Physical stabilization of proteins in aqueous solution.
نویسندگان
چکیده
The formulation scientist’s key goal is to achieve long-term stability of a drug compound. In the case of protein drugs, stabilization means not only maintaining the native chemical structure, but the native secondary and higher order structures necessary for biological activity (Cleland et al., 1993; Manning et al., 1989). Denaturation, as it is defined in this context, will be any non-native physical or chemical state of the protein. Physical and chemical denaturations are often accompanied by covalent and non-covalent aggregates that not only can destroy the activity of the drug, but also cause adverse side effects (Carpenter and Chang, 1996; Thornton and Ballow, 1993). Without the ability to stabilize native protein structures, even the most efficacious protein therapeutics will fail to make viable drug products. How does a formulation scientist develop a formulation that stabilizes native protein structure against physical and chemical stresses in solution, and what are the relevant stresses that cause denaturation? These are the questions that this chapter will address. Although the chemical and physical stabilities of a protein may seem separate parameters, they are actually closely tied to one another (Brange, 1992; Khossravi et al., 2000; McCrossin et al., 1998; RahuelClermont et al., 1997). Physical degradation of a protein can lead to covalent changes (oxidation, hydrolysis, disulfide scrambling). The reverse is also true; reduction of disulfide bonds, hydrolysis, and other covalent changes can cause a loss of the protein native state. For chemical degradations that are linked to denaturation, formulations that stabilize the native state will necessarily stabilize against the chemical degradation. Understanding these relationships between physical and chemical stabilities are currently a major goal in formulation research.
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ورودعنوان ژورنال:
- Pharmaceutical biotechnology
دوره 13 شماره
صفحات -
تاریخ انتشار 2002