NO321168B1 - Krystall av benzimidazolforbindelse, farmasoytisk sammensetning som omfatter et slikt krystall, samt anvendelse derav ved behandling av digestivt magesar - Google Patents
Krystall av benzimidazolforbindelse, farmasoytisk sammensetning som omfatter et slikt krystall, samt anvendelse derav ved behandling av digestivt magesar Download PDFInfo
- Publication number
- NO321168B1 NO321168B1 NO20016087A NO20016087A NO321168B1 NO 321168 B1 NO321168 B1 NO 321168B1 NO 20016087 A NO20016087 A NO 20016087A NO 20016087 A NO20016087 A NO 20016087A NO 321168 B1 NO321168 B1 NO 321168B1
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- Norway
- Prior art keywords
- crystal
- methyl
- benzimidazole
- pharmaceutical composition
- acid
- Prior art date
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- HELXLJCILKEWJH-NCGAPWICSA-N rebaudioside A Chemical compound O([C@H]1[C@H](O)[C@@H](CO)O[C@H]([C@@H]1O[C@H]1[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O1)O)O[C@]12C(=C)C[C@@]3(C1)CC[C@@H]1[C@@](C)(CCC[C@]1([C@@H]3CC2)C)C(=O)O[C@H]1[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O1)O)[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O HELXLJCILKEWJH-NCGAPWICSA-N 0.000 description 1
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- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 239000000892 thaumatin Substances 0.000 description 1
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- AOBORMOPSGHCAX-DGHZZKTQSA-N tocofersolan Chemical compound OCCOC(=O)CCC(=O)OC1=C(C)C(C)=C2O[C@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C AOBORMOPSGHCAX-DGHZZKTQSA-N 0.000 description 1
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- 230000032258 transport Effects 0.000 description 1
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- UJMBCXLDXJUMFB-UHFFFAOYSA-K trisodium;5-oxo-1-(4-sulfonatophenyl)-4-[(4-sulfonatophenyl)diazenyl]-4h-pyrazole-3-carboxylate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)C1=NN(C=2C=CC(=CC=2)S([O-])(=O)=O)C(=O)C1N=NC1=CC=C(S([O-])(=O)=O)C=C1 UJMBCXLDXJUMFB-UHFFFAOYSA-K 0.000 description 1
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- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
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Classifications
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Oncology (AREA)
- Communicable Diseases (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Description
Den foreliggende oppfinnelsen vedrører et krystall av en benzimidazolforbindelse som viser anti-magesårvirkning. Foreliggende oppfinnelse vedrører også en farmasøytisk sammensetning som omfatter et slikt krystall.
2-[[[3-metyl-4-(2,2,2-trifluoretoksy)-2-py^ eller et salt derav med en anti-magesårvirkning er rapportert i JP-A^1-50978.
Det er et behov for et mer stabilt og bedre absorberbart anti-mågesårmiddel.
Ved at chiralt svovel er i molekylstrukturen derav, forekommer 2-[[[3-metyl-4-(2,2,2-trifluoretoksy)-2-pyridinyl]metyl]sulfinyl]-lH-benzimidazol som to typer optiske isomerer. Etter omfattende undersøkelser lyktes de foreliggende oppfinnerne i å optisk løse opp og krystallisere (R)-isomeren av 2-[[[3-metyl-4-(2,2,2-trifluoretoksy)-2-pyridinyl]metyl]sulfinyl]-lH-benzimidazol og de fant for første gang at dette krystallet tjener som et tilfredsstillende legemiddel, og utførte ytterligere undersøkelser basert på dette runnet, og utviklet den foreliggende oppfinnelsen.
Følgelig vedrører den foreliggende oppfinnelsen:
[1] et krystall av (R)-2-[[[3-metyl-4-(2,2,2-trifluoretoksy)-2-pyridinyl]metyl]sulfinyl]-lH-benzimidazol eller et salt derav;
[2] et krystall av imidazolforbindelsen på fri form ifølge [1] over der røntgenpulver-diffraksjonsanalysemønsteret har karakteristiske topper ved interplanare avstander (d) på 11,68,6,77,5,84,5,73,4,43,4,09,3,94,3,89,3,69,3,41 og;3,ll Ångstrøm;
[3] en farmasøytisk sammensetning som omfatter krystallet ifølge [1] over;
[4] anvendelse av krystallet ifølge [1] over til fremstilling av én farmasøytisk sammensetning for å behandle eller forebygge digestivt magesår.
"Saltet" av " (R)-2-[[[3-metyl-4-(2,2(2-tirfluoretoksy)-2-pyridinyl]metyl]sulfmyl]-lH^ benzimidazol eller et salt derav" inkluderer for eksempel metallsaltet, salter med organiske baser, salter med basiske aminosyrer, og så videre. Fysiologisk akseptable salter er foretrukne.
Metallsalter inkluderer for eksempel alkalimetallsalter, slik som natriumsalt og kalium-salt; og jordalkalimetallsalter, slik som kalsiumsalt, magnesiuihsalt og bariumsalt. Salter med organiske baser inkluderer for eksempel salter med trimetylamin, trietylamin, pyridin, pikolin, etanolamin, dietanolamin, trietanolamin, dicykloheksylamin, N,N-dibenzyletylendiamin, etc. Salter med basiske aminosyrer inkluderer for eksempel salter med arginin, lysin, etc.
Krystallet av(R)-2-[[[3-metyl-4-(2,2,2-tirfluoretø benzimidazol eller et salt derav kan være et hydrat eller ikke.
"Hydratet" inkluderer 0,5 hydratvann til 5,0 hydratvann. Blant annet er 0,5 hydratvann, 1,0 hydratvann, 1,5 hydratvann, 2,0 hydratvann og 2,5 hydratviann foretrukket. Mer foretrukket er 1,5 hydratvann.
Krystallet av (R)-2-[[[3-metyl-4-(2,2,2-tirfluoretoksy)-2-pyridinyl]metyl]sulfinyl]-1H-benzimidazol eller et salt derav kan fremstilles ved å underkaste 2-[[[3-metyl-4-(2,2,2-trifluoretoksy)-2-pyridinyl]metyl]sulfonyl]-lH-benzimidazol eller et salt derav for en optisk oppløsning eller å underkaste 2-[[[3-metyl-4-(2,2,2-trifluoretoksy)-2-pyridinyl]metyl]tio]-lH-benzimidazol for en asymmetrisk oksidasjon for å oppnå (R)-isomeren, etterfulgt av krystallisasjon av den oppnådde isomeren.
Fremgangsmåter for optisk oppløsning inkluderer per se kjente fremgangsmåter, for eksempel en fraksjonen omkrystallisasjonsfremgangsmåte, en chiral kolonnefremgangsmåte, en diastereomer fremgangsmåte, og så videre. Asymmetrisk oksidasjon inkluderer per se kjente fremgangsmåter.
"Fraksjonen onik^stallisasjonsfremgangsmåte" inkluderer en fremgangsmåte der et salt dannes mellom et racemat og en optisk aktiv forbindelse [for eksempel (+)-mandelsyre, (-)-mandelsyre, (+)-vinsyre, (-)-vinsyre, (+)-l-fenetylamin, (-)rl-fenetylamin, cinkonin, (-)-cinkonidin, brucin, etc], der saltet separeres ved fraksjonell omkrystallisering etc, og, om ønskelig, underkastes en nøytraliseirngsprosess, for å gi en fri optisk isomer.
"Chiral kolonnefremgangsmåte" inkluderer en fremgangsmåte; der et racemat eller et salt derav påføres en kolonne for optisk isomerseparering (chiral kolonne). I tilfelle av væskekromatografi separeres for eksempel optisk isomerer ved å tilsette et racemat til en chiral kolonne, slik som ENANTIO-OVM (fremstilt av Tosoh Corporation) eller DAICEL CHIRAL seriene (fremstilt av Daicel Corporation), og å utvikle racematet i vann, en buffer (for eksempel fosfatbuffer), et organisk løsningsmiddel (for eksempel heksan, etanol, metanol, isopropanol, acetonitril, trifluoreddiksyre, dietylamin, trietylamin, etc), eller en løsningsmiddelblanding derav. Ved tilfelle gasskromatografi benyttes for eksempel en chiral kolonne, slik som CP-ChirasiUDeX CB (fremstilt av GL Science) for å separere optiske isomerer.
"Diastereomerrfemgangsmåten" inkluderer en fremgangsmåte der et racemat og et otisk aktivt reagens reageres (foretrukket et optisk aktivt reagens reageres til 1-posisjonen i benzoimidazol-gruppen) for å gi en diastereomerblanding, som deretter underkastes ordinære separasjonsmidler (for eksempel fraksjonell omkrystållisering, kromatografi, etc.) for å oppnå enten diastereomer, som underkastes en kjemisk reaksjon (for eksempel syrehydrolyse, basehydrolyse, hydrogenolyse, etc.) for å spalte av den oprisk aktive reagensenheten, hvorved den ønskede optiske isomeren;oppnås. "Optisk aktiv reagens" inkluderer for eksempel en optisk aktiv organisk syre som MTPA [oc-metoksy-a-(trifluormetyl)fenyleddiksyre] og (-)-metoksyeddiksyre; og et optisk aktivt alkoksy-metylhalid, slik som (lR-endo)-2-(klormetoksy-l,3,3-trimetylbicyklo[2.2.1]heptan, etc.
2-[[[3-metyl-4-(2,2,2-trifluoretoksy)-2-pyridinyl]metyl]sulfinyl]-lH-benzimidazol eller et salt derav fremstilles ved fremgangsmåter som beskrevet i JP-A-61-50978, US-patent 4,628,098, eller analoge fremgangsmåter derav.
Fremgangsmåter for krystallisering inkluderer per se kjente fremgangsmåter, for eksempel en krystallisering fra løsning, en krystallisering fra dam, og en krystallisering fra smeltet form.
Fremgangsmåter ifølge "krystallisering fra løsening" inkluderér for eksempel en konsentrasjons fremgangsmåte, en langsom avkjølingsfremgangsmåte, en reaksjons-fremgangsmåte (diffusjonsrfemgangsmåte, elektrolysefremgarigsmåte), en hydrotermisk vekstfremgangsmåte, en smeltemiddelrfemgangsmåte, og så videre. Løsningsmidler som benyttes inkluderes for eksempel aromatiske hydrokarboner (for eksempel benzen, toluen, xylen, etc), halogenerte hydrokarboner (for eksempel diklormetan, kloroform, etc), mettede hydrokarboner (for eksempel heksan, heptan, cykloheksan, etc), etere (for eksempel dietyleter, diisopropyleter, tetrahydrofuran, dioksan, etc), nitriler (for eksempel acetonitril, etc), ketoner (for eksempel aceton, etc),;sulfoksider (for eksempel dimetylsulfoksid, etc), syreamider (for eksempel N,N-dimetylformamid, etc), estere (for eksempel etylacetat, etc), alkoholer (for eksempel metanol, etanol, isopropyl-alkohol, etc), vann osv. Disse løsningsmidlene kan benyttes alene eller i blanding av to eller flere typer i passende forhold (for eksempel 1:1 til 1:100).
Fremgangsmåter ifølge 'Tcrystallisering fra damp" inkluderer for eksempel en gassifiseringsfremgangsmåte (lukket rør fremgangsmåte, gassfrømfremgangsmåte), en gassfasereaksjonsfremgangsmåte, en kjemisk transporteringsfremgangsmåte, og så videre.
Fremgangsmåter ifølge "krystallisering fra smeltet form" inkluderer for eksempel en normal frysefremgangsmåte (opptrekksfremgangsmåte, temperaturgradientfremgangs-måte, Bridgeman-fremgangsmåte), en sonesmeltefremgangsmåte (sonenivårfemgangs-måte, flytsonefremgangsmåte), en spesialvekstfremgangsmåte:(VLS-fremgangsmåte, væskefase-epitaksisk fremgangsmåte), og så videre.
For å analysere krystallet som er oppnådd er det vanlig å benytte røntgendiffraksjons-krystallografianalyse. I tillegg kan krystalloirentering også bestemmes ved en mekanisk metode, en optisk metode, etc.
Således er det oppnådd et krystall av (R)-2-[[[3-metyl-4-(2,2,2-trifluoretoksy)-2-pyridinyl]metyl]sulifnyl]-lH-benzimidazol eller et salt derav (heretter også referert til som "krystall ifølge den foreliggende oppfinnelsen") som er nyttig som et legemiddel, fordi det viser fortreffelig anti-magesårvirkning, magesyresekresjonshemmende virkning, mageslimhinnebeskyttende virkning, anti- Helicobacter pylori virkning, etc, og fordi den har lav toksisitet. Videre forbedres ikke kun stabiliteten ved å krystallisere (R)-isomeren, men dets håndtering forenkles også slik at det kan fremstilles som en fast farmasøytisk sammensetning med god reproduserbarhet. Krystallet ifølge foreliggende oppfinnelse er derfor nyttig som et legemiddel med lave doserjog lav alminnelig forekomst av uheldige reaksjoner.
Krystallet ifølge den foreliggende oppfinnelsen er nyttig for pattedyr (for eksempel mennesker, aper, sauer, kveg, hester, hunder, katter, kaniner, rotter, mus, etc.) ved behandlingen og forebyggingen av digestivt magesår (for eksempel gastrisk magesår, duodenalt magesår, stomalt magesår, Zollinger-Ellison syndrom, etc), gastritt, refluks-esofagitt, NUD (non-ulcer dyspepsia), magekreft og gastrisk MALT lymfom; Helicobacter pylori utrydding; undertrykkelse av øvre mage-tårmblødning på grunn av digestivt magesår, akutt stress-magesår og blødende gastritt; undertrykkelse av øvre mage-tarmblødning på grunn av invasivt stress (stress fra størré kirurgisk inngrep som nødvendiggjør intensiv behandling etter inngrepet, og fra cerebralt vaskulære for-styrrelser, hodetraumer, flerorgansvikt og alvorlig forbrenning: som nødvendiggjør intensiv behandling); behandling og forebygging av magesår forårsaket av et ikke-steroid anti-inflammatorisk middel; behandling og forebygging av økt syreinnhold og magesår på grunn av post-operativt stress; pre-anestesi-administrering, etc.
Krystallet ifølge oppfinnelsen har lav toksisitet og kan sikkert administreres oralt eller ikke oralt (for eksempel topisk, rektalt og intravenøs administrering, etc), som sådan eller på form av farmasøytiske sammensetninger formulert med en farmakologisk akseptabel bærer, for eksempel tabletter (inkludert sukkerbelagte tabletter og film-belagte tabletter), pulvere, granuler, kapsler (inkludert myke kapsler), orale oppløsende tabletter, væsker, injiserbare preparater, stikkpillere, forsinkede frigivelsespreparater og plastere, ifølge en alminnelig kjent fremgangsmåte.
Innholdet av krystaller ifølge den foreliggende oppfinnelsen i den farmasøytiske sammensetningen ifølge den foreliggende oppfinnelsen er omtrent 0,01 til 100 vekt-%, relativt til hele sammensetningen. Varierende, avhengig av subjektet som skal administreres, administreringruten, sykdommen som skal behandles, etc, er dosen normalt omtrent 0,5 til 1.500 mg/dag, foretrukket omtrent 5 til 150 mg/dag, basert på den aktive ingrediensen, for eksempel når den administreres oralt som et anti-magesårmiddel til et voksent menneske (60 kg). Krystaller ifølge den foreliggende oppfinnelsen kan administreres én gang pr. dag eller i 2 til 3 oppdelte porsjoner pr. dag.
Farmakologisk akseptable bærere som kan benyttes for å fremstille den farmasøytiske sammensetningen ifølge foreliggende oppfinnelse inkludere forskjellige organiske eller uorganiske bærende substanser som er vanlige å benytte som farmasøytiske materialer, inkludert eksipienter, smøremidler, bindemidler, oppløsende midler, vannløselige polymerer og basiske, uorganiske salter ved faste preparater; og oppløsningsmidler, oppløsende hjelpemidler, suspenderingsmidler, isotoniserende midler, buffere og beroligende midler for flytende preparater. Andre ordinære farmasøytiske additiver, slik som konserveringsmidler, antioksidanter, fargestoffer, søtninginidler, surgj ørende midler, boblende midler og smaksstoffer kan også benyttes om nødvendig.
Slike "eksipienter" inkluderer for eksempel laktose, sukrose, D-mannitol, stivelse, maisstivelse, krystallinsk cellulose, svakt surt anhydrid og titandioksid.
Slike "smøremidler" inkluderer for eksempel magnesiumstearåt, sukrose, fettsyreestere, polyetylenglykol, talkum og stearinsyre.
Slike "bindemidler" inkluderer for eksempel hydroksypropylcéllulose, hydroksypropylmetylcellulose, krystallinsk cellulose, a-stivelse, polyvinylpyrrolidon, arabisk gummipulver, gelatin, pullulan og lav-substitusjonell hydroksypropylcéllulose.
Slike "oppløsende midler" inkluderer (1) kryssbindende povidpn, (2) det som kalles super-disintegranter, slik som kryssbundet kannallose-natrium (FMC-Asahi Chemical) og karmellose-kalsium (Gotoku Yakuhin), (3) karboksymetylstivelse-natrium (for eksempel produkt fraMatsutani Chemical), (4) lav-substituert hydroksypropylcéllulose (for eksempel produkt fra Shin.Etsu Chemical), (5) maisstivelse, og så videre. "Kryssbundet pyrrolidon" kan være enhver kryssbundet polymer med det kjemiske navnet l-etanyl-2-pyrrolidinon-homopolymer, inkludert polyvinylpyrrolidon (PVPP) og l-vinyl-2-pyrrolidinon-homopolymer, og er eksemplifisert ved Colidon CL (fremstilt av BASF), Polyplasdon XL (produsert av ISP), Polyplasdon XL-10 (fremstilt av ISP) og Polyplasdon INF-10 (fremstilt av ISP).
Slike "vann-løselige polymerer" inkluderer for eksempel etanpl-løselige vann-løselige polymerer [for eksempel cellulosederivater, slik som hydroksypropylcéllulose (heretter også referert til som HPC), polyvinylpyrrolidon] og etanol-uløselige vann-løselige polymerer [for eksempel cellulosederivater, slik som hydroksypropylmetylcellulose (heretter også referert til som HPMC), metylcellulose og karboksymetylcellulose-natrium, natriumpolyakrylat, polyvinylalkohol, natriumalginati guargummi].
Slike "basiske uorganiske salter" inkluderer for eksempel basiske uorganiske salter av natrium, kalium, magnesium og/eller kalsium. Foretrukket er basiske uorganiske salter av magnesium og/eller kalsium. Mer foretrukket er basiske uorganiske salter av magnesium. Slike basiske uorganiske salter av magnesium inkluderer for eksempel natriumkarbonat, natriumhydrogenkarbbnat, dinatriumhydrogénfosfat, etc. Slike basiske uorganiske salter av kalium inkluderer for eksempel kaliumkarbonat, kaliumhydrogen-karbonat, etc. Slike basiske uorganiske salter av magnesium inkluderer for eksempel tungmangnesiumkarbonat, magnesiumkarbonat, magnesiumoksid, magnesiumhydroksid, magnesium-metasilikataluminat, magnesiumsilikatj magnesiumaluminat, syntetisk hydrotalcitt [Mg6Al2(OH)i6 • CO3 • 4H20], aluminahydroksidmagnesium, og så videre. Blant annet er tungmagnesiumkarbonat, magnesiumkarbonat, magnesiumoksid, magnesiumhydroksid etc. foretrukne. Slike basiske uorganiske salter av kalsium inkluderer for eksempel utfelt kalsiumkarbonat, kalsiumhydroksid, etc.
Slike "løsningsmidler" inkluderer for eksempel vann for injeksjon, alkohol, propylen-glykol, makrogol, sesamolje, maisolje og olivenolje. Slike "oppløsende hjelpemidler" inkluderer for eksempel polyetylenglykol, porpylen-glykol, D-mannitol, benzylbenzoat, etanol, trisaminometan, kolesterol, trietanolamin, natriumkarbonat og natriumcitrat.
Slike "suspenderende midler" inkluderer for eksempel surfaktanter, slik som stearyl-trietanolamin, natriumlaurylsulfat, laurylaminopropionsyre, lecitin, benzalkoniumklorid, benzetoniumklorid og monostearinglyserol; og hydrofile polymerer, slik som polyvinylalkohol, polyvinylpyrrolidon, karboksymetylcellulosenatrium.imetylcellulose, hydroksymetylcellulose, hydroksyetylcellulose og hydroksypropylcéllulose.
Slike "isotoniserende midler" inkluderer for eksempel glukose, D-sorbitol, natrium-klorid, glyserol og D-mannitol.
Slike "buffere" inkluderer for eksempel bufferløsninger av fosfater, acetater, karbonater, citrater etc.
Slike "beroligende midler" inkluderer for eksempel benzylalkohol.
Slike "konserveringsmidler" inkluderer for eksempel p-oksybenzosyreestere, klor-butanol, benzylalkohol, fenetylalkohol, dehydroieddiksyre og sorbinsyre.
Slike "antioksidanter" inkluderer for eksempel sulfitter, askorbinsyre og a-tokoferol.
Slike "fargestoffer" inkluderer for eksempel matfargestoffer, slik som Food Color Yellow nr. 5, Food Color Red nr. 2 og Food color Blue nr. 2; og matlakkfarger og rødoksider.
Slike "støtningsmidler" inkluderer for eksempel sakkarin-natrium, dikalium-glycyrrhetinat, aspartam, stevia og thaumatin.
Slike "surgjørende midler" inkluderer for eksempel sitronsyre (sitronanhydrid), vinsyre og eplesyre.
Slike "boblende midler" inkluderer for eksempel natriumbikarbonat.
Slike "smaksstoffer" kan være syntetiske substanser eller naturlig forekommende substanser, og inkluderer for eksempel sitron. Lime, appelsin, mentol og jordbær. Krystaller ifølge den foreliggende oppfinnelsen kan fremstilles som et preparat for oral administrering ifølge en vanlig kjent fremgangsmåte ved for eksempel å kompresjons-forme det i nærvær av en eksipient, et oppløsende middel, et bindemiddel, et smøre-middel, eller lignende, og deretter belegge det, om nødvendig,; ved en alminnelig kjent fremgangsmåte med hensyn på smaksmaskering, tarmoppløsning eller forsinket frigivelse. For et tarmpreparat, kan et mellomliggende lag frembringes ved en alminnelig kjent fremgangsmåte mellom tannlaget og det legemiddelholdige laget i den hensikt å separere de to lagene.
i
For å fremstille krystallet ifølge den foreliggende oppfinnelsen som en oral oppløsende
tablett inkluderer tilgjengelige fremgangsmåter for eksempel en fremgangsmåte der en kjeme inneholder krystallinsk cellulose og laktose belegges på krystallet ifølge den foreliggende oppfinnelsen og et basisk, uorganisk salt, og belgges ytterligere med et beleggingslag som inneholder en vannløselig polymer, for å gi en sammensetning, som belegges med et enterisk beleggingslag som inneholder polyetylenglykol, som videre belegges med enterisk beleggingslag som inneholder trietylcitrat, og som ytterligere belegges med et enterisk beleggingslag som inneholder polyetylenglykol, og som igjen ytterligere belegges med mannitol, for å gi fine granuler som blandes med tilsetnings-stoffer og formes. Det ovenfor nevnte "enteriske beleggingslaget" inkluderer for eksempel vandige, enteriske polymersubstrater, slik som celluioseacetatftalat (CAP),
hydroksvpropylmetylcelluloseftalat, hydroksvmetylcelluloseaætatsuksinat, metakrylin-syre-kopolymerer [f.eks. Eudragit L30D.55 (handelsnavn; fremstilt av Rohm), Colicoat MAE30DP (handelsnavn; fremstilt av BASF), Polykid PA30 (handelsnavn; fremstilt av San-yo Chemical)], karboksymetyletylcellulose og skjellakk; forsinkede frigivelses-substrater, slik som metakrylinsyrepolymerer [f.eks. Eudragit NE30D (handelsnavn), Eudragit RL30D (handelsnavn), Eudragit RS30D (handelsnavn), etc.]; vannløselige polymerer; myknere, slik som trietylcitrat, polyetylenglykol, acetylerte monoglyserider, triacetin og lakserolje; og blandinger derav. Det ovenfor nevntie "additivet" inkluderer for eksempel vannløselige sukkeralkoholer (f.eks. sorbitol, mannitol, multitol, reduserte stivelsessakkarider, xylitol, redusert paratinose, erythritol, etc), krystallinsk cellulose [f. eks. Ceolas KG 801, Avicel PH 101, Avicel PH 102, Avicel PH 301, Avicel PH 302, Avicel RC-591 (krystallinsk cellulose, karmellosenatrium)], lay-substituert hydroksypropylcéllulose [f.eks. LH-22, LH-32, LH-23, LH-33 (Shin-Eteu Chemical) og blandinger derav]; bindemidler, surgjørende midler, boblende midler, søtningsmidler, smaksstoffer, smøremidler, fargestoffer, myknere, eksipienter,^ oppløsende midler, etc benyttes også.
Krystaller ifølge den foreliggenden oppfinnelsen kan benyttes i kombinasjon med 1 til 3 andre aktive ingredienser.
Slike "andre aktive ingredienser" inkluderer for eksempel antirHelicobacterpylori aktive substranser, imidazolforbindelser, bismutsalter, quinolonforbindelser, og så videre. Av disse substansene er anti- Helicobacter pylori virkningssubstanser, imidazolforbindelser etc. foretrukne. Slike " znti- Helicobacterpylori vij-kningssubstanser" inkluderer for eksempel antibiotiske penicilliner (f.eks. amoksicillin, benzylpenicillin, piperacillin, cefaklor, etc), antibiotiske cefemer (f.eks. cefiksim, cefaklor, etc), antibiotiske makrolider (f.eks. erythromycin, klarithromycin, etc); antibiotiske tetracykliner (f.eks. tetracyklin, minocyklin, streptomycin, etc), antibiotiske aminoglykosider (f.eks. gentamicin, amikacin, etc), imipenem, og så videre. Av disse substansene er antibiotiske penicilliner, antibiotiske makrolider, etc. foretrukne. Slike ""midazol-forbindelser" inkluderer for eksempel metronidazol, mikonazol, etc. Slike "bismutsalter" inkluderer for eksempel bismutacetat, bismutcitrat, etc.:Slike "quinolonforbindelser" inkluderer for eksempel ofloksacin, ciploksacin, etc.
Slike "andre aktive ingredienser" og krystallet ifølge den foreliggende oppfinnelsen kan også benyttes i kombinasjon som en blanding fremstilt som eri enkel farmasøytisk sammensetning [f.eks. tabletter, pulvere, granuler, kapsler (inkludert myke kapsler), væsker, injiserbare preparater, stikkpillere, forsinket frigivelsebpreparater, etc], ifølge en alminnelig kjent fremgangsmåte, og kan også fremstilles som separater preparater og administreres til den samme pasienten samtidig eller ved tidsintervall.
Den foreliggende oppfinnelsen blir heretter beskrevet i mer detalj ved hjelp av, men er ikke begrenset til, de følgende referanseeksemplene, eksempler og eksperimentelle eksempler.
I de følgende referanseeksemplene og eksemplene indikerer uttrykket "romtemperatur" omtrent 15 til 30°C.
Smeltepunkter ble målt ved å benytte Micro Melting Point Apparatus (fremstilt av Yanagimoto Seisakusho), og ukorrigerte verdier er vist.
'H-NMR-spektra ble bestemt med CDCI3 som løsningsmiddelet ved å benytte Varian Gemini-200; data er vist i kjemiske skift 5 (ppm) fra den interne standarden tetrametyl-silan.
IR ble bestemt ved å benytte SHIMADZU FTIR-8200.;
UV ble bestemt ved å benytte HITACHI U-3200 spektrofotometeret.
Optisk rotasjon [a]o ble bestemt ved 20°C ved å benytte DIP-370 digital polarimeter (fremstilt av JASCO).
Optisk renhet ble bestemt ved HPLC (kolonne:CHIRALCEL OD 4,6 mm dia. x 250 mm, temperatur: omtrent 20°C, mobil fase: heksan/2-propanol;= 80/20 eller heksan/2-propanol = 85/15, strømningshastighet: 1,0 ml/min., deteksjonjsbølgelengde: 285 nm) ved å benytte en chiral kolonne.
Kxystall-røntgendiffraksjonsdata for å bestemme den absolutte strukturen av sulfoksid ble oppnådd ved hjelp av et 4-sirkel diffraktometer (RIGAKU;AFC5R) ved å benytte Cu-Kxa stråling. Etter den initielle fasen var bestemt ved den direkte fremgangsmåten, ble den endelige strukturen analysert ved å benytte SHELXL-93. Røntgenpulver-diffraksjon ble bestemt ved å benytte røntgenpulverdiffraksjorismeter Rigaku RINT2500 (ultraX18) nr. PX-3.
De andre symbolene som her er benyttet har de følgende definisjoner:
s: singlet
d: dublett
t: triplen
q: kvartett
m: multiplett
bs: bred singlet
J: bindingskonstant
Eksempler
Referanseeskempel 1
Isolering av (R)-2-[[[3-metyl-4-(2,2,2-Mfluoretoksy)-2-pyrimnyl] benzimidazol (R(+)-lansoprazol)
2-[[[3-metyl-4-(2,2,2-trifluoretoksy)-2-pyri^
(lansoprazol) (racemat) (3,98 g) ble oppløst i følgende mobile iase (330 ml) og acetonitril (37 ml) og fraksjonert ved HPLC (kolonne: CHIRALCEL OD 20 mm dia. x 250 mm, temperatur: 30°C, mobil fase: heksan/2-propanol/etanol = 255/35/10, strømningshastighet: 16 ml/min., deteksjonsbølgelengde: 285 hm, 1 skudd; 20-25 mg). Fraksjoner av optiske isomerer med kortere retensjonstid ble forenet og konsentrert; de individuelle mengdene ble forenet og oppløst i etanol og filtrert gjennom et 0,45 nm filter; etter at heksan ble tilsatt ble filtratet igjen fordampet til tørrhet til å gi R(+)-lansoprazol (1,6 g, optisk renhet > 97,6 % ee) som en amorf substans.
Den amorfe substansen som ble oppnådd ble underkastet fraksjonering og isolering på samme måte som over for å gi R(+)-lansoprazol (1,37 g, optisk renhet > 99,9 % ee) som en amorf substans.
[o]D = +174.3C (c = 0,994 %, CHC13)
Referanseeksempel 2
Isolering av (R)-2-[[[3-metyl-4-(2,2,2-tirfluoretoksy)-2-pyridihyl]metyl]sulifnyl]-lH-benzimidazol (R(+)-lansoprazol)
Lansoprazol (racemet) (34,2 g) ble oppløst 12-propoanol (1,710 ml) og heksan (1,140 ml) som inneholdt trietylamin (0,2 %) og fraksjonert ved HPLC (kolonne. CHIRALCEL OD 50 mm dia. x 500 mm, temperatur: romtemperatur, mobil fase: heksan/2-propanol = 85/15, strømningshastighet: 60 ml/min., deteksjonbølgelengde: 285 nm, 1 skudd: omtrent 300 mg) for å isolere de individuelle optiske isomerer. Fraksjoner av en optisk isomer med kortere retensjonstid ble forenet og konsentrert; de individuelle metodene ble forenet og oppløst i etanol (250 ml); etter trietylamin (3 ml) ble tilsatt, ble løsningen filtrert gjennom et 0,45 um filter. Etter filtratet var konsentrert ble heksan tilsatt og filtratet ble igjen fordampet til tørrhet for å gi R(+)-lansoprazol (9,31 g, optisk renhet 98,3 % ee) som en amorf substrans.
Eksempel 1
Krystall av (R)-2-[[[3-metyl-4-(2,2,2-triflM benzimidazol (R(+)-lansoprazol)
Amorf R(+)-lansoprazol som ble oppnådd i referanseeksempel 1 (100 mg) ble oppløst i acetonitril (1 ml), som gradivis ble fordampet ved romtemperatur i en nitrogenstrøm. Etter et krystall begynte å dannes ble dietyleter (1,5 ml) tilsatt og beholderen ble lukket og holdt stående ved romtemperatur.
Krystallet som således ble dannet be underkastet røntgenstrukturell analyse, og den absolutte konfigurasjonen av sulfoksid ble funnet å være R-konfigurasjonen ved en fremgangsmåte ved å benytte et Flack-parameter. Den gjenværende delen av krystallet ble samlet opp ved filtrering, vasket to ganger med dietyleter (1 ml) og tørket under redusert trykk, for å gi krystaller av R(+)-lansoprazol (38 mg)
Smp.: 144,0-l44,5°C(dek.)
Elementanalyse
Beregnet: C: 52,03, H: 3,82, N: 11,38, S: 8,68, F: 15,43,0: 8,66
Funnet: C: 52,08, H: 3,76, N: 11,58, S: 8,75, F: 15,42
'H-NMR: 2,25(3H,s), 4,40(2H,q,J=7,8Hz), 4,68(1 H,d,J=13,8Hz), 4,85(lH,d,J=13,8Hz), 6,69(lH,d,J=6,0Hz), 7,29-7,39(2H,m), 7,52(lH,m), 7,81(lH,m), 8,37(lH,d,J=6,0Hz), ll,00(lH,bs).
IR( v cm<*1>): 3081, 3042,2984,1586,1478,1441, 1306,1267,1163 UVmaks.(CHCl3): 283,7 nm ;[a}D =+199,2° (c = 0,202 %, CHC13) ;;Eksempel 2 ;Krystall av (R)-2-[[[3-metyl-4-(2,2,2-trifluoertoksy)-2-p benzimidazol (R(+)-lansoprazol) ;Amorf (R)-2-[[[3-metyl-4-(2,2,2-trifluoretoksy)-2-pyirdinyl]metyl]su^ benzimidazol (R(+)-lansoprazol) som oppnådd i referanseeksempel 2 (9,17 g) ble oppløst i aceton (20 ml), og vann (IS ml) ble tilsatt under forsiktig oppvarming. Etter løsningen var hensatt ved romtemperatur over natten ble vann (20 ml) tilsatt etterfulgt av ultralyd. Etter at det faste stoffe var oppsamlet ved filtering ble det vasket med vann (30 ml, 20 ml), deretter vasket med diisopropyleter (20 ml), og tørket under redusert trykk, til å gi et fast stoff (9,10 g). Det faste stoffet som ble oppnådd (9,00 g) ble oppløst i aceton (30 ml), og etter løsningen var filtrert, ble diisopropyleter (50 ml) tilsatt til filtratet. En krystallkim ble plassert, og blandingen ble holdt stående ved romtemperatur over natten. Utfelte krystaller ble oppsamlet ved filtrering, vasket tre ganger med diisopropyleter (10 ml) og tørket under redusert trykk, til å gi krystaller (7,85 g). Krystallene som ble oppnådd (7,80 g) ble oppløst under oppvarming i acetpn (22,5 ml) og vann (30 ml), og denne løsningen ble hensatt ved romtemperatur i 1 time. Et utfelt faststoff ble oppsamlet ved filtrering, vasket med aceton-vann (1:4) (15 ml), og tørket under redusert trykk, til å gi et faststoff (3,88 g). Det faste stoffet som ble oppnådd (3,88 g) ble oppløst under oppvarming i aceton (4 ml) og diisopropyleter (14 ml) ble tilsatt. Denne løsningen ble hensatt ved romtemperatur i 30 minutter. Utfelte krystaller ble samlet opp ved filtrering, vasket to ganger med diisopropyleter (6 ml), og {tørket under redusert trykk, til å gi krystaller av R(+)-lansoprazol (3,40 g, optisk renhet 99,8 % ee). ;Smp.: 147,0-148,0oC (dek.) ;Elementanalyse ;Beregnet: C: 52,03, H: 3,82, N: 11,38, S: 8,68, F: 15,43,0: 8,é6 ;Funnet: C: 51,85, H: 3,92, N: 11,26, S: 8,82, F: 15,22 ;'H-NMR: 2,24(3H,s), 4,38(2H,q,J=7,8Hz), 4,74(lH,d,J=13,6HZ), 4,87(lH,d,J=13,6Hz), 6,68(lH,d,J=5,8Hz), 7,26-7,36(2H,m), 7,45(lH,m), 7,78(lH,m), 8,35(lH,d,J=5,8Hz). ;IR( v cm"<1>): 3083,3034,2975, 1586,1478,1441,1306,1267,1163 ;UVmaks.(CHCl3): 283,6 nm ;[a]D = +180,3° (c = 1,004 %, CHC13) ;;Eksempel 3 ;KrystaU av (R)-2-[[[3-metyl-4-(2,2,2-tri^ benzimidazol (R(+)-lansoprazol) 1,5 hydrat ;Amorf (R)-2-[[[3-metyl-4-(2,2,2-tirfluoretoksy)-2-pyridinyl]metyl]sulfinyl]-lH-benzimidazol som oppnådd i referanseeksempel 1 (100 mg) ble oppløst i etanol (0,15 ml), og vann (0,15 ml) ble tisatt. Etter et kim var plassert, ble løsningen hensatt ved romtemperatur i 1 time. Utfelte krystaller ble samlet opp ved filtrering, vasket to ganger med vann (2 ml), og tørket under redusert trykk, til å gi krystaller av (R)-2-[[[3-metyl-4-(2,2,2-trilfuoretoksy)-2-pyridinyl]metyl]sulfinyl]-lH-benzimidazol (R(+)-lansoprazol) 1,5 hydrat (96 mg). ;Smp.: 76,0-80,0°C ;Elementanalyse ;Beregnet: C: 48,48, H: 4,32, N: 10,60, S: 8,09, F: 14,38,0:14,13 ;Funnet: C: 48,52, H: 4,44, N: 10,49 ;Eksperimentelt eksempel 1 ;Undertrykt virkning på magslimhinneskade grunnet stress av yann-nedsenkelsestvang hos rotter ;Hann-SD-rotter (7 uker gamle, som veide 230 til 250 g) ble holdt fastende i 24 timer, hvoretter de ble stresset ved at de ble holdt i frihetsberøvende bur og neddykket til under brystbensspissen i en stående posisjon i et 23°C konstant temperatur vann-kammer. Etter 5 timer ble rottene fjernet fra buret og avlivet ved å benytte gassformig karbondioksid, og deres mager ble skåret ut. Etter den nedre delen av esofag var klippet over, ble en 1 % formalinløsning (10 ml) injisert i magen via duodenum, som deretter ble lukket, og magen ble nedsenket i den samme løsningen. Etter 10 minutter ble det lagd et innsnitt langs den store krumningen, og lengden (mm) av hver slimhinneskade ble målt under et stereomikroskop. Den samlede summe av skadelengdene i hver mage ble tatt som en mageslimhinneskadeindeks. ;Krystaller av (R)-2-[[[3-metyl-4-(2,2,2-trifluoretoksy)-2-pyridinyl]metyl]sulfinyl]-lH-benzimidazol (R(+)-lansoprazol) som var oppnådd i eksempel 2 ble suspendert i 0,2 % metylcellulose (pH 9,5) som inneholdt 0,05 M NaHCo3 og administrert oralt 30 minutter før stressing (doseringsvolum 2 ml/kg). Hver behandlingsgruppe omfattet 9 dyr. Kontrollgruppen (løsningsmiddeladministrert gruppe) og den legemiddel-administerte gruppen ble sammenlignet ved Steel's test. ;Resultatene er vist i tabell 4. ;;Hvert tall for mageslimhinneskadeindeks er gjennomsnittlig ±;standardawik for de 9 dyrene i hver gruppe. ;<*>p < 0,01 (mot kontrollgruppe, Steel's test)
Ekseperimentelt eksempel 2
Krystallene av R(+)-lansoprazol som ble oppnådd i eksempel 2 (omtrent 5 mg) og amorft R(+)-lansoprazol som ble oppnådd i referanseeksempel 1 (omtrent 5 mg) ble hver for seg fylt i en fargeløs glassflaske, og deres stabilitet under lagring ved 60°C
(korken var fjernet) ble undersøkt. En 25 ml løsning (konsentrasjon: omtrent 0,2 mg/ml) av prøven etter fullført lagring i den mobile fasen, sammen med en standardløsning som ble fremstilt ved å benytte den initielle mengden, ble analysert; under HPLC-betingelser som vist nedenfor, og R(+)-lansoprazol-innholdet (gjenværende prosent) ble beregnet fra topparealet som ble oppnådd. Resultatene er vist i tabell 5.
HPLC analytiske betingelser
Deteksjonsbølgelengde : UV 275 nm
Kolonne : YMC Pro Cl8,4,6 x 150 mm
Mobil fase : Fluid fremstilt ved å tilsbtte fosforsyre til vann/
Acetonitril/trietylamin (63:37:1) for å np pH 7.
Strømningshastighet : 1,0 ml/min.
Kolonnetemperatur : 40°C
Prøveinjeksjonsvolum : 10 ul
Når prøven ble lagret ved 60°C (åpent), holdt krystallet ifølge eksempel 2 tilbake et innhold som oversteg 90 % i opptil 4 uker, mens den amorfe førmen ifølge referanseeksempel 1 viste reduksjon i innhold til 78,8 % etter 1 uke og 57,5 % etter 2 uker. Dette funnet viser at krystallet av R(+)-lansoprazol er mer stabilt og mer foretrukket for anvendelse som et legemiddel etc. enn den amorfe formen.
INDUSTRIELL ANVANDBARHET
Krystallet ifølge den foreliggende oppfinnelsen er nyttig som et legemiddel fordi det viser fortreffelig anti-magesårvirkning, magesyreutskillelseshemmende virkning, mukosa-beskyttende virkning, anti- Helicobacter pylori virkning etc, og fordi den har lav toksisitet. Videre forbedres ikke bare dens stabilitet, men dens håndtering lettes også, slik at det kan fremstilles som en fast farmasøytisk sammensetning med god reproduserbarhet ved å krystallisere (R)-isomeren. Krystallet ifølge foreliggende oppfinnelse er derfor nyttig som et legemiddel i lave doser og med alv alminnelig forekomst av ugunstige reaksjoner.
Claims (5)
1.
Et krystall av (R)-2-[[[3-metyl-4-(2,2,2-trifluor^ benzimidazol eller et salt derav.
2.
Et krystall ifølge krav 1, av (R)-2-[[[3-metyl-4-(2,2,2-trifluoretoksy)-2-pyridinyl]metyl] sulfinyl] -1 H-benzimidazol.
3.
Et krystall ifølge krav 2, der røntgenpulverdiffraksjonsanalysemønsteret har karakteristiske topper ved interplane avstander (d) på 11,68,6,77, 5,84,5,73,4,43,4,09, 3,94, 3,89,3,69, 3,41 og 3,11 Ångstrøm.
4.
En farmasøytisk sammensetning som omfatter krystallet ifølge krav 1.
5.
Anvendelse av krystallet ifølge krav 1, til fremstilling av en farmasøytisk sammensetning til behandling eller forebygging av digestivt magesår.
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