CA2232930A1 - Oral application of (+)-o-demethyltramadol as a pain killing drug - Google Patents
Oral application of (+)-o-demethyltramadol as a pain killing drug Download PDFInfo
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- CA2232930A1 CA2232930A1 CA002232930A CA2232930A CA2232930A1 CA 2232930 A1 CA2232930 A1 CA 2232930A1 CA 002232930 A CA002232930 A CA 002232930A CA 2232930 A CA2232930 A CA 2232930A CA 2232930 A1 CA2232930 A1 CA 2232930A1
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- celluloses
- demethyltramadol
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- oral
- weight
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- UWJUQVWARXYRCG-HIFRSBDPSA-N O-Desmethyltramadol Chemical compound CN(C)C[C@H]1CCCC[C@]1(O)C1=CC=CC(O)=C1 UWJUQVWARXYRCG-HIFRSBDPSA-N 0.000 title claims abstract 5
- 229940079593 drug Drugs 0.000 title claims description 4
- 239000003814 drug Substances 0.000 title claims description 4
- 230000003119 painkilling effect Effects 0.000 title 1
- 208000002193 Pain Diseases 0.000 claims abstract description 10
- 230000001154 acute effect Effects 0.000 claims abstract 2
- -1 aromatic carboxylic acids Chemical class 0.000 claims description 8
- 229920002678 cellulose Polymers 0.000 claims description 6
- 235000010980 cellulose Nutrition 0.000 claims description 5
- 239000011159 matrix material Substances 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 4
- 230000003111 delayed effect Effects 0.000 claims description 3
- 239000004480 active ingredient Substances 0.000 claims 2
- 239000003826 tablet Substances 0.000 claims 2
- 229920002134 Carboxymethyl cellulose Polymers 0.000 claims 1
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 claims 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims 1
- 239000007864 aqueous solution Substances 0.000 claims 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 claims 1
- 229920003086 cellulose ether Polymers 0.000 claims 1
- 235000010944 ethyl methyl cellulose Nutrition 0.000 claims 1
- 239000012458 free base Substances 0.000 claims 1
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 claims 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims 1
- 239000013563 matrix tablet Substances 0.000 claims 1
- 229920000609 methyl cellulose Polymers 0.000 claims 1
- 235000010981 methylcellulose Nutrition 0.000 claims 1
- 229920003087 methylethyl cellulose Polymers 0.000 claims 1
- 150000007524 organic acids Chemical class 0.000 claims 1
- 235000005985 organic acids Nutrition 0.000 claims 1
- 239000000126 substance Substances 0.000 claims 1
- 208000000094 Chronic Pain Diseases 0.000 abstract description 2
- 208000005298 acute pain Diseases 0.000 abstract 1
- 241000700159 Rattus Species 0.000 description 4
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 description 4
- 241000699670 Mus sp. Species 0.000 description 3
- 235000008733 Citrus aurantifolia Nutrition 0.000 description 2
- 101100353161 Drosophila melanogaster prel gene Proteins 0.000 description 2
- 235000011941 Tilia x europaea Nutrition 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 239000004571 lime Substances 0.000 description 2
- 229960005181 morphine Drugs 0.000 description 2
- 238000013421 nuclear magnetic resonance imaging Methods 0.000 description 2
- 229940005483 opioid analgesics Drugs 0.000 description 2
- IOVGROKTTNBUGK-SJCJKPOMSA-N ritodrine Chemical compound N([C@@H](C)[C@H](O)C=1C=CC(O)=CC=1)CCC1=CC=C(O)C=C1 IOVGROKTTNBUGK-SJCJKPOMSA-N 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- MNIPYSSQXLZQLJ-UHFFFAOYSA-N Biofenac Chemical compound OC(=O)COC(=O)CC1=CC=CC=C1NC1=C(Cl)C=CC=C1Cl MNIPYSSQXLZQLJ-UHFFFAOYSA-N 0.000 description 1
- 101150106671 COMT gene Proteins 0.000 description 1
- VVNCNSJFMMFHPL-VKHMYHEASA-N D-penicillamine Chemical compound CC(C)(S)[C@@H](N)C(O)=O VVNCNSJFMMFHPL-VKHMYHEASA-N 0.000 description 1
- 101100114828 Drosophila melanogaster Orai gene Proteins 0.000 description 1
- 244000228957 Ferula foetida Species 0.000 description 1
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 241000283986 Lepus Species 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 241000282320 Panthera leo Species 0.000 description 1
- 101100126298 Rickettsia conorii (strain ATCC VR-613 / Malish 7) iscS gene Proteins 0.000 description 1
- 241001052560 Thallis Species 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 229940075911 depen Drugs 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 230000000474 nursing effect Effects 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 210000001550 testis Anatomy 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Chemical & Material Sciences (AREA)
- Pain & Pain Management (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Emergency Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The use of (+)-O-demethyltramadol for oral application in the treatment of severe, acute and/or chronic pain is described.
Description
1() 20Patent Application of Grunentllal GmbH
D-52078 Aachen Internal reference: G 2601 Oral applicalioll of (+)-O-demethyltlamadol ~s a pain-killillg dl ug rrhis invclllioll rclalcs lo ll1c oral application ol (+)-O-dclnclllyltmlmldol lor ttlC tlCalmCll Or illtcnsc, aculc and/or scvcrc cllronic pain.
30 In pain therapy, opioids havc an unass.lilahlc suprcmacy 1' ~r lhc Irc.ltmcnt ol' scvere pain (Zcn:~, M., Jurna 1. (19~3) Lcl1rh-lch ~3cr Scllmcr/~llcmpic. Wissens~h.lfl1i~hc Vcrla~s-gesclls~llal't Slutlglrt) This al~plic~s to llle lrcatmcnt ol' bolll aelllc an~ chronie pclin eon-ions wllcrcin tllc ~si~c-cl'l'cc~s whicll arc typical ol' (lpioi~ls alc ac-~cplc~l sucll I.S rc.sl-ira-tory ~Icpression an~l ohs~ip;llioll all~l in parlicular Illc ~lcvclopmclll ol' lolcrltlcc all~l ~Icpcn-Llcrley whic~ll occllns whcll lhcy arc usc~l l'or clllonic p~lill con(lilioll~s 'I'hcr~lpculic pra~ c~
5 h.l~ shown Illal sul-slmccs wllicll ~an l~c a~lminislcrc~ or.llly alc p/~ icl~ rly wcll suilc~ lo Ihc lrcalmenl Or cllronie paill sincc Illcy e.ln casily l~c a~1millislcrc~ in ~loscs all~l in conlta~sl to injccli(ln prepar.lliolls c.m hc a~ lillislerc~l by Illc p.llicnl an-l/or hy nursing st.ll'l' wilhoul any parlicuklr cf'l'orl an(i wi~houl allxili.lry mcans (Chcrny N~ J el al., Mc~i-kamenl(i~sc Therapic von Tumolsclllncr;~cll Il Anwcn-lullg von Opioi~lcn Dcr Schmcr~ 9 1() 3 - l9 (1995); Evan~s P J Opi.llcs in Illc Man.lgclllclll ol' Chrollic Paill in Clinics an~
Anaeslhcology Vol I No 1 7] - 94) 'TllC prcrc~luisitc iS lllal tllc subs~.lnec.s cxhibi~ goo~l oral availahili~y ~m-l havc .I sul'l'icicnlly long-lasling cl'lcct llMh-ir cl'l'cet is sul'l'icicnlly lon~-lasling which may bc brouglll aboul hy u~sc in eonjullclioll wilh pharmaecu~ieal a(ljlLIvant suhslanecs sucll as l'or cx.lmplc ~]cposil prcl~aralions Ille l'rc~lucncy ~-r applic.llion 15 pcr ~lay ~an he rc~lu~e~3 wilhoul lhis rcsulling in a ~Iccrcclsc ol' lhc unil'orm Icvcl ol' cl'l'ic.lcy which is nc~cssary l'or optilll~lm lllcrll~y (Strllbcll O ~ Phlrmclkolo~ic Toxikologic un~l Vcrs~hrcibungvon Opioi~ls Inlcrnisl 3b IX5 - 19~ 4)) Oral ~claye~-release morpllillc h~s bccn in-~rcasingly usc-l in r~c~cnl ycars l'or lllc trccllmcn 2() of sevcrc chronic pain con~lilions (7cn~ ~t al., (19X9) Relar~licrlcs Morphin ~Jur Lang-~ei~-thcrapic schwcrer Tumors~hmcr~ll DLSCI1 mc~l Wsclll 114 43 - 47; 7cn7 et al.
(199()) Oral Opiallllcrapic hci Paliclll~ll mil "nicllt-lllaligrlcn" Schmcr~cn Dcr Schmcri~ 4 14; Vcnl.ll'ri~l~la et al, ( 1~9()), S;~IC-CI'ICCLS ~n~l Limils ol' ll~ng-Tcrm Oral Morphinc Thcrapy in Trcltlllcnt ol' Chrollic l'aill pp 25( - 2(~ M Mumcnthalcr PA V.lll 25 Zwictcn J M Falcol E~ls llarwoo~l Ac~l~lclllie P~ lishcrs C'hur (l9~(~)) so lll.ll or.ll morphinc prcpar.llions nowa~lays conslilulc Ihc convcnlion ll choicc evcn Illo~lgll morphinc l1aS a ~scrics Ol' ~lisl~lvanllgcous prol~cllics OnC S;~l1;l';Cal1l ~I;S~IVaI1lagC 0I mOrPI1;nC jS jlS
IO~A/ oral avail~lbility wllicll is ~IUC lo consi~lcrablc l'irsl-pl~ss ~Icaclivllion in lhe inlcslinal w~lll an~l on passagc lhrough tll.' livcr Ch~lngcs in mcklbolic c.ll~acily whicll ~rc ~luc to agc 3() or iillncss can thcrcl'orc ch.lnge Ihc oral availal-ility ~r morl-hinc an(l call makc spccial a~lap-tations ol' thc dosc ncccssary in or~lcr ~o prcvcnt incorr-ct ~losagcs Anothcr ncgalivc cll'ccl of morpI1ine is ils pronouIlee~ s~ipAtory si-le-erle-l. whieh re.s-ll~s in c~Il.slip.llion whcn or~l morplline Iherilpy is employe~l~ an~l ohligalorily m.lkes IIlc use ol Iax.ltives neeess.lry (Cherny e~ ~1. lY~5 lo~ ~il ). A tl1rlIIel SCliOUS side-cIlc~l is III-' occlIrrctlce ol I~Icr.lnce .In~l Or pllysic.ll .a~ psyellologieal ~Icpcll~lcIley whieII has given risc lo I h In On morphilIc 5 under lhe IegisIalion rcIaling to alIacslllelies The low oral availabilily oL morphille ne~essil.lles a speei.ll ph.armaeulie.-l prepar.llion e.g.
in delayed-release lorm in order lo m.lke morphine .aI-pIi~.lhle oraIly Tllis low oral appIi-~ahilily is ~lue in p.lrlicuI.Ir lo the phenoIie hy-ll-oxyI grollp ol morI-Iline A low oral av.lil.l-1(1 hilily l1-1.$ aIs~ been delecled l~r mIny olher eompoun~s .simillr IO morpllille SUCI1 ~Is n~lhupIline n.aIoxone and n-aIlrex~ne whicIl .IIso eolll.lill I I~henoIiu group.
The underlying ohie~l Or Ille pr( senl invenlioll w.as lherel'ore to provi~le ~ eompoulId whicll ean be applie~i or.ally in .a drug l(ll sevcrc, aeute .an~l/(Ir cIlronic p~in and whi~h h.ls .In 15 eLLeclive slren~th u(Imp.lr.lbIc wilh Ih ll (Il m(Irphine hul wilh(Iul the si-le-eLlc~ls Ihere(Il Il has surprisingly l-een lound th.lt the (+~ en.alltiomer ol O-~lemelIlyltr.llll.ldoI and physio-logie~lly eompatihlc S.llt.s there~l' po~s~sc~ss .all outstall~lillg el'lective strength and .aceordillgly exhibil a consider-lhIe all-llgcsi(: cllccl~ ~In~ c.spite Illcir pllcllolic hydroxyl group exhihil 2() consideral-Iy heuer oraI av.lilal-iIity lh.m th.lt ol eollvelltion~ll eoml~unds .Inalogous lo opioids. This makes po.s~sil-Ie a lower ~lo.sc on appIic;ltiolI together with enh.lneing the sal'ety oL the dose.
In add;l;On~ l;nd;I1gS IrOI11 CXI~r;mCI1LS On an;malS l1.1VC Sl1OWn ll1.ll (+)-~ICmClhYIlramadOI
25 exhihils .I rc~ucc~l obstil-;llory cl Iccl col~ ;lrc~1 wilIl morphillc Moreover tIle risk ol psy(:I1ologie~ Iepell-leney ;Irising ~luling Iong-lelln tre;llmenl is Iess than wi~h morpllille.
'rhc goo~l or~ll av~ bilily ~lll~l ;Ill~llgc~si~ cll'i~ y ol (+)-O-~ Illclllyllr.lln~lol wllcn u~c~
a~or~lin~ lo Ihe invenli(Ill as ;In aclive ingre~lielll in ;l ~Iru~ has l-ecn I~rovc~l in allaIgesi;
3() lesl. on miee and r;lls Thc phalma~ologi-al inve. ligaliol1s wcre c arric(l out I.s lollows:
TC.stillg lor .IllalgCSia USill~ hC Wrillling lcsl -n IniCC
Testing lor an~lgesic el'l'icacy was In~rl'orme~l u.sing lhe phenyl~luinone~ luce(1 wrill1ing ~esl on mice (modilie-3 ~ccor-ling lo l.C Hender.shot J. Forslith J. Phlrmacol. Exp. Ther.
125 237-24() (19SY)). Male NMRI IlliCC with a WCigh~OI' 25 to 3(J g were use~ lor tl1is pUrp0~SC. FOrCaC~ O.SC Ol'SU17.Sliln~'~', grOUp,S O~ )anillnll.SICCCiVC~I~ 1() minutes al'ler Ihe 1() oral t~mini.slr~lion ~n~l 3() minules II'ler Ihe oral a~lmillislra~ion ol' the comp0undls ~o be use(l according to ~he invenliol1 ().3 ml pCI mou.se ol' an ().()2 ~ a~lueou~s solution or l~henyl~luillonc (pllenylhell:~,o~luillone: man~ll'aclurc~ y siglna, Dciscnhol'cn; solulion prepale~l wilh Ihe a~l~ilion ol S ~ CllnallOI an~l kepl on a water bAth al 45~C) a~lninistere~l intraperitone.llly. The anilllals were place~l in~livi(lually in ohserv Ition cages. an~l the 15 numl7er Or pain-in(luce~l slrelehing movemen~s (so-cllle-l wrilhing reactions = str.ligl1lening ol' lhe ho(ly wilh slrelcl1ing ol ll1e re(n extremities) 5 lo 2() minules alter the a(lmil1istralion Or phenykluil1one was counte~l hy meal1s ol a pusl1-l7ut~0n coun~er. The ED~" value lor tl1e inhil~ition ~f the wrilllillg re.lclion was ~llcullted l~y means or re~ression anlly is (evalualion prograln supplie~ l-y M lrlens EDV Servicc Eckenlal) Irom lhc ~lose-~lepen~lent 2() decl-ease in the wrilhing reaclions l~y colnp Irison witl1 colltrol gro-ll7s whiclI were teste~l in parclllel alI~l which were lreate~l witlI l~henyl(luil1one only.
Tes~ing lor ~Inalgc~sia USillg lhC t lil 11ick le.sl on rats an~l mice 25 The an.llgesic elricacy ol the coll1poun(1 to he use(l a~cor~ling lo the invel1lion W-IS
invcsligatc(l in lhe lhermal ra~li.ltiol1 (tail llick) te.sl 0n l-l~S USillg ~hc IllC~hO(I ot' D~AmOUr all-l Smilh (J. Pharm. Exp. rl hcr. 72, 74 - 7'~ (1(J41)). M~llc NMRI micc wilh a weight ol' 2() to 25 g or Iemale Sprag-le Dawley r als wilh a weiglIl ol l2() lo Ih() g were u.se(l l'or lhis purpose. The al1imals werc place~l in~livi~lually in tesl e I~C.S al1~1 ll1e h.lscs ol' lllcir l.lils were 3() exp0se~1 to the locuse~l ll1erlIl.ll ril~lialiol1 l'rom an electric lamp (Rhem.l Analgesiemeter).
The lamp intensi~y wa.s a(ljus~e~ ~so ~hat ~he lime l'rom swilching on the lamp until the sud~len twitcllillg away ~-r thc tail (lalency (lf pain) was 3 to (~ SCCOIl(lS l'~-r untreale(l anirnal.s. Bel'ore the a~ islr(llioll (~ lle colllpoul~ IISC(I acc~r~ling to tl1e invenlion tl1e anim-lls werc tcsle~l lwiec wilhill l'ivc IllillUICS .In(3 lhC ~lVt~r.lgC valuc 01' lhcsc measuremcnls was calcul.lle~ .I.S thc prc-lesl avcrllgc. 'I'hc p.lil1 me.lsurclllelll was ma(lt 2() 5 4~) an~l ~() minutes arter intr.lveno-l.s a(lminisll.lli~ll all(l 3() (~ 3() an~l 12() minules al'ler oral a~ministration. When the latency oi' p.lin incre.lsc~l lhe maximull1 lime ol exposure was restricte(l to 12 secon-ls an~ an increasc in ll~e lalenl perio~l lo > 15(1 'Y ol' the pre-test average value was assesse~l as all analgesie el'l'ecl. In or~ler to ~etcrmine ~he dosage-~cllen~ency ~he coml~o~ln~s wcre a~llnil1istere~ in ~ ses increasing l~garithmie.llly l~y a 1() faclor ol' 3 - 5 whieh in-lu-le~ the Illrcsllol~ all~l lhe m.lxilnum el'leelive Llose eacl1 time.
The ED~(, values were (Ictc~rmine~l t'rom thc n-lmller ol' .u1im.lls which cxhihi~e~ an anillgesic efl'ec~ ty the metho-l ol' Li~cl1t'iel-1 an~l Wilcoxon (.1. Ph.lrm. Ex. Ther. ~6 ~t) to 113 (194~)). The ED~I, was calculalc~l at the elleclivc m~lxillluln 2() millules al'ter intr.lvenous .l~miniS~r.ltiOn ol'thc SUt-St.lnCCin CilCIlCilSt' an~ 3() minutes al'~ct Orill .l~milliS~r.l~iOIl ol' ~he 15 sub tance in e.-cl1 case.
The erleclive ~ral avail.l~ y was ~etermine~l l'r~m thc ralio ol' Ille ED~, values l'or intravenous (i.v.) an(l oral (p.o) a(3ministr.lti~n.
2() Efl'ective availabilily = ED~ v ED;~ p o.
Tahle 1 Anal~csie clli~acy an~l or.ll avail.lhilily oi morphinc an~l (+)-0-~lcnlclllyllr~lma~l0l Tesl IllO~CI ED~(~ V.IIUCS (mg/kg) ( + )-O- morphillc ~lcln~lllyllr~ln~
tail llick, micc, i.v. 1.41 1.1)5 lail llick, mice, p.o. 3.75 lX.~(I
oral availallilily ().3X ().()~
writhing, micc, i.v. ().4~ ().33 wri~hing, micc, p.o. l.X7 4.7(1 ~ral avail.lbilily ().2(~ ().()7 ail llick, rats, i.v. 1.()1 ().~3 lail llick, rals, p ~ 4.',~() 75.()() oral avail.lllilily ().21 ().()1 Thc (+)-(lcmclllyllram.l(lol usc~l accor~ g lo thc invcntion cxhihitc~l a pronoullcc~l 5 analgesic cflcel in lllc writlling tcsl on micc an~l in Ihc l.lil llick tcsl on ral,s. Whcrcas lor morphinc the faelol- I'or cllccliv~ oral av.lil.lllility was (~ in thc tail llick Icsl an(l ().()7 in the writhing Icsl lor micc, an~l wa.s ().()1 in lhc lail llick tcst lor rat~s, lor (+)-0-~lcmethyltrama~lol lhc valuc ot lhc crlcclivc oral av.lil.lhilily was (~.3X in thc lai] ilick Ics an~l ().2( in Illc wrillliny tcsl l'or micc, .In~l WilS ().21 lor rials. Thc compoun(l u.sc~
1() accor(ling lo lhc invcnlion lhus cxhil)ils all oral av.lilahility which is alloul 5 limc~s hctlcr thalli lln.ll of morpllinc l'or micc an~l whicll is ahoul 2() limcs hcllcr th~lll thal ~-r morphinc lor rats., an~l i.s thus collsi~lcr.ll-ly hcllcr Ih.lll morpllinc l'or lh~ oral Illcr.ll-y ol paill.
Whcn (+)-O-~lcmclllyllr.lma-lol is usc~ accor~lillg lo Illc hlvclllion as all analgcsic activc 15 ingrc~licnl in a ~Irug, lhc lallcr collklills sullpoll malcriills, lillcrs, solvcnls, ~lilucnls, eoloranls an-l/or hin~lcrs~ in ~ lilioll lo lhc ( + ) cllallliolllcl all(l/or al Ica.sl onc physiologically comt~alit)lc sall ol (+)-O-~lcmclllyllram.l-lol. In lorms ol prcpar.llion whieh can he alllllic t orally, thc (-~)-O-~lclllclllyllralna~lol C.lll hc use~l cilllcr as lllc Ircc hasc or as a sall Or inorganic all~l organic aci~ls~ for example aromalic c.lrhoxylic aci~ls such as hcn:~oic itCi~lOrpllenylitCCtiCitci~.silllsOl' lipopl1ilic ~-rganic aci~l.s for example ~l C~-C221itl~yilci~s such ilS sleilric ilci~l or palmilie aci-l are pillliculilrly prelerre~l. The salt~s ol (+)-O-~lcnlclllyllrilma~lol whicll arc l'ormc~l wilh lipopllilic or~ani~ aci~ls ill-C pilrliculilrly ,sui~ill-lc lor (:Ielaye-l-releilse l'onIl.s ol' ~Irllgs whicl1 releil~se lhe c )mpoun~l u.se~l accor~ g lo lhe 5 invenlion in a (Ielaye~ mill1ner.
In (~elaye~l-releise I'orms? (+)-O-~lemell1ylIrillnil~ol is prel'erithly u~se~l il.Sil millrix lahlCl~
Cellulose elhers an~l/or cellulose eslclS Whicllll.lvcilviscO.sily l-elween 1() ()()() an~l 15() ()()() mPas in a 2 OO by weighl a~llleous soluliol1 at 2()~C are piuliculilrly suililhlc il.S millrix 1() I'ormcrs~ Malrix l'l)rrmcrs whicll arC pilrliculillly pllilrlll.lcculicillly ilcccplilhlc arc sclccl rrom the group comprisilIg methyll1y~lroxypropyl cellulo~ses hy~lroxyell1yl celluloses hy~lroxypropyl ccllulosc,s, mclllyl ccllllloscs, clllyl cclluloscs .111(1 cilrhoxymelllyl celluloses an~l are selecle-l in pilrticulilr Irom lhc group complising mell1yl-hy~lr~xyprol-yl cellulosc.s, hy~lloxyclllyl cclluloscs an~l hy~lroxyprollyl ccllulo.sc~s In ~ e ~rug whielI is lo I-e use-l tl1e eol1lenl ol ~3elilye~1-releit.se aclive ingre~licnl i.s prererably helween 1() an~ XS O by wciglll~ itn~l lllc conlenl ol' pllarmilcculically ace~epllhle matrix lormer is helweelI 1() an(l 4(1 ~ I~y weighl Drugs will1 it('onlenlol ~lelilye~l-releilse aclive ingre~liel1t helween 25 an(l 7() ~ hy wei~hl an~l a contenl ol' 2() pharmilceuticillly accel~l.ll-le miltrix Iormer helween I () iu1~1 4() ~ hy weigl1l are par~iculiIrly prel'erre-l.
The (Jrugs lo he u.se(l acc~-r~ling 1~ lhc invenlion mily contain as lullller cons~i~uenls a~ljuv.lnl substilnce.s whicl1 are pl1ilrlIlilceulie.llly culstoll1ilry~ .sueh a.s l'illers l'or example 25 lactose micro~ry.stalline ce~lllllose or ciIleium hy~lrogelI pho~spl1.Ite~ a.s well as parling agel1ls lul-ricilnl~s im~l l'll)w-reg-llillilIg ilgenls lor example micro~li.sperse~l sili~a l'rcncll chillk, magllcsi-llll ,slcill(llc all~ -r .slcilric ilci~ hc lolill colllc[ll ~-1' whicll in tllc lahlel i~s belween () an~l X() hv weiglIl prelerahly helweel1 5 al1~1 25 i. hy weigl1l.
3() The amounl ol' aelive ingre~ient lo l~e a~lminislere~l lo the r~atient varies depen(lillg on the wei~,ht o~ the patienl on lhe type ol applicatioll, on tlle in~licalion an~l on lhe iegree ol .severily ol ttlC ilhless. I() lo 4()() mg/kg, prclerahly l(~ lo 2()(~ mg/kg (+)-0-icmctllylllam~ cll-c u~u.llly ~ s~
s Fur~hermore, in soli~ oral l'orms ol ia~lministr.llion, the (+)-O-~Iellletl1yltrallla~lol wllicl is use~l aeeor~ing to tlle invention can he employe~l as tll-~ Iree hase an~l/or in the lorm ol a physiologically comp.ltihle salt in pow~els, ~rall-lles, pellets, tal-lets, ~Iragees ~In~l capsules. The selection ol the colnr)osition all~3 ol the plo~luclion process lor s~ l lonlls 1() ol ~Irugs ean he ma(le in aceor~l.lnee willl the known specilicaliolls ol pharlnaeeLItieal lcchnology .
In tahlcl lorm, eilller siml-le lahlels or eoate~ lahlels, I'or example lilm-co.lle(l lahlels or (Iragees, ean he u~e~l. One or ml)re ~oalil1~ hlyers ean l-e use~l I'or eoale~l tahlels.
D-52078 Aachen Internal reference: G 2601 Oral applicalioll of (+)-O-demethyltlamadol ~s a pain-killillg dl ug rrhis invclllioll rclalcs lo ll1c oral application ol (+)-O-dclnclllyltmlmldol lor ttlC tlCalmCll Or illtcnsc, aculc and/or scvcrc cllronic pain.
30 In pain therapy, opioids havc an unass.lilahlc suprcmacy 1' ~r lhc Irc.ltmcnt ol' scvere pain (Zcn:~, M., Jurna 1. (19~3) Lcl1rh-lch ~3cr Scllmcr/~llcmpic. Wissens~h.lfl1i~hc Vcrla~s-gesclls~llal't Slutlglrt) This al~plic~s to llle lrcatmcnt ol' bolll aelllc an~ chronie pclin eon-ions wllcrcin tllc ~si~c-cl'l'cc~s whicll arc typical ol' (lpioi~ls alc ac-~cplc~l sucll I.S rc.sl-ira-tory ~Icpression an~l ohs~ip;llioll all~l in parlicular Illc ~lcvclopmclll ol' lolcrltlcc all~l ~Icpcn-Llcrley whic~ll occllns whcll lhcy arc usc~l l'or clllonic p~lill con(lilioll~s 'I'hcr~lpculic pra~ c~
5 h.l~ shown Illal sul-slmccs wllicll ~an l~c a~lminislcrc~ or.llly alc p/~ icl~ rly wcll suilc~ lo Ihc lrcalmenl Or cllronie paill sincc Illcy e.ln casily l~c a~1millislcrc~ in ~loscs all~l in conlta~sl to injccli(ln prepar.lliolls c.m hc a~ lillislerc~l by Illc p.llicnl an-l/or hy nursing st.ll'l' wilhoul any parlicuklr cf'l'orl an(i wi~houl allxili.lry mcans (Chcrny N~ J el al., Mc~i-kamenl(i~sc Therapic von Tumolsclllncr;~cll Il Anwcn-lullg von Opioi~lcn Dcr Schmcr~ 9 1() 3 - l9 (1995); Evan~s P J Opi.llcs in Illc Man.lgclllclll ol' Chrollic Paill in Clinics an~
Anaeslhcology Vol I No 1 7] - 94) 'TllC prcrc~luisitc iS lllal tllc subs~.lnec.s cxhibi~ goo~l oral availahili~y ~m-l havc .I sul'l'icicnlly long-lasling cl'lcct llMh-ir cl'l'cet is sul'l'icicnlly lon~-lasling which may bc brouglll aboul hy u~sc in eonjullclioll wilh pharmaecu~ieal a(ljlLIvant suhslanecs sucll as l'or cx.lmplc ~]cposil prcl~aralions Ille l'rc~lucncy ~-r applic.llion 15 pcr ~lay ~an he rc~lu~e~3 wilhoul lhis rcsulling in a ~Iccrcclsc ol' lhc unil'orm Icvcl ol' cl'l'ic.lcy which is nc~cssary l'or optilll~lm lllcrll~y (Strllbcll O ~ Phlrmclkolo~ic Toxikologic un~l Vcrs~hrcibungvon Opioi~ls Inlcrnisl 3b IX5 - 19~ 4)) Oral ~claye~-release morpllillc h~s bccn in-~rcasingly usc-l in r~c~cnl ycars l'or lllc trccllmcn 2() of sevcrc chronic pain con~lilions (7cn~ ~t al., (19X9) Relar~licrlcs Morphin ~Jur Lang-~ei~-thcrapic schwcrer Tumors~hmcr~ll DLSCI1 mc~l Wsclll 114 43 - 47; 7cn7 et al.
(199()) Oral Opiallllcrapic hci Paliclll~ll mil "nicllt-lllaligrlcn" Schmcr~cn Dcr Schmcri~ 4 14; Vcnl.ll'ri~l~la et al, ( 1~9()), S;~IC-CI'ICCLS ~n~l Limils ol' ll~ng-Tcrm Oral Morphinc Thcrapy in Trcltlllcnt ol' Chrollic l'aill pp 25( - 2(~ M Mumcnthalcr PA V.lll 25 Zwictcn J M Falcol E~ls llarwoo~l Ac~l~lclllie P~ lishcrs C'hur (l9~(~)) so lll.ll or.ll morphinc prcpar.llions nowa~lays conslilulc Ihc convcnlion ll choicc evcn Illo~lgll morphinc l1aS a ~scrics Ol' ~lisl~lvanllgcous prol~cllics OnC S;~l1;l';Cal1l ~I;S~IVaI1lagC 0I mOrPI1;nC jS jlS
IO~A/ oral avail~lbility wllicll is ~IUC lo consi~lcrablc l'irsl-pl~ss ~Icaclivllion in lhe inlcslinal w~lll an~l on passagc lhrough tll.' livcr Ch~lngcs in mcklbolic c.ll~acily whicll ~rc ~luc to agc 3() or iillncss can thcrcl'orc ch.lnge Ihc oral availal-ility ~r morl-hinc an(l call makc spccial a~lap-tations ol' thc dosc ncccssary in or~lcr ~o prcvcnt incorr-ct ~losagcs Anothcr ncgalivc cll'ccl of morpI1ine is ils pronouIlee~ s~ipAtory si-le-erle-l. whieh re.s-ll~s in c~Il.slip.llion whcn or~l morplline Iherilpy is employe~l~ an~l ohligalorily m.lkes IIlc use ol Iax.ltives neeess.lry (Cherny e~ ~1. lY~5 lo~ ~il ). A tl1rlIIel SCliOUS side-cIlc~l is III-' occlIrrctlce ol I~Icr.lnce .In~l Or pllysic.ll .a~ psyellologieal ~Icpcll~lcIley whieII has given risc lo I h In On morphilIc 5 under lhe IegisIalion rcIaling to alIacslllelies The low oral availabilily oL morphille ne~essil.lles a speei.ll ph.armaeulie.-l prepar.llion e.g.
in delayed-release lorm in order lo m.lke morphine .aI-pIi~.lhle oraIly Tllis low oral appIi-~ahilily is ~lue in p.lrlicuI.Ir lo the phenoIie hy-ll-oxyI grollp ol morI-Iline A low oral av.lil.l-1(1 hilily l1-1.$ aIs~ been delecled l~r mIny olher eompoun~s .simillr IO morpllille SUCI1 ~Is n~lhupIline n.aIoxone and n-aIlrex~ne whicIl .IIso eolll.lill I I~henoIiu group.
The underlying ohie~l Or Ille pr( senl invenlioll w.as lherel'ore to provi~le ~ eompoulId whicll ean be applie~i or.ally in .a drug l(ll sevcrc, aeute .an~l/(Ir cIlronic p~in and whi~h h.ls .In 15 eLLeclive slren~th u(Imp.lr.lbIc wilh Ih ll (Il m(Irphine hul wilh(Iul the si-le-eLlc~ls Ihere(Il Il has surprisingly l-een lound th.lt the (+~ en.alltiomer ol O-~lemelIlyltr.llll.ldoI and physio-logie~lly eompatihlc S.llt.s there~l' po~s~sc~ss .all outstall~lillg el'lective strength and .aceordillgly exhibil a consider-lhIe all-llgcsi(: cllccl~ ~In~ c.spite Illcir pllcllolic hydroxyl group exhihil 2() consideral-Iy heuer oraI av.lilal-iIity lh.m th.lt ol eollvelltion~ll eoml~unds .Inalogous lo opioids. This makes po.s~sil-Ie a lower ~lo.sc on appIic;ltiolI together with enh.lneing the sal'ety oL the dose.
In add;l;On~ l;nd;I1gS IrOI11 CXI~r;mCI1LS On an;malS l1.1VC Sl1OWn ll1.ll (+)-~ICmClhYIlramadOI
25 exhihils .I rc~ucc~l obstil-;llory cl Iccl col~ ;lrc~1 wilIl morphillc Moreover tIle risk ol psy(:I1ologie~ Iepell-leney ;Irising ~luling Iong-lelln tre;llmenl is Iess than wi~h morpllille.
'rhc goo~l or~ll av~ bilily ~lll~l ;Ill~llgc~si~ cll'i~ y ol (+)-O-~ Illclllyllr.lln~lol wllcn u~c~
a~or~lin~ lo Ihe invenli(Ill as ;In aclive ingre~lielll in ;l ~Iru~ has l-ecn I~rovc~l in allaIgesi;
3() lesl. on miee and r;lls Thc phalma~ologi-al inve. ligaliol1s wcre c arric(l out I.s lollows:
TC.stillg lor .IllalgCSia USill~ hC Wrillling lcsl -n IniCC
Testing lor an~lgesic el'l'icacy was In~rl'orme~l u.sing lhe phenyl~luinone~ luce(1 wrill1ing ~esl on mice (modilie-3 ~ccor-ling lo l.C Hender.shot J. Forslith J. Phlrmacol. Exp. Ther.
125 237-24() (19SY)). Male NMRI IlliCC with a WCigh~OI' 25 to 3(J g were use~ lor tl1is pUrp0~SC. FOrCaC~ O.SC Ol'SU17.Sliln~'~', grOUp,S O~ )anillnll.SICCCiVC~I~ 1() minutes al'ler Ihe 1() oral t~mini.slr~lion ~n~l 3() minules II'ler Ihe oral a~lmillislra~ion ol' the comp0undls ~o be use(l according to ~he invenliol1 ().3 ml pCI mou.se ol' an ().()2 ~ a~lueou~s solution or l~henyl~luillonc (pllenylhell:~,o~luillone: man~ll'aclurc~ y siglna, Dciscnhol'cn; solulion prepale~l wilh Ihe a~l~ilion ol S ~ CllnallOI an~l kepl on a water bAth al 45~C) a~lninistere~l intraperitone.llly. The anilllals were place~l in~livi(lually in ohserv Ition cages. an~l the 15 numl7er Or pain-in(luce~l slrelehing movemen~s (so-cllle-l wrilhing reactions = str.ligl1lening ol' lhe ho(ly wilh slrelcl1ing ol ll1e re(n extremities) 5 lo 2() minules alter the a(lmil1istralion Or phenykluil1one was counte~l hy meal1s ol a pusl1-l7ut~0n coun~er. The ED~" value lor tl1e inhil~ition ~f the wrilllillg re.lclion was ~llcullted l~y means or re~ression anlly is (evalualion prograln supplie~ l-y M lrlens EDV Servicc Eckenlal) Irom lhc ~lose-~lepen~lent 2() decl-ease in the wrilhing reaclions l~y colnp Irison witl1 colltrol gro-ll7s whiclI were teste~l in parclllel alI~l which were lreate~l witlI l~henyl(luil1one only.
Tes~ing lor ~Inalgc~sia USillg lhC t lil 11ick le.sl on rats an~l mice 25 The an.llgesic elricacy ol the coll1poun(1 to he use(l a~cor~ling lo the invel1lion W-IS
invcsligatc(l in lhe lhermal ra~li.ltiol1 (tail llick) te.sl 0n l-l~S USillg ~hc IllC~hO(I ot' D~AmOUr all-l Smilh (J. Pharm. Exp. rl hcr. 72, 74 - 7'~ (1(J41)). M~llc NMRI micc wilh a weight ol' 2() to 25 g or Iemale Sprag-le Dawley r als wilh a weiglIl ol l2() lo Ih() g were u.se(l l'or lhis purpose. The al1imals werc place~l in~livi~lually in tesl e I~C.S al1~1 ll1e h.lscs ol' lllcir l.lils were 3() exp0se~1 to the locuse~l ll1erlIl.ll ril~lialiol1 l'rom an electric lamp (Rhem.l Analgesiemeter).
The lamp intensi~y wa.s a(ljus~e~ ~so ~hat ~he lime l'rom swilching on the lamp until the sud~len twitcllillg away ~-r thc tail (lalency (lf pain) was 3 to (~ SCCOIl(lS l'~-r untreale(l anirnal.s. Bel'ore the a~ islr(llioll (~ lle colllpoul~ IISC(I acc~r~ling to tl1e invenlion tl1e anim-lls werc tcsle~l lwiec wilhill l'ivc IllillUICS .In(3 lhC ~lVt~r.lgC valuc 01' lhcsc measuremcnls was calcul.lle~ .I.S thc prc-lesl avcrllgc. 'I'hc p.lil1 me.lsurclllelll was ma(lt 2() 5 4~) an~l ~() minutes arter intr.lveno-l.s a(lminisll.lli~ll all(l 3() (~ 3() an~l 12() minules al'ler oral a~ministration. When the latency oi' p.lin incre.lsc~l lhe maximull1 lime ol exposure was restricte(l to 12 secon-ls an~ an increasc in ll~e lalenl perio~l lo > 15(1 'Y ol' the pre-test average value was assesse~l as all analgesie el'l'ecl. In or~ler to ~etcrmine ~he dosage-~cllen~ency ~he coml~o~ln~s wcre a~llnil1istere~ in ~ ses increasing l~garithmie.llly l~y a 1() faclor ol' 3 - 5 whieh in-lu-le~ the Illrcsllol~ all~l lhe m.lxilnum el'leelive Llose eacl1 time.
The ED~(, values were (Ictc~rmine~l t'rom thc n-lmller ol' .u1im.lls which cxhihi~e~ an anillgesic efl'ec~ ty the metho-l ol' Li~cl1t'iel-1 an~l Wilcoxon (.1. Ph.lrm. Ex. Ther. ~6 ~t) to 113 (194~)). The ED~I, was calculalc~l at the elleclivc m~lxillluln 2() millules al'ter intr.lvenous .l~miniS~r.ltiOn ol'thc SUt-St.lnCCin CilCIlCilSt' an~ 3() minutes al'~ct Orill .l~milliS~r.l~iOIl ol' ~he 15 sub tance in e.-cl1 case.
The erleclive ~ral avail.l~ y was ~etermine~l l'r~m thc ralio ol' Ille ED~, values l'or intravenous (i.v.) an(l oral (p.o) a(3ministr.lti~n.
2() Efl'ective availabilily = ED~ v ED;~ p o.
Tahle 1 Anal~csie clli~acy an~l or.ll avail.lhilily oi morphinc an~l (+)-0-~lcnlclllyllr~lma~l0l Tesl IllO~CI ED~(~ V.IIUCS (mg/kg) ( + )-O- morphillc ~lcln~lllyllr~ln~
tail llick, micc, i.v. 1.41 1.1)5 lail llick, mice, p.o. 3.75 lX.~(I
oral availallilily ().3X ().()~
writhing, micc, i.v. ().4~ ().33 wri~hing, micc, p.o. l.X7 4.7(1 ~ral avail.lbilily ().2(~ ().()7 ail llick, rats, i.v. 1.()1 ().~3 lail llick, rals, p ~ 4.',~() 75.()() oral avail.lllilily ().21 ().()1 Thc (+)-(lcmclllyllram.l(lol usc~l accor~ g lo thc invcntion cxhihitc~l a pronoullcc~l 5 analgesic cflcel in lllc writlling tcsl on micc an~l in Ihc l.lil llick tcsl on ral,s. Whcrcas lor morphinc the faelol- I'or cllccliv~ oral av.lil.lllility was (~ in thc tail llick Icsl an(l ().()7 in the writhing Icsl lor micc, an~l wa.s ().()1 in lhc lail llick tcst lor rat~s, lor (+)-0-~lcmethyltrama~lol lhc valuc ot lhc crlcclivc oral av.lil.lhilily was (~.3X in thc lai] ilick Ics an~l ().2( in Illc wrillliny tcsl l'or micc, .In~l WilS ().21 lor rials. Thc compoun(l u.sc~
1() accor(ling lo lhc invcnlion lhus cxhil)ils all oral av.lilahility which is alloul 5 limc~s hctlcr thalli lln.ll of morpllinc l'or micc an~l whicll is ahoul 2() limcs hcllcr th~lll thal ~-r morphinc lor rats., an~l i.s thus collsi~lcr.ll-ly hcllcr Ih.lll morpllinc l'or lh~ oral Illcr.ll-y ol paill.
Whcn (+)-O-~lcmclllyllr.lma-lol is usc~ accor~lillg lo Illc hlvclllion as all analgcsic activc 15 ingrc~licnl in a ~Irug, lhc lallcr collklills sullpoll malcriills, lillcrs, solvcnls, ~lilucnls, eoloranls an-l/or hin~lcrs~ in ~ lilioll lo lhc ( + ) cllallliolllcl all(l/or al Ica.sl onc physiologically comt~alit)lc sall ol (+)-O-~lcmclllyllram.l-lol. In lorms ol prcpar.llion whieh can he alllllic t orally, thc (-~)-O-~lclllclllyllralna~lol C.lll hc use~l cilllcr as lllc Ircc hasc or as a sall Or inorganic all~l organic aci~ls~ for example aromalic c.lrhoxylic aci~ls such as hcn:~oic itCi~lOrpllenylitCCtiCitci~.silllsOl' lipopl1ilic ~-rganic aci~l.s for example ~l C~-C221itl~yilci~s such ilS sleilric ilci~l or palmilie aci-l are pillliculilrly prelerre~l. The salt~s ol (+)-O-~lcnlclllyllrilma~lol whicll arc l'ormc~l wilh lipopllilic or~ani~ aci~ls ill-C pilrliculilrly ,sui~ill-lc lor (:Ielaye-l-releilse l'onIl.s ol' ~Irllgs whicl1 releil~se lhe c )mpoun~l u.se~l accor~ g lo lhe 5 invenlion in a (Ielaye~ mill1ner.
In (~elaye~l-releise I'orms? (+)-O-~lemell1ylIrillnil~ol is prel'erithly u~se~l il.Sil millrix lahlCl~
Cellulose elhers an~l/or cellulose eslclS Whicllll.lvcilviscO.sily l-elween 1() ()()() an~l 15() ()()() mPas in a 2 OO by weighl a~llleous soluliol1 at 2()~C are piuliculilrly suililhlc il.S millrix 1() I'ormcrs~ Malrix l'l)rrmcrs whicll arC pilrliculillly pllilrlll.lcculicillly ilcccplilhlc arc sclccl rrom the group comprisilIg methyll1y~lroxypropyl cellulo~ses hy~lroxyell1yl celluloses hy~lroxypropyl ccllulosc,s, mclllyl ccllllloscs, clllyl cclluloscs .111(1 cilrhoxymelllyl celluloses an~l are selecle-l in pilrticulilr Irom lhc group complising mell1yl-hy~lr~xyprol-yl cellulosc.s, hy~lloxyclllyl cclluloscs an~l hy~lroxyprollyl ccllulo.sc~s In ~ e ~rug whielI is lo I-e use-l tl1e eol1lenl ol ~3elilye~1-releit.se aclive ingre~licnl i.s prererably helween 1() an~ XS O by wciglll~ itn~l lllc conlenl ol' pllarmilcculically ace~epllhle matrix lormer is helweelI 1() an(l 4(1 ~ I~y weighl Drugs will1 it('onlenlol ~lelilye~l-releilse aclive ingre~liel1t helween 25 an(l 7() ~ hy wei~hl an~l a contenl ol' 2() pharmilceuticillly accel~l.ll-le miltrix Iormer helween I () iu1~1 4() ~ hy weigl1l are par~iculiIrly prel'erre-l.
The (Jrugs lo he u.se(l acc~-r~ling 1~ lhc invenlion mily contain as lullller cons~i~uenls a~ljuv.lnl substilnce.s whicl1 are pl1ilrlIlilceulie.llly culstoll1ilry~ .sueh a.s l'illers l'or example 25 lactose micro~ry.stalline ce~lllllose or ciIleium hy~lrogelI pho~spl1.Ite~ a.s well as parling agel1ls lul-ricilnl~s im~l l'll)w-reg-llillilIg ilgenls lor example micro~li.sperse~l sili~a l'rcncll chillk, magllcsi-llll ,slcill(llc all~ -r .slcilric ilci~ hc lolill colllc[ll ~-1' whicll in tllc lahlel i~s belween () an~l X() hv weiglIl prelerahly helweel1 5 al1~1 25 i. hy weigl1l.
3() The amounl ol' aelive ingre~ient lo l~e a~lminislere~l lo the r~atient varies depen(lillg on the wei~,ht o~ the patienl on lhe type ol applicatioll, on tlle in~licalion an~l on lhe iegree ol .severily ol ttlC ilhless. I() lo 4()() mg/kg, prclerahly l(~ lo 2()(~ mg/kg (+)-0-icmctllylllam~ cll-c u~u.llly ~ s~
s Fur~hermore, in soli~ oral l'orms ol ia~lministr.llion, the (+)-O-~Iellletl1yltrallla~lol wllicl is use~l aeeor~ing to tlle invention can he employe~l as tll-~ Iree hase an~l/or in the lorm ol a physiologically comp.ltihle salt in pow~els, ~rall-lles, pellets, tal-lets, ~Iragees ~In~l capsules. The selection ol the colnr)osition all~3 ol the plo~luclion process lor s~ l lonlls 1() ol ~Irugs ean he ma(le in aceor~l.lnee willl the known specilicaliolls ol pharlnaeeLItieal lcchnology .
In tahlcl lorm, eilller siml-le lahlels or eoate~ lahlels, I'or example lilm-co.lle(l lahlels or (Iragees, ean he u~e~l. One or ml)re ~oalil1~ hlyers ean l-e use~l I'or eoale~l tahlels.
Claims (7)
1. The use of (+)O-demethyltramadol as the free base and/or in the form of a physiologically compatible salt for oral application in the treatment of severe, acute and/or chronie pain.
2. A use according to claim 1, characterised in that the salts of (+)O-demethyltramadol are formed with organic acids, particularly C8-C22 falty and aromatic carboxylic acids.
3. A use of (+)O-demethyltramadol according to claim 1 or 2 in a drug in tablet form with delayed release of the active ingredient.
4. A use according to claim 3, characterised in that the tablet form is a matrix tablet.
5. A use according to claim 3, characterised in that at least one cellulose ether and/or cellulose ester which has a viscosity between 3000 and 150,000 mPas, preferably between 10,000 and 150,000 mPas, in a 2% by weight aqueous solution at 20'C is contained as a pharmaceutically acceptable matrix former.
6. A use according to claims 3 to 5, characterised in that at least one substance selected from the group comprising methylhydroxypropyl celluloses, hydroxyethyl celluloses, hydroxypropyl celluloses, methyl celluloses, ethyl celluloses and carboxymethyl celluloses is used as a pharmaceutically acceptable matrix former.
7. A use according yo any one of claims 3 to 6, characterised in that the content of delayed-release active ingredient is between 10 and 85% by weight, preferably between 25 and 70% by weight, and the content of pharmaceutically acceptable matrix formers is between 10 and 40% by weight.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19712398A DE19712398A1 (en) | 1997-03-25 | 1997-03-25 | Oral use of (+) - 0-demethyltramadol as a pain reliever |
| DE19712398.8 | 1997-03-25 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2232930A1 true CA2232930A1 (en) | 1998-09-25 |
Family
ID=7824498
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002232930A Abandoned CA2232930A1 (en) | 1997-03-25 | 1998-03-23 | Oral application of (+)-o-demethyltramadol as a pain killing drug |
Country Status (14)
| Country | Link |
|---|---|
| EP (1) | EP0870499A1 (en) |
| JP (1) | JPH1112166A (en) |
| KR (1) | KR19980080580A (en) |
| CN (1) | CN1196932A (en) |
| AU (1) | AU5951798A (en) |
| BR (1) | BR9801839A (en) |
| CA (1) | CA2232930A1 (en) |
| DE (1) | DE19712398A1 (en) |
| HU (1) | HUP9800623A3 (en) |
| IL (1) | IL123788A0 (en) |
| NO (1) | NO981320L (en) |
| PE (1) | PE62399A1 (en) |
| PL (1) | PL325509A1 (en) |
| UY (1) | UY24934A1 (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| PE20010623A1 (en) * | 1999-10-05 | 2001-07-07 | Gruenenthal Chemie | USE OF (+) - TRAMADOL AND / OR O-DEMETILTRAMADOL FOR TREATMENT OF INCREASED URINARY URGENCY AND / OR URINARY INCONTINENCE |
| DE10108123A1 (en) * | 2001-02-21 | 2002-10-02 | Gruenenthal Gmbh | drug combination |
| US20110251286A1 (en) | 2010-03-10 | 2011-10-13 | Gruenenthal Gmbh | Crystalline salts and/or co-crystals of O-desmethyltramadol |
| US10702485B2 (en) | 2011-07-09 | 2020-07-07 | Syntrix Biosystems Inc. | Compositions and methods for overcoming resistance to tramadol |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE69215316T2 (en) * | 1991-09-06 | 1997-03-20 | Mcneilab Inc | Compositions containing tramadol and any codeine, oxycode or hydrocode and their use |
| AU661723B2 (en) * | 1991-10-30 | 1995-08-03 | Mcneilab, Inc. | Composition comprising a tramadol material and a non-steroidal anti-inflammatory drug |
| DE4315525B4 (en) * | 1993-05-10 | 2010-04-15 | Euro-Celtique S.A. | Pharmaceutical composition |
| DE4329794C2 (en) * | 1993-09-03 | 1997-09-18 | Gruenenthal Gmbh | Tramadol salt-containing drugs with delayed release |
| DE19525137C2 (en) * | 1995-07-11 | 2003-02-27 | Gruenenthal Gmbh | 6-Dimethylaminomethyl-1-phenyl-cyclohexane compounds as intermediates for the preparation of pharmaceutical agents |
| DE19601744C2 (en) * | 1996-01-19 | 1998-04-16 | Gruenenthal Gmbh | Process for the preparation of the enantiomers of O-demethyltramadol |
-
1997
- 1997-03-25 DE DE19712398A patent/DE19712398A1/en not_active Ceased
-
1998
- 1998-03-05 EP EP98103874A patent/EP0870499A1/en not_active Withdrawn
- 1998-03-21 CN CN98107860A patent/CN1196932A/en active Pending
- 1998-03-23 IL IL12378898A patent/IL123788A0/en unknown
- 1998-03-23 HU HU9800623A patent/HUP9800623A3/en unknown
- 1998-03-23 CA CA002232930A patent/CA2232930A1/en not_active Abandoned
- 1998-03-24 PE PE1998000210A patent/PE62399A1/en not_active Application Discontinuation
- 1998-03-24 NO NO981320A patent/NO981320L/en unknown
- 1998-03-24 UY UY24934A patent/UY24934A1/en not_active Application Discontinuation
- 1998-03-24 PL PL98325509A patent/PL325509A1/en unknown
- 1998-03-24 JP JP10075995A patent/JPH1112166A/en not_active Withdrawn
- 1998-03-24 KR KR1019980010058A patent/KR19980080580A/en not_active Application Discontinuation
- 1998-03-25 AU AU59517/98A patent/AU5951798A/en not_active Abandoned
- 1998-03-25 BR BR9801839-6A patent/BR9801839A/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| PE62399A1 (en) | 1999-07-10 |
| PL325509A1 (en) | 1998-09-28 |
| HUP9800623A3 (en) | 1999-03-29 |
| JPH1112166A (en) | 1999-01-19 |
| NO981320L (en) | 1998-09-28 |
| NO981320D0 (en) | 1998-03-24 |
| CN1196932A (en) | 1998-10-28 |
| EP0870499A1 (en) | 1998-10-14 |
| HUP9800623A2 (en) | 1999-01-28 |
| IL123788A0 (en) | 1998-10-30 |
| HU9800623D0 (en) | 1998-05-28 |
| DE19712398A1 (en) | 1998-10-01 |
| KR19980080580A (en) | 1998-11-25 |
| BR9801839A (en) | 2000-01-18 |
| AU5951798A (en) | 1998-10-01 |
| UY24934A1 (en) | 1998-04-21 |
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Legal Events
| Date | Code | Title | Description |
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| FZDE | Discontinued |