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. For complex programs that require specialized formulation expertise, such as solubility enhancement, modified release, or pediatric development, the challenges in achieving clinical and commercial success are even greater.
At Quotient Sciences, our scientific teams leverage our fully integrated capabilities, along with over 30 years of drug development expertise, to support our customers with challenging drug programs. Using our unique Translational Pharmaceutics® platform, we fully integrate drug substance, drug product, and clinical testing within a single organization and under a single program manager, which enables us to accelerate molecules from candidate development through to commercial product manufacturing. 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.
In this piece, we highlight case studies that explore how Translational Pharmaceutics has been applied to help overcome formulation challenges in complex drug programs and discuss the best strategies and technologies to quickly and cost-effectively get new medicines to patients in need.
Case study 1: Formulation development and screening of solubility-enhancing formulations using Translational Pharmaceutics
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. At Quotient Sciences, 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. By understanding the drivers of poor exposure to a drug, formulation efforts can be focused on appropriate techniques to 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. With Quotient Sciences’ integrated service offerings from the drug substance to the clinic, solubility enhancement can be addressed at the drug substance and drug product stage.
This case study (1) involves a poorly soluble NCE 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 these 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. These 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.
In Part 1 of the study, the Translational Pharmaceutics platform 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 of the study, higher doses were administered to establish safety margins for patient studies, and dose linearity was determined based on the area under the curve (AUC). By using the Translational Pharmaceutics approach of integrating solubility-enhancing formulation development, clinical manufacturing, and testing in humans, a new lead formulation was identified in a short timeframe of about 6 months, which overcame the solubility barriers and enabled progression of the compound into patient studies.
Case study 2: Formulation development and optimization of a modified-release (MR) dosage form to meet the target product profile (TPP) using Translational Pharmaceutics
Numerous formulation strategies are available for designing MR dosage forms. One of the key challenges when developing an MR formulation is to identify the in-vivo release rate and dose required to achieve the 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 MR 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), and surface area, and differing permeability. Similarly, there are recognized challenges and risks of using pre-clinical models to design MR formulations due to significant inter-species anatomical and physiological differences. The use of Translational Pharmaceutics, which combines formulation development, clinical manufacturing, and testing in humans, is extremely valuable in identifying the optimal platform, dose, and release rate to meet the TPP of specific molecules of interest.
In one case study, 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.
At Quotient Sciences, we carried out two studies to achieve these objectives. In the first 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.
The second study built on the results of the first study and was designed to evaluate a proprietary technology platform, DiffCORE™, from the client, with the goal of overcoming the food effect. The use of 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. This integrated Translational Pharmaceutics approach allowed multiple formulation iterations to be tested in the same individuals in both the fed and fasted state within a short timeframe, resulting in rapid identification of the most optimal formulation enabling QD dosing (2).
Case study 3: Pediatric formulation development, taste assessment, and relative bioavailability evaluation using Translational Pharmaceutics
Developing a suitable formulation is a critical requirement for drug development programs with potential pediatric indications. As young children may have difficulty swallowing tablets and capsules, special dosage forms may need to be developed depending on the age of the target population. Liquid formulations such as solutions or suspensions, multiparticulates such as granules (dispersible, dissolvable powder), or minitablets are the formulations of choice. However, the taste of these formulations needs to be considered to ensure patient compliance. Developing formulations for a pediatric population requires special consideration of the excipients. Certain excipients that are acceptable in adult dosage forms may not be acceptable in pediatric dosage forms. Depending on the age and indication, some patients may require enteral feeding by tube, so compatibility with the dosing units is an important consideration. When a medication is designed to be administered with or sprinkled on food/juices, compatibility and stability with food and taste-masking becomes critical, and suitable flavors and sweeteners may need to be a key component of the dosage form.
In one case study, the client wanted to develop an oral suspension formulation as a potential pediatric formulation for patients aged 3 months to 12 years (3). The goal was to select and identify a suitable, novel oral suspension formulation, with an optimal flavor and/or sweetener combination to improve palatability in the target population.
At Quotient Sciences, using an integrated Translational Pharmaceutics program, we carried out a two-part study to achieve these objectives. Part 1 of the study was designed to profile the taste characteristics of the API and identify a suitable flavor system. Five formulations with different flavor and sweetener combinations were compared to the reference drug suspension. Taste assessments were performed by administering formulations using the sip-and-spit technique 30 minutes apart with palate cleansing in between. The subjects filled out a questionnaire (immediately after each sip-and-spit part) to rate the overall acceptability and seven key taste characteristics (smell, sweetness, bitterness, flavor, mouth feel/texture, grittiness, and aftertaste) on a nine-point Likert scale. Statistical analysis of the data enabled the selection of the optimal formulation. Part 2 of the clinical study enabled a relative bioavailability assessment of the suspension formulation identified in Part 1 compared to the reference adult formulation (oral tablet).
Quotient Sciences has pioneered the integration of formulation development incorporating taste-masking strategies, Good Manufacturing Practice (GMP) manufacturing, and taste assessment and PK studies to meet the expectations of regulators and patients. Using this integrated Translational Pharmaceutics approach, the client was able to seamlessly enter pediatric clinical trials with a palatable drug product in a time- and cost-effective manner.
Summary
By integrating drug substance, drug product, and clinical testing activities, Translational Pharmaceutics has been proven to accelerate molecules through development. This streamlined approach seamlessly supports our customers’ programs across the full development lifecycle, from candidate development to commercial products. Key applications include:
- fast-tracking molecules from FIH to proof of concept (POC)
- development and optimization of clinical formulations, including solubility enhancement, modified release, and pediatric dosage forms
- lifecycle management of late-stage and marketed products
- evaluation of novel drug delivery technologies for all routes of administration.
The major benefit of utilizing Translational Pharmaceutics, which was quantified in a recent study published by the Tufts Center for the Study of Drug Development (CSDD), is significant time and cost savings in reaching key milestones as quickly and efficiently as possible. On average, development timelines are reduced by over 12 months, delivering financial gains of more than $200 million per approved new drug through a combination of reduced R&D costs and earlier access to commercial sales. This enables better decision-making based on human data and more streamlined outsourcing.
We are currently the only outsourcing partner able to offer the ability to develop, manufacture, release, and dose drug products within one organization. This maximizes the probability of success and significantly reduces development time and costs for our customers, getting new medicines to patients faster (4).
For more information about Quotient Sciences’ Translational Pharmaceutics platform, click here.
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. Willson A, Beville M, Schueller O, Regev G, Singh N, Kanji N. Taste Assessment Study of Belumosudil to Inform an Integrated Paediatric Formulation Development Program. Poster presented at EuPFI, September 2021.
4. DiMasi J and Wilkinson M. The Financial Benefits of Faster Development Times: Integrated Formulation Development, Real-Time Manufacturing, and Clinical Testing. TIRS, June 2020.