208:Rats, Wistar; D013482:Superoxide Dismutase / Q000008:administration & dosage* / Q000493:pharmacokinetics
D013482:Superoxide Dismutase