Drug Delivery (eBook)

Principles and Applications

Binghe Wang, Longqin Hu, Teruna J. Siahaan (Herausgeber)

eBook Download: EPUB

2016 | 2. Auflage
John Wiley & Sons (Verlag)
9781118833308 (ISBN)

Infos

Following its successful predecessor, this book covers the fundamentals, delivery routes and vehicles, and practical applications of drug delivery. In the 2nd edition, almost all chapters from the previous are retained and updated and several new chapters added to make a more complete resource and reference.

• Helps readers understand progress in drug delivery research and applications
• Updates and expands coverage to reflect advances in materials for delivery vehicles, drug delivery approaches, and therapeutics
• Covers recent developments including transdermal and mucosal delivery, lymphatic system delivery, theranostics
• Adds new chapters on nanoparticles, controlled drug release systems, theranostics, protein and peptide drugs, and biologics delivery

Binghe Wang, PhD, is Regents' Professor of Chemistry and Associate Dean for Natural and Computational Sciences at Georgia State University as well as Georgia Research Alliance Eminent Scholar in Drug Discovery. He is Editor-in-Chief of the journal Medicinal Research Review and founding series editor of the Wiley Series in Drug Discovery and Development. He has published over 230 papers in medicinal chemistry, pharmaceutical chemistry, new diagnostics, and chemosensing.

Longqin Hu, PhD, is Professor of Medicinal Chemistry and Director of the Graduate Program in Medicinal Chemistry at Rutgers University. Among his major research interests are the synthesis and evaluation of anticancer prodrugs for the targeted activation in tumor tissues and the discovery of novel small molecule inhibitors of protein-protein interactions.  He has published over 80 papers and 8 patents in bioorganic and medicinal chemistry.
Teruna Siahaan, PhD, is a Professor and Associate Chair of the Department of Pharmaceutical Chemistry and serves as the Director of the NIH Biotechnology Training Program at the University of Kansas. In addition to co-editing the first edition of Drug Delivery, he has written almost 195 journal papers and book chapters and received the 2014 PhRMA Foundation Award in Excellence in Pharmaceutics.

Textauszug

1
FACTORS THAT IMPACT THE DEVELOPABILITY OF DRUG CANDIDATES

Chao Han1 and Binghe Wang2

1 Biologics Clinical Pharmacology, Janssen R&D LLC, Spring House, PA, USA

2 Department of Chemistry, Georgia State University, Atlanta, GA, USA

1.1 CHALLENGES FACING THE PHARMACEUTICAL INDUSTRY

Drug discovery and development is a long, arduous, and expensive journey. It was estimated that the total cost of developing a new drug in the US pharmaceutical industries was well over a billion dollars in the 2000s, and this figure has been increasing [1, 2]. This figure may be slightly better for biotechnology-based research and development (R&D) [1]. The entire process may take up to 14 years [1, 3]! Yet, only 2 out of 10 marketed drugs would return revenues that match or exceed R&D costs according to a recent analysis [4]. There has been a tremendous amount of pressure on the industry to maximize efficiency, shorten development time, and reduce the cost during discovery and development. In order to accomplish such objectives, one needs to analyze the entire drug discovery and development process so as to identify steps where changes can be made to increase efficiency.

The entire endeavor of developing a new drug from an idea to the market is generally divided into several stages: target identification, hit identification/discovery, hits’ optimization, lead selection and further optimization, candidate identification, and preclinical and clinical development [5]. Among these, each stage has many interrelated aspects and components. A target is identified in early discovery when there is sufficient evidence to suggest a relationship between the intervention of a target and treatment of the disease or conditions. Tens of thousands new molecules are then synthesized and screened against the target to identify a few molecules (hits) with desired biological activities. Analogs of these selected molecules are then made and screened further for improved activities and drug-like properties. Optimization results in identifying a small number of compounds for testing in pharmacological and other models. Those active compounds (leads) are further optimized for their biopharmaceutical properties, and the most drug-like compound(s) (drug candidates, only 1–2 in most cases) are then selected for further preclinical and clinical development. The drug discovery and development path with an emphasis on the discovery stages is schematically illustrated in Figure 1.1.

Figure 1.1 A schematic illustration of the drug discovery and development process with the estimated number of compounds shown for each step.

Having been through the screening and optimization processes, however, of those drug candidates with most drug-like properties, only about 40% successfully make their way into the evaluations in humans (first-in-human or FIH clinical trial) [6]. Unfortunately, data from historical average reveals an almost 90% overall attrition rate in clinical development [6]. In another word, only one molecule successfully makes into the market from 10 compounds tested in humans. Results from another statistical analysis gave a similar success rates for new chemical entities or new molecular entities (NCEs/NMEs) for which an investigational new drug (IND) application or a biologic license application (BLA) was filed in almost four decades [7], and the figure has not changed much [8]. This high attrition rate obviously does not meet the needs of long-term success desired by both the pharmaceutical industry and health care system.

Prentis et al. [9] analyzed many factors that potentially were attributable for such a high attrition rate based on the data from seven UK-based pharmaceutical companies from 1964 through 1985. The results from this statistical analysis revealed that a 39% failure was due to poor pharmacokinetic properties in man, 29% was due to a lack of clinical efficacy, 21% was due to toxicity and adverse effects, and about 6% was due to commercial limitations. Although not enough information was available in a great detail, it is believed that some intrinsic relations of these factors existed. For instance, toxicity or lack of efficacy can be precipitated by undesired drug metabolism and pharmacokinetic (DMPK) properties of the molecule. Based on the assumptions that most failures was not due to the lack of “biologic activities” per se as defined by in vitro testing, there has been a drive to incorporate the evaluation of drug delivery properties, which may potentially precipitate developmental failures, into the early drug discovery and candidate selection processes with the intention of reducing the proportion of late stage failures, which is obviously most costly.

Rapid development in biology, and in rational and structure-based chemical design in addition to new technologies such as generation of diversity libraries, automation in high throughput screening, and advanced instrumentation in bioanalysis have significantly accelerated lead identification and discovery process [10, 11] for a given target. In light of these scientific and technical advances and under the pressure to reduce the cost and shorten the time of discovery and development, many major organizations in the pharmaceutical industry went through rapid and drastic changes from the late 1990s to early 2000s. A conference entitled “Opportunities for integration of pharmacokinetics, pharmacodynamics, and toxicokinetics in rational drug development” [12] was a landmark of this fundamental change in the pharmaceutical industry [13]. The developability concept was introduced to pharmaceutical R&D with an organizational and functional integration in early drug discovery and development [14]—optimization of DMPK properties of drug candidates in conjunction with toxicology and pharmaceutical development. These changes were successful in addressing some of the specific causes of the attrition. Early investment in optimizing absorption, distribution, metabolism, and elimination (ADME) in drug discovery [15] has successfully reduced attrition rate due to poor human pharmacokinetics from about 39% in the previous survey [9] to approximately 10% in the year of 1991–2000 [16]. A top cause of failures appeared to have shifted to toxicology related. Furthermore, failures due to other reasons, such as the lack of clinical efficacy, remain to be a major issue.

Being encouraged by the successes in addressing ADME issues early on in the discovery and preclinical development, R&D in pharmaceutical industry bolstered the number of drug candidates entering into clinical trials during the early 2000s. Unfortunately, this did not make the expected positive impact on the output in terms of the number of new medicines into the market. The success rate, instead, fell to approximate 5% in the year of 2006–2008 [17]. Thus there is a need of improved understanding of disease mechanism(s) and issues in drug delivery. It shouldn’t be forgotten that waves of mergers and acquisitions aim at boosting R&D performance in the pharmaceutical industry apparently failed to effectively address the issues either [18].

Nevertheless, the march goes on. A fairly recent analysis indicated that the number of approved new drugs from pharmaceutical companies has essentially been relatively constant during the past 60 years [19]. Over a thousand new drugs had been approved by the US Food and Drug Administration (FDA) in this period of time. There is no doubt that these medicines helped enormously in treating diseases, managing health conditions, and improving the quality of life. Indeed, life expectancy and cancer survival rate improved due to new treatments [20, 21]. Death rates in cardiovascular diseases decreased significantly [22]. Average cholesterol level in adults in the United States fell to the ideal level—below 200 mg/dl [23, 24]. The most striking example was the dramatic drop in HIV/AIDS death rate since the approvals of antiretroviral treatments [25]. These testimonial facts are the demonstration of the value of pharmaceutical R&D of new medicine.

Since the first therapeutic monoclonal antibody—muromonab-CD3 (Orthoclone OKT3®)—was approved by the US FDA in 1986 [26], more than 30 therapeutic monoclonal antibodies have been approved, and probably hundreds based on the same platform of therapeutics are under clinical development. This class of molecules mimics the human immune system and very specifically intervene cell membrane-bound or soluble targets by antagonizing (a few agonists too) the pathway or neutralizing the ligand [27]. Monoclonal antibody therapeutics along with other biologics such as recombinant or fusion proteins are commonly referred as large molecule to differentiate from synthetic drugs or small molecules. Based on an analysis [8] of the data up to 2004, clinical approval success rate for large molecule therapeutics more than doubled that for small molecules. An in-depth survey on only monoclonal antibody-based therapeutics reveals similar encouraging trend [28]. The discovery and development of biologics are seeing rapid growth. It is expected that the top list of sales will be dominated by biologics in a few years according to Slatko’s analysis based on the observations made in 2010 [29].

Taking advantage of the high specificity of a monoclonal antibody as a guided carrier to deliver chemotherapeutic agent specifically to the tumor cells was truly an innovation in drug delivery. This class of coupled molecules is commonly referred as antibody–drug...

Produkt-Details

• Erscheint lt. Verlag: 9.3.2016
• Reihe/Serie: Wiley series in drug discovery and development
• Reihe/Serie: Wiley series in drug discovery and development
• Reihe/Serie: Wiley Series in Drug Discovery and Development
• Sprache: englisch
• Themenwelt: Medizin / Pharmazie ► Pflege
• Themenwelt: Medizin / Pharmazie ► Pharmazie ► PTA / PKA
• Themenwelt: Naturwissenschaften ► Chemie ► Technische Chemie
• Themenwelt: Technik ► Umwelttechnik / Biotechnologie
• Schlagworte: Biochemie • Biochemie u. Chemische Biologie • Biochemistry (Chemical Biology) • biologics delivery • Chemie • Chemistry • Controlled Drug Release • Drug Delivery • drug delivery methods • drug delivery vehicles • Drug Formulation & Delivery • lymphatic system delivery • macromolecular drug delivery • Medical Science • Medizin • Pharmacology & Pharmaceutical Medicine • Pharmakologie u. Pharmazeutische Medizin • routes of drug administration • Targeted drug delivery • Theranostics • Wirkstoffformulierung, Wirkstofftransport • Wirkstofffreisetzung
• ISBN-13: 9781118833308 / 9781118833308