MEIHGI‘LQ
`author—
`All such.
`that pen
`2‘ samurai
`
`shat" has
`xm other
`rrsement
`{wt been
`u mafia»
`
`bask by
`"ei‘red.
`
`rcmse 9f
`‘refiimi-‘Qm
`ii an the
`rug {ex},
`"matimzj.
`
`gamma}?
`Le anther
`(:32 of the
`his infer-t
`‘ any pen
`‘2 caused;
`
`Lmfifi V, Mk)“, “5%.. Phil?
`Professor and Chair
`
`Sepactmam Q“? Marjicinafi Charnistw
`and Pharmaceutias
`
`
`
`Coifiege of Pharmaw
`Universiw 0f Okla?!me Heaith Sciencas Cenmr
`kiahoma City, Oklahama
`
`Amerimn Nfimn‘mawtimfi Aam‘cfia‘tim
`
`Washington, m3.
`
`CIPéfiQTEX_AZFL 0132304
`Argentum Pharmaceuticals LLC v. Cipla Ltd.
`|PR2017-00807 PTX0167-00001
`
`

`

`fimer’man Warmxmmmaa Asmaiafigm
`Washing-mm, 0.6.
`
`Editor: Limit), Voting
`Cover Layout: Christopher Ba,qu
`interior Design: Nina Bridges/Suzanne Iaceby
`Production Services: Suzanne Ian‘st
`Indexihg: Mary (foe
`EdiL‘dfinl Servigzes; Publicationa Prcxfessiormls, Inc“
`
`Cover [thzfi'z‘ratiunt Chris Lockwood
`©1997
`
`Re‘pffnted wifh the pemusgion m“ the Internatiormi foumaé of Pharmaceutical Campamding
`
`mery of Ccmgress Cataloging-in-Pubfiimtim‘x Dam.
`
`
`
`Alien. Lays! “I,
`Theaz’h. science, and iazuhxmlogy of'pha1m1fiacél1timl mmpoundmg /
`Laydk’, Ailm, [1:
`p.
`Cm.
`includes bibliographical referencegs and index“
`ISBN 0-917330-88-9 (hurdmver)
`‘3, Drugs - Damage? farms.
`1. Titie.
`RS'ZGG‘AiS 1998
`615';~§~d’c21
`
`© 1998 Loyd V Allen, Ir.
`Ail rights rescrvccl
`Publisl‘wdftfii the Americuzi lernmceuficul Asmciaiirm
`2215 Cumfimflan Avenue; NW
`‘x’x’a'shingt'oh, EMT. 2003745983
`
`Nu pm? af‘filés bask may be repradgzced, stared in. a Miriam? sysfem.. 0r transmitted if? my farm
`ctr by any Imam, elecfmninz, mechanical, pfwrmtw).~*fng, (wording; at athei’wise wifiioui wria‘ée'n
`permission {Tom thé’ publisher:
`
`Printed in the United States of America
`
`353044
`Haw m
`By phone:86?}8786729—7VISAEE, Mastnggzdfifi, and American Express® mrcis accepted»
`{8028624095 from outside the Un‘iteclrsm't‘es)
`
`AOTEAZFL 0132305
`
`PTX0167-00002
`
`

`

`Ellesgm‘m l?"
`
`:liplion.
`
`Elam
`
`ten in step
`
`: thoroughly.
`
`ln this Cl’lt'lgfiffm mmpflumled pz’oductg {1m gmuped by mute Qf adminiximtion
`mlhe: than by (lowg
`forms. For film: reason Elm chapter is divided mm three
`major secllcnss apl‘lihalmiij, Mic, and ncmll prepam‘llens.
`
`
`
`One {if this. early lrwlmemi’s of (aw C(Indl‘tiill’ls with {:3 liquid involved the 113:2 of
`film juiflg m” (1 liver. This pregzm'alim'a W115 Ema 9f the emli-{sr observations mm apply
`irlg Substances topically to the eye was Effective, In Hm; case, lha Vimmln A commit
`{)f the juice was effective in treating the conditimm llu‘ouglwm history various
`plant wanna have {1153 beer; pl‘epa‘lred and med. for eye amdifimm deay‘ss vein”
`{1:35 far mphthcglmlc liiguiilsl include prll‘nmlly Eterile, buffered mqumus syaétems “{1th
`mntain presermtives.
`"EVE salves” were; prepared during the perlwd {llf the early Rmmm’: Empire by
`“medial {mulca‘iif’ or men who spedallzed in the preparation of such xalvea. One
`guch pmduct was described 011 (3 piece 0f green statue as [Humming "crows 0f
`Lucius Vallatinus fer affectmions of the eyes} Evidence exists that aphthalmk: 011m
`ments were used throughflut the Roman Empire and even in such muflying areas as
`Smhlaad. Ointments developed later mgr} mils and fats as their vehicles, More
`EECGXEHSI, the petmmlumg were used as; vel'licles for l'hefia Qpl'lthalmiu prepamifimnx
`
`@phihalmla llmgmmfimm
`
`Defimlfiamllww
`
`Uplamalmic solutions are: sterile, free fmm 'fm'aign particles, and prepared espe_
`.cially for instillation into the eye‘ mphtlmll-nic susmnglons are sterile liquid prepara‘
`{lam that contain solid yarticles in a vehicle suitable for instillatien mm the eye.
`Ophthalmic aimmenis‘ are sterile prepm'atiang designed fm application to the eye‘
`The}! ham rm omlmeml' base (and may 91’ may mt include an active drug.
`
`lllfimfical Essa
`
`APOTEX_AZFL 013206
`
`PTX0167-00003
`
`

`

`Cgmgzmifigm
`
`In addition to the active £111.;szr u;:1’xfl'x.r,1§3m§c preparations contain a number m
`emipiemmfinclmlimg vehicles, buffers, preservmfives, ioniciW~acij1 ting agents, (1min
`xxxidunm and vfiagmi‘ty ershancers. 'E‘ngreciiems used in. me ferrmflrx'éiiim process mm?
`be mmir‘ri'tming icy-and compatible with The. eyes,
`
`Efrepamfiflm
`
`A}: mapqmflon must be done in a clean air envijgionmem by a qualified asep—
`tic cempoundmg yhzmnacisf. The phqfifiudst his): emureth’at alli'fi'geingredients
`are of ihehighest gmée Chm cw: be reusthbe Qbmmed. lhe be}: (m 9:336 221 USES
`file amps "involved in preparing Qphfmlm‘ifi stulmib’m, suspensions, and emu/mus
`
`'Phygimszkemimfi Camidm‘afimm
`
`En ixrepmzmg ephfhulmic minnow, we must consider the genera]. physicw
`chemical parameters; clarity/r ftmniciizy, pH/buffers, and, steriiiiy The ufiditkm of
`excipients such as preservatives, ‘antioxidums. and vismsity Qi‘lhOI’lCéi‘S, aswe‘tl as
`potenfial izm‘qmgrafibflifles beemr‘een these excipienirs and active druga, should also
`be (:03risiniereti
`
`fiim-‘ity
`
`Amfiimfiflm
`Ophthaimi: preparations are used it) hear u’llergieg, bacterial and Vimk infaacu
`Hams; gtaucmm, and numerous other eyewndfii‘pns; T'hfiyévglfi
`:'
`.‘tamfly axpose‘d
`m {he mtmwsphem. dust, poliutanm allergens! bacteria, and for-alga budiea. When
`the eye’s natural dafiemive mechanimm are compromised or overcome, cm niph‘
`thalmic product, in either a mimian, suspensitm, or mintmem fpfm may be indL
`sated; Solutions are‘used‘mmt aftegn to deliver a drug: to 1cm eye-.- Althcugh mlutiom
`have a 1'e}ativeiy' Sheri durafion‘ of action, they spread easi‘iy‘ (War the globe and
`ctwerwx-fli. Suspensionshave a slightly‘ilonger duration 01' actionbemuse the mm
`(1195 will. lsnsual'iy settie in the lower mniunctjvai 5m: and‘refiease-flm drug as the par~
`tides dissolve. {)énmaents have an even longer dalmatian of actim}. The ointment
`spreads over the eye, mini mm the mnéunctiml
`The active drug is reimsed $10»in
`as the vehicle is slowiy removed from the eye.
`
`
`
`Ophthaimic animations must be free from fareign partidea Ffltmtfian is genemily
`used its remove Iberia particles and to achigve darityofi' the 55311211011, Pdly301‘mte
`am} Poiysmbu'ie 80, int; maximum mme‘ntmtim (if 2%; can also be? used m achieve
`Clarity:
`
`{swam
`
`Lacrimat fluid has; an isotonivzity Value equivgieni: to that of a {19% Sadium abla—
`I‘éde solutiun, However. the {eye {1cm miemte-IQ value as Raw as 0.6% and at; high as
`1,894: Efldium Chlafidevequiv‘wemya Some Ogfihihalmic sait;_t10§1swill,m hyperix3ni::..by
`223mm 01‘ the high mntemmtim :‘equiréd affine drug Subsfiaglce. Others MEI be 31ypc3~
`mm; am will neqm'ré‘ adjustment :0 attain the {(1rd reftcmdty range; sadimn Chla-
`ridir, htsric Quid, " dextrose we commonly used tcx:z%”th:is purpose. The idealtcmicfl
`1:}; is; 300 EIIOSIIME} however, LL mth of 200 ’60 600 mOSm/‘L it; acceptabIe.
`
`pH and "Buffering
`
`Ophthaimii: sukufions are .ordinarfi}; buffered at fixes gal-E of maximum stahiiity
`far the drug(s) they contain The buffers are inciuded {a minimize any charge in
`
`' AOEX_AZFL 012307 N
`
`PTX0167-00004
`
`

`

`WWW.”kaka.7»;............. r
`: lrgniiraliaris.
`
`a ..
`
`alum:
`
`.
`
`Accurately weigh m immune each ingredient.
`Z. Dissolve the ingredients in about three. fourths 0'!" film quantiiy 01' sterile warm" fiat
`iiijeciia'fl and mix Well.
`I‘. Add sufficiem sterile water fl)?" injectim mrvalume and mix well.
`. lake (1 sample of the soluiion and defzermim the pH». Clarity, and 0th quality
`control facmm.
`
`‘
`
`‘
`
`. lenge in {a suitable container for au‘inclaving.
`. Aut‘oclava, coal, and label.
`
`1 ifn large number Qi‘ suspensims me la be prepared, select a mncifim gamma iii)
`he a ssmyed and checked fox-isleriliiy:
`
`Sawfim‘mim‘m (Mgi‘hmi 2‘)
`'. Acmmtely weigh or measure Each ingresigliem.
`>riliza each ingredient by 01 suitable metlmd.
`Uismlve the ingi'ediems in «built lilies fourths. oi ills: quail-lily 0f sigrile writer for
`lmjectiun and mix well.
`a Add sufficient sterile Wfllfill‘ far inie-ctimn ‘i’o Winnie and mix well.
`". Take a sample of file aizripeiision marl, datmiiine '1 hi“. pH and either qimli‘ty mime:
`Mums.
`
`Package axial lobe},
`. if (,1 large Ilimjibier (if soluticmsqre to be meg-area, select a: madam Siixiiple in be
`assay-ed and checked for 5ieriliiy.
`Gimmems
`
`
`
`
`
`. Filter through >21 sterile 0.2.1.1 {liter mm as Media, api‘ithmlmic: container.
`. imclqage and label.
`7. if a large mimbei‘ 0f sfilti‘l'imm. we it) be pmgmmd, girl at, a mmlmm smnple to
`assayed and checkeefi for sierlli iy;
`Suspemi‘ims {Meilmd 1}
`1. Accumiely weigh or mequ each ingredient.
`2. Dissolve the ingredients; in (about three foul-ills 0f the quantity of sterile water‘ibr
`‘mje‘ctim‘i mailimix well.
`_ A,le S‘
`Vclz‘em sterile waterfor injectinn to valume and mix well.
`. Take ‘n’l sl’c‘imple of the aului'ion and demmlim the pH and other qualiija comm
`fcmims.
`
`
`
`{Ragga Ell
`
`a 0. number
`9 agents, mm}
`m “pmcem mum
`
`ml viral infecd
`
`tanlly exposed
`initializes. When
`
`‘ome, cm. mph»
`, may be it
`Jugh soiuiimns
`theiglobe and
`muse the partb
`mg
`{lie purv
`The ointment
`released Sluwly
`
`qualified (may
`he ingredients
`l png 221. lists
`ind aimmems.
`
`let»
`rieml plug;
`me mddititm 0f
`:ez‘s, as well as
`gs, slicmld, also
`
`9n is~genem13y
`Palyserbate .20
`“155ml to caéllieve
`
`l’o soilium cliiw
`and as high (13
`3 liyperionic by
`78 will he hype-
`*; sodium chlo~
`be ideal tonirci~
`1W.
`
`imum stability
`[my change in
`
`i. Accurately weigh or memme each ingredient.
`’
`. Starilize each. Stigmdlemlw a suitable ’méihmi.
`. Mix the ingredients will“: the sterile val-aide.
`. “fake Ci sample 0f the claimant and determine the quality camml Emmi-3.
`.. Package (mil lubél.
`\. if aalmge number (lf ointment; (AFC m be prepared, select @- mmflam sample {0 be
`rifssayed (incl checkea‘l for sieriiliy:
`1..............................................................................M.................
`.AW......................“M
`
`‘
`
`pH film’s may occur during. the..stomge lire of the drug; ihia illiflligi? can. result from
`{garbon cliaxicle absorbed fromilieulr m fh.)m~.h.ydrc)xyl. ions absorbed item a glass
`maintainer: Changes in pfi can affect the solubility and the stability of drugfig con—
`Se‘quenily, it is important to minimize such fluctimfim’is. The buffér system should
`he designed so» Khalil: maimamsl‘he pH ithi'mighout llie expecieil shelf‘life (ii the
`
`APOTEX_AZFL 0132308
`
`PTX0167-00005
`
`

`

`pmduct, but has; cs bufi‘er caga'city that is 10%;; engugh that when Ehe ophthalmic
`Solutién i's d3‘cappzed'int:cx “the eye. the buffer‘sysmm affine tears Wm rapidly bring The?
`yfl‘of‘the soimion back to That 03: he items. Mama, 'ihzé'phcmnmzist31:01:15? use a cam
`mmmfion of buffer suit that 25 eife
`re but: <25; haw as: pxmsibliz. Gemmlha a bu?“
`carspacity of Less than 0.05 is desimd; g}
`_ n‘the range at 4: m 8 is aimsédfired optitr'rmm.
`
`Sierfliiy
`
`O‘piiathalmsic solutith must be meme. Sterility is best achieveéi thmugh sterile
`ffitmtioh, whichinvolvzes usng a Merile membmné finer 0160.45 u m (3.2 1.1 pore‘aize‘
`and fittering into a sterile container. Other methods of "sterilizing ingredients or
`componentva .ophflmlmz’winclude Shy heat,- ateam under pressure. that .is,‘ 4.111%
`clawing "(see Figure ZG-ih)’, images ‘steri'liza‘tirzm with ethylene oxide.
`'
`.. «wwwnwmvwm>
`
`
`
`
`
`Since mam ophthaimic minnow and wspemions are prepared in :g'smltri.~use
`contamij they‘inust be presmv‘sd. The: preservative usegi"rr1.usme compmzi‘rfiyz with
`the (14; Va fiwgfias we“ as with all the other EXCgpifii’lt‘} in the pmduct Can‘me
`piesenafivesfar ophthalmic pmducts are ghmm in fable 20»?
`Anfiexidams may be ~1'e‘3gl1ircd‘fm' flied-ed active. drug ingredients. 'E'mble 3&2
`lists (.1 number a}? uniiuxiziun'ts that
`be
`in qphthdfimi‘c‘pi‘épamtigns,
`if the viswsii'y of an aphfl/mlméii pmfiui‘é: increases... the giratxriuct Win remain in
`the eye Iongsr and thereby anew mare time for drug absorption and effect
`[:3
`increase the viscosity. V’fSCO’Sfiy enhancers; acute usedz the most Gammon (sf whim is
`methyleeflula‘se, g‘emmfly'in a szmmentzutéen QE'mmuL 0 25‘5"; if the 4000cps grade.
`is used. if mathy‘lcellulese is uutoclavad, it‘will come aut‘
`_ oiution; howewn if m n
`be..md§"sper
`after coming, e3» {Emily if placed in a refl'igemtt'm Either quad Choic‘a
`es Lare'hyr
`a Aypmpylméihylmllukxse m" mfitiiykeliuime in Ihe range of 0.5%:5m 1%.
`Aim mceptahie is polyvinyl ulmjhoi in a range of 0.5% to 1.5% weightg’wflume.
`Saiutionvisc'esity ranging fmm 25 m 5(3- rips is ccmamxHL With an 0f these, enhancers,
`however. it is impmmm that thé elm-it}? of the mimic.“ 'S we mmmuimfi. Additives. that:
`increase Viscosity am Show] in Table
`Qpi'nthqlméc ointmenm must be preparedso that the}? do not irritate ihe eye, per-
`mit diffusion of the drug, (mi: retain file fictirvi by 0f the drug Em u masons-.1319 period
`05 {mm “when mum} pmperiy. The buss; prh‘marfiy used fur dphthaiméc fiinfi’nmfis is
`
`Figurg 2%»? MEtffifimCfififiWfiflfl’ifi‘flEimfi ymfiéfiamfaumiting fig. amm‘ém Maw;
`fl. gmmm view.
`
`miner cipienta
`
`APOTEX_AZFL 0132309
`
`PTX0167-00006
`
`

`

`Qphééwimén 53h; 52 E‘ée:
`
`E
`
`'
`
`“game-s EMU @ragawmgwa {:figfimmméy 1.3m Es’s {Epmhafimiag {Fm seam? mgafi
`fiadmfis
`
`Maya
`3am.
`Usuafi
`
`Ema. We} Range (“/53 flows.“ (“m Enmmpafiifliities
`Wmerm‘tiw Name
`Chlmmbumn 01
`0,5
`
`Quaternary ammmmum
`campmmds
`
`Benzalkonium chfioride
`Bermethomum chloride
`
`0.61
`
`0.004032
`
`Organic mercuricxls
`
`0.001~~-0.€31
`
`Phenylmercturic: acetate
`Phenyimercuric nitrate
`
`Thimemaai
`
`Pmai‘gy‘dnJKi/benzomea
`
`Snaps, anionic
`materials, salicy—
`Eaters, nitrates
`
`Certain builder;
`with phenylmer—
`curic acetate
`
`Adsorption by
`macromolecules
`
`{3.0M
`{L004
`
`{3.01
`
`0.}
`
`“The 501% Advisosy Ravéew Panel {m OTC Ophthalmic flmg Pma‘um {12 9??) 1352‘s them car}
`cemmfians fbr pmpumliuns £55m have dirtrl {mind wiih {his eye iésa'uezs and HUI I‘m :30}-
`Iw device‘s: such as mmmi‘ lens pméwffs,
`
`“mm 2% ‘2 Améaxidmfi 3.3m far fiphfimfimia am Emmi Premvafiam
`
`Antiaxiflant
`Ethylenedmminetetmacetic acid.
`Sodium bisulfite
`Sadium membisuifite
`Thiourm
`
`1591.255 Maxamqm Eancamm’tiafi PM
`
`“mm 3&3, Vimegfity Emmch Mr fighthagméfi Wagmmtkma
`
`L4
`‘1 7
`
`we mphthalmic
`aidiy bring fihe
`Mid 1154-: a con-
`zmliy, a muffler
`ared cnpt'imum.
`
`Waugh sterile
`02 g; pom size
`ingredients. or
`that is,‘ mm}w
`
`mains“ views;
`
`)3 in multi-use
`mpatible with
`1311 (iammon
`
`USS. labia 3&2
`smtim'w.
`m3: remuim in
`and effesi. To
`DH 0f WhiCE'I 15
`
`LOGO cps
`Lowevei; it can
`er
`(thaw
`of {3.5% m 1%.
`
`reig ht/‘voi um e.
`4338 enk‘im‘jcem.
`Aédm‘ves than
`
`pen
`te the
`mnabie permd
`it oimmems iii
`
`
`
`% “mi Maxiflfimfifififififlwm.W
`Hydm thylteklulose
`0. 8
`Hydz‘oxypmpfl methylceliuimse
`3.0
`Met'hyic'eihflme
`Poiy'viny} aimi‘ml
`Pub-vi nylpynclidane
`
`white petmlatum) Aqueous salutions of tha dmg can be inmrpm‘ated by using am
`abmrption base, as iong as it (flares next irritm the eye. One
`is anhydrous
`1031103111 mixeci with white ge’tiroicz'iium. The {)hcu'mucigéi Hum? be? aware that surfawi‘a m};
`
`APOTEX_AZFL 0132310
`
`PTX0167-00007
`
`

`

`used if} nuke Qb5£)i’§}7i"’)n bases may cause eye irritation. Fowcfiem incorpsmteci in
`ii pmpumtimi must bamicz nffid and sferilfzeni t0 ensure that the final product
`is mat gritty and mus mnirrii ting.
`The 3128 {if the pamtiesi in cm cipmhaimiv suspension must be imxzifl emth
`ma“: tiwy (it; not irritate andmr fiCi‘iZLiiZlflfthE {ZQHIQCL ‘Ehxa mitmnimj farm of the drug
`is required. Oph‘thuimic suspensions must he frees {mm agghmtzemtim or mixing,
`
`inmmpmfihiififi£35
`
`Because. ziricmlts can form insoluble hydmxkiem iii: (a. pH above 6.4, u‘bmic acid
`,mmxiim vehicle may be used. Emit acid saiuiion misc: has cs ‘szmrysz (about pH 5)
`and a flight: bufferingucrion,
`Min-mas m srili(:y]{1'i‘es we incompatible with soiutinns Bf benmliumiuzm ch10»,
`ride. Therefore, imhbuld be replacecfi with 300294) phenyimercmic nitrate.
`Sodium chioride canmt be usedtm adjust the tanicity of silver nitrate soimiom;
`ijecaum silver chioride would precipitate. .Tmieml, sudium nitrate shculd be used to
`adjust the mnicity, (ma phenylmer‘curic nitrate can be 1.13mi
`{if-5’ the prayervative 11:21.
`this Sif'ljm‘ifll‘l,
`
`
`
`Rewind—use times fer waterwcomammg.fmmuiaticms are no later than 14 days,
`when stored (ii: mid ten‘zpei'atums, for products; prepared fmm ingracfients in selid
`farm;
`Ei’ nmmqueom:
`liquids are impaired using a manufactured product, the
`beyomi~use rezcmnmendczimn Lam: mte‘i than 25% of tin? time remaining {in ihe
`pmduc’t‘g expiration date 01‘ 6 months, whichever is mrfiehiim c111 othefS, therea—
`ommended beyondmsy? date is the imerideri tiumztikm of iiiem'py 'or 30 days, whi
`i,-
`QVEE is 6mm}: These beyond-use remmmendmions can has extendedif miidfsci221~
`iific iniormmtigm is; umiiable to giiggmt me stubilii‘y 0f the: pmduct, as dimmed in
`Chapman“ 4., “Sicihility 0f Compmmded PE'GCEUCES.”
`
`Quaiiiy {Swim}
`
`The atrimpaumiing pharmacis’r should foiiow standard qiiq'iirszy contmi proce~
`dureg Theae include checking. the sterility, dmiiy, .uppmmni'fl, pH, and vuhuuef
`weight. Eiteriiiiyr,t:cii1 be c:he<‘ked.by plaiing a sumpie 0f the pmduci on an agar pigm-
`cand. Checking "for micm‘biai gmwih. ifihis procedure is net femihilef pmiimti mm»
`pies can be 56m ta a‘iubmmmy Em inesi'ii‘ag,
`
`PackagEng/{fimréigwiigbflii’ig
`in stm‘iie dropper boities. hiriiyiduul
`Qifihiémimifi golutians shouldbe puma
`doses can also be placed; iii sterilersyririgm without medias} Generally, thege‘pr’e‘puu
`I'OUGL’IE shouldbe stored at either mam 0r refrigerated. temperamres. They 'shzmiii
`not be fmmn. Ophthalmic preparaiium should be labeled "Fm i‘lhi‘f Eye?” “Do N01:
`Tough: the Eye m7 Eyelid, 5’ "Store as Indicated,” ca11d“'Dispo&e after [approprime datel.”
`
`fimbiii‘iry
`
`Fflfiéflfl‘ Qwumefiflg
`
`Paiientrs zaheuid be insirmimi (in how t0 administer drain, or ointmemts. t0 the
`eye. Specifically, ihe-y‘ shamid be cauticmmii 11m; to allow the tip 0f the dmpper or
`mintment tube t0 much any part: of the (3318‘ They siiouldsalso be imimct‘ed Ivor alluw
`the drug to fall..~freely into the eye and not in ailOw the drug to touch the eye {and
`than be di‘awnbuck into the bottle.
`
`' APOEX_AZFL 012311
`
`PTX0167-00008
`
`

`

`Sazflgfie Vsfifiécém
`The amps listed for Solutions in the hm; Prepumtmn {if Ophthalmic Products
`shculd be fo'flflwegi $10 prepare finesse vehiclea
`
`0.3 g
`“5210,3013
`1m mi,
`
`qs
`
`mm?
`
`m S
`
`am’ium chimide USP
`Benzaikonium chim’ide
`Sigma water far Ehjection
`
`M_________________________________________________________________________________________..
`
`Boric acid USP
`Benzamunium chloride
`$terila~ water fur injection
`
`L9 9}
`1:13.086
`“10 mi.
`
`QB
`
`Same {thugs may be inmmpatibis with 3nffer301ui‘éw UK because of cm imam»
`panbiiity with benmlkomum ch10 E‘idii, Eufifer Solutim: 18 (jamming a éiffermt passer»
`vative! phenylmez‘mflc nitrate, Sodium suifite has; been addad t0 pmvem discs!"
`Gratiang’axidamm of some of the mugs in
`miegory. Drugs that are incompatible
`in Buffer Soiution {A but C811 he prepared using Buffer Salution EB indudfi the fab
`aning Ciass EB 63111.95:
`v Physosfigmine,
`a ?henylephrine, and
`" Epinephring
`
`fl
`g
`Lmzp'kai 5.5}
`
`orgmmtmi in
`mm pmduct
`
`mail encugh
`71 ofthe drug
`or taking.
`
`, :2 Peoria acid
`
`fabcsur pH 5)
`
`onium chlo~
`We.
`:ate soluticms
`[d be used as
`eservut’we in
`
`mtrol piece»
`and walmmj
`n {agar pm
`mmurt smnn
`
`5v Individqu
`
`these prepu--
`They should
`*6," "Us No?
`Mute date} . "
`
`1cm 1% days,
`tents in solid
`
`the
`product
`Ring (m the
`mm, the 178:}-
`days, which»
`: valid scien—
`oiismssgd in
`
`newts Eat} the
`
`e dropper or
`:tedi ’LD afluw
`
`the Eye and
`
`Three buffer solutions have been suggested far certain drugs when they are pram
`pared as aphmalmic amlutium, These drugs have been divided mm three chases
`and mm Eisted with the recommended buffer solution far that classy
`The foilmwing drugs in mass IA can be placed in Buffer Solut‘mn IA, which.
`has a pH of about 5:
`Cocaine;
`Dihticsais'te {‘N’upermine),
`Keostégmme (Pi’osiigmm‘),
`Phemmilze (Melamine),
`Pipemcame (Mmyw 5 m3},
`Ejn’ocaim;
`Yetmwim (Pantramine), mm
`23216.
`
`
`
`Eufi‘m gfifiufim E5?
`
`Eerie acid USP
`Sodium suh‘ite, anhydrous
`Phenyimemurm nitrate
`Steriia water 'Em' injectmn
`
`0:3
`
`1.3 g
`0.1 g
`1:53.0{36
`100 ml.
`
`APOTEX_AZF 0132312
`
`PTX0167-00009
`
`

`

`.{Zémga in 531mg H mm can be preparedé in gaffer Soiutiem E} inch/Hie the fab
`ivwing;
`
`* Arrqyini‘,
`> Ephedrima,
`r Humatmpme.‘ and
`>
`i’ilacurpme‘
`
`Bummer gamma Efimmw.
`
`WM
`
`Sadium acid phcrspham,
`anhyds'oua
`mwdium phuwhat‘ey
`anhydroufi
`3miinm chloride USE?
`Disudium animate
`Sen‘za‘ikonium chloride
`fiteé'ila water f0: injection
`
`Q5635} g
`
`{3,2382% 1;;
`
`8.5 g
`(m g
`12%),303
`Q3 mo mL
`
`
`
`.. Caiculate the qumltéty of each ingredient required for
`xunuely weigfi 0r measum each ingredient.
`‘. Dias-Delve QB. ingredirents in the steriie 833% maiium chimide solution.
`-. Pater 'flwoug}: a 0,2 L1 films: mm (1 sterile Ophthalmic. matuiner.
`‘ Package and labei.
`
`gamma §0m1umfi9m
`
`Polyvinyi aiml‘mi
`Pavicéane
`{ihlordbutami
`E).9% Sodium chimédfi
`sotmion
`
`prescriptian.
`
`WE .
`
`5 5.;
`{Sesame hydmchéorfda
`BEthyiehgdiamineietraacetic acid H) mg:
`fieriialkunium chloride
`19mg
`31:131116‘ 0.29% gmdium
`figs: ma mL.
`chlm’ide ssiutim
`
`' APOTEX_AZFL 012313
`
`PTX0167-00010
`
`

`

`Hide the: {at
`
`A
`
`?“
`
`fiwmhw fiwmfifiwéfia figmémméez fififiufim {mama}
`
`. Cciélculme the quantity cu" reach ing radiant: required 5133‘ the gamscription,
`. Accurateiy weigh 91‘ mmsure each ingmdiem.
`. Diswlve the mmine hydrathinfide, ethylmediaminetetmace‘tiw acid; and
`benmlkonium chloride in sufficient sterile {3.9% sodium chlaride smution‘ to
`make 100 mL
`
`4. Filter threth (1 starile 0.2 gl filter into a smile {suntuinen
`. Package and lahei,
`
`Clxrcicaspm‘ine
`Com 0%? or 055m 0E}
`
`2%
`qs
`
`1. Cmécufirmz the quantity of each ingredient I'éaquired for the prescriptien.
`I. Actumtely weigh m immature each ingrecfiiem,
`. Use aimhol :0 data the COIHQHEE‘I 10 be waqu for mixing the 0m} (3‘ Cmspmima
`13% 5011mm and 011‘
`
`{3mm (1 cmmnfifcmi mniainer of Cydasporine EGG/a Suimizm with almhol;
`0pm the {Gamma and place: it in
`laminar flow hand for (about: 34 hours
`to u’i’iuw the minim} m evupm‘ute.
`. Mix four volumes; 0f com {31’} or olive mi} with one miwrm of the 30% siycmu
`sparine 0m}. saluiim; mix tharoughly in the previauaiy cieaned container.
`. filter.“ through a 022 p. filter into a sterile, dry ophthalmic container.
`. i’aclmge and Rabel.
`
`
`
`ipfionu
`
`firm.
`
`..
`Wmfifimifi... .
`thxyinphrima hydrochlori‘de
`9.125%
`Paiwmyi aimhni
`1.4%
`Dismii‘xm‘x emigrate
`mm
`Sodium ase‘iate
`0.1%
`
`..
`
`.
`
`Mmebasic andium gjhosphate
`[Jibasic maiium phngphate
`Smfium H‘Iiosulfate
`SEWER»: water far inflection
`
`qa’
`
`{3.1%
`8mm
`(391%
`138%
`
`‘1“ Calculate the qufimdty (if each. ingredient requimfi far the presmiptian.
`Argmmtefiy weigh 0:- measure E‘QCh ingredient
`Dissolve ail the ingredients in sterike water for trajectiora
`4‘ Finer ‘l‘hfflthgh a sterile 0.2 ,u filter mm a shame cwtainan
`5‘ Package and label.
`
`APOTEX_AZFL 0132314
`
`PTX0167-00011
`
`

`

`'
`
`v"
`
`figghihsalméez Labyigzamr
`
`patrizlamm
`
`‘
`
`- ma! all
`Lanofin aslmml‘
`9mm Stadium Chiaridg injectim
`
`1.. Calculate Elle quamiw of?
`
`ingradlem" required. filter the wescription.
`
`23. Acmmtely weigh or measure, each ingredient.
`’3, Mix The while penuldium, mmeml oil, and Rummy: alcohol together, 113mg.
`(1: watt-2: bath.
`
`4-. Siwrl‘liae‘: the mixture with my ham;
`5.. Using aseptic: i'aclquue, moi {the sterile mixture in a lmnmm‘ flow heed;
`Ellen incorpcxrate the. sterile 0.9% mdium chloride lngmitlnra. cmcl mm.
`6. Package in :a'ézetlle garflainem
`
`
`
`7*
`
`“E‘etabmra‘aycén Fumfie‘dflgshéhalmét $i§§3§i€§fi§§3
`
`Tobmmya'gn oamhaimlc
`salutiofi
`‘mbramycén Ersjec’sicm,
`30 mg/Zml.
`
`5 ml.
`
`3 We)...
`
`‘
`
`, Calculate the quantity m‘ each ingredient required fer the prescrlplimi,
`. Prepme the prqducl using {lSEleCI lemmique,
`5, Auturateiy mecwure {earth ingredient.
`
`4. Mix wally package, gang}. lull-39L
`
`a: wwfi“
`
`Acgtylcysmine
`indium ed‘aiam
`Chlgmbgia‘m!
`Artificial tears salution
`
`133%
`£3.{§25%
`{9.5%
`(13
`
`2‘ g (m ml ‘01" a 2m salmiom
`5
`108 mg
`23 mL
`
`(N933: Frepcu‘g in a clean air environments}
`
`3.. Calculate. the gum utity a}? {scam ingrecfiem‘ requl
`2. Jmmmteély Vs'eig‘h or meafiure each ingredient.
`3. Flam: the {:lfalmejbumrml in a Clean, previouga’ly glarilized beaker:
`:21. Add 9 ml; of amme tem‘saolutian,
`
`fer Elm pyescriplmn.
`
`5. Cover: and 3hr {With a rrmgx’tetic mixay will}. stir boar) unitijl cliswlved.
`6.. Add rim dismium (MG-tutu? to the aqlutim.
`
`f?) Add. 10 mL pf 20% metyl‘cyatw’ine0nd inhalation snlutlmfl.
`8. filter
`salution thwugh a. 0.2 31 filter into a Ste‘i‘lle‘ ophthalmic mnmmer‘.
`9. Package and label.
`
`APOEX_AZFL 0132315
`
`PTXO167-00012
`
`

`

`{Eghfilfiéx‘l’ili‘ a}:
`
`-;." fiqéglfiggglaléam
`
`g, “fi‘i‘slafimiafiewfiy
`Tromcarrslde
`Hydmxyamphetamime hydmbr‘wmide
`Benzaik,mawillm chlmide
`Disadium acetate
`303mm uhlorlde
`Sodium hydmxide gr
`l'lydrochloric acid in adjust pH to 4.2 $0 5.8
`S'Earile water for lniection
`
`325%
`1%
`B.G05%
`
`3,3
`
`100%
`
`we mi-
`
`:rlpltlum.
`
`gather, using
`
`r flow head;
`1 12112:.
`
`:mpiiom
`
`3% solution)
`
`crlptmfl.
`
`1:: container.
`
`
`
`Defimlzémmg’l‘fim§
`Ulric: prapa ratiom can be in liquid, Ointment! 01' powder (image farms. 80th will:
`miminm and .mspemicms, izhe liquid. dosage farms, are ympmed for :imtiilmiun mm
`the em: fjolutiam: are iéquiti preparations in WhiEh «all ingredients are dissolved
`while suspensions are licguid piepumfiom {Unfamihg insolubk materials. 50111113312;
`are (.1193 used far irrigating {he ear. Cilia ainrmmis are semlsalid pt‘eparufi:ms mm
`are (applied to the exmrior of the ear“ Insufi‘latiom are preparatians made of finely
`divided powder that (are administered to the ear canal. Insufflqtmg a powder into
`the ear canal is nut mm mmmcm because the Ear lacks; fluids and a powderawax
`buildup may mam:
`
`. Calculate the: quantity of each ingredient required for the prescription.
`. Accurately weigh or measure each ingredient.
`. Dissulve the solid: ingmdients in approximmely 50 ml. of asterile water fur
`injection.
`, Add the benmllaonium chloride dilutions m the wlu'giml {mt} mix well
`. Add sufficient water; {0‘ make almm 90 ml and mix well.
`
`. Adjust the pH to belwem 4.2 mm 58; using the sodium lwijrcmme 0r
`hyda’achlorifl {1 Cl do
`. Add sufficient sterile water for injection 1‘s maize we ml“.
`.l Filter through 0; {)2 y; filter into sterile camainexs‘
`'
`. Package and label.
`
`The benzalhonium chlm‘lzie far this: pmsarlpfima can be prepared as {ohm/“5:
`
`. Accurately measure 1' ml. of 50% benmlimnium Chloride solution.
`2‘ 331mm in a IUD-ml graduated cylinder.
`3. Add sufficient sterile water for injection to make 100 ml. anti mix wall.
`4. Remmre 1 mL m" the solution, which contains 5 mg of hemcxllwnium chlo»
`ride, and, add life the salutlml amiainlng the active drug.
`
`Gila: Fmpamfiwm
`
`APOTEX_AZFL 0132316
`
`PTX0167-00013
`
`

`

`Efifimficaé Uf§€
`
`Wrong{mutahistory mecEicm‘iom have been administered :0 the ear £0: a local
`affix-,1. Early otic preparations were appliefi by making {mimicme such as cloth,
`wmsd; m: plants, in vurimus. mm or extracts from pitiffifi or cmimais and they; plCi‘C“
`flag the Empmgmrted z‘mtetiala in this am,
`mama recent method th appEying otic
`pregmmtions HWQIVES placing a liquid in The ear and inserting a cotton plug 21:0 keep
`the medicm‘io'r: from dimming nut m" the. am: This methodis 5111]. user} Luday, aicmg
`with tm: 12% Wear irrigcmts, which Clem: debris from the em: 37,1115; datum LS the muse
`Di" mum! 0th: infections.
`
`Appfim’ifiam
`Otic irrigating solutions, which may mnsist nfanrfarri:ams, weak stadium bicar»
`bamtetf, bm‘ifl. acid (O;5’3’u~1%}, or aluminum acetate mimions, may bewmmeti m
`<1‘E‘:0u‘t3-7'°C ‘befum instillation mm the'ear‘ These irrigating Sofiutions may be used
`to remave em: wax} pur'xflem discharges uf infectmn, and forfiégn bmdiea fruir‘ri; the
`ear canal”
`01:16; suspe'usims can be'useci when u Eong duration of drug; Effie-rt '11-; desired or“
`wheia iihL" drug is net gamble in the vshig‘fler; commoniy used in otic pygpmutiona
`Tine pawéera's used as, irisutflcmon’s may canmiflmx mfiibac’ierigl’(indict (m
`mmifimga} agen't‘that will create a :prsitcjry‘ form drug, A 3mg}: rubber ‘0”: plus»-
`ticrizmlb ins‘u‘filmor (powder Newer; ;mffér}’ {an be mad. m Maw, or insufflu
`the
`gmwdex into the em:
`£32m {)immema are seldgm used Amy miniment huge Earl be used in their prefiflv-
`ration, hizaweveai; and. they".ch Mme mltibu‘cte‘rml; mutifuflgui, or corticostgmid
`ingrediwix These Ointm'mts. uré‘ appiéed {'11
`"‘Ttl‘y to the exi‘er’ior partions 0f the em;
`
`
`
`fiampmifiam
`Categorieg of medicatith cornmmzly useci in the mr im::h,:de 10ml anesthetics?
`clesas'azaisugugents {pa1'c>,x.iciesfiP m‘i'i-szegttives, and cmt‘ifungals. mm inciudeci are no;
`aids for cleaning; wayming, or drying theextmnm mr‘mk] for removing any fluids
`that may be Ql'x‘ilrmfirgjed by a km:le waxy buildup.
`‘
`Vehicleg med most Mien in Otic preparatiom are glycerin, propylene glycim‘h
`and the iowm“ molecular weight polyethylene giyq‘: ,
`.(PEGS), cgpxrg'jui'iy PEG 5%.
`These whides are Viscous am} will dd‘h‘
`‘ m the ear doing}; Wafer and akth
`{ethwol mm isopmpyl) can be used aswhides and solvents; fur <0ch medicatibm;
`hmw‘ever, they/me, us’ed pflmarfly for ix‘r’igafcian,~sinc:e am: of the m qpeutit um /
`these preparatjomi is m keepithe E<tu'cm1r.11d1
`‘ minimize bactezial/fflngal’growtlm
`Alr;q};101.cm’1 be used full sirength. Vgetdble 1.1.5,. peciul‘ly‘nfiwe 011, am 3150 gmd
`vehiclea. M2111
`a} mi: has heien Used {IS a vehida for smile- unfihiotz‘ca and anti-
`inflfimma‘iiejry‘ :‘flédimflons. Otic ointmen primarily cat/1min p‘e’émlatum <12; (1 vehiu
`tie, Whereua mic powdeifi‘ may {‘onmin {$3153 or hic‘iose as (.1 vehicle.
`
`Premmfim
`The methfid 0f farmumtim ~""i£‘ grepgmtions is 511131191; for UH Emu: duscage
`foxms‘ The km): on the 316:: p
`.Eigts the Specific steps irwoived in pmpaflng 0th:
`Eczluriuns, Silspmmiiifi'jfi, and amtmem and‘powdms.
`
`Phjgzgim: hemimi Cunaicimuflom
`Physicochemiml considermimas in developing oiic prepumtmnslinciuds sein-
`bilifiy; viscosi’qz ionicii’y, swrfact’afit properties, and prefihrvimg-‘E’s. Alfhcfiugh :1. {13%
`m notgmemfly a (ionsideltafimi~;.'fhe graham}; weed to be “dam.”
`
`APOTEX_AZFL 0132317
`
`PTXO167-00014
`
`

`

`{Egii’iiiiafmég {iii-i 51 F56:qu fiemiaimni
`
`Soiutinm
`
`.1... Accurately weigh 0r mmsme each Of the ingredients.
`2. Dismive The ingredients in about flares: fmirihs of the quantity 0f the vehicle and
`mix weii ..
`Add sufficient vehicle in Winnie mini mix well.
`
`4, Take a sample of the aviation and {ietarmine the pH, clarity. and ether qualify
`comm} factors.
`
`3. Package and Mimi.
`
`Saspensémts
`i. Accumi‘eiy Weigh m: measure each of The ingredienm.
`2. Dismive or mix ihe ingredients in about three fourths (if the quantity of the vehi-
`cie anti mix weii.
`3. Add sufficient vehicle: to vulume and mix welL
`
`4. Take Ci sample of the suspension and deiermiiie the pH, and other quaiity caniml
`mania.
`
`
`
`1r fer a 10m!
`id: {13 mm.
`id their: pinc-
`zppiyirig mic
`.ylug it: keep
`'tiicluy. along
`.5; is the cause
`
`iociium bicar—
`ie warmed in
`
`may iii-2 used
`dies from the
`
`5: is desired or
`reparations.
`mi andfm‘ {m
`ibbei’ 0E pii18~
`iisufflfltifi, The
`
`[1 their prepa»
`coriiixssteroid
`ms Of ihe em.
`
`ii firiES’ihEfiCS,
`Zi'iided am iiq—
`ing any fluid-a
`
`pylene glycol,
`ally PEG 3&0.
`r and u’iccaimi
`a i‘nadimfiom;
`pautic aims of
`ungai growih.
`are aim gimd
`tics; and. mm}
`mm (is. a vehi-
`
`f'iiiir dosage
`ii
`preparing 0151c
`
`i include 30in»
`
`mugh sieriiity
`
`
`
`Mmiy drugs are :smiiibie in the vehicles mmmonly used in these preparations.
`if a drug is insoiuhie in these vehicles, the preparation can be prepared as :3 ms—
`pensjon. Because most (if these vehiiiies am}. i’eimiiveiy viscous agents, the aciiiii‘iim
`of suspmding agema may amt be mergessciry.
`The visa sity of the pi‘€pamii0n is important in keeping the medicatimi in the
`em fiLiB‘iifi]. if Elie pi’i?p€.iif(li’im‘i
`is too thin, the medicaitiafl will cimin {mi of the em. On
`the other hand, if the rrleriimtiom is too thick, ii may not reach the inner recwses of
`the sear.
`
`
`
`3, Package in (1 suitable Container.
`6. Labeé.
`
`mama/gems
`
`i. Accurately weigh L'ii' IK-leiib'ure' with of the ingmémms.
`2. Mix 90:233.
`the iiigrt’dieri’i‘s with We vehiirie.
`3. Take u suiiipie iii Lite ointment and defiermme the 'qiiciiiiy wnimi fucmrs,
`Package mid iabei
`ikmdei‘s
`
`., Acwmieiy weigh 01* measure with 9f the-iiigredienis.
`. Geometricully mix the powdem iogeiher, starting with the powders: present in the
`smailest quantity.
`. mice a amnpie 0f the powder and determine the qumiity semi-oi factors.
`. Package and label.
`
`Hygmsmpicity mid iOIIiCiiy {ire imperimii in the pmduci‘s miiiiity to aid in
`withdrawing fluids imm iiie iii'liifififjifl'i'iz‘. men of the em: if the precinct is i‘iypertxm—
`it, some fluid may be withdrawn from the ear, thereby ramming some of ihe pres—
`sure. if the product is hypoionic. however. same fluid may flow into the area.
`Because many ear mnciitions are related to The difficuity in cleaning the ear,
`the presence of a surfuetiiri‘i in the pmpamflom hejps The medicaifim spread «311i and
`mm in breaking my ear mm. This (ifliiari makes it easier to remove any foreign
`material.
`
`TEX_AZFL 01328
`
`PTX0167-00015
`