Drug Delivery: Principles and Applications / Edition 1

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Since the first edition of Drug Delivery published, therehave been significant advances in the field – new materialsfor delivery vehicles, new approaches to deliver drugs, and newtherapeutics requiring new delivery methods. As a result, a newedition to reflect these advances is both timely and necessary. The2nd edition expands to 31 chapters, divided into 5sections. The first focuses on general concepts, fundamentalmethods, and principles, the second on routes of drugadministration, the third on approaches to improve drug delivery,the fourth on targeted drug delivery systems, and the fifth on thedelivery of macromolecular drugs. While almost all chapters fromthe prior edition are retained and updated, several new chaptersare added to make a more complete resource and reference.  Newchapters cover recent developments including transdermal andmucosal delivery, nanoparticles, controlled drug release, lymphaticsystem delivery, theranostics, protein and peptide drugs, andbiologics delivery.

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Editorial Reviews

From the Publisher
“…this text provides an excellentoverview…” (Chemistry & Industry, No 24,19th December 2005)

“…a concise but highly readable text…Irecommend this well presented and well written book…”(Chemistry World, Vol. 2 (10), October 2005)

"...the broad overview of drug delivery technology presented inthis book makes it well suited as a reference volume…"(E-STREAMS, September 2005)

"…systematically examines various subject areas importantto drug delivery." (Drug Discovery & Development, June2005)

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Product Details

Meet the Author

BINGHE WANG, PhD, is a professor and Georgia Research AllianceEminent Scholar in Drug Discovery, and Georgia Cancer CoalitionDistinguished Cancer Scientist in the Department of Chemistry,Georgia State University. He is Editor in Chief of MedicinalResearch Reviews and a member of the Long-Range Planning Committeeof the American Chemical Society, Division of Medicinal Chemistry.

TERUNA SIAHAAN, PhD, is a professor in the PharmaceuticalChemistry Department, University of Kansas, and a Fellow of theAmerican Association of Pharmaceutical Scientists.

RICHARD A. SOLTERO, PhD, President of PharmaDirections, Inc., isan executive- level scientist with extensive experience managingmultisite and multinational pharmaceutical and biotechnologylabs.

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Read an Excerpt

Drug Delivery

Principles and Applications

John Wiley & Sons

Copyright © 2005 John Wiley & Sons, Inc.
All right reserved.

ISBN: 0-471-47489-4

Chapter One


Chao Han GlaxoSmithKline, Collegeville, PA 19426

Binghe Wang Department of Chemistry, Georgia State University, Atlanta, GA 30303

1.1. Issues facing the pharmaceutical industry 1.2. Factors that impact developability 1.2.1. Commercial goal 1.2.2. The chemistry efforts 1.2.3. Target validation in animal models 1.2.4. Pharmacokinetics and drug metabolism 1.2.5. Preparation for pharmaceutical products 1.2.6. Remarks on developability criteria

1.3. Drug delivery factors that impact developability



Drug discovery is a long, arduous, and expensive process. It was estimated that the total expenditure for research and development in the U.S. pharmaceutical industries was over $20 billion a year in the late 1990s,' and this figure has been increasing. The average cost for every new drug (a new chemical entity, NCE) from research laboratory to patients is a staggering number: $400 to $650 million, and the whole process may take up to 14 years! Because of the high cost, there is tremendous pressure to maximize efficiency and minimize the time it takes to discover and bring a drug to the market. In order to do this, it is necessary to analyze the entire drug discovery and development process and identify steps where changes can be made to increase efficiency and save time. Analyzing the entire drug discovery and development process will help reveal where maximal improvements can be expected with some effort.

The entire endeavor of bringing a new drug from idea to market is generally divided into several stages: target/disease identification, hit identification/discovery, hit optimization, lead selection and further optimization, candidate identification, and clinical trials. Each stage has many aspects and components. A target is identified early in the discovery period, when there is sufficient evidence to validate the relationship between this target and a disease of interest. Tens of thousands of new compounds are then synthesized and screened against the target to identify a few compounds (hits) with the desired biological activity. Analogs of these selected compounds are then screened further for better activity and optimized in order to identify a small number of compounds for testing in pharmacological models. These efficacious compounds (leads) are further optimized for their biopharmaceutical properties, and the most drug-like compounds (drug candidate, only one or two) are then selected for further development. The drug discovery and development path, with emphasis on the discovery stages, is schematically illustrated in Figure 1.1.

Of those drug candidates with most drug-like properties, only about 40% make their way to evaluation in humans (Phase I clinical trial). Unfortunately, the historical average reveals an almost 90% overall attrition rate in clinical trials; in another words, only 1 compound makes it to market from among 10 compounds tested in humans. Results from another statistical analysis gave a similar success rates for NCEs for which an IND (investigational new drug) was filed during 1990-1992. This high attrition rate obviously does not produce the long-term success desired by both the pharmaceutical and health care industries.

In order to reduce the failure rate, it is necessary to analyze how and where failures occur. More than 10 years ago, Prentis et al. analyzed the cause of the high attrition rate based on data from seven UK-based pharmaceutical companies from 1964 to 1985. The results revealed that 39% of the failure was due to poor pharmacokinetic properties in humans; 29% was due to a lack of clinical efficacy; 21% was due to toxicity and adverse effects; and about 6% was caused by commercial limitations. Although not enough detailed information was available, it is believed that some of these causes are interrelated. For instance, toxicity or lack of efficacy can be caused by poor or undesired pharmacokinetic properties. With the understanding that most failure was not due to a lack of "biological activities" per se as defined by in vitro testing, there is a drive to incorporate the evaluation of the other major factors that may potentially precipitate developmental failures in the early drug discovery and candidate selection processes. This is intended to reduce the rate of late-stage failures, which is most costly. This point is further substantiated by the studies indicating that the major cost in drug discovery and development occurs at late stages. For example, in a $400 million total R&D cost, preclinical research costs probably account for only tens of million dollars, whereas clinical studies cost hundreds of millions of dollars (Figure 1.2)

Another factor that is fueling the movement for early integration of multiple disciplines in the drug discovery and development processes is the rapid development of chemical and biological sciences. The past decade has seen tremendous advances in both areas. Advances in combinatorial chemistry, molecular and cellular biology, high-throughput screening, and genomic research have provided both great opportunities and challenges to the pharmaceutical industry. With the rapid development in biological sciences, current interests in therapeutic targets are more focused on rational targets such as receptors, enzymes, and hormones with well-characterized structures and functions. New technologies such as combinatorial chemistry, automation in high-throughput screening, and better instrumentation in bioanalysis have also significantly accelerated the lead identification and discovery process for a given target. With these new technologies, large pharmaceutical research organizations are capable of synthesizing and screening several thousand compounds or more in a year or two to find potential drug candidates. These efforts typically result in the discovery of many lead compounds or potential candidates for a target in the drug discovery process. Then there is the question of how to pick a winner and how to minimize failures. This requires a thorough evaluation of all the factors that are known to affect the developability of a NEC at the early stages. These factors may include efficacy, pharmacokinetics, pharmacodynamics, toxicology, and drug-drug interactions based on the metabolism and substrate properties of certain transporters and enzymes, as well as physicochemical properties, many of which are related to drug delivery issues. For this reason, a drug discovery and development program is more like a symphony (not just a cross-functional action) of multiple sciences including chemistry, biology, toxicology, clinical science, and pharmaceutical engineering.

Under the pressure to reduce the cost and shorten the time needed to bring an NCE to the market, many major pharmaceutical organizations have undergone rapid and drastic changes in the past decade, both in terms of organizational structures and fundamental approaches, in order to develop an integrated approach to drug discovery and development. A conference entitled "Opportunities for Integration of Pharmacokinetics, Pharmacodynamics, and Toxicokinetics in Rational Drug Development" was the landmark event in this fundamental change in the pharmaceutical industry. A brand new concept, "ensuring developability," was introduced and well accepted, which employs criteria for drug development throughout the entire drug discovery and development processes. Under the guidance of such criteria, a drug discovery and development team will not only maximize the chance of success by selecting the best developable drug candidate, but will also play off the failures faster and more cheaply.

The paradigm shifts mostly involve the integration of research activities in functional areas such as pharmacokinetics and drug metabolism, pharmaceutical development, safety assessment, and process chemistry into drug discovery and development process in the very early stages of discovery. The inputs from these functional areas, as well as those from clinical, regulatory, commercial, and marketing groups in the early stages, help to minimize costly mistakes in late stages of development and have become more and more important to the success of the drug discovery and development process. Developability is an overall evaluation of the drug-like properties of a NCE. Many of the recent changes in the pharmaceutical industry have been driven by the concept of ensuring developability. These changes, that is, the integration of multifunctional areas in drug discovery and development, ensure that the NCEs of interest will be successful in every step toward the final goal.

Below is a brief introduction to the factors that impact developability and a discussion on why the examination of drug delivery issues is very important in helping to ensure the developability of a drug candidate.


In most pharmaceutical companies, many efforts have been made to create a clear framework for selecting compound(s) with minimal ambiguity for further progression. Such a framework is not a simple list of the factors that impact the quality of a drug-like molecule. This framework, which is more often referred as "developability criteria," is a comprehensive summary of the characteristics, properties, and qualities of the NCE(s) of interest, which normally consist of preferred profiles with a minimally acceptable range. The preferred profile describes the optimal goal for selection and further progression of a candidate, whereas the minimum range gives the acceptable properties for a compound that is not ideal but may succeed. Molecules that do not meet the criteria will not be considered further. Such criteria cover all the functional areas in drug development. Some of the major developability considerations are briefly described in the following subsections.

1.2.1. Commercial Goal

It does not need to be emphasized that we are in a business world. Generally speaking, a product needs to be profitable to be viable. Therefore, early inputs from commercial, marketing, and medical outcome professionals are very important for setting up a projective product profile, which profoundly affects the creation of the developability criteria for the intended therapeutics. In general, this portfolio documents the best possible properties of the product and the minimum acceptable ones that may succeed based on the studies of market desires. These studies should be based on the results of professional analyses of the medical care needs, potential market, and existing leading products for the same, similar, or related indications. The following aspects need to be well thought out and fully justified before the commencement of a project: (1) therapeutic strategy; (2) dose form and regimen; and (3) the best possible safety profile, such as the therapeutic window, potential drug interactions, and any other potentially adverse effects. Using the development of an anticancer agent as an example for therapeutic strategy selection, one may consider the choice of developing a chemotherapeutic (directly attacking the cancer cells) versus an antiangiogenic agent (depriving cancer cells of their nutrients), or combined or stand-alone therapy. In deciding the optimal dose form and regimen, one may consider whether an oral or intravenous (iv) formulation, or both, should be developed, and whether the drug should be given once daily or in multiple doses. The results of such an analysis form the framework for developing the developability criteria and become the guideline in setting up the criterion for each desired property. For example, pharmacokinetic properties such as the half-life and oral bioavailability of a drug candidate will have a direct impact on developing a drug that is to be administered orally once a day.

1.2.2. The Chemistry Efforts

Medicinal chemistry is always the starting point and driver of drug discovery programs. In a large pharmaceutical R&D organization, early discovery of bioactive compounds (hits) can be carried out either by random, high-throughput screening of compound libraries, by rational design, or both. Medicinal chemists will then use the structural information of the pharmacophore thus identified to optimize the structures. Chemical tractability needs to be examined carefully at the very beginning when a new chemical series is identified. Functional modifications around the core structure are carefully analysed. After the examination of a small number of compounds, the initial exploratory structure-activity relationship (SAR) or quantitative SAR (QSAR) should be developed. Blackie et al. described how the establishment of exploratory SAR helped the discovery of a potent oral bioavailable phospholipase [A.sub.2] inhibitor. In this example, numerous substructural changes were made, leading to the most active compounds; this is normally done in parallel with several different chemical series. For medicinal chemists, it is important that many different SARs are considered, developed, and integrated into their efforts at the same time, providing more opportunities to avoid undesirable properties unrelated to their intended biological activities. Such factors, again, may include potential P450 inhibition, permeability, selectivity, stability, solubility, etc.

Structural novelty of the compounds (i.e., can this product be patented?), complexity of synthetic routes, scalability (can the syntheses be scaled up in an industrial way?) and the cost of starting materials (cost of goods at the end of the game), and potential environmental and toxicity issues will all need to be closely examined at early stages of the drug discovery and development processes. It is never too early to put these thoughts into action.

1.2.3. Target Validation in Animal Models

Although drug discovery efforts almost always start with in vitro testing, it is well recognized that promising results of such testing do not always translate into efficacy. There are numerous reasons for this to happen, some of which are well understood and others that are not. Therefore, target validation in animal models before clinical trials in humans is a critical step. Before a drug candidate is fully assessed for its safety and brought to a clinical test, demonstration of the efficacy of a biologically active compound (e.g., active in an enzyme binding assay) in pharmacological models (in vivo, if available) is considered a milestone in the process of discovering a drug candidate. Many cases exemplify the challenges and importance of pharmacological models. For example, inhibitors of the integrin receptor [[alpha].sub.v][ss.sub.3] have been shown to inhibit endothelial cell growth, which implies their potential as clinically useful antiangiogenic agents for cancer treatment. However, the proposed mechanism did not work in animal models, although compounds were found to be very active in vitro. What has been recognized is that the integrin receptor [[alpha].sub.v][ss.sub.3] may not be the exclusive pathway on which cell growth depends. Its inhibition may induce a compensatory pathway for angiogenesis.

Ideally, an in vivo model should comprise all biochemical, cellular, and physiological complexities, as in a real-life system, which may predict the behavior of a potential drug candidate in human much more accurately than an in vitro system. In order to have a biological hypothesis tested in the system with validity, a compound has to be evaluated in many other regards. Knowing the pharmacokinetic parameters such as absorption, distribution, and metabolism in the animal species that is used in the pharmacological model is critical. Showing successful drug delivery in an animal model serves as an important milestone.

The pharmacokinetics/pharmacodynamics relationship, systemic and tissue levels of drug exposure, frequency of dosing following which the drug may demonstrate efficacy, and the strength of efficacy are very important factors that may affect further development of an NEC. They are all directly or indirectly related to drug delivery.


Excerpted from Drug Delivery Copyright © 2005 by John Wiley & Sons, Inc.. Excerpted by permission.
All rights reserved. No part of this excerpt may be reproduced or reprinted without permission in writing from the publisher.
Excerpts are provided by Dial-A-Book Inc. solely for the personal use of visitors to this web site.

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Table of Contents


List of Contributors.

1. Factors that Impact the Developability of Drug Candidates-AnOverview (Chao Han and Binghe Wang).

2. Chemical, Biochemical, and Physiological Barriers to OralDrug Delivery (Teruna Siahaan).

3. Pathways for Drug Delivery to the Central Nervous System (YanZhang and Donald W. Miller).

4. Physiochemical Properties, Formulation and Drug Delivery (E.Munson).

5. Targeted Bioavailability: A Fresh Look at Pharmacokinetic andPharmacodynamic Issues in Drug Delivery (William F. Elmquist).

6. Pre-Systemic and First-pass Metabolism (W. GriffithHumphreys).

7. Cell Culture Models for Drug Transport Studies (D. NedraKarunaratne, Peter S. Silverstein, Veena Vasabdabi, Amber M. Young,Erik Rytting, Bradley Yops and Kenneth L. Audus).

8. Prodrug Approaches to Drug Delivery (Longqin Hu).

9. Receptor-Mediated Drug Delivery (Chirstopher P. Leamon andPhilip S. Low).

10. Oral Protein and Peptide Drug Delivery (Rick Soltero).

11. Metabolic Activation and Drug Targeting (XiangmingGuan).

12. Ultrasound Mediated Drug Delivery (Ka-yun Ng’ andTerry O. Matsunaga).

13. Polycationic Peptides and Proteins in Drug Delivery: Focuson Non-Classical Transport (Lisa A. Kueltzo and C. RussellMiddaugh).

14. Gene Therapy and Gene Delivery (Naoki Kobayashi, MakiyaNishikawa and Yoshinobu Takakura).

15. Parenteral Formulations for Peptide and Protein Delivery,and Monoclone Antibody Drugs (John Bontempo).

16. Pulmonary Drug Delivery – Pharmaceutical Chemistry andAerosol Technology (Anthony J. Hickey).

17. Antibody-Directed Drug Delivery (Hervé Le Calvez, JohnMountzouris, Kosi Gramatikoff and Fang Fang).

18. Efflux Transporters in Drug Excretion (Shuzhong Zhang andMarilyn E. Morris).

19. Liposome as Drug Delivery Vehicles (Guijun Wang).

20. Regulatory and IP Issues in Drug Delivery Research (ShihongNicolaou).


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