1..-
`
`D9
`
`Val. 53: Na. 8, Ax;ng 1964
`
`definite bearing on the usefulness of may whim
`packing prepared. The pfifamances of the seven
`suppm‘ta mentionecl previoust were examined under
`the same operating candifians. The sung that
`can he used for lightly loaded paczfings are: glass
`beads, Gas Chmm—P, and. Chromosmb WsHMDS.
`Thé a}:th fam- suppm'ts mat be. used far lightly
`loaded autumn packing since their interaction with
`thg antibiatamines {33.11535 excessive peak tafling.
`The hydrogen flame detector used in wnjmcfian
`with the. 0.018481. stain‘iess capillary column wauld
`nut wand m mmpaunds with boiling minis above
`330°. This limitation prevented mlmfian at? this
`comm for tha analysis of these antihistamines.
`The 100~fL 0.055411. capper apex! tubular column
`was mama with KEE-IISO and evaluated using the
`above group if sinfihistmiues. The St" ionisation
`detecmr was used. with a whim flaw of 35 1:11.]
`
`zjnute. The tetautian times ubtainezi were. com-
`parable: to flu 6«ft.~XF‘1150 packed column, but the‘
`yeah ham: widths were oonsidembiy wider. 33mm
`of this imam in base width. the 110553.11. cesium
`
`
`was Ems efficient than flan til-ff. packed comma
`
`A ESQ-ft. 0.065611. m1
`wanna an a I‘frin.
`diameth mandrel has been Hammad to be more
`
`efficient than a guitar! caiunm {15). Thu: are mo
`pasaible reascms why efficiancy was 1833 than pre-
`fiousi? matted: (a) the whims: was shatter (100
`it}, and (32} the: finding mnfigumfian wag makwfly
`different. The mlum was wnund on a 11!; x
`‘frin. bar which rmflted in a definite flattening of
`the talk: wand the edge uf the bar.
`
`CONCLUSIONS
`
`891
`
`for
`except
`investigated,
`The aufihistamines
`attaching. can be sapamted. identifieé, and cam-
`trafion esfiflated using (in: Gamma: 20M. PDEAS,
`and 3131150 (3:11an fiesctibed. The PDEAS
`wlumn is the mast effldmt of the three far the
`analysis of antihistamines.
`The usesfuiness of the; 0.911043. capillary and the
`
`3.1365411. apex: mbmar columns cannot be: pmpefly
`evaluated until the mefitionad
`are me
`waved.
`
`MMCES
`
`{1} Enchantmme 3., mm Svendm, A .3, Tm
`Iowan. 53.3 swam.»
`2 C12
`3.. W... A8133. 6.3:!!!" 35, 3560.053).
`3 Pa; qé, K. I}. and mrk. P. L. fluid“ 33, 423(1933).
`rm, 3, 13?§{1§31 .
`(5 Bmvfimm. 3.. and mm, A. 13.. Tina
`Jamar. 51, 938(9363}.
`(6) Parka K. D. Fenian, C. R... m Kirk, E. L" Anal.
`61$ch 34, lfiififlafiefi
`,
`.
`(mg; Bales. 8:. M... and 19233110. I. J... 31ml}. 33m” 3. 33?
`(3 Parks. K. 1}... Batman. (2. R. and Kirk. P. L... Anal.
`01:513., 34. Tfifimfigée'
`7 aggé M.
`., and Manning. ‘3. J... I. Cbumatogq
`’(10) Parka. E. 13., Foam. C. 8.. and Eric. 9. Ln £1361,
`cam... 35, 356(1933).
`,
`.
`{11) Bhutan, C. R... Smth, W. (1., and Kirk. P. L" find"
`35, 531(1963).
`(112; Znhyk, W. L. and Emma, AL 3, £513., 33,. 912(1955}.
`rap 3'.
`z
`.
`, mun
`.
`aw
`‘%3 ’93-...“ ‘3" WWW“fif‘fitmi‘a‘i’ “‘5 mm”???
`Yul-k. N. ‘5?" 196g}: :1.
`5.
`(14) Wanna, A., Jr... and mm R. '33., M Emma
`52, 8183963).
`“8‘ ) Quinn. 3. E... A3413. Cfimq 35. 593(1963}.
`
`Castor Oil as a Vehicle for Parenteral
`
`Administration of Steroid Hormenes
`
`By C. RIFFKIN, R. HUBER; and C. H. KEYSSER.
`
`Stamid hormones may be administered pmnmafly in high concentrafinns as ail
`minions. In this form they exhibit a pwlonged actian and reciuce the samba: af
`miections required. To accommadam the demagd 59x iqcreaséngly grease; mamas.
`'txations of homcnas in solution, mm: Gil in combmmen With other suitable ml.
`mi3dbia sulvents. has been {Quad in fulfill. a. need.‘ Th: davdupmgqt of sievcrfil
`fomuiafians togethet with the results of animal Easting, as well as (anneal trials to
`humans, was: to the acceptability at" thia 011 is; the purpuses intended.
`
`my mm are handed in file “United StateS
`
`thmacopeia XVI" as nonaqueaus vehicles
`far injection and are, characterized as being of
`Vegetable migin. essentially odorless, and with
`nut mggesfim 0f randdity. They must also
`mp1}: with certain mwable physical limits
`metified fer the aaponificafian, 313:1, anti iodine.
`
`values.
`‘
`
`Rumiwé _S umber? 1933. from the Pharmaqu
`Mama Rmci 8: Deveéwmwt Sectiuns.
`Inshtut: fur Madical Rum, New Emmi-mick, N. I.
`Amem for puhumfim Eavember 19, was.
`The. MEth m mama to the chewing! Gama-mi Lawm—
`“tits for their assistance with the assays; 1:0 Dr. N. Guy and
`3. Rabat: a? the Playing»! and Analyfiml Smfiun. far the}:
`dmflwrmnt a! 6:3»:an mars;
`ta G. Lackvmod. at the
`Phaxmmk
`Sabina im- the animal muck imitation tests*
`and cap-ma:
`ta 1):. a. c. Rcifwstein. a. at the median!
`“83. for the:
`amatim cannt the
`’
`trials.
`
`gala
`mb‘n
`
`1235851853.)? and
`After subcutaneous injecticn,
`Parka (I) observed the persistence at olive ail
`and casts: 051 in Wall tissue. Clampariug ether
`oflé Bmwn, at (1.5. (2), raparted that sesame and
`earn ails were: superb: to mattan and peanut
`oils {amuse they were less imitating, less anti
`genie, more: quiekty reieased {mm fiasue, and
`pqsséssaci superior physical pmparfies.
`Maxi: may the use of stemid home
`
`medication has expanded mnsiflerab‘iy. Due. in
`
`lititazi water solubfiity, harmones have been
`administered as aqueous mansions or 301%
`
`{59:13 in oil. It has been claimed that: the: Iattex
`
`pmvified 1113 Shaw mime prefmefi in cyclical
`
`InnoPharma Exhibit 1033.0001
`
`

`

`Sam. fglsue
`1m-
`.3
`
`182.?
`133%;
`189.8
`1935.0
`13:23.6
`191.?
`11304193
`195.9
`
`mmflgug
`gig
`
`84.5
`Iflgfififi
`333.9
`111.8
`194.?
`108.2
`109416
`111.3
`
`7 .9
`3g
`.
`0.5
`1.4%
`a. 3’5
`8A5
`2.0
`. . .
`
`234333
`an???
`.
`.
`23%,?
`26953
`333%
`29981
`13.83. specs‘
`496%
`W
`w
`2 .0
`33.3.13“.
`119.1
`194.5
`1.0
`53148 mes
`124.4
`191*;
`1,2
`36?15
`125.0
`189.3
`1.2
`33435
`we
`zégfiiis
`3
`33%” W,
`.
`IL JR.
`94A
`1112.0
`1.3
`22168
`93 .2
`1:31.?“
`1.4
`29993
`8?.8
`1&3 . 1
`{3.8
`33833
`
`
`
`1.2 max251?! 1333
`¢ The $.83.
`Wafiutfiafimfiundfmfactyafida‘énmflmamufiawautm?wii“9.133183%08
`which $1? thaw bit 333 m1. of 5.652 3? N583.
`
`gm
`Jag;va of Pharmafica} 3m
`
`Tum waaxm 03 Cam (33.5 m Gamma: 9:: {£33. m Manama
`1312.19.82 straw
`Equiv. to 16m
`31m acid a:
`lmfim Sung}:
`35 .0!
`12‘:
`
`an
`cam
`oi:
`
`~
`
`3.93: Na.
`*spw.
`$333:
`
`5mm
`
`e {m
`
`(inflamed 0i:
`
`cm
`
`‘
`mi
`
`SSS.
`
`.
`
`3mm: mi
`
`Twas ammm as Smoma m {1.3.131
`
`' my: 25‘
`
`Shag-aid
`
`ngfim
`Cum:
`Sesame haunt
`ca
`m1
`0a
`
`1?-K?dmmmgemmm
`2?.9
`23A
`55.8
`capmata
`8.1
`5A:
`3&5
`TWM
`Estrafiial Wants
`60.6
`16.1
`18.8
`fiama
`53.0
`22.9
`23.8
`
`
`thetapy (3}. Using withdrawal blaming in
`human females as the. mitexian, Master, s: a3.
`
`(4}, mugged the: éurafion of acting at an.
`
`
`
`aquwus mspemsien at yragesterone with
`oil
`
`salutian. and wafirmad the supeliority of the
`latter. The pmlmgatinn {If activity was gem
`My mind in: garage in the fatty depnts a!
`me had? (5}.
`
`In 195:? gm (a) gamma that a.
`testaetmnn afar dismiwad in W oil pm.
`imgeti the mtirngwic-efiects in castrateci rats.
`
`“Davis and Wiaé ('4‘) dewmstmtafi that pm»
`imaged activity was aim ofimineé in mamas
`when oil 531me {if a pragcstamue daivatiw
`ware injactatL “mar: ma still a limiting facim,
`hawwm in that 31213 a waive}? swan amount
`mi immune: could b6: éissoirwed in the Emma
`(£15. Ta increase the wheat pmar cf the aft
`it was necesmry ta mm flammable ami nam-
`itritating cosowm* Each additians consistea
`of baggy-r1 human, Emmy} almhol, ethyl lactate,
`ethyi cleata, ate. Tim 13.83. recagflized the
`need in: such “Elmer vehicles," with the re~
`Was that. they 2mm be safa in the mime:
`cf injaafinn administered. anti that may should
`
`mat inime with the thaws; flew; nf the.
`PTeil’at‘afian arr Eta hating.
`
`Ema: far mm home mammfians
`
`
`per float, furthered the search far
`acceptahis
`9:31 with grate: solung paws: 1557 .53. Ba?»
`chasm: {3). in 1954, am that; I’Lhydmxwmv
`gestemm: capmate in a caster uikethyi lang
`Wale was viral migrata¢ In addition, pmie
`mmmunicatims {mm clinicians in West Ger-
`rany repurted germ tolermm Prolutua-l)§§of
`cant 3 caster ail—hm} bemmate when:
`
`Since then ether humans have been usacl
`
`
`m
`sniuti
`in ddmieic aciti estera, "as wail
`caster of};
`(9&1).
`accordingly,
`ax;
`investigav
`flan W38 mamas: mm the suitability of 2.39
`tar uii as a m:th in: 12th When
`of steroid hermenea.
`
`WQBS AN!) RESULTS
`Emma gamma: (if 33.3}. ails ohm
`
`firms: camarcial m M W in murdanca
`with the with} matimd for free: fatty acid mam“:
`fiapwificatim, anti inéim values. The
`3173
`1m in Tm: I aiming with ma 3-5.9. XVI spwfiw
`films for these Gila.
`*
`,
`Slath no!" seith stuuids in Was 0118 Wis;
`dammed in the faflawing manner. An £33835
`stun/iii was stirred. far é ham at was: WWW“
`{35“} i1: fin: test oil. aim: w ’cfi:
`the: wéxfial‘iafii
`mlids were rammed by filtmficm, and the clam 50 ‘1
`flan mam far Maid content. Table 11 same the
`ranks abuinei
`.
`Anattempt was madetr;reducethefreerams-2%
`
`in (593th oil by Mama; with M $316
`Y
`1
`.
`.
`» Rm. 133mg“;- 2 Dr:
`Egrggg €i¢§€§$§§e§oaa§§sramwmm gnzrig‘
`*
`‘tntavauwklipflg mem‘g;
`I? '
`9" mum-let; fingveixmfimmvmummmi. wanna.
`
`InnoPharma Exhibit 1033.0002
`
`

`

`Val. 5'3, Na. 8, August 194%
`
`393
`
`Tww III—MABWN a? 01:. mm: W
`Emma“
`
`
`animai muscle irritating tesfiag prim: ta raieasa for
`
`fig
`:ajmfim:
`143
`
`1-3
`
`LS
`
`Residual an in
`Muscle timid.)
`Gil
`1 day mm c.
`Easter oil
`3 dayswzn
`{aged}
`1 day “30
`Easmr oil
`3 days—~10 9
`33.3}.
`1 533! "-3253
`Sesame ail
`3 éawfifl‘fig
`11.32.
`* . . Mining If)
`A31 51‘}:
`$06
`m 2%
`
`“fighmfiy
`Emir.
`53
`
`13
`
`1.4
`
`*‘ 1 m1. hjmel in?» back Invade 0f mm.
`
`
`draw sodium smifate. Three: grams Inf dried. flaw
`
`dared, warpth aluminum axigda (Merck Na, 100'?)
`
`and 6 Gm. sf anhyflmm sodinm “liaise, {agent
`gradammpendmiin mm‘ufafiandheated
`at 8‘1" unis: a blanket n! nitmgm for 1,5 Imam"
`Eta: gnawing the nil tn coal in mm implanting,
`tha wfids wen £1th ofi and tilt: asifis {ith in
`the usual manner. A significant. mfincfian in fm
`fatty :5de «23 mt obtained,
`Thefibsurptian uhamctaxisfics af 0&15 with. varying
`fatty 3:21sz mama; were examinmi amt mix-112m an a
`hiulugical basis. Aged castar ail with a high free
`fatty W921 mutant was {363233an to flesh H.313.
`caster ail with 9.1m» mini muteut and 13.5.29. We
`ail by injecting 1 ml. of ail ism; the hack muscles Inf
`rabbits, apprame 2 in, fmm the Elias: wt.
`.8».
`mum‘an pattern 6f injectinn was used and the: ail
`samplas were: swine/:1 to aid visibility in the $521351
`The animais were smflficsafi ami the muscles Med
`
`and examined smash The: results WW: :3me
`and mm in Table III.
`mammmmmamigmdm married
`tn the hath, and wary $333.11 amounts remained for
`30 days. magma degammfian profinceri by the
`high acid value; castar uii was Basal-am? healad in ’3
`days, and the law acid value. casts: ail appearati in
`he no mare irritating than sesame oil.“
`. In a Specific: fast in: imitation 0.25 ml. of the album
`nil samples we aim inin into the WM Wadi:
`Wafxabhits. After? €33.33
`thaanimaiswm
`sacrifimd 3am}. the
`names examined 3105st
`far Mame sf Mafia.
`It was fauna that the
`W cat wntainjng a high ievai of {we fatty maid.
`{Induced a Man aim n1ng apgmfimamy 121
`m‘i The iesion itsalf m characterized mainiy by
`dementia}; uf Inca! tissue; withmxt necrosis.
`(133*
`ta: ail with law frat fatty acid and we cacti,e on
`015: ether hand! proénwzi an mewmble lesim at the
`wattfim Kite.
`Cambimfions cf WE almhai am: Magi beam
`ngwithboihmail wdsasmeuilwmam
`mlmmd’into the: mats: mm mastic; of rabbits
`and. Table: IV lists the lasian sizes maximized.
`i Salufians which were fmmulated for clinical trials
`in humans were prepared by mashing the smoid
`hfztmones in amrwziate vehkles at 60" ands:
`mimgm The mlufim were than 53mm Waugh
`94 cm shared-gigs? fiita: with the aiti 0f flange);
`P395531”, filled into fish, quid sterilized by 3111:3213»
`3% in: 2 ham at; 121° {15 23). steam pressure}. Th5
`
`Masts were then mhmiftuci fur assay; safety. and
`1 D
`.
`msgmwmnsmmgammy?or
`“hmuw less than 3
`T.
`+1 N N393 15 m1. 6! 9.3 N
`“303) 13:: ID Gm. 131‘ 5231313 0
`{
`
`»
`
`QISCIJSSIQN
`
`Through-at the mvesfigafian it was desirabl: tn:
`have; a mfwca ail m we as a am far camparisom
`Since,- sasame (3i! is universafly acctptafl as a parew
`tam} oil which. it was chasm-n as the: “star “
`vegetahla’ 053 to he: wmpared w W mil, with ané
`without ether? Wis. The physiml, chamiml,
`amt biweng properties of we ail m «211
`
`
`WWW am! regain: :a mmts haze.
`{theminaflm caster ail mists {if the: mgiymfifim
`of ridnoleic acid, together with mail quantities a?
`glytzrifias cf mixer was. The: quanfitafiva mum
`pagitjan is given by Brakes? (12} as fallmm:
`ticinaleie
`mid 873%, akin acid 14%, finaleic mid 3,15%, glib?»
`dxmricinoleic: imixi 0.6%, anti misceflaneans acids
`2.4%. firm: W m commanly imam is this
`why-413 13:1. 1 which is mid passed ail, and
`Us. No. 3 which is ail Wei fmm the pram
`
`take; 031}? WWEusedfm' madidnalpumam
`The high Wait? 01' mm: oil mmpmd to other
`"vegetable ails i3 undwhtefily Maw to hydragm
`bondixxg anti it :13 probabky the hydmxy gwupa
`which mntribnte tn the. mar palmity and amnesia:
`sulmt 90W! cf the {1111. $5 iadicated in Tabla I,
`
`the sapanifimtian turd iadina values 9f mmcisai
`casts: ail amass: to be: glightlyW than the “£3.33.
`231111 limits fax sails £1553. far
`0:: the ether
`hand, rim mtmt a! Ema fatty arias even in fresh ail,
`vaxies maiden.ny and armada the traditianal
`limits for injentahle aim. The: significance 01’ this is
`samewhat abscissa, althangh “Mngmfs Pmfim
`0f Pharmacy, 12th @6333,” 1133a 38?. States “319w
`free fatty acid mum is essential aim: is; inflates a
`Email and pan: mama and mat an: that is likely to
`313% 11mm; aid anti heavily mataminatad with has»
`terial prawns."
`Despita better salubifity of stemids in caste: ail.
`athei- E30513}?th were: necessary to {fiasoiw the
`
`Tam IV.-—»1am mum-:20»: Pmnum m
`Ewan Mt:ng a? mmman a? Vanna 01L
`Vnmmms“
`
`was sin.
`mm!
`+31
`
`Identifiqu
`SHYfiT-fi
`
`SKY-.14de
`
`SHY—é’i’fi
`
`SEE-14:3
`
`5‘ 13L 0354211. qmtity :96 the: oil wide: was Mme: into 2M
`9mg: Walk muscle at the ta.th Tm: :16;
`Raw: the.
`maxi: was: united uni {kg fer-inn 31:4:mm mn'.
`
`InnoPharma Exhibit 10330003
`
`Comasifiun
`Sesame trial 98%
`33ml almlml 2%
`W4?4 {Easter ail 98%
`fimyl 931201101 2%
`Swami: ail 95%
`SH?—§:?~3
`Benny} almim! 5%
`
`SfiY~é7w5 Castsr ail 95%
`Ems?! aknha‘i 5%
`SEE-mm: vi! 135%
`Beam?! mu: 35%
`SHY~1$5 Castor ail 35%
`23ml Wife 35%
`8353311: Oil 53%
`33ml Watt 35%
`law} alcohul 2%
`3334?”? M: vii 03%
`Remy} benzmte 35%
`'
`
`
`
`EW} akohai 2%
`it {til 58%
`331ml 13mm. 59%
`158
`swam Casth 95$ 50%
`3W1 banana—t: 50%
`
`Tax: small to
`measure
`506
`
`:06
`
`29?.
`
`184
`
`207
`
`252
`
`2911.
`
`

`

`394
`a
`q
`meaneg higher mmhafions requf'red by
`mmpmfic regimens. often these matamls cun-
`tn‘butexl mammal admmges. For example, “the:
`addifim of benzyi 33mm} or benzyl Inmate to
`mtg: ail resulted in. a lower and mate Emma
`mm making it easier to infect. Also. 116312371
`31mm: was an MW. pmmfim and Inca!
`mass;
`The nature of the imitative resgonse depeugied an
`the parficzflar hormone, its mnemtrafiun m the
`immulations, ande tha empom’tim of tha "vehicle.
`Although BB.th mm are mare sensitive than
`human Invades, they were. selected pfimaxilybemuse
`
`lucal changes in tha muscle. wen! charred easily.
`It was mi: always passihle, however, an mutilate
`musclairr‘rtaficninmimalstathatafihmm.
`A nflma-ical assignmaut to Iasian size was used
`snidy as a mnvem'mce for grading response. The
`numbers alum:
`:11: mt adequately (Imam the
`mam: uf the. mama. harm. More compkteiy
`
`it is characterized by the amount cf hmorrhaga and
`
`Edam and the. inddfime, dams, and extant of local
`degenerafim mama by the injecfim A slight,
`mm mm: Immz may cover a large: area
`and a. severe irrevergihla one. may be campmfiwly
`small. A time in the size 21f the degenmtefi
`area. inclinates a reversible «audition. The preseace
`
`of necmsis, which is the most damaging situation,
`means that the. «2111113.: mm was dzsfmyad and
`repair must take place. The debris must he ra-
`moveéandtheariginalcefluhrmasahthemm-
`placad with fibmus mnmtiva fissure. The. extent
`ofthiafibmsisorfmfimnfscarfissucgiwsan
`mafia: fif the ammmt a? irreversible damage; For-
`mte‘x‘y nmsis was not encountered, iadicsa’dug the
`Ian‘s: of pennanmt mnscla damaga Sines these
`
`Wanting, Mmemmtoftkeefiects caf
`an inimfiun in the muscle frequently required
`nbmafian far '2' days a: longar.
`It is unfarmwe that pain war heW by
`
`a}: mom mama of animal taking. The animal
`
`usualiy down nut wand was the painful $2?QO
`is marked. Marmara, the pain magi by injec-
`tion 521m human muscle “m not wally Importian
`
`tn tut ’m'izafiun pmduceé either in animal 1x11152122
`at in human muck. Realizing that these Emil?»
`fians are inherent in animal tea methods. it re«
`
`mined fact final mytahifity ta he dammed in
`man.
`
`man itwas discavarefi that 17~hydmxmmgester~
`one came gamed high pmgasmfiflnal activity,
`potencies of the (min: of 55 mg.11111. were used. By
`increasing the dose, additimal pmianga’cian of ac-
`fian wag obtained, and eventnafly mammfinns 9f
`the: «533$ of 250 mtg/m}. were required“ Such a.
`whim: in sesame oil produced maptahla animal
`muscle tnIemnce, but the. pain anti 10ml reaction in
`humans was 50 great as to yrshibit the adoption of
`the formulation is a cummflciai prom (59:: Table
`V. Lot Pr. amnam}! &h1timas wen aka
`prepared using castor oil as the vehicle, and Table V
`fists the: fannulatim tested and the results ob-
`tainal.
`Infomafim obtained from the clinical
`fiiais (14-21) awed tn the maptability and
`safety cf the adopted farmtflsficms.
`
`V Inherent in the development cf an acceptable
`
`fiurmulafinn af 17‘hydmxypmgestemne cam-oats: was
`
`at;ng in excess 0! HEB mannsidmd Wt»
`
`Journal of I’th Sm‘m
`
`Vebicle
`Campasitinu
`Sesame mi] 50%
`3323:3371 bensmate
`50%
`Cami: oil 58%
`Benzyi baumte
`$0?
`139212370} almhel 2%
`Sesame 0&1 60%
`
`3233?} Inmate
`35%
`Suzy} admiral 5%
`Casts: oil 54%
`B
`lbenznate
`45%
`
`691
`
`697
`
`258
`
`Twas V.—Evumnon o? 250 tug/ml. 17wfiy.
`nmmmnmam OuaaAm Seaman 3;
`11mm 01:. Vnmm
`fin‘xmsl
`Mafia}:
`Ixsim
`Size, mm."
`1049
`
`Lat Number and
`Remarks by misfits!
`Tasting
`Pr:1;42~53/15-7--%3
`1mmfims,
`fgfifi‘x
`mum. refine-ad
`Pr:1f}2~§3/15—8-2?0
`mimfiams, 23.2%
`mum. {aim
`
`Pr.142:53/‘15«10-~
`18$ mjwfinng,
`189?% W,
`rejected
`Pr.142~5§{1§~11m
`503 ingecuops,
`{13% mums,
`Exempted
`6&3 H.142:5§/1§«13-~
`{Eastm- ail 52%
`92% mjccjmns,
`Benzyi bmte
`1.3% mafia-:13.
`416%
`
`Banal almhol 2% accepted
`5 mm a? 3.355 ml. ink: QMKES
`319335712 0!" mbbit!
`and taint: size dawn-mined 2 dame aftcr mm
`Tm VL—Eum‘mmn or Esmm fixme
`
`:2»: unu's 0n- VW
`M3331
`
`m mm: m
`1
`—'
`I
`E53 -
`Commercially
`availabie
`
`‘
`DEK~98r2wylfat
`tested gimmlfy’;
`. {fng mamasefl
`to $0 mtg/ml.
`Esfil—SB-VjNfit i
`tasted glmmih’.
`dasage:Wed
`to 40 313me
`
`.2 .
`1m
`maxi Bhutan?
`
`.. _
`33.31%231 1!:
`jeetans.
`3.2%
`whorls, rel
`
`3623‘:
`Size. mm.“
`197
`
`336
`
`194
`
`8&3
`
`496
`
`250
`
`Compaaifion.
`253 1115me in Cas-
`to: oil 518%.
`Bml mm
`30%, Bmfifi al-w
`£01101 2%
`30 21$.me in Ses-
`me nil 60%.
`Benny} teammate
`40%
`
`30 mg.fml. in Cm-
`w (:31 80%,
`Benz?! benzoata
`20%
`41} ng525-
`me o
`9,
`Benz?! humane
`33%, Benzyl ala
`cabal 5%
`£10 mgdml. in Ses-
`am: oil 53%,
`Benzyl bmte
`40131311 215mm?) 3.1--
`_
`.
`(33 D
`a
`BSfil-fig'fiflsga
`48 ngm in Cas~
`injecyan5.2-5'r'%
`tar 0'1} 53%,
`Imetmnfi (33
`Remy] Wm
`mild), amapted
`40%, Benzyl a1~
`cabal 2%
`v
`ink: afim 1mg“, “mad: 9
`G I “satin at (3.55 ml.
`mhlxifi and lesion aim dammed 2 énys aft” 131% _
`17315 requireddwelapmentof3.3213mm: maymefigg.
`This was mmpfished by 12¢};ng and F1mey< 3
`1151113 paw-strip chmma’mgmp 3:.
`Sim: WEEDS aré mar:path pwgestugfwfi
`
`and mqfifi 1&3 Pct dense. an mpmble farnulatgw:
`of estradiol "93.1mm was easiex‘ to prepare. has
`Sideg 1153 it: estrogen therapy!
`far
`found utility in the treatmmt of mama. mi can,
`that 1131131388 high deaages were raquired. Can “6
`barium were. increased. mm 10 ta $0 ngfllL
`
`f
`
`InnoPharma Exhibit 1033.0004
`
`

`

`WCBS
`
`895
`
`19g; Dmasly. EL, and Mes, A. 5.. I. Pfifiialu 3'3, 155
`(3 Brawn. W. BL. man. ‘3. M... Schwartz. E1. J. Loin
`' armour: m
`ranficn.’
`a
`. Bahamas.
`2Q, 2594?“).
`in P
`t 2 ‘1 ad.
`‘
`3.. Br. Erich Elaschker.
`£1111, 1‘854, 3;, mg.
`3&5 Mm 157. EL. Grady. m. a. and Magma», :3. 1x.
`I.
`fix. Esa‘minoh. 13 1445 1952}.
`:5) "mam Tmés En
`“Gammon,” E. (Ending:-
`Eifl ed.Q P. B. Katha”, 1958,
`. 233.
`“($3352 W. 1.. am.
`yd. Paw. Pkmakol.‘ 215.
`t: Davis. M. 2.. and ma. (3. I... J“. Eliza. Endows‘ml.
`H336 .. 13. 928(1'952.
`{1
`Wu Aw. Worshsmckr" 9 (35) 591
`Eta Bus-hm".
`0 Brit.
`315.53?
`93 mnhter, U. S. at. 2,322,816.
`
`:11 Ems! . L, U. S.
`1‘" 3.983;.M9.
`12 Belay. 3* W.
`“Va gable Fats and 03:15," Les.
`Mann
`1311. mad mm ‘ g (143., New York, 2:. “£1.
`Quite:
`a. 1%.}: . 587-591
`13 3.913%; K,Mdmm,&,m3omm51fl9§ _
`{I 82‘.‘
`12.. 3.. Am. Prndflio‘nm' 233:. Tremamm. 11.
`ngtwsségm.
`(a 1 mam.
`(153: Granular; R. 13., and mm s. n, Aria Mada Is
`2£15;gm 195%. M... and Baker. w. 3., Km 3m. J. Med...
`filmed , n. 1.. J. Am. Med. Assoc” 154, wanna).
`18 Denim-(g, Du 24.. 11nd Burkinghnm, J" C” Party”.
`Meet. 32, 345mm 1952}._
`as? ma kw" can. oasm_esmsa:.,s 11660362).
`20 Eiffel, 1.. cam-2. W., 21. 66603335.
`21 P a
`a, L., 6mm Than . Rm 4, 30139633.
`2
`m:
`. Clin. N. Am...
`2 M mald.I..and Yama,
`.,
`4&3. amamzt.
`05x3} Eichnu E 3mm 255.. and Sasha; M, J. Imus.
`c .Smgm,§2,§9¢{19593.
`
`J I
`
`Yd. 53, No. 8, august 1564
`
`again {armaflations containing casts: oil in the ve-
`
`hicle unveil ta be lesskzitafiagthan a‘mflarprepm»
`fions cantaining sesame: ail. Physicafiy and chem-
`icafiy bath nil anhiticns were mama. Based on
`mele pmfimimry diam, fomulafians Such as
`flwse fisted in Table VI were prepared and tested.
`Amptahflity in humans was confirmeéi by diaidans
`and dasefihed in the literamm {22, 33) and if: case
`reparts.‘
`
`WY
`
`1. The éavdcpment and. testing 0f mm
`Maid humane. famulatians has been descfihed,
`using Castor oil as a which.
`E
`2. After ascertaining stability and animal muscle
`irritation, selected fmflafiam ma mlnatad in
`humans. Titles: exhibited a prolmgefi action, were
`effective and well initiated.
`8.
`3333113115 cf mmmarcialw available products
`are the Magma estradiol Mama“ at 213 mg.me
`and 40 mgij, and the ngen, 17-hydmxy~
`
`progesterone: capme at 250 mg.{1311.
`
`émxlgju fists: nil
`REE? mw?: “Moi mm 30
`tam? mmammfg?5:115:1thregacfimmm
`mutate 6E0 m§JzuL is: mint oil 58%. hmzyi Ewan: «£053.
`hm! a31th EVWSI mama. Number Dim)th nut
`campiflfly min-11m. nae ram is ingress.
`3:2??? as Dalestragen by 3.. IL quibh 8: $0115, Rm
`t Marketed as Deinlufiu by E. a. Squibb a: Sons. New
`Ymgm Y.
`
`Isolation of Marmbiin, 3. 81:61:01, and a
`' Sesquiterpene fmm Mambium mlgare
`
`By HARGLD }. NICHGIAS“ V
`
`sun
`Ia column chromatographic méthad f0: isolafing the hie?ch take-mane
`armliiin from acetone and ethanal extracts ef 51mm mlgare L. is éésatibed.
`n manuateti 5:23:01 0f the ad
`W0
`l scfiefi, presem‘. in esterified form, and 3
`sesquiterpene (6:432:02) have been imbued from theW
`
`AI
`
`nA
`
`N mrmflox for radioactive tracer work on
`
`the biosynthesis ui mmbiin it was necessary
`
`in examine extracts uf the piant for maimed
`
`tflywaid substancea.
`J‘s. canvaniut calm
`chmmatagmphie mi:th was magma devised
`in: separating relativaly pars; manubiin from
`crude matting extracts. Two new terpemid
`substances wwe detected it! the extracts.
`
`EXFERWTAL
`
`Maferiais and Malinda—Grams! M. wlgare L.
`
`was fibtainefi from the Wanderfichnniaz Corp.,
`
`:5, magnet”; the Department 13?
`03mm august
`mm and gnmlqu, 13:11me a! Kansas Medmal
`5mm: fur pa mfian Number 6, 1983+
`t fmm the
`“T2118 mefignfian was anpparkmi by n
`3:33:33: means. of 21mm, U. a. mm: mm: Mm,
`“Tin .mthm ia' {mama to mm Iationra anvil Sharon
`
`‘ lama! im- flmu- tzchnical “sigma.
`R Present matings: Institute at Main}! Muenfion and
`sgmflchq St. Louis. M9,, and Dapmmt est aiochemishry.
`Louis UnlwmityW of Machining, St. Lama, Mu.
`
`
`Hashmuck Heights, N. I.‘ This mam-$3.1 was
`exhausfively mad with hot. acetone at hot
`ethane}. Eithnr solufinn m1 remaval of when
`by distiflatian (the: last sages in mass} yielded
`blank, viscous material which was used far furthar
`examinafionx Melting points were fletaminesi cm a
`Fisher-Johns melting poipt appmma. 033W
`mfnfians (in CECE) and C—Ji analyses were
`detexmimd by Bra.
`‘1}. Weflm‘ and F, B. Strauss,
`Wmanaiyfical Labmtcry, Dxfard, England. An
`inhm'ed spam 9f the unidentified diterpene was
`determined an a PerkimEImer spectmphctometer
`by the KB: disk wetland? Am infrared swam
`of the stem} Was determined in chloroform solution
`in a {ll-m stalled celL waywath with CBC!“
`an a Beckman 112:4 recording inframi spectro-
`phutometer,‘ and by the KB: disk metho¢ Thv:
`
`1 Thin firm has sham magma: that the material iuyw'm
`ted was M. WIsz at white Earthade mt 23am lama
`black hmumd).
`3 We an inflamed to the Department of Psihnlugy.
`Unitmsity ai Kansas for this fittermimfiam
`*
`a DFWeé by Emma: Research Labmmfiw, mug.
`(1:131:15, Pa.
`
`InnoPharma Exhibit 1033.0005
`
`