KR20230017553A - Coforms of vonoprazan, and method for preparing the same - Google Patents
Coforms of vonoprazan, and method for preparing the same Download PDFInfo
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- KR20230017553A KR20230017553A KR1020210099201A KR20210099201A KR20230017553A KR 20230017553 A KR20230017553 A KR 20230017553A KR 1020210099201 A KR1020210099201 A KR 1020210099201A KR 20210099201 A KR20210099201 A KR 20210099201A KR 20230017553 A KR20230017553 A KR 20230017553A
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- vonoprazan
- coformer
- coformate
- acid
- powder xrd
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- 229950003825 vonoprazan Drugs 0.000 title claims abstract description 111
- BFDBKMOZYNOTPK-UHFFFAOYSA-N vonoprazan Chemical compound C=1C=CN=CC=1S(=O)(=O)N1C=C(CNC)C=C1C1=CC=CC=C1F BFDBKMOZYNOTPK-UHFFFAOYSA-N 0.000 title claims abstract description 110
- 238000000034 method Methods 0.000 title claims abstract description 15
- 238000004519 manufacturing process Methods 0.000 claims abstract description 18
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 7
- 239000004480 active ingredient Substances 0.000 claims abstract description 5
- 239000013078 crystal Substances 0.000 claims description 48
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 33
- 238000001228 spectrum Methods 0.000 claims description 28
- QAIPRVGONGVQAS-DUXPYHPUSA-N trans-caffeic acid Chemical group OC(=O)\C=C\C1=CC=C(O)C(O)=C1 QAIPRVGONGVQAS-DUXPYHPUSA-N 0.000 claims description 28
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 24
- DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 claims description 18
- ACEAELOMUCBPJP-UHFFFAOYSA-N (E)-3,4,5-trihydroxycinnamic acid Natural products OC(=O)C=CC1=CC(O)=C(O)C(O)=C1 ACEAELOMUCBPJP-UHFFFAOYSA-N 0.000 claims description 14
- PEZXHFCDQXDVCT-UHFFFAOYSA-N OC(=O)CCCCCCCOC1=CC=CC=C1OCCCCCCCC(O)=O Chemical compound OC(=O)CCCCCCCOC1=CC=CC=C1OCCCCCCCC(O)=O PEZXHFCDQXDVCT-UHFFFAOYSA-N 0.000 claims description 14
- 229940074360 caffeic acid Drugs 0.000 claims description 14
- 235000004883 caffeic acid Nutrition 0.000 claims description 14
- QAIPRVGONGVQAS-UHFFFAOYSA-N cis-caffeic acid Natural products OC(=O)C=CC1=CC=C(O)C(O)=C1 QAIPRVGONGVQAS-UHFFFAOYSA-N 0.000 claims description 14
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 14
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 14
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 14
- 239000002904 solvent Substances 0.000 claims description 14
- YKUMMVKKGLHCPO-UHFFFAOYSA-N 8-(2-acetylphenoxy)octanoic acid Chemical compound CC(=O)C1=CC=CC=C1OCCCCCCCC(O)=O YKUMMVKKGLHCPO-UHFFFAOYSA-N 0.000 claims description 13
- UOENJXXSKABLJL-UHFFFAOYSA-M sodium;8-[(2-hydroxybenzoyl)amino]octanoate Chemical compound [Na+].OC1=CC=CC=C1C(=O)NCCCCCCCC([O-])=O UOENJXXSKABLJL-UHFFFAOYSA-M 0.000 claims description 13
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 9
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 9
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- 239000011259 mixed solution Substances 0.000 claims description 9
- 229960003966 nicotinamide Drugs 0.000 claims description 9
- 235000005152 nicotinamide Nutrition 0.000 claims description 9
- 239000011570 nicotinamide Substances 0.000 claims description 9
- 239000003960 organic solvent Substances 0.000 claims description 7
- 238000003756 stirring Methods 0.000 claims description 7
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 6
- DFPAKSUCGFBDDF-ZQBYOMGUSA-N [14c]-nicotinamide Chemical compound N[14C](=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-ZQBYOMGUSA-N 0.000 claims description 6
- DKPFZGUDAPQIHT-UHFFFAOYSA-N butyl acetate Chemical compound CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 claims description 6
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 6
- YKYONYBAUNKHLG-UHFFFAOYSA-N propyl acetate Chemical compound CCCOC(C)=O YKYONYBAUNKHLG-UHFFFAOYSA-N 0.000 claims description 6
- 208000007107 Stomach Ulcer Diseases 0.000 claims description 4
- 208000000718 duodenal ulcer Diseases 0.000 claims description 4
- 201000005917 gastric ulcer Diseases 0.000 claims description 4
- 208000021302 gastroesophageal reflux disease Diseases 0.000 claims description 4
- PHTQWCKDNZKARW-UHFFFAOYSA-N isoamylol Chemical compound CC(C)CCO PHTQWCKDNZKARW-UHFFFAOYSA-N 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 4
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 claims description 3
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 claims description 3
- 238000001704 evaporation Methods 0.000 claims description 3
- 238000010438 heat treatment Methods 0.000 claims description 3
- 208000000689 peptic esophagitis Diseases 0.000 claims description 3
- 230000002496 gastric effect Effects 0.000 claims description 2
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical group CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 claims description 2
- WWZKQHOCKIZLMA-UHFFFAOYSA-N octanoic acid Chemical compound CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 claims 2
- OBETXYAYXDNJHR-UHFFFAOYSA-N alpha-ethylcaproic acid Natural products CCCCC(CC)C(O)=O OBETXYAYXDNJHR-UHFFFAOYSA-N 0.000 claims 1
- 238000003860 storage Methods 0.000 abstract description 4
- 239000004615 ingredient Substances 0.000 abstract 1
- 239000003814 drug Substances 0.000 description 10
- 229940079593 drug Drugs 0.000 description 9
- 239000002253 acid Substances 0.000 description 8
- 238000001938 differential scanning calorimetry curve Methods 0.000 description 7
- 238000001144 powder X-ray diffraction data Methods 0.000 description 7
- 230000002829 reductive effect Effects 0.000 description 7
- 238000004821 distillation Methods 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 238000001757 thermogravimetry curve Methods 0.000 description 6
- 238000001291 vacuum drying Methods 0.000 description 6
- 238000002441 X-ray diffraction Methods 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- 102100021904 Potassium-transporting ATPase alpha chain 1 Human genes 0.000 description 3
- 108010083204 Proton Pumps Proteins 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 102000019057 Cytochrome P-450 CYP2C19 Human genes 0.000 description 2
- 108010026925 Cytochrome P-450 CYP2C19 Proteins 0.000 description 2
- 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 2
- 150000001875 compounds Chemical class 0.000 description 2
- 208000010643 digestive system disease Diseases 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 230000000857 drug effect Effects 0.000 description 2
- 235000012631 food intake Nutrition 0.000 description 2
- 210000004211 gastric acid Anatomy 0.000 description 2
- 230000027119 gastric acid secretion Effects 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229960003174 lansoprazole Drugs 0.000 description 2
- 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 2
- 230000007774 longterm Effects 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- 229940126535 potassium competitive acid blocker Drugs 0.000 description 2
- 229910001414 potassium ion Inorganic materials 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- LECZXZOBEZITCL-UHFFFAOYSA-N revaprazan Chemical compound C1CC2=CC=CC=C2C(C)N1C(C(=C(C)N=1)C)=NC=1NC1=CC=C(F)C=C1 LECZXZOBEZITCL-UHFFFAOYSA-N 0.000 description 2
- 229950000859 revaprazan Drugs 0.000 description 2
- 150000003839 salts Chemical group 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- WMOVHXAZOJBABW-UHFFFAOYSA-N tert-butyl acetate Chemical compound CC(=O)OC(C)(C)C WMOVHXAZOJBABW-UHFFFAOYSA-N 0.000 description 2
- PWILYDZRJORZDR-MISYRCLQSA-N (7r,8r,9r)-7-(2-methoxyethoxy)-2,3-dimethyl-9-phenyl-7,8,9,10-tetrahydroimidazo[1,2-h][1,7]naphthyridin-8-ol Chemical compound C1([C@@H]2[C@@H](O)[C@@H](C3=C(C4=NC(C)=C(C)N4C=C3)N2)OCCOC)=CC=CC=C1 PWILYDZRJORZDR-MISYRCLQSA-N 0.000 description 1
- ROGSHYHKHPCCJW-WLHGVMLRSA-N (e)-but-2-enedioic acid;1-[5-(2-fluorophenyl)-1-pyridin-3-ylsulfonylpyrrol-3-yl]-n-methylmethanamine Chemical compound OC(=O)\C=C\C(O)=O.C=1C=CN=CC=1S(=O)(=O)N1C=C(CNC)C=C1C1=CC=CC=C1F ROGSHYHKHPCCJW-WLHGVMLRSA-N 0.000 description 1
- PYKJFEPAUKAXNN-UHFFFAOYSA-N 2-(2-methyl-8-phenylmethoxy-3-imidazo[1,2-a]pyridinyl)acetonitrile Chemical compound C=1C=CN2C(CC#N)=C(C)N=C2C=1OCC1=CC=CC=C1 PYKJFEPAUKAXNN-UHFFFAOYSA-N 0.000 description 1
- 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 1
- GHVIMBCFLRTFHI-UHFFFAOYSA-N 8-[(2,6-dimethylphenyl)methylamino]-n-(2-hydroxyethyl)-2,3-dimethylimidazo[1,2-a]pyridine-6-carboxamide Chemical compound C=1C(C(=O)NCCO)=CN2C(C)=C(C)N=C2C=1NCC1=C(C)C=CC=C1C GHVIMBCFLRTFHI-UHFFFAOYSA-N 0.000 description 1
- 206010013710 Drug interaction Diseases 0.000 description 1
- 206010063655 Erosive oesophagitis Diseases 0.000 description 1
- 208000018522 Gastrointestinal disease Diseases 0.000 description 1
- 206010071602 Genetic polymorphism Diseases 0.000 description 1
- 241000590002 Helicobacter pylori Species 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- NPYPAHLBTDXSSS-UHFFFAOYSA-N Potassium ion Chemical compound [K+] NPYPAHLBTDXSSS-UHFFFAOYSA-N 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- -1 YH4808 Chemical compound 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 230000002860 competitive effect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000000113 differential scanning calorimetry Methods 0.000 description 1
- 230000001079 digestive effect Effects 0.000 description 1
- 210000002249 digestive system Anatomy 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000009246 food effect Effects 0.000 description 1
- 230000037406 food intake Effects 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 208000018685 gastrointestinal system disease Diseases 0.000 description 1
- 229940037467 helicobacter pylori Drugs 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 230000009610 hypersensitivity Effects 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 229960000381 omeprazole Drugs 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- 229920000333 poly(propyleneimine) Polymers 0.000 description 1
- 229940126409 proton pump inhibitor Drugs 0.000 description 1
- 239000000612 proton pump inhibitor Substances 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
- 239000007787 solid Substances 0.000 description 1
- 229950004825 soraprazan Drugs 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
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- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
-
- 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
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
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- 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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- 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
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- 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
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- Chemical Kinetics & Catalysis (AREA)
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Abstract
Description
본 발명은 보노프라잔 공형성화물, 및 이의 제조방법에 관한 것이다.The present invention relates to a vonoprazan coformate and a method for preparing the same.
위산 관련 질환은 소화기 질환 중 가장 흔한 유형으로, 과도한 위산 분비 또는 위산에 대한 특수한 과민성으로 인해 유발되는 위장 질환의 일종이며, 일반적으로 위식도 역류 질환이라고 한다. 일반적인 소화기 질환 치료를 위해 사용하는 양성자 펌프 억제제(Proton Pump Inhibitor, PPI) 계열 약물은 현재 오메프라졸, 란소프라졸, 라베프라졸 등이 있으며, 산 억제 효과가 강하여 널리 쓰이고 있다.Gastric acid-related disease is the most common type of digestive disease, and is a type of gastrointestinal disease caused by excessive gastric acid secretion or special hypersensitivity to gastric acid, commonly referred to as gastroesophageal reflux disease. Currently, omeprazole, lansoprazole, and rabeprazole are proton pump inhibitor (PPI) drugs used for the treatment of general digestive disorders, and are widely used because of their strong acid inhibitory effect.
그러나, PPI 계열 약물은 활성형 펌프에만 작용하기 때문에 약효 발현이 느리고, 야간 위산분비 억제가 쉽지 않으며, 음식물 섭취에 따른 영향으로 인해 복용시 시간 제한 등이 존재하며, PPI 계열 약물이 주로 대사되는 CYP2C19의 유전자 다형성으로 인해 개인간의 큰 약효 차이, CYP2C19 효소와 관련된 약물 상호작용으로 인한 제한 등이 단점으로 존재한다. However, since PPI-type drugs act only on active pumps, the onset of drug effects is slow, suppression of gastric acid secretion at night is not easy, there is a time limit when taking due to the effect of food intake, and CYP2C19, in which PPI-type drugs are mainly metabolized Disadvantages include large differences in drug efficacy between individuals due to genetic polymorphisms and limitations due to drug interactions related to the CYP2C19 enzyme.
반면 산 억제제의 새로운 개발 방향인 칼륨이온경쟁적 산 차단제(P-CAB)는,기존 PPI와 달리 양성자 펌프에서 칼륨이온을 경쟁적으로 억제하여 작용하며, 이 약물의 산 억제 효과는 양성자 펌프 활성화와는 무관하기 때문에 야간에도 산 억제 효과가 줄어드는 것을 방지할 수 있으며, 음식물 섭취와 무관하게 복용 가능하고, PPI 약물 대비 빠른 약효발현을 나타낼 수 있다. On the other hand, potassium ion competitive acid blockers (P-CABs), a new development direction of acid inhibitors, act by competitively inhibiting potassium ions in the proton pump, unlike existing PPIs, and the acid inhibitory effect of this drug is independent of proton pump activation. Therefore, it is possible to prevent the acid inhibitory effect from being reduced even at night, it can be taken regardless of food intake, and it can show a faster drug effect compared to PPI drugs.
이러한 P-CAB 약물에는 보노프라잔(TAK-438), 소라프라잔(soraprazan)(BY359), 레바프라잔(revaprazan)(YH1885), AZD0865, YH4808, SCH 28080, 및 CS-526 등이 알려져 있으며, 다케다의 P-CAB 약물인 보노프라잔은 2014년 12월 일본 시판 승인되었으며 위궤양, 십이지장 궤양, 미란성 식도염, 헬리코박터 파일로리 치료에 사용된다.Such P-CAB drugs are known such as vonoprazan (TAK-438), soraprazan (BY359), revaprazan (YH1885), AZD0865, YH4808, SCH 28080, and CS-526. , Takeda's P-CAB drug, vonoprazan, was approved for sale in Japan in December 2014 and is used for the treatment of gastric ulcer, duodenal ulcer, erosive esophagitis, and Helicobacter pylori.
또한, 보노프라잔은 양성자 펌프를 억제하는 능력이 란소프라졸의 400배에 달하고 장기간 효과가 유지된다는 장점이 있다.In addition, vonoprazan has the advantage that the ability to inhibit the proton pump reaches 400 times that of lansoprazole and the effect is maintained for a long period of time.
다만, 수용해도가 매우 좋지 않고, 쥐의 경구 비임상시험에서 생체이용률이 10% 정도에 불과할 정도로 생체이용률도 비교적 좋지 않은 편이다.However, the water solubility is not very good, and the bioavailability is relatively poor, with only about 10% bioavailability in oral non-clinical tests in rats.
이에 따라, 종래기술에서는 보노프라잔의 다양한 염과 결정형 연구를 통해 용해도를 향상시키는 연구가 이루어져 왔으나, 이러한 종래기술은 아직 용해도가 만족할 만한 수준이 아니고, 또한 용해도를 개선한 경우라도 흡습성 등을 나타내어 장기 보관 안정성이 떨어지는 등의 문제점이 발생하여, 아직 개선의 여지가 매우 크다. 이에 대한 종래기술 내용에 대해서는 하기 특허문헌 1 내지 3를 참조하여 이해할 수 있고, 이로써, 특허문헌 1 내지 3의 내용 전부는 본 명세서의 종래기술의 인용·합체된다.Accordingly, in the prior art, research on improving the solubility has been conducted through research on various salts and crystal forms of vonoprazan, but such prior art is not yet at a satisfactory level of solubility, and even when the solubility is improved, it exhibits hygroscopicity, etc. Problems such as poor long-term storage stability occurred, and there is still a great room for improvement. The prior art content for this can be understood by referring to
이에 본 발명자들은 용해도, 안정성, 비흡습성, 제형으로의 가공성 등에서 우수한 보노프라잔의 약제학적으로 허용가능한 염을 연구한 결과, 보노프라잔 공결정형이 물리화학적 성질에 비해 동등 이상의 장점을 가지면서, 장기 보관 시 유연물질의 발생을 최소화하며, 용해도는 극대화할 수 있다는 것을 확인하여, 본 발명을 완성하였다.Accordingly, the present inventors studied pharmaceutically acceptable salts of vonoprazan that were excellent in solubility, stability, non-hygroscopicity, and processability into formulations. The present invention was completed by confirming that generation of related substances can be minimized and solubility can be maximized during long-term storage.
본 발명은 물리화학적 안정성, 비흡습성 등이 우수하여 제품 취급, 보관이 유리하고 대량 생산이 가능하며, 용해도가 우수하여 생체이용률이 증진된 의약품을 제공할 수 있는 보노프라잔 공형성화물, 및 이의 제조방법을 제공하는 것을 구체적인 해결과제로 한다.The present invention provides a vonoprazan coformate capable of providing a pharmaceutical product with improved bioavailability due to excellent physicochemical stability, non-hygroscopicity, etc., which is advantageous in product handling and storage, enabling mass production, and excellent solubility, and its A specific problem is to provide a manufacturing method.
본 발명의 상술한 종래기술의 문제점을 해결하기 위해 안출된 것으로서,As devised to solve the above-mentioned problems of the prior art of the present invention,
보노프라잔 및 약제학적으로 허용 가능한 공형성체로 이루어진 공형성화물을 제공한다.A coformate consisting of vonoprazan and a pharmaceutically acceptable coformer is provided.
또한 본 발명에 있어서, 상기 공형성체가 카페인산, 니코틴아마이드, 8,8'-(1,2-phenylenebis(oxy))dioctanoic acid. 및 8-(2-acetylphenoxy)octanoic acid에서 선택되는 1종 이상인 것이고, 공결정형으로 이루어진 것을 특징으로 하는 보노프라잔의 공형성화물을 제공한다.In addition, in the present invention, the coformer is caffeic acid, nicotinamide, 8,8'-(1,2-phenylenebis(oxy))dioctanoic acid. and 8-(2-acetylphenoxy)octanoic acid, and provides a co-formation product of vonoprazan characterized in that it consists of a co-crystal form.
또한 본 발명에 있어서, 보노프라잔 및 공형성체인 카페인산으로 이루어지고, 분말 XRD 스펙트럼상의 회절각(2θ)이 13.60, 14,12, 15.93, 17.52, 17.68, 19.92, 20.30, 20.89, 24.41, 25.63, 26.99인 것을 특징으로 하는 보노프라잔의 공형성화물을 제공한다.In addition, in the present invention, it is composed of vonoprazan and caffeic acid as a coformer, and the diffraction angles (2θ) on the powder XRD spectrum are 13.60, 14,12, 15.93, 17.52, 17.68, 19.92, 20.30, 20.89, 24.41, 25.63 , 26.99.
또한 본 발명에 있어서, 보노프라잔 및 공형성체인 니코틴아마이드로 이루어지고, 분말 XRD 스펙트럼상의 회절각(2θ)이 9.68, 10.21, 15.04, 16.55, 18.05, 25.11, 25.62, 26.10, 27.56인 것을 특징으로 하는 보노프라잔의 공형성화물을 제공한다.In addition, in the present invention, it is composed of vonoprazan and nicotinamide as a coformer, and the diffraction angles (2θ) on the powder XRD spectrum are 9.68, 10.21, 15.04, 16.55, 18.05, 25.11, 25.62, 26.10, and 27.56. It provides a co-former of vonoprazan.
또한 본 발명에 있어서, 보노프라잔 및 공형성체인 8,8'-(1,2-phenylenebis(oxy))dioctanoic acid로 이루어지고, 분말 XRD 스펙트럼상의 회절각(2θ)이 6.66, 11.17, 12.49, 19.89, 20.34, 21.57, 23.04인 것을 특징으로 하는 보노프라잔의 공형성화물을 제공한다.In addition, in the present invention, it is composed of vonoprazan and 8,8'-(1,2-phenylenebis(oxy))dioctanoic acid as a coformer, and the diffraction angles (2θ) on the powder XRD spectrum are 6.66, 11.17, 12.49, A coformate of vonoprazan characterized in that 19.89, 20.34, 21.57, 23.04 is provided.
또한 본 발명에 있어서, 보노프라잔 및 공형성체인 8-(2-acetylphenoxy)octanoic acid로 이루어지고, 분말 XRD 스펙트럼상의 회절각(2θ)이 8.24, 10.82, 11.91, 12.83, 14.65, 16.45, 16.81, 22.81, 24.45인 것을 특징으로 하는 보노프라잔의 공형성화물을 제공한다.In addition, in the present invention, it is composed of vonoprazan and 8-(2-acetylphenoxy)octanoic acid as a coformer, and the diffraction angles (2θ) on the powder XRD spectrum are 8.24, 10.82, 11.91, 12.83, 14.65, 16.45, 16.81, A coformate of vonoprazan characterized in that 22.81 and 24.45 is provided.
또한 본 발명에 있어서, 상기 공형성체가 폴리비닐피로리돈, 및 살카프로제이트 나트륨에서 선택되는 1종 이상인 것이고, 공동무정형으로 이루어진 것을 특징으로 하는 보노프라잔의 공형성화물을 제공한다.In addition, the present invention provides a co-formation product of vonoprazan, characterized in that the co-former is at least one selected from polyvinylpyrrolidone and salcaprozate sodium, and is in a co-amorphous form.
또한 본 발명에 있어서, 보노프라잔 및 공형성체인 폴리비닐피로리돈으로 이루어지고, 분말 XRD 스펙트럼상의 회절각(2θ)이 도 7과 같은 무정형인 것을 특징으로 하는 보노프라잔의 공형성화물을 제공한다.In addition, the present invention provides a co-formation product of vonoprazan, which is composed of vonoprazan and polyvinylpyrrolidone as a co-former, and is characterized in that the diffraction angle (2θ) on the powder XRD spectrum is amorphous as shown in FIG. do.
또한 본 발명에 있어서, 보노프라잔 및 공형성체인 살카프로제이트 나트륨으로 이루어지고, 분말 XRD 스펙트럼상의 회절각(2θ)이 도 9와 같은 무정형인 것을 특징으로 하는 보노프라잔의 공형성화물을 제공한다.In addition, in the present invention, the coformate of vonoprazan, which is composed of vonoprazan and salcaprozate sodium as a coformer, and is characterized in that the diffraction angle (2θ) on the powder XRD spectrum is amorphous as shown in FIG. 9 to provide.
또한, 보노프라잔, 및 약제학적으로 허용 가능한 공형성체를 유기용매에 용해시켜 혼합용액을 제조는 단계; 및In addition, preparing a mixed solution by dissolving vonoprazan and a pharmaceutically acceptable coform in an organic solvent; and
상기 혼합용액의 용매를 증발시키는 단계를 포함하는 보노프라잔 공형성화물물의 제조방법을 제공한다.It provides a method for preparing a vonoprazan co-formed product comprising the step of evaporating the solvent of the mixed solution.
또한 본 발명의 제조방법에 있어서, 상기 혼합용액을 제조하는 단계는 교반 또는 가온 공정을 포함하는 것임을 특징으로 하는 보노프라잔 공형성화물의 제조방법을 제공한다.In addition, in the production method of the present invention, the preparation of the mixed solution provides a method for preparing a vonoprazan co-formed product, characterized in that it includes a stirring or heating process.
또한 본 발명의 제조방법에 있어서, 상기 유기용매는 메탄올, 에탄올, 이소프로필알콜, n-프로판올, 아이소아밀알코올, 아세톤, 에틸메틸케톤, 메틸이소부틸케톤, 아세트산에틸, n-프로필아세테이트, n-부틸아세테이트, t-부틸아세테이트, 톨루엔, 다이클로로메탄, 아세토니트릴 또는 이들의 혼합물인 것을 특징으로 하는 보노프라잔 공형성화물의 제조방법을 제공한다.In addition, in the production method of the present invention, the organic solvent is methanol, ethanol, isopropyl alcohol, n-propanol, isoamyl alcohol, acetone, ethyl methyl ketone, methyl isobutyl ketone, ethyl acetate, n-propyl acetate, n- Provided is a method for preparing vonoprazan co-formed product, characterized in that it is butyl acetate, t-butyl acetate, toluene, dichloromethane, acetonitrile or a mixture thereof.
또한 본 발명의 제조방법에 있어서, 상기 공형성체가 카페인산, 니코틴아마이드, 폴리비닐피로리돈, 살카프로제이트 나트륨, 8,8'-(1,2-phenylenebis(oxy))-dioctanoic acid, 및 8-(2-acetylphenoxy)octanoic acid에서 선택되는 1종 이상인 것을 특징으로 하는 보노프라잔 공형성화물의 제조방법을 제공한다.In addition, in the production method of the present invention, the coformer is caffeic acid, nicotinamide, polyvinylpyrrolidone, salcaprozate sodium, 8,8'-(1,2-phenylenebis(oxy))-dioctanoic acid, and Provided is a method for producing a vonoprazan co-formed product, characterized in that it is at least one selected from 8-(2-acetylphenoxy)octanoic acid.
또한, 본 발명의 보노프라잔 공형성화물을 유효성분으로 포함하는 위 십이지장 궤양 및 역류성 식도염 치료용 약학 조성물을 제공한다.In addition, a pharmaceutical composition for treating gastric and duodenal ulcer and reflux esophagitis containing the vonoprazan coformate as an active ingredient is provided.
본 발명의 보노프라잔 공형성화물은, 약제조성물의 활성성분으로서 요구되는 용해도 등의 사항을 모두 만족하면서도, 높은 안정성을 나타내어, 의약품 제제 시에 매우 유용하게 사용될 수 있을 것이다.The vonoprazan coformate of the present invention satisfies all requirements such as solubility required as an active ingredient of a pharmaceutical composition, and exhibits high stability, so that it can be used very usefully in pharmaceutical preparation.
도 1은, 보노프라잔에 대한 분말 XRD 패턴이다.
도 2는, 보노프라잔에 대한 DSC 열분석도이다.
도 3은, 보노프라잔과 카페인산 공결정에 대한 분말 XRD 패턴이다.
도 4는, 보노프라잔과 카페인산 공결정에 대한 DSC 열분석도이다.
도 5는, 보노프라잔과 니코틴아마이드 공결정에 대한 분말 XRD 패턴이다.
도 6은, 보노프라잔과 니코틴아마이드 공결정에 대한 DSC 열분석도이다.
도 7은, 보노프라잔과 폴리비닐피로리돈 공결정에 대한 분말 XRD 패턴이다.
도 8은, 보노프라잔과 폴리비닐피로리돈 공결정에 대한 DSC 열분석도이다.
도 9는, 보노프라잔과 살카프로제이트 나트륨 공결정에 대한 분말 XRD 패턴이다.
도 10은, 보노프라잔과 살카프로제이트 나트륨 공결정에 대한 DSC 열분석도이다.
도 11은, 보노프라잔과 8,8'-(1,2-phenylenebis(oxy))dioctanoic acid 공결정에 대한 분말 XRD 패턴이다.
도 12는, 보노프라잔과 8,8'-(1,2-phenylenebis(oxy))dioctanoic acid 공결정에 대한 DSC 열분석도이다.
도 13은, 보노프라잔과 8-(2-acetylphenoxy)octanoic acid 공결정에 대한 분말 XRD 패턴이다.
도 14는, 보노프라잔과 8-(2-acetylphenoxy)octanoic acid 공결정에 대한 DSC 열분석도이다.
도 15는, 보노프라잔과 본원발명 보노프라잔 공결정형 및 공동무정형과의 안정성 비교실험 결과를 나타낸 그래프이다.1 is a powder XRD pattern for vonoprazan.
2 is a DSC thermogram for vonoprazan.
3 is a powder XRD pattern of vonoprazan and caffeic acid co-crystals.
4 is a DSC thermogram of vonoprazan and caffeic acid co-crystals.
5 is a powder XRD pattern for vonoprazan and nicotinamide co-crystals.
6 is a DSC thermogram of vonoprazan and nicotinamide co-crystals.
7 is a powder XRD pattern of vonoprazan and polyvinylpyrrolidone co-crystal.
8 is a DSC thermogram of a co-crystal of vonoprazan and polyvinylpyrrolidone.
9 is a powder XRD pattern for vonoprazan and salcaprozate sodium co-crystals.
10 is a DSC thermogram of vonoprazan and salcaprozate sodium co-crystals.
Fig. 11 is a powder XRD pattern of co-crystals of vonoprazan and 8,8'-(1,2-phenylenebis(oxy))dioctanoic acid.
12 is a DSC thermogram of vonoprazan and 8,8′-(1,2-phenylenebis(oxy))dioctanoic acid co-crystal.
13 is a powder XRD pattern for co-crystals of vonoprazan and 8-(2-acetylphenoxy)octanoic acid.
14 is a DSC thermogram of a co-crystal of vonoprazan and 8-(2-acetylphenoxy)octanoic acid.
15 is a graph showing the results of a stability comparison experiment between vonoprazan and the co-crystalline and co-amorphous forms of vonoprazan of the present invention.
이하, 본 발명에 대하여 상세히 설명한다.Hereinafter, the present invention will be described in detail.
본 발명의 일측면은, One aspect of the present invention,
보노프라잔 및 약제학적으로 허용 가능한 공형성체로 이루어진 공형성화물이다.It is a coformate consisting of vonoprazan and a pharmaceutically acceptable coformer.
본 발명에 있어서, 상기 공형성체가 보노프라잔과 공결정을 이룰 수 있는 물질이고, 공결정형으로 이루어진 것일 수 있으며, 이에 대한 예로, 상기 공형성체가 카페인산, 니코틴아마이드, 8,8'-(1,2-phenylenebis(oxy))dioctanoic acid. 및 8-(2-acetylphenoxy)octanoic acid에서 선택되는 1종 이상인 것을 들 수 있다. In the present invention, the co-former is a material capable of forming a co-crystal with vonoprazan, and may be in a co-crystal form. For example, the co-former is caffeic acid, nicotinamide, 8,8'-( 1,2-phenylenebis(oxy))dioctanoic acid. and 8-(2-acetylphenoxy)octanoic acid.
여기서, 공결정은 하나의 결정격자 안에 일정한 화학양론 비율(stoichiometric ratio)로 두 개 이상의 다른 분자가 결정 구조를 형성하고 있는 형태를 의미한다.Here, the co-crystal means a form in which two or more different molecules form a crystal structure at a constant stoichiometric ratio in one crystal lattice.
특히, 공결정(co-crystals)은 O,OH,N등과 같은 수소결합을 이룰 수 있는 작용기가 풍부하거나 pKa 차이가 3이하 차이가 나는 공동분자(coformer)와 수소결합을 통해 규칙적 비율로 결합하는 것등을 통해, 새로운 결정구조를 갖을 수 있다. 이런 공결정들은 2분자 이상의 화합물을 포함하기 때문에, 복합체 형태로 표현될 수 있다. In particular, co-crystals are rich in functional groups capable of forming hydrogen bonds, such as O, OH, N, etc., or bond with coformers with a pKa difference of 3 or less in a regular ratio through hydrogen bonding. Through this, it is possible to have a new crystal structure. Since these co-crystals contain two or more molecules of compounds, they can be expressed in the form of complexes.
구체적으로는, 보노프라잔 및 공형성체인 카페인산으로 이루어지고, 분말 XRD 스펙트럼상의 회절각(2θ)이 13.60, 14,12, 15.93, 17.52, 17.68, 19.92, 20.30, 20.89, 24.41, 25.63, 26.99인 것이거나; Specifically, it was composed of vonoprazan and caffeic acid as a coformer, and the diffraction angles (2θ) on the powder XRD spectrum were 13.60, 14,12, 15.93, 17.52, 17.68, 19.92, 20.30, 20.89, 24.41, 25.63, 26.99 is;
보노프라잔 및 공형성체인 니코틴아마이드로 이루어지고, 분말 XRD 스펙트럼상의 회절각(2θ)이 9.68, 10.21, 15.04, 16.55, 18.05, 25.11, 25.62, 26.10, 27.56인 것이거나;It consists of vonoprazan and nicotinamide as a coformer, and the diffraction angles (2θ) on the powder XRD spectrum are 9.68, 10.21, 15.04, 16.55, 18.05, 25.11, 25.62, 26.10, 27.56;
보노프라잔 및 공형성체인 8,8'-(1,2-phenylenebis(oxy))dioctanoic acid로 이루어지고, 분말 XRD 스펙트럼상의 회절각(2θ)이 6.66, 11.17, 12.49, 19.89, 20.34, 21.57, 23.04인 것이거나;It is composed of vonoprazan and
보노프라잔 및 공형성체인 8-(2-acetylphenoxy)octanoic acid로 이루어지고, 분말 XRD 스펙트럼상의 회절각(2θ)이 8.24, 10.82, 11.91, 12.83, 14.65, 16.45, 16.81, 22.81, 24.45인 것일 수 있다.It is composed of vonoprazan and co-former 8-(2-acetylphenoxy)octanoic acid, and the diffraction angles (2θ) on the powder XRD spectrum may be 8.24, 10.82, 11.91, 12.83, 14.65, 16.45, 16.81, 22.81, 24.45. there is.
또한, 본 발명에 있어서, 상기 공형성체가 보노프라잔과 공동무정형(co-amorphous)을 이룰 수 있는 물질이고, 공동무정형으로 이루어진 것일 수 있으며, 이에 대한 예로, 폴리비닐피로리돈, 및 살카프로제이트 나트륨에서 선택되는 1종 이상인 것을 들 수 있다.In addition, in the present invention, the co-former is a material capable of co-amorphous with vonoprazan, and may be co-amorphous. and at least one selected from sodium.
여기서, 상기 공동무정형(co-amorphous)은 2분자 이상의 화합물 분자의 상호작용은 존재하지만 결정배열을 이루지 못하는 고체 상태를 의미한다. Here, the co-amorphous means a solid state in which two or more compound molecules interact but do not form a crystal arrangement.
구체적으로, 보노프라잔 및 공형성체인 폴리비닐피로리돈으로 이루어지고, 분말 XRD 스펙트럼상의 회절각(2θ)이 도 7과 같은 무정형인 것이거나;Specifically, it is composed of vonoprazan and polyvinylpyrrolidone as a coformer, and the diffraction angle (2θ) on the powder XRD spectrum is amorphous as shown in FIG. 7;
보노프라잔 및 공형성체인 살카프로제이트 나트륨으로 이루어지고, 분말 XRD 스펙트럼상의 회절각(2θ)이 도 9와 같은 무정형인 것일 수 있다.It may be composed of vonoprazan and sodium salcaprozate as a coformer, and may be amorphous as shown in FIG. 9 with a diffraction angle (2θ) on the powder XRD spectrum.
본 발명의 다른 측면은,Another aspect of the present invention is
보노프라잔, 및 약제학적으로 허용 가능한 공형성체를 유기용매에 용해시켜 혼합용액을 제조는 단계; 및preparing a mixed solution by dissolving vonoprazan and a pharmaceutically acceptable coform in an organic solvent; and
상기 혼합용액의 용매를 증발시키는 단계를 포함하는 보노프라잔 공형성화물의 제조방법이다.A method for producing a vonoprazan co-formation product comprising evaporating the solvent of the mixed solution.
상기 혼합용액을 제조하는 단계는 교반 또는 가온 공정을 포함하는 것일 수 있다.Preparing the mixed solution may include a stirring or heating process.
상기 유기용매는, 보노프라잔, 및 공형성체에 대해서 공통적으로 용해도가 적어도 50mg/ml 이상 나타내는 용매를 사용할 수 있고, 가능한 용매의 예시로, 메탄올, 에탄올, 이소프로필알콜, n-프로판올, 아이소아밀알코올, 아세톤, 에틸메틸케톤, 메틸이소부틸케톤, 아세트산에틸, n-프로필아세테이트, n-부틸아세테이트, t-부틸아세테이트, 톨루엔, 다이클로로메탄, 아세토니트릴 또는 이들의 혼합물인 것을 들 수 있다.As the organic solvent, a solvent having a solubility of at least 50 mg/ml or more for vonoprazan and the coformer may be used. Examples of possible solvents include methanol, ethanol, isopropyl alcohol, n-propanol, and isoamyl. alcohol, acetone, ethyl methyl ketone, methyl isobutyl ketone, ethyl acetate, n-propyl acetate, n-butyl acetate, t-butyl acetate, toluene, dichloromethane, acetonitrile, or mixtures thereof.
상기 공형성체는 카페인산, 니코틴아마이드, 폴리비닐피로리돈, 살카프로제이트 나트륨, 8,8'-(1,2-phenylenebis(oxy))-dioctanoic acid, 및 8-(2-acetylphenoxy)octanoic acid에서 선택되는 1종 이상인 것일 수 있다.The coforms are caffeic acid, nicotinamide, polyvinylpyrrolidone, salcaprozate sodium, 8,8'-(1,2-phenylenebis(oxy))-dioctanoic acid, and 8-(2-acetylphenoxy)octanoic acid It may be one or more selected from.
본 발명의 또 다른 측면은,Another aspect of the present invention is
상기 본 발명의 보노프라잔 공형성화물을 유효성분으로 포함하는 약제학적 조성물이다.A pharmaceutical composition comprising the vonoprazan coformate of the present invention as an active ingredient.
상기 약제학적 조성물은, 다양한 인체 또는 동물에 대한 질병의 예방 또는 치료 목적으로 사용될 수 있고 특별히 제한되지는 것은 아니지만, 위궤양, 십이지장 궤양, 또는 역류성 식도염 치료용 등 소화기관 치료용 약제으로서 바람직하게 사용될 수 있다.The pharmaceutical composition can be used for the purpose of preventing or treating various diseases in humans or animals, and is not particularly limited, but is preferably used as a drug for treating the digestive system, such as for treating gastric ulcer, duodenal ulcer, or reflux esophagitis. there is.
이하, 실시예 및 실험예를 들어 본 발명에 대해 보다 더 상세히 설명한다. 다만, 이하의 실시예는 발명의 상세한 설명을 위한 것일 뿐, 이에 의해 권리범위를 제한하려는 의도가 아님을 분명히 해둔다.Hereinafter, the present invention will be described in more detail with examples and experimental examples. However, it is made clear that the following examples are only for detailed description of the invention, and are not intended to limit the scope of rights thereby.
실시예Example
실시예Example 1 - One - 보노프라잔과with vonoprazan 카페인산의 caffeic 공결정co-crystal 제조 (1: Manufacturing (1: 1비율1 rate ))
보노프라잔(1g)을 상온에서 메탄올(10ml)에 교반하여 용해시킨다. 이 반응액에 카페인산(1g)을 첨가하여 2시간 교반한 후, 감압증류를 통하여 용매를 제거하고, 짧은 시간 안에 보노프라잔과 카페인산 공결정의 결정형이 형성되었다. 진공 건조 하에 결정만 회수하여 1.94g 수득 하였다. 상기 실시예 1에서 제조된 보노프라잔과 카페인산 공결정에 대한 분말 XRD 스펙트럼(X-ray Diffraction Spectrum), 시차주사 열량 기록도 (Differential Scanning Calorimeter Thermogram)는 각각 도 3 및 도 4에 첨부하였다.Vonoprazan (1 g) was stirred and dissolved in methanol (10 ml) at room temperature. After adding caffeic acid (1 g) to the reaction solution and stirring for 2 hours, the solvent was removed through distillation under reduced pressure, and a crystalline form of vonoprazan and caffeic acid co-crystal was formed within a short time. Only crystals were recovered under vacuum drying to obtain 1.94 g. Powder XRD spectra and differential scanning calorimeter thermograms for the co-crystal of vonoprazan and caffeic acid prepared in Example 1 are attached to FIGS. 3 and 4, respectively.
실시예Example 2 - 2 - 보노프라잔과with vonoprazan 니코틴아마이드의of nicotinamide 공결정co-crystal 제조 (1: Manufacturing (1: 1비율1 rate ))
보노프라잔(1g)을 상온에서 메탄올(5ml)에 교반하여 용해시킨다. 이 반응액에 니코틴아마이드(1g)를 첨가하여 2시간 동안 교반한 후, 감압증류를 통하여 용매를 제거하고, 짧은 시간 안에 보노프라잔과 니코틴아마이드 공결정의 결정형이 형성되었다. 진공 건조 하에 결정만 회수하여 1.96g 수득 하였다. 상기 실시예 2에서 제조된 보노프라잔과 니코틴아마이드 공결정에 대한 분말 XRD 스펙트럼(X-ray-Diffraction Spectrum), 시차주사 열량 기록도 (Differential Scanning Calorimeter Thermogram)는 각각 도 5 및 도 6에 첨부하였다.Vonoprazan (1 g) was stirred and dissolved in methanol (5 ml) at room temperature. Nicotinamide (1 g) was added to the reaction solution and stirred for 2 hours, and then the solvent was removed through distillation under reduced pressure, and a crystalline form of vonoprazan and nicotinamide co-crystal was formed within a short time. Only crystals were recovered under vacuum drying to obtain 1.96 g. Powder XRD spectrum (X-ray-Diffraction Spectrum) and Differential Scanning Calorimeter Thermogram of the co-crystal of vonoprazan and nicotinamide prepared in Example 2 are attached to FIGS. 5 and 6, respectively. .
실시예Example 3 - 3 - 보노프라잔과with vonoprazan 폴리비닐피로리돈의of polyvinylpyrrolidone 공결정co-crystal 제조(1: Manufacturing (1: 1비율1 rate ))
보노프라잔(1g)을 상온에서 메탄올(5ml)에 교반하여 용해시킨다. 이 반응액에 폴리비닐피로리돈(1g)을 첨가하여 2시간 동안 교반한 후, 감압증류를 통하여 용매를 제거하고, 짧은 시간 안에 보노프라잔과 폴리비닐피로리돈 공결정의 결정형이 형성되었다. 진공 건조 하에 결정만 회수하여 1.98g 수득 하였다. 상기 실시예 3에서 제조된 보노프라잔과 폴리비닐피로리돈 공결정에 대한 분말 XRD 스펙트럼(X-ray-Diffraction Spectrum), 시차주사 열량 기록도 (Differential Scanning Calorimeter Thermogram)는 각각 도 7 및 도 8에 첨부하였다.Vonoprazan (1 g) was stirred and dissolved in methanol (5 ml) at room temperature. After adding polyvinylpyrrolidone (1g) to the reaction solution and stirring for 2 hours, the solvent was removed through distillation under reduced pressure, and a crystalline form of vonoprazan and polyvinylpyrrolidone co-crystal was formed in a short time. Only crystals were recovered under vacuum drying to obtain 1.98 g. Powder XRD spectrum (X-ray-Diffraction Spectrum) and Differential Scanning Calorimeter Thermogram of the co-crystal of vonoprazan and polyvinylpyrrolidone prepared in Example 3 are shown in FIGS. 7 and 8, respectively. attached.
실시예Example 4 - 4 - 보노프라잔과with vonoprazan 살카프로제이트Salcaprozate 나트륨의 of sodium 공결정co-crystal 제조(1: Manufacturing (1: 1비율1 rate ))
보노프라잔(1g)을 상온에서 메탄올(10ml)에 교반하여 용해시킨다. 이 반응액에 살카프로제이트 나트륨(1g)을 첨가하여 2시간 동안 교반한 후, 감압증류를 통하여 용매를 제거하고, 짧은 시간 안에 보노프라잔과 살카프로제이트 나트륨 공결정의 결정형이 형성되었다. 진공 건조 하에 결정만 회수하여 1.94g 수득 하였다. 상기 실시예 4에서 제조된 보노프라잔과 살카프로제이트 나트륨 공결정에 대한 분말 XRD 스펙트럼(X-ray-Diffraction Spectrum), 시차주사 열량 기록도 (Differential Scanning Calorimeter Thermogram)는 각각 도 9 및 도 10에 첨부하였다.Vonoprazan (1 g) was stirred and dissolved in methanol (10 ml) at room temperature. Sodium salcaprozate (1 g) was added to the reaction solution, stirred for 2 hours, and the solvent was removed through distillation under reduced pressure, and a crystalline form of vonoprazan and sodium salcaprozate co-crystal was formed in a short time. . Only crystals were recovered under vacuum drying to obtain 1.94 g. Powder XRD spectrum (X-ray-Diffraction Spectrum) and Differential Scanning Calorimeter Thermogram of the vonoprazan and salcaprozate sodium co-crystals prepared in Example 4 are shown in FIGS. 9 and 10, respectively. attached to.
실시예Example
5 - 5 -
보노프라잔과with
보노프라잔(1g)을 상온에서 메탄올(10ml)에 교반하여 용해시킨다. 이 반응액에 8,8'-(1,2-phenylenebis(oxy))dioctanoic acid(1g)을 첨가하여 2시간 동안 교반한 후, 감압증류를 통하여 용매를 제거하고, 짧은 시간 안에 보노프라잔과 8,8'-(1,2-phenylenebis(oxy))dioctanoic acid 공결정의 결정형이 형성되었다. 진공 건조 하에 결정만 회수하여 1.95g 수득 하였다. 상기 실시예 5에서 제조된 보노프라잔과 8,8'-(1,2-phenylenebis(oxy))dioctanoic acid 공결정에 대한 분말 XRD 스펙트럼(X-ray-Diffraction Spectrum), 시차주사 열량 기록도 (Differential Scanning Calorimeter Thermogram)는 각각 도 11 및 도 12에 첨부하였다.Vonoprazan (1 g) was stirred and dissolved in methanol (10 ml) at room temperature. After adding 8,8'-(1,2-phenylenebis(oxy))dioctanoic acid (1g) to the reaction solution and stirring for 2 hours, the solvent was removed by distillation under reduced pressure, and vonoprazan and A co-crystal of 8,8'-(1,2-phenylenebis(oxy))dioctanoic acid was formed. Only crystals were recovered under vacuum drying to obtain 1.95 g. Powder XRD spectrum (X-ray-Diffraction Spectrum) of the co-crystal of vonoprazan and 8,8'-(1,2-phenylenebis(oxy))dioctanoic acid prepared in Example 5, differential scanning calorimetry ( Differential Scanning Calorimeter Thermogram) is attached to FIGS. 11 and 12, respectively.
실시예Example 6 - 6 - 보노프라잔과with vonoprazan 8-(2- 8-(2- acetylphenoxyacetylphenoxy )) octanoicoctanoic acid의 of acid 공결정co-crystal 제조(1:1비율) Manufacturing (1:1 ratio)
보노프라잔(1g)을 상온에서 메탄올(10ml)에 교반하여 용해시킨다. 이 반응액에 8-(2-acetylphenoxy)octanoic acid(1g)을 첨가하여 2시간 동안 교반한 후, 감압증류를 통하여 용매를 제거하고, 짧은 시간 안에 보노프라잔과 8-(2-acetylphenoxy)octanoic acid 공결정의 결정형이 형성되었다. 진공 건조 하에 결정만 회수하여 1.95g 수득 하였다. 상기 실시예 6에서 제조된 보노프라잔과 8-(2-acetylphenoxy)octanoic acid 공결정에 대한 분말 XRD 스펙트럼(X-ray-Diffraction Spectrum), 시차주사 열량 기록도 (Differential Scanning Calorimeter Thermogram)는 각각 도 13 및 도 14에 첨부하였다.Vonoprazan (1 g) was stirred and dissolved in methanol (10 ml) at room temperature. After adding 8-(2-acetylphenoxy)octanoic acid (1g) to the reaction solution and stirring for 2 hours, the solvent was removed through distillation under reduced pressure, and vonoprazan and 8-(2-acetylphenoxy)octanoic acid were prepared in a short time. A crystalline form of the acid co-crystal was formed. Only crystals were recovered under vacuum drying to obtain 1.95 g. The powder XRD spectrum and differential scanning calorimeter thermogram of the co-crystal of vonoprazan and 8-(2-acetylphenoxy)octanoic acid prepared in Example 6 are shown respectively. 13 and 14 are attached.
시험예test example
안정성 시험stability test
본 발명의 보노프라잔의 다양한 결정다형의 온도에 대한 안정성을 확인하기 위하여, 하기의 실험방법을 실시하여 안정성을 비교하였다.In order to confirm the temperature stability of various polymorphs of vonoprazan of the present invention, the stability was compared by conducting the following experimental method.
<실험방법><Experiment method>
상온과 65℃ 오븐에서 보노프라잔과 보노프라잔 결정다형을 4주 동안 방치한 후에, 고성능 액체크로마토그래피(HPLC)로 분석하여 순도를 측정하였다.After leaving vonoprazan and vonoprazan polymorphs in an oven at room temperature and 65° C. for 4 weeks, they were analyzed by high-performance liquid chromatography (HPLC) to measure purity.
결과는 하기 표 1 및 도 15에 나타낸 바와 같았다.The results were as shown in Table 1 and FIG. 15 below.
상기 데이터에서 확인할 수 있듯이, 본 발명의 보노프라잔의 다양한 결정다형 실시예 1 내지 6은 기존의 보노프라잔과 비교해볼 때, 보다 안정성이 높고, 이는 약제, 제조에 보다 유용한 장점이 있다.As can be seen from the above data, the various polymorphs of Examples 1 to 6 of vonoprazan of the present invention have higher stability compared to the existing vonoprazan, which is more useful for pharmaceuticals and manufacturing.
용해도 시험solubility test
메탄올, 및 물 용매에 대한 용해도를 측정하였다. 결과는 하기 표 2(메탄올 용매) 및 표 3(물용매)과 같았다.Solubility in methanol and water solvents was measured. The results were shown in Table 2 (methanol solvent) and Table 3 (water solvent).
Claims (14)
상기 혼합용액의 용매를 증발시키는 단계를 포함하는 보노프라잔 공형성화물물의 제조방법.preparing a mixed solution by dissolving vonoprazan and a pharmaceutically acceptable coform in an organic solvent; and
A method for preparing a vonoprazan co-formed product comprising the step of evaporating the solvent of the mixed solution.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN106632246A (en) | 2015-10-30 | 2017-05-10 | 江苏柯菲平医药股份有限公司 | Crystalline form of pyrrole-type gastric acid secretion inhibitor compound salt and preparation thereof |
| CN107778289A (en) | 2016-08-31 | 2018-03-09 | 江苏柯菲平医药股份有限公司 | 5‑（2 fluorophenyls）N methyl 1（3 pyridyl sulfonyls）The polymorph of the first ammonia acetate of 1H pyrroles 3 |
| CN108689991A (en) | 2018-06-11 | 2018-10-23 | 杭州中美华东制药有限公司 | Wo Nuolazan novel crystal forms salt and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106632246A (en) | 2015-10-30 | 2017-05-10 | 江苏柯菲平医药股份有限公司 | Crystalline form of pyrrole-type gastric acid secretion inhibitor compound salt and preparation thereof |
| CN107778289A (en) | 2016-08-31 | 2018-03-09 | 江苏柯菲平医药股份有限公司 | 5‑（2 fluorophenyls）N methyl 1（3 pyridyl sulfonyls）The polymorph of the first ammonia acetate of 1H pyrroles 3 |
| CN108689991A (en) | 2018-06-11 | 2018-10-23 | 杭州中美华东制药有限公司 | Wo Nuolazan novel crystal forms salt and preparation method thereof |
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