Large molecule drug products produce highly effective medicines, but formulation can be challenging because of their complexity, sensitivity, and potential for instability. It is crucial that formulation strategies ensure their bioavailability and efficacy to develop new and successful products.
Protein stabilization techniques
Temperature, pH, agitation, and oxidation can degrade the stability of large molecules. Methods for counteracting that potential include pH adjustment, optimizing the pH of the formulation, buffer selection, excipients, and protein engineering. It is critical that pre-formulation screening includes selecting the right counterion and its concentration to support the stability profile of the biologic. A pH condition, for example, can be created with different buffer excipients and compositions.
Excipients can stabilize the effect of pH on the chemical stability of a protein, but selecting the appropriate agent is challenging because of the limited number of substances approved for such use. Buffer excipients, such as salts and amino acids, increase ionic strength and minimize electrostatic interactions between protein molecules.
Excipient selection
Common excipients include stabilizers, tonicity modifiers, and preservatives. Stabilizers are primarily buffers, salts, amino acids, polyols, disaccharides, polysaccharides, surfactants, and antioxidants. The native conformation of biologics can be maintained with high concentrations of saccharides like sucrose, trehalose, and lactose, as well as polyhydric alcohols such as sorbitol, mannitol, and polyethylene glycol. Adjusting the tonicity of the formulation with salts or sugar alcohols helps preserve protein stability.
Approximately one-third of multidose biological products require antimicrobial preservatives to avoid microbial growth , usually m-cresol, benzyl alcohol or phenol, phenoxyethanol, or chlorobutanol. When testing preservatives, they should be evaluated both alone and in combination before making a selection.
Lyophilization
Lyophilization, or freeze-drying, is widely used to stabilize large molecule drugs and extend their shelf life. Cryoprotectants circumvent degradation or disassociation during the process, and most include monosaccharides, polysaccharides, or polyols. The importance of their quality cannot be overstated, as impurities negatively impact freezing, sublimation, and stability.
Understanding the resistance of the product, heat flow, and the temperature at the sublimation interface is crucial to a product’s long-term stability. It enables researchers to establish and verify an optimized primary drying cycle quickly and devote more time to other value-added features.
Finally, the freezing rates and temperatures of vials are factors. Inconsistent moisture content and closure collapse compromises product homogeneity and yield, extending the time frame to correct errors and, it follows, incurring additional costs.
Delivery systems
Large molecule drugs sometimes require specialized delivery systems, including liposomes, microspheres, nanoparticles, and transdermal patches. Liposomes are phospholipid-based vesicles that can encapsulate and transport large molecules. Used in many pharmaceutical products, they are non-toxic, biodegradable, and non-immunogenic. They can also serve as a drug reservoir, alter the pharmacokinetics of the drug, and reduce toxicity while protecting the drug from premature degradation or inactivation after entering the body.
Few sustained-release delivery systems have been approved for larger proteins, but microspheres enable sustained release for up to six months and serve as a model that can be applied to various other therapeutics. Nanoparticles allow modifications that enhance drug half-life and targeted delivery to specific tissues through interactions with the microenvironment and minimize side effects.
Novel formulation approaches
Innovative approaches to drug formulation include microneedles and inhalation delivery. Microneedle arrays deliver medications through the skin via a patch with numerous tiny needles loaded with medicine. They do not reach the nerves, so delivery is painless, and they do not require refrigeration or special disposal methods, making them suitable for at-home use. This also is a boon to low-resource communities with limited access to providers or traditional storage facilities. Another highly promising area of research is formulating biologics as solids that enable noninvasive administration through simple inhalation.
Multiple stages of development require multiple levels of insight
Drug formulation is never simple, and large molecule products present an even higher bar for clearance. The factors that play a role in stabilization, shelf life, and delivery are key to developing new medicines that reach their targets with ever higher levels of precision and effectiveness. A process that is, in fact, a series of initiatives and ideas can only be helped by engaging with professionals who are thoroughly experienced in every stage, from the first idea’s development in the lab to placing the finished product on the store shelf. Every stakeholder makes an investment and real ROI is determined by how many people suffer less or, better yet, recover faster or even completely because of the dedication and collaboration of all. Partner with a Syner-G expert.