CA2362888C - Use of r-aryl propionic acids for producing medicaments to treat diseases in humans and animals, whereby said diseases can be therapeutically influenced by inhibiting the activation of nf-kb - Google Patents
Use of r-aryl propionic acids for producing medicaments to treat diseases in humans and animals, whereby said diseases can be therapeutically influenced by inhibiting the activation of nf-kb Download PDFInfo
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Abstract
The invention relates to the use of R-antimers of aryl propionic acids or aryl propionic acid derivatives for producing medicaments that inhibit the NF-.kappa.B activation cascade. Said medicaments are therefore suitable for treating diseases that can be positively influenced by the inhibition of NF-.kappa.B formation from a therapeutic standpoint.
Description
USE OF R-ARYL PROPIONIC ACIDS FOR PRODUCING MEDICAMENTS TO
TREAT DISEASES IN HUMANS AND ANIMALS, WHEREBY SAID DISEASES
CAN BE THERAPEUTICALLY INFLUENCED BY INHIBITING THE
ACTIVATION OF NF-KB
Use of R-arylpropionic acidG for the production of medicaments for the treatment of diseases in humans and animals which can be therapeutically influenced by the inhibition of the activation of NF-uB.
The subject of the present invention is the use of R-arylpropionic acids for the production of medicaments for the treatment of diseases in humans and animals which can be therapeutically influenced by the inhibition of the activation of NF-KB.
Ary-lpropionic acids and their derivatives have long since been used as~nonsteroidal anti-inflammatory and analgesicall,q effective medicaments. Known representatives of the ac~ive material group are ibuprofen, flurbiprofen, ketoprofen, napoxen,. tiaprofenic acid and fenoprofen 15 ropionic acid derivatives: Goodman and Gilman's, The pharmacological basis of therapeutics, ChapE-er 27, p. 637 (.ninth edition, 19967.
On the basis of the molecular structure with an asymmetrical C-atom, ar,qlpropionic acids and their derivatives. are chiral, t his occur as R- and S-enantio-' meric forms. In the case of the chemical synthesis,. these active materials normally occur as racemate. Ap-art from S-naproxen LZilliams:. Enantiomers in Borthritic disorders;
Pharmec. Ther.,, Vol... 26, pp. 273-295 (1.990); Evans: :
Enantioselective pharmacodynamics and pharmacokine~ics of chiral non -steroidal anti-inflammatory drugs, Eur. Jr.
P.harmacol.. , 42, 237-256 (1.992~,7and recentlv dexibuprofen /Symposium: Update on S(+)-ibuprofen; Goin4 Z$itzbuhl., 2 to 4 Fabruary, 1~)96% and dexketoprofen LScrip I-1o, 1831, June 22nd.1993, p. 7, Scrip Pro, 2144, Julq 9th 1996, P. 167, these active materials have hitherto been u4-ed as racemateR.
The therapeutically des-ired inflammation-inhi_biting and pain ameliorating action of ar,ylpropionic acuds and their derivatives is essentially ascribed to the iahibition of the prostaR:landi,n biosyntheQis /Vane and Botting: Overview -- mechanisir, of action of anti--in.flammatorv drugs. In: 2mpxovecL non-steroidal anti-infZammatorv dru=a -COX-2 enz,yme xnhibitora, p. 1. - 2?, Lancester --- YZuwer Academic t'ubl.isher= (1995)7. This take= place via the inhibition of the enzymes crvclooxv,:~,enases 1 and 2(COX-1 and COX-2 or PGHS-1_ and PGHS-2) participating, xn the formation of prostsjglandins. Due to the reduced formation of prostaglandinG, the inflammation symptoms; such as pain, 4welli.ngr, reddening, oedema formation, heatlng and function limitation, the inflammation 4ymptoms standinm in conj%knction with these inflammation mediators are weakened. The inhibition of the prostaglandin bio-=ynthesi4 is taken as general, characteristic of the mechanism of the anti-inflammatorv and of the analgeRic action. The therapeu.tical.ly desired inhibition of the pxostaglandin production in the dieeased ob,ject tissue leads in other orgpn syQtemG, which indicate the presence of certain prosta=clardin concentrations, to undesired AMENDED
SHEET
. 3 nmedicament aationQ. ,Gpeciall,q af ected %q the undesired actions are th!!. stcmach-intestire tract, the kidneys, the 1.ungs and the blood p:ia teletc.
It is known that, with reference to the prpstaPlai~din synthewis irhi.biti.on, subGtantial differences exist between the enanta.orneric forms of the arv].propionic acids /Ri11S.ams (v. sut,X'a); EvrCns (v. al:.pra); RroOirCs and r1a7: New nonsteroidal antJI,.-inflammatory drugs, Birkhauser Verlag, Basel, p. 119-12(n (1935)7. WhAreas all S-enantiomerfi of these subRtances show an outstardir,- rrostaSland.in s,ynthesis inhibition, in tne case of the 'R-euantiomers this is not found i_n the therapeutica:Ll.y relevant concent-ration range. Consequentlv, in ther2peutic concentrations, to the R-ar;qlpropzonic acids and their derivata.ves are ascribed neither the desired nor the undesired medicinal actions whic:, stand in conjunction with the inhibityon of the nxoSEAglandzn production. Independ.entl.y of the absence of these action mechan:ism-specific undesired actzons, the R-enaratiomers of thie active material class diapla,y substance--4pecifxc undesired actions.
Because of the hitherto therapeutic and econonlic importance of the axyipropionic eeid4 uQed as racemate, it is sought to estabLish the reaQonableness of the ..se of raceimic active materials. In the ca5e of ibuprofen, the use of the mcemate is e.sentiall;y based on the fact that, in the humaii or animal organism, a more or 1.eti=
marked inversion of R-isopr. ofen to S-ibupro"en takes --~_,-_ AME=ET
S 1~--_ place /Caldwell et al., The rnetabolic chiral inversion and dispositional, enantioGelectivit,q of the 2-ar,q1-propionic acids and tkaeir biolorical consequEnceG;
Biochemical Pharmac:ology, VoZ. 37, No. 1, pp. 105-114 5(1988)7 so that also a part of the R-form, after i7vereion to the S-form, can be effective as prostat-.1andin s7,nthesi.s inhibitor. Furthermore, for R-ibuprofen, an inhibition of the pol,ymorpronuclear leukocytes in vitro is described which could prove to be advanta-eous in the ca4e of 1C inflammator,y ditieases /`Vil.lanueva et al. ,rquipotent inhibition by R(-)--, S(+)- and racemic ibuprofer of human pol,ymorphonuclear ce1.1, function in vitro; Br_. J.
Pharmac., 35, 235-242 (1993)7. However, the therapeutic relevance o.f this mechanism ir_ the case of use of r.aceTic 15 iboprofen could not be !~hown. For Fs-flurb-iprofen, the inversion can be ne.,lected.
The faci; that the t,herapeutic action of the arvl-propionic acids is essentiall.,y aacribed to the prosta-Flandin sqnthesis :inhj_bition has led to t--e xeco7:~ition 20 that the use of the pure S-enantxomers, possibl,y of the racemic compounds but not of the pure H-enantiomers is meaningful. First with the surprisin~ discovery that R-flurbiprofen displaqs an antinociceptive effect whidh does not stand in connection with the inhibS.tion pf 25 the peripheral prostaglandin bios.ynthesis was the development of inedic:aments based on R-flurbiprofen /-tE
40 28 906 C2; EP C (-:)07 1.28 Bl ; LTSA 5,206,029 and AMENDED
SF-iEET
5,2cC,1987 a4 analgeG1c without inflammation-inhibiting active component initiated. Later, a pain-ameliorating action waG also deQcribed for R-ketoprofen /I)E
43 19 438 01; WO 95/176627.
5 Recent publxcat:i ons confirm the antinociceptive effect of R-flurbiprofen /Geis4J.xnger, Schaible: New insights into the site and mode of anti.noci.ceptive action of flubiprofen enantiomers? J. Clin. Pharmacol., 36, 513-520 (1996), Buritova, BeGson, Peripheral and/or central effects of racemic, S(+)- and R(-)-flurbiprofen on inflammatory nocsiceptive processes: a c--Foti protein study in the rat spi.nel cord; British J. Pharmacolog;y, 125, 87-101 (1999~)7. In clinical ctudies on patients, the paxn-amelioratin~' action of R-flurbinrofen 17 and R-ketoprofen L~ooper et al., Analaes~.c eff-icacy and safety of R-ketoprofeTi in postoperative dental Qai.n;
j. Clin. Pharmacol.,,, 38, 11S-18S (1998)7 could be der:onstrated.
Fig. 1 Placebo-controlled double blind study on 1f30 women with acute post-episiotomy pa'in (avera;e value curves) The ho4pxtaliQed pateintti were randomised in three medication groupa each with 50 patients and a placebo group (30 patients). Within 49 bourR, each patient received, after otherwise normally Q~=oceeding deliverv, a single dose of t'ae stud.y medication to be i.nvestioated (25 mg R(-)-flurbiprofern cr 100 mg (R)-flurbiprofen or ,AMENaEa SMEET
JOCC mg paracetamol) or a placebo, administered orally.
Short].y before the oral admi.r_istration of the teti t preparati'on or of t:he placebo and at preciaely fixed investigation point: of time (15, 30, 45, 60, 120, 18R), 240, 300 and 350 minutee), the patil~nts were queetioned with re-ard to their fee].ir.- of pain. The effectiveness of the individual preparations were asGessed on the baQis of a pain feeling scale (0 - none, I = rtild, 2 moderate, 3-- stron=). The t:ir.le courses are summarised in the average value curveR of the-individual patient;s given in ri~ure 1, Animai. expPri-enta, studies verify that the action of R-flurbipxofer. <;an be explained via the inflammation-inhibiting and. ant'i-nociceptive action on t-re central nervouG s,ystem /`~uritova (v, supra) ; Iveu;ebauer et al. , Anti.nociceptive effects of R(-)- and S(+)--- flurb:iprofen pr. rst aninal dor:.al horn 'ne+xrons rendered '-~vper-excitable bv an acute knee -ioXnt inflamn:aticn; J.
Phermacol. Exn. Ther; 275, 0-18-52~ (1995)7. The known peripheral inflamYr.a tion --inhzbiting Snd antirrociceptive action of flurb iprofen could, on the other hand, be found exclusi.vel.y in the caGe of the S-enantioaers /_Ss:ritova (v, cupra ) and 'Neugebauer (vq supra)-7, According to the present state of knowledF;e, there results therefro-, the significant concequ.er_ce that, for the cpti~:al treatment of the peripheral inflammator,q disea4eq, S-erylpropionic acids are to be u4ed as a~-ents of choice. For the reduc-tion of the unde4ired ectivities on ~~,e s~om_ach-AMENDED
SHEET
- __, intetitinal txoct etc. connectedwith the pro4tacrlandin QbnthesiG inh.ititic)n, e.-. S--flurbiprofer should not be taken orally but rather administered locaZZv to t;he inflammed or painful place. However, because of t: he central action, R-f'lurbinrofen ::zhould be adrr,inistexed systemically /Surit'ova (v. sGpra)7,e.~, orall;y,~.r.tra-muscularl,y or intravenoualv.
Contrery to this neweat kr,owledrne for the practicall,y exclusive central action of R--fl.ur"c;~,rofen, it waw noia =urprieinPl,y found. that R-flurbiprofen in certain concentrations is a potent and specific inhibitor of the activation of the nuclear transcription factor NF-KB.
r7F--KB ia a u.biquitaue tranecription factor which takes up a central role in cells in t'^e case of im-mune and inflamm-ation reaction[, as well as in the exnreaa 4on of c,qto-kines, cheRiokYnes, cell adheR=ior molecules, rrowth factore, immune receptors, acute phaee proteins , diverfie enzymes and other tranGcription factore /Lee, Burcl-,art:
Nlzclear factor kappa 3: Zmpzrtant trar.scription factor and therapeutic tarC;et, J. Clin. Pharrs., 38, 981-01,93 (Z998)7.
The 1:'F-K3 activation can be inhibited by variou-s-active materials at different steps of the activation cascade. Thus, Tluc()col'ticoide inhibit NF-KB by direct associati.on or by strenzthening of the expression.
Cycloepoxins. and ta:;rol.im~:~ prevent the '_~,r'--KB activation by inhibition of the calcineurin action of tre pho:phatasec AMENDED
SMEET
which indirectly induce the 1-=cB decompositi.on. Deox,q-spargualin inhibit4 Nr-KB by blockade of its nucleus displacement. Aspir:in and salicylates inhibit present occurances which induce the 1-KB phosphoryl8tion, Tepoxalin and anta.oxidante inhibit the NF-kB activation by changi..ng of the redox state of the cell. Further researches are necessary in order tcr develop specific inhibitors of the treatment of diaeasee which are _ influenced by NF-KB Ltee, Burckart: Nuclear factor kappa B;
Important transcription factor and therapeutic target, J. Clin,. Pharm,, 38, 981-992 (1998)_7.
It is known that R-ibuprofen and S-ibuprofen inhibit the activation of t'he transcriptuon factor NF-KB by phorbol esters (TPA), which is attributed to a rerrulation of the protein kinase C (PKC) activated by phorbol esters and thereb.y brought about phosphorylation and inactivation of the 1-KB but is not able to influence an NF-KB activation by PGE2 pr lipopolyeacr_harides (LPS). The usability of ibuprofen is, therefore, limited LN. Scheuren et al., "modulation of transcription factors by nonsteroidal anti-inflammatorg drugs", Naunyn-Schmiedeberg's Arch. Pharmacol., Vol. 354, No.. 4, suppl,. 1, 1996; N. Scheuren et al.,, "Enantiomer4 of the nonsteroidal anti-inflammatory drug ibuprofen are potent and Gpecific inhibitors of tran4-cription factor NF-'kappa, beta, "Naunyn-Schmiederberg's Arch. Pharmacol., Vol. 357, No. 4 suppl., 1998; N. Schueren et al. "Viodulation of tranacription factor NF-kappa,beta ----,-,._ AMENDED
_t_SHEET
.....1 9 by enantiomers of the nonsteroidal drug ibuprofen, Br. J.
Pharmacol., Vol. 123, No. 4, 1998; N. Scheuren et al., "Weak inh~bitors of cycloox,qgenases may exert their antinociceptive effects by modulation of trenscription factors, Adv, Exp. Med, Biol., Vol, 433, 19927.
The invention has now set itself the task to find further active materi.als which inhibit NF-i<B activation.
S'urprisino17, it has now been found that other n.on-xacemising R-arylpropionic acids can intervene via the specific inhibition of stepe within the NF--KB cascade in the disease happenings. Because of the ubiquitous function of the tranRcription factor NF-KB in the caee of the gene regulation, medXCaments with N-arylpropionic acids or their derivatives are suitable not only for the known pain amelioration via the antinociceptive action on the central nervous system ZDE 40 28 906 C27 but, in the case of suitable use and dosage, can also be used in the case of all di4ea5e4 in which an inhibition of the NF-%B can be therapeuti.call,q advantageously used.
Aacording to the invention, these medicaments can be used not on ly in the case of pain and rheumatism but also in the case of immune diseases, asthma, s hoek, inflammatory intestinal diaea4ee (C.rohn's disesse, colitis ulcerosa), radiation damages, arteriosclerosis, in the treatment of rejection reactions after tlsQue and organ transplants etc_, in each case in appropriate doses and pharma-ceutical formulatio-ns.
IAMENDED
SHEE7`~
~ l0 The here reported observation of the inhibition of the NF-KB formation is surpriezng, because, according to the prior art, the pharmacological effects of the aryl-propionic acids were ascribed to other mechanisms. This has hitherto led to the use of the racemates or of the S-enantiomers in comparatively emall doQes in the case of painF and infI.gmmationa.
Furthermore, in WO 98/09603 ie described the usabilit9 of R-NSAID'd in neoplaRtic diseases, especially colon and breast cancer, cystic f ibrosis and Alzheimer's disease.
Surprisingly, it has now been found that R-flur-biprofen and other R-ery'l.propionic acids not metabolising to CoA-thioesters and thus racemising inhibit the NF-KB
activation about 100 times more potently than the corresponding S-enantiomerG. However, in order to achieve a sufficient action, they must be used ira higher dosages than are usual in the case of the known there-peutic use of racFmic arylpropioni.c eaids. However, because of the good compatability on the basis of the practically absent action of these R-arylpropionic acid dosageQ on the peripheral prostaglandin bio-eynthesis and the racemising to the S-enantiomers not taking place, it is possible, in the case of use of the R--enantiomers, to make the dose so high that the desired inhibiting action on the NF=-KB activation is achieved without having to fear the undesired actions AMENDED
SHEET
brought about by the Srforrn. The active materials are, therefore, preferably used substantially free of the S-enanti onaerg, i_. e. with an optical purity of over 90*-, especially over 99q~, if, as "side effect", the known pain-and inflammation-inhibiting action of the S-enantiomers i.s also not desired. In contradistinction to R-ibuprofen, in this regard undesired actions because of the absent R-)~ S~ inversion in the case of the R-ar9lpropion:ic acids not metabolising to the CoA thioecters are not to be expected. ThuG, the medicaments according to the invention permit an improved therapeutic breadth to be expected in compariRon with the use of the racemic arylpropionic acide or of their S-enantiomers, The investigations carried out on humans verify the good gastrointestinal compata-bila.ty of R-flurbi.profen and other R-arylpropionic aczde LJerussi et al., Clitiical endoscopic evaluation of the gastroduodenal tolers-nce to ketoprofen, fl.urbiproferi, racemic ketoprofen and paracetamol: A randomised, single-blind, placebo-controlled trial; J, Clin. Pharmacol., 38, 19S--24S (1998)7, which has been indicated in previously carried out animal experiments L15L 40 28 906 C27.
Since the discovery of the nuclear transcription factor NF-KB before about one decade, extensive research works have been carriedt for the biological function and ,25 ffor the influencing of the NF-xB formation by endogenic and exogenic substances. Of the known pharmacological substances, hitherto inter alia gl.ucocorticoids, such as AMENL7EDS-1EET ~
_ 12 dexamethasone and prednisone, immune suppressivea, such as cyclospor:i.n, tacrolimus and deoxy-spergualin in therapeutic concentrations have bee-n described as effective on the NF-KB activation. Bor the metabolites intermediately fo,rmed in the case of the biochemical inversion of R-ibiaprofen to S-ibuprofen, an inhibition of the NF-icB activation was also demonstrated for an R-ibuprofen coenz,yme A thioester and specul.atively assumed that also R-ibuprofen, via the known metabolic activation in the human body to the R-ibuprofen-Cok thioester, would show an action which R-ibuprofen itself does not possess. ZErune et al., Medicament containing ibuprofen thioe4ter as inhibitor of the Nf-KB-dependent formation of inediators of inflammationQ and pa i.n , DE 19'J 16 713 Al, WO 98/475027.
Surpriaingly, it has' now been found that otber thexapeuticall.y used arylpropionie acid derivatives, such as flurbiprofen, ketoprofen, naproxan, tiaprofenic acid and fenoprof'en, which display no noteworthy formation of CoA-thioester-z in humans and, therefore, not racemi.sing bring about an outstanding inhibition of the activation of NF--+tB and thus possess the potential for the therepeutic effects associated with the influencing of this mechanism. In the followi'ng, this group i.e designated with "not racemising (abbr4~viated n. r. ) R-gryl.propionic a cids AMENDED
SHEET_j 12a More specifically, the present invention provides use, in the treatment of a disease influenced by the inhibition of NF-KB production, of an R-enantiomer of an arylpropionic acid, or a derivative thereof which does not metabolise to CoA thioesters, comprising R-flurbiprofen, R-ketoprofen, R-naproxen, R-tiaprofenic acid, or R-fenoprofen, or a combination of two, or more thereof, wherein the medicament comprises the R-arylpropionic acid, or the R-arylpropionic acid derivative, in an amount from 100 to 1,000 mg/dose.
The present invention also provides a pharmaceutical composition for treatment of a disease influenced by the inhibition of NF-KB production, the pharmaceutical composition comprising an R-enantiomer of an arylpropionic acid, or a derivative thereof which does not metabolise to CoA thioesters, comprising R-flurbiprofen, R-ketoprofen, R-naproxen, R-tiaprofenic acid or R-fenoprofen, or a combination of two or more thereof, together with a pharmaceutically acceptable diluent or carrier, wherein the pharmaceutical composition comprises the R-arylpropionic acid or the R-arylpropionic acid derivative in an amount from 100 to 1,000 mg/dose.
The medicamentE+ 8ccording- to the invention based on n.r. R_arylpropioni.c acids and their derTvatives as inhibitors of the NE-kB actx.}vation for the therapy of diseases which are influenced by the modification of,the NF-kB activation are based on the following experi.mental investigations:
Fig. 2: Concentration-dependent influence of R- and S-flurbiprofen on the activation of the trans-cri.ption factor NF-kB i,n RAW cells, The gel retention analy4is (electromobility Rhift assap:
DIG gel shift kit, Boehrri.nger Mannheim) Ghows that LPS (1 r,g/ml) leads to an activation of NF-KB
(p50/p65 complex of NF--AcB (trace No. 2 and 10).
Ma.cromolor concentrations of R-flurbiprofen (trace No. 3,4,5,6, 7 against trace No. 2 as control) were in the position to inhibit this LPS-induced activation of NF-ticB. A densitometric evaluation showed tbat S-flurbiprofen was, with regard to theGe properties, about 100 ti.;ne4 less potent (trace No. 11, 12, 13, 14 against trace No. 10 as control). Trace No. 1 and 8 each showed unstimulated control cellG.
Since the nuclear tran4cription factor IQF-kB i.s, inter alis, responsible for the formation of a series of enzymes with pro-a.nflammatorq ehd oedema-forming properties, the influence of R-flurbiprofen on the z7mosan-induced rat paw oedema was determined (Methods described bq:
A,MENDED
SHEET
Meller S.T. and Gebhart G.F.: Tntraplantar zymosan as a reliabl.e, quantifiabl.e model of thermal and mechanical hyperalgesia in the rat: European Journal of Pain, 1, 53-52 (1997). Figure 3a-c summarises the results.
Fig. 3a--cr Time-dependent increase of the rat paw volume (measured with a pleth,ysmograph) after intra-planat administration of zymosan. After admin-istration of zymosan L"Ieller and Gebhart (v.
supra27 into a rear paw of the rat, as indication of an inflammation, it comes to an increase of the paw volume (placebo group, administration of vehicle = phosphate buffer (PP)). Or the basis of the inhibiting acti.on of R-flurbipxofen on the NF-kB activation, in the case of dosages in the range between 1 and 27 mg/kg lfiodj weight (administration: intra-peritonea].), a surprising decrease of the paw volume can be seen. This effect was especialZ,y, marked between the 2nd and 6th hour after 20' zymosan administration. IIIexaumethasone (0,5 mg/kg body wei.ght), a known inhibitor of the NF-KB
activation, was used as poQitive control. As expected, S-flurbiprofen also showed a reduction of the paw volume, whereby, however, this effect is explicable not via an inhibition of the I&-KB acta.vation but rather via an inhibition of the synthesis of pro-inflarumatory iiiWif prostaglendins. S-Flurbiprofen is a known inhibitor of the c9clooxy Qenasea.
Fig,.. 4; Summary of the effects of 9 mg/kg R-flurbiprofen, 9 mg/kg S-flurbiprofen and 0..5 mg/kg dexametlsa-5 sone against placebo (V) over 24 hnurs. The effects after 9 mg/kg R-flurbiprofen were comparable with those after 0.5 mg/kg dexa--methasone. .
The preparation and chiral separa-tion of the aryl-10 propionic acids and of their derivatives is known. By way of example, reference is made to WO 93-17677 and the literature mentioned therein.
B,y arylpropionic acid derivatives, there are under-stood, according to the invention, the derivati.vee split 15 back into ar;qlprop_Lonic aczds in the stomach/intestinal tract (in the case (Df oral administration) or in the blood, such as alkyl esters with 1- 6 C-atoms which can possibl.y ydrox,yl groups, amidee or al.kylamides contain amino or h, with 1 - 6 C-atoms, as well as pharmaceutically compatible salts, eapeciall9 alkali metal, alkaline earth metal, smmonium, amino acid salts, preferably l7sinate, megl:uminate, trometamine, arginate or aluminium salts.
Such compounds are also known.
The meaning of ;q proph,qlactic or therapeutic admin-istration of n.r. R-arqlpropionic acid in the acute or chronic treatment of diseases is varied correRponding to the Qeverity of the ailment to be treated. The doze and AMENDEL.:1 frequency of the dosin;s are also to be dif-lerentiated according to the age, body weight and reaction of the individual patients. In zeneral., the daily dose of n. r.
R-arylpropionic acid for the described ailments pre4ent lies between about 150 mg and about 200C mg, admi-nistered in one or more doses. Preferably, the daily dosP lies between about 10C m;g and about 500 mg, administered in one or more doQeQ. In the case of the care of the patient, the treatment should be begun with a lower dosing, pos4ib17 of 20 mg to 200 mg and increased up to about 1000 mg or higher, depending upon the general reaction of the patient. Furthermore, it is recommended that infants, children, patients over 65 years and tho$e with impaired kidney and liver function first r_eceive:a lower do4e and titrated based on the individual reaction and the blood level. In some ea4es, it can be nece4qar=q to use a dosing outside this range, which is obvious to the expert. Furthermore:, it is to be noted thPt the treating house ph,qsician or clinical specialist knowq, in conjunc-tion with the general reaction of the patient, how and when the treatment is to be interrupted, ad~usted or discontinued. The espression "an amount which is sufficient for t}e NF'-KB inhibition but is not sufficient in order to initiate disadvantageous reactions (,prorta-glandin eyntheqi4 'i.nhi_bition)" is included by the given dosage amounts and dosage instructions. An,7 desired form of administration can be used in order to provide the patient with an effective dosing of the n. r_ R_ arylpr.opionic acid. For example, oral, rectal, trans-dermal, parenteral (subcutaneous, intramuscular, intra-venous), intrathecal, epi- and peridural and similar forms of administration can be used. Possible forms of sdministration are e,gõ tablets, dispersions, suspensions, solutions, plasters and the like.
The pharmaceutical formulations of the present invention include n,r. R-8rylpropioTlic acid ag active mateatsl or a pharmaceutically compatible derivative thereof and a pharuaaceuticall.y compatible carrier material and, if deaired, other therapeutic derivatives.
The expres9ion "pharmaceutically aDmpatible deriv-atives" or "a pharmaceuticall,q compatible derivative thereof" refer to derivatives prepared from pharmaceutic-ally compatible, non-toxic a cidr or bases, including inorganic acids and bas+as and organic acids and base4r Since the component of the present invention is adidic, derivatives with pbarmaceutically compatible, non-toxic basve, including inorganic and organic bases, can be pre-pared, Suitable pharmaceuticallycomp tible basic additive derivatives for the components of the present invention include metal salts, prepared from aluminium, calcium, lithium, magnesium, potassium, sodium and zinc, or organic salts prepared from lysine, N,N'-dibenzyl-ethylenedi.amine, cho7.ine, diethanolamine, ethylenediamine, meglumin (N-methylglucamine), tromethamine, arginine and alkylamineG with I-- 6 C-atoms.
,_.. .
The formulations of the present invention include formulations such a4 suspensions, sol.utions, elixirs and aerosola. Carrier material.s, such as starch, sugar, micro-cr~stall~.ne cellulose, diluents, granulation adjuvan ts, ll;ubricants, binding agents, solubilisers and the like can be used in the caee of the solid oral forms of administration. Solid oral forme of administration (such a's powders, capsules- and tablets) are preferred to the liquid oral forms of administration. The preferred solid oral forms of administration are tabletQ. If desired, the tablets can be c;oated with standardised water or water-free coating agents.
In additzon to the usual above-mentioned forms of administration, the component according to the-.invention can be administered with per se known agents in retarded ilflowing and/or rapidly inflowing form. For example, hydrophobing additives to oral forms of administration act delayingl,q, disintegrating agents and tensides promote dissolving and thus=scceleratingly and, as known, both forma can be mixed 'in granulate form in order to allow a p'art of the active material to flow in quickly and the rest delayed.
Pharmaceutical formulati.ons_ of the present invention which sre suitable for the oral, form of administretion can, a~e separate units, such as capsules, dragees or tablets, in each case contain a pregiven amount of the active mlaterial in the form of powder or granulate or aq 4olution oir suspension in an aqueous liquid, a non-aqueous liquid, an oil-in-water emulsi.on or a liquid water-in-oil emulsion. S'uch formulations can be prepared according to any pharmaceuti.cal method but all methods comprise a mixing of the active material with a carrier substance which consists of one or more of the necessarT components.
In general, the formulations are prepared by uniform and thorough mixing of the-active material with liquid carrier substances or fir,ely divided solid carrier oubstances or both and then, if necessary, forming of the product into the desired form of administration.
For exampJ.e, a tablet can be produced by pre$sing or forming, if deQired ws_th one or more additi.opal components.
Pressed tableta c43n be produced b,q pressing in an approp-riate device when the active material is present in a friable form, such as powder or granulate, optional.ly mixed with a binding aagent, lubricant, inert diluent, dispersing or surface-active agent. F.ormed tablets can also be produced by shaping of a mixture of the pulverised components, moistened with an inert liquid diluent, in a suitable device and subsequent dr,ying.. Preferably, each tablet contains between 50 ng and 1000 mg of the active material and each dragee or capsule contai.na between about 50 mg and a'bout 600 mg of the acEive material.
Especially pacefe.rabl,q, the tablet, dragee or capsule containe one of four dosages, namely, 50 mg, 100 mg, 200 mg or 500 mg of the active material.
TREAT DISEASES IN HUMANS AND ANIMALS, WHEREBY SAID DISEASES
CAN BE THERAPEUTICALLY INFLUENCED BY INHIBITING THE
ACTIVATION OF NF-KB
Use of R-arylpropionic acidG for the production of medicaments for the treatment of diseases in humans and animals which can be therapeutically influenced by the inhibition of the activation of NF-uB.
The subject of the present invention is the use of R-arylpropionic acids for the production of medicaments for the treatment of diseases in humans and animals which can be therapeutically influenced by the inhibition of the activation of NF-KB.
Ary-lpropionic acids and their derivatives have long since been used as~nonsteroidal anti-inflammatory and analgesicall,q effective medicaments. Known representatives of the ac~ive material group are ibuprofen, flurbiprofen, ketoprofen, napoxen,. tiaprofenic acid and fenoprofen 15 ropionic acid derivatives: Goodman and Gilman's, The pharmacological basis of therapeutics, ChapE-er 27, p. 637 (.ninth edition, 19967.
On the basis of the molecular structure with an asymmetrical C-atom, ar,qlpropionic acids and their derivatives. are chiral, t his occur as R- and S-enantio-' meric forms. In the case of the chemical synthesis,. these active materials normally occur as racemate. Ap-art from S-naproxen LZilliams:. Enantiomers in Borthritic disorders;
Pharmec. Ther.,, Vol... 26, pp. 273-295 (1.990); Evans: :
Enantioselective pharmacodynamics and pharmacokine~ics of chiral non -steroidal anti-inflammatory drugs, Eur. Jr.
P.harmacol.. , 42, 237-256 (1.992~,7and recentlv dexibuprofen /Symposium: Update on S(+)-ibuprofen; Goin4 Z$itzbuhl., 2 to 4 Fabruary, 1~)96% and dexketoprofen LScrip I-1o, 1831, June 22nd.1993, p. 7, Scrip Pro, 2144, Julq 9th 1996, P. 167, these active materials have hitherto been u4-ed as racemateR.
The therapeutically des-ired inflammation-inhi_biting and pain ameliorating action of ar,ylpropionic acuds and their derivatives is essentially ascribed to the iahibition of the prostaR:landi,n biosyntheQis /Vane and Botting: Overview -- mechanisir, of action of anti--in.flammatorv drugs. In: 2mpxovecL non-steroidal anti-infZammatorv dru=a -COX-2 enz,yme xnhibitora, p. 1. - 2?, Lancester --- YZuwer Academic t'ubl.isher= (1995)7. This take= place via the inhibition of the enzymes crvclooxv,:~,enases 1 and 2(COX-1 and COX-2 or PGHS-1_ and PGHS-2) participating, xn the formation of prostsjglandins. Due to the reduced formation of prostaglandinG, the inflammation symptoms; such as pain, 4welli.ngr, reddening, oedema formation, heatlng and function limitation, the inflammation 4ymptoms standinm in conj%knction with these inflammation mediators are weakened. The inhibition of the prostaglandin bio-=ynthesi4 is taken as general, characteristic of the mechanism of the anti-inflammatorv and of the analgeRic action. The therapeu.tical.ly desired inhibition of the pxostaglandin production in the dieeased ob,ject tissue leads in other orgpn syQtemG, which indicate the presence of certain prosta=clardin concentrations, to undesired AMENDED
SHEET
. 3 nmedicament aationQ. ,Gpeciall,q af ected %q the undesired actions are th!!. stcmach-intestire tract, the kidneys, the 1.ungs and the blood p:ia teletc.
It is known that, with reference to the prpstaPlai~din synthewis irhi.biti.on, subGtantial differences exist between the enanta.orneric forms of the arv].propionic acids /Ri11S.ams (v. sut,X'a); EvrCns (v. al:.pra); RroOirCs and r1a7: New nonsteroidal antJI,.-inflammatory drugs, Birkhauser Verlag, Basel, p. 119-12(n (1935)7. WhAreas all S-enantiomerfi of these subRtances show an outstardir,- rrostaSland.in s,ynthesis inhibition, in tne case of the 'R-euantiomers this is not found i_n the therapeutica:Ll.y relevant concent-ration range. Consequentlv, in ther2peutic concentrations, to the R-ar;qlpropzonic acids and their derivata.ves are ascribed neither the desired nor the undesired medicinal actions whic:, stand in conjunction with the inhibityon of the nxoSEAglandzn production. Independ.entl.y of the absence of these action mechan:ism-specific undesired actzons, the R-enaratiomers of thie active material class diapla,y substance--4pecifxc undesired actions.
Because of the hitherto therapeutic and econonlic importance of the axyipropionic eeid4 uQed as racemate, it is sought to estabLish the reaQonableness of the ..se of raceimic active materials. In the ca5e of ibuprofen, the use of the mcemate is e.sentiall;y based on the fact that, in the humaii or animal organism, a more or 1.eti=
marked inversion of R-isopr. ofen to S-ibupro"en takes --~_,-_ AME=ET
S 1~--_ place /Caldwell et al., The rnetabolic chiral inversion and dispositional, enantioGelectivit,q of the 2-ar,q1-propionic acids and tkaeir biolorical consequEnceG;
Biochemical Pharmac:ology, VoZ. 37, No. 1, pp. 105-114 5(1988)7 so that also a part of the R-form, after i7vereion to the S-form, can be effective as prostat-.1andin s7,nthesi.s inhibitor. Furthermore, for R-ibuprofen, an inhibition of the pol,ymorpronuclear leukocytes in vitro is described which could prove to be advanta-eous in the ca4e of 1C inflammator,y ditieases /`Vil.lanueva et al. ,rquipotent inhibition by R(-)--, S(+)- and racemic ibuprofer of human pol,ymorphonuclear ce1.1, function in vitro; Br_. J.
Pharmac., 35, 235-242 (1993)7. However, the therapeutic relevance o.f this mechanism ir_ the case of use of r.aceTic 15 iboprofen could not be !~hown. For Fs-flurb-iprofen, the inversion can be ne.,lected.
The faci; that the t,herapeutic action of the arvl-propionic acids is essentiall.,y aacribed to the prosta-Flandin sqnthesis :inhj_bition has led to t--e xeco7:~ition 20 that the use of the pure S-enantxomers, possibl,y of the racemic compounds but not of the pure H-enantiomers is meaningful. First with the surprisin~ discovery that R-flurbiprofen displaqs an antinociceptive effect whidh does not stand in connection with the inhibS.tion pf 25 the peripheral prostaglandin bios.ynthesis was the development of inedic:aments based on R-flurbiprofen /-tE
40 28 906 C2; EP C (-:)07 1.28 Bl ; LTSA 5,206,029 and AMENDED
SF-iEET
5,2cC,1987 a4 analgeG1c without inflammation-inhibiting active component initiated. Later, a pain-ameliorating action waG also deQcribed for R-ketoprofen /I)E
43 19 438 01; WO 95/176627.
5 Recent publxcat:i ons confirm the antinociceptive effect of R-flurbiprofen /Geis4J.xnger, Schaible: New insights into the site and mode of anti.noci.ceptive action of flubiprofen enantiomers? J. Clin. Pharmacol., 36, 513-520 (1996), Buritova, BeGson, Peripheral and/or central effects of racemic, S(+)- and R(-)-flurbiprofen on inflammatory nocsiceptive processes: a c--Foti protein study in the rat spi.nel cord; British J. Pharmacolog;y, 125, 87-101 (1999~)7. In clinical ctudies on patients, the paxn-amelioratin~' action of R-flurbinrofen 17 and R-ketoprofen L~ooper et al., Analaes~.c eff-icacy and safety of R-ketoprofeTi in postoperative dental Qai.n;
j. Clin. Pharmacol.,,, 38, 11S-18S (1998)7 could be der:onstrated.
Fig. 1 Placebo-controlled double blind study on 1f30 women with acute post-episiotomy pa'in (avera;e value curves) The ho4pxtaliQed pateintti were randomised in three medication groupa each with 50 patients and a placebo group (30 patients). Within 49 bourR, each patient received, after otherwise normally Q~=oceeding deliverv, a single dose of t'ae stud.y medication to be i.nvestioated (25 mg R(-)-flurbiprofern cr 100 mg (R)-flurbiprofen or ,AMENaEa SMEET
JOCC mg paracetamol) or a placebo, administered orally.
Short].y before the oral admi.r_istration of the teti t preparati'on or of t:he placebo and at preciaely fixed investigation point: of time (15, 30, 45, 60, 120, 18R), 240, 300 and 350 minutee), the patil~nts were queetioned with re-ard to their fee].ir.- of pain. The effectiveness of the individual preparations were asGessed on the baQis of a pain feeling scale (0 - none, I = rtild, 2 moderate, 3-- stron=). The t:ir.le courses are summarised in the average value curveR of the-individual patient;s given in ri~ure 1, Animai. expPri-enta, studies verify that the action of R-flurbipxofer. <;an be explained via the inflammation-inhibiting and. ant'i-nociceptive action on t-re central nervouG s,ystem /`~uritova (v, supra) ; Iveu;ebauer et al. , Anti.nociceptive effects of R(-)- and S(+)--- flurb:iprofen pr. rst aninal dor:.al horn 'ne+xrons rendered '-~vper-excitable bv an acute knee -ioXnt inflamn:aticn; J.
Phermacol. Exn. Ther; 275, 0-18-52~ (1995)7. The known peripheral inflamYr.a tion --inhzbiting Snd antirrociceptive action of flurb iprofen could, on the other hand, be found exclusi.vel.y in the caGe of the S-enantioaers /_Ss:ritova (v, cupra ) and 'Neugebauer (vq supra)-7, According to the present state of knowledF;e, there results therefro-, the significant concequ.er_ce that, for the cpti~:al treatment of the peripheral inflammator,q disea4eq, S-erylpropionic acids are to be u4ed as a~-ents of choice. For the reduc-tion of the unde4ired ectivities on ~~,e s~om_ach-AMENDED
SHEET
- __, intetitinal txoct etc. connectedwith the pro4tacrlandin QbnthesiG inh.ititic)n, e.-. S--flurbiprofer should not be taken orally but rather administered locaZZv to t;he inflammed or painful place. However, because of t: he central action, R-f'lurbinrofen ::zhould be adrr,inistexed systemically /Surit'ova (v. sGpra)7,e.~, orall;y,~.r.tra-muscularl,y or intravenoualv.
Contrery to this neweat kr,owledrne for the practicall,y exclusive central action of R--fl.ur"c;~,rofen, it waw noia =urprieinPl,y found. that R-flurbiprofen in certain concentrations is a potent and specific inhibitor of the activation of the nuclear transcription factor NF-KB.
r7F--KB ia a u.biquitaue tranecription factor which takes up a central role in cells in t'^e case of im-mune and inflamm-ation reaction[, as well as in the exnreaa 4on of c,qto-kines, cheRiokYnes, cell adheR=ior molecules, rrowth factore, immune receptors, acute phaee proteins , diverfie enzymes and other tranGcription factore /Lee, Burcl-,art:
Nlzclear factor kappa 3: Zmpzrtant trar.scription factor and therapeutic tarC;et, J. Clin. Pharrs., 38, 981-01,93 (Z998)7.
The 1:'F-K3 activation can be inhibited by variou-s-active materials at different steps of the activation cascade. Thus, Tluc()col'ticoide inhibit NF-KB by direct associati.on or by strenzthening of the expression.
Cycloepoxins. and ta:;rol.im~:~ prevent the '_~,r'--KB activation by inhibition of the calcineurin action of tre pho:phatasec AMENDED
SMEET
which indirectly induce the 1-=cB decompositi.on. Deox,q-spargualin inhibit4 Nr-KB by blockade of its nucleus displacement. Aspir:in and salicylates inhibit present occurances which induce the 1-KB phosphoryl8tion, Tepoxalin and anta.oxidante inhibit the NF-kB activation by changi..ng of the redox state of the cell. Further researches are necessary in order tcr develop specific inhibitors of the treatment of diaeasee which are _ influenced by NF-KB Ltee, Burckart: Nuclear factor kappa B;
Important transcription factor and therapeutic target, J. Clin,. Pharm,, 38, 981-992 (1998)_7.
It is known that R-ibuprofen and S-ibuprofen inhibit the activation of t'he transcriptuon factor NF-KB by phorbol esters (TPA), which is attributed to a rerrulation of the protein kinase C (PKC) activated by phorbol esters and thereb.y brought about phosphorylation and inactivation of the 1-KB but is not able to influence an NF-KB activation by PGE2 pr lipopolyeacr_harides (LPS). The usability of ibuprofen is, therefore, limited LN. Scheuren et al., "modulation of transcription factors by nonsteroidal anti-inflammatorg drugs", Naunyn-Schmiedeberg's Arch. Pharmacol., Vol. 354, No.. 4, suppl,. 1, 1996; N. Scheuren et al.,, "Enantiomer4 of the nonsteroidal anti-inflammatory drug ibuprofen are potent and Gpecific inhibitors of tran4-cription factor NF-'kappa, beta, "Naunyn-Schmiederberg's Arch. Pharmacol., Vol. 357, No. 4 suppl., 1998; N. Schueren et al. "Viodulation of tranacription factor NF-kappa,beta ----,-,._ AMENDED
_t_SHEET
.....1 9 by enantiomers of the nonsteroidal drug ibuprofen, Br. J.
Pharmacol., Vol. 123, No. 4, 1998; N. Scheuren et al., "Weak inh~bitors of cycloox,qgenases may exert their antinociceptive effects by modulation of trenscription factors, Adv, Exp. Med, Biol., Vol, 433, 19927.
The invention has now set itself the task to find further active materi.als which inhibit NF-i<B activation.
S'urprisino17, it has now been found that other n.on-xacemising R-arylpropionic acids can intervene via the specific inhibition of stepe within the NF--KB cascade in the disease happenings. Because of the ubiquitous function of the tranRcription factor NF-KB in the caee of the gene regulation, medXCaments with N-arylpropionic acids or their derivatives are suitable not only for the known pain amelioration via the antinociceptive action on the central nervous system ZDE 40 28 906 C27 but, in the case of suitable use and dosage, can also be used in the case of all di4ea5e4 in which an inhibition of the NF-%B can be therapeuti.call,q advantageously used.
Aacording to the invention, these medicaments can be used not on ly in the case of pain and rheumatism but also in the case of immune diseases, asthma, s hoek, inflammatory intestinal diaea4ee (C.rohn's disesse, colitis ulcerosa), radiation damages, arteriosclerosis, in the treatment of rejection reactions after tlsQue and organ transplants etc_, in each case in appropriate doses and pharma-ceutical formulatio-ns.
IAMENDED
SHEE7`~
~ l0 The here reported observation of the inhibition of the NF-KB formation is surpriezng, because, according to the prior art, the pharmacological effects of the aryl-propionic acids were ascribed to other mechanisms. This has hitherto led to the use of the racemates or of the S-enantiomers in comparatively emall doQes in the case of painF and infI.gmmationa.
Furthermore, in WO 98/09603 ie described the usabilit9 of R-NSAID'd in neoplaRtic diseases, especially colon and breast cancer, cystic f ibrosis and Alzheimer's disease.
Surprisingly, it has now been found that R-flur-biprofen and other R-ery'l.propionic acids not metabolising to CoA-thioesters and thus racemising inhibit the NF-KB
activation about 100 times more potently than the corresponding S-enantiomerG. However, in order to achieve a sufficient action, they must be used ira higher dosages than are usual in the case of the known there-peutic use of racFmic arylpropioni.c eaids. However, because of the good compatability on the basis of the practically absent action of these R-arylpropionic acid dosageQ on the peripheral prostaglandin bio-eynthesis and the racemising to the S-enantiomers not taking place, it is possible, in the case of use of the R--enantiomers, to make the dose so high that the desired inhibiting action on the NF=-KB activation is achieved without having to fear the undesired actions AMENDED
SHEET
brought about by the Srforrn. The active materials are, therefore, preferably used substantially free of the S-enanti onaerg, i_. e. with an optical purity of over 90*-, especially over 99q~, if, as "side effect", the known pain-and inflammation-inhibiting action of the S-enantiomers i.s also not desired. In contradistinction to R-ibuprofen, in this regard undesired actions because of the absent R-)~ S~ inversion in the case of the R-ar9lpropion:ic acids not metabolising to the CoA thioecters are not to be expected. ThuG, the medicaments according to the invention permit an improved therapeutic breadth to be expected in compariRon with the use of the racemic arylpropionic acide or of their S-enantiomers, The investigations carried out on humans verify the good gastrointestinal compata-bila.ty of R-flurbi.profen and other R-arylpropionic aczde LJerussi et al., Clitiical endoscopic evaluation of the gastroduodenal tolers-nce to ketoprofen, fl.urbiproferi, racemic ketoprofen and paracetamol: A randomised, single-blind, placebo-controlled trial; J, Clin. Pharmacol., 38, 19S--24S (1998)7, which has been indicated in previously carried out animal experiments L15L 40 28 906 C27.
Since the discovery of the nuclear transcription factor NF-KB before about one decade, extensive research works have been carriedt for the biological function and ,25 ffor the influencing of the NF-xB formation by endogenic and exogenic substances. Of the known pharmacological substances, hitherto inter alia gl.ucocorticoids, such as AMENL7EDS-1EET ~
_ 12 dexamethasone and prednisone, immune suppressivea, such as cyclospor:i.n, tacrolimus and deoxy-spergualin in therapeutic concentrations have bee-n described as effective on the NF-KB activation. Bor the metabolites intermediately fo,rmed in the case of the biochemical inversion of R-ibiaprofen to S-ibuprofen, an inhibition of the NF-icB activation was also demonstrated for an R-ibuprofen coenz,yme A thioester and specul.atively assumed that also R-ibuprofen, via the known metabolic activation in the human body to the R-ibuprofen-Cok thioester, would show an action which R-ibuprofen itself does not possess. ZErune et al., Medicament containing ibuprofen thioe4ter as inhibitor of the Nf-KB-dependent formation of inediators of inflammationQ and pa i.n , DE 19'J 16 713 Al, WO 98/475027.
Surpriaingly, it has' now been found that otber thexapeuticall.y used arylpropionie acid derivatives, such as flurbiprofen, ketoprofen, naproxan, tiaprofenic acid and fenoprof'en, which display no noteworthy formation of CoA-thioester-z in humans and, therefore, not racemi.sing bring about an outstanding inhibition of the activation of NF--+tB and thus possess the potential for the therepeutic effects associated with the influencing of this mechanism. In the followi'ng, this group i.e designated with "not racemising (abbr4~viated n. r. ) R-gryl.propionic a cids AMENDED
SHEET_j 12a More specifically, the present invention provides use, in the treatment of a disease influenced by the inhibition of NF-KB production, of an R-enantiomer of an arylpropionic acid, or a derivative thereof which does not metabolise to CoA thioesters, comprising R-flurbiprofen, R-ketoprofen, R-naproxen, R-tiaprofenic acid, or R-fenoprofen, or a combination of two, or more thereof, wherein the medicament comprises the R-arylpropionic acid, or the R-arylpropionic acid derivative, in an amount from 100 to 1,000 mg/dose.
The present invention also provides a pharmaceutical composition for treatment of a disease influenced by the inhibition of NF-KB production, the pharmaceutical composition comprising an R-enantiomer of an arylpropionic acid, or a derivative thereof which does not metabolise to CoA thioesters, comprising R-flurbiprofen, R-ketoprofen, R-naproxen, R-tiaprofenic acid or R-fenoprofen, or a combination of two or more thereof, together with a pharmaceutically acceptable diluent or carrier, wherein the pharmaceutical composition comprises the R-arylpropionic acid or the R-arylpropionic acid derivative in an amount from 100 to 1,000 mg/dose.
The medicamentE+ 8ccording- to the invention based on n.r. R_arylpropioni.c acids and their derTvatives as inhibitors of the NE-kB actx.}vation for the therapy of diseases which are influenced by the modification of,the NF-kB activation are based on the following experi.mental investigations:
Fig. 2: Concentration-dependent influence of R- and S-flurbiprofen on the activation of the trans-cri.ption factor NF-kB i,n RAW cells, The gel retention analy4is (electromobility Rhift assap:
DIG gel shift kit, Boehrri.nger Mannheim) Ghows that LPS (1 r,g/ml) leads to an activation of NF-KB
(p50/p65 complex of NF--AcB (trace No. 2 and 10).
Ma.cromolor concentrations of R-flurbiprofen (trace No. 3,4,5,6, 7 against trace No. 2 as control) were in the position to inhibit this LPS-induced activation of NF-ticB. A densitometric evaluation showed tbat S-flurbiprofen was, with regard to theGe properties, about 100 ti.;ne4 less potent (trace No. 11, 12, 13, 14 against trace No. 10 as control). Trace No. 1 and 8 each showed unstimulated control cellG.
Since the nuclear tran4cription factor IQF-kB i.s, inter alis, responsible for the formation of a series of enzymes with pro-a.nflammatorq ehd oedema-forming properties, the influence of R-flurbiprofen on the z7mosan-induced rat paw oedema was determined (Methods described bq:
A,MENDED
SHEET
Meller S.T. and Gebhart G.F.: Tntraplantar zymosan as a reliabl.e, quantifiabl.e model of thermal and mechanical hyperalgesia in the rat: European Journal of Pain, 1, 53-52 (1997). Figure 3a-c summarises the results.
Fig. 3a--cr Time-dependent increase of the rat paw volume (measured with a pleth,ysmograph) after intra-planat administration of zymosan. After admin-istration of zymosan L"Ieller and Gebhart (v.
supra27 into a rear paw of the rat, as indication of an inflammation, it comes to an increase of the paw volume (placebo group, administration of vehicle = phosphate buffer (PP)). Or the basis of the inhibiting acti.on of R-flurbipxofen on the NF-kB activation, in the case of dosages in the range between 1 and 27 mg/kg lfiodj weight (administration: intra-peritonea].), a surprising decrease of the paw volume can be seen. This effect was especialZ,y, marked between the 2nd and 6th hour after 20' zymosan administration. IIIexaumethasone (0,5 mg/kg body wei.ght), a known inhibitor of the NF-KB
activation, was used as poQitive control. As expected, S-flurbiprofen also showed a reduction of the paw volume, whereby, however, this effect is explicable not via an inhibition of the I&-KB acta.vation but rather via an inhibition of the synthesis of pro-inflarumatory iiiWif prostaglendins. S-Flurbiprofen is a known inhibitor of the c9clooxy Qenasea.
Fig,.. 4; Summary of the effects of 9 mg/kg R-flurbiprofen, 9 mg/kg S-flurbiprofen and 0..5 mg/kg dexametlsa-5 sone against placebo (V) over 24 hnurs. The effects after 9 mg/kg R-flurbiprofen were comparable with those after 0.5 mg/kg dexa--methasone. .
The preparation and chiral separa-tion of the aryl-10 propionic acids and of their derivatives is known. By way of example, reference is made to WO 93-17677 and the literature mentioned therein.
B,y arylpropionic acid derivatives, there are under-stood, according to the invention, the derivati.vee split 15 back into ar;qlprop_Lonic aczds in the stomach/intestinal tract (in the case (Df oral administration) or in the blood, such as alkyl esters with 1- 6 C-atoms which can possibl.y ydrox,yl groups, amidee or al.kylamides contain amino or h, with 1 - 6 C-atoms, as well as pharmaceutically compatible salts, eapeciall9 alkali metal, alkaline earth metal, smmonium, amino acid salts, preferably l7sinate, megl:uminate, trometamine, arginate or aluminium salts.
Such compounds are also known.
The meaning of ;q proph,qlactic or therapeutic admin-istration of n.r. R-arqlpropionic acid in the acute or chronic treatment of diseases is varied correRponding to the Qeverity of the ailment to be treated. The doze and AMENDEL.:1 frequency of the dosin;s are also to be dif-lerentiated according to the age, body weight and reaction of the individual patients. In zeneral., the daily dose of n. r.
R-arylpropionic acid for the described ailments pre4ent lies between about 150 mg and about 200C mg, admi-nistered in one or more doses. Preferably, the daily dosP lies between about 10C m;g and about 500 mg, administered in one or more doQeQ. In the case of the care of the patient, the treatment should be begun with a lower dosing, pos4ib17 of 20 mg to 200 mg and increased up to about 1000 mg or higher, depending upon the general reaction of the patient. Furthermore, it is recommended that infants, children, patients over 65 years and tho$e with impaired kidney and liver function first r_eceive:a lower do4e and titrated based on the individual reaction and the blood level. In some ea4es, it can be nece4qar=q to use a dosing outside this range, which is obvious to the expert. Furthermore:, it is to be noted thPt the treating house ph,qsician or clinical specialist knowq, in conjunc-tion with the general reaction of the patient, how and when the treatment is to be interrupted, ad~usted or discontinued. The espression "an amount which is sufficient for t}e NF'-KB inhibition but is not sufficient in order to initiate disadvantageous reactions (,prorta-glandin eyntheqi4 'i.nhi_bition)" is included by the given dosage amounts and dosage instructions. An,7 desired form of administration can be used in order to provide the patient with an effective dosing of the n. r_ R_ arylpr.opionic acid. For example, oral, rectal, trans-dermal, parenteral (subcutaneous, intramuscular, intra-venous), intrathecal, epi- and peridural and similar forms of administration can be used. Possible forms of sdministration are e,gõ tablets, dispersions, suspensions, solutions, plasters and the like.
The pharmaceutical formulations of the present invention include n,r. R-8rylpropioTlic acid ag active mateatsl or a pharmaceutically compatible derivative thereof and a pharuaaceuticall.y compatible carrier material and, if deaired, other therapeutic derivatives.
The expres9ion "pharmaceutically aDmpatible deriv-atives" or "a pharmaceuticall,q compatible derivative thereof" refer to derivatives prepared from pharmaceutic-ally compatible, non-toxic a cidr or bases, including inorganic acids and bas+as and organic acids and base4r Since the component of the present invention is adidic, derivatives with pbarmaceutically compatible, non-toxic basve, including inorganic and organic bases, can be pre-pared, Suitable pharmaceuticallycomp tible basic additive derivatives for the components of the present invention include metal salts, prepared from aluminium, calcium, lithium, magnesium, potassium, sodium and zinc, or organic salts prepared from lysine, N,N'-dibenzyl-ethylenedi.amine, cho7.ine, diethanolamine, ethylenediamine, meglumin (N-methylglucamine), tromethamine, arginine and alkylamineG with I-- 6 C-atoms.
,_.. .
The formulations of the present invention include formulations such a4 suspensions, sol.utions, elixirs and aerosola. Carrier material.s, such as starch, sugar, micro-cr~stall~.ne cellulose, diluents, granulation adjuvan ts, ll;ubricants, binding agents, solubilisers and the like can be used in the caee of the solid oral forms of administration. Solid oral forme of administration (such a's powders, capsules- and tablets) are preferred to the liquid oral forms of administration. The preferred solid oral forms of administration are tabletQ. If desired, the tablets can be c;oated with standardised water or water-free coating agents.
In additzon to the usual above-mentioned forms of administration, the component according to the-.invention can be administered with per se known agents in retarded ilflowing and/or rapidly inflowing form. For example, hydrophobing additives to oral forms of administration act delayingl,q, disintegrating agents and tensides promote dissolving and thus=scceleratingly and, as known, both forma can be mixed 'in granulate form in order to allow a p'art of the active material to flow in quickly and the rest delayed.
Pharmaceutical formulati.ons_ of the present invention which sre suitable for the oral, form of administretion can, a~e separate units, such as capsules, dragees or tablets, in each case contain a pregiven amount of the active mlaterial in the form of powder or granulate or aq 4olution oir suspension in an aqueous liquid, a non-aqueous liquid, an oil-in-water emulsi.on or a liquid water-in-oil emulsion. S'uch formulations can be prepared according to any pharmaceuti.cal method but all methods comprise a mixing of the active material with a carrier substance which consists of one or more of the necessarT components.
In general, the formulations are prepared by uniform and thorough mixing of the-active material with liquid carrier substances or fir,ely divided solid carrier oubstances or both and then, if necessary, forming of the product into the desired form of administration.
For exampJ.e, a tablet can be produced by pre$sing or forming, if deQired ws_th one or more additi.opal components.
Pressed tableta c43n be produced b,q pressing in an approp-riate device when the active material is present in a friable form, such as powder or granulate, optional.ly mixed with a binding aagent, lubricant, inert diluent, dispersing or surface-active agent. F.ormed tablets can also be produced by shaping of a mixture of the pulverised components, moistened with an inert liquid diluent, in a suitable device and subsequent dr,ying.. Preferably, each tablet contains between 50 ng and 1000 mg of the active material and each dragee or capsule contai.na between about 50 mg and a'bout 600 mg of the acEive material.
Especially pacefe.rabl,q, the tablet, dragee or capsule containe one of four dosages, namely, 50 mg, 100 mg, 200 mg or 500 mg of the active material.
Claims (25)
1. Use, in the treatment of a disease influenced by the inhibition of NF-.kappa.B production, of a medicament comprising an R-enantiomer of an arylpropionic acid, or a derivative thereof which does not metabolise to CoA thioesters, comprising R-flurbiprofen, R-ketoprofen, R-naproxen, R-tiaprofenic acid, or R-fenoprofen, or a combination of two, or more thereof, wherein the medicament comprises the R-arylpropionic acid, or the R-arylpropionic acid derivative, in an amount from 100 to 1,000 mg/dose.
2. A use according to claim 1, wherein the R-arylpropionic acid or R-arylpropionic acid derivative contains less than 10% of S-arylpropionic acids or S-arylpropionic acid derivatives.
3. A use according to claim 1 or 2, wherein the R-arylpropionic acid or arylpropionic acid derivative is present as a salt of an alkali metal, an alkaline earth metal, an ammonium, an amino acid, or aluminum.
4. A use according to claim 3, wherein the salt is a lysinate salt, a metagluminate salt, a trometamine salt or an arginate salt.
5. A use according to any one of claims 1 to 4, wherein the medicament comprises at least one adjuvant and/or a carrier material.
6. A method according to claim 5, wherein the medicament is an orally usable form.
7. A method according to claim 6, wherein the orally usable form is a tablet or a dragee.
8. A use according to any one of claims 1 to 7, wherein the R-arylpropionic acid or R-arylpropionic acid derivative is used in a timed-release form.
9. A use according to claim 8, wherein the timed-release form comprises a rapidly inflowing form.
10. A use according to claim 8, wherein the timed-release form comprises a retardedly inflowing form.
11. A method according to claim 8, wherein the timed-release form comprises both a rapidly inflowing form and a retardedly inflowing form in combination.
12. A use according to any one of claims 1 to 11, wherein the medicament is for the treatment of a rheumatic disease, asthma, a tumor, an immune disease, shock, an inflammatory intestinal disease, radiation damage, arteriosclerosis or a rejection reaction after tissue or organ transplantation, or a combination of two or more thereof.
13. A use according to claim 12, wherein the inflammatory intestinal disease comprises Crohn's disease or colitis ulcerosa.
14. A pharmaceutical composition for treatment of a disease influenced by the inhibition of NF-.kappa.B production, the pharmaceutical composition comprising an R-enantiomer of an arylpropionic acid, or a derivative thereof which does not metabolise to CoA thioesters, comprising R-flurbiprofen, R-ketoprofen, R-naproxen, R-tiaprofenic acid or R-fenoprofen, or a combination of two or more thereof, together with a pharmaceutically acceptable diluent or carrier;
wherein the pharmaceutical composition comprises the R-arylpropionic acid or the R-arylpropionic acid derivative in an amount from 100 to 1,000 mg/dose.
wherein the pharmaceutical composition comprises the R-arylpropionic acid or the R-arylpropionic acid derivative in an amount from 100 to 1,000 mg/dose.
15. A pharmaceutical composition according to claim 14, wherein the R-arylpropionic acid or R-arylpropionic acid derivative contains less than 10% of S-arylpropionic acids or S-arylpropionic acid derivatives.
16. A pharmaceutical composition according to claim 14 or 15, wherein the R-arylpropionic acid or arylpropionic acid derivative is present as a salt of an alkali metal, an alkaline earth metal, an ammonium, an amino acid, or aluminium.
17. A pharmaceutical composition according to claim 16, wherein the salt is a lysinate salt, a metagluminate salt, a trometamine salt or an arginate salt.
18. A pharmaceutical composition according to any one of claims 14 to 17, wherein the pharmaceutical composition is an orally usable form.
19. A pharmaceutical composition according to claim 18, wherein the orally usable form is a tablet or a dragee.
20. A pharmaceutical composition according to any one of claims 14 to 19, wherein the R-arylpropionic acid or R-arylpropionic acid derivative is in a timed-release form.
21. A pharmaceutical composition according to claim 20, wherein the timed-release form comprises a rapidly inflowing form.
22. A pharmaceutical composition according to claim 20, wherein the timed-release form comprises a retardedly inflowing form.
23. A pharmaceutical composition according to claim 20, wherein the timed-release form comprises both a rapidly inflowing form and a retardedly inflowing form in combination.
24. A pharmaceutical composition according to any one of claims 14 to 23, wherein the pharmaceutical composition is for the treatment of a rheumatic disease, asthma, a tumor, an immune disease, shock, an inflammatory intestinal disease, radiation damage, arteriosclerosis or a rejection reaction after tissue or organ transplantation, or a combination of two or more thereof.
25. A pharmaceutical composition according to claim 24, wherein the inflammatory intestinal disease comprises Crohn's disease or colitis ulcerosa.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19907895A DE19907895A1 (en) | 1999-02-24 | 1999-02-24 | Use of R-arylpropionic acids for the production of medicaments for the treatment of diseases in humans and animals which can be influenced therapeutically by inhibiting the activation of NF-kB |
| DE19907895.5 | 1999-02-24 | ||
| PCT/EP2000/000323 WO2000050019A2 (en) | 1999-02-24 | 2000-01-17 | USE OF R-ARYL PROPIONIC ACIDS FOR PRODUCING MEDICAMENTS TO TREAT DISEASES IN HUMANS AND ANIMALS, WHEREBY SAID DISEASES CAN BE THERAPEUTICALLY INFLUENCED BY INHIBITING THE ACTIVATION OF NF-λB |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2362888A1 CA2362888A1 (en) | 2000-08-31 |
| CA2362888C true CA2362888C (en) | 2009-02-24 |
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ID=7898653
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002362888A Expired - Fee Related CA2362888C (en) | 1999-02-24 | 2000-01-17 | Use of r-aryl propionic acids for producing medicaments to treat diseases in humans and animals, whereby said diseases can be therapeutically influenced by inhibiting the activation of nf-kb |
Country Status (11)
| Country | Link |
|---|---|
| EP (1) | EP1154766B1 (en) |
| JP (1) | JP2002537325A (en) |
| AT (1) | ATE350027T1 (en) |
| CA (1) | CA2362888C (en) |
| CY (1) | CY1108004T1 (en) |
| DE (2) | DE19907895A1 (en) |
| DK (1) | DK1154766T3 (en) |
| ES (1) | ES2280196T3 (en) |
| PT (1) | PT1154766E (en) |
| RU (1) | RU2250103C2 (en) |
| WO (1) | WO2000050019A2 (en) |
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| DE10047319A1 (en) * | 2000-09-25 | 2002-04-18 | Paz Arzneimittelentwicklung | Use of R-arylpropionic acids for the production of medicaments for the treatment of diseases which can be therapeutically influenced by inhibiting the activation of the nuclear transcription factor AP-1 |
| ITMI20012434A1 (en) * | 2001-11-20 | 2003-05-20 | Dompe Spa | 2-ARYL-PROPIONIC ACIDS AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM |
| ITMI20030312A1 (en) * | 2003-02-21 | 2004-08-22 | Chiesi Farma Spa | DERIVATIVES OF 2-FENYL-2-ALCHYL-ACETIC ACIDS FOR THE TREATMENT OF ALZHEIMER DISEASE. |
| JP2007528857A (en) * | 2003-07-11 | 2007-10-18 | ミリアド ジェネティクス， インコーポレイテッド | Pharmaceutical methods, dosing regimens and dosage forms for the treatment of Alzheimer's disease |
| EP2387391B1 (en) | 2009-07-24 | 2017-01-11 | MIKA Pharma Gesellschaft für die Entwicklung und Vermarktung pharmazeutischer Produkte mbH | Method for developing a liquid composition to be applied to the skin as a foam and a composition that can be applied topically |
| GB2485169A (en) * | 2010-11-03 | 2012-05-09 | Univ Jw Goethe Frankfurt Main | (R)-flurbiprofen for use in the treatment of multiple sclerosis |
| EP2468270A1 (en) | 2010-12-21 | 2012-06-27 | GALENpharma GmbH | (R)-2-(3-fluoro-4-phenylphenyl)propionic acid for use in the treatment of skin diseases |
| RU2457840C1 (en) * | 2011-03-09 | 2012-08-10 | Российская Федерация, От Имени Которой Выступает Министерство Образования И Науки Российской Федерации | Medication influencing activity of some nuclear transcription factors |
| WO2014007780A1 (en) | 2012-07-06 | 2014-01-09 | Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi | Orally-disintegrating formulations of dexketoprofen |
| WO2014007779A1 (en) | 2012-07-06 | 2014-01-09 | Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi | Orally-disintegrating formulations of dexketoprofen |
| RU2675693C1 (en) * | 2017-11-16 | 2018-12-24 | Федеральное государственное автономное образовательное учреждение высшего образования "Белгородский государственный национальный исследовательский университет" (НИУ "БелГУ") | Method of inhibiting kappa nuclear factor with the use of potassium 5-hydroxynicotinate in a cell culture |
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| DE4028906A1 (en) * | 1990-09-12 | 1992-03-19 | Paz Arzneimittelentwicklung | MEDICINAL PRODUCTS AND THEIR PREPARATION AND THEIR USE IN THE CONTROL OF PAIN AND / OR DEFENSE AND / OR FEVER OF ANIMALS AND PEOPLE |
| JP3265680B2 (en) * | 1992-03-12 | 2002-03-11 | 大正製薬株式会社 | Oral pharmaceutical composition |
| DE4319438C1 (en) * | 1993-06-11 | 1994-06-01 | Gerd Dr Dr Geislinger | Analgesic and/or antiinflammatory medicaments - contg. sepd enantiomers of ketoprofen |
| US6160018A (en) * | 1995-03-13 | 2000-12-12 | Loma Linda University Medical Center | Prophylactic composition and method for alzheimer's Disease |
| DE19716713A1 (en) * | 1997-04-21 | 1998-10-22 | Paz Arzneimittelentwicklung | Medicines containing ibuprofenthioester as inhibitors of Nf-kappaB-dependent formation of mediators of inflammation and pain |
| WO2000013684A2 (en) * | 1998-09-03 | 2000-03-16 | Loma Linda University Medical Center | Pharmaceutical composition and method for treatment of inflammation |
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2000
- 2000-01-17 JP JP2000600631A patent/JP2002537325A/en active Pending
- 2000-01-17 DE DE50013934T patent/DE50013934D1/en not_active Expired - Lifetime
- 2000-01-17 DK DK00904922T patent/DK1154766T3/en active
- 2000-01-17 ES ES00904922T patent/ES2280196T3/en not_active Expired - Lifetime
- 2000-01-17 CA CA002362888A patent/CA2362888C/en not_active Expired - Fee Related
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- 2000-01-17 EP EP00904922A patent/EP1154766B1/en not_active Expired - Lifetime
- 2000-01-17 WO PCT/EP2000/000323 patent/WO2000050019A2/en active IP Right Grant
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| ATE350027T1 (en) | 2007-01-15 |
| RU2250103C2 (en) | 2005-04-20 |
| CY1108004T1 (en) | 2013-09-04 |
| JP2002537325A (en) | 2002-11-05 |
| DK1154766T3 (en) | 2007-05-14 |
| WO2000050019A3 (en) | 2000-12-14 |
| ES2280196T3 (en) | 2007-09-16 |
| EP1154766B1 (en) | 2007-01-03 |
| PT1154766E (en) | 2007-03-30 |
| EP1154766A2 (en) | 2001-11-21 |
| WO2000050019A2 (en) | 2000-08-31 |
| DE19907895A1 (en) | 2000-11-16 |
| DE50013934D1 (en) | 2007-02-15 |
| CA2362888A1 (en) | 2000-08-31 |
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