Cover Page

Oral Formulation Roadmap from Early Drug Discovery to Development

 

Edited by Elizabeth Kwong

 

 

 

 

 

 

 

 

 

 

 

 

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List of Contributors

Steven Booth Merck Sharpe & Dohme, Hoddesdon, Hertfordshire, UK

Gerard Byrne Merck Sharpe & Dohme, Hoddesdon, Hertfordshire, UK

Lorenzo Capretto Merck Sharpe & Dohme, Hoddesdon, Hertfordshire, UK

Pierre Daublain Discovery Pharmaceutical Sciences, Merck Research Laboratories, Boston, MA, USA

Lee Dowden Merck Sharpe & Dohme, Hoddesdon, Hertfordshire, UK

Kung‐I Feng Discovery Pharmaceutical Sciences, Merck Research Laboratories, Kenilworth, NJ, USA

Shayne Cox Gad Gad Consulting Services, Cary, NC, USA

Mengwei Hu Discovery Pharmaceutical Sciences, Merck Research Laboratories, Kenilworth, NJ, USA

Elizabeth Kwong Kwong Eureka Solutions, Montreal, Quebec, Canada

Dennis H. Leung Small Molecule Pharmaceutical Sciences, Genentech, Inc., South San Francisco, CA, USA

Mark McAllister Drug Products Design, Pfizer Ltd., Sandwich, UK

Caroline McGregor Merck Research Laboratories, Kenilworth, NJ, USA

Evan A. Thackaberry Genentech, Inc., Safety Assessment, South San Francisco, CA, USA

Sarah Trenfield Merck Sharpe & Dohme, Hoddesdon, Hertfordshire, UK

Mei Wong Drug Products Design, Pfizer Ltd., Sandwich, UK

Preface

The discovery and development of new drugs is a very complex machine. Despite increasing investments in research and development, the number of new drug approvals has not increased, while the attrition rate of new drug candidates has increased. Many of these challenges are due to failure to properly identify formulations that are translatable from preclinical to the clinic due to lack of effective predictions of therapeutic and toxicological responses in the preclinical stages. Moreover, efforts spent to integrate the formulation scientists in the early discovery that leads to the lead candidate selection had been disappointing. Most of the time, the lack of understanding of the interplay of the physiological system to the formulation contributed to the failure to integrate the right expertise at the right time, which leads to poor clinical successes. The lack of collaboration and proper integration between the formulation and discovery scientists is the root cause of most of the failure in the clinic. Lastly, the understanding of regulatory requirements for formulations also can add to the burden of the timeline and cost of bringing a drug candidate forward.

This book describes and explains key factors that will help determine the types of formulation needed at the different stages of discovery. The considerations of limited amount of API in early stages to the use of the formulation to determine key efficacious or toxicological end point that will not interfere with readouts will be discussed. The formulation selection stage‐dependent approach will be detailed up to the planning for the regulatory filing. The interplay of drug metabolism, absorption, and physicochemical properties of the active will be laid out to help understand when a formulation can be improved and when a different lead candidate should be selected. Current formulation approaches based on the biopharmaceutics classification system (BCS) of the lead will be explained. The book will also focus on the relationships between various disciplines like physical chemistry, analytical chemistry, biology, DMPK, toxicology, and medicinal chemistry in determining the appropriate formulation to deliver the candidate in different forms. API sparing approaches including in vitro and fit‐for‐purpose formulation to support first‐in‐human study will also be covered in the book. Partnership considerations with contract manufacturing organization (CMO) will also be described and shared to increase the probability of meeting tight timelines and to ensure the proper selection of formulation to support an early stage development and how this can impact the late stage development of the drug candidate. Introduction of current formulation approaches including enabling formulations such as solid dispersions used in the industry will widen partnership with emerging innovators and sponsors, making it possible for the otherwise difficult drug candidate to be studied in the clinic.

This book will be the first in detailing the formulation approaches by stage of discovery to early development to help scientists of different disciplines. Practical challenges and solutions will be discussed. The content of the book will guide the proper use of resources to lead scientists to generate the proper database that can help in quick decision‐making. The target audience for the book will be drug discovery scientists including medicinal chemists, leaders in pharmaceutical industry (big pharma or start‐up companies), and academics who are interested in bringing a potential drug candidate to the clinic. The book will provide real case studies of challenging candidates that allows readers to understand the importance of formulation to their cases. My numerous years (>23 years) working in big pharmaceutical companies, especially the intimate involvement with discovery in the last 15 years of my career and my recent interaction with small‐ and medium‐sized pharmaceutical companies, allowed me to identify collaborators for this book to address the real problems and solutions in drug discovery related to all types of formulations.

The editor wishes to thank all the authors for their expertise in their respective sections and their patience during the revision procedures that were necessary to arrive at this juncture of delivering a well‐outlined roadmap.

July 2016                                                                                                                                                                               Elizabeth Kwong