E15b
`
`RF.SOME
`onJ£CTIF: Pfe{;iser !es pacantetres de la pentox.ifylline et de ses
`metabolites suiVant l'adminis11alion orale (bid et tid) de doses multiples
`·
`chez des patients presentant une dysfonction n!rmle.
`
`ot vi.s EXPliRIMKIIII"AL r.'1' Lmo Oil 1..'rn1>ll: Etude ouverte, rnndo111iste, en
`chasse-croise et avcc groupes paralleles, realisee dans un centre de
`rech.ccche cliniquc.
`PATIJl.>ns: Les volontaites not ete regrou¢s en foaction de !a vrueur de
`leur claitance a la creatinine (Cl«) estimee a partir d' une collecte
`urinalre cle 24 heurcs: groupe 1 =Cl.,> 80 mUmin (n = 9); groupc ll =
`Cl., 3~80 mllmin (n = 6); el groupe m =CJ.,< 30 mllmin (n = IO).
`MtT1100F.S: La pentoxifylline a ete administree a raison de 400 mg bid
`ou tid !es jours l 1t 7 et 400 mg lid ou bid les jours 14 a 20 avec une
`periode de retrait de 7 jours. Des prises de s.wg ont ete cffcctuees aux
`joms l, 7, et '20. Les ~chantillons sanguins ontete analyses quanta !cur
`contenu en pentoxify!lineet en metabolites de la pentoxifylline (M-1,
`M-rv. ec M-V) pard1romatographie tiquide en phase {lazeuse.
`Ml!SURES OE L'Ef!U: Les vaJcurs de Cm,.,• t...,.. c11,, .. ,. et SSC;q Ont ete
`detemiinees. L'analyse de variance, le test de 1, el al regression Linea.ire
`ont ete utiLises avec un valeur de p < 0.05.
`
`Research Repqrfs
`
`.RESULTATS: Les rapports SSC1q (ud):SSCi.i (bid) pour la pentoxifyllLrtc ct
`SSC,~ (bid el ticl) pour M-1 ne se sont pas averes significativement
`differents entre le.~ groupcs (p > 0.6). Des differences significativcs ont
`cependant ete observees en ce qui conceme lac __ de M-fV et M-V, I<!·
`SSC1q, la C"=,• et les rapports SSC,.. (M-N:pentoxifyUine) emre les
`groupes (p < 0.05). Une modification de la posologie cle tid 1'l bid a
`prcduit des changements significatifs au niveau de la 0".,., de M-IV el
`M-V chez Jes individus ay11m une fonccion renale nonnale ou unc
`dysfonction renale moderee rnais pas che-, !es individus ayant une
`dysfonction renale !,'Tave.
`coNCL~1011s: La dysfonclion rcnalc n'entratnc pas d'accumulation
`si~>nificative de pcntoxjfyllinc ou de M·I aprcs l'adminiscration bid et tid
`de doses multiples. Cependa.nt, les mt!tabolites M· rv et .M-V
`s'accumulcnt de fa~on significalivc lors d'insuffisa.'lce renale. Une
`modification de la posologie (400 mg bit! si insuffisance renale mudcrec
`et 200 lt 400 mg qd si insuffisancc renale grave) et un monitorJge
`clinique c11oil sont recommande.~ et ce,jusqu 'Ace q11c Jes interactions
`phnrmacologiqucs complexc.~ entre 111 peotoxifyUine et ses metabolites
`soicnt mieux dcfinies.
`
`ALAIN MARC01'T8
`
`General Medicine
`
`This material m b
`copyright law (/Y1 a Protected by
`n e 17· U.S. Code).
`
`PAIN ASSESSMENI' OF SUBCUTANEOUS INJECTIONS
`
`Jan '1' J.0rgensen, Janne R.0m.sing, Mette Rasmussen, Js:Jm Mf6ller-Sonnergaa.rd,
`Lisbeth V a.ng, and Lise Musreus
`
`OBJECTIVE: To compare injection pain after subcutaneous
`administration of four different solution volumes.
`OEStGN: Double-bl.incl, ramlornized, prospective, multiple cro~sover
`s!udy.
`SETl'.L"IG: Steno Diabetes Centre, Gentoftc. Denmnrk.
`l'Ml"nCmwrs: Eighteen healthy volunteers, 9 women an<l 9 m,::n,
`aged 21-30 yellrS.
`ME111oos: The subjects were injected wilh four different volumes
`(0.2, 0.5, LO, 1.5 mL) of NaCl 0.9%. The study was pcrfonncd on 2
`days with a I-week washout period bctwe;;n the study days. On
`each sludy day the subjects rc.ceived four injections in em:;h thigh.
`To evaluate lhe validity of our pain asse.%ing model the subjects
`received eight injection~ of 0.5 mL on one of Lhe study days. Pain
`
`Jun 1' J11rgen.m1 Pl,O. Rc,earch Fellow, Oepar1me,1l oil"i1onnaccutics, T~c Ruyat
`Danish School of fha.•,nacy, Copenhagen. Dcnroa.rk
`Jnnnc Rpmslna PhD, Assistont Prnfessor. Depnttment of Phnrmneeu,ics. 'file Roy(cid:173)
`al Donish. SchOot ofl'hon113cy. Cope"1lagen
`Mette Rasmussen PhD. Assceiote Professor. Deportment of !'hn:mace,iics, The
`Royal Danish School of Phnm,ocy. Univcrsilc1s1>9.rkc111., OK-2100 Co('('n·
`hagen, Demnnrk, C'AX +4SJS37 l277
`Juen Ml!ller-Sonnergnurd PhD, Associate Profc=r, Ocpor1mcn(off'hannaccutics.
`The Royal D:mi•h School of Ph~mn<y, Copenhagen
`LM>elh Vnng RN. Steno Oiobctc-s Ccnt,e, Gcntof<c. Denmark
`L•se fvht~mns RN. Director of Nursing, Steno Oi3betes Ccncr~. Gc.ntnftr:
`Reprints: Mcne Rasmusseo PhD
`The sludy was snpponcd by Novo Nordisk NS, Oeotofce, Dcnma,k.
`
`assessment was done immediately after each injection using both a
`I 0-cm visual analog scale 01 AS) and a six-item verbal rating scale
`(YRS).
`1wsu1.TS: A si~rrt.ificant difference in pain score on both the VAS (p <
`0.05) and the VRS (p < 0.01) was seen between the fow· i.ttjcction
`volumes. The pain was significantly increased with volumes of 1.0
`and t.S mL. No signilicllllt difference in injection p?..in could be
`detected between 0.2 and 0.5 mL and between 1.0 and 1.5 mL. No
`significant period or carryover effect could be detected in the study.
`A significant correlation between the pau1 score on the VAS and !he
`pain score on the YRS was found (r= 0.79, p< 0.0001).
`CONCLUSIO.'IS: The pain of a subcutaneous injection is reiated to
`i,tjcction volume in the thigh. Tlte. results show that increasing the
`volume from 0.5 to I .0 mL increases the pain significantly. The
`findings from this st1.1dy should be considered when injection
`preparations for subcutaneous 11dministr.1tion are fonnulutcd. The
`volume should generally be less than l.O mL iI injected into the
`thigh.
`
`A,111 Plumnacother 1996;30:729-32.
`
`!NffiCTION J>AtN TS A PROnU:.M for many patients in rnlation
`to the daily subcutaneous administration of differeJ1t medi(cid:173)
`cations, such as insulin ru1d growth hormone. The pain in(cid:173)
`duced by a subcutaneous injection depends on several fac-
`
`The Annals of Plwrmacotherapy • 1996 J11ly/August, Volume 30 • 729
`I
`
`Page 1 of 4
`
`KOIOS Exhibit 1005
`
`

`
`tors, such as choice of preservative in the solution,1 needle
`size (gauge),2 type of needle insertion,3 and injection site.4.s
`Other factors, such as the pH and the osmolality of a solu(cid:173)
`tion, may also contribute to injection pain.
`The volume of the solution may also have an influence
`on injection pain.6•7 Only one previous stndY.7 has focused
`on this subject. In that study, five different volumes of in(cid:173)
`sulin which ranged from 0.025 to 0.5 mL were compared.
`No significant differences in pain perception were seen be(cid:173)
`tween these volumes. For comparison of injection pain, a
`21-cm visual analog scale (VAS) was used,7 which is less
`reliable than a IO- or 15-cm VAS.8
`'The purpose of our study was to compare the injection
`pain of subcutaneous administration of four different vol(cid:173)
`umes ranging from 0.2 to 1.5 mL. For measurement of the
`injection pain, a 10-cm standard VAS ruid a 6-item verbal
`rating scale (VRS) were used.
`
`klethod.,;
`
`SUBJECTS
`
`Eighteen healthy volunteers (9 women, 9 men), 21-30 years old
`(mean 25.2), weighing between 5 l.8 and 95.6 kg (mean 73. l) were in·
`eluded in the study. Based on weight and height, the body mass index
`(BMI) was calculated according to the fomiula [(bo<ly weight in kilo(cid:173)
`grams)+ (height in meters)1).9 The .BMI ranged from L9.4 to 27.9 kg/m1
`(mean 23.5). The subjects were insouctc<l not to to.lee aoy ll!lalgesics or
`corsume any ulcohol dwing the 48 hours prior to the study. Before initi(cid:173)
`ation U1e protocol was approved by the Regional E!lucs Committee, and
`written informed consent was obtained from each subject.
`
`PROTOCOL
`
`This was a double-blind. random;ze<l, multiple crossover study, in
`which tho injection pain of four different volu!lles (0.2. 0.5, l.O. 1.5 mL)
`of NaCl 0.9% was compared. The syringes were covered with opaque
`tape. The injections were given subcutaneously by two diabetes nurses
`u~iag a conventional 2-ntL disposable syrL'lge mounted with a 27-gaugc
`need!:: (Neolus Terumo, 27 G x 3/3"). For each subject all inje<:tions
`were given by the same nurse. The study was done on 2 days with a 1-
`week washouL period between the study days. On ench study day lhe
`subjects received fcur injections in each thigh (Figure I). Both the lateral
`and the medial positions were used. For each thigh. two injections were
`
`given proximally and two distally. According to the randomization code,
`each of the four volumes was given once proximally and once distally.
`On each of the two study days the subjects received either 0.5 mL in all
`eight injection sites, or four different injection volumes iwice - once
`distally and once proidmally. The assessment of the injection pain was
`done immediately after each injection using both a 10-cm VAS and ;i
`sbt-item VRS. The YRS was catego1ized as follows: no pain, mild pain,
`moderate pain, severe pain. very severe 1,1ain. and worst possible pain.
`The extremes 011 the VAS were no pain and worst possible pain.
`The VAS and the VRS data were analy1.ed with the Wilcoxon test.
`the Mann-Whitney test. and the Krusl'.al- Wallis test. Toe VAS and VRS
`data were compared by means of the Spearman tank con:elation test.
`
`Results
`
`The pain scores resulting from the VAS and the VRS for ·
`all volunteers following injection of the four different vol(cid:173)
`umes are shown in Figures 2 and 3, respectively. A signifi(cid:173)
`cant difference in pain score on both the VAS (p < 0.05)
`and YRS (p < 0.01) was seen among the four volumes.
`When examining the individual injection volumes in de·
`tail, signiJicant differences were found between 0.5 and 1.0
`mL and between 0.5 :md 1.5 mL. No significant difference
`was seen between 0.2 and 0.5 mL or hetween 1.0 and l.5
`mL.
`The validity of our pain assessing model was tested us(cid:173)
`ing a volume of 0.5 mL in all eight injection sites. The in(cid:173)
`dividual pain scores from this volume did not show any
`significant trend toward decrease or increase in pain score
`with the eight injections. Furthermore, the comparison be(cid:173)
`tween pain scores on the fast and the second injection day
`showed no significant difference. No significant period or
`carryover effect could be detected.
`
`6
`
`.
`
`6
`
`<
`:>
`
`q)
`i..
`0
`
`0 "' c:
`t a
`
`1
`
`0
`
`~ I
`
`...
`
`t
`
`1
`!
`
`er. :~
`~ ..
`
`Figure 1. The fou, i1tjee1io,~ sites on the thigh.
`
`1.e
`e.2
`0,6
`1.5
`Injection volun1e (mL)
`Figure 2, Multiple box-and -whiskec plot based on visuat :ooal<>g•calc (VAS) pa iu
`sc<>res from lhe 18 volunteers !ollowir.g injection of1.hc fm1r volumes. For each vol(cid:173)
`ume. the box encloses the middle 50% of the VAS datn, or.d the whiskers indicate
`mi1~i1"um antl maximum v:iiues. A cross indic:ites L~e mean aRO :l horizontal line th.e
`mc<lian. (Krus~:ll-Wnllis test. p < O.OS).
`
`730 • The Annals of f>hamiacotherapy • 1996 July/August. Volwne 30
`
`Page 2 of 4
`
`KOIOS Exhibit 1005
`
`

`
`The pain scores from the nvo scales were compared. A
`statistically significant correlation between the pain scores
`on the VAS and the pain scores on the YRS was found (r =
`0.79, p < 0.0001).
`
`Discussion
`
`To our knowledge this study is the first to demonstrate
`that the pain of a subcutaneous injection is related to the
`solution volume. Only one study' has previously dealt with
`this subject, but failed to show any correlation. TI1e main
`reasons for this may be that the largest volume injected
`was 0.5 mL and that a nonstandardized VAS was used.
`The results from our study show that pain is significantly
`increased at an injection volume greater than or equal to
`l.OmL.
`The study was carefully designed to rule out any contri(cid:173)
`bution 10 injection pain from known factors such as needle
`si7,e, preservative, and injection mode. H All injections of
`the NaCl 0.9% were performed by trained diabetes nurses
`using syringes mounted with a 27-gauge needle. The vol(cid:173)
`umes in the range from 0.2 to 1.5 mL were chosen because
`this interval was regarded as being clinically relevant for
`subcutaneous injections. It is also known that injection
`pain varies with the injection site.4.s A pmvious study in in(cid:173)
`sulin-dependent diabetic patients show~d that pain was
`significantly greater distally on the thigh compared with
`the proximal position.5 To avoid any systematic errors in
`the study design, the randomization was performed in such
`a way that each of the four different volumes was injected
`once proximally and once distally.
`
`rn
`.i::
`;;>,
`Q) ...
`0 u
`"'
`i:: i
`
`4 -
`
`3
`
`2
`
`1
`
`0
`
`l
`
`1
`
`·•
`
`+
`
`l
`
`1.0
`0.5
`1,6
`0,2
`Injection voh.une (mt)
`
`'Flgure 3. Mllhiple box-and-whisker plot based on ve(ba! tatini: sca!e (YRS) pain
`scores from the I a volunteers following injccuon of the four volumes. ~'or cnch vol(cid:173)
`ume, the box encloses the mldt!lr. 50% of lite I/RS <lata, a,ld the whiskers indicate
`minimum and maximum v~hl¢3. A CCOS$ indicates the meon and a hOfiiontal line the
`median. (Knosk:il- Wtillis test, p < 0.01 ),
`
`Research Reports
`
`To assess the validity of our pain-assessing model, 0.5
`mL was administered to the volunteers at all eight injection
`sices on one of the two study days. Using these data we
`showed that there was no significant period or carryover
`effect. The 0.5 mL volume wa.s chosen because it was re ..
`garded as being a clinically relevant injection volume. 'The
`BMI from the individual sul:,jects can also be regarded as
`being representative for the normal population. Our model
`proved to be reliable for healthy subjects and valid for the
`purpose of this study. The con-elation between the pain
`scores of the VAS and the VRS was high, indicating that
`the subjects had understood and used the pain scales cor(cid:173)
`rectly.
`Since compliance is a problem in many types of medical
`therapy, issues relating to compliance should be considered
`during drug development.3 One way to improve compli(cid:173)
`ance could be through an improvement in patient conve(cid:173)
`nience. From this point of view, the volume of a subcuta ..
`neous injection should be less than 1.0 mL. We therefore
`recommend that the results from this study be considered
`when injection preparations for subcutaneous administra(cid:173)
`tion are formulated.
`
`Summar_y
`
`The pain of a subcutaneous i1tjection is related to the in(cid:173)
`jection volume in the thigh. The results show that increas(cid:173)
`ing the volume from 0.5 ta 1.0 m.L increases the pain sig(cid:173)
`nilicantly. In order to optimize patient convenience in rela(cid:173)
`tion to subcutaneous administration, the results from this
`study should be considered in relation to the formulation
`of injection fluids. The volume should generally be less
`than 1.0 mL if injected into the thigh.;;:;;
`
`We ll1onk phannaey assistan< Ruth HMscn, phnnruicy srudent Ulln S Jensen, Md ph.'lf·
`for tcchniCJJ ~ssistaccc nud ndvicc, and medical
`macy student Mello Mu11k·P¢tC!S¢n
`writer Noelle Holten Pind for linguistic advice. We al,o !hank chief physician Hans·
`He nrik Pnrving, Stenn l)iabe<cs c~ntre, for his sopport .
`
`References
`
`I. Bridges A, Stirli11g H. McDowell J, Jensen S, Jl)rgcosen JT, Keio.tr C.
`Double-blind srudy to comc>ar~ the local tolcranc.: of three differem sol(cid:173)
`vents used to reconstitute growth hom,one (nostmct). Presented at the
`British Pharmacological Society Meeting, London Univcr~ity College,
`London, England, December 17-19, 1991.
`2. Coley RM, f3utltor CD, Beck l3t, Mullane JP. Effect or needle sire on
`pain and hematoma formation with subcutnneous injection of heparin
`sodium. Cl.in Phann 1987;6:725-7.
`3. J0rgenscn n·. lrnprovemcm of paticm convcnimcc in tcentmcnt wi!h
`growll1 hom:-011c. J Pcdiatr F.ndocrinol 1994;7:175-80.
`4. Lee OM. How painfol is ln1cnsivc insulin injection therapy'! Z Gc~'am,c
`[nn Med !992;47:266·9.
`5. Chmlim,sen JS, Sorensen JP, Hansen 'O, ChristeMen T. A double blind,
`ro11llomize.d study on the degree of pain on l)Cnetration by r nsuject and
`Novopcn needle eithec proximally or distaUy oF the 1h.ir,h (abstract), Pre(cid:173)
`sented at 8th Workshop of the AIDSPff Study Group, lgls, Aumia, Jan.
`uary 29- 31, 1989.
`6. J!llrgenscn JT, Moncnscn HD, J11rgensen JOL. Patient acceptance of
`Nordiject a new drog delivery system for grow1h hormone. DICP Ann
`PhrumacoU1cr 1991:25:585·8.
`7. Chancclau E. Lee OM, Hemmann DM. Zipfel U. Echterhoff S. What
`makes insulin injection painful? BMJ 1991;303:26·7.
`8. Seymour RA, Simpson JM, Clw ltcn JE. Ph.illips tvffi. An cvnluation of
`length and cnd·phrasc of visunl analog ~Cates in dental [)<!in. Pain 1985;
`21:177·85.
`9. Olcfsky MJ. Obesity. In: Brnunw~l<J E, lssclbacher JK. Petersdorf RG,
`Wilson·JD, !vfortin JB. Fauci AS , eds. Harrison's principles of internal
`
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`The A1m<zls of Phanru,cotherapy • 1996 July/August, Volume 30 • 731
`- -~ ---~
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`
`Page 3 of 4
`
`KOIOS Exhibit 1005
`
`

`
`medicine. J Ith ed. New Yock: McGraw-Hill Book Company, l987:
`1671-6.
`
`ElCTRACf'O
`OllJe'l'JVO: Comparar el dolor asocindo u la inyecci6n subcut..1.11ea de
`cuauo voh1menes distint<>-~ de soluci6n isot6nica de c.loruro de sodio.
`01si,:Flo: Estudio en doblc ciego, aleatorio, prospect:ivo, de dosis
`multiples, y cn1iado.
`£.SellNAIUO; Cemro Diabetico Steno, Gcntofte, De;imark.
`11-rtrooos: Se inycctaron 4 volumr:nes distintos (0.2, 0.5, 1.0, y 1.5 mL)
`de soluci6n isot6nica de cloruro de sodio (isotonic sodium chloride, 9
`mgfmL, DAK) a 18 vo!untarios sanos. El csrudio se realizo en 2 tlfas
`separados uno de otro por una semana Jibrc de la adrninistrnci6n de las
`soluciones de estudio. En cada uno de los dras de cstudio, los
`voluntarios recibiercn 4 inyecciones en cada mnslo. Pora <leterminar la
`validez de! modelo de eva!uaci6n de dolor utiliza<lo los voluntaries
`recibieron. bien sea un volumcn de 0.5 rnL en cada mus!o o 4
`vohimenes distintos de inyccci6n por dnplicado. La evaluaci6n de dolor
`se rcaliz6 in.media1amente despues de cada inyecci6n u5ando una e.~alll
`anal6gica visual (EA V) de 10 cm de longicud y una escala de
`cl~silicacion verbal (ECV) de 6 elernentos.
`RflM.:l'ADOS: Se observ6 unn diterencia significativa enttc los 4
`vohlmcnes de inyet:ci6n con respecto al dolor repoctado usando la EA V
`(p < 0.05) y la EVC (p < 0.0 l ). El dolor sc incremcnto con el volumcn
`dt: inyecci6n de l .O mL y 1.5 ml. Nose detectaron difcreocias
`significaciv:is en dolor encre los volt'imenes de 0.2 y 0.5 mL y los
`volumcnes de 1.0 )' I j
`inL. Tampoco de detcct6 illfluencia de!
`tratruuiento prccede111e. Hubo una correlaci6n significativa en cuanto a
`dolor entre la EA V y la EVC .(r = 0. 79, p < 0.000 I).
`CONCLUStON!IS: Se concluye que el dolor asociado a la inyecci6n
`subcutanea do una soluci6n estA relacionado al volwnen de inyecci6o co
`cl muslo. Los rcsultados demuesrran que el incrementar el volumcn de
`inyccd6n de 0.5 mL a 1.0 mL inc1t:mcnta el dolor significativamente.
`Los hallazgos de e.~tc estu<lio deberfan ser tornados en consideraci6n
`cuando se formulen prcpa1aciones pacenterales de administraci6n
`subcutAnen. So recomiendn que el volumen <le inyecci6n sea 111encr de
`i .0 mL cuando se inyecta en el mus lo.
`
`ENCARNACl6N C SU,\R£2.
`
`RF.SUM£
`ODJECTI.F: Comparer la doulcur resultant de l'injection sous-cutanee de
`quatre volumes differcnts de liquide.
`oev1s EXP£tUMENn1.: Etude prospective, ccoisc!e pour !cs quarre
`volumes, randomisee, ct A doubte-avcuglc.
`Lmu ot vt,wi,:: Steno l)iabeles Cenlfe, Gentofte, Dancmnrk.
`PARTIC.ll'ANTS: Dix-huit volontaircs sains. 9 hommes et 9 fcm.'llcs. ages
`dc2l UOans.
`ME'fl{OOOLOGJE: On a injccte aux pruticipancs quarre volumes diffc!rcnts
`de solution saline isotonique (0.2, 0.5, 1.0, et I .5 mL}. L't!tudc ;1 et~ faicc
`sur 2 jours separes d 'un intcrvallc (l'une semainc ct tous !es sujei,~ one
`re,;u, ll chaque jour, quall'e injections sur chacune des dcux cuisscs. Afin
`de verifier la validite du mode.le choisi pour I' evaluation de la dou!eur,
`chaque participant a re~u huit irtjections de 0.5 rnL au coucsde l'uncdes
`deux joumres d'etude. L'evaluation de la douleurc,ait faire
`immediatemeot ~pr~s chaquc iruec!ion en uti!isanc une &heUe visueUe
`analogue (EV A) de 10 cm et une ~chelle vcrbale (EV) comporumt six
`!CffllCS.
`Rflsu,:rATS: Une difference ~ignificative a etc detectee entre !es volumes
`A l'etude selon !cs deux modalite.s d'evafoation utilisces (EVA, p < 0.05;
`et EV, p < 0.01). La doulcur etait significativement plus importantc avec
`Jes volumes de 1.0 et 1.5 rnL. Les auteurs n • ont pas detecte de diftcrcnce
`significative entre !es volumes de 0.2 et 0.5 mL de m~me qu'cntrc ceux
`de l.O ct 1.5 mL. 11 n'y a pas cu non plus de <liffer~nce atuibuable au
`facteur temps. Les auteur:. ont trouve une bonnc correlation entre lcs
`dcux echcUes utilisees lorsqu'i!s en om compare lcs rcsuhats (r "'0.79,
`p<0.0001) .
`CONCl,tJStONs: La douleur resscntic apres une injection sous-tu!lll1ce
`dans ia cuisse sero.it relieeau volume injecte. Les rcsultats ici montrent
`que passer d'un volume iajectc de 0.5 a 1.0 mL augmente
`significativemcnt la dou!eur. Les auteurs sugg~rent que ce«e ttudc soit
`pcise en consideration par !'industrie pharmaceuµquc au moment de
`fonnuler Jes liquides ~tines a !'injection ~ous-cutant!e. Au niveau de la
`cuis.,;c, le volume devrait genernlement i:tre infeiieur ~ I .0 mL.
`MJCHELe PI.ANTe
`
`i
`i
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`732 • The An,wls of Phannacotherapy • 1996 July/A11g11sl, Volume 30
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`Page 4 of 4
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`KOIOS Exhibit 1005