Osmolalities of Propylene Glycol ... Containing Drug
`Forrn.ulations for Parenteral Use. Should Propylene Glycol
`Be Used as a Solvent?
`Alfred Doenicke, MD1 Alexander E. Nebauer, Rainer Hoerneckel PhI\ iVIkhael Mayer, Mn,
`and Jvficha.el F. Roizen, .MD
`Institute \Jf · Anaesthesiology, Ludwfg-Maximilians-Onivernitat, Ivfnnkh,. Germany, and the Department of Anesthi•sJ.a
`and Critical C:ire, Un.ivers.ity or Chkil.g9, Chi.cago, UHnnis
`
`Propylene glycol (PG) is. a widely mmd vehide for
`,vatednsofable drugs, Injection of drugs fonnulated
`with this solvent often results in pain, thrombosis, or
`thrornbC!phkbitis th.ate.an be reduced by premedka•
`tJnn with l,xal anesthetics or opidds, Because osmo•
`fali~:l ztnd pH that are unphysio!ogk may cause these
`adverse eff't'.'cts, we asstfssed the contribution of PG to
`the osmofoUty . of parerrternl drug . formu1atic,rts,
`Osrrtol<1litv of PG measured in distilled water showed
`that PG ccmtent and osmeila!lty ,vere directly related:
`2% wt!voJ .PG, 264 m(.¼m/L; HJ!.)1% PG, 15,200 rnOsrn/L
`
`Theosmolali.ties of commen::blljt available preparations
`of dmgs di'.:lsolvt:'d in PG ranged from 365 mOsn1/L
`(2% PG content) to 1.2,$(!(.} mOsm/L (83.4{)% PG},. with
`rnoM $how l{XXI mOsrn/L R.eplacenwnt of p(',; by a
`solvent with lower osrnolality in Germany has effec(cid:173)
`tively reduced llw incidence of side effects for one drug:
`Until PG can be rep)aoed in drugs, we recommend
`diluting drugs in .a large voiuine of saline solu.tion; this
`1nay help to rnldmlze the undr½\ir<1ble .effot-ts of this
`solvt.~nt ,
`
`(A,wslh Analg 1992;75:iBl-,5)
`
`·p·· ain on injection and thrombosis or throm·•
`
`· bophlebitis after intravenous · administration of
`• •
`. · · various drugs are freqt.u:mt, undesired: side ef(cid:173)
`fects (1<3), Besides causing direct cht:':motoxic effects,
`the unphysiofogk osmolality and pH of these drugs
`are :m.echanisnis of inflammation and histologic
`changes in ~/esscls (4-,.•6) and. may cause hemolysis (7),
`Etomidate, for exan,ple.- kno1Nn to be painfol tm
`injection . and to frequently cause thro1T1.bophlebHis
`(2), has an osmoJality of 4965 mOsm/L (8)..
`·
`·1 · A
`d ·•
`· d
`· t' · ·
`M.u.:,ce uam.ags, an•·· increase· . crea niute p11ns-
`1,ur
`L
`phokinase activity in plasma are directly associated
`1..vith both the voim:ne and the osmolality of sub(cid:173)
`stances injected intrnmuscufa.r1y (9) .. Most of the
`irritant properties on intra1nusculat infection of a
`chiordiazepcixide preparation have been attributed to
`the osmolality and pH conveyed by propylene g:lycql
`(PG), the solvent in which it is ptE.'pared. and admin•
`isttr:'.red {3), Propylene glycol is also the solvent.vehicle
`for many other drugs that anesthe$iokigists adminis•
`
`Atoeptd for publkatlon :April 13, 1992,
`.
`.
`.
`Address correspc,ndem;e ti, . Dr., Doenids:e, lnstitut for Amies·
`thesiokiµ•..> dm: LMU•Munchen, Innenst.idtkliniken,. PettenkiJfop
`Mr. !kl, D,$000 ~lunchen 2, Germany,
`
`t.'1991 bv the lnt{'rn::.ttk)il~l i\nf.;~th·esi:i R~cSt"ard1-·St~detV
`OC:03-W99f9'.l/S5:00
`.
`'
`
`ter, for example~ etomidate, nitroglycerin, diazJtpam,
`forazepam, and dexamethaso:rw,
`Although the osrnolahties of many parenteral
`drugs often used in anesthesia h;we been measured,
`their solvents have not been listed ($}. The purpose of
`this study was to assess the proportion contributed
`by th(: !';olvent PG to the overall osn.1olaHty of drug
`preparation~:; Wt: measured the osmolalitv of stan~
`dar~i scilutions of PG in distfll!';.,d water andihe osmo·
`fa:hty and pH of drug formulations cont,dning PG,
`These values were also determined for hvo nev11
`preparations of etomidate, apparently devoid of
`venous side effects (2; 10), and for propofot knv·wn to
`be p,o1infoI on intravenous inJedion (H).
`
`iv!ethods
`Eighteen commerdal.ly available drugs for pa.rt.·nteral
`administration with PG conte.nts ranging from 2% to
`83.64% (wt/vol) were investigated, Included lvere an
`induction hypnotic, benzodiazepines, cortkoids, an
`antibii;:,tic, five drugs often used by anesthesiologists
`in emergency or intensive care settings, ?.nd · di(cid:173)
`clofonac formulations for intramuscurarinje1;tion, In
`addition to PG, 10 of these drugs contained other
`
`
`
`Novo Nordisk A/S Ex. 2016, P. 1
`Mylan Institutional v. Novo Nordisk
`IPR2020-00324
`
`

`

`.
`.
`OOENJCKE Et AL
`0$\-10.l.AL!l!fS OF PR()!'YLENE GLYCOL FORMl.HAHONS
`
`ANE$JH ANALG
`!992_:7~i:A3l--$
`
`solvents or preservatives, such -ii.S. benzyt alcohol,
`benzok ,ldd, ethanol, and · sodium d.isulfite.
`Efornidate in lipid emttlsion (10% medium-cha.in
`triglyceride and 10%, soybe.u.1 emulsion., B, Hraun,
`Mdsungen1 Germany) and etomidate in hydroxypro(cid:173)
`pyl-{h:yckJdextrin (Jansseh, Neuss,, Germany), two
`tH:.V preparnth:.ms currently under tlinica! investig;i(cid:173)
`Hon; \Vere supplied by the manufocturets, Stork
`solutkm of PG (Caelo, i:1Uden, Germany) w.:,1,s. used ,
`For dilt.1Jion we used .d.oubleNdistHied water and com(cid:173)
`merda11y available O::Yk saline solution ot glucose
`5% , Three series of meas me men.ts were pt>rformed:
`1. Osmolahty oi solutions containing 0%-100% PG
`dissolved in distil.led v,ater.
`2 Osmolahty and pf-l of an selected drugs after
`dilution, as indicated by product inform.atforL
`Etomidate ird'G v1as diluted 1:2 in 0.9% saline
`solution,
`3. OsmolaHty mtd pI--1 of seven drugs kept in Sy'ringes
`over a 24-h period, Measurements were per•
`formed immediately after drawing the drttg into -a
`syringe and after 2, 4, 6, and 24 h , During the first
`6 h, syringes were stored at room temperature
`(23'-'() and thereafter in a refrigerator.
`
`Osrnolalitv was :m.easured on art osmornetn
`(Kn-~uet Sem:i-micro Osmometer, .BerHn,, Germany)
`with an c1.nalogic., hiple-tange scale (0--400, 0---800,
`and 0-160{} mOstn/L) , Drugs 1Nith osmolatity
`> 1600 tnOsm/L \\!ere · dHuted. 1. ; lQ with doubk(cid:173)
`distmed tvater using a 1000-;J.L Eppendorf pipette
`and n 10 (±(L04)-mL volumetric flask, The result was
`multiplied hy 10, Mean osmola!ihes were c.1kulated
`from five different measurem.e11ts .. The coefficient of
`variation in meas.un:m'lent v,.,Jth this osm.timeter v;as
`:t:1% . Values > 8Cl0 mOstnJL were rqunded to the
`nearest Hl Values of osn1obiitv were also cakttbted
`according to the fqrmHh-t of theciretica! osrrwlality:
`
`,vhere 4> is the osmotic coeffident (<b = 1); rt the
`nrnnber of particles into which each molecule in
`sQlution dissociates (n ""- 1 ); and C the concE.,ntration
`in n.1ok1sper kJJogram {12), The pH value of the drug
`undiluted in solutk:,n \Vat, measured using a pH
`mehtt and an electwde (Vi/TVV pH meter 521 and
`ekctrod¾' ESO, \VeHheim, Gennany),
`
`Results
`
`Table L '.Measured and Theoretical. Os1nol;1Hties of
`Standard Solutions of Propy!eri.e Glycol. Diluted in
`Distilled }Vater
`·
`
`Prnpykm 0e
`glyc,:,J
`
`Prnp-ykne. glyc.ol
`dis,olvrd ih
`di.shlkd waler
`(mOsnl/Lj
`
`Cakub!:ed dtet,rdh:al
`,J5molali(y (m()sm/L)
`
`0
`2
`10.
`20.
`40
`60
`an
`100
`
`0
`20
`wn
`20U
`400
`600
`800
`
`D
`2h4
`1.440
`2,570"
`5>35~
`8,3(KY'
`11,.200"
`
`263
`1,314
`2,629
`
`'7,885
`101514
`IJ,142
`
`Table z, ()srnohlity and pH of Etomidate and of
`Propofol ------
`tn0$n:ti'L
`--------------------
`4900
`24$()
`
`Etomidate in PG (3.5'k vol, 362.fi mg/inL)"
`Etomidr,\e in PG (diluted to 175 vri! %,
`HU3 mgilnL, L2 <lih.ttinn with 0.9%
`1'hlC!Y
`EtoinhJ,1!6 iii 2·hydioxyprbpy1•$•e:ydodextdn
`Etomld;\h; in lipid enwbior(
`Proprloi"~
`f!mpofol (l :4 dilu bop with ghKOify 5%.Y'
`
`307
`400
`29..5
`285.
`
`pH
`'Ll
`5 .. 5
`
`PG_. prnpy!ene g\frnj.
`~c:~..smrr-u:n:jaJ prcp~ritio·n.
`
`show thf! linear relationship betv<'een PG contet,t and
`the osmolaHty of the drug preparation (Figure J) ,
`The qsmoialities of didofonac pre1':Jarati.o.ns con~
`taining at !east mie additional substance (benzyl
`alco-hol, .sodlurn disulfitr, c.1r both, or H.docaine) ,vere
`between .3150 and 6210 m.Osm/L,. depending <m PC
`content (194---400 mg/m.L) . O~mola.Hti:es of th.est·
`preparatkms were higher than calculated fn:.-im their
`PG content.. Glucocortirnids for in.travenous adtnin:(cid:173)
`isttatiot1 i-ri.easuted were dexarnethasorw, 2% PG,
`365 mOsm/L, and prednisolone, 15%, and 2.0% PG,.
`1850 and 2970 rnOsrn/L, respectively,
`Osmob!Hy a,nd pl1 did not change fot tht· .follo~v(cid:173)
`ing drugs stored in a .syrin:g1: fo.r 14 h: etomidate,
`diluted etornidate, etomldate in hydroxypropyI-#(cid:173)
`cyclodextrin, etomidate in lipid e011.dsion., propofoL
`lormetazepanJ, diluted, lor:m.etnrepam, dl,izep,rm,
`and diluted diazepam.
`
`The •;.ralues of osmu!aHty for standard soh.iJions of PG
`dissolved in water (T(ible 1) correspond well vvith
`those i::akulated, Tables 2 and 3 contain os:molalHy
`\md pH n1t,asurements of drugs of interest to a:rR'::h
`thesiologists .. The graphic ptesentatkm of the~,;:: data
`
`Discussion
`Osmolalitv is a measure of the number of solute
`particles ~iissolved in 1 L of solvent For a. given
`concentration., sofotes vvith a knv molecular \-Veight/
`
`
`
`Novo Nordisk A/S Ex. 2016, P. 2
`Mylan Institutional v. Novo Nordisk
`IPR2020-00324
`
`

`

`ANESTH ANAtG
`!.99.2 p•:,:;,n1-'5
`
`DOEN1CK£ HAL
`OSMOLALfrtES OF PROJ'YLENE GLYC{)l .J!ORMU/.J\TJONS
`
`433
`
`Table 3. Osmolality and pH of Drugs Administered Parenterally
`
`Propylene glyl'o1
`
`Dilu!lon ratio arH.! ~oltition
`
`mg/mL
`
`mOsm!L
`
`pH
`Drng;
`---------------------------- -------~-------
`Lor met a z e pa m f2 mg}"
`Lonnetaz('pam ['.2 mg)."
`DiauJpam (10 mgY,"'
`Dlaz~pam (10 mg)"'·''
`Lt)tAzepam (2 rng)""
`Lornzepam (2 mg)"""
`Urnpidi! {50 mg/
`UrapidH {2 mgimlY
`Tht,ophyUib {1$() mg)!
`prnxyphylHri (400 m.g)
`Nitroglycerin um pg)"
`NitrogJyctdn (200 i,g/mL)"
`DigHt~-xln {0 .. 25 rngt'·.i
`Digl(Qxh{•''
`Cotrimi.,xa,:(lJ (6D/40Q mg}"·'
`Cotrimpx,,7,ql (80!400 mg}"-"
`Pht:NJbarhitil! {:Z,fh.') mgtf
`
`500
`250
`450
`7,5
`834.6
`4lt
`1()()
`-40
`200
`
`66,3
`415
`BS.J
`i14A
`3JW
`Not dedated
`
`6,750
`'.);510
`'),9()(1
`485
`12,8(JO
`5,7(JQ
`1,530
`75()
`J,020
`
`4,550
`1,240
`7,&Xl
`1,8H}
`B)90f}
`608
`:t3~2GH
`
`l:60 with 5% glucose
`
`1:2 with distilled water
`
`LS with tiistiHed '><,'<,ter
`
`l:26 with H11ine suluti.on
`
`5,7
`5. l
`
`3,7
`4.3
`
`JOA
`9.6
`JO.;,
`
`"Cmn.merri.al prep~r.ation,
`i'l,Vith: !x1n:.'.yl itkohol_, 3{) mg; benzoic acid, 16 mg; sodi"'m beuw,ite, 1\16 mg; e th,mol l2,& vol % ,
`-:With bt,1ityl ak\,hq!, 2(1.9 mg; M,m·,;,g,>l -100, 202Srng.
`•With eth,wol H 1ml 'it.
`:it'Vfith_::~t.h~ra)l ~KM rn.g1 b~tityl .4h.·•tth~>L SO ~.n:g;; 1.;odi!Jfff dt~ntfite, 5 tPg.
`lVefitl, alr6hoJ in vol 7).
`
`such as PG (76.1) or ethanol (46.1)., contribute con·
`siderably more to the osrnolality of a drug fonnula(cid:173)
`tJon than to its weight or volume (13). Figttre 1 shmvs
`that the drug itself and especially addiHonal solvents
`and preservatives add to the total ostnolality. The
`measurement of osmofality with the osmometer used
`had a coefficient of variation of ± 1%, a negligible
`error rate by comparison to that fqr rneam.m:::ment
`afrer dilution and s1ipetco0Jing.
`Propylene glycol (1,2-p.ropanediol), a polyhydrk'.
`alcohol, b a viscous, colorless .liquid widdy used as a
`solvent for water-insoluble drug,., and as a preserva·
`tive in parenteral, oral, and topical formvlations. It is
`regarded ,-i,s less toxk than other glycols and is
`harmless when taken orally, ,vith acceptable daily
`oral intake estimated at 25 rng/kg (13). Propylene
`glycol is metabolized by hepatic alcohol and aldehyde
`dehydmg€rtases
`to pyruvate and lactate, ,vhkh can
`en ter gluconeogenk pathways, It does not a.ccumJJ·
`late _in organ tissues, but plasm.a levels of PG _may
`increase rnpidly \-';'ith impaired renal function (14,15).
`In recent years there have bf:en many reports
`about side effects with PG. Hyperosrnolality, in•
`creased osnH)lal gap, and lactic addosis are consid(cid:173)
`ered responsible for neuwlogh: symph::.H:ns, induding
`stupor, t.:lma, and seizutes (14-16). Cardiovascular
`disturbances indodi.ng sinus arrhythmia (17), mtdio(cid:173)
`respiratory arrest {16), myocardial in.fotctinn, and
`asvstole {19) have been associated v/ith drugs con(cid:173)
`tai-ning PG, Pentobarbital anesthesia in · sh~ep re·
`
`su!b:d in pulmonary hypertension attributed to PG
`(20}. In tats, both PG and etomidate diluted with PG
`inhibited the hepatic metabolism Qf enflurane (21),
`The most frequent adverse d'fects are pain on
`intravenous injoction and thrnmbophlebitis {l,2),
`Histology after injection of a diaz.epam formulation
`containh1g PG and of PC alone revealed vessel dUa·,
`tion, interstitial edema., ,md polymorphonudear leu(cid:173)
`kocyte infiltration with subsequent thrombqtic orgah
`nlzatton, Addition of lidocaine did not alter the
`inflammatory reaction (4).
`In vitro studies reported hemolysis when PG had
`been added in vark1us concentrations _ to blood sam(cid:173)
`ples (22); however, hemolysis has also been observt'<l
`in animals {7,23) and in humans {16), Radiologists
`have long been a1.vare of the detrimental effects of
`high osmolaHty contrast media. on cells. Erythrocyte
`damage is caused by loss of intrncellu.Iar fluid, lead(cid:173)
`ing to form.;ition of deskcocvtes, •.vhkh, because of
`rigidity, can decrease capHl~ry blood flow and in~
`creast' pulmomuy arterial pressure (23}. Endothelial
`damage led to increased perrneabilHy in rat aortic
`endothelium at threshold levels M approximately
`1400--1600 mOsm/ L (S), Hype:rosmotk soh.,tions have
`triggered histamine release from human basophiJs in
`vitro (24), Finally, heparin resistance has been attrib(cid:173)
`uted to a protaminelike effect of PG (2.5),
`To reduce the 1.mc01r.fortabl€
`sensat.ions for pa•
`tients receivin.g etotnidah.\ prenwdication with local
`anesthetk;s nr opioids is <'ommon,. PrerneJkation,
`
`
`
`Novo Nordisk A/S Ex. 2016, P. 3
`Mylan Institutional v. Novo Nordisk
`IPR2020-00324
`
`

`

`4-34 DOENlCKEEf'AL
`OSMCKAUHES OF f'ROPYLENE Gl.YCOL fORMtJLAllONS
`
`l ~_Nt~StH t\N·,~\ LC~
`1 ~'92;7!i: 43 l~5
`
`.~ -0
`
`>
`
`100
`
`90
`
`70
`
`60
`
`40
`
`30
`
`20
`
`,.
`N '
`
`•~
`
`"'<·
`
`,,..
`
`.... r ,.,._
`
`,...
`
`.........
`
`, ....
`
`t
`
`'
`
`'
`
`'
`
`'
`
`'
`. .,
`
`........
`
`..,,.
`
`"'" . .
`
`.
`
`[ormetoz&.pom
`~~~ .... ~ .....
`........ ,.,
`t
`~- ·
`i
`~
`.......................... ~,.,._
`,
`. ,
`, Oi®:zepmm
`Dig\toxin ,
`411
`,
`~ ;,.A ~'· .... ~ ......
`-
`.,;,
`'.....
`.,}
`'
`Cotritnoxdzo! '
`
`I
`
`'
`
`•>•
`
`•><-
`
`'
`
`•>.
`
`•·IC•
`
`"'
`
`,.-,.
`
`:,.,
`
`=- J -~
`
`....
`
`.J
`
`....
`
`Lorrn'eto zepam 1 :2 '
`,., TJitqoghylLinN '~ _ _ _
`
`!
`
`I,
`
`.·f
`
`'
`
`+.
`
`f
`
`_ _ ,_
`
`,
`,.
`
`'
`
`j
`
`,
`
`900
`
`80Q
`
`700
`
`500
`
`400
`
`300
`
`.200
`
`. ......,
`
`-
`
`i-.,
`
`~ ._J
`
`....
`
`.,., ~ ....
`
`...
`
`t..,..
`
`.,.,.
`
`,l.
`
`....
`
`.,.)
`
`.,.
`
`100
`o ,....,.......,__ ............... _ .............. _.._.......,._.._ __ ._ _______ _..._o
`Dlozeparr, 11 :60
`0 Cottimoxl:26
`
`5000
`
`10000
`
`15000
`
`Figute l , Pn'.ipylerw glycol .:(cid:144)ntenf and osmc,la!Hy •Of various drug,; administered parenkrnlly. Solid line, standard su!utions d PG in
`dislillcd ,-11<1te.r; sqwm·s, frRmulatiqns of •~tmnidak; drcks, Uw !wm'.odiilzepil.ws; f r.imigk;, vnrintrn drugs used .in Jnesthesi4 {w,;• Td,Je 3).
`
`i1ot abolish the underlving ttiecha(cid:173)
`however, dti€S
`nism of tissue damage. Limited hemolysi;· and the
`release of mediators such as histamine are difficult to
`detect, and the venous seque!ae that may arise dur(cid:173)
`ing the first or- second 1Neek after an opet.':\tion are not
`ah,.;ays seen by an anesthesiologist.
`Osrrwialities of didofenac preparations of
`>3000 mOsm/L cause p,lin on intramuscuhr inJection
`and an increase in m{'.,:U1 treatlnine phosphokinase
`plasma activity by 120 mU/mL (3,9). [)rug pre,
`pa.rations tested that use PG as a solvent vehkle
`have osmolaHties >1000 mOsm/L, with ,nost
`>3000 mOsmfL These values exceed those of hy(cid:173)
`perosmolar soiuhons that produced pain sensatk;n
`in veins 011 the back of the hand aftet infusion
`(LS mL/min) or injection (1 mL/s) (6)..
`Diluting :a drug reduces its osn,olalitv, Osmola!Hv
`is reduced by half, for exa1npie, in dilution ofa drug
`with an equal volun.10 of distilled water (designated
`1: 2); howe'/t•r, large volumes i-vouid have to be
`infused to reduce osmolalitv of some drugs td near
`plasma osmolality, 2$5"-,295 rnOsm/L Th;s, neces-
`
`siry dilution is · seldom practicable for intramuscular
`adrrdi1istration tNhen large vohunes are unacceptable.
`All drugs exce'pt nitroglycerin {3-7) have pH values
`between A and U,. bidow and abbve \<\'hkh levels pain
`is evoked (6),
`Pharmareutkal manufacturers in the United States
`,m? not tequi..red to · report the osmolalitfes of their
`drug preparations, Most package inserts of the drugs
`we tested fisted painand venous sequelae as possible
`adverss! effe.:ts without giving their qtuse, Package
`inserts vvarned against intxaattedal in1ection of etnmiN
`date (35% PG), Iormetazepam (50% PG), and
`lorazepam (,S4%, PG) because of subseqttent necrosis,
`and mandtl.led dilutioh for lorazepam and cohimt>x(cid:173)
`azol (41.4\1·, PG}.
`\>Ve beUt"./e that it might be benefidai to redu.:e the
`osrnolality of dtug fo:rmuiahons to more physkllogk
`levds and to teevah1atr the us.e of PG in parenteral
`drug formulations such as nitroglvceri1t soiutiotis
`(1•6)~ Replacement of PG in formulatt<Jns of diazeparn
`(1) and of 0tomidahi (2,10} has sun:essfoUy reduced
`adverse effocts, Possibly, new solvents such as .2"
`
`
`
`Novo Nordisk A/S Ex. 2016, P. 4
`Mylan Institutional v. Novo Nordisk
`IPR2020-00324
`
`

`

`ANESTH ANALC
`J9\l2:75:4Jl--S
`
`DOFNlCKE C( AL
`__
`0$MOLAUrlfS ()F PROPYLr->JE Gl:,YCOL FORMULATIONS
`
`435
`
`hydroxypropyl-{J~cydodextdn or a lipid emulsion
`may prove to be better aHernatives.
`
`VV,e thank Dr. Viktoda 1\.fom:h ,;1nd Dr. Wolfgang Sn.cugst _()f the
`Univt}rsity Vharm<lty. lvhrrtkh, for tht<ii' M-1,istani:e in p,,rforrnJng
`the rneasurri:uents .'1nd provi.dirq:;, the drugs ..
`
`References
`
`l\,fossberg T, Svim,-;son H. Fat
`l.. Von Darcie! O_, Meb'ms C
`emulskm as il whi.de for dir.iiepa.m. A ·stvdy of 9492 p,,Hents.
`Br) An(l.esfh 19$3;5.5:41-7.
`2. 0()titkhe A, Kugler A, \/ol!mann N, Si1ttmann H, Taeggr K(cid:173)
`Etorrddat inH dnern ne1-irn Losun~sverrnittld'. KHnbch(cid:173)
`expetimentdfo Untersi.1chungen zur Venenvertriiglkhkeit und
`Biciverf:ugbarh•lt. Ana,,stlwsist 1990;39:475-/3:0,
`:L Greenblatt Pl, Shw.for RL K,;ith•i'Vr.>st'r J. Sr.>n.1m cwlifaw phos·
`phokin<1se tor1centnrHnns ,1ftet i!ltrnmu,icufar chlordl.a:wp~
`oxide and its S(Ilvm,t, J Gin Piunnm::ol 1976;16:J 18---:!L
`4, Graham CW, Pag,m,l RR,- K;~t;~ RL Thn!mlwphkbitis after
`intravt~!lt.ms dia:e:epiim--tan it be prevented? Aneslh Arwlg
`1977;56:4{)9:._13.
`5, Rafoinko R !hk of hyperkmidty in the. iindotlwlial h1jmy
`caused by .tngiugr.rphic c(1ntra1it media, At b RMHo! fDiagfiI
`1979;20 :4 l(.W:t-
`6; Kk.ment 'W, Amdt JO. I'ain on iv injetthm oi som"' .imiesthetk
`agimt,, is li!V(1kNi by tfai unphysiulog)ni! nsmOJqhly cir pH o(
`their formufohon, fk J.A.naedh E\91;66:189-%.
`7~ P0Ht1t ~J., 11:~iemoglobin.uda c~used: by ·pn:~pyh1.r..t! gfycol in
`sheep. Br J Pharma.a·,I 1958;12:385--9.
`tt Brctschnelder fl o~mofaHtie, of co,nmt•tdallysupp!kd dn.igs
`often used in :rnesthesia. Anes.th Anal.: 1987:66:.361-2,
`9. SiddlfR, Cuh-'er OL, .Ka.mi:ns!ds A-Ser'.~m ,r~atim• phosphokl•
`nate r.rtivity after intrnmuscu!ar ininition. JA1'v1A l974;229:
`1894-7.
`Hl. Doenkke A, Ang,~t,,r R, BegcH:Hntzea H, VoHm~rrn j,
`
`IL
`
`12,
`
`13.
`
`16.
`
`17
`
`19.
`
`2L
`
`,,
`4,
`
`2
`
`15.
`
`f\Jel:~ato:tt i~s.-, The n.:~t"-t S<ilVr:r1t 2>-hydrti)~VPJ'Q(ry]--1}-rvd.'t)de:,::.triO
`rdu.t:es frw side effetis ofe!mnidite-(?,hstractf Ane;tt-,e~idogy
`199l;75:AJ8L
`.
`K!ethe_nt W, Arndt JC.!: P.afo r.m injidon nf pmpofoi: ,,fi,xfa of
`i:01Kentrafom and dil uent. Hr J Ana,~~.th 1991:67:281---4,
`Frefor EL Qstnnmdrv. hi: Ti.dz l'·Nv', ed. Textbook of dinka.\
`chemistry. Philadelphia: 1,,vs·s.,mndets, .l98t/!29<}5.
`.Rey1.r1.lds JEF, ed. The ,,:,c:Jq phNntacvpe.ia. 29th td. L6ndon:
`The Phanniltentk,1! fJtQs:., 1989:1129,
`'tu DK, E!mqufo! 'WF, $<1wchuk HJ . .PhamH.rnkinetlrn d pn:v
`pylene g!yclll h'i hum,ir,.t§ during multipk dosing n?girrwn,.
`J Pfrnnn Sd 1985;74:876-9.
`Clirbtoplwr MM,.. Eckfoldt _ jl:{ Eaton )lN f'ropylrne glyc:ni
`ingestion eswse5 o-fodic: addosb, Lab Invt,s( J.990;62, ll•!--iL
`D1rnwy HE, Daekmmis RA, V.np,)ohw GA, rt at fiopylene
`gly1:<1!:ind,1eed side effects dtning nitwg!ycerili therapy, 1ntcn·-
`th:c Care l'vfod 1988;14;221.-6.
`·
`·
`Ma.rth, G,.. Finht'rg L Propylene giyci.:i!: a potentkd1y tn\k
`Vl.'hk:le in liquid dosage frmn, p,,tliatri@ 1970;77:877-8.
`Higrwr CL, Jad, R Twiggs GA,. RiiiS)'-'> VA _ Hypetosmobhty
`indut'ed r,y propylene glyrnL JAMA 1985;25J:l 6Q6--9,
`Va,ri t.fen Hurk AV\!, 'fi?ifirn HJ. (,1rdiac <:omplkations d•.nfag
`use of etomidate, .Anil,mihesia 198038:J.lt\J-A.
`f'e;;r! RC, Rke SA, Propylene-glycol•mdus:,2d puhnom,ry hy
`pettenskln in sheep, Ph,.trnacok,gy 19S9;J9:3flJ .. 'J.
`Margaiy L Ritt' SA, Fish K,L Prnpyle.ne gl.y,;:o! and amrd«k
`i.nbibii. sonHvr,-irw rr,etabo!bm in Fbi:her 344 rnb (abstrntt),
`AilbllJ.:•siobgy 1986;65;A249.
`l.t!_hm~n-A), t<'e'wToan HW. Pr6ov(ene.glvcd: rat~ of metabo·
`Hsm,. absorption, . .and ('X<:refo:m, \;·W-1 a n1'.ethod for -l'~timillkm
`i.n bodv fluids I Phan:i,aml Ew·Tlwr 1937;1.\0:112~-n
`Asrdi;, r< Effect ,A ionk arid 11tiri•ilA1k i:6ntrnst medfa on tfd
`cdl dd1-;rtnahHHy in 11\!n>. Acta Radid \Diagn) I919;2t}J-l1.
`Findlay SR, Dvou,k AM, K,;,,gey-$0!:mtka A., Ucht(mskin UJ,
`H.y}"wro:mwlar triggt:ring t)f hii;fa,minr rde;1se from lwm0.n
`hasophils, J Clinlriv.:•,;t 1981;67:1604--13,
`Cd L Cd·Dt.>bt<y~ C, L<1.11t'rme·PanJogt,e £, M,:,ert P, Herirks L,
`Brnze MC,Jvh)d,iu M. Propyknt< glycol•.ir .. ':iiked h'Parinrr'sb-(cid:173)
`lance during nHmg!yrntit'l infodon Arn Heart J 1985;!:l(i;
`171-3.
`
`
`
`Novo Nordisk A/S Ex. 2016, P. 5
`Mylan Institutional v. Novo Nordisk
`IPR2020-00324
`
`