CN117797108A - Bisoprolol fumarate composition tablet - Google Patents
Bisoprolol fumarate composition tablet Download PDFInfo
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- CN117797108A CN117797108A CN202410002055.XA CN202410002055A CN117797108A CN 117797108 A CN117797108 A CN 117797108A CN 202410002055 A CN202410002055 A CN 202410002055A CN 117797108 A CN117797108 A CN 117797108A
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- bisoprolol fumarate
- tablet
- mixing
- chitosan
- composition tablet
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- RZPZLFIUFMNCLY-WLHGVMLRSA-N (e)-but-2-enedioic acid;1-(propan-2-ylamino)-3-[4-(2-propan-2-yloxyethoxymethyl)phenoxy]propan-2-ol Chemical compound OC(=O)\C=C\C(O)=O.CC(C)NCC(O)COC1=CC=C(COCCOC(C)C)C=C1 RZPZLFIUFMNCLY-WLHGVMLRSA-N 0.000 title claims abstract description 82
- 229960005400 bisoprolol fumarate Drugs 0.000 title claims abstract description 78
- 239000000203 mixture Substances 0.000 title claims abstract description 33
- 238000002156 mixing Methods 0.000 claims abstract description 64
- 229920001661 Chitosan Polymers 0.000 claims abstract description 23
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 claims abstract description 19
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 claims abstract description 19
- 239000000811 xylitol Substances 0.000 claims abstract description 19
- 235000010447 xylitol Nutrition 0.000 claims abstract description 19
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 claims abstract description 19
- 229960002675 xylitol Drugs 0.000 claims abstract description 19
- 239000000314 lubricant Substances 0.000 claims abstract description 8
- 238000004519 manufacturing process Methods 0.000 claims abstract description 6
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 26
- 235000019359 magnesium stearate Nutrition 0.000 claims description 13
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 claims description 12
- 229920002472 Starch Polymers 0.000 claims description 7
- 239000002994 raw material Substances 0.000 claims description 7
- 229940032147 starch Drugs 0.000 claims description 7
- 239000008107 starch Substances 0.000 claims description 7
- 235000019698 starch Nutrition 0.000 claims description 7
- 239000000945 filler Substances 0.000 claims description 6
- 239000007884 disintegrant Substances 0.000 claims description 5
- 229920002785 Croscarmellose sodium Polymers 0.000 claims description 4
- 239000011734 sodium Substances 0.000 claims description 4
- 229910052708 sodium Inorganic materials 0.000 claims description 4
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 claims description 3
- 235000013539 calcium stearate Nutrition 0.000 claims description 3
- 239000008116 calcium stearate Substances 0.000 claims description 3
- OKODKVMXHLUQSW-JITBQSAISA-M sodium;(e)-4-hydroxy-4-oxobut-2-enoate;octadecanoic acid Chemical compound [Na+].OC(=O)\C=C\C([O-])=O.CCCCCCCCCCCCCCCCCC(O)=O OKODKVMXHLUQSW-JITBQSAISA-M 0.000 claims description 3
- 239000000454 talc Substances 0.000 claims description 2
- 235000012222 talc Nutrition 0.000 claims description 2
- 229910052623 talc Inorganic materials 0.000 claims description 2
- VJHCJDRQFCCTHL-UHFFFAOYSA-N acetic acid 2,3,4,5,6-pentahydroxyhexanal Chemical compound CC(O)=O.OCC(O)C(O)C(O)C(O)C=O VJHCJDRQFCCTHL-UHFFFAOYSA-N 0.000 claims 1
- 229960005168 croscarmellose Drugs 0.000 claims 1
- 239000001767 crosslinked sodium carboxy methyl cellulose Substances 0.000 claims 1
- 238000002360 preparation method Methods 0.000 abstract description 20
- 230000000750 progressive effect Effects 0.000 abstract description 3
- 239000000825 pharmaceutical preparation Substances 0.000 abstract description 2
- 229940045110 chitosan Drugs 0.000 abstract 1
- 239000003826 tablet Substances 0.000 description 48
- 230000000052 comparative effect Effects 0.000 description 20
- 238000007873 sieving Methods 0.000 description 17
- 238000003825 pressing Methods 0.000 description 12
- 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 description 10
- 238000000034 method Methods 0.000 description 9
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 8
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 8
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 8
- 239000008108 microcrystalline cellulose Substances 0.000 description 8
- 229940016286 microcrystalline cellulose Drugs 0.000 description 8
- 235000019640 taste Nutrition 0.000 description 7
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 239000011575 calcium Substances 0.000 description 5
- 229910052791 calcium Inorganic materials 0.000 description 5
- 239000008187 granular material Substances 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 4
- 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 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 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 description 4
- 229930195725 Mannitol Natural products 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- 238000000576 coating method Methods 0.000 description 4
- 229960000913 crospovidone Drugs 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 239000008101 lactose Substances 0.000 description 4
- 239000000594 mannitol Substances 0.000 description 4
- 235000010355 mannitol Nutrition 0.000 description 4
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 4
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 239000011248 coating agent Substances 0.000 description 3
- 239000007919 dispersible tablet Substances 0.000 description 3
- 239000004570 mortar (masonry) Substances 0.000 description 3
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 3
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 239000002904 solvent Substances 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
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 2
- 206010020772 Hypertension Diseases 0.000 description 2
- 230000001133 acceleration Effects 0.000 description 2
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Substances CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 2
- 239000000783 alginic acid Substances 0.000 description 2
- 235000010443 alginic acid Nutrition 0.000 description 2
- 229920000615 alginic acid Polymers 0.000 description 2
- 229960001126 alginic acid Drugs 0.000 description 2
- 150000004781 alginic acids Chemical class 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- LFVGISIMTYGQHF-UHFFFAOYSA-N ammonium dihydrogen phosphate Chemical compound [NH4+].OP(O)([O-])=O LFVGISIMTYGQHF-UHFFFAOYSA-N 0.000 description 2
- 229910000387 ammonium dihydrogen phosphate Inorganic materials 0.000 description 2
- 229910000019 calcium carbonate Inorganic materials 0.000 description 2
- 239000011247 coating layer Substances 0.000 description 2
- 229940075614 colloidal silicon dioxide Drugs 0.000 description 2
- 208000029078 coronary artery disease Diseases 0.000 description 2
- 238000007907 direct compression Methods 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
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- 238000000227 grinding Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 2
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 2
- 229960001375 lactose Drugs 0.000 description 2
- 235000019837 monoammonium phosphate Nutrition 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 229940069328 povidone Drugs 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000012488 sample solution Substances 0.000 description 2
- 239000007962 solid dispersion Substances 0.000 description 2
- 238000013112 stability test Methods 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- GUBGYTABKSRVRQ-UHFFFAOYSA-N 2-(hydroxymethyl)-6-[4,5,6-trihydroxy-2-(hydroxymethyl)oxan-3-yl]oxyoxane-3,4,5-triol Chemical compound OCC1OC(OC2C(O)C(O)C(O)OC2CO)C(O)C(O)C1O GUBGYTABKSRVRQ-UHFFFAOYSA-N 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- 108010011485 Aspartame Proteins 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 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 description 1
- 235000019739 Dicalciumphosphate Nutrition 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- 229920003081 Povidone K 30 Polymers 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 229920002125 Sokalan® Polymers 0.000 description 1
- 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 description 1
- 230000002411 adverse Effects 0.000 description 1
- 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 description 1
- 239000000605 aspartame Substances 0.000 description 1
- 235000010357 aspartame Nutrition 0.000 description 1
- 229960003438 aspartame Drugs 0.000 description 1
- 239000002876 beta blocker Substances 0.000 description 1
- 229960002781 bisoprolol Drugs 0.000 description 1
- VHYCDWMUTMEGQY-UHFFFAOYSA-N bisoprolol Chemical compound CC(C)NCC(O)COC1=CC=C(COCCOC(C)C)C=C1 VHYCDWMUTMEGQY-UHFFFAOYSA-N 0.000 description 1
- 235000019658 bitter taste Nutrition 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 210000000621 bronchi Anatomy 0.000 description 1
- 239000004067 bulking agent Substances 0.000 description 1
- 229960003563 calcium carbonate Drugs 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229960001631 carbomer Drugs 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 229960001681 croscarmellose sodium Drugs 0.000 description 1
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 description 1
- 229940038472 dicalcium phosphate Drugs 0.000 description 1
- 229910000390 dicalcium phosphate Inorganic materials 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
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- 238000010828 elution Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 239000007941 film coated tablet Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 230000037406 food intake Effects 0.000 description 1
- 238000010438 heat treatment Methods 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
- 238000009776 industrial production Methods 0.000 description 1
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- 239000012046 mixed solvent Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 210000002464 muscle smooth vascular Anatomy 0.000 description 1
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 1
- 238000000643 oven drying Methods 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- -1 polyox N12K Chemical compound 0.000 description 1
- 102220045258 rs587781957 Human genes 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 229920003109 sodium starch glycolate Polymers 0.000 description 1
- 239000008109 sodium starch glycolate Substances 0.000 description 1
- 229940079832 sodium starch glycolate Drugs 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
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- 238000012795 verification Methods 0.000 description 1
- 230000004580 weight loss Effects 0.000 description 1
- 238000005550 wet granulation Methods 0.000 description 1
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- Medicinal Preparation (AREA)
Abstract
The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a bisoprolol fumarate composition tablet and a preparation method thereof. The bisoprolol fumarate tablet disclosed by the invention consists of bisoprolol fumarate, chitosan, xylitol, a disintegrating agent and a lubricant, wherein the chitosan and the xylitol are used for synergistically improving the content uniformity of the tablet, the tablet has excellent stability, and meanwhile, the preparation process is simple, direct mixing is adopted, multiple equal-amount progressive mixing is not needed, and the tablet is suitable for industrial mass production.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a bisoprolol fumarate composition tablet.
Background
Bisoprolol fumarate is a beta receptor blocker, has high affinity to beta 1-receptors of bronchus and vascular smooth muscle, thereby expanding blood vessels and reducing blood pressure, is suitable for hypertension, coronary heart disease, moderate to severe chronic stable heart failure and other diseases, and has the following structure:
CN101467985B discloses a bisoprolol fumarate dispersible tablet and a preparation method thereof, wherein the prescription contains 55% of calcium hydrophosphate, when the prescription is tested, the problem that the proportion of calcium hydrophosphate is too high, the color is blackened during tabletting, and the stability is poor in the storage process is found. CN103127016B discloses a bisoprolol fumarate tablet composition and a preparation method thereof, wherein an equivalent increasing method is adopted in the process to uniformly mix raw materials and auxiliary materials. The equivalent progressive addition process is complex, equipment mismatch exists in production, equipment needs to be replaced for many times, and the problem of low final content of small-specification compounds can be caused. CN112245401a discloses a pharmaceutical tablet for treating hypertension and coronary heart disease and a preparation method thereof, wherein a wet granulation process is adopted in the process, and the stability is not ideal. GB2444904B improves the mixing uniformity by controlling the particle sizes of bisoprolol fumarate and various auxiliary materials.
Formulation and evaluation of bisoprolol fumarate OptiZorb dispersible tablet to improve tablet disintegration, b.lavanay et al j.world Journal Of Pharmacy And Pharmaceutical sciences.2015,4 (1), 561-576 based on OptiZorb technology using super disintegrants such as alginic acid and calcium carbonate, obtained bisoprolol fumarate dispersible tablets that dissolve faster, but it was difficult to maintain sufficient stability as tablets with minimal long-term decomposition in the unpackaged state.
The product Concor is a film coated tablet, the solvent used in the coating process may have adverse effect on related substances in the preparation, the coating layer is removed to improve the stability of the preparation, but calcium hydrophosphate is used in the original preparation, and after the masking of the coating layer is lost, the core appears grey and has bitter taste.
In addition, in the prior art, in order to reduce the influence of the preparation process on the stability of substances to the greatest extent, a powder direct compression process is adopted, but the direct compression process has the challenge of content uniformity for low-dose medicines, particularly in mass production, the risk of layering raw materials and auxiliary materials in the production process possibly exists, and the bisoprolol fumarate tablet is a scored tablet, so that the content uniformity of half tablet is extremely challenging.
Therefore, there is a need for a bisoprolol fumarate composition tablet with simple preparation process, high content uniformity and good stability.
Disclosure of Invention
In view of the shortcomings of the existing small-dose bisoprolol fumarate tablets, the invention provides a bisoprolol fumarate composition tablet. The bisoprolol fumarate composition tablet disclosed by the invention has the advantages of excellent content uniformity, high stability, good taste and simple preparation process.
The invention is realized by the following scheme:
a bisoprolol fumarate composition tablet comprising bisoprolol fumarate, chitosan, a filler, a disintegrant and a lubricant.
Preferably, the bulking agent is xylitol.
Preferably, the weight ratio of bisoprolol fumarate to chitosan is 1:0.2-1.
Further preferably, the weight ratio of bisoprolol fumarate to chitosan is 1:0.5.
preferably, the weight ratio of bisoprolol fumarate to xylitol is 1:15-25.
Further preferably, the weight ratio of bisoprolol fumarate to xylitol is 1:18-23.
Most preferably, the weight ratio of bisoprolol fumarate to xylitol is 1:20.
preferably, the lubricant is one or more of magnesium stearate, calcium stearate, talcum powder and sodium stearate fumarate.
Preferably, the weight ratio of bisoprolol fumarate to lubricant is 1:0.2-1.
Preferably, the disintegrating agent is one or more of sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose and crosslinked carboxymethyl cellulose.
Preferably, the weight ratio of bisoprolol fumarate to disintegrant is 1:0.2-0.8.
In a preferred embodiment, the bisoprolol fumarate composition tablet is composed of the following raw materials in parts by weight:
in a preferred embodiment, the bisoprolol fumarate composition tablet is composed of the following raw materials in parts by weight:
the invention also provides a preparation method of the bisoprolol fumarate composition tablet, which comprises the steps of fully mixing bisoprolol fumarate with chitosan, continuously and fully mixing after adding a filler, finally adding a disintegrating agent and a lubricant, uniformly mixing, and pressing into tablets.
Compared with the prior art, the invention has the following advantages: the bisoprolol fumarate composition tablet disclosed by the invention has good taste, is simple in production process, adopts direct mixing, does not need repeated equal progressive mixing, and has the advantages that the xylitol and the chitosan synergistically improve the content uniformity of bisoprolol fumarate, and the bisoprolol fumarate composition tablet has good stability, so that the bisoprolol fumarate composition tablet is suitable for industrial production.
Detailed Description
The invention is further illustrated by the following examples. It should be correctly understood that: the examples of the present invention are given solely for the purpose of illustration and are not to be construed as limitations of the present invention, and therefore, simple modifications to the invention that are set forth herein are intended to be within the scope of the appended claims.
The bisoprolol fumarate tablets of the examples and comparative examples of the present invention were 5 mg/tablet.
Example 1
Fully mixing the prescription dose of bisoprolol fumarate with chitosan, adding xylitol, uniformly mixing, finally adding low-substituted hydroxypropyl cellulose and talcum powder, uniformly mixing, and pressing into tablets.
Example 2
Fully mixing the prescription dose of bisoprolol fumarate with chitosan, adding xylitol, uniformly mixing, finally adding sodium carboxymethyl starch and magnesium stearate, uniformly mixing, and pressing into tablets.
Example 3
Fully mixing the prescription dose of bisoprolol fumarate with chitosan, adding xylitol, uniformly mixing, finally adding the crosslinked carboxymethyl cellulose and sodium stearate fumarate, uniformly mixing, and pressing into tablets.
Example 4
Fully mixing the prescription dose of bisoprolol fumarate with chitosan, adding xylitol, uniformly mixing, finally adding low-substituted hydroxypropyl cellulose and talcum powder, uniformly mixing, and pressing into tablets.
Example 5
Fully mixing the prescription dose of bisoprolol fumarate with chitosan, adding xylitol, uniformly mixing, finally adding sodium carboxymethyl starch and calcium stearate, uniformly mixing, and pressing into tablets.
Example 6
Fully mixing the prescription dose of bisoprolol fumarate with chitosan, adding xylitol, uniformly mixing, finally adding low-substituted hydroxypropyl cellulose and talcum powder, uniformly mixing, and pressing into tablets.
Example 7
Fully mixing the prescription dose of bisoprolol fumarate with chitosan, adding xylitol, uniformly mixing, finally adding low-substituted hydroxypropyl cellulose and talcum powder, uniformly mixing, and pressing into tablets.
Example 8
Fully mixing the prescription dose of bisoprolol fumarate with chitosan, adding mannitol, uniformly mixing, finally adding low-substituted hydroxypropyl cellulose and talcum powder, uniformly mixing, and pressing into tablets.
Example 9
Fully mixing the prescription dose of bisoprolol fumarate with chitosan, adding microcrystalline cellulose, uniformly mixing, finally adding low-substituted hydroxypropyl cellulose and talcum powder, uniformly mixing, and pressing into tablets.
Example 10
Fully mixing the prescription dose of bisoprolol fumarate with chitosan, adding sorbitol, uniformly mixing, finally adding low-substituted hydroxypropyl cellulose and talcum powder, uniformly mixing, and pressing into tablets.
Comparative example 1
Fully mixing the prescription dose of bisoprolol fumarate with xylitol, adding low-substituted hydroxypropyl cellulose and talcum powder, uniformly mixing, and pressing into tablets.
Comparative example 2
Adding bisoprolol fumarate, alginic acid, calcium carbonate and lactose with the prescription amount into a No. 22 sieve, mixing and sieving, putting into a mortar, adding starch paste into the mortar, mixing with a pestle, drying, adding magnesium stearate and talcum, mixing, and tabletting the preparation by using a 16-station rotary tablet press to obtain the pharmaceutical composition.
Comparative example 3
Mixing bisoprolol, mannitol, starch and microcrystalline cellulose for 15 minutes, adding magnesium stearate, mixing for 2 minutes, and tabletting.
Comparative example 4
Weighing half of prescription amount of microcrystalline cellulose PH101 and crospovidone and prescription amount of calcium hydrophosphate; mixing, granulating with water, oven drying at 50deg.C for 2 hr, sieving with 30 mesh sieve, mixing the granule with bisoprolol fumarate, silica gel micropowder, magnesium stearate, and the rest microcrystalline cellulose PH101 and crospovidone, and tabletting with 6mm dimple.
Comparative example 5
Weighing the components according to the prescription amount, and sieving bisoprolol fumarate with a 100-mesh sieve; uniformly mixing bisoprolol fumarate, lactose, mannitol 200SD, microcrystalline cellulose, low-substituted hydroxypropyl cellulose and povidone by adopting an equivalent incremental method; adding magnesium stearate with the prescription amount, and uniformly mixing; tabletting, wherein the pressure is controlled to be 1.0-3.0 KN, so that the hardness of the tablet is 40-60N.
Comparative example 6
Adding the prescription dose of bisoprolol fumarate, polyox N12K, carbomer 940P, PVP K-30 and dicalcium phosphate into a mortar, grinding and mixing uniformly, sieving with a No. 60 sieve, adding sodium bicarbonate, magnesium stearate and talcum powder, mixing fully and compressing, and tabletting on a 9-station rotary tablet press by using a 9mm round flat punch to obtain the tablet.
Comparative example 7
Mixing bisoprolol fumarate with lactose, placing into a fluidized bed granulator, preparing 5% ethanol solution of hydroxypropyl cellulose with prescription dose of hydroxypropyl cellulose, spraying, drying the obtained powder in the fluidized bed, sieving with a 22-mesh sieve, adding low-substituted hydroxypropyl cellulose and magnesium stearate, mixing uniformly, and tabletting by using a rotary tablet press to obtain the product.
Comparative example 8
Sequentially sieving bisoprolol fumarate, silicified microcrystalline cellulose, croscarmellose sodium and sodium starch glycolate with a 20-mesh sieve, adding into a double-cone stirrer (15+ -2 rpm), stirring and mixing, sieving magnesium stearate with a 20-mesh sieve, adding into the stirrer, continuously stirring for 5min, and tabletting with a rotary tablet press to obtain the final product.
Comparative example 9
The preparation method comprises the steps of sieving bisoprolol fumarate and corn starch with a 40-mesh sieve together, sieving with anhydrous calcium hydrophosphate together, adding mixed powder into a wet granulating pot, performing wet granulating with a proper amount of water, adding the obtained granules into a fluidized bed, drying until the dry weight loss value is not more than 2%, sieving the dried granules with a 40-mesh sieve, crushing, sieving with a 40-mesh sieve until all the granules can pass through a 40-mesh sieve, sieving microcrystalline cellulose, crospovidone and colloidal silicon dioxide together with a 30-mesh sieve, adding the microcrystalline cellulose, the crospovidone and colloidal silicon dioxide together with the obtained dried granules into a mixing hopper, mixing for 30min, sieving magnesium stearate with a 60-mesh sieve into the mixing hopper, performing total mixing, and tabletting.
Comparative example 10
Mixing microcrystalline cellulose, lactose and starch, adding 50% povidone ethanol solution containing bisoprolol fumarate, stirring, sieving with 20 mesh sieve, granulating, drying at 60deg.C for 30min, sieving with 18 mesh sieve, adding magnesium stearate, mixing, and tabletting.
Comparative example 11
Sieving bisoprolol fumarate and excipient with No. 80 sieve, mixing the medicine and all materials uniformly, and tabletting.
Comparative example 12
Dissolving bisoprolol fumarate in a mixed solvent of methanol and dichloromethane (1:1), pouring a mixture of 4.5 times of ethyl cellulose and 4.5 times of hypromellose into the solvent containing the medicine, stirring uniformly until the solvent is completely evaporated, sieving, and reserving bisoprolol fumarate solid dispersion powder with the particle size of 100-200 mu m for later use. Mixing 50 parts of bisoprolol fumarate solid dispersion with 100-200 μm of auxiliary materials PVP K30, mannitol and aspartame, adding magnesium stearate, mixing uniformly, and tabletting.
Verification embodiment
1. Taste and content uniformity test
Taste testing: the example, comparative example tablets and reference formulation (with the coating removed) were taken for oral ingestion by healthy volunteers and taste assessed.
The content uniformity was examined by referring to the fourth section of the chinese pharmacopoeia 2020 edition <0941 content uniformity inspection method >.
Content uniformity of the whole tablet: taking 10 tablets to be tested (reference preparation Concor needs to remove a coating film), respectively placing each tablet in a 50ml (5 mg specification) measuring flask, adding water to dissolve bisoprolol fumarate, diluting to scale, shaking uniformly, filtering, taking the subsequent filtrate as a sample solution, and measuring the content. Uniformity of the half-chip content: taking 5 tablets to be tested (reference preparation Concor needs to remove a coating film), breaking into two halves along a central notch uniformly, respectively placing into 50ml (5 mg specification) measuring bottles, adding water to dissolve bisoprolol fumarate and dilute to scale, shaking uniformly, filtering, taking the subsequent filtrate as a sample solution, and measuring the content.
Table 1 taste and content uniformity test results
Through experiments, the bisoprolol fumarate composition tablet containing chitosan and xylitol has good taste and content uniformity, and is superior to the composition tablet in the prior art.
2. Stability test
Stability investigation is carried out by referring to the fourth part of the Chinese pharmacopoeia 2020 edition <9001 raw material medicine and preparation stability test guiding principle >.
Acceleration test: tablets obtained in examples and comparative examples and reference preparation Concor (all except for outer package) were taken, placed under the conditions of 40 ℃ + -2 ℃ and 75%RH+ -5%RH for 6 months, sampled and tested for impurity content by HPLC. Three replicates were run and the results averaged.
Related substances HPLC chromatographic conditions: octadecylsilane chemically bonded silica is used as a filler; taking 0.05mol/L ammonium dihydrogen phosphate solution (pH value is adjusted to 5.5 by phosphoric acid) -acetonitrile (70:30) as a mobile phase A, and 0.05mol/L ammonium dihydrogen phosphate solution (pH value is adjusted to 5.5 by phosphoric acid) -acetonitrile (35:65) as a mobile phase B, and performing gradient elution; the flow rate is 1.0ml per minute; column temperature 25 ℃; the detection wavelength is 225nm; the sample volume was 10. Mu.l.
TABLE 2 accelerated test results
Through experiments, the bisoprolol fumarate composition tablet containing chitosan and xylitol has the advantages of insignificant increase of related substances after 6 months of acceleration and excellent stability. Comparative example 4, comparative example 6 and comparative examples 9 and 12 have more initial related substances, probably due to the longer heating time and the wet preparation used in the preparation method of comparative examples 4 and 9, the grinding operation of comparative example 6, and the longer contact time with air.
Claims (10)
1. A bisoprolol fumarate composition tablet, which is characterized by comprising bisoprolol fumarate, chitosan, a filler, a disintegrating agent and a lubricant.
2. Bisoprolol fumarate composition tablet according to claim 1, wherein the filler is xylitol.
3. Bisoprolol fumarate composition tablet according to claim 1, characterized in that the weight ratio of bisoprolol fumarate to chitosan is 1:0.2-1.
4. The bisoprolol fumarate composition tablet of claim 3, wherein the weight ratio of bisoprolol fumarate to chitosan is 1:0.5.
5. bisoprolol fumarate composition tablet according to claim 2, wherein the weight ratio of bisoprolol fumarate to xylitol is 1:15-25; preferably 1:18-23.
6. The bisoprolol fumarate composition tablet of claim 1, wherein the lubricant is one or more of magnesium stearate, calcium stearate, talc, sodium stearate fumarate.
7. The bisoprolol fumarate composition tablet of claim 1, wherein the disintegrant is one or more of sodium carboxymethyl starch, low substituted hydroxypropyl cellulose, and croscarmellose.
8. Bisoprolol fumarate composition tablet according to claim 1, characterized in that it consists of the following raw materials in parts by weight:
9. bisoprolol fumarate composition tablet according to claim 1, characterized in that it consists of the following raw materials in parts by weight:
10. a process for preparing a tablet of bisoprolol fumarate composition as claimed in any one of claims 1 to 9, wherein bisoprolol fumarate is thoroughly mixed with chitosan, and after addition of filler, the mixture is further thoroughly mixed, and finally, a disintegrant and a lubricant are added, and after uniform mixing, the mixture is compressed into tablets.
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