Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.5.1.1 (asparaginase)
 2,695 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The antileukemia enzyme, Erwinia L-asparaginase, occurs as a tetramer which can be dissociated by the stresses of lyophilization into four subunits (subunit M(r) 34 000 Da). Dissociation can be reduced by adding protectants to the formulation to stabilize the biopolymer, while the product should dry to form a pharmaceutically elegant, shelf-stable cake which is readily soluble. Using analytical ultracentrifugation, HPLC, and circular dichroism we have related structural dissociation of the enzyme during lyophilization to biological activity. Additives such as mannitol prevent ablation loss of vial contents and dry to form cosmetically elegant cakes but provide little biological protection, since during freezing they crystallize and are removed from the preparation. Excipients persisting throughout the cycle in the amorphous state provide improved biological protection, although high molecular weight compounds such as Dextran (M(r) 70000 Da) are most effective only during product freezing or storage. Low molecular weight sugars are protective throughout the cycle although formulations containing monosaccharides often exhibit low collapse temperatures (Tc) measured using a freeze-drying microscope or glass transition temperatures (Tg') measured by thermal analysis, but these formulations distort as drying progresses to form a collapsed, cosmetically unacceptable cake, with reduced activity, poor stability, a high moisture content, and reduced solubility. Collapse can be avoided by formulating with disaccharides, which display higher Tc temperatures than monosaccharides, or drying below Tc. Dried samples which persist in the amorphous state can also collapse when stored above their solid-state collapse temperatures when they decay at a faster rate than predicted by Arrhenius kinetics. The solid-state collapse temperature can be significantly decreased by the diffusion of moisture from the stopper into the dry product resulting in an increase in sample water content. Lyophilization cycle times can be reduced by analyzing collapse characteristics so that the relationship between product temperature and chamber pressure can be controlled so that drying rates can be optimized while ensuring that the product does not melt or collapse during sublimation.
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PMID:Optimizing the lyophilization cycle and the consequences of collapse on the pharmaceutical acceptability of Erwinia L-asparaginase. 896 Nov 43