CN104888207A - Injection bivalirudin preparation process - Google Patents
Injection bivalirudin preparation process Download PDFInfo
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- CN104888207A CN104888207A CN201510368447.9A CN201510368447A CN104888207A CN 104888207 A CN104888207 A CN 104888207A CN 201510368447 A CN201510368447 A CN 201510368447A CN 104888207 A CN104888207 A CN 104888207A
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Abstract
The invention belongs to the field of medicine preparation and particularly relates to an injection bivalirudin preparation process. The obtained bivalirudin has the advantages of high purity, few impurities and high stability. The method includes 1, preparing bivalirudin solution, namely adding citrate-disodium hydrogen phosphate buffer solution into a high-speed dispersion device, adding bivalirudin raw material medicine, stirring, dissolving, adding injection water till 100L, and obtaining bivalirudin filling solution; 2, filling; 2, obtaining injection bivalirudin after freezing and drying.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, be specifically related to a kind of preparation technology of injection Angiomax.
Background technology
Angiomax (Bivalirudin) is a kind of direct thrombin inhibitor (DTI), comes from hirudin derivative, is a synthesis small peptide be made up of 20 aminoacid.Angiomax is a kind of reversible inhibitor of effective, high selectivity, can not only suppress the thrombin of sequestered and conjunction type, can also suppress by the platelet activation of thrombin-mediated and gathering.Angiomax drug effect is fast, the half-life is short, in body not with plasma protein and erythrocyte binding, ?thrombocytopenia syndrome (HIT/HITTS) is become to there is not risk to heparin-induced thrombocytopenia with heparin-induced blood bolt shape, in addition, in treatment, do not need in conjunction with cofactors such as antithrombase, also need not activate platelet, these features make Angiomax become a desirable heparin succedaneum.
Angiomax (being also called bivalirudin) is a kind of polypeptide by 28 seed amino acid chemosynthesis.Its structural formula is as follows:
D-Phe-L-Pro-L-Arg-L-Pro-Gly-Gly-Gly-Gly-L-Asn-Gly-L-Asp-L-Phe-L-Glu-L-Glu-L-Ile-L-Pro-L-Glu-L-Glu-L-Tyr-L-Leu
In December, 2000, the injectable dosage forms of this medicine of Medicines company of U.S. exploitation is gone on the market in the U.S., and commodity are called Angiomax, general Bivalirudin by name, and Chinese Angiomax by name, listing dosage form is lyophilized injectable powder, and specification is that 250mg/ props up.
1 ~ February in 2005, Medicines company the subsidiary Nycomed in Europe Angiox (Bivalirudin is in the trade name in Europe) Austria, Denmark.Finland, Germany, Switzerland and Britain's listing, intervene patient for percutaneous arteria coronaria.The specification of its listing is the aseptic freeze-dried powder of 250mg/ bottle.Angiomax is used for intravenous injection and instillation.
The technique of preparation injection Angiomax preparation has patent report:
US Patent No. 7,582,727 and US7,598,343 disclose a kind of method preparing injection Angiomax, adopt the liquid dispensing device with extremely high-revolving agitating device (rotation speed requirements more than 600 turns), adopt first with part aqueous solution Angiomax, add under high velocity agitation and configure sodium hydroxide solution, regulate solution ph to 4 ~ 6, obtain known impurities ASP9 ?Angiomax and D ?Phe12 ?Angiomax must not solution more than 0.6%.Namely injection bivalirudin is obtained after lyophilizing.But in layoutprocedure, because Angiomax uses its trifluoroacetate clinically, but loosening after freeze drying of Angiomax trifluoroacetate, very easily produce floating thing, this for preparation dosing operation material add the problem bringing dust floating, pollution can be brought to the environment at dosing operation place.Cycle setup time is longer, and during large production 20,000, liquid preparation time can more than 4 hours, and medicinal liquid exposes the clean rank A level district specified at non-GMP for a long time to the open air, brings the probability of microbial contamination.
Chinese patent CN200810084299 adopts sodium carbonate as pH adjusting agent, first in water, adopts sodium bicarbonate solution adjust ph 4 ~ 6 after solution Angiomax, and preferably 5.5.Whole layoutprocedure be only laboratory-scale other, do not carry out industrialization checking, there is cycle setup time in addition equally longer, commercial process always brings the probability of microbial contamination.In addition, my company reappears bivalirudin aqueous solution in layoutprocedure and inherently easily bubbles, and adds sodium carbonate liquor in whipping process, produces a large amount of bubble, be difficult to cancellation for a long time, and the standardize solution for medicinal liquid produces very large interference.In addition the single impurity that the sodium carbonate liquor that CN200810084299 prepares prepares sample arrives 0.33%, and under the related substance item of the injection Angiomax specified in national drug standards YBH02912011, require known impurities ASP9 ?Angiomax and D ?Phe12 ?Angiomax must not more than 0.5%, single unknown impuritie is no more than 0.2%, in keeping life, likely there is product quality problem according to the injection Angiomax of this explained hereafter.
US Patent No. 7,985,733 patent discloses employing buffer solution dissolves bivalirudin, after the solution dilution of preparation higher than bivalirudin isoelectric point, IP, preparation injection Angiomax, the buffer solution reported is the preparation Angiomax solution such as hac buffer, obtains reasonable effect, but the stability that sample is prepared into injection Angiomax after lyophilizing is unknown.
There is following shortcoming in the preparation technology of the preparation of above-mentioned Angiomax:
1. Angiomax trifluoroacetate is soluble in water, but course of dissolution is slow, easily forms gelling material and adheres on the wall, need fair speed stirring and compared with the washing of big yield to container, just can make it well to be dispersed into aqueous solution.
2. in known compound method practical operation, according to batch production 10000 injection Angiomaxes, the time of its obtain solution all more than 4 hours, solution Prolonged exposure under ambient non-sterile, for later stage filtration sterilization brings pressure.
3. in known dosing process, adopt alkaline matter as the solution such as sodium hydroxide, sodium carbonate join in Angiomax solution time, because the isoelectric point, IP of Angiomax is 4.87, when solution ph reaches near isoelectric point, IP, solution muddiness can be produced, form the gel solution of Angiomax, needing high mixing speed and the mode that adds fast just likely to avoid gel solution to occur, there is certain technical risk in the preparation of preparation.Meanwhile, when adding alkaline solution, Angiomax can produce degraded, and the change of preparation related substance can affect product quality.
4. the stability of the product of known buffer preparation is unknown, and before the deadline, it is on the knees of the gods that can Related substances separation item meet national drug standards YBH02912011.
Summary of the invention
The object of the present invention is to provide a kind of preparation method of injection Angiomax.The Angiomax obtained by preparation method of the present invention has that purity is high, impurity is few, the feature of good stability.
Preparation method of the present invention, comprises the following steps:
(1) bivalirudin solution is joined: by Ning Meng Suan ?disodium hydrogen phosphate buffer solution access high speed dispersing device, add Angiomax crude drug, stirring and dissolving, inject and be settled to 100L with water, bivalirudin fill solution can be obtained;
(2) fill;
(3) injection bivalirudin is obtained after lyophilization.
Wherein, step (1) Ning Meng Suan ?disodium hydrogen phosphate buffer solution to be ph value be 5.0 ~ 5.5 buffer solution.
Ning Meng Suan ?the preparation of disodium hydrogen phosphate buffer solution: get citric acid 450 ~ 600g, sodium hydrogen phosphate 650 ~ 850g, mannitol 225g is dissolved in 100L water for injection, obtains the buffer solution that pH value is 5.0 ~ 5.5.
Described high speed dispersing device is ZC 0 type powder body dispersion machine.
Wherein, freeze-dry process described in step (3) is-40 DEG C of pre-freezes 6 hours, is evacuated to 10 to 50Pa, and trunk is dry is warming up to-5 DEG C of maintenances about 28 hours, note the ice crystal Disappearance Scenarios observing goods, the ice crystal Disappearance Scenarios according to goods can suitably shorten or extend this phases-time; Ice crystal is warming up to 25 DEG C and keeps about 4 hours after disappearing, then is warming up to 30 DEG C and keeps outlet after about 22 hours, obtains injection Angiomax finished product.
Preferably, preparation method of the present invention comprises the following steps:
(1) by Ning Meng Suan ?disodium hydrogen phosphate buffer solution access high speed dispersing device, Angiomax crude drug is added in the hopper of high speed dispersing device, discharging opening connects Agitation Tank, start runs, liquid is pumped in high speed dispersing device by Agitation Tank and circulates, until bivalirudin crude drug all dissolves, the liquid filling obtained in Agitation Tank is penetrated and is settled to prescription volume 100L with water
After above-mentioned standardize solution, solution is through membrane filtration, obtains fill liquid,
(2) fill,
(3) open cold lyophilizer, put into and divide the bivalirudin installed semi-finished product, lyophilizing is carried out :-40 DEG C of pre-freezes 6 hours by the freeze-drying curve of setting, be evacuated to 10 to 50Pa, trunk is dry is warming up to-5 DEG C of maintenances about 28 hours, note the ice crystal Disappearance Scenarios observing goods, the ice crystal Disappearance Scenarios according to goods can suitably shorten or extend this phases-time; Ice crystal is warming up to 25 DEG C and keeps about 4 hours after disappearing, then is warming up to 30 DEG C and keeps outlet after about 22 hours, obtains injection Angiomax finished product.
Preferably, preparation method of the present invention comprises the following steps:
Step 1: bivalirudin solution allocation:
In B level clean area, get citric acid 450 ~ 600g, sodium hydrogen phosphate 650 ~ 850g, 225g mannitol is dissolved in 100L water for injection, obtains the buffer solution of pH5.0 ~ 5.5.
In B level clean area, by buffer solution access high speed dispersing device (the such as ZC 0 type powder body dispersion machine obtained, Quadro company), the Angiomax crude drug 12.5kg of prescription ratio is added (with without trifluoroacetic acid in the hopper of high speed dispersing device, anhydride calculates), discharging opening connects Agitation Tank, start, after inlet flow rate set (11 ~ 45L/min) runs, liquid is pumped in high speed dispersing device by Agitation Tank and circulates, until bivalirudin crude drug all dissolves, homogeneous solution is formed in Agitation Tank, liquid preparation time is no more than 60min, the liquid filling obtained in Agitation Tank is penetrated and is settled to prescription volume 100L with water and can obtains stable bivalirudin fill solution.
Solution filters through the filter membrane (Millipore Corp.) of 0.22um, obtains fill liquid.
Step 2: fill
Adopt filling machine, according to the regulation loading amount of States Pharmacopoeia specifications fill 5.0ml, after the army of telling, crown liquid divides and is filled in the neutral borosilicate pipe-produced glass bottle of channel tunnel road baking oven sterilizing, adds the brominated butyl rubber plug through moist heat sterilization, is transferred in freeze dryer after half tamponade.
The standard of solution before fill: main peak purity>=99.9%, known impurities ASP
9?Angiomax and D ?Phe
12?Angiomax all must not more than 0.1%, bacterial endotoxin conforms with the regulations.
Step 3: lyophilizing
Open cold lyophilizer, put into and divide the bivalirudin installed semi-finished product, lyophilizing is carried out :-40 DEG C of pre-freezes 5 ~ 8 hours by the freeze-drying curve of setting, be evacuated to 10 to 50Pa, trunk is dry is warming up to-5 ~ 25 DEG C of maintenances about 25 ~ 30 hours, note the ice crystal Disappearance Scenarios observing goods, the ice crystal Disappearance Scenarios according to goods can suitably shorten or extend this phases-time; Ice crystal is warming up to 25 DEG C and keeps about 2 ~ 6 hours after disappearing, then is warming up to 30 DEG C and keeps outlet after about 20 hours, obtains injection Angiomax finished product.
Preferred further, preparation method of the present invention comprises the following steps:
(1) citric acid 500g is got, sodium hydrogen phosphate 750g, 225g mannitol is dissolved in 100L water for injection, obtain the buffer solution of pH5.3, by the buffer solution access high speed dispersing device obtained, Angiomax crude drug 12.5kg is added in the hopper of high speed dispersing device, discharging opening connects Agitation Tank, start, after inlet flow rate set runs, liquid is pumped in high speed dispersing device by Agitation Tank and circulates, until bivalirudin crude drug all dissolves, homogeneous solution is formed in Agitation Tank, liquid preparation time is about 30min, the liquid filling obtained in Agitation Tank is penetrated and is settled to prescription volume 100L with water, after above-mentioned standardize solution, solution is through the membrane filtration of 0.22um, obtain fill liquid,
(2) filling machine is adopted, according to the regulation loading amount of States Pharmacopoeia specifications fill 5.0ml,
(3) open cold lyophilizer, put into and divide the bivalirudin installed semi-finished product, lyophilizing is carried out :-40 DEG C of pre-freezes 6 hours by the freeze-drying curve of setting, be evacuated to 10 to 50Pa, trunk is dry is warming up to-5 DEG C of maintenances about 28 hours, note the ice crystal Disappearance Scenarios observing goods, the ice crystal Disappearance Scenarios according to goods can suitably shorten or extend this phases-time; Ice crystal is warming up to 25 DEG C and keeps about 4 hours after disappearing, then is warming up to 30 DEG C and keeps outlet after about 22 hours, obtains injection Angiomax finished product.
Injection Angiomax trimmed size 250mg of the present invention.
The present invention also provides the method for detecting purity of Angiomax.
Angiomax HPLC method for detecting purity: according to high performance liquid chromatography < Chinese Pharmacopoeia version in 2010 two annex V 0) measure.
Chromatographic condition and system suitability
Chromatographic column: Agilent Extend-C
18post (250 × 4.6m 5 μm), with 0.1mol/L sodium phosphate buffer (14.2g anhydrous sodium sulfate, the about 800ml that adds water dissolves, add phosphoric acid 5.4ml, by triethylamine adjust ph to 7.0, be settled to 100ml) be mobile phase A, with water: second dried meat (10:90) is Mobile phase B; Flow velocity is 1.0ml/min; Column temperature 25 DEG C; Determined wavelength is 214nm; Number of theoretical plate should be not less than 3000 by Angiomax, and Angiomax peak and the high and steep separating degree of impurity should conform with the regulations.By following gradient:
Get this product appropriate, accurately weighed, with water dissolution and the solution be diluted to containing 0.5mg Angiomax in 1ml, shake up, as need testing solution; Precision measures test sample liquation 50 μ L injection liquid chromatography, and record need testing solution chromatogram to 2 times of main constituent peak retention time calculate main peak purity according to area normalization method.
The present invention mainly improves with existing methodical difference and is, comprises the following aspects:
(1) the new composition of the buffer solution of existing patent and bibliographical information is different from, have employed new pH value 5.0 ~ 5.5 Ning Meng Suan ?sodium hydrogen phosphate system substitute known buffer solution as buffer solution, the product prepared by the present invention is in 24 months, and related substance change meets the national drug standards.And sample prepared by additive method is all defective in 24 months.
(2) when preparing the fill solution of Angiomax, adopt high speed dispersing device, the time of dissolving Angiomax crude drug tapered within 30 minutes from 4 ~ 6 hours, avoided liquid medicine contamination.
(3) the present invention adopts new freeze-drying curve, the solution after Angiomax is filled and after product lyophilizing, and the related substance of product is unchanged, ensure that product quality.
Accompanying drawing explanation
Fig. 1: the related substance testing result of this product Angiomax solution after filtration sterilization before step 2 fill
Fig. 2: the related substance testing result of this product Angiomax crude drug after step 3 lyophilizing
Detailed description of the invention:
By following specific embodiment, the present invention is further illustrated, but not as restriction of the present invention.
Embodiment 1
Step one: bivalirudin solution allocation:
(1) in B level clean area, get citric acid 500g, sodium hydrogen phosphate 750g, 225g mannitol is dissolved in 100L water for injection, obtains the buffer solution of pH5.3.
(2) in B level clean area, by buffer solution access ZC 0 type powder body dispersion machine (Quadro company) obtained, the Angiomax crude drug 12.5kg of prescription ratio is added (with without trifluoroacetic acid in the hopper of high speed dispersing device, anhydride calculates, purity 99.9%), discharging opening connects Agitation Tank, start, after inlet flow rate set (20L/min) runs, liquid is pumped in high speed dispersing device by Agitation Tank and circulates, until bivalirudin crude drug all dissolves, homogeneous solution is formed in Agitation Tank, liquid preparation time is about 30min, the liquid filling obtained in Agitation Tank is penetrated and is settled to prescription volume 100L with water.
(3) after above-mentioned standardize solution, solution filters through the filter membrane (Millipore Corp.) of 0.22um, obtains fill liquid.Sampling inspection results shows: always assorted 0.19%, known impurities ASP9 ?Angiomax (retention time is 29.910min) and D ?Phe12 ?Angiomax (retention time is 34.100min) all more than 0.1% (accompanying drawing 1)
Step 2: fill
Adopt filling machine (model), according to the regulation loading amount of States Pharmacopoeia specifications fill 5.0ml, after the army of telling, crown liquid divides and is filled in the neutral borosilicate pipe-produced glass bottle of channel tunnel road baking oven sterilizing, adds the brominated butyl rubber plug through moist heat sterilization, is transferred in freeze dryer after half tamponade.
Step 3: lyophilizing
Open cold lyophilizer, put into and divide the bivalirudin installed semi-finished product, lyophilizing is carried out :-40 DEG C of pre-freezes 6 hours by the freeze-drying curve of setting, be evacuated to 10 to 50Pa, trunk is dry is warming up to-5 DEG C of maintenances about 28 hours, note the ice crystal Disappearance Scenarios observing goods, the ice crystal Disappearance Scenarios according to goods can suitably shorten or extend this phases-time; Ice crystal is warming up to 25 DEG C and keeps about 4 hours after disappearing, then is warming up to 30 DEG C and keeps outlet after about 22 hours, obtains injection Angiomax finished product.
Measure injection Angiomax finished product related substance, sampling inspection results shows: always assorted 0.20%, known impurities ASP9 ?Angiomax (retention time is: 29.975min) and D ?Phe12 ?Angiomax (retention time is: 34.200min) be 0.03% (accompanying drawing 2).
The large explained hereafter equipment of injection Angiomax
| Title | Model | Manufacturer originates |
| Dilute preparing tank | 250L | Nanjing Jin Kou machinery Group Co., Ltd |
| Receiving tank | 250L | Nanjing Jin Kou machinery Group Co., Ltd |
| Sterile liquid filling machine | ZGS16 | Nanjing Bojian Science Co., Ltd |
| Laminar flow dry heat sterilization tunnel | GMS1200L1 | Nanjing Bojian Science Co., Ltd |
| Rotary drum ultrasonic bottle washing machine | XXC30120 | Nanjing Bojian Science Co., Ltd |
| Vacuum freeze drier A | Lyoliner20.0 | Shandong Medical Devices Co., Ltd. of Xinhua |
| Roll aluminium lid machine | PZL16 | Nanjing Bojian Science Co., Ltd |
Embodiment 2
We have carried out long-time stability investigation for the sample produced according to embodiment, reference preparation is the obtained corresponding product according to the preparation method of publication, its 0 to the 24 month stability data under 25 DEG C of conditions is detected according to Angiomax HPLC method for detecting purity, result shows, and the existing preparation technology of my company obtains product stability and is obviously better than other products.In following table: impurity A is Asp
9-Angiomax, impurity B is D-Phe
12-Angiomax.
Related substance testing result (impurity A)
Related substance testing result (impurity B)
Related substance testing result (always mixing)
Specify under the Related substances separation item of national drug standards YBH02912011, in 24 months, impurity A is Asp
9-Angiomax should cross 0.5%, and impurity B is D-Phe
12-Angiomax should cross 0.5%, always must not mix 1.5%, there is above-mentioned experimental result known, product prepared by present patent application embodiment 1 specifies under the Related substances separation item that can meet national drug standards YBH02912011, and other product is all defective the study on the stability result display of 24 months.
Claims (6)
1. an injection Angiomax preparation method, comprises the following steps:
(1) bivalirudin solution is joined: by Ning Meng Suan ?disodium hydrogen phosphate buffer solution access high speed dispersing device, add Angiomax crude drug, stirring and dissolving, inject and be settled to 100L with water, bivalirudin fill solution can be obtained;
(2) fill;
(3) injection bivalirudin is obtained after lyophilization.
2. preparation method according to claim 1, it is characterized in that, Ning Meng Suan ?the preparation of disodium hydrogen phosphate buffer solution: get citric acid 450 ~ 600g, sodium hydrogen phosphate 650 ~ 850g, mannitol 225g is dissolved in 100L water for injection, obtains the buffer solution that pH value is 5.0 ~ 5.5.
3. preparation method according to claim 1, is characterized in that, comprises the following steps:
(1) by Ning Meng Suan ?disodium hydrogen phosphate buffer solution access high speed dispersing device, Angiomax crude drug is added in the hopper of high speed dispersing device, discharging opening connects Agitation Tank, start runs, and liquid is pumped in high speed dispersing device by Agitation Tank and circulates, until bivalirudin crude drug all dissolves, the liquid filling obtained in Agitation Tank is penetrated and is settled to prescription volume 100L with water, after above-mentioned standardize solution, solution is through membrane filtration, obtains fill liquid
(2) fill,
(3) open cold lyophilizer, put into and divide the bivalirudin installed semi-finished product, lyophilizing is carried out :-40 DEG C of pre-freezes 6 hours by the freeze-drying curve of setting, be evacuated to 10 to 50Pa, trunk is dry is warming up to-5 DEG C of maintenances about 28 hours, note the ice crystal Disappearance Scenarios observing goods, the ice crystal Disappearance Scenarios according to goods can suitably shorten or extend this phases-time; Ice crystal is warming up to 25 DEG C and keeps about 4 hours after disappearing, then is warming up to 30 DEG C and keeps outlet after about 22 hours, obtains injection Angiomax finished product.
4. preparation method according to claim 1, is characterized in that, comprises the following steps:
(1) bivalirudin solution allocation:
In B level clean area, get citric acid 450 ~ 600g, sodium hydrogen phosphate 650 ~ 850g, 225g mannitol is dissolved in 100L water for injection, obtains the buffer solution of pH5.0 ~ 5.5.
In B level clean area, by the buffer solution access high speed dispersing device obtained, the Angiomax crude drug 12.5kg of prescription ratio is added in the hopper of high speed dispersing device, discharging opening connects Agitation Tank, start, after inlet flow rate set runs, liquid is pumped in high speed dispersing device by Agitation Tank and circulates, until bivalirudin crude drug all dissolves, homogeneous solution is formed in Agitation Tank, liquid preparation time is no more than 60min, the liquid filling obtained in Agitation Tank is penetrated and is settled to prescription volume 100L with water and can obtains stable bivalirudin fill solution, solution is through the membrane filtration of 0.22um, obtain fill liquid,
(2) fill
Adopt filling machine, according to the regulation loading amount of States Pharmacopoeia specifications fill 5.0ml, after the army of telling, crown liquid divides and is filled in the neutral borosilicate pipe-produced glass bottle of channel tunnel road baking oven sterilizing, adds the brominated butyl rubber plug through moist heat sterilization, is transferred in freeze dryer after half tamponade,
(3) lyophilizing
Open cold lyophilizer, put into and divide the bivalirudin installed semi-finished product, lyophilizing is carried out :-40 DEG C of pre-freezes 5 ~ 8 hours by the freeze-drying curve of setting, be evacuated to 10 to 50Pa, trunk is dry is warming up to-5 ~ 25 DEG C of maintenances about 25 ~ 30 hours, note the ice crystal Disappearance Scenarios observing goods, the ice crystal Disappearance Scenarios according to goods can suitably shorten or extend this phases-time; Ice crystal is warming up to 25 DEG C and keeps about 2 ~ 6 hours after disappearing, then is warming up to 30 DEG C and keeps outlet after about 20 hours, obtains injection Angiomax finished product.
5. preparation method according to claim 1, is characterized in that, described high speed dispersing device, is ZC 0 type powder body dispersion machine.
6. preparation method according to claim 1, it is characterized in that, freeze-dry process described in step 3 is-40 DEG C of pre-freezes 6 hours, be evacuated to 10 to 50Pa, trunk is dry is warming up to-5 DEG C of maintenances about 28 hours, note the ice crystal Disappearance Scenarios observing goods, the ice crystal Disappearance Scenarios according to goods can suitably shorten or extend this phases-time; Ice crystal is warming up to 25 DEG C and keeps about 4 hours after disappearing, then is warming up to 30 DEG C and keeps outlet after about 22 hours, obtains injection Angiomax finished product.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107638298A (en) * | 2017-08-13 | 2018-01-30 | 发贵科技（贵州）有限公司 | A kind of production method of the solid preparation of traditional Chinese medicine of low stain |
| CN111450242A (en) * | 2019-01-22 | 2020-07-28 | 上海上药第一生化药业有限公司 | Bivalirudin injection preparation and preparation method and application thereof |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101244043A (en) * | 2008-03-31 | 2008-08-20 | 李振国 | Bivalirudin freeze-dried injection and preparation thereof |
| US7582727B1 (en) * | 2008-07-27 | 2009-09-01 | The Medicinces Company | Pharmaceutical formulations of bivalirudin and processes of making the same |
| US7598343B1 (en) * | 2008-07-27 | 2009-10-06 | The Medicines Company | Pharmaceutical formulations of bivalirudin and processes of making the same |
| US7985733B1 (en) * | 2010-01-06 | 2011-07-26 | The Medicines Company | Buffer-based method for preparing bivalirudin drug product |
-
2015
- 2015-06-29 CN CN201510368447.9A patent/CN104888207B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101244043A (en) * | 2008-03-31 | 2008-08-20 | 李振国 | Bivalirudin freeze-dried injection and preparation thereof |
| US7582727B1 (en) * | 2008-07-27 | 2009-09-01 | The Medicinces Company | Pharmaceutical formulations of bivalirudin and processes of making the same |
| US7598343B1 (en) * | 2008-07-27 | 2009-10-06 | The Medicines Company | Pharmaceutical formulations of bivalirudin and processes of making the same |
| US7985733B1 (en) * | 2010-01-06 | 2011-07-26 | The Medicines Company | Buffer-based method for preparing bivalirudin drug product |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107638298A (en) * | 2017-08-13 | 2018-01-30 | 发贵科技（贵州）有限公司 | A kind of production method of the solid preparation of traditional Chinese medicine of low stain |
| CN111450242A (en) * | 2019-01-22 | 2020-07-28 | 上海上药第一生化药业有限公司 | Bivalirudin injection preparation and preparation method and application thereof |
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| CN104888207B (en) | 2017-11-14 |
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