CN105213319A - A kind of blood lipid-lowering medicine Pitavastatin calcium composition dry suspension - Google Patents
A kind of blood lipid-lowering medicine Pitavastatin calcium composition dry suspension Download PDFInfo
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- CN105213319A CN105213319A CN201510590238.9A CN201510590238A CN105213319A CN 105213319 A CN105213319 A CN 105213319A CN 201510590238 A CN201510590238 A CN 201510590238A CN 105213319 A CN105213319 A CN 105213319A
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Abstract
The present invention relates to a kind of blood lipid-lowering medicine Pitavastatin calcium composition dry suspension, belong to medical art, described compositions dry suspension is made up of Pitavastatin Calcium, mannitol, sucrose, BHA, arabic gum, dehydrated alcohol.Described Pitavastatin Calcium is crystal compound, the X-ray powder diffraction pattern that the measurement of use Cu-K alpha ray obtains as shown in Figure 1, it is a kind of Pitavastatin Calcium being different from prior art report, find that the dry suspension that this compound is made has the effect significantly improving Pitavastatin Calcium and suppress HMG-CoA reductase activity while improving stability by experimental study, thus significantly improve its lipid-lowering effect.
Description
Technical field
The invention belongs to medical art, relate to a kind of blood lipid-lowering medicine Pitavastatin calcium composition dry suspension.
Background technology
Pitavastatin Calcium is first complete synthesis HMG-CoA reductase inhibitor of Nissan Chemical company and Kowa company Ltd's exploitation, be the another potent stanin fat-reducing medicament after atorvastatin and Rosuvastatin, be mainly used in treating hypercholesterolemia, familial hypercholesterolemia.In November, 1999 at Japan registration, and on July 17th, 2003 first in Japan's approval listing, follow-up in succession in Korea S, Thailand, China and U.S.A listing.Abroad be described as " superstatin " with the powerful blood fat reducing effect shown in its clinical trial.In the face of the raising day by day of hyperlipidemia sickness rate, we need to find medicine more efficiently.
The invention provides a kind of Pitavastatin Calcium crystal compound, it is a kind of Pitavastatin Calcium being different from prior art report, find that the dry suspension that this compound is made has the effect significantly improving Pitavastatin Calcium and suppress HMG-CoA reductase activity while improving stability by experimental study, thus significantly improve its lipid-lowering effect.
Summary of the invention
Goal of the invention of the present invention is to provide a kind of blood lipid-lowering medicine Pitavastatin calcium composition dry suspension.
In order to complete object of the present invention, the technical scheme of employing is:
The present invention relates to a kind of blood lipid-lowering medicine Pitavastatin calcium composition dry suspension, described compositions is made up of Pitavastatin Calcium, mannitol, sucrose, BHA, arabic gum, dehydrated alcohol; Described Pitavastatin Calcium is crystal, and the X-ray powder diffraction pattern that the measurement of use Cu-K alpha ray obtains as shown in Figure 1.
First optimal technical scheme of the present invention is: with parts by weight, and described compositions dry suspension is made up of the Pitavastatin Calcium of 0.2 weight portion, the mannitol of 8-12 weight portion, the sucrose of 64-64.8 weight portion, the BHA of 1.5-1.7 weight portion, the arabic gum of 4.4-4.6 weight portion, the dehydrated alcohol of 18-22 weight portion.
Second optimal technical scheme of the present invention is: with parts by weight, and described compositions dry suspension is made up of the Pitavastatin Calcium of 0.2 weight portion, the mannitol of 10 weight portions, the sucrose of 64.4 weight portions, the BHA of 1.6 weight portions, the arabic gum of 4.5 weight portions, the dehydrated alcohol of 20 weight portions.
3rd optimal technical scheme of the present invention is: the preparation method of described compositions dry suspension comprises the following steps:
1) weigh: weigh according to technology preparation amount;
2) co-grinding: select three-dimensional motion mixer, the mode that Pitavastatin Calcium and mannitol equivalent are progressively increased mixed, mixing velocity 12r/min, mixes 5min at every turn, after having mixed, mixed powder pulverizer is pulverized 100 mesh sieves;
3) mixing granulation: the sucrose of supplementary material complete for co-grinding and recipe quantity, BHA, arabic gum are added in wet mixing pelletizer, open stirring motor and be dry mixed 10 minutes, add the dehydrated alcohol wet mixing cutting soft material processed of recipe quantity, select 18 order nylon wires to be arranged in oscillating granulator and carry out soft material granulation;
4) dry granulate: regulate boiling drier inlet temperature 50-55 DEG C, wet granular is placed in boiling drier and carries out drying, be dried to moisture < 3.0%, by after drying with swing drying machine 18 order granulate;
5) always mix: the dry granule after granulate is entered in mixer, mixing velocity 12r/min, open mixer and mix 10 minutes;
6) pack: granule is joined particles packing machine intermediate package, control content uniformity and meet inner quality standard.
4th optimal technical scheme of the present invention is: the preparation method of the crystal of described Pitavastatin Calcium comprises the following steps:
Get pitavastatin calcium raw material drug, the volume adding 45 DEG C is that in the mixed solvent of the methanol of Pitavastatin Calcium weight 8 times, cyclohexane extraction, N-methylacetamide, methanol, cyclohexane extraction, N-methylacetamide volume ratio are 3:1:1, obtain solution; Then in the horizontal direction of the liquid level of gained solution, apply the stationary magnetic field that magnetic field intensity is 1.2T, and under the condition of this stationary magnetic field, drip volume in solution be Pitavastatin Calcium weight 10 times of ethanol; After being added dropwise to complete, be cooled to-10 DEG C, leave standstill 3 hours, filter, washing, vacuum drying, obtains described Pitavastatin Calcium crystal.
Below technical scheme of the present invention is made further explanation:
The polymorphism of solid chemical is the natural phenomena that a kind of general material exists, this phenomenon refers to that a kind of solid chemical can exist 2 kinds or two or more crystal form state, be also called the polymorphic state of material, the polymorphic state of material is also referred to as " allomorphism " phenomenon.Although its chemical nature of allomorphous solid matter is identical, its physicochemical property may be different.For " allomorphism medicine " that physicochemical property is different, also can show the curative effect of different disease preventing and treating clinically, directly affect application and the clinical effectiveness of medicine.
The present inventor obtains a kind of Pitavastatin Calcium novel crystal forms structure being different from prior art through a large amount of tests, and by test, show that the dry suspension that this crystal compound is made has the effect significantly improving Pitavastatin Calcium and suppress HMG-CoA reductase activity while improving stability, thus significantly improve its lipid-lowering effect.
Accompanying drawing explanation
Fig. 1 is the X-ray powder diffraction that the Pitavastatin Calcium crystal of the embodiment of the present invention 1 preparation uses the measurement of Cu-K alpha ray to obtain.
Detailed description of the invention
Below by specific embodiment, summary of the invention of the present invention is described in further detail, but does not therefore limit content of the present invention.
embodiment 1:the preparation of Pitavastatin Calcium crystal
Get pitavastatin calcium raw material drug, the volume adding 45 DEG C is that in the mixed solvent of the methanol of Pitavastatin Calcium weight 8 times, cyclohexane extraction, N-methylacetamide, methanol, cyclohexane extraction, N-methylacetamide volume ratio are 3:1:1, obtain solution; Then in the horizontal direction of the liquid level of gained solution, apply the stationary magnetic field that magnetic field intensity is 1.2T, and under the condition of this stationary magnetic field, drip volume in solution be Pitavastatin Calcium weight 10 times of ethanol; After being added dropwise to complete, be cooled to-10 DEG C, leave standstill 3 hours, filter, washing, vacuum drying, obtains described Pitavastatin Calcium crystal.
As shown in Figure 1, its purity of high-performance liquid chromatogram determination is 99.9% to the X-ray powder diffraction pattern that the Pitavastatin Calcium crystal prepared uses the measurement of Cu-K alpha ray to obtain.
embodiment 2:the preparation of Pitavastatin calcium dried suspension
Prescription: with parts by weight, the Pitavastatin Calcium 0.2 part that embodiment 1 is obtained, 8 parts, mannitol, sucrose 64 parts, BHA 1.5 parts, arabic gum 4.4 parts, dehydrated alcohol 18 parts.
Preparation method:
1) weigh: weigh according to technology preparation amount;
2) co-grinding: select three-dimensional motion mixer, the mode that Pitavastatin Calcium and mannitol equivalent are progressively increased mixed, mixing velocity 12r/min, mixes 5min at every turn, after having mixed, mixed powder pulverizer is pulverized 100 mesh sieves;
3) mixing granulation: the sucrose of supplementary material complete for co-grinding and recipe quantity, BHA, arabic gum are added in wet mixing pelletizer, open stirring motor and be dry mixed 10 minutes, add the dehydrated alcohol wet mixing cutting soft material processed of recipe quantity, select 18 order nylon wires to be arranged in oscillating granulator and carry out soft material granulation;
4) dry granulate: regulate boiling drier inlet temperature 50-55 DEG C, wet granular is placed in boiling drier and carries out drying, be dried to moisture < 3.0%, by after drying with swing drying machine 18 order granulate;
5) always mix: the dry granule after granulate is entered in mixer, mixing velocity 12r/min, open mixer and mix 10 minutes;
6) pack: granule is joined particles packing machine intermediate package, control content uniformity and meet inner quality standard.
embodiment 3:the preparation of Pitavastatin calcium dried suspension
Prescription: with parts by weight, the Pitavastatin Calcium 0.2 part that embodiment 1 is obtained, 10 parts, mannitol, sucrose 64.4 parts, BHA 1.6 parts, arabic gum 4.5 parts, dehydrated alcohol 20 parts.
Preparation method:
1) weigh: weigh according to technology preparation amount;
2) co-grinding: select three-dimensional motion mixer, the mode that Pitavastatin Calcium and mannitol equivalent are progressively increased mixed, mixing velocity 12r/min, mixes 5min at every turn, after having mixed, mixed powder pulverizer is pulverized 100 mesh sieves;
3) mixing granulation: the sucrose of supplementary material complete for co-grinding and recipe quantity, BHA, arabic gum are added in wet mixing pelletizer, open stirring motor and be dry mixed 10 minutes, add the dehydrated alcohol wet mixing cutting soft material processed of recipe quantity, select 18 order nylon wires to be arranged in oscillating granulator and carry out soft material granulation;
4) dry granulate: regulate boiling drier inlet temperature 50-55 DEG C, wet granular is placed in boiling drier and carries out drying, be dried to moisture < 3.0%, by after drying with swing drying machine 18 order granulate;
5) always mix: the dry granule after granulate is entered in mixer, mixing velocity 12r/min, open mixer and mix 10 minutes;
6) pack: granule is joined particles packing machine intermediate package, control content uniformity and meet inner quality standard.
embodiment 4:the preparation of Pitavastatin calcium dried suspension
Prescription: with parts by weight, the Pitavastatin Calcium 0.2 part that embodiment 1 is obtained, 12 parts, mannitol, sucrose 64.8 parts, BHA 1.7 parts, arabic gum 4.6 parts, dehydrated alcohol 22 parts.
Preparation method:
1) weigh: weigh according to technology preparation amount;
2) co-grinding: select three-dimensional motion mixer, the mode that Pitavastatin Calcium and mannitol equivalent are progressively increased mixed, mixing velocity 12r/min, mixes 5min at every turn, after having mixed, mixed powder pulverizer is pulverized 100 mesh sieves;
3) mixing granulation: the sucrose of supplementary material complete for co-grinding and recipe quantity, BHA, arabic gum are added in wet mixing pelletizer, open stirring motor and be dry mixed 10 minutes, add the dehydrated alcohol wet mixing cutting soft material processed of recipe quantity, select 18 order nylon wires to be arranged in oscillating granulator and carry out soft material granulation;
4) dry granulate: regulate boiling drier inlet temperature 50-55 DEG C, wet granular is placed in boiling drier and carries out drying, be dried to moisture < 3.0%, by after drying with swing drying machine 18 order granulate;
5) always mix: the dry granule after granulate is entered in mixer, mixing velocity 12r/min, open mixer and mix 10 minutes;
6) pack: granule is joined particles packing machine intermediate package, control content uniformity and meet inner quality standard.
test example 1
Pitavastatin calcium dried suspension prepared by Example 2-4, detects related substance (see table 1), vitro inhibition HMG-CoA reductase activity (see table 2) respectively.
1, animal strains, body weight and sex
Sprague-Dawley rat, 180-220g, male
2, hyperlipemia model of rats preparation
Hyperlipemia model of rats adopts high lipid food to cause hyperlipemia method.High lipid food formula is as follows: normal feedstuff 86.3%, cholesterol 3%, Adeps Sus domestica 10%, methylthiouracil 0.2%, Fel Sus domestica salt 0.5%, ensures l composition mix homogeneously, continuous 2 weeks.High lipid food is given every other day during administration.
3, vitro inhibition HMG-CoA reductase activity test
With sheet power of going on the market clear for positive control, not adding any inhibitor is negative control, simultaneously with without HMG-CoA and unrestraint agent for blank.
3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) is under HMG-CoA reductase catalysis, consume two molecule reduced form NADPs (NADPH) and generate 3-methyl-3,5-dihydroxy valeric acid and nicotinamide adenine dinucleotide (NADP).NADPH has absorption maximum at ultraviolet 340nm, and NADP at this wavelength without absorption, measure this system and can obtain in the speed that 340nm ultraviolet absorption value declines the speed that this reduction reaction carries out, after adding inhibitor, the rejection ability of inhibitor to enzyme can be calculated by the change of ultraviolet absorption value.The present composition is measured to the inhibit activities of HMG-CoA reductase by the method.
Measure Pitavastatin calcium dried suspension prepared by three embodiments to the inhibitory action of HMG-CoA reductase, matching suppresses curve, and obtain half-inhibition concentration (IC50), the positive control drug measured, the IC50 of the embodiment of the present invention the results are shown in Table 2.
table 1 related substance and dissolution test result
As seen from Table 1: Pitavastatin calcium dried suspension of the present invention, impurity content well below listing sheet power clear it.
table 2 each group of IC to HMG-CoA reductase
50
As seen from Table 2: Pitavastatin calcium dried suspension of the present invention, what sheet power of comparatively going on the market was clear has the activity better suppressing HMG-CoA reductase.
test example 2 embodiment accelerated test and long term test
Accelerated test: according to the requirement of " Chinese Pharmacopoeia version in 2010 " stability test guideline, long term test has been carried out to Pitavastatin calcium dried suspension of the present invention.By embodiment 2-4 sample commercially available back, be placed in climatic chamber, 40 DEG C ± 2 DEG C, place 6 months under relative humidity 75% ± 5% condition, detect by stability high spot reviews project.
Long term test: according to the requirement of " Chinese Pharmacopoeia version in 2010 " stability test guideline, long term test has been carried out to Pitavastatin calcium dried suspension of the present invention.By embodiment 2-4 sample commercially available back, be placed in climatic chamber, 25 DEG C ± 2 DEG C, place 24 months under relative humidity 60% ± 10% condition, detect by stability high spot reviews project.
Result shows: the Pitavastatin calcium dried suspension accelerated test 6 months prepared by embodiment of the present invention 2-4 or long term test are after 24 months, and indices has no significant change, good stability, and impurity content is low.
Claims (5)
1. a blood lipid-lowering medicine Pitavastatin calcium composition dry suspension, is characterized in that: described compositions is made up of Pitavastatin Calcium, mannitol, sucrose, BHA, arabic gum, dehydrated alcohol; Described Pitavastatin Calcium is crystal, and the X-ray powder diffraction pattern that the measurement of use Cu-K alpha ray obtains as shown in Figure 1.
2. blood lipid-lowering medicine Pitavastatin calcium composition dry suspension according to claim 1, it is characterized in that: with parts by weight, described compositions dry suspension is made up of the Pitavastatin Calcium of 0.2 weight portion, the mannitol of 8-12 weight portion, the sucrose of 64-64.8 weight portion, the BHA of 1.5-1.7 weight portion, the arabic gum of 4.4-4.6 weight portion, the dehydrated alcohol of 18-22 weight portion.
3. blood lipid-lowering medicine Pitavastatin calcium composition dry suspension according to claim 2, it is characterized in that: with parts by weight, described compositions dry suspension is made up of the Pitavastatin Calcium of 0.2 weight portion, the mannitol of 10 weight portions, the sucrose of 64.4 weight portions, the BHA of 1.6 weight portions, the arabic gum of 4.5 weight portions, the dehydrated alcohol of 20 weight portions.
4. prepare the method according to the arbitrary described blood lipid-lowering medicine Pitavastatin calcium composition dry suspension of claim 1-3, it is characterized in that, comprise the following steps:
1) weigh: weigh according to technology preparation amount;
2) co-grinding: select three-dimensional motion mixer, the mode that Pitavastatin Calcium and mannitol equivalent are progressively increased mixed, mixing velocity 12r/min, mixes 5min at every turn, after having mixed, mixed powder pulverizer is pulverized 100 mesh sieves;
3) mixing granulation: the sucrose of supplementary material complete for co-grinding and recipe quantity, BHA, arabic gum are added in wet mixing pelletizer, open stirring motor and be dry mixed 10 minutes, add the dehydrated alcohol wet mixing cutting soft material processed of recipe quantity, select 18 order nylon wires to be arranged in oscillating granulator and carry out soft material granulation;
4) dry granulate: regulate boiling drier inlet temperature 50-55 DEG C, wet granular is placed in boiling drier and carries out drying, be dried to moisture < 3.0%, by after drying with swing drying machine 18 order granulate;
5) always mix: the dry granule after granulate is entered in mixer, mixing velocity 12r/min, open mixer and mix 10 minutes;
6) pack: granule is joined particles packing machine intermediate package, control content uniformity and meet inner quality standard.
5. blood lipid-lowering medicine Pitavastatin calcium composition dry suspension according to claim 1, it is characterized in that, the preparation method of the crystal of described Pitavastatin Calcium comprises the following steps:
Get pitavastatin calcium raw material drug, the volume adding 45 DEG C is that in the mixed solvent of the methanol of Pitavastatin Calcium weight 8 times, cyclohexane extraction, N-methylacetamide, methanol, cyclohexane extraction, N-methylacetamide volume ratio are 3:1:1, obtain solution; Then in the horizontal direction of the liquid level of gained solution, apply the stationary magnetic field that magnetic field intensity is 1.2T, and under the condition of this stationary magnetic field, drip volume in solution be Pitavastatin Calcium weight 10 times of ethanol; After being added dropwise to complete, be cooled to-10 DEG C, leave standstill 3 hours, filter, washing, vacuum drying, obtains described Pitavastatin Calcium crystal.
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Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20090176987A1 (en) * | 2003-12-26 | 2009-07-09 | Nissan Chemical Industries, Ltd. | Crystal form of quinoline compound and process for its production |
| CN101637452A (en) * | 2008-07-28 | 2010-02-03 | 东莞太力生物工程有限公司 | Atorvastatin calcium dried suspension and preparation method thereof |
| EP2500339A1 (en) * | 2003-02-12 | 2012-09-19 | Nissan Chemical Industries, Ltd. | Crystalline forms of pitavastatin calcium |
| CN104844506A (en) * | 2015-05-15 | 2015-08-19 | 苗怡文 | Medicinal pitavastatin calcium compound for treating hyperlipidemia |
| CN104860882A (en) * | 2015-05-15 | 2015-08-26 | 苗怡文 | Drug pitavastatin calcium composition for treating hyperlipidemia |
| CN104873511A (en) * | 2015-05-15 | 2015-09-02 | 苗怡文 | Medical lansoprazole composition for treating gastric ulcer |
-
2015
- 2015-09-17 CN CN201510590238.9A patent/CN105213319A/en not_active Withdrawn
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2500339A1 (en) * | 2003-02-12 | 2012-09-19 | Nissan Chemical Industries, Ltd. | Crystalline forms of pitavastatin calcium |
| US20090176987A1 (en) * | 2003-12-26 | 2009-07-09 | Nissan Chemical Industries, Ltd. | Crystal form of quinoline compound and process for its production |
| CN101637452A (en) * | 2008-07-28 | 2010-02-03 | 东莞太力生物工程有限公司 | Atorvastatin calcium dried suspension and preparation method thereof |
| CN104844506A (en) * | 2015-05-15 | 2015-08-19 | 苗怡文 | Medicinal pitavastatin calcium compound for treating hyperlipidemia |
| CN104860882A (en) * | 2015-05-15 | 2015-08-26 | 苗怡文 | Drug pitavastatin calcium composition for treating hyperlipidemia |
| CN104873511A (en) * | 2015-05-15 | 2015-09-02 | 苗怡文 | Medical lansoprazole composition for treating gastric ulcer |
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Application publication date: 20160106 |