CN106937952A - The preparation of Ezetimibe and Simvastatin - Google Patents
The preparation of Ezetimibe and Simvastatin Download PDFInfo
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Abstract
The invention belongs to field of pharmaceutical preparations, the pharmaceutical preparation more particularly to containing Ezetimibe and Simvastatin effective component.The preparation of Ezetimibe and Simvastatin is made up of the Ezetimibe and Simvastatin of effective dose, composite type antioxidant agent and pharmaceutically acceptable auxiliary material；The composite type antioxidant agent is made up of tertiary butyl-4-hydroxy anisole, propylgallate and DL- tartaric acid.The preparation of the present invention, active component is Ezetimibe and Simvastatin, and both can play synergy in anti-curing hyperlipemia and atherosclerosis, by adding composite type antioxidant agent, antioxidant effect effectively has been greatly enhanced, it is final that the product formulation having good stability is made.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, the pharmaceutical preparation more particularly to containing Ezetimibe and Simvastatin effective component.
Background technology
High fat of blood refers to that blood lipid level is too high, and it is to cause the one of the main reasons of coronary heart disease and apoplexy, can directly cause the disease of some serious harm healths, such as atherosclerosis, coronary heart disease, pancreatitis.With living standard and the raising of China human mortality aging, with high fat of blood, people crowd is more and more.
On the diagnostic criteria of hyperlipidemia, current international and national there is no unified method.Previously think that total cholesterol density of blood plasma ＞ 5.17mmol/L (200mg/dl) can be set to hypercholesterolemia, blood plasma triacylglycerol concentration ＞ 2.3mmol/L (200mg/dl) are hypertriglyceridemia.
Plasma cholesterol is mainly derived from intestinal absorption or is endogenously synthesized.Ezetimibe and the formation of Simvastatin both lipid-lowering compositions are a kind of complementary mechanisms, can reduce the T-CHOL, LDL, ApoB, TG and non-HDL levels of enrichment, and pass through the absorption synthesis increase HDL of double inhibition cholesterol level.
Ezetimibe reduces Blood Cholesterol level by suppressing small intestine to cholesterol absorption.The molecular target for having shown Ezetimibe at present is sterol carrier Niemann-Pick C1-like 1 (NPC1L1), and this carrier is relevant with the intestinal absorption of cholesterol and phytosterol.During 18 hypercholesterolemiapatients patients are carried out with the clinical researches of 2 weeks by a definite date at one, compared with placebo, small intestine can be suppressed to the absorption of cholesterol up to 54%.Ezetimibe does not have the influence of clinical meaning, the generation of Corticosteroid is not reduced to fat-soluble A, D, E plasma concentration.Ezetimibe is attached to the brush border of Epithelium of intestinal villus, suppress the absorption of cholesterol, so as to reduce in small intestine cholesterol to hepatic transport, this causes the reduction of hepatic cholesterol reserves to increase the removing of Blood Cholesterol, the action compensating that this unique mechanism of action just can be with HMG-CoA reductase inhibitor.
Simvastatin is converted into mevalonic acid (a kind of early stage step of Biosynthesis of cholesterol approach) by suppressing HMG-CoA and reduces cholesterol level.In addition, Simvastatin can reduce VLDL (VLDL), triglycerides (TG) level, and increase HDL-C (HDL-C).
Ezetimibe bulk drug is unstable under acid, alkalescence and oxidizing condition, relatively stablizes under conditions of illumination, high temperature, high humidity.Simvastatin bulk drug is unstable in acid, alkaline environment；Relatively stablize under illumination, super-humid conditions.Simvastatin high-temperature oxydation degradation process is complicated, and in addition to principal degradation impurity is produced, therefore also a lot of other oxidative degradation impurity, cause the unstable active components of Ezetimibe and Simvastatin preparation.
The content of the invention
Present inventor has found that oxidation reaction is active ingredient breaks down failure, the increased principal element of relevant material in practice process.Delaying the method for active component oxidation Decomposition has removing oxygen, adds the method such as antioxidant and regulation pH value.The present invention is by adding the method for composite type antioxidant agent come the stability of protection activity composition, and after appropriate antioxidant is added, the stability of active component is significantly improved.
In view of this; the purpose of the present invention first consists in the preparation for providing a kind of Ezetimibe and Simvastatin; the preparation of the present invention; active component is Ezetimibe and Simvastatin; both can play synergy in anti-curing hyperlipemia and atherosclerosis, by adding the method for composite type antioxidant agent come the stability of protection activity composition.
To achieve the above object, the technical scheme is that：
A kind of preparation of Ezetimibe and Simvastatin, the preparation is made up of the Ezetimibe and Simvastatin of effective dose, composite type antioxidant agent and pharmaceutically acceptable auxiliary material；The composite type antioxidant agent is made up of tertiary butyl-4-hydroxy anisole, propylgallate and DL- tartaric acid.
Further, the preparation of a kind of described Ezetimibe and Simvastatin, the weight ratio of tertiary butyl-4-hydroxy anisole, propylgallate and DL- tartaric acid is 1-1000: 1-1000: 1-1000 in the composite type antioxidant agent.
It is preferred that, the weight ratio of tertiary butyl-4-hydroxy anisole, propylgallate and DL- tartaric acid is 1-10: 1-10: 50-100 in the composite type antioxidant agent.
Further, the preparation of a kind of described Ezetimibe and Simvastatin, the consumption of the composite type antioxidant agent is the 0.003%-3% of Ezetimibe, Simvastatin and auxiliary material summation.
The present invention also specifically provides the preparation of a kind of Ezetimibe and Simvastatin, and the preparation is comprised the following raw materials by weight percent：
The composite type antioxidant agent is made up of tertiary butyl-4-hydroxy anisole, propylgallate and DL- tartaric acid.
It is preferred that, the preparation is comprised the following raw materials by weight percent：
Further, the preparation of a kind of described Ezetimibe and Simvastatin, the filler is the one or more in lactose, starch and microcrystalline cellulose.
Further, the preparation of a kind of described Ezetimibe and Simvastatin, the disintegrant is the one or more in Ac-Di-Sol, carboxyrnethyl starch sodium and PVPP.
Further, the preparation of a kind of described Ezetimibe and Simvastatin, the binding agent is the one or more in PVP, Hydroxypropyl methylcellulose and hydroxypropylcellulose.
Further, the preparation of a kind of described Ezetimibe and Simvastatin, the lubricant is the one or more in magnesium stearate, talcum powder and silica.
It is preferred that, the weight ratio of tertiary butyl-4-hydroxy anisole, propylgallate and DL- tartaric acid is 1-1000: 1-1000: 1-1000 in the composite type antioxidant agent.
It is preferred that, the weight ratio of tertiary butyl-4-hydroxy anisole, propylgallate and DL- tartaric acid is 1-10: 1-10: 50-100 in the composite type antioxidant agent.
Present invention also offers a kind of composite type antioxidant agent, the composite type antioxidant agent is made up of tertiary butyl-4-hydroxy anisole, propylgallate and DL- tartaric acid.Tertiary butyl-4-hydroxy anisole (BHA), propylgallate (PG) are accumulation type antioxidant, in the oxidation reaction, it is possible to provide electronics or effective hydrogen ion, supply free radical receives, autoxidation chain reaction is interrupted, the generation of oxidation reaction is effectively prevented.DL- tartaric acid (TA) is synergetic antioxidant, can greatly improve the antioxidant effect of first two accumulation type antioxidant.Research shows that the combination of the composite type antioxidant agent of the present invention can effectively improve the stability containing Ezetimibe and Simvastatin medicine.Composite type antioxidant agent is not the simple addition of the antioxidation of various antioxidants, nor the relation being multiplied, but various antioxidants play a role in oxidation resistant different aspect, greatly enhance, as act synergistically so as to show as antioxidant effect on the whole.Synergy between a variety of antioxidants may come from the different site of action that these antioxidant constitute redox cycle system, or there is obvious complementation between the different mechanism of action of these antioxidants.
It is preferred that, the weight ratio of tertiary butyl-4-hydroxy anisole, propylgallate and DL- tartaric acid is 1-1000: 1-1000: 1-1000 in the composite type antioxidant agent.
It is preferred that, the weight ratio of tertiary butyl-4-hydroxy anisole, propylgallate and DL- tartaric acid is 1-10: 1-10: 50-100 in the composite type antioxidant agent.
Other objects of the present invention also reside in application of the composite type antioxidant agent described in providing in the preparation containing Ezetimibe and Simvastatin is prepared, final that the product formulation having good stability is made.
Beneficial effects of the present invention：
(1) composite type antioxidant agent of the invention, by the synergy of three kinds of antioxidants, can be effectively reduced the generation of oxidation reaction, antioxidant effect is greatly enhanced.The combination of the composite type antioxidant agent of the present invention can effectively improve the stability containing Ezetimibe and Simvastatin medicine.The composite type antioxidant agent is applied to prepare the preparation containing Ezetimibe and Simvastatin, final that the product formulation having good stability is made.
(2) preparation of Ezetimibe of the invention and Simvastatin; active component is Ezetimibe and Simvastatin; both can play synergy in anti-curing hyperlipemia and atherosclerosis, by adding the method for composite type antioxidant agent come the stability of protection activity composition.
Embodiment
In order that the object, technical solutions and advantages of the present invention are clearer, the preferred embodiments of the present invention are described in detail below.
The preparation of the Ezetimibe of embodiment 1 and Simvastatin
(1) raw material proportioning：
(2) preparation method：
Tertiary butyl-4-hydroxy anisole, propylgallate, DL- tartaric acid are added in a certain proportion of alcohol solution, wetting agent is made.After Ezetimibe, Simvastatin, lactose, microcrystalline cellulose, Ac-Di-Sol are well mixed, wetting agent is added and pelletized, dried, then add compressing tablet after magnesium stearate is well mixed.
Embodiment 2
(1) raw material proportioning：
(2) preparation method：
Tertiary butyl-4-hydroxy anisole, propylgallate, DL- tartaric acid are added in a certain proportion of alcohol solution, wetting agent is made.After Ezetimibe, Simvastatin, lactose, microcrystalline cellulose, Ac-Di-Sol are well mixed, wetting agent is added and pelletized, dried, then add compressing tablet after magnesium stearate is well mixed.
Embodiment 3
(1) raw material proportioning：
(2) preparation method：
Tertiary butyl-4-hydroxy anisole, propylgallate, DL- tartaric acid are added in a certain proportion of alcohol solution, wetting agent is made.After Ezetimibe, Simvastatin, lactose, microcrystalline cellulose, Ac-Di-Sol are well mixed, wetting agent is added and pelletized, dried.Then the well mixed rear compressing tablet of magnesium stearate is added.
Embodiment 4
(1) raw material proportioning：
(2) preparation method：
After Ezetimibe, Simvastatin, lactose, microcrystalline cellulose, Ac-Di-Sol are well mixed, a certain proportion of alcohol solution granulation is added, is dried, compressing tablet after magnesium stearate is well mixed then is added.
Embodiment 5
(1) raw material proportioning：
(2) preparation method：
Tertiary butyl-4-hydroxy anisole is dissolved in a certain proportion of alcohol solution, wetting agent is made, then by Ezetimibe, Simvastatin, lactose, microcrystalline cellulose, Ac-Di-Sol it is well mixed after, add wetting agent granulation, dry.Then the well mixed rear compressing tablet of magnesium stearate is added.
Embodiment 6
(1) raw material proportioning：
(2) preparation method：
Propylgallate is dissolved in a certain proportion of alcohol solution, wetting agent is made, then by Ezetimibe, Simvastatin, lactose, microcrystalline cellulose, Ac-Di-Sol it is well mixed after, add wetting agent granulation, dry.Then the well mixed rear compressing tablet of magnesium stearate is added.
Embodiment 7
(1) raw material proportioning：
(2) preparation method：
DL- tartaric acid is dissolved in a certain proportion of alcohol solution, wetting agent is made, then by Ezetimibe, Simvastatin, lactose, microcrystalline cellulose, Ac-Di-Sol it is well mixed after, add wetting agent granulation, dry.Then the well mixed rear compressing tablet of magnesium stearate is added.
Embodiment 8
(1) raw material proportioning：
(2) preparation method：
Tertiary butyl-4-hydroxy anisole, DL- tartaric acid are dissolved in a certain proportion of alcohol solution, wetting agent is made, then by Ezetimibe, Simvastatin, lactose, microcrystalline cellulose, Ac-Di-Sol it is well mixed after, add wetting agent granulation, dry.Then the well mixed rear compressing tablet of magnesium stearate is added.
Embodiment 9
(1) raw material proportioning：
(2) preparation method：
Tertiary butyl-4-hydroxy anisole, propylgallate are dissolved in a certain proportion of alcohol solution, wetting agent is made, after being again well mixed Ezetimibe, Simvastatin, lactose, microcrystalline cellulose, Ac-Di-Sol, wetting agent granulation is added, is dried.Then the well mixed rear compressing tablet of magnesium stearate is added.
Embodiment 10
(1) raw material proportioning：
(2) preparation method：
Propylgallate, DL- tartaric acid are dissolved in a certain proportion of alcohol solution, wetting agent is made, then by Ezetimibe, Simvastatin, lactose, microcrystalline cellulose, Ac-Di-Sol it is well mixed after, add wetting agent granulation, dry.Then the well mixed rear compressing tablet of magnesium stearate is added.
Embodiment 11
The tablet for taking above example 1-10 to prepare respectively, sample is placed under the conditions of 60 DEG C of high temperature and investigated, using Ezetimibe content, Simvastatin content and relevant material as quality index, each content of material detection method is determined with reference to high performance liquid chromatography (two annex V D of Chinese Pharmacopoeia version in 2010), investigates result data as shown in table 1.
Assay：
Determined with reference to high performance liquid chromatography (two annex V D of Chinese Pharmacopoeia version in 2010).
1st, Ezetimibe：
It is filler with phenyl silane bonded silica gel；With 0.1% phosphoric acid solution-acetonitrile-methanol (51: 40: 9) for mobile phase A, using acetonitrile as Mobile phase B, gradient elution is carried out.Flow velocity is 1.0ml per minute, and Detection wavelength is 231nm, and column temperature is 45 DEG C.This product 10 is taken, accurately weighed, finely ground, precision is weighed (is approximately equivalent to Ezetimibe 10mg) in right amount, put in 50ml measuring bottles, solubilizer (1) is appropriate, shake 60 minutes, solubilizer (1) is diluted to scale, shake up, filter, take subsequent filtrate as need testing solution.Another to take Ezetimibe reference substance appropriate, accurately weighed, solubilizer (1), which dissolves and diluted, is made solution in every 1ml containing about Ezetimibe 0.2mg, it is used as reference substance solution, precision measures need testing solution and each 10 μ l of reference substance solution, is injected separately into liquid chromatograph, records chromatogram.By external standard method with calculated by peak area, produce.
2nd, Simvastatin：
It is filler with octadecylsilane chemically bonded silica；For mobile phase, stayed overnight with 0.025mol/L sodium dihydrogen phosphates (if necessary with phosphoric acid or sodium hydroxide solution regulation pH to 4.5)-acetonitrile (35: 65) as 1.5ml per minute.Detection wavelength is 231nm, and column temperature is 45 DEG C.Accurately weighed, finely ground, precision, which is weighed, (to be approximately equivalent to Simvastatin 10mg) in right amount and puts in 100ml measuring bottles, solubilizer (1) is appropriate, shakes 60 minutes, solubilizer (1) is diluted to scale, shake up, filter, take subsequent filtrate as need testing solution；Another to take Simvastatin reference substance appropriate, accurately weighed, solubilizer (1), which dissolves and diluted, is made solution in every 1ml containing about Simvastatin 0.1mg, is used as reference substance solution.Precision measures need testing solution and each 30 μ l of reference substance solution, is injected separately into liquid chromatograph, records chromatogram.By external standard method with calculated by peak area, produce.
3rd, propylgallate and tertiary butyl-4-hydroxy anisole：
It is filler with phenyl silane bonded silica gel；With 0.025mol/L sodium dihydrogen phosphates (with phosphorus acid for adjusting pH value to 4.0) ,-acetonitrile (80: 20) is mobile phase A, using acetonitrile as Mobile phase B, carries out gradient elution；Flow velocity 1.5ml per minute；Detection wavelength 290nm；Column temperature is 30 DEG C.This product 10 is taken, accurately weighed, finely ground, precision, which is weighed, (to be approximately equivalent to Simvastatin 50mg) in right amount and put in 25ml measuring bottles, solubilizer (2) is appropriate, shakes 60 minutes, solubilizer (2) is diluted to scale, shake up, filter, take subsequent filtrate as need testing solution；It is another to take propylgallate each appropriate with tertiary butyl-4-hydroxy anisole reference substance, it is accurately weighed, solubilizer (2) dissolves and diluted the solution being made in every 1ml containing about the μ g of propylgallate 1 and the μ g of tertiary butyl-4-hydroxy anisole 1, is used as reference substance solution；Precision measures need testing solution and each 100 μ l of reference substance solution, is injected separately into liquid chromatograph, records chromatogram.By external standard method with calculated by peak area.
3rd, relevant material：
1. Ezetimibe catabolite：
The reference substance solution that precision is measured under Ezetimibe assay is appropriate, and solution of every 1ml containing about 0.2 μ g is made as reference substance solution in solubilizer (1) dilution.According to the chromatographic condition under Ezetimibe assay, take the μ l of reference substance solution 10 to inject liquid chromatograph, adjust detection sensitivity, the peak height for making principal component peak is about the 5% of full scale；It is accurate again to measure reference substance solution and each 10 μ l of need testing solution under Ezetimibe assay, liquid chromatograph is injected separately into, chromatogram is recorded, then calculates content.
2. Simvastatin catabolite：
A.6- oxo-Simvastatin：
The chromatographic condition under item is determined according to propylgallate and tertiary butyl-4-hydroxy anisole, precision measures propylgallate and the reference substance solution and each 100 μ l of need testing solution under tertiary butyl-4-hydroxy anisole measure item, liquid chromatograph is injected separately into, chromatogram is recorded, then calculates content.
B, Simvastatin oxidative degradation impurity：
Simvastatin reference substance 10mg is taken, it is accurately weighed, put in 100ml measuring bottles, plus acetonitrile 50ml makes dissolving, solubilizer (2) is diluted to scale, shakes up, be used as stock solution.Precision measures 2ml, puts in 50ml measuring bottles, and solubilizer (2) is diluted to scale, shakes up, is used as reference substance solution.Separately take stock solution 1ml, put in 10ml measuring bottles, plus 3% hydrogenperoxide steam generator 1ml, close plug, 60 DEG C are put to heat 180-210 minutes, take out, let cool, plus hydrochloric acid 1-2 drops, shake up, plus propylgallate determines the reference substance solution under item with tertiary butyl-4-hydroxy anisole and is diluted to scale, shakes up, is used as system suitability solution.The chromatographic condition under item is determined according to propylgallate and tertiary butyl-4-hydroxy anisole, only Detection wavelength is changed to 205nm, takes the μ l of system suitability solution 100, injects liquid chromatograph, records chromatogram.The retention time at Simvastatin peak is about 25 minutes, and the separating degree at propylgallate peak and dihydroxy-Simvastatin peak should meet regulation.Take the μ l of reference substance solution 100 to inject liquid chromatograph, adjust detection sensitivity, the peak height for making principal component peak is about the 25% of full scale；Precision measures reference substance solution and determines each 100 μ l of need testing solution under item with the BHA of the tert-butyl group -4 with propylgallate again, is injected separately into liquid chromatograph, records chromatogram, then calculates content.
Other degradation impurities of c, Simvastatin：
Precision measures that the lower reference substance solution of Simvastatin assay is appropriate, and solubilizer (1), which dilutes, is made solution in every 1ml containing about 0.1 μ g as reference substance solution.According to the chromatographic condition under Simvastatin assay, take the μ l of reference substance solution 30 to inject liquid chromatograph, adjust detection sensitivity, the peak height for making main composition peak is about the 5% of full scale；The accurate each 30 μ l of need testing solution measured under reference substance solution and Simvastatin assay, are injected separately into liquid chromatograph, record chromatogram, then calculate content again.
The embodiment 1-10 of table 1 product stability is investigated
Interpretation of result：Embodiment 410 is compared with embodiment 13, and sample is after the high temperature investigation of 10 days, and each impurity has growth, and the oxidation impurities of embodiment 410 rise appreciably.
Embodiment 12
Tablet prepared by Example 1, accelerates June and 25 DEG C of (RH75%) long-term 36 months stability to be investigated in sample, result data is as shown in table 2 and table 3 in 40 DEG C.
1 40 DEG C of 2 embodiment of table accelerates the study on the stability in June
3 embodiment of table, 1 25 DEG C of (RH75%) long-term 36 months study on the stability
Interpretation of result：40 DEG C of June of embodiment 1 and 25 DEG C of RH75% are under conditions of long-term 36 months, and each impurity is stable, within controlled range.
What is finally illustrated is, the above embodiments are merely illustrative of the technical solutions of the present invention and it is unrestricted, although the present invention is described in detail with reference to preferred embodiment, it will be understood by those within the art that, technical scheme can be modified or equivalent, without departing from the objective and scope of technical solution of the present invention, it all should cover among scope of the presently claimed invention.
Claims (10)
1. the preparation of a kind of Ezetimibe and Simvastatin, it is characterised in that the preparation is by effective dose
Ezetimibe and Simvastatin, composite type antioxidant agent and pharmaceutically acceptable auxiliary material composition；It is described compound
Type antioxidant is made up of tertiary butyl-4-hydroxy anisole, propylgallate and DL- tartaric acid.
2. the preparation of a kind of Ezetimibe according to claim 1 and Simvastatin, it is characterised in that
The weight of tertiary butyl-4-hydroxy anisole, propylgallate and DL- tartaric acid in the composite type antioxidant agent
Amount is than being 1-1000:1-1000:1-1000.
3. the preparation of a kind of Ezetimibe according to claim 1 and Simvastatin, it is characterised in that
The consumption of the composite type antioxidant agent is the 0.003%-3% of Ezetimibe, Simvastatin and auxiliary material summation.
4. the preparation of a kind of Ezetimibe and Simvastatin, it is characterised in that the preparation is by following weight hundred
Divide the raw material composition of ratio：
The composite type antioxidant agent is by tertiary butyl-4-hydroxy anisole, propylgallate and DL- tartaric acid
Composition.
5. the preparation of a kind of Ezetimibe according to claim 4 and Simvastatin, it is characterised in that
The filler is the one or more in lactose, starch and microcrystalline cellulose.
6. the preparation of a kind of Ezetimibe according to claim 4 and Simvastatin, it is characterised in that
The disintegrant is the one or more in Ac-Di-Sol, carboxyrnethyl starch sodium and PVPP.
7. the preparation of a kind of Ezetimibe according to claim 4 and Simvastatin, it is characterised in that
The binding agent is the one or more in PVP, Hydroxypropyl methylcellulose and hydroxypropylcellulose.
8. the preparation of a kind of Ezetimibe according to claim 4 and Simvastatin, it is characterised in that
The lubricant is the one or more in magnesium stearate, talcum powder and silica.
9. a kind of composite type antioxidant agent, it is characterised in that the composite type antioxidant agent is by the tert-butyl group -4-
BHA, propylgallate and DL- tartaric acid composition.
10. composite type antioxidant agent described in claim 9 is being prepared containing Ezetimibe and Simvastatin
Application in preparation.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610006552.2A CN106937952A (en) | 2016-01-04 | 2016-01-04 | The preparation of Ezetimibe and Simvastatin |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610006552.2A CN106937952A (en) | 2016-01-04 | 2016-01-04 | The preparation of Ezetimibe and Simvastatin |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN110407799A (en) * | 2019-05-21 | 2019-11-05 | 青岛大学附属医院 | A kind of substance and application thereof inhibiting PTL and NPC1L1 |
| WO2022062961A1 (en) * | 2020-09-23 | 2022-03-31 | 海南通用三洋药业有限公司 | Method for detecting content of 6-oxosimvastatin in ezetimibe-simvastatin tablets |
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| CN110407799A (en) * | 2019-05-21 | 2019-11-05 | 青岛大学附属医院 | A kind of substance and application thereof inhibiting PTL and NPC1L1 |
| WO2022062961A1 (en) * | 2020-09-23 | 2022-03-31 | 海南通用三洋药业有限公司 | Method for detecting content of 6-oxosimvastatin in ezetimibe-simvastatin tablets |
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Application publication date: 20170711 |