CN103239449A - Ezetimibe, simvastatin and nicotinic acid compound preparation and preparation method of ezetimibe, simvastatin and nicotinic acid compound preparation - Google Patents
Ezetimibe, simvastatin and nicotinic acid compound preparation and preparation method of ezetimibe, simvastatin and nicotinic acid compound preparation Download PDFInfo
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- CN103239449A CN103239449A CN2012105724566A CN201210572456A CN103239449A CN 103239449 A CN103239449 A CN 103239449A CN 2012105724566 A CN2012105724566 A CN 2012105724566A CN 201210572456 A CN201210572456 A CN 201210572456A CN 103239449 A CN103239449 A CN 103239449A
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- ezetimibe
- simvastatin
- nicotinic acid
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- 229960002855 simvastatin Drugs 0.000 title claims abstract description 46
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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 44
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Abstract
The invention belongs to the field of pharmaceutical preparations and particularly relates to a compound preparation which takes ezetimibe, simvastatin and nicotinic acid as effective components and has the effects of reducing blood pressure and blood lipid and a preparation method of the compound preparation. The compound preparation is a sustained release tablet. Aiming at the problems of poor water solubility of the ezetimibe, unstability of the simvastatin to acid and oxygen, and the like, the preparation method of the compound preparation adopts a melt extrusion technology for improving the dissolution rate of the ezetimibe, and adopts a cladding membrane technology for enhancing the stability of the simvastatin in a body so as to give full play to the efficacy of all components of the compound preparation and have the best synergy effect. The specific process comprises the steps of preparing the nicotinic acid into a tablet core as a sustained release part, spraying an isolating layer on the tablet core, then spraying the simvastatin and the ezetimibe on an outer layer of the sustained release part as a quick release layer, and then carrying out film coating on the quick release layer. The compound preparation provided by the invention is mainly applied to the treatment or prevention of diseases and indications associated with heart and cerebral vessels.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, specifically is a kind of being the compound preparation with decompression lipid-lowering effect of active component according to Ezetimibe, simvastatin and nicotinic acid.
Background technology
Cardiovascular and cerebrovascular disease is the principal element that 21 century threatens the human life, and cardiovascular and cerebrovascular disease death accounts for 40.8% of the chronic diseases in China cause of the death.Cardiovascular and cerebrovascular disease all is vascular lesion in essence.
Clinical research shows that the rising of T-CHOL, low density lipoprotein, LDL (LDL), apolipoprotein level can cause human body artery atherosis.In addition, the reduction of high density lipoprotein (HDL) level also can cause atherosclerosis.Epidemiological study shows that the level of cardiovascular disease incidence rate and mortality rate and T-CHOL and LDL is directly proportional, and is inversely proportional to the level of HDL.And the lipoprotein of triglyceride enrichment, very low density lipoprotein (VLDL) (VLDL), intermediated-density lipoprotein (IDL) and residue thereof also can both cause atherosclerosis.Hyperlipidemia is the one of the main reasons that causes coronary heart disease and apoplexy, and along with China's aged tendency of population and growth in the living standard, the hyperlipidemia patient is also increasing.
The main action pathway of statins is suppress cholesterol in the liver synthetic, and is to play a role by optionally suppressing the absorption of cholesterol in intestinal according to Ezetimibe.
Absorption position according to Ezetimibe is being positioned at intestinal brush border with active position, suppress the absorption of cholesterol, can reduce intestinal cholesterol to the transportation of liver, can reduce cholesterol like this in the storage of liver, increase cholesterol from the rate of evacuation of blood, Du Te mechanism is to the HMG-COA(hydroxy-methyl-glutaryl coenzyme A like this) reductase inhibitor additional.
It is hardly by the cytochrome P 450 enzymes metabolism, few with the other drug interphase interaction according to Ezetimibe,, safety and toleration are good.According to the Ezetimibe half-life be 22 hours, take 10mg every day, can suppress cholesterol absorption average out to 54%, can make LDL-C reduce about 18%.
Simvastatin belongs to the HMG-CoA reductase inhibitor, can suppress the biosynthesis of cholesterol in early days.In addition, it can also reduce VLDL and TG, increases the level of HDL.This medication is imitated high, and side effect is little, has become the most frequently used class hypolipidemic in the whole world.But simultaneously simvastatin is all unstable to light, wet, heat, oxygen, and violent a little condition just may cause related substance to increase, product quality decline.
Nicotinic acid is the most frequently used nicotinic acid class fat regulation medicine.It is the synthetic and release that reduces very low density lipoprotein (VLDL) (VLDL) in the liver that nicotinic acid mainly acts on, because VLDL is the precursor of intermediated-density lipoprotein (IDL) and low density lipoprotein, LDL (LDL), thus after an amount of nicotinic acid is treated in the blood concentration of IDL and LDL be minimized.Nicotinic acid can also reduce the quantity that adipose cell discharges free fatty, thereby reduces the synthetic material of triglyceride (TG), and the synthetic TG level of liver is reduced.Latest find nicotinic acid has the effect of protection blood vessel endothelium.
The CN101518518A patent disclosure niacin simvastatin sustained-release preparation and preparation method thereof; The CN101961492A patent has been announced according to Ezetimibe simvastatin compound preparation; The CN102349909A patent disclosure according to the compound preparation of Ezetimibe nicotinic acid.
Recent study shows that blood pressure lowering can reduce the generation of hyperpietic's cardiovascular event in conjunction with the blood fat reducing treatment.But the hyperpietic seldom can adhere to taking hypotensor, hypolipidemic more than a kind or a kind.And compound recipe monolithic medicine can improve patient's drug compliance.The invention provides a kind of method of disposable administration, to improve patient's drug compliance.
The invention provides and a kind ofly contain compound preparation according to Ezetimibe, simvastatin and nicotinic acid and preparation method thereof, and confirmed that this compound recipe is in treatment and prevention such as the effect aspect the cardiovascular and cerebrovascular disease of hypertension, diabetes, coronary heart disease, atherosclerosis, complicated hypertension and hyperlipemia etc.
Summary of the invention
It is a kind of by the compound preparation according to Ezetimibe, simvastatin and nicotinic acid that the object of the invention is to provide, and confirm that this compound recipe has good blood pressure lowering, the effect of blood fat reducing, is used for the treatment of or disease and indication that prevention is relevant with cardiovascular and cerebrovascular vessel.
Contain according to Ezetimibe, simvastatin, nicotinic acid and acceptable accessories in the compound preparation of the present invention.This compound preparation is a kind of slow releasing preparation, and slow-released part is nicotinic acid and pharmaceutically acceptable carrier, and immediate release section is that simvastatin reaches according to Ezetimibe and pharmaceutically acceptable carrier.
The pharmaceutically acceptable carrier of slow-released part is binding agent, disintegrating agent and lubricant; The pharmaceutically acceptable carrier of immediate release section is solubilizing agent, antioxidant, binding agent.
Binding agent optional in polyvidone, hydroxypropyl methylcellulose, carmethose, ethyl cellulose, microcrystalline Cellulose one or more, preferably microcrystalline cellulose, hydroxypropyl methylcellulose.
Disintegrating agent can be selected from one or more of pregelatinized Starch, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, crospolyvinylpyrrolidone, preferred pregelatinized Starch.
Lubricant is magnesium stearate.
Antioxidant can be selected from one or more in butylhydroxy anisole, propyl gallate, vitamin C, the tertiary butyl-4-hydroxy methyl phenyl ethers anisole, preferred tertiary butyl-4-hydroxyanisol.
Solubilizing agent is optional from polyoxyethylene sorbitan monoleate, sodium lauryl sulphate, replacement HPMC, preferably sodium dodecyl sulfate.
Sealing coat coating between slow release layer and the release layer is enteric coating, and the material of enteric coating is selected from Opadry (OPadry), polyvinyl alcohol phthalic acid ester (PVAP), Eudragitl30D-55, preferred Opadry.The material of the film-coat that release layer is outer is the gastric solubleness coating, and the gastric solubleness coating is optional from polyethylene acetal diethylin acetate (AEA), Opadry, polyvinylpyrrolidone (PVP), HPMC, preferred Opadry (OPadry).
The consumption of stomach dissolution type Opadry is generally 2% ~ 3% of label weight, and the consumption of enteric solubility Opadry is generally 6% ~ 10% of label weight.
The input percentage ratio according to the Ezetimibe unit formulation in the compound preparation of the present invention is 1-20%, preferred 5%.The input amount of the unit formulation of nicotinic acid is 1-75%, preferred 25%.The unit formulation input amount of simvastatin is 1-20%, preferred 5%.
Another object of the present invention is to provide the preparation method of a kind of effective increase according to the Ezetimibe dissolution, we adopt the hot melt extruding technology to increase according to Ezetimibe dissolution in vivo, thereby improve its bioavailability in vivo.Almost insoluble in water according to Ezetimibe, to mention surfactants such as adding solubilizing agent in the existing patent and improve water solublity, it is remarkably productive according to the dissolution of Ezetimibe that this patent adopts the hot melt extruding technology to compare the raising of previous patent adding surfactant.
The hot melt extruding technology is mainly used in improving the dissolution of insoluble drug, preparation sustained-release preparation and local administration preparation, and showing unique advantage, be subjected to the extensive concern of researcher in recent years.
Hot melt extruding technology process conditions are investigated in this patent:
This technology makes according to Ezetimibe and the abundant combination of water-solubility carrier, wherein water-solubility carrier is optional from Polyethylene Glycol (PEG), polyoxyethylene, polyvidone, copolymerization of ethylene ketopyrrolidine (Kollidon VA64), by testing preferred copolymerization of ethylene ketopyrrolidine (Kollidon VA64).There are four temperature options in hot device zone: be made as Zone1=110 ° C respectively, Zone2=120 ° C, Zone3=130 ° C, Zone4=130 ° C; Or Zone1=120 ° C, Zone2=130 ° C, Zone3=130 ° C, Zone4=130 ° C is by testing preferred Zone1=120 ° C, Zone2=130 ° C, Zone3=130 ° C, Zone4=130 ° C.
The detailed process that the present invention adopts the hot melt extruding technology to implement:
To fully be mixed with according to the good carrier Kollidon VA64 of Ezetimibe and water solublity and be physical mixture, by Double helix hot melt extruder (Coperion KEYATE-20) extruding as physical mixture, physical mixture is put into feeder earlier, be sent in the heater area by the Double helix rotation again, by the temperature in double-helical high mechanical force and the heater area physical mixture is extruded, the article of extruding (glassy state shape, more crisp) cool to room temperature with its pulverize, crosses 100 mesh sieves with grinder.There are four temperature options in hot device zone: be made as Zone1=120 ° C respectively, Zone2=130 ° C, Zone3=130 ° C, Zone4=130 ° C; Rate of feeding and twin screw extruded velocity are made as 2Hz.Below each group investigate for adopting the dissolution under two groups of temperature and the different water-solubility carrier condition respectively.
After table 1 adopts the hot melt extruding technology of different condition to handle according to the Ezetimibe dissolution
The result shows: wherein the 3rd group dissolution effect is the most obvious, its condition that adopts is: water-solubility carrier is vinylpyrrolidone, and there are four temperature option Zone1=120 ° of C, Zone2=130 ° C in hot device zone, Zone3=130 ° C, Zone4=130 ° C.
Simvastatin is insoluble and extremely unstable in water, acid, alkali, water, illumination, oxygen etc. all can cause the degraded of simvastatin, compound preparation among the present invention has suitably postponed the release of simvastatin, in addition, the active degradation product simvastatin acid of simvastatin can be destroyed by the enzyme in the stomach, avoids the generation of untoward reaction by adding antioxidant and peplos among the present invention.
Nicotinic acid is as the blood fat reducing time spent, and its dosage is bigger about 10 times than general consumption, so untoward reaction is many, because the skin expansion blood vessel causes that flushing and pruritus are the most common; Common in addition also have nausea,vomiting,diarrhea, dyspepsia etc., can increase the weight of or cause Peptic Ulcers sometimes.The present invention has adopted slow release method, has alleviated these to the bigger side effect of human body harm.
Three kinds of medicines in the compound recipe are can every day once oral, thus utilize a kind of increase active component dissolution, stability approach with these three kinds of active components be combined in independent one can be oral dosage units, in capsule or tablet, can be useful.At first, solve the problem of simvastatin stability by the peripheral hardware film-coat.Moreover, avoid the activated water hydrolysis products simvastatin acid of simvastatin to be destroyed by the enzyme in the stomach by the release of suitable delay simvastatin, be conducive to improve curative effect.Take compound preparation of the present invention, only needed take once in one day, can reach stable blood pressure lowering in a day, lipid-lowering effect.
Compound preparation of the present invention is slow releasing tablet or enteric coated capsule, and wherein enteric coated capsule is that medicine with compound recipe is sealed in the enteric coated capsule.Slow releasing tablet comprises the gentle lamella of releasing of rapid release lamella, and the slow release lamella contains treatment effective dose nicotinic acid and a certain amount of pharmaceutically acceptable carrier; The rapid release lamella contains simvastatin and a certain amount of pharmaceutically acceptable carrier for the treatment of effective dose.
The preparation method of slow releasing tablet comprises the steps:
(1) slow-released part
Tabletting made label after nicotinic acid and pharmaceutically suitable carrier mixed; To the label coating;
(2) immediate release section
With simvastatin and pharmaceutically suitable carrier and solvent, make lapping liquid in proportion; With this lapping liquid above-mentioned label is carried out coating, in proportion with active component according to Ezetimibe and water solublity well carrier mix adopt melt extrusion technology handle the hot melt extrudate, more above-mentioned label is carried out coating, form release layer; The bag film-coat.
The concrete preparation method of above-mentioned release layer is as follows:
(1) with the simvastatin of recipe quantity and a certain amount of cosolvent, antioxidant, binding agent mix homogeneously, the lapping liquid with the solvent preparation carries out coating with this muddiness liquid to the slow release label;
(2) with recipe quantity prepare the hot melt extrudate according to Ezetimibe and Kollidom VA 64 by the hot melt extruding technology, with it above-mentioned gained label skin is carried out coating;
(3) dryly carry out film coating after fully, make every weightening finish 2-3%.Form release layer.
Compared with prior art, the present invention has following advantage:
Preparation method provided by the present invention, the employing melt extrusion technology effectively raises the dissolution according to Ezetimibe, makes this compound preparation better bring into play drug effect;
Preparation method provided by the present invention; simple to operate; be convenient to large-scale production; and product of the present invention is slow releasing preparation; make three kinds of effective ingredient better bring into play synergism; the influence that is vulnerable to variations such as soda acid and moisture (as gastric acid) is reduced the many one decks protections of composition of drug action, improved simvastatin stability in vivo.
The specific embodiment
Below in conjunction with the specific embodiment the present invention is further described in detail, the embodiment that provides is only in order to illustrate the present invention, and do not limit the scope of the invention.
Embodiment 1: nicotinic acid/according to Ezetimibe/simvastatin composite
This enforcement will fully be mixed with according to the good carrier Kollidon VA64 of Ezetimibe and water solublity and be physical mixture, by Double helix hot melt extruder (Coperion KEYATE-20) extruding as physical mixture, physical mixture is put into feeder earlier, be sent in the heater area by the Double helix rotation again, by the temperature in double-helical high mechanical force and the heater area physical mixture is extruded, the article of extruding (glassy state shape, more crisp) cool to room temperature with its pulverize, crosses 100 mesh sieves with grinder.There are four temperature options in hot device zone: be made as Zone1=120 ° C respectively, Zone2=130 ° C, Zone3=130 ° C, Zone4=130 ° C; Rate of feeding and twin screw extruded velocity are made as 2Hz.
This enforcement mixes with nicotinic acid and prepares label with corresponding pharmaceutic adjuvant, corresponding OPadry suspension spray figure prepares nicotinic acid and simvastatin and according to the sealing coat of the hot melt extrudate of Ezetimibe and Kollidom VA 64 on label, the lapping liquid suspension of simvastatin mixes and is sprayed on the label that is equipped with sealing coat with corresponding excipient substance, at last at the hot melt extrudate of spraying one deck according to Ezetimibe and Kollidom VA 64, the suspension film coating of OPadry.
The preparation of table 2-label
Technology: nicotinic acid, microcrystalline Cellulose, pregelatinized Starch and magnesium stearate, mix homogeneously, by the direct compression technology, preparation label.
The preparation of table 3-sealing coat
Technology: OPadry is dispersed in the water uniformly, adjusts the coating parameter: the coating suspension is uniformly sprayed on label, and weightening finish 6-10% gets final product.
Table 4-simvastatin layer preparation
Technology: simvastatin and 10% hydroxypropyl methylcellulose are prepared solid dispersion by the liquid feeding grinding technique, add the pure water dilution, add sodium lauryl sulphate again and improve dissolution, the tertiary butyl-4-hydroxy methyl phenyl ethers anisole as the abundant mixing of antioxidant as coating solution, adjust the coating parameter, uniformly spray and having on the label of sealing coat, reuse mixes with Killidom VA 64 (1:4) according to Ezetimibe to be prepared the hot melt extrudate by the hot melt extruding technology and carries out coating.
Table 5-film coating layer
Sheet weighs 415
Technology: OPadry is dispersed in the water, adjusts the coating parameter, evenly be sprayed on simvastatin layer skin, weightening finish 2-3% gets final product.
Embodiment 2Nicotinic acid/according to Ezetimibe/simvastatin composite
Table 6 recipe quantity
The preparation technology of embodiment 2 is with reference to embodiment 1.
Embodiment 3
Table 7 recipe quantity
The preparation technology of embodiment 3 is with reference to embodiment 1.
Embodiment 4Dissolution is investigated
Three kinds of tablets that embodiment 1,2,3 is prepared adopt the device of dissolution method (2010 editions appendix XC first methods of Chinese Pharmacopoeia), with water as release medium, (37 ℃ of constant temperature
0.5 ℃) rotating speed is 100r/min, respectively 1,3,6,10,20, locates to get 2mL solution in 24 hours, adds blank release medium 2mL after getting liquid at every turn, with high effective liquid chromatography for measuring according to the accumulative total release of Ezetimibe at each time point; The results are shown in Table 8.
Table 8 is according to the experimental result of Ezetimibe dissolution determination
| Time (h) | 1 | 3 | 6 | 10 | 20 | 24 |
| Embodiment 1 | 24.3% | 36.4% | 58.6% | 79.2% | 86.7% | 98.5% |
| Embodiment 2 | 26.7% | 37.8% | 54.8% | 78.3% | 86.5% | 99.3% |
| Embodiment 3 | 25.8% | 36.7% | 55.5% | 78.7% | 85.7% | 98.9% |
By table 8 as seen,, evenly release slow in 24 hours, lasting according to Ezetimibe have good releasing effect.
Embodiment 5The experiment of animal effectiveness
10 of beasle dogs are adopted in experiment, and body weight 5-7Kg, blood pressure are divided into normal control group beasle dog or carry out the modeling processing in 85 ~ 155mmHg scope.Normal group is fed with conventional solid feed, adapts to begin experiment after a week.The experiment beasle dog adopts the compound high fat diet feeding legal system of improving one's methods of " two kidneys, one folder " renal hypertension model to be equipped with the compound hyperlipemia model of hypertension.Operation uses the 0.25mm acupuncture needle to be close to parallel placement with the renal artery blood vessel, uses the chorda serica chirurgicalis sterilis ligation, extracts acupuncture needle then out, and the result causes one-sided renal artery stenosis.Penicillin lumbar injection prevention infection in the postoperative 3 days.Treat that the beasle dog functional recovery is normal, give standard feed and lipomul and irritate stomach, continued for 4 weeks, measure non-fasting blood pressure and triglyceride, cholesterol levels to confirm whether modeling is successful.The beasle dog of modeling success is divided into 5 groups at random: A(is according to Ezetimibe+simvastatin), B(simvastatin+nicotinic acid), C(is according to Ezetimibe+simvastatin+nicotinic acid), D(is according to Ezetimibe), E(is according to Ezetimibe sheet+simvastatin sheet+nicotinic acid tablet).Wherein the medicine of A, B, C, D group is to be made into slow releasing tablet respectively according to the method in the embodiment of the invention 1, wherein compares the drug moiety that the C group lacks in A, B, the D group and replaces with medicinal supplementary product starch; The medicine of E group is that three kinds of single component tablets simply mix, and presses the medicine grouping oral administration of following prompting.
All animals are all measured the preceding blood pressure of taking medicine, and according to the body weight of beasle dog, according to following dosage oral administration: A, B, C, D group press the administration of 10mg/kg oral way respectively, and E organizes according to according to Ezetimibe 1mg/kg, simvastatin 2mg/kg, nicotinic acid 10mg/kg oral administration.
According to dosage irritate stomach every day once by said medicine, for three days on end after, begin to measure blood pressure, each organizes 4 weeks of successive administration.Get the content of hematometry triglyceride and T-CHOL after the last administration.The results are shown in Table 9, table 10.
Blood pressure determination
Measure blood pressure with laboratory animal blood pressure determination instrument, its meansigma methods is got in every continuous measurement 3 times.
(1) to the influence of blood pressure
Table 9---medicine to the influence of animal blood pressure (mmHg,
S)
(2) to the influence of blood fat
Table 10---medicine to the influence of animal lipid (mmol/L,
S)
Conclusion: to sum up test as can be known, according to the compound preparation of Ezetimibe, simvastatin and nicotinic acid, blood pressure lowering and effect for reducing fat all significantly are better than other groups.Compound preparation of the present invention is than having good result according to Ezetimibe associating simvastatin and the medication of simvastatin associating nicotinic acid aspect the hypertension and hyperlipemia.
Claims (8)
1. the compound preparation according to Ezetimibe is characterized in that: by forming according to Ezetimibe, simvastatin, nicotinic acid and pharmaceutically acceptable carrier.
2. according to claim 1, it is characterized in that: described compound preparation is a kind of slow releasing preparation, and slow-released part is made up of nicotinic acid and pharmaceutically acceptable carrier, and immediate release section is formed by simvastatin with according to Ezetimibe and pharmaceutically acceptable carrier.
3. according to claim 2, it is characterized in that: slow-released part nicotinic acid unit formulation input amount is 1-75%; Immediate release section simvastatin unit formulation input amount is 1-20%; Be 1-20% according to Ezetimibe unit formulation input amount.
4. according to claim 3, it is characterized in that: slow-released part nicotinic acid unit formulation input amount is 25%; Immediate release section simvastatin unit formulation input amount is 5%; Be 5% according to Ezetimibe unit formulation input amount.
5. according to claim 2, it is characterized in that the pharmaceutically acceptable carrier of slow-released part is binding agent, disintegrating agent, lubricant; The pharmaceutically acceptable carrier of described immediate release section is binding agent, solubilizing agent, antioxidant; The described binding agent of slow-released part is microcrystalline Cellulose, and disintegrating agent is pregelatinized Starch, and lubricant is magnesium stearate; The described binding agent of immediate release section is 10% hydroxypropyl methylcellulose, and solubilizing agent is sodium lauryl sulphate, and antioxidant is the tertiary butyl-4-hydroxy methyl phenyl ethers anisole.
6. the described preparation method according to the Ezetimibe compound preparation of claim 1 is characterized in that,
Comprise the steps:
(1) slow-released part
Tabletting made label after nicotinic acid and pharmaceutically suitable carrier mixed; To the label coating;
(2) immediate release section
With simvastatin and pharmaceutically suitable carrier and solvent, make lapping liquid in proportion; With this lapping liquid above-mentioned label is carried out coating, in proportion with active component according to the good carrier of Ezetimibe and water solublity mix adopt melt extrusion technology handle the hot melt extrudate, more above-mentioned label is carried out coating, form release layer; The bag film-coat.
7. the good carrier of the described water solublity of claim 6 is selected from a kind of of polyvidone, polyoxyethylene, Polyethylene Glycol (PEG), copolymerization of ethylene ketopyrrolidine (Kollidon VA64).
8. the described compound preparation of claim 1, its effect aspect blood pressure lowering, blood fat reducing is in treatment or the prevention disease relevant with cardiovascular and cerebrovascular vessel and the application aspect the indication.
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| CN104382896A (en) * | 2014-11-04 | 2015-03-04 | 万全万特制药江苏有限公司 | Pharmaceutical composition containing ezetimibe and simvastatin |
| CN104771378A (en) * | 2015-04-20 | 2015-07-15 | 鲁南贝特制药有限公司 | Simvastatin tablet |
| CN113166195A (en) * | 2018-08-24 | 2021-07-23 | 艾斯柏伦治疗公司 | Ways to reduce diabetes risk in patients who are treating high cholesterol-related conditions |
| CN117771248A (en) * | 2023-11-30 | 2024-03-29 | 宁波高新区美诺华医药创新研究院有限公司 | Ezetimibe rosuvastatin calcium preparation and preparation method thereof |
| CN118892469A (en) * | 2024-07-12 | 2024-11-05 | 宁波高新区美诺华医药创新研究院有限公司 | A kind of ezetimibe and rosuvastatin calcium preparation composition |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104382896A (en) * | 2014-11-04 | 2015-03-04 | 万全万特制药江苏有限公司 | Pharmaceutical composition containing ezetimibe and simvastatin |
| CN104771378A (en) * | 2015-04-20 | 2015-07-15 | 鲁南贝特制药有限公司 | Simvastatin tablet |
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| CN113166195A (en) * | 2018-08-24 | 2021-07-23 | 艾斯柏伦治疗公司 | Ways to reduce diabetes risk in patients who are treating high cholesterol-related conditions |
| CN117771248A (en) * | 2023-11-30 | 2024-03-29 | 宁波高新区美诺华医药创新研究院有限公司 | Ezetimibe rosuvastatin calcium preparation and preparation method thereof |
| CN118892469A (en) * | 2024-07-12 | 2024-11-05 | 宁波高新区美诺华医药创新研究院有限公司 | A kind of ezetimibe and rosuvastatin calcium preparation composition |
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