ENCYCLOPE
`
`DIA OF
`
`CONTI
`ROLLED DRUG
`
`VOLUME
`
`1
`
`Edith Mathiow
`Brown University
`le Island
`Providence, Rho(
`
`itZ
`
`A Wiley- Interscience
`John Wiley &
`New York / Chiches
`
`Publication
`ions, Inc.
`ter / Weinheim / Brisbane / Singapore / Torontc
`
`Y Gougle
`
`Li N V
`
`ALL 2200 ZZ
`PROLLENIUM V. ALLERGAN
`IPR2019-01505, et al.
`
`

`

`This book is printed on acid -fr
`se paper. (4
`
`ey & Sons, Inc. All rights reserved.
`Copyright © 1999 by John Wil
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`drug delivery / Edith Mathiowitz.
`
`ring -in- Publication Data:
`Library of Congress Catalog
`Mathiowitz, Edith, 1952
`Encyclopedia of controlled
`p. cm.
`Includes index.
`cloth : alk. paper). -ISBN
`ISBN 0- 471- 14828 -8 (set :
`iper). -ISBN 0- 471 -166634 (vol 2 :
`0- 471 -16662 -6 (vol 1 : alk- pE
`alk. paper)
`1. Drugs - Controlled relef
`I. Title.
`ise Encyclopedias.
`[DNLM: 1. Drug Delivery f.
`systems Encyclopedias - English.
`Carriers Encyclopedias -En,
`glish. QV 13 M431e 1999]
`RS201.C64M38 1999
`615.7 -dc21
`DNLM/DLC
`for Library of Congress
`
`2. Drug
`
`99 -24907
`CIP
`
`Printed in the United States 01
`
`['America.
`
`10 9 8 7 6 5 4 3 2 1
`
`Digitized b.
`
`Go gle
`
`Original from
`ERSITY OF MICHIGAN
`
`

`

`:00D AND DRUG ADMINISTRATION REQUIREMENTS FOi
`
`t CONTROLLED RELEASE PRODUCTS
`
`381
`
`Hubert, and E. Nieachlag, J. Clin.
`84. H.M. Behre, D. Nashan, W. :
`Endoerinol. Metab. 74, 84-f
`)0(1992).
`85. I.T. Cameron and D.T. Bs
`Lird, Contraception 33, 121 -125
`(1986).
`86. M. Bygdeman et al., Contra
`
`ception 27, 141-151 (1983).
`
`FOOD AND DRUG AD/
`MINISTRATION
`REQUIREMENTS FOR CI
`ONTROLLED RELEASE
`PRODUCTS
`
`HENRY J. MALINOWSKI
`PATRICK J. MARROUM
`U.S. Food and Drug Adminie
`Rockville, Maryland
`
`Itration
`
`KEY WORDS
`
`Area under the curve (AL
`JC)
`Bioavailability
`Bioequivalence
`Controlled release
`Delayed release
`Dissolution
`Extended release
`In vitro in vivo correlatioi
`Modified release
`n (Cm,)
`Peak plasma concentratic
`Pharmacokinetics
`
`n (IVIVC)
`
`OUTLINE
`
`uidances for Controlled -
`
`Introduction
`Types of Controlled -Reles
`sae Products
`Definitions
`Laws, Regulations and G'
`Release Products
`Need for Clinical Stud
`ies
`tequirements for Controlled
`Bioavailability Study I
`Release Products
`Controlled -Release Ne
`w Drug Applications
`Information to Character
`ize the Drug Entity
`acterization
`Physicochemical Char,
`Pharmacokinetic Char
`acterization
`Information to Character
`ize the Dosage Form
`icterization
`Physicochemical Char,
`ivalence Studies
`BioavailabilityBioequ
`Dissolution Testing for
`Controlled- Release Drug
`Products
`Setting Dissolution Sp
`Bibliography
`
`ecifications
`
`INTRODUCTION
`
`utical dosage forms may offer
`Controlled- release pharmace
`one or more advantages over
`r conventional (immediate re-
`
`Digitized by
`
`Go plc
`
`ms of the same drug, including a reduced
`lease) dosage for
`a decreased incidence and /or intensity of
`dosing frequency
`adverse effects,
`3 greater selectivity of pharmacologic ac-
`tivity, and a redu
`ction in drug plasma fluctuation resulting
`it or prolonged therapeutic effect. In some
`in a more constaz
`cases, controlled
`-release products may be therapeutically
`imarily for certain subpopulations of pa-
`advantageous pr
`tienta. For exam]
`ple, a controlled- release drug product may
`ttend school without drug administration
`allow a child to a
`during the schc
`>ol day. In other instances, controlled -
`may have no significant advantages or
`release products
`less effective or more hazardous than con-
`may actually be
`forms of the same drug. Therefore, not all
`ventional dosage
`:andidates for formulation as controlled-
`drugs are good c
`)ducts (1). For example, some drugs are
`release drug pre
`fluctuation in plasma concentrations oc-
`more effective if
`cur. For such do
`ugs, tolerance to drug effect may develop
`with the constan
`t levels seen with controlled -release drug
`irily, oral controlled -release dosage forms
`products. Ordine
`result in a long,
`er recommended dosing interval for the
`e dosage form, usually twice as long, corn -
`controlled -releas
`pared with the c
`losing interval for the immediate release
`dosage form. Ale
`;o, a controlled -release drug product may
`be warranted if
`significant clinical advantages for the
`e dosage form can be demonstrated, for
`controlled -releas
`sed side effects resulting from a lower
`example, decrea
`centration with the controlled -release dos -
`peak plasma cony
`age form relativ(
`) to the immediate -release dosage form.
`
`TYPES OF CONTI
`
`ROLLED -RELEASE PRODUCTS
`
`>n type of controlled- release products are
`The most comme
`s. These products normally provide for a
`oral dosage form
`sing interval. Dosing intervals for oral
`12- or 24 -h dos
`controlled -releas
`e products beyond once -a -day dosing are
`>logic characteristics of the human gastro-
`limited by physic
`intestinal tract.
`Gastrointestinal transit time, which nor -
`i4 h but can vary from a few hours to sev-
`mally averages
`its oral controlled -release products with a
`eral days, prever
`beyond 24 h. Other types of controlled -
`dosing interval
`include transdermal patches that are ap-
`release products
`plied to the skin
`for periods of 1 day to perhaps 1 week. In
`lied- release implants are dosage forms
`addition, contro
`that are implant
`ed below the skin surface and have been
`itinuous therapy for as long as 5 years.
`developed for cor
`
`DEFINITIONS
`
`Before beginning
`menta of control]
`stand several cor
`products:
`
`a discussion of the regulatory require -
`led- release products, it is useful to under -
`nmonly used definitions for these types of
`
`Controlled -reg
`ticals or other
`drug is releas
`predictable, a
`Modified -relec
`a dosage form
`of time course
`
`:ease dosage forms. A class of pharmaceu-
`biologically active products from which a
`ed from the delivery system in a planned,
`nd slower- than -normal manner (2).
`zse dosage form. This refers, in general, to
`for which the drug- release characteristics
`and /or location are chosen to accomplish
`
`Original from
`=RSITY OF MICHIGAN
`
`

`

`382
`
`FOOD AND DRUC
`
`ADMINISTRATION REQUIREMENTS FOR CONTROLLED RI
`
`ELEASE PRODUCTS
`
`therapeutic or convenii
`ence objectives not offered by con-
`ventional dosage form,
`s (2).
`ge form. This is a specific type of
`Extended- release doses
`;e form that allows at least a two-
`modified -release dosag
`fold reduction in dosas
`;.e frequency as compared to that
`drug presented as an
`L immediate- (conventional -) re-
`lease dosage form (2).
`? form. This is a specific type of
`Delayed - release dosage
`;e form that releases a drug at a
`modified -release doses
`time other than prom
`ptly after administration. An ex-
`ample is enteric- coatei
`tablets (2).
`
`cussed in this article cover all
`The requirements dia
`e dosage forms. The primary fo-
`types of controlled -releas
`[led- release drug products, which
`cus will be on oral contro]
`iuirements for other types of
`are most common. Rec
`products, such as transdermal
`controlled -release drug
`similar to those described in this
`patches or implants, are
`article.
`
`D GUIDANCES
`LAWS, REGULATIONS AN
`SE PRODUCTS
`FOR CONTROLLED -RELEß
`
`Need for Clinical Studies
`
`i of a controlled- release product
`Premarketing evaluation
`should include considera
`fion of the possible development
`of tolerance to the drug,
`the occurrence of sensitivity re-
`actions or local tissue
`damage due to dosage -form-
`localization of the drug, the clini-
`dependent persistence or
`dumping or of an unexpected
`cal implications of dose
`decrease in bioavailabili
`ity by physiological or physico-
`d a quantitative alteration in the
`chemical mechanisms, an
`ug related to nonlinear or site-
`metabolic fate of the dr
`specific disposition.
`Il therapeutic advantages of a
`Specific claims for a
`t over the conventional dosage
`controlled -release produc
`forms should be based on
`adequate clinical studies, the re-
`available to health professionals
`sults of which should be
`upon request. Where no t
`herapeutic advantage is claimed,
`the need for clinical studi
`Les may be lessened.
`3ration for the development of
`An important considi
`ts as original new drugs is the
`controlled- release produc
`ed in particular circumstances to
`quantity of evidence need
`oof of effectiveness. The usual
`establish substantial pr
`:ular entities is to accept as proof
`practice for all new molec
`lies that conclusively define the
`two or more clinical stuc
`drug. Within the U.S. Food and
`safety and efficacy of the
`A) Modernization Act of 1998 are
`Drug Administration (FD
`rhich alternative approaches re-
`described situations in v
`garding the quantity of E
`rvidence to support effectiveness
`,e include (1) situations in which
`may be possible (3). Thee
`effectiveness of a new ui
`se may be extrapolated entirely
`lies; (2) situations in which a sin -
`from existing efficacy stuc
`trolled study of a specific new use
`gle adequate and well -con
`rmation from other related ade-
`can be supported by info
`studies, such as studies in other
`quote and well -controlled
`phases of a disease; in c
`losely related diseases; or other
`conditions of use (differen
`t dose, duration of use, regimen),
`or of different endpoints; and
`of different dosage formi
`
`Digitized b.
`
`Go gte
`
`(3) situations
`in which a single multicenter study, without
`iformation from other adequate and well -
`supporting it
`Ldies, may provide evidence that a use is ef-
`controlled stu
`:h of these situations, it is assumed that any
`fective. In eac
`studies relied
`on to support effectiveness meet the require -
`quate and well -controlled studies in 21 CFR
`ments for ade
`314.126 (4). Ii
`t should also be appreciated that reliance on
`or with sub-
`r of a given use, whether
`a single stud
`stantiation fr
`orn related trial data, leaves little room for
`actions or contradictory (nonsupportive) in-
`study imperfi
`formation. In
`all cases, it is presumed that the single study
`has been apf
`Iropriately designed; that the possibility of
`bias due to
`baseline imbalance, unblinding, post hoc
`changes in ar
`ialysis, or other factors is judged to be min-
`mal; and that
`t the results reflect a clear prior hypothesis
`documented i
`n the protocol. Moreover, a single favorable
`failed to sup -
`several similar attempts
`study among
`of effectiveness would not constitute persua-
`port a finding
`br a product use unless there were a strong
`sive support I
`discounting the outcomes in the studies that
`argument for
`failed to show
`effectiveness (e.g., if the study was obviously
`powered or there was a lack of assay sensi-
`inadequately
`onstrated in a three -arm study by failure of
`tivity as demi
`the study to s
`how efficacy of a known active agent).
`Whether ti
`3 rely on a single study to support an effec-
`mination is not often an issue in contempo-
`tiveness deter
`relopment. In most drug development situa-
`rary drug de,.
`ed to find an appropriate dose, to study
`dons, the ne
`cater and lesser complexity or severity of dis-
`patients of gri
`are the drug with other therapy, to study an
`ease, to comp
`nber of patients for safety purposes, and to
`adequate nur
`otherwise km
`)w what needs to be known about a drug be-
`keted will result in more than one adequate
`fore it is marl
`rolled study upon which to base an effective -
`and well -cont
`iation.
`ness determir
`In certain
`cases, effectiveness of a new controlled -
`product may be demonstrated without addi-
`release drug ]
`te and well- controlled clinical efficacy trials.
`tional adequa
`is will be because other types of data provide
`Ordinarily, th
`the known effectiveness to a new population
`a way toappl3
`or a different
`dose, regimen, or dosage form. Controlled -
`a forms may be approved on the basis of phar-
`release dosage
`lata linking the new dosage form to a previ-
`macokinetic c
`immediate- release dosage form. Because the
`ously studied
`atic patterns of modified - and immediate -
`pharmacokini
`e forms are not identical, it is generally im-
`release dosag
`portant to ha,
`ve some understanding of the relationship of
`ration to response, including an understand -
`blood concent
`ing of the tin
`ie course of that relationship, to extrapolate
`the immediat
`e- release data to the modified- release dosage
`form (3).
`
`Bioavailability
`Products
`
`The bioavaili
`products are
`fions under é
`quirements a
`are met:
`
`Study Requirements for Controlled Release
`
`ability requirements for controlled- release
`covered in the U.S. Code of Federal Regula-
`;1 CFR 320.25(f) (5). The aims of these re-
`re to determine that the following conditions
`
`Original from
`=RSITY OF MICHIGAN
`
`

`

`FOOD AND DRUG ADMINISTRATION REQUIREMENTS FOI
`
`t CONTROLLED RELEASE PRODUCTS
`
`383
`
`u
`
`s the controlled - release claims
`
`The drug product meet
`made for it.
`)file established for the drug
`The bioavailability pr(
`product rules out the c
`occurrence of clinically signifi-
`is usually achieved by the
`cant dose dumping. Tl
`conduct of a food effec
`t study whereby the drug is
`administered with and
`without a high -fat breakfast.
`steady -state performance is
`The drug product's
`equivalent to a current
`ly marketed noncontrolled- or
`g product that contains the
`controlled -release drug
`same active drug ingr
`edient or therapeutic moiety
`and that is subject to s
`in approved full new drug ap-
`plication.
`mulation provides consistent
`The drug product's for
`wmance between individual
`pharmacokinetic perfi
`dosage units.
`
`The reference material fa
`T such a bioavailability study
`shall be chosen to permit ax
`u appropriate scientific evalu-
`ise claims made for the drug
`ation of the controlled -reles
`product. The reference mate
`rial is normally one of the fol-
`lowing:
`
`n of the active drug ingredient
`
`A solution or suspensio
`or therapeutic moiety
`A currently marketed
`immediate -release drug prod -
`uct containing the sal
`ne active drug ingredient or
`d administered according to
`therapeutic moiety an
`Iodations in the labeling of
`the dosage recommei
`immediate -release drill
`g product
`A currently marketed
`controlled -release drug prod -
`uct subject to an appro
`ved full new drug application
`containing the same a,
`ctive drug ingredient or ther-
`'ministered according to the
`apeutic moiety and ac
`ns in the labeling proposed for
`dosage recommendatio
`the controlled- release c
`írug product
`
`Guidelines for the evaluat
`ion of controlled -release phar-
`ovide assistance to those de-
`maceutical dosage forms pr
`aluating studies. However, a
`signing, conducting, and ev
`)roperties that require consid-
`drug may possess inherent F
`erations specific to that drug
`and its dosage form that may
`override the generalities oft]
`hese guidelines. Guidances re-
`lated to the evaluation of cox
`itrolled- release drug products
`as well as many other types
`of guidances are available on
`the Internet at the Center
`for Drug Evaluation and Re-
`search Web site (http: / / ww,
`w.fda.gov /cder I).
`
`Controlled- Release New Drug
`Applications
`lamental question in evaluat-
`As mentioned earlier, a func
`ing a controlled -release prod
`luct is whether formal clinical
`studies of the dosage form's
`safety and efficacy are needed
`kinetic evaluation will provide
`or whether only a pharmacol
`val. A rational answer to this
`adequate evidence for appro
`question must be based on E
`evaluation of the pharmacoki-
`concentration /effect relation -
`netic properties and plasma
`ship of the drug. Where the:
`re is a well -defined predictive
`plasma concentrations of the
`relationship between the p
`drug and the clinical respon
`se (regarding both safety and
`
`efficacy), it may I
`data alone as a
`release product.
`that clinical dat
`controlled -releas
`
`* possible to rely on plasma concentration
`basis for the approval of the controlled -
`In the following situations, it is expected
`a be submitted for the approval of the
`e New Drug Application (NDA):
`
`When the c
`that is an u
`there is no i
`equivalence
`When the
`efficacy anc
`When a chi
`for the coni
`When then
`reversible t
`Where thei
`tionship be
`peutic and
`defined rely
`and either
`Where the]
`codynamic)
`Where pea]
`release fort
`
`controlled- release product involves a drug
`Lnapproved new molecular entity, because
`approved reference product to which a bio-
`claim could be made
`rate of input has an effect on the drug's
`i toxicity profile
`Lim of therapeutic advantage is intended
`;rolled- release product
`e are safety concerns with regards to ir-
`oxicity
`re are uncertainties concerning the rela-
`stween plasma concentration and thera-
`adverse effects or in the absence of a well -
`ationship between plasma concentrations
`therapeutic or adverse clinical response
`-e is evidence of functional (i.e., pharma-
`i tolerance
`k- to-trough differences of the immediate -
`n are very large
`
`In all of these
`NDA could be su
`ulations for sucl
`314.54. These re
`approval of a do
`of a listed drug,
`dosage form, anc
`availability or bi
`approval of the
`tion. However, s
`under this sectii
`whose only differ
`the extent of abs
`that of the refere
`is unintentional
`drug (6).
`
`instances except for the first, a 505(bX2)
`bmitted for approval to the FDA. The reg-
`a application are covered under 21 CFR
`sgulations state that any person seeking
`ig product that represents a modification
`for example, a new indication or a new
`i for which investigations other than bio-
`ioequivalence studies are essential to the
`changes may submit a 505(bX2) applica-
`uch an application may not be submitted
`an of the regulations for a drug product
`'ence from the reference-listed drug is that
`sorption or rate of absorption is less than
`nce-listed drug or if the rate of absorption
`ly less than that of the reference -listed
`
`INFORMATION 1
`
`7O CHARACTERIZE THE DRUG ENTITY
`
`Physicochemical
`Although the ri
`characterize the
`form should gene
`entity in an im
`physicochemical
`tion, stability, a
`the drug under e
`the physiologic
`form is necessar
`
`Characterization
`equired physicochemical information to
`drug entity in a controlled -release dosage
`rally be no different from that for the drug
`mediate -release dosage form, additional
`information related to solubility, dissolu-
`nd other release -controlling variables of
`onditions that may mimic the extremes of
`environment experienced by the dosage
`Y (7).
`
`Pharmacokinetic
`
`Absorption. II
`bioavailability at
`
`Characterization
`t is necessary to characterize the relative
`ad the fractional absorption profile versus
`
`Digitized b.
`
`Go gte
`
`Original from
`=RSITY OF MICHIGAN
`
`

`

`384
`
`FOOD AND DRUG A
`DMINISTRATION REQUIREMENTS FOR CONTROLLED RELI
`
`EASE PRODUCTS
`
`time for the drug entity in
`the controlled- dosage form to
`evaluate the input profile c
`if the controlled- release dosage
`form. This can be achieve(
`I by using deconvolution tech -
`niques that allow one to c
`ietermine the fraction of drug
`absorbed versus time. Two
`commonly used techniques are
`d, which is used for drugs ex-
`the Wagner- Nelson metho
`)harmacokinetics, and the Loo
`hibiting one - compartment F
`s with two -compartment phar-
`Riegelman method, for drug
`macokinetic characteristics
`s. The fractional absorption in-
`put profile can serve to ass
`ess the drug -release claims for
`that formulation. Further
`drug- release -rate and release -
`rate constants can be deter
`rmined from the fractional ab-
`sorption data. Moreover, t]
`his information, together with
`tics for the drug entity, can be
`the disposition characteris
`used to characterize and pi
`edict changes in the bioavaila-
`+hen input is modified for the
`bility of the drug entity v
`forms. For example, the drug
`controlled -release dosage i
`may exhibit saturable fi
`rst -pass hepatic metabolism,
`which could result in decree
`ised systemic availability when
`the input rate is decreased.
`Although it may not be s
`signing a controlled- releas(
`to determine the absorptior
`tity in various segments of
`ticularly the colon for dosai
`in the color) (8).
`
`regulatory requirement in de-
`dosage form, it may be useful
`characteristics of the drug en-
`the gastrointestinal tract (par-
`se forms that may release drug
`
`Disposition. The inform
`ation required to characterize
`r the drug entity in a controlled-
`the disposition processes foi
`release dosage form should
`include those generally deter -
`mined for the drug entity i]
`n an immediate -release dosage
`form. This may include the
`following:
`
`rs-clearance, volume of distri-
`Disposition paramete.
`n residence time, or model de-
`bution, half -life, meal
`rtmental parameters
`pendent or noncompa
`Linearity or character
`ization of nonlinearity over the
`ition range that could possibly
`dose and /or concentri
`be encountered
`Accumulation of drug
`doses
`Ratio of parent drug i
`to metabolites if different from
`)ducts
`immediate- release pr(
`
`in the blood following multiple
`
`on is usually not included in a
`The following informatil
`t is known from the develop -
`controlled- release NDA bu
`ment of the molecular entii
`:y as an immediate- release for-
`mulation:
`
`Metabolic profile anc
`i excretory organ dependence
`with special attentior
`to active metabolites and ac-
`tive enantiomers of ra
`icemic mixtures
`Enterohepatic circula
`Lion
`neters and dialyzeability
`Protein- binding parar.
`r, race, and relevant disease
`Effect of age, gende
`Lion from the controlled -release
`states on drug disposii
`drug product.
`Plasma/blood ratio
`
`Digitized b.
`
`Go gle
`
`In addition, in
`morning or at
`the clinical res
`the time of the
`ability in the d
`codynamics
`bE
`changes in the i
`on safety and e
`
`cases where the drug can be given in the
`bed time or where there is evidence that
`ponse varies significantly as a function of
`day, it is recommended that circadian vari-
`rug's disposition parameters and pharma-
`characterized to determine whether
`-ate of drug input with time have an impact
`fficacy.
`
`INFORMATION
`
`TO CHARACTERIZE THE DOSAGE FORM
`
`Physicochemical
`Similar charact
`of the dosage fc
`entity. Dissolut
`obtained, with
`mulation chant
`mination of wh
`mulation is del
`as pH, rotation
`Characterizatic
`in purely aque
`small amounts
`where bile salti
`
`I Characterization
`erization of the physicochemical properties
`)rm should be undertaken as for the drug
`ion profiles from pH 1 to pH 7.4 should be
`particular attention to the effect of the for-
`es on dissolution characteristics. A deter -
`ether the release of the drug from the for -
`)endent on the dissolution conditions such
`speed, and type of apparatus and medium_
`In of formulations that are highly insoluble
`ous systems may require the addition of
`of surfactant to mimic in vivo conditions,
`3 act as surfactants, more closely.
`
`Bioavailability /E
`The type of bio.
`out depends up
`clinical pharm
`whether bioequ
`basis for produc
`controlled -relea
`oped to allow fi
`over the recomc
`keted immediat
`is sometimes pi
`the controlled -r
`Each strengi
`be included in
`erence treatme
`lation whether
`or a suspensior
`the bioequivale
`sessed. Also, a i
`highest dose of
`a reference pro
`Comparison of
`and fluctuation
`be made betwe
`reference prods
`teristics in its
`state study wou
`est strength.
`In the case <
`the dosage stre
`amount of iden
`dose and a muli
`dosage strengt:
`New Drug App
`ported by dissol
`be categorized i
`
`tioequivalence Studies
`availability studies that need to be carried
`on how much is known about the drug, its
`Lacokinetics and biopharmaceutics, and
`ivalence studies are intended to be the sole
`t approval. Several dosage strengths of the
`use dosage form should normally be devel-
`exibility for clinicians to titrate the patient
`nended therapeutic dose range of the mar-
`e- release dosage form. Scoring of the tablet
`)ssible in the case where it does not affect
`.elease mechanism of the formulation.
`th of the controlled -release product should
`a single -dose crossover that involves a ref -
`nt that can consist of an approved formu-
`immediate or controlled- release, a solution
`1. In certain cases for substitution claims,
`nce of the different strengths should be as-
`multiple-dose, steady -state study using the
`the controlled -release dosage form versus
`duct is required for NDA approval (9,10).
`such parameters such as AUC, Cm,, Tmu,
`index as well as Cm;n at steady state should
`en the controlled -release product and the
`ict. If the drug exhibits nonlinear charac-
`absorption or disposition, then a steady -
`ad also be required for the lowest and high-
`
`)f a controlled -release dosage form, where
`mgths differ from each other only in the
`tical beaded material contained, a single -
`tiple -dose steady -state study at the highest
`h will be sufficient for NDA/Abbreviated
`lication (ANDA) approval as long as sup -
`ution data. The types of studies needed can
`n the following sections.
`
`Original from
`=RSITY OF MICHIGAN
`
`

`

`FOOD AND DRUG ADMINISTRATION REQUIREMENTS FO
`
`It CONTROLLED RELEASE PRODUCTS
`
`385
`
`e Oral Dosage Form of a Mar -
`Case I: Controlled- Releas
`rug for which Clinical Studies
`keted Immediate -Release Di
`e following studies would be
`Have Been Conducted. Th
`[- release dosage forms. If ap-
`needed for most controlled
`out clinical trials, it is recom-
`provai is to be sought with
`nsultation with the regulatory
`mended that there be preco
`n adequate database exists for
`authorities to ensure that a
`such approval.
`!udy. A single -dose crossover
`Single -Dose Crossover Si
`following treatments: the
`study would include the
`rm administered under fasting
`controlled -release dosage fo:
`-elease dosage form admi.nis-
`conditions, an immediate -i
`)ns, and the controlled -release
`tered under fasting conditic
`dosage form administered ix
`nmediately after completion of
`onsisting of the following: two
`a high -fat meal typically cc
`eggs fried in butter, two str
`ips of bacon, two slices of toast
`with butter, 4 oz of hash bra
`awn potatoes, and 8 oz of whole
`her meals with 1,000 -calorie
`milk (11). Alternatively, o1
`ones derived from fat, could be
`content, with 50% of the cal
`)uld be administered immedi-
`used. The dosage form she
`:ion of the breakfast or meal.
`ately following the complet
`concluded when the 90% con-
`Absence of food effect will bi
`fidence interval for the ratic
`of means (population geomet-
`sformed data) of fed and fasted
`ric means based on log tram
`treatments fall within 80-1
`25% for AUC and 70 -143% for
`nificant differences seen in the
`Cm (11). If there are no sig
`)availability of the controlled-
`rate (Cn, ..) or extent of bic
`! effect study, then no further
`release product in this fooc
`food effect studies are necei
`3sary. If significant differences
`it would be useful to define the
`in bioavailability are found,
`cause of the food effect on
`the controlled -release dosage
`F time between meal and drug
`form as well as the effect 01
`administration on the food -
`-drug effect.
`The purposes of this stuc
`ly are to assess bioavailability,
`termine whether there is any
`rule out dose dumping, dei
`need for labeling specificai
`:ions regarding special condi-
`tions for administration wit'.
`h respect to meals, and provide
`pattern of absorption of the
`information concerning the
`controlled -release dosage fa
`arm (12). The drug input func-
`tion should be defined for ci
`ontrolled- release dosage forms
`1, for example, the Wagner -
`by an appropriate methoc
`other deconvolution methods.
`Nelson, Loo -Riegelman, or
`This will aid in assessing t:
`he release -rate characteristics
`oduct as well as in the devel-
`of the controlled- release pr
`opment of an appropriate in
`vitro dissolution test. For dos -
`age forms that exhibit high
`intrasubject variability, repli-
`cate design studies, in
`which subjects receive each
`treatment twice, are sugges
`;ted.
`An illustration of the im]
`portance of the study of the ef-
`feet of food on the bioav
`ailability of a drug from a
`ion is the case of nisoldipine
`controlled -release formulat
`(13). Nisoldipine is formula
`ted as a once -a -day controlled -
`release formulation of a dif
`iydropyridine calcium channel
`blocker that is approved in t
`;he United States for the treat-
`ment of hypertension.
`During the course of del
`relopment, a food effect study
`i that a high -fat breakfast had
`was conducted that revealec
`a profound effect on the bioa
`availability of nisoldipine from
`this formulation. As can lx
`seen from Figure 1, food in-
`acentration (C) from 2.75 to
`creased the peak plasma cot
`.75 -fold, while the area under
`7.5 ng /mL, an increase of 2
`
`Geometric means
`
`8
`
`i
`
`20
`
`i
`
`i
`
`40
`30
`Time (h)
`
`i
`
`50
`
`1
`60
`
`70
`
`Figure 1. Nisoldi
`without the admi)
`
`Tine plasma concentration time profile with and
`nistration of a high -fat breakfast.
`
`the curve (AUC
`These results ri
`efficacy of this c
`with food.
`However, an
`(PK/PD) model
`soldipine plasm,
`pressure. This i
`study in which
`were given, on E
`of nisoldipine a
`ECso was estim
`pressed as the
`23.9 mm of Hg(
`ment of the clini
`of bioavailabilit'
`formulation wh
`ship between d
`linear (the dose
`to observe an eft
`drop in diastoli)
`pose any harmf
`with some addit
`from the clinica
`bility of nisoldip
`cerns to the pati
`it was recommE
`empty stomach
`Multiple -Dosi
`the immediate -
`macokinetics, a
`release product
`dosage range) u
`a control shoulc
`trough concentr
`day should be t.
`steady state. Cc
`terval of the cc
`
`;) decreased from 70.4 to 53 ng x h /mL.
`used a question related to the safety and
`;ontrolled- release formulation when taken
`
`Emau pharmacokinetic pharmacodynamic
`established the relationship between ni-
`a concentrations and the reduction in blood
`model was constructed using data from a
`23 patients with essential hypertension
`m escalating basis, 30, 60, 90, and 120 mg
`s could be tolerated by the patients. The
`ated to be 3.54 ng /mL, and the Ems, ex-
`maximum drop in diastolic pressure, was
`14). The PK/PD model enabled the assess -
`ical impact of the rapid increase in the rate
`y of nisoldipine from this controlled- release
`en taken with food. Because the relation -
`ose and blood pressure lowering was log
`of drug would have to be increased greatly
`ect on the blood pressure) and the maximal
`blood pressure would not be expected to
`ul hemodynamic effect to the patient and,
`:ional experience in the fed state available
`I trials, the effect of food on the bioavaila-
`ine was not deemed to pose any safety con -
`ents. However, in the labeling of this drug,
`nded that Sular4, be administered on an
`for optimal efficacy (15).
`Steady -State Studies. When data exist for
`release product establishing linear phar-
`steady -state study with the controlled -
`at one dose level (at the high end of the
`sing an immediate- release formulation as
`I be conducted. At least three consecutive
`ations (Cmin) taken at the same time of the
`aken to ascertain that the subjects are at
`)ncentrations over at least one dosage in-
`)ntrolled- release product should be mea-
`
`Digitized b.
`
`Go gle
`
`Original from
`=RSITY OF MICHIGAN
`
`

`

`386
`
`FOOD AND DRUG
`
`ADMINISTRATION REQUIREMENTS FOR CONTROLLED RE
`
`LEASE PRODUCTS
`
`)ssover study. In cases where the
`sured in each leg of the crc
`interval is not 24 h, it may be
`controlled -release dosage
`centrations over an entire day in
`preferable to measure con
`asessing diurnal variation.
`each leg for purposes of a:
`deration must be given to the
`Where it exists, consi
`"therapeutic window." of
`the drug. The occupancy time,
`erce ntage of time over a dosage
`which is defined as the pi
`tration lies within the therapeu-
`interval where the concen
`tic window, should be detf
`armined.
`tion measurements should in-
`Appropriate concentra
`d major active metabolites. For
`dude unchanged drug an
`Lion should be given to specific
`racemic drugs, considerai
`measurement of the act:
`ive enantiomers. However, ap-
`lease product is based on the re-
`provai of the controlled -re
`sults of the clinical trial:
`3. The pharmacokinetic data is
`rmacokinetic and bioavailability
`used to establish the phai
`characteristics of the cont
`rolled -release formulation.
`e product is aimed at a specific
`If the controlled -releas
`le, children, it should be tested
`subpopulation, for examp
`in that subpopulation. A
`controlled -release dosage form
`to be administered at the same
`does not necessarily have
`mmediate- release reference. For
`total daily dose as for the i
`etabolism was greater for the
`example, if first -pass mi
`form, the total daily dose may be
`controlled -release dosage
`dose of the immediate release
`more than the total daily
`al patches may contain a reser-
`product. Also, transdermi
`be absorbed during the time of
`voir of drug that will not
`of differences in treatment dos -
`use of the patch. The goal
`age is to achieve equal exj
`posure.
`Steady -state studies
`in selected pat