Optimizing storage stability of lyophilized recombinant human interleukin-11 with disaccharide/hydroxyethyl starch mixtures
Optimizing storage stability of lyophilized recombinant human interleukin-11 with disaccharide/hydroxyethyl starch mixtures
Published Online: 23 Dec 2003
Received: 31 July 2003; Revised: 8 September 2003; Accepted: 8 September 2003
William Garzon-Rodriguez 1, Rebecca L. Koval 2, Suchart Chongprasert 1, Sampathkumar Krishnan 1, Theodore W. Randolph 3, Nicholas W. Warne 2, John F. Carpenter 1 *
Journal of Pharmaceutical Sciences
Volume 93, Issue 3 , Pages 684 - 696
Wiley InterScience
1Center for Pharmaceutical Biotechnology, School of Pharmacy, University of Colorado Health Sciences Center, Denver, Colorado 80262
2Wyeth BioPharma, Drug Product Development Group, Andover, Massachusetts 01810
3Department of Chemical Engineering, University of Colorado, Boulder, Colorado 80302

email: John F. Carpenter (John.Carpenter@UCHSC.edu)
*Correspondence to John F. Carpenter, Center for Pharmaceutical Biotechnology, School of Pharmacy, University of Colorado Health Sciences Center, Denver, Colorado 80262. Telephone: 303-315-6074; Fax: 303-315-6281
Keywords
interleukin-11 ? proteins ? stability ? oxidation ? protein aggregation ? glass transition ? infrared spectroscopy
Abstract
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 J Pharm Sci 93:684-696, 2004
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