CN104434820A - Preparation method for methylprednisolone sodium succinate freeze-dried powder injection for injection - Google Patents
Preparation method for methylprednisolone sodium succinate freeze-dried powder injection for injection Download PDFInfo
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- CN104434820A CN104434820A CN201410670438.0A CN201410670438A CN104434820A CN 104434820 A CN104434820 A CN 104434820A CN 201410670438 A CN201410670438 A CN 201410670438A CN 104434820 A CN104434820 A CN 104434820A
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Abstract
The invention discloses a preparation method for a methylprednisolone sodium succinate freeze-dried powder injection for injection. The preparation method comprises the following steps: 1) weighing sodium phosphate dibasic dodecahydrate and sodium phosphate monobasic monohydrate with a mass ratio of 1: (0.63 to 3), and preparing a buffer solution with a pH value of not greater than 6.5; 2) weighing methylprednisolone sodium succinate according to a mass ratio of methylprednisolone sodium succinate to sodium phosphate dibasic dodecahydrate being 3.81:1, adding the buffer solution in the step 1), stirring and then transferring into a volumetric flask, metering the volume and uniformly shaking to obtain a preparation liquid; 3) quantitatively transferring the preparation liquid into an injection bottle prepared by a glass tube for sub-packaging; and 4) freeze-drying the sub-packaged preparation liquid according to a rapid heating-cooling freeze-drying curve to obtain the freeze-dried powder injection. According to the preparation method disclosed by the invention, methylprednisolone sodium succinate buffer solution with a low preparation pH value is used for preparing the freeze-dried powder injection, the freeze-dried powder injection has high activity stability, moreover, the preparation method is simple and convenient, the freeze-drying time is short, the previous preparation defects of the preparation are overcome, and the use range of the preparation is expanded.
Description
Technical field
The present invention relates to lyophilized formulations field, particularly relate to a kind of preparation method of methylprednisolone sodium succinate for inj lyophilized injectable powder.
Background technology
Methylprednisolone has antiinflammatory, antiallergic, rheumatism, immunosuppressive action, be widely used in treatment anaphylaxis and autoimmune inflammation type disease, as lupus erythematosus, connective tissue disease, rheumatoid arthritis, activeness rheumatism, serious bronchial asthma etc., also for some severe infections and Comprehensive Treatment that is poisoning, malignant lymphoma.Because it is the organic compound of indissoluble, therefore for the ease of being prepared into injection, can prepare to become being easy to water-soluble salt, as Urbason Solubile.Existing Urbason Solubile injection is lyophilized injectable powder, is divided into the specification of multiple metering.Chinese patent CN200610076703.8 discloses a kind of methylprednisolone sodium succinate lyophilized composition and preparation method thereof, but its freeze-drying time length consuming time, and production efficiency is low and activity-maintaining time is short.
Summary of the invention
For solving the problems of the technologies described above, the invention provides a kind of preparation method of methylprednisolone sodium succinate for inj lyophilized injectable powder, methylprednisolone sodium succinate lyophilized injectable powder prepared by the method, owing to reducing pH value, substantially prolongs its active effect duration.
The preparation method of a kind of methylprednisolone sodium succinate for inj lyophilized injectable powder of the present invention, step is:
1) take disodium hydrogen phosphate dodecahydrate and a hypophosphite monohydrate sodium dihydrogen that mass ratio is 1:0.63-3, dissolve with water for injection, shake up the phosphate buffer making pH≤6.5, for subsequent use;
2) Urbason Solubile is taken, described Urbason Solubile: disodium hydrogen phosphate dodecahydrate=3.81:1, slowly add step 1) phosphate buffer prepared, after being constantly stirred to solution clarification, transfer is put in volumetric flask, shake up with water for injection standardize solution, obtain preparing liquid;
3) by step 2) transfer of the preparation liquid that obtains puts injection bottles made of glass tubes and carries out subpackage;
4) by step 3) preparation liquid after subpackage carries out lyophilizing by heating and cooling freeze-drying curve rapidly, obtain lyophilized injectable powder, the described freeze-drying curve of heating and cooling is rapidly that room temperature rapid cooling is to-30 DEG C ~-40 DEG C,-5 DEG C ~ 0 DEG C is warming up to again after temperature stabilization, insulation a period of time, be then warming up to 30 DEG C ~ 40 DEG C and temperature rapidly and keep stable freeze-drying curve.
Further, described step 1) phosphate buffer pH be 6.5 or 6.2.
Further, described step 4) the freeze-drying curve of heating and cooling be rapidly: in 1h by room temperature state rapid cooling to-40 DEG C, in 2h, be at the uniform velocity warming up to-5 DEG C after keeping 2h, after then keeping 10h, in 1h, be warming up to 40 DEG C rapidly, keep 5h, complete lyophilizing operation.
The freeze-drying curve of heating and cooling rapidly in the technical program is different from freeze-drying curve in the past, by room temperature rapid cooling extremely-40 DEG C in short time in 1h, about-5 DEG C are warming up to again after stable, 40 DEG C are warming up to rapidly again after insulation a period of time, step of freeze drying is completed after insulation is stable, the operation of this heating and cooling rapidly makes sample lyophilizing rear stability improve, and after lyophilizing, the loss of effective components of product reduces.
The preparation method of a kind of methylprednisolone sodium succinate for inj lyophilized injectable powder of the present invention is by adopting preparation lower ph, the Urbason Solubile phosphate buffer of pH≤6.5, and make lyophilized injectable powder, there is higher activity stability, and preparation method is easy, freeze-drying time shortens, and overcomes the preparation defect of said preparation in the past, greatly expands the scope of application of said preparation.
Detailed description of the invention
The technological means realized to make the present invention, creation characteristic, reaching object and effect is easy to understand, below in conjunction with specific embodiment, setting forth the present invention further.
The Urbason Solubile NEWCHEM SPA company that following examples adopt produces (moisture: 0.4%, high-efficient liquid phase content: 99.5%), disodium hydrogen phosphate dodecahydrate and a hypophosphite monohydrate sodium dihydrogen are Hunan Jiudian Pharmaceutical Co., Ltd and produce.
Embodiment 1
A preparation method for methylprednisolone sodium succinate for inj lyophilized injectable powder, step is:
1) take 1.0974g disodium hydrogen phosphate dodecahydrate and 689.94mg mono-hypophosphite monohydrate sodium dihydrogen, dissolve with 32mL water for injection, shake up the phosphate buffer making pH=6.5, for subsequent use;
2) take 4.1812g Urbason Solubile, slowly add step 1) phosphate buffer prepared, after being constantly stirred to solution clarification, transfer is put in 50mL volumetric flask, shakes up, obtain preparing liquid with water for injection standardize solution;
3) by step 2) the preparation liquid that the obtains transfer injection bottles made of glass tubes of putting 2mL/ bottle carries out subpackage;
4) by step 3) preparation liquid after subpackage carries out lyophilizing by heating and cooling freeze-drying curve rapidly, obtain lyophilized injectable powder, the described freeze-drying curve of heating and cooling is rapidly by room temperature state rapid cooling extremely-40 DEG C in 1h, in 2h, at the uniform velocity-5 DEG C are warming up to after keeping 2h, then in 1h, 40 DEG C are warming up to rapidly after keeping 10h, keep 5h, complete lyophilizing operation.
Embodiment 2
A preparation method for methylprednisolone sodium succinate for inj lyophilized injectable powder, step is:
1) take 1.0974g disodium hydrogen phosphate dodecahydrate and 3060.6mg mono-hypophosphite monohydrate sodium dihydrogen, dissolve with 32mL water for injection, shake up the phosphate buffer making pH=6.2, for subsequent use;
2) take 4.1812g Urbason Solubile, slowly add step 1) phosphate buffer prepared, after being constantly stirred to solution clarification, transfer is put in 50mL volumetric flask, shakes up, obtain preparing liquid with water for injection standardize solution;
3) by step 2) the preparation liquid that the obtains transfer injection bottles made of glass tubes of putting 2mL/ bottle carries out subpackage;
4) by step 3) preparation liquid after subpackage carries out lyophilizing by heating and cooling freeze-drying curve rapidly, obtain lyophilized injectable powder, the described freeze-drying curve of heating and cooling is rapidly by room temperature state rapid cooling extremely-40 DEG C in 1h, in 2h, at the uniform velocity-5 DEG C are warming up to after keeping 2h, then in 1h, 40 DEG C are warming up to rapidly after keeping 10h, keep 5h, complete lyophilizing operation.
Reference examples 1
A preparation method for methylprednisolone sodium succinate for inj lyophilized injectable powder, step is:
1) take 1.0974g disodium hydrogen phosphate dodecahydrate and 26.9mg mono-hypophosphite monohydrate sodium dihydrogen, dissolve with 32mL water for injection, shake up the phosphate buffer making pH=8.0, for subsequent use;
2) take 4.1812g Urbason Solubile, slowly add step 1) phosphate buffer prepared, after being constantly stirred to solution clarification, transfer is put in 50mL volumetric flask, shakes up, obtain preparing liquid with water for injection standardize solution;
3) by step 2) the preparation liquid that the obtains transfer injection bottles made of glass tubes of putting 2mL/ bottle carries out subpackage;
4) by step 3) preparation liquid after subpackage carries out lyophilizing by heating and cooling freeze-drying curve rapidly, obtain lyophilized injectable powder, the described freeze-drying curve of heating and cooling is rapidly by room temperature state rapid cooling extremely-40 DEG C in 1h, in 2h, at the uniform velocity-5 DEG C are warming up to after keeping 2h, then in 1h, 40 DEG C are warming up to rapidly after keeping 10h, keep 5h, complete lyophilizing operation.
Reference examples 2
A preparation method for methylprednisolone sodium succinate for inj lyophilized injectable powder, step is:
1) take 1.0974g disodium hydrogen phosphate dodecahydrate and 46.0mg mono-hypophosphite monohydrate sodium dihydrogen, dissolve with 32mL water for injection, shake up the phosphate buffer making pH=7.8, for subsequent use;
2) take 4.1812g Urbason Solubile, slowly add step 1) phosphate buffer prepared, after being constantly stirred to solution clarification, transfer is put in 50mL volumetric flask, shakes up, obtain preparing liquid with water for injection standardize solution;
3) by step 2) the preparation liquid that the obtains transfer injection bottles made of glass tubes of putting 2mL/ bottle carries out subpackage;
4) by step 3) preparation liquid after subpackage carries out lyophilizing by heating and cooling freeze-drying curve rapidly, obtain lyophilized injectable powder, the described freeze-drying curve of heating and cooling is rapidly by room temperature state rapid cooling extremely-40 DEG C in 1h, in 2h, at the uniform velocity-5 DEG C are warming up to after keeping 2h, then in 1h, 40 DEG C are warming up to rapidly after keeping 10h, keep 5h, complete lyophilizing operation.
Reference examples 3
A preparation method for methylprednisolone sodium succinate for inj lyophilized injectable powder, step is:
1) take 1.0974g disodium hydrogen phosphate dodecahydrate and 93.8mg mono-hypophosphite monohydrate sodium dihydrogen, dissolve with 32mL water for injection, shake up the phosphate buffer making pH=7.5, for subsequent use;
2) take 4.1812g Urbason Solubile, slowly add step 1) phosphate buffer prepared, after being constantly stirred to solution clarification, transfer is put in 50mL volumetric flask, shakes up, obtain preparing liquid with water for injection standardize solution;
3) by step 2) the preparation liquid that the obtains transfer injection bottles made of glass tubes of putting 2mL/ bottle carries out subpackage;
4) by step 3) preparation liquid after subpackage carries out lyophilizing by heating and cooling freeze-drying curve rapidly, obtain lyophilized injectable powder, the described freeze-drying curve of heating and cooling is rapidly by room temperature state rapid cooling extremely-40 DEG C in 1h, in 2h, at the uniform velocity-5 DEG C are warming up to after keeping 2h, then in 1h, 40 DEG C are warming up to rapidly after keeping 10h, keep 5h, complete lyophilizing operation.
Reference examples 4
A preparation method for methylprednisolone sodium succinate for inj lyophilized injectable powder, step is:
1) take 1.0974g disodium hydrogen phosphate dodecahydrate and 255.3mg mono-hypophosphite monohydrate sodium dihydrogen, dissolve with 32mL water for injection, shake up the phosphate buffer making pH=7.0, for subsequent use;
2) take 4.1812g Urbason Solubile, slowly add step 1) phosphate buffer prepared, after being constantly stirred to solution clarification, transfer is put in 50mL volumetric flask, shakes up, obtain preparing liquid with water for injection standardize solution;
3) by step 2) the preparation liquid that the obtains transfer injection bottles made of glass tubes of putting 2mL/ bottle carries out subpackage;
4) by step 3) preparation liquid after subpackage carries out lyophilizing by heating and cooling freeze-drying curve rapidly, obtain lyophilized injectable powder, the described freeze-drying curve of heating and cooling is rapidly by room temperature state rapid cooling extremely-40 DEG C in 1h, in 2h, at the uniform velocity-5 DEG C are warming up to after keeping 2h, then in 1h, 40 DEG C are warming up to rapidly after keeping 10h, keep 5h, complete lyophilizing operation.
The lyophilized injectable powder of the preparation of embodiment 1,2 and comparative example 1-4 is put into 60 DEG C of couveuses store, and carry out the storage test of 0,5,10 days respectively, this test comprises high performance liquid chromatography detection, spectrophotometry detects and the detection of color and pH value.
High performance liquid chromatography testing conditions is:
Immobile phase: octadecylsilane chemically bonded silica;
Mobile phase: 3% glacial acetic acid solution (get glacial acetic acid 30ml, add water and be settled to 1000ml, shake up, to obtain final product): acetonitrile=67:33;
Determined wavelength: 254nm;
Sample size: 10ul;
Writing time: 3.5 times of main peak retention time;
Theoretical cam curve: calculate by Methylprednisolone succinate peak and be not less than 3000.
Algoscopy: according to high-efficient liquid phase chromatogram, carries out peak position comparison confirmation, calculates each list mix and always assorted content by area normalization method, observes single assorted and total assorted variation tendency.
Solution preparation method to be measured: get lyophilized injectable powder 1 bottle, be dissolved in water for injection, standardize solution in 100mL measuring bottle, makes the solution containing methylprednisolone 1.25mg in every 1mL; Get a sample injection bottle, after repeatedly rinsing 3 times with the solution be mixed with, then this solution is placed in sample injection bottle, carries out efficient Liquid Detection.
Spectrophotometry detection method is:
Get lyophilized injectable powder 2 bottles, dissolve with 2.5mL water for injection respectively, after mixing, on spectrophotometry instrument, carry out the absorbance measurement of 450nm and 550nm wavelength.
Color and pH value detection method:
Solution example after being detected by spectrophotometry collects, and carries out colorimetric with yellow and yellow green standard color solution, detects after terminating, carries out the mensuration of pH value.
Testing result is in table 1.Table 1 is that the different pH preparation stability of methylprednisolone sodium succinate for inj investigates result of the test.What detect when in table 1, retention time is 13min is free methylprednisolone, what retention time detected when being 15min is 17-Methylprednisolone succinate, what retention time detected when being 19min is unknown impuritie, and what detect when retention time is 29min is Urbason Solubile (main peak).
Show that the percentage composition of the embodiment 1 of pH≤6.5 and embodiment 2 Urbason Solubile (main peak) when to preserve natural law be 0,5,10 day is the highest by the data of table 1, total assorted minimum, less Urbason Solubile is decomposed into free methylprednisolone and 17-Methylprednisolone succinate in storage, and the unknown impuritie amount occurred in storage is also relatively less, comparative example 1-4 is the comparative sample of pH > 6.5, comparative example is 0 at preservation natural law, 5, when 10 days, the percentage composition of Urbason Solubile (main peak) is on the low side, total assorted rate is higher than the little sample of pH, because pH is higher, more Urbason Solubile changes free methylprednisolone in storage, and in storage process, there is more unknown impuritie, reduce the effective content of methylprednisolone sodium succinate lyophilized injectable powder, and Urbason Solubile is difficult to after changing free methylprednisolone into dissolve, the phenomenon of solution muddiness after easily causing lyophilized injectable powder to be dissolved in water.
450nm absorbance in table 1 is test solution color, and 550nm absorbance is test turbidity, has table 1 result to show the absorbance of each sample all in allowed band.
Carry out yellow and yellow green colorimetric to testing sample in color comparison in table 1, result display is and is less than 1, for colourless.
The preparation method of a kind of methylprednisolone sodium succinate for inj lyophilized injectable powder of above embodiment is by adopting preparation lower ph, the Urbason Solubile phosphate buffer of pH≤6.5, and make lyophilized injectable powder, there is higher activity stability, and preparation method is easy, freeze-drying time shortens, and overcomes the preparation defect of said preparation in the past, greatly expands the scope of application of said preparation.
The different pH preparation stability of table 1 methylprednisolone sodium succinate for inj investigates result of the test
Claims (3)
1. a preparation method for methylprednisolone sodium succinate for inj lyophilized injectable powder, is characterized in that, step is:
1) take disodium hydrogen phosphate dodecahydrate and a hypophosphite monohydrate sodium dihydrogen that mass ratio is 1:0.63-3, dissolve with water for injection, shake up the phosphate buffer making pH≤6.5, for subsequent use;
2) Urbason Solubile is taken, described Urbason Solubile: disodium hydrogen phosphate dodecahydrate=3.81:1, slowly add step 1) phosphate buffer prepared, after being constantly stirred to solution clarification, transfer is put in volumetric flask, shake up with water for injection standardize solution, obtain preparing liquid;
3) by step 2) transfer of the preparation liquid that obtains puts injection bottles made of glass tubes and carries out subpackage;
4) by step 3) preparation liquid after subpackage carries out lyophilizing by heating and cooling freeze-drying curve rapidly, obtain lyophilized injectable powder, the described freeze-drying curve of heating and cooling is rapidly that room temperature rapid cooling is to-30 DEG C ~-40 DEG C,-5 DEG C ~ 0 DEG C is warming up to again after temperature stabilization, insulation a period of time, be then warming up to 30 DEG C ~ 40 DEG C and temperature rapidly and keep stable freeze-drying curve.
2. the preparation method of a kind of methylprednisolone sodium succinate for inj lyophilized injectable powder according to claim 1, is characterized in that, described step 1) phosphate buffer pH be 6.5 or 6.2.
3. the preparation method of a kind of methylprednisolone sodium succinate for inj lyophilized injectable powder according to claim 1, it is characterized in that, described step 4) the freeze-drying curve of heating and cooling be rapidly: in 1h by room temperature state rapid cooling to-40 DEG C, in 2h, at the uniform velocity-5 DEG C are warming up to after keeping 2h, then in 1h, 40 DEG C are warming up to rapidly after keeping 10h, keep 5h, complete lyophilizing operation.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106176632A (en) * | 2016-08-16 | 2016-12-07 | 海南合瑞制药股份有限公司 | A kind of methylprednisolone sodium succinate for injection compositions |
| CN108498468A (en) * | 2018-05-25 | 2018-09-07 | 福安药业集团湖北人民制药有限公司 | Methylprednisolone sodium succinate for injection |
| CN111249240A (en) * | 2020-02-24 | 2020-06-09 | 武汉人福药业有限责任公司 | Methylprednisolone sodium succinate powder injection for injection and preparation method thereof |
| US20210161822A1 (en) * | 2018-06-18 | 2021-06-03 | Docu-Med Limited | Oral compositions comprising methylprednisolone sodium succinate |
| CN113694032A (en) * | 2021-07-20 | 2021-11-26 | 江苏盈科生物制药有限公司 | Methylprednisolone sodium succinate freeze-dried powder injection for injection and preparation method thereof |
-
2014
- 2014-11-20 CN CN201410670438.0A patent/CN104434820A/en active Pending
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106176632A (en) * | 2016-08-16 | 2016-12-07 | 海南合瑞制药股份有限公司 | A kind of methylprednisolone sodium succinate for injection compositions |
| CN106176632B (en) * | 2016-08-16 | 2019-09-03 | 海南合瑞制药股份有限公司 | A kind of methylprednisolone sodium succinate for injection composition |
| CN108498468A (en) * | 2018-05-25 | 2018-09-07 | 福安药业集团湖北人民制药有限公司 | Methylprednisolone sodium succinate for injection |
| US20210161822A1 (en) * | 2018-06-18 | 2021-06-03 | Docu-Med Limited | Oral compositions comprising methylprednisolone sodium succinate |
| CN111249240A (en) * | 2020-02-24 | 2020-06-09 | 武汉人福药业有限责任公司 | Methylprednisolone sodium succinate powder injection for injection and preparation method thereof |
| CN111249240B (en) * | 2020-02-24 | 2022-05-06 | 武汉人福药业有限责任公司 | Methylprednisolone sodium succinate powder injection for injection and preparation method thereof |
| CN113694032A (en) * | 2021-07-20 | 2021-11-26 | 江苏盈科生物制药有限公司 | Methylprednisolone sodium succinate freeze-dried powder injection for injection and preparation method thereof |
| CN113694032B (en) * | 2021-07-20 | 2022-11-15 | 江苏盈科生物制药有限公司 | Methylprednisolone sodium succinate freeze-dried powder injection for injection and preparation method thereof |
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