NO319782B1 - Pantoprazol-magnesiumdihydrat, medikamenter inneholdende denne og anvendelsen derav - Google Patents
Pantoprazol-magnesiumdihydrat, medikamenter inneholdende denne og anvendelsen derav Download PDFInfo
- Publication number
- NO319782B1 NO319782B1 NO20010718A NO20010718A NO319782B1 NO 319782 B1 NO319782 B1 NO 319782B1 NO 20010718 A NO20010718 A NO 20010718A NO 20010718 A NO20010718 A NO 20010718A NO 319782 B1 NO319782 B1 NO 319782B1
- Authority
- NO
- Norway
- Prior art keywords
- pantoprazole
- magnesium
- magnesium dihydrate
- dihydrate
- sodium sesquihydrate
- Prior art date
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- 239000003814 drug Substances 0.000 title claims description 6
- -1 Pantoprazole-magnesium dihydrate Chemical class 0.000 title claims description 5
- IQPSEEYGBUAQFF-UHFFFAOYSA-N Pantoprazole Chemical compound COC1=CC=NC(CS(=O)C=2NC3=CC=C(OC(F)F)C=C3N=2)=C1OC IQPSEEYGBUAQFF-UHFFFAOYSA-N 0.000 claims abstract description 29
- 229960005019 pantoprazole Drugs 0.000 claims abstract description 27
- RDRUTBCDIVCMMX-UHFFFAOYSA-N magnesium;5-(difluoromethoxy)-2-[(3,4-dimethoxypyridin-2-yl)methylsulfinyl]benzimidazol-1-ide Chemical compound [Mg+2].COC1=CC=NC(CS(=O)C=2[N-]C3=CC=C(OC(F)F)C=C3N=2)=C1OC.COC1=CC=NC(CS(=O)C=2[N-]C3=CC=C(OC(F)F)C=C3N=2)=C1OC RDRUTBCDIVCMMX-UHFFFAOYSA-N 0.000 claims description 18
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 5
- 229940079593 drug Drugs 0.000 claims description 5
- 201000010099 disease Diseases 0.000 claims description 4
- 230000027119 gastric acid secretion Effects 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 230000002265 prevention Effects 0.000 claims description 3
- 229940000425 combination drug Drugs 0.000 claims 4
- 239000000546 pharmaceutical excipient Substances 0.000 claims 1
- 159000000003 magnesium salts Chemical class 0.000 abstract description 10
- 150000004683 dihydrates Chemical class 0.000 abstract description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
- 150000001875 compounds Chemical class 0.000 description 11
- PWWDEIMGEBPTJL-UHFFFAOYSA-N 1-(pyridin-2-ylmethylsulfinyl)benzimidazole Chemical class C1=NC2=CC=CC=C2N1S(=O)CC1=CC=CC=N1 PWWDEIMGEBPTJL-UHFFFAOYSA-N 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 5
- 239000008213 purified water Substances 0.000 description 5
- 238000000354 decomposition reaction Methods 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- CRGZYKWWYNQGEC-UHFFFAOYSA-N magnesium;methanolate Chemical compound [Mg+2].[O-]C.[O-]C CRGZYKWWYNQGEC-UHFFFAOYSA-N 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- YNWDKZIIWCEDEE-UHFFFAOYSA-N pantoprazole sodium Chemical compound [Na+].COC1=CC=NC(CS(=O)C=2[N-]C3=CC=C(OC(F)F)C=C3N=2)=C1OC YNWDKZIIWCEDEE-UHFFFAOYSA-N 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 2
- SUBDBMMJDZJVOS-UHFFFAOYSA-N 5-methoxy-2-{[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]sulfinyl}-1H-benzimidazole Chemical compound N=1C2=CC(OC)=CC=C2NC=1S(=O)CC1=NC=C(C)C(OC)=C1C SUBDBMMJDZJVOS-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 125000004786 difluoromethoxy group Chemical group [H]C(F)(F)O* 0.000 description 2
- DHRRIBDTHFBPNG-UHFFFAOYSA-L magnesium dichloride hexahydrate Chemical compound O.O.O.O.O.O.[Mg+2].[Cl-].[Cl-] DHRRIBDTHFBPNG-UHFFFAOYSA-L 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 125000006216 methylsulfinyl group Chemical group [H]C([H])([H])S(*)=O 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 229960004048 pantoprazole sodium Drugs 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 150000003839 salts Chemical group 0.000 description 2
- 230000035945 sensitivity Effects 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 108091006112 ATPases Proteins 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 102000057290 Adenosine Triphosphatases Human genes 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- RGHNJXZEOKUKBD-SQOUGZDYSA-M D-gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O RGHNJXZEOKUKBD-SQOUGZDYSA-M 0.000 description 1
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000004703 alkoxides Chemical class 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000036765 blood level Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 238000002845 discoloration Methods 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 229940050410 gluconate Drugs 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 229960003174 lansoprazole Drugs 0.000 description 1
- MJIHNNLFOKEZEW-UHFFFAOYSA-N lansoprazole Chemical compound CC1=C(OCC(F)(F)F)C=CN=C1CS(=O)C1=NC2=CC=CC=C2N1 MJIHNNLFOKEZEW-UHFFFAOYSA-N 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- QWDJLDTYWNBUKE-UHFFFAOYSA-L magnesium bicarbonate Chemical compound [Mg+2].OC([O-])=O.OC([O-])=O QWDJLDTYWNBUKE-UHFFFAOYSA-L 0.000 description 1
- 229960002337 magnesium chloride Drugs 0.000 description 1
- 235000011147 magnesium chloride Nutrition 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- 229940050906 magnesium chloride hexahydrate Drugs 0.000 description 1
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 description 1
- 239000000347 magnesium hydroxide Substances 0.000 description 1
- 229910001862 magnesium hydroxide Inorganic materials 0.000 description 1
- 229940091250 magnesium supplement Drugs 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 229960000381 omeprazole Drugs 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229960005235 piperonyl butoxide Drugs 0.000 description 1
- 239000003495 polar organic solvent Substances 0.000 description 1
- IKNCGYCHMGNBCP-UHFFFAOYSA-N propan-1-olate Chemical compound CCC[O-] IKNCGYCHMGNBCP-UHFFFAOYSA-N 0.000 description 1
- 229960004157 rabeprazole Drugs 0.000 description 1
- YREYEVIYCVEVJK-UHFFFAOYSA-N rabeprazole Chemical compound COCCCOC1=CC=NC(CS(=O)C=2NC3=CC=CC=C3N=2)=C1C YREYEVIYCVEVJK-UHFFFAOYSA-N 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
Classifications
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- 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
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- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
- Medicinal Preparation (AREA)
- Drying Of Gases (AREA)
- Solid-Sorbent Or Filter-Aiding Compositions (AREA)
- Detergent Compositions (AREA)
- Manufacture And Refinement Of Metals (AREA)
Description
Oppfinnelsens felt
Foreliggende oppfinnelse omhandler en ny saltforra av den aktive forbindelsen pantoprazol, nemlig pantoprazol-magnesiumdihydrat. Den nye saltformen kan anvendes i den farmasøytiske industrien for fremstillingen av medika-menter, inklusive kombinasjonsmedikamenter og er spesielt egnet for forebyggingen eller behandlingen av sykdommer knyttet til økt magesyresekresjon.
Tidligere teknikk
Pyridin-2-ylmetylsulfinyl-lH-benzimidazoler, som fremlagt, for eksempel, i EP-A-0005129, EP-A-0166287, EP-A-0174726 og EP-A-0268956, har, på grunn av deres H+/K+ ATPase-inhi-berende virkning, betydelig viktighet i terapien av sykdommer som skyldes øket magesyresekresjon. Eksempler på kommersielt tilgjengelige aktive forbindelser fra denne gruppen er 5-metoksy-2-[(4-metoksy-3,5-dimetyl-2-pyri-dinyl)metylsulfinyl]-lH-benzimidazol (INN: omeprazol), 5-difluormetyoksy-2-[{3,4-dimetoksy-2-pyridinyl)-metylsul-finyl]-lH-benzimidazol (INN: pantoprazol), 2-[3-metyl-4-(2,2,2-trifluoretoksy)-2-pyridinyl)metylsulfinyl]-1H-benzimidazol (INN: lansoprazol) og 2-{[4-(3-metoksyprop-oksy)-3-metylpyridin-2-yl]metylsulfinyl}-lH-benzimidazo (INN: rabeprazol).
En felles egenskap ved ovennevnte pyridin-2-ylmetylsul-finyl-lH-benzimidazoler er syre-sensitiviteten - som til slutt er uunnvaerlig for deres virkning - til disse aktive forbindelsene, som ses i deres sterke tendens til å dekomponere i et nøytralt og, spesielt surt miljø, der sterkt fargede dekomponeringsprodukter dannes.
Tidligere, har det vært betraktelig innsats, på tross av syre-sensitiviteten til pyridin-2-ylmetylsulfinyl-lH-ben-zimidazolene, for å oppnå stabile og lagringsdyktige orale administrasjonsformer som inneholder disse pyridin-2-ylmetylsulfinyl-lH-benzimidazolene. Slike stabile og lagringsdyktige orale administrasjonsformer (f.eks. tabletter eller kapsler) er nå oppnåelige. Preparatene av disse orale administrasjonsformene er imidlertid forholdsvis kompliserte og visse forholdsregler må tas med hensyn til pakningen for at administrasjonsformene skal ha en passende lagringsstabilitet selv under ekstreme lagringsbetingelser (f.eks. i tropene ved høy temperatur og høy atmosfærisk fuktighet).
Den internasjonale patentsøknad W097/41114 beskriver en spesifikk prosess for fremstillingen av magnesiumsalter av pyridin-2-ylmetylsulfinyl-lH-benzimidazoler. Blant annet er fremstillingen av magnesiumsaltet av pantoprazol også be-skrevet via eksempler. Ifølge de indikerte analysedata er det fremstilte saltet pantoprazol-magnesium i vannfri form.
Beskrivelse av oppfinnelsen
Det har nå blitt funnet at dihyratet av magnesiumsaltet av pantoprazol har svært overraskende stabilitetsegenskaper som gjør at det synes å være spesielt egnet for anvendelse i faste eller orale administrasjonsformer. Det utviser svært betydelige forbedrede stabilitetsegenskaper både sammenlignet med pantoprazol-natriumsesquihydrat (den aktive forbindelsesformen på markedet siden 1994, europeisk patent 0 589 981), eller sammenlignet med pantoprazolnatrium-monohydrat (mellomproduktformen anvendt i det industrielle preparatet, europeisk patent 0 533 790).
Således er pantoprazol-magnesiumdihydrat fullstendig stabilt i 4 dager ved 90 °C og foreviser omtrent ingen misfarging eller dekomponering, mens pantoprazol-natriumsesquihydrat og monohydrat blir brunn-rød i den samme perioden med dannelse av betydelige mengder dekomponeringsprodukter.
Oppfinnelsen omhandler derfor dihydratet av magnesiumsaltet av pantoprazol (pantoprazol-magnesiumdihydrat)•
Pantoprazol-magnesiumdihydrat kan anvendes for behandling og forebygning av alle sykdommer som anses å være behandlerbare eller unngåelige ved anvendelsen av pyridin-2-ylmetylsulfinyl-lH-benzimidazoler. Spesielt, kan Pantoprazol-magnesiumdihydrat anvendes i behandlingen av for-styrrelser i magen knyttet til økt magesyresekres]on.
På grunn av dets løseligehetsegenskaper, er anvendelsesmu-ligheter for pantoprazol-magnesiumdihydrat mulige for visse realisering som til nå måtte gjøres av spesielle farma-søytiske preparater. Derfor er anvendelse av pantoprazol-magnesiumdihydrat spesielt passende, blant annet, der den aktive forbindelsen skal frigis og absorberes over en relativ lang periode (se, f.eks., europeisk patentsøknad 0 841 903). Ved hjelp av en kombinasjon av magnesiumsaltet av pantoprazol med natriumsaltet, kan en løsning laget for visse ønskede aktive forbindelsesblodnivåforløp oppnås.
Pantoprazol-magnesiumdihydrat fremstilles på en måte kjent 1 seg selv ved reaksjon av pantoprazol eller et lett løselig pantoprazolsalt (f.eks. pantoprazolnatrium) med et magnesiumsalt i vann eller i blandinger av vann med polare organiske losningsmidler (f.eks. alkoholer, foretrukket etanol eller isopropanol, eller ketoner, f.eks. aceton eller butanon).
Passende magnesiumsalter som kan anvendes ifølge prosessen er, f.eks. magnesiumklorid, -bromid, -fluorid, -jodid, -format, -acetat, -propionat, -sulfat, -glukonat eller -karbonat. Alkoksider av magnesium (f.eks. magnesium-metoksid, -etoksid, -(iso)propoksid, -butoksid, -heksoksid eller -fenoksid), eller magnesiumhydroksid kan også reageres med pantoprazol eller pantoprazolnatrium i vandig medium.
Eksempel
Magnesium bis[ 5-[ difluormetoksy]- 2-[[ 3, 4- dimetoksy- 2-pyridinyl] metyl] sulfinyl]- lH- benzimidazolid] dihydrat
3,85 kg (8,9 mot) pantoprazol-Na-sesquihydrat [natrium [5-[difluormetoksy]-2-[[3,4-dimetoksy-2-pyridinyl]metyl]-sul-finyl]-lH-benzimidazolid]sesquihydrat løses ved 20-25 °C i 38,5 1 renset vann i en omrørt beholder. En løsning av 1,0 kg (4,90 mot) magnesiumdiklorid-heksahydrat i 8 1 renset vann tilsettes med omrøring ved 20-30 °C i løpet av 3 til 4 timer. Etter omrøring i ytterligere 18 timer sentrifugeres det utfelte faststoff, vaskes med 23 1 renset vann, omrøres ved 20-30 °C i 1 til 2 timer i 35 1 renset vann, sentrifugeres igjen og vaskes igjen med 30-50 1 renset vann. Det faste produkt tørkes ved 50 °C i vakuum (30-50 mbar) inntil et restvanninnhold på < 4,8% oppnås. Produktet males deretter.
Tittelforbindelsen oppnås nom et hvitt til beige pulver, som anvendes direkte for videre farmasøytisk bearbeidelse.
Utbytte: 3,40 kg (90 % av teori); vanninnhold: 4,5-4,6 %; smeltepunkt: 194-196 °C med dekomponering.
Alternativt kan tittelforbindelsen fremstilles ved anvendelse av blandinger av organiske løsningsmidler med vann. For dette løses pantoprazol-Na-sesquihydrat i et organisk løsningsmiddel ved 50-60 °C. 0,5 molekvivalenter av magnesiumsaltet (f.eks. magnesiumklorid-heksahydrat), oppløst i vann, tilsettes dråpevis og løsningen tillates å kjøle med omrøring. Det utfelte faststoff filtreres fra, vaskes med det tilsvarende organiske løsningsmiddel og tørkes i vakuum ved 50 °C til konstant vekt. Tittelforbindelsen oppnås som et fargeløs pulver. Eksempler med ulike løsningsmidler er gitt i den følgende tabell 1.
Alternativt kan tittelforbindelsen fremstilles ved å reagere pantoprazol med et basisk magnesiumsalt, slik som magnesiummetylat, for eksempel på følgende måte: 90 g pantoprazol løses i 700 ml 2-propanol ved 60-70 °C. 13,4 g (0,5 mol) av fast magnesiummetylat tilsettes, løsningen tillates å kjøle med omrøring og filtreres. Etter til-setning av 36 ml vann filtreres det dannede krystallinske faststoff fra, vaskes med vann og tørkes i vakuum ved 50 °C til konstant vekt. Tittelforbindelsen med smeltepunkt 194-196 °C (vanninnhold 4,8 %) oppnås som beige faststoff.
Claims (8)
1. Pantoprazol-magnesiumdihyrat.
2. Medikament omfattende pantoprazol-magnesiumdihydrat sammen med vanlige hjelpestoffer.
3. Anvendelse av pantoprazol-magnesiumdihydrat for fremstillingen av et medikament egnet for forebyggingen eller behandlingen av sykdommer knyttet til økt magesyre-sekres jon.
4. Kombinasjonsmedikament omfattende pantoprazol-magnesiumdihydrat og pantoprazol-natriumsesquihydrat.
5. Kombinasjonsmedikament ifølge krav 4, i vektforhold (basert på pantoprazol) 10 % pantoprazol-magnesiumdihydrat og 90 % pantoprazol-natriumsesquihydrat til 90 % pantoprazol-magnesiumdihydrat og 10 % pantoprazol-natriumsesquihydrat.
6. Kombinasjonsmedikament ifølge krav 4, i vektforhold (basert på pantoprazol) 25 % pantoprazol-magnes-i-umd-i-hydr-at og 75 % pantoprazol-natriumsesquihydrat til 75 % pantoprazol-magnesiumdihydrat og 25 % pantoprazol-natriumsesquihydrat.
7. Kombinasjonsmedikament ifølge krav 4, i vektforhold (basert på pantoprazol) 40 % pantoprazol-magnesiumdihydrat og 60 % pantoprazol-natriumsesquihydrat til 60 % pantoprazol-magnesiumdihydrat og 40 % pantoprazol-natriumsesquihydrat.
8. Kombinasjonsmedikament ifølge krav 4, i vektforhold (basert på pantoprazol) 50 % pantoprazol-magnesiumdihydrat og 50 % pantoprazol-natriumsesquihydrat.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19843413A DE19843413C1 (de) | 1998-08-18 | 1998-08-18 | Neue Salzform von Pantoprazol |
| PCT/EP1999/005928 WO2000010995A1 (en) | 1998-08-18 | 1999-08-12 | Novel salt form of pantoprazole |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| NO20010718L NO20010718L (no) | 2001-02-12 |
| NO20010718D0 NO20010718D0 (no) | 2001-02-12 |
| NO319782B1 true NO319782B1 (no) | 2005-09-12 |
Family
ID=7881823
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO20010718A NO319782B1 (no) | 1998-08-18 | 2001-02-12 | Pantoprazol-magnesiumdihydrat, medikamenter inneholdende denne og anvendelsen derav |
Country Status (33)
| Country | Link |
|---|---|
| US (2) | US6410569B1 (no) |
| EP (1) | EP1105386B1 (no) |
| JP (1) | JP2002523411A (no) |
| KR (1) | KR100657835B1 (no) |
| CN (1) | CN1146558C (no) |
| AT (1) | ATE219074T1 (no) |
| AU (1) | AU761715B2 (no) |
| BG (1) | BG65255B1 (no) |
| BR (1) | BR9914288A (no) |
| CA (1) | CA2341031C (no) |
| CZ (1) | CZ293734B6 (no) |
| DE (3) | DE19843413C1 (no) |
| DK (1) | DK1105386T3 (no) |
| EA (1) | EA004431B1 (no) |
| EE (1) | EE04278B1 (no) |
| ES (1) | ES2178896T3 (no) |
| HK (1) | HK1037616A1 (no) |
| HR (1) | HRP20010117B1 (no) |
| HU (1) | HU226618B1 (no) |
| IL (3) | IL141328A0 (no) |
| ME (1) | ME00562A (no) |
| MX (1) | MXPA01001758A (no) |
| NO (1) | NO319782B1 (no) |
| NZ (1) | NZ509761A (no) |
| PL (1) | PL198801B1 (no) |
| PT (1) | PT1105386E (no) |
| RS (1) | RS50071B (no) |
| SI (1) | SI1105386T1 (no) |
| SK (1) | SK285105B6 (no) |
| TR (1) | TR200100287T2 (no) |
| UA (1) | UA58605C2 (no) |
| WO (1) | WO2000010995A1 (no) |
| ZA (1) | ZA200100934B (no) |
Families Citing this family (26)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE19843413C1 (de) * | 1998-08-18 | 2000-03-30 | Byk Gulden Lomberg Chem Fab | Neue Salzform von Pantoprazol |
| MY137726A (en) | 2000-11-22 | 2009-03-31 | Nycomed Gmbh | Freeze-dried pantoprazole preparation and pantoprazole injection |
| TW200410955A (en) | 2002-07-29 | 2004-07-01 | Altana Pharma Ag | Novel salt of (S)-PANTOPRAZOLE |
| DE10234617B4 (de) * | 2002-07-29 | 2013-04-04 | Nycomed Gmbh | Neues Salz von (S)-Pantoprazol |
| CA2510849A1 (en) * | 2002-12-19 | 2004-07-08 | Teva Pharmaceutical Industries Ltd | Solid states of pantoprazole sodium, processes for preparing them and processes for preparing known pantoprazole sodium hydrates |
| AU2004237362A1 (en) * | 2003-05-06 | 2004-11-18 | Altana Pharma Ag | Proton pump inhibitors for the treatment of lower abdominal disorders |
| CL2004000983A1 (es) * | 2003-05-08 | 2005-03-04 | Altana Pharma Ag | Composicion farmaceutica oral en forma de tableta que comprende a pantoprazol magnetico dihidratado, en donde la forma de tableta esta compuesto por un nucleo, una capa intermedia y una capa exterior; y uso de la composicion farmaceutica en ulceras y |
| PE20050150A1 (es) * | 2003-05-08 | 2005-03-22 | Altana Pharma Ag | Una forma de dosificacion que contiene (s)-pantoprazol como ingrediente activo |
| CN1791406A (zh) * | 2003-05-19 | 2006-06-21 | 普利瓦研究与发展有限公司 | 5－(二氟甲氧基)－2－[[(3,4－二甲氧基－2－吡啶基)甲基]亚硫酰基]－1h－苯并咪唑(泮托拉唑)钠水络合物的固态形式 |
| EP1615913A2 (en) | 2003-06-10 | 2006-01-18 | Teva Pharmaceutical Industries Limited | Process for preparing 2-(pyridinyl)methyl sulfinyl-substituted benzimidazoles and novel chlorinated derivatives of pantoprazole |
| WO2005012289A1 (en) * | 2003-07-17 | 2005-02-10 | Altana Pharma Ag | Novel salt of (r) - pantoprazole |
| DK1651217T3 (da) * | 2003-07-23 | 2008-06-16 | Nycomed Gmbh | Alkalisalte af protonpumpeinhibitorer |
| CN100457104C (zh) * | 2003-07-23 | 2009-02-04 | 尼科梅德有限责任公司 | 质子泵抑制剂的碱性盐 |
| CA2554260A1 (en) * | 2004-01-28 | 2005-08-18 | Altana Pharma Ag | Calcium, potassium, zinc, lithium and aluminium salts of pantoprazole and (s)-pantoprazole |
| WO2005074898A2 (en) * | 2004-01-28 | 2005-08-18 | Altana Pharma Ag | Composition comprising (s) pantoprazole and an antibiotic for treating helicobacter pylori |
| WO2005074932A1 (en) * | 2004-01-28 | 2005-08-18 | Altana Pharma Ag | The use of (s) - pantoprazole magnesium for the treatment of airway disorders |
| WO2005074930A1 (en) * | 2004-01-28 | 2005-08-18 | Altana Pharma Ag | Pharmaceutical combinations of (s) -pantoprazole with nsaid or corticosteroids |
| WO2005074931A1 (en) * | 2004-01-28 | 2005-08-18 | Altana Pharma Ag | Pharmaceutical combinations comprising (s) -pantoprazole |
| EP1716136A1 (en) * | 2004-02-11 | 2006-11-02 | Ulkar Kimya Sanayii Ve Ticaret A.S. | Pyridine benzimidazole sulfoxides of high purity |
| WO2005082888A1 (en) * | 2004-03-01 | 2005-09-09 | Milen Merkez Ilac Endustrisi A.S. | Process for the preparation of magnesium salt of omeprazole |
| JP2007536349A (ja) * | 2004-05-07 | 2007-12-13 | ニコメッド ゲゼルシャフト ミット ベシュレンクテル ハフツング | 新規の医薬剤形及び製造方法 |
| WO2007041790A1 (en) * | 2005-10-14 | 2007-04-19 | Jon Pty Limited | Salts of proton pump inhibitors and process for preparing same |
| WO2007146341A2 (en) | 2006-06-12 | 2007-12-21 | Teva Pharmaceutical Industries Ltd. | Amorphous and crystalline forms of pantoprazole magnesium salt |
| WO2008057559A1 (en) * | 2006-11-06 | 2008-05-15 | Teva Pharmaceutical Industries Ltd. | Processes for preparing substantially pure pantoprazole magnesium |
| EP3187494A1 (en) * | 2015-12-30 | 2017-07-05 | KRKA, tovarna zdravil, d.d., Novo mesto | Process for the preparation of pantoprazole sodium sesquihydrate |
| EP3397630B1 (en) * | 2015-12-30 | 2021-05-26 | KRKA, tovarna zdravil, d.d., Novo mesto | Process for the preparation of pantoprazole sodium sesquihydrate |
Family Cites Families (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SE7804231L (sv) * | 1978-04-14 | 1979-10-15 | Haessle Ab | Magsyrasekretionsmedel |
| IL75400A (en) * | 1984-06-16 | 1988-10-31 | Byk Gulden Lomberg Chem Fab | Dialkoxypyridine methyl(sulfinyl or sulfonyl)benzimidazoles,processes for the preparation thereof and pharmaceutical compositions containing the same |
| JPS6150978A (ja) * | 1984-08-16 | 1986-03-13 | Takeda Chem Ind Ltd | ピリジン誘導体およびその製造法 |
| FI90544C (fi) * | 1986-11-13 | 1994-02-25 | Eisai Co Ltd | Menetelmä lääkeaineina käyttökelpoisten 2-pyridin-2-yyli-metyylitio- ja sulfinyyli-1H-bensimidatsolijohdannaisten valmistamiseksi |
| DE4018642C2 (de) * | 1990-06-11 | 1993-11-25 | Byk Gulden Lomberg Chem Fab | Neue Salzform des 5-Difluormethoxy-2-[(3,4-dimethoxy-2-pyridyl) methylsulfinyl]-1H-benzimitazol-Natriumsalzes |
| YU48263B (sh) * | 1991-06-17 | 1997-09-30 | Byk Gulden Lomberg Chemische Fabrik Gmbh. | Postupak za dobijanje farmaceutskog preparata na bazi pantoprazola |
| SE9302396D0 (sv) * | 1993-07-09 | 1993-07-09 | Ab Astra | A novel compound form |
| SE9600070D0 (sv) * | 1996-01-08 | 1996-01-08 | Astra Ab | New oral pharmaceutical dosage forms |
| SE508669C2 (sv) * | 1996-04-26 | 1998-10-26 | Astra Ab | Nytt förfarande |
| DE19843413C1 (de) * | 1998-08-18 | 2000-03-30 | Byk Gulden Lomberg Chem Fab | Neue Salzform von Pantoprazol |
-
1998
- 1998-08-18 DE DE19843413A patent/DE19843413C1/de not_active Expired - Fee Related
-
1999
- 1999-08-12 DK DK99941605T patent/DK1105386T3/da active
- 1999-08-12 PT PT99941605T patent/PT1105386E/pt unknown
- 1999-08-12 US US09/762,303 patent/US6410569B1/en not_active Expired - Lifetime
- 1999-08-12 RS YUP-113/01A patent/RS50071B/sr unknown
- 1999-08-12 TR TR2001/00287T patent/TR200100287T2/xx unknown
- 1999-08-12 AT AT99941605T patent/ATE219074T1/de active
- 1999-08-12 SI SI9930096T patent/SI1105386T1/xx unknown
- 1999-08-12 BR BR9914288-0A patent/BR9914288A/pt not_active Application Discontinuation
- 1999-08-12 IL IL14132899A patent/IL141328A0/xx unknown
- 1999-08-12 DE DE69901840T patent/DE69901840T2/de not_active Expired - Lifetime
- 1999-08-12 PL PL345993A patent/PL198801B1/pl unknown
- 1999-08-12 ES ES99941605T patent/ES2178896T3/es not_active Expired - Lifetime
- 1999-08-12 CN CNB998098000A patent/CN1146558C/zh not_active Expired - Fee Related
- 1999-08-12 AU AU55156/99A patent/AU761715B2/en not_active Ceased
- 1999-08-12 SK SK236-2001A patent/SK285105B6/sk not_active IP Right Cessation
- 1999-08-12 IL IL14115799A patent/IL141157A0/xx active IP Right Grant
- 1999-08-12 CZ CZ2001621A patent/CZ293734B6/cs not_active IP Right Cessation
- 1999-08-12 DE DE1999601840 patent/DE122005000049I2/de active Active
- 1999-08-12 ME MEP-847/08A patent/ME00562A/xx unknown
- 1999-08-12 EP EP99941605A patent/EP1105386B1/en not_active Expired - Lifetime
- 1999-08-12 EA EA200100208A patent/EA004431B1/ru not_active IP Right Cessation
- 1999-08-12 MX MXPA01001758A patent/MXPA01001758A/es active IP Right Grant
- 1999-08-12 HU HU0103257A patent/HU226618B1/hu not_active IP Right Cessation
- 1999-08-12 EE EEP200100054A patent/EE04278B1/xx unknown
- 1999-08-12 KR KR1020017001911A patent/KR100657835B1/ko not_active IP Right Cessation
- 1999-08-12 CA CA002341031A patent/CA2341031C/en not_active Expired - Lifetime
- 1999-08-12 WO PCT/EP1999/005928 patent/WO2000010995A1/en active IP Right Grant
- 1999-08-12 JP JP2000566268A patent/JP2002523411A/ja active Pending
- 1999-08-12 NZ NZ509761A patent/NZ509761A/en not_active IP Right Cessation
- 1999-12-08 UA UA2001021133A patent/UA58605C2/uk unknown
-
2001
- 2001-01-23 BG BG105173A patent/BG65255B1/bg unknown
- 2001-01-29 IL IL141157A patent/IL141157A/en not_active IP Right Cessation
- 2001-02-02 ZA ZA200100934A patent/ZA200100934B/en unknown
- 2001-02-12 NO NO20010718A patent/NO319782B1/no not_active IP Right Cessation
- 2001-02-16 HR HR20010117A patent/HRP20010117B1/xx not_active IP Right Cessation
- 2001-11-20 HK HK01108172A patent/HK1037616A1/xx not_active IP Right Cessation
-
2002
- 2002-05-01 US US10/135,528 patent/US6686379B2/en not_active Expired - Lifetime
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| CHAD | Change of the owner's name or address (par. 44 patent law, par. patentforskriften) |
Owner name: TAKEDA GMBH, DE |
|
| CHAD | Change of the owner's name or address (par. 44 patent law, par. patentforskriften) |
Owner name: TAKEDA GMBH, DE |
|
| MM1K | Lapsed by not paying the annual fees |