CN104688696A - Pharmaceutical composition containing candesartan cilexetil - Google Patents
Pharmaceutical composition containing candesartan cilexetil Download PDFInfo
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- CN104688696A CN104688696A CN201310641049.0A CN201310641049A CN104688696A CN 104688696 A CN104688696 A CN 104688696A CN 201310641049 A CN201310641049 A CN 201310641049A CN 104688696 A CN104688696 A CN 104688696A
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- Prior art keywords
- candesartan cilexetil
- pharmaceutical composition
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- mesh sieves
- mixture
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- GHOSNRCGJFBJIB-UHFFFAOYSA-N Candesartan cilexetil Chemical compound C=12N(CC=3C=CC(=CC=3)C=3C(=CC=CC=3)C3=NNN=N3)C(OCC)=NC2=CC=CC=1C(=O)OC(C)OC(=O)OC1CCCCC1 GHOSNRCGJFBJIB-UHFFFAOYSA-N 0.000 title claims abstract description 97
- 229960004349 candesartan cilexetil Drugs 0.000 title claims abstract description 93
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 23
- ILRRQNADMUWWFW-UHFFFAOYSA-K aluminium phosphate Chemical compound O1[Al]2OP1(=O)O2 ILRRQNADMUWWFW-UHFFFAOYSA-K 0.000 claims abstract description 39
- 239000000314 lubricant Substances 0.000 claims abstract description 11
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 9
- 239000000203 mixture Substances 0.000 claims description 43
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 26
- 229920002472 Starch Polymers 0.000 claims description 22
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 22
- 239000000741 silica gel Substances 0.000 claims description 22
- 229910002027 silica gel Inorganic materials 0.000 claims description 22
- 239000008107 starch Substances 0.000 claims description 22
- 235000019698 starch Nutrition 0.000 claims description 22
- 238000002360 preparation method Methods 0.000 claims description 18
- 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 14
- 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 14
- 239000001768 carboxy methyl cellulose Substances 0.000 claims description 14
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 claims description 14
- 238000004132 cross linking Methods 0.000 claims description 14
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 claims description 14
- 239000011734 sodium Substances 0.000 claims description 14
- 229910052708 sodium Inorganic materials 0.000 claims description 14
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 claims description 14
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 claims description 14
- 238000007907 direct compression Methods 0.000 claims description 13
- 238000013467 fragmentation Methods 0.000 claims description 13
- 238000006062 fragmentation reaction Methods 0.000 claims description 13
- 239000008187 granular material Substances 0.000 claims description 13
- 238000001291 vacuum drying Methods 0.000 claims description 13
- 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 11
- 235000019359 magnesium stearate Nutrition 0.000 claims description 11
- 238000007873 sieving Methods 0.000 claims description 7
- 239000002053 C09CA06 - Candesartan Substances 0.000 claims description 5
- 229960000932 candesartan Drugs 0.000 claims description 5
- 239000007884 disintegrant Substances 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- 238000004090 dissolution Methods 0.000 abstract description 3
- 239000003814 drug Substances 0.000 abstract description 2
- GUBGYTABKSRVRQ-DCSYEGIMSA-N Beta-Lactose Chemical compound OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-DCSYEGIMSA-N 0.000 abstract 1
- 238000009776 industrial production Methods 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 15
- 238000012360 testing method Methods 0.000 description 14
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- 238000000034 method Methods 0.000 description 9
- PBCJIPOGFJYBJE-UHFFFAOYSA-N acetonitrile;hydrate Chemical compound O.CC#N PBCJIPOGFJYBJE-UHFFFAOYSA-N 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Chemical compound 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 6
- 239000012535 impurity Substances 0.000 description 6
- 238000004811 liquid chromatography Methods 0.000 description 5
- 239000013558 reference substance Substances 0.000 description 5
- CWRYPZZKDGJXCA-UHFFFAOYSA-N acenaphthene Chemical compound C1=CC(CC2)=C3C2=CC=CC3=C1 CWRYPZZKDGJXCA-UHFFFAOYSA-N 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 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 3
- 229930195725 Mannitol Natural products 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 229960000583 acetic acid Drugs 0.000 description 3
- 239000011230 binding agent Substances 0.000 description 3
- 239000012362 glacial acetic acid Substances 0.000 description 3
- 239000000594 mannitol Substances 0.000 description 3
- 235000010355 mannitol Nutrition 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- -1 phosphoric acid aluminum Chemical compound 0.000 description 3
- XUKUURHRXDUEBC-SXOMAYOGSA-N (3s,5r)-7-[2-(4-fluorophenyl)-3-phenyl-4-(phenylcarbamoyl)-5-propan-2-ylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-SXOMAYOGSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 229920001213 Polysorbate 20 Polymers 0.000 description 2
- HXGDTGSAIMULJN-UHFFFAOYSA-N acetnaphthylene Natural products C1=CC(C=C2)=C3C2=CC=CC3=C1 HXGDTGSAIMULJN-UHFFFAOYSA-N 0.000 description 2
- 230000003276 anti-hypertensive effect Effects 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 2
- 125000002933 cyclohexyloxy group Chemical group C1(CCCCC1)O* 0.000 description 2
- 239000012738 dissolution medium Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000000945 filler Substances 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 238000005286 illumination Methods 0.000 description 2
- 230000014759 maintenance of location Effects 0.000 description 2
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 2
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 2
- 229940068977 polysorbate 20 Drugs 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000009825 accumulation Methods 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
- 229940003145 candesartan cilexetil 4 mg Drugs 0.000 description 1
- 229940003097 candesartan cilexetil 8 mg Drugs 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000011978 dissolution method Methods 0.000 description 1
- 238000007922 dissolution test Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000010812 external standard method Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
Abstract
The invention specifically relates to a pharmaceutical composition containing candesartan cilexetil, belonging to the field of medicine. The pharmaceutical composition contains candesartan cilexetil, a disintegrating agent, a lubricant, lactose anhydrous and aluminum phosphate. The pharmaceutical composition has good stability, complete dissolution and more excellent quality; and a production method for the pharmaceutical composition is easy and practical to operate and applicable to industrial production.
Description
Technical field
The invention belongs to medical art, be specifically related to a kind of containing the pharmaceutical composition of candesartan Cilexetil and the preparation method of tablet thereof.
Background technology
Candesartan is a kind of novel Angiotensin II receptor antagonist, and this drug selectivity ground blocks the effect of AngII in circulation and tissue, and antihypertensive effect is remarkable.Candesartan Cilexetil is the prodrug of Candesartan, can complete hydrolysis and change into the Candesartan with antihypertensive active in the gastrointestinal tract.
Candesartan Cilexetil is white or off-white color crystalline powder; Easily molten in chloroform, dissolve in acetone, slightly molten in methanol, slightly soluble in ethanol, almost insoluble in water.Candesartan Cilexetil is to heat, moisture-sensitive, and in oral formulations preparation, the water of trace also may cause candesartan Cilexetil to decompose.Takede Chemical Industries Ltd fully mixes with candesartan Cilexetil by adding low melting point oiliness compound (ZL93100008.4), and wrap up candesartan Cilexetil and form the hydrophobic layer that can press, avoid its granulate and in tableting processes because of high pressure friction etc. produce the candesartan Cilexetil decomposition that the minor amount of water in heat and adjuvant causes.
Summary of the invention
Object of the present invention provides a kind of pharmaceutical composition containing candesartan Cilexetil newly, and said composition makes conventional tablet.
Object of the present invention provides a kind of pharmaceutical composition containing candesartan Cilexetil newly, and should contain the good stability of the pharmaceutical composition of candesartan Cilexetil, stripping is complete.
Another object of the present invention is the preparation method providing a kind of pharmaceutical composition containing candesartan Cilexetil, and the method is applicable to commercial production.
Specifically, the invention provides:
A pharmaceutical composition containing candesartan Cilexetil, contains: candesartan Cilexetil, disintegrating agent, lubricant, Lactis Anhydrous and aluminum phosphate.
The described pharmaceutical composition containing candesartan Cilexetil is tablet.
The described pharmaceutical composition containing candesartan Cilexetil, the weight ratio of each component is:
Candesartan Cilexetil 10 ~ 40 weight portion
Disintegrating agent 4 ~ 20 weight portion
Lubricant 1 ~ 5 weight portion
Lactis Anhydrous 35 ~ 85 weight portion
Aluminum phosphate 12 ~ 15 weight portion.
Described disintegrating agent is selected from one or more in dried starch, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, crospolyvinylpyrrolidone, cross-linking sodium carboxymethyl cellulose.
Described lubricant is selected from one or more in micropowder silica gel, Pulvis Talci, magnesium stearate.
The described pharmaceutical composition containing candesartan Cilexetil is prepared into tablet, and its preparation method comprises the following steps:
(1), after being mixed by the Lactis Anhydrous of the candesartan Cilexetil of 10 ~ 40 weight portions, 35 ~ 85 weight portions, microwave vacuum drying is carried out;
(2) step (1) gained candesartan Cilexetil and Lactis Anhydrous mixture are carried out fragmentation, cross 80 ~ 100 mesh sieves, for subsequent use;
(3) after 12 ~ 15 parts by weight of phosphoric acid aluminum, 4 ~ 20 part by weight of disintegrant, 1 ~ 5 weight portion lubricant being crossed 80 ~ 100 mesh sieves respectively, for subsequent use;
(4) by 12 ~ 15 parts by weight of phosphoric acid aluminum, disintegrating agent, the lubricant after sieving, the mixture of step (2) gained is poured in mixer and is mixed;
(5) mixture of step (4) is carried out low temperature to pulverize at a slow speed, cross 80 ~ 100 mesh sieves;
(6) the granule direct compression of step (5) gained is obtained candesartan cilexetil.
The present invention compared with prior art has the following advantages and good effect:
1, product stability of the present invention is good, and stripping is complete.
2, operation is simple for production of the present invention, is suitable for commercial production.
Detailed description of the invention
Below by way of the description of detailed description of the invention, the invention will be further described, but this is not limitation of the present invention, those skilled in the art are according to basic thought of the present invention, various amendment or improvement can be made, but only otherwise depart from basic thought of the present invention, all within the scope of the present invention.
Test method
Dissolution gets candesartan cilexetil, according to dissolution method (Chinese Pharmacopoeia version in 2010 two annex Ⅹ C second methods), be dissolution medium with 0.35% polysorbate 20 phosphate buffer (pH6.5) (get potassium dihydrogen phosphate 0.68g, polysorbate 20 0.35g, add 0.1mol/L sodium hydroxide solution 15.2ml, add water to 100ml) 900ml, rotating speed is 50 turns per minute, operate in accordance with the law, through 45 minutes time, get solution and filter, discard just filtrate 10ml, get subsequent filtrate as need testing solution; Separately get candesartan Cilexetil reference substance and be about 10mg, accurately weighed, put in 50ml measuring bottle, add acetonitrile and dissolve and be diluted to scale, shake up, precision measures 1ml, puts in 25ml measuring bottle, is diluted to scale with dissolution medium, shake up, in contrast product solution.Precision measures need testing solution and each 10 μ l of reference substance solution, measures, calculate the stripping quantity of every sheet according to the method under assay item.
Related substance gets candesartan cilexetil fine powder appropriate (being about equivalent to candesartan Cilexetil 8mg), put in 20ml measuring bottle, add acetonitrile-water (3:2) appropriate, supersound process 10 minutes, makes candesartan Cilexetil dissolve, lets cool, scale is diluted to acetonitrile-water (3:2), shake up, filter, get subsequent filtrate as need testing solution; Precision measures 1ml, puts in 100ml measuring bottle, is diluted to scale, shakes up, in contrast solution with acetonitrile-water (3:2).Separately get candesartan Cilexetil system suitability reference substance 5mg(and contain impurity A, B and F), put in 10ml measuring bottle, add acetonitrile-water (3:2) and dissolve and be diluted to scale, shake up, as system suitability solution.Test according to high performance liquid chromatography (Chinese Pharmacopoeia version in 2010 two annex V D).Be filler (Waters Nove-Pak 3.9mm × 150mm, 4 μm) with octadecylsilane chemically bonded silica; With acetonitrile-water-glacial acetic acid (57:43:1) for mobile phase A, with acetonitrile-water-glacial acetic acid (90:10:1) for Mobile phase B, carry out gradient elution, determined wavelength is 254nm.Get system suitability solution 10 μ l injection liquid chromatography, peak sequence is impurity A, impurity B, candesartan Cilexetil, impurity F (relative retention time is respectively 0.4,0.5,1.0,2.0), and candesartan Cilexetil retention time is about 11 minutes; Number of theoretical plate calculates by candesartan Cilexetil peak and is not less than 3000, and the separating degree of impurity A and B should be not less than 4; Precision measures need testing solution and each 10 μ l of contrast solution, respectively injection liquid chromatography, record chromatogram.
Impurity A:
Chinese name: ethyl 2-ethyoxyl-1-[[2'-(1H-tetrazolium-5-base) biphenyl-4-base] methyl]-1H-benzimidazole-7-carboxylic acid, ethyl ester
Impurity B:
Chinese name: (1RS)-1-[[(cyclohexyloxy) carbonyl] oxygen] ethyl-2-oxo-3-[[2'-(1H-tetrazolium-5-base) biphenyl-4-base] methyl]-2,3-dihydro-1H-benzimidazole-4-t-butyl formates.
Impurity F:
Chinese name: (1RS)-1-[[(cyclohexyloxy) carbonyl] oxygen] ethyl-2-ethyoxyl-1-[[2'-(2-ethyl-2H-tetrazolium-5-base) biphenyl-4-base] methyl]-1H-benzimidazole-7-carboxylic acid, ethyl ester
Assay measures according to high effective liquid chromatography for measuring (Chinese Pharmacopoeia version in 2010 two annex V D).
Chromatographic condition and system suitability octadecylsilane chemically bonded silica are filler; With acetonitrile-water-glacial acetic acid (57:43:1) for mobile phase; Determined wavelength is 254nm; Get system suitability solution (get acenaphthene 0.2g, accurately weighed, put in 100ml measuring bottle, make dissolving with acetonitrile and be diluted to scale, shaking up; Separately get candesartan Cilexetil reference substance and be about 10mg, accurately weighed, put in 50ml measuring bottle, make dissolving with acetonitrile and be diluted to scale, shaking up, precision measures acenaphthene solution 5ml, Candesartan ester solution 20ml with putting in 100ml measuring bottle respectively, scale is diluted to acetonitrile-water (3:2), shake up, precision measures 10 μ l injection liquid chromatographies, record chromatogram.
Algoscopy gets this product 20, accurately weighed, porphyrize, precision takes in right amount (being about equivalent to candesartan Cilexetil 4mg), puts in 100ml measuring bottle, adds acetonitrile-water (3:2) appropriate, supersound process 10 minutes, candesartan Cilexetil is dissolved, lets cool, be diluted to scale with acetonitrile-water (3:2), shake up, filter, precision measures subsequent filtrate 10 μ l injection liquid chromatography, record chromatogram; Separately get candesartan Cilexetil reference substance and be about 10mg, accurately weighed, put in 50ml measuring bottle, add acetonitrile and dissolve and be diluted to scale, shake up, precision measures 5ml, puts in 25ml measuring bottle, is diluted to scale with acetonitrile-water (3:2), shake up, be measured in the same method, by external standard method with calculated by peak area, to obtain final product.
Test example 1: binding agent screens
Get candesartan Cilexetil 30g(content 99.9% respectively, always mix 0.09%), Lactis Anhydrous 70g, cross-linking sodium carboxymethyl cellulose 8g, micropowder silica gel 3g, aluminum phosphate 15g, by following formula preparation candesartan Cilexetil tablet.
Table 1 Formulation-binding agent screening
Preparation method:
(1), after being mixed by the Lactis Anhydrous of the candesartan Cilexetil of 30g, 70g, microwave vacuum drying is carried out;
(2) step (1) gained candesartan Cilexetil and milk-sugar mixture are carried out fragmentation, cross 80 mesh sieves, for subsequent use;
(3) after 15g aluminum phosphate, 8g cross-linking sodium carboxymethyl cellulose, 3g micropowder silica gel being crossed 80 ~ 100 mesh sieves respectively, for subsequent use;
(4) by the 15g aluminum phosphate after sieving, 8g cross-linking sodium carboxymethyl cellulose, 3g micropowder silica gel, the mixture of step (2) gained is poured in mixer and is mixed;
(5) mixture of step (4) is carried out low temperature to pulverize at a slow speed, cross 100 mesh sieves;
(6) by the granule direct compression of step (5) gained, candesartan cilexetil is obtained.
The results are shown in Table 2.
Table 2 dissolution test result
As seen from the above table, when selecting aluminum phosphate as binding agent, the accumulation dissolution of different time keeps stable, illustrates, and equal constant product quality of gained of the present invention more than 95%, result of extraction is good.
Test example 2: influence factor tests
Example 3,5,6,8 product carries out influence factor's test, the results are shown in Table 3.
Table 3 influence factor test data
Conclusion: road as seen from the above table, the product prepared by the inventive method, the stability under high temperature and illumination is very outstanding.
Test example 3: accelerated test
Example 3,5,6,8 product carries out accelerated test, the results are shown in Table 4.
Table 4 accelerated test data
Packaging: commercially available back, investigates condition: temperature 40 DEG C, humidity 75%
Conclusion: road as seen from the above table, the product prepared by the inventive method, the stability under high temperature and illumination is outstanding.
Preparation example
Embodiment 1
Prescription
Candesartan Cilexetil 10g
Lactis Anhydrous 50g
Dried starch 4g
Micropowder silica gel 1.8g
Aluminum phosphate 13.6g.
Preparation method
(1), after being mixed by the Lactis Anhydrous of the candesartan Cilexetil of 10g, 50g, microwave vacuum drying is carried out;
(2) step (1) gained candesartan Cilexetil and Lactis Anhydrous mixture are carried out fragmentation, cross 80 mesh sieves, for subsequent use;
(3) after 13.6g aluminum phosphate, 4g dried starch, 1.8g micropowder silica gel being crossed 80 mesh sieves respectively, for subsequent use;
(4) aluminum phosphate after step (3) being sieved, dried starch, micropowder silica gel, the mixture of step (2) gained is poured in mixer and is mixed;
(5) mixture of step (4) is carried out low temperature to pulverize at a slow speed, cross 80 mesh sieves;
(6) by the granule direct compression of step (5) gained, candesartan cilexetil is obtained.
Embodiment 2
Prescription
Candesartan Cilexetil 15g
Lactis Anhydrous 45g
Carboxymethyl starch sodium 8g
Pulvis Talci 2.8g
Aluminum phosphate 12.0g.
Preparation method
(1), after being mixed by the Lactis Anhydrous of the candesartan Cilexetil of 15g, 45g, microwave vacuum drying is carried out;
(2) step (1) gained candesartan Cilexetil and Lactis Anhydrous mixture are carried out fragmentation, cross 80 mesh sieves, for subsequent use;
(3) after 12g aluminum phosphate, 8g carboxymethyl starch sodium, 2.8g Pulvis Talci being crossed 80 mesh sieves respectively, for subsequent use;
(4) aluminum phosphate, carboxymethyl starch sodium, Pulvis Talci after step (3) being sieved, the mixture of step (2) gained is poured in mixer and is mixed;
(5) mixture of step (4) is carried out low temperature to pulverize at a slow speed, cross 80 mesh sieves;
(6) by the granule direct compression of step (5) gained, candesartan cilexetil is obtained.
Embodiment 3
Prescription
Candesartan Cilexetil 20g
Lactis Anhydrous 40g
Low-substituted hydroxypropyl cellulose 12g
Micropowder silica gel 2.5g
Aluminum phosphate 12.8g.
Preparation method
(1), after being mixed by the Lactis Anhydrous of the candesartan Cilexetil of 20g, 40g, microwave vacuum drying is carried out;
(2) step (1) gained candesartan Cilexetil and Lactis Anhydrous mixture are carried out fragmentation, cross 100 mesh sieves, for subsequent use;
(3) after 12.8g aluminum phosphate, 12g low-substituted hydroxypropyl cellulose, 2.5g micropowder silica gel being crossed 100 mesh sieves respectively, for subsequent use;
(4) by aluminum phosphate, low-substituted hydroxypropyl cellulose, the micropowder silicon after sieving, the mixture of step (2) gained is poured in mixer and is mixed;
(5) mixture of step (4) is carried out low temperature to pulverize at a slow speed, cross 100 mesh sieves;
(6) by the granule direct compression of step (5) gained, candesartan cilexetil is obtained.
Embodiment 4
Prescription
Candesartan Cilexetil 25g
Lactis Anhydrous 35g
Crospolyvinylpyrrolidone 15g
Magnesium stearate 2.5g
Aluminum phosphate 14.3g.
Preparation method
(1), after being mixed by the Lactis Anhydrous of the candesartan Cilexetil of 25g, 35g, microwave vacuum drying is carried out;
(2) step (1) gained candesartan Cilexetil and Lactis Anhydrous mixture are carried out fragmentation, cross 100 mesh sieves, for subsequent use;
(3) after 14.3g aluminum phosphate, 15g crospolyvinylpyrrolidone, 2.5g magnesium stearate being crossed 80 mesh sieves respectively, for subsequent use;
(4) by aluminum phosphate, crospolyvinylpyrrolidone, the magnesium stearate after sieving, the mixture of step (2) gained is poured in mixer and is mixed;
(5) mixture of step (4) is carried out low temperature to pulverize at a slow speed, cross 100 mesh sieves;
(6) by the granule direct compression of step (5) gained, candesartan cilexetil is obtained.
Embodiment 5
Prescription
Candesartan Cilexetil 30g
Lactis Anhydrous 80g
Cross-linking sodium carboxymethyl cellulose 16g
Micropowder silica gel 1.2g
Magnesium stearate 0.5g
Aluminum phosphate 13.2g.
Preparation method
(1), after being mixed by the Lactis Anhydrous of the candesartan Cilexetil of 30g, 80g, microwave vacuum drying is carried out;
(2) step (1) gained candesartan Cilexetil and Lactis Anhydrous mixture are carried out fragmentation, cross 80 mesh sieves, for subsequent use;
(3) after 13.2g aluminum phosphate, 16g cross-linking sodium carboxymethyl cellulose, 1.2g micropowder silica gel, 0.5g magnesium stearate being crossed 80 mesh sieves respectively, for subsequent use;
(4) by aluminum phosphate, cross-linking sodium carboxymethyl cellulose, micropowder silica gel, magnesium stearate, the mixture of step (2) gained is poured in mixer and is mixed;
(5) mixture of step (4) is carried out low temperature to pulverize at a slow speed, cross 100 mesh sieves;
(6) by the granule direct compression of step (5) gained, candesartan cilexetil is obtained.
Embodiment 6
Prescription
Candesartan Cilexetil 35g
Lactis Anhydrous 85g
Dried starch 6g
Carboxymethyl starch sodium 4g
Pulvis Talci 0.8g
Magnesium stearate 0.5g
Aluminum phosphate 15.0g.
Preparation method
(1), after being mixed by the Lactis Anhydrous of the candesartan Cilexetil of 35g, 85g, microwave vacuum drying is carried out;
(2) step (1) gained candesartan Cilexetil and Lactis Anhydrous mixture are carried out fragmentation, cross 100 mesh sieves, for subsequent use;
(3) after 15g aluminum phosphate, 6g dried starch, 4g carboxymethyl starch sodium, 0.8g Pulvis Talci, 0.5g magnesium stearate being crossed 100 mesh sieves respectively, for subsequent use;
(4) by aluminum phosphate, dried starch, carboxymethyl starch sodium, Pulvis Talci, magnesium stearate, the mixture of step (2) gained is poured in mixer and is mixed;
(5) mixture of step (4) is carried out low temperature to pulverize at a slow speed, cross 100 mesh sieves;
(6) by the granule direct compression of step (5) gained, candesartan cilexetil is obtained.
Embodiment 7
Prescription
Candesartan Cilexetil 40g
Lactis Anhydrous 60g
Low-substituted hydroxypropyl cellulose 7g
Cross-linking sodium carboxymethyl cellulose 5g
Micropowder silica gel 4g
Aluminum phosphate 14.2g.
Preparation method
(1), after being mixed by the Lactis Anhydrous of the candesartan Cilexetil of 40g, 60g, microwave vacuum drying is carried out;
(2) step (1) gained candesartan Cilexetil and milk-sugar mixture are carried out fragmentation, cross 80 mesh sieves, for subsequent use;
(3) after 14.2g aluminum phosphate, 7g low-substituted hydroxypropyl cellulose, 5g cross-linking sodium carboxymethyl cellulose, 4g micropowder silica gel being crossed 80 mesh sieves respectively, for subsequent use;
(4) by the aluminum phosphate after sieving, low-substituted hydroxypropyl cellulose, cross-linking sodium carboxymethyl cellulose, micropowder silica gel, the mixture of step (2) gained is poured in mixer and is mixed;
(5) mixture of step (4) is carried out low temperature to pulverize at a slow speed, cross 80 mesh sieves;
(6) by step (5) gained direct compression, candesartan cilexetil is obtained.
Embodiment 8
Prescription
Candesartan Cilexetil 10g
Lactis Anhydrous 35g
Carboxymethyl starch sodium 5g
Low-substituted hydroxypropyl cellulose 9.2g
Micropowder silica gel 1.5g
Aluminum phosphate 12.3g.
Preparation method
(1), after being mixed by the Lactis Anhydrous of the candesartan Cilexetil of 10g, 35g, microwave vacuum drying is carried out;
(2) step (1) gained candesartan Cilexetil and milk-sugar mixture are carried out fragmentation, cross 100 mesh sieves, for subsequent use;
(3) after 12.3g aluminum phosphate, 5g carboxymethyl starch sodium, 9.2g low-substituted hydroxypropyl cellulose, 1.5g micropowder silica gel being crossed 100 mesh sieves respectively, for subsequent use;
(4) by aluminum phosphate, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, micropowder silica gel, the mixture of step (2) gained is poured in mixer and is mixed;
(5) mixture of step (4) is carried out low temperature to pulverize at a slow speed, cross 100 mesh sieves;
(6) by the granule direct compression of step (5) gained, candesartan cilexetil is obtained.
Embodiment 9
Prescription
Candesartan Cilexetil 20g
Lactis Anhydrous 55g
Crospolyvinylpyrrolidone 6g
Cross-linking sodium carboxymethyl cellulose 3g
Pulvis Talci 3g
Aluminum phosphate 13.2g.
Preparation method
(1), after being mixed by the Lactis Anhydrous of the candesartan Cilexetil of 20g, 55g, microwave vacuum drying is carried out;
(2) step (1) gained candesartan Cilexetil and Lactis Anhydrous mixture are carried out fragmentation, cross 100 mesh sieves, for subsequent use;
(3) after 13.2g aluminum phosphate, 6g crospolyvinylpyrrolidone, 3g cross-linking sodium carboxymethyl cellulose, 3g Pulvis Talci being crossed 80 ~ 100 mesh sieves respectively, for subsequent use;
(4) by aluminum phosphate, crospolyvinylpyrrolidone, cross-linking sodium carboxymethyl cellulose, Pulvis Talci, the mixture of step (2) gained is poured in mixer and is mixed;
(5) mixture of step (4) is carried out low temperature to pulverize at a slow speed, cross 80 mesh sieves;
(6) by the granule direct compression of step (5) gained, candesartan cilexetil is obtained.
Embodiment 10
Prescription
Candesartan Cilexetil 40g
Lactis Anhydrous 70g
Mannitol 10g
Carboxymethyl starch sodium 9g
Low-substituted hydroxypropyl cellulose 10g
Micropowder silica gel 5g
Aluminum phosphate 14.1g.
Preparation method
(1), after being mixed by the Lactis Anhydrous of the candesartan Cilexetil of 40g, 70g, microwave vacuum drying is carried out;
(2) step (1) gained candesartan Cilexetil and Lactis Anhydrous mixture are carried out fragmentation, cross 80 mesh sieves, for subsequent use;
(3) after 14.1g aluminum phosphate, 10g mannitol, 9g carboxymethyl starch sodium, 10g low-substituted hydroxypropyl cellulose, 5g micropowder silica gel being crossed 80 mesh sieves respectively, for subsequent use;
(4) by the aluminum phosphate after sieving, mannitol, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, micropowder silica gel, the mixture of step (2) gained is poured in mixer and is mixed;
(5) mixture of step (4) is carried out low temperature to pulverize at a slow speed, cross 100 mesh sieves;
(6) by the granule direct compression of step (5) gained, candesartan cilexetil is obtained.
Claims (6)
1. the pharmaceutical composition containing candesartan Cilexetil, is characterized in that pharmaceutical composition contains: candesartan Cilexetil, disintegrating agent, lubricant, Lactis Anhydrous and aluminum phosphate.
2., according to the pharmaceutical composition containing candesartan Cilexetil described in claim 1, it is characterized in that pharmaceutical composition is prepared into tablet.
3., according to the pharmaceutical composition containing candesartan Cilexetil described in claim 1, it is characterized in that the weight ratio of each component is:
Candesartan Cilexetil 10 ~ 40 weight portion
Disintegrating agent 4 ~ 20 weight portion
Lubricant 1 ~ 5 weight portion
Lactis Anhydrous 35 ~ 85 weight portion
Aluminum phosphate 12 ~ 15 weight portion.
4. according to described in claim 1 containing the pharmaceutical composition of candesartan Cilexetil, it is characterized in that one or more that described disintegrating agent is selected from dried starch, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, crospolyvinylpyrrolidone, cross-linking sodium carboxymethyl cellulose.
5. according to described in claim 1 containing the pharmaceutical composition of candesartan Cilexetil, it is characterized in that one or more that described lubricant is selected from micropowder silica gel, Pulvis Talci, magnesium stearate.
6. the pharmaceutical composition containing candesartan Cilexetil according to claim 2, the wherein preparation method of tablet, comprises the following steps:
(1), after being mixed by the Lactis Anhydrous of the candesartan Cilexetil of 10 ~ 40 weight portions, 35 ~ 85 weight portions, microwave vacuum drying is carried out;
(2) step (1) gained candesartan Cilexetil and Lactis Anhydrous mixture are carried out fragmentation, cross 80 ~ 100 mesh sieves, for subsequent use;
(3) after 12 ~ 15 weight portion candesartan Cilexetils, 4 ~ 20 part by weight of disintegrant, 1 ~ 5 weight portion lubricant being crossed 80 ~ 100 mesh sieves respectively, for subsequent use;
(4) by candesartan Cilexetil, disintegrating agent, the lubricant after sieving, the mixture of step (2) gained is poured in mixer and is mixed;
(5) mixture of step (4) is carried out low temperature to pulverize at a slow speed, cross 80 ~ 100 mesh sieves;
(6) by the granule direct compression of step (5) gained, candesartan cilexetil is obtained.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110354086A (en) * | 2019-07-25 | 2019-10-22 | 天地恒一制药股份有限公司 | A kind of preparation method of candesartan Cilexetil tablet |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1684665A (en) * | 2002-09-24 | 2005-10-19 | 贝林格尔·英格海姆国际有限公司 | Solid pharmaceutical formulations comprising telmisartan |
| CN101312714A (en) * | 2005-11-22 | 2008-11-26 | 特瓦制药工业有限公司 | Medicament composition of telmisartan |
| CN103127010A (en) * | 2012-03-19 | 2013-06-05 | 迪沙药业集团有限公司 | Stable candesartan cilexetil tablet combination |
| CN103284966A (en) * | 2013-04-17 | 2013-09-11 | 昆明源瑞制药有限公司 | Candesartan cilexetil dispersible tablet |
-
2013
- 2013-12-04 CN CN201310641049.0A patent/CN104688696B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1684665A (en) * | 2002-09-24 | 2005-10-19 | 贝林格尔·英格海姆国际有限公司 | Solid pharmaceutical formulations comprising telmisartan |
| CN101312714A (en) * | 2005-11-22 | 2008-11-26 | 特瓦制药工业有限公司 | Medicament composition of telmisartan |
| CN103127010A (en) * | 2012-03-19 | 2013-06-05 | 迪沙药业集团有限公司 | Stable candesartan cilexetil tablet combination |
| CN103284966A (en) * | 2013-04-17 | 2013-09-11 | 昆明源瑞制药有限公司 | Candesartan cilexetil dispersible tablet |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110354086A (en) * | 2019-07-25 | 2019-10-22 | 天地恒一制药股份有限公司 | A kind of preparation method of candesartan Cilexetil tablet |
| CN110354086B (en) * | 2019-07-25 | 2021-05-11 | 天地恒一制药股份有限公司 | Preparation method of candesartan cilexetil tablets |
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Address after: 130012, 672, pioneering street, hi tech Zone, Jilin, Changchun Applicant after: CHANGCHUN HAIYUE PHARMACEUTICAL Co.,Ltd. Address before: 130012, 672, pioneering street, hi tech Zone, Jilin, Changchun Applicant before: Changchun Haiyue Pharmaceutical Co.,Ltd. |
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Denomination of invention: A drug composition containing candesartan ester Effective date of registration: 20231226 Granted publication date: 20171219 Pledgee: China Construction Bank Co.,Ltd. Changchun Science and Technology Sub branch Pledgor: CHANGCHUN HAIYUE PHARMACEUTICAL Co.,Ltd. Registration number: Y2023220000149 |
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