the challenge

Protein solubility ranges from low micrograms per ml to several hundreds of milligrams per ml and is very compound-specific. Most antibodies are known to reach solubilities of hundreds of mg per ml, whereas beta amyloid protein has very low solubility. Small structural changes could lead to significant changes in solubility, for example, cryo-immunoglobulins may be almost insoluble. Also, the dose and route of administration may demand a higher concentration than possible in simple formulations, posing a challenge to the development of a clinically or commercially viable product.

One important challenge is that proteins are typically administered via injections due to poor bioavailability by other delivery modes, which restricts the types and levels of excipients. Further constraints are imparted by the small volume of administration appropriate for subcutaneous and intramuscular delivery routes which need to be consistent with patient compliance and ease of delivery. This can be very different from the volume/ concentration constraints of intravenous administration.

For therapeutic doses in the mg/kg levels, the less than approximately 1.2 mL acceptable volume for subcutaneous delivery may necessitate formulations containing hundreds of mg/mL protein. Moreover, toxicological studies may assess approximately 10- fold higher doses than those planned for clinical studies in order to establish a safety window. This necessitates even higher concentrations for non-clinical formulations than for clinical formulations.

the answer

Working in close collaboration with key client's in the biopharmaceutical arena, Synectix Pharmaceutical Solutions Ltd have developed a novel high-throughput platform for the rapid screening and identification of sterile liquid and aqueous freeze-dried formulations for parenteral delivery of therapeutic peptides and proteins.

The screening program employs the key benefits of the original Solent™ Array (namely high-throughput formulation screening on small sample masses) with a proprietary formulation matrix consisting of GRAS excipients and solvents suitable for parenteral administration. The matrix has been specifically designed so that each successful formulation composition identified can easily undergo sterile filtration and formulation processing to produce stable liquid solutions for direct injection or suitable for freeze-drying and subsequent reconstitution with Water For Injection (WFI).

Supporting the high throughput formulation screening capabilities, we can also perform detailed biophysical analysis on the active material pre and post formulation to determine the relationship between structure and function/activity, essential for rapid and effective formulation development.

Key Scientific Benefits Include:

1. In-vitro testing of injectability using a novel micro-viscocity measurement technique
2. Highly concentrated solutions can be analysed without the need for dilution. This allowa for analysis to be provided at concentrations close to clinical doses and is more representative of "real world" situations.
3. In many cases the techniques are non-destructive so, in principal, multiple measurements may be made from the same sample, reducing the volume of material needed.
4. Analysis is generally non-perturbing and does not affect the sample during the measurement process. As a result, there is a greater chance of detecting aggregates, therefore forewarning manufacturers of any potential immunogenic and processing concerns.
5. The sampling conditions are representative of the "real" environment experienced by a protein therapeutic and results better demonstrate the effects of molecular interaction.
6. Small sample sizes, down to microlitres, can easily be examined. Consequently, the toolkit is particularly useful in the very early stages of development where the cost of producing clinical trial grade samples prohibits extensive analysis.
7. Extensive characterisation and better understanding of your protein will strengthen your case when dealing with the regulatory authorities.

For more information about the Solent-Bio™ Array or to request a project evaluation, please contact us directly.