Optimizing Storage Stability of Lyophilized Recombinant Human Interleukin-11 with Disaccharide/Hydroxyethyl Starch Mixtures

Optimal storage stability of a protein in a dry formulation depends on the storage temperature relative to the glass transition temperature (Tg) of the dried formulation and the structure of the dried protein. We tested the hypothesis that optimizing both protein structure and Tg—by freeze-drying re...

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Bibliographic Details
Published in:Journal of pharmaceutical sciences 2004-03, Vol.93 (3), p.684-696
Main Authors: Garzon-Rodriguez, William, Koval, Rebecca L., Chongprasert, Suchart, Krishnan, Sampathkumar, Randolph, Theodore W., Warne, Nicholas W., Carpenter, John F.
Format: Article
Language:English
Subjects:
Biological and medical sciences
Disaccharides - analysis
Disaccharides - chemistry
Drug Stability
Drug Storage
Freeze Drying - methods
General pharmacology
glass transition
Humans
Hydroxyethyl Starch Derivatives - analysis
Hydroxyethyl Starch Derivatives - chemistry
infrared spectroscopy
interleukin-11
Interleukin-11 - analysis
Interleukin-11 - chemistry
Medical sciences
oxidation
Pharmaceutical technology. Pharmaceutical industry
Pharmacology. Drug treatments
protein aggregation
proteins
Recombinant Proteins - analysis
Recombinant Proteins - chemistry
stability
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Summary:Optimal storage stability of a protein in a dry formulation depends on the storage temperature relative to the glass transition temperature (Tg) of the dried formulation and the structure of the dried protein. We tested the hypothesis that optimizing both protein structure and Tg—by freeze-drying recombinant human interleukin-11 (rhIL-11) with mixtures of disaccharides and hydroxyethyl starch (HES)—would result in increased storage stability compared with the protein lyophilized with either disaccharide or hydroxyethyl starch alone. The secondary structure of the protein in the dried solid was analyzed immediately after lyophilization and after storage at elevated temperatures by infrared spectroscopy. After rehydration, aggregation was monitored by size exclusion chromatography. Oxidation levels and cleavage products were quantified by reversed-phase chromatography. For the formulation with HES alone, which has a relatively high Tg, storage stability of rhIL-11 was poor, because HES failed to inhibit lyophilization-induced unfolding. The sugar formulations inhibited unfolding, and had intermediate Tg values and storage stabilities. Addition of hydroxyethyl starch to sucrose or trehalose increased Tg without affecting the capacity of the sugar to inhibit protein unfolding during lyophilization. Optimal storage stability of lyophilized rhIL-11 was achieved by using a mixture of disaccharide and polymeric carbohydrates. © 2004 Wiley-Liss, Inc. and the American Pharmacists Association
ISSN:0022-3549
1520-6017
DOI:10.1002/jps.10587