`

`Editor: Donna Balado
`Managing Editor: Jennifer Schmidt
`Marketing Ivlariager: Christine Kushner
`
`Copyright © 1999 Lippincott Williams 8: “Wilkins
`351 West Camden Street
`Baltimore, Maryland 21201-2436 USA
`
`227 East Washington Square
`Philadelphia, PA 19106
`
`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 of product liability, negligence, or otherwise)
`for any injury resulting from any material contained herein. This publication contains in-
`formation relating to general principles of medical care which should not be construed as
`specific instructions for individual patients. Manufacturersproduct information and pack-
`age inserts should be reviewed for current information, including contraindications,
`dosages, and precautions.
`
`Printed in the United States ofAmerica
`
`Library of Congress Cataloging-in-Publication Data
`
`Ansel, Howard C., 1933-
`Pharmaceutical dosage forms and dnig delievery systems / Howard C.
`Ansel, LoydV. Allen, Jr., Nicholas G. Popovich. -— 7th ed.
`p.
`cm.
`Includes bibliographical references and index.
`ISBN 0—683—30572—7
`2. Drug delivery systems.
`1. Drugs—-Dosage forms.
`Il. Popovich, Nicholas G.
`Ill. Title.
`[DNLM: 1. Dosage Forms.
`2. Drug Delivery Systems. QV 785 A618i 1999]
`RS200.A57
`1999
`615’.1—dc21
`DNLM/DLC
`for Library of Congress
`
`1. Allen, T..oydV.
`
`9947498
`CI?
`Thepublishers have made every efiort to trace the copyright holders for borrowed material. Ifthey
`have inadvertently overlooked any, they will be pleased to make the necessary arrangements at
`the first Opportunity.
`
`The use of portions of the text of USP23/NF18, copyright 1994, is by permission of the USP
`Convention, lnc.The Convention is not responsible for any inaccuracy of quotation or for
`any false or misleading implication that may arise from separation of excerpts from the
`original context or by obsolescence resulting from publication of a supplement
`
`To purchase additional copies of this book call our customer service department at (800)
`633-3030 or fax orders to (301) 824-7390. International customers should call (301)
`714-2324.
`
`99 00 O1 02
`1 2 3 4 5 6 7 8 9 10
`
`|nnoPharma Exhibit 10910002
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`

`

` Contents
`
`
`
`Prefate
`
`Acknowledgments
`
`Section I. PRINCIPLES OF DOSAGE FORM DESIGN AND DEVELOPMENT
`
`I
`
`2
`
`3
`
`4
`
`5
`
`Introduction to Drugs and Pharmacy
`
`New Drug Development and Approval Process
`
`Dosage Form Design: Pharmaceutic and
`Formulation Considerations
`A
`
`Dosage Form Design: Biopharmaceutic and
`Pharmacokinetic Considerations
`
`Current Good Manufacturing Practices and Good
`Compounding Practices
`
`Section II. SOLID DOSAGE FORMS AND MODIFIED-RELEASE DRUG DELIVERY SYSTEMS
`
`6
`
`7
`
`8
`
`Powders and Granules
`
`Capsules and Tablets
`
`‘
`
`Modified~Release Dosage Forms and Drug Delivery Systems
`
`Section III. SEMI-SOLID AND TRANSDERMAL SYSTEMS
`
`9
`
`I0
`
`Ointments, Creams, and Gels
`
`Transdermal Drug Delivery Systems
`
`v
`
`vii
`
`1
`
`23
`
`60
`
`101
`
`142
`
`164
`
`179
`
`229
`
`_
`
`'244
`
`263
`
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`

`

`x
`
`Contents
`
`Section IV. PHARMACEUTICAL INSERTS
`
`I I
`
`Suppositories and Inserts
`
`Section V. LIQUID DOSAGE FORMS
`
`I2
`
`I3
`
`Solutions
`
`Disperse Systems
`
`Section VI. STERILE DOSAGE FORMS AND DELIVERY SYSTEMS
`
`T4
`
`I 5
`
`I6
`
`Parenterals
`
`Biologicals
`
`Ophthalmic Solutions and Suspensions
`
`Section VII. NOVEL AND ADVANCED DOSAGE FORMS, DELIVERY SYSTEMS, AND DEVICES
`
`Radiopharmaceuticals
`
`Products of Biotechnology
`
`Novel Dosage Forms and Drug Delivery Technologies
`
`Systems and Techniques ofPharmaceut1'ca1 Measurement
`
`I 7
`
`I8
`
`I9
`
`Appendix
`
`Index
`
`279
`
`296
`
`346
`
`397
`
`450
`
`469
`
`487
`
`503
`
`535
`
`552
`
`563
`
`|nnoPharma Exhibit 1091.0004
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`

`

` A DOSAGE FORM DESIGN:
`
`BIOPHARMACEUTIC
`AND PHARMACOKINETIC
`CONSIDERATIONS
`
`Chapter at at Glance
`
`General Principles of Drug
`Absorption
`Passive Dzjfusion
`Specialized Transport Mechanism
`Dissolution and Drug Absorption
`Surface Area
`Crystal or Amorphous Drug Farm
`Salt Forms
`Othzr Factors
`
`Bioavailabihty and Bioequivalence
`FDA Biaazrnifabilify Submission
`Requirements
`Blood (or Serum or Plasma) Cmtcenmzh'rm-
`Time Curve
`
`Routes of Drug Administrafion
`Ora! Route
`Dosage Farms Applicable
`Absorption
`Rectal Route
`Parenteral Route
`
`Dosage Farms Applicable
`Subcutaneous Injections
`Intramuscular Injettinns
`Intravenous Injections
`Inlraderrnal Injections
`Epiculaneous Route
`Ocular, Oral and Nasal Routes
`Other Routes
`
`Perametersfor Assessment and Comparison
`ofBioavaiI:zbi1ity
`Peak Height
`Time of Peak
`Area Under the Scrum Comzntrafiun Time
`Curve
`
`Bfoequimlence of Drug Products
`
`Fate of Drug After Absorption
`Drug Metabolism (Biotnznsfarmation)
`Excretion of Drugs
`Pharmacokinetic Principles
`Haif-Life
`Concept of Clearance
`Dosage Regimen Considerations
`
`As DISCUSSED in the previous chapter, the biologic
`response to a drug is the Iesultlof an interaction be-
`tween the drug substance and fixnctionidy impor-
`tant cell receptors or enzyme systems.Th/a response
`is due to an alteration in the biologic processes that
`were present prior to the drug's administ:a1:lon.T11e
`magnitude of the response is related to the Conn
`centration of the drug achieved at the site of its ac-
`
`I:ion.This drug concentration depends on the dosage
`of the drug adrrtirdsterecl. the extent of its absorp-
`tion and d.istJ:1'bution to the site, and the rate and ex-
`tent of its elimination from the body. The physical
`and chemical constitution of the drug sul:-stan1:e—
`particularly its lipid solubility, dagree of lOl'li.'£3fiOI'i,
`and molecular Size-—determine5 to a great extent
`its ability to affect its biological activity. The area of
`101
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`|nnoPharma Exhibit 1091.0005
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`

`

`1&3
`
`Eumge farm Esesign: Biapisannacenfic mat Fhmmnmigfizefic Qmsfidemtéam
`
`study embracing this reéationship between, the
`pfiysirzah crhemixtai, and bioltngical sciences as they
`apply ta drugs, iiesage farms, and tr) cimg acticm has
`been gvan the descriptiva fiezm birrphnn-nacetztfxzz.
`In general. far a drug to exert its bielngixr effect, it
`.mus% be iransparted by the bady fmiria, traverse
`the mquimd hiixlagic membrane: barriers, escape
`wide3pm~aci distributissn to mnwantaeszi areas, ensime
`metabnflir; attack, peneirate in adequate mncemra»
`titan to the sites mi actmn, and interact in a spsacifiva
`Eashicm, camssing an alteratiatm nf mflular fnmxtizzm. A
`simpfified diagram af this mmpiex series «of events
`bemresn an drugs adminigtration and its e1im3na«»
`rim is presented in Figure 41.1.
`The absorpfimn; ciigrributinrn, himransfcmnatiarn
`(metabolism), and eiiminaiimn {If a drug from the
`bx;-dy are azigmamim processes that mntinue fimn the
`time 2 drug is taken until all at the drug has been
`rem-Wed {mm the b-miy. ‘Ska mites at which {base
`
`pmcesses mccux affect the armset. intensity; anti the
`duratiun of the émgs activity wiihin the b{::.iy.T§1e
`area (315 may which elucifiates me me marge nf
`drug canmnixatiarz in the bland and tissues is
`termed gzfizsznmmicinafim. It is the smciy vi the k:i~
`metrics sf absmrptictn, dish‘ibuEi+::n,metaba1§sm and
`esccr-E-titan £Ai)M’E.) nf fimgs and their r:oI1‘espom:i«
`ing pharmamiagic, thexapemticg or tcrxic zespanse
`in animals and man. Fuxthezg since cane: timg may
`site: the alzmrpticm, dishiburziam metabolism pr
`exirretion of at-Lather drug, pharmacakineiics aim:
`may be appiieci in the stmiy sf imeraciions heme»:-n
`drugs.
`Once a szimg is auizninistersai and cimg absmp»
`rim begins, the rimg dam not remain in :2 single
`body lacatim, but rather fig digtxibutexi ihrmzghmrzt
`the body until 515$ ultimate eiirrxinatimt. Far inw
`stances, faflcmrmg the ma; sadzrxinistmican at’ a drug
`and its nanny into the gastrcsirxtesainal tract, 3 par:-«
`
`
`
` Elm!
`
`administratlcm
`
`Gastreintestinai
`tract
`
`
`
`it
`
`
`
`
`intramuaomar
`iniaction
`
`Snbcutanaous
`
`injection
`
`Tissues
`
`Fig. si.1 Echmzxris: reprasmmrmn -:}'£i3e?:E raj’:11:-mrptim, metaémiisrn. azrnfi excreéém zafdmgs tgfisr their azérnérgismstim by mr«
`Eons rams.
`
`|nnoPharma Exhibit 1091.0006
`
`Intravenous
`
`injactinn
`
`
`
` E-xcreticm
`
`Circuiatory
`systems
`
`

`

`Swag: Ema mséga: Biapfmnmzmiéx: «mi Pksrmasakinsfic flansiéezmiexzs
`
`163
`
`am :25 the drug is absnrbed irttvs the circxziafmy syaw
`mm fmm which it is rziisnribut-ed to the wsarixms other
`miy Eluieis, tissues, ami argans. Fmm these sites
`the clmg may re,-mm tea the firiznlamzy system anti
`be exximtesi thrmgh. the kiciney as such can the riniag
`may be matahofiaed E2}? the £3‘?-er er ether cellular
`sites and be exmteé as metabmites. 3&3 shmm
`in Figure M. dnggs aciamzistezreci by inixavenam
`injecticrn arr: gflaceti dirently mm the cirmhtmry
`system; thereby zmziriing the absezrption pmcem,
`wizich is requireti from all other msuhéa of adminis-
`iraiion far systemic affects.
`The variant; baciy larafions 1:: which a fimg traw
`$15 may be vieweci as separate mmpamnents, each
`mmainirag mme frachbn cf the acirrsinistered rinse
`:2Ec§1:ugfI‘he kransfer ofdrug {mm the bleed tn: other
`may incaiicms is generally a rapid pmness and is
`meezsible; that is, the drug may aiififuae back mm
`the ::ir~:::;;1ati:m.‘Iha xfiI’L1g in the blood therafme :2»-
`im in equflibmzm with the cimg in the arhar mm«
`gartmasms. Hewever, in this equilibrium stat»; the
`mmremratfinn of the dmg in the bland may be quite
`aziiflfermt (gmaier or lesser} than the mncanixatmn
`«:36 the zimg in the ether +:cmpa:tments.'Z‘}zis is due
`largely in flwe physimrhemical pmpszrties 0f the drug
`and its are:-mltant ability m Ieam {ha blomi and Era»
`wage the bimlogical membranes. Certain cirugs may
`imre the tirculatary szystmn mpialy anti ccnmplaiseiy,
`whereas other drugs may do 5:: smwifrand with dif-
`ficnity. A number crf drugs belzeme bcmnd m blond
`prmteinfi, particularlfs the allmmins, and nnlya small
`fraction :3? the wing agiministnsreszi my acmaiiybe
`fmmd at iucatians mmizrie of the circuiatary system
`at a given time. This transfer of drug fmm one
`mmpamrgant to anmcher is mathematically assay
`tsiated with a sgezritific ram: czcznstant describing that
`pattimlar transfezz Generally: the rate of tranfifm
`sf a drug from am: sznmpartzmmt m annthar is
`pmportimal to the czmcentmtien rcnf the drug in
`the cmmpmhnant fitmn wfiich it exits: Ema: greater
`the mncentraticitn, aha greater is that zrmmunt of
`iimg transfer.
`Metaimlism is the map: pmstesz-2 by which fnreigrx
`substances, imziuciing rimgz are alirninateci mm the
`imzijz. In {he pmcass afmatahnliam a drug snbsfamm
`may be biszitrssrzsfmneri inm pharmacc:laug;icaI}y av.:u
`rim: var inactive metabsliies. Qfim. ‘mil: the drug
`suhstante and its mambafitefs} are active and mm
`phamxacnlngic efiects. fiat mermpiez, that antianxiefy
`thug prazepaxn {Ce-max) metahztziizes, in part, tn :3:-:~
`azagam {Serra}, winch alsszt has amiamciety Eifffifisi.
`In same irxatances 2: phamtamh:-gicaliy ixwacfive efimg
`(firmed a pmdnxg} may be anizninisiwarsd for the
`kmswr: efifacbs csf its active mebaimiites. Dipiwzfrin,
`
`far exarnplt, is a ggmémg cf epmaphrim farmed by
`the asterificafimn of episxegri-mine and pivaiic. am.
`This enhamzes the lipaphilic character :25 the émg,
`and. as 3 mnsequente its peneixation mm the any»
`tin: chambm :35 the eye is 1? timax that uf epineph-
`rine. Within the eye, cfipivefrin Hill is mrwsxteci hy
`enzymatic Exydruiysis tn epinepinrim.
`‘I'h.e zrzgtahoiism csi a shrug am inactive pmniucts is
`usuaily an irreversible pmcess which culminates in
`the axcretimn sf fine dmg Earn the bani}: usualiyvia
`the ur§.nc:.’.I'he phannaccxkiimticist may aaiaulate an
`eiiminakzicm rage camtant itarmaci kg) far: a vzimg
`11:: describe its ‘rate :35 elimination from the body.
`111*: term efimiriaziisn refers I:-I3 bmh metabmlism.
`
`ami excretion. Fm drugs that are acififinisiered 1'm~
`%ra*m:1::xusI},r, and therefore irsmive rm abmrpticsn
`process, the Eras}; is much ‘less compie:-t than far
`dmgs adminisiezmci uraily -at by rather m11tes.In tbs:
`Latter ingtamzes, érug absnrptmn and drug elimina-
`tmn are ecmzrriztg sixnultanetmsly but at different
`rates.
`
`firmeral Principles
`:11? 13mg Absmptiun
`
`Bezfmre ax afixnirtistered xirug can axriva at ifsssita
`sf acting: in affeethre ezoneezmtratians; it must my-»
`mmmr a number 21:! barriers. Them barriers; are
`chiefly a aur:c+as~:-inn uf biaimgic membranes such
`as those emf the ystrzzintestirzal Ezpitheiium hangs,
`bland, and brairs. Body memhxanes am gen-zzvxaliy
`cziassifieri 2:5 thrsaa main types: (ex) those crmmpased
`snf several layexs mt’ mils, as the skin; rib} mega z'::::m~
`pmsed azzf a single iayez cof 53113, as the integtinal ep-
`ithefium; and (c) ihtmz nf Kass thamtme seilin thick-»
`mm, :92. the mamhrana sf 3 single; cell. in mm?
`instances a drug substance must’ pass mare than
`name of timse m-embzsana types haefme it reaches its
`site 43% acticm. For inszance. a zimg taken gran}: must
`first naverse me gagrrmintestinaf membranes; {stam-
`aezh, mm-all amt iarge intastina, gain entrance: mm
`the general cirirulaticm, pas;-2 tn the mgan or tissue
`with whiszh it hm afifinity, gain Entrance inm fhat
`tissue, ami than ante: info its indivirinal 123133.
`Althrmgix the chemigtxy of bani}: memhramag
`differs ram: from ancather, the tnembranes may be
`viewed in genarai
`ass. a himuieérrfiar iipc:-id {fat-
`fiflntairling) 153%: attachati an bath fifties in 3 pm»
`£12:-in laytér. Snags are ‘Ehmzght to panesirate thesa bi-
`nlogk: memisranm in mm general wazya: 1) by pay
`Siva diffusmn, and 2} thmugh spaciaiized transport
`mwechanifims. Wifhin «Each 1:-E them»: main cataganes,
`mare ciaariy éarfined pmcesses have been ascfiilezi
`in drug transfm:
`
`|nnoPharma Exhibit 10910007
`
`

`

`1&4
`
`ilhssctgc Farm E3:-.'s:g}*t: fiingrknnnasevatir and P’hx1r1r.q::m1‘z'3mri:: Csnsffigmtéasm
`
`Passive i}:t}"f::si:m
`
`The tam’: gazzssizae cfifjfingiszn '25 msexi m rinmtxiltse the
`passage mi ijcimg) msimfles thmugh a membrane
`which brahavaaa int.-err}? in that It times not av:;i:i~::e}y
`gxarficipare in the: pmce.-ss. flrugs absmrhed accura-
`ing in 61.23 metimé am said ‘m be gsszziaefy aésawrbaé.
`The ahsmpfim gzrmcass is émeen $2}: $112 c:mcam:ca-
`kicsn graxiienf (1.2, the siifiermceza in rzartczamftaiirsn}
`mgmg a.:.~:w:-as the membrane‘ with tha passage af
`aimg maiezruma szzmx;-“ring pxémarily Emm the gixia 23:‘
`high simg mnaantmfimn. M;-st émgrs passes. {mugs
`E:£::.E::»g,ic membranes by diffaxsicm.
`Passive diffusixim is fimrsibeti by Figrix‘.-3 first fem,
`whiah statefi that the rate: 1:}? €i§ff'L1Si£;m £3: Etranspmf
`acrms a mermbrsme {mat} is pmpurtimal its the
`dirkmire in drug cnnmntsaiion an bath fiidefi ca!
`the membrane:
`
`in 1»-'hi<:.'n Q and 411; ram 1:: she rimg cancentrafiama
`an each zsigie. cf the membrane anti 9 is .2, 'pe:nm:~
`ability cnefficirant «er mnstant. Tm: term t’.;_._ is £115»-
`tismarfig umaci ta: zagmmnt the mmpafiment with
`tha gzrsalm mrsceniratiun :1? Chang and thus t:':'na
`trampcm ::.~f émg prcmeaés fmm mrmparzmenz me
`{e.g.. absarpticm site} an mmpartmmmt hem (~:-.05.,
`izaicrrzsszt}.
`fiecauae the mncenimtitrn 1:3? rimg at the aim «:3:
`abfinrptimn {C13 :2. usuaiiy rm§::i'1 main: 2313:: cm the
`aim: side oé‘ the rnemhrane, dug in the rapixi ziislrm
`{inn :1!“ the drug &I: the blrsmd and its sabsaqnent
`tiéstsébaxtican tn the tiss.-ma-s_. far practicai puzpn:-ms
`am 1:31:32 :::£ :25 M £22 may bx? tamer: simpigg 3!»: that :33’
`$3 anti me equatian m-*ti1:ten in the siamiaxd font:
`Eu: 3 flax: :::-niszr rate equatién:
`
`The gastmifimsfinal ahmrpfinn caf mm‘. drugs fmm
`sstxiufinn vs:-Erma in this manner in accmrdancae with
`}‘;Er.s§ mfiifi“ Rfsxatics an whinh the rate is-.u flaapemient an
`aimg cstrnasentriatioa, i.a._, émnhiing than fins? rimhies
`{he transfer me. fine magnimcie -sf {hr ;:aa=rmeabiI—
`mtg mnstam. xfmprmés men the: fiiffmirm c:c:;a-Eficaent vi
`the «cimg, the thickness am? area of the absmbing
`mamizamne, emni the pfiflrxeabiiity ::f the meamizrane
`ms the paxtimiar drug.
`3E:£tat!%€
`azrf fim Eipztei-si msmm {sf Eh»: mil rrmm-«
`’::mna2; 1'? E3 Eaighiy pemaable ta: Eipid samhle anis-
`stances. The rate reef eiiffuafim <3? a drug ass:-1:553 the
`membrane daspemiifi mat arzxiy upcxn Em mamm-
`tiszan but aim ssgrcm the relatiwe men: :2? its afifinity
`Eur iipisi anti rsjxerctirzrn sf semis: (ea high iipiri pariitican
`
`::£mffi«:§ent}.The greater in; affinity fur iigiri and tim
`mare Ezyfimgnézalniar it is. tha faster MB be its sate ezuf
`pemzstratimn inks; the Eipizi »~ris:h mambmnn. Eqthrm
`mycin ham, Fm: example, passesaes a higher gaasrki-«
`{inn x:c;:s:§ficiam~ than me: e:zy+,ixmmynin mmm:-uncis,
`»;«z.g.¢ emzrlaze, ghaceptaxe‘ Ecznsaquemiy. the
`is
`the pmfiarre-d agent far the m;:~:‘::a1 mammt em? amt
`where pemtraticrn into the 33:11: is dssimi.
`Bamuse hialagc tells am alas: parmeateci by
`water and 1:’pi:i~§nse§nI:}e subsfanms; it is ihezugfirt
`that the memhrana 315:: nmtaing wafer» iiii-sci paras
`K}! charmeia {hat perxraii the passage :2? them fyprs
`oi subahanscersx As water primes in ‘mm: acmss 3
`pmmxxs memhrane, any disscaiveé. salute :*m::ie»;:z;:~
`115213: amafi emugkw. ta trma-::z:s.-2 the pares games
`1:3;fifrmtim. Aqumus paras vary in me {mm In$‘m~
`Irrrane kc membrane arm} thus in their individual
`
`permeability nharacterisiics fr;-r certain drugs am
`mm: mhstansas.
`
`The magmiiyr +23% timgs mday are weak csxganéc
`acids :22: ixase:-:3. Kncrmedge {sf their isxsiiariciraai iasv
`iaaticm or aissnrriaticn chaxamrzrisfiizs fa émpgzriamg
`be-names than abmrption is gxmzrneci in a large axe»
`mm by mai: degrees «:2? iezniaatiun as they age pm»
`sented re the fruamhrane barriers. {Z1213 memi-mamas
`
`-rzrf
`are mam gun-mnmizrie 15:; the unitsniaeci frtxnm.
`xiimgza than in their icenizeé Emma. mainiy because
`01‘ the ggar-ariipici sniuhility mf the unionized femzs
`ami it: the higkfly thaxrgaci namra mi than sail meta»
`mane which semflts in the ixinfiing rm“ repeliing car?
`the iamiaeci :.2.:1.:g and thereby riecreases mi} pvesnv
`tratixm A155; ixzms became hydrated thramgin assa»
`ciaziszrn with water maziecules, xeesuiicing in iarger
`parkicies than the undismcéatafi maieztfie and again
`ciacieasezi penetrating aapahiiity
`The deagmfi :3? a tiI‘ug’§ icnzzatéan £ie:};:«»<smi3 bath
`an the pH nf rim seiutéan in which it is presented
`32:: the izifiililgirr membrane and cm the pig, #3? dis»
`mziatéazmrcn xgmnatang sf ithe dmg {whether an aria or
`hase}.’;£'h-2: amntapt cf pig is dexiurad mm the Plan-
`derson-E-iasaeibalch racguatiun and ‘:5.-
`Far 3:: acisfs
`
`innimé cane (gait;
`PR 1‘ px” ‘*0 mg urzimizasrai Emit. {aeniii}
`.F=:mz?x:2se:
`
`pg 3 §,K_ +1. 1,:
`
`imiaad mnc. {galfl
`
`Eiimte the pH mi b<:~&y fluids ifiiiiefi {st-:::mm:h, pl: 1;
`Imam 43? the inirzsfine, pH E16; hiucsei plassma, pf‘?
`?.-'i); the akaracurgntiszrs cf 3 drug; {mm various baniy Em»
`isle: will differ and may iiictate in same man: the
`typrce nf zfimage farm and the mate *3? axiimirzisfran
`flan pmfarreé fssr a gimn ziimg.
`
`|nnoPharma Exhibit 1091.0008
`
`

`

`Samgefmm flesfgrz: Sévzéxarrxzzzseizrfc and Fkfismezcrskfiflatfs: Cazzségmfimm
`
`1135
`
`By reamznging tins; eqmtriarm for an acid;
`
`gig m PH : mg unianizefi azmcentrafian gacid)
`ixrmlzed vznnsentzatim {salt}
`
`(ma tam themmficaiiy xieterrnimz the relatm: aaztem
`gr; which a drug Iemainfi mflmizad under varinus
`comiiticms sf pH.‘I'his £3 parrimfiady useful what:
`applied 1:} canéiunns :;>£ Ezxtzsiy fluicis. Fur instancsz, if
`a weak acid having a 9313 of 1; ix a:;smmed m be in
`an eswimrment sf gamfir: jzxice mm :3 333% cf 1, the
`Eat’? side {If the equatimn “m::r-uni yield the number 3,
`which wrmid mean that W: ram cf nnimnizeri tn
`
`Emnized drug pasiicles vmuld be abmxt 1930 tn L
`and gaatxic ahsorptmn wcruid be s:<:::a11em:.A: the
`pH of plasma the merge wmfid be true, an-:1 in tha
`1:115:20 ti‘;-3 drug would be largely in the irxmized
`F1:+nn.Tabie 4.1 presents the affech :31‘ pH on the km -
`ézaafiezn sf weak t§}e£tr‘(}}}r’tE$, and Tahle 4.2 ceffers
`mama representative pig "values of mmmarm cimg
`sat-atances.
`
`From the equafim and Ecom “Same =11, it may be
`gear: that 2}. dmg Substance is E:a1E ianixed at a pH
`value which is equal to its plfigfixua pig may be der
`fined as the 911 at Wfxich a drug E5 30% iscmim-:I.Fx:rr
`re:-zample, phennhazbitai has a 33K, ‘trains: cf almm
`?.é, and in yiasma {pH '.3’.&) it is gmzsem as imized
`and mmimized famxs in equal amounlz-rs, Hnwmrer, a
`drug suhstafice eannm reach the blues: piasma fa:
`distrihnfitsn ihmcxghauf the bcuziy unless it is placed
`them dizentily ihrougim imravemus inieciimn or is £a~
`mrably absarbed from a 3il:e aimxg its mute cxfemm
`as the gashninheafianal met. and alicswed in pass
`inm {he general rzircuiatim. A3 shmvn in ‘E532 13.2,.
`pheanbmbita a weak acizi, with 3 312122;, cf 3%: wcmld
`
`‘Fairies -3.1. The mm: 91 gr} on the irmizatinn nf
`Weak Eiectrnlyicfl pig-{:51 ‘fix Uninnfmeécl
`zgwm Asia?
`mm
`9.99::
`m9
`me
`am:
`33.?
`am:
`M3
`ma
`$3»;
`9:33
`99;;
`99.9
`
`a§*1sv.«:«a;: Base
`99.9
`99.0
`93.9
`33.;
`75.13
`51.2-
`50.?
`33.‘?
`24.9
`ma
`9.39
`21999
`mrm
`
`-33:
`-«E33
`—«:m3
`-9.?
`~35
`-mg:
`9
`-3‘{EI'§
`+9.5
`+m'
`+1323
`+2.2:
`+3.»:
`
`’Iiepr:meci with pemsissixim {mm flnluisim IT, Ewin»
`task}! 5?: Am} Fharm 1365;133:143.
`
`Table 4.2. pig Sfiluas far Snma mam am}
`Basic flmgs
`
`Aciés:
`
`Bases:
`
`Acergtsaiiarggiic 221::
`Eafizitai
`Senzylpeificilfim
`Emiri acid
`Dimzsmaxal
`Pixambmbizai
`
`Suifanilamistie
`’I‘hec:phy1Iina
`Thiagmtal
`‘fmlbummizie
`Wazfacin
`éfimphetaxnine
`Apamcxrphinrz
`
`ffsafieine
`
`C3r:3;3~:diam'§;3a:—:-tirie
`Ctmaixm
`Ctadeina
`Gmnethidima
`Meet;-‘rhina
`f*‘:m::\irr.e
`Qnsminfiz
`Rcsszapine
`
`PK;
`
`3.5
`‘}’.‘}
`2.3
`9+2
`5.?
`‘E23
`8.3
`il{3.Ii.-
`9.3
`‘ME
`5.5
`4.3
`3.3
`33.8
`9.?‘
`5.3
`
`4.8
`3.5:
`$3
`11.8
`53,9
`9.13
`3.61
`5.6
`
`has largely unciisaaciated in the gastric: anfisimnment
`M’ pH 1 am} wssmié likaiy he weal} abmrheé. A drug
`may ante: me circulatinn rapiciiy and at high com
`centsatinns if mgmbrane penerrakion is easily ac»
`mmplished ms: at a 3m»: rate and law levei if the drug
`is 11-3: raacifigr abaurheai {mm its wake 1:.-f ermy. The
`pf! of the mugs mzrenir emsfironment influences the
`ate and thazv degraa sf its further ciieézibutiatm be»
`came it Ezmsmes mate m: 1255 unixsnized anti them-~«
`
`fare rmtnre car 3353 Iigrid ~pmee:rating under same now
`aiifimn of pfi than Lmder amth-at. If an unicznisaad
`malemle is ahie ta ntfiffzzse zhrmgh we lipici barrier
`and remain umonizeci in the new environment, it
`may remm ta 1&3 fsmmxeriocatim or go an ta a new
`me. Howevezz ifin the: naw exmmnmentitisgreafiy
`icenizeti due in the influence czf rhe pH 3f the saoonci
`fluid, it liken; will be unable to cross the membrane
`witlw its finmmr abiiitry. Thus as mncentrafian gsraciiw
`em of a drug umally is l.‘EaEZ}i1t‘~3X.3 at equiiibriurn cm
`aaszh side mi .3 membrane zine m :3;if§ex:em: degrees nf
`iomgatinn mzurring on eachsis:1e.A summary of the
`concepts at‘ dissxaciatienfiuniaatiun is {mm} in me
`physical pharmaqr capsule antitiesi Ҥ2Ka!I3isaacia-
`rim Crfinstzntsfln Cha§;«g7EI‘ 3.
`It is man desigable fm pharmaceutical scientists
`in make sirmzrmral mofiificatmnfi in srganic timgs
`
`|nnoPharma Exhibit 1091.0009
`
`

`

`1:35;
`
`{image Farm fimign: Bfephammanflc mm? Pfianvgsrcezkfrarfic .C::;rséam2:§::n.a
`
`ami thereby famraizxiy aim: tiaeir lipid scalability.
`partition mefficienis, anti ziissczciafitan mnmants
`while maintaining the seam: basic pharmacaimgi-2
`activity. These ef£c:rts freaguentiy 0252111 in imrmaseri
`absarptiozx, better tharapeutic mfipxmae, and Iuwer
`xicrsagwe,
`
`3pec:‘aI£:e:;f Trmtsparf Mecinzrzisms
`
`tn the passive iransfer :3? drugs.
`In mzntrast
`and mhar stabstancfis
`a hicfiogéc memiwranét.
`czertain subsstantaa, imfluding same rfutuga ami bier
`Ragicr meiabolifras, are cixndxmted acrcrsa .3 mmnbrmya
`thmugh one «sf sevaral ptiltaizilatefi spfitialfzed mm-
`grcrrt meclmemismg. "His type tzaf tnsmsfer seems In
`acccmm is: those sxzbsiances; many namxxally c3»::::ur~
`sing as amim adds and glucose, that are me iipid-«
`irmlubia to dissaive in the izmzndary and tea; large
`in fiazrw 4:}: filfizrflnraugh the pastas. This type 9? t£ax1s--
`part Ea themght in invmlve membrane components
`that maybe en..*«:yrn:=-:3 cs: mm: other type ef agent :3-
`pabie of femaing a mnxplex with the drug {arr other
`agent} at the surface membrane, after which the
`mmplex mama as:-rciass the meazniarane where the
`mg is released, with the carrier ramming m the
`nriginai surface? Figure %.2 piesents the simpfifieci
`scheme Bf this pm-sass. Spetfalized transport maybe
`diffarentiateci {mm passive tramfer in that the £-;:.~r-
`mer pmzzess may became “‘.-=.:amxated’*as the aammxni
`azvf aaxrier present for a given suhatance becomes
`cssmpietely brmrzd with that snbstancemsuftingin a
`delay in the”femging”s;=r transgmrt pmcess. Qther
`features sf speciaiizaed trarnspnrt inciude the maxi»
`Eazity by a carrier far 22 paztimlar type of chemical
`
`stmcmre m that H mm substambas are tmnspmteti
`in}; the same mechanism me wili cmmpefifixaiy in-
`hibit the transport :31’ the othsaz. Furthszn the mans-
`prart mechanism is irmibiteci in genata} by sub
`sfances that interfm-as with cell metabniiam. Ths
`farm actizxs rnrmsparz; as an subciasszificatimn of spa-
`ciaiizeszi iranspmt, danmzes a procesg with the a_ridi-«
`timm} feature am‘ the salute +3-r mag inning mmefi
`acmsa the membrane against a mmzentratsion gnaw
`tiiernt, that is, mm a smiutinn cf iewer mmant::&~
`timn ts: ram? :3? 3 higher mnmmtm-tmn rm if the fiflltiffi
`is an ion, agaimt an -rzlectrmzhamital potential gray
`tiient. in contrast as active transport, fszrsféémesi eizjl
`fusétm is 3 spetialia-ad Erransspori mechanism having
`all :25 the ahmse charantesistfics except that the 9::-lute
`is mt transferred agaénst ea ctzncentratian gradiam
`and may attain the same ccmceniraticrn inside the
`all as that an the cmtside,
`
`Many busty nutrients, 22$ sugars and amim: acizia.
`axe transparteci amass the membranes ef the gas»
`txoinxestinal tract by carrier processes. Ceztain vita~
`mains, as thiarmne, nia::iz1,ri‘&:«:2§Iavin am} vitaxnin B5.
`and drug substances as methjgldrapa and 5~fi1m:~
`muracii xequiza active trzanspcart mechanisms; for
`Eheix absengptisrx.
`Irweatigiiczns of intestinal tzsanspczri have often
`utilized in mm {at the site} or in zrim {in tha body} an ~
`imal mmdels ar armais {autside the bezzvdy?) trampert
`modem; hm»-ersrar, recently :91; mimre mmitzls czsf kw
`mar: gmall-intnastine absnrpfive I:-312,5 lme hemme
`availabie me invesfigate transpmt acmss inbesrimi
`agrithaimm {.1}. Bcxth pamw ami trarmpnrt~mediate:i
`smcties have been conduezed 1-:2 mvesszigate me{;1‘h’é~
`mam as well as rates :25 transport.
`
`Dissainiinn anti Drug Ahsorptinn
`
`Far 2 drug in be atzsurhxeai, it must am he riisr
`mlved in the Emisl at the ahsarption site. Em: in»
`rstance, as cimg aciministered oraily in table»: at ca;:-—
`sale farm C3113‘:-Eli be absarized mfil the dmgparticleg
`aré riissizhred by the fluids at artsme paint wifimirt the
`@$t:r(3iI%x‘.E§$:i1‘:aI tract. in irLs::ana:-E3. in which the sol-
`ubiiity of a zimg is dependent uprm either an aticiie
`as basis medium, the {hug wmzld he ciiszaalved in
`me stomach as intestines respersfively {Fig 4.3} ffhe
`pmmss by which a dmg partirile riissalves is tE§II:(1Ei3
`siésszzinatim.
`
`As 2; drug gzarficle zmziezgmes riissaxzizsiirm, the
`dmg snc:-Iemies cm the surface are the first in aruar
`inm solxxtmn maafing a mmxatesci Iaye: :1? »:img-
`saiufiun aarixizin E‘nTs*E}:3ps rm: smface of the smfizi
`drug particke. Ihis layer csf smlutican is referred tr) as
`the éififitsiast 553:9: Fmm this difiusian layer, the
`
`|nnoPharma Exhibit 10910010
`
`3
`i
`F
`I
`
`E
`
`c
`
`%
`
`Eta-ii} >¢fi
`
`f
`1
`3
`f
`
`E E E ;
`
`inside
`
`membmne
`
`i i
`
`mrtsida
`
`23:25:»: trmcspari macfxémésrrz. I} negmsmés :2 simgg
`Fig. «£2
`nmimtie; C rapresanm E-‘us’ mania?fr: 233 3:-gem-EIrz2::eA f3\;ia:$;}E:s.:i
`fnzrri Q’Rz2fi‘Iy W Azxséf Pfnim ‘Z3?!§§:e§?:5§8.}
`
`

`

`Damage Fmm Destggn: Eiopkczrmezcentic rm: Pimrvrznmkinetic Cmsisiemtims
`
`‘iii?
`
`ifiaififimus
`
`far 4 to 10 hours‘ aithough {here is substantial vari-
`atim between pecvpie, anti even in the: same person
`rm c£i1‘fersam::c:asin:1s.‘\?axir:11s techniques have been
`nsaci m cieterrnina gastric emptying time and ma
`gastmintestinal passage 0:‘ drug fmm variotxs ma}
`damage fauna, Excluding time irarking :52? damage
`fcrrrns labeiecl with gamma—e-mitting rariimnuclides
`iixmngh ganxrna geinkigmphy (2, 3). 113:: gastric;
`emptying time: £21»: a ximg is mm: rapid with a; fast»
`Eng skmnach, bemmmg flawgr as the foctfi cmment
`is increased» Clzangea in gastm: emptying time
`amzlfoz in imestinal mmtfliiy can afieci: cimg transit
`time ami thus {Ire ngzpaxtunity Em: drag dissalnzitm
`and absrmrption.
`Ihesa changes mm be afirscfezazi by drugs 2112 par
`iiam may be taking. Cfifififii timgs with 2:.mithaaiin«
`ergjc pzmparfifis, 2.3,, dicydominrr HC1 a;rn3tz'ipty~
`Zine HCL, have me abihty m stem; dmxm gastric:
`emptying, This can enhance the rate: cf abarzrptisztrs
`sf aimgs mzrmaily abaofi-m:1 mm the zstmnacim mini
`reduce the me ask’ abanrpticm sf drugs that are pra-
`marily ahsmtbed {mm the smail intestine. skiterrw
`tivefga cimgs whifl enhance mstric mmflity; rs.g.,
`lmcativesg may name some ti:-ugs tr: mime Si} quie:k}y
`through the gastraintestinal system and past their
`absorptive: sit: as sash 3 mtg m mange the arnrmm:
`of drug auritualfy absmbed. This effect has been
`tiemmnsitrated wiih digckxing whase aiasczrptirm Ea
`siguficantiy decreased by accetemking gastmim
`tvestinal motfiity,
`The aging prmcess itsaff may aiscs infiueme gas»
`absarzkkian. In the aidarljg. gastric 2u:i{i*
`it; we nmnher af aiasstzsrptrima ceils; imestinai bland
`ficrw, éhe rate of gastxic eznptying anti ittiesfinal
`rrmtrility are all decreased. However, zimgs in which
`abzaurpfimn depends an pagsiwz pzrczcasses are not
`affected by these factors as much as mass that cia-
`pemi an active tranaprm: mechanisms, e.g., cai-
`cium, iron, fhiarz-zine, axufi -sugars‘ A decrease in gas-
`tric empfying time wszuki be axivantageuus far {hose
`dmgs that are absmrbexfi [mm Em smmach but dim
`advantageous fr}: thuss: fimgs which are prone tn
`aritid degmdatiorag ag, penicillins, &K3!Th{Om?£f,iIl,, or
`igxactivaieai by stamach enzymas, ag... L~ci~:>p»a.
`The riismiafian :32‘ a subsfance may ba éemflbefl
`by the mmiifiad wages ~‘»N’1rt&tne:;,+ aqua:-man:
`
`~‘j§- = ksfcs - ~:.>
`in which cicskit is the: rate xzfaiiasaiufinn, k :3 the dis»
`sczhmzm rate czznstant, S is the anxfaca area of the
`diammng srzlid, :5 is their samratfion mncantxalian
`of drug in the diffusion iayar {which may be agw
`prmimatad by icha maximum mlubility mi the drug;
`
`|nnoPharma Exhibit 1091.0011
`
`rmmus.
`KILL -mum:-sn
`gunman
`Mass in 7!
`-15%!an8131}
`EMA)
`E M if e
`
`up mm s
`
`"
`
`
`
`116RSSEWM.‘ atfltflfi
`§EE££-9h=?i'»‘.'x I33:-5'8
`Jté-Ea-hliki [pi -ml
`’;EE§I&fi-I'D cmm»
`
`!'LE|.§HI‘;
`
`Fig. 6.3 Aarzzzammzsaai diagram siwzzring the rf§g235.‘§z»2 sgisiem
`immiéng she famziimzs firms}-mi in ximgzilzsarptfan smi ghair
`F:£’&“;¥!.‘£2£§t1e£* pf‘? s'IiIncs
`
`dmg meiemias pass mmngixaaat the disseiving fluid
`anti make cszmtartné with the bioimgic membranaas and
`ahmzpzican ezrsmaeawrtlxe makacnles ofdmg mnfinue
`l't}1'£3a‘&r’£“.' the ciiifizsiaan Eager, the layer is repiezfisheci
`with ciissczkveé drug Emm that su:Fa.r:e afthe d.mgpar~
`tide and the: process of ahssrgfizlnn cctniinm-:5.
`if the prmess of ziiasmxtion {or a given drug par~
`‘circle 1*; rapid, or if the xsimgix &dmini:.=.temd as 3 59-
`lnfi-an and remains present in am: bmiiy as such, the
`rate as) which mt“: drug becomes absrsrbed WDLIM Eve
`prirmriiy dependent upm its ability ta traverse fire
`mrzzmbrane barring. Htswatzczx; if the rake of r3iss<31u-
`than for 3 érug particle is slczw, as may be due km the
`phfssiachamical charactafistics cf the cimg sub-
`starme as the dosage §m:m,. the niiasolminn pzzmzess
`itseif wauici be a rate-Eimiking step in 21113 a};r5x:>rp~
`than prncass. Siawiy soluble drug smzhas fiigaxin,
`may not arxly he abfimrbed at e aimw rate, may may
`be incomggrlifieiy absmxfiefi, m, in aamé cases iargeljr
`msabambed Ecrilczwirtg ma! agirninistratinzm, $119 in
`the naturai Eimitatirm cf time that they may mmain
`within the sfmraach G1‘ the intestinal tract. Thus»
`pmriy scsiubie rimg or poaziy famnilated ximg
`gmziucts may result in a dmgs zimzmp-late abgoxpw
`than and its passage, unahanged; mt xzsf the samrem
`via the feees.
`
`Under rmzrma}. r:i;mum$ta:1ces.a drug may be e:-:-
`perztea tn mmain in the shaman far 212:: :1 hamcg
`{gastric rsmpiyirsg rm) and in the small imtesfines
`
`

`

`13$
`
`I}»::r5:zg:: Firm: Elasrfgn: Bippfizrrmcaereuiia anti Phsmwmfiréneééc {E-:sr2§:£s.-mir'::r:as
`
`in the salvant simse the diffzmimn iayer is cxmgidered
`saturated); anti at is the xtszntentration of the drug in
`the dismlufion xrxedimn at time t {rag ~ :5 is irh-a can»
`ztszntratixm g::aci§em).°I'Ine rate :15 diasmlufien iii gem-
`ameseff E5; the rate of diffilaimn cf mute maiemlas
`thzmzgh rm difmsinn Layer intrs the brflxijf cf the am
`Iuiian. The equafim wreaks that the dissnlution
`rate nm‘ a drug mag: be mcreasasi by imzreasing the
`smrzface area imrimmg the garficie aim} of the drug,
`hgrinmteasing the sniubiiitg; cf t