CN106924179B - Liquid preparation containing Vonoprazan fumarate and preparation method thereof - Google Patents
Liquid preparation containing Vonoprazan fumarate and preparation method thereof Download PDFInfo
- Publication number
- CN106924179B CN106924179B CN201511016558.XA CN201511016558A CN106924179B CN 106924179 B CN106924179 B CN 106924179B CN 201511016558 A CN201511016558 A CN 201511016558A CN 106924179 B CN106924179 B CN 106924179B
- Authority
- CN
- China
- Prior art keywords
- vonoprazan fumarate
- liquid preparation
- cyclodextrin
- beta
- acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Links
- 229950003825 vonoprazan Drugs 0.000 title claims abstract description 93
- 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 title claims abstract description 90
- 238000002360 preparation method Methods 0.000 title claims abstract description 90
- 239000007788 liquid Substances 0.000 title claims abstract description 62
- 239000000243 solution Substances 0.000 claims description 86
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 54
- 239000000203 mixture Substances 0.000 claims description 42
- 229920000858 Cyclodextrin Polymers 0.000 claims description 32
- 239000001116 FEMA 4028 Substances 0.000 claims description 28
- 229960004853 betadex Drugs 0.000 claims description 28
- 150000001413 amino acids Chemical class 0.000 claims description 26
- WHGYBXFWUBPSRW-FOUAGVGXSA-N beta-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO WHGYBXFWUBPSRW-FOUAGVGXSA-N 0.000 claims description 26
- 235000011175 beta-cyclodextrine Nutrition 0.000 claims description 26
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 26
- 239000004475 Arginine Substances 0.000 claims description 23
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 claims description 23
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 22
- 239000012669 liquid formulation Substances 0.000 claims description 19
- ODLHGICHYURWBS-LKONHMLTSA-N trappsol cyclo Chemical compound CC(O)COC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)COCC(O)C)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1COCC(C)O ODLHGICHYURWBS-LKONHMLTSA-N 0.000 claims description 19
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 14
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 9
- 229940097346 sulfobutylether-beta-cyclodextrin Drugs 0.000 claims description 9
- 239000000725 suspension Substances 0.000 claims description 9
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 8
- 239000004376 Sucralose Substances 0.000 claims description 7
- 235000019408 sucralose Nutrition 0.000 claims description 7
- BAQAVOSOZGMPRM-QBMZZYIRSA-N sucralose Chemical compound O[C@@H]1[C@@H](O)[C@@H](Cl)[C@@H](CO)O[C@@H]1O[C@@]1(CCl)[C@@H](O)[C@H](O)[C@@H](CCl)O1 BAQAVOSOZGMPRM-QBMZZYIRSA-N 0.000 claims description 7
- 239000000796 flavoring agent Substances 0.000 claims description 6
- 235000013355 food flavoring agent Nutrition 0.000 claims description 6
- 239000001530 fumaric acid Substances 0.000 claims description 6
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 6
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 claims description 5
- 108010011485 Aspartame Proteins 0.000 claims description 5
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims description 5
- IAOZJIPTCAWIRG-QWRGUYRKSA-N aspartame Chemical compound OC(=O)C[C@H](N)C(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 IAOZJIPTCAWIRG-QWRGUYRKSA-N 0.000 claims description 5
- 239000000605 aspartame Substances 0.000 claims description 5
- 235000010357 aspartame Nutrition 0.000 claims description 5
- 229960003438 aspartame Drugs 0.000 claims description 5
- 239000001630 malic acid Substances 0.000 claims description 5
- 235000011090 malic acid Nutrition 0.000 claims description 5
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 4
- 239000011975 tartaric acid Substances 0.000 claims description 4
- 235000002906 tartaric acid Nutrition 0.000 claims description 4
- UEDUENGHJMELGK-HYDKPPNVSA-N Stevioside Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1O[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 UEDUENGHJMELGK-HYDKPPNVSA-N 0.000 claims description 3
- 238000009472 formulation Methods 0.000 claims description 3
- 239000004310 lactic acid Substances 0.000 claims description 3
- 235000014655 lactic acid Nutrition 0.000 claims description 3
- 229940013618 stevioside Drugs 0.000 claims description 3
- OHHNJQXIOPOJSC-UHFFFAOYSA-N stevioside Natural products CC1(CCCC2(C)C3(C)CCC4(CC3(CCC12C)CC4=C)OC5OC(CO)C(O)C(O)C5OC6OC(CO)C(O)C(O)C6O)C(=O)OC7OC(CO)C(O)C(O)C7O OHHNJQXIOPOJSC-UHFFFAOYSA-N 0.000 claims description 3
- 235000019202 steviosides Nutrition 0.000 claims description 3
- 238000009210 therapy by ultrasound Methods 0.000 claims description 3
- 239000008215 water for injection Substances 0.000 claims description 3
- 238000005303 weighing Methods 0.000 claims description 3
- NOOLISFMXDJSKH-UTLUCORTSA-N (+)-Neomenthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@@H]1O NOOLISFMXDJSKH-UTLUCORTSA-N 0.000 claims description 2
- WBZFUFAFFUEMEI-UHFFFAOYSA-M Acesulfame k Chemical compound [K+].CC1=CC(=O)[N-]S(=O)(=O)O1 WBZFUFAFFUEMEI-UHFFFAOYSA-M 0.000 claims description 2
- NOOLISFMXDJSKH-UHFFFAOYSA-N DL-menthol Natural products CC(C)C1CCC(C)CC1O NOOLISFMXDJSKH-UHFFFAOYSA-N 0.000 claims description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 2
- 206010013911 Dysgeusia Diseases 0.000 claims description 2
- 235000010358 acesulfame potassium Nutrition 0.000 claims description 2
- 229960004998 acesulfame potassium Drugs 0.000 claims description 2
- 239000000619 acesulfame-K Substances 0.000 claims description 2
- 230000000595 bitter masking effect Effects 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 235000015165 citric acid Nutrition 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 claims description 2
- 235000011087 fumaric acid Nutrition 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 229940041616 menthol Drugs 0.000 claims description 2
- 239000003002 pH adjusting agent Substances 0.000 claims 4
- 244000246386 Mentha pulegium Species 0.000 claims 1
- 235000016257 Mentha pulegium Nutrition 0.000 claims 1
- 235000004357 Mentha x piperita Nutrition 0.000 claims 1
- 235000001050 hortel pimenta Nutrition 0.000 claims 1
- 239000012535 impurity Substances 0.000 abstract description 15
- 238000002347 injection Methods 0.000 abstract description 4
- 239000007924 injection Substances 0.000 abstract description 4
- 238000004806 packaging method and process Methods 0.000 abstract description 3
- 239000005022 packaging material Substances 0.000 abstract description 2
- 230000002829 reductive effect Effects 0.000 abstract description 2
- 230000015556 catabolic process Effects 0.000 abstract 1
- 238000006731 degradation reaction Methods 0.000 abstract 1
- 229930182555 Penicillin Natural products 0.000 description 22
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 22
- 229940049954 penicillin Drugs 0.000 description 22
- 238000007789 sealing Methods 0.000 description 22
- 238000011835 investigation Methods 0.000 description 20
- 235000001014 amino acid Nutrition 0.000 description 19
- 239000000843 powder Substances 0.000 description 18
- 238000012360 testing method Methods 0.000 description 16
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 238000004108 freeze drying Methods 0.000 description 11
- 230000000694 effects Effects 0.000 description 9
- 230000000052 comparative effect Effects 0.000 description 7
- 230000001133 acceleration Effects 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- 235000019640 taste Nutrition 0.000 description 5
- 235000019658 bitter taste Nutrition 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 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 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 238000011156 evaluation Methods 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 3
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 2
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 2
- 239000004472 Lysine Substances 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 230000027119 gastric acid secretion Effects 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- YZOUYRAONFXZSI-SBHWVFSVSA-N (1S,3R,5R,6R,8R,10R,11R,13R,15R,16R,18R,20R,21R,23R,25R,26R,28R,30R,31S,33R,35R,36R,37S,38R,39S,40R,41S,42R,43S,44R,45S,46R,47S,48R,49S)-5,10,15,20,25,30,35-heptakis(hydroxymethyl)-37,39,40,41,42,43,44,45,46,47,48,49-dodecamethoxy-2,4,7,9,12,14,17,19,22,24,27,29,32,34-tetradecaoxaoctacyclo[31.2.2.23,6.28,11.213,16.218,21.223,26.228,31]nonatetracontane-36,38-diol Chemical compound O([C@@H]([C@H]([C@@H]1OC)OC)O[C@H]2[C@@H](O)[C@@H]([C@@H](O[C@@H]3[C@@H](CO)O[C@@H]([C@H]([C@@H]3O)OC)O[C@@H]3[C@@H](CO)O[C@@H]([C@H]([C@@H]3OC)OC)O[C@@H]3[C@@H](CO)O[C@@H]([C@H]([C@@H]3OC)OC)O[C@@H]3[C@@H](CO)O[C@@H]([C@H]([C@@H]3OC)OC)O3)O[C@@H]2CO)OC)[C@H](CO)[C@H]1O[C@@H]1[C@@H](OC)[C@H](OC)[C@H]3[C@@H](CO)O1 YZOUYRAONFXZSI-SBHWVFSVSA-N 0.000 description 1
- PCWPQSDFNIFUPO-VDQKLNDWSA-N (1S,3R,5R,6S,8R,10R,11S,13R,15R,16S,18R,20R,21S,23R,25R,26S,28R,30R,31S,33R,35R,36R,37S,38R,39S,40R,41S,42R,43S,44R,45S,46R,47S,48R,49S)-37,39,41,43,45,47,49-heptakis(2-hydroxyethoxy)-5,10,15,20,25,30,35-heptakis(hydroxymethyl)-2,4,7,9,12,14,17,19,22,24,27,29,32,34-tetradecaoxaoctacyclo[31.2.2.23,6.28,11.213,16.218,21.223,26.228,31]nonatetracontane-36,38,40,42,44,46,48-heptol Chemical compound OCCO[C@H]1[C@H](O)[C@@H]2O[C@H]3O[C@H](CO)[C@@H](O[C@H]4O[C@H](CO)[C@@H](O[C@H]5O[C@H](CO)[C@@H](O[C@H]6O[C@H](CO)[C@@H](O[C@H]7O[C@H](CO)[C@@H](O[C@H]8O[C@H](CO)[C@@H](O[C@H]1O[C@@H]2CO)[C@@H](O)[C@@H]8OCCO)[C@@H](O)[C@@H]7OCCO)[C@@H](O)[C@@H]6OCCO)[C@@H](O)[C@@H]5OCCO)[C@@H](O)[C@@H]4OCCO)[C@@H](O)[C@@H]3OCCO PCWPQSDFNIFUPO-VDQKLNDWSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- IAJILQKETJEXLJ-UHFFFAOYSA-N Galacturonsaeure Natural products O=CC(O)C(O)C(O)C(O)C(O)=O IAJILQKETJEXLJ-UHFFFAOYSA-N 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- 235000006679 Mentha X verticillata Nutrition 0.000 description 1
- 235000002899 Mentha suaveolens Nutrition 0.000 description 1
- 235000001636 Mentha x rotundifolia Nutrition 0.000 description 1
- NPYPAHLBTDXSSS-UHFFFAOYSA-N Potassium ion Chemical compound [K+] NPYPAHLBTDXSSS-UHFFFAOYSA-N 0.000 description 1
- 102100021904 Potassium-transporting ATPase alpha chain 1 Human genes 0.000 description 1
- 108010083204 Proton Pumps Proteins 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- IAJILQKETJEXLJ-QTBDOELSSA-N aldehydo-D-glucuronic acid Chemical compound O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)C(O)=O IAJILQKETJEXLJ-QTBDOELSSA-N 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 235000019606 astringent taste Nutrition 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 230000002860 competitive effect Effects 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 210000004211 gastric acid Anatomy 0.000 description 1
- 210000001914 gastric parietal cell Anatomy 0.000 description 1
- 229940097043 glucuronic acid Drugs 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 229910001507 metal halide Inorganic materials 0.000 description 1
- 150000005309 metal halides Chemical class 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 125000000467 secondary amino group Chemical group [H]N([*:1])[*:2] 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 230000007928 solubilization Effects 0.000 description 1
- 238000005063 solubilization Methods 0.000 description 1
- 235000019614 sour taste Nutrition 0.000 description 1
Classifications
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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
- A61K9/08—Solutions
-
- 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
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
- A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
-
- 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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/40—Cyclodextrins; Derivatives thereof
-
- 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- 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
- A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
- A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
-
- 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
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Abstract
The invention discloses a liquid preparation containing vonoprazan fumarate and a preparation method thereof. The vonoprazan fumarate in the liquid preparation containing vonoprazan fumarate is high in solubility, good in stability and less in generated degradation impurities, and can be prepared into small-volume injection easily, the dosage requirement can be met by using a small volume, the use of a packaging material can be reduced, and the packaging and the transportation are facilitated.
Description
Technical Field
The invention relates to the field of pharmaceutical preparations, in particular to a liquid preparation containing vonoprazan fumarate and a preparation method thereof.
Background
The chemical name of the vonoprazan fumarate is- (2-fluorophenyl) -N-methyl-1- (3-pyridylsulfonyl) -1H-pyrrole-3-methylamine, and the molecular formula is C17H16FN3O2S.C4H4O4The structural formula is as follows:
vonoprazan fumarate (TAK-438) belongs to a new class of inhibitors of potassium ion (K +) competitive acid blockers (p-CAB), can stop the secretion of gastric acid in advance by inhibiting the combination of K + on H + -K + -ATP enzyme (proton pump) in the last step of gastric acid secretion of gastric parietal cells, and has strong and durable inhibition effect on gastric acid secretion.
While vonoprazan fumarate is currently marketed as a tablet, research data on vonoprazan fumarate, which is submitted by the national institute of pharmaceutical and medical devices (pMDA) in wutian, japan, show that vonoprazan fumarate is poorly soluble in acidic aqueous solutions, is easily reactive with organic acids in acids, and is also unstable in neutral or alkaline environments. Furthermore, there is a document (CN104582687A) that further discloses that when an organic acid salified with voronoi is released into a liquid, it will undergo covalent reaction with a secondary amino group in the structure of voronoi to give an adduct in the form of an analogue. CN104582687A provides a stable liquid formulation, in which the stability of the liquid formulation is improved by adding metal halide and adjusting the pH range to 3.0-5.0, but this method only obtains the maximum solubility of vonoprazan fumarate in the liquid formulation to be about 1-2 mg/ml.
Disclosure of Invention
In order to solve the technical problems of low solubility, poor stability and the like of a liquid preparation containing the vonoprazan fumarate, the invention provides the liquid preparation containing the vonoprazan fumarate, which has high solubility, good stability and simple preparation process, a preparation method thereof and the like. Wherein the liquid preparation containing the vonoprazan fumarate contains beta-cyclodextrin and derivatives thereof and amino acid.
In the liquid preparation containing vonoprazan fumarate, the molar mass ratio of the beta-cyclodextrin and the derivatives thereof to the amino acid is 3.5: 1-0.5: 1; preferably 2:1 to 1: 1.
In the liquid preparation containing the vonoprazan fumarate, the concentration of the vonoprazan fumarate in the liquid preparation is 0.1-120 mg/ml; preferably 1 to 100mg/ml, more preferably 10 to 20 mg/ml.
In the liquid preparation containing the vonoprazan fumarate, the concentration of the beta-cyclodextrin and the derivative thereof in the liquid preparation is 1-400 mg/ml; preferably 20 to 200mg/ml, more preferably 40 to 100 mg/ml.
In the liquid preparation containing the vonoprazan fumarate, the concentration of the amino acid in the liquid preparation is 1-200 mg/ml; preferably 12 to 100mg/ml, and more preferably 24 to 60 mg/ml.
In the above liquid preparation containing vonoprazan fumarate, the pH of the liquid preparation is 3.0 to 8.0, preferably 4.0 to 7.0, and more preferably 5.0 to 6.0.
The invention discloses a liquid preparation containing Vonoprazan fumarate, which is found in practical experiments, after the mass ratio of beta-cyclodextrin and derivatives thereof to amino acid is controlled, when the beta-cyclodextrin and the derivatives thereof are one or more of beta-cyclodextrin, hydroxypropyl-beta-cyclodextrin, sulfobutyl ether-beta-cyclodextrin, methyl-beta-cyclodextrin, hydroxyethyl-beta-cyclodextrin, glucosyl-beta-cyclodextrin, 2-hydroxypropyl-beta-cyclodextrin and 2, 6-dimethoxy-beta-cyclodextrin, the solubility of Vonoprazan can be effectively increased, and the stability of Vonoprazan can be improved, wherein one or two or even more of beta-cyclodextrin, hydroxypropyl-beta-cyclodextrin and sulfobutyl ether-beta-cyclodextrin can be better combined, when the sulfobutyl ether-beta-cyclodextrin is used, the effect is better. The liquid preparation containing the vonoprazan fumarate has better solubility and stability when the amino acid is one or more of arginine, lysine, histidine and aspartic acid, and has better effect when the amino acid is arginine.
The liquid preparation containing the vonoprazan fumarate can also contain a pH regulator, when the pH regulator is one or more of tartaric acid, citric acid, fumaric acid, malic acid, lactic acid, sulfuric acid, hydrochloric acid and acetic acid, the solubility is increased and the stability is greatly improved, the effect is better for one or more of citric acid, hydrochloric acid and fumaric acid, and the effect is best for one or two of citric acid and hydrochloric acid.
In the liquid preparation containing the vonoprazan fumarate, a flavoring agent can be optionally added for improving the taste; the flavoring agent can be one or more selected from acesulfame potassium, sucralose, aspartame, stevioside, menthol, orange taste bitter masking agent, mint essence, etc.; preferably, one or both of sucralose and aspartame are used, and sucralose is more preferred.
The invention also provides a preparation method of the liquid preparation containing the vonoprazan fumarate, which comprises the following steps:
completely dissolving the beta-cyclodextrin and the derivative thereof in the prescription dose into water for injection to be used as solution A; adding the vonoprazan fumarate with the prescription amount into the solution A to form a suspension B; weighing amino acid with the formula amount, placing the amino acid into the suspension B, performing ultrasonic treatment to fully mix the amino acid with the suspension B, and adjusting the pH value with a pH regulator to obtain the compound.
The liquid preparation containing the vonoprazan fumarate can also be prepared into a freeze-dried preparation, and the invention also provides a method for preparing the liquid preparation containing the vonoprazan fumarate into a freeze-dried preparation, which comprises the following steps:
completely dissolving the beta-cyclodextrin and the derivative thereof in the prescription dose into water for injection to be used as solution A; adding the vonoprazan fumarate with the prescription amount into the solution A to form a suspension B; weighing amino acid with the formula amount, placing the amino acid into the suspension B, performing ultrasonic treatment to fully mix the amino acid with the suspension B, and adjusting the pH value by using a pH regulator; subpackaging the liquid in penicillin bottles, freeze-drying to obtain powder, and sealing for storage; or directly freeze drying the liquid, packaging in penicillin bottle, and sealing for storage.
Compared with the prior art, the liquid preparation containing the vonoprazan fumarate provided by the invention has the following advantages:
1. the liquid preparation containing the vonoprazan fumarate provided by the invention has the advantages of high solubility and good stability.
2. The liquid preparation containing the vonoprazan fumarate provided by the invention is easy to prepare into a small-volume injection, the dosage requirement can be met by using a small volume, the use of a packaging material can be reduced, and the packaging and the transportation are convenient.
3. The liquid preparation containing the vonoprazan fumarate provided by the invention can be used for injection, can be stably stored for a long time under the condition of near-neutral pH, and can obtain a satisfactory injection effect because the preparation is close to the pH value of a human body.
4. The liquid preparation containing the vonoprazan fumarate provided by the invention can be used for oral administration, has no sour and astringent taste, and can improve the compliance of patients in taking medicines.
5. The liquid preparation containing the vonoprazan fumarate provided by the invention is reasonable in formula and preparation process, low in manufacturing cost and suitable for industrial production.
Detailed Description
The following detailed description of specific embodiments of the present invention is provided to illustrate and explain the present invention and to be understood not to limit the present invention.
In the embodiment or the specific embodiment of the invention, the detection method and the evaluation indexes of the stability, the taste and the content of the liquid preparation are as follows:
1. method for detecting stability and content of medicine
The system comprises the following steps: thermofeisher ultitime 3000
A detector: ultraviolet absorption spectrophotometer
Measuring wavelength: 254nm
A chromatographic column: inertsil ODS-Sp C18, 5 μm, 4.6 mm. times.250 mm
Column temperature: constant temperature of 30 DEG C
Mobile phase A: 100% methanol
Mobile phase B: 0.01mol/L KH2pO4，pH＝2.5
Flow rate: 1.0ml/min
Wherein the gradient elution conditions are as follows:
| time (min) | Mobile phase A (%) | Mobile phase B (%) |
| 0 | 30 | 70 |
| 3 | 30 | 70 |
| 20 | 85 | 15 |
| 26 | 85 | 15 |
| 28 | 30 | 70 |
2. Taste detection and evaluation
The taste of the oral liquid preparation was evaluated by 3 subjects, and the number of no bitterness, slight bitterness, bitterness and extreme bitterness was used as evaluation indexes, and finally the maximum index number was used as the taste of the granule.
In an embodiment or specific embodiment of the present invention, the drugs, reagents and instruments used are as follows:
vonoprazan fumarate (Kyoho pharmaceutical group Co., Ltd.); arginine (Tianjin Tianan pharmaceutical Co., Ltd.); sodium hydroxide (metropolis chemical reagent plant); disodium hydrogen phosphate (Jiuxiang pharmaceutical Co., Ltd., Hunan); beta-cyclodextrin (roguett); hydroxypropyl-beta-cyclodextrin (Chengmeisek science and technology, Inc.); sulfobutyl ether-beta-cyclodextrin (Zibo Qianji Biotech, Inc.); citric acid (lake nan Er kang pharmaceuticals GmbH); fumaric acid (lake nan Er kang pharmaceuticals GmbH); hydrochloric acid (Chengdu Kelong chemical reagent factory); acetic acid (Tianjin, Kemiou Chemicals, Inc.); tartaric acid (research and development center for chemical reagent engineering in Guangdong province); malic acid (Chengmeiske pharmaceutical science and technology, Inc.); lactic acid (metropolis chemical reagent plant); fumaric acid (Hunan Er kang pharmaceutical Co., Ltd.)
High performance liquid chromatography (thermolfisher ultitime 3000); an ultrasonic cleaner (Kunshan ultrasonic instruments Co., Ltd.); a freeze dryer (Beijing Bilang laboratory instruments Co., Ltd.).
3. Influence of different auxiliary material combinations on solubility and stability of Vonoprazan fumarate
The experimental research finds that the solubility of the vonoprazan fumarate in water is about 1mg/ml, in order to remarkably improve the solubility and stability of the vonoprazan fumarate in water, the applicant adopts different auxiliary materials and the vonoprazan fumarate to carry out combined research, and accidentally finds that the solubility and stability of the vonoprazan fumarate can be greatly improved after the combination of the beta-cyclodextrin and the derivatives thereof with the amino acid, and particularly, the combination of arginine, the beta-cyclodextrin and the derivatives thereof can provide a liquid preparation containing the vonoprazan fumarate with excellent stability and solubility.
The preparation method comprises the following steps: completely dissolving a prescribed amount of beta-cyclodextrin and derivatives thereof in a prescribed amount of water to obtain a solution A; then adding the vonoprazan fumarate into the solution A, and ultrasonically mixing the mixture uniformly to obtain a solution B; and adding other components into the solution B, adjusting the pH value by using a proper amount of pH regulator, taking 3ml of sample, putting the sample into a clean penicillin bottle, sealing, storing in the dark, and carrying out accelerated investigation at the temperature of 60 ℃.
TABLE 1 prescription screening of different combinations of adjuvants
The specific experimental results are shown in Table 2
Table 2 results of the study on the solubilization effect and stability of Vonoprazan fumarate by different auxiliary material combinations
| Prescription | Solubility in water | 7-day accelerated addition of simple impurity | Accelerating for 14 days to increase single impurity | Appearance phenomenon |
| Prescription 1 | 4.7mg/ml | 0.07％ | 0.14％ | Partially dissolved |
| Prescription 2 | 4.8mg/ml | 0.08％ | 0.13％ | Partially dissolved |
| Prescription 3 | 5.1mg/ml | 0.06％ | 0.11％ | Partially dissolved |
| Prescription 4 | 3.5mg/ml | 0.09％ | 0.17％ | Partially dissolved |
| Prescription 5 | 6.5mg/ml | 0.07％ | 0.15％ | Partially dissolved |
| Prescription 6 | 8.5mg/ml | 0.21％ | 0.34％ | Partially dissolved |
| Prescription 7 | 6.9mg/ml | 0.15％ | 0.26％ | Partially dissolved |
| Prescription 8 | 20mg/ml | 0.05％ | 0.10％ | Completely dissolve |
| Prescription 9 | 20mg/ml | 0.02％ | 0.05％ | Completely dissolve |
| Prescription 10 | 20mg/ml | 0.04％ | 0.09％ | Completely dissolve |
| Prescription 11 | 20mg/ml | 0.07％ | 0.12％ | Completely dissolve |
| Prescription 12 | 20mg/ml | 0.03％ | 0.07％ | Completely dissolve |
| Prescription 13 | 20mg/ml | 0.06％ | 0.11％ | Completely dissolve |
Accelerated tests were performed at 60 ℃.
The solubility of the Vonoprazan cannot be obviously improved by singly using the beta cyclodextrin or the derivative or the amino acid thereof, and the pH value is adjusted by adding acid and alkali on the basis of adding the cyclodextrin, so that the solubility is not obviously improved, and the stability is poor; if arginine is added on the basis of adding cyclodextrin, the solubility can be obviously improved, and the stability of the medicament is also obviously improved.
4. Influence of the amount of auxiliary materials
The preparation method comprises the following steps: completely dissolving the hydroxypropyl-beta-cyclodextrin with the prescription amount in 1ml of water to obtain a solution A; then adding the vonoprazan fumarate into the solution A, and ultrasonically mixing the mixture uniformly to obtain a solution B; and adding arginine into the solution B, adjusting the pH value to 3 by using a proper amount of hydrochloric acid, placing a sample with the maximum solubility of the Vonoprazan under each formula into a clean penicillin bottle, sealing, storing in a dark place, and performing accelerated investigation at the temperature of 60 ℃. The specific prescription and the test results are shown in Table 3.
Table 3 comparison of the amounts of cyclodextrin and amino acid used to determine the solubility of voronozan fumarate and its stability
5. Influence of different amino acids on stability and solubility of vonoprazan fumarate-containing liquid preparations table 4 influence of different amino acids on stability and solubility of vonoprazan fumarate-containing liquid preparations
The preparation method comprises the following steps:
completely dissolving the prescription amount of hydroxypropyl-beta-cyclodextrin in the prescription amount of water to obtain solution A; then adding the vonoprazan fumarate into the solution A, and ultrasonically mixing the mixture uniformly to obtain a solution B; adding amino acid in the formula amount into the solution B, adding a proper amount of citric acid or hydrochloric acid to adjust the pH value, taking 3ml of sample, putting the sample into a clean penicillin bottle, sealing, storing in the dark, and carrying out accelerated investigation at the temperature of 60 ℃. The specific test results are shown in Table 5.
TABLE 5 influence of different amino acids on solubility of Vonoprazan fumarate and its stability results
| Prescription | 7 days of acceleration of newly added single impurity | Accelerating the growth of new single impurity for 14 days | Content (wt.) |
| Prescription 26 | 0.05％ | 0.09％ | 10mg/ml |
| Prescription 27 | 0.08％ | 0.18％ | 10mg/ml |
| Prescription 28 | 0.07％ | 0.10％ | 10mg/ml |
| Prescription 29 | 0.05％ | 0.12％ | 10mg/ml |
| Prescription 30 | 0.09％ | 0.21％ | 10mg/ml |
| Prescription 31 | 0.04％ | 0.07％ | 10mg/ml |
| Prescription 32 | 0.07％ | 0.14％ | 10mg/ml |
| Prescription 33 | 0.05％ | 0.10％ | 10mg/ml |
| Prescription 34 | 0.04％ | 0.07％ | 10mg/ml |
| Prescription 35 | 0.08％ | 0.17％ | 10mg/ml |
6. Effect of different pH conditions on stability
The prescription composition is as follows:
the preparation method comprises the following steps:
completely dissolving the prescription amount of hydroxypropyl-beta-cyclodextrin in the prescription amount of water to obtain solution A; then adding the vonoprazan fumarate into the solution A, and ultrasonically mixing the mixture uniformly to obtain a solution B; adding the arginine with the prescription amount into the solution B, adding a proper amount of citric acid to adjust the pH value, taking 3ml of sample in a clean penicillin bottle, sealing and keeping away from light at 60 ℃ for accelerated investigation, wherein the detection results are shown in Table 6.
TABLE 6 Effect on sample stability at different pH values
| Prescription | pH value | 7 days of acceleration of newly added single impurity | Accelerating the growth of new single impurity for 14 days | Content (wt.) |
| Prescription 36 | 2 | 0.09％ | 0.21％ | 10mg/ml |
| Prescription 37 | 3 | 0.03％ | 0.15％ | 10mg/ml |
| Prescription 38 | 4 | 0.02％ | 0.09％ | 10mg/ml |
| Prescription 39 | 5 | 0.02％ | 0.04％ | 10mg/ml |
| Prescription 40 | 6 | 0.01％ | 0.07％ | 10mg/ml |
| Prescription 41 | 7 | 0.06％ | 0.12％ | 10mg/ml |
| Prescription 42 | 8 | 0.06％ | 0.18％ | 10mg/ml |
| Prescription 43 | 9 | 0.21％ | 0.34％ | 10mg/ml |
As can be seen from the results of the measurements in Table 6, the formulations of the present invention all have satisfactory solubility and good stability at a pH of 3-8.
7. Comparative examples
Comparative example 1
The prescription composition is as follows:
the preparation method comprises the following steps:
completely dissolving the prescription amount of hydroxypropyl-beta-cyclodextrin in the prescription amount of water to obtain solution A; then adding the vonoprazan fumarate into the solution A, and ultrasonically mixing the mixture uniformly to obtain a solution B; adding arginine with the amount of the prescription into the solution B, adding a proper amount of hydrochloric acid to adjust the pH value, taking 2ml of sample, freeze-drying the sample into powder in a clean penicillin bottle, sealing and storing the powder at 60 ℃ in a dark place for accelerated investigation.
Comparative example 2
The prescription composition is as follows:
the preparation method comprises the following steps:
completely dissolving the prescription amount of hydroxypropyl-beta-cyclodextrin in the prescription amount of water to obtain solution A; then adding the vonoprazan fumarate into the solution A, and ultrasonically mixing the mixture uniformly to obtain a solution B; adding arginine with the amount of the prescription into the solution B, adding a proper amount of glucuronic acid and sodium hydroxide to adjust the pH value, taking 2ml of sample, freeze-drying the sample into powder in a clean penicillin bottle, sealing and storing the powder at 60 ℃ in a dark place for accelerated investigation.
Comparative example 3
The prescription composition is as follows:
the preparation method comprises the following steps:
completely dissolving the prescription amount of hydroxypropyl-beta-cyclodextrin in the prescription amount of water to obtain solution A; then adding the vonoprazan fumarate into the solution A, and ultrasonically mixing the mixture uniformly to obtain a solution B; adding arginine with the amount of the prescription into the solution B, adding a proper amount of hydrochloric acid and sodium hydroxide to adjust the pH value, taking 2ml of sample, freeze-drying the sample into powder in a clean penicillin bottle, sealing and storing the powder at 60 ℃ in a dark place for accelerated investigation.
Comparative example 4
The prescription composition is as follows:
the preparation method comprises the following steps:
completely dissolving the prescription amount of hydroxypropyl-beta-cyclodextrin in the prescription amount of water to obtain solution A; then adding the vonoprazan fumarate into the solution A, and ultrasonically mixing the mixture uniformly to obtain a solution B; adding arginine in a prescription amount into the solution B, adding a proper amount of citric acid and sodium hydroxide to adjust the pH value, taking 2ml of sample, freeze-drying the sample in a clean penicillin bottle to obtain powder, sealing and storing the powder at 60 ℃ in a dark place for accelerated investigation.
Comparative example 5
The prescription composition is as follows:
the preparation method comprises the following steps:
completely dissolving the prescription amount of hydroxypropyl-beta-cyclodextrin in the prescription amount of water to obtain solution A; then adding the vonoprazan fumarate into the solution A, and ultrasonically mixing the mixture uniformly to obtain a solution B; adding arginine with the amount of the prescription into the solution B, adding a proper amount of phosphoric acid to adjust the pH value, taking 2ml of sample, freeze-drying the sample into powder in a clean penicillin bottle, sealing and keeping away from light at 60 ℃ for accelerated investigation.
TABLE 7 test results of comparative examples 1 to 5
Accelerated tests were performed at 60 ℃.
Example 1
The prescription composition is as follows:
the preparation method comprises the following steps:
completely dissolving the prescription amount of hydroxypropyl-beta-cyclodextrin in the prescription amount of water to obtain solution A; then adding the vonoprazan fumarate into the solution A, and ultrasonically mixing the mixture uniformly to obtain a solution B; adding arginine with the amount of the prescription into the solution B, adding a proper amount of citric acid to adjust the pH value, uniformly mixing, taking a sample of 3ml in a clean penicillin bottle, sealing and keeping in the dark at 60 ℃ for accelerated investigation. The results are shown in Table 8.
Table 8 test results of the liquid formulation in example 1
| Examples | pH value | 7 days of acceleration of newly added single impurity | Accelerating the growth of new single impurity for 14 days | Content (wt.) |
| Example 1 | 7 | 0.08％ | 0.15％ | 120mg/ml |
Example 2
The prescription composition is as follows:
the preparation method comprises the following steps:
completely dissolving the prescription amount of hydroxypropyl-beta-cyclodextrin in the prescription amount of water to obtain solution A; then adding the vonoprazan fumarate into the solution A, and ultrasonically mixing the mixture uniformly to obtain a solution B; and adding lysine in a prescribed amount into the solution B, adding an appropriate amount of citric acid to adjust the pH value, taking 3ml of sample in a clean penicillin bottle, sealing, keeping in the dark and storing at 60 ℃ for accelerated investigation. The results are shown in Table 9.
Table 9 test results of the liquid formulation in example 2
| Examples | pH value | 7 days of acceleration of newly added single impurity | Accelerating the growth of new single impurity for 14 days | Content (wt.) |
| Example 2 | 7 | 0.01％ | 0.04％ | 1mg/ml |
Example 3
The prescription composition is as follows:
the preparation method comprises the following steps:
completely dissolving the prescription amount of hydroxypropyl-beta-cyclodextrin in the prescription amount of water to obtain solution A; then adding the vonoprazan fumarate into the solution A, and ultrasonically mixing the mixture uniformly to obtain a solution B; adding arginine in the amount of the prescription into the solution B, adding a proper amount of citric acid to adjust the pH value, taking 3ml of sample in a washed penicillin bottle, sealing and storing in a dark place at 60 ℃ for accelerated investigation. The results are shown in Table 10.
Table 10 test results of the liquid formulation in example 3
| Examples | pH value | 7 days of acceleration of newly added single impurity | Accelerating the growth of new single impurity for 14 days | Content (wt.) |
| Example 3 | 7 | 0.02％ | 0.06％ | 0.1mg/ml |
Example 4
The prescription composition is as follows:
the preparation method comprises the following steps:
completely dissolving the beta-cyclodextrin in the prescription amount into the water in the prescription amount to obtain solution A; then adding the vonoprazan fumarate into the solution A, and ultrasonically mixing the mixture uniformly to obtain a solution B; adding arginine with the amount of the prescription into the solution B, adding a proper amount of malic acid to adjust the pH value, taking 3ml of sample in a clean penicillin bottle, sealing and storing in a dark place at 60 ℃ for accelerated investigation. The results are shown in Table 11.
Table 11 test results of the liquid formulation in example 4
| Examples | pH value | 7 days of acceleration of newly added single impurity | Accelerating the growth of new single impurity for 14 days | Content (wt.) |
| Example 4 | 7 | 0.05％ | 0.14％ | 20mg/ml |
Example 5
The prescription composition is as follows:
the preparation method comprises the following steps:
completely dissolving the beta-cyclodextrin in the prescription amount into the water in the prescription amount to obtain solution A; then adding the vonoprazan fumarate into the solution A, and ultrasonically mixing the mixture uniformly to obtain a solution B; adding the arginine and the sucralose into the solution B according to the prescription amount, uniformly mixing, adding a proper amount of malic acid to adjust the pH value, taking 3ml of sample, placing the sample in a clean penicillin bottle, sealing and keeping away from light at 60 ℃ for accelerated investigation. The results are shown in Table 12.
Table 12 test results of the liquid formulation in example 5
Example 6
The prescription composition is as follows:
the preparation method comprises the following steps:
completely dissolving the prescription amount of hydroxypropyl-beta-cyclodextrin in the prescription amount of water to obtain solution A; then adding the vonoprazan fumarate into the solution A, and ultrasonically mixing the mixture uniformly to obtain a solution B; adding the arginine and the aspartame into the solution B according to the prescription amount, uniformly mixing, adding a proper amount of tartaric acid to adjust the pH value, taking 3ml of sample, placing the sample into a clean penicillin bottle, sealing and keeping away from light, and performing accelerated investigation at the temperature of 60 ℃. The results are shown in Table 13.
Table 13 test results of the liquid formulation in example 6
Example 7
The prescription composition is as follows:
the preparation method comprises the following steps:
completely dissolving the formula amount of sulfobutyl ether-beta-cyclodextrin in the formula amount of water to obtain a solution A; then adding the vonoprazan fumarate into the solution A, and ultrasonically mixing the mixture uniformly to obtain a solution B; adding arginine with the prescription amount into the solution B, adding a proper amount of citric acid to adjust the pH value, taking 2ml of sample, freeze-drying the sample into powder in a clean penicillin bottle, sealing and storing the powder at 60 ℃ in a dark place for accelerated investigation. The results are shown in Table 14.
Table 14 test results of the liquid formulation in example 7
Example 8
The prescription composition is as follows:
the preparation method comprises the following steps:
completely dissolving the prescription amount of hydroxypropyl-beta-cyclodextrin in the prescription amount of water to obtain solution A; then adding the vonoprazan fumarate into the solution A, and ultrasonically mixing the mixture uniformly to obtain a solution B; adding arginine with the prescription amount into the solution B, adding a proper amount of citric acid to adjust the pH value, taking 2ml of sample, freeze-drying the sample into powder in a clean penicillin bottle, sealing and storing the powder at 60 ℃ in a dark place for accelerated investigation. The results are shown in Table 15.
TABLE 15 test results of the liquid formulation in example 8
Example 9
The prescription composition is as follows:
the preparation method comprises the following steps:
completely dissolving the prescription amount of hydroxypropyl-beta-cyclodextrin in the prescription amount of water to obtain solution A; then adding the vonoprazan fumarate into the solution A, and ultrasonically mixing the mixture uniformly to obtain a solution B; adding the arginine and stevioside into the solution B according to the prescription amount, mixing uniformly, adding a proper amount of citric acid to adjust the pH value, taking 3ml of sample into a clean penicillin bottle, sealing and keeping away from light at 60 ℃ for accelerated investigation. The results are shown in Table 16.
Table 16 test results of the liquid formulation in example 9
Example 10
The prescription composition is as follows:
the preparation method comprises the following steps:
completely dissolving the formula amount of sulfobutyl ether-beta-cyclodextrin in the formula amount of water to obtain a solution A; then adding the vonoprazan fumarate into the solution A, and ultrasonically mixing the mixture uniformly to obtain a solution B; adding arginine with the amount of the prescription into the solution B, adding a proper amount of citric acid to adjust the pH value, taking 3ml of sample, freeze-drying the sample in a clean penicillin bottle to obtain powder, sealing and storing the powder at 60 ℃ in a dark place for accelerated investigation. The results are shown in Table 17.
TABLE 17 test results of the liquid formulation in example 10
Example 11
The prescription composition is as follows:
the preparation method comprises the following steps:
completely dissolving the formula amount of sulfobutyl ether-beta-cyclodextrin in the formula amount of water to obtain a solution A; then adding the vonoprazan fumarate into the solution A, and ultrasonically mixing the mixture uniformly to obtain a solution B; adding arginine with the prescription amount into the solution B, adding a proper amount of citric acid to adjust the pH value, taking 2ml of sample, freeze-drying the sample into powder in a clean penicillin bottle, sealing and storing the powder at 60 ℃ in a dark place for accelerated investigation. The results are shown in Table 18.
Table 18 test results of the liquid formulation in example 11
Claims (19)
1. The liquid preparation containing vonoprazan fumarate is characterized by containing beta-cyclodextrin and derivatives thereof and amino acid, wherein the amino acid is selected from arginine, the mass ratio of the beta-cyclodextrin and the derivatives thereof to the amino acid is 3.5-0.5: 1, the pH value of the liquid preparation is 3.0-8.0, and the beta-cyclodextrin and the derivatives thereof are selected from one or more of beta-cyclodextrin, hydroxypropyl-beta-cyclodextrin and sulfobutyl ether-beta-cyclodextrin.
2. The liquid preparation containing vonoprazan fumarate according to claim 1, wherein the mass ratio of the beta-cyclodextrin and the derivatives thereof to the amino acid is 2: 1-1: 1.
3. The liquid preparation containing vonoprazan fumarate according to claim 1, wherein the concentration of vonoprazan fumarate in the liquid preparation is 0.1-120 mg/ml.
4. The liquid preparation containing vonoprazan fumarate according to claim 3, wherein the concentration of vonoprazan fumarate in the liquid preparation is 1-100 mg/ml.
5. The liquid preparation containing vonoprazan fumarate according to claim 4, wherein the concentration of the vonoprazan fumarate in the liquid preparation is 10-20 mg/ml.
6. The liquid preparation containing vonoprazan fumarate according to claim 1, wherein the concentration of the β -cyclodextrin and its derivatives in the liquid preparation is 1-400 mg/ml.
7. The liquid preparation containing vonoprazan fumarate according to claim 6, wherein the concentration of the β -cyclodextrin and its derivatives in the liquid preparation is 20-200 mg/ml.
8. The liquid preparation containing vonoprazan fumarate according to claim 7, wherein the concentration of the β -cyclodextrin and its derivatives in the liquid preparation is 40-100 mg/ml.
9. The liquid voronoazan fumarate-containing formulation according to claim 8, wherein the β -cyclodextrin and its derivatives are selected from sulfobutyl ether- β -cyclodextrin.
10. The liquid formulation of vonoprazan fumarate-containing according to claim 1, wherein a pH adjusting agent is contained in the liquid formulation.
11. The liquid preparation containing vonoprazan fumarate according to claim 10, wherein the pH adjusting agent is one or more selected from tartaric acid, citric acid, fumaric acid, malic acid, lactic acid, sulfuric acid, hydrochloric acid, and acetic acid.
12. The liquid preparation containing vonoprazan fumarate according to claim 11, wherein the pH adjusting agent is one or more selected from citric acid, hydrochloric acid and fumaric acid.
13. The liquid preparation containing vonoprazan fumarate according to claim 12, wherein the pH adjusting agent is one or two selected from citric acid and hydrochloric acid.
14. The vonoprazan fumarate-containing liquid formulation according to claim 1, wherein a flavoring agent is contained in the vonoprazan fumarate-containing liquid formulation.
15. The liquid preparation containing vonoprazan fumarate according to claim 14, wherein the flavoring agent is selected from one or more of acesulfame potassium, sucralose, aspartame, stevioside, menthol, orange taste bitter masking agent, and peppermint essence.
16. The liquid preparation containing vonoprazan fumarate according to claim 15, wherein the flavoring agent is one or both of sucralose and aspartame.
17. The liquid formulation of vonoprazan fumarate-containing according to claim 16, wherein the flavoring agent is sucralose.
18. A production method for producing the liquid preparation containing vonoprazan fumarate according to any one of claims 1 to 13, comprising the steps of: completely dissolving the beta-cyclodextrin and the derivative thereof in the prescription dose into water for injection to be used as solution A; adding the vonoprazan fumarate with the prescription amount into the solution A to form a suspension B; weighing amino acid with the formula amount, placing the amino acid into the suspension B, performing ultrasonic treatment to fully mix the amino acid with the suspension B, and adjusting the pH value with a pH regulator to obtain the compound.
19. The liquid preparation containing vonoprazan fumarate according to any one of claims 1-17, wherein the liquid preparation is prepared as a lyophilized preparation.
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| CN113350271B (en) * | 2020-03-04 | 2025-01-17 | 广东东阳光药业股份有限公司 | Proton pump inhibitor composition and preparation method thereof |
| CN114904001A (en) * | 2021-02-06 | 2022-08-16 | 南京柯菲平盛辉制药有限公司 | A kind of pharmaceutical composition containing vonoprazan acetate and preparation method thereof |
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| CN101020059A (en) * | 2006-02-15 | 2007-08-22 | 中国科学院上海药物研究所 | Medicine composition containing docetaxel matter and its prepn process |
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| CN102892310A (en) * | 2010-03-13 | 2013-01-23 | 伊斯顿庞德实验室有限公司 | Fat-binding compositions |
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| CN1250372A (en) * | 1997-03-13 | 2000-04-12 | 赫克萨尔股份公司 | Stabilization of acid sensitive benzimidazoles with amino acid/cyclodextrin combinations |
| CN101020059A (en) * | 2006-02-15 | 2007-08-22 | 中国科学院上海药物研究所 | Medicine composition containing docetaxel matter and its prepn process |
| CN102892310A (en) * | 2010-03-13 | 2013-01-23 | 伊斯顿庞德实验室有限公司 | Fat-binding compositions |
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