Antibody formulations
a technology of antibodies and formulations, applied in the direction of antibody medical ingredients, drug compositions, peptides, etc., can solve the problems of chemical instability, physical instability, special problems in the formulation of such proteins
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example 1
Effects of Excipient Solubility on mAb Stability in Frozen Trehalose Formulations
[0280]This study was designed to assess the effects of freeze rate, storage temperature, and formulation composition on trehalose phase distribution and protein stability in frozen solutions. In addition to elucidating the phase distribution of trehalose crystallization in frozen solutions, the results of this study have numerous practical implications. Presumably, the effectiveness of trehalose as a stabilizer of proteins depends on the phase distribution of trehalose in solution. Thus, understanding the phase distribution of trehalose that result from different compositions, freeze rates, and storage temperatures inform the development of robust formulations and freeze processes.
[0281]Materials and Methods
Materials and Sample Preparation
[0282]Three IgG1 full length monoclonal antibodies (mAb1, bevacizumab, and mAb3) with an approximate molecular weight of 145 kilodatons were cloned, expressed in Chine...
example 2
Effects of Excipient Crystallization on mAb Stability in Frozen Trehalose Formulations
[0302]Crystallization of carbohydrates during freezing, freeze-drying, and frozen storage has been shown to impact the physical stability of protein drugs. For example, mannitol has been shown to crystallize during freeze-drying and result in conformational changes, aggregation, and loss of activity for various proteins (Sharma, V. K. and Kalonia, D. S. (2004) AAPS Pharm Sci Tech. 5:E10; Cavatur, R. K., et al. (2002) Pharm. Res. 19:894-900); Izutsu, K., et al. (1994) Chem. Pharm. Bull. (Tokyo) 42:5-8); and Izutsu, K., et al. (1993) Pharm. Res. 10:1232-7). Although at <40° C. trehalose is more soluble than mannitol, it is significantly less soluble than sucrose, which is generally regarded as a non-crystallizing excipient (FIG. 2A).
[0303]To evaluate the effects of excipient solubility on protein stability in frozen solutions, bevacizumab solutions were prepared with equivalent concentrations of sucr...
example 3
Effects of Freezing Rate on mAb Stability in Frozen Trehalose Formulations
[0305]The SEC data for the three mAb formulations demonstrated that freezing rate does impact protein stability (see Table 1 below).
TABLE 1Summary of trehalose phases after 12 months frozen storageΔCrystallizedAmorphousTotalAggregationTrehaloseTrehaloseTrehaloseFreeze(%)(% wt / v)(% wt / v)Protein(% wt / v)Rate−20° C.−14° C.−8° C.−20° C.−14° C.−8° C.−20° C.−14° C.−8° C.mAb12.1Fast0.10.60.20.20.10.21.81.91.9Normal0.00.00.10.00.10.12.02.02.1Slow0.00.00.10.00.00.02.02.02.1Bevacizumab5.4Fast1.71.40.42.52.51.63.02.93.8Normal0.10.00.10.30.30.35.15.15.2Slow0.20.20.10.30.30.25.15.25.2mAb38.2Fast3.12.10.95.15.75.53.22.52.7Normal0.00.00.10.10.50.28.17.78.0Slow0.00.00.10.30.20.27.98.18.0
[0306]In general, the monoclonal antibodies aggregated following freezing at the fast rate (>100° C. / min) and did not aggregate at the slower freezing rates (100° C. / min) showed significant increases in aggregation over time (Table 1). Even fas...
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