`
`NF 21
`
`THE NATIONAL FORMULARY
`
`By authority of the United States Pharmacopeial
`Convention, Ina, meeting at Washington, DC,
`April 12—16, 2000. Prepared by the Council of Experts
`and published by the Board of Trustees
`
`Oflicial from January 1, 2003
`
`The designation on the cover of this publication, “USP NF
`2003,” is for ease of identification only. The publication
`contains two separate compendia: The Pharmacopeia of the
`United States Twenty-sixth Revision, and the National
`Formulary, Twenty-first Edition.
`
`AQUESTIVE EXHIBIT 1044
`
`AQUESTIVE EXHIBIT 1044 page 0001
`
`page 0001
`
`

`

`NOTICE AND WARNING
`
`Concerning US. Patent or Dademark Rights
`
`The inclusion in the Pharmacopeia or in the National Formulary of a monograph on any drug in respect
`to which patent or trademark rights may exist shall not be deemed, and is not intended as, a grant of, or
`authority to exercise, any right or privilege protected by such patent or trademark. All such rights and
`privileges are vested in the patent or trademark owner, and no other person may exercise the same with-
`out express permission, authority, or license secured fiom such patent or trademark owner.
`
`Concerning Use of USP or NF Text
`
`Attention is called to the fact that USP and NF text is fully copyrighted. Authors and others wishing to
`use portions of the text should request permission to do so from the Secretary of the USPC Board of
`Trustees.
`
`Copyright © 2002 The United States Pharmacopeial Convention, Inc.
`12601 Ninbrook Parkway, Rockville, MD 20852
`All rights reserved.
`lSSN 0195-7996
`ISBN 1-889788-13-9
`Printed in Canada by Webcom Limited, Toronto, Ontario
`
`AQUESTIVE EXHIBIT 1044
`
`AQUESTIVE EXHIBIT 1044 page 0002
`
`page 0002
`
`

`

`2334
`
`(1088) In Vitro and ln Vivo Evaluation / General Information
`
`
`
`USP 2‘_:_i
`
`.SP 2
`
`such as hydrodynamics (e.g., test apparatus, and disk rotation speed
`or fluid flow) and test conditions (e.g.. temperature, fluid viscosity,
`pH, and buffer strength in the case of ionizable compounds). By ex-
`posing the surface area ofa material to an appropriate dissolution me-
`dium while maintaining constant temperature, stirring rate, and pH,
`the intrinsic dissolution rate can be determined. Typically the intrinsic
`dissolution is expressed in terms of mg per minute per cm’..
`Apparatus—A typical apparatus consists of a punch and die fab-
`ricated out of hardened steel. The base of the die has three threaded
`holes for the attachment of a surface plate made of polished steel,
`providing a mirror-smooth base for the compacted pellet. The die
`has a 0.1-cm to 1.0-crn diameter cavity into which is placed a mea-
`sured amount of the material whose intrinsic dissolution rate is to be
`
`9.4—“).1 mdlamotor
`
`40.7—41.5 mdiameter
`
`-i
`
`76.2 mm
`
`‘
`
`|
`
`Holder 8. Shall
`
`Assembly
`
`
`determined. The punch is then inserted in the die cavity and the
`material is compressed with a benchtop tablet press. [NOT'B\A ht? -
`through the head of the punch allows insertion of the metal red It
`facilitate removal from the die afier the test] A compacted Pellet it,
`
`the material is formed in the cavity with a single face of defined
`“f” .
`exposed on the bottomofthe die (see accompanying figure). The ”95‘ '
`tom of the die cavity is threaded so that at least 50% to 75% of:-
`
`j'
`._
`compacted pellet can dissolve without its falling out of the die
`
`" .
`top of the die has a threaded shoulder that allows it to be attacheél
`
`d K .
`holder. The holder is mounted on a laboratory stirring device,
`entire die, with thecompacted pellet still in place, is merged iniii“
`
`dissolution medium and rotated by'the stirring device (see D1386! _'_- .
`tion (711)).
`t- .
`:I‘I
`
`Die Underside
`
`
`
`Surface Plato
`
`|4_-_— term—“pl
`
`101 mm
`
`15,9 m
`
`t
`34.9 mm
`
`Punch
`Now—Hardened and polished creeL
`
`
`
`Neoprene Gasket
`
`Die
`Non—4316 type stamens stML
`
`Swine. Plate
`Note—Harden“! and enriched noel.
`
`Apparatus for Intrinsic Dissolution
`
`Test Preparation—Weigh the material to be tested onto a piece of
`tared weighing paper. Attach the surface plate to the underside of the
`die, and secure it with the three screws provided. Transfer the ac-
`curately weighed portion ofthe material under test into the die cavity.
`Place the punch into the chamber, and secure the metal plate on top of
`the assembly. Compress the powder on a hydraulic press for 1 minute
`at the minimum compression pressure necessary to form a nondisin-
`tegrating compacted pellet. Detach the surface plate, and screw the
`die with punch still in place into the holder. Tighten securely. Remove
`all loose powder from the surface of the die by blowing compressed
`air or nitrogen.
`'
`ProcedurenSIide the die-holder assembly into the dissolution test
`chuck, and tighten. Position the shaft in the spindle so that when the
`tested head is lowered, the exposed surface of the compacted pellet
`will be 3.8 cm from the bottom of the vessel. The disk assembly
`should be aligned to minimize wobble, and air bubbles should not
`be allowed to form on the compacted pellet or die surface as this
`could alter fluid flow. [NOTE—Air bubbles may be avoided by using
`an apparatus with a difi‘erent configuration, such as a die holder that
`holds the compacted pellet in a fixed vertical position with agitation
`provided by a paddle positioned 6 mm from the surface ofthe pellet]
`Perform the analysis as directed in the individual monograph. If pos-
`sible, sink conditions should be maintained throughout the test. The
`data for the cumulative amount dissolved at each time point should be
`corrected for sampling losses. To calculate the intrinsic dissolution
`rate, plot the cumulative amount of test specimen dissolved per unit
`
`
`area of the compacted pellet against time until 10% is dissolved- ..
`cumulative amount dissolved per unit area is given by the cum“ . =
`amount dissolved at each time point divided by the suffix:6 “Fr.
`
`posed (0.5 cmz). Linear regression should then be perform“: 0.” .'
`points up to and including the time point beyond which 1W”
`solved. The intrinsic dissolution rate of the test specimen, “l mu.
`
`minute per cmz, is determined fi'om the slope of the regIeSSIOT'r-
`
`
`(1088) IN VITRO AND 1N VIWT-
`
`EVALUATION OF DOSAGE -
`FORMS
`
`-
`
`.
`tan,"
`
`The Phamiacopeia provides for dissolution and drug 3168:? , 1:"
`
`-__
`in the majority of monographs for solid oral and “gusderm
`
`forms. In recognition of the sensitivity of dissolutIOIl,‘5.stsil
`'
`valid bioavailability-bioequivalcnce (BA-BE) study 15 mfion .
`
`policy of this Phamracopeia has been to give this inforfl'lamcti.t
`nant consideration in setting dissolution standards. Early P rfO .‘
`
`to develop dissolution requirements based on the in V10“ Pa
`
`AQUESTIVE EXHIBIT 1044 page 0003
`
`page 0003
`
`AQUESTIVE EXHIBIT 1044
`
`

`

`General Information / (1088) In Vitro and In Vivo Evaluation
`
`2335
`
`fclinically successfirl formulations. Similarity in dissolution beha-
`9, rhas long been sought from the perspectives of both bioavailabil-
`“08nd quality control considerations.
`-
`all is the goal of the pharmaceutical scientist to find a relationship
`twee“ an in vitro characteristic of a dosage form and its in vivo
`be ormance. The earliest achievable in vitro characteristic thought
`Pagortend an acceptable in vivo'perfonnance was tablet and capsule
`E'integration. A test for disintegration was adopted in USP XIV
`. 950), At that time, no quantitative work was done in attempting
`' demonstrate such a relationship, especially in regard to in vivo
`30‘1““ performance. However, advances in instrumental methods
`{analysis ultimately opened up prospects for this werk. The disin-
`fegmfion test was recognized as being insufficiently sensitive by the
`asp-NF Joint Panel on Physiologic Availability, and in 1968 the Pa-
`rel directed the identification of candidate articles for the first twelve
`otficial dissolution tests that used Apparatus I.
`The state of science is such that conduct of in vivo testing is neces-
`m, jn-the deVelopment and evaluation of dosage forms. Also. no
`pruduct, including suspensions and chewable tablets, should be de-
`wmed without dissolution or drug release characterization where
`asolid phase exists. This chapter sets forth, for products intended
`{or human use, guidelines for characterizing a drug that include:
`(I)
`dgveloping in vitro test methods for immediate-release and modified-
`release dosage forms, (2) designing in viva protocols, and (3) demon-
`grating and assessing in vitro-in vivo correlations for modified-re-
`lease dosage forms.
`
`IN VITRO EVALUATION
`
`Dissolution and Drug Release Testing—Method
`Development for Immediate-release Dosage Forms
`
`Dissolution testing is required for all solid oral Pharmacopeial dos-
`age forms in which absorption ofthe drug is necessary for the product
`to exert the desired therapeutic effect. Exceptions are for tablets meet-
`ing a'requirement for completeness of solution or for rapid (10 to 15
`minutes) disintegration for soluble or radiolabeled drugs. The appae
`ntus and procedure conform to the requirements and specifications
`given in the general chapter Dissolution (711). Generally, experi-
`ments are conducted at 37°.
`- The dissolution medium preferably is deaerated water or, if sub-
`stantiated by the solubility characteristics of the drug or the formula-
`lion, a buffered aqueous solution (typically pH 4 to 8) or a dilute acid
`(0.001 N to 0.1 N hydrochloric acid) may be used. The usual volume
`ofthe medium is 500 to 1000 mL, with the use of greater volumes (up
`£02000 mL) allowed for drugs having limited solubility. The quantity
`0fmedium used should be not less than 3 times that required to form a
`situated solution of the drug substance. The significance of deaera-
`tton of the medium should be determined. Addition. of sclutes (i.e..
`Shrfactants) and electrolytes to aid in solubilization of the drug must
`be balanced against the loss of the discriminatory power of the test.
`The use of hydroalcoholic media is generally not favored. The use of
`such media should be supported by a documented in vitro-in vivo
`C0ne1ation.-Conversely, it should be recognized that this discrimina-
`‘OTY power could in some circumstances be excessive in that it may
`lWilt in detection of differences in dissolution that are not clinically
`SIElllficant.
`The choice of apparatus should be based on knowledge of the for-
`mlllation design and actual dosage form performance in the in vitro
`"it System. Since dissolution apparatuses tend to become less discri-
`m“lilting when operated at faster speeds, lower stirring speeds should
`be Waluated and an appropriate speed chosen in accordance with the
`list data. The most common operating speeds are 100 rpm for Appa-
`ralas I (basket)'and 50 rpm for Apparatus 2 (paddle) for solid—oral
`pillage forms and 25 rpm for suspensions. A 40-mesh screen is used
`Wflmost all baskets, but other mesh sizes may be used when the need
`'3 ducumented by supporting data.
`Apparatus 2 is generally preferred for tablets. Apparatus I is gen-
`my preferred for capsules and for dosage forms that tend to float or
`lb; disintegrate slowly. A sinker, such as a few turns of platinum
`g may be used to prevent a capsule from floating. Other types
`:meker devices that achieve minimal coverage of dosage form sur—
`:36 are commercially available. Where the use of a sinker device is
`umployed, it is incumbent on the analyst to assure that the device used
`fies not alter the dissolution characteristics of the dosage form.
`
`Dissolution testing should be conducted on equipment that con-
`forms to the requirements in the chapter Dissolution (7.11) and that
`has been calibrated with both the USP Salicylic Acid and Prednisone
`Calibrator Tablets. The method of analysis should be validated in ac-
`cordance with the ‘rocedures given in the chapter Validation ofCom—
`pendial Methods 1225).
`The testtime is generally 30 to 60 minutes, with a single time point
`specification for pharmacopeial purposes. To allow fortypical disin-
`tegration times, test times of less than 30 minutes should be based on
`demonstrated need. Industrial and regulatory concepts of product
`comparability and performance may require additional time points,
`and this may also be a feature required for product registration or ap-
`proval. For registration purposes, a plot of percentage of drug dis-
`solved versus timc should be determined. Enough time points
`should be selected to characterize adequately the ascending and pla-
`teau phases of the dissolution curve.
`Dissolution test times and specifications usually are established on
`the basis of an evaluation of dissolution profile data. Typical specifi-
`cations for the amount of active ingredient dissolved, expressed as a
`percentage of the labeled content (Q), are in the range of 70% to 80%
`Q dissolved. A Q value in excess of 80% is not generally used, as
`allowance needs to be made for assay and content uniformity ranges.
`For products containing more than a single active ingredient, dis-
`solution normally should be determined for each active ingredient.
`Where a dissolution test is added to an existing monograph, the dis-
`integration test is deleted. However, in the case of sublingual prepara-
`tions, 3 short disintegration time may be retained as a monograph
`specification in addition to a dissolution requirement.
`
`Dissolution and Drug Release Testing—Method
`Development for Modified-release Dosage Forms
`
`Drug release testing is required for all modified-release dosage
`forms in which absorption of the drug is necessary for the product
`to exert the desired therapeutic effect. The apparatus and procedure
`conform to the requirements and specifications given in the general
`chapter Drug Release (724).
`The dissolution medium preferably is dcacratcd water or, if sub-
`stantiated by the solubility characteristics of the drug or the formula-
`tion, buffered aqueous solutions.(typic,ally pH 4 to 8,) or dilute acid
`(0.001 N to 0.1 N hydrochloric acid) may be used. (See above under
`Dissolution and Drug Release Testing—Method Developmentjbr Im-
`mediate-release Dosage Farms.) For modified—release dosage forms,
`the pI-I- and surfactant-dependence of the dosage form should be
`evaluated by in vitro testing in media of various compositions. The
`volume ofmedium will vary depending- on the apparatus used and the
`formulation under test.
`The choice of apparatus should be based on lcnowledge of the for-
`mulation design and actual dosage form performance in the in vitro
`test system. Apparatus 1 (basket) or Apparatus 2 (paddle) may be
`more useful at higher rotation fi'equencies (e. g., the paddle at 100
`rpm). Apparatus 3 (reciprocating cylinder) has been found to be espe-
`cially usefiil for bead-type modified-release dosage forms. Apparatus
`4 (flow cell) may offer advantages for modified-release dosage forms
`that contain active ingredients having very limited solubility. Appa-
`ratus 7 (reciprocating disk) has been shown to have application to
`nondisintegrating oral modified-release dosage fomis, as well as to
`transdermal dosage forms. Apparatus 5 (paddle over disk) and Appa-
`ratus 6 (cylinder) have been shown to be useful for evaluating and
`testing transdermal dosage forms.
`.
`At least three test times are chosen to characterize the in vitro drug
`release profile for Pharmacopeial purposes. Additional sampling
`times may be required for drug approval purposes. An early time
`point, usually 1 to 2 hours, is chosen to show that potential dose
`dumping is not probable. An intermediate time point is chosen to de-
`fine the in vitro release profile of the dosage form, and a final time
`point is chosen to show essentially complete release of the drug. Test
`times and specifications are usually established on the basis of an
`evaluation of drug release profile data. For products containing more
`than a single active ingredient, drug release should be determined for
`each active ingredient
`Where a single set of specifications cannot be established to cover
`multisource monograph articles, application of a Case Three standard
`is appropriate. In Case Three, multiple drug release tests are included
`under the same monograph heading, and labeling requirements are
`
`AQUESTIVE EXHIBIT 1044 page 0004
`
`AQUESTIVE EXHIBIT 1044
`
`page 0004—
`
`

`

`#—
`
`2336
`
`(1088) In Vitro and In Vivo Evaluation / General Information
`
`USP 26
`
`included to indicate with which drug release test a specific product
`comtgéies and, in some cases, the biological performance to be ex-
`pec
`.
`-
`.
`. Drug release testing should be conducted on equipment that con-
`fomis to the requirements in the chapter-Drug Release (724) and that
`has been calibrated with the appropriate USP calibrators. The-method
`of analysis should be validated in accordance with. the rocedures
`given in the chapter Validation of Compendial Methods 1225).
`
`IN VIVO EVALUATION OF MODIFIED?
`RELEASE DOSAGE FORMS
`In evaluating a modified—release product, a fundamental issue is the
`types of studies that should be performed to give reasonable assur-
`ance of safety and emcacy. While providing important infermation
`concerning the release characteristics of the drug from the dosage
`form, at present in Vitro studies are most useful for such purposes
`as monitoring drug product Stability and manufacturing process con-
`trol. The assessment of safety and eflieacy of a modified~release d0a
`sage form is best achieved through observing in‘ vivo
`pharmacodynamics or pharmacokinetics. Moreover, where there is
`a well-defined, predictive relationship between the plasma concentra—
`tions ofthe drug or active metabolites and the clinical response (ther-
`apeutic and adverse), it may be possible to use plasma drug
`concentration'data alone as' a' basis for the approval of a modified-re-
`lease preparation that is designed to replace an immediate-release
`reparation.
`-
`The following guidelines are intended to provide guidance in drug
`substance evaluation and the design, conduct, and evaluation of stud-
`ies involving modified-release dosage forum. While these guidelines
`will focus on oral drug delivery systems, the principles may be appli-
`cable to other routes of drug administration (e.g., transdermal, subcu-
`taneous, intramuscular, etc.). -
`,
`
`Characterization of Drug Substance
`PHYSICOCHEMCAL PROPERTIES
`
`Physicochemical information necessary to characterize the drug
`substance in a modified-release dosage form should generally be no
`less than for the drug substance in an immediate-release dosage form.
`Additional physicochemical information may be needed on poly-
`morphism, particle siZe distribution, solubility, dissolution rate, sta—
`bility, and other release—controlling variables of the active dmg entity
`under conditions that may react to the extremes of the physiologic
`environment experienced by the dosage form. For purposes of this
`chapter, active drug entity is taken to be the official drug substance.
`
`PHARMACOKINETIC PROPERTIES
`
`It is recommended to characterize thoroughly the input absorption
`profile of the active drug entity from a rapidly available preparation
`(an intravenous solution or oral solution or a well—characterized FDA-
`approved immediate-release drug product), which serves in turn as a
`reference to evaluate the input profile of the modified-release dosage
`form. This information together with the biological disposition char-
`acteristics for the active drug entity can characterize and predict
`changes in the bioavailability of the drug when input is modified as
`in the case "of the modified-release dosage form. For example, if the
`‘ active drug entity exhibits saturable firSt—pass hepatic metabolism, a
`reduction in systemic availability could result after oral administra-
`tion if the input rate is decreased.
`-
`In designing an oral modified-release dosage form, it may be usefiil
`to determine the absorption of the active drug entity in various seg-
`ments ofthe gastrointestinal tract (particularly in the colon in the case
`of dosage forms that may release drug in this region). The effects of
`food also may be important, and should be investigated.
`
`
`
`DISPOSITION PROPERTIES
`
`.
`The information required to characterize the processes Ofdis
`tionof the active drug entity from a modified-release dOSage $3131;
`should include those generally determined for the same drug in
`immediate-release dosage form. This may include the follow, . a"
`(l) Disposition parameters—clearance, volume ofdistributicmgfia] -
`life, mean residence time, or model-dependent or nonmfimf‘
`mental parameters.
`(2) Linearity or characterization of nonlinearity oygr the (less
`,
`4 concentration. range which could possibly be encountered.
`(3) ~Accumulation.
`.
`-.
`.
`‘
`(4) Metabolic profile and excretory organ dependence, with Speci l
`, attentionto the active metabolites and active enantiomers oft:
`cemic mixtures.
`_.
`.
`‘
`'
`(5) Enterohepatic circulation.
`(6) Protein binding parameters and dialyzability.
`(7) The effects of age, gender, race, and relevant disease states.
`(8) Plasma/blood ratios.
`.
`(9) A narrow therapeutic index or a_ clinical response that varies sig-
`nrficantly as a firnctron of the time of day.
`
`0r
`
`PHARMACODYNAMIC PROPERTIES
`Prior to developing a modified-release dosage form, infonmtion
`described below should be gathered.
`Concentration-response relationships should be available over a
`dose range sufficiently wide to encompass important therapeutic
`and adverse responses. In addition, the equilibration timel character-
`istics between plasma concentration and efl‘ect should be evaluated.
`These concentration-response relationships should be sufficiently
`characterized so that a reasonable prediction of the safety margin
`can be made if dose-dumping from the modified-release dosage form
`should occur. Ifthere'is a well-defined relationship between the'plas—
`ma concentration of the active drug entity or active metabolites and
`the clinical response (therapeutic and adverse), the clinical perfor-
`mance of a new modified-release dosage form could be characterizad
`by plasma concentration-time data. If such data are not available.
`clinical trials of the modified-release dosage form should be camgd
`out with concurrent pharmacoki'netic—pharr‘nacodynamic measure-
`mim-
`
`‘
`
`.
`.
`.
`-
`-
`-
`Characterization of the Dosage Form
`
`PHYSICOCIEMICAL PROPERTIES
`
`e {0110‘
`'. .‘fiedq-e]
`.stitutc &
`f. a] is to
`_..ded that
`'nsure thz
`'5, .e types
`,5
`' rise A'—
`_ .56 A ap
`. ctive dru
`‘1. which en
`
`a higIe-do:
`ff.grog:
`-_"conditi01
`1': er fastifll
`
`_ -istered at
`”is £136
`"113.3 - y
`2‘13”
`:I
`.0 5
`g.
`-I "31 mir
`I bf” a;
`at ‘f‘tyd(
`'
`. °9fi e
`ingmhc‘
`Ih 02
`"3"”
`e
`etheeplllp
`H eitidnsetl
`vide info]
`"release
`m e
`,
`fie $22!
`
`
`‘ e rn‘viu
`
`ability, n
`-"se the fi
`
`The variables employed to characterize the physicochcmlcal Pm?!
`.
`‘1an W(
`
`erties of the active drug entity as it exists or is discernible In the 9!
`_ of a co;
`sage form should be the same as those employed to characterize
`. form, st
`
`drug substance, Solubility and dissolution profiles over a relevant
`eficct is
`
`range, usually from pH 1 to pH 7.4, should be obtained, “"‘htflea ,-
`lated ch
`
`ular attention given to the effect of the formulation (as comp . ".t
`dosage
`
`the active drug entity). Characterization offormulations that are f' 1‘. .'
`'-
`gfisuoir.
`a
`uble in aqueous systems may require the addition of 50drum a -
`dlStribu
`sulfate or other surfactant
`
`.
`
`.
`
`
`
`PHARMACOKINETIC PROPERTIES
`
`
`
`it
`The types ofpharmacokinetic studies that should be 60 .
`
`a function ofhow much is known about the active drug 6n ty,
`l1
`ical pharmacokinetic and biopharmaceutic pmperti65._3nd W
`
`prOFl'.
`
`Pharmacokinetic studies are intended to be the sole basis {Offer 3%
`
`approval. As a minimum, (1) a single-dose crossover SWdY ‘ng ‘
`
`strength of a modified-release dosage form and (2) a mulnl’easeiifi
`steady-state study using the highest strength ofa modified“
`I',‘
`
`
`
`' Equilibration time is a measure ofthe time—dependent disconfifl‘” ntmuml
`-
`
`measured plasma concentrations and measured efiects. The ““216”
`more ofien characterized by the degree of hysteresis ohseI'Ved w w
`
`feet-concentration plot for increasing concentrations is cqu . very.
`
`for decreasing concentrations. Where the equilibration ume film '
`'
`(to, rapid equilibration with no active metabolites generated)» {0, a
`
`little or no hysteresis. That is, the same effect will be obsch
`dosing
`.‘IEPEFNe
`concentrnfinn inr‘lnrmnrlont nf H19 interval hemeen the time of
`
`the time
`1!] teXleI
`
`AQUESTIVE EXHIBIT 1044
`
`page 0005
`
`AQUESTIVE EXHIBIT 1044 page 0005
`
`

`

`
`
`General Information / (1088) In Vitro and In Vivo Evaluation
`
`2337
`
`6.
`
`5.
`
`not fat-loaded. In this case, an alternative meal composition
`should be considered.
`The entire single—dose, modified-release absorption profile
`should be monitored. Where appropriate (e.g., in a multiple-dose
`study), for specific drugs and drug delivery systems, blood sama
`ples should be taken following breakfast on the second day, be-
`fore the second dose is administered. This sampling schedule is
`particularly important for once-a—day products.
`.
`For delayed-release (entelic-coated) dosage forms, bioavailabil—
`ity studies to characterize adequately the food efl’ects and to sup-
`port the dosing claims stated in the labeling should be
`performed.
`Multiple-dose, Steady—state Studies——
`STUDY I—When data demonstrating linear pharmacokinetics exist
`for an immediate—release dosage form, a steady-state study should be
`conducted with the modified-release dosage form at one dose rate
`(preferably 'at the high end ofthe usual dose-rate range) using an im-
`mediate-release dosage form as a control. At least three trough-plas-
`ma drug concentration (Cain) determinations should be made to
`ascertain that steady-state conditions have been achieved. Plasma-
`drug concentration determinations, over at least one dosing intewal
`ofthe modified-release dosage form, shou‘ld'be made in each phase of
`the crossover study. It may be preferable (as in the case of rhythmic
`variation in absorption or disposition ofthe drug) to measure concen-
`trations over an entire day in each phase. The presence or absence of
`circadian variation should be verified. The modified-release dosage
`form should produce an AUC that is equivalent to the immediate-rc-
`lease dosage form. The degree of fluctuation for the modified-release
`product should be the same as, or less than, that for the immediate-
`release dosage form given by the approved regimen. Appropriate
`concentration measurements should include unchanged drug and ma-
`jor active metabolites. For racemic drug entities, consideration should
`be given. to the measurement of the active enantiomers [enantiomer/
`diasteriomer distinction].
`-
`STUDY II—Where comparisons of the pharmacokinetic properties
`of an inlmediate—rel'ease dosage form at different doses are not avail-
`able, or where the data show nonlinearity, steady-state crossover stu-
`dies comparing effects of the modified-release dosage form with
`those of the immediate-release dosage form should he conducted- at
`two different dose rates:
`one at the low end of the recommended
`dosing range and the second at the high end of the dosing range. In
`each case, the modified-release dosage form must merit the criteria
`described in Study I with respect to AUC and fluctuations in plasma
`drug concentrations. 11' there are significant differences between the
`modified-release dosage form and the irrunediate-release'dosage form
`at either the low or the high dosing rate,'these data alone are not ade-
`quate to characterize the product.
`Data can be misleading when obtained from subjects with atypical
`drug disposition or physiologic characteristics, relative to the target
`population. Therefore, subject selection should be randomized or
`from an appropriate target population. If the modified-release desage
`form’is for use in a specific subpopulation (e.g., for children), it
`should be tested in that population. Regardless ofwhether a drug ex-
`hibits linear ornonlinear pharmacokinetics, the basis for characteriza-
`tion is equivalence ofAUC and ofthe relative degree offluctuation cf
`concentrations of the modified-release and immediate-release dosage
`forms.
`Steady-state studies in selected patient population groups or drug
`interaction studies may also be necessary, depending upon the thera-
`peutic use ofthe drug and the types ofindividuals for whom the mod-
`ified-release dosage form will be recommended. For drugs having
`narrow therapeutic indices, it may be necessary to perform more ex-
`tensive plasma concentration measurements to determine the poten—
`tial for unusual drug—release patterns in certain subpopulations. In
`such studies, it is advisable to perform more than one AUC measure-
`ment per patient to assess variability with both the modified-release
`and the immediate-release dosage forms.
`‘ Case B— '
`~
`Case B applies'to a non-oraI, modified-release dosage form of an
`already marketed active drug entity for which extensive pharmacody-
`namic/pharmacokinetic data exist.
`'
`Case A studies (omitting the food effect studies) would be appro-
`priate for the evaluation ofa modified-release dosage form designed
`for a non-oral route of administration if the pattern of bionansforma-
`tion to active metabolites is identical for the two routes. If the bio—
`transformation patterns are different. then clinical efficacy studies
`should be performed with the modified-release dosage form. In addi-
`
`AQUESTIVE EXHIBIT 1044
`
`AQUESTIVE EXHIBIT 1044 page 0006
`
`page 0006
`
`: states.
`‘
`v .
`anes SHE-
`
`
`
`lfo
`
`6 form are required to characterize the product. Some appropriate
`1'
`
`53g e.dose crossover-and multiple-dose steady-state studies are de-
`iofdisp .
`'bed below.
`'
`‘
`‘
`'
`.
`osage f
`
`9% some modified-release capsule dosage forms, the strengths difi‘er
`’ drug iii?
`m'each other Only in the amount of identical beaded material con-
`flowing“
`fined in:each capsule. In this case, a single-dose and a multiple-dose
`
`lution, ha
`“Edy—state study at‘the highest dosage strength are suflicient. Other
`
`.oncomp'
`mflgths may be characterized on' the basis of comparative in vitro
`' oluthI'l data
`,.
`'
`'
`
`the desefi
`The following pharmacokinetic studies would be needed for most
`Jtered,
`ll modified—release dosage forms. Such studies may, in this instance,
`' nsfimtc the basis for characterization of the dosage form. If ap-
`‘1’ Val is to be sought without conducting clinical trials, it is recom-
`nth Sp 3'
`mers ofit} gilded that there be preconsultation with the regulatory authorities
`-. p e“sure that an adequate database exists for such approval.
`.
`The types of studies generally conducted can becategorizedas fol-
`_ page A— .
`Case ‘A applies to the original modifiedarelease oral dosage form of
`,” active drug entity already marketed in inunediate—relea‘se form and
`for which extensive phannacodynamic/pharmacokinctic data exist.
`Single-dose Crossover Studv—
`,
`_
`.
`g
`A single-dose crossover study should include the following treat-
`ments:
`the modified-release dosage form administered-under fast-
`
`ing conditions; a dosage form that is rapidly available administered
`
`rmangn under fasting conditions; and the modified-release dosage form ad-
`ble 0v
`ministered at the same time as a high-fat meal (‘or another type ofmeal
`
`lera 6°? mat‘has potential foricausing maximum perturbation).
`'
`shag; c
`The study of food effects should include provision for control of
`
`evaluate;
`the fluid intake (e.g., ‘6 to 8 oz.) and temperature (e.g., ambient) at the
`
`lflicienil
`lime ofdrug administration. The dosage form should be administered
`ty mar .5' within 5 minutes after'completion-of the meal.
`,
`
`sage fogri:
`Ifthere are no significant differences in'therate or extent of bica-
`
`1 the p135.
`vailability (AUC, Cm, and Tm) as 'a function of the meal, then addi-
`
`Olites and
`tonal food elfect studies are not necessary.
`‘
`'
`al perfor-
`Ifsignifith differences in bioava‘lla‘bility are found, it is necessary
`
`racterizdl
`redefine how food afi‘ects the modified-release dosage form, as well
`
`availahlé
`as how the food-dnlg effect relates to the.
`'
`
`)6 cal-rial
`The purpose of these studies is twofold:
`first, to determine
`measure- whether there is a need for labeling inStructions describing special
`
`conditions for administration with respect to meals and Second, to
`
`provide information concerning the pattern ofabsorption of the mod-
`
`ified-release .dosage form compared to that of the iminediate—‘re‘lease
`
`dosage form. The drug input fimction should be defined for modified-
`
`release dosage forms. This will aid in the development of an appro-
`
`priate in vitro dissolution test. For dosage forms that exhibit-high
`
`variability,replicate studies are recommended.
`
`.
`Use-the following guidelines in evaluating food efi'eCL
`If no wellecontrolled studies have previously defined the effects
`of a concurrent high-fat meal on an immediate-release dosage
`form, studies should be performed to deter