Prediction of long-term polysorbate degradation according to short-term degradation kinetics
Sisi ZhangCaterina RiccardiDane P. CarlsonDouglas E. KamenKenneth S. GrahamMohammed ShameemHanne BakHui XiaoNing Li
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Abstract:
Polysorbates (PSs) are a class of surfactants commonly used in the formulation of protein therapeutic agents to provide protection against denaturation and aggregation. When the PS in these drug formulations degrades, loss of stabilization of the protein therapeutic and formulation may occur, resulting in particulate formation or other undesirable changes in product critical quality attributes. Here, we present a simplified platform to predict long-term PS20 and PS80 degradation for monoclonal antibody drugs containing the PS-degrading enzyme lysosomal acid lipase. The platform was based on a temperature-dependent equation derived from existing PS20 degradation stability data. Accurate prediction of both PS20 and PS80 hydrolysis for as long as 2 years was achieved through short-term kinetics studies performed within 2 weeks. This platform substantially shortens the time required to determine the long-term stability of PS degradation and therefore can be used to guide the purification process and optimization of antibody formulations.Keywords:
Degradation
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For obtaining lipase of special quality,lipase-producing strains were directional screened from 27 samples which collected from extreme environments. Various strains constructed a library of lipase-proudcing strains.Among them,yeast L112’s lipase activity could reach 18.6u/ml at 20℃ and pH 5.0.As a reasult the characteristic of acid lipase was studied in this essay.The lipase activity could reach the highest at pH5.4 and 25～30℃,and survival 60% below 50℃ for 40min at pH4.8.Different metal ions showed adverse effects on the lipase activity.Mg~(2+) and Ca~(2+) enhanced the lipase activity,whereas Zn~(2+),Fe~(2+),Cu~(2+) and EDTA cause inhibition.The lipase-proudcing strain was certificated as Cryptococcus laurentii(Kufferath) C.E. Skinner by Institute of Microbiology,Acadmy of Sciences,Beijing,China.
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The effects of selected nonionic emulsifiers on the physicochemical characteristics of astaxanthin nanodispersions produced by an emulsification/evaporation technique were studied. The emulsifiers used were polysorbates (Polysorbate 20, Polysorbate 40, Polysorbate 60 and Polysorbate 80) and sucrose esters of fatty acids (sucrose laurate, palmitate, stearate and oleate). The mean particle diameters of the nanodispersions ranged from 70 nm to 150 nm, depending on the emulsifier used. In the prepared nanodispersions, the astaxanthin particle diameter decreased with increasing emulsifier hydrophilicity and decreasing carbon number of the fatty acid in the emulsifier structure. Astaxanthin nanodispersions with the smallest particle diameters were produced with Polysorbate 20 and sucrose laurate among the polysorbates and the sucrose esters, respectively. We also found that the Polysorbate 80- and sucrose oleate-stabilized nanodispersions had the highest astaxanthin losses (i.e., the lowest astaxanthin contents in the final products) among the nanodispersions. This work demonstrated the importance of emulsifier type in determining the physicochemical characteristics of astaxanthin nano-dispersions.
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The hydrolysis of oils and fats by lipases is a feasible alternative to chemical processes. The hydrolysis of babassu fat, palm oil and olive oil by fungal lipase F-AP (Amano Pharmaceutical Co.) was studied. The extent of hydrolysis and the lipolytic activity as a function of hydrolysis time (from 15 to 180 min), mass of lipase powder (from 0.20 to 2.0 mg) and pH (from 4.0 to 7.0) was evaluated. The degrees of hydrolysis obtained were: 9.0-63.8% for babassu fat, 7.9-44.2% for palm oil and 8.8-41.6% for olive oil. The specific lipase activities obtained ranged from 4.1 × 10 3 to 107 × 10 3 U/g. The higher values of enzymatic activities were obtained at low mass of lipase and low time of hydrolysis. At 0.20 mg of lipase powder (30 U), the rates of hydrolysis for the three substrates were similar. On the other hand, at 2.0 mg of lipase powder (300 U), the rate of hydrolysis of babassu fat was accelerated. No appreciable change occurred in the extent of lipolysis as pH ranged between 4.0 and 7.0
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40 strains producing lipase were isolated from rich oil soil.The lipase from 060805 has the highest activity to catalyze glycerolysis of oil.Strain 060805 was identified as Brevundimonas according to its characteristics.Lipase production conditions of Brevundimonas 060805 were studied in details.The results showed that lipase production of 060805 depended on fat and Mg2+.Some saccharides restrained lipase production.The optimal pH and temperature of the lipase were pH 6.0 and 35 ℃ respectively.Activity of lipase was no much change at 60 ℃ for 60 min,and stable from pH 5.0 to pH 8.0.
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The article is concerned with the modification of lipase with Tween-80. We can use formaldehyde or glutaraldehyde to connect Tween-80 and lipase covalently. Comparing the difference between modified lipase and nature lipase, we can get some conclusion. The results are follows: with the same concentration of formaldehyde and glutaraldehyde, the activity of lipase modified by formaldehyde is higher than lipase which was modified by glutaraldehyde; while the lipase modified by glutaraldehyde has higher connecting efficiency than lipase modified by formaldehyde. With the different concentration of formaldehyde, the modified lipase has the highest activity when the concentration of formaldehyde is 1. 25 mg · mL-1. When the pH of phosphate is higher than 7, the modified lipase has higher activity; when the pH of phosphate is lower than 7, the nature lipase has higher activity.
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