From the |')epat‘tmcn1 of Pharmacology. Johann Wolliyang (Joctltc-«Univt:rsitiil, Frankli.t|'t/l\/laiit
`(Federal Republic ()l'Gc:'many)
`
`Determination ofthe Bioawtilability of the Qttatmnary Corripotmd
`Trospium Chloride in Man frorn Urinary tixctetiorl Data
`
`By G. Schladitz-Kei|"l. H. Spahn. and E. Mtttschlcr
`
`Dedicated to Professor Dr. Herbert Oelschléiger on the occasion othis 65th birthday
`
`Summary: For the qtrr.u'm'r1r.tr'_): comprmnd fl'(15‘{).llH?'l c.‘it/r»'r'de
`(Spasme.\®) iv/tic}: is used as an ann'c.l1r)i':'net'gi'r' agent or new
`mtiririve rtia'.:ry men‘-mrl liar been developer! that (Wows the
`rmmitilmive de.‘erim’rtm1’rm rifrlie tiling in immrm mine and
`plrmncr. U.ring n'u'.t' me{l'Iud it Wm.’ pumrf)/e I0 ribfctiit pl'rarmrl-
`t'0l't'1'.'re.'."c' ct'rilc.'_/i'orJr p/a.s‘ma levels ant.’ un'.trm'y ex('t'elio.Ir, rum’
`Ir) cfererrr.-me the biortvat't'abr'l'it_v in mrm. Qum-irlmrive deter-
`m."ru:tl'r'rm t'.\' perfwmerl‘ by at/crilriie }rycl'J'oly.s'l'5' to the cw'r‘e-
`.s'poncl'r'ng .s‘pr‘r'r).r.'lr:rn'm!.
`t'0tt-pun‘ extrrrclirm wt‘!/r
`ci’i'pr'r.'r_y!-
`amine, .t'rtb3eqtre.t1! cl'el‘t'mtizatz'0n with tI'Ieflurn'rJpI'mt' l')er1r),\’(r-
`pr'rJ_)’i.'n clilnrfde. and ."ort-pair‘ cltrotnalogmplifr .repru'u!i'mt
`on (I r'r‘ver.s'erl'-pl:(me cm'tmH1 with C/1i’or‘r'de as the eomtIei'-i'rm
`tiring (I .'?Ii.\‘tm'e 0_frtc‘eloi1irl'i/e and wr.'!ei'. In I'1ert.ll'i.'_I' voltm-
`reers (H 2 6) the p."a.\'mri conrrenlmrirtit time rttrrve r.gffer r'mra-
`venous admz'm'.sn'aI1'on of 0.5 trig n'o.s'pi'um c/1/orfde could be
`ct'esc:'ibed by on open I'lWPC'()H?j)£l‘l'N?I(3Iili' mode/. The mean
`l1aI)‘1h've.s' were 2.7 arm‘ 97 min,
`r‘e.<pe(:lr't*e:'y. xlfier mm’ (id-
`mim's1rcm'0i1 of 10 mg the [ugliest r,'nnc'entr'aIi'or1_/outta’ in
`_r)lr:.s'mrr W(I.\' [.4 ng n'0.t'pi1IrJt L‘ht’m'fcle/n1I'. 55% of the given
`date were e.\"cr'eIed trnciim-iged into m':'ne wi'I:’u'n 48}: offer 1'. v.
`at/n-ir‘n:'.s'!ra!ioJ2,
`the c.'m'i'et'p0tra'."Irg value rifler om.’ mlm:'m's-
`Im.f."nn wan.‘ 1.6%. I/"no ii_tJ(i't'0l'_1Isis
`ix crtrrierl out in tmirte
`mmp[e.s'
`the .rpii'r)aIcrJ.lroi can be delecteri rm‘ metabolite of
`1ro.r;Ji'mn.
`l’l/lllllll 48 I: offer I'.t’. rrrinmrlnrrnimr 4% mac} at/Fer
`oral’ admr'm'.rh'rm'0n 0.3% ofrhe given dose are excreted’ into
`mine as .t'pfl‘0£tl'L'()I'Ir)l'. From the eunmfcm've ear-reIi’on of
`tr0.s‘pl'trm info m‘r'r1e wi'.'.l'u'n 421’
`it a mean br'or1vriiiuI'J."l‘r'.'_)* of
`2.9% was eal'cm'aterl'.
`
`Zusammenfassung: Brts'.'.Uir1i1tmg o'er BI'ot=eijfiigbr1r'lcer'! dew
`
`l/ei'h:'r.'cl'r.tl1g Tt‘0.rpit.nm'/tl'oi'io' curs" c."r'r Lr'r'r'm'ms-
`qum':r'.t'r'eu
`.s'r'he.v'dm1g helm Men.sc.'l'ren
`(Sprmire.\*1‘l')
`FiTr'r dos xl:m'c/.t0l'inergiltum '1l'o5pt't.rn1c'/item?‘
`wmrie ein enip_firm'lfr,*Itr=.t
`/lart/_v.s'ent=ei;fi.'in'en ertrtiiiefreir, mi‘!
`(fem er mr'J'gl'fc)'i WEN’.
`llharrttak0icme1isc'lie Daren cm.s' den
`I('r)nzc’lm‘rr!ir)rt.\‘-Zeft-Ktrrtren Em PI'a.srmt mid der Ar.'s.\‘cl1ei-
`clung rm Urin zu erhalfen mid damus die Bi'overft'lgbai-'kei1
`beim /l/lenscheri ZLI be.s'(.~'mmen. Ztrr c,ruarm'.'ar:'veri Besl:'m-
`mtmg wi'rd die .S‘irfJ.vmnz zitm enl.r,w'err}ieii(l'ei1 .S”1Ji’roaIl'm!rol'
`((I”Ci,’l:'.l.'t'C'll'} l1ya'r'0!_vsr'ert, clear air Ionenpaar mi! Dipicrylanrin
`ex.'r'rrhr'et'l mid (In.t'elrt'r'e_[ir*ricI' mi! dent Flur)i'e.v2eJ-izmar'ker'
`Beu0.\‘a/Jrojiaricfilurid der'i'vrm'.r:'eri' wim’. Die e!ri'0n1aIog.v‘ri—
`1)/Iisclie Tremrtmg er/i).t'g! a'trrc)'r Hortlidt‘rmfg/it'i.r.ri'gke.il'scI'tJ'0-
`n1a.'0grrIphie rm"! einer Revei'.re(.t'—,m'm.re-SEitrI'<'* rtrtrl Cl'tl'orirl'
`cits Gegerriorl
`in einem Aee:oniri':'l»Wasser—Gemisc."1. Die
`P:'Li.m1rr/criitze.vm'atr'0ns—Ze.t'{I'ctri'ven Wm ge.t'tm(leH Pr'r2.’Jrirtderi
`{H = 6) march iv. Gabe van 0,5 mg Trospitm1cl1lo1‘fn' lietien
`.s':'r;li
`rt’urr.‘I‘.' efn rijjertet‘ 2we1'-Krmtpm‘lfment—A/Iridell bes(.'I'1rei—
`hen. Die chuclisclmmitt‘/rel: H(Il'bwer!_vzei'!en helrrrgeir 2,7
`bzw. 97 min. Die lro'r'/me ge/imdene Konzerm'atr'oi1 rm Plas-
`ma nae}: antler‘ Gabe van I0 mg ?"rospr'trmchlorml bemrg 1,4
`Hg/mi. 55% cler rrppfiziertel-r Dosis warden nacli 2'. v. Gabe in-
`nerliriib von 48 It mtvcrr'r'ncferI Em Urin ru.o'gesc/riec:'cn, (fer
`en.f.t'pr'ec/tend? l'Vt’.’l'l' uric}? arwfer‘ Gabe fag bet l',6%. Etjfolgl
`bet’ def’ cma/ytiscflett Beslimtmtrtg /cefne Hychoiyse, .t‘0 kcmn
`o'er Spii‘0ctl'krJ:'r()l'
`cits‘ Me!al'Jr)i'i.' won Trr).s‘pr'urJ1
`int Urn?
`irctcligewiesen werden.
`Imien'ia.’b von 48 /-i ncrcii
`iv. Gabe
`wrtt'(/en 4% into’ rrrmlt 0t'a/er’ Gabe (13% der appi'i'zi’et'.'eH D0~
`sis alt Spirorill'c(Jiiol' atrsgesclifrarleii. Airs o'er Jrimnr/rrtfven
`Trospt'mn—/lirssdreirfrmg in? Urin wurrl'e eine rfiii'clt.t'c'iitiiI!;
`fiche Bf0t=eljIi‘igI)oi'/ceir von 2, 9% ei'r'ec;'me.f.
`
`Key words: Aim'c'l1olt'nergics- Spa.s'me,\*3‘- Spii'rml'c-alto! C/i."oi'i‘de, biorrvaiiability, c/i'i1:'cal rrua’le.s'- ’i"rospii.mi cliloric/e,
`!n'rJr7mr'i'ciiJiIify. Cl'r'm"c(Il .t'.‘udfe.t'
`
`1. Introduction
`
`The quaternary compound trospium chloride (Spasmex®’)',
`see formula diagram) is used as an anticholincrgic agent. lt
`has atropine-like effects, etlects in the ganglion and a direct
`ctlect in thc muscle-fibre, the latter being as strong as that of
`papaverinc. The spasmolytic activity is predominant. Other
`
`'l Part ol‘thc Ph.D. thesis oFG. Schladitz-Keil.
`9) Manufacturer: Dr, R, Pllcger Chemische Fabrik GmbH, Bambcrg
`(Fede1'al Republic ol'Gcrmany).
`
`984
`
`anticholinergic effects are of little or no importance (central
`effects) [I].
`The drug was postulated to be mainly excreted as the corre-
`sponding “spiroalcohol" (see formula diagram) [2]. As the
`compound and its metabolite could not be determined In
`plasma and urine until recently, the bioavailability was esti-
`mated from pharmacodynamic properties. Albrecht et al. E3]
`found an oral bioavailability of 5—l0% using the so-called
`ptapillomctry.
`ll is also known from other quaternary compounds that t_l1€Y
`are only poorly absorbed from the human gastrointestinal
`
`Amicim.-l"oisch.: Drug Res. 36 (I). NE 6 £193“
`Schlnclitz-Kcil et al. — Trospium chloride
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2035 - 0001
`
`

`
`Q , Cl“
`
`0 on
`
`o-E=jC>
`
`trospium
`chloride
`
`cl"
`
`n H
`
`spiroalcohol
`(chloride salt)
`
`tract. The oral bioavailability oi‘ ipratropiurn bromide is for
`example 12.9% [4]. The intestinal absorption ol‘1l~l-N-butyl
`scopolamine bromide in man appears to amount to a maxi-
`mum of l0‘%, the urinary excretion within three days was
`found to be 1.7 : 0.3% olthe given dose [5].
`As the doses oitrospium chloride are low. plasma and urine
`concentrations were expected to be low,
`too. Tliercfore, a
`new sensitive procedure for the quantitative determination
`of trospium and its metabolite in urine (and plasma) was
`developed by our group [6] containing hydrolysis, ion-pair
`extraction, and fluorescent derivatisation with henoxaprofen
`chloride.
`
`Using this method it was possible to determine the concen-
`trations of trospium and the corresponding spiroalcohol in
`human urine after intravenous and oral administration and
`thus to determine the bioavailability of this quaternary com-
`pound from urinary excretion data. Plasma levels of tres-
`pinm in man after
`i.v.
`and oral adrninistration were
`also investigated.
`
`2. Experimental
`2.1. Chemicals
`
`The reference compounds trospium chloride and spiroalcohol ClIl0-
`ride were supplied by Dr. R. Plleger Chemischc Fabrik GmbH. Ilen-
`oxaproli:n was made available by Eli Lilly (Bad I-lomburg, FR Ger-
`many). Benoxaprofen chloride was synthesized according to [7].
`Solvents (analytical grade or LiCl1roso|v’~“’) and reagents were ob-
`tained from E. Merck (Darmstadt, FR Germany). Dipicrylaminc
`contains 50% olwater. lngotcst“ water (Boehringer Ingelhcim KG,
`lngelheirn/Rhein, FR Germany) was used for HPLC.
`2.2. Instruments
`
`A chromatograph LC 601 with a fluorescence detector 605—__l0 S
`and a recorder 56 (all three instruments From Perkin Elmer, Uber-
`lingen, FR Germany) were used For HPLC.
`The analytical columns (|2.S cm x4.6 mm ID) were purchased hem
`Dr. Herbe1‘l Knauer (Bad l"-lomburg, FR Germany) and tilled with
`l.iChrosorb RP—8 material, particle size 5 am (for urine samples),
`and Nucleosil C-8 material, particle size 5 mn (for plasma samples).
`
`3. Analytical methods
`3.] . Urine
`
`3.] . I. Determination of total compounds (trospium and spiro-
`alcohol)
`5 ml o|‘nrinc were mixed with l ml oi‘ I mot/l sodium hydroxide so-
`iution and kept at
`l40—l45 “C For 90 min. After cooling 0.2 ml of"
`25% HCl and 0.6 ml ol‘dipicrylamine solution (32.9 mg dipic1‘yla-
`mine + 10 ml 0.1 mol/l NaOH) were added. After centrifugation (10
`min. 5000 rpm) 5 ml ol‘ this mixture were extracted into 4.5 ml oi‘
`eltloroliorm and centrifuged (20 min, 6000 rpm). 4 ml of the organic
`phase were re-extracted into 2.3 ml ot'O.l moi/l HCI. Alter centrifu-
`gation 2 ml olthc aqueous phase were mixed with 2 ml ofmcthanol
`and evaporated to dryness in a vacuum centrifuge. The residue was
`washed several times with methanol (6-7 ml in total) by evaporating
`the methanol to dryness under a nitrogen stream. Then 0.2 ml of
`benoxaprotian chloride solution (10 mg bcnoxaprofcn chloride + 1
`ml of dried acelonitrilc) was added and heated in a glycerin bath
`(l40—l45 "C‘) For 30 min. The solvent was evaporated in vacuum
`and the residue was dissolved in I ml of water and 1.2 ml of ethyl
`acetate. Alter shaking and centrifugation the organic phase was dis-
`ca1'dcd. Again the aqueous phase was extracted with i ml of ethyl
`acetate.
`1 ml ofthe aqueous phase was evaporated to dryness.
`The residue was dissolved in 100 iii of water-acetonitrile (60/40,
`v/v).
`Injection volume: 20 ,ul; column temperature: 50"C‘; flow
`
`Araneiin,—IVorsclt./ Drug Res. .36 (I). Nr. 6 (1986)
`Scliladilz-Keil et al. - Trospium eliloritie
`
`(|t.‘I_'5 bar : l0.=l Ml’:i)‘, Inobile plinric‘. nti.\‘liIre oi
`llll."I'I)llt
`2’.
`rate;
`}v:llt:I'—:tcctorittrile (O0/40, vfv) t‘.ot1l'.tit1iug0.ll8 tool/I r.orlitI1n ::hloI‘-
`idc and 0.0§l moifl choline chio_ride, toll l_oi'll1isri1ixitii‘c l0 ml of
`!. mol/l llCl were atldctl‘, (lclt*t:tIoI'I:
`t".Xt.2tlilllt)l| \v:t\'cli3ngtlI _'ll3 nut,
`Will-‘$31011 W'<|\’€ll’-|1t?.il|
`370 Hm: retention little ol‘ the derivative: 6
`mm.
`
`3.1.2. |)etermination ol’s;>iroa|i:nl1ol
`3 ml of urine were mixed with 0.6 ml of dipierylaminc solution
`(32.9 mg dtptcrylan11n_e —t— 10 ml ().| mo]/I NaOI-l -I-- 200 mg dried
`Nt12C0i) and treated in the same way as described for total com-
`pounds.
`3.2. Plasma
`
`5 ml of plasma were hydrolyzed for I05 min as described lbr urine.
`Alter‘ cooling to about 40 "C 0.2 ml ol‘2'J'% l-[Cl were added and cen-
`trii'tIgcd for I0 min (5000 rpm). Again the mixture was heated up for
`10 min (l20”C) and centrifuged after cooling. 5 ml of the hydro-
`lyzed plasma were mixed with 0.5 ml of dipierylamine solution
`(98.7 mg dipicrylamine -1- 10 ml 0.1 111017! NaOl-l -l- 600 mg dried
`l\la,;(?O.). 5 ml oftliis mixture were extracted into 4.8 ml ol‘chloro-
`Form and centrifuged (130 min, 6000 rpm). The furtlier extraction
`and derivatisation procedure was the same as described for urine
`samples except one step: the amount of methanol to wash the resi-
`due alter rc-extraction was l0—l1 ml
`in total. Alter dcrivatisatioit
`the residue was dissolved in I00 ,ul ofwatei‘-acetonitrilc (69/3 I, v/v).
`This mixture was also used lor the mobile phase containing the
`same amounts otsalts and HCl as described for urine samples. Injec-
`tion volume, Ilow rate (91 bar = 9.0 MI-‘a), and detection were the
`same as For urine samples; colunm temperature: 55 "C; retention
`time ol'thc derivative: 7.5 mitt.
`
`3.3. Subjects and procedure
`T'hc study was carried out with a group of six healthy male volun-
`teers. The average age of the group was 24.7 years (22-27 years).
`The average weight was 73.3 kg (65-80 kg).
`After collection of blank urine and blank plasma samples I0 1ng tres-
`pium chloride (2 tablets it
`5 mg) were administered orally with
`water.
`I
`ii after administration a light breakfast was taken.
`L.'rinc was collected during 48 ll at the following intervals: 0—2_. 2-4.
`4—6. 6—8. 8—|0.
`l0—l2. 12-24. 2-4~36. and 36-48 h. The urine
`fractions were tested lot‘ pH-value and total volume. 50 ml portions
`were stored at —20 “C until analysis.
`I2 tnl of blood were taken at the following times: 20, 40, 60, 120,
`I80, 240, 360, and 480 min alter administration. The actual times
`of sampling were noted on the record sheets. The blood samples
`were collected in heparin treated tubes and the plasma was separat-
`ed by centrilugation. The samples were stored at -20 “C until analy-
`sis.
`
`three days, 05 mg trospium
`least
`Alter a wash-out period of at
`chloride (Spasnw):
`Injektionslosung, Dr. R, Pllcger Cliernisclic
`Fabrik GmbH) were administered intravenously.
`Again, urine was collected. Collection periods were identical with
`those described for oral administration. Plasma was collected at the
`following times alter administration: 5, 10, 20, 30, 60, 120, 180. and
`240 min.
`
`3.4. Data analysis
`From the amounts oi‘ trospium, spiroalcohol, and total compounds
`excreted into urine during the dillercnt collection periods, the cumu-
`lative urinary excretions could be calculated. The cumulative
`amount of trospium excreted after 48 h (Acaii i.) was used to deter-
`mine the absolute bioavailability of trospium. The values are ex-
`pressed as arithmetical mean (i) and standard deviation.
`Maximal plasma concentrations (Cam) observed alter oral adminis-
`tration were determined.
`If possible terminal half-lives were estimated by linear regression an-
`alysis including the valucs ofthc teruliual log-linear phase‘, from the
`slope ofthis phase (1,) tm_ was calculated. 'l‘i;;;,u was determined us-
`ing the residual method. The constants Ct, /11, and C2, A2 were also
`estimated using the BMDP (Software Development, Midrllcbury,
`USA) program (two~compartment open model) on a DEC 10 (Digi-
`tal Equipment Corp., Maynard, MA, USA).
`Other pharrnacokinetic parameters (area under the curve: AUC. to-
`tal clearance: CL. and renal clearance: CLR) were calculated for to-
`tal compounds according to the following equations [8]:
`
`1
`
`.
`In-.l
`
`1'1‘;
`
`_ E523 .
`'
`A]
`1
`0.693
`Z T T
`/it
`
`985
`
`Patent Owner,
`
`UCB Pharma GmbH — Exhibit 2035 - 0002
`
`

`
`C
`AtJ(I(0-—tx-):——'+
`/11
`
`(:
`
`2
`2.;
`
`dose
`:T '
`AIJC (0— ml
`
`: _ Ae(4l_i li)__ .
`AUC (0-48)
`
`CL
`
`CLR
`
`4. Results
`
`Cumulative urinary excretion data wil.hin 48 h lbr each yol-
`untecr and administration are given in Table !. Fig.
`l
`illus-
`trates the mean cumulative urinary excretion curves 01' tres-
`pium, spiroalcohol, and total compounds after iv. and oral
`administration.
`
`Table I: Ctnnnl-alive urinary excretion cl" trospium, spimatcnliol. and total
`compounds within 48 h alter administration of0.5 mg trospium chloride i. v.
`and 10 mg trospium chloride orally (values calculated as trnspinm chloride
`and spiroalcohol chloride}.
`
`Volunteer
`
`l.v.
`1
`2
`3
`4
`5
`6
`
`Oral
`I
`2
`3
`4
`5
`6
`
`Trospiiun
`—~
`nmol
`
`pg
`
`S[}l1‘0£ll(.‘Ol10l
`—
`——
`pg
`nmnl
`
`
`
`.
`
`Total
`
`nmoi
`
`
`
`257.44
`227.51
`263.03
`393.05
`274.53
`251.87
`
`1 136.23
`141.10
`171.85
`181.16
`96.69
`219.47
`
`_,
`.
`
`(101.5
`531.6
`614.6
`918.4
`641.4
`588.5
`
`318.3
`320.7
`401.5
`423.2
`225.9
`512.8
`
`15.20
`14.18
`8.82
`6.63
`7.58
`13.74
`
`.
`
`30.25
`. 29.22
`3.08
`7.77
`5.73
`l7.92
`
`69.8
`65.1
`40.5
`30.4
`34.8
`40.2
`
`E389
`I 54.2
`14.2
`35.7
`2(a.3
`82.3
`
`671.3
`596.7
`655.1
`948.13
`676.2
`628.7
`
`457.2
`463.9
`415.7
`458.9
`252,2
`595.1
`
`There is no signilicant difference between the excretion of
`trospium and total compounds after administration of 0.5
`mg trospium chloride i.v. and after 10 mg orally, whereas
`the diliercnees in the excretion ofspiroalcohol are statistical-
`ly
`significant
`(non-parametric Wilcoxon matched-pairs
`signed rank test)
`[9]. The average amount of metabolite
`found after oral administration is higher than after i.v. ad-
`ministration and amounts 15.80% of total compounds ex-
`creted into urine. The range is 3.4 to 30.4%. The corre-
`sponding value for
`i.v. administration is 7.12% (range
`3.2—l0.9%).
`Bioavailability (F) was determined from the trospium excre-
`tion into urine within 48 h. From the data that are given in
`Table 2, a mean bioavailability value of 2.91% was calcu-
`lated.
`If F is determined from the total amount of com-
`pounds excreted into urine within 48 h a mean bioavailabili-
`ty value of3.25°/n results.
`After oral administration the highest concentration (C,....,.)
`found in plasma was 1.4 ng trospium (calculated as chloride)
`per ml plasma (volunteer 6). Most of the maximum concen-
`trations were already in the range of the detection limit
`(O.5~—1 ng trospium chloride/ml plasma). Therefore it was
`not possible to quantify trospium at all sampling times.
`Thus the plasma concentration time curves are incomplete.
`5 min after i.v. administration a mean plasma concentration
`of 15.7 ng trospium chloride/ml plasma was found (range;
`7.8—20.I ng/ml).
`Some pharmacokinetic parameters (Ci, 2;, C1, A2, tum, l.|,~2,
`AUC (0-—oo), CL, and CL“) estimated for the plasma con-
`centration time curves after i.v. administration are summar-
`ized in Table 3.
`ll‘ liallllives were determined using the resi-
`dual method the following values result:
`E.g.'. volunteer4: ll/2)_| = 5.5 min; [:72 =222 min
`volunteer 6: tum = 5.0 l'1‘1l1’1;C[,-2 = 108 min
`
`986
`
`W
`
`300 -
`
`901.]
`
`100-
`
`300 -
`
`200-
`
`100
`
`
`
`_[.-
`4
`
`-.T....
`8
`
`....
`12
`
`0
`
`.
`
`24
`
`__
`
`r
`36
`
`._V_
`4Bh
`
`Fig. 1: Mean cumulative urinary excretion curves oftotal compounds (at), Iro-
`spium [la], and spirnalcohol (c) after administration oF0.5 mg trospium chlo-
`ride i.v. (OTC) and 10 mg orally (./_\.——-TA); all comnouncls calculat-
`ed as trospium chloride equivalents.
`
`lrospium chloride (TrC.‘|) and total
`Ilia-availability values (F) liar
`Table 2:
`componnds_(t.c.) For oral adininistralimi 01' 10 mg trospinm chloride fi'om cu-
`mulative urinary excretion within 48 11,
`
`Volunteer
`I
`y 2
`3
`4
`5
`6
`
`E
`SD
`
`Fgg.._«,) (“/n)
`Fm-.-5|; (%)
`
`2.65
`3.4 I
`3.10
`3.89
`3.27
`3.17
`2.30
`2.42
`1,76
`1.87
`4.36
`4.73
`
`2.91
`28.19
`
`3.25
`31.46
`
`
`The arithmetical means of the half-lives found are 2.7 and
`97 min, the mean total clearance amounts to 1405.3 ml/min
`and is significantly higher than the mean renal clearance
`which is 806.6 ml/min.
`Plasma concentration time curves obtained from volunteers
`after i.V. and oral administration are shown in Fig. 2. As the
`curves are incomplete, especially after oral administration,
`the absolute bioavailability could only be determined from
`urine and not from plasma data.
`
`Arzneitn.—Fo|'su|i./ Dlug Res. 36 (1), Nr. 15 (I986)
`SCl1ltJ(lliZ-KClilElHl.+ Trospium chloride
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2035 - 0003
`
`

`
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`Fig. 2: Plasma concentration time curves after
`tion ol"0.5 mg and oral (A
`A) adniinistration of IO rug trospium chlo-
`ride. 9) Subject 5; I1) subject 6.
`
`5. Discussion
`
`The investigations clearly show that trospium is mostly ex-
`creted unchanged into urine. The concentrations found in
`plasma are “total concentrations”, as the components can
`only be quantified ii‘ the plasma is hydrolyzed; i.e., the por-
`tion of spiroalcohol in plasma remains unknown. However,
`it is supposed to be rather low, because of the low urinary
`excretion rate of this metabolite, especially after i.v. admin-
`istration. The concentration time curve of total compounds
`
`in plasma after i.v. administration can be described by an
`open two—compartment model. The oral bioavailability ct‘
`about 3% for
`tmspium chloride is
`in the same range
`as the one described for other qttaternary compounds (e.g.
`scopolamine N-hutyl bromide).
`in a
`recent
`investigation an oral dose 01‘ 5 mg trospium
`chloride thrice daily was shown to be efleetive in patients
`[10]. These results agree with those obtained from the phar~
`macokinetie investigations. An oral bioavailabilily of 2.9%
`means that 0.29 mg reach the systemic circulation, if 10 mg
`are administered, and 0.l45 mg, if 5 mg, are administered.
`The spasmolytic activity of trospium chloride was found to
`be four times higher than that of atropine sulfate [1]. 0.145
`mg trospittm chloride would therefore be equivalent to 0.58
`mg ofatropine sulfate, which is an effective dose.
`
`6. Literature
`
`[1] Antweiler, H., Lauterbach, F., Lehmann, H.-D., Uebel, H., Vo-
`gcl, G., Arzneirn.-Forsch./Drug Res. I6,
`I58] (i966) — [2] Dr. R.
`Plleger Cltemischc Fabrik, Baniberg, data on tile — [31 Albrecht, H.,
`Bruhn, R., Lorenz, D., Liieker, P. W., Schumacher, M., Meth. Find.
`Exp. Clin. Pharmacol, 5, 585 (1933) — [4] Adlung, .l., i-iohle, K. D.,
`Zcren, S.. Wahl, D., Arzncim.-l<'orsch./Drug Res. 26, I005 (I976) —
`[5] Hellstrijm, l(., Rosen, A., Séiclerlund, K., Scand. J. Gastroente-
`rol. 5, 585 (1970) - [6] Schladitz-Kcil, G., Spahn, i-1., Mutschlcr, E.,
`.l, Chromatogt‘. 345, 99 (I985) — [7] Spahn, H., Weber,
`l-l.,
`Mutschler, E., Mfihrkc, W., J. Chromatogr. 310,
`I6? (1984) — [8]
`Klotz, U., Klinische Pharmakokinetik. Springer, Stuttgart—New
`York (I984) — [9] Sachs, L., Angcwandle Statistik. Springer, Berlin-
`Heidelberg~New York (l9'/'8) ~ [IO] May, P., Stikeland, .l., Valen-
`cic, M., Kopf, l-l., Prakt. Arzt 21, 2283 (1984)
`
`For the authors: Prof. Dr. Dr. E. Mutschler, l’harmz1l<ologisches En-
`stitut
`liir Naturwissenschaftler
`de1' Johann Wolfgang Goethe-
`Univcrsitiit, Theodor—Stern—l{ai 7, Gebiiude 75 A, D-6000 Franl —
`furl/Main 7'0 (Federal Republic ofGcrmany)
`
`ArLncim_-F(|r5c§\,/ Drug RC§. 36 (5), Nil’. 5
`Scliltliiitz-Keil et al. — TrnspIltn1 chlcrllic
`
`987
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2035 - 0004