Solubility enhancement techniques to increase clinical success
Numerous formulation strategies are available for designing modified release dosage forms, but a key challenge when developing a modified release formulation is to identify the in-vivo release rate and dose required to achieve a desired target product profile (TPP).
While in-vitro dissolution data are generated to describe formulation release, the assumption that this will represent in-vivo performance is unproven until clinical data are available. Often, with modified release formulations, a reduction in overall exposure (AUC) is observed when delivering to lower regions in the gastrointestinal (GI) tract, where absorption can be reduced. Contributing factors include reduced fluid volumes (for dissolution and solubilization), surface area, and differing permeability.
Similarly, there are recognized challenges and risks of using pre-clinical models to design modified release formulations due to significant inter-species anatomical and physiological differences.
What advantage does Translational Pharmaceutics® offer in the development of modified release formulations?
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.
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 unified approach supports formulation design by enabling the rapid screening of multiple technologies and dosage forms using biorelevant in vitro tools and physiologically based in silico models to identify potential developability challenges. Promising candidates can then be quickly advanced into human pharmacokinetic (PK) studies, providing early insight into a molecule’s full potential for clinical success.
How we apply Translational Pharmaceutics®: Optimizing a modified-release dosage form to meet a target product profile
In this client program, an NCE in development for the treatment of inflammatory diseases was being dosed twice a day (BID) or three times a day (TID) during early trials due to a short half-life and a slower terminal phase.
The client wanted to develop a once-a-day (QD) product to increase patient compliance and therapeutic outcomes. The TPP had a lower peak-to-trough ratio compared to the immediate-release (IR) product and coverage of the lowest efficacious concentration over the desired duration.
Matrix-based MR dosage forms were proposed to reduce the dosing frequency, and two clinical studies were designed to achieve these objectives:
- In the first clinical study, matrix minitablets in capsule or monolithic matrix tablets were developed and evaluated using in-vitro dissolution rates of 80% release over 8 and 12 hours. While a QD PK profile was achieved in the fasted state with the slower in-vitro dissolution rate with both types of matrix-based drug products, the formulation was susceptible to a food effect when administered with a high-fat meal. This resulted in most of the exposure occurring within the first 12 hours of dosing, which is not optimal for QD dosing.
- In the second clinical study, building on the first, a proprietary technology platform (DiffCORE™) was evaluated from the client with the goal of overcoming the food effect.
Translational Pharmaceutics® enabled the evaluation of multiple variables in this two-part adaptive clinical study, including formulation modifications, food effect, and dose levels/tablet strengths.
Flexibility was maximized by the inclusion of a two-dimensional formulation design space in the regulatory submission, which allowed quantitative changes in release rate and dosing during the clinical study to achieve the desired PK profile.
Summary
Integrating solubility-enhancing formulation development, clinical manufacturing, and FIH testing using Translational Pharmaceutics®allowed the client's compound to progress to patient studies faster. Multiple formulation iterations were tested in the same individuals in both the fed and fasted state within a short timeframe, rapidly identifying the most optimal formulation that enabled QD dosing (2).
Achieving clinical and commercial success are even greater for complex programs requiring specialized formulation expertise, such as modified release formulations, making it critical to work with an experienced CRDMO partner. Explore more about how Translational Pharmaceutics® and formulation design spaces are applied.
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.