caa a22 4500 477127436 CHVBK 20180405111654.0 cr unu---uuuuu 170330e19970401xx s 000 0 eng 10.1023/A:1012031012367 doi (NATIONALLICENCE)springer-10.1023/A:1012031012367 The Stability of Recombinant Human Growth Hormone in Poly(lactic-co-glycolic acid) (PLGA) Microspheres [Elektronische Daten] [Jeffrey Cleland, Anne Mac, Brooks Boyd, Janet Yang, Eileen Duenas, Douglas Yeung, Dennis Brooks, Chung Hsu, Herman Chu, Venkat Mukku, Andrew Jones] Purpose. The development of a sustained release formulation for recombinant human growth hormone (rhGH) as well as other proteins requires that the protein be stable at physiological conditions during its in vivo lifetime. Poly(lactic-co-glycolic acid) (PLGA) microspheres may provide an excellent sustained release formulation for proteins, if protein stability can be maintained. Methods. rhGH was encapsulated in PLGA microspheres using a double emulsion process. Protein released from the microspheres was assessed by several chromatrographic assays, circular dichroism, and a cell-based bioassay. The rates of aggregation, oxidation, diketopiperazine formation, and deamidation were then determined for rhGH released from PLGA microspheres and rhGH in solution (control) during incubation in isotonic buffer, pH 7.4 and 37°C. Results. rhGH PLGA formulations were produced with a low initial burst (<20%) and a continuous release of rhGH for 30 days. rhGH was released initially from PLGA microspheres in its native form as measured by several assays. In isotonic buffer, pH 7.4 and 37°C, the rates of rhGH oxidation, diketopiperazine formation, and deamidation in the PLGA microspheres were equivalent to the rhGH in solution, but aggregation (dimer formation) occured at a slightly faster rate for protein released from the PLGA microspheres. This difference in aggregation rate was likely due to the high protein concentration used in the encapsulation process. The rhGH released was biologically active throughout the incubation at these conditions which are equivalent to physiological ionic strength and pH. Conclusions. rhGH was successfully encapsulated and released in its fully bioactive form from PLGA microspheres over 30 days. The chemical degradation rates of rhGH were not affected by the PLGA microspheres, indicating that the internal environment of the microspheres was similar to the bulk solution. After administration, the microspheres should become fully hydrated in the subcutaneous space and should experience similar isotonic conditions and pH. Therefore, if a protein formulation provides stability in isotonic buffer, pH 7.4 and 37°C, it should allow for a safe and efficacious sustained release dosage form in PLGA microspheres. Plenum Publishing Corporation, 1997 growth hormone nationallicence stability nationallicence poly(lactic-co-glycolic acid) nationallicence microencapsulation nationallicence degradation nationallicence sustained release nationallicence Cleland Jeffrey Department of Pharmaceutical Research & Development, Genentech, Inc., South San Francisco, California aut Mac Anne Department of Pharmaceutical Research & Development, Genentech, Inc., South San Francisco, California aut Boyd Brooks Department of Pharmaceutical Research & Development, Genentech, Inc., South San Francisco, California aut Yang Janet Department of Pharmaceutical Research & Development, Genentech, Inc., South San Francisco, California aut Duenas Eileen Department of Pharmaceutical Research & Development, Genentech, Inc., South San Francisco, California aut Yeung Douglas Department of Pharmaceutical Research & Development, Genentech, Inc., South San Francisco, California aut Brooks Dennis Department of Pharmaceutical Research & Development, Genentech, Inc., South San Francisco, California aut Hsu Chung Department of Pharmaceutical Research & Development, Genentech, Inc., South San Francisco, California aut Chu Herman Department of Quality Control, Genentech, Inc., South San Francisco, California aut Mukku Venkat Department of Quality Control, Genentech, Inc., South San Francisco, California aut Jones Andrew Department of Analytical Chemistry, Genentech, Inc., South San Francisco, California aut Pharmaceutical Research Kluwer Academic Publishers-Plenum Publishers 14/4(1997-04-01), 420-425 0724-8741 14:4<420 1997 14 11095 https://doi.org/10.1023/A:1012031012367 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1023/A:1012031012367 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Cleland Jeffrey Department of Pharmaceutical Research & Development, Genentech, Inc., South San Francisco, California aut NATIONALLICENCE 700 1- Mac Anne Department of Pharmaceutical Research & Development, Genentech, Inc., South San Francisco, California aut NATIONALLICENCE 700 1- Boyd Brooks Department of Pharmaceutical Research & Development, Genentech, Inc., South San Francisco, California aut NATIONALLICENCE 700 1- Yang Janet Department of Pharmaceutical Research & Development, Genentech, Inc., South San Francisco, California aut NATIONALLICENCE 700 1- Duenas Eileen Department of Pharmaceutical Research & Development, Genentech, Inc., South San Francisco, California aut NATIONALLICENCE 700 1- Yeung Douglas Department of Pharmaceutical Research & Development, Genentech, Inc., South San Francisco, California aut NATIONALLICENCE 700 1- Brooks Dennis Department of Pharmaceutical Research & Development, Genentech, Inc., South San Francisco, California aut NATIONALLICENCE 700 1- Hsu Chung Department of Pharmaceutical Research & Development, Genentech, Inc., South San Francisco, California aut NATIONALLICENCE 700 1- Chu Herman Department of Quality Control, Genentech, Inc., South San Francisco, California aut NATIONALLICENCE 700 1- Mukku Venkat Department of Quality Control, Genentech, Inc., South San Francisco, California aut NATIONALLICENCE 700 1- Jones Andrew Department of Analytical Chemistry, Genentech, Inc., South San Francisco, California aut NATIONALLICENCE 773 0- Pharmaceutical Research Kluwer Academic Publishers-Plenum Publishers 14/4(1997-04-01), 420-425 0724-8741 14:4<420 1997 14 11095 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer