In early development, the main goal for a new chemical entity (NCE) is to demonstrate proof of concept (POC) in patients in the most time- and cost-effective way possible. Typically, simple, fit-for-purpose formulations are used in first-in-human (FIH) studies, in order to minimize upfront development time and CMC (chemistry, manufacturing, and controls) costs prior to generating clinical safety and pharmacokinetic (PK) data. However, given the increasing number of poorly soluble active pharmaceutical ingredients (APIs) in the industry development pipeline, this approach has limitations, especially where enabling formulation technologies may be required to ensure adequate bioavailability. Relying on surrogate tools to predict human exposure presents risks, and there is a high probability that a bridging study to a suitable dosage form will be needed prior to the patient POC trial. This points to a need for a more streamlined strategy for the development of poorly soluble molecules.
With over 30 years of experience, the team at Quotient Sciences has established a broad suite of technologies and formulation strategies to address complex solubility challenges, including particle size reduction (micronization), spray-dried dispersions (SDDs), hot melt extrusion (HME), and lipid-based formulations. Using our unique Translational Pharmaceutics® platform, which integrates drug substance, drug product development, real-time adaptive manufacturing, and clinical testing, we are able to streamline the development of poorly soluble molecules. Flexible study protocols and rapid ‘make-test’ cycles enable optimization of formulations in real time based on arising human clinical data. This reduces development risks, maximizes the probability of clinical and commercial success, and saves time and costs.
In this article, we review some recent scientific posters published by Quotient Sciences that highlight innovative strategies to overcome challenges with poorly soluble molecules in early development.
"Flexible formulation assessments in FIH studies for poorly soluble drugs accelerates dosage form development, manufacturing and supply for patient POC trials", presented by Quotient Sciences  at the American Association of Pharmaceutical Scientists (AAPS) PharmSci 360 conference in October–November 2020
The purpose of this study was to investigate how the integration of formulation development and drug product manufacturing activities can affect FIH-to-POC programs for poorly soluble drugs. Integrated early development programs were designed for two molecules, based on their physicochemical and biopharmaceutic properties. In both programs, drug products were prepared either by pharmacy compounding of the NCE, compounding of a GMP (Good Manufacturing Practice) intermediate, or GMP manufacture of the finished drug products. All formulations were prepared in real time during the FIH clinical study, using arising safety and PK data to inform the drug product selection for the next study period as part of an adaptive clinical protocol. In both studies, an optimized solubility-enhanced formulation was efficiently identified to take forward into patient POC trials – a lipidic capsule formulation in the first study, and a micronized API capsule formulation in the second study.
This poster highlights how the integration of flexible compounding and GMP manufacturing within FIH-to-POC programs can streamline development, maximize the potential for clinical success, and save time and costs for poorly soluble molecules. Drug development programs using this approach have been shown to save, on average, 18 months of time when compared to traditional manufacturing practices.
“A First-in-Human (FIH) Study to Assess the Safety, Tolerability and Pharmacokinetics of Single and Multiple Doses, and Alternative Formulations of R941552 (R552): A Selective Receptor Interacting Protein 1 (RIP1) Kinase Inhibitor”, presented by Quotient Sciences  and Rigel Pharmaceuticals  at the American Society for Clinical Pharmacology & Therapeutics (ASCPT) conference in March 2022
R552, a potent and selective RIPK1 inhibitor, is being developed by Rigel Pharmaceuticals for the treatment of autoimmune and inflammatory disorders, and pre-clinical data suggested that solubility may limit exposure. The purpose of this FIH study was to assess the safety, tolerability, and PK of R552 when administered in a lipid solution, as well as alternative SDD suspension and tablet formulations. It was found that R552 was generally safe and well tolerated at the dose levels tested, the PK of R552 was linear, and no clinically significant food effect was observed. A suitable SDD tablet formulation for R552 was identified for future patient studies.
This poster highlights how SDDs can offer an effective strategy to overcome challenges with solubility-limited exposure.
“Applications of Lipid-based Formulations and the Benefits of Integrating Manufacturing and Clinical Testing in Formulation Selection”, presented by Quotient Sciences  at the Pharmaceutics, Biopharmaceutics, and Pharmaceutical Technology (PBP) conference in March 2022
The purpose of this study was to analyze pharmaceutical and clinical data from multiple development programs conducted by Quotient Sciences over 16 years to understand the drivers for, and outcomes from, selecting and dosing different lipid formulations. Data from 34 lipid formulation programs were analyzed for the following features: formulation application, Biopharmaceutical Classification System (BCS), and in-vitro characterization methods. Various lipid-based dosage forms were developed, including solutions, suspensions, SDDs, and modified-release (MR) tablets.
This poster highlights how lipid formulations can successfully be used for solubilization, enhancing oral bioavailability, and reducing food effects for BCS Class II and IV drugs. Conventional in-vitro testing methods for different lipid formulations are poor predictors of in-vivo performance, whereas our integrated Translational Pharmaceutics platform enables the rapid identification of optimal lipid formulations based on clinical performance.
With a strong emphasis on science and innovation, Quotient Sciences continues to research new and improved ways to overcome solubility challenges with NCEs in early development, in order to get molecules to patients in need faster.
To find out more about how Quotient Sciences can help you overcome your solubility challenges, click here.
1. Quotient Sciences: Peter Scholes (Chief Scientific Officer), Wu Lin (Senior Research Fellow), Vanessa Zann (Senior Drug Development Consultant), Nutan Gangrade (Global Vice President, Pharmaceutical Sciences)
3. Rigel Pharmaceuticals: Lucy Yan, Gary Park, Donna Chow, Simon Shaw, David Blasingame, Andrew Chow