CN105106198B - A kind of Simvastatin Tablets of high stability and preparation method thereof - Google Patents
A kind of Simvastatin Tablets of high stability and preparation method thereof Download PDFInfo
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- CN105106198B CN105106198B CN201510595499.XA CN201510595499A CN105106198B CN 105106198 B CN105106198 B CN 105106198B CN 201510595499 A CN201510595499 A CN 201510595499A CN 105106198 B CN105106198 B CN 105106198B
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- RYMZZMVNJRMUDD-HGQWONQESA-N simvastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)C(C)(C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 RYMZZMVNJRMUDD-HGQWONQESA-N 0.000 title claims abstract description 110
- 229960002855 simvastatin Drugs 0.000 title claims abstract description 110
- 238000002360 preparation method Methods 0.000 title claims description 30
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 68
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- 239000002245 particle Substances 0.000 claims abstract description 40
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- 235000019282 butylated hydroxyanisole Nutrition 0.000 claims abstract description 24
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- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims abstract description 23
- 239000004255 Butylated hydroxyanisole Substances 0.000 claims abstract description 22
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims abstract description 22
- CZBZUDVBLSSABA-UHFFFAOYSA-N butylated hydroxyanisole Chemical compound COC1=CC=C(O)C(C(C)(C)C)=C1.COC1=CC=C(O)C=C1C(C)(C)C CZBZUDVBLSSABA-UHFFFAOYSA-N 0.000 claims abstract description 22
- 229940043253 butylated hydroxyanisole Drugs 0.000 claims abstract description 22
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- 235000019813 microcrystalline cellulose Nutrition 0.000 claims abstract description 22
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- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims abstract description 21
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- 239000003826 tablet Substances 0.000 claims description 74
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- 229920003081 Povidone K 30 Polymers 0.000 claims description 28
- 235000019441 ethanol Nutrition 0.000 claims description 17
- 239000002994 raw material Substances 0.000 claims description 17
- 238000001035 drying Methods 0.000 claims description 16
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- 238000000034 method Methods 0.000 claims description 14
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- 239000000843 powder Substances 0.000 claims description 6
- 239000007891 compressed tablet Substances 0.000 claims description 4
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- HSHXDCVZWHOWCS-UHFFFAOYSA-N N'-hexadecylthiophene-2-carbohydrazide Chemical compound CCCCCCCCCCCCCCCCNNC(=O)c1cccs1 HSHXDCVZWHOWCS-UHFFFAOYSA-N 0.000 description 14
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 10
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- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 8
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- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 4
- -1 and it act as:1st Chemical compound 0.000 description 4
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- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
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- CABVTRNMFUVUDM-VRHQGPGLSA-N (3S)-3-hydroxy-3-methylglutaryl-CoA Chemical compound O[C@@H]1[C@H](OP(O)(O)=O)[C@@H](COP(O)(=O)OP(O)(=O)OCC(C)(C)[C@@H](O)C(=O)NCCC(=O)NCCSC(=O)C[C@@](O)(CC(O)=O)C)O[C@H]1N1C2=NC=NC(N)=C2N=C1 CABVTRNMFUVUDM-VRHQGPGLSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
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- 102000007330 LDL Lipoproteins Human genes 0.000 description 2
- PCZOHLXUXFIOCF-UHFFFAOYSA-N Monacolin X Natural products C12C(OC(=O)C(C)CC)CC(C)C=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 PCZOHLXUXFIOCF-UHFFFAOYSA-N 0.000 description 2
- 108090000854 Oxidoreductases Proteins 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical class [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 2
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- PCZOHLXUXFIOCF-BXMDZJJMSA-N lovastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 PCZOHLXUXFIOCF-BXMDZJJMSA-N 0.000 description 2
- 229960004844 lovastatin Drugs 0.000 description 2
- QLJODMDSTUBWDW-UHFFFAOYSA-N lovastatin hydroxy acid Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CC(C)C=C21 QLJODMDSTUBWDW-UHFFFAOYSA-N 0.000 description 2
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- 238000012216 screening Methods 0.000 description 2
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- 238000010268 HPLC based assay Methods 0.000 description 1
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- 102000000853 LDL receptors Human genes 0.000 description 1
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- RCEAADKTGXTDOA-UHFFFAOYSA-N OS(O)(=O)=O.CCCCCCCCCCCC[Na] Chemical compound OS(O)(=O)=O.CCCCCCCCCCCC[Na] RCEAADKTGXTDOA-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
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- JKQOBWVOAYFWKG-UHFFFAOYSA-N molybdenum trioxide Chemical compound O=[Mo](=O)=O JKQOBWVOAYFWKG-UHFFFAOYSA-N 0.000 description 1
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- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 1
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- 229940103121 simvastatin 80 mg Drugs 0.000 description 1
- XWLXKKNPFMNSFA-HGQWONQESA-N simvastatin hydroxy acid Chemical compound C1=C[C@H](C)[C@H](CC[C@@H](O)C[C@@H](O)CC(O)=O)[C@H]2[C@@H](OC(=O)C(C)(C)CC)C[C@@H](C)C=C21 XWLXKKNPFMNSFA-HGQWONQESA-N 0.000 description 1
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- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical class [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- KKCBUQHMOMHUOY-UHFFFAOYSA-N sodium oxide Chemical compound [O-2].[Na+].[Na+] KKCBUQHMOMHUOY-UHFFFAOYSA-N 0.000 description 1
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- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 238000002604 ultrasonography Methods 0.000 description 1
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Landscapes
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a kind of Simvastatin Tablets of high stability, the Simvastatin Tablets include following component by weight：5 20 parts of Simvastatin, 8 20 parts of pregelatinized starch, 0.03 0.06 parts of butylated hydroxy anisole, 0.3 1 parts of PVP K30,45 55 parts of lactose, 35 45 parts of microcrystalline cellulose, 35 parts of hydroxypropylcellulose, 0.5 2 parts of hydroxypropyl methylcellulose, 0.2 1.2 parts of magnesium stearate, 0.6 2.4 parts of differential silica gel.Prepared by Simvastatin Tablets of the present invention is pelletized using two parts, and Simvastatin uses absolute ethyl alcohol with pregelatinized starch, is toasted with lower temperature, avoids the degraded of Simvastatin；Toasted using higher temperature other part.Particle compressibility and mobility prepared by the present invention is preferable.The disintegration time of obtained tablet is suitable, and tablet content, uniformity of dosage units and dissolution rate meet the requirements, and has high stability, production method is simple, is suitable for industrialized production.
Description
Technical field
The present invention relates to technical field of pharmaceuticals, Simvastatin Tablets and its preparation side of a kind of high stability are more particularly to
Method.
Background technology
Simvastatin is the competitive inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, is one
The efficient hypolipidemic of kind.Simvastatin can block the synthesis of cholesterol, and it act as：1st, cholesterol biosynthesis is competitively suppressed
Rate-limiting enzyme-methylhydroxyglutaryl CoA reductase in enzyme system, is suppressed cholesterol biosynthesis.2nd, surface of hepatocytes is increased
LDL receptor, LDL-C is removed increase, while also make the precursor of low-density lipoprotein extremely low
Density lipoprotein removes increase.3rd, increase HDL-C synthesis, be advantageous to the transhipment and removing of cholesterol.The medicine
Curative effect is high, Small side effects, it has also become the most frequently used a kind of hypolipidemic in the whole world.
Simvastatin stability is poor, is degraded easily by hydrolyzing and aoxidizing two kinds of approach：Lactone under conditions of high humidity
Key ring open loop generates its active metabolite Simvastatin carboxylic acid；Slow oxygen occurs for the ethylene linkage of intramolecule two under the high temperature conditions
Change copolyreaction generation dimer or polymer.
CN103356494 A are used Simvastatin is coated after again with other auxiliary materials dry pressing twice, to improve pungent cut down
The stability of statin piece, solves Simvastatin Tablets less stable of the prior art, but this method will to production equipment
Ask high, production is cumbersome.
CN103330692 A provide a kind of Simvastatin component for improving stability and preparation method thereof, take and are added without
The mode reasonable selection accessory formula and dosage and feed postition of antioxidant, Simvastatin stability is kept, but this method is
Direct tablet compressing is higher to auxiliary material and equipment requirement.
The content of the invention
(1) technical problems to be solved
The technical problem to be solved in the present invention is how the dissolution rate of raising Simvastatin Tablets, increases Simvastatin Tablets
Stability, and a kind of Simvastatin Tablets of high stability and preparation method thereof are provided.
(2) technical scheme
In order to solve the above-mentioned technical problem, the invention provides a kind of Simvastatin Tablets of high stability, the Simvastatin
Piece includes following component by weight：Simvastatin 5-20 parts, pregelatinized starch 8-20 parts, butylated hydroxy anisole 0.03-
0.06 part, PVP K30 0.3-1 parts, lactose 45-55 parts, microcrystalline cellulose 35-45 parts, hydroxypropylcellulose 3-5 parts, hydroxypropyl first
Cellulose 0.5-2 parts, magnesium stearate 0.2-1.2 parts, differential silica gel 0.6-2.4 parts.
Preferably, the Simvastatin Tablets include following component by weight：Simvastatin 10-20 parts, pregelatinized starch
10-15 parts, butylated hydroxy anisole 0.04-0.05 parts, PVP K30 0.3-0.8 parts, lactose 48-52 parts, microcrystalline cellulose
38-42 parts, hydroxypropylcellulose 3.5-4.5 parts, hydroxypropyl methylcellulose 0.8-1.5 parts, magnesium stearate 0.4-1.0 parts, differential silica gel
0.8-1.8 parts.
Preferably, the Simvastatin Tablets include following component by weight：10 parts of Simvastatin, pregelatinized starch 15
Part, 0.05 part of butylated hydroxy anisole, 0.5 part of PVP K30,50 parts of lactose, 40 parts of microcrystalline cellulose, hydroxypropylcellulose 4
Part, 1 part of hydroxypropyl methylcellulose, 0.6 part of magnesium stearate, 1.2 parts of differential silica gel.
The PVP K30 is provided in the form of 10-15% PVP K30 ethanol solutions；The hypromellose
Element is provided in the form of the 1-3% hydroxypropyl methylcellulose aqueous solution.
The present invention considers from factors such as the requirements of disintegration behavior, particle compressibility and mobility, and auxiliary material used is selected
Select.Simvastatin is soluble in ethanol, acetone or acetonitrile, it is more difficult to ether is dissolved in, it is several not soluble in water.Pregelatinized starch is that tablet is commonly used
Filler, pelletized using absolute ethyl alcohol, granule fines are more, therefore use the preferable pregelatinized starch of mobility；PVP
K30Hydrophily it is very strong, have solubilization, therefore, selection PVP K30 is adhesive；Microcrystalline cellulose, lactose are used as and filled out
Fill agent and microcrystalline cellulose has disintegrant effect concurrently and can accelerate the disintegration of tablet, improve the dissolution of medicine；Hydroxypropylcellulose is
Disintegrant, three's mixing granulation can increase the release of medicine, reach release standard.Magnesium stearate is lubricant, differential silica gel is
Glidant, two kinds share, and mobility of particle is good, and tablet weight variation is small.Above-mentioned formula is obtained by strict, science screening.
Present invention also offers the preparation method of the Simvastatin Tablets of high stability, this method comprises the following steps：
Step 1：Stock：Each component is weighed by formula, each component is crossed into 60-100 mesh sieves respectively, it is standby；Toast pregelatinated
Starch, it is standby；PVP K30 is dissolved in absolute ethyl alcohol, the ethanol solution that mass concentration is 10-15% is made, it is standby；
Hydroxypropyl methylcellulose is dissolved in water second, the aqueous solution that mass concentration is 1-3% is made, it is standby；
Step 2：Prepare particle 1：Simvastatin and pregelatinized starch are uniformly mixed, butylated hydroxy anisole is dissolved in
In absolute ethyl alcohol；Softwood is made in said components with above-mentioned PVP K30 ethanol solution, 15-20 mesh sieves is crossed, pelletizes, dry
It is dry, after 15-20 mesh sieves, whole grain, particle 1 is obtained, it is standby；
Step 3：Prepare particle 2：Lactose, microcrystalline cellulose and hydroxypropylcellulose are uniformly mixed, it is fine with above-mentioned hydroxypropyl first
Tie up the plain aqueous solution and said components are made softwood, cross 15-20 mesh sieves, pelletize, drying, after 15-20 mesh sieves, whole grain obtains
Grain 2, it is standby；
Step 4：Preparation of preparation raw material：Particle 1 and particle 2 are uniformly mixed with magnesium stearate and differential silica gel, made
Agent raw material, it is standby；
Step 5：Compressed tablets:It is with tablet press machine that above-mentioned preparation raw material is tabletted, produce.
Preferably, in step 1, the temperature of the baking pregelatinized starch is 100-110 DEG C, and the time is 2-3 hours.
Preferably, in step 2, the drying temperature is 35-45 DEG C.
Preferably, in step 3, the drying temperature is 55-65 DEG C.
Preferably, the preparation method of the Simvastatin Tablets of described high stability, this method comprise the following steps：
Step 1：Stock：Each component is weighed by formula, each component is crossed into 80 mesh sieves respectively, it is standby；Pregelatinized starch is existed
105 DEG C are toasted 2 hours, standby；PVP K30 is dissolved in absolute ethyl alcohol, it is molten that the absolute ethyl alcohol that mass concentration is 12% is made
Liquid, it is standby；Hydroxypropyl methylcellulose is dissolved in water second, the aqueous solution that mass concentration is 2% is made, it is standby；
Step 2：Prepare particle 1：Simvastatin and pregelatinized starch are uniformly mixed, butylated hydroxy anisole is dissolved in
In absolute ethyl alcohol；Softwood is made in said components with above-mentioned PVP K30 ethanol solution, crosses 18 mesh sieves, granulation, at 40 DEG C
Drying, after 18 mesh sieves, whole grain, obtains particle 1, standby；
Step 3：Prepare particle 2：Lactose, microcrystalline cellulose and hydroxypropylcellulose are uniformly mixed, it is fine with above-mentioned hydroxypropyl first
Tie up the plain aqueous solution and said components are made softwood, cross 18 mesh sieves, granulation, in 60 DEG C of drying, after 18 mesh sieves, whole grain obtains
Grain 2, it is standby；
Step 4：Preparation of preparation raw material：Particle 1 and particle 2 are uniformly mixed with magnesium stearate and differential silica gel, made
Agent raw material, it is standby；
Step 5：Compressed tablets:It is with tablet press machine that above-mentioned preparation raw material is tabletted, produce.
Preferably, the pressure of the tablet press machine is 4-5kg.
Preferably, the mould that the tablet press machine uses is shallow concave punch.
The specification of Simvastatin Tablets of the present invention is every 10mg containing Simvastatin, 20mg.
Because Simvastatin is to moisture-sensitive, pregelatinized starch is aqueous higher, small in 105 DEG C of bakings 2 using preceding needing
When, it is standby.Simvastatin is several not soluble in water in order to improve dissolution, it is desirable to which tablet disintegration times should be less than 3 minutes.It is required that tablet
Hardness is controlled in 4-5kg, can meet movement requirement, and can reaches Fast Stripping.
(3) beneficial effect
The present invention is from the requirement of disintegration behavior, particle compressibility and mobility, and the particularly factor such as stability considers, to institute
Selected with auxiliary material.Pelletized using absolute ethyl alcohol, granule fines are more, therefore use the preferable pregelatinized starch of mobility；
The hydrophily of PVP K30 is very strong, there is solubilization, therefore, selection 30 POVIDONE K 30 BP/USP30For adhesive；Microcrystalline cellulose, which has concurrently, to be collapsed
Solution agent effect can accelerate the disintegration of tablet, improve the dissolution of medicine；Hydroxypropylcellulose is also disintegrant, can increase releasing for medicine
Put.Magnesium stearate is lubricant, differential silica gel is glidant, and two kinds share, and mobility of particle is good, and tablet weight variation is small.In a word, pass through
Cross the strict, screening of science and obtain above-mentioned formula.Prepared by Simvastatin Tablets of the present invention is pelletized using two parts, Simvastatin with it is pre-
Gelling starch uses absolute ethyl alcohol, is toasted with lower temperature, avoids the degraded of Simvastatin；Dried using higher temperature other part
It is roasting.Particle compressibility and mobility prepared by the present invention is preferable.The disintegration time of obtained tablet is suitable, tablet content, contains
The amount uniformity and dissolution rate meet the requirements, and have high stability, production method is simple, is suitable for industrialized production.
Embodiment
Embodiments of the present invention are described in further detail with reference to embodiment.Following examples are used to illustrate this
Invention, but can not be used for limiting the scope of the present invention.
The present invention is raw materials used can be by being commercially available：
(1) Simvastatin:Shangyu Jingxin Pharmaceutical Co., Ltd. produces, quality standard：WS1-(X-064-2003Z)
(2) pregelatinized starch:Huzhou prospect medicine company auxiliary material Co., Ltd, meets Chinese Pharmacopoeia 2010 edition two
(3) lactose:Shanghai Huamao Pharmaceutical Co, meet Chinese Pharmacopoeia 2010 edition two
(4) microcrystalline cellulose:Anhui Shanhe Medical Accessary Material Co., Ltd., meet Chinese Pharmacopoeia 2010 edition two
(5) PVP K30:Anhui Shanhe Medical Accessary Material Co., Ltd., meet Chinese Pharmacopoeia 2010 edition two
(6) magnesium stearate:Anhui Shanhe Medical Accessary Material Co., Ltd., meet Chinese Pharmacopoeia 2010 edition two
(7) silica:Anhui Shanhe Medical Accessary Material Co., Ltd., meet Chinese Pharmacopoeia 2010 edition two
(8) hydroxypropylcellulose:Anhui Shanhe Medical Accessary Material Co., Ltd., meet Chinese Pharmacopoeia 2010 edition two
(9) hydroxypropyl methylcellulose:Tso Tat Co., Ltd., Japan
(10) butylated hydroxy anisole (BHA):Shanghai Import and Export Co., Ltd. of Gionee Thailand
Embodiment 1
Simvastatin Tablets include following component：Simvastatin 10g, pregelatinized starch 15g, butylated hydroxy anisole 0.05g,
PVP K30 0.5g, lactose 50g, microcrystalline cellulose 40g, hydroxypropylcellulose 4g, hydroxypropyl methylcellulose 1g, magnesium stearate
0.6g, differential silica gel 1.2g.
Above-mentioned Simvastatin Tablets are prepared as follows：
Each component is weighed by formula, each component is crossed into 80 mesh sieves respectively, it is standby；Pregelatinized starch is small in 105 DEG C of bakings 2
When, it is standby；PVP K30 is dissolved in absolute ethyl alcohol, the ethanol solution that mass concentration is 12% is made, it is standby；By hydroxyl
Third methylcellulose is dissolved in water second, and the aqueous solution that mass concentration is 2% is made, standby；
Simvastatin and pregelatinized starch are uniformly mixed, butylated hydroxy anisole is dissolved in absolute ethyl alcohol；With above-mentioned
Softwood is made in said components by PVP K30 ethanol solution, crosses 18 mesh sieves, granulation, in 40 DEG C of drying, after 18 mesh sieves,
Whole grain, particle 1 is obtained, it is standby；
Lactose, microcrystalline cellulose and hydroxypropylcellulose are uniformly mixed, will be above-mentioned with the above-mentioned hydroxypropyl methylcellulose aqueous solution
Softwood is made in component, crosses 18 mesh sieves, granulation, in 60 DEG C of drying, after 18 mesh sieves, whole grain, obtains particle 2, standby；
Particle 1 and particle 2 are uniformly mixed with magnesium stearate and differential silica gel, obtain preparation raw material, it is standby；
With tablet press machine that above-mentioned preparation raw material is tabletted, mould is ф 6.5mm shallow concave punch, and Stress control exists
4.5kg, produce.
Embodiment 2
Simvastatin Tablets include following component：Simvastatin 10g, pregelatinized starch 10g, butylated hydroxy anisole 0.04g,
PVP K30 0.3g, lactose 48g, microcrystalline cellulose 38g, hydroxypropylcellulose 3.5g, hydroxypropyl methylcellulose 0.8g, magnesium stearate
0.4g, differential silica gel 0.8g.
Above-mentioned Simvastatin Tablets are prepared as follows：
Each component is weighed by formula, each component is crossed into 60 mesh sieves respectively, it is standby；Pregelatinized starch is small in 100 DEG C of bakings 2
When, it is standby；PVP K30 is dissolved in absolute ethyl alcohol, the ethanol solution that mass concentration is 10% is made, it is standby；By hydroxyl
Third methylcellulose is dissolved in water second, and the aqueous solution that mass concentration is 1% is made, standby；
Simvastatin and pregelatinized starch are uniformly mixed, butylated hydroxy anisole is dissolved in absolute ethyl alcohol；With above-mentioned
Softwood is made in said components by PVP K30 ethanol solution, crosses 15 mesh sieves, granulation, in 35 DEG C of drying, after 15 mesh sieves,
Whole grain, particle 1 is obtained, it is standby；
Lactose, microcrystalline cellulose and hydroxypropylcellulose are uniformly mixed, will be above-mentioned with the above-mentioned hydroxypropyl methylcellulose aqueous solution
Softwood is made in component, crosses 15 mesh sieves, granulation, in 55 DEG C of drying, after 15 mesh sieves, whole grain, obtains particle 2, standby；
Particle 1 and particle 2 are uniformly mixed with magnesium stearate and differential silica gel, obtain preparation raw material, it is standby；
With tablet press machine that above-mentioned preparation raw material is tabletted, mould is ф 6.5mm shallow concave punch, Stress control in 4kg,
Produce.
Embodiment 3
Simvastatin Tablets include following component：Simvastatin 20g, pregelatinized starch 15g, butylated hydroxy anisole 0.05g,
PVP K30 0.8g, lactose 52g, microcrystalline cellulose 42g, hydroxypropylcellulose 4.5g, hydroxypropyl methylcellulose 1.5g, magnesium stearate
1.0g, differential silica gel 1.8g.
Above-mentioned Simvastatin Tablets are prepared as follows：
Each component is weighed by formula, each component is crossed into 100 mesh sieves respectively, it is standby；Pregelatinized starch is toasted 3 at 110 DEG C
Hour, it is standby；PVP K30 is dissolved in absolute ethyl alcohol, the ethanol solution that mass concentration is 15% is made, it is standby；Will
Hydroxypropyl methylcellulose is dissolved in water second, and the aqueous solution that mass concentration is 3% is made, standby；
Simvastatin and pregelatinized starch are uniformly mixed, butylated hydroxy anisole is dissolved in absolute ethyl alcohol；With above-mentioned
Softwood is made in said components by PVP K30 ethanol solution, crosses 20 mesh sieves, granulation, in 45 DEG C of drying, after 20 mesh sieves,
Whole grain, particle 1 is obtained, it is standby；
Lactose, microcrystalline cellulose and hydroxypropylcellulose are uniformly mixed, will be above-mentioned with the above-mentioned hydroxypropyl methylcellulose aqueous solution
Softwood is made in component, crosses 20 mesh sieves, granulation, in 65 DEG C of drying, after 20 mesh sieves, whole grain, obtains particle 2, standby；
Particle 1 and particle 2 are uniformly mixed with magnesium stearate and differential silica gel, obtain preparation raw material, it is standby；
With tablet press machine that above-mentioned preparation raw material is tabletted, mould is ф 6.5mm shallow concave punch, Stress control in 5kg,
Produce.
Embodiment 4
Simvastatin Tablets include following component：Simvastatin 5g, pregelatinized starch 8g, butylated hydroxy anisole 0.03g, gather
Tie up ketone K30 0.3g, lactose 45g, microcrystalline cellulose 35g, hydroxypropylcellulose 3g, hydroxypropyl methylcellulose 0.5g, magnesium stearate
0.2g, differential silica gel 0.6g.
Its preparation method is the same as embodiment 1.
Embodiment 5
Simvastatin Tablets include following component：Simvastatin 20g, pregelatinized starch 20g, butylated hydroxy anisole 0.06g,
PVP K30 1g, lactose 55g, microcrystalline cellulose 45g, hydroxypropylcellulose 5g, hydroxypropyl methylcellulose 2g, magnesium stearate 1.2g,
Differential silica gel 2.4g.
Its preparation method is the same as embodiment 1.
Test example：The detection of Simvastatin Tablets
Take the tablet of above-described embodiment 1,2,3 and existing domestic listing Simvastatin Tablets (Kamp Pharmaceuticals Co., Ltd. batch
Number 140201) be control 1, import Simvastatin Tablets (the simvastatin lot number 130583 of Hangzhou Mo Shadong pharmaceutical Co. Ltds) for pair
According to 2, check experiment is carried out.
Simvastatin Tablets assay：
Tested according to regulation under Chinese Pharmacopoeia two annex VD (high performance liquid chromatography) items of version in 2010.
(1) chromatographic condition and system suitability：
It is filler with octadecylsilane chemically bonded silica；Phosphoric acid or hydrogen (are used with 0.025mol/L sodium dihydrogen phosphates
Sodium oxide molybdena test solution adjusts pH value to 4.5)-acetonitrile (35：65) it is mobile phase；Detection wavelength is 238nm, takes Simvastatin reference substance
It is each appropriate with Lovastatin reference substance, take Simvastatin Tablets fine powder appropriate, add mixed solution acetonitrile -0.05mol/L sodium acetates molten
Liquid (adjusting pH value to 4.0 with glacial acetic acid) (8：2)) in right amount, shaking dissolves Simvastatin and diluted to be made in every lml containing about 20
μ g solution, 20 μ l are taken to note people's liquid chromatograph, the separating degree between Simvastatin peak and Lovastatin peak should be greater than 3, theory
Plate number is calculated by Simvastatin peak is not less than 2000.
(2) content assaying method
Assay method is takes this product 20, and accurately weighed, finely ground, precision weighs (is approximately equivalent to Simvastatin in right amount
10mg), put in 100ml measuring bottles, add mixed solution appropriate, ultrasound dissolves Simvastatin, is diluted to scale with mixed solution, shakes
Even, filtration, precision measures the μ l of subsequent filtrate 20 injection liquid chromatographs, records chromatogram；Simvastatin reference substance separately is taken, is surveyed with method
It is fixed.By external standard method with calculated by peak area, produce.
Precision weighs test sample (product of embodiment 1,2,3) and (Kamp Pharmaceuticals Co., Ltd.'s production of control 1 respectively
Simvastatin Tablets), compare 2 (simvastatins of Hangzhou Mo Shadong pharmaceutical Co. Ltds), by content assaying method prepare solution, essence
It is close to measure the μ l of subsequent filtrate 20 injection liquid chromatographs, record chromatogram；Simvastatin reference substance separately is taken, is measured in the same method.By external standard
Method the results are shown in Table 1 with the content of Simvastatin in calculated by peak area test sample.
Table 1：HPLC assay results
| Sample | Embodiment 1 | Embodiment 2 | Embodiment 3 | Control 1 | Control 2 |
| Content (%) | 100.1 | 99.9 | 99.6 | 102.1 | 101.2 |
Assay result shows：Three batches of sample sizes meet Simvastatin Tablets quality standard regulation, containing Simvastatin
It should be the 90.0%-110.0% of labelled amount.
(3) Determination of Content Uniformity
Tested by regulation under Chinese Pharmacopoeia version in 2010 two annex XE (uniformity of dosage units detection method) item.Respectively take 10
Piece (product of embodiment 1,2,3), takes this product 1, is placed in 100ml measuring bottles, add mixed solution acetonitrile -0.05mol/L respectively
Sodium acetate solution (adjusting pH value to 4.0 with glacial acetic acid) (8：2)) in right amount, fully vibration dissolves Simvastatin, uses mixed solution
Scale is diluted to, is shaken up, is filtered, is taken subsequent filtrate, determined according to the method under assay item and calculate content and standard deviation, as a result
It is shown in Table 2, wherein A is the absolute value (A=| 100-X |) for representing labelled amount and average X difference, and S is standard deviation.
Table 2：Determination of Content Uniformity result
According to Determination of Content Uniformity result, A+1.80S≤15.0 of Simvastatin Tablets, i.e. uniformity of dosage units meet rule
It is fixed.
(4) Dissolution profiles and dissolution determination
Dissolution profiles assay method：According to dissolution determination method (two annex XC (second of Chinese Pharmacopoeia version in 2010
Method)) regulation is tested under item, (product of embodiment 1,2,3, (pungent the cutting down of Kamp Pharmaceuticals Co., Ltd.'s production of control 1
Statin piece), 2 (simvastatins of Hangzhou Mo Shadong pharmaceutical Co. Ltds) of control are respectively with containing 0.5% lauryl sodium sulfate
0.01mol/L phosphate sodium dihydrogen buffer solutions (adjusting pH value to 7.0 with 50% sodium hydroxide) 900ml is dissolution medium, rotating speed
For 50 turns per minute, operate in accordance with the law, 10ml was sampled at 5,10,15,20,30 minutes, filtering, takes subsequent filtrate, and supplement in time molten
Go out medium 10ml, filtered with 0.45 μm of miillpore filter, take subsequent filtrate separately to take Simvastatin reference substance, essence as need testing solution
It is close to weigh, add dissolution medium to dissolve and be quantitatively diluted to the solution for containing 12 μ g in every ml as reference substance, according under assay item
Chromatographic condition, need testing solution and each 20 μ l injections liquid chromatograph of reference substance solution are taken, records chromatogram.By external standard method with peak
The stripping quantity of areal calculation every, limit are the 80% of labelled amount.It the results are shown in Table 3,4,5,6,7.
Table 3：The accumulation dissolution rate (embodiment 1) of Simvastatin Tablets
Table 4：The accumulation dissolution rate (embodiment 2) of Simvastatin Tablets
Table 5：The accumulation dissolution rate (embodiment 3) of Simvastatin Tablets
Table 6：The accumulation dissolution rate of the Simvastatin Tablets of Kamp Pharmaceuticals Co., Ltd.'s production
Table 7：The accumulation dissolution rate of the simvastatin of Hangzhou Mo Shadong pharmaceutical Co. Ltds
Result of the test shows：The product of embodiment 1,2,3 and the dissolution rate of control sample 1 and control sample 2 at 15 minutes
It is all higher than 85%, it is believed that dissolved corrosion is basically identical.
(5) stability test
Relevant substance-measuring takes this product fine powder appropriate (being approximately equivalent to Simvastatin 80mg), puts in 100ml measuring bottles, solubilizer
(containing with Simvastatin under quantifier) in right amount, shake well, dissolves Simvastatin and is diluted to scale, shake up, and filters, takes continuous filter
Liquid (determines) as need testing solution in 3 hours；Precision measures lml, puts in 100ml measuring bottles, is diluted to scale with solvent, shakes
It is even, as contrast solution.Determined according to Simvastatin about the method under material item.If any impurity in the chromatogram of need testing solution
Peak, deducts the auxiliary material peak before 0.3 times of relative retention time, and single impurity peak area cannot be greater than the main peak area of contrast solution
(1.0%), each impurity peak area and cannot be greater than 3 times (3.0%) of contrast solution main peak area.It is any in need testing solution
Peak of 0.05 times less than contrast solution main peak area can be neglected.
10 days influence factor experiments, 6 months accelerated tests are carried out, it is as a result as follows：
(a) Simvastatin Tablets (embodiment 1) are after high humidity (72.5%) is tested 10 days, color sample, content and degraded production
Thing is 3% or so without significant change, moisture absorption weightening compared with 0 day data.Through (60 DEG C) illumination (4500 ± 500LX), high temperature examinations
After testing, for color sample without significant change, content has certain reduction, impurity content increase.Simvastatin Tablets (embodiment 2,3,4,5)
After high wet test 10 days, color sample, content and catabolite are 3% without significant change, moisture absorption weightening compared with 0 day data
Left and right.After illumination, hot test, color sample is without significant change, and content is in a slight decrease, and impurity content has increased slightly.Experiment
Prove in Simvastatin Tablets, adding 0.03g, 0.04g, 0.05g, 0.06g butylated hydroxy anisole can stablize that main ingredient is pungent to be cut down
Statin, but the relevant material of 0.03g, 0.04g butylated hydroxy anisole is added than adding 0.05g, 0.06g in Simvastatin Tablets
Butylated hydroxy anisole stablize slightly worse, add the basic indifference of relevant material of 0.05,0.06g butylated hydroxy anisole,
Therefore selection adds 0.05g butylated hydroxy anisoles in 10g Simvastatin Tablets.
The influence factor result of the test of table 8
(b) three batches of samples (embodiment 1, (the listing Simvastatin Tablets batch of Kamp Pharmaceuticals Co., Ltd. of control sample 1
Number 140201), control sample 2 (Simvastatin Tablets of Hangzhou Mo Shadong pharmaceutical Co. Ltds, trade name simvastatin, lot number
130583) carry out adding for 6 months under the conditions of 40 DEG C ± 2 DEG C, relative humidity 75% ± 5% by commercially available back (the closed preservation of shading)
Speed experiment, the sampling of the 1st, 2,3,6 the end of month, three batches of sample appearance lusters, dissolution rate, content and about material and 0 month data
Compare no significant change, relevant material deducts the auxiliary material peak before 0.3 times of relative retention time, and single impurity peak area cannot be greater than
The main peak area (1.0%) of contrast solution, it is each impurity peak area and cannot be greater than contrast solution main peak area 3 times
(3.0%).Any peak less than 0.05 times of contrast solution main peak area can be neglected in need testing solution.Show that the present invention is pungent
Cut down statin piece and deposit 6 months its steady qualities under this condition.Prove that Simvastatin tablet stability of the present invention is high.
Table 9：The accelerated test result of embodiment 1
Table 10：The accelerated test result of control sample 1
Table 11：The accelerated test result of control sample 2
Result of the test shows：Simvastatin Tablets of the present invention deposit 6 months its steady qualities under this condition.Prove the present invention
Simvastatin tablet stability is high.
Embodiment of above is merely to illustrate the present invention, rather than limitation of the present invention.Although with reference to embodiment to this hair
It is bright to be described in detail, it will be understood by those within the art that, to technical scheme carry out it is various combination,
Modification or equivalent substitution, without departure from the spirit and scope of technical solution of the present invention, the right that all should cover in the present invention is wanted
Ask among scope.
Claims (8)
1. a kind of Simvastatin Tablets of high stability, it is characterised in that the Simvastatin Tablets include following component by weight：
Simvastatin 10-20 parts, pregelatinized starch 10-15 parts, butylated hydroxy anisole 0.04-0.05 parts, PVP K30 0.3-0.8
Part, lactose 48-52 parts, microcrystalline cellulose 38-42 parts, hydroxypropylcellulose 3.5-4.5 parts, hydroxypropyl methylcellulose 0.8-1.5 parts, firmly
Fatty acid magnesium 0.4-1.0 parts, superfine silica gel powder 0.8-1.8 parts；
The preparation method of the Simvastatin Tablets of the high stability comprises the following steps：
Step 1：Stock：Each component is weighed by formula, each component is crossed into 60-100 mesh sieves respectively, it is standby；Pregelatinated is toasted to form sediment
Powder, it is standby；PVP K30 is dissolved in absolute ethyl alcohol, the ethanol solution that mass concentration is 10-15% is made, it is standby；Will
Hydroxypropyl methylcellulose is dissolved in water second, and the aqueous solution that mass concentration is 1-3% is made, standby；
Step 2：Prepare particle 1：Simvastatin and pregelatinized starch are uniformly mixed, butylated hydroxy anisole are dissolved in anhydrous
In ethanol；Softwood is made in said components with above-mentioned PVP K30 ethanol solution, 15-20 mesh sieves is crossed, pelletizes, drying, then
15-20 mesh sieves are crossed, whole grain, obtain particle 1, it is standby；
Step 3：Prepare particle 2：Lactose, microcrystalline cellulose and hydroxypropylcellulose are uniformly mixed, with above-mentioned hydroxypropyl methylcellulose
Softwood is made in said components by the aqueous solution, crosses 15-20 mesh sieves, is pelletized, and drying, after 15-20 mesh sieves, whole grain, obtains particle 2,
It is standby；
Step 4：Preparation of preparation raw material：Particle 1 and particle 2 are uniformly mixed with magnesium stearate and superfine silica gel powder, obtain preparation original
Material, it is standby；
Step 5：Compressed tablets：It is with tablet press machine that above-mentioned preparation raw material is tabletted, produce.
2. the Simvastatin Tablets of high stability according to claim 1, it is characterised in that the Simvastatin Tablets are by weight
Part includes following component：10 parts of Simvastatin, 15 parts of pregelatinized starch, 0.05 part of butylated hydroxy anisole, PVP K30 0.5
Part, 50 parts of lactose, 40 parts of microcrystalline cellulose, 4 parts of hydroxypropylcellulose, 1 part of hydroxypropyl methylcellulose, 0.6 part of magnesium stearate, micro mist silicon
1.2 parts of glue.
3. the Simvastatin Tablets of high stability according to claim 1, it is characterised in that in step 1, the baking
The temperature of pregelatinized starch is 100-110 DEG C, and the time is 2-3 hours.
4. the Simvastatin Tablets of high stability according to claim 1, it is characterised in that in step 2, the drying
Temperature is 35-45 DEG C.
5. the Simvastatin Tablets of high stability according to claim 1, it is characterised in that in step 3, the drying
Temperature is 55-65 DEG C.
6. the Simvastatin Tablets of the high stability according to claim 1, it is characterised in that this method includes following step
Suddenly：
Step 1：Stock：Each component is weighed by formula, each component is crossed into 80 mesh sieves respectively, it is standby；By pregelatinized starch 105
DEG C baking 2 hours, it is standby；PVP K30 is dissolved in absolute ethyl alcohol, the ethanol solution that mass concentration is 12% is made,
It is standby；Hydroxypropyl methylcellulose is dissolved in water second, the aqueous solution that mass concentration is 2% is made, it is standby；
Step 2：Prepare particle 1：Simvastatin and pregelatinized starch are uniformly mixed, butylated hydroxy anisole are dissolved in anhydrous
In ethanol；Softwood is made in said components with above-mentioned PVP K30 ethanol solution, crosses 18 mesh sieves, granulation, in 40 DEG C of bakings
It is dry, after 18 mesh sieves, whole grain, particle 1 is obtained, it is standby；
Step 3：Prepare particle 2：Lactose, microcrystalline cellulose and hydroxypropylcellulose are uniformly mixed, with above-mentioned hydroxypropyl methylcellulose
Softwood is made in said components by the aqueous solution, is crossed 18 mesh sieves, granulation, in 60 DEG C of drying, after 18 mesh sieves, whole grain, is obtained particle 2,
It is standby；
Step 4：Preparation of preparation raw material：Particle 1 and particle 2 are uniformly mixed with magnesium stearate and superfine silica gel powder, obtain preparation original
Material, it is standby；
Step 5：Compressed tablets：It is with tablet press machine that above-mentioned preparation raw material is tabletted, produce.
7. the Simvastatin Tablets of the high stability according to claim 1 or any one of 3-6, it is characterised in that the tabletting
The pressure of machine is 4-5kg.
8. the Simvastatin Tablets of the high stability according to claim 1 or any one of 3-6, it is characterised in that the tabletting
The mould that machine uses is shallow concave punch.
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Denomination of invention: The invention relates to a high stability simvastatin tablet and a preparation method thereof Effective date of registration: 20210730 Granted publication date: 20180223 Pledgee: Hunan Hanshou Rural Commercial Bank Co.,Ltd. Pledgor: KAMP PHARMACEUTICALS Co.,Ltd. Registration number: Y2021430000029 |
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Date of cancellation: 20211014 Granted publication date: 20180223 Pledgee: Hunan Hanshou Rural Commercial Bank Co.,Ltd. Pledgor: KAMP PHARMACEUTICALS Co.,Ltd. Registration number: Y2021430000029 |
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Address after: No.8 Kangpu Avenue, high tech Industrial Park, Hanshou County, Changde City, Hunan Province, 415900 Patentee after: KAMP PHARMACEUTICALS Co.,Ltd. Address before: 12 / F, building B, Lugu information port, 658 Lugu Avenue, high tech Zone, Changsha City, Hunan Province, 410205 Patentee before: KAMP PHARMACEUTICALS Co.,Ltd. |
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Denomination of invention: The invention relates to a high stability simvastatin tablet and a preparation method thereof Effective date of registration: 20211028 Granted publication date: 20180223 Pledgee: Hunan Hanshou Rural Commercial Bank Co.,Ltd. Pledgor: KAMP PHARMACEUTICALS Co.,Ltd. Registration number: Y2021980011259 |
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