CN101647797B - Pharmaceutical composition containing Amlodipine besilate and valsartan and preparation method thereof - Google Patents
Pharmaceutical composition containing Amlodipine besilate and valsartan and preparation method thereof Download PDFInfo
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- CN101647797B CN101647797B CN 200910307306 CN200910307306A CN101647797B CN 101647797 B CN101647797 B CN 101647797B CN 200910307306 CN200910307306 CN 200910307306 CN 200910307306 A CN200910307306 A CN 200910307306A CN 101647797 B CN101647797 B CN 101647797B
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- 239000004072 C09CA03 - Valsartan Substances 0.000 title claims abstract description 74
- 229960004699 valsartan Drugs 0.000 title claims abstract description 74
- SJSNUMAYCRRIOM-QFIPXVFZSA-N valsartan Chemical compound C1=CC(CN(C(=O)CCCC)[C@@H](C(C)C)C(O)=O)=CC=C1C1=CC=CC=C1C1=NN=N[N]1 SJSNUMAYCRRIOM-QFIPXVFZSA-N 0.000 title claims abstract description 74
- 238000002360 preparation method Methods 0.000 title claims abstract description 51
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 43
- 229960000528 amlodipine Drugs 0.000 title claims abstract description 15
- HTIQEAQVCYTUBX-UHFFFAOYSA-N amlodipine Chemical compound CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1Cl HTIQEAQVCYTUBX-UHFFFAOYSA-N 0.000 title abstract description 24
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims abstract description 104
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims abstract description 104
- 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 abstract description 63
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims abstract description 52
- 235000019359 magnesium stearate Nutrition 0.000 claims abstract description 52
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims abstract description 52
- 239000008108 microcrystalline cellulose Substances 0.000 claims abstract description 52
- 229940016286 microcrystalline cellulose Drugs 0.000 claims abstract description 52
- 239000000377 silicon dioxide Substances 0.000 claims abstract description 52
- 235000012239 silicon dioxide Nutrition 0.000 claims abstract description 52
- 238000000034 method Methods 0.000 claims abstract description 49
- 239000003826 tablet Substances 0.000 claims description 133
- ZPBWCRDSRKPIDG-UHFFFAOYSA-N amlodipine benzenesulfonate Chemical compound OS(=O)(=O)C1=CC=CC=C1.CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1Cl ZPBWCRDSRKPIDG-UHFFFAOYSA-N 0.000 claims description 90
- 239000011248 coating agent Substances 0.000 claims description 82
- 238000000576 coating method Methods 0.000 claims description 82
- 229960004005 amlodipine besylate Drugs 0.000 claims description 76
- 239000001768 carboxy methyl cellulose Substances 0.000 claims description 62
- 238000004132 cross linking Methods 0.000 claims description 62
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 claims description 62
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 claims description 62
- 238000002156 mixing Methods 0.000 claims description 49
- 238000005303 weighing Methods 0.000 claims description 43
- 239000011812 mixed powder Substances 0.000 claims description 37
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 21
- 239000008213 purified water Substances 0.000 claims description 20
- 238000001035 drying Methods 0.000 claims description 18
- 229940043102 valsartan and amlodipine Drugs 0.000 claims description 12
- 239000007941 film coated tablet Substances 0.000 claims description 10
- 239000000843 powder Substances 0.000 claims description 6
- 238000007873 sieving Methods 0.000 claims description 6
- 239000000890 drug combination Substances 0.000 claims description 3
- 238000004090 dissolution Methods 0.000 abstract description 22
- 239000003795 chemical substances by application Substances 0.000 abstract description 14
- 238000004519 manufacturing process Methods 0.000 abstract description 11
- 238000009702 powder compression Methods 0.000 abstract description 7
- 229920002785 Croscarmellose sodium Polymers 0.000 abstract 1
- 229960001681 croscarmellose sodium Drugs 0.000 abstract 1
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 abstract 1
- 238000001514 detection method Methods 0.000 abstract 1
- 239000004615 ingredient Substances 0.000 abstract 1
- 239000003814 drug Substances 0.000 description 27
- 239000002994 raw material Substances 0.000 description 22
- 238000005516 engineering process Methods 0.000 description 20
- 238000005507 spraying Methods 0.000 description 19
- 238000003756 stirring Methods 0.000 description 18
- 238000012360 testing method Methods 0.000 description 15
- 229940079593 drug Drugs 0.000 description 13
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical group C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 10
- 229960000913 crospovidone Drugs 0.000 description 10
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 10
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 10
- 206010020772 Hypertension Diseases 0.000 description 9
- 238000007664 blowing Methods 0.000 description 9
- 239000003974 emollient agent Substances 0.000 description 9
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- 239000002904 solvent Substances 0.000 description 9
- 239000007921 spray Substances 0.000 description 9
- 239000007888 film coating Substances 0.000 description 8
- 238000009501 film coating Methods 0.000 description 8
- 239000012530 fluid Substances 0.000 description 8
- 239000002356 single layer Substances 0.000 description 8
- 208000024172 Cardiovascular disease Diseases 0.000 description 6
- 229940125364 angiotensin receptor blocker Drugs 0.000 description 6
- 238000007908 dry granulation Methods 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 230000036772 blood pressure Effects 0.000 description 5
- 239000007909 solid dosage form Substances 0.000 description 5
- 238000005550 wet granulation Methods 0.000 description 4
- 239000000203 mixture Substances 0.000 description 3
- 238000011020 pilot scale process Methods 0.000 description 3
- 229940127291 Calcium channel antagonist Drugs 0.000 description 2
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 2
- 229920003110 Primojel Polymers 0.000 description 2
- 230000003276 anti-hypertensive effect Effects 0.000 description 2
- 239000002220 antihypertensive agent Substances 0.000 description 2
- 229940127088 antihypertensive drug Drugs 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 238000007907 direct compression Methods 0.000 description 2
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 2
- 230000007774 longterm Effects 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 238000005070 sampling Methods 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- HTIQEAQVCYTUBX-KRWDZBQOSA-N (S)-amlodipine Chemical compound CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)[C@@H]1C1=CC=CC=C1Cl HTIQEAQVCYTUBX-KRWDZBQOSA-N 0.000 description 1
- 239000002947 C09CA04 - Irbesartan Substances 0.000 description 1
- 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 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- 208000027418 Wounds and injury Diseases 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
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- 210000004204 blood vessel Anatomy 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 229960004349 candesartan cilexetil Drugs 0.000 description 1
- 208000015606 cardiovascular system disease Diseases 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
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- 229940127292 dihydropyridine calcium channel blocker Drugs 0.000 description 1
- 239000002866 dihydropyridine calcium channel blocker Substances 0.000 description 1
- 230000003292 diminished effect Effects 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
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- 208000014674 injury Diseases 0.000 description 1
- 229960002198 irbesartan Drugs 0.000 description 1
- YCPOHTHPUREGFM-UHFFFAOYSA-N irbesartan Chemical compound O=C1N(CC=2C=CC(=CC=2)C=2C(=CC=CC=2)C=2[N]N=NN=2)C(CCCC)=NC21CCCC2 YCPOHTHPUREGFM-UHFFFAOYSA-N 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 229950008554 levamlodipine Drugs 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 238000005453 pelletization Methods 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000005180 public health Effects 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 238000011125 single therapy Methods 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 230000035488 systolic blood pressure Effects 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention relates to a pharmaceutical composition containing Amlodipine besilate and valsartan and a preparation method thereof. The pharmaceutical composition is prepared from the following ingredients in parts by weight: 5 parts of Amlodipine besilate, 80 parts of valsartan, 60 parts of microcrystalline cellulose, 4.7-13.2 parts of croscarmellose sodium, 4.8 parts of silicon dioxide and 1.6 parts of magnesium stearate. The pharmaceutical composition is prepared by using a direct powder compression technique. The invention can reach the dissolution rate of more than 90% by using less disintegrating agent, and has advantages of good stability and faster disintegrating. The preparation method of the invention has simpler production process, reduces the investment of corresponding equipment and plants and saves the production cost; the tablet produced by using direct powder compression technique has faster disintegrating and is helpful to improve the dissolving of pharmaceutical; through detection, the tablet prepared by using the method is dissolved out by more than 90% within 15 min.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, relate to a kind of pharmaceutical composition that contains Amlodipine Besylate Tablet and valsartan and preparation method thereof.
Background technology
Hypertension is modal cardiovascular disease, is that the great public health in the global range does not have a difficult problem.China 1991 has carried out sample census to 940,000 crowds more than 15 years old, and statistics shows: China's hypertension prevalence has reached 11.26%, and than increasing 25% in the period of the 1979-1990 10, the existing hyperpietic of China surpasses 1.3 hundred million.And the impetus of this rising is still continuing.Statistics shows that also hypertension therapeutic rate city is 17.4%, and the rural area is 5.4%; Control rate (through treatment systolic pressure＜140mmHg, diastolic pressure＜90mmHg) only 2.9%.From above-mentioned statistics as can be seen China's hypertension prevalence constantly increase, but treatment rate, control rate are low, form huge contrast.According to the WHO prediction, will account for 79% of China's cause of death to the year two thousand twenty noninfectious, wherein the cardiovascular diseases will account for the first place.In order to contain the arrival on this cardiovascular diseases peak, carry out the control of hypertension energetically, the active treatment hyperpietic, very urgent.
The bad hypertension of long-term control can produce grievous injury to target organs such as the heart, brain, kidneys, actively main cardiovascular diseases's M ﹠ M can be significantly lowered in the blood pressure lowering treatment, and most hypertensive patients need could be with controlling of blood pressure in ideal target blood pressure level with depressor.The evidence-based medicine EBM evidence shows, low dose of use in conjunction variety classes antihypertensive drugs is better and untoward reaction is less with heavy dose of a certain medicine antihypertensive effect than single.Efficacy of antihypertensive treatment improves in therapeutic alliance section, in and the untoward reaction that causes of different pharmaceutical, blood pressure reduces the compensation response that triggers when preventing single therapy, increases patient's toleration, improves compliance.
Amlodipine (amlodipine) or its salt are dihydropyridine calcium channel blocker of new generation (CCB) as Amlodipine Besylate Tablet; And valsartan (valsartan) is a kind of angiotensin receptor blocker (ARB).Both all have effects such as blood pressure lowering, expansion blood vessel, can be used for preventing and treating cardiovascular system diseases such as hypertension, coronary heart disease, heart failure.
Have now and studies show that CCB and ARB share can certain synergism, disclose the compound antihypertensive drug of a kind of amlodipine and irbesartan as patent documentation CNZL03150996.7; CN1765362A discloses a kind of compositions that comprises amlodipine and angiotensin ii receptor antagonist (ARB), is the weight proportion of wherein having mentioned amlodipine and candesartan Cilexetil 1: 10? 0: 1; WO2006/034631 discloses the compositions of a kind of amlodipine and ARB; CN200610081591.5 discloses a kind of pharmaceutical composition that comprises the treatment hypertension and cardiovascular disease of Levamlodipine officinal salt and ARB.Yet the absolute oral availability of valsartan only has an appointment 25%, and the scope of broad is 10-35%.Valsartan also has the dissolubility that depends on pH, its scope solvable in from the slightly soluble sour environment to the gastrointestinal neutral environment.In addition, development makes things convenient for the challenge of the valsartan peroral dosage form that the patient uses to be that its bulk density is very low.Amlodipine Besylate Tablet is slightly soluble in water, and absolute bioavailability is 64-90%.Because the solid dosage forms that these complicated biopharmacy cause developing with bioequivalent valsartan of independent assortment and Amlodipine Besylate Tablet fixed combination faces the challenge.And Amlodipine Besylate Tablet and valsartan share the usage ratio that will reach preferable synergy very big difference is arranged also.
Publication number is that the Chinese patent application of 101237859A discloses a kind of monolayer tablet or bilayer tablet form that contains valsartan and Amlodipine Besylate Tablet, and used disintegrating agent is crospovidone, primojel, L-hydroxypropyl cellulose and their combination.For the monolayer tablet, the preferred consumption of disintegrating agent be this solid dosage forms weight about 2% to about 40%, more preferably from about 13%, wherein solid dosage forms weight is meant before the optional film coating.Since crospovidone have extremely strong draw moist, the monolayer tablet stability of prepared valsartan and Amlodipine Besylate Tablet is bad, disintegrate and stripping are slow, preparation method is a dry granulation, though this method has many having a few than wet granulation, but apparatus expensive complexity, equipment Factory Building investment is big, adopts stable bad, the disintegrate and the stripping of monolayer tablet of the valsartan of this method preparation and Amlodipine Besylate Tablet also slow.Though its dissolution of prepared tablet also can reach more than 90%, reach more than 15% of recipe quantity as the used in amounts of the crospovidone of disintegrating agent, as seen its large usage quantity.
At above-mentioned defective, the inventor has carried out the adjustment of prescription and technology to the tablet that contains valsartan and Amlodipine Besylate Tablet, adopt more a spot of disintegrating agent to prepare to have good stability, disintegrate and stripping is fast, dissolution big more than 90% valsartan and the tablet of Amlodipine Besylate Tablet, and production technology is simpler, reduced the investment of corresponding apparatus Factory Building, save production cost, adopted the disintegration of tablet of this explained hereafter faster, thus the stripping that helps to improve medicine.
Summary of the invention
First purpose of the present invention is to provide a kind of pharmaceutical composition that contains Amlodipine Besylate Tablet and valsartan, and this pharmaceutical composition has and has good stability, and disintegrate is faster, thereby helps to improve the advantage of the stripping of medicine.
Second purpose of the present invention is to provide a kind of preparation of drug combination method that contains Amlodipine Besylate Tablet and valsartan of the present invention, direct pressed powder, compare with dry granulation with wet granulation, saved the process of granulating, this method is not only simpler, has reduced the investment of corresponding apparatus Factory Building, saved production cost, the more important thing is that the disintegration of tablet that adopts this method to prepare is faster, thus the stripping that helps to improve medicine, and have good stability.
For realizing first purpose of the present invention, the present invention adopts following technical scheme:
The pharmaceutical composition of a kind of Amlodipine Besylate Tablet and valsartan, wherein, described pharmaceutical composition is made up of following prescription:
Amlodipine Besylate Tablet 5 weight portions
Valsartan 80 weight portions
Microcrystalline Cellulose 60 weight portions
Cross-linking sodium carboxymethyl cellulose 4.7～13.2 weight portions
Silicon dioxide 4.8 weight portions
Magnesium stearate 1.6 weight portions;
Preferably, described pharmaceutical composition is made up of following prescription:
Amlodipine Besylate Tablet 5 weight portions
Valsartan 80 weight portions
Microcrystalline Cellulose 60 weight portions
Cross-linking sodium carboxymethyl cellulose 8 weight portions
Silicon dioxide 4.8 weight portions
Magnesium stearate 1.6 weight portions;
Wherein the amount of Amlodipine Besylate Tablet is in amlodipine, and promptly the amount of Amlodipine Besylate Tablet is 6.94 weight portions, corresponding to 5 weight portion amlodipine free bases.
According to aforesaid pharmaceutical composition, wherein, described pharmaceutical composition is a tablet, the preferred film garment piece.
According to aforesaid pharmaceutical composition, wherein, described Film coated tablets is to adopt following method preparation:
1) valsartan and Amlodipine Besylate Tablet are sieved respectively, standby;
2) microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose, silicon dioxide and magnesium stearate are carried out drying respectively, sieve, standby;
3) take by weighing above-mentioned standby valsartan, microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose, silicon dioxide and magnesium stearate by recipe quantity, mixing obtains mixed powder;
4) take by weighing the Amlodipine Besylate Tablet of recipe quantity,, obtain pharmaceutical composition with the resulting mixed powder mixing of step 3);
5) resulting pharmaceutical composition is carried out tabletting, coating, obtain described Film coated tablets.
For realizing second purpose of the present invention, the present invention adopts following technical scheme:
A kind of described preparation of drug combination method, this method comprises:
1) valsartan and Amlodipine Besylate Tablet are sieved respectively, standby;
2) microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose, silicon dioxide and magnesium stearate are carried out drying respectively, sieve, standby;
3) take by weighing above-mentioned standby valsartan, microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose, silicon dioxide and magnesium stearate by recipe quantity, mixing obtains mixed powder;
4) take by weighing the Amlodipine Besylate Tablet of recipe quantity,, obtain described pharmaceutical composition with the resulting mixed powder mixing of step 3).
According to aforesaid preparation method, wherein, described preparation method also further comprises carries out tabletting, coating with resulting pharmaceutical composition, obtains Film coated tablets.
According to aforesaid preparation method, wherein, sieving described in the step 1) to crossing 80～100 mesh sieves.
According to aforesaid preparation method, wherein, step 2) in, described drying is to dry by the fire 2～4 hours under 60～80 ℃ of conditions, described sieving was 60～80 mesh sieves.
According to aforesaid preparation method, wherein, the mixing described in the step 4) is to adopt the equivalent method of progressively increasing to carry out mixing.
According to aforesaid preparation method, wherein, described tabletting is at 5～8kg with the slice, thin piece Hardness Control.
According to aforesaid preparation method, wherein, described coating is that the coating solution that adopts Opadry II and purified water to form carries out coating.
Below be detailed description of the present invention:
One aspect of the present invention provides the pharmaceutical composition of a kind of Amlodipine Besylate Tablet and valsartan, and this pharmaceutical composition has and has good stability, and disintegrate is faster, thereby helps to improve the advantage of medicine stripping.
Pharmaceutical composition provided by the present invention is made up of following prescription:
Amlodipine Besylate Tablet 5 weight portions
Valsartan 80 weight portions
Microcrystalline Cellulose 60 weight portions
Cross-linking sodium carboxymethyl cellulose 4.7～13.2 weight portions
Silicon dioxide 4.8 weight portions
Magnesium stearate 1.6 weight portions;
Wherein the amount of Amlodipine Besylate Tablet is in amlodipine.
Publication number is that the Chinese patent application of 101237859A discloses a kind of monolayer tablet or bilayer tablet form that contains valsartan and Amlodipine Besylate Tablet, and used disintegrating agent is crospovidone, primojel, L-hydroxypropyl cellulose and their combination.For the monolayer tablet, the preferred consumption of disintegrating agent be this solid dosage forms weight about 2% to about 40% (before any optional film coating), 13% (before any optional film coating) more preferably from about, wherein solid dosage forms weight is meant before the optional film coating.Because crospovidone has that the extremely strong monolayer tablet stability that draws moist, prepared valsartan and Amlodipine Besylate Tablet is bad, disintegrate and stripping are slow.
The inventor is after having carried out a large amount of prescription screening tests, and after the consumption of supplementary material carried out test of many times, when finding to adopt crospovidone to make disintegrating agent, when its consumption when 15% (before any optional film coating) of recipe quantity is above, the dissolution of the slice, thin piece that makes can reach more than 90%; And when the consumption of crospovidone when 10% (before any optional film coating) of recipe quantity is following, the dissolution of the slice, thin piece that makes is lower.The present invention is disintegrating agent with the cross-linking sodium carboxymethyl cellulose, and when consumption only was 3% (before any optional film coating) of recipe quantity, the stripping of the slice, thin piece that makes just can reach more than 90%; And the dissolution of tablet increases with the increase of cross-linking sodium carboxymethyl cellulose consumption.But when the consumption of cross-linking sodium carboxymethyl cellulose is 8% (before any optional film coating) of recipe quantity when above, continue to increase its consumption, dissolution increases not obvious.So determine that above-mentioned prescription is the prescription of its pharmaceutical composition provided by the present invention.Be its optimization formula with following prescription again:
Amlodipine Besylate Tablet 5 weight portions
Valsartan 80 weight portions
Microcrystalline Cellulose 60 weight portions
Cross-linking sodium carboxymethyl cellulose 8 weight portions
Silicon dioxide 4.8 weight portions
Magnesium stearate 1.6 weight portions;
Wherein the amount of Amlodipine Besylate Tablet is in amlodipine.
Pharmaceutical composition of the present invention can adopt conventional method to make tablet, the preferred film garment piece.
The following method of preferred employing is prepared into Film coated tablets:
1) valsartan and Amlodipine Besylate Tablet are sieved respectively, standby;
2) microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose, silicon dioxide and magnesium stearate are carried out drying respectively, sieve, standby;
3) take by weighing above-mentioned standby valsartan, microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose, silicon dioxide and magnesium stearate by recipe quantity, mixing obtains mixed powder;
4) take by weighing the Amlodipine Besylate Tablet of recipe quantity,, obtain pharmaceutical composition with the resulting mixed powder mixing of step 3);
5) resulting pharmaceutical composition is carried out tabletting, coating, obtain described Film coated tablets.
The inventor finds that adopting measured result angle of repose of the resulting pharmaceutical composition of said method is 36.8 °, and powder flowbility is good, satisfies the requirement of direct compression, adopts the method for direct powder compression to prepare Film coated tablets then.Further, the inventor is unexpected to be found because Amlodipine Besylate Tablet and valsartan all are the little medicines of dissolubility, and the disintegration of tablet that adopts technique of direct powder compression to produce is faster, thereby helps to improve the medicine stripping.
The present invention provides need not the granulating of a kind of pharmaceutical composition that contains Amlodipine Besylate Tablet and valsartan of the present invention, the direct preparation method of pressed powder on the other hand, this method is not only simpler, reduced the investment of corresponding apparatus Factory Building, saved production cost, the more important thing is that the disintegration of tablet that adopts this method to prepare is faster, thereby help to improve the stripping of medicine, and have good stability.
Preparation method provided by the present invention comprises:
1) valsartan and Amlodipine Besylate Tablet are sieved respectively, standby;
2) microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose, silicon dioxide and magnesium stearate are carried out drying respectively, sieve, standby;
3) take by weighing above-mentioned standby valsartan, microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose, silicon dioxide and magnesium stearate by recipe quantity, mixing obtains mixed powder;
4) take by weighing the Amlodipine Besylate Tablet of recipe quantity,, obtain described pharmaceutical composition with the resulting mixed powder mixing of step 3).
Adopting measured result angle of repose of the mixed-powder of said method drug prepared compositions is 36.8 °, and powder flowbility is good, satisfies the requirement of direct compression.
Preparation method of the present invention also further comprises carries out tabletting, coating with resulting pharmaceutical composition, obtains Film coated tablets.
Publication number is that the Chinese patent application of 101237859A discloses a kind of monolayer tablet that contains valsartan and Amlodipine Besylate Tablet or the bilayer tablet form is to adopt the dry granulation tablet forming technique, its equipment Factory Building investment is big, the production cost height, the more important thing is because Amlodipine Besylate Tablet and valsartan all are the little medicines of dissolubility, the disintegration of tablet that adopts the dry granulation tablet forming technique to produce is slow, is unfavorable for the stripping of medicine.The common technology of tablet technology will be granulated, and pelletization will solve exactly material fluidity is improved, and tabletting process tablet weight variation is diminished.Generally be to adopt wet granulation, this technology traditional classical is reliable, but this method equipment is many, and process route is long, and cost height, dry granulation are directly to become solid with the high pressure sheeted product and smash, and are screened into granule, and be simpler than wet granulation technology, but apparatus expensive.
The present invention adopts the preparation method of direct powder compression, compares with the dry granulation tablet forming technique, has following advantage:
(1) production technology is simpler, has reduced the investment of corresponding apparatus Factory Building, saves production cost;
(2) Amlodipine Besylate Tablet and valsartan all are the little medicines of dissolubility, and the disintegration of tablet that adopts technique of direct powder compression to produce is faster, the stripping that helps to improve medicine, and after testing, the tablet stripping in 15 minutes of adopting method preparation of the present invention is more than 90%.
In the preparation method of the present invention, sieving described in the step 1) to crossing 80～100 mesh sieves.
In the preparation method of the present invention, step 2) in, described drying is to dry by the fire 2～4 hours under 60～80 ℃ of conditions, described sieving was 60～80 mesh sieves.
In the preparation method of the present invention, the mixing described in the step 4) is to adopt the equivalent method of progressively increasing to carry out mixing.
Amount owing to Amlodipine Besylate Tablet in the prescription is less, the present invention adopts and earlier valsartan is mixed with other adjuvant, again Amlodipine Besylate Tablet is mixed by the equivalent incremental method with the mixed powder of gained, can guarantee that the mixed powder of Amlodipine Besylate Tablet and gained is blended more even.
In the preparation method of the present invention, described tabletting is at 5～8kg with the slice, thin piece Hardness Control.
In the preparation method of the present invention, described coating can adopt conventional coating solution to carry out coating, but the coating solution that preferably adopts Opadry II and purified water to form carries out coating.
Coating of the present invention can adopt this area method commonly used to carry out coating, preferably adopts following method to carry out coating:
1) purified water that takes by weighing recipe quantity is put in the agitator tank, open to stir to make liquid level just form whirlpool, and the Opadry II of recipe quantity at the uniform velocity is added in the whirlpool, behind reinforced the finishing, adjusts mixing speed whirlpool is just disappeared, and continues to stir 45 minutes, and is standby;
2) getting label puts in the coating pan, open compressed air, start the coating machine, coating pan is slowly rotated, and the preheating label is opened spray gun to about 40 ℃ the time, on the label with coating solution spraying and rotation, spraying is carried out drying with demulcent hot blast simultaneously, and spraying to coating solution finishes, and continues blowing hot-air the coating solvent evaporates is done.
Compared with prior art, the present invention has following advantage:
(1) pharmaceutical composition provided by the present invention has and has good stability, and disintegrate is faster, thereby helps to improve the advantage of medicine stripping;
(2) preparation method production technology provided by the present invention is simpler, has reduced the investment of corresponding apparatus Factory Building, saves production cost;
(3) Amlodipine Besylate Tablet and valsartan all are the little medicines of dissolubility, the disintegration of tablet that adopts technique of direct powder compression of the present invention to produce is faster, help to improve the stripping of medicine, after testing, the tablet stripping in 15 minutes of adopting method preparation of the present invention is more than 90%.
The specific embodiment
Below be the specific embodiment of the present invention, described embodiment is in order to further describe the present invention, rather than restriction the present invention.
Embodiment 1
1, prescription
The label prescription:
Amlodipine Besylate Tablet (corresponding to the 5g amlodipine free base) 6.94g
Valsartan 80g
Microcrystalline Cellulose 60g
Cross-linking sodium carboxymethyl cellulose 8g
Silicon dioxide 4.8g
Magnesium stearate 1.6g
Make 1000
Coating fluid prescription:
Opadry II 4.8g
Purified water 24g
28.8g/1000 sheet
2, preparation technology
(1) valsartan raw material, Amlodipine Besylate Tablet raw material are crossed 80 mesh sieves respectively.
(2) microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose, silicon dioxide, magnesium stearate were dried by the fire 2 hours respectively at 80 ℃, cross 60 mesh sieves.
(3) take by weighing valsartan, microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose, silicon dioxide and magnesium stearate by recipe quantity, fully mixing obtains mixed powder.
(4) take by weighing the Amlodipine Besylate Tablet of recipe quantity and above-mentioned mixed powder by equivalent incremental method mixing.
(5) measure drug content, it is heavy to calculate sheet, with diameter 8mm punch die tabletting, and control tablet hardness 5kg.
(6) purified water that takes by weighing recipe quantity is put in the agitator tank, open to stir to make liquid level just form whirlpool, and the Opadry II of recipe quantity at the uniform velocity is added in the whirlpool, behind reinforced the finishing, adjusts mixing speed whirlpool is just disappeared, and continues to stir 45 minutes, and is standby.
(7) getting label puts in the coating pan, open compressed air, start the coating machine, coating pan is slowly rotated, and the preheating label is opened spray gun to about 40 ℃ the time, coating solution is sparged on the label of rotation, spraying is carried out drying with demulcent hot blast simultaneously, and spraying to coating solution finishes, and continues blowing hot-air the coating solvent evaporates is done.
Embodiment 2
1, prescription
The label prescription:
Amlodipine Besylate Tablet (corresponding to the 5g amlodipine free base) 6.94g
Valsartan 80g
Microcrystalline Cellulose 60g
Cross-linking sodium carboxymethyl cellulose 4.7g
Silicon dioxide 4.8g
Magnesium stearate 1.6g
Make 1000
Coating fluid prescription:
Opadry II 4.8g
Purified water 24g
28.8g/1000 sheet
2, preparation technology
(1) valsartan raw material, Amlodipine Besylate Tablet raw material are crossed 100 mesh sieves respectively.
(2) microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose, silicon dioxide, magnesium stearate were dried by the fire 4 hours respectively at 60 ℃, cross 70 mesh sieves.
(3) take by weighing valsartan, microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose, silicon dioxide and magnesium stearate by recipe quantity, fully mixing obtains mixed powder.
(4) take by weighing the Amlodipine Besylate Tablet of recipe quantity and above-mentioned mixed powder by equivalent incremental method mixing.
(5) measure drug content, it is heavy to calculate sheet, with diameter 8mm punch die tabletting, and control tablet hardness 8kg.
(6) purified water that takes by weighing recipe quantity is put in the agitator tank, open to stir to make liquid level just form whirlpool, and the Opadry II of recipe quantity at the uniform velocity is added in the whirlpool, behind reinforced the finishing, adjusts mixing speed whirlpool is just disappeared, and continues to stir 45 minutes, and is standby.
(7) getting label puts in the coating pan, open compressed air, start the coating machine, coating pan is slowly rotated, and the preheating label is opened spray gun to about 40 ℃ the time, coating solution is sparged on the label of rotation, spraying is carried out drying with demulcent hot blast simultaneously, and spraying to coating solution finishes, and continues blowing hot-air the coating solvent evaporates is done.
Embodiment 3
1, prescription
The label prescription:
Amlodipine Besylate Tablet (corresponding to the 5g amlodipine free base) 6.94g
Valsartan 80g
Microcrystalline Cellulose 60g
Cross-linking sodium carboxymethyl cellulose 13.2g
Silicon dioxide 4.8g
Magnesium stearate 1.6g
Make 1000
Coating fluid prescription:
Opadry II 4.8g
Purified water 24g
28.8g/1000 sheet
2, preparation technology
(1) valsartan raw material, Amlodipine Besylate Tablet raw material are crossed 90 mesh sieves respectively.
(2) microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose, silicon dioxide, magnesium stearate were dried by the fire 3 hours respectively at 70 ℃, cross 80 mesh sieves.
(3) take by weighing valsartan, microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose, silicon dioxide and magnesium stearate by recipe quantity, fully mixing obtains mixed powder.
(4) take by weighing the Amlodipine Besylate Tablet of recipe quantity and above-mentioned mixed powder by equivalent incremental method mixing.
(5) measure drug content, it is heavy to calculate sheet, with diameter 8mm punch die tabletting, and control tablet hardness 6kg.
(6) purified water that takes by weighing recipe quantity is put in the agitator tank, open to stir to make liquid level just form whirlpool, and the Opadry II of recipe quantity at the uniform velocity is added in the whirlpool, behind reinforced the finishing, adjusts mixing speed whirlpool is just disappeared, and continues to stir 45 minutes, and is standby.
(7) getting label puts in the coating pan, open compressed air, start the coating machine, coating pan is slowly rotated, and the preheating label is opened spray gun to about 40 ℃ the time, coating solution is sparged on the label of rotation, spraying is carried out drying with demulcent hot blast simultaneously, and spraying to coating solution finishes, and continues blowing hot-air the coating solvent evaporates is done.
Embodiment 4
1, prescription
The label prescription:
Amlodipine Besylate Tablet (corresponding to the 5g amlodipine free base) 6.94g
Valsartan 80g
Microcrystalline Cellulose 60g
Cross-linking sodium carboxymethyl cellulose 10.0g
Silicon dioxide 4.8g
Magnesium stearate 1.6g
Make 1000
Coating fluid prescription:
Opadry II 4.8g
Purified water 24g
28.8g/1000 sheet
2, preparation technology
(1) valsartan raw material, Amlodipine Besylate Tablet raw material are crossed 90 mesh sieves respectively.
(2) microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose, silicon dioxide, magnesium stearate were dried by the fire 3.5 hours respectively at 75 ℃, cross 65 mesh sieves.
(3) take by weighing valsartan, microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose, silicon dioxide and magnesium stearate by recipe quantity, fully mixing obtains mixed powder.
(4) take by weighing the Amlodipine Besylate Tablet of recipe quantity and above-mentioned mixed powder by equivalent incremental method mixing.
(5) measure drug content, it is heavy to calculate sheet, with diameter 8mm punch die tabletting, and control tablet hardness 7kg.
(6) purified water that takes by weighing recipe quantity is put in the agitator tank, open to stir to make liquid level just form whirlpool, and the Opadry II of recipe quantity at the uniform velocity is added in the whirlpool, behind reinforced the finishing, adjusts mixing speed whirlpool is just disappeared, and continues to stir 45 minutes, and is standby.
(7) getting label puts in the coating pan, open compressed air, start the coating machine, coating pan is slowly rotated, and the preheating label is opened spray gun to about 40 ℃ the time, coating solution is sparged on the label of rotation, spraying is carried out drying with demulcent hot blast simultaneously, and spraying to coating solution finishes, and continues blowing hot-air the coating solvent evaporates is done.
Embodiment 5
1, prescription
The label prescription:
Amlodipine Besylate Tablet (corresponding to the 5g amlodipine free base) 6.94g
Valsartan 80g
Microcrystalline Cellulose 60g
Cross-linking sodium carboxymethyl cellulose 5.8g
Silicon dioxide 4.8g
Magnesium stearate 1.6g
Make 1000
Coating fluid prescription:
Opadry II 4.8g
Purified water 24g
28.8g/1000 sheet
2, preparation technology
(1) valsartan raw material, Amlodipine Besylate Tablet raw material are crossed 90 mesh sieves respectively.
(2) microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose, silicon dioxide, magnesium stearate were dried by the fire 3.5 hours respectively at 75 ℃, cross 65 mesh sieves.
(3) take by weighing valsartan, microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose, silicon dioxide and magnesium stearate by recipe quantity, fully mixing obtains mixed powder.
(4) take by weighing the Amlodipine Besylate Tablet of recipe quantity and above-mentioned mixed powder by equivalent incremental method mixing.
(5) measure drug content, it is heavy to calculate sheet, with diameter 8mm punch die tabletting, and control tablet hardness 7kg.
(6) purified water that takes by weighing recipe quantity is put in the agitator tank, open to stir to make liquid level just form whirlpool, and the Opadry II of recipe quantity at the uniform velocity is added in the whirlpool, behind reinforced the finishing, adjusts mixing speed whirlpool is just disappeared, and continues to stir 45 minutes, and is standby.
(7) getting label puts in the coating pan, open compressed air, start the coating machine, coating pan is slowly rotated, and the preheating label is opened spray gun to about 40 ℃ the time, coating solution is sparged on the label of rotation, spraying is carried out drying with demulcent hot blast simultaneously, and spraying to coating solution finishes, and continues blowing hot-air the coating solvent evaporates is done.
Embodiment 6
1, prescription
The label prescription:
Amlodipine Besylate Tablet (corresponding to the 5g amlodipine free base) 6.94g
Valsartan 80g
Microcrystalline Cellulose 60g
Cross-linking sodium carboxymethyl cellulose 6.9g
Silicon dioxide 4.8g
Magnesium stearate 1.6g
Make 1000
Coating fluid prescription:
Opadry II 4.8g
Purified water 24g
28.8g/1000 sheet
2, preparation technology
(1) valsartan raw material, Amlodipine Besylate Tablet raw material are crossed 90 mesh sieves respectively.
(2) microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose, silicon dioxide, magnesium stearate were dried by the fire 3.5 hours respectively at 75 ℃, cross 65 mesh sieves.
(3) take by weighing valsartan, microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose, silicon dioxide and magnesium stearate by recipe quantity, fully mixing obtains mixed powder.
(4) take by weighing the Amlodipine Besylate Tablet of recipe quantity and above-mentioned mixed powder by equivalent incremental method mixing.
(5) measure drug content, it is heavy to calculate sheet, with diameter 8mm punch die tabletting, and control tablet hardness 7kg.
(6) purified water that takes by weighing recipe quantity is put in the agitator tank, open to stir to make liquid level just form whirlpool, and the Opadry II of recipe quantity at the uniform velocity is added in the whirlpool, behind reinforced the finishing, adjusts mixing speed whirlpool is just disappeared, and continues to stir 45 minutes, and is standby.
(7) getting label puts in the coating pan, open compressed air, start the coating machine, coating pan is slowly rotated, and the preheating label is opened spray gun to about 40 ℃ the time, coating solution is sparged on the label of rotation, spraying is carried out drying with demulcent hot blast simultaneously, and spraying to coating solution finishes, and continues blowing hot-air the coating solvent evaporates is done.
Embodiment 7
1, prescription
The label prescription:
Amlodipine Besylate Tablet (corresponding to the 5g amlodipine free base) 6.94g
Valsartan 80g
Microcrystalline Cellulose 60g
Cross-linking sodium carboxymethyl cellulose 9.6g
Silicon dioxide 4.8g
Magnesium stearate 1.6g
Make 1000
Coating fluid prescription:
Opadry II 4.8g
Purified water 24g
28.8g/1000 sheet
2, preparation technology
(1) valsartan raw material, Amlodipine Besylate Tablet raw material are crossed 90 mesh sieves respectively.
(2) microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose, silicon dioxide, magnesium stearate were dried by the fire 3.5 hours respectively at 75 ℃, cross 65 mesh sieves.
(3) take by weighing valsartan, microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose, silicon dioxide and magnesium stearate by recipe quantity, fully mixing obtains mixed powder.
(4) take by weighing the Amlodipine Besylate Tablet of recipe quantity and above-mentioned mixed powder by equivalent incremental method mixing.
(5) measure drug content, it is heavy to calculate sheet, with diameter 8mm punch die tabletting, and control tablet hardness 7kg.
(6) purified water that takes by weighing recipe quantity is put in the agitator tank, open to stir to make liquid level just form whirlpool, and the Opadry II of recipe quantity at the uniform velocity is added in the whirlpool, behind reinforced the finishing, adjusts mixing speed whirlpool is just disappeared, and continues to stir 45 minutes, and is standby.
(7) getting label puts in the coating pan, open compressed air, start the coating machine, coating pan is slowly rotated, and the preheating label is opened spray gun to about 40 ℃ the time, coating solution is sparged on the label of rotation, spraying is carried out drying with demulcent hot blast simultaneously, and spraying to coating solution finishes, and continues blowing hot-air the coating solvent evaporates is done.
Embodiment 8
1, prescription
The label prescription:
Amlodipine Besylate Tablet (corresponding to the 5g amlodipine free base) 6.94g
Valsartan 80g
Microcrystalline Cellulose 60g
Cross-linking sodium carboxymethyl cellulose 11.8g
Silicon dioxide 4.8g
Magnesium stearate 1.6g
Make 1000
Coating fluid prescription:
Opadry II 4.8g
Purified water 24g
28.8g/1000 sheet
2, preparation technology
(1) valsartan raw material, Amlodipine Besylate Tablet raw material are crossed 90 mesh sieves respectively.
(2) microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose, silicon dioxide, magnesium stearate were dried by the fire 3.5 hours respectively at 75 ℃, cross 65 mesh sieves.
(3) take by weighing valsartan, microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose, silicon dioxide and magnesium stearate by recipe quantity, fully mixing obtains mixed powder.
(4) take by weighing the Amlodipine Besylate Tablet of recipe quantity and above-mentioned mixed powder by equivalent incremental method mixing.
(5) measure drug content, it is heavy to calculate sheet, with diameter 8mm punch die tabletting, and control tablet hardness 7kg.
(6) purified water that takes by weighing recipe quantity is put in the agitator tank, open to stir to make liquid level just form whirlpool, and the Opadry II of recipe quantity at the uniform velocity is added in the whirlpool, behind reinforced the finishing, adjusts mixing speed whirlpool is just disappeared, and continues to stir 45 minutes, and is standby.
(7) getting label puts in the coating pan, open compressed air, start the coating machine, coating pan is slowly rotated, and the preheating label is opened spray gun to about 40 ℃ the time, coating solution is sparged on the label of rotation, spraying is carried out drying with demulcent hot blast simultaneously, and spraying to coating solution finishes, and continues blowing hot-air the coating solvent evaporates is done.
Embodiment 9
1, form:
Amlodipine Besylate Tablet (corresponding to the 5g amlodipine free base) 6.94g
Valsartan 80g
Microcrystalline Cellulose 60g
Cross-linking sodium carboxymethyl cellulose 11.2g
Silicon dioxide 4.8g
Magnesium stearate 1.6g
Make 1000
2, preparation technology
(1) valsartan raw material, Amlodipine Besylate Tablet raw material are crossed 90 mesh sieves respectively.
(2) microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose, silicon dioxide, magnesium stearate were dried by the fire 3.5 hours respectively at 75 ℃, cross 65 mesh sieves.
(3) take by weighing valsartan, microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose, silicon dioxide and magnesium stearate by recipe quantity, fully mixing obtains mixed powder.
(4) take by weighing the Amlodipine Besylate Tablet and the above-mentioned mixed powder mixing of recipe quantity, obtain described pharmaceutical composition.
Embodiment 10
1, form:
Amlodipine Besylate Tablet (corresponding to the 5g amlodipine free base) 6.94g
Valsartan 80g
Microcrystalline Cellulose 60g
Cross-linking sodium carboxymethyl cellulose 5.0g
Silicon dioxide 4.8g
Magnesium stearate 1.6g
Make 1000
2, preparation technology
(1) valsartan raw material, Amlodipine Besylate Tablet raw material are crossed 90 mesh sieves respectively.
(2) microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose, silicon dioxide, magnesium stearate were dried by the fire 3.5 hours respectively at 75 ℃, cross 65 mesh sieves.
(3) take by weighing valsartan, microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose, silicon dioxide and magnesium stearate by recipe quantity, fully mixing obtains mixed powder.
(4) take by weighing the Amlodipine Besylate Tablet and the above-mentioned mixed powder mixing of recipe quantity, obtain described pharmaceutical composition.
Embodiment 11
1, form:
Amlodipine Besylate Tablet (corresponding to the 5g amlodipine free base) 6.94g
Valsartan 80g
Microcrystalline Cellulose 60g
Cross-linking sodium carboxymethyl cellulose 12.5g
Silicon dioxide 4.8g
Magnesium stearate 1.6g
Make 1000
2, preparation technology
(1) valsartan raw material, Amlodipine Besylate Tablet raw material are crossed 90 mesh sieves respectively.
(2) microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose, silicon dioxide, magnesium stearate were dried by the fire 3.5 hours respectively at 75 ℃, cross 65 mesh sieves.
(3) take by weighing valsartan, microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose, silicon dioxide and magnesium stearate by recipe quantity, fully mixing obtains mixed powder.
(4) take by weighing the Amlodipine Besylate Tablet of recipe quantity and above-mentioned mixed powder by equivalent incremental method mixing, obtain described pharmaceutical composition.
Test example 1
This test example is to investigate the influence of the consumption of disintegrating agent cross-linking sodium carboxymethyl cellulose to the dissolution of prepared tablet.Its result of the test is shown in Table 1:
Table 1
As can be seen from Table 1, when the consumption of disintegrating agent cross-linking sodium carboxymethyl cellulose be 4.8g be recipe quantity 3% the time, its dissolution just can reach more than 90%, and the dissolution of tablet increases with the increase of cross-linking sodium carboxymethyl cellulose consumption, but when the consumption of cross-linking sodium carboxymethyl cellulose is to be 5% when above of recipe quantity more than the 8g, continue to increase its consumption, dissolution increases not obvious or does not increase, and when the consumption of cross-linking sodium carboxymethyl cellulose greater than 13.2 promptly surpass recipe quantity 8% the time, its dissolution is less than 90%.Therefore, the consumption of determining cross-linking sodium carboxymethyl cellulose among the present invention is 4.7～13.2g, promptly 3～8% of recipe quantity.
Test example 2
This test example is to investigate the influence to the dissolution of prepared tablet of disintegrating agent crospovidone and cross-linking sodium carboxymethyl cellulose and consumption thereof, is shown in Table 2:
Table 2
As can be seen from the above table, when making disintegrating agent with crospovidone, when its consumption was 26.7g (be recipe quantity 15%), the slice, thin piece dissolution that makes just can reach more than 90%; The consumption of crospovidone is 16.8g (be recipe quantity 10%) when following, and the dissolution of the slice, thin piece that makes is lower.And when adopting cross-linking sodium carboxymethyl cellulose to be disintegrating agent, its consumption only is 4.7 when (be recipe quantity 3%), and its dissolution just can reach more than 90%.
Test example 3
This test example is stability of drug test of the present invention.
1, accelerated test
Adopt method pilot-scale (10000) the preparation three batch samples (lot number: 081001,081002,081003) press commercially available back of the embodiment of the invention 1,40 ℃ of temperature, placed 6 months under the condition of relative humidity 75%, take a sample respectively 1st month, 2 months, 3 months, 6 the end of month at duration of test, sample for reference outward appearance, dissolution, related substance, content etc., with comparison in 0 month, the results are shown in following table:
Table 3
With comparison in 0 month, sample appearance, dissolution, related substance and content were all constant substantially, and properties of samples is stable.
2, long term test
Adopt method pilot-scale (10000) the preparation three batch samples (lot number: 081001,081002,081003) press commercially available back of the embodiment of the invention 1,25 ℃ of temperature, place under the condition of relative humidity 60%, sampling in per 3 months once, sample for reference outward appearance, dissolution, related substance, content etc., with comparison in 0 month, the results are shown in following table 4:
Table 4
With comparison in 0 month, sample appearance, dissolution, related substance and content were all constant substantially, and properties of samples is stable.
Comparative example 1
This comparative example is medicine more of the present invention and commercially available stability comparison.
Adopt method pilot-scale (10000) the preparation one batch sample (lot number: 081001) press commercially available back of the embodiment of the invention 1, get commercially available medicine simultaneously, 25 ℃ of temperature, place under the condition of relative humidity 60%, sampling in per 3 months once, sample for reference outward appearance, dissolution, related substance, content etc. with comparison in 0 month, the results are shown in following table 5:
Table 5
As can be seen from the above table, having good stability of Amlodipine Besylate Tablet of the present invention and valsartan tablet, and the dissolution of commercially available Amlodipine Besylate Tablet and valsartan tablet, related substance and sign content are changed significantly over time, and its stability is obviously not as the present invention.
The Amlodipine Besylate Tablet of other embodiment of the present invention has also carried out identical test with the valsartan tablet, and its result is similar.
Claims (8)
1. a pharmaceutical composition that contains Amlodipine Besylate Tablet and valsartan is characterized in that, described pharmaceutical composition is made up of following prescription:
Amlodipine Besylate Tablet 5 weight portions
Valsartan 80 weight portions
Microcrystalline Cellulose 60 weight portions
Cross-linking sodium carboxymethyl cellulose 4.7～13.2 weight portions
Silicon dioxide 4.8 weight portions
Magnesium stearate 1.6 weight portions
Wherein the amount of Amlodipine Besylate Tablet is in amlodipine;
Described pharmaceutical composition is a Film coated tablets, adopts following method preparation:
1) valsartan and Amlodipine Besylate Tablet are sieved respectively, standby;
2) microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose, silicon dioxide and magnesium stearate are carried out drying respectively, sieve, standby;
3) take by weighing above-mentioned standby valsartan, microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose, silicon dioxide and magnesium stearate by recipe quantity, mixing obtains mixed powder;
4) take by weighing the Amlodipine Besylate Tablet of recipe quantity,, obtain pharmaceutical composition with the resulting mixed powder mixing of step 3);
5) resulting pharmaceutical composition is carried out direct pressed powder, coating, obtain described Film coated tablets.
2. the pharmaceutical composition that contains Amlodipine Besylate Tablet and valsartan according to claim 1 is characterized in that, described pharmaceutical composition is made up of following prescription:
Amlodipine Besylate Tablet 5 weight portions
Valsartan 80 weight portions
Microcrystalline Cellulose 60 weight portions
Cross-linking sodium carboxymethyl cellulose 8 weight portions
Silicon dioxide 4.8 weight portions
Magnesium stearate 1.6 weight portions;
Wherein the amount of Amlodipine Besylate Tablet is in amlodipine.
3. claim 1 or 2 described preparation of drug combination methods is characterized in that described preparation method comprises:
1) valsartan and Amlodipine Besylate Tablet are sieved respectively, standby;
2) microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose, silicon dioxide and magnesium stearate are carried out drying respectively, sieve, standby;
3) take by weighing above-mentioned standby valsartan, microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose, silicon dioxide and magnesium stearate by recipe quantity, mixing obtains mixed powder;
4) take by weighing the Amlodipine Besylate Tablet of recipe quantity,, obtain pharmaceutical composition with the resulting mixed powder mixing of step 3);
5) resulting pharmaceutical composition is carried out direct pressed powder, coating, obtain described Film coated tablets.
4. preparation method according to claim 3 is characterized in that, sieving to crossing 80～100 mesh sieves described in the step 1).
5. preparation method according to claim 3 is characterized in that step 2) in, described drying is to dry by the fire 2～4 hours under 60～80 ℃ of conditions, described sieving was 60～80 mesh sieves.
6. preparation method according to claim 3 is characterized in that, the mixing described in the step 4) is to adopt the equivalent method of progressively increasing to carry out mixing.
7. preparation method according to claim 3 is characterized in that, described tabletting is at 5～8kg with the slice, thin piece Hardness Control.
8. preparation method according to claim 3 is characterized in that, described coating is that the coating solution that adopts Opadry II and purified water to form carries out coating.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101987098A (en) * | 2010-11-29 | 2011-03-23 | 天津市汉康医药生物技术有限公司 | Valsartan amlodipine medicine composition |
| TR201102067A1 (en) * | 2011-03-03 | 2012-09-21 | Sanovel İlaç Sanayi̇ Ve Ti̇caret Anoni̇m Şi̇rketi̇ | Valsartan and amlodipine combinations. |
| CN102743381B (en) * | 2011-04-22 | 2014-08-27 | 重庆市力扬医药开发有限公司 | Stable candesartan cilexetil amlodipine pharmaceutical composition and its preparation method |
| CN102335176B (en) * | 2011-07-14 | 2013-06-05 | 海南锦瑞制药股份有限公司 | Brand-new oral solid medicinal composition and preparation method thereof |
| CN103211815B (en) * | 2012-02-18 | 2015-01-07 | 北京红太阳药业有限公司 | Valsartan amlodipine tablet composition and preparation method |
| CN102697778B (en) * | 2012-06-21 | 2014-04-30 | 上海医药集团股份有限公司 | Valsartan amlodipine compound solid preparation and preparation method thereof |
| CN102988364A (en) * | 2012-12-17 | 2013-03-27 | 天津亚宝药业科技有限公司 | Pharmaceutical composition containing valsartan and amlodipine besylate and preparation method |
| CN103006649B (en) * | 2012-12-27 | 2014-06-25 | 石家庄市华新药业有限责任公司 | Compound preparation of valsartan amlodipine tablet (I) and preparation method thereof |
| CN104840460B (en) * | 2014-02-13 | 2017-12-01 | 长春海悦药业股份有限公司 | A kind of pharmaceutical composition containing Valsartan and Amlodipine |
| CN104367574A (en) * | 2014-10-11 | 2015-02-25 | 江西施美制药有限公司 | Valsartan amlodipine pharmaceutical composition and preparation method thereof |
| CN109875972B (en) * | 2015-07-08 | 2021-08-03 | 南京正大天晴制药有限公司 | Olmesartan medoxomil and amlodipine pharmaceutical composition |
| CN112773792A (en) * | 2019-11-11 | 2021-05-11 | 上海博志研新药物技术有限公司 | Preparation method of valsartan amlodipine compound preparation |
| CN110693884A (en) * | 2019-11-22 | 2020-01-17 | 江苏亚邦强生药业有限公司 | Compound preparation valsartan amlodipine tablet and preparation method thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101237859A (en) * | 2005-08-17 | 2008-08-06 | 诺瓦提斯公司 | Solid dosage forms of valsartan and amlo dipine and method of making the same |
| CN101485657A (en) * | 2009-03-04 | 2009-07-22 | 浙江华海药业股份有限公司 | Diovan compound preparation and preparation method thereof |
-
2009
- 2009-09-18 CN CN 200910307306 patent/CN101647797B/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101237859A (en) * | 2005-08-17 | 2008-08-06 | 诺瓦提斯公司 | Solid dosage forms of valsartan and amlo dipine and method of making the same |
| CN101485657A (en) * | 2009-03-04 | 2009-07-22 | 浙江华海药业股份有限公司 | Diovan compound preparation and preparation method thereof |
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