1...
`
`D9
`
`‘WI. 53, Na. 8, Augzzsl 1964
`
`definite bearing on the usefulness of any tznlumn
`packing prepared.
`’I'he_;ue‘.rfonn:a.nc:e5 offithe seven
`suppurta mentioned presmusly were exammed under
`the sauna operating carnditians. Thgsuppoxts fiaat
`can be used for lightly loaded pacznngs axe: glass
`beads, Gas C1hmm—P, and Cihromosorb W‘-HMDS.
`The rather fan: supports cannot be used far lightly
`leader! cnlumn pacldng since their intarax.-tiozu with
`the antihistamines csusas excessive peak taflirng.
`The hydrogen 3.-me detector used in canjnnction
`with the 0.018-—iu. sbainiess capillary coiunm xwuld
`nut rmpnnd ta canmpountis with boiling points above
`330°.
`‘This limitation prevented evalnzfian :11? this
`comma for tha analysis of these antihistaxnines.
`The 100-ft. 0.055-in. copper open tubular column
`was coatbesci with X?-1150 anti evaluated using the
`above group of émihistsmsiues. The Sr“ ionisation
`detects: was used. with a column flow of 36 1111.]
`zjnute. The tetautian times abtainezi were com-
`parable to the 6~ft.~XF«115G pa.-chad column, but the‘
`gym}: base widths were oonsiciembiy wider. Became;
`of this iucwase in base width, the 0.055»-in. celumn
`was Ims eizfinient than flan 6-ff. packed column.
`A 350-ft. £4.0=65—in. col
`wrmnd an :3. 1’f¢-in.
`diameter mandrel has been reparted to be more
`efierient than a pankead coiumn (15). That: are mo
`passable reascms why eficiancy was less than pre-
`avian.-siar Ifirtflrtfidt (ca) the cmhzmn was shatter (100
`it}, and ((2) the windizzg canfiguratian was maxkeviiy
`different. The cnlumn was wnund on 3 11!; X
`3}’;-in. bar which rmflted in 2. definite flattening of
`the tube amuud the edge uf the has’.
`
`CCJNCLUSIONS
`
`391
`
`for
`except
`The m investigated,
`mowlizfns. can ha separated. identifiei, and cemen-
`trafion estimated using the Caxbowax EDM, PDEAS,
`and KP-1150 cozzlnmna described. The PIJEAS
`column is the most etfidmt of the three far the
`analysis of m a.
`The usefulness of the B.U10—in. capiliaty and the
`t'}.055~in. amen tubular columns cammt ha praperly
`evaluated anti‘. tha mantionexi
`are re-
`moved.
`
`REFERENCES
`
`{1} Zamcfnnatmwflanas.-an, 3., and Svendsan, A .13., Tara
`J‘oUn.:mr.._ 51, azsuaasg.
`2 C22
`3. W2, Am:-3. G!::m., 35, 3560.953}.
`3
`qé, E. D. and mrk. P. L» ibid.. 35; §s2B(19€-3).
`rm, 3, 137a’:,:.ms1 .
`(5 Brochmann-Eansssm, 3.. and Svmvxism, A. 28.. ‘£313
`Iotrnzmt. 51, 'B38(1H33}.
`(6) Parker K. D. Bantam C. K, mfi Kirk, LE’. Lu Ami.
`C§:m:.. 34, 1safa::19s2i,
`,
`_
`{mg Bales. B5. 121.. and Puzano. I. J... ximxl. .Bwu=&em., 3, 33’?
`(3 Parks. E. I}... Faumm C. R. and Kirk. P. I... Andi.
`01:513., 34. 7fi?f19&%%E'
`6
`,
`.
`1' 3(£:I8)( M.
`., and 2923;132:1315‘. G. J... J’. Cimn-ma£og.,
`(10) Parke.-r. 3‘. D0, Fenian. C. K. and Erk, P. Lu £19121.
`mm. 35. 35511933).
`,
`_
`{11) Fuutun, C. R... Smth, W. (1., and Kirk. P. I». s'&vi.,
`35, 5’Q1{1S63).
`C12 Znhyk, W. )2. and Camztr, A. 2., §b1‘nf., 31%; 912(!95£}).
`(£3 ’ W" “Pmgr;va3 hfiffxdsimggl Gas Chmmxigrngo
`ra
`z
`, mun: Phase.
`aw
`*s:§}13:'N. ‘E. 196b1{ :1. $5.
`'
`(14) mammmm, A., J’:-., and Ffianm, R. '33., 11:33 Earm-
`§2, 8163963).
`M35) Qukw, B. 3... £343. Cfiemq 35. 59341963}.
`
`Castor Oil as 3. Vehicle for Parenteral
`
`Administration of Steroid Hormones
`
`By C. RIFFKIN, R. HUBER; and C. H. KEYSSIER.
`
`Stamid hormones may be administered parentazafly in high concentrations as nil
`soimionx. In this form Ihfljf exhibit a pralonged acticn and reciuce the nmmbar cf
`iniecticsns required.
`‘lfo accognmn-date thq dgmagd £9: iqcreasfingly greats-.§ concep-
`'t:s.tions of hormones m soluuon, castn: 01.1 m combmauon with other smtable ml-
`misdbla sulvents, has bfzen fmznd in fulfill. ;: nend.‘ The dnveluymgqt of s_ev£:r§1
`formuiatians togethet with the resugtg of anm_1a1 gesung, as well as ghmcal tnals m
`humans, attest to the acceptabxlxty uf thus 011 fo; the purpuses mtendad.
`
`12:21: 0315. are included in fine. “United States
`
`Phmmacopeia XVI" as nonaqneaus vehicles
`far injection and are characterized as being of
`vegetable m-igin, essentially odorless, and with-
`out sxzggesticn af ranmidity. They must also
`campijr with cartain meastzrable physical limits
`specified for the saponificatian, ma, and iodine.
`
`values.
`‘
`
`Rccaiveé S 4.-ember? 1933. from the Pharmscelu
`1’513.x;ma:¢ati
`Biastami & Devekspinnut Sectiuns.
`Inshtuisc for Mcdimi Rusemth, New Bnznswick, N. I.
`-‘hmelfi-ed for puhucatiun Nmrember 19, was.
`The nuthnm emu: 3mi:btcxi to the Cizemicai Etmtmi I.»a§:vc:;ra.-
`Mria for their assistance with the assays; to Dr. N. Guy and
`H. Rubtrta cf iha Phgxicai and Analyiical Smfiun. for the}:
`‘W93?-‘fimwt cf spams: mmxsra;
`ta G. Lackvrood at the
`Phaxmamja
`Sexzbiun for the animal musciz-. irritation tests‘
`mi ¢$.P=ua§
`ta 1):. 2:. c. Ruifaastein.
`x-..
`:11 the median!
`“R3: far the
`armatism cnncerning the
`’ W
`
`anti
`uibh
`
`After subcutaneous injacticn. Deanesiy and
`Parke: (1) obsaxwred the persistence at olive evil
`and casts: 931 in animal tissue. Clampariug ether
`ailé Emma, :55 Cd. (2), reparied that sesame and
`corn ails were supexiar to mttnnseed and peanut
`oils beazausa thay were less irritating, ‘lass anti-
`genic, more: quiekty reieased {mm tissue, and
`pqssessacl supeztior physical pmpetties.
`Mam recently the use of stercsid hexmrme
`me.dix:a;f;ion has expanded consi<:Iera.b‘£y. Due. tn
`liztzitazi water sombfiity, hnrzmmxes have been
`administered as aqueous susyensinns or saolw
`tins in oi}. It has been clafinad that the lathe:
`
`pruirisiefi file slow release prefarreti in cyclical
`
`|nnoPharma Exhibit 10330001
`
`

`

`3333
`
`Jo:-zmzal ofPh Saiesucss
`
`Tum I.--azmmsxa as Ca (33.5 ms Caaummozar 9:: 33.3.1‘. xv: arwmnaxsss
`mi. am srmam
`Rqttiv. in 26:12:
`am am: 2::
`1§«'{'.§m. Sasxzpha
`35 .0“
`1:2
`
`gglsue
`$3:
`
`182.’?
`:s’§"ii%a
`159.3
`1935.0
`18$ . 6
`191 . ‘iv’
`19U-~198
`195.9
`1§§ai33
`W
`194.5
`191.§
`189.3
`$135
`1112.0
`IQ]. J?
`1&3 . 1
`1%3fl.*I-.
`
`Infine Vdua
`83-%
`$3
`
`8&5
`m§L“§a
`was
`111.8
`I04. 3’
`108.2
`199-116
`111.3
`
`119.1
`124.4
`125.0
`sliiigc
`94.»;
`93 .2
`8?‘.$
`Q3 .9
`
`7 .9
`3%
`..
`0.5
`IA
`0 . €35
`GAE
`2.0
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`2 .0
`1.0
`1.2
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`$3
`132
`1.4
`(3.3
`1 .2
`
`an
`cast,“
`Q“
`
`gem
`
`° mi
`
`Cattanseed 03:
`
`cm
`
`‘
`M
`
`ymfit
`
`«'3:
`it
`
`.
`
`Lot Na.
`. spasm.
`$5
`
`SSS.
`
`.
`
`234.63
`%~3§*§
`.
`.
`2335-$93.3?
`26953
`333%
`28981
`‘U.S.P. specs.
`496%
`‘km
`.
`.
`?§§§ W25
`36'?1fi
`33435
`%ҤE% W
`géxss‘
`20993
`33533
`EEK’!
`
`“ The T.T.S.P..
`x9u:EEathatt£::fitntiu::u£fre¢£ac£yac£daEn-mtlmuiaucsiaruil:iha31aut¢x:;¢‘::d?'u!i*6&9-ifffififln
`which in -exmal in 33.8 11:}. cf 5.65% 32’ 35:03.
`
`Tum: Ilmsaxmxzxrss as S-smaoxw 1:: 11.3.1’.
`'
`0:z..u~.-..- 25‘
`
`Sm-aid
`
`.s-----v-vn:g..»"m1..--~‘~‘---~
`Castur saw Feszuxt
`051
`an
`oi:
`
`gestzam
`
`1’?-'3 fix
`cagfmafiypm
`Testastxxctnn
`Estradianl vaiexate
`1>‘rcsgwte:z1:sna
`
`M 55.8:
`38,5
`60.6
`52.0
`
`23.4
`5.4:
`16.1
`23.9
`
`2'32?
`8.1
`18.8
`23.3
`
`Enexrapy (3). Using withdrawal bleeciizzg in
`human females as the criterian, Master, 5: cl.
`(4), wmpaiad the éuratiozz of actian at an
`aqueaus snspe.-mien of gsragesterone with
`oil
`saluiion. and eanfixmad the superiority of the
`latter. The prnlnngatian of activity was gem
`araligr ralateti ta starage in the fatty ciepats of
`the had? (5}.
`In 1952 I (3) éataxmiaad that a.
`testaetarann ester clisaaiwaxi in sesame oil pram».
`Zcmgeti the ancirngeuic-e_fi’e:cts in casbratezi rats.
`.Davis and Wieri
`ziexszusnstrateti that pm-
`izmgect activity was aim ofitained in hzmaxss
`when oil sczltrtiaus cf 3. progtsteraxle. ziarivatiw.
`were injacmi. “fixer: was still a limiting faxriar,
`hcnwcver, in that unity 3. relatively 3121311 awaunt
`mi ftmrmune; coulci be siimoirxred in the tzcafiticmal
`0515.
`T12: htztaasa the suivmt pcswer sf the ail
`it was necessary to: acid mmpatihle and, mznw
`itxitatirzg ccaoimzirts. Such adfiitians ggngistgg,
`01‘ bmsyl bmmoata, fienzyx almhoi, ethyl lactate,
`ethgyi eleate, ate. The U.S.}?. recagnized the
`‘need in: such ”s:t31er vehicles," with the re.
`Stt‘i.r::fifltt§ thitt they must be safe in the valmng-_
`cf mjaatmn administered, ansi that tiny shouki
`
`mat ixsmfens: with the thaagetxfisz eficaay nf the
`preparafiun arr Eta tesfimg.
`Bemaud far iznmmsati Imrmmze czmcezztaratians
`per «float, furthered. the search far
`aocepiahifi
`1:33 with grmtsu soluhiiizing paw: :56 -58- 305*
`chasm (3). in 1954, ahsavui that I7-§§YdI£!XYPf3"
`gefitartzcne: caproate in a caste: ui1«~ethy’1 lafifi‘-”w¢
`vehicze was mi ta1&zata¢ In adctitiou. prrvaie
`mmmtmicatimms from clinicians in West 13:61“-
`maujfl repurted. goad tolemncata Prolutua-131$?“
`mntfining 3 caster cxil-bamayl benmate: vehacia
`Since then other hurmcuea have been usati
`*3
`sniuti
`in ritfmnleic aciti es1:»zra,'8s W!‘-11
`wstar oii £9»-11). maraingly,
`ax:
`invewfiw
`than was undmrfakzen mm the suitabilitfi’ Of
`ta: uii 35 fl *smh.i¢::h: fur parenteral uon
`of steroid hcnrmones.
`
`MRTHQBS ANI3 RESULTS
`Representafive sampies af -‘£3.33’. ‘ails nhfismmi
`frmm uammuttial waxes; wera tateti 1:z0§:=*=*'»*¥¢13’1"*
`with the qfiicial methad for free: fattr mil cam‘-'-“**
`zaapunizfircatim, and inéine values. The
`313
`mud in ‘maxi: I afung with the U.S.P. Xvi speclfiw
`tions for these aik.
`*
`_
`Saainhiiity of sesiected am-aids in wwus 0118 “:5;
`detarminad in the following manner. An #233355
`stezrcici was stirred for :3: hours at room t£:1n13:€5"?-‘Egg
`{35°}ix1t1:u: test oil. aftsr W ‘ch am u:ac’:1S5°11 ‘
`selids were remuveti by filtxaticm, and the 619%? 59*;
`tian assstyeai far starnid, content. Table II shew
`rank; chained.
`.
`An,attmpt was madetr;reducethefreef3‘~‘7Wa:‘:é‘:'
`
`in exam}: oil by 't:taa.;:!1ent with alumma @313
`Y
`1
`‘
`'
`gnhsuia. 3331?“; 2 Dr‘.
`%a£‘§§f;.: §i¢:‘3't’§"n‘§$'é'3s'?e*:§i“-%’fi‘.3‘§z‘xe _m~mns«.:sm1c, gfierfgfi
`.
`.. Wmbw
`12-
`—
`.9“.
`Dc. Ranmfies. én£ mBr:§umflm&. Vim“
`
`|nnoPharma Exhibit 10330002
`
`

`

`Val 53, Na. 8:. Aagrm 1954
`
`893
`
`TABLE III.--~Aasoam'.:;o1~z as 01:. mm: Ammz.
`Masmv
`
`aazxftmai. muscle irrftafioss. tesfizxg wins: ta raieasa far
`
`Egg‘
`iajmfian
`143
`
`1-3
`
`L3
`
`?-4513
`
`an
`{Easter 031
`fagad}
`Easmr oil
`U.S.P.
`Se-same 2351
`‘£1.32.
`A31 6115
`
`miwghasfix
`Equiv.
`53
`
`L3
`
`1.4
`
`. . .
`
`Ruizdxui an in
`Mmd: {Mich}
`1 day ~50 g.
`3 days--~2D
`1 day *-30
`3 da3ra——1£‘% 9
`1 3:13! —-—-3{.1
`3 <3a*g9j~3B?§
`fledming 10
`‘ha 2%
`
`*‘ 1 ml. injactad int» hack maid: af zabhit.
`
`dxcrus stadium sulfate. Three: grams of drieci, pa:m'-
`dared, 8.I£!,m'phm!s alwzziinma azicla (Merck Na. 109?}
`and 6 Gm. sf anhysirmza sodium sulfate, reagent
`yadawerestrspendadin ‘I3DmI.<s3fc:fian<{31e:a.te::t
`at 83’ 11:12:15: a blanket of ni-tmggu for 1,5 hams."
`Aim" atimv-Eng the nil tn mol to mom tempemtxms,
`the maids were fitters-.6; oif and tha acifis titmtexl in
`the usual manner. A significant rexinctian in frame
`fatty acid W33 not ofitaincd.
`Th1’:_3.bSu1‘§:ti€7n nhamctaxistics of 0515 with varying
`fatty acid zzontimt mere exnminexi and mmpareszi an 9,
`hialugiml basis. Agad mstcr ail with a high free
`fatty aciii content was camparead to fresh U".S.P.
`caster :11} with 9. law axzifi mnteut and U.S.Z9. altsame
`oil by injecting 1 ml. of oil into the hack mnscies nf
`rabbits, appmximatciy 2 in. fmm the flint: crwt. A.
`rutatizmal pattezn vi ixxjcctinn was used and the ail
`samples were stainexl to aid visibility in the 15352133.
`The animais were sacrifiaeé and the muscles amcised
`and entwined grcsshn The results were averaged
`and swam: in Table III.
`Thatestdisdeseétkatciimigatadar wascarried
`tn the fascia. and wary smaii amwnts remained for
`332* days.
`Iamfized degzmaratinn prodncrexi by the
`high acid value ezastnr uii was essential}? healed in ’E
`days. and the law acid value. caster ail appaatfli in
`he no mare irritating than marge oil.‘
`. In 3 spescific teat fur irritation 8.25 ml. of the above:
`nil samples were aim injected into the WM Icciarerfiis
`rzmsaclwafxzzhhits. After? €3.a.;5r§
`thaanimalswene
`sxunifimed and the
`museias axamineaai grossir
`far efidemzme sf ixritatiarn.
`It was fmzmci that the
`aster cat cuntaining a high ievci of frat: fang axsid.
`induced 2 Ensign size mmsming appraximamiy 121
`mm}. The iesion ism-if was cham.c:ter‘ize;d.ma£:1£3r by
`dagenazafian -of Inca! tissue; withmxt nec:‘casis. Cats-
`ta: ail with low frat: fatty acid and mama oil, «:2
`ya; other hand. pr:-éamezi an meammble Iesiua at the
`Inaectian sita.
`Cambismtions cf benwi alctahoi ami benzyi Bengt»
`ffifgwitlzhothaastaroil asxdsasameuilwareaisa
`mlmtedinto the mam: fintamiéx mrzscles of mbhiis
`and Table IV lists the Iasian sizes gzemcluced.
`_ Salutians which were formulated for clinical trials
`52:1 humans were prepared by aissmhhag the steroid
`hgztmones
`in apprapziata vehicles at 68*’ under
`mtrvaezn The aolzxficns were then fiiiereaei thmngh
`9« cuam si:1tx=:red—gIas3 fiitar with the aiti af xiitxngan
`?f*‘=5531!‘E. filled into viala, and sterilized by auinclaxw
`ma £12: 2 ham at; 121° (15 23;». mam pregame}. The
`
`Frflducsts were then suxhxcuittuci fur assay. safety. am!
`1
`.
`w€F;§:A:;:P£:2*:a%;%€fia%:5:.:£::t*re*§u%:¢:3“
`ntutxaiizail
`1
`than 3
`1.
`0+1 N 373023 15 £81.
`3' 9.3 3::
`R303} lwctcfi} Earn. 9:? flgflg
`{
`G
`
`>
`
`12332336135-$Ii3N
`
`Thmughc-at the investigating it was desirablc to
`have a reiexance ail to mm as ts basis for comparison.
`Since: sasamze (xi! is txniversafly acctptafl as 3 paranw
`tam} ail vehicle. it was chosen as the "stamiarti”
`vegetable’ 053 to he cccmpax-ed ta castur ail. with ané
`without other wscslvents. The physiml, chemical,
`and biofogfcai properties of awe ail am weli
`riewmanted am! tequita :13 cs;-m:;wts haze.
`Chmnallr. mstar ail consists iii‘ the: t:-igiycerisies
`of ridzaoleic acid, togethar with 5323.11 quantities oi
`glyuezitius :22‘ what acitis. Thn quantitative cmzm
`porgitlon is given by Eckey U2} as fa-llcmrs: ricizmleie
`acid 8?%, elem acid 524%, Iixzaleic Mir} 3,.1‘Fi3, ziihy»
`cixcajrriciuoleic.-. imixi 0.6%, anti miscellaneazzs acids
`2.-$92. irwo grads-.3 am commaanly taxsagnizexi is this
`wmtry---"L13. Eu. 1 which is mid passed nail, and
`U.S. No. 3 which is nil ex-E:-agate-A from the pressesi
`taket. C3103 theiflwmuisusedfar maditinalpxxrpeses.
`‘I‘he. high viawzfity cf msmr ail mmparred to other
`vegetable @113 is uazcdemhtefily ralatmci in hydrogen
`bondixxg am! it is probabky the hydmxy gwups
`which cantribnte to the g:rmtet pnlarity and supetimr
`sulveut grower cf the ail.
`Ens iadicatezi in Tam: I,
`the sapmifitxatian 31:4! icrdina values sf cnmmzxciai
`castar ail appas: to be srlightly lmvzer than the “£3.33.
`218311 limits fax ails ussé. far
`0:: the other
`hand, the tntmteat mi Ema fatty’ arrifis even in frfih (331.
`vaxies co:a.sixi«;*.zab1y and axceeds the traditiunal
`Iimifs for injentahle aim. The signifi»:-ms-:22 cf this is
`samewhat ahscnre. aithazzgh "Re.m:'ngmn*s Pramzim
`of Pharmacy, 12%}: cadifzimx,” gage 38?. states ‘*3 law
`free fatty acid. cantm: is essential since it indimtns a
`fresis. and para pbzxiuet and mat an: that is likely £9
`haw I:+::cam.e aid and hmvily cantamiszated with bat»
`texial ppa&unts.*'
`Despita hatter scslubifity of stexaids in caste: ail.
`anther ccrsulvcnts were: nanasary to dissolve the
`
`Igmrxz-scum Pmntrrzan xxx:
`Twas IV.——~L<:caL
`INJBCEIOH av VAREQUE 013.
`Rganxr Megan 31'
` Vnmmmé
`1.1955115 $13!;
`mms
`+31
`
`Igientilimfiun
`S«E‘Y~«=§'f-2
`
`SH?-§:?~3
`
`SH?‘-—M-2
`
`SHY-4%?-3
`
`Comxmsiiiun
`ffesamc trial 98%
`Ewzyl akzohnl 2%
`SE?-é??«é Caster oil 98%
`fienzyl 93:01:01 2%
`Sesame oil 95%
`Benny} almhax 5%
`SE’lL"SE'—<af:*r'e-5 Casts: ail 95%
`ifltznzyi alcnh-ad 5%
`Sm-mm: oil fi5%
`Benxyl benzaata. 35%
`SHT':£"~1é~fi Castor rail 55%
`Emmi benzoate 35%
`83533113 oil 53%
`Bmzyl benzaate 35%
`Bexzxyl a1c:oha::1 2%
`SE31’-4?-‘T %3ast:>r oi} 333%
`‘
`Benzyi benzsarate 35%
`Eenzyi aktohal 3%
`13 {xii 533%
`"ilemzyl bmmadbe. 30%
`SE?-1:58 Casts: 95$ 50%
`Bemfl bezlmadtz 50%
`
`Tax: small to
`measure
`536
`
`316
`
`1291
`
`184
`
`207
`
`252
`
`291
`
`158
`
`SKY-14:3
`
`“ A 035«—x2:.1. qtumtity -36 the: oil «hide was iajaetsd ism: that
`Emu laiefaif: muscle ui the rabbit Tm: sia
`Raw: the.
`mania was unified uni (ha {avian sin:m mm‘.
`
`|nnoPharma Exhibit 10330003
`
`

`

`394
`a
`q
`mcteasxngly higher canwutrationa reqflfred bf
`therapeutic regimens. omen ‘these matmals cun-
`tritmte.r1 adaifianal advantages. Far smmples, the:
`adclifinn uf benzyi alculml or hezzzyl benzoate to
`ggtm ail xestxlted in a lower and mate favnzcaflle
`vkcosity. making it easier to infect. A150. beflfiyi
`almhol was an Efiexztive preservative: and Inca!
`anasthertirs.
`The nature of tha ixfitatfrve resgonse depeugied. an
`the pariricuiar humane, its cugxganuatiun an the
`iurmulations, amifur tha cumpomtwn of Q1; vehicle.
`Although rnhbit nmscias are more sensitive than
`human muscles, they were selected primarily bemflse
`ducal changes in tba muscle were ohgerved aasfly.
`It was nut always possible, however‘, to carreiate
`musclaixritafixsninanimalstntlaatofihunaam.
`A nitznericai assignmaut to Iesian size was used
`sniely as 9. cnnvenimee for grading response. The
`numbers alane dab nut adequately describe the
`namm uf the respunsfi. htmetrer. Mom compizteiy
`it is chatacsfiexizesi by the amount txf kxemorrhaga and
`edana and the inddeawe, define. and extant of local
`degerneratixm prarincad by the injectim. A slight,
`rstversible izzifativa IB3pm.‘~5!.‘.* may cave: an large area
`and :3. severe irresvararihla one may be nnmpsn-ativaly
`small. A decrease in the size uf the degeneraizexi
`area. imlicates a, rezwrsible canditian. The presence
`of necrosis. which is the most damaging sitnatimz,
`means that the. mama; stmcztnxe was dastmyed and
`repair must take place. The debris must he re-
`mave:1andtI1earigina1ce3Iu}armassint}:eareare-
`placed with fibrtms connectivr: tissue. The wctent
`ofthiafibmsisorfmmafianufscartiaucgixresan
`indmt af the ammmt of inevatsihla damage. For-
`txgnateiy necrosis was not enwtmtared, indicating the
`‘lack of permanent muscle damage. Sims thise
`changestaketicne, finalassessmmtoftiteefiects af
`an iniecfirm in the muscle ixaquently required
`obsmvatian far 7 days :3: longer.
`It is uufarmnate that pain camzcut be measured by
`a:3? kmmm mestlmd cf animal taking. The: animal
`usualiy flea mt teapond unless the painful ginmlus
`is marked. Furthaxmare, the pain caused by injec-
`fltion intn human muscle E not 11sna11y1m::porfiana.te
`ti: tee btzizafiun pmfiucezé either in animal zmtscle
`ur in human muscle. Realizing that than 1in1i1'a~
`fians are iniherant in animal test methods, it re«
`mined fear final aceeptatzility ta fie determined in
`man.
`
`When itwas discmra-refi that 17-hy -
`one mpmate puswad high pmgastafinnal activity,
`potencies of the cards: cf 55 mg./ml. were used. By
`increasing the dose. additional pruiongatian af 3:-
`fian was obtained, and eventnaily cancezntrafinns cf
`the cards: of 250 mg./ml. were rwemaired. Such a.
`snluiian in sesame oil produced ameptabla animal
`muscle tnlerance, but the pain and local reaction in
`humans was 50 gxeat as to 1:roh1”hit the adoption of
`the fmmulation as a commttrci:-fl product (sex: Tahie
`V. Lot Pr. 142453/15-10).‘ Sahxtinns were alaa
`prepared using castor oil as the vehicle, and Table V
`iists the formulations tested and the results ob-
`taginetl.
`Iniormatiazu obtainad from the clinical
`fznais (14«-£1) attested ta than amzaptability and
`safety cf the adopted farnzulsticms.
`0
`Inharezut in the develupment of an acceptable
`
`fcnmulafinn of 17-hgrdroxjgprogatetone craproate was
`
`nbigiwctium in cxzccss oi 5-6% mm cnnsidsred uzmcccpto
`
`Journal ofFh Scizncgs
`
`Taaw V.*—EYa!LLUA'.!‘I0H 03 250 mg./ml. 1’i~H?.
`nnnxmmugsmnmam Quaagm S£:sLtrnam; m
`Vamczrtm On. Vnmcms
`finimsi
`Muse}:
`Lesion
`Sim. mm."
`1049
`
`Vefixicle
`C-uxgapasitinu
`Se-same ad] 50%
`Besxzyi bensmate
`50%
`@123: oil 58%
`Benzyi bezuuate
`40?!
`Benz}; alcohol 2%
`Sesame ail 60%
`Bauzyi benzaate
`35%
`Banzyi aicohol 5%
`Caster nil 54%
`33
`1 benznate
`46%,
`
`Caster 951 52%
`Benzyi bzuzoate
`43%
`Benzyi almhol 2%
`
`Lat Number and
`Remarks on Clinitai
`Tasting
`Pr:1§2~53/15-7--S33
`xngecfions, 33.6%
`reactants. regected
`Pr:1f}2~E:3/15-8-~2?O
`mrecgms, §3.2%
`rrzaztmns. rajectexi
`
`Pr.142;53/‘1§«10--
`18$} mjwtmng,
`10_.?'% rmctmns,
`rejwed
`Pr.142~5$/1§*11*'“
`503 ingectmps,
`é.2% xeactmns,
`weep
`
`Pr.142:5f:}{1§«13—-
`92% 12t}cC:i10I35:
`1.3% rmchnns,
`accepted
`
`691
`
`897
`
`258
`
`6&3
`
`sigsxsclt (:5 rabbit!
`“ Iniaufim of £1.35 ml. inta amiss
`and iminn size. am-xminea 2 days aftcr mmhma
`Twm ‘G'I.—EvAz.mwIcN or Eszrmanon Vanzazum
`:2: V.-mrmrs On. Vamcsuxs
`
`Animal
`
`m
`Size. mm.“
`19'?
`
`sea
`
`194.
`
`SE33
`
`495
`
`259
`
`Ciompazsitiosa,
`2&3 mg.,.’mL in Cas-
`tu: oil 118%,
`Bmzyl benzaate.
`30%, Bcnzyi a1-r
`mhol 2%
`an mg.;mL in Ses~
`me 9?] 60%.
`Benny} benzaate
`40%
`30 tr-Lg.fmI. in Ens»
`131:: an 30%,
`Benzyl benzoata
`20%
`413 mg.f1§Ié&es-
`3.1318 0
`9,
`Benzyl bsnzuate
`33%, Benzyl 3.1-—
`cuhpl 5%
`40 mg.z’m1. in 335-
`amt: oil 53%,
`Benzyl bfite
`403733 2Be:nz3rI al-
`_
`(33 D
`a
`43 mg'.,’m in Eas~
`tar 0'11 53%,
`Benzyl henzcaata
`40%, Benzyl a1-
`cabal 2%
`*I1!3ec:iiuz: of 9.25 mi. Eula mam la£:w3I'-‘. !“,”;.,g.,“°w 9;.
`aftzcr in:
`mhbitz and lesion aim dezzmxinad 2 -riaya
`
`Lat Ntxmizef find
`Efimfifh
`Es.31-53/15-B—
`Cammerfiaflf
`availabie
`
`.
`
`‘
`nr:1:~9a»2~;~1;:oc
`tested ghmm-lfyi
`dcssagfi me?‘-*35B‘1
`to 4:9 mg./ml
`Es‘31—53-V.—;Nfit
`tasted ghmmllf:
`<3G588’3 13333535
`to 49 wg~fm1-
`SH_}{_;t9:-»t~£"g'*T;‘¢>::;
`1m
`,i _
`testeli E1111-W33?
`
`__
`~
`I
`Es.31«§3—S—-*5‘?-i} £13
`%
`ifictififigv
`I&Ct£033a 59!
`
`.
`35,3}-saj—A—~82fi 9,,
`51113-‘-§1°n5*=2‘6? 5
`Ifilcfififis (33
`mild). ECCEPW1
`
`as requireddzvelfipmentofastfitabia asaa?m3*h°§‘*
`This was aczompiished by Rnrhgts and F1::rt:5?(1 3
`using pagaes:-strip chxcmamgrap 3:.
`Sine: estmgens aria mom yatantthan PT°3“~'5t"g‘?33
`and require: 1233 pt: dc-sea, an agceptable farnubmnan
`of esttadiol valfirata was easier 150 P3‘$Pa“' hi:
`sides use in estrogazn therapy, estzadiulvfi-191"”: f I
`immd. utility in the treatment of caminnmfiv 335* 9‘
`155375 llurpuse high desagas were reéltiiffii mncwé
`‘lmtians were increased. Emm 10 tan is ms-/mi 9-“
`
`|nnoPharma Exhibit 1033.0004
`
`

`

` CBS
`
`895
`
`9%; Deanasly. EL, and Paflces, A. S... I. P5i_1m'a£.. 3'3, L55
`:2 ‘Jam-u. W. 3.. Wiiéiex. v. ma. Schwartz. :e.. J. Lot.
`nxmnme
`era
`'
`:1
`can
`w’E%}M-'5§' 29' 25g'?i19’m'
`in Practicc,’ 2 :1 ad. Sch ‘
`“figs “:°~W;
`3
`"
`J’. éaau. £msae};~.~wE..1é 14431952}.
`'3”
`M’
`f
`gs) “‘.EKm1e-.rn rmés in mxmcznszagsr." H. Guémnmo
`am eat. 12. 3. Hashes”, 1953, £233.
`8553352 unkmann. 1;. xircb.
`gut. Pstiwi. P.§nrma§:oL. 215.
`Mg“
`fiavia. M. 2.. and Wm. <3. 1... J‘. 5152:. Esxciacfiaml.
`, 13. Qfifilfifig.
`(mi? Busshamn.
`Wu Arfl.
`n‘?‘I7'¥>s!¢-::1:d:r., 9 (35) 591
`9 Riuhter, 1:. s.
`ai:.2,322,S16.
`a max. at.31?.%1.
`11 Etu:1..&.,"U'.S.
`t.2.9S3,64i9.
`12 Belay, R. W.
`‘Va atahlc Fats and Oils," .A..C.S.
`Mega
`ph. Reinhaié run.
`‘ g c:a., New York, 2!. “£2,
`34:31::
`as. ma 3;
`. 537-592‘.
`(1% Rubarti,
`2'sL.sndI§‘Iure3,KI.,'raJaIo:':n2¢ax.S1,Sr'9«§ _
`mgxagasézgnn. £1. 33.. Am. Prnzdirio-rzrx 233:. Treatmmr. 11,
`(Q 1 211991).
`(15% rmznum. R. 13.. and Dutta. s. rat, Avis. .&!ad.. is
`2(£1631gm 195;. M..anr1 mm-. w. 3.. mm am. .1. Med...
`18 Dania
`D. M... and Burlnnghnm, J’. C.. Pmfigad.
`Kenueggi :5. 1.. J’. Am. Med: .4;so¢.,, 154, ?53(1aaa).
`Med. 32, 345-(Oct. 1952}._
`mi £;1smwy£Lw., czm. 0I!s:::.G:1mcca£.,S zmazmaa).
`20 sag:-.1, 1.. 0?:-ab.-2. £?.svr:.esaz.. 2:. -566(£9E35.
`21 P :
`an. L., Curran: Irlzms - Rss. 4, 30139533.
`22 Mac maid, L, and Yesbk:-a,
`.,
`. Ctin. N. Am...
`.
`, a’:1(1959;«
`Sssrgmss,
`, Sfilsfifl
`6&3} Eit:i1z1ez'§2E.é Bmwn3.M., wd Sable!» M, J’. Intaizs.
`
`J I
`
`$3
`
`V95. 53; N0v 8: gag”:
`
`agdn formulations containing ctasmr nil in the ve-
`hicle 11rC£V'ed ta be less izritatiag than aimilarpnzgxam»
`-Eons cantaining sesame: ail. Physically and chem-
`icaliy bath nil aelxitions were stabie. Based on
`ameptahle p data, formulations 531:2}: as
`tlwse Iisteti in Table VI were prepared and tmted.
`Awsptahility in humans was coznfirmeét by clinicians
`and daserihed in the litemtmre (22, 33) and if: case
`reparis.‘
`
`SUMMARY
`
`1. The éavekspment and. testing af pareuhaml
`stemid humane farmulafians has been destziihed,
`using xrastor oil as a vehiclc.
`v
`2. After ascertaining stability and animal muscle
`irritation, szalezted fcrmtflatiuna were rzmlnatad in
`humans.
`‘ifhesr eraflfihited =3. prolongeni action, were
`effective and well toierated.
`8. Emmpim nf eummarcialiy available products
`are the estxogau, estradiol valemte.‘ at 20 mg./‘mi.
`and 40 zm-.g.}’ml., and the progwlzugen, 17-hydmxy-»
`
`pmgesterone: capmatefl at 250 mg.1/ml.
`
`331“, §1*é'¢Ii3.%‘a»”*i:’;:§.
`u*£*““§°$i§:g$“5‘°m2'a%;.'“’.i.:
`tixmafin -as patimtn.
`‘rem him Iomi reanfimas. Emma
`wlcrate 6&0 u1§.!znl. is: csstur oil 58%, nexxzyi h;:§:c::9‘.¢ 643%.
`buxxzyi aslwhca 3%’---51 patients. Number oimjactznna n-at
`camplemly tahnlaitxi. one rcpmrt is inspress.
`‘R; as Delastragen by B. R. quibh 8: $0115, Rm
`* Marketed as Dcinlutiu by E. R. Squibb 6: Sons. New
`Ya:k‘1~T. ‘Sf.
`
`Isolation of Marrubiin, 3. Stern}, and :3.
`‘ Sesquiterpene frem Mawmbium vz;£'gm*e
`
`By HARGLD }. NIClHOI.AS* V
`
`AI
`
`5315113 column chromatographic method fa: isalafing the bicziclfc ciitezgaene
`n
`3.!‘
`Sin from acetone and ethanal extracts cf Ma-méirxm mlgare L. :3 riesatlbed.
`fin unsanmiteti stetol cf the sci
`gxmtsrnna
`I sex-“fies, present in esterified form, and 3
`sesquitezperxe (C:5H:a02} have been isnlaxed from the emracts.
`
`N rmnraxtzmtxon for radioactive tracer work on
`
`the biozynthesis of mszrubiin it was necessary
`in mamizne extracts of the piant for associated
`tetpemid substances.
`.5.
`cunvaniazit
`ccnlumn
`cizramatagraphie methml was therfimre devised
`for separating miatively purg mazmtbiin from
`421116»:
`acct-::rn~:=: extracts. Two new terpenoid
`Substances were detected in the extracts.
`
`mmmmmrwrm.
`
`Materials and Mathads.—Gmum-1 M‘. wlgasare L.
`
`was rzbtainesi from the W11nder1ic:’n~DiE2: Corp..
`E
`.
`313....:53an%mE}uftmi?3s3!;98g£i§:§§?ty“§
`mm B
`3.:
`8
`I1
`{E
`t f
`Tfimnhis
`pg
`éazian Nuwmbug; 1933.
`3I”§:‘Ei‘;:31& 35?§§iEn1@:ne£wI§5m1tt§:p€ITf§.d 1’ub1£:: %n<:.:1i:h -Service,
`Mgr?” .wthnr'
`ia_ inéebtea no Fuad Iarioxxra. anvil Sharon
`, ‘£5335’ fur fim: tzchnical nssistnnee.
`_
`R
`resent adwirgss: Institute at mum-12.1 faéqeanon and
`shmflch, St. Loans. Mm, am.-I Deparxmmt at lgwchemistry.
`Tvmfis Unlwmity Sxzhnui of Medinina, St. Luuxa, Ma.
`
`Hashmuck Keighfs, N. I.‘ This xnaterial was
`exhaustively extracted with hot. acetone at hot
`ethane-I. Either solufinn an remarval
`-of sahrent
`by distillaticn (the: last smges in memo} yielded
`black, viscous material which was used ft): ftlrthar
`examination. Melting poinm were rietexminesi cm a
`Fisher-Johns melting poipt
`appmatnza. Oyatical
`mfntians (in (33813) and C-——I.-I analyses were
`determined by Bra. *1}. Weiler and B‘. B. Strauss,
`B£ cfl Labomtcry, Dxfard, England. An
`infrared specmzm of the unidentified ditex-pane was
`determined. an 9. Per3:in~fB3Imer spectrophotometer
`by the KB: disk method.‘ An infrared speczirum
`of the stem} was detennined in chloroform solution
`in a 0.1-mm. sealed cell, vaumpwated with Clfifih,
`an a Beckman 112:4 recording inframi spectro-
`phatometerfi and by the KB: disk method. The
`
`1 This Em: has ghraa msumnce that the material in-_w:s'Li~
`ted was M‘. 13338376 as white hnrehaund, mt Batista larsuta
`black bonito».-.ud.).
`3 We are ‘mziabttd tn the Department of PsJ:Em1ugy_
`Uniwrsity af Kansas for this tieterminatian.
`3 Ilgtermined by éaaae: Reseuarck Lahcnrataaies,
`dciglua, Pa.
`
`I’I:iIa~
`
`|nnoPharma Exhibit 1033.0005
`
`