Oral Formulation Roadmap from Early Drug Discovery to Development

Elizabeth Kwong, Elizabeth Kwong

• Publisher: Wiley
• Year: 2017
• ISBN:
  9781118907870
• Edition: 1
• Topic: Medicine
• Subtopic: Pharmacology

Detailing formulation approaches by stage of discovery to early development, this book gives a "playbook" of practical and efficient strategies to formulate drug candidates with the least chance of failing in clinical development. • Comes from contributing authors with experience developing formulations on the frontlines of the pharmaceutical industry
• Focuses on pre (or non-) clinical and early stage development, the phases where most compounds are used in drug research
• Features case studies to illustrate practical challenges and solutions in formulation selection
• Covers regulatory filing, drug metabolism and physical and chemical properties, toxicology formulation, biopharmaceutics classification system (BCS), screening approaches, early stage clinical formulation development, and outsourcing

1
Introduction

Elizabeth Kwong

Kwong Eureka Solutions, Montreal, Quebec, Canada

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1. 1.1 Overcoming Challenges in Big Pharma and Evolution of Start‐Up Companies
2. 1.2 Overview of Activities Involved in Current Drug Discovery and Development
3. 1.3 Value of the Right Formulation at the Right Time
4. References

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1.1 Overcoming Challenges in Big Pharma and Evolution of Start‐Up Companies

The discovery and development of new drugs is a very complex process. No matter how you implement Lean Six Sigma Black Belt or in‐depth data mining into the process, cost and success rate of commercializing drugs had not improved. It was estimated that it takes at least 10 years for a drug to make the journey from discovery to consumer at an average cost of $5 billion (Herper, 2013). Another study conducted by BIO and BioMedTracker (Hay et al., 2011), which collects data on drugs in development, had reviewed more than 4000 drugs from small and large companies that indicated that overall success rate for drugs moving from early stage phase I clinical trials to FDA approval is about 1 in 10, down from 1 in 6 seen in reports earlier. 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.

Recent publication in Fortune entitled “Big Pharma Innovation in Small Places” (Alsever, 2016) quoted several big pharma executives as to the current nature of big pharmaceutical companies where the focus of R&D is diminished to sorting out changes in the company and reprioritizing programs. Furthermore, with investor money flooding in and shift of drug pipelines from internal R&D to start‐ups licensing opportunities, big pharma is acquiring small companies at faster pace than before. Small start‐ups are now becoming the “new” innovative machines, which offer the high risk–high reward paradigm. According to surveys, last year, 64% of the approved phase I studies originated at a smaller start‐ups.

1.2 Overview of Activities Involved in Current Drug Discovery and Development

There had been many surveys that revealed the cause of attrition of molecule in clinical development through the years. The major factors for discontinuation of clinical candidates are lack of efficacy (~30%) and toxicity (~30%). Kola & Landis (2004) further revealed that a 10% drop in attrition in 2000 was partly due to advancement in formulation technologies. Furthermore with increase in molecular obesity in drug candidates in recent years, majority of new drug development is poorly water soluble (Hann, 2011). About 40% of drugs with market approval and nearly 70–90% of molecule in discovery are poorly water soluble, which can lead to low bioavailability with conventional formulations (Kalepu & Nekkanti, 2015). With the introduction of various drug delivery technologies, numerous drugs associated with poor solubility and low bioavailability have been formulated into successful drug products. In fact, recently an increase in NDA file under 505(b)(2) is gaining more importance. New dosage forms with improved solubility and enhanced bioavailability such as prodrugs/active metabolite of drug and reformulation of poorly absorbed drugs using new technologies are turning into lucrative business. According to the Q&A with Ken Phelps, president of Camargo Pharmaceutical Services, which provides services for drug development for 505(b)(2) applications, approximately 20% of new drug approved in 2006 is through 505(b)(2) process. By 2008 more than half of new drug approval was based on 505(b)(2) process (Phelps, 2013).

Poor solubility of development candidates can limit drug concentration at the biological target site, which can lead to loss of therapeutic effect. Increasing the dose can overcome this lack of therapeutic effect but can lead to high variability in absorption, which can be detrimental to the safety and efficacy profile. For these reasons, solubility‐enhancement technologies are being used increasingly in the pharmaceutical field. A formulation scientist’s approach to solubility enhancement of a poorly water‐soluble drug can vary. Often, physicochemical characterization, solid‐state modifications, nonconventional formulation technologies, and enabling formulations are often utilized. There are numerous literature resources available to provide guidance toward formulation development from discovery to development of development candidates; however, a single reference where formulation approaches are described in each stage is lacking. 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 fit for purpose formulation to get candidates into development will also be covered in the book. Each stage of formulation (see Table 1.1) development has its goals, degree of complexity, and increasing availability of information, which ultimately leads to candidate that will have properties that can be administered in humans.

Table 1.1 Activity definition from discovery to preclinical development.

Standardized solutions for in vitro HTS and in vivo PK screen No vehicle screen Usually contains DMSO or other standardized cosolvent vehicle (such as PEG/EtOH), low dose PK with IV/oral for %F	Dose range finding to identify exposure multiples Resort to vehicle screen decision tree^a,b,c,d Goal of formulation selection are: Vehicles do not have any biological adverse effect Achieve exposure at the highest toxicological dose Can reach up to 2 g/kg Key is to identify adverse effects	Vehicle identified and dose range identified for GLP tox Repeat preparation of vehicle using optimized API Characterize physical properties of API in vehicle Meet GLP requirements
Pharmacology studies—needed a sustained plasma level use of Alzet Osmotic pumps^e	PK–PD studies—use solution at low dose and suspension at high dose to assess relationship	CTM development—based on physical properties, such as flow, stability, particle size, and BCS, bioavailability

^a Higgins et al. (2012).

^b Maas et al. (2007).

^c Li & Zhao (2007).

^d Palucki et al. (2010).

^e Neervannan (2006).

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Table of contents

• Cover
• Title Page
• Table of Contents
• List of Contributors
• Preface
• 1 Introduction
• 2 Lead Identification/Optimization
• 3 Oral Drug Formulation Development in Pharmaceutical Lead Selection Stage
• 4 Bridging End of Discovery to Regulatory Filing
• 5 Planning the First Clinical Trials with Clinical Manufacturing Organization (CMO)
• 6 Formulation Strategies for High Dose Toxicology Studies
• 7 Formulation, Analytical, and Regulatory Strategies for First‐in‐Human Clinical Trials
• Index
• End User License Agreement