CN112773792A - Preparation method of valsartan amlodipine compound preparation - Google Patents
Preparation method of valsartan amlodipine compound preparation Download PDFInfo
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- CN112773792A CN112773792A CN201911092248.4A CN201911092248A CN112773792A CN 112773792 A CN112773792 A CN 112773792A CN 201911092248 A CN201911092248 A CN 201911092248A CN 112773792 A CN112773792 A CN 112773792A
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- Prior art keywords
- valsartan
- tablet
- compound tablet
- amlodipine compound
- valsartan amlodipine
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- 239000004072 C09CA03 - Valsartan Substances 0.000 title claims abstract description 109
- 229960004699 valsartan Drugs 0.000 title claims abstract description 109
- 229960000528 amlodipine Drugs 0.000 title claims abstract description 88
- -1 valsartan amlodipine compound Chemical class 0.000 title claims abstract description 72
- 238000002360 preparation method Methods 0.000 title claims abstract description 28
- 239000000203 mixture Substances 0.000 claims abstract description 45
- 238000000034 method Methods 0.000 claims abstract description 41
- 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 claims abstract description 37
- 239000011248 coating agent Substances 0.000 claims abstract description 33
- 238000000576 coating method Methods 0.000 claims abstract description 33
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims abstract description 32
- 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 abstract description 31
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims abstract description 27
- 229940075614 colloidal silicon dioxide Drugs 0.000 claims abstract description 22
- 238000002156 mixing Methods 0.000 claims abstract description 22
- 235000019359 magnesium stearate Nutrition 0.000 claims abstract description 16
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims abstract description 15
- 229960004005 amlodipine besylate Drugs 0.000 claims abstract description 15
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims abstract description 15
- 239000008108 microcrystalline cellulose Substances 0.000 claims abstract description 15
- 229940016286 microcrystalline cellulose Drugs 0.000 claims abstract description 15
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims abstract description 12
- 229960000913 crospovidone Drugs 0.000 claims abstract description 12
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims abstract description 12
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims abstract description 12
- 238000005303 weighing Methods 0.000 claims abstract description 10
- 229920001903 high density polyethylene Polymers 0.000 claims abstract description 7
- 239000004700 high-density polyethylene Substances 0.000 claims abstract description 7
- 239000000463 material Substances 0.000 claims description 13
- 229920001328 Polyvinylidene chloride Polymers 0.000 claims description 10
- 229920000915 polyvinyl chloride Polymers 0.000 claims description 10
- 239000004800 polyvinyl chloride Substances 0.000 claims description 10
- 239000005033 polyvinylidene chloride Substances 0.000 claims description 10
- 238000010902 jet-milling Methods 0.000 claims description 9
- 238000003825 pressing Methods 0.000 claims description 9
- 238000004806 packaging method and process Methods 0.000 claims description 8
- 239000002245 particle Substances 0.000 claims description 6
- 239000008119 colloidal silica Substances 0.000 claims description 5
- 239000005022 packaging material Substances 0.000 claims description 3
- 238000004090 dissolution Methods 0.000 abstract description 17
- 239000003814 drug Substances 0.000 abstract description 14
- 239000000843 powder Substances 0.000 abstract description 9
- 238000007907 direct compression Methods 0.000 abstract description 8
- 238000005469 granulation Methods 0.000 abstract description 5
- 230000003179 granulation Effects 0.000 abstract description 5
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- 238000001035 drying Methods 0.000 abstract description 3
- 238000007908 dry granulation Methods 0.000 description 7
- 238000011049 filling Methods 0.000 description 6
- 238000007873 sieving Methods 0.000 description 6
- 238000007906 compression Methods 0.000 description 5
- 230000006835 compression Effects 0.000 description 5
- 230000001133 acceleration Effects 0.000 description 4
- 230000000052 comparative effect Effects 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 4
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 230000004584 weight gain Effects 0.000 description 3
- 235000019786 weight gain Nutrition 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 230000002411 adverse Effects 0.000 description 2
- 230000003276 anti-hypertensive effect Effects 0.000 description 2
- 230000036772 blood pressure Effects 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 238000010298 pulverizing process Methods 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 238000005550 wet granulation Methods 0.000 description 2
- QWCYQCQLAZCPHO-FTBISJDPSA-N 3-o-ethyl 5-o-methyl 2-(2-aminoethoxymethyl)-4-(2-chlorophenyl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate;(2s)-3-methyl-2-[pentanoyl-[[4-[2-(2h-tetrazol-5-yl)phenyl]phenyl]methyl]amino]butanoic acid Chemical compound CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1Cl.C1=CC(CN(C(=O)CCCC)[C@@H](C(C)C)C(O)=O)=CC=C1C1=CC=CC=C1C1=NNN=N1 QWCYQCQLAZCPHO-FTBISJDPSA-N 0.000 description 1
- 208000007530 Essential hypertension Diseases 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 206010030124 Oedema peripheral Diseases 0.000 description 1
- 239000008351 acetate buffer Substances 0.000 description 1
- 229940051123 amlodipine / valsartan Drugs 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 238000002651 drug therapy Methods 0.000 description 1
- 230000008451 emotion Effects 0.000 description 1
- 238000004134 energy conservation Methods 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000001077 hypotensive effect Effects 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 230000029865 regulation of blood pressure Effects 0.000 description 1
- 230000036454 renin-angiotensin system Effects 0.000 description 1
- 238000009818 secondary granulation Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 210000002820 sympathetic nervous system Anatomy 0.000 description 1
- 229940043102 valsartan and amlodipine Drugs 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4422—1,4-Dihydropyridines, e.g. nifedipine, nicardipine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
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- Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical & Material Sciences (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Medicinal Preparation (AREA)
- Heart & Thoracic Surgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Cardiology (AREA)
Abstract
The invention discloses a preparation method of a valsartan amlodipine compound preparation, which comprises the following steps: 1. weighing valsartan, amlodipine besylate, microcrystalline cellulose, colloidal silicon dioxide and crospovidone, and uniformly mixing to obtain a mixture A; 2. uniformly mixing the mixture A obtained in the step 1 with magnesium stearate to obtain a mixture B; 3. tabletting the mixture B obtained in the step 2 to obtain a tablet C; 4. and (4) coating the tablet C obtained in the step (3) to obtain the finished product of the valsartan amlodipine compound tablet. The preparation method of the invention adopts a powder direct compression process, greatly simplifies the process, does not need granulation and drying, saves energy and time, protects the stability of the medicament, greatly improves the disintegration of the medicament, improves the dissolution of the medicament, has high industrial automation degree, obviously reduces the production cost and has strong process adaptability. And the invention adopts high density polyethylene bottle package, which can solve the problem that the dissolution of the product is obviously reduced in the accelerating process.
Description
Technical Field
The invention relates to a preparation method of a valsartan amlodipine compound preparation.
Background
Valsartan amlodipine tablet (I) with trade name pbot; valsartan amlodipine tablets are developed and produced by the pharmaceutical company Limited, Nuohua Switzerland, and approved to be marketed in the United states and European Union in 2007, wherein the specifications of marketed in the United states include: 160mg/5mg, 160mg/10mg, 320mg/5mg, 320mg/10mg (amlodipine/valsartan) 4 specifications, and the specifications listed in the European Union are as follows: 80mg/5mg, 160mg/5mg, 160mg/10mg (valsartan/amlodipine) 3 specifications. The tablet is marketed in China in 2009-9 months, and each tablet of the specification contains 80mg of valsartan and 5mg of amlodipine, and the English commodity name is
The common name of Chinese is valsartan amlodipine tablet (I) with the trade name of
Can be used for treating essential hypertension, and for patients with insufficient blood pressure control due to single drug therapy. Amlodipine is effective for treating hypertension at 2.5-10mg 1 time per day, while valsartan is effective at 80-320 mg. In a clinical trial of 1 valsartan amlodipine tablet treatment per day, with 5-10mg of amlodipine and 80-320mg of valsartan, the hypotensive effect increases with increasing dose. The adverse effects of valsartan are generally dose independent; adverse effects of amlodipine are both dose-dependent (mainly peripheral edema) and dose-independent, the former being more common than the latter. The valsartan and amlodipine composition activates the sympathetic nervous system through the antihypertensive effect of amlodipine in pharmacology, so that the dependence of blood pressure regulation on a renin-angiotensin-aldosterone system is improved, and the antihypertensive effect of valsartan can be enhanced. Clinically, the compound preparation with a fixed prescription can reduce the medicine taking times, relieve the conflict emotion of a patient caused by the large medicine taking times, and cover the compliance of the patient in medicine taking, thereby achieving the purpose of controlling blood pressure, and on the other hand, can also reduce the side effect caused by the increase of the dosage of a single medicine.
At present, the preparation methods of valsartan amlodipine compound tablets reported include the following methods:
in CN103006649B, dry granulation is adopted, and in order to solve the problem that the content of a medicine is not uniform easily in the dry granulation process, an equivalent progressive mixing mode and secondary granulation are adopted, so that the process steps are complicated, and the production cost is high.
In the CN102670485B example, wet granulation is adopted, and impurities are easily brought in the wet granulation, hydrolysis impurities need to be controlled, and the water content is controlled to be less than 3.5%, so that the time and energy consumption are large.
Therefore, the finding of a preparation process of the valsartan amlodipine compound tablet which has simple process, energy conservation and good disintegrability and dissolution of the prepared product is a technical problem which is urgently needed to be solved at present.
Disclosure of Invention
The invention aims to overcome the defects that in the prior art, a dry granulation method is adopted, rollers are adhered in the granulation process, the material loss is large, and the prepared valsartan amlodipine compound tablet has low amlodipine content and incomplete dissolution, and the like, so that the preparation method of the valsartan amlodipine compound preparation is provided. The preparation method of the invention adopts a powder direct compression process, greatly simplifies the process, does not need granulation and drying, saves energy and time, protects the stability of the medicament, greatly improves the disintegration of the medicament, improves the dissolution of the medicament, has high industrial automation degree, obviously reduces the production cost and has strong process adaptability.
The invention provides a preparation method of a valsartan amlodipine compound tablet, which comprises the following steps:
1. weighing valsartan, amlodipine besylate, microcrystalline cellulose, colloidal silicon dioxide and crospovidone, and uniformly mixing to obtain a mixture A;
2. uniformly mixing the mixture A obtained in the step 1 with magnesium stearate to obtain a mixture B;
3. tabletting the mixture B obtained in the step 2 to obtain a tablet C;
4. and (4) coating the tablet C obtained in the step (3) to obtain the finished product of the valsartan amlodipine compound tablet.
In the step 1, the valsartan is preferably crushed firstly; the pulverizing method is preferably jet pulverizing; the particle size of the crushed particles is preferably D90 less than or equal to 10 mu m.
In step 1, the colloidal silicon dioxide is preferably sieved; the screened particle size is preferably 10 to 50 meshes, and more preferably 20 to 30 meshes.
In step 3, the hardness of the tablet is preferably 4kg to 10 kg.
In the step 3, the main pressing pressure of the pressed sheet is preferably 20KN to 22 KN.
In the step 4, the temperature of the coating material is preferably 40-50 ℃.
In the step 4, the preferable coating weight of the coating is increased by 5 to 7 percent, and the weight gain of the coating is equal to (the mass of the finished valsartan amlodipine compound tablet obtained in the step 4-the mass of the tablet C obtained in the step 3)/the mass of the tablet C obtained in the step 3 is multiplied by 100 percent.
In the invention, the finished valsartan amlodipine compound tablet is preferably packaged, and the packaging material is preferably a polyvinyl chloride/polyvinylidene chloride or high-density polyethylene bottle.
The preparation method of the valsartan amlodipine compound tablet preferably comprises the following steps:
firstly, valsartan is subjected to jet milling, and colloidal silicon dioxide is sieved by a 20-mesh sieve for later use;
weighing valsartan, amlodipine besylate, microcrystalline cellulose, colloidal silicon dioxide and crospovidone, and uniformly mixing to obtain a mixture A;
thirdly, uniformly mixing the mixture A obtained in the step II with magnesium stearate to obtain a mixture B;
fourthly, tabletting the mixture B obtained in the third step to obtain a tablet C;
fifthly, coating the tablet C obtained in the step IV to obtain a finished product of the valsartan amlodipine compound tablet;
and sixthly, packaging the finished product of the valsartan amlodipine compound tablet prepared in the fifth step to obtain the valsartan amlodipine compound tablet.
The invention also provides the valsartan amlodipine compound tablet prepared by the preparation method.
The above preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention without departing from the common general knowledge in the art.
The reagents and starting materials used in the present invention are commercially available.
In the invention, the room temperature refers to the environment temperature of 10-35 ℃.
The positive progress effects of the invention are as follows: the preparation method of the invention adopts a powder direct compression process, greatly simplifies the process, does not need granulation and drying, saves energy and time, protects the stability of the medicament, greatly improves the disintegration of the medicament, improves the dissolution of the medicament, has high industrial automation degree, obviously reduces the production cost and has strong process adaptability. And the dissolution of the product can be obviously reduced under the acceleration condition (40 ℃/75 percent RH) by adopting the polyvinyl chloride/polyvinylidene chloride package, and the problem of the obvious reduction of the dissolution of the product in the acceleration process can be solved by adopting the high-density polyethylene bottle package.
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.
Example 1
| Name of raw and auxiliary materials | Single slice (mg) |
| Valsartan | 80.00 |
| Amlodipine besylate | 6.94 |
| Microcrystalline cellulose | 69.40 |
| Cross-linked polyvidone | 6.94 |
| Colloidal silica | 2.08 |
| Magnesium stearate | 1.74 |
The preparation method of the valsartan amlodipine compound tablet adopts a powder direct compression process, and specifically comprises the following steps:
(1) jet milling valsartan (D90 is less than or equal to 10 μm), and sieving colloidal silicon dioxide with 20 mesh sieve for use.
(2) Weighing 80.00mg of valsartan, 6.94mg of amlodipine besylate, 69.40mg of microcrystalline cellulose, 2.08mg of colloidal silicon dioxide and 6.94mg of crospovidone, and uniformly mixing to obtain a mixture A.
(3) And (3) uniformly mixing the mixture A obtained in the step (2) with 1.74mg of magnesium stearate to obtain a mixture B.
(4) And (4) tabletting the mixture B obtained in the step (3) to obtain a tablet C, wherein the tablet thickness is 2.6mm, the pre-pressing thickness is 4.0mm, the filling depth is 7.9mm, the main compression pressure is 21 KN-22 KN, and the tablet hardness is 7 kg-10 kg.
(5) And (3) coating the tablet C obtained in the step (4) to obtain a finished product of the valsartan amlodipine compound tablet, wherein the temperature of a coating material is 45 +/-2 ℃, and the weight of the coating is increased by 5.7% (the weight of the coating is increased by 5% (the mass of the finished product of the valsartan amlodipine compound tablet obtained in the step (5) -the mass of the tablet C obtained in the step (4))/the mass of the tablet C obtained in the step (4) × 100%).
(6) And (5) packaging the finished product of the valsartan amlodipine compound tablet obtained in the step (5) by using polyvinyl chloride/polyvinylidene chloride to obtain the valsartan amlodipine compound tablet.
Example 2
| Name of raw and auxiliary materials | Single slice (mg) |
| Valsartan | 80.00 |
| Amlodipine besylate | 6.94 |
| Microcrystalline cellulose | 41.64 |
| Cross-linked polyvidone | 34.70 |
| Colloidal silica | 2.08 |
| Magnesium stearate | 1.74 |
The preparation method of the valsartan amlodipine compound tablet adopts a powder direct compression process and specifically comprises the following steps:
(1) jet milling valsartan (D90 is less than or equal to 10 μm), and sieving colloidal silicon dioxide with 20 mesh sieve for use.
(2) Weighing 80.00mg of valsartan, 6.94mg of amlodipine besylate, 41.64mg of microcrystalline cellulose, 2.08mg of colloidal silicon dioxide and 34.70mg of crospovidone, and uniformly mixing to obtain a mixture A.
(3) And (3) uniformly mixing the mixture A obtained in the step (2) with 1.74mg of magnesium stearate to obtain a mixture B.
(4) And (3) tabletting the mixture B obtained in the step (3) to obtain a tablet C, wherein the tablet thickness is 2.6mm, the pre-pressing thickness is 3.9mm, the filling depth is 4.3mm, the tabletting main pressure is 21 KN-22 KN, and the tablet hardness is as follows: 4 kg-10 kg.
(5) And (3) coating the tablet C obtained in the step (4) to obtain a finished product of the valsartan amlodipine compound tablet, wherein the temperature of a coating material is 45 +/-2 ℃, and the weight of the coating is increased by 6.0% (the weight gain of the coating is equal to the mass of the finished product of the valsartan amlodipine compound tablet obtained in the step (5) -the mass of the tablet C obtained in the step (4)/the mass of the tablet C obtained in the step (4) is multiplied by 100%).
(6) And packaging the finished product of the valsartan amlodipine compound tablet by using polyvinyl chloride/polyvinylidene chloride to obtain the valsartan amlodipine compound tablet.
Example 3
| Name of raw and auxiliary materials | Single slice (mg) |
| Valsartan | 80.00 |
| Amlodipine besylate | 6.94 |
| Microcrystalline cellulose | 48.58 |
| Cross-linked polyvidone | 27.76 |
| Colloidal silica | 2.50 |
| Magnesium stearate | 1.67 |
The preparation method of the valsartan amlodipine compound tablet adopts a powder direct compression process and specifically comprises the following steps:
(1) jet milling valsartan (D90 is less than or equal to 10 μm), and sieving colloidal silicon dioxide with 20 mesh sieve for use.
(2) Weighing 80.00mg of valsartan, 6.94mg of amlodipine besylate, 48.58mg of microcrystalline cellulose, 2.50mg of colloidal silicon dioxide and 27.76mg of crospovidone, and uniformly mixing to obtain a mixture A.
(3) And (3) uniformly mixing the mixture A obtained in the step (2) with 1.67mg of magnesium stearate to obtain a mixture B.
(4) And (4) tabletting the mixture B obtained in the step (3) to obtain a tablet C, wherein the tablet thickness is 2.5mm, the pre-pressing thickness is 4.2mm, the filling depth is 5.2mm, the main compression pressure is 21 KN-22 KN, and the tablet hardness is 7 kg-10 kg.
(5) And (3) coating the tablet C obtained in the step (4) to obtain a finished product of the valsartan amlodipine compound tablet, wherein the temperature of a coating material is 45 +/-2 ℃, and the weight of the coating is increased by 7.0% (the weight gain of the coating is equal to the mass of the finished product of the valsartan amlodipine compound tablet obtained in the step (5) -the mass of the tablet C obtained in the step (4)/the mass of the tablet C obtained in the step (4) is multiplied by 100%).
(6) And packaging the finished product of the valsartan amlodipine compound tablet by using polyvinyl chloride/polyvinylidene chloride to obtain the valsartan amlodipine compound tablet.
Example 4
The preparation method of the valsartan amlodipine compound tablet adopts a powder direct compression process and specifically comprises the following steps:
(1) jet milling valsartan (D90 is less than or equal to 10 μm), and sieving colloidal silicon dioxide with 20 mesh sieve for use.
(2) Weighing 80.00mg of valsartan, 6.94mg of amlodipine besylate, 55.89mg of microcrystalline cellulose, 1.67mg of colloidal silicon dioxide and 20.00mg of crospovidone, and uniformly mixing to obtain a mixture A.
(3) And (3) uniformly mixing the mixture A obtained in the step (2) with 2.50mg of magnesium stearate to obtain a mixture B.
(4) And (4) tabletting the mixture B obtained in the step (3) to obtain a tablet C, wherein the tablet thickness is 2.8mm, the pre-pressing thickness is 3.5mm, the filling depth is 5.0mm, the main compression pressure is 20 KN-21 KN, and the tablet hardness is 5 kg-8 kg.
(5) And (3) coating the tablet C obtained in the step (4) to obtain a finished product of the valsartan amlodipine compound tablet, wherein the temperature of a coating material is 45 +/-2 ℃, and the weight of the coating is increased by 6.5% (the weight of the coating is increased by the percentage (the mass of the finished product of the valsartan amlodipine compound tablet obtained in the step (5) -the mass of the tablet C obtained in the step (4))/the mass of the tablet C obtained in the step (4) × 100%).
(6) And packaging the finished product of the valsartan amlodipine compound tablet by using polyvinyl chloride/polyvinylidene chloride to obtain the valsartan amlodipine compound tablet.
Example 5
| Name of raw and auxiliary materials | Single slice (mg) |
| Valsartan | 80.00 |
| Amlodipine besylate | 6.94 |
| Microcrystalline cellulose | 69.40 |
| Cross-linked polyvidone | 6.94 |
| Colloidal silica | 2.08 |
| Magnesium stearate | 1.74 |
The preparation method of the valsartan amlodipine compound tablet adopts a powder direct compression process, and specifically comprises the following steps:
(1) jet milling valsartan (D90 is less than or equal to 10 μm), and sieving colloidal silicon dioxide with 20 mesh sieve for use.
(2) Weighing 80.00mg of valsartan, 6.94mg of amlodipine besylate, 69.40mg of microcrystalline cellulose, 2.08mg of colloidal silicon dioxide and 6.94mg of crospovidone, and uniformly mixing to obtain a mixture A.
(3) And (3) uniformly mixing the mixture A obtained in the step (2) with 1.74mg of magnesium stearate to obtain a mixture B.
(4) And (4) tabletting the mixture B obtained in the step (3) to obtain a tablet C, wherein the tablet thickness is 2.6mm, the pre-pressing thickness is 4.0mm, the filling depth is 7.9mm, the main compression pressure is 21 KN-22 KN, and the tablet hardness is 7 kg-10 kg.
(5) And (5) coating the tablet C obtained in the step (4) to obtain the finished product of the valsartan amlodipine compound tablet.
(6) And (5) packaging the finished product of the valsartan amlodipine compound tablet obtained in the step (5) by using a high-density polyethylene bottle to obtain the valsartan amlodipine compound tablet.
Comparative example 1
The preparation method of the valsartan amlodipine compound tablet adopts a dry granulation process and specifically comprises the following steps:
(1) jet milling valsartan (D90 is less than or equal to 10 μm), and sieving colloidal silicon dioxide with 20 mesh sieve for use.
(2) 80.00mg of valsartan, 6.94mg of amlodipine besylate, 55.89mg of microcrystalline cellulose, 1.67mg of colloidal silicon dioxide, 12.50mg of crospovidone (internal addition part) and 1.50mg of magnesium stearate (internal addition part) are weighed and mixed uniformly to obtain a mixture 1.
(3) And (3) granulating the mixture 1 obtained in the step (2) by a dry granulation process, wherein roller adhesion phenomenon is serious in the dry granulation process.
(4) And (3) uniformly mixing the granulated material in the step (3) with 7.50mg of crospovidone (an additional part) and 1.00mg of magnesium stearate (an additional part) to obtain a mixture 2.
(5) And (4) tabletting the mixture 2 obtained in the step (3) to obtain a tablet 3, wherein the tablet thickness is 2.7mm, the pre-pressing thickness is 3.8mm, the filling depth is 4.2mm, the main compression pressure is 20 KN-21 KN, and the tablet hardness is 4 kg-7 kg.
(6) And (3) coating the tablet 3 obtained in the step (5) to obtain a finished product of the valsartan amlodipine compound tablet, wherein the temperature of a coating material is 45 +/-2 ℃, and the weight of the coating is increased by 6.7% (the weight of the coating is increased by the percentage (the mass of the finished product of the valsartan amlodipine compound tablet obtained in the step (6) -the mass of the tablet 3 obtained in the step (5))/the mass of the tablet 3 obtained in the step (5) × 100%).
(7) And packaging the finished product of the valsartan amlodipine compound tablet by using polyvinyl chloride/polyvinylidene chloride to obtain the valsartan amlodipine compound tablet.
Dissolution data Table of Compound tablet of Valsartan amlodipine prepared in examples 1-4 and comparative example 1 in hydrochloric acid solution of pH1.2 (temperature 37. + -. 0.5 ℃ C.)
Dissolution data of the valsartan amlodipine compound tablets prepared in examples 1 to 4 and comparative example 1 in acetic acid solution at pH4.5 (temperature 37. + -. 0.5 ℃ C.)
The above experiments show that:
1. comparative example 1 the adhesion of the roller during the dry granulation process was severe, and the content of amlodipine intermediate and the content of the tablet were both low due to the low amlodipine content and the easy loss during the granulation process. And the prepared granules are hard, are slowly disintegrated in the dissolution process and are not completely dissolved.
2. The embodiment 1-4 of the invention has the advantages of direct powder pressing, simple operation, better disintegration phenomenon in the dissolution process, complete dissolution and solving the content problem of amlodipine.
EXAMPLES 1 AND 5 dissolution data of Compound Valsartan amlodipine tablets prepared in example 1 and example 5 in acetate buffer pH4.5 (accelerated conditions of 40 deg.C/75% RH)
The dissolution data show that the dissolution can be remarkably reduced under the acceleration condition (40 ℃/75% RH) by adopting the polyvinyl chloride/polyvinylidene chloride package, and the problem of the remarkable reduction of the dissolution of the product in the acceleration process can be solved by adopting the high-density polyethylene bottle package.
Claims (10)
1. The preparation method of the valsartan amlodipine compound tablet is characterized by comprising the following steps of:
1. weighing valsartan, amlodipine besylate, microcrystalline cellulose, colloidal silicon dioxide and crospovidone, and uniformly mixing to obtain a mixture A;
2. uniformly mixing the mixture A obtained in the step 1 with magnesium stearate to obtain a mixture B;
3. tabletting the mixture B obtained in the step 2 to obtain a tablet C;
4. and (4) coating the tablet C obtained in the step (3) to obtain the finished product of the valsartan amlodipine compound tablet.
2. The method for preparing a valsartan amlodipine compound tablet according to claim 1, wherein the valsartan amlodipine compound tablet comprises the following steps:
in the step 1, valsartan is firstly crushed;
and/or the presence of a gas in the gas,
in step 1, the colloidal silica is first screened.
3. The method for preparing a valsartan amlodipine compound tablet as claimed in claim 2, wherein the method comprises the following steps:
in the step 1, the crushing method is jet milling;
and/or the presence of a gas in the gas,
in the step 1, the particle size of the crushed material is D90 not more than 10 μm;
and/or the presence of a gas in the gas,
in the step 1, the particle size of the colloidal silicon dioxide is 10-50 meshes.
4. The method for preparing the valsartan amlodipine compound tablet as claimed in claim 3, wherein the method comprises the following steps: in the step 1, the particle size of the colloidal silicon dioxide is 20-30 meshes.
5. The method for preparing a valsartan amlodipine compound tablet according to claim 1, wherein the valsartan amlodipine compound tablet comprises the following steps:
in the step 3, the hardness of the pressed sheet is 4 kg-10 kg;
and/or the presence of a gas in the gas,
in the step 3, the main pressing pressure of the pressed sheet is 20 KN-22 KN.
6. The method for preparing a valsartan amlodipine compound tablet according to claim 1, wherein the valsartan amlodipine compound tablet comprises the following steps: in the step 4, the temperature of the coating material is 40-50 ℃;
and/or the presence of a gas in the gas,
in the step 4, the weight of the coating is increased by 5-7%, wherein the weight increase of the coating is (the mass of the finished valsartan amlodipine compound tablet obtained in the step 4-the mass of the tablet C obtained in the step 3)/the mass of the tablet C obtained in the step 3 is multiplied by 100%.
7. The method for preparing a valsartan amlodipine compound tablet according to claim 1, wherein the valsartan amlodipine compound tablet comprises the following steps: the finished product of the valsartan amlodipine compound tablet is packaged, and the packaging material is polyvinyl chloride/polyvinylidene chloride or a high-density polyethylene bottle.
8. The method for preparing a valsartan amlodipine compound tablet according to claim 1, wherein the valsartan amlodipine compound tablet comprises the following steps: the preparation method of the valsartan amlodipine compound tablet comprises the following steps:
firstly, valsartan is subjected to jet milling, and colloidal silicon dioxide is sieved by a 20-mesh sieve for later use;
weighing valsartan, amlodipine besylate, microcrystalline cellulose, colloidal silicon dioxide and crospovidone, and uniformly mixing to obtain a mixture A;
thirdly, uniformly mixing the mixture A obtained in the step II with magnesium stearate to obtain a mixture B;
fourthly, tabletting the mixture B obtained in the third step to obtain a tablet C;
fifthly, coating the tablet C obtained in the step IV to obtain a finished product of the valsartan amlodipine compound tablet;
and sixthly, packaging the finished product of the valsartan amlodipine compound tablet prepared in the fifth step to obtain the valsartan amlodipine compound tablet.
9. The method for preparing a valsartan amlodipine compound tablet according to claim 8, wherein the valsartan amlodipine compound tablet comprises the following steps: the packaging material is a polyvinyl chloride/polyvinylidene chloride or high-density polyethylene bottle.
10. The valsartan amlodipine compound tablet prepared by the preparation method of the valsartan amlodipine compound tablet according to any one of claims 1 to 9.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101647797A (en) * | 2009-09-18 | 2010-02-17 | 海南锦瑞制药股份有限公司 | Pharmaceutical composition containing Amlodipine besilate and valsartan and preparation method thereof |
| 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 |
| CN104840460A (en) * | 2014-02-13 | 2015-08-19 | 长春海悦药业有限公司 | Pharmaceutical composition containing valsartan and amlodipine |
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2019
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101647797A (en) * | 2009-09-18 | 2010-02-17 | 海南锦瑞制药股份有限公司 | Pharmaceutical composition containing Amlodipine besilate and valsartan and preparation method thereof |
| CN104840460A (en) * | 2014-02-13 | 2015-08-19 | 长春海悦药业有限公司 | 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 |
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Application publication date: 20210511 |