CN102086178B - Cinepazide maleate disesquihydrate and preparation method thereof - Google Patents
Cinepazide maleate disesquihydrate and preparation method thereof Download PDFInfo
- Publication number
- CN102086178B CN102086178B CN2009102503112A CN200910250311A CN102086178B CN 102086178 B CN102086178 B CN 102086178B CN 2009102503112 A CN2009102503112 A CN 2009102503112A CN 200910250311 A CN200910250311 A CN 200910250311A CN 102086178 B CN102086178 B CN 102086178B
- Authority
- CN
- China
- Prior art keywords
- water
- preparation
- dioxane
- sesquialter
- hydrates
- 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.)
- Active
Links
- 0 COc(cc(C=CC(N1CCN(CC(*2CCCC2)=O)CC1)=O)cc1C=O)c1OC Chemical compound COc(cc(C=CC(N1CCN(CC(*2CCCC2)=O)CC1)=O)cc1C=O)c1OC 0.000 description 1
Images
Abstract
The invention relates to cinepazide maleate disesquihydrate and a preparation method thereof and belongs to the field of medical technology. The cinepazide maleate disesquihydrate of the invention has the structure shown as a formula (I) and higher chemical stability than cinepazide maleate and improves the administration safety; the dissolution speed and the solubility of the cinepazide maleate disesquihydrate in water are better than those of the cinepazide maleate; and the cinepazide maleate disesquihydrate has important meaning for preparing various preparations and improves the absorption rate of stomach intestinal walls.
Description
Technical field
The invention belongs to medical technical field, be specifically related to MD-67350 two sesquialter hydrates and preparation method thereof.
Background technology
MD-67350 is a known compound, and chemistry is by name: (E)-1-{4-[(3 ', 4 ', 5 '-trimethoxy cinnamoyl)]-1 piperazine } acetyl-pyrrole pyridine maleic acid salt, structural formula is following:
MD-67350 is a calcium ion channel blocker, through stoping Ca
2+Stride in the film intravasation smooth muscle cell, make vascular smooth muscle relaxation, the cerebrovascular, coronary vasodilator and peripheral blood vessel expansion, thus the alleviating vascular spasm, reduce vascular resistance, blood flow increasing.MD-67350 can strengthen the effect of adenosine and cyclic monophosphate (cAMP), reduces the oxygen consumption.MD-67350 can also improve erythrocytic snappiness and deformability, improves its ability through capillary vessel, reduces the viscosity of blood, and microcirculation improvement has provide protection to the organ of ischemic.Clinically, MD-67350 is mainly used in the treatment cardiovascular and cerebrovascular diseases.
MD-67350 is deposited in the process secular, and its cis isomerism body burden can obviously raise, and this cis-isomeride has bigger toxicity, and bigger to the drug safety influence, brings certain risk to clinical application.Therefore the stability that effectively improves MD-67350 has very high realistic meaning for drug safety.
Document Interaction between cinepazide maleate, a new cerebral vasodilator, and water (YakugakuZasshi; 1983; 103 (1): disclose the MD-67350 duohydrate 28-33), its solubleness in water is very little, and MD-67350 is as the medicine of treatment cardiovascular disorder; Be to process aqua mostly, so this duohydrate is little for the value of MD-67350 industrial application.
Summary of the invention
Deficiency to above-mentioned MD-67350; The inventor is through the experimental study of a large amount of systems; Through various analysis/characterizing methods such as single crystal diffraction, thermogravimetric analysis (TG), ultimate analyses; The final beat all two sesquialter hydrates that obtained MD-67350, it is two sesquialter hydrates of MD-67350 of the present invention that its form with monocrystalline exists.
MD-67350 two sesquialter hydrates of the present invention have higher chemicalstability than MD-67350, and in the study on the stability experiment, the content of its cis isomerism and foreign matter content are all low than MD-67350, have improved drug safety; And its dissolution rate and solubleness in water is better than MD-67350, has improved the uptake rate of gastrointestinal wall, for preparing the significant of the various preparations of using always clinically.
The present invention also provides the preparation method of MD-67350 two sesquialter hydrates.
MD-67350 two sesquialter hydrates is characterized in that containing 2.5 water moleculess in the 1 molecule MD-67350, and its structure is shown in (I).
The preparation method of MD-67350 two sesquialter hydrates is that MD-67350 is dissolved in water-1, in the 4-dioxane, leaves standstill under the lucifuge, separates out crystal.
The volume content of dioxane is preferably 0.5～70% in said water-dioxane, the add-on of MD-67350 and water-1, and the ratio of the volume of 4-dioxane is preferably 1g: 0.5～10ml, and time of repose is preferably 12～120 hours under the lucifuge.
Preferred said water-1; In the 4-dioxane 1; The volume content of 4-dioxane further is preferably 0.5～30%; The add-on of MD-67350 and water-1, the ratio of the volume of 4-dioxane further is preferably 1g: 1～2.5ml, and time of repose further is preferably 72-120 hour under the lucifuge.
MD-67350 two sesquialter hydrates treat and/or prevent the application in the medicine of cardiovascular and cerebrovascular diseases in preparation.
A kind of pharmaceutical composition contains MD-67350 two sesquialter hydrates and pharmaceutically acceptable arbitrary excipient.
The inventor is through behind the experimental study of a large amount of systems; At water-1; Add MD-67350 in the 4-dioxane, after the dissolving, room temperature leaves standstill and separates out crystal under the lucifuge; Prove conclusively the MD-67350 two sesquialter hydrates that this crystal is a structure shown in the formula (I) through single crystal diffraction (seeing accompanying drawing 1), ultimate analysis and thermogravimetric analysis (seeing accompanying drawing 2), and to exist with the monocrystalline form be MD-67350 two sesquialter hydrates of the present invention.
Among the preparation method of above-mentioned MD-67350 two sesquialter hydrates, water-1, in the 4-dioxane 1, the volume content of 4-dioxane is preferably 0.5～70%, further is preferably 0.5～30%.
Among the preparation method of above-mentioned MD-67350 two sesquialter hydrates, the add-on of MD-67350 and water-1, the ratio of the volume of 4-dioxane can according to circumstances be confirmed, be preferably 1g: 0.5～10ml further is preferably 1g: 1～2.5ml.If water-1, the volume of 4-dioxane is big, only needs heating a little during the MD-67350 dissolving, if water-1, the volume of 4-dioxane is little, then can form a hot saturated solution after the heating.
Because under the illumination condition, the chemicalstability of MD-67350 is bad, therefore among the preparation method of above-mentioned MD-67350 two sesquialter hydrates; When leaving standstill the crystallization process; Adopt the lucifuge condition, according to the water-1 of MD-67350, the degree of saturation of 4-dioxane solution; Time of repose is preferably 12-120 hour, further is preferably 72-120 hour.Generally, within the specific limits, time of repose is long more, and it is high more to obtain the crystalline yield at last.
MD-67350 two sesquialter hydrates of the present invention have the purposes identical with MD-67350, promptly can be used for preparing the medicine that treats and/or prevents cardiovascular and cerebrovascular diseases.
MD-67350 two sesquialter hydrates of the present invention can be formed pharmaceutical composition with one or more pharmaceutical carriers and/or thinner; Can be made into pharmaceutically acceptable arbitrary formulation, comprise conventional solid preparation (like tablet, capsule, pill, granule etc.), oral liquid (like oral solution, oral suspensions, syrup etc.), injection (like injection liquid, sterile powder for injection pin etc.) etc.In water, have the advantage that dissolution rate is fast, solubleness is big according to MD-67350 two sesquialter hydrates, be preferably and process effervescent tablet, dissolving tablet and sterile powder for injection pin.
The experiment proof; MD-67350 two sesquialter hydrates of the present invention have very superior stable crystal form property and chemicalstability; At room temperature placed 10 days or at 60 ℃ of held no change almost after 24 hours; In the study on the stability test, the content of MD-67350 cis-isomeride effectively reduces, and can improve clinical drug safety property greatly; And its quality homogeneity is good, helps suitability for industrialized production, is easy to guarantee the quality homogeneity of preparation; And its dissolution rate in water is fast, solubleness is big, is fit to process various preparations, especially effervescent tablet, instant and aseptic powder injection; Its faster dissolution rate helps improving the absorption rate of gastrointestinal wall simultaneously.MD-67350 two sesquialter hydrates of the present invention also have advantages such as percent crystallinity height, even particle size distribution, good product mobility, any surface finish.
Description of drawings
Fig. 1 is the single crystal diffraction figure of MD-67350 two sesquialter hydrates, utilizes single crystal diffractometer: Bruker SMARTAPEX2 obtains.
The thermogravimetric analysis figure of Fig. 2 MD-67350 two sesquialter hydrates utilizes Japan to lead Tianjin DSC-40M DTA-40MThermal Analysis and obtains, and length axis is represented sample quality, and axis of abscissa is represented temperature.
Embodiment
Below, foregoing of the present invention is done further to specify through the embodiment of embodiment form.But should this scope that is interpreted as the above-mentioned theme of the present invention only not limited to following examples.All technology that realizes based on foregoing of the present invention all belong to scope of the present invention.
The preparation of embodiment MD-67350 two sesquialter hydrates
Method one: stir down, at 9ml water and 1ml 1, in the mixed solvent of 4-dioxane; Add MD-67350 10.0g, low-grade fever makes its dissolving, filters; Filtrating lucifuge room temperature is placed 96h, filters and collects crystal, and crystal room temperature constant pressure and dry 2h obtains MD-67350 two sesquialter hydrates.
Method two: stir down, at 8ml water and 2ml 1, in the mixed solvent of 4-dioxane; Add MD-67350 7.0g, low-grade fever makes its dissolving, filters; Filtrating lucifuge room temperature is placed 96h, filters and collects crystal, and crystal room temperature constant pressure and dry 2h obtains MD-67350 two sesquialter hydrates.
Method three: stir down, at 7ml water and 3ml 1, in the mixed solvent of 4-dioxane; Add MD-67350 4.0g, low-grade fever makes its dissolving, filters; Filtrating lucifuge room temperature is placed 96h, filters and collects crystal, and crystal room temperature constant pressure and dry 2h obtains MD-67350 two sesquialter hydrates.
Method four: stir down, at 5ml water and 5ml 1, in the mixed solvent of 4-dioxane; Add MD-67350 4.0g, low-grade fever makes its dissolving, filters; Filtrating lucifuge room temperature is placed 96h, filters and collects crystal, and crystal room temperature constant pressure and dry 2h obtains MD-67350 two sesquialter hydrates.
Method five: stir down, at 4ml water and 6ml 1, in the mixed solvent of 4-dioxane; Add MD-67350 3.0g, low-grade fever makes its dissolving, filters; Filtrating lucifuge room temperature is placed 96h, filters and collects crystal, and crystal room temperature constant pressure and dry 2h obtains MD-67350 two sesquialter hydrates.
Experimental example
1, structural identification
Trial-product: MD-67350 two sesquialter hydrates of the present invention are made by method 1.
Method:
Single crystal diffraction: single crystal diffractometer, Bruker SMART APEX2;
Thermogravimetric analysis: Japan leads Tianjin DSC-40M, DTA-40M Thermal Analysis, 10 ℃/min of temperature rise rate, nitrogen atmosphere, flow 40ml/min;
Ultimate analysis: moral ELEMENTAR VarioELIII;
Result and conclusion:
Single crystal diffraction: single crystal diffraction figure (see figure 1) is perfectly clear and has shown that intuitively gained crystal of the present invention is the two sesquialter hydrates of toxilic acid shown in the formula (A), and molecular formula is C
22H
31N
3O
5C
4H
4O
42.5H
2O (C
26H
40N
3O
11.5).
Thermogravimetric analysis: the thermogravimetric analysis (see figure 2) shows that first stage of sample is sloughed crystal water, and weightlessness 7.63% is with calculated value 7.78% (2.5H
2The molecular weight 578.61=7.78% of the molecular weight 45.04/ MD-67350 two sesquialter hydrates of O) conforms to, also conform to the result of single crystal diffraction.
Ultimate analysis: observed value is N 7.250%, H 6.805%, C 54.26%, conforms to theoretical value N 7.265%, H 6.965%, C 53.98%, also conforms to the result of single crystal diffraction.
The test-results of single crystal diffraction, thermogravimetric analysis, ultimate analysis shows that all the inventor can obtain MD-67350 two sesquialter hydrates through the described method of embodiment, and for the monocrystalline form be MD-67350 two sesquialter hydrates of the present invention.
2, stability test
Trial-product: MD-67350 two sesquialter hydrates of the present invention, self-control; The listing MD-67350, the Beijing Sihuan Pharmaceutical Co., Ltd provides, the accurate word H20020124 of traditional Chinese medicines.
The investigation condition: high temperature (60 ℃), high humidity (92.5%) or strong illumination (4500Lx) were placed 10 days.
Investigate index: the content of cis-isomeride and other impurity (cis-isomeride has bigger toxicity, and is bigger to the drug safety influence, so can investigate security through the content of investigating its cis-isomeride).
Table 1 chemicalstability is investigated the result
Result's (seeing table 1): after placing 10 days under various conditions, the cis-isomeride of listing MD-67350 all obviously raises with other foreign matter content, and especially the cis isomerism body burden significantly raises under illumination condition; And the cis-isomeride of MD-67350 two sesquialter hydrates of the present invention does not almost raise with other foreign matter content, shows unexpected chemicalstability.
Conclusion: the chemicalstability of MD-67350 two sesquialter hydrates of the present invention, especially under illumination condition, significantly be superior to the MD-67350 that goes on the market, security is of great importance to clinical administration.
3, quality homogeneity experiment
Trial-product: MD-67350 two sesquialter hydrates of the present invention, self-control; The listing MD-67350, the Beijing Sihuan Pharmaceutical Co., Ltd provides, the accurate word H20020124 of traditional Chinese medicines; Each 10 batches.
Investigate index: the content of content and cis-isomeride and other impurity.
Table 2 quality homogeneity is investigated the result
Result's (seeing table 2): the content of 10 batches of MD-67350 two sesquialter hydrates of the present invention generally is higher than the MD-67350 that gone on the market; The content of the most outstanding is cis-isomeride generally is lower than the MD-67350 that gone on the market, shows surprising high quality.
Conclusion: the quality of MD-67350 two sesquialter hydrates of the present invention is higher, is beneficial to very much suitability for industrialized production, can better guarantee the quality homogeneity of preparation, and then guarantees that clinical application is safer.
4, solubleness and dissolution rate experiment
Trial-product: MD-67350 two sesquialter hydrates of the present invention, self-control; The listing MD-67350, the Beijing Sihuan Pharmaceutical Co., Ltd provides, the accurate word H20020124 of traditional Chinese medicines.
Investigate index: water solubility under the differing temps and dissolution rate.
Solubleness under table 3 differing temps in the water (%)
*: the data of MD-67350 duohydrate are selected from document Interaction between cinepazide maleate, a new cerebralvasodilator, andwater (Yakugaku Zasshi, 1983,103 (1): 28-33.).Because the present invention attempted method and other method in the document, all do not obtain the MD-67350 duohydrate, so can only the citing document value.
Result's (seeing table 3) and conclusion: the discovery that the inventor is surprised MD-67350 two sesquialter hydrates of the present invention have very high water solubility, and dissolution rate is fast.
Conclusion: MD-67350 two sesquialter hydrates of the present invention can improve the for example preparation property of injection of parenteral formulations, make things convenient for suitability for industrialized production; But also can process oral prepns, have important biopharmaceutics advantage for the oral administration of medicine, because the uptake rate that the solubleness behavior of dissolution rate and Geng Gao more rapidly can make active medicine pass through gastrointestinal wall improves greatly.
5, preparation
The preparation of preparation 1 MD-67350 two sesquialter hydrate effervescent tablets
Prescription:
MD-67350 two sesquialter hydrate 320g (in MD-67350)
Tartrate 300g
Sodium hydrogencarbonate 320g
Sucrose 800g
NaCl 10g
Pigment is an amount of
Essence is an amount of
Soluble oil 30g
Prepare 1000 altogether
Preparation technology:
MD-67350 two sesquialter hydrates, tartrate are crossed 80 mesh sieves, after mixing, prepare softwood, cross 12 mesh sieves and granulate 50 ℃ of drying for standby with 95% alcoholic acid pigment solution;
Get sodium hydrogencarbonate, sucrose (100 order) in addition, NaCl mixes, and adds essence (part) aqueous solution system softwood, crosses 12 mesh sieves, and 50 ℃ of dryings are mixed the whole grain in back with above-mentioned particle, add the essence ethanol solution;
Dry a moment, the adding water soluble lubricant, mixing, compressing tablet promptly gets.
The preparation that preparation 2 MD-67350s two sesquialter hydrates are instant
Prescription:
MD-67350 two sesquialter hydrate 80g (in MD-67350)
N.F,USP MANNITOL 100g
Water for injection 1000ml
Prepare 1000 altogether
Technology:
With MD-67350 two sesquialter hydrates, N.F,USP MANNITOL adds purified water and dissolves fully, divides to install in the tablet mould, carries out lyophilize, and pre-freeze was to-35 ℃ of insulations 2 hours, and-35～-5 ℃ distilled 10 hours, were warmed up to 30 ℃ of insulations 2 hours.Freeze-drying finishes, and the tablet packing promptly gets.
The preparation of preparation 3 MD-67350s two sesquialter hydrate aseptic powder injections
Prescription:
MD-67350 two sesquialter hydrate 500g (in MD-67350)
Prepare 1000 altogether
Technology:
The antibiotic glass bottle that preparation is used, plug etc. carry out aseptically process; Take by weighing raw material (feeding intake after the conversion) and auxiliary material (if having) by prescription, place the portioning machine packing, the detection at any time loading amount; Jump a queue, gland, finished product is examined entirely, the packing warehouse-in.
The preparation of preparation 4 MD-67350s two sesquialter hydrate injection liquids
Prescription:
MD-67350 two sesquialter hydrate 320g (in MD-67350)
SODIUM PHOSPHATE, MONOBASIC is an amount of
Water for injection 5000ml
Prepare 1000 altogether
Technology:
SODIUM PHOSPHATE, MONOBASIC is made into 10% solution for standby; MD-67350 two sesquialter hydrates are added the dissolving of water 4000ml water for injection; Regulate pH value not 4.0 with 10% sodium dihydrogen phosphate, add water for injection, add the injection-use activated carbon of dosing amount 0.1% to 5000ml; Whip attachment 15min filters.The filter membrane essence that soup is crossed 0.45 micron, 0.22 micron is respectively filtered.The inspection of semifinished product, embedding, 121 degree sterilization 15min, leak detection, lamp inspection, full inspection, packing.
The preparation of preparation 5 MD-67350s two sesquialter hydrate sheets
Prescription:
MD-67350 two sesquialter hydrate 80g (in MD-67350)
Starch 50g
Microcrystalline Cellulose 45g
Magnesium Stearate 1.5g
Sodium starch glycolate 4.5g
50% ethanolic soln of 2%HPMC is an amount of
Prepare 1000 altogether
Technology:
It is subsequent use that main ingredient was pulverized 100 mesh sieves.Main ingredient, starch, Microcrystalline Cellulose mix, and 50% ethanolic soln that adds 2%HPMC is made softwood in right amount, and softwood is crossed 20 order nylon mesh and granulated; 50 degree are dry, and dry back adds Magnesium Stearate and sodium starch glycolate and mixes with the whole grain of 20 order piano-wire screens; The check work in-process, compressing tablet, packing.
Claims (6)
1. MD-67350 two sesquialter hydrates is characterized in that containing in the 1 molecule MD-67350 2.5 water moleculess, its structural formula shown in (I),
2. the preparation method of the described MD-67350 two sesquialter hydrates of claim 1 is that MD-67350 is dissolved in water-1, in the 4-dioxane, leaves standstill under the lucifuge, separates out crystal.
3. the described preparation method of claim 2, said water-1 is in the 4-dioxane 1; The volume content of 4-dioxane is 0.5～70%; The add-on of MD-67350 and water-1, the ratio of the volume of 4-dioxane is 1g: 0.5～10ml, time of repose is 12～120 hours under the lucifuge.
4. the described preparation method of claim 3, said water-1 is in the 4-dioxane 1; The volume content of 4-dioxane is 0.5～30%; The add-on of MD-67350 and water-1, the ratio of the volume of 4-dioxane is 1g: 1～2.5ml, time of repose is 72-120 hour under the lucifuge.
5. the described MD-67350 two sesquialter hydrates of claim 1 treat and/or prevent the application in the medicine of cardiovascular and cerebrovascular diseases in preparation.
6. a pharmaceutical composition contains the described MD-67350 two sesquialter hydrates of claim 1 and pharmaceutically acceptable arbitrary vehicle.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2009102503112A CN102086178B (en) | 2009-12-03 | 2009-12-03 | Cinepazide maleate disesquihydrate and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2009102503112A CN102086178B (en) | 2009-12-03 | 2009-12-03 | Cinepazide maleate disesquihydrate and preparation method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102086178A CN102086178A (en) | 2011-06-08 |
| CN102086178B true CN102086178B (en) | 2012-11-07 |
Family
ID=44098200
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2009102503112A Active CN102086178B (en) | 2009-12-03 | 2009-12-03 | Cinepazide maleate disesquihydrate and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102086178B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105832662A (en) * | 2016-05-12 | 2016-08-10 | 河北仁合益康药业有限公司 | Maleic acid cinepazide injection composition and preparing method thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101058568A (en) * | 2006-04-21 | 2007-10-24 | 车冯升 | Novel medicinal salt for cinepazide and preparation method thereof |
-
2009
- 2009-12-03 CN CN2009102503112A patent/CN102086178B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101058568A (en) * | 2006-04-21 | 2007-10-24 | 车冯升 | Novel medicinal salt for cinepazide and preparation method thereof |
Non-Patent Citations (2)
| Title |
|---|
| HIROAKI KITAOKA, et al..Interaction between Cinepazide maleate, a New Cerebral Vasodilater, and Water.《YAKUGAKU ZASSHI》.1983,第103卷(第1期),第28-33页. * |
| HIROAKIKITAOKA et al..Interaction between Cinepazide maleate |
Also Published As
| Publication number | Publication date |
|---|---|
| CN102086178A (en) | 2011-06-08 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101092413B (en) | Hydrate of medicinal salt of Fasudil | |
| CN103396328B (en) | Meclofenoxate hydrochloride compound and pharmaceutical composition thereof | |
| CN100451023C (en) | Levo-ornidazole phosphate, preparing process and use thereof | |
| CN101095670B (en) | Luteolin phospholipid complexes and method for preparing the same and application thereof | |
| CN103159769A (en) | Doxofylline compound and medicine composition thereof | |
| WO2009155757A1 (en) | A pharmaceutical composition containing oligosaccharide obtained from morinda root and the procedure thereof | |
| CN105801568B (en) | One maleate crystal form of Afatinib and preparation method thereof and pharmaceutical composition | |
| CN101597272B (en) | Sodium salt compound of Iguratimod, preparation method thereof and pharmaceutical use thereof | |
| TWI697498B (en) | Hydrobromide of benzodiazepine derivative and its preparation method and use | |
| CN102285970B (en) | Esomeprazole compound, preparation method and pharmaceutical compoistion | |
| CN102086178B (en) | Cinepazide maleate disesquihydrate and preparation method thereof | |
| CN103214382B (en) | Meclofenoxate hydrochloride compound and pharmaceutical composition thereof | |
| CN103980279B (en) | A kind of methotrexate compound and methotrexate for injection | |
| CN101314045B (en) | Sulphur butyl ether-beta-cyclodextrin clathrate compound of cinnarizine, formulated product and preparation method thereof | |
| CN101088492A (en) | Stable supersaturated gemcitabine hydrochloride solution and its prepn process | |
| CN105997941A (en) | Amphipathic micelle nanometer capsule and preparing method and application thereof | |
| CN103570657A (en) | Phenyl-glucoside derivative containing gem-dimethyl, preparation method and use thereof | |
| CN114053236B (en) | Nano-carrier sustained-release preparation for treating cardiovascular diseases and preparation method thereof | |
| CN102697740B (en) | Gemcitabine hydrochloride lyophilized powder for injection and preparation method thereof | |
| CN102670524B (en) | Pantoprazole sodium freeze-dried preparation for injection and preparation method thereof | |
| CN101491495B (en) | Salvianolic acid B magnesium injection, preparation method and use thereof | |
| CN107445938A (en) | Crystal form, preparation method and the Pharmaceutical composition containing the crystal form of the tartrates of Yi Ligelusita half | |
| CN114835715A (en) | PF-06651600 maleate and preparation method thereof | |
| CN104876942B (en) | isosorbide mononitrate hemihydrate | |
| CN107184548A (en) | A kind of safe L-ornidazole injection liquid and preparation method thereof |
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 | ||
| C53 | Correction of patent for invention or patent application | ||
| CB03 | Change of inventor or designer information |
Inventor after: Che Fengsheng Inventor after: Huang Xiaoxia Inventor before: Che Fengsheng |
|
| COR | Change of bibliographic data |
Free format text: CORRECT: INVENTOR; FROM: CHE FENGSHENG TO: CHE FENGSHENG HUANG XIAOXIA |
|
| EE01 | Entry into force of recordation of patent licensing contract |
Application publication date: 20110608 Assignee: Langfang high Bojing State Pharmaceutical Co. Ltd. Assignor: Beijing Sihuan Pharmaceutical Co., Ltd. Contract record no.: 2014990000967 Denomination of invention: Cinepazide maleate disesquihydrate and preparation method thereof Granted publication date: 20121107 License type: Exclusive License Record date: 20141225 |
|
| LICC | Enforcement, change and cancellation of record of contracts on the licence for exploitation of a patent or utility model |