Solubility enhancement techniques to increase clinical success
All drug development programs are challenging, given the numerous stages an active lead molecule or new chemical entity (NCE) must transition through to gain regulatory approval and demonstrate its benefits in patients.
The challenges in achieving clinical and commercial success are even greater for complex programs requiring specialized formulation expertise, such as solubility enhancement technologies or modified release formulations.
What advantage does Translational Pharmaceutics® offer in the development of new small molecule treatments?
Translational Pharmaceutics® supports drug programs across the full development pathway, offering many benefits when it comes to the integration of CRDMO services typically found through using numerous providers, enabling a more streamlined supply chain. Where it has a distinct advantage is in optimizing clinical formulations through solubility enhancement techniques.
Using Translational Pharmaceutics®, Quotient Sciences' platform for integrated drug development, we combine integrate real-time cGMP manufacturing with clinical testing within a single organization and under the guidance of a single program manager. This approach can aid formulation design with the ability to screen a range of technologies and dosage forms using biorelevant in-vitro screening tools and physiologically based in-silico models to flag developability problems, before quickly transitioning drug candidates into human pharmacokinetic (PK) studies to understand a molecule's full potential for success.
How we apply Translational Pharmaceutics®: Formulation development and screening of solubility-enhancing formulations
Poor aqueous solubility, leading to solubility-limited exposure, has been recognized as a major challenge in the development and evaluation of NCEs during early discovery, pre-clinical, and clinical development stages. There are various formulation strategies to improve solubility, with the primary goal of improving oral bioavailability.
Our approach to solubility enhancement is based on an understanding of molecular properties, using the Developability Classification System (DCS) to choose the most appropriate formulation approach for a molecule. Understanding the drivers of poor exposure to a drug allows formulation efforts to be focused on appropriate techniques that provide meaningful improvements for in-vivo performance. We have the capability to evaluate chemical modifications, such as salt and polymorph screening, and physical modifications, such as particle size reduction, complexation, solubilization using a lipid-based approach, and stabilization using amorphous forms. Solubility enhancement can be addressed at different stages.
In one client program, a poorly soluble NCE was facing challenges of low oral exposure, non-linear PK, high variability, and a large positive food effect in the first-in-human (FIH) study. These issues were preventing the client from advancing the compound into patient studies.
To overcome the client's challenges, drug products based on three solubility-enhancing formulation platforms were developed: a micronized formulation using particle size reduction of the active pharmaceutical ingredient (API), a self-emulsifying drug delivery system using a lipid-based formulation, and an amorphous formulation using a spray-dried dispersion. The drug products were produced on a small scale for quick clinical assessment in human subjects without the need to conduct larger-scale, cost-prohibitive process development and lengthy stability programs for multiple technologies.
A two-part study was designed for the drug program:
- In part 1, Translational Pharmaceutics® enabled the integration of clinical manufacturing and dosing in healthy volunteers using a six-period cross-over design to obtain comparative human PK data from the three enabling formulations.
- In part 2, higher doses were administered to establish safety margins for patient studies, and dose linearity was determined based on the area under the curve (AUC).
Summary
Integrating solubility-enhancing formulation development, clinical manufacturing, and FIH testing using Translational Pharmaceutics®, a new lead formulation was identified for the client in about 6 months. The formulation overcame the solubility barriers and allowed the client's compound to progress to patient studies.
Quotient Sciences' scientific teams leverage integrated capabilities as a CRDMO, along with decades of drug development expertise, to support clients through the most challenging drug programs, including those requiring advanced solubility enhancement techniques to ensure clinical success.
Explore how our integrated CRDMO services and Translational Pharmaceutics® have been applied to overcome solubility challenges, making us a leading CRDMO for small molecule manufacturing.
References
1. Zann V, McKenzie L, Crowley K, Sweet-Smith S, Shabir-Ahmed A, Andreas K, Mountfield R, Milton A. A Phase I Study Allowing Clinical Screening of Multiple Solubility-Enhancement Formulation Technologies, and an Assessment of Food, PPI and Dose Linearity Assessment with the Selected Formulation of BOS172767, in Healthy Volunteers. Poster presented at AAPS meeting, November 2019.
2. Tompson D, Whitaker M, Pan R, Johnson G, Fuller T, Zann V, McKenzie L, Abbott-Banner K, Hawkins S, Powell M. Development of a Once‑Daily Modified‑Release Formulation for the Short Half‑Life RIPK1 Inhibitor GSK2982772 using DiffCORE™ Technology. Pharm. Res. 2022;39(4).doi.org/10.1007/s11095-021-03124-7.
3. DiMasi J and Wilkinson M. The Financial Benefits of Faster Development Times: Integrated Formulation Development, Real-Time Manufacturing, and Clinical Testing. TIRS, June 2020.