CN113827574A - Vonoprazan fumarate oral instant tablet and preparation method thereof - Google Patents
Vonoprazan fumarate oral instant tablet and preparation method thereof Download PDFInfo
- Publication number
- CN113827574A CN113827574A CN202111211008.9A CN202111211008A CN113827574A CN 113827574 A CN113827574 A CN 113827574A CN 202111211008 A CN202111211008 A CN 202111211008A CN 113827574 A CN113827574 A CN 113827574A
- Authority
- CN
- China
- Prior art keywords
- vonoprazan fumarate
- cyclodextrin
- parts
- agent
- oral
- 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.)
- Pending
Links
- 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 94
- 229950003825 vonoprazan Drugs 0.000 title claims abstract description 94
- 238000002360 preparation method Methods 0.000 title abstract description 26
- 239000003814 drug Substances 0.000 claims abstract description 45
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 43
- 239000000463 material Substances 0.000 claims abstract description 25
- 229920000858 Cyclodextrin Polymers 0.000 claims abstract description 18
- 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 claims abstract description 18
- 239000000796 flavoring agent Substances 0.000 claims abstract description 17
- 235000013355 food flavoring agent Nutrition 0.000 claims abstract description 17
- 239000003086 colorant Substances 0.000 claims abstract description 12
- 238000004108 freeze drying Methods 0.000 claims abstract description 10
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 36
- 238000003756 stirring Methods 0.000 claims description 29
- 239000007788 liquid Substances 0.000 claims description 28
- 239000000203 mixture Substances 0.000 claims description 28
- 229920001450 Alpha-Cyclodextrin Polymers 0.000 claims description 25
- 229940043377 alpha-cyclodextrin Drugs 0.000 claims description 25
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 22
- 108010010803 Gelatin Proteins 0.000 claims description 22
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 22
- 229930195725 Mannitol Natural products 0.000 claims description 22
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- BAQAVOSOZGMPRM-QBMZZYIRSA-N sucralose Chemical group 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 16
- 235000019408 sucralose Nutrition 0.000 claims description 16
- -1 sulfobutyl Chemical group 0.000 claims description 16
- 238000000034 method Methods 0.000 claims description 11
- 238000002156 mixing Methods 0.000 claims description 10
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 claims description 9
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- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-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 4
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 4
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims description 4
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 claims description 4
- 150000001720 carbohydrates Chemical class 0.000 claims description 4
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- 239000001630 malic acid Substances 0.000 claims description 4
- 235000015165 citric acid Nutrition 0.000 claims description 3
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 claims description 2
- 229920001817 Agar Polymers 0.000 claims description 2
- 241000416162 Astragalus gummifer Species 0.000 claims description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 claims description 2
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- 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
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- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims description 2
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- 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 2
- 229920001615 Tragacanth Polymers 0.000 claims description 2
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 2
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- 235000010419 agar Nutrition 0.000 claims description 2
- HFHDHCJBZVLPGP-RWMJIURBSA-N alpha-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)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 HFHDHCJBZVLPGP-RWMJIURBSA-N 0.000 claims description 2
- 125000003118 aryl group Chemical group 0.000 claims description 2
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- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 2
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 2
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 2
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 2
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 2
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 claims description 2
- 229920000609 methyl cellulose Polymers 0.000 claims description 2
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- 235000010981 methylcellulose Nutrition 0.000 claims description 2
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- 229910000403 monosodium phosphate Inorganic materials 0.000 claims description 2
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- 102000004169 proteins and genes Human genes 0.000 claims description 2
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- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 claims description 2
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 claims description 2
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 claims description 2
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- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
-
- 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
- A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/69—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
- A61K47/6949—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
- A61K47/6951—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
-
- A—HUMAN NECESSITIES
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- 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
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
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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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
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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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2063—Proteins, e.g. gelatin
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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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
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Abstract
The invention provides a vonoprazan fumarate oral instant tablet and a preparation method thereof, belongs to the technical field of medicines, and particularly relates to the oral instant tablet prepared by freeze-drying a vonoprazan fumarate raw material, a framework material, cyclodextrin, a suspending material, a flavoring agent, a pH regulator, a coloring agent and water. The preparation process is simple, the industrial production is easy, the prepared oral instant tablets have good appearance and small friability, the oral instant tablets can be taken without water, the medicine is quickly dissolved and absorbed in the oral cavity within seconds after being taken, the medicine dissolution rate is greatly increased, the bioavailability of the medicine is improved, the carrying is convenient, and the medicine taking compliance is good.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to an oral instant tablet containing vonoprazan fumarate.
Background
Gastric diseases are almost the most common diseases in sub-health people, and the common gastric diseases comprise acute and chronic gastritis, duodenal ulcer, gastric ulcer, functional dyspepsia, reflux esophagitis and the like. Worldwide patients with gastric disorders have risen from 1.5 to over 5 billion in 1985 and at a rate of 17.43% per year.
Vonoprazan fumarate (Vonoprazan fumarate) was used under the code TAK-438, is a novel gastric acid secretion inhibitor developed by Wutian corporation of Japan, has quick-acting, strong and lasting inhibitory action on gastric acid secretion, and inhibits K + to H + in the last step of gastric acid secretion in parietal cells+-K+The binding action of ATPases (proton pumps), also has a premature termination effect on gastric acid secretion. Vonoprazan fumarate was first marketed in japan in 2014 under the trade name Takecab. Vonoprazan fumarate is used for treating non-erosive gastroesophageal reflux disease, duodenal ulcer, gastric ulcer and erosive esophagitis (curing and maintaining treatment).
Most oral solid preparations need to be absorbed into blood after administration, and can take effect after reaching a certain blood concentration, so that the dissolution or release of the preparation is a key factor influencing the absorption of the medicine in vivo. Currently, the commercially available vonoprazan fumarate only has common tablets, and because the water solubility of the vonoprazan fumarate is poor and the bioavailability is low, the raw material medicines of the orally-taken common tablets need to be crushed into smaller particle sizes to increase the dissolution rate. Therefore, it is important to adopt proper technology or method to increase the solubility or dissolution rate of vonoprazan fumarate so as to improve the bioavailability of the vonoprazan fumarate.
Japanese wutian pharmaceutical filed in chinese patent application No. CN 102743330B provides a solid preparation with improved stability during light irradiation, which contains a pharmaceutically active ingredient, titanium dioxide, a plasticizer and an organic acid, the organic acid is fumaric acid, the preparation process is wet (fluidized bed) granulation, drying, total mixing, tabletting, coating and the like, the process is complicated, and the wet granulation process (high temperature and high humidity condition) of the patent adversely affects the pharmaceutically active ingredient.
Chinese patent CN 110538153 a provides a high stability, fast release solid preparation and its preparation method, the solid preparation is prepared from the following raw materials: co-pulverizing the active ingredient and organic acid, and excipient. The co-crushing powder provided by the patent has the advantages of lower yield in actual operation, obvious material static electricity, poor powder fluidity and unfavorable product preparation process, and the powder direct-pressing process has higher requirements on material fluidity and the like and is not favorable for large-scale production.
The development of a method with simple preparation process, stable and controllable process and high production efficiency, and the solid preparation which can obtain higher dissolution rate and is convenient to swallow has great significance. The oral instant tablet can be rapidly disintegrated in the oral cavity under the anhydrous condition or only a small amount of water exists in the oral cavity, enters the digestive tract along with swallowing, is absorbed in the oral cavity without a mucous membrane, and has the same absorption and metabolism processes in vivo as those of a common tablet. Is convenient for some people to take medicine, such as the old, children, patients with dysphagia or special environment. Compared with the common preparation, the preparation has the advantages of convenient taking, quick absorption, high bioavailability, small irritation to digestive tract mucous membrane and the like, and is widely concerned. Therefore, the development of the vonoprazan fumarate oral fast dissolving tablet has important market value and social benefit.
Disclosure of Invention
The technical problem to be solved by the invention is to provide the Vonoprazan fumarate freeze-dried oral instant tablet which is short in dissolving time, quick in medicine release, free of water for swallowing, good in taste and easy to swallow. The medicine of the invention is used for treating and maintaining acid-related diseases such as non-erosive gastroesophageal reflux disease, duodenal ulcer, gastric ulcer, erosive esophagitis and the like.
The invention aims to solve another technical problem of providing a preparation method of the vonoprazan fumarate freeze-dried oral instant tablets, the method is simple in process, and the prepared oral instant tablets have high mechanical strength.
In order to solve the technical problems, the technical scheme adopted by the invention is as follows:
firstly, discloses a vonoprazan fumarate freeze-dried oral instant tablet, which comprises the following components: vonoprazan fumarate, cyclodextrin, a framework material, a suspending agent, a flavoring agent, a pH regulator and a coloring agent.
The weight parts of each component are as follows: 5-30 parts of vonoprazan fumarate, 5-50 parts of cyclodextrin, 20-80 parts of framework material, 1-10 parts of suspending agent, 0.1-2 parts of flavoring agent, 0.1-2 parts of pH regulator and 0.001-0.05 part of coloring agent.
Preferably, 10-20 parts of vonoprazan fumarate, 20-40 parts of cyclodextrin, 50-70 parts of framework material, 2-5 parts of suspending agent, 0.5-1 part of flavoring agent, 0.3-1 part of pH regulator and 0.001-0.02 part of coloring agent.
Most preferably, 10 parts of vonoprazan fumarate, 30 parts of cyclodextrin, 56 parts of framework material, 2.5 parts of suspending agent, 0.5-1 part of flavoring agent, 0.3-1 part of pH regulator and 0.01 part of coloring agent.
Wherein the cyclodextrin is selected from any one or a mixture of any more of alpha-cyclodextrin, methyl-alpha-cyclodextrin, carboxymethyl-alpha-cyclodextrin, hydroxypropyl-alpha-cyclodextrin and sulfobutyl ether-alpha-cyclodextrin according to any proportion; preferably hydroxypropyl-alpha-cyclodextrin or sulfobutyl ether-alpha-cyclodextrin, most preferably sulfobutyl ether-alpha-cyclodextrin.
The framework material is selected from any one or a mixture of any two of glucose, sucrose, mannitol, sorbitol, lactose, dextrose, glucan and starch according to any proportion; preferably a mixture of mannitol and lactose in a weight ratio of (2-1): 1; most preferred is a mixture of mannitol and lactose in a weight ratio of 1.8: 1.
The suspending agent is selected from any one or a mixture of any two of xanthan gum, polyvinyl alcohol, tragacanth, sodium alginate, gelatin, acacia, methylcellulose, agar, hydroxypropyl methylcellulose, hydroxypropyl cellulose and sodium carboxymethylcellulose according to any proportion; preferably a mixture of xanthan gum and gelatin according to the weight ratio of (6-3): 1; most preferred is a mixture of gelatin and xanthan gum gelatin in a weight ratio of 5: 1.
The pH regulator is selected from one or a mixture of two of citric acid, tartaric acid, malic acid and sodium dihydrogen phosphate according to any proportion; preferably citric acid or malic acid, most preferably citric acid.
The flavoring agent comprises pharmaceutically acceptable sweetener, aromatic, mucilage, effervescent, taste-masking agent, fatty substance (including lecithin and surfactant), modified starch carbohydrate, cyclodextrin, saccharide and protein; sucralose is preferred.
The invention further discloses a preparation method of the vonoprazan fumarate oral instant tablet, which comprises the following steps:
(1) dissolving the cyclodextrin with the prescription amount in purified water accounting for 80 percent of the total amount of the water used for the prescription, heating the mixture to 50-60 ℃ under the stirring state, slowly adding the vonoprazan fumarate with the prescription amount, and continuously stirring the mixture for 1-6 hours; dissolving the raw materials with small amount of organic solvent such as ethanol, propylene glycol, glycerol, etc. to help dissolving;
(2) weighing the framework material and the flavoring agent according to the prescription amount, and adding the framework material and the flavoring agent into the solution obtained in the step (1);
(3) weighing a suspending agent according to the prescription amount, dissolving the suspending agent in purified water with the water consumption of 20 percent of the prescription amount, and heating until the suspending agent is completely dissolved;
(4) mixing the two solutions, stirring uniformly, adjusting the pH value to 5.5-7.0 by using a pH regulator, and adding a coloring agent;
(5) after the content of Vonoprazan fumarate in the liquid medicine is measured, the liquid medicine is subpackaged in a mould, and the mould filled with the liquid medicine is placed in a vacuum freeze drying oven for freeze drying;
(6) and packaging the freeze-dried tablets with double aluminum to obtain the Vonoprazan fumarate frozen oral instant tablets.
The method of the invention can ensure that the prepared oral instant tablets have higher mechanical strength and wear resistance, can ensure that the medicine film does not break when being packaged, transported and taken, and keeps good appearance.
In the composition of the vonoprazan fumarate freeze-dried oral instant tablet, the types and the dosage of the cyclodextrin, the framework material and the suspending agent have obvious influence on the appearance, the taste and the dissolving time of the vonoprazan fumarate freeze-dried oral instant tablet. The sulfobutyl ether-alpha-cyclodextrin has special affinity and inclusion property to nitrogen-containing drugs, and can be well included with drug molecules to form a non-covalent complex, so that the stability, water solubility and safety of the drugs are improved, the renal toxicity is reduced, the hemolysis of the drugs is alleviated, the release rate of the drugs is controlled, the unpleasant odor is covered, and the like. Under the condition of other components and certain dosage, when the sulfobutyl ether-alpha-cyclodextrin is used as the cyclodextrin, the taste of the vonoprazan fumarate freeze-dried oral instant tablets is obviously improved. When the weight ratio of the sulfobutyl ether-alpha-cyclodextrin to the raw material (namely the vonoprazan fumarate) is 30:10, the mouth feel is the best, and the framework material is a mixture formed by mannitol and lactose according to a certain proportion, the friability of the prepared vonoprazan fumarate oral instant tablet is obviously improved compared with that of the framework material which is a single auxiliary material; when the ratio of the mannitol to the lactose is 1.8:1, the dissolving time limit of the prepared Vonoprazan fumarate freeze-dried oral instant tablets is obviously shorter than that of the Vonoprazan fumarate oral instant tablets prepared by the mannitol and the lactose according to other ratios, and the Vonoprazan fumarate freeze-dried oral instant tablets are good in taste, free of granular sensation and small in friability; when the gelatin and the xanthan gum are used as the suspending agent according to the weight ratio of 5:1, the melting time limit of the prepared Vonoprazan fumarate freeze-dried oral instant tablet is obviously shorter than that of the gelatin and the xanthan gum which are used as single auxiliary materials, and the Vonoprazan fumarate freeze-dried oral instant tablet has good content uniformity and small friability.
In conclusion, the invention finally determines that the composition of the oral instant tablets of vonoprazan fumarate comprises 10 parts of vonoprazan fumarate, 30 parts of cyclodextrin, 56 parts of framework material, 3 parts of suspending agent, 0.5 part of flavoring agent, 0.49 part of pH regulator and 0.01 part of coloring agent. The prepared Vonoprazan fumarate freeze-dried oral instant tablets are good in appearance, small in friability, free of granular sensation, good in taste and short in dissolving time limit. The vonoprazan fumarate oral instant tablets can be added with a proper amount of colorant or essence according to needs.
Compared with the prior art, the technical scheme of the invention has the following beneficial effects:
the Vonoprazan fumarate freeze-dried oral instant tablet is convenient to carry, can be quickly dissolved in the oral cavity, releases the medicine, is not required to be swallowed by water, has good compliance, is particularly suitable for the old and patients with difficulty in swallowing, has stable quality, and quickly takes effect, thereby overcoming the defects of slow effect taking, inconvenient carrying of oral liquid, unfavorable quantitative taking and the like of the Vonoprazan fumarate tablet and the capsule. The Vonoprazan fumarate freeze-dried oral instant tablets disclosed by the invention are small in auxiliary material consumption, simple in preparation process and low in cost, and have considerable economic and social benefits.
Detailed Description
The invention will be further described with reference to specific embodiments, and the advantages and features of the invention will become apparent as the description proceeds. It is to be understood that the described embodiments are exemplary only and are not limiting upon the scope of the invention. It will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention, and that such changes and modifications may be within the scope of the invention.
Example 1
Each tablet contains 10.0mg of vonoprazan fumarate, and the composition of 1000 oral fast dissolving tablets of vonoprazan fumarate is as follows:
the preparation method comprises the following steps:
(1) dissolving the formula amount of sulfobutyl ether-alpha-cyclodextrin in purified water accounting for 80% of the total amount of the formula water, heating to 50 ℃ under a stirring state, slowly adding the formula amount of vonoprazan fumarate, and continuously stirring for 2 hours;
(2) weighing the mannitol, the lactose and the sucralose with the prescription amount, and adding the mannitol, the lactose and the sucralose into the solution in the step (1).
(3) Weighing gelatin and xanthan gum according to the prescription amount, dissolving in purified water which is 20% of the total amount of water used in the prescription, and heating until the gelatin and the xanthan gum are completely dissolved;
(4) mixing the above two solutions, stirring, adjusting pH to 6.0 with citric acid, and adding lemon yellow;
(5) after the content of Vonoprazan fumarate in the liquid medicine is measured, the liquid medicine is subpackaged in a mould, and the mould filled with the liquid medicine is placed in a vacuum freeze drying oven for freeze drying;
(6) and (3) rapidly packaging the freeze-dried tablets in double aluminum to obtain the Vonoprazan fumarate frozen oral instant tablets.
The oral instant tablet has good appearance, small friability, no granular sensation, good taste, and short dissolution time (only 3 s).
Example 2
Each tablet contains 10.0mg of vonoprazan fumarate, and the composition of 1000 oral fast dissolving tablets of vonoprazan fumarate is as follows:
the preparation method comprises the following steps:
(1) dissolving the formula amount of sulfobutyl ether-alpha-cyclodextrin in purified water accounting for 80% of the total amount of the formula water, heating to 50 ℃ under a stirring state, slowly adding the formula amount of vonoprazan fumarate, and continuously stirring for 2 hours;
(2) weighing the mannitol, the lactose and the sucralose with the prescription amount, and adding the mannitol, the lactose and the sucralose into the solution in the step (1).
(3) Weighing gelatin and xanthan gum according to the prescription amount, dissolving in purified water which is 20% of the total amount of water used in the prescription, and heating until the gelatin and the xanthan gum are completely dissolved;
(4) mixing the above two solutions, stirring, adjusting pH to 6.0 with citric acid, and adding lemon yellow;
(5) after the content of Vonoprazan fumarate in the liquid medicine is measured, the liquid medicine is subpackaged in a mould, and the mould filled with the liquid medicine is placed in a vacuum freeze drying oven for freeze drying;
(6) and (3) rapidly packaging the freeze-dried tablets in double aluminum to obtain the Vonoprazan fumarate frozen oral instant tablets.
The oral instant tablet has good appearance, small friability, no granular sensation, good taste, and short dissolution time (only 6 seconds).
Example 3
Each tablet contains 10.0mg of vonoprazan fumarate, and the composition of 1000 oral fast dissolving tablets of vonoprazan fumarate is as follows:
the preparation method comprises the following steps:
(1) dissolving the formula amount of sulfobutyl ether-alpha-cyclodextrin in purified water accounting for 80% of the total amount of the formula water, heating to 50 ℃ under a stirring state, slowly adding the formula amount of vonoprazan fumarate, and continuously stirring for 2 hours;
(2) weighing the mannitol, the lactose and the sucralose with the prescription amount, and adding the mannitol, the lactose and the sucralose into the solution in the step (1).
(3) Weighing gelatin and xanthan gum according to the prescription amount, dissolving in purified water accounting for 20% of the total amount of water used in the prescription, and heating until the gelatin and the xanthan gum are completely dissolved;
(4) mixing the above two solutions, stirring, adjusting pH to 6.0 with citric acid, and adding lemon yellow;
(5) after the content of Vonoprazan fumarate in the liquid medicine is measured, the liquid medicine is subpackaged in a mould, and the mould filled with the liquid medicine is placed in a vacuum freeze drying oven for freeze drying;
(6) and (3) rapidly packaging the freeze-dried tablets in double aluminum to obtain the Vonoprazan fumarate frozen oral instant tablets.
The oral instant tablet has good appearance, small friability, no granular sensation, good taste, and short dissolution time (only 17 seconds).
Example 4
Each tablet contains 10.0mg of vonoprazan fumarate, and the composition of 1000 oral fast dissolving tablets of vonoprazan fumarate is as follows:
the preparation method comprises the following steps:
(1) dissolving the formula amount of sulfobutyl ether-alpha-cyclodextrin in purified water accounting for 80% of the total amount of the formula water, heating to 50 ℃ under a stirring state, slowly adding the formula amount of vonoprazan fumarate, and continuously stirring for 2 hours;
(2) weighing the mannitol, the lactose and the sucralose with the prescription amount, and adding the mannitol, the lactose and the sucralose into the solution in the step (1).
(3) Weighing gelatin and xanthan gum according to the prescription amount, dissolving in purified water which is 20% of the total amount of water used in the prescription, and heating until the gelatin and the xanthan gum are completely dissolved;
(4) mixing the above two solutions, stirring, adjusting pH to 6.0 with citric acid, and adding lemon yellow;
(5) after the content of Vonoprazan fumarate in the liquid medicine is measured, the liquid medicine is subpackaged in a mould, and the mould filled with the liquid medicine is placed in a vacuum freeze drying oven for freeze drying;
(6) and (3) rapidly packaging the freeze-dried tablets in double aluminum to obtain the Vonoprazan fumarate frozen oral instant tablets.
The oral instant tablet has good appearance, small friability, no granular sensation, good taste, and short dissolution time (only 8 s).
Example 5
Each tablet contains 10.0mg of vonoprazan fumarate, and the composition of 1000 oral fast dissolving tablets of vonoprazan fumarate is as follows:
the preparation method comprises the following steps:
(1) dissolving the formula amount of sulfobutyl ether-alpha-cyclodextrin in purified water accounting for 80% of the total amount of the formula water, heating to 50 ℃ under a stirring state, slowly adding the formula amount of vonoprazan fumarate, and continuously stirring for 2 hours;
(2) weighing the mannitol, the lactose and the sucralose with the prescription amount, and adding the mannitol, the lactose and the sucralose into the solution in the step (1).
(3) Weighing gelatin and xanthan gum according to the prescription amount, dissolving in purified water which is 20% of the total amount of water used in the prescription, and heating until the gelatin and the xanthan gum are completely dissolved;
(4) mixing the above two solutions, stirring, adjusting pH to 6.0 with citric acid, and adding lemon yellow;
(5) after the content of Vonoprazan fumarate in the liquid medicine is measured, the liquid medicine is subpackaged in a mould, and the mould filled with the liquid medicine is placed in a vacuum freeze drying oven for freeze drying;
(6) and (3) rapidly packaging the freeze-dried tablets in double aluminum to obtain the Vonoprazan fumarate frozen oral instant tablets.
The oral instant tablet has good appearance, small friability, no granular sensation, good taste, and short dissolution time (only 5 seconds).
Example 6
Each tablet contains 10.0mg of vonoprazan fumarate, and the composition of 1000 oral fast dissolving tablets of vonoprazan fumarate is as follows:
the preparation method comprises the following steps:
(1) dissolving the formula amount of sulfobutyl ether-alpha-cyclodextrin in purified water accounting for 80% of the total amount of the formula water, heating to 55 ℃ under a stirring state, slowly adding the formula amount of vonoprazan fumarate, and continuously stirring for 4 hours;
(2) weighing the mannitol, the lactose and the sucralose with the prescription amount, and adding the mannitol, the lactose and the sucralose into the solution in the step (1).
(3) Weighing gelatin and xanthan gum according to the prescription amount, dissolving in purified water which is 20% of the total amount of water used in the prescription, and heating until the gelatin and the xanthan gum are completely dissolved;
(4) mixing the above two solutions, stirring, adjusting pH to 6.5 with citric acid, and adding lemon yellow;
(5) after the content of Vonoprazan fumarate in the liquid medicine is measured, the liquid medicine is subpackaged in a mould, and the mould filled with the liquid medicine is placed in a vacuum freeze drying oven for freeze drying;
(6) and (3) rapidly packaging the freeze-dried tablets in double aluminum to obtain the Vonoprazan fumarate frozen oral instant tablets.
The oral instant tablet has good appearance, small friability, no granular sensation, good taste, and short dissolution time (only 6 seconds).
Example 7
Each tablet contains 10.0mg of vonoprazan fumarate, and the composition of 1000 oral fast dissolving tablets of vonoprazan fumarate is as follows:
the preparation method comprises the following steps:
(1) dissolving the formula amount of sulfobutyl ether-alpha-cyclodextrin in purified water accounting for 80% of the total amount of the formula water, heating to 55 ℃ under a stirring state, slowly adding the formula amount of vonoprazan fumarate, and continuously stirring for 4 hours;
(2) weighing the mannitol, the lactose and the sucralose with the prescription amount, and adding the mannitol, the lactose and the sucralose into the solution in the step (1).
(3) Weighing gelatin and xanthan gum according to the prescription amount, dissolving in purified water which is 20% of the total amount of water used in the prescription, and heating until the gelatin and the xanthan gum are completely dissolved;
(4) mixing the above two solutions, stirring, adjusting pH to 6.5 with citric acid, and adding lemon yellow;
(5) after the content of Vonoprazan fumarate in the liquid medicine is measured, the liquid medicine is subpackaged in a mould, and the mould filled with the liquid medicine is placed in a vacuum freeze drying oven for freeze drying;
(6) and (3) rapidly packaging the freeze-dried tablets in double aluminum to obtain the Vonoprazan fumarate frozen oral instant tablets.
The oral instant tablet has good appearance, small friability, no granular sensation, good taste, and short dissolution time (only 6 seconds).
Claims (8)
1. The vonoprazan fumarate oral instant tablet is characterized by comprising the following components: 5-30 parts of vonoprazan fumarate, 5-50 parts of cyclodextrin, 20-80 parts of framework material, 1-10 parts of suspending agent, 0.1-2 parts of flavoring agent, 0.1-2 parts of pH regulator and 0.001-0.05 part of coloring agent.
2. The vonoprazan fumarate oral fast dissolving tablet according to claim 1, wherein the oral fast dissolving tablet comprises the following components in parts by weight: 10-20 parts of vonoprazan fumarate, 20-40 parts of cyclodextrin, 50-70 parts of framework material, 2-5 parts of suspending agent, 0.5-1 part of flavoring agent, 0.3-1 part of pH regulator and 0.001-0.02 part of coloring agent.
3. The vonoprazan fumarate oral fast dissolving tablet according to claim 2, wherein the oral fast dissolving tablet comprises the following components in parts by weight: 10 parts of vonoprazan fumarate, 30 parts of cyclodextrin, 56 parts of framework material, 2.5 parts of suspending agent, 0.5-1 part of flavoring agent, 0.3-1 part of pH regulator and 0.01 part of coloring agent.
4. The vonoprazan fumarate oral fast dissolving tablet according to claim 1, wherein the cyclodextrin is selected from any one or a mixture of any more of α -cyclodextrin, methyl- α -cyclodextrin, carboxymethyl- α -cyclodextrin, hydroxypropyl- α -cyclodextrin and sulfobutyl ether- α -cyclodextrin in any proportion; the framework material is selected from any one or a mixture of any two of glucose, sucrose, mannitol, sorbitol, lactose, dextrose, glucan and starch according to any proportion; the suspending agent is selected from any one or a mixture of any two of xanthan gum, polyvinyl alcohol, tragacanth, sodium alginate, gelatin, acacia, methylcellulose, agar, hydroxypropyl methylcellulose, hydroxypropyl cellulose and sodium carboxymethylcellulose according to any proportion; the pH regulator is selected from one or a mixture of two of citric acid, tartaric acid, malic acid and sodium dihydrogen phosphate according to any proportion; the flavoring agent comprises pharmaceutically acceptable sweetener, aromatic, mucilage, effervescent, screen flavoring agent, fatty substance, modified starch carbohydrate, cyclodextrin, saccharide and protein.
5. The Vonoprazan fumarate oral fast dissolving tablet according to claim 4, wherein the cyclodextrin is hydroxypropyl- α -cyclodextrin or sulfobutyl ether- α -cyclodextrin; the skeleton material is a mixture consisting of mannitol and lactose according to a weight ratio of (2-1): 1; the suspending agent is a mixture of xanthan gum and gelatin according to a weight ratio of (6-3) to 1; the pH regulator is citric acid or malic acid; the flavoring agent is sucralose.
6. A method for preparing the vonoprazan fumarate oral fast dissolving tablet of claim 1 or 2, comprising the steps of:
(1) dissolving the cyclodextrin with the prescription amount in purified water accounting for 80 percent of the total amount of the water used for the prescription, heating the mixture under the stirring state, slowly adding the vonoprazan fumarate with the prescription amount, and continuously stirring the mixture;
(2) weighing the framework material and the flavoring agent according to the prescription amount, and adding the framework material and the flavoring agent into the solution obtained in the step (1);
(3) weighing a suspending agent according to the prescription amount, dissolving the suspending agent in purified water with the water consumption of 20 percent of the prescription amount, and heating until the suspending agent is completely dissolved;
(4) mixing the two solutions, stirring, adjusting pH with pH regulator, and adding colorant;
(5) after the content of Vonoprazan fumarate in the liquid medicine is measured, the liquid medicine is subpackaged in a mould, and the mould filled with the liquid medicine is placed in a vacuum freeze drying oven for freeze drying;
(6) and packaging the freeze-dried tablets with double aluminum to obtain the Vonoprazan fumarate frozen oral instant tablets.
7. The method for preparing the vonoprazan fumarate oral fast-dissolving tablet according to claim 6, wherein in the step (1), the vonoprazan fumarate in a prescribed amount is slowly added while heating to 50 ℃ to 60 ℃ under stirring, and the stirring is continued for 1 to 6 hours.
8. The method for preparing the vonoprazan fumarate oral fast-dissolving tablet according to claim 6, wherein the pH value of the (4) is adjusted to 5.5-7.0 by using a pH adjusting agent.
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| US20200163881A1 (en) * | 2017-07-10 | 2020-05-28 | Takeda Pharmaceutical Company Limited | Preparation comprising vonoprazan |
| CN110538153A (en) * | 2019-09-26 | 2019-12-06 | 扬子江药业集团四川海蓉药业有限公司 | High-stability and quick-release solid preparation and preparation method thereof |
| TW202207905A (en) * | 2020-06-26 | 2022-03-01 | 美商阿普雷奇亞製藥有限責任公司 | Rapidly-orodispersible tablets having an interior cavity |
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Application publication date: 20211224 |