Parenteral Delivery of Peptides and Proteins - Challenges in Delivery of Therapeutic Genomics and Proteomics - page 539

Figure 11.3 Various degradative pathways for P/P drugs.
stability of a pharmaceutical protein can be impaired during deamidation, isomeriza-
tion, hydrolysis, racemization, oxidation, disulfide formation, and -elimination. Figure
11.3 illustrates various modes of chemical and physical degradation of P/P drugs.
Physical stability is generally defined as the ability of a protein to retain at least
its tertiary structure crucial for the biological activity. Briefly, physical degrada-
tion involves reversible or irreversible denaturation through a loss of tertiary struc-
ture and unfolding with further reactions like chemical degradation, aggregation, and
precipitation.
The pharmaceutical efficacy of therapeutic proteins (and hence their three-dimen-
sional integrity) should be assessed by monitoring the biological activity at the end
of the formulation process. Also, the control of antigenicity is needed to guarantee
the efficacy of protein therapeutics like vaccines or to exclude any protein degrada-
tion (as aggregation often causes increased antigenicity) [82] . When designing any
delivery system, protein stability is a serious problem in pharmaceutical research
during the manufacturing and storage of P/P drugs. Ideally, in vitro-in vivo correla-
tion and a structural analysis of a protein should be done to ensure its stability in the
formulation. A strong emphasis is placed on factors responsible for instability and
stabilization techniques [83-95] .
For protein degradation to be preferentially avoided or at least reduced, an accu-
rate stabilization rationale is required. The influence of process parameters should
also be evaluated. However, most of the time, it is not possible to adopt a general
strategy for all proteins [96,97] .
Stabilizing additives used in the formulation of proteins are diverse and include pro-
teins, sugars, polyols, amino acids, chelating agents, and inorganic salts. These addi-
tives can stabilize proteins in solutions as well as in frozen and dried states, although
not all the additives confer stability on the protein or peptide under all three conditions.
The stabilization mechanism in a frozen state differs from that which occurs in the dried
state, and carbohydrates in particular have the ability to stabilize in the dried state when
compared with the liquid state. A stable liquid protein formulation is a prerequisite