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`
`PHARMACEUTICAL
`
`DOSAGE FORMS
`
`DELIVERY SYSTEMS
`
`Nicholas G. Popovich
`
`AND DRUG
`
`Howard C. Ansel
`
`Loyd V. Allen, Jr.
`
`InnoPharma Exhibit 1091.0001
`
`

`

`Editor: Donna Balado
`Managing Editor: jennifer Schmidt
`Marketing Manager: Christine Kushner
`
`Copyright © 1999 Lippincott Williams (S: 'erkins
`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. Manufacturers’product 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 (2., 1933—
`Pharmaceutical dosage forms and drug delievery systems / Howard C.
`Ansel, Lode. Allen, In, Nicholas G. Popovich. '— 7th ed.
`p.
`cm.
`Includes bibliographical references and index.
`ISBN 07683—30572—7
`2. Drug delivery systems.
`1. Drugs—Dosage forms.
`11. Popovich, Nicholas G.
`Ill. Title.
`[DNLM: ’l. Dosage Forms.
`2. Drug Delivery Systems. QV 785 A618i 1999]
`R3200.A57
`1999
`615’.1—dc21
`DNLM/DLC
`for Library of Congress
`
`1. Allen, Lode.
`
`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, Inc.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)
`638-3030 or fax orders to (301) 824—7390. International customers should call (301)
`714-2324.
`
`99 00 01 02
`1 2 3 4 5 6 7 8 9 10
`
`InnoPharma Exhibit 1091.0002
`
`

`

` Contents
`
`
`
`Prefare
`
`Acknowledgments
`
`Section I. PRINCIPLES OF DOSAGE FORM DESIGN AND DEVELOPMENT
`
`1
`
`2
`
`3
`
`4
`
`5
`
`Introduction to Drugs and Pharmacy
`
`New Drug Development and Approval Process
`
`Dosage Form Design: Pharmaceutic and
`Formulation Considerations
`'
`
`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
`
`TO
`
`Ointments, Creams, and Gels
`
`Transdermal Drug Delivery Systems
`
`v
`
`Vii
`
`1
`
`23
`
`60
`
`101
`
`142
`
`164
`
`179
`
`229
`
`_
`
`244
`
`263
`
`InnoPharma Exhibit 1091.0003
`
`

`

`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
`
`TC)
`
`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 of Pharmaceutical Measurement
`
`I 7
`
`I8
`
`I9
`
`Appendix
`
`Index
`
`279
`
`296
`
`346
`
`397
`
`450
`
`469
`
`487
`
`503
`
`535
`
`552
`
`563
`
`InnoPharma Exhibit 1091.0004
`
`

`

` In.
`
`‘ DOSAGE FORM DESIGN:
`BIOPHARMACEUTIC
`
`AND PHARMAC OKINETIC
`
`CONSIDERATIONS
`
`
`
`Chapter at a Glance
`
`Gal-[era] Principles of Drug
`Absorption
`Passive Difi‘usion
`Specialized Transport Mechanisms
`Dissolution and Drug Absorption
`Swface Area
`Crystal or Amorphous Drug Form
`Salt Forms
`Othzr Factors
`
`Bioavailability and Bioequivalenne
`FDA Bicamitability Submission
`Requirements
`Blood (or 52mm or Plasma) Cmicentmh'on-
`Time Curve
`
`Rmttes of Drug Administration
`Om! Route
`Dosage Forms Applicable
`Absorption
`Rectal Route
`Parmtem! Route
`
`Dosage Farms Applicable
`Subcutaneous Injections
`Intramuscular Injections
`Intravenous Injections
`mhndmnai Injections
`Epicutaneous Route
`Ocular, Oral and Nasal Routes
`Other Routes
`
`Parmtersfor Assessmm and Comparison
`ofBioamiIabflity
`Peak Height
`Time of Peak
`Area UndEr the Sam Commfion Time
`Curve
`
`Bfoequimience of Drug Products
`
`Fate of Drug After Absorption
`Drug Metabolism (Biatransfarmation)
`Excretion of Drugs
`Pharmacokinefic Principlw
`Hatf-Lifi:
`Concept of Cteamnce
`Dosage Regimen Consideratims
`
`As DISCUSSED in the previous chapter, the biologic
`response to a drug is the Iesult'of an interaction bev
`tween the drug substance and fimctiona‘dy impor—
`tant cell receptors or enzyme systemaThe response
`is due to an alteration in the biologic processes that
`were present prior to the dmg’s administration.le
`magnitude of the response is related to the con:
`centration of the drug achieved at the site of its at:-
`
`nonl‘his drug concentration dapends on the dosage
`of the drug admirdstered. the extent of its absorp-
`tion and distribution to the site, and the rate and ex-
`tent of its elimination from the body. The physical
`and chemical constitution of the drug S'UbSIal'lte—
`particularly its lipid solubility, degree of ionization,
`and molecular size—detarrfines to a great extent
`its ability to attract its bioiogicaj activity. The area of
`101
`
`InnoPharma Exhibit 1091.0005
`
`

`

`mg
`
`£35ng £33??? Besign: Biapimmenfi: ans: Fhmamkfnefic Cansidemms
`
`study embracing this miafiomifip between the
`physirzah chemicai, and hislagical menses as they
`apply ta drugs, {image farms, and in émg actian has
`been given the desmpziva £61m Mfipkszmmtfm
`In general; far a drug :0 mart its bialngix: effestg it
`musf he fianspamd “by the handy £11262, maverse
`ffhfi mguimd hmlagic membram: barriers, escape
`widggpmaci distributim to unwanmi areas, endure
`metabtzlin attack, grammars in adequate mncmtra»
`titan to the sitea mi actim, and interact in a spam:
`Kashms massing an alteratim nf mania function. A
`simpfified diagram 0f this campiex seriea nf events
`hemem a dmg’a admirfigtraflmn anti its. eliminw
`rim is pmsemad in Figure 4L}.
`The gbsmptism tiimibmim; himransfamatim
`(metabolism), and efimimtimn mi 3 drug fmm the
`bed}; are dynamim grammes that mnfinue frm the
`time a dmg is taken until all at the drug has been
`rammed {mm the may Tim was at which {base
`
`grammes am afiesi the anger, intensity; and the
`dmatmn uni the émg’s; activity wiflfin the 13mg. The
`ama m? 51:11:33: which flatmates rhe firm flame 3f
`{1mg mnmkatim in the 131on and mafia is
`termed phanmmkifiafim It is the Staci}: 3f the km
`metrics 0f absmptim, dish‘ibutimg matahafism and
`extrema ELSA/IE) af thugs and their coflegpmm
`ing pharmamiagic, therapemfic; a: tat-viz: :espanse
`in animals and man. Further; since one timg may
`sitar the absurptim, digmbufiam metabolism in“
`axfleficm of anather drug, pharmacakinefics aim
`may be appiied in the 513163; 0f magnetism bgmwn
`dmgfi.
`Once a drug is afiministemfi and cimg aha-mp»
`firm begins, the rimg dam not remain in a single
`body Imafimm but rather fig gamma mnaghmt
`the had}? until 112$ ultimate efiminatian. Far Em
`3mm, fallan the mai adminismtim a? a drug
`and its entry mm the gastmintesfinal tract, 3 912%
`
`
` {ital
`administraflm
`
`
`Gastreimesfinai
`tract
`
`
`
`it
`
`
`Intravenous
`
`
`
`
`
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`
`Circuiamry
`systems
`
` Excretian
`
`
`
`
`
`
`intramuacmar
`iniection
`
`Tisosues
`
`Snbcu‘tanams
`
`injaciinn
`
`matabsliias
`
`Fig. :11 Echmszfic mpmsmtezz‘m gm min-93mm, meiafiaiz‘sm arm? mama {glimgg qfigr their Wfigismlim by 7mm
`2mm mum
`
`InnoPharma Exhibit 10910006
`
`

`

`Garage Ema firségrr: Biwimnmmréc «mi Pkmkmrrir {l‘msr'rfrrrrrirrzr
`
`163
`
`than {:3 the drug is absrrrberi rm that circuiafrrry syrw
`mm {mm which it is distributed to the: mafia other
`bad}: fluiris, tissues, anri argans. me there sites
`the drag may remm m the rfirmlamry sysram rm}
`be excreted thrmrgh the hiring? as such err the rimg
`may be metabofized E3}? the Ever arr anther cellular
`rites and be amazed as metabrrlitrsr As 31mm
`in Figure? 41.1. rimgs administrred by inmvemur
`injectirrn are: 313mm direrrtly mm the mammary
`system; thereby waifiing the absmptim premiers;
`wraith is. raquireri from all other mama of aflmirris-
`rrarirm far mtemic warts.
`“The variant; harry lemmas m which a drug travw
`r15 may be virweci as separata mmpartmrzntsr each
`remaining mine fractinn {sf the administered rinse
`at?drug: The transfer 9fdrug {mm the him 13:: ether
`{may incafians is generally a rapid pmcess and i5
`rerersible; first 113, the drug may dififure back mm
`the circulafirm. Tim mg in {hr blend thrrrfmre ex?
`£51.13 in aquflibfium with the thug in the arher mm
`grammrms. Barrera, in this equilibrium state; the
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`Mrmt (gear-er or lesser} khan rm: mncmimfirm
`rrf the drug in the ether rampartmentsfi‘his is dug
`largely m the physimhrmical pmpertirs of the 23mg
`and its remnant ability m 133% {hr 25191311 and firm
`mare the bialrngical membranes. Certain @135 may
`Erma the Watery 3323mm rapirfly anti camplareiy,
`whereas other drugs may d0 36:: stawiyand with dif-
`fimhy. A number sf drugs bemme Errand m broad
`mam particuiarly the albamins, and mlya small
`framim iii the mug ariministrrefi may armafly’bg
`row: at Martians amide of the cirruiamry sygmm
`at a giver: time. The transfer 9f drug fram me
`mmpartmerrr to marker is mathematically 233m
`riared with a sgecific rate warrant describing that
`particular transfer. Generally the rate of tranafar
`rrf a :1ng from one mmpartmrrm m summer is
`pmprsrtrrrrral to the mncentmfion rrf the drug: in
`the ramparrmanr {mm which fr exits: rhrz greater
`tire mnemtrarrrm‘ the greater is the ammunt of
`fimg transfer.
`Mahabnlism is the majrrr prams by which fareign
`substanms, Warring {hugs are aliminateri {mm the
`339113?“ In {her pmcass 11fmemhrfliam a drug substance
`may he? biamrrsfrrrmer} 311m phmamkrgfirafiy at“
`five rrr inactive metabrfiiier. Qfim, birth the drug
`Wm 31rd its matabafitrfis} arr. active and arm
`phmamlrzgir: Efffittfi‘ 55hr examgflrr, the: anfianxifiiy
`ding Frazepam {8mm} Wham, in part: tn mx~
`331136.111 {Serra}, which aim has Wary affem.
`In 3mm instances a phamtamlagimfiy ’rnzmfive 93mg
`(farmed a mdnrg} may be admirfisirrrd for the
`imam: efifecm rrf its active memhmfites. Dipiwfrm,
`
`far armpit; is a grmémg cf rpmrphn‘m farmed by
`the arterificatirm r35 epmeghrine and pirafir; am.
`This «enhances the lipaphilic rharartar :35 the: mg,
`and. as a mnseqrrrnce its penetrating. mm the ante»
`rim: mm :35 the aw i}: ‘1? firmer that 13E epmepb
`fine. Within the rye; érprrefrin Hill is rarrvrrteci hy
`enzymatic hydmiysis m epinephrine.
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`m desrn‘be its rare {:5 elirmmarion mm the hardy.
`The term elimimrim refers Err barb marabmlirm
`
`ami excretion. Far drugs that are arirrfimgiered in~
`trammmsly, and therefore irrmire rm abmrption
`prams; the has}; is much “less compier than far
`drugs administered wally nr by Either mates. In the
`Latter infirm; érug absurprmn and drug elimina-
`tirm are ecmrfing rrrmrlmnermsly but at airman:
`rater
`
`genera} Principles
`m? 13mg Absurptiun
`
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`crf acting in Efrem mnemrratima it must mar»
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`chiefly a marsim mi biaimgir membranes such
`as those af rim gasrmirrtestinal apitheh‘m hang;
`bland, and hairs. Sorry membranes are gemrfiiy
`ciarsified a5 {brag main types: (a) those mmposed
`mf revered layers inf rails; as the skin; {b} more mm
`Pager} r216 3 single layer 01‘ mils, as: the intertinal ep—
`ithafium; and (-3) mm: 0E Lesa thanm‘re reflin mick»
`mas, ar the membrane sf 3 single; cell. In mam
`instances a drug rubstarme must» pass mare than
`{me of $9512 mrmbrana typer hrfma it warmer. its
`site 13E artisan. For insrmce, a drug taken man}: must
`first traverse the garrminresrina} membranrr; {stam-
`arh, mull and iarge intestiné}, gain Entrance: mm
`the general Wham; p335: tr: the mgan er fissile
`rm}: whirh it hag affinity. gain antrame ram rhat
`tissue, m then enter info its individual c3133.
`Aldlrmgh the cherrfirtry cf boar}; membranes;
`differs arm: from anather, the membranes may he
`viewerd in genrrai
`ass. a himnrrrmrar firm-id {Earr-
`mrr’rainirrg) 353a: rattarhrrri rm birth riches m 3 mm
`tat-Err layrr. ngs are ‘Ehnght m panarrara these bi-
`nlogir: membranas in mm general m: 1) by par
`Siva diffusmm arm‘ 2} thmugh spammed transport
`machanirms. Wiiirtin ram 05 there mam magmas,
`mare cigar-1y érfined pmmssas have been ascr‘iheé
`in drug transfer:
`
`InnoPharma Exhibit 10910007
`
`

`

`1M
`
`flaw Siam flag}: gimnnamafir {2:232 Pmmmafimis: Csmfmtéam
`
`Passive mfim’nfl
`
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`passage mi aifimg) msiemlas thmngh a membrane
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`gamcipare in that mamas. mugs abmmed “carat
`Eng 1:; 6135 method am said ha be yassr‘mfy 3mg.
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`Eamiagic membrmes by difffisim.
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`Maia}: mm that the rate: a? {£an 43: gramme“?
`swim a mambram {mm} i5 pmptmimal m the
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`
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`bland}.
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`
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`m the pnflmim drug.
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`mam: if £3 higfiiy magma m Rpm salable sub
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`whem pamtratim into the skin is desimfi.
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`mm: gauging-m.
`
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`M the gmamriipid minhiiity {zf the manned farms
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`
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`
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`Imam {If the inmsfine, pH 2516;102:9121 plasmas. pfi
`3%); the ammtim cf 3 drug {mm minua may H11»
`My wfil differ rmd may flimm 223 game mam {he
`types 31’ émage farm and the mats: 1:3? aflwimsrran
`firm pmfgrmé far a gym fimg.
`
`InnoPharma Exhibit 10910008
`
`

`

`£3me {Migm Emmamzfic mg: ngwkiflaflc Cam‘cfmzim
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`
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`
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`applied m candiflnns ("K may mm. “Fur instants; if
`a weak amid having a 9K3 Bf 3; i’S assmmed it} be in
`an mfimment sf gastric juice mm a 133% (if L the
`Eel“? side {If the aquatimn mam yield the nmmhez 3,
`which wmid mean that the ram :35 Magnified m
`
`maize-d drug pasmles maid be 211201;? 1930 m L
`and gastric ahsomfinn wmid be assailant. A: the
`pH of plasma the meme: wmfid ha mm, anti in the:
`Emmi the drug woulfi be largely in the imaged
`mefi‘abie 4.1 {2:953:15 the affect‘ (if pE-i {m the km -
`imam sf weak eiecmhr’ces, anti Tame 4.2 ceffers
`Emma representatiw pig "names of mmmm mg
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`3mm the equafim and from “Eagle $1; it may be
`gear: that a. drug substance is haIE baked at a {M
`Me which 13 equal to Eta pKwThus pKA may he, der
`fined as the 911 at which a thug $5 33% imizeci.¥m
`ample, phennhmhi’cai has a 33K, mine 3f 33mm
`”M, and in {31351113 {pi-I 3%) it is man? as imimd
`and minimized famxs in equal 3310mm Hume: a
`drug suhstsmcr: :33an new}: the films: pimma fa:
`distrihnfim flmughaut the bgdy unless it is placed
`Wm dizecfl? {hmugh inkmvemns mienfim or is £a~
`wrably absmbed from a site 33mg its mate czfmm
`as the gastminmfimal tract and aliawad in pass
`inm me general nimflafim. A3 $113M: in 'Ifaifle 11.2,
`phembarbital, a weak mini, “with a 915;: sf M wcmlfi
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`Table: M. The W: at pH on the imizatim nf
`Weak Eiemnlyics" pig-FBI % Uninnfmaéd
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`99.9
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`13K; wine’s Ear 3mm man: and
`Table 4.2.
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`Basis 13mg;
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`PK;
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`mm:
`
`Bases:
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`Aceqfififiqmc 321d
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`Tm largely undisamigtad in the gawk anfimnmem
`m pH 1 anti mam likely $22 weal} abmrhed. A drug
`may entex me circulatim mpicfly and. at high mm
`cenfiafinns if mgmbrane penetration is easily at—
`mmpfished m. at a 3m»: rate and law levai if the drug
`is 1m; warm? abambeé :5er its mute {ref entry. The
`pH :16 the mugs amen? environment Memes the
`am and the degraa if “its flirting: ciiséfibahmn he»
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`fare mm miflm Iiprid~pmetrating under Emma new
`{man mi 191% than mder ammar. If an Manned
`molecule i3 abie m flame {Maugh trim lipici barrier
`and remain umongd in the new Environment, it
`may remm ta its manner 198mm 0: gm an m 3 mm
`me. Haws/vex; ifin tha naw mmentitisgmafiy
`innizefi due in the influence Inf we pH at? the 342-0321;}
`fluid, it likely will be unable m was the mmhrane
`with its game: ahfiim Thus a mncetmafim gméiw
`em 13E a drug nanny is mashed as: aqufiibfium rm
`each side 9f a membrane cine :5 Megan: éegrees nf
`ionimtmn manning on eachgidefi summary 13f the
`camepts 5f disamiatimfimiaafim is Emmi in me
`physical pharmagy capsule animal ”pKaIDismcia-
`rim Cmstzntsfln Clhapmr 3.
`It fa men desimble {m pharmacenfical scianfists
`m make 3mm mnfiifimfiflnfi in axganic drugs
`
`InnoPharma Exhibit 10910009
`
`

`

`113:3
`
`3mg! Fm: fim‘gn: Bfaphammflc mm? Pfiammkmm‘c Cmégmsa‘ms
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`ami thmaby fawrabiy aim: their lipid mlubflit};
`partition mefficimm anti dissmiafifln mnmants
`while maintaining the same? basin phamamimgic
`activity. These sfiarts frequenfly pawl: in inmaseé
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`dwagm
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`Epeciaiizesf Trafisparf Mechmzismx
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`In mntrast m the passive flansffir {1? drugs
`and mm substancm anrmg a bicfimgfic memlwrana
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`Raga: metabblitrszs, are candxmted amasa a membrme
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`pcm mechmismfi. This type 3f Wafer seems he
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`part 13 Waugh: m imam: membrane cnmponents
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`camplm mm amasg the membrane Wham the
`11mg is released with the carrier ramming m the
`arigmai amfam Figure- 11.2 pfasems the simpijfiaci
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`stmcmre m that H hm substanms are trampmted
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`across the membrane against a mmentration gm»
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`11mm m ma {31:3 higher mmmmfim m. if the salute
`is an ion, agaimt an electmnhamiml potential gar
`diam. in contrast in active transpafi, facilézaiasi sis}:
`imam is a spenialized transport mechaxfism having
`all m? the ahme charaflesisficg Except that the salute
`is mt transferred against a cmcentrafim gradimf
`and may attain the same mnnenirafim inside £112
`mail as that an the: miside,
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`Many b35131 mtn‘ema as sugars and amim 36:35:
`am {mummified mags the membranes ef the gas»
`mimestmal tract by carrier pramssea (Imam vita-
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`and drug substances 35 methyldnpa and 331239
`mam mquim active Rampart mechanisms far
`thai: abmrptian
`Imeatigafims of Mammal trampm have often
`attained in ms; {at the: site} 131‘ In mm {in the body} an »
`imai madels {3: arm»: {3911de king bed?) trampmt
`modem; hawmar, recent}? (:91: mam mmials a? 1mm
`man mall-intestine absnrpfive 03125 lme hemme
`avaflabie 1:3 investigate transpmt amass inmsfimi
`apithafinm {1}. Bath pagsiw anti trampummediated
`sméies have been emanated m mvestigate mecha»
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`
`Dissolnfinn and Drug Absorptinn
`
`Fm a drug in he absurhefi, it must first be fliy
`mlved in the am a: tha ahsarpfion aim Fm in»
`31821128; a drug administered orally in table: 0: my
`sake fmn cams: be 3333mm mm} the dragpartideg
`are fissmved by the fluids. at some paint mm: the
`gamamtemnal mm in Wm in which the m1-
`ubflit}? mi a timg is dependent 111mm eiflmr an aticifie
`a: bash? mediam the {hug M21210 he dissalved in
`me stamach a? intestines respectively {Fig 4.313216
`pmegs by which a drug partifle {119%}st is tigrme‘x}
`dissalnfim.
`
`As a drug parfi-rsle 1mziergmes diemmmm the
`drug mmlemEeg {m the amiasze are the first 2:: mar
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`drug pam'cke. Ihisr layer 5f smlutien is referred ta 6.3
`the éfimim Em Pram this difiusim layer, the
`
`InnoPharma Exhibit 1091.0010
`
`3
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`

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`Fig. 3.3 nmmmfl diagram slanting the élgzsfivz system
`winning {he lamiim final-mi in simgnfimpfim will hair
`ream pH values
`
`dmg mnlemlns pass mmnghaut the dimlving fluid
`anti make cnntacl will“: the filnlfigit memfimnm and
`afisfiz‘pnfin 8113113333312 mfilmlles mfdmg mnfinue
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`with glissolmi drug 15mm film smlam nfihe dmgpan
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`if the waning of flissfilmion {or a given drug pap
`tide in rapid, a: if the dmglx ndnnnlntemd as a 51:“
`Inner: and remains present in that: may as finch, the
`ran: a!) which lnn dung fiemmes absnrbed mule! Eve
`primarily dfipgndent npfin its ability tn traverse fine
`mmfirnne barriax. Hawaver, if the rain of £35011;-
`tim for a firfig particle is 51mm an my be due to the
`physlnchamicnl charactarintics 0f the cimg sub—
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`itself wnulcl be a rate—Emiling step in the afimxp»
`film mamas. Slnwly soluble fimgs saunas filgnzdn,
`may not Lani? he absmbecl at a alfiw rate, ihey may
`be lnmmylnlely absm‘bncl, m, in 51min canes largely
`nnahnmbefi £0316ng anal admfinlstratinn, clues in
`the natural llmitafien ml time Ihn? they may :nmain
`witlfin the sfmnach fir the mtesfinal tract. Thug;
`pmrly salable clings or penny {emulated fimg
`mailman may result in .2: drugs mcfimplete :11me
`nan and its gassage, unmanned; nut ml the system
`via the lanes.
`
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`pmea m sea-main in the 5mm En: 2 13:; 11 ham
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`in: 4 fit; 10 hams: although {here is substantial van»
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`gasnnmtesfinal passage of drug fmm nations final
`(lasagna fnmln mclmiing the flanking an? (image
`lemma labeled with gamma—emitting radinnmiiden
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`Emptying time £22: a fimg 15 mm: rapid with a 11351:“
`Eng 5.19:2:1rlve21ml}P becoming slnwnr as film fonfi filament
`is increased Qhangw in gannc emptying time
`analog in mfnstinal maxim? can affect drug finnslt
`lime and thus the figpmmnity Em: 6mg nissnlniim
`and abmrntinn.
`Ihfisn Changes nan be afiefleii by dmgs me 1351*
`Elam may be taking. Cnnnin {Raga with ammhnlim
`ergic: pmpaffinn n.3,, dicytlomlnn HEEL nnétz‘lpty-
`line HCL have me ability m slaw dmxm gaafi‘i:
`nmpfiing This can enhance the rate: :1? nbfinrptlnn
`sf :1ng nfirmally Emma lmm the stnmach anal
`reduce the me {3f abanrpn‘on :31? drugs that are pri-
`marily afisntlfiefi {mm the small intentine. Alterna—
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`laxatives; may name: name drugs tn mania fit} gunk}?
`through the gantmmtfisfiml ayatgm and past their
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`91‘ drug actually afisfirheé. This effect has been
`demnnsnated with dignxin whims amnrpfim in
`3Wcantly decreased by amelmling gastmn
`nesting} motility,
`The: aging pram-33 itsnlf may also mfineme gas»
`1:041an absfirpllfin. In khan mean gantrlc atlw
`it}; in: manner nf alasmptivn calla; Mammal filnfid
`film the rate of gastric empnring anti inlesfi‘nal
`mnfillty are all damanaed. Howwez‘, flmgs in whlfih
`abanrpfifin clepeznds an pansive pram-mes are net
`aligned by these factors as much as flame that {in
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`acmnragems frn than: nmga Wd‘l are prune In
`mid degradatinn; £ng panicllllns, awfiwomynn, m:
`macmaleil by stnmach ems-,5; mg... belfipn
`The difimlnfinn nf 8 311135th may fin gamma
`by the mnrlifiad Mfiyes ~Wfi§mey equal-inn:
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`«if = min - c.)
`in which field: is the: rate filmssnlufifing k :3 the dis»
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`of drug in {he diffizsinn layer {which may be an
`pmximatad by the maximum snlfifiility m.“ the drug;
`
`InnoPharma Exhibit 1091.0011
`
`

`

`1:13
`
`13953313 Fem: flaign: Bipptmmacmis mm? Phanmmtémtéc: timsfimtfiam
`
`in the mlvent Sifltfie the mam Eager ES mfitdemti
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`amezfi by the rate of diffimimn of“ statute matemflas
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`lumen. The: equatitm meals that the dissatution
`rate at a drug may be mamasati by increasing the
`surface area {trimming the gamete aim} at the drug,
`hfinmasing the 593121311183? at the drug in tha mm;-
`sitm Eager, and by tutors emfiadiezi in the: dignity
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`the matting drug. Fm: a given drag, the fiififusitnn
`(inefficient anti usually the mmmtmtim if the
`émg tn the {3132;151:311 layer will immase with inmm«
`mg tampemmre. Aim, massaging the: rate: at agita—
`tim of the {321339in meriinm Mil increase 1:111: rate
`of éiamiutian. A retiugtim 131 the tismm'ty 1:1me wk
`vent emplayed ta manner mtamt whtrh may be meat
`13:: enhance the: titsmtutim rate at a ctmg. Changes in
`the pH at the mm at“ the 331133211 which M13310?
`the mtuhifity at the drug may be used tr;- advantage
`in incteaging 12115501110331 rate. Effervescent, buffemi
`mpifin tablet fnmulatimm use $113318 at them prim?
`pies m mat! advantage! Data m the alkalizm adju»
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`enhancea mm 1‘th Wflfit’i} tagger and the 330111“
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`ahsmbefi mm the 133me 15 faster than that
`
`aflfimaci fmm a mavemmm} aspirin tablet mums»
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`gain (glitz? Earn a tmubiestzme heafiache; Many
`manufacmmm will tttitize a partimfla: ammphfims,
`mystalfinaf $311; at“ state: farm :31? a drug that M}! m:-
`hibtt tint! saluhflity tharactefisticg needmi m achiew,
`the {flawed timiufian ahmctefistim when admtm
`istereti Same at these fatten that affect fimg dissm
`{mm-a briefly are We} in the 5:235ng para-
`graphfi, where-as athats wit} be dammd in
`succeeding magma; in whisk fitsyam mtmmnt.
`Tim chemical anti physical charantaristics (If a
`timg snbstance that tan affect dmgi‘dmg precinct
`safEty, Efificam and stability meat be mew}! tit?
`Emmi by appmpriate tiranéards in an applinatim t0:
`WA appmtral amt than substaimd and mmmlled
`thmughmt pméuct manufatrtum
`
`Suffice Area
`
`War: a drug partisie is minced to a targgt nmw
`bar a? smafler particles, the total Mam area mam
`
`ateti is tnmseé. Par timg aubatamea that are
`Emmi}: m- slmiy gambit; this genmfly msults in an
`immase in the mate 9!: dimiufian. This is expiaimti
`in thE Physiml Pharmacy Gamma, “Pattitie 3122*
`Emma Mtg-a and Dissatufim Rate