`
`
`
`Howard C. Ansel, Ph.D.
`Professor and Dean Emeritus
`College of Pharmacy
`The University. of Georgia
`
`,
`
`Loyd V. Allen, Jr., Ph.D.
`Professor Emeritus
`College of Pharmacy
`University of Oklahoma, and
`Editor—in—Chief
`
`Intemationaljoumal ofPhaflnaceufical Compounding
`Nicholas G. Popovich, PhD.
`Professor and Associate Head
`Department of Pharmacy Practice
`School of Pharmacy and Pharmacal Sciences
`PurduerUniversity
`
`éll’e LlPPlNCOTT WILLIAMS e WILKINS
`
`A Wolters Kluwer Company
`Philadelphia - Baltimore
`- New York - London
`Buenos Aires -
`Hong Kong - Sydney . Tokyo
`
`Page 1
`
`

`

`Managing Editor: Jennifer Schmidt
`Marketing Manager: Christine Kushner
`
`Copyright © 1999 Lippincott Williams & Mikins
`351 West Camden Street
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`
`227 East Washington Square
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`
`All rights reserved. This book is protected by copyright. No part of this book may be re-
`produced in any form or by any means, including photocopying, or utilized by any infor-
`mation storage and retrieval system without written permission from the copyright owner.
`
`The publisher is not responsible (as a matter ot' product liability, negligence, or otherwise}
`for any injury resulting from any material contained herein. This publicalion contains in-
`formation relating to general principles of medical care which should nol be construed as
`speeific instructions for individual patients. Manufacturm's' product iI liennatiun and parit-
`age inserts should be refiewed for current
`information,
`including contraimlirat Inns.
`dosages, and precautions.
`
`Printed in the United States ofAmerica
`
` Editor: Donna Balado
`
`Library of Congress Cataloging—in-Publication Data
`
`Ansel, Howard C., 1933—
`Pharmaceutieal dosage forms and drug delievery systems / Howard C.
`Ansel, Loyd V. Allen, Jr., Nicholas G. Popovich. — 7th ed.
`.
`cm.
`_
`
`Includes bibliographical references and index.
`ISBN 0—683—30572—7
`2. Drug delivery systems.
`1. l'ngsl—Dosage forms.
`II. l‘opuvich, Nicholas G.
`llI.'I'1tle.
`IDNLM: 1. Dosage Forms.
`2. Drug Delivery Systems. QV 785 A618i 1999]
`RSZOO.A57
`1999
`615'.1——-dc21
`DNLMIDLC
`for Library of Congress
`
`1. Allen, Loyd V.
`
`99—17498CI?
`
`The publishers have made every efirort to trace the Copyright holdersfor borrowed material. If they
`have inadvertently overlooked any, they will be pleased to make the necessary arrangements at
`thefirst opportunity.
`
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`Convention, Inc. The Convention is not responsible for any inaccuracy of quotation or for
`any false or misleading implication thal may arise from separation of excerpts from the
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`Page 2
`
`

`

` NEW DRUG DEVELOPMENT
`
`AND APPROVAL PROCESS
`
`
`
`Chapter at a Glance
`
`THE FEDERAL Food, Drug, and Cosmetic Act, as reg-
`ulated through Title 21 of the U.S. Code of Federal
`Regulations, requires a new drug to be approved by
`the Food and Drug Administration (FDA) before it
`may be legally introduced1n interstate commerce
`(1). The regulations apply to drug products manu—
`' factured domestically as well as those imported
`into the United States
`
`To gain approval for marketing, a drug’s sponsor
`(e.g., a pharmaceutical company) must demon—
`strate, through supporting scientific evidence, that
`the new drug/drug product is safe and effective for
`its proposed use. The sponsor must also demon-
`strate that the various processes and controls used
`in producing the drug substance and in manufac-
`turing, packaging, and labeling the drug product
`
`D1 up Discovery and Drug Design
`Somecs ofNeto Drugs
`ACool Drug"
`Methods of Drug Discovery
`A’Lead Compound”
`Prodrugs
`PDA’s Definition of a New Drug
`Drug Nomenclature
`Biological Characterization
`Pharmacology
`Drug Metabolism
`-
`Toxicology
`Early Formulation Studies
`Preformulation Studies
`Initial Product Formulation and Clinical
`Trial Materials (CTM)
`The Investigational New Drug (IND)
`Application
`Content of the IND
`The Clinical Protocol
`
`”Treatment IND ”
`
`lNDfor an Orphan Drug
`Withdrawal or 'Temiinatlmi of an IND
`The New Drug Application (NDA)
`General Content of the NDA Submission
`Drug Product Labeling
`FDA Review and ”Action Letters’
`Phase 4. Studies and Postmarketing
`Surveillance
`
`Postmarketing Reporting ofAdverse Drug
`Experiences
`Annual Reports
`Supplemental, Abbreviated, and Other
`Applications
`Supplemental New Drug Application
`(SNDA)
`Abbreviated New Drug Application
`(ANDA)
`
`Pre—IND Meetings
`l-"DA Review of an IND Application
`FDA Drug Classification System
`Phases of a Clinical Investigation
`Requirements for Registration of
`Pharmaceuticals for Human
`Clinical Study Controls and Designs
`Drug Dosage and Termimilogy
`Use (ICH)
`
`Biologics License Application (BLA)
`Animal Drug Applications
`Medical Devices
`The International Conference on
`Harmonization of Technical
`
`23
`
`Page 3
`
`

`

`24
`
`New Drug Development and Approval Process
`
`are properly controlled and validated, to ensure the
`production of a product
`that meets esialznlished
`standards of quality.
`The procass and time—course from drug discov
`cry to approval for marketing can be lengthy and
`tedious, but are well defined and understood
`within the pharmaceutical industry. A Schematic.
`representation of the process for new drug devel—
`opment is shown in Figure 2.1 and the usual time—
`course is depicted in Figure 2.2. After the discovery
`(err, synthesis) of a proposed new drug, the agent
`is biologically cl'iaracterized for pharmacologic and
`toxicologic effects and for potential therapeutic ap—
`plication. Prefomtuiation studies are initiated to
`define the physical and chemical properties of the
`agent. Formulation studies follow, to develop the
`initial
`features of the proposed pl'iarmaccutica]
`product or dosage form. To obtain the required ev—
`idence that will demonstrate the drug’s safety and
`effectiveness for its proposed use, a carefully de—
`signed and progressive sequence of preclinical
`(e.g., cell culture, whole animal) and clinical (hu
`man) studies are undertaken.
`Only when the preclinical studies demonstrate
`adequate safety and the new agent shows promise
`as a useful drug will the drug’s sponsor File an in-
`vestigational NewDrugApplication (1ND) with the
`FDA for initial
`testing in humans.
`if
`the drug
`demonstrates adequate safety in these initial hu-
`man studies, termed Phase '1, progressive human
`trials through Phases 2 and 3 are undertaken to as-
`sess both safety and efficacy. As the clinical trials
`progress, laboratory work continues toward defin—
`ing the agent’s basic and clinical pharmacology and
`toxicology, product design and development, man—
`ufacturing scale—up and process controls, analytical
`methods development, proposed labeling and
`package design, and initial plans for marketing. At
`the completion of the carefully designed preclinical
`and clinical studies, the drug’s sponsor may file a
`New Drug Application [N DA) seeking approval to
`market the new product.
`.
`The FDA’S approval of an NDA indicates that the
`body of scientific evidence submitted sufficiently
`demonstrates that the drug/drug product is safe
`and effective for the proposed clinical indications;
`that there is adequate assurance of its proper man-
`ufacture and control; and that the final labeling or —
`curately presents the necessary information for its
`proper use.
`The content of a product‘s approved labeling,
`represented by the package insert, is a summary of
`the entire drug development process because it
`con tains the essential chemistry, pl'iarmncoloigy.
`toxicology,
`indications and contraindications for
`
`formulation composition,
`use. adverse effects,
`dosage, and storage retpiit'i-inents, as ascertt-‘Iined
`during the research and developrmrnl process.
`In addition to the general new drug approval
`process, special I'egpllations apply for the approval
`of certain new drugs to ireal serious or life threat"
`ening illnesses, as AIDS and cancer/These may he
`placed on an accelerated or“l'asl track"program for
`approval. Also, in instances in which there are no
`satisfactory approved—drill; or treatment alterna—
`tives to treat a serious medical condition, special
`protocols may be issued permitting use of an in—
`vestigational chug to treat some patients prior to
`approval of the NDA. This type of protocol
`is
`termed a “Treatment lNl')."'l‘reatment TN US often
`are sought for‘fiarphan drugs,”which are targeted
`for small numbers of patients who have rare condi—
`lioris or diseases for which there are no satisfactory
`alternative treatments.
`For certain changes in a previously approved
`NDA, such as a labeling or formulation change, a
`manufacturer is required to submit for approval a
`Supplemental New Drug Application (SNDA).
`An Abbreviated New Drug Application (ANDA)
`is used to gain approval to market a duplicate prod—
`uct (usually a crunpeting generic product) to one
`that had been approved previously and marketed
`by the pioneer, or original sponsor, of the drug. in
`these instances, the sponsor of the ANDA provides
`documentation on lltE.‘ chemistry, manufacluring,
`controls, and bioavailability of lhe proposed prod—
`uct
`to demonstrate biologic enltiivalency to the
`original product {2). Clinical data on the drug’s
`safety and efficacy are not required because clinical
`studies were. previously provided by the pioneer
`SPDIWSUI.
`Federal regulati: this are varied and specific for an-
`tibiotic {.ll ups {3),- for biologics, such as human blood
`precincts and vaccines, which require approval of a
`liiologics licensing AppLicrilion (BLA) for distribu
`lion {4); for Ul‘i.‘ drugs (5),- and for animal drugs,
`which they require an investigational New Animal
`Drug Application {lNADA}, a New Animal Drug
`Application (NADA) or a Supplemental New Ani—
`inal
`lilrug Application (SNADA) (6). Medical de—
`vices, sun:h as catheters and cardiac pacemakers, fol.-
`low a separate prcmarket approval process as
`defined in the Code of Federal Regulations (7).
`The following sections are intended to serve as
`an overview of the new drug development and ap-
`pr: ival prn tress, More specific and detailed informa—
`tion may be lJl'Jlflil'll'h'l directly from the referenced
`sections; o! the Code of Federal Regulations {ll—'7).
`from rr-rlevanl
`l'illTiQEa in the Federal Register (8),
`and from other treatises on the topic (9—13).
`
`
`
`Page 4
`
`

`

`New Drug Development and Approval Process
`
`25
`
`sources:
`
` New Chemical Entity
`
`
`
`
`
`- Organic Synthesis
`- Molecular Modification
`- Isolation from Plants
`
`
`
` Preclinical Studies
`
`inciuo'ing:
`' Chemistry
`- Physical Properties
`
`. Biological
`- Pharmacology
`
`- ADME
`- Toxicology
`
`- Preformulation
`
` lnvestigatiohal New
`Drug Application (IND)
`
`
`- Submission
`. FDA Review
`
`
`Clinical Trials
`- Phase I
`. Phase II
`- Phase III
`
`
`
`
`
`Preclinical Studies (continued)
`plus:
`
`- Long-term Animal Toxicity
`
`
`0 Product Formulation
`
`. Manufacturing and Controls
`
`
`- Package and Label Design
`
`
`
`
`
`New Drug Application (NDA)
`- Submission
`- FDA Review
`- Pre-approval Plant inspection
`~ FDAAction
`
`
`
`
`
`Postmarketing
`- Phase IV Clinical Studies
`
`
`. Clinical Pharmacology/
`
`
`Toxicology
`- Additional Indications
`
`
`
`- Adverse Reaction Reporting
`- Product Defect Reporting
`
`- Product Line Extension
`Fig-.11 Schematic representation of the new drug development process,from drug discovery, through preclinical and clinical
`““9““, FDA review ofthe new drug application, and postmarkeling activities.
`
`
`
`Page 5
`
`

`

`New Drug Development and Approval Process
`
`
`Post-Marketing
`
`
`NDA Review
`
`Solve-llance
`
`
`Clinical
`Pre-Clinical
`Research and Development
`Research and
`
`
`
`Development
`
`Adverse
`
`
`
`Reaction
`
`
`Reporting
`initial Synthesis
`
`and
`
`
`Characterization
`
`
`
`Surveys I Sampling
`Testing
`
`Animal Testing
`
`
`Short-term
`
`
`\ong-lernr
` Inspections
`
`
`
`
`
`Average 1‘1: years
`
`
`
`Average Slayoaro
`Average 7yeys
`
`
`FDA 30—Day Satetv Renew
`NDA
`NDA
`Submitted
`Approved
`
`._-—-—-F'
`l-Q—a————-- Average ol Approx 15 years trom initial synthes-s to approval 0! NDA
`Fig.2.2 Time courseforthedevelopmentofanewdrug. (Adaptedfrom FDA Consumer; 21:5, 1987andNew DrugApprovals
`in 1997, Pharmaceutical Research and Manufacturers Association,January, 1998.)
`
`Drug Discovery and Drug Design
`The discovery of new drugs and their develop—
`ment into commercial products takes place acmss
`the broad scope ofthe pharmaceutical industry.The
`basic underpinning for this effort is the cumulative
`body of scientific and biomedical information gen
`eratcd worldwide in research institutes, academic
`centers, and industry. The combined efforts of
`chemists, biologists, molecular biologists, pharma—
`cologist's,
`toxicologists, statisdcians, physicians,
`pharmacists and pharmaceutical scientists, engi-
`neers, and many others are involved in the drug
`discovery and development process.
`Some phanriaceutical firms focus their research
`and development (1%ch activities on new pic
`scription drugs for human use, whereas other
`firms concentrate on the development of OTC
`medications, generic drugs, biotechnology prod—
`ucts, animal health-care drugs,.dlagnostic prod
`octs, audio: medical devices. Many of the large
`pl‘rarmaccutical companies develop and u'ianufac-
`
`ture products of various types, with some firms
`having subsidiary companies for specialized func-
`tions and products.
`intiuslty in the United
`The pharmaceutical
`States grew rapidly during World War II and in the
`years immediately Following. The upsurge in the
`domestic production of drugs and pharmaceutical
`products stemmed in part from the wartime haz-
`ards and consequent undcpendability of overseas
`shipping, the unavailability of drugs from previ‘
`ous sources, and the incrcascd need for drugs of
`all kinds, but especially those with lifesaving ca-
`pabilities. One such drug is penicillin, the antibi—
`otic which became commercially available in
`1944, 1.5 years after its discovery in [in gland by Sir
`NrTXiilltlE-PI' Fleming and '1 year before the end [If
`the war.
`Alter the war, other antibiotics were developed
`and today there is a host of thorn, with effectiveness
`against a range of pathogens'l‘hc postwar boom in
`drug discovery continued With the development of
`
`26
`
`
`
`Page 6
`
`

`

`many new agents, as vaccines to protect against
`poliomyelitis, measles, and influenza, and new
`pharmacologic categories of drugs including oral
`hypoglycemic drugs effective against certain types
`of diabetes mellitus, antineoplastic or anticancer
`drugs, immunosuppressive agents which assist the
`body’s acceptance of organ transplants, oral con-
`traceptives to prevent pregnancy, and a host of
`tranquilizers and antidepressant drugs to treat the
`emotionally distressed.
`In recent years, many new and important inno-
`vative therapeutic agents have been developed
`and approved by the FDA, including drugs to treat:
`acquired immune deficiency syndrome, AIDS
`(indinavir, Crba'vau}; refractory benign prostatic
`hyperplasia
`(finasten'de,
`Proscar); migraine
`headaches (mmatriptau, Imitrex); ovarian carci—
`noma (paclitaxel,Taxol); gastric ulcers (cimetidine,
`Tagamet); hyperlipidemia (gemfibrozil, Lopid);
`hypertension (enalapril,Vasotec),' congestive heart
`failure (carvedilol, Coreg); coronary artery disease
`(fluvastatin, Lescol); obsessive compulsive disor-
`ders (fluoxetine, Prozac); arthritis (nedocromil,
`Tilade); osteoporosis
`(alendronate, Fosamax);
`male impotence (sildenafil citrate, Viagra), infec-
`tious disease (ciprofloxacin, Cipro); and other dis-
`eases and conditions, with literally hundreds of
`potential therapeutic agents in various stages of
`clinical evaluation. Annually, approximately 40
`new molecular entities (NM'E) receive FDA ap-
`for marketing.
`In addition, many new
`dosage strengths and dosage forms of previously
`approved drugs, new generic products, and new
`biologics are approved each year.
`Not all drugs are discovered, developed, and
`first approved in the United States'There are many
`pharmact-mtical companies involved in drug re—
`search and development in other countries and
`many drugs are first marketed abroad. Many of the
`world's largest pharmaceutical companies are
`multinational iinns and have facilities for research
`{Incl development, manu facturing, and distribution
`In countries around the world.
`irrespective of
`country of origin, a drug may be proposed by its
`SPODSOI' for regulatory approval for marketing in
`ll‘le United States andi‘or in other countries. These
`:Eprovals do not occur simultaneously, as they are
`will: “ll-l“? lam, regmlations, and requirements
`Howey; GHQ-”tell country's governing authority.
`l‘eglllat-iai
`_ Ilenlntematronal effort
`to harmonize
`left‘ren? ' “011811 the work of the international
`.e on i-larmonlzation (ICE) as described
`‘
`'
`'
`-
`W C end ”I this chapfm rosters multinational
`tigapprovals.
`
`New Drug Development and Approval Process
`
`27
`
`Sources of New Drugs
`
`New drugs may be discovered from a variety of
`natural sources or created synthetically in the lab-
`oratory. They may be discovered by accident or as
`the result of many years of tireless pursuit.
`Throughout history, plant materials have served
`as a reservoir of potential new dnrgs. Yet,'only a
`small portion of the approximate 270,000 known
`plants thus far have been investigated for medici—
`nal activity. Certain major contributions to modern
`drug therapy may be attributed to the successful
`conversion of botanic folklore remedies into mod—
`ern wonder drugs. The chemical reserpine, a tran—
`quilizer and hypotensive agent, is an example of a
`medicinal chemical
`isolated by design from the
`folklore remedy Rairwolfia serpentine. Another plant
`drug, periua‘nkie or Vii-ice insert, was first scientifi—
`cally investigated as a result of its reputation in
`folklore as an agent useful in the treatment of dia-
`betes mellitus. Plant extractives from Vince rosea
`yielded two potent drugs, which when screened for
`pharmacologic activity surprisingly exhibited anti—
`turnor capabilitiesThese two materials, vinblastine
`and vincristine, since have been used successfully
`in the treatment of certain types of cancer includ—
`ing acute leukemia, Hodgkin’s disease, lympho-
`cytic lymphoma, and other malignancies. Another
`example, paclitaxel (Taxol), prepared from an ex-
`tract from the Pacific yew tree, is used in the treat—
`ment of ovarian cancer.
`After the isolation and structural identification of
`
`active plant constituents, organic chemists may
`recreate them by total synthesis in the laboratory or
`more importantly use the natural chemical as
`the starting material in the creation of slightly dif-
`ferent chemical structures through molecule ma—
`nipulation procedures. The new structures, termed
`semisynthetic drugs, may have a slightly or vastly
`different pharmacologic activity than the starting
`substance, depending on the nature and extent of
`chemical alteration. Other plant constituents that in
`themselves may be inactive or rather unimportant
`therapeutically may be chemically modified to yield
`important drugs with profound pharmacologic ac—
`tivity. For example, the various species of Dioscorea,
`popularly known as Mexican yarns, are rich in the
`chemical steroid structure from which cortisone and
`estrogens are semisynthetically produced.
`Animals have served humans in their search for
`drugs in a number of ways. They not only have
`yielded to drug testing and biologic assay proce-
`dures bul also have provided drugs that are man—
`nered from their tissues or through their biologic
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
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`
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`
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`Page 7
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`

`

`28
`
`New Drug Development and Approval Process
`
`processes. Hormonal substances such as thyroid ex—
`tract, insulin, and pituitary hormone obtained Erorn
`the endocrine glands of caltle, sheep, and swine are
`lifesaving drugs used daily as replacement therapy in
`the human body. The urine of pregnant mar-es is a
`rich source of estrogens. Knowledge of the structural
`architecture of the individual hormonal substances
`has produced a variety of synthetic and semisyu-
`thetic compounds with hormone—like activity. The
`synthetic chemicals need as oral contraceptives are
`notable examples.
`The use of animals in the production of various
`biologic products,
`including serums, antitoxins,
`and vaccines, has been of lifesaving significance
`ever since the pioneering work of Dr. Edward Jen—
`ner on the smallpox vaccine in England in ‘t796.'Io--
`day, the poliomyelitis vaccine is prepared in cul—
`tures of renal monkey tissue,
`the mumps and
`influenza vaccines in tiuids of chick embryo, the
`rubella (German measles] vaccine in duck embryo,
`and the smallpox vaccine from the skin of bovine
`calves inoculated with vaccinia virus. New vaccines
`for diseases as AIDS and cancer: are being devel—
`oped through the use of cell and tissue cultures.
`Today, we are witnessing a new era in the devel—
`opment of phannaceutical products due to the ad-
`vent of genetic engineering, the sub—microscopic
`manipulation of the”double helix,”the spiral DNA
`chain of liloThrough this process, will come more
`abundant and vastly purer antibiotics, vaccines,
`and yet unknown chemical and biological products
`to combat human disease.
`There are two basic technologies that drive the
`genetic field of drug development; they are recom—
`binant DNA (rDNA) and monoclonal antibody
`(MoAB) production (14—16). Common to each
`technique is the ability to manipulate and produce
`proteins, the building blocks of living matter. Pro—
`teins represent an almost infinite source of drugs,
`Made up of long chains of amino acids, their se—
`quence and spatial configuration otter a staggering
`number of possibilities. Both recombinant DNA
`and monoclonal antibody production techniques
`influence cells in their ability to produce proteins.
`"the more fundamental of the two techniques is
`recombinant DNA. it can potentially produce at—
`most any protein. Genetic material can be trans--
`planted from higher species, such as humans, into
`a lowly bacterium. This so—calied "gone splicing"
`can induce the lower organism to make proteins, it
`would not otherwise have made. Such dnrg prod—
`ucts as human insulin, human growth hormone,
`hepatitis B vaccine, epoetiu alpha, and interferon
`are being produced in this manner.
`
`Whereas recombinant DNA techniques involve
`the manipulation of proteins Witl'rirr the cells of
`lower animals, monoclonal antibody production is
`conducted entirely within the cells of higher ani—
`mals, including the patient'l'lre technique exploits
`the ability of cells that have the potential to produce
`a desired antibody and stimulates an unending
`stream of pure antibody production. These anti-
`bodies then have the capacily to combat the spe—
`cific target.
`Monoclonal on tihr idles have an enormous poten-
`tial to change the face of medicine and pharmacy in
`the next decade and applications for their use are al -
`ready in progress. Diagnostically, for example, mon—
`oclonal antibodies are used in home pregnancy test
`ing products. Their use ensures that a Woman can
`perform the test easily, in a short period, with high
`reproducibility, and in an inexpensive manner. in
`these tests, the monoclr ii 1.31 antibody is highly sensi --
`tive to binding on one site on the human chorionic
`gonadotropin (NCO) molecule, a specific marker to
`pregnancy because in healthy women, HCG is syn—
`thesized exclusively by the placenta. in medicine,
`monoclonal antibodies are being used to stage and
`to localize malignant cells of cancer, and it is antici—
`pated that [boy will be used in the future to combat
`disease sum as lupus crytlrernatosus, juvenile—onset
`diabetes, and myaslhenia gr'avis.
`Human gene therapy, used to prevent, lreat, cure,
`diagnose, or mitigate human disease caused by ge—
`netic disorders, represents another promising1 new
`technology. The human body contains up to
`100,000 genes. Genes that are aligned on a double
`strand of DNA in the nucleus of every cell control
`all of the body's tr r nctions. Base pairs of adenine (A)
`and thymine (I), and cytosine (C), and guanine
`(G), constitute the instructions on a gene. Only
`those genes necessary for a specific cell's {unction
`are active or expressed, When H gene is expressed,
`a specific type of protein rs produced. in genetic-
`based diseases, gene expression may be altered
`andlor ger're sequences may be mismatcherzl, partly
`missing, or repeated too many times, causing cellu—
`lar malfunction and disease.
`Gene therapy is .4 medical intervention based on
`the rrim‘liiication of the genetic material of living
`cells. Cells may he n'mrliiietl outside the body (ex
`vivo) for subsequent adrr'rrnistration, or they may
`be modified within llrc body (in vivo) by gene ther-
`apy products given directly to the patient. in either
`case, gene therapy involves the transfer of new
`genetic material ll: the cells of a patient atfliClDd
`with a'gerroiic discaso'l‘lrc genetic rrrrrterial, usually
`clor'red UNA, may he transferred into the paticrfil'S
`
`
`
`Page 8
`
`

`

`New Drug Development and Approval Process
`
`29
`
`cells physically, as through rnicroinjection, through
`chemically mediated transfer procedures, or through
`disabled retroviral gene transfer systems that inte—
`grate genetic material directly into the host cell chro—
`mosomes (17—19)
`The first human gene therapy used was to treat
`adenosine deaminase {ADA} deficiency, a condition
`that results in a bnormal functioning of the immune .
`syslem. Therapy consisted of the administration of
`genetically modified cells capable of producing
`ADA (18). Many emerging biopharrnaceutical com—
`panies are exploring the application of gene therapy
`to treat sickle cell anemia, malignant melanoma, re—
`nal cell cancer, heart disease, Familial hypercholes~
`teremia, cystic Fibrosis, lung and colorectal cancer.
`and AIDS. The first commercialized gene therapy
`product is expected to reach the market soon after
`the publication date of this textbook {20}.
`Although there is justified excitement and great
`expectation for the potential of the new biotech—
`nologies in the development of advanced thera—
`pies, the work of the synthetic organic chemist re-
`mains today’s most usual source of new drugs. The
`modern chemists’s work is enhanced by computer-
`based molecular modeling, access to hugh chemi-
`cal libraries, and through the use of high through~
`put screening in discovering compounds having an
`affinity for specific biological target sites (21—22).
`
`A ”Goal Drug”
`
`In theory, a”goal drug”would produce the specif—
`ically desired effect, be administered by the most
`desired-route (generally orally) at minimal dosage
`and dosing frequency, have optimal onset and do—
`ralion of activity, exhibit no side effects, and fol-
`lowing its desired effect would he etimina ted from
`the body efficiently, completely, and without resid—
`ual effect. It would also be easily produced at low
`“35*, he pharmaceutically elegant, and physically
`and chemically stable under various conditions of
`use and storage. Although not completely attain—
`able in practice, these qualities and features are
`”Ugh! in drug and dosage form design.
`
`Methods of Drug Discovery
`‘1 Allh'fmlll': some drugs may be ”'18 result of fortu—
`lfi‘fi“ d'SLi‘WBF)’. most drugs are the result of care-
`3” deslfined research programs of screening,
`.
`.
`_
`iloleml‘“ nmdllttfalton, and mechanism—based
`‘ mil design (23),
`Random
`.
`‘
`’
`.
`.
`_
`DI' nontvu‘ua
`:
`in red screwing involves the
`(J‘
`-
`-
`-‘
`'
`1 large numbers of synthetic organlc com—
`
`pounds or substances of natural origin for biologic ac-
`tivity. Random screens may be used initially to detect
`an unknown activity of the test compound or sub-
`stance or to identify the most promising compounds
`to be studied by more sophisticated rmrurmrlom or tar—
`geted screens to determine a specific activity.
`Although random and nonrandom screening
`programs can examine a host of new compounds
`for activity, sometimes promising compounds may
`be overlooked if the screening models are not sen -
`sitive enough to reflect accurately the specific dis—
`ease against which the agent, or its metabolites,
`may be useful (24).
`To detect and evaluate biological activity, bioes-
`sriys are used to differentiate the effect and potency
`(strength of effect) of the test agent compared with
`controls of known acljon and effect. The initial
`bioassays may be performed in vilro using cell cul -
`Lures to test the new agent’s effect against enzyme
`systems or tumor cells, whereas subsequent blues--
`says may be performed in Vivo and involve more
`expensive and disease—specific animal models.
`Newer methods, as high throughput screening,
`are capable of ez'ramining 15,000 chemical com—
`pounds a week using 10—20 biological assays (22).
`To be effective, this requires a sizeable and chemi—
`cally diverse collection of compounds to examine,
`Which many pharmaceutical and chemical compa-
`nies have in"chemical libraries.” Frequently these
`libraries, which may contain hundreds of thou—
`sands of compounds, are purchased or licensed
`from academic or commercial sourceslVlfith the ad-
`vent of techniques as combinatorial chemistry, it
`has become feasible to increase substantially the
`size and diversity of a chemical library (22).
`Molecular modification involves the chemical ul-
`teral'ion of a knoWn and previously characterized
`organic compound (frequently a feed compound; see
`next section) for the purpose of entrancing its use
`futoess as a drug. This could mean—enhancing its
`specificity for a particular body target site; increas—
`ing its potency; improving its rate and extent ofah—
`sorption; modifying to advantage its time—course in
`die body; reducing its toxicity; or changing its phys—
`ical or chemical properties {e.g., solubility) to pm‘
`vide pharmaceutically desired features (2.3). The
`molecular modifications may be slight or substan-
`tial, involving changes in functional groups, ring
`structures, or configuration. Knowledge of chemi-
`cal structure—pharmacologic activity relationships
`{BAR} plays an important role in designing new
`drug molecules. Through molecular modification,
`new chemical entities and improved therapeutic
`
`agents result. Figures EBA and 2.313 present the
`
`Page 9
`
`

`

`30
`
`New Drug Development and Approval Process
`
`
`BETA-BLOCKERS
`
`Cl
`
`Cl
`
`CHa
`OH
`CH3
`/
`I
`/
`“cs.
`I.
`|( )]—CH—_CH2— NH—Ctl “CH—CHZ— NH —cn
`AV
`_
`CH3
`_CH3
`
`|
`o— CHE—CH
`
`CH3
`/
`CHZW NH ~cu
`.
`CH3
`
`Dichloroisoproterenol
`1957
`
`—> Pronethalol
`1962
`
`——h— Propranolol’
`1964
`
`Progress leading to the first commercial beta-blocker. Dichloroisoproterenol—iirst compound
`with beta-adrenoceptor blocking action; had partial agonist (sympathomimetic) activity.
`Pronethalol—beta-adrenoceptor blocking agent, relatively free from sympathomimetic activity.
`Clinical use limited by side effects, including light-headedness, incoordination, nausea and
`vomiting. Propranolol—beta-adrenoceptor blocking agent. free of sympathomimetic activity,
`and lacking side effects of pronethalol in humans.
`
`(CH2)4NHCNHCH3
`Fri
`
`H2 ANTAGONISTS
`
`CHZS(CHZ)2NH CNHCHa
`0H3
`H-t
`v
`HN
`N
`
`H30
`‘ 2
`
`”bl/<1
`
` oral bioavailability. Produced reversible agranulocytosis in some people. Cimetidine—
`histamine H2-receptor blocking agent, good oral bioavailability. No agranulocytosis in man. “Final Compound
`
`CHZS(CH2)2NH CNHCHa
`it
`
`NOE N
`
`Burimamide
`1972
`
`-—-—-II- Metiamide —I-- Cimetidine"
`1973
`1975
`
`Progress leading to the first commercial ulcer drug. Burimamide—first histamine H2-receptor
`blocking agent. poor oral availability. Metiamide—histamine H2-receptor blocking agent. good
`
`Fig. 2.3 Molecular modifications leading to the development of thefirst commercial beta blocker, propranolol, and the first com-
`mercial histamine Hz—receptor blocking agent, cimetidine. (Reprinted with permission from Maxwell RA "the state of the art ofthe
`science ofdrug discovery. Drug Development Research 1984;4:375—389; through Pharmaceutical Research: Therapeutic and Eco-
`nomic Wine ofIncremental Improvements, 1990, p. 12. Courtesy ofNational Pharmaceutical Council, Reston, VA).
`
`molecular modifications that led to the discoveries
`
`of the first commercial beta blocker, propranolol,
`and the first commercial histamine Hz-receptor
`blocking agent, cimetidine.
`Mechanism-based drug design involves molecular
`modification in designing a drug that interferes
`specifically with the known or suspected biochem-
`ical pathway or mechanism of a disease process.
`The intention is the interaction of the drug with
`specific cell receptors, enzyme systems, or the
`metabolic processes of pathogens or tumor cells,
`
`resulting in a blocking, disruption, or reversal of the
`disease process. In designing drugs on this basis, it
`is essential to understand the biochemical pathway
`of th