CN101972260A - Rosuvastatin calcium oral drug composition - Google Patents
Rosuvastatin calcium oral drug composition Download PDFInfo
- Publication number
- CN101972260A CN101972260A CN 201010555675 CN201010555675A CN101972260A CN 101972260 A CN101972260 A CN 101972260A CN 201010555675 CN201010555675 CN 201010555675 CN 201010555675 A CN201010555675 A CN 201010555675A CN 101972260 A CN101972260 A CN 101972260A
- Authority
- CN
- China
- Prior art keywords
- calcium
- rosuvastatin calcium
- lactose
- meglumine
- preparation
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Abstract
The invention relates to a rosuvastatin calcium oral drug composition and a preparation method thereof. The rosuvastatin calcium oral drug composition is characterized by comprising the following components in proportion: 10-80mg of rosuvastatin calcium, 20-160mg of hydroxypropyl betadex, 5-40mg of meglumine, 2-16mg of sodium sulfite, 100-800mg of lactose, 50-400mg of microcrystalline cellulose, 20-160mg of croscarmellose sodium, 2-16mg of magnesium stearate and a proper amount of 80 percent ethanol solution. The preparation method comprises the following steps of: dissolving hydroxypropyl betadex, meglumine and magnesium stearate into a proper amount of 80% ethanol solution; adding rosuvastatin calcium and mixing until the rosuvastatin calcium is completely dissolved; evenly mixing lactose, microcrystalline cellulose and croscarmellose sodium for later use; quantitatively adding the solution into an evenly-mixed accessory for pelletization; and obtaining a finished product by drying, palletizing, totally mixing, checking an intermediate body, pressing into pieces, coating and packing. The prepared rosuvastatin calcium tablet has good stability and high bioavailability.
Description
Technical field
The invention belongs to medical technical field, or rather, relate to rosuvastain calcium combination of oral medication and preparation method thereof.
Background technology
Rosuvastain calcium (Rosuvastatin Calcium); chemistry is by name: two-[(E)-the fluorine-based phenyl of 7-[4-(4-)-6-isopropyl-2-[methyl (mesyl) amino]-pyrimidine-5-yl] (3R; 5R)-3,5-dihydroxy heptyl-6-olefin(e) acid] calcium salt (2:1).
Its structural formula is:
Molecular formula: (C
22H
27FN
3O
6S)
2Ca
Molecular weight: 1001.13
The pharmacology type:Rosuvastatin is 3-hydroxyl-methyl glutaryl coenzyme A (HMG-CoA) reductase inhibitor, and cholesterol levels descends in the blood plasma so can make.
Mechanism of action:Rosuvastatin can suppress the synthetic rate-limiting enzyme HMG-CoA of cholesterol reductase in the liver by selectivity, liver albumen is generated reduce, and low-density lipoprotein cholesterol (LDL-C) expression of receptor increases, so blood plasma cholesterol level descends.
Indication:This product is applicable to primary hypercholesterolemia (the Iia type comprises the heterozygote familial hypercholesterolemia) or the mixed type lipidemia unusual (Iib type) that still can not suitably control dyslipidemia through diet control and other non-drug therapy (as: exercise therapy, lose weight).
This product also is applicable to the patient of homozygote familial hypercholesterolemia, as the auxiliary treatment of diet control and other blood fat reducing measure (removing therapy as LDL), or uses when these methods are inapplicable.
Usage and dosage:Before the treatment beginning, should give the cholesterol reducing diet control of patient's standard, and during treating, keep diet control.The use of this product should be followed principle of individuation, takes all factors into consideration the cholesterol levels of individual patients, the cardiovascular risk of expection and the potential danger that untoward reaction takes place.
Oral.This product initial dose commonly used is 5 mg, 1 time on the 1st.The selection of initial dose should be taken all factors into consideration the cholesterol levels of individual patients, the cardiovascular risk of expection and the potential danger that untoward reaction takes place.Need the patient who reduces LDL-C can consider 10 mg for those, 1 time on the 1st this dosage can be controlled the blood lipid level of Most patients as initial dose more potently.If necessary, can adjust the dosage level of the paramount one-level of dosage in 4 week of treatment back.This product maximal dose every day is 20 mg.
This product can be in one day administration whenever, can take on the feed or on an empty stomach.
Along with the raising of people's living standard, the change of custom, the sickness rate of hyperlipemia increases year by year, patient's age trend rejuvenation.According to statistics, the normal population sickness rate is 20%～40%, and China has hyperlipemia patient 8,000 ten thousand people approximately, and every day is still with ten thousand people's speed increase.And hyperlipemia is the principal element of incidence of atherosclerosis, can cause serious cardiovascular and cerebrovascular disease, influences people's healthy and quality of life.Therefore, in recent years, people are for the more and more attention of hyperlipemia.
Hyperlipemia (hyperlipidemia) is meant body fat mass in human body metabolism or running unusually, the content of the T-CHOL in the blood plasma (TC), triacylglycerol (TG), LDL-C, C-VLDL (VLDL-C) surpasses arm's length standard, the content of HDL-C (HDL-C) in blood plasma is low excessively in addition, also belongs to the category of dyslipidemia.Hyperlipemia is produced too much by VLDL or removing obstacles and VLDL be transformed into LDL too much due to.Obesity, diabetes, ethanol are excessive, nephrotic syndrome or genetic flaw can cause that liver VLDL produces too much.The removing obstacles of LDL is relevant with the fault of construction of apolipoprotein B (ApoB).In addition, removing obstacles also may be because ldl receptor quantity reduces or dysfunction (vigor reduction), and this may be for due to gene or the dietary factor.
General hyperlipemia can be classified by following characteristics: can be divided into six types by clinical manifestation.The I type: TG significantly increases, and cholesterol is normal, and mainly due to the congenital deficiency lipoproteinesterase, exogenous triacylglycerol can not be decomposed and accumulate in the blood plasma, so claim exogenous high triglyceride mass formed by blood stasis, this kind of is rare; II a type: TC significantly increases, and TG is normal, is the inborn errors of metabolism of familial, so claim familial hypercholesterolemia again, this kind of is more sees; II b type: TC significantly increases, and TG is high slightly, for familial or hypercholesterolemia hyperphagia cause, morely sees; III type: TC and TG all obviously increase, and are heritability, thus claim familial hyperlipidemia again, rare; The IV type: TG significantly increases, and TC is normal or high slightly, and how unusual carbohydrate tolerance test is, is to cause owing to liver is converted into triacylglycerol with sugar too much, so also claim sugar hyperlipemia or endogenous high triglyceride mass formed by blood stasis, morely sees; V type: TG is very high, and TC is high slightly, is exogenous and endogenic, has the feature of I type, IV amphitypy concurrently, thus claim Combination high triglyceride mass formed by blood stasis again, rare.Can be divided into constitutional and Secondary cases by cause of disease branch hyperlipemia.Wherein Primary hyperlipemia belongs to hereditary disorders of lipid metabolism disease.
Clinically, hyperlipemia is concealment, carrying out property and general to the infringement of health, and its direct infringement is to cause systemic atherosclerosis, and then causes numerous relevant diseases.Arteriosclerosis as heart and brain can cause diseases such as coronary heart disease, angina pectoris, myocardial infarction and cerebrovascular accident; Serious chylomicronemia can cause acute pancreatitis; Fat is piled up in liver and is formed fatty liver, increases the weight of for a long time to develop into liver cirrhosis; One of the blood capillary sclerosis of kidney, obstruction not only can cause renal failure, intractable hypertension and uremia etc., or the major reason of transplanted kidney repulsion and afunction.Xanthoma around tendon shape, nodositas, palm plane and the eye socket, arcus juvenilis etc. also can appear in some constitutional and familial hyperlipidemia patient.In addition, hyperlipemia can promote impaired glucose tolerance, diabetes and complication development thereof, causes peripheral vascular disease, hyperuricemia etc.
Hyperlipemia is high morbidity in mid-aged population, and along with the raising of people's living standard, the change of living habit, the sickness rate of hyperlipemia increases year by year, and patient's age is tending towards rejuvenation.There is hyperlipemia 8,000 ten thousand in China, and increases with ten thousand people's quantity every day, and hyperlipidemia is threatening people's health at any time just as time bomb.The most direct infringement of hyperlipidemia is the arteriosclerosis that causes whole body, and then causes the disease of being correlated with, and can cause diseases such as coronary heart disease, angina pectoris, myocardial infarction and cerebrovascular accident as the arteriosclerosis of heart and brain.Clinical the most common hyperlipemia is hypercholesterolemia (Iia type) and combined hyperlipidemia familial (Iib type).Cholic acid chelating agent class medicine is difficult for tolerance in the existing curative commonly used, and the special class of shellfish reduces TC and LDL poor effect, and nicotinic acid badness reaction ambassador uses limited, so the most frequently used curative is a statins.In the existing statins, Time To Markets such as lovastatin, pravastatin, simvastatin, fluvastatin are longer, problem such as untoward reaction and unsatisfactory curative effect manifests gradually, eliminates for market gradually, uses maximum be atorvastatin and Rosuvastatins now clinically.
The main site of action of Rosuvastatin is efficient selective HMG-CoA reductase inhibitor at liver, the liver lipoprotein is generated reduce, and the LDL-C expression of receptor increases, and blood plasma cholesterol level is descended.It can also make VLDL and TG significantly descend, and increases antiatherogenic HDL.By the reduction blood plasma lipide, thereby suppress accumulating and interior pachyhymenia of lipid.
Existing clinical research data shows, atorvastatin is compared with Rosuvastatin, safety is suitable, compliance is good, but the 10th European annual meeting announces that two relate to 470,000 and take statins and transfer the large-scale investigation of fat effect studies show that according to International Pharmaceutical economics and clinical final result research association, and Rosuvastatin transfers the fat effect the strongest, the consumption minimum reduces the cardiovascular event effect and also is better than other statinses.STELLAR research is extensive a, multicenter, parallel grouping, open trial, the curative effect that has compared simvastatin, pravastatin, atorvastatin and each dosage range of Rosuvastatin, patient's 2431 examples that are selected in hypercholesterolemia altogether, use Rosuvastatin 10,20 or 40mg/d respectively, atorvastatin 10,20,40 or 80 mg/d, simvastatin 10,20,40 or 80 mg/d, pravastatin 10,20 or 40 mg/d.Result of study shows, the curative effect that LDL-C totally falls in Rosuvastatin after 6 weeks obviously is better than other his spit of fland.The Rosuvastatin of 10mg can make patient LDL-C descend 46%～55%.By comparison, accept only have 72% to reach this target among the patient of atorvastatin 80mg treatment.This shows that more low dose of Rosuvastatin can reach than the better therapeutic effect of atorvastatin.
According to the latest news, Rosuvastatin obtains the new indication of FDA approval primary prevention, can be used for not being in the mood for the disease of ZANG-organs clinical manifestation but the patient of potential risk of cardiovascular diseases, to reduce myocardial infarction, apoplexy and to carry out the risk that coronary artery reproduces.
This shows that compare with atorvastatin, the Rosuvastatin consumption is littler, better efficacy, and also safety and compliance are good.In addition, Rosuvastatin also has preventive effect, and the scope of application is wider, can reduce those potential patients' sickness rate, protection people's health.So we have reason to believe that Rosuvastatin will inevitably replace atorvastatin in the near future, become the choice drug of vast hyperlipemic patients.
A shortcoming of rosuvastain calcium is: in some cases, in the hot and humid photoenvironment, it is easy to degraded, the primary product that forms is the lactone catabolite, oxidative breakdown product and illumination degrading product, thereby cause the configuring product operating difficulties, and the pharmaceutical composition for preparing does not reach the requirement of storage life, this unstability is determined by itself, β in the rosuvastain calcium molecule on the heptenoic acid chain, δ-hydroxyl is highly stable, and wherein, the hydroxyl that carbon-to-carbon double bond is adjacent is easy to be oxidized to ketone, also molecule inner ring condensation can take place, generate lactone.
A kind of stabilization medicines compositions that contains statin compound is disclosed among the Chinese patent CN93100650, said composition is to remain on 8 alkaline medium (for example carbonate or bicarbonate) at least by the pH value that adds a kind of aqueous solution that can make said composition or dispersion liquid to reach Stabilization.Yet the inventor repeatedly finding in the experiment, and the pH value of control combination thing separately also is not enough to solve the stability problem of Rosuvastatin calcium composition.
Disclose a kind of stabilizing pharmaceutical composition that contains Rosuvastatin or its officinal salt among the Chinese patent CN00122484, said composition is to be that three alkali valency phosphate (for example three alkali valency calcium phosphate) reach and stablize purpose by the cation that adds as stabilizing agent.Yet, the disclosed prescription that contains three alkali valency calcium phosphate during the inventor all finds according to patent CN00122484 in repeatedly testing, adopt domestic wet granulation technique commonly used to granulate, in 40 ℃ of heated-air circulation oven dry runs, composition grain gradually becomes faint yellow even yellowish-brown by pure white.Especially in the industrialized great production process, wet granular output is big, and drying time is longer, and this variable color can't be avoided.This significant variation can directly cause the failure of producing.According to the compositions that disclosed method among the patent CN00122484 prepares, be placed on 30 ℃, under relative humidity 75% condition, the obvious flavescence of compositions after seven days illustrates to have generated other foreign pigment.
Chinese patent CN00122484 adopts dry method direct compression or fluid-bed drying to reduce the open-assembly time of described compositions under wet condition, though these two kinds of methods have been evaded the phenomenon of Rosuvastatin calcium composition flavescence in preparation process, show no sign of the fact that changes said composition storage meeting flavescence under super-humid conditions.
Chinese patent ZL200710024860.9 discloses a kind of stable combination of oral medication, relates to particularly containing rosuvastain calcium, micropowder silica gel and the pharmaceutical composition of proper supplementary material pharmaceutically, with and its production and use.The defective of this patent is, the domestic micropowder silica gel of still not having medicinal registration permission causes this Pharmaceutical composition not implement, and can't realize industrialization.Adopt the compositions of this patent preparation, though the storage color does not change under super-humid conditions, placed 10 days under illumination and hot conditions, its oxidative breakdown product and light degradation product all rise appreciably.Also be not enough to solve the stability problem of Rosuvastatin calcium composition.
Chinese patent 200780034516.6 discloses a kind of new pharmaceutical composition, it comprises amorphous rosuvastatin calcium and as magnesium hydroxide and/or calcium acetate or calcium gluconate or the calcium glycerophosphate or the aluminium hydroxide of stabilization additives, and one or more medicinal acceptable excipient.Adopt the compositions of this patent preparation, though the storage color does not change under super-humid conditions, placed 10 days under illumination and hot conditions, its light degradation product all rises appreciably.Also be not enough to solve the stability problem of Rosuvastatin calcium composition.
According to above-mentioned prior art, the stabilizing pharmaceutical composition that comprises rosuvastain calcium that needs preparation to be easy to prepare.
In order to address the above problem, the inventor gropes by long-term a large amount of test, the astonishing pharmaceutical composition of having found a kind of new rosuvastain calcium, said composition is under preparation, storage, super-humid conditions, its lactone degradation product, oxidative degradation thing, illumination degrading thing all no longer increase, can guarantee the stability of long term store, thereby solve the problem that always perplexs the rosuvastain calcium preparation stability.The present invention after 36 months time, measures its related substance at ambient temperature, basic not degraded.Has more good quality stability.By being carried out PROCESS FOR TREATMENT, it has improved said preparation quality and stability thereof greatly.Simultaneously, said composition has prescription, technology is simple, need not special handling production equipment, advantage such as with low cost, thereby is the extensive popularization of this medicine in clinical, has played more positive effect.
Summary of the invention
According to existing adjuvant and working condition, guaranteeing to have lower production cost and simple preparation technology, be suitable under the prerequisite of large-scale industrial production, be necessary to work out a kind of stable prescription and form and preparation technology, make rosuvastain calcium have good stability of drug products.
The present invention relates to pharmaceutical composition that comprises rosuvastain calcium and preparation method thereof.In some preferred embodiment, described dosage form is tablet or capsule.The amount of rosuvastain calcium is 10mg, 20mg, 40mg or 80mg, wherein is preferably 10mg, and 20mg most preferably is 10mg.
Purpose of the present invention provides a kind of Rosuvastatin calcium tablet, and the prescription that it is characterized in that making 1000 is composed as follows:
| Supplementary material | Weight |
| Rosuvastain calcium | 10g |
| HYDROXYPROPYL BETA-CYCLODEXTRIN | 20g |
| Meglumine | 5g |
| Sodium sulfite | 2g |
| Lactose | 100g |
| Microcrystalline Cellulose | 50g |
| Cross-linking sodium carboxymethyl cellulose | 20g |
| 80% alcoholic solution | 0.025-0.05ml |
| Magnesium stearate | 2g |
| Gastric solubleness premix coating powder | In right amount |
Second portion of the present invention relates to the preparation method of preparation Rosuvastatin calcium tablet, and its step comprises:
1) with the preparation and the processing of supplementary material: with rosuvastain calcium, and adjuvant to cross 100 mesh sieves respectively standby.
2) weighing: take by weighing above-mentioned supplementary material respectively through the double calculating inventory of checking according to recipe quantity.
3) recipe quantity HYDROXYPROPYL BETA-CYCLODEXTRIN, meglumine and sodium sulfite are dissolved in an amount of 80% alcoholic solution, the rosuvastain calcium that adds recipe quantity again is stirred to dissolving fully, as binding agent.
4) with recipe quantity lactose, microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose mix homogeneously, standby.
5) add 3 granulation: to 4)), granulate with 30 eye mesh screens.
6) drying:: 45 ℃ ± 5 ℃ dryings.
7) granulate: select 30 mesh sieve granulate for use.
8) total mixing: adding adds lubricant, mix homogeneously.
9) intermediate check: sampling is pressed quality standard and is measured granule content, and it is heavy to calculate sheet.
10) tabletting: heavy according to the actual sheet of result of calculation gained, regulate sheet and weigh tabletting.
11) coating.
12) packing back warehouse-in.
Below by test data beneficial effect of the present invention is described.
With the product of the embodiment of the invention 1, in the CN00122484 patent embodiment 4, the embodiment 1 in the CN200710024860.9 patent, that the product of embodiment 10 in the CN200780034516.6 patent compares the stability test result is as follows:
Constant temperature accelerated stability test result
CN00122484 embodiment 4 and CN200710024860.9 embodiment 1 quicken 3 months its light degradation products, lactonize catabolite and oxidative breakdown product all obviously increase, and it is against regulation that CN200780034516.6 embodiment 10 places after 6 months its light degradation product and oxidative breakdown product.
Long term test stability test result
Last table shows that the embodiment of the invention 1 all has more advantages of excellent stability in constant temperature accelerated test and long term test.
The invention has the advantages that, by adding the adjuvant of basic auxiliary and antioxidant, the stability of rosuvastain calcium under accelerated test condition and long term test condition is improved greatly, adopt the good coating powder of shading performance to make the heliosensitivity of the preparation behind its coating reduce greatly, overcome the shortcoming of said preparation poor stability, produce and have more stabilized quality and quality, make that the safety in the clinical practice improves greatly.
Below by conceptual design and prescription screening explanation the present invention.
The rosuvastain calcium physicochemical property: this product is white or off-white powder: bitter in the mouth.This product is atomic in water, and is almost insoluble in methanol or ethanol.
It is a certain amount of to get raw material, test method according to influence factor in the medicine stability guideline, respectively under 4500LX ± 500LX illumination condition, in 60 ℃ of pyritous calorstats and 25 ℃ of relative humidity 92.5% ± 5%(KNO3 saturated solutions) calorstat placed 10 days, investigate appearance character and related substance, result of the test sees Table:
Shown that by above result of the test rosuvastain calcium is under influence factor's condition, related substance obviously increases, instability.Moisture absorption is serious under super-humid conditions, and illumination, high temperature, high humidity all have a significant effect to it.So in the time of the design prescription, must consider, make preparation prescription have advantages of excellent stability by adjuvant and PROCESS FOR TREATMENT.
Have bibliographical information to show, major ingredient is in alkaline environment, and its impurity growth obtains certain inhibition.So consider by adding basic auxiliary, because its major ingredient itself has unsettled characteristic, so consider to add a certain amount of alkaline diluent.We select meglumine, and meglumine is white to light yellow crystalline powder, and odorless or little smelly is a kind of organic base, mainly is to do the pH regulator agent, with acid effect salify.Because the major ingredient influence factor tests demonstration, principal agent has all shown unstable character to illumination, high temperature, high humidity, so select HYDROXYPROPYL BETA-CYCLODEXTRIN it is wrapped and, so select hydroxypropyl by his cyclodextrin, consider to add a certain amount of antioxidant in addition, as sodium sulfite, further guarantee stability of formulation.The design prescription is as follows:
| The prescription number | Prescription 1 | Prescription 2 |
| Supplementary material | Weight | Weight |
| Rosuvastain calcium | 10g | 10g |
| HYDROXYPROPYL BETA-CYCLODEXTRIN | 20g | / |
| Meglumine | 5g | / |
| Sodium sulfite | 2g | / |
| Lactose | 100g | 100g |
| Microcrystalline Cellulose | 50g | 50g |
| Cross-linking sodium carboxymethyl cellulose | 20g | 20g |
| 80% alcoholic solution | In right amount | In right amount |
| Magnesium stearate | 2g | 2g |
1 preparation technology writes out a prescription: recipe quantity HYDROXYPROPYL BETA-CYCLODEXTRIN, meglumine and sodium sulfite are dissolved in an amount of 80% alcoholic solution, and the rosuvastain calcium that adds recipe quantity again is stirred to dissolving fully, as binding agent; With recipe quantity lactose, microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose mix homogeneously, standby; With above-mentioned two kinds of mixed soft materials of mixture, cross 30 eye mesh screens and granulate; 45 ℃ ± 5 ℃ dryings; Granulate; After adding adds the magnesium stearate mix homogeneously; Tabletting; Preparation prescription 1.
2 preparation technologies write out a prescription: with recipe quantity rosuvastain calcium, lactose, microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose mix homogeneously; Adopt 80% alcoholic solution to make soft material in right amount, cross 30 eye mesh screens and granulate; 45 ℃ ± 5 ℃ dryings; Granulate; After adding adds the magnesium stearate mix homogeneously; Tabletting; Preparation prescription 2.
Prescription 1 prescription 2 mass ratioes are to research
Shown by above result of the test: prescription 2 preparation back related substances obviously increase, and stripping trend is slower.1 quality of writing out a prescription obviously is better than writing out a prescription 2.
To write out a prescription 1 be placed under 4500LX ± 500LX illumination condition, in 60 ℃ of pyritous calorstats and 25 ℃ of relative humidity 92.5% ± 5%(KNO3 saturated solutions) calorstat placed 10 days, investigate appearance character and related substance, result of the test sees Table:
Show by above result of the test: this prescription steady quality, stripping trend is fast, still its prescription is amplified, and will investigate its accelerated test and long term test, investigate its quality of stability.
The specific embodiment
Below in conjunction with embodiment the present invention is described in further detail, but should understands the non-scope that only limits to these embodiment of scope of the present invention.
Embodiment 1
The prescription of making 1000 is composed as follows:
| Supplementary material | Weight |
| Rosuvastain calcium | 10g |
| HYDROXYPROPYL BETA-CYCLODEXTRIN | 20g |
| Meglumine | 5g |
| Sodium sulfite | 2g |
| Lactose | 100g |
| Microcrystalline Cellulose | 50g |
| Cross-linking sodium carboxymethyl cellulose | 20g |
| 80% alcoholic solution | 0.025-0.05L |
| Magnesium stearate | 2g |
| Gastric solubleness premix coating powder | In right amount |
Second portion of the present invention relates to preparation rosuvastain calcium preparation of drug combination method, and its step comprises:
1) with the preparation and the processing of supplementary material: with rosuvastain calcium, and adjuvant to cross 100 mesh sieves respectively standby.
2) weighing: take by weighing above-mentioned supplementary material respectively through the double calculating inventory of checking according to recipe quantity.
3) recipe quantity HYDROXYPROPYL BETA-CYCLODEXTRIN, meglumine and sodium sulfite are dissolved in an amount of 80% alcoholic solution, the rosuvastain calcium that adds recipe quantity again is stirred to dissolving fully, as binding agent.
4) with recipe quantity lactose, microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose mix homogeneously, standby.
5) add 3 granulation: to 4)), granulate with 30 order nylon screens.
6) drying:: 45 ℃ ± 5 ℃ dryings.
7) granulate: select 30 mesh sieve granulate for use.
8) total mixing: adding adds lubricant, mix homogeneously.
9) intermediate check: sampling is pressed quality standard and is measured granule content, and it is heavy to calculate sheet.
10) tabletting: heavy according to the actual sheet of result of calculation gained, regulate sheet and weigh tabletting.
11) coating.
12) packing back warehouse-in.
Embodiment 2
The prescription of making 1000 is composed as follows:
| Supplementary material | Weight |
| Rosuvastain calcium | 20g |
| HYDROXYPROPYL BETA-CYCLODEXTRIN | 40g |
| Meglumine | 10g |
| Sodium sulfite | 4g |
| Lactose | 200g |
| Microcrystalline Cellulose | 100g |
| Cross-linking sodium carboxymethyl cellulose | 40g |
| 80% alcoholic solution | 0.05-0.1L |
| Magnesium stearate | 4g |
| Gastric solubleness premix coating powder | In right amount |
Its step is with embodiment 1.
Embodiment 3
The prescription of making 1000 is composed as follows:
| Supplementary material | Weight |
| Rosuvastain calcium | 40g |
| HYDROXYPROPYL BETA-CYCLODEXTRIN | 80g |
| Meglumine | 20g |
| Sodium sulfite | 8g |
| Lactose | 400g |
| Microcrystalline Cellulose | 200g |
| Cross-linking sodium carboxymethyl cellulose | 80g |
| 80% alcoholic solution | 0.1-0.15L |
| Magnesium stearate | 8g |
| Gastric solubleness premix coating powder | In right amount |
Its step is with embodiment 1.
Embodiment 4
The prescription of making 1000 is composed as follows:
| Supplementary material | Weight |
| Rosuvastain calcium | 80g |
| HYDROXYPROPYL BETA-CYCLODEXTRIN | 160g |
| Meglumine | 40g |
| Sodium sulfite | 16g |
| Lactose | 800g |
| Microcrystalline Cellulose | 400g |
| 16 | 80g |
| 80% alcoholic solution | 0.15-0.2L |
| Magnesium stearate | 16g |
| Gastric solubleness premix coating powder | In right amount |
Its step is with embodiment 1.
The comparative example 1
Embodiment 4 in the CN00122484 patent
| Supplementary material | Weight |
| Rosuvastain calcium | 2.50mg |
| Polyvinyl pyrrolidone | 2.50mg |
| Three alkali valency calcium phosphate | 20.0mg |
| Microcrystalline Cellulose | 34.5mg |
| Lactose monohydrate | 34.0mg |
| Sodium starch glycolate | 6.00mg |
| Magnesium stearate | 1.00mg |
| 2,6 ditertiary butyl p cresol | 0.05mg |
A part of three alkali valency calcium phosphate and 2; the 6-ditertbutylparacresol mixed in bag 30 seconds; with reagent of the present invention, polyvinyl pyrrolidone, remaining three alkali valency calcium phosphate, microcrystalline Cellulose, lactose monohydrate, three alkali valency calcium phosphate/2; 6-ditertbutylparacresol mixture and a part of sodium starch glycolate close in the granulator south of a town and mixed 30 seconds; with purifying waste water mixture of powders was granulated 1 minute, adding speed be the 70mg/ sheet/minute.In fluidized bed dryer, granule drying under 50 ℃ is lost less than 2%w/w after drying.With dried granules by grinding machine (for example passing through Comil).Granule and remaining sodium starch glycolate after grinding were mixed about 5 minutes, magnesium stearate after 40 orders (425um) sieve sieves, is joined in the said mixture, continue again to mix 3 minutes, the homogeneous mixture that obtains is pressed into tablet.
The comparative example 2
Embodiment 1 in the CN200710024860.9 patent
| The supplementary material title | 1000 consumptions (g) |
| Rosuvastain calcium | 10.4(be equivalent to Rosuvastatin 10g) |
| Micropowder silica gel | 6 |
| Microcrystalline Cellulose | 60 |
| Lactose | 95 |
| Polyvinylpolypyrrolidone (in add) | 8 |
| Polyvinylpolypyrrolidone (adding) | 8 |
| 30 POVIDONE K 30 BP/USP 30 | 5 |
| Water | In right amount |
| Magnesium stearate | 2 |
| Stomach dissolved film coating pre-mix dose | In right amount |
Mix homogeneously behind 100 mesh sieves is crossed in rosuvastain calcium and micropowder silica gel, add microcrystalline Cellulose, lactose, polyvinylpolypyrrolidone (in add), the polyvidone of mistake 80 mesh sieves of recipe quantity, abundant mix homogeneously, in powder, add suitable quantity of water system soft material, crossing 20 mesh sieves granulates, 45 ℃ of air blast oven dry, dried granule is crossed 20 mesh sieve granulate, adds the polyvinylpolypyrrolidone (adding) of recipe quantity, suitably mix the magnesium stearate that the back adds recipe quantity, mix homogeneously.Detect tabletting behind intermediate content and the moisture, carry out film coating after label is removed fine powder.
The comparative example 3
Embodiment 10 in the CN200780034516.6 patent
| Main component | Ratio in compositions (w/w %) |
| Rosuvastain calcium | 6.93 |
| Lactose | 55.00 |
| Microcrystalline Cellulose | 27.07 |
| Calcium acetate | 5.00 |
| Polyvinylpolypyrrolidone | 5.00 |
| Magnesium stearate | 1.00 |
Conclusion: investigate by accelerated test and long term test, the embodiment of the invention has the advantage of tangible quality stability.
Claims (6)
1. Rosuvastatin calcium medicine compound, it is characterized in that, described each component and proportioning are: rosuvastain calcium 10-80mg, HYDROXYPROPYL BETA-CYCLODEXTRIN 20-160mg, meglumine 5-40mg, sodium sulfite 2-16mg, lactose 100-800mg, microcrystalline Cellulose 50-400mg, cross-linking sodium carboxymethyl cellulose 20-160mg, magnesium stearate 2-16mg, 80% alcoholic solution 0.05ml-0.2ml.
2. rosuvastain calcium preparation of drug combination method according to claim 1 is characterized in that described described preparation method comprises the following steps:
1) with the preparation and the processing of supplementary material: with rosuvastain calcium, and adjuvant to cross 100 mesh sieves respectively standby.
2) weighing: take by weighing above-mentioned supplementary material respectively through the double calculating inventory of checking according to recipe quantity.
3) recipe quantity HYDROXYPROPYL BETA-CYCLODEXTRIN, meglumine and sodium sulfite are dissolved in an amount of 80% alcoholic solution, the rosuvastain calcium that adds recipe quantity again is stirred to dissolving fully, as binding agent.
4) with recipe quantity lactose, microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose mix homogeneously, standby.
5) add 3 granulation: to 4)), granulate with 30 order nylon screens.
6) drying:: 45 ℃ ± 5 ℃ dryings.
7) granulate: select 30 mesh sieve granulate for use.
8) total mixing: adding adds lubricant, mix homogeneously.
9) intermediate check: sampling is pressed quality standard and is measured granule content, and it is heavy to calculate sheet.
10) tabletting: heavy according to the actual sheet of result of calculation gained, regulate sheet and weigh tabletting.
11) coating.
12) packing back warehouse-in.
3. Rosuvastatin calcium medicine compound according to claim 1, it is characterized in that, described each component and proportioning are rosuvastain calcium 10mg, HYDROXYPROPYL BETA-CYCLODEXTRIN 20mg, meglumine 5mg, sodium sulfite 2mg, lactose 100mg, microcrystalline Cellulose 50mg, cross-linking sodium carboxymethyl cellulose 20mg, magnesium stearate 2mg, 80% alcoholic solution 0.025ml-0.05ml.
4. Rosuvastatin calcium medicine compound according to claim 1, it is characterized in that, described each component and proportioning are rosuvastain calcium 20mg, HYDROXYPROPYL BETA-CYCLODEXTRIN 40mg, meglumine 10mg, sodium sulfite 4mg, lactose 200mg, microcrystalline Cellulose 100mg, cross-linking sodium carboxymethyl cellulose 40mg, magnesium stearate 4mg, 80% alcoholic solution 0.05ml-0.1ml.
5. Rosuvastatin calcium medicine compound according to claim 1, it is characterized in that, described each component and proportioning are rosuvastain calcium 40mg, HYDROXYPROPYL BETA-CYCLODEXTRIN 80mg, meglumine 20mg, sodium sulfite 8mg, lactose 400mg, microcrystalline Cellulose 200mg, cross-linking sodium carboxymethyl cellulose 80mg, magnesium stearate 8mg, 80% alcoholic solution 0.1ml-0.2ml.
6. the application of Rosuvastatin calcium medicine compound according to claim 1 in preparation treatment and prevention hyperlipidemia, hypercholesterolemia and atherosclerotic medicine.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2010105556754A CN101972260B (en) | 2010-11-24 | 2010-11-24 | Rosuvastatin calcium oral drug composition |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2010105556754A CN101972260B (en) | 2010-11-24 | 2010-11-24 | Rosuvastatin calcium oral drug composition |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101972260A true CN101972260A (en) | 2011-02-16 |
| CN101972260B CN101972260B (en) | 2012-05-02 |
Family
ID=43572192
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2010105556754A Active CN101972260B (en) | 2010-11-24 | 2010-11-24 | Rosuvastatin calcium oral drug composition |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101972260B (en) |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102860994A (en) * | 2011-07-04 | 2013-01-09 | 石药集团中奇制药技术（石家庄）有限公司 | Rosuvastatin calcium tablet and preparation method |
| CN103860498A (en) * | 2014-03-18 | 2014-06-18 | 孙常成 | Rosuvastatin calcium dispersible tablet and preparation method thereof |
| CN104644591A (en) * | 2013-11-25 | 2015-05-27 | 天津市汉康医药生物技术有限公司 | Saxagliptin medicinal composition and preparation method thereof |
| CN104644579A (en) * | 2013-11-25 | 2015-05-27 | 天津市汉康医药生物技术有限公司 | Avanafil pharmaceutical composition |
| CN105120845A (en) * | 2013-03-14 | 2015-12-02 | 保宁制药株式会社 | Pharmaceutical combination drug |
| CN112353768A (en) * | 2020-11-23 | 2021-02-12 | 浙江江北药业有限公司 | Preparation method of rosuvastatin tablet |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101336920A (en) * | 2007-07-05 | 2009-01-07 | 江苏正大天晴药业股份有限公司 | Stable medicine combination |
| CN101516349A (en) * | 2006-09-18 | 2009-08-26 | 里克特格登有限公司 | Pharmaceutical compositions containing rosuvastatin calcium |
| CN101766578A (en) * | 2010-02-09 | 2010-07-07 | 鲁南贝特制药有限公司 | Tablet containing Rosuvastatin calcium and preparation process thereof |
| WO2010081824A2 (en) * | 2009-01-14 | 2010-07-22 | Lek Pharmaceuticals D.D. | Active coating of pharmaceutical dosage forms |
-
2010
- 2010-11-24 CN CN2010105556754A patent/CN101972260B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101516349A (en) * | 2006-09-18 | 2009-08-26 | 里克特格登有限公司 | Pharmaceutical compositions containing rosuvastatin calcium |
| CN101336920A (en) * | 2007-07-05 | 2009-01-07 | 江苏正大天晴药业股份有限公司 | Stable medicine combination |
| WO2010081824A2 (en) * | 2009-01-14 | 2010-07-22 | Lek Pharmaceuticals D.D. | Active coating of pharmaceutical dosage forms |
| CN101766578A (en) * | 2010-02-09 | 2010-07-07 | 鲁南贝特制药有限公司 | Tablet containing Rosuvastatin calcium and preparation process thereof |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102860994A (en) * | 2011-07-04 | 2013-01-09 | 石药集团中奇制药技术（石家庄）有限公司 | Rosuvastatin calcium tablet and preparation method |
| CN105120845A (en) * | 2013-03-14 | 2015-12-02 | 保宁制药株式会社 | Pharmaceutical combination drug |
| CN110123771A (en) * | 2013-03-14 | 2019-08-16 | 保宁制药株式会社 | Pharmaceutical composition drug |
| CN104644591A (en) * | 2013-11-25 | 2015-05-27 | 天津市汉康医药生物技术有限公司 | Saxagliptin medicinal composition and preparation method thereof |
| CN104644579A (en) * | 2013-11-25 | 2015-05-27 | 天津市汉康医药生物技术有限公司 | Avanafil pharmaceutical composition |
| CN103860498A (en) * | 2014-03-18 | 2014-06-18 | 孙常成 | Rosuvastatin calcium dispersible tablet and preparation method thereof |
| CN103860498B (en) * | 2014-03-18 | 2016-05-04 | 孙常成 | A kind of Rosuvastatin calcium dispersible tablet and preparation method thereof |
| CN112353768A (en) * | 2020-11-23 | 2021-02-12 | 浙江江北药业有限公司 | Preparation method of rosuvastatin tablet |
Also Published As
| Publication number | Publication date |
|---|---|
| CN101972260B (en) | 2012-05-02 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| AU2010210123B2 (en) | Process for the preparation of a pharmaceutical composition comprising ezetimibe | |
| CN102008477B (en) | Method for preparing tablet drug composition containing Rosuvastatin calcium | |
| CN101972260B (en) | Rosuvastatin calcium oral drug composition | |
| CN103800322B (en) | Fluvastatin composition of sodium | |
| WO2009024889A2 (en) | Pharmaceutical composition comprising a hmg-coa reductase inhibitor and ezetimibe | |
| CN103585157A (en) | Double-layer tablet containing ezetimibe and rosuvastatin and preparation method thereof | |
| US20040167085A1 (en) | Pharmaceutical compositions comprising a hmg-coa reductase inhibitor | |
| EP2370061B1 (en) | Pharmaceutical composition comprising ezetimibe and simvastatin | |
| CN107126423B (en) | Pitavastatin calcium tablet pharmaceutical composition and dry or wet preparation method thereof | |
| US20150037414A1 (en) | Stable controlled release pharmaceutical compositions containing fenofibrate and pravastatin | |
| CN103239725A (en) | Compound preparation for treating cardiovascular and cerebrovascular diseases | |
| CN103550205B (en) | Simvastatin solid composition | |
| EP1651194B1 (en) | Stable controlled release pharmaceutical compositions containing fenofibrate and pravastatin | |
| US20090306024A1 (en) | Combination preparations of o-acetylsalicylic acid salts | |
| CA2730665A1 (en) | Dosage form containing a statin | |
| AU2014230304B2 (en) | Complex preparation including valsartan and rosuvastatin calcium and manufacturing method therefor | |
| CN107811989B (en) | Rosuvastatin calcium pharmaceutical composition and preparation method thereof | |
| CN111836620B (en) | Pharmaceutical composition of ezetimibe and HMG-CoA reductase inhibitor | |
| CN102600131A (en) | Medicine composition containing ezetimibe and simvastatin and preparation method of medicine composition | |
| KR101302306B1 (en) | complex for improving, alleviating, treating or preventing of hyperlipidemia | |
| AU2003254428B2 (en) | Stable controlled release pharmaceutical compositions containing Fenofibrate and Pravastatin | |
| CN103599081A (en) | Novel niacin compound slow-release preparation for treating hyperlipoidemia | |
| CN103845301A (en) | Atorvastatin calcium pharmaceutical composition and preparation method thereof | |
| KR20100112292A (en) | Stable pharmaceutical composition comprising fluvastatin and method for preparing the same |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| TR01 | Transfer of patent right | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20181010 Address after: 300409 88 Huashi Road, Beichen science and Technology Park, Tianjin Patentee after: TIANJIN HANRUI PHARMACEUTICAL CO., LTD. Address before: 300203 Tianjin Hexi District Dagu South Road 4 Dagu road 3 Patentee before: Tianjin Hankang Pharmaceutical Biotechnology Co., Ltd. |