Introduction
Protein-based drugs have revolutionized the field of biopharmaceuticals, offering highly effective treatments for various diseases. However, these complex molecules are inherently unstable outside of their natural biochemical environment, making their formulation and stabilization crucial for ensuring their quality, safety, and efficacy. Excipients play a vital role in enhancing the manufacturability, stability, and delivery of these drugs. This article provides a detailed overview of the excipients commonly used in protein-based drugs, their mechanisms of action, and the challenges associated with their selection and use.
Excipients Used in Protein-Based Drugs
Excipients are substances added to pharmaceutical formulations to enhance their stability, solubility, and bioavailability. In the case of protein-based drugs, excipients are used to prevent aggregation, denaturation, and degradation of the protein molecules. The most commonly used excipients in protein formulations include buffers, salts, amino acids, polyols/disaccharides/polysaccharides, surfactants, and antioxidants.
Mechanisms of Action
Excipients interact with proteins through various mechanisms to prevent aggregation and degradation. For instance, buffers control the pH of the solution, which is critical for protein stability. Salts and amino acids increase the ionic strength of the solution, minimizing electrostatic interactions between protein molecules. Polyols/disaccharides/polysaccharides stabilize proteins through preferential hydration or preferential exclusion, allowing the rearrangement and stabilization of a hydrate shell around the protein surface. Surfactants protect proteins against interaction with hydrophobic surfaces, while antioxidants prevent oxidation.
Challenges in Excipient Selection
The selection of excipients for protein-based drugs is a complex task due to the limited number of approved excipients. The quality of excipients can have a significant impact on protein stability, and the use of non-compendial excipients can lead to unexpected issues during manufacturing and storage. Additionally, the introduction of novel excipients requires additional safety data, which can be a significant resource and time commitment.
Alternative Excipients
In recent years, there has been a growing need for alternative excipients to polysorbates, which have been widely used for their efficiency in protecting protein integrity. However, the presence of peroxides in polysorbates can compromise protein stability during storage. Alternative excipients such as alkylsaccharides, sucrose esters, and sugar monoesters have shown promise in improving the surface-active properties of excipients and enhancing protein stability.
Conclusion
Excipients play a critical role in the formulation and stabilization of protein-based drugs. The selection of excipients must be based on a thorough understanding of their mechanisms of action, compatibility with the protein and other formulation components, and the manufacturing process. The use of alternative excipients and excipient mixtures can provide a viable option for enhancing protein stability and reducing the risk of adverse reactions. As the biopharmaceutical industry continues to evolve, the development of novel excipients and formulations will be crucial for ensuring the quality, safety, and efficacy of protein-based drugs.
“The quality of the excipients can have a dramatic impact on protein stability. For example, common surfactants such as polysorbates are well known to contain trace amounts of peroxides that can become significant during storage and consequently compromise protein stability through oxidation of susceptible amino acids, particularly exposed methionine.” – Kang
References
- High Throughput Screening of Protein Formulation Stability: A List of Commonly Used Excipients
- Excipient Selection for Protein Stabilization
- Interactions of Formulation Excipients with Proteins in Solution and in the Dried State
- Alternative Excipients for Protein Stabilization in Protein Therapeutics
- A Comprehensive Scientific Survey of Excipients Used in Currently Approved Biotechnology-Derived Drug Products
