Blog Post 2: Overcoming Formulation Challenges in Targeted Protein Degraders


The pharmaceutical industry is increasingly focusing on the development of protein degraders, particularly Proteolysis Targeting Chimeras (PROTACs), as a novel therapeutic approach. These small molecules have shown great promise in targeting disease-causing proteins for degradation. However, their development faces significant formulation challenges, particularly in terms of permeability and bioavailability.

This post delves into these challenges, and discusses how SeraNovo's eutectic technology has significantly enhanced the bioavailability of these molecules.

The Challenge of Size and Permeability

One of the primary challenges in formulating PROTACs is overcoming their bioavailability limitation imposed on by their relatively large size. PROTAC molecules typically have molecular weights exceeding 700-900 (g/mol), far above the 500 (g/mol) set by Lipinski’s rule of five. A large size can concomitantly bring a large polar surface area which negatively impacts the permeability through cell membranes. Moreover, large molecules tend to be good substrates for permeability-glycoprotein (P-gp)-mediated efflux. These combined effects greatly limit the amount of API that permeates through, and whatever permeates through is pumped out the cell efficiently.

The Challenge of Solubility

A poor aqueous solubility can also be a major contributor to inadequate bioavailability. Solubility-limited bioavailability is a product of the dose, permeability and aqueous solubility. In other words, the aqueous solubility is insufficient to dissolve the required dose during the absorptive window. As PROTACs are poorly permeable, the required aqueous solubility should be even higher when compared to permeable APIs (for the same dose). Unfortunately, PROTACs typically have solubility values in intestinal conditions of <10 µg/mL, albeit VHL-based or CRBN-based.  

SeraNovo's Eutectic Technology: A Game Changer

 

SeraNovo has effectively addressed the formulation challenges associated with PROTACs through its expertise in formulating highly crystalline, poorly soluble, and high melting point small molecules. We utilize the eutectic phenomenon, creating FDA-approved excipient combinations that are immiscible in their solid state but become liquid upon exposure to biorelevant conditions, aiding in hydration and dissolution. Additionally, we incorporate permeability-enhancers into these eutectic mixtures, offering a comprehensive solution to enhance the formulation of PROTACs and other protein degraders.

 

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