The biological activity of protein molecules is determined by their chemical structure, particularly the sequence and arrangement of amino acids, the position of terminal groups, peptide chains, and disulfide bonds. Additionally, the drug's spatial structure, including its two-dimensional and three-dimensional shapes, also plays a significant role in its activity. Proteins and peptides have molecular weights ranging from thousands to hundreds of thousands, and their particle size typically falls within the 1–100 nm range, which makes them unable to penetrate semi-permeable membranes effectively.
Protein drugs often face stability challenges both in vivo and in vitro, as they can undergo various forms of chemical degradation and physical changes, including coagulation, precipitation, racemization, hydrolysis, and deacylation. These factors may contribute to their inactivation. To enhance the stability of protein drugs, several strategies can be employed:
1.Optimizing production conditions: This includes controlling temperature, mechanical agitation, solvent choice, and aseptic conditions, along with minimizing moisture and utilizing low-temperature storage.
2.Formulation improvements: This involves selecting the appropriate pH, buffer pairs, electrolytes, and stabilizers. The use of lyophilization protectants, polymerization inhibitors like nonionic surfactants (e.g., PEG, mannitol, sorbitol), and additives such as human serum albumin can further improve stability.
Protein drugs also have absorption challenges due to their large molecular size, short half-life, high clearance, and susceptibility to degradation by enzymes and bacteria. As a result, their bioavailability via non-injection routes is often very low. For example, the bioavailability of oral leuprorelin acetate in dogs is less than 3%. To improve the absorption of protein drugs, methods such as chemical modification, precursor drug development, the use of enzyme inhibitors, absorption enhancers, and the careful selection of protective dosage forms are commonly employed.
