CN117562900A - New apixaban preparation composition with obvious clinical advantage and preparation method thereof - Google Patents
New apixaban preparation composition with obvious clinical advantage and preparation method thereof Download PDFInfo
- Publication number
- CN117562900A CN117562900A CN202311635911.7A CN202311635911A CN117562900A CN 117562900 A CN117562900 A CN 117562900A CN 202311635911 A CN202311635911 A CN 202311635911A CN 117562900 A CN117562900 A CN 117562900A
- Authority
- CN
- China
- Prior art keywords
- apixaban
- hydroxypropylcellulose
- formulation composition
- composition according
- filler
- 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
- QNZCBYKSOIHPEH-UHFFFAOYSA-N Apixaban Chemical compound C1=CC(OC)=CC=C1N1C(C(=O)N(CC2)C=3C=CC(=CC=3)N3C(CCCC3)=O)=C2C(C(N)=O)=N1 QNZCBYKSOIHPEH-UHFFFAOYSA-N 0.000 title claims abstract description 62
- 229960003886 apixaban Drugs 0.000 title claims abstract description 61
- 238000002360 preparation method Methods 0.000 title claims abstract description 30
- 230000008901 benefit Effects 0.000 title claims abstract description 7
- 239000000203 mixture Substances 0.000 title abstract description 21
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims abstract description 50
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims abstract description 50
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims abstract description 50
- 239000011230 binding agent Substances 0.000 claims abstract description 18
- 239000000945 filler Substances 0.000 claims abstract description 18
- 239000000853 adhesive Substances 0.000 claims abstract description 16
- 230000001070 adhesive effect Effects 0.000 claims abstract description 16
- 239000000314 lubricant Substances 0.000 claims abstract description 14
- 239000000796 flavoring agent Substances 0.000 claims abstract description 13
- 235000013355 food flavoring agent Nutrition 0.000 claims abstract description 13
- 239000002904 solvent Substances 0.000 claims abstract description 13
- 239000007884 disintegrant Substances 0.000 claims abstract 3
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 16
- 238000002156 mixing Methods 0.000 claims description 15
- 239000003795 chemical substances by application Substances 0.000 claims description 14
- 239000013022 formulation composition Substances 0.000 claims description 14
- 239000000463 material Substances 0.000 claims description 10
- 238000000034 method Methods 0.000 claims description 10
- 239000002245 particle Substances 0.000 claims description 10
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 9
- 238000001035 drying Methods 0.000 claims description 9
- 235000019359 magnesium stearate Nutrition 0.000 claims description 8
- 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 7
- 229930195725 Mannitol Natural products 0.000 claims description 7
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 claims description 7
- 239000000594 mannitol Substances 0.000 claims description 7
- 235000010355 mannitol Nutrition 0.000 claims description 7
- 235000019333 sodium laurylsulphate Nutrition 0.000 claims description 7
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 6
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 6
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 6
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 6
- 239000000243 solution Substances 0.000 claims description 6
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 5
- 239000004376 Sucralose Substances 0.000 claims description 5
- 229940075614 colloidal silicon dioxide Drugs 0.000 claims description 5
- 229960000913 crospovidone Drugs 0.000 claims description 5
- 239000000686 essence Substances 0.000 claims description 5
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims description 5
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims description 5
- 235000019408 sucralose Nutrition 0.000 claims description 5
- 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 5
- 239000007864 aqueous solution Substances 0.000 claims description 4
- 239000008369 fruit flavor Substances 0.000 claims description 4
- 239000007779 soft material Substances 0.000 claims description 4
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 3
- 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 3
- 239000008101 lactose Substances 0.000 claims description 3
- 230000008569 process Effects 0.000 claims description 3
- 239000011734 sodium Substances 0.000 claims description 3
- 235000015424 sodium Nutrition 0.000 claims description 3
- 229910052708 sodium Inorganic materials 0.000 claims description 3
- 238000005507 spraying Methods 0.000 claims description 3
- 108010011485 Aspartame Proteins 0.000 claims description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 2
- 229920002261 Corn starch Polymers 0.000 claims description 2
- 229920002785 Croscarmellose sodium Polymers 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
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 claims description 2
- CTKXFMQHOOWWEB-UHFFFAOYSA-N Ethylene oxide/propylene oxide copolymer Chemical compound CCCOC(C)COCCO CTKXFMQHOOWWEB-UHFFFAOYSA-N 0.000 claims description 2
- 229920002472 Starch Polymers 0.000 claims description 2
- 235000021355 Stearic acid Nutrition 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
- 239000000605 aspartame Substances 0.000 claims description 2
- 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 2
- 235000010357 aspartame Nutrition 0.000 claims description 2
- 229960003438 aspartame Drugs 0.000 claims description 2
- 239000011575 calcium Substances 0.000 claims description 2
- 229910052791 calcium Inorganic materials 0.000 claims description 2
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 claims description 2
- 239000008120 corn starch Substances 0.000 claims description 2
- 229960001681 croscarmellose sodium Drugs 0.000 claims description 2
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 claims description 2
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 claims description 2
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 claims description 2
- -1 glidant Substances 0.000 claims description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims description 2
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 claims description 2
- 229920001993 poloxamer 188 Polymers 0.000 claims description 2
- 229940044519 poloxamer 188 Drugs 0.000 claims description 2
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 claims description 2
- 229920000053 polysorbate 80 Polymers 0.000 claims description 2
- 239000000377 silicon dioxide Substances 0.000 claims description 2
- 235000012239 silicon dioxide Nutrition 0.000 claims description 2
- 229940080313 sodium starch Drugs 0.000 claims description 2
- 229940045902 sodium stearyl fumarate Drugs 0.000 claims description 2
- 239000000600 sorbitol Substances 0.000 claims description 2
- 235000010356 sorbitol Nutrition 0.000 claims description 2
- 229940032147 starch Drugs 0.000 claims description 2
- 239000008107 starch Substances 0.000 claims description 2
- 235000019698 starch Nutrition 0.000 claims description 2
- 239000008117 stearic acid Substances 0.000 claims description 2
- 239000003814 drug Substances 0.000 abstract description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 8
- 208000019505 Deglutition disease Diseases 0.000 abstract description 2
- 239000000825 pharmaceutical preparation Substances 0.000 abstract description 2
- 210000000214 mouth Anatomy 0.000 abstract 1
- 230000000052 comparative effect Effects 0.000 description 34
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- 229940079593 drug Drugs 0.000 description 7
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- 239000006191 orally-disintegrating tablet Substances 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 238000005550 wet granulation Methods 0.000 description 6
- 239000008186 active pharmaceutical agent Substances 0.000 description 4
- 229940088679 drug related substance Drugs 0.000 description 4
- 238000011835 investigation Methods 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 238000005259 measurement Methods 0.000 description 4
- 239000007916 tablet composition Substances 0.000 description 4
- 238000009472 formulation Methods 0.000 description 3
- 238000005469 granulation Methods 0.000 description 3
- 230000003179 granulation Effects 0.000 description 3
- 230000002035 prolonged effect Effects 0.000 description 3
- 239000008213 purified water Substances 0.000 description 3
- 238000010008 shearing Methods 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 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 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 238000007599 discharging Methods 0.000 description 2
- 238000007908 dry granulation Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000011361 granulated particle Substances 0.000 description 2
- 238000000227 grinding Methods 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 229960001375 lactose Drugs 0.000 description 2
- 238000000691 measurement method Methods 0.000 description 2
- 239000006187 pill Substances 0.000 description 2
- 239000011148 porous material Substances 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000002002 slurry Substances 0.000 description 2
- 239000007962 solid dispersion Substances 0.000 description 2
- 208000004043 venous thromboembolism Diseases 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- 230000004580 weight loss Effects 0.000 description 2
- PGOHTUIFYSHAQG-LJSDBVFPSA-N (2S)-6-amino-2-[[(2S)-5-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-4-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-5-amino-2-[[(2S)-5-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S,3R)-2-[[(2S)-5-amino-2-[[(2S)-2-[[(2S)-2-[[(2S,3R)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-5-amino-2-[[(2S)-1-[(2S,3R)-2-[[(2S)-2-[[(2S)-2-[[(2R)-2-[[(2S)-2-[[(2S)-2-[[2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-1-[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-amino-4-methylsulfanylbutanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-5-carbamimidamidopentanoyl]amino]propanoyl]pyrrolidine-2-carbonyl]amino]-3-methylbutanoyl]amino]-4-methylpentanoyl]amino]-4-methylpentanoyl]amino]acetyl]amino]-3-hydroxypropanoyl]amino]-4-methylpentanoyl]amino]-3-sulfanylpropanoyl]amino]-4-methylsulfanylbutanoyl]amino]-5-carbamimidamidopentanoyl]amino]-3-hydroxybutanoyl]pyrrolidine-2-carbonyl]amino]-5-oxopentanoyl]amino]-3-hydroxypropanoyl]amino]-3-hydroxypropanoyl]amino]-3-(1H-imidazol-5-yl)propanoyl]amino]-4-methylpentanoyl]amino]-3-hydroxybutanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-5-carbamimidamidopentanoyl]amino]-5-oxopentanoyl]amino]-3-hydroxybutanoyl]amino]-3-hydroxypropanoyl]amino]-3-carboxypropanoyl]amino]-3-hydroxypropanoyl]amino]-5-oxopentanoyl]amino]-5-oxopentanoyl]amino]-3-phenylpropanoyl]amino]-5-carbamimidamidopentanoyl]amino]-3-methylbutanoyl]amino]-4-methylpentanoyl]amino]-4-oxobutanoyl]amino]-5-carbamimidamidopentanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-4-carboxybutanoyl]amino]-5-oxopentanoyl]amino]hexanoic acid Chemical compound CSCC[C@H](N)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](Cc1cnc[nH]1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCCN)C(O)=O PGOHTUIFYSHAQG-LJSDBVFPSA-N 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 229920003081 Povidone K 30 Polymers 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- KZNIFHPLKGYRTM-UHFFFAOYSA-N apigenin Chemical compound C1=CC(O)=CC=C1C1=CC(=O)C2=C(O)C=C(O)C=C2O1 KZNIFHPLKGYRTM-UHFFFAOYSA-N 0.000 description 1
- 229940117893 apigenin Drugs 0.000 description 1
- XADJWCRESPGUTB-UHFFFAOYSA-N apigenin Natural products C1=CC(O)=CC=C1C1=CC(=O)C2=CC(O)=C(O)C=C2O1 XADJWCRESPGUTB-UHFFFAOYSA-N 0.000 description 1
- 235000008714 apigenin Nutrition 0.000 description 1
- 239000012752 auxiliary agent Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000001186 cumulative effect Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 238000007922 dissolution test Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 210000004394 hip joint Anatomy 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- 229960003943 hypromellose Drugs 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 210000000629 knee joint Anatomy 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 229960001855 mannitol Drugs 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000002572 peristaltic effect Effects 0.000 description 1
- 239000008055 phosphate buffer solution Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 230000002980 postoperative effect Effects 0.000 description 1
- 238000010298 pulverizing process Methods 0.000 description 1
- 239000013558 reference substance Substances 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 102220042174 rs141655687 Human genes 0.000 description 1
- 210000003296 saliva Anatomy 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—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
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
-
- 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
- A61K9/0053—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
-
- 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
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- 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
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Zoology (AREA)
- Nutrition Science (AREA)
- Physiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention discloses a new apixaban preparation composition with obvious clinical advantages and a preparation method thereof, belonging to the field of pharmaceutical preparations. The apixaban new preparation composition comprises the following components: apixaban, filler, binder, disintegrant, solubilizer, glidant, lubricant and flavoring agent; wherein the adhesive is hydroxypropyl cellulose, and the adhesive accounts for 1.0-3.0% by weight percent. The apixaban new preparation composition provided by the invention has short disintegration time in the oral cavity, and is not required to be swallowed with water, so that the convenience and compliance of administration are improved, the safety of medicine taking of special people is improved, and a better choice is provided for patients who have dysphagia or need to crush tablets after operation and then take orally or nasally feed.
Description
Technical Field
The invention belongs to the field of pharmaceutical preparations, and in particular relates to a new apixaban preparation composition with obvious clinical advantages and a preparation method thereof.
Background
Apixaban is a blood coagulation factor Xa inhibitor, and is clinically used for adult patients with hip joint or knee joint preferential replacement, and is used for preventing Venous Thromboembolic Events (VTE), and a common clinical dosage form is a common tablet (oral administration). However, conventional tablets are not suitable for patients who have difficulty swallowing or who need to crush the tablets for oral or nasal feeding use after surgery. Therefore, development of an apixaban orally disintegrating tablet composition which does not need to be swallowed with water, improves the administration convenience and compliance of patients, and improves the administration safety of special people so as to avoid potential risks such as choking caused by inhalation into the lung during administration is very significant.
Apixaban was originally disclosed by U.S. patent No. 6967208B2 under the chemical name 1- (4-methoxyphenyl) -7-oxo-6 [4- (2-oxopiperidin-1-yl) phenyl ] -4,5,6, 7-tetrahydro-1H-pyrazolo [3,4-c ] pyridine-3-carboxamide, the apixaban having the formula:
apixaban is insoluble in water, has the defects of low dissolution rate, low dissolution rate and low bioavailability, and has certain influence on the absorption of the medicine in vivo.
Chinese patent CN104095823 discloses a method for preparing apixaban tablet, which is prepared from apixaban, lactose, microcrystalline cellulose, crosslinked cellulose sodium, sodium dodecyl sulfate and magnesium stearate, and comprises the following specific steps: mixing apixaban with water-soluble materials, and pulverizing; mixing the crushed mixture with one or more auxiliary agents, and directly tabletting to obtain apixaban tablets. The dissolution rate of the apigenin Sha Bansha class tablet prepared by the method can reach more than 80% in 15 minutes on average, and can reach more than 90% in 30 minutes on average, and the dissolution rate is low and the impurity content is high.
Chinese patent application CN102770126a discloses an apixaban composition, which adopts a dry granulation process. The dry granulation is used for preparing the granules, and the problems of high consumption, low production efficiency, poor reproducibility, low finished product yield and the like exist in industrial production.
The Chinese patent application CN102908324A discloses an apixaban tablet prepared by adopting a solid dispersion technology, wherein apixaban raw materials are added into hot polyethylene glycol for dispersion, and are crushed after solidification and cooling, so that apixaban solid dispersion is prepared, the requirements on workshops on mass production are relatively high, the steps are complicated, industrial production is not easy to realize, and the practicability is poor.
Aiming at the problems existing in the prior art, a apixaban preparation which is simple in preparation, quick in effect and good in dissolution effect and is suitable for mass production in modern industry and a preparation method thereof are still needed to be found.
Disclosure of Invention
In view of the above, the present invention aims to provide a new apixaban formulation composition with obvious clinical advantages and a preparation method thereof. Compared with the prior art, the apixaban new preparation composition provided by the invention has the characteristics of convenience in administration, simplicity in preparation, quick response and good dissolution effect, and is suitable for mass production in modern industry.
In order to achieve the above object, the present invention has the following technical scheme:
in one aspect, the present invention provides a new formulation composition of apixaban with clinical advantage comprising the following ingredients:
apixaban, a filler, an adhesive, a disintegrating agent, a solubilizer, a glidant, a lubricant and a flavoring agent, wherein the adhesive is hydroxypropyl cellulose, and the adhesive accounts for 1.0-3.0% by weight percent.
Preferably, the hydroxypropyl cellulose comprises at least one of hydroxypropyl cellulose ELF PHARM, hydroxypropyl cellulose EF PHARM, hydroxypropyl cellulose LF PHARM, hydroxypropyl cellulose JF PHARM and hydroxypropyl cellulose GF PHARM.
Further preferably, the hydroxypropyl cellulose comprises at least one of hydroxypropyl cellulose ELF PHARM and hydroxypropyl cellulose EF PHARM.
Most preferred is hydroxypropyl cellulose EF phasar.
Preferably, the apixaban new preparation composition comprises, by weight, 2-3% of apixaban, 75-85% of filler, 1-3% of hydroxypropyl cellulose, 1-15% of disintegrating agent, 0.5-3.5% of glidant, 0.1-2% of flavoring agent, 0.1-1% of lubricant and 0.1-2% of solubilizer.
Further preferably, the apixaban new preparation composition comprises, by weight, 2.5% of apixaban, 78% of filler, 2% of hydroxypropyl cellulose, 12% of disintegrating agent, 3% of glidant, 1% of flavoring agent, 0.5% of lubricant and 1% of solubilizer.
Preferably, the apixaban is in a micronized form, and D90 is less than or equal to 40 mu m; the filler is at least one selected from mannitol, microcrystalline cellulose, lactose and anhydrous calcium hydrophosphate; the disintegrating agent is at least one selected from crospovidone, croscarmellose sodium, carboxymethyl starch sodium and corn starch; the solubilizer is at least one selected from sodium dodecyl sulfate, poloxamer 188 and tween 80; the glidant is at least one selected from silicon dioxide and colloidal silicon dioxide; the lubricant is at least one of magnesium stearate, stearic acid, sodium stearyl fumarate and talcum powder; the flavoring agent is at least one selected from fruit flavor essence, sucralose, aspartame and sorbitol.
Further preferably, the particle size of apixaban is 5-20 μm; the filler is at least one selected from mannitol and microcrystalline cellulose; the disintegrating agent is crospovidone; the solubilizer is sodium dodecyl sulfate; the glidant is colloidal silicon dioxide; the lubricant is magnesium stearate; the flavoring agent is at least one selected from fruit flavor essence and sucralose.
Wherein the new formulation includes, but is not limited to, tablets, granules, powders, pills, and the like.
Preferably, the new preparation is at least one of a tablet, a granule, a powder and a pill.
Still preferably, the new formulation is a tablet.
More preferably, and as an example of the invention, the new formulation is an orally disintegrating tablet.
In yet another aspect, the present invention provides a method for preparing the novel apixaban formulation composition described above, comprising the steps of:
(1) Uniformly mixing apixaban, filler accounting for more than or equal to 70% of the total filler, disintegrating agent accounting for more than or equal to 30% of the total disintegrating agent, and flavoring agent accounting for more than or equal to 50% of the total flavoring agent as internal granulating auxiliary materials, spraying into a pre-prepared aqueous solution of a binding agent, and wet granulating to obtain a soft material;
(2) Drying the soft material obtained in the step (1), granulating, adding the rest filler, disintegrating agent, solubilizer, glidant, lubricant and correctant, mixing, and tabletting.
Preferably, in the step (1), the filling agent, the disintegrating agent and the flavoring agent can be added according to different types, and a glidant accounting for more than or equal to 30 percent of the total glidant can also be added.
Preferably, in step (1), the specific steps of mixing are: and (3) weighing the internal granulating auxiliary materials according to the formula, adding the internal granulating auxiliary materials into a wet granulator, starting equipment for premixing, and stirring at 400rpm and shearing at 1000rpm for 5min.
Preferably, in step (1), the concentration of the aqueous binder solution is 1.5 to 10%.
Further preferably, in step (1), the concentration of the aqueous binder solution is 3 to 10%.
Most preferably, in step (1), the aqueous binder solution has a viscosity of 300 to 600 mpa.s.
Preferably, in step (1), the wet granulation is performed by a granulator, wherein the mesh size is 3 x 3mm, and the rotation speed is 500rpm.
Preferably, in the step (2), the drying is to put the wet granulated material into a fluidized bed for drying, and the air inlet quantity is set to be 40-80m 3 And (3) discharging when the air inlet temperature is set to 60 ℃ and the drying weight loss is less than or equal to 2.0%.
Preferably, in the step (2), the dried material is granulated by a granulator, the aperture of a screen is 1.0mm, and the rotating speed is 500rpm.
Preferably, in the step (2), the specific steps of mixing are:
mixing the additive (except lubricant) with the dried and granulated particles at a rotating speed of 10rpm for 15min; and adding the lubricant for mixing after the completion, wherein the rotating speed is 10rpm, and mixing for 5min.
Preferably, in the step (2), the tabletting is a self-grinding preparation pressed by a round 6mm die, the theoretical tablet weight is 100mg tablet, and the hardness is 3-4kgf.
The beneficial effects of the invention are as follows:
(1) The invention adopts micronized raw material medicines, reduces the granularity of the raw material medicines and improves the dissolution rate. The invention avoids the blockage of the granularity of the raw material medicine to the release of the medicine, and compared with the original medicine, the invention has obviously enhanced release, more reasonable dissolution curve and quick effect.
(2) The invention examines the types of the binders, and selects the hydroxypropyl cellulose as the binder to be matched with other components, so that the yield of the apixaban orally disintegrating tablet composition can be effectively improved by about 15%, wherein the apixaban, the filler and the binder have good synergistic coordination.
(3) The invention examines the dosage of the adhesive, so that the particles are more uniform, the difference of dissolution curves among the tablets is reduced, the uniformity of the product quality is better, and the administration is safer.
(4) The invention adopts wet granulation process, has simple process steps, can greatly improve the production efficiency and save the cost.
(5) The orally disintegrating tablet prepared by the invention is convenient to carry, does not need to chew, can be rapidly disintegrated or dissolved by saliva without being taken with water, is easy to swallow, and improves the administration convenience and compliance of dysphagia people or postoperative patients.
Detailed Description
In order to make the technical means, the creation features, the achievement of the purpose and the effect of the present invention easy to understand, the present invention will be further elucidated with reference to the specific embodiments, but the following embodiments are only preferred embodiments of the present invention, not all of them. Based on the examples in the embodiments, those skilled in the art can obtain other examples without making any inventive effort, which fall within the scope of the invention. In the following examples, unless otherwise specified, the methods of operation used were conventional, the equipment used was conventional, and the materials used in the examples were the same.
Where numerical ranges are provided in the examples, it is understood that unless otherwise stated herein, both endpoints of each numerical range and any number between the two endpoints are significant both in the numerical range. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
It is to be noted that the raw materials used in the present invention are commercially available unless otherwise specified.
Example 1
The apixaban orally disintegrating tablet composition comprises the following components in percentage by weight: 2.5% of apixaban, 60.5% of mannitol, 12% of crospovidone, 2% of hydroxypropyl cellulose EF PHARM, 3% of colloidal silicon dioxide, 0.5% of sucralose, 1% of sodium dodecyl sulfate, 102.5% of microcrystalline cellulose, 0.5% of magnesium stearate and 0.5% of powdered orange essence. Wherein, the micronized apixaban bulk drug is adopted, and the granularity D90=12 μm of the bulk drug is adopted.
The preparation method comprises the following steps:
1. wet granulation:
and (3) preparing an adhesive: a 4.5% strength adhesive slurry was prepared using hydroxypropyl cellulose EF phasr and purified water.
Premixing: and (3) weighing the internal granulating auxiliary materials according to the formula, adding the internal granulating auxiliary materials into a wet granulator, starting equipment for premixing, and stirring at 400rpm and shearing at 1000rpm for 5min.
Adding liquid and granulating: setting stirring rotation speed 600rpm, shearing rotation speed 1500rpm, atomizing and spraying adhesive slurry, peristaltic pump rotation speed 60rpm, adding liquid time not more than 180s, granulating time 90s.
Wet finishing: and (3) granulating by adopting a granulator after granulating, wherein the pore diameter of a screen is 3mm, and the rotating speed is 500rpm.
2. And (3) drying:
the wet granulated material is put into a fluidized bed for drying, and the air inlet quantity is set to be 40-80m 3 And (3) discharging when the air inlet temperature is set to 60 ℃ and the drying weight loss is less than or equal to 2.0%.
3. Dry granule
And (3) granulating the dried material by adopting a granulating machine, wherein the pore diameter of a screen is 1.0mm, and the rotating speed is 500rpm.
4. Mixing:
the added auxiliary materials (except magnesium stearate) are mixed with the dried and granulated particles (mixing 1) for 15min at the rotating speed of 10 rpm. After the end of the mixing 1, magnesium stearate was added to the mixture and the mixture was mixed (mixing 2) at a rotational speed of 10rpm for 5 minutes.
5. Tabletting:
the self-grinding preparation is pressed by a round 6mm die, the theoretical tablet weight is 100mg, and the hardness is 3-4kgf.
Examples 2 to 5
Comparative example 1, in which only the hydroxypropyl cellulose EF phasr was changed to equal amounts of hydroxypropyl cellulose ELF phasr, hydroxypropyl cellulose LF phasr, hydroxypropyl cellulose JF phasr, hydroxypropyl cellulose GF phasr, respectively, all other conditions were the same; examples 2, 3,4 and 5, respectively.
Examples 6 to 9
In comparative example 1, only the content of hydroxypropyl cellulose EF phasar was changed to 0.5%, 1%, 1.5%, 3%, respectively, and the corresponding mannitol content was adjusted to 62.0%, 61.5%, 61.0%, 59.5%, respectively, with the same other conditions; examples 6,7, 8 and 9 are respectively.
Examples 10 to 13
In comparative example 8, the concentration of the hydroxypropyl cellulose EF PHARM aqueous solution was changed to 3%, 5%, 7% and 10% respectively, and the other conditions were the same; examples 10, 11, 12 and 13, respectively.
Comparative example 1
Comparative example 1, no binder was added; in wet granulation, purified water is sprayed in the steps of liquid adding and granulation, and the rest are the same.
Comparative example 2
Comparative example 1, using apixaban drug substance without micronization, d90=117 μm; no adhesive is added; in wet granulation, purified water is sprayed in the steps of liquid adding and granulation, and the rest are the same.
Comparative example 3
In comparative example 1, the binder was changed to povidone K30 alone, and the other conditions were the same.
Comparative example 4
In comparative example 1, the binder was changed to hypromellose E5 alone, and the other conditions were the same.
Comparative example 5
In comparative example 1, the content of hydroxypropyl cellulose EF phasr was only 8% and the corresponding mannitol content was adjusted to 54.5% with the same other conditions.
Comparative example 6
Apixaban tablet prepared according to example 1 of patent CN113041227 a.
Result detection
1. Investigation of adhesive types
Examples 1, comparative example 3, comparative example 4 used micronized apixaban drug substance with a drug substance particle size d90=12 μm, and comparative example 2 used apixaban drug substance without micronization, d90=117 μm. Comparative examples 1 and 2 were free of binder, had a low total mixed particle content, and exhibited a loss of content during the granulation and drying steps. The addition of different types of binders in example 1 and comparative examples 3 and 4 significantly increased the total mixed particle content after the addition of the binder, but significantly prolonged the disintegration time, and the requirements of ChP2020 were not met by comparative examples 3 and 4 (not exceeding 60 s). Example 1 achieves a unification of the high content of the total mixed particles and the suitable disintegration time of the tablets.
2. Investigation of different types of hydroxypropyl cellulose
The results show that the content of particles can be improved by adding different types of hydroxypropyl cellulose in the prescription, and the requirement of 95.0-105.0% of the content can be met. Different types of hydroxypropyl cellulose correspond to different molecular weights and viscosities, and along with the increase of the viscosity of the hydroxypropyl cellulose, the disintegration time of tablets with the same hardness is prolonged. The disintegration time limit and the content of the hydroxypropyl cellulose EF PHARM and ELF PHARM can meet the requirements.
3. Investigation of the amount of hydroxypropyl cellulose
The results show that the disintegration time of the preparation with the same hardness is prolonged along with the increase of the dosage, the dosage of the hydroxypropyl cellulose EF PHARM is in the range of 0.5-3.0%, and the disintegration time limit meets the requirements of ChP 2020. The dosage of the hydroxypropyl cellulose EF PHARM in the embodiment 6 is 0.5%, the total mixed particle yield is lower than 95%, and the requirements of 95-105% are not met. Therefore, the dosage of the hydroxypropyl cellulose EF PHARM is 1.0-3.0 percent, the process yield can be improved, and the product can be rapidly disintegrated and released.
4. Investigation of the adhesive concentration
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The results show that the content and disintegration time of the hydroxypropyl cellulose EF PHARM tablet meet the requirements of ChP2020 at the concentration of 3-10% (w/w). The viscosity of the hydroxypropyl cellulose EF PHARM with the concentration of 3-10% (w/w) is 300-600 mPa.s.
5. Content uniformity test measurement
Samples of the comparative examples of each example and commercially available normal tablet formulations were taken separatelyThe content uniformity of the preparation was measured according to the content measurement method (four preparations rule 0941 in the year 2020 edition of Chinese pharmacopoeia). The measurement results were as follows:
| sample of | Content uniformity (%) | A+2.2 |
| Example 1 | 97 | 5.7 |
| Example 2 | 97 | 6.4 |
| Example 3 | 99 | 4.4 |
| Example 4 | 96 | 7.2 |
| Example 5 | 96 | 7.4 |
| Example 6 | 94 | 8.7 |
| Example 7 | 97 | 5.7 |
| Example 8 | 97 | 6.2 |
| Example 9 | 99 | 3.7 |
| Example 10 | 99 | 4.2 |
| Example 11 | 97 | 6.2 |
| Example 12 | 98 | 5.4 |
| Example 13 | 97 | 5.7 |
| Comparative example 1 | 85 | 18.2 |
| Comparative example 2 | 84 | 19.4 |
| Comparative example 3 | 97 | 5.7 |
| Comparative example 4 | 98 | 5.2 |
| Comparative example 5 | 99 | 4.1 |
| Comparative example 6 | / | 3.6 |
| Ai Letuo | 99 | 6.3 |
The results show that: the content uniformity of the tablet composition meets the requirements of the 2020 edition of Chinese pharmacopoeia, and the product quality is uniform.
6. Dissolution test measurement
Samples of the comparative examples of each example and commercially available normal tablet formulations were taken separatelyTaking dissolution rate measurement method (second method of four preparations rule 0931 of Chinese pharmacopoeia 2020 edition), taking pH6.8 phosphate buffer solution+0.05% SDS,900ml as solvent, rotating at 75 rpm, sampling from 5, 10, 15, 20, 30 and 45min at 60 min, taking 10ml each time, filtering with 0.45 μm filter membrane, discarding primary filtrate 3ml, taking the subsequent filtrate as a sample solution; the apixaban reference substance is taken out and dried for 4 hours under reduced pressure at 105 ℃, precisely weighed, dissolved in water and quantitatively diluted to prepare a solution with 10 mug in each 1 ml. Taking the two solutions, measuring absorbance at 280nm wavelength according to ultraviolet-visible spectrophotometry (Chinese pharmacopoeia 2020 edition four preparations rule 0401), and calculating the percentage of each tablet. The measurement results were as follows:
| Time | 5min | 10min | 15min | 20min | 30min | 45min |
| example 1 | 85 | 89 | 91 | 91 | 92 | 97 |
| Example 2 | 84 | 90 | 90 | 93 | 94 | 94 |
| Example 3 | 67 | 76 | 82 | 85 | 89 | 92 |
| Example 4 | 61 | 71 | 83 | 87 | 95 | 96 |
| Example 5 | 50 | 64 | 78 | 86 | 90 | 93 |
| Example 6 | 86 | 96 | 98 | 100 | 101 | 101 |
| Example 7 | 85 | 89 | 91 | 91 | 92 | 97 |
| Example 8 | 85 | 92 | 94 | 95 | 96 | 97 |
| Example 9 | 85 | 89 | 90 | 91 | 92 | 96 |
| Example 10 | 90 | 96 | 97 | 98 | 99 | 99 |
| Example 11 | 85 | 92 | 94 | 95 | 96 | 97 |
| Example 12 | 84 | 92 | 94 | 95 | 96 | 97 |
| Example 13 | 83 | 91 | 94 | 95 | 95 | 96 |
| Comparative example 1 | 73 | 82 | 83 | 83 | 84 | 84 |
| Comparative example 2 | 12 | 37 | 58 | 71 | 81 | 86 |
| Comparative example 3 | 36 | 62 | 72 | 77 | 82 | 88 |
| Comparative example 4 | 56 | 67 | 78 | 85 | 89 | 92 |
| Comparative example 5 | 42 | 61 | 74 | 81 | 87 | 93 |
| Comparative example 6 | 77.6 | 96.3 | 99.5 | / | 99.3 | / |
| Ai Letuo | 36 | 62 | 72 | 77 | 82 | 91 |
The results show that the tablet compositions of the present invention can rapidly collapse or dissolve relative to the commercial products. Wherein, the cumulative dissolution rate of examples 1, 2 and 6-13 reaches 15min to reach a dissolution platform of more than or equal to 85%, so that the release is faster, the drug absorption is facilitated, and the curative effect is rapidly exerted.
In summary, the invention provides a new apixaban preparation composition, which adopts micronized raw material medicines, reduces the granularity of the raw material medicines to improve the dissolution rate; the hydroxypropyl cellulose is selected as the adhesive to be matched with other components for use, so that the yield of the apixaban orally disintegrating tablet composition can be effectively improved; the specific adhesive dosage is selected, so that the particles are more uniform, and the uniformity of the product quality is improved; the wet granulation process is adopted, the process steps are simple, the production scale can be greatly improved, and the production efficiency is improved, and the cost is saved.
The foregoing description of the preferred embodiments of the invention is not intended to be limiting, but rather is intended to cover all modifications, equivalents, alternatives, and improvements that fall within the spirit and scope of the invention.
Claims (10)
1. A new formulation composition of apixaban with clinical advantage, characterized in that it comprises the following components:
apixaban, filler, binder, disintegrant, solubilizer, glidant, lubricant and flavoring agent; wherein the adhesive is hydroxypropyl cellulose, and the adhesive accounts for 1.0-3.0% by weight percent.
2. The apixaban new formulation composition according to claim 1, wherein the binder is formulated as an aqueous solution at a concentration of 1.5-10% prior to preparation for use.
3. The apixaban new formulation composition according to claim 2, wherein the viscosity of the aqueous binder solution is 300-600 mPa-s.
4. The apixaban new formulation composition according to claim 1, wherein the hydroxypropylcellulose comprises at least one of hydroxypropylcellulose ELF phasr, hydroxypropylcellulose EF phasr, hydroxypropylcellulose LF phasr, hydroxypropylcellulose JF phasr, and hydroxypropylcellulose GF phasr.
5. The apixaban new formulation composition according to claim 4, wherein the hydroxypropylcellulose comprises at least one of hydroxypropylcellulose ELF phasr, hydroxypropylcellulose EF phasr.
6. The apixaban new formulation composition according to claim 5, wherein the hydroxypropylcellulose is hydroxypropylcellulose EF phasar.
7. The apixaban new formulation composition according to claim 1, wherein the apixaban new formulation composition comprises, by weight, 2-3% apixaban, 75-85% filler, 1-3% hydroxypropyl cellulose, 1-15% disintegrant, 0.5-3.5% glidant, 0.1-2% flavoring agent, 0.1-1% lubricant, and 0.1-2% solubilizer.
8. The apixaban new formulation composition according to claim 1, wherein the apixaban is in micronized form, d90+.40 μm; the filler is at least one selected from mannitol, microcrystalline cellulose, lactose and anhydrous calcium hydrophosphate; the disintegrating agent is at least one selected from crospovidone, croscarmellose sodium, carboxymethyl starch sodium and corn starch; the solubilizer is at least one selected from sodium dodecyl sulfate, poloxamer 188 and tween 80; the glidant is at least one selected from silicon dioxide and colloidal silicon dioxide; the lubricant is at least one of magnesium stearate, stearic acid, sodium stearyl fumarate and talcum powder; the flavoring agent is at least one selected from fruit flavor essence, sucralose, aspartame and sorbitol.
9. The apixaban new formulation composition according to claim 8, wherein the particle size of apixaban is 5-20 μιη; the filler is at least one selected from mannitol and microcrystalline cellulose; the disintegrating agent is crospovidone; the solubilizer is sodium dodecyl sulfate; the glidant is colloidal silicon dioxide; the lubricant is magnesium stearate; the flavoring agent is at least one selected from fruit flavor essence and sucralose.
10. Process for the preparation of a new apixaban formulation composition according to any one of claims 1 to 9, characterized in that it comprises the following steps:
(1) Mixing apixaban, filler accounting for more than or equal to 70% of total filler, disintegrating agent accounting for more than or equal to 30% of total disintegrating agent, and correctant accounting for more than or equal to 50% of total correctant as internal granulating auxiliary materials, spraying into binder aqueous solution, and wet granulating to obtain soft material;
(2) Drying the soft material obtained in the step (1), granulating, adding the rest filler, disintegrating agent, solubilizer, glidant, lubricant and correctant, mixing, and tabletting.
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