CN102114015A - Solid oral preparation containing telmisartan and preparation method thereof - Google Patents
Solid oral preparation containing telmisartan and preparation method thereof Download PDFInfo
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- CN102114015A CN102114015A CN2010100036433A CN201010003643A CN102114015A CN 102114015 A CN102114015 A CN 102114015A CN 2010100036433 A CN2010100036433 A CN 2010100036433A CN 201010003643 A CN201010003643 A CN 201010003643A CN 102114015 A CN102114015 A CN 102114015A
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- Prior art keywords
- telmisartan
- orally ingestible
- solid orally
- alkaline reagent
- preparation
- Prior art date
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- RMMXLENWKUUMAY-UHFFFAOYSA-N telmisartan Chemical compound CCCC1=NC2=C(C)C=C(C=3N(C4=CC=CC=C4N=3)C)C=C2N1CC(C=C1)=CC=C1C1=CC=CC=C1C(O)=O RMMXLENWKUUMAY-UHFFFAOYSA-N 0.000 title claims abstract description 137
- 239000005537 C09CA07 - Telmisartan Substances 0.000 title claims abstract description 72
- 229960005187 telmisartan Drugs 0.000 title claims abstract description 64
- 239000007787 solid Substances 0.000 title claims abstract description 19
- 238000002360 preparation method Methods 0.000 title abstract description 17
- 238000000034 method Methods 0.000 claims abstract description 29
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 28
- 239000004094 surface-active agent Substances 0.000 claims abstract description 10
- 239000008187 granular material Substances 0.000 claims description 32
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical group [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 27
- 239000000203 mixture Substances 0.000 claims description 25
- 239000012456 homogeneous solution Substances 0.000 claims description 15
- 239000012530 fluid Substances 0.000 claims description 9
- 239000007921 spray Substances 0.000 claims description 8
- 239000007864 aqueous solution Substances 0.000 claims description 7
- 239000003937 drug carrier Substances 0.000 claims description 7
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- 229960003194 meglumine Drugs 0.000 claims description 6
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- 239000000758 substrate Substances 0.000 claims description 5
- 150000008044 alkali metal hydroxides Chemical class 0.000 claims description 4
- 150000001413 amino acids Chemical class 0.000 claims description 4
- 239000003086 colorant Substances 0.000 claims description 3
- 239000000945 filler Substances 0.000 claims description 3
- 239000000314 lubricant Substances 0.000 claims description 3
- 239000004475 Arginine Substances 0.000 claims description 2
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 claims description 2
- 239000002245 particle Substances 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 238000009472 formulation Methods 0.000 claims 1
- 210000001035 gastrointestinal tract Anatomy 0.000 abstract description 5
- 239000013598 vector Substances 0.000 abstract 1
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 14
- 239000000243 solution Substances 0.000 description 11
- 239000008194 pharmaceutical composition Substances 0.000 description 9
- 238000005469 granulation Methods 0.000 description 8
- 230000003179 granulation Effects 0.000 description 8
- 229940101564 micardis Drugs 0.000 description 8
- 238000002156 mixing Methods 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 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 description 7
- 229930195725 Mannitol Natural products 0.000 description 7
- 235000019359 magnesium stearate Nutrition 0.000 description 7
- 239000000594 mannitol Substances 0.000 description 7
- 235000010355 mannitol Nutrition 0.000 description 7
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 7
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 7
- 239000003826 tablet Substances 0.000 description 7
- 229920002261 Corn starch Polymers 0.000 description 6
- 239000008120 corn starch Substances 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- UQSXHKLRYXJYBZ-UHFFFAOYSA-N Iron oxide Chemical compound [Fe]=O UQSXHKLRYXJYBZ-UHFFFAOYSA-N 0.000 description 4
- 239000003513 alkali Substances 0.000 description 4
- 239000001768 carboxy methyl cellulose Substances 0.000 description 4
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 4
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 4
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 4
- 229960003943 hypromellose Drugs 0.000 description 4
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 description 4
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 3
- 229920000881 Modified starch Polymers 0.000 description 3
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 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 3
- 239000011230 binding agent Substances 0.000 description 3
- 238000004132 cross linking Methods 0.000 description 3
- 239000003085 diluting agent Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 3
- 239000008108 microcrystalline cellulose Substances 0.000 description 3
- 229940016286 microcrystalline cellulose Drugs 0.000 description 3
- 229960000502 poloxamer Drugs 0.000 description 3
- 229920001983 poloxamer Polymers 0.000 description 3
- 239000001253 polyvinylpolypyrrolidone Substances 0.000 description 3
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 3
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 3
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 3
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 3
- 238000001694 spray drying Methods 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 206010020772 Hypertension Diseases 0.000 description 2
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 239000012738 dissolution medium Substances 0.000 description 2
- 238000011978 dissolution method Methods 0.000 description 2
- 239000007941 film coated tablet Substances 0.000 description 2
- 210000004051 gastric juice Anatomy 0.000 description 2
- 230000008676 import Effects 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 239000007962 solid dispersion Substances 0.000 description 2
- OKMWKBLSFKFYGZ-UHFFFAOYSA-N 1-behenoylglycerol Chemical compound CCCCCCCCCCCCCCCCCCCCCC(=O)OCC(O)CO OKMWKBLSFKFYGZ-UHFFFAOYSA-N 0.000 description 1
- ILYSAKHOYBPSPC-UHFFFAOYSA-N 2-phenylbenzoic acid Chemical compound OC(=O)C1=CC=CC=C1C1=CC=CC=C1 ILYSAKHOYBPSPC-UHFFFAOYSA-N 0.000 description 1
- 229910002012 Aerosil® Inorganic materials 0.000 description 1
- 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 1
- 229920002134 Carboxymethyl cellulose 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
- 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 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 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 1
- 240000007594 Oryza sativa Species 0.000 description 1
- 235000007164 Oryza sativa Nutrition 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 239000002333 angiotensin II receptor antagonist Substances 0.000 description 1
- 229940126317 angiotensin II receptor antagonist Drugs 0.000 description 1
- 238000006701 autoxidation reaction Methods 0.000 description 1
- 238000005422 blasting Methods 0.000 description 1
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 229940105329 carboxymethylcellulose Drugs 0.000 description 1
- 229940084030 carboxymethylcellulose calcium Drugs 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- 239000006184 cosolvent Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 235000019700 dicalcium phosphate Nutrition 0.000 description 1
- 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 1
- 239000002552 dosage form Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 description 1
- 239000000576 food coloring agent Substances 0.000 description 1
- 229940049654 glyceryl behenate Drugs 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 229940071676 hydroxypropylcellulose Drugs 0.000 description 1
- 230000002427 irreversible effect Effects 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229940045902 sodium stearyl fumarate Drugs 0.000 description 1
- 230000007928 solubilization Effects 0.000 description 1
- 238000005063 solubilization Methods 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
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- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a solid oral preparation without a surfactant. The solid oral preparation comprises the following components in percentage by weight: 5-25% of telmisartan, an alkaline reagent and the balance of pharmaceutically acceptable vectors, wherein the weight of the alkaline reagent is equal to 7-20% of that of telmisartan. The invention also provides a method for preparing the solid oral preparation. The preparation prepared by the method can be quickly and sufficiently released in the psychophysical pH range of gastrointestinal tracts; and compared with the prior art, the preparation method has the advantages that the process is simpler, the quality of the soli oral preparation is more stable, the cost is greatly saved, and the efficiency is improved.
Description
Technical field
The present invention relates to a kind of solid orally ingestible that comprises telmisartan, more specifically relate to the tablet that comprises telmisartan.The present invention also provides the method for preparing tablet of suitable suitability for industrialized production.
Background technology
Telmisartan is a kind of for treating the angiotensin ii receptor antagonist that hypertension and other medical symptoms are developed.Its chemical name is the generalization formal name used at school of 4 '-[2-n-pro-pyl-4-methyl-6-(1-tolimidazole-2-yl) benzimidazole-1-ylmethyl] biphenyl-2-formic acid.The CAS registration number is 144701-48-4.Molecular formula is C
33H
30N
4O
2, its molecular weight is 514.63.Has following structure.
The telmisartan sheet is that commodity are called Micardis by German Boehringer Ingelheim company development product
The preparation specification is the 20mg/40mg/80mg sheet.Micardis
In 1999 in U.S.'s Initial Public Offering, 2002 in China's listing, at present in the listing of a plurality of countries and regions in Britain listing in 2000.Because it has good effect, effect is lasting, side effect is little, the listing back has been subjected to extensive concern on resisting hypertension market.
Telmisartan is usually with sour form manufacturing of freedom and supply.Disclosed as the WO00/43370 patent, the crystallization telmisartan is to exist with two kinds of polycrystalline forms with different melting points.Under the influence of heat and humidity, the irreversible polymorph A that is transformed into higher melt of more low-melting polymorph B.All there is the water solubility of non-constant in two kinds of form features between pH1 to 7 gastrointestinal tract physiological pH scope.
The raw material telmisartan is to provide with the sour form of freedom, and dissolubility is very poor, and in being prepared into the preparation process, existing several different methods is used to improve its dissolubility up to now, and these methods are all reported by pertinent literature and patent.
EP1545467 discloses a kind of pharmaceutical composition, and it has improved the dissolubility of telmisartan greatly.Main dissolubility substrate is alkaline reagent, surfactant and most water-soluble diluent in its described pharmaceutical composition.This patent has proposed tablet and capsular dosage form simultaneously, and fluidized bed granulation and spray-drying process are set forth.Surfactant poloxamer and most water-soluble diluent in the described pharmaceutical composition of this patent are absolutely necessary.
WO2007061415 discloses a kind of pharmaceutical composition of telmisartan, and it has improved the dissolubility of telmisartan greatly.Mainly comprise telmisartan, alkaline reagent, surfactant in its described pharmaceutical composition and be less than the water-soluble diluent of 25% weight.The described surfactant of this patent is absolutely necessary.
CN200710041363.X discloses a kind of pharmaceutical composition of telmisartan, and it has improved the dissolubility of telmisartan greatly.Its described pharmaceutical composition mainly comprises telmisartan, alkaline reagent and polyvidone, and this patent is also set forth fluid bed preparation technology.This method is by being dissolved in the dissolubility that the method for making solid dispersion is together improved telmisartan with telmisartan, alkaline reagent and polyvidone.Telmisartan, alkaline reagent and polyvidone three must be dissolved in and form solution together and carry out pelletize again in this method, and this method neutral and alkali reagent dosage is more, the inclined to one side alkali of gastric juice can take place after the patient takes unavoidably cause dyspeptic phenomenon.
Document " telmisartan Film coated tablets preparation technology's research " (Tian Jingxuan, Wei Jianping. modern biomedical progress, 2006,6 (10): 42-45) proposed the prescription of stable telmisartan Film coated tablets, it adopts the alkaline reagent solubilising, and adopts spray-drying process.What adopt when the document prepares telmisartan tablet is the spray drying process of relatively wasting time and energy.
Summary of the invention
The object of the present invention is to provide a kind of solid orally ingestible that contains telmisartan, it does not need surface active agent solubilization just can make active substance quick and complete stripping of energy in gastrointestinal tract pH value environment, and steady quality adopts common fluidized bed granulation method to prepare.
In practice process, the inventor finds that telmisartan has relatively poor dissolubility in gastrointestinal tract pH scope, must add suitable cosolvent such as alkaline reagent or alkaline reagent and surfactant to improve its dissolubility.Surfactant poloxamer among the patent EP1545467 can increase the dissolubility of telmisartan greatly, but poloxamer is usually used in injectable emulsion and the various gel, is not the adjuvant commonly used of tablet.Patent CN200710041363.X can improve for the rice stripping as the binding agent process for granulating really preferably by telmisartan, alkaline reagent and polyvidone being dissolved in together in aqueous solution or the alcohol-water solution, but this method also exists two to select deficiency: at first used more alkaline reagent in this method, the inclined to one side alkali of gastric juice can take place after the patient takes unavoidably cause dyspeptic phenomenon; Secondly inventor's aqueous solution thickness comparatively of finding telmisartan and alkaline reagent in practice, add the viscosity that polyvidone then can aggravate this solution again, and adopt this heavy-gravity solution to carry out fluidized bed prilling is very difficult, the careless slightly bed that collapses that promptly can cause causes the pelletize failure in the technical process, address this problem and have only two kinds of methods, a kind of is dilute aqueous solution, to lower solution viscosity, can cause the fluidized bed prilling time lengthening but do like this, lose the time saving and energy saving advantage of fluidized bed prilling; Another kind is to be about to telmisartan, alkaline reagent and polyvidone as the method for optimizing in the patent be dissolved in jointly in the high alcohol-water solution, this method no doubt can lower solution viscosity greatly, but owing to used the ethanol pelletize of high dose, increased the risk of blasting in producing, equipment and workshop have all been had higher requirement.
By practice, if the inventor find to regulate prescription neutral and alkali reagent dosage telmisartan weight 7～20% between, promptly can increase the dissolubility of telmisartan in water fully, to satisfy the needs of fluidized bed granulation, and need not to increase again extra alkaline reagent or binding agent, the granulation solution of this improvement prescription has lower viscosity than the disclosed granulation solution of CN200710041363.X, and does not have the risk of organic solvent blast.According to the present invention, adopt the technology controlling and process of fluidized bed granulation fairly simple, the granulation time is short, and efficient is higher.And can make the tablet that active substance can fully discharge fast in gastrointestinal tract physiological pH scope, and this tablet has better stability at storage process.
Based on above situation, the invention provides a kind of solid orally ingestible that contains telmisartan, it does not need to become solid dispersion by the surfactant hydrotropy or with medication preparation, only needs to add a spot of alkaline reagent and an amount of disintegrating agent, adopts common fluidized bed granulation method to prepare.This solid orally ingestible comprises 5～25% the telmisartan in the substrate of being scattered in, and described substrate comprises: the alkaline reagent that (a) is equivalent to telmisartan weight 7～20%; (b) and other pharmaceutically acceptable carriers, above all the components sum is 100%.
According to the preferred embodiments of the invention, the ratio that the telmisartan consumption is equivalent to the pharmaceutical composition gross weight is 5～25%, is preferably 10～22%, more preferably 14～19%, be preferably 16～17%.
Suitable alkaline reagent of the present invention can be selected from one or more in alkali metal hydroxide or the basic amino acid.In alkaline reagent of the present invention, alkali metal hydroxide can be selected from sodium hydroxide, potassium hydroxide or both mixture; Basic amino acid can be selected from meglumine (N-methyl D-glycosamine), arginine or both mixture.Alkaline reagent according to a preferred embodiment of the present invention is a sodium hydroxide.
According to the preferred embodiments of the invention, the alkaline reagent consumption is to be equivalent to 7～20% of telmisartan weight, is 8～18% preferably, better is 9～15%, and best is 10～13%.
In the suitable optional Autoadhesive of other pharmaceutically acceptable carriers of the present invention, filler, disintegrating agent, lubricant, fluidizer, the coloring agent one or more.
According to the present invention, described filler can be selected from one or more in xylitol, sorbitol, mannitol, lactose, corn starch, pregelatinized Starch, microcrystalline Cellulose, Powderd cellulose, the calcium hydrogen phosphate.
According to the present invention, described binding agent can be selected from one or more in hypromellose, hydroxypropyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, vinylpyrrolidone vinyl acetate co-polymer (copolyvidone), the pregelatinized Starch.
According to the present invention, one or more in the optional self-crosslinking polyvidone of described disintegrating agent, carboxymethylcellulose calcium, cross-linking sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, carboxymethyl starch sodium, corn starch, the partially pregelatinized starch.According to the present invention, add, add in the adding mode of disintegrating agent can be selected or in add.
According to the present invention, described lubricant can be selected from one or more in stearic acid, magnesium stearate, calcium stearate, sodium stearyl fumarate, the Glyceryl Behenate.
According to the present invention, described fluidizer can be selected from one or more in aerosil, Pulvis Talci, the silicon dioxide.
According to the present invention, one or more in the optional autoxidation iron oxide red of described coloring agent, iron oxide yellow, food coloring, the titanium dioxide.
According to the preferred embodiments of the invention, the total consumption of wherein pharmaceutically acceptable carrier is to be equivalent to 70～90% of pharmaceutical composition gross weight, and more excellent is 75～88%, and more excellent is 78～85%, and optimum is 79～83%.
Another object of the present invention is to provide a kind of preparation method that contains the solid orally ingestible of telmisartan, described method comprises: (a) telmisartan, alkaline reagent are dissolved in the aqueous solution, obtain homogeneous solution, (b) pharmaceutically acceptable carrier is sieved mix and be placed in the fluid bed, spray is granulated with above-mentioned solution and is dry, (c) the gained dried particles is sieved add the pharmaceutic adjuvant mix homogeneously of Extra Section behind the granulate, carry out tabletting then.
Description of drawings:
Fig. 1 is illustrated in the pH1.0 hydrochloric acid medium, according to the same Micardis of telmisartan sheet of embodiments of the invention 1 preparation
The stripping property of telmisartan sheet is verified and is compared.
Fig. 2 is illustrated in the pH7.5 phosphate-buffered liquid medium, according to the same Micardis of telmisartan sheet of embodiments of the invention 1 preparation
The stripping property of telmisartan sheet is verified and is compared.
The specific embodiment:
In order better to understand the present invention, provide some one exemplary embodiment below as a reference, but the present invention is not limited to following examples.
Embodiment 1:
Telmisartan, 15.5g sodium hydroxide and the 8.5g meglumine of 200g be dissolved in the 200g water jointly obtain homogeneous solution; 60g hypromellose, 681.8g mannitol, 180g corn starch, 36.0g polyvinylpolypyrrolidone are crossed φ 2.0mm rotary screen mix, obtain granulate mixture; Granulate mixture is placed fluid bed, and spray obtains wet granular with above-mentioned homogeneous solution; 60 ℃ of dry backs of wet granular are crossed φ 2.0mm rotary screen granulate and are obtained dried granule; Tabletting behind the dried granule adding magnesium stearate mixing.
According to dissolution method (2005 editions appendix XC second methods of Chinese Pharmacopoeia), be dissolution medium with the pH1.0 hydrochloric acid solution of 900ml, rotating speed is 75rpm, to embodiment 1 slice, thin piece and import telmisartan sheet (Micardis
, manufacturer: carry out stripping German Boehringer Ingelheim company) and measure, measurement result sees Table 1 and Fig. 1.
Table 1:
According to dissolution method (2005 editions appendix XC second methods of Chinese Pharmacopoeia), be dissolution medium with the pH7.5 phosphate buffer of 900ml, rotating speed is 75rpm, to embodiment 1 slice, thin piece and import telmisartan sheet (Micardis
, manufacturer: carry out stripping German Boehringer Ingelheim company) and measure, measurement result sees Table 2 and Fig. 2.
Table 2:
The comparative study of stripping curve shows, according to the Micardis of selling on telmisartan sheet of the present invention and the market
The telmisartan sheet has identical external stripping behavior.
Embodiment 2
Telmisartan, the 14.0g sodium hydroxide of 200g be dissolved in about 400g water jointly obtain homogeneous solution; The common φ of mistake of 8g hypromellose, 214g mannitol, 320g microcrystalline Cellulose and 40g cross-linking sodium carboxymethyl cellulose 2.0mm rotary screen is mixed, obtain granulate mixture; Granulate mixture is placed fluid bed, and spray obtains wet granular with above-mentioned homogeneous solution; 60 ℃ of dry backs of wet granular are crossed φ 2.0mm rotary screen granulate and are obtained dried granule; Dried granule adds tabletting behind the above-mentioned magnesium stearate mixing.
Embodiment 3
Telmisartan, 16.0g sodium hydroxide and the 24.0g meglumine of 200g be dissolved in about 400g water jointly obtain homogeneous solution; The common φ of mistake of 2048g mannitol, 1600g microcrystalline Cellulose and 40.0g polyvinylpolypyrrolidone 2.0mm rotary screen is mixed, obtain granulate mixture; Granulate mixture is placed fluid bed, and spray obtains wet granular with above-mentioned homogeneous solution; 60 ℃ of dry backs of wet granular are crossed φ 2.0mm rotary screen granulate and are obtained dried granule; Dried granule adds tabletting behind the above-mentioned magnesium stearate mixing.
Embodiment 4
Telmisartan, the 20.0g sodium hydroxide of 200g be dissolved in about 400g purified water jointly obtain homogeneous solution; 874g mannitol, 200g corn starch are crossed φ 2.0mm rotary screen mix, obtain granulate mixture; Granulate mixture is placed fluid bed, and spray obtains wet granular with above-mentioned homogeneous solution; 60 ℃ of dry backs of wet granular are crossed φ 2.0mm rotary screen granulate and are obtained dried granule; Dried granule adds above-mentioned magnesium stearate mixing tabletting after adding 15g polyvinylpolypyrrolidone mixing again.
Embodiment 5
Telmisartan, 15.5g sodium hydroxide, the 10.5g meglumine of 200g be dissolved in about 400g purification of aqueous solutions jointly obtain homogeneous solution; 71g hypromellose, 386g mannitol, 129g corn starch and 353g low-substituted hydroxypropyl cellulose are crossed φ 2.0mm rotary screen mix, obtain granulate mixture; Granulate mixture is placed fluid bed, and spray obtains wet granular with above-mentioned homogeneous solution; 60 ℃ of dry backs of wet granular are crossed φ 2.0mm rotary screen granulate and are obtained dried granule; Dried granule adds tabletting behind the above-mentioned magnesium stearate mixing.
Embodiment 6
Telmisartan, 15.5g sodium hydroxide and the 10.5g meglumine of 200g be dissolved in about 400g purification of aqueous solutions jointly obtain homogeneous solution; 48g copolyvidone, 544g mannitol, 182g corn starch and 97g low-substituted hydroxypropyl cellulose are crossed φ 2.0mm rotary screen mix, obtain granulate mixture; Granulate mixture is placed fluid bed, and spray obtains wet granular with above-mentioned homogeneous solution; 60 ℃ of dry backs of wet granular are crossed φ 2.0mm rotary screen granulate and are obtained dried granule; Dried granule adds and adds tabletting behind the above-mentioned magnesium stearate mixing behind the 97g low-substituted hydroxypropyl cellulose mixing again.
Embodiment 7
With embodiment 1 slice, thin piece and Micardis
Sheet was directly exposed to 60 ℃ and two kinds of environment of 75% humidity respectively following 10 days, and the result shows that embodiment 1 has better appearance stability, the results are shown in Table 3.
Table 3:
Claims (8)
1. solid orally ingestible that does not contain surfactant, it is characterized in that: it comprises the telmisartan in the substrate of being scattered in that is equivalent to total formulation weight amount 5～25%, and wherein said substrate comprises: the alkaline reagent that (a) is equivalent to telmisartan weight 7～20%; (b) and other pharmaceutically acceptable carriers, above all the components sum is 100%.
2. the solid orally ingestible that comprises telmisartan as claimed in claim 1 is characterized in that described alkaline reagent is selected from one or more in alkali metal hydroxide, the basic amino acid.
3. the solid orally ingestible that comprises telmisartan as claimed in claim 2 is characterized in that described alkali metal hydroxide is selected from sodium hydroxide, potassium hydroxide or both mixture.
4. the solid orally ingestible that comprises telmisartan as claimed in claim 2 is characterized in that described basic amino acid is selected from meglumine (N-methyl D-glycosamine), arginine or both mixture.
5. the solid orally ingestible that comprises telmisartan as claimed in claim 1 is characterized in that the alkaline reagent consumption is to be equivalent to 8～18% of telmisartan weight, preferably 9～15%, be more preferably 10～13%.
6. the solid orally ingestible that comprises telmisartan as claimed in claim 1 is characterized in that in the optional Autoadhesive of described pharmaceutically acceptable carrier, filler, disintegrating agent, lubricant, fluidizer, the coloring agent one or more.
7. the solid orally ingestible that comprises telmisartan as claimed in claim 1 is characterized in that described solid orally ingestible is a tablet.
8. one kind prepares the method that comprises the solid orally ingestible of telmisartan as claimed in claim 1, may further comprise the steps: (a) telmisartan, alkaline reagent are dissolved in the aqueous solution, obtain homogeneous solution, (b) pharmaceutically acceptable carrier is sieved mix and be placed in the fluid bed, spray is granulated with above-mentioned homogeneous solution, and dry, (c) the gained dried particles is sieved add the pharmaceutic adjuvant mix homogeneously of Extra Section behind the granulate, carry out tabletting then.
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| CN103271908A (en) * | 2013-05-23 | 2013-09-04 | 浙江华海药业股份有限公司 | Oral tablet containing telmisartan and amlodipine besylate and preparation method thereof |
| CN104826115A (en) * | 2015-04-19 | 2015-08-12 | 浙江巨泰药业有限公司 | Anti-heart failure pharmaceutical composition and preparation method thereof |
| JP2017025043A (en) * | 2015-07-27 | 2017-02-02 | エルメッド エーザイ株式会社 | Telmisartan-containing pharmaceutical composition |
| CN107811984A (en) * | 2017-12-13 | 2018-03-20 | 南京双科医药开发有限公司 | A kind of preparation method of telmisartan tablet |
| CN107982232A (en) * | 2018-01-29 | 2018-05-04 | 威特(湖南)药业有限公司 | Telmisartan Tablets and preparation method thereof |
| CN110934848A (en) * | 2019-12-20 | 2020-03-31 | 江西杏林白马药业有限公司 | Telmisartan capsule and preparation method thereof |
| CN111265488A (en) * | 2020-03-18 | 2020-06-12 | 重庆康刻尔制药有限公司 | Telmisartan tablets and preparation method thereof |
| CN111700866A (en) * | 2020-06-30 | 2020-09-25 | 重庆康刻尔制药有限公司 | Preparation method of telmisartan tablets |
| CN115245497A (en) * | 2021-04-26 | 2022-10-28 | 武汉伯睿科医药科技有限公司 | Telmisartan capsule and preparation process thereof |
| WO2023108895A1 (en) * | 2021-12-14 | 2023-06-22 | 上海现代制药股份有限公司 | Telmisartan oral solid preparation with stable product performance, and preparation method therefor |
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| CN104826115A (en) * | 2015-04-19 | 2015-08-12 | 浙江巨泰药业有限公司 | Anti-heart failure pharmaceutical composition and preparation method thereof |
| JP2017025043A (en) * | 2015-07-27 | 2017-02-02 | エルメッド エーザイ株式会社 | Telmisartan-containing pharmaceutical composition |
| CN107811984A (en) * | 2017-12-13 | 2018-03-20 | 南京双科医药开发有限公司 | A kind of preparation method of telmisartan tablet |
| CN107982232A (en) * | 2018-01-29 | 2018-05-04 | 威特(湖南)药业有限公司 | Telmisartan Tablets and preparation method thereof |
| CN110934848A (en) * | 2019-12-20 | 2020-03-31 | 江西杏林白马药业有限公司 | Telmisartan capsule and preparation method thereof |
| CN110934848B (en) * | 2019-12-20 | 2022-02-15 | 江西杏林白马药业股份有限公司 | Telmisartan capsule and preparation method thereof |
| CN111265488A (en) * | 2020-03-18 | 2020-06-12 | 重庆康刻尔制药有限公司 | Telmisartan tablets and preparation method thereof |
| CN111265488B (en) * | 2020-03-18 | 2021-11-12 | 重庆康刻尔制药股份有限公司 | Telmisartan tablets and preparation method thereof |
| CN111700866A (en) * | 2020-06-30 | 2020-09-25 | 重庆康刻尔制药有限公司 | Preparation method of telmisartan tablets |
| CN115245497A (en) * | 2021-04-26 | 2022-10-28 | 武汉伯睿科医药科技有限公司 | Telmisartan capsule and preparation process thereof |
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