CN105061285A - Atorvastatin calcium drug compound for treating coronary heart disease and preparation method therefor - Google Patents
Atorvastatin calcium drug compound for treating coronary heart disease and preparation method therefor Download PDFInfo
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- CN105061285A CN105061285A CN201510434363.0A CN201510434363A CN105061285A CN 105061285 A CN105061285 A CN 105061285A CN 201510434363 A CN201510434363 A CN 201510434363A CN 105061285 A CN105061285 A CN 105061285A
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- atorvastatin calcium
- calcium compound
- atorvastatincalcuim
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- methyl alcohol
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
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Abstract
The present invention discloses an atorvastatin calcium drug compound for treating coronary heart disease, and belongs to the technical field of medicines. By carrying out Cu-K alpha ray measurement on the atorvastatin calcium compound, an X-ray powder diffraction pattern, as shown in FIG. 1, is obtained. According to the atorvastatin calcium compound provided by the invention, the hygroscopicity of the compound is significantly improved; the solubility of the drug in an acid medium and in water is improved; the drug is low in water and impurity content, and good in stability; the atorvastatin calcium is prevented from being destroyed in a gastric acidic environment, so that the stability of the drug is improved, the incidence rate of myalgic side effect of the drug is reduced, and a better drug effect can be achieved; and the drug is convenient for a patient to take.
Description
Technical field
The invention belongs to medical art, relate to a kind of medicine atorvastatin calcium compound for the treatment of coronary heart disease and preparation method thereof.
Background technology
Atorvastatincalcuim (AtorvastatinCalcium) belongs to hydroxyl first glutaryl CoA (HMG-CoA) reductase inhibitor, by suppressing the biosynthesizing of HMG-COA reductase enzyme and cholesterol in liver thus reducing cholesterol and serum lipoprotein concentration in blood plasma, and by the low density lipoprotein receptor in rat liver that increases cell surface to strengthen picked-up and the metabolism of low-density lipoprotein.Atorvastatincalcuim effectively can reduce homozygote and heterozygote familial hypercholesterolemia, non-familial hypercholesterolemia and mixed type disorder of lipid metabolism patients blood plasma total cholesterol, low density lipoprotein cholesterol, lipophorin and triglyceride levels, simultaneously high density lipoprotein increasing cholesterol and aPoA l level to some extent.Atorvastatincalcuim has the plurality of specifications such as 10mg, 20mg, 40mg and 80mg, and formulation has tablet, dispersible tablet, capsule etc.
Atorvastatincalcuim it there is highly lipophilic, poorly water-soluble, and there is stronger bitter taste, all responsive to humidity, light, heat and low pH etc., the fact of lactone can be degraded to especially in low pH situation.Atorvastatincalcuim solvability in sour environment is poor, in under sour environment, all atorvastatincalcuims mixed in formula of medicine all can not dissolve, because the solubleness of atorvastatincalcuim is low, make to prepare the preparation that biological activity is stablized, effect is consistent.After testing, commercially available product (Lipitor, Pfizer) in pH1.2 hydrochloric acid medium 10min dissolution rate probably about 36%.How to improve preparation stability and medicine dissolution rate in acidic medium annoyings pharmaceutics personnel always.
In acid condition, concretely, be can be degraded to its lactone form under hydrochloric acid in gastric juice condition, the molecule of this lactone form does not have Lipid-lowering activities to atorvastatincalcuim, but can cause the side effect of the myalgia of well-known statins.
As everyone knows, health adult's gastric juice becomes acid, roughly suitable with 0.1M hydrochloric acid, and the normal medicine gastric emptying time is approximately 2 hours, after the solid preparation oral administration of atorvastatincalcuim, is detained 2 hours, inevitably can degrades in gastric juice.
For the substance characteristics of atorvastatincalcuim instability, bibliographical information was once had to attempt to solve this difficult problem by optimizing atorvastatin pharmaceutical formulation technique.Such as, in formula prepared by tablet, add alkalescence or buffer reagent (W000/35425, W094/16603), namely according to specially apply for that the method similar approach for Pravastatin sodium described in W001/93860 strengthens the stability of atorvastatincalcuim.But in the imperfect crystal formation process that preparation is stable, in method disclosed in W001/93860, Slovenia patent application P-9900271 and W001/42209, the homogeneity that above-mentioned patent is not all described in detail about the physical parameter (being respectively crystallization and amorphous form) of atorvastatincalcuim provides the bioavailability of atorvastatincalcuim formula of medicine and bioactive relativity problem with relevant.
On the other hand, the purity of pharmaceutically active substance is considered to the important factor guaranteeing drug safety and quality always.In the synthesis production process of atorvastatincalcuim, the complicated synthesis step that multistep is different inevitably produces a large amount of structure and characteristics except target product and the similar impurity compound of atorvastatin calcium compound.In addition, because it is responsive on the impact of environment in the synthesis production process of atorvastatincalcuim, such as, oxygen in temperature, pH, humidity, light, air and carbonic acid gas and in process or storage process surrounding medium etc., these factors all likely cause atorvastatin calcium compound to be degraded, thus its biological activity is reduced, impurity compound improves.Be possible simultaneously and patient is taken to the preparation prepared future bring less desirable side effect, thus make to have a negative impact to the security of medicine.Therefore, the bulk drug active constituents of medicine as preparation requires stable and purifying to greatest extent.
In a word, in method prepared by the atorvastatincalcuim crystal-form compound of existing research report and patent literature, the various crystal formation of acquisition or non-crystalline forms atorvastatincalcuim still total impurities is higher, optical purity is lower, and bioavailability is little.In view of the conventional crystal formation of atorvastatincalcuim to the susceptibility of the air ambient factor, bioactive unstable, formulation processing conditions harshness,
The present inventor starts with from the research of atorvastatincalcuim solid chemical material existence, a kind of new atorvastatincalcuim crystalline compounds has been prepared through a large amount of tests, surprisingly find through overtesting, the water absorbability that atorvastatin calcium compound tool provided by the invention has clear improvement, improve the solvability of medicine in acidic medium and water, moisture and foreign matter content low, good stability, avoid atorvastatincalcuim destroyed in stomach acidity environment, enhance the stability of medicine, reduce the incidence of its myalgia side effect, the effect of better performance medicine, patient is facilitated to take.
Summary of the invention
Primary and foremost purpose of the present invention is to propose a kind of medicine atorvastatin calcium compound for the treatment of coronary heart disease.
Second goal of the invention of the present invention is the preparation method proposing this atorvastatin calcium compound.
To achieve these goals, the technical solution used in the present invention is:
Treat a medicine atorvastatin calcium compound for coronary heart disease, it is characterized in that, the X-ray powder diffraction pattern that described atorvastatin calcium compound uses the measurement of Cu-K alpha-ray to obtain as shown in Figure 1.
Polymorph in pharmaceuticals phenomenon is ubiquitous problem in present drug research.The polymorphism of medicine can affect its physico-chemical property, and then may have influence on the clinical efficacy of medicine.Atorvastatincalcuim water absorbability of the prior art is strong, poor stability.The present inventor obtains a kind of new atorvastatincalcuim crystal-form compound by a large amount of tests, the water absorbability that this crystal-form compound tool has clear improvement, improve the solvability of medicine in acidic medium and water, moisture and foreign matter content is low, good stability, avoid atorvastatincalcuim destroyed in stomach acidity environment, enhance the stability of medicine, reduce the incidence of its myalgia side effect, the effect of better performance medicine, facilitates patient to take.
The preparation method of described atorvastatin calcium compound, the method comprises the steps:
(1) atorvastatincalcuim crude product is ground, sieve, then join in the mixing solutions of methyl alcohol and N-methylacetamide, stir 20 minutes;
(2) add methyl alcohol under stirring, heat up simultaneously;
(3) after solution adds, leave standstill 2-3 hour, drip the deionized water of 0 DEG C-5 DEG C under the condition of stirring, at the uniform velocity dropwise in 2h;
(4) be added dropwise to complete rear cooling, continue to stir 2-3h, leave standstill 4-5h crystallize out, filter, vacuum-drying obtains atorvastatincalcuim crystal.
As preferably, sieve described in step (1) as crossing 90 ~ 100 mesh sieves.
As preferably, the volume of the mixing solutions of step (1) described methyl alcohol and N-methylacetamide be the 8-10 of atorvastatincalcuim weight doubly.
As preferably, the volume ratio of step (1) described methyl alcohol and N-methylacetamide is 5:1.
As preferably, step (1) described stirring velocity is 80-100 rev/min, and step (2) described stirring velocity is 120-150 rev/min, and step (3) described stirring velocity is 75-80 rev/min, and step (4) described stirring velocity is 100-120 rev/min.
As preferably, the volume of step (2) described methyl alcohol is 4 times of atorvastatincalcuim weight.
As preferably, step (2) described intensification is for being warming up to 35-40 DEG C.
As preferably, the volume of step (3) described deionized water be the 10-12 of atorvastatincalcuim weight doubly.
As preferably, step (4) described cooling is for being cooled to-10 DEG C-5 DEG C.
The present inventor is after having carried out large quantifier elimination to it, obtain above-mentioned preparation method, prepare a kind of atorvastatincalcuim crystalline compounds being different from prior art, surprisingly find through overtesting, the water absorbability that this crystal-form compound tool has clear improvement, improve the solvability of medicine in acidic medium and water, moisture and foreign matter content is low, good stability, avoid atorvastatincalcuim destroyed in stomach acidity environment, enhance the stability of medicine, reduce the incidence of its myalgia side effect, better play the effect of medicine, facilitate patient to take.
accompanying drawing illustrates:
Fig. 1 is the X-ray powder diffraction pattern of atorvastatin calcium compound prepared by embodiment 1.
Embodiment
The specific embodiment of the present invention is only limitted to explain further and the present invention is described, does not limit Composition of contents of the present invention.
embodiment 1:the preparation of atorvastatin calcium compound
(1) atorvastatincalcuim crude product is ground, cross 90 mesh sieves, then joining volume is that in the methyl alcohol of 8 times of atorvastatincalcuim weight and the mixing solutions of N-methylacetamide, the volume ratio of methyl alcohol and N-methylacetamide is 5:1, and 80 revs/min are stirred 20 minutes;
Add the methyl alcohol that volume is 4 times of atorvastatincalcuim weight under (2) 120 revs/min of stirrings, be warming up to 35 DEG C simultaneously;
(3) after solution adds, leave standstill 2 hours, drip the deionized water of 0 DEG C under 75 revs/min of conditions stirred, the volume of deionized water is 10 times of atorvastatincalcuim weight, at the uniform velocity dropwises in 2h;
(4) be cooled to-10 DEG C after being added dropwise to complete, continue to stir 2h under the stir speed (S.S.) of 100 revs/min, leave standstill 4h crystallize out, filter, vacuum-drying obtains atorvastatincalcuim crystal.
The X-ray powder diffractogram using the measurement of Cu-K alpha-ray to obtain to prepared atorvastatin calcium compound as shown in Figure 1.
embodiment 2:the preparation of atorvastatin calcium compound
(1) atorvastatincalcuim crude product is ground, cross 95 mesh sieves, then joining volume is that in the methyl alcohol of 9 times of atorvastatincalcuim weight and the mixing solutions of N-methylacetamide, the volume ratio of methyl alcohol and N-methylacetamide is 5:1, and 90 revs/min are stirred 20 minutes;
Add the methyl alcohol that volume is 4 times of atorvastatincalcuim weight under (2) 135 revs/min of stirrings, be warming up to 37.5 DEG C simultaneously;
(3) after solution adds, leave standstill 2.5 hours, drip the deionized water of 2.5 DEG C under 77.5 revs/min of conditions stirred, the volume of deionized water is 11 times of atorvastatincalcuim weight, at the uniform velocity dropwises in 2h;
(4) be cooled to 0 DEG C after being added dropwise to complete, continue to stir 2.5h under the stir speed (S.S.) of 110 revs/min, leave standstill 4.5h crystallize out, filter, vacuum-drying obtains atorvastatincalcuim crystal.
The X-ray powder diffractogram using the measurement of Cu-K alpha-ray to obtain to prepared atorvastatin calcium compound is similar to embodiment 1.
embodiment 3:the preparation of atorvastatin calcium compound
(1) atorvastatincalcuim crude product is ground, cross 100 mesh sieves, then joining volume is that in the methyl alcohol of 10 times of atorvastatincalcuim weight and the mixing solutions of N-methylacetamide, the volume ratio of methyl alcohol and N-methylacetamide is 5:1, and 100 revs/min are stirred 20 minutes;
Add the methyl alcohol that volume is 4 times of atorvastatincalcuim weight under (2) 150 revs/min of stirrings, be warming up to 40 DEG C simultaneously;
(3) after solution adds, leave standstill 3 hours, drip the deionized water of 5 DEG C under 80 revs/min of conditions stirred, the volume of deionized water is 12 times of atorvastatincalcuim weight, at the uniform velocity dropwises in 2h;
(4) be cooled to 5 DEG C after being added dropwise to complete, continue to stir 3h under the stir speed (S.S.) of 120 revs/min, leave standstill 5h crystallize out, filter, vacuum-drying obtains atorvastatincalcuim crystal.
The X-ray powder diffractogram using the measurement of Cu-K alpha-ray to obtain to prepared atorvastatin calcium compound is similar to embodiment 1.
test example 1:wettability test
This test example compares the water absorbability of atorvastatin calcium compound provided by the invention and import atorvastatin calcium raw material drug.
Test method: respectively under the condition of humidity 60% and 90%, room temperature, each sample thief 1g is placed on electronic balance, and time recording weight, to detect moisture absorption degree, the results are shown in Table 1.
Table 1, sample water absorbability measurement result
Wherein:
Sample 1: the atorvastatincalcuim that the embodiment of the present invention 1 is obtained;
Sample 2: the atorvastatincalcuim that the embodiment of the present invention 2 is obtained;
Sample 3: the atorvastatincalcuim that the embodiment of the present invention 3 is obtained;
Sample 4: imported raw material medicine product.
As can be seen from above-mentioned test-results, compared with the atorvastatincalcuim of prior art, the water absorbability that atorvastatincalcuim tool provided by the present invention has clear improvement.
test example 2:solubility property and lactone content determination test
Simulate the solubility property of atorvastatincalcuim crystalline compounds of the present invention in acidic stomach environment and lactone content in vitro.Being about the simulated gastric fluid of 3 at PH, is carry out dissolubility test in the HCL aqueous solution of 900ml0.001M in particular, and the concentration of the atorvastatin of then interval measurement dissolving in 10 minutes and lactone content, the results are shown in Table 2:
Table 2 solubility property and lactone content determination test result
From above-mentioned test-results, the solvability of atorvastatincalcuim crystalline compounds of the present invention in gastric acid environment improves greatly, and lactone content is low, change little, avoid atorvastatincalcuim destroyed in stomach acidity environment, enhance the stability of medicine, reduce the incidence of its myalgia side effect, the effect of better performance medicine, facilitates patient to take.
test example 3:water-soluble experiment
Measure by the method for Chinese Pharmacopoeia, the solubleness of atorvastatincalcuim crystalline compounds of the present invention in water is 0.75mg/ml, and the solubleness of imported product is less than 0.24mg/ml.
test example 4:stability test
The chemical stability of contriver to the crystal formation of the embodiment of the present invention 1 is studied, and investigation condition is high temperature (60 DEG C ± 2 DEG C), strong illumination (4500Lx ± 500lx), and high humidity (92.5%, RH) inspection target is outward appearance, moisture and related substance.
Table 3 stability test result
From above-mentioned test-results, the embodiment of the present invention 1 product not only moisture, lactone and total assorted content is low, and substantially unchanged under high temperature, high humidity and intense light conditions, good stability.
Above-mentioned test shows, the water absorbability that crystal-form compound tool of the present invention has clear improvement, improve the solvability of medicine in acidic medium and water, moisture and foreign matter content is low, good stability, avoid atorvastatincalcuim destroyed in stomach acidity environment, enhance the stability of medicine, reduce the incidence of its myalgia side effect, the effect of medicine can better be played, facilitate patient to take.
Claims (10)
1. treat a medicine atorvastatin calcium compound for coronary heart disease, it is characterized in that, the X-ray powder diffraction pattern that described atorvastatin calcium compound uses the measurement of Cu-K alpha-ray to obtain as shown in Figure 1.
2. atorvastatin calcium compound according to claim 1, is characterized in that, the preparation method of described atorvastatin calcium compound is:
(1) atorvastatincalcuim crude product is ground, sieve, then join in the mixing solutions of methyl alcohol and N-methylacetamide, stir 20 minutes;
(2) add methyl alcohol under stirring, heat up simultaneously;
(3) after solution adds, leave standstill 2-3 hour, drip the deionized water of 0 DEG C-5 DEG C under the condition of stirring, at the uniform velocity dropwise in 2h;
(4) be added dropwise to complete rear cooling, continue to stir 2-3h, leave standstill 4-5h crystallize out, filter, vacuum-drying obtains atorvastatincalcuim crystal.
3. atorvastatin calcium compound according to claim 2, is characterized in that, sieves as crossing 90-100 mesh sieve described in step (1).
4. atorvastatin calcium compound according to claim 2, is characterized in that, the volume of the mixing solutions of step (1) described methyl alcohol and N-methylacetamide is 8-10 times of atorvastatincalcuim weight.
5. atorvastatin calcium compound according to claim 2, is characterized in that, the volume ratio of step (1) described methyl alcohol and N-methylacetamide is 5:1.
6. atorvastatin calcium compound according to claim 2, it is characterized in that, step (1) described stirring velocity is 80-100 rev/min, step (2) described stirring velocity is 120-150 rev/min, step (3) described stirring velocity is 75-80 rev/min, and step (4) described stirring velocity is 100-120 rev/min.
7. atorvastatin calcium compound according to claim 2, is characterized in that, the volume of step (2) described methyl alcohol is 4 times of atorvastatincalcuim weight.
8. atorvastatin calcium compound according to claim 2, is characterized in that, step (2) described intensification is for being warming up to 35-40 DEG C.
9. atorvastatin calcium compound according to claim 2, is characterized in that, the volume of step (3) described deionized water is 10-12 times of atorvastatincalcuim weight.
10. atorvastatin calcium compound according to claim 2, is characterized in that, step (4) described cooling is for being cooled to-10 DEG C-5 DEG C.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101395132A (en) * | 2006-03-01 | 2009-03-25 | 特瓦制药工业有限公司 | Process for preparing a crystalline form of atorvastatin hemi-calcium |
| CN102070505A (en) * | 2011-01-28 | 2011-05-25 | 海南美大制药有限公司 | Atorvastatin calcium compounds and novel preparation method thereof |
| CN102249978A (en) * | 2011-06-09 | 2011-11-23 | 浙江金立源药业有限公司 | KY crystal form of Atorvastatin calcium and preparation method thereof |
| CN102311377A (en) * | 2010-06-29 | 2012-01-11 | 山东新华制药股份有限公司 | Refining method capable of obtaining atorvastatin calcium in form of crystal |
| CN102351771A (en) * | 2011-08-11 | 2012-02-15 | 天津市汉康医药生物技术有限公司 | Atorvastatin calcium compound with high bioavailability |
-
2015
- 2015-07-23 CN CN201510434363.0A patent/CN105061285A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101395132A (en) * | 2006-03-01 | 2009-03-25 | 特瓦制药工业有限公司 | Process for preparing a crystalline form of atorvastatin hemi-calcium |
| CN102311377A (en) * | 2010-06-29 | 2012-01-11 | 山东新华制药股份有限公司 | Refining method capable of obtaining atorvastatin calcium in form of crystal |
| CN102070505A (en) * | 2011-01-28 | 2011-05-25 | 海南美大制药有限公司 | Atorvastatin calcium compounds and novel preparation method thereof |
| CN102249978A (en) * | 2011-06-09 | 2011-11-23 | 浙江金立源药业有限公司 | KY crystal form of Atorvastatin calcium and preparation method thereof |
| CN102351771A (en) * | 2011-08-11 | 2012-02-15 | 天津市汉康医药生物技术有限公司 | Atorvastatin calcium compound with high bioavailability |
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