CN104888207B - A kind of preparation technology of injection Angiomax - Google Patents
A kind of preparation technology of injection Angiomax Download PDFInfo
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- CN104888207B CN104888207B CN201510368447.9A CN201510368447A CN104888207B CN 104888207 B CN104888207 B CN 104888207B CN 201510368447 A CN201510368447 A CN 201510368447A CN 104888207 B CN104888207 B CN 104888207B
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Abstract
The invention belongs to field of pharmaceutical preparations, and in particular to a kind of preparation technology of injection Angiomax.The Angiomax obtained by the preparation method of the present invention has the characteristics of purity is high, impurity is few, stability is good.Preparation method of the present invention, comprises the following steps:(1) bivalirudin solution is matched somebody with somebody:Citrate-phosphate disodium hydrogen cushioning liquid is accessed into high speed dispersing device, Angiomax bulk drug is added, stirring and dissolving, adds water for injection to be settled to 100L, you can to obtain the filling solution of bivalirudin;(2) it is filling;(3) injection bivalirudin is obtained after being freeze-dried.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, and in particular 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
One synthesis small peptide being made up of 20 amino acid.Angiomax is a kind of effective, reversible inhibitor of high selectivity, not only
Sequestered and the fibrin ferment of mating type can be suppressed, moreover it is possible to suppress the platelet activation by thrombin-mediated and aggregation.Angiomax
Drug effect is fast, half-life short, in body not with plasma protein and erythrocyte binding, to heparin-induced thrombocytopenia and liver
Risk is not present in thrombosis-decrease of platelet syndrome (HIT/HITTS) of element induction, in addition, in treatment, it is not necessary to reference to
The confactors such as antithrombase, without activation blood platelet, these features make Angiomax turn into a preferable heparin replacement
Product.
Angiomax (also known as bivalirudin) is a kind of polypeptide synthesized by 28 kinds of chemistry of amino acids.Its structural formula is such as
Under:
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 the medicine of Medicines companies of U.S. exploitation list in the U.S., trade name
For Angiomax, general entitled Bivalirudin, the entitled Angiomax of Chinese, listing formulation is freeze drying powder injection, and specification is
250mg/ branch.
1~2 month 2005, in the subsidiary Nycomed in Europe Angiox, (Bivalirudin existed for Medicines companies
The trade name in Europe) in Austria, Denmark.Finland, Germany, Switzerland and Britain's listing, intervene patient for percutaneous coronary artery.Its
The specification of listing is the aseptic freeze-dried powder of 250mg/ bottles.Angiomax is used to be injected intravenously and instil.
The technique for preparing injection Angiomax preparation has had patent report:
United States Patent (USP) US 7,582,727 and US7,598,343 disclose a kind of method for preparing injection Angiomax,
Using the liquid dispensing device with extremely high-revolving agitating device (more than 600 turns of rotating speed requirement), using first with part aqueous solution ratio
Lu Ding is cut down, adds configured good sodium hydroxide solution under high velocity agitation, regulation solution ph obtains known impurities to 4~6
ASP9- Angiomaxes and D-Phe12- Angiomaxes must not exceed 0.6% solution.Injection bivalirudin is produced after lyophilized.
But in configuration process because Angiomax clinically uses its trifluoroacetate, but Angiomax trifluoroacetate
It is loose after lyophilized, floating object is easily produced, this is the problem of addition with liquid process material of preparation brings dust to float, can be right
Pollution is brought with the environment where liquid process.Cycle setup time is longer, and liquid preparation time can be small more than 4 when producing 20,000 greatly
When, decoction exposes the possibility in clean rank A levels area as defined in non-GMP, bringing microorganism pollution to the open air for a long time.
Chinese patent CN200810084299, as pH adjusting agent, is first adopted using sodium carbonate in water after solution Angiomax
With sodium bicarbonate solution adjust pH value 4~6, preferably 5.5.Whole configuration process is only laboratory level, does not carry out industry
Chemical examination card, equally exists that cycle setup time is longer, commercial process always brings the possibility of microorganism pollution in addition.This
Outside, my company reappears the bivalirudin aqueous solution in configuration process and is easy for bubbling in itself, adds sodium carbonate liquor in whipping process
It is middle to produce a large amount of bubbles, it is difficult to eliminate for a long time, very big interference is produced for the constant volume of decoction.In addition CN200810084299 matches somebody with somebody
The single impurity that the sodium carbonate liquor of system prepares sample has arrived at 0.33%, and is advised in national drug standards YBH02912011
Under the relevant material item of fixed injection Angiomax, it is desirable to known impurities ASP9- Angiomaxes and D-Phe12- Angiomaxes
0.5% is must not exceed, single unknown impuritie is no more than 0.2%, in keeping life, according to the injection ratio of this technique productions
Cut down Lu Ding and be possible to product quality problem occur.
The patents of United States Patent (USP) US 7,985,733 disclose dissolves bivalirudin using cushioning liquid, prepares and is higher than than cutting down Lu
After the solution dilution for determining isoelectric point, injection Angiomax is prepared, the cushioning liquid reported is that hac buffer etc. is prepared
Angiomax solution, obtains relatively good effect, but sample it is freeze-dried after be prepared into injection Angiomax stability it is unknown.
The preparation technology of the preparation of above-mentioned Angiomax has the following disadvantages:
1. Angiomax trifluoroacetate is soluble in water, but course of dissolution is slow, easily forms gelling material and is adhered to appearance
, it is necessary to which the stirring of fair speed and compared with washing of the big yield to container, can just be allowed to be dispersed into the aqueous solution well on wall.
It is molten according to 10000 injection Angiomaxes of batch production, its preparation in compound method practical operation known to 2.
More than the 4 hours time of liquid, solution Prolonged exposure bring pressure under ambient non-sterile, for later stage filtration sterilization.
3. it is known with during liquid, Angiomax is added to using the alkaline matter such as solution such as sodium hydroxide, sodium carbonate
When in solution, because the isoelectric point of Angiomax is 4.87, when solution ph reaches near isoelectric point, it is muddy solution to be produced
It is turbid, the gel solution of Angiomax is formed, it is necessary to which high mixing speed and the mode rapidly joined are possible to avoid gel
Solution occurs, and the preparation of preparation has certain technical risk.Meanwhile when adding alkaline solution, Angiomax can produce drop
Solution, change of the preparation about material can influence product quality.
4. the stability of the product of buffer preparation known to is unknown, and before the deadline, can Related substances separation item
It is on the knees of the gods to meet national drug standards YBH02912011.
The content of the invention
It is an object of the invention to provide a kind of preparation method of injection Angiomax.Pass through the preparation method of the present invention
Obtained Angiomax has the characteristics of purity is high, impurity is few, stability is good.
Preparation method of the present invention, comprises the following steps:
(1) bivalirudin solution is matched somebody with somebody:Citrate-phosphate disodium hydrogen cushioning liquid is accessed into high speed dispersing device, adds ratio
Lu Ding bulk drugs are cut down, stirring and dissolving, add water for injection to be settled to 100L, you can obtain the filling solution of bivalirudin;
(2) it is filling;
(3) injection bivalirudin is obtained after being freeze-dried.
Wherein, step (1) citrate-phosphate disodium hydrogen cushioning liquid is the cushioning liquid that ph values are 5.0~5.5.
The preparation of citrate-phosphate disodium hydrogen cushioning liquid:Take 450~600g of citric acid, disodium hydrogen phosphate 650~
850g, mannitol 225g are dissolved in 100L waters for injection, obtain the cushioning liquid that pH value is 5.0~5.5.
The high speed dispersing device, it is the type powder dispersion machines of ZC 0.
Wherein, the lyophilized technique described in step (3) is -40 DEG C of pre-freezes 6 hours, is evacuated to 10 to 50Pa, the dry liter of trunk
Extremely -5 DEG C of temperature is kept for about 28 hours, pays attention to observing the ice crystal Disappearance Scenarios of product, can be appropriate according to the ice crystal Disappearance Scenarios of product
Shorten or extend this phases-time;Ice crystal is warming up to 25 DEG C and kept for about 4 hours after disappearing, then is warming up to 30 DEG C and is kept for about 22 hours
Outlet afterwards, produce injection Angiomax finished product.
Preferably, preparation method of the invention comprises the following steps:
(1) citrate-phosphate disodium hydrogen cushioning liquid is accessed into high speed dispersing device, in the hopper of high speed dispersing device
Angiomax bulk drug, discharging opening connection Agitation Tank are added, start is run, and liquid is pumped into high speed dispersing device by Agitation Tank again
Circulation, until bivalirudin bulk drug all dissolves, the liquid filling obtained in Agitation Tank is penetrated is settled to prescription volume with water
100L,
Solution obtains filling liquid through membrane filtration after above-mentioned constant volume,
It is (2) filling,
(3) freeze drier is opened, the bivalirudin semi-finished product dispensed is put into, is frozen by the freeze-drying curve of setting
It is dry:- 40 DEG C of pre-freezes 6 hours, are evacuated to 10 to 50Pa, and trunk is dry to be warming up to -5 DEG C and kept for about 28 hours, pays attention to observation product
Ice crystal Disappearance Scenarios, suitably can shorten or extend this phases-time according to the ice crystal Disappearance Scenarios of product;Ice crystal rises after disappearing
Temperature to 25 DEG C keep about 4 hours, then be warming up to 30 DEG C keep about 22 hours after outlet, produce injection Angiomax finished product.
Preferably, preparation method of the invention comprises the following steps:
Step 1:Bivalirudin solution allocation:
In B level clean areas, 450~600g of citric acid is taken, disodium hydrogen phosphate 650~850g, 225g mannitol is dissolved in
In 100L waters for injection, the cushioning liquid of pH5.0~5.5 is obtained.
In B level clean areas, by obtained cushioning liquid access high speed dispersing device (such as type powder dispersion machines of ZC 0,
Quadro companies), the Angiomax bulk drug 12.5kg of prescription ratio is added in the hopper of high speed dispersing device (with without trifluoro
Acetic acid, anhydride calculate), discharging opening connection Agitation Tank, start, after inlet flow rate set (11~45L/min) operation, liquid
It is pumped into high speed dispersing device and is circulated by Agitation Tank again, until bivalirudin bulk drug all dissolves, is formed in Agitation Tank equal
One solution, liquid preparation time are no more than 60min, and the liquid filling obtained in Agitation Tank is penetrated is settled to prescription volume 100L i.e. with water
The stable filling solution of bivalirudin can be obtained.
Filter membrane (Millipore Corp.) filtering of the solution through 0.22um, obtains filling liquid.
Step 2:It is filling
Using bottle placer, according to the filling 5.0ml of States Pharmacopoeia specifications regulation loading amount, coronal liquid is dispensed to through tunnel after the army of telling
In the neutral borosilicate pipe-produced glass bottle of baking oven sterilizing, add the brominated butyl rubber plug through moist heat sterilization, be transferred to after half tamponade lyophilized
In machine.
The standard of filling preceding solution:Main peak purity >=99.9%, it is known that impurity A SP9- Angiomax and D-Phe12- ratio is cut down
Lu Ding must not exceed 0.1%, and bacterial endotoxin meets regulation.
Step 3:It is lyophilized
Freeze drier is opened, the bivalirudin semi-finished product dispensed is put into, is frozen by the freeze-drying curve of setting
It is dry:- 40 DEG C of pre-freezes 5~8 hours, are evacuated to 10 to 50Pa, and trunk is dry to be warming up to -5~25 DEG C and kept for about 25~30 hours, note
The ice crystal Disappearance Scenarios of meaning observation product, suitably can shorten or extend this phases-time according to the ice crystal Disappearance Scenarios of product;Ice
Crystalline substance disappear after be warming up to 25 DEG C keep about 2~6 hours, then be warming up to 30 DEG C keep about 20 hours after outlet, produce injection ratio
Cut down Lu Ding finished products.
It is further preferred that the preparation method of the present invention comprises the following steps:
(1) citric acid 500g is taken, disodium hydrogen phosphate 750g, 225g mannitol is dissolved in 100L waters for injection, obtained
PH5.3 cushioning liquid, obtained cushioning liquid is accessed into high speed dispersing device, ratio is added in the hopper of high speed dispersing device
Lu Ding bulk drug 12.5kg are cut down, discharging opening connection Agitation Tank, start, after the operation of inlet flow rate set, liquid is again by Agitation Tank
It is pumped into high speed dispersing device and circulates, until bivalirudin bulk drug all dissolves, homogeneous solution is formed in Agitation Tank, is matched somebody with somebody
Liquid time about 30min, the liquid filling obtained in Agitation Tank is penetrated is settled to prescription volume 100L with water, and solution passes through after above-mentioned constant volume
0.22um membrane filtration, filling liquid is obtained,
(2) bottle placer is used, according to the filling 5.0ml of States Pharmacopoeia specifications regulation loading amount,
(3) freeze drier is opened, the bivalirudin semi-finished product dispensed is put into, is frozen by the freeze-drying curve of setting
It is dry:- 40 DEG C of pre-freezes 6 hours, are evacuated to 10 to 50Pa, and trunk is dry to be warming up to -5 DEG C and kept for about 28 hours, pays attention to observation product
Ice crystal Disappearance Scenarios, suitably can shorten or extend this phases-time according to the ice crystal Disappearance Scenarios of product;Ice crystal rises after disappearing
Temperature to 25 DEG C keep about 4 hours, then be warming up to 30 DEG C keep about 22 hours after outlet, produce 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 two annex V of high performance liquid chromatography < Chinese Pharmacopoeias version in 2010
0) determine.
Chromatographic condition and system suitability
Chromatographic column:Agilent Extend-C18Post (5 μm of 250 × 4.6m), with 0.1mol/L sodium phosphate buffers
(14.2g anhydrous sodium sulfates, water about 800ml is added to dissolve, phosphorate sour 5.4ml, adjusts pH value to 7.0 with triethylamine, is settled to
It is 100ml) mobile phase A, with water:Second dried meat (10:90) it is Mobile phase B;Flow velocity is 1.0ml/min;25 DEG C of column temperature;Detection wavelength is
214nm;Number of theoretical plate should be not less than 3000 based on Angiomax, and Angiomax peak should meet regulation with the high and steep separating degree of impurity.
By following gradients:
Take this product appropriate, it is accurately weighed, dissolved with water and be diluted to the solution of the Angiomax containing 0.5mg in 1ml, shaken up,
As need testing solution;Precision measures the μ L of test sample liquation 50 injection liquid chromatographs, record need testing solution chromatogram to master
2 times into swarming retention time calculate main peak purity according to area normalization method.
The difference of the present invention and existing method, which mainly improves, to be, including the following aspects:
(1) it is different from the new composition of the cushioning liquid of existing patent and document report, employs new pH value 5.0~5.5
Citrate-phosphate disodium hydrogen system as cushioning liquid substitute known to cushioning liquid, by the product for preparing of the present invention 24
In individual month, relevant material change meets the national drug standards.And sample prepared by other method is unqualified in 24 months.
(2) when preparing the filling solution of Angiomax, using high speed dispersing device, dissolving Angiomax bulk drug when
Between tapered to from 4~6 hours within 30 minutes, avoid liquid medicine contamination.
(3) present invention uses new freeze-drying curve, solution after Angiomax is filled and after product is lyophilized, product
Relevant material is unchanged, it is ensured that product quality.
Brief description of the drawings
Fig. 1:The relevant material testing result of this product Angiomax solution after the filling preceding filtration sterilization of step 2
Fig. 2:The relevant material testing result of this product Angiomax bulk drug after step 3 is lyophilized
Embodiment:
By specific examples below, the present invention is further illustrated, but not as the limitation of the present invention.
Embodiment 1
Step 1:Bivalirudin solution allocation:
(1) in B level clean areas, citric acid 500g is taken, disodium hydrogen phosphate 750g, 225g mannitol is dissolved in 100L injections
In water, pH5.3 cushioning liquid is obtained.
(2) in B level clean areas, obtained cushioning liquid is accessed into the type powder dispersion machines (Quadro companies) of ZC 0, in height
In the hopper of fast dispersal device add prescription ratio Angiomax bulk drug 12.5kg (with without trifluoroacetic acid, anhydride calculating,
Purity 99.9%), discharging opening connection Agitation Tank, start, after inlet flow rate set (20L/min) operation, liquid is again by with liquid
Tank is pumped into high speed dispersing device and circulated, until bivalirudin bulk drug all dissolves, homogeneous solution is formed in Agitation Tank,
Liquid preparation time about 30min, the liquid filling obtained in Agitation Tank is penetrated is settled to prescription volume 100L with water.
(3) filter membrane (Millipore Corp.) filtering of the solution through 0.22um after above-mentioned constant volume, obtains filling liquid.Sampling detection knot
Fruit shows:Total miscellaneous 0.19%, it is known that impurity A SP9- Angiomaxes (retention time 29.910min) and D-Phe12- ratios cut down reed
Fixed (retention time 34.100min) is not less than 0.1% (accompanying drawing 1)
Step 2:It is filling
Using bottle placer (model), according to the filling 5.0ml of States Pharmacopoeia specifications regulation loading amount, after the army of telling coronal liquid dispense to
In neutral borosilicate pipe-produced glass bottle through tunnel oven sterilizing, add the brominated butyl rubber plug through moist heat sterilization, shifted after half tamponade
To freeze dryer.
Step 3:It is lyophilized
Freeze drier is opened, the bivalirudin semi-finished product dispensed is put into, is frozen by the freeze-drying curve of setting
It is dry:- 40 DEG C of pre-freezes 6 hours, are evacuated to 10 to 50Pa, and trunk is dry to be warming up to -5 DEG C and kept for about 28 hours, pays attention to observation product
Ice crystal Disappearance Scenarios, suitably can shorten or extend this phases-time according to the ice crystal Disappearance Scenarios of product;Ice crystal rises after disappearing
Temperature to 25 DEG C keep about 4 hours, then be warming up to 30 DEG C keep about 22 hours after outlet, produce injection Angiomax finished product.
The relevant material of parenteral solution Angiomax finished product is determined, sampling inspection results are shown:Total miscellaneous 0.20%, it is known that impurity
(retention time is ASP9- Angiomaxes:29.975min) and D-Phe12- Angiomaxes (retention time is:34.200min)
For 0.03% (accompanying drawing 2).
The big technique productions equipment of injection Angiomax
Title | Model | Manufacturer source |
Dilute preparing tank | 250L | Nanjing Jin Kou machineries Group Co., Ltd |
Receiving tank | 250L | Nanjing Jin Kou machineries Group Co., Ltd |
Sterile liquid bottle placer | ZGS16 | Nanjing Bojian Science Co., Ltd |
Laminar flow hot air 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 are directed to has carried out long-time stability investigation according to the sample of embodiment production, and reference preparation is according to disclosed
The obtained corresponding product of the preparation method of patent, its 0 to 24 month is detected 25 according to Angiomax HPLC method for detecting purity
Stability data under the conditions of DEG C, as a result shows, the existing preparation technology of my company obtains product stability and is substantially better than other
Product.In following table:Impurity A is Asp9- Angiomax, impurity B D-Phe12- Angiomax.
Relevant material testing result (impurity A)
Relevant material testing result (impurity B)
Relevant material testing result (total miscellaneous)
Provided under national drug standards YBH02912011 Related substances separation item, impurity A is Asp in 24 months9- ratio
0.5% must not be crossed by cutting down Lu Dingying, impurity B D-Phe12- Angiomax should must not cross 0.5%, it is total it is miscellaneous must not cross 1.5%, have on
State experimental result to understand, product prepared by present patent application embodiment 1 can meet national drug standards YBH02912011
Provided under Related substances separation item, and other products shown in the study on the stability result of 24 months it is unqualified.
Claims (1)
1. a kind of preparation method of injection Angiomax, comprises the following steps:
Step 1:Angiomax solution allocation:
In B level clean areas, citric acid 500g is taken, disodium hydrogen phosphate 750g, 225g mannitol is dissolved in 100L waters for injection, obtained
To pH5.3 cushioning liquid;
In B level clean areas, obtained cushioning liquid is accessed into ZC0 type powder dispersion machines, added in the hopper of high speed dispersing device
Enter Angiomax bulk drug 12.5kg, discharging opening connection Agitation Tank, start shooting, after inlet flow rate set 20L/min operations, liquid
It is pumped into high speed dispersing device and is circulated by Agitation Tank again, until Angiomax bulk drug all dissolves, is formed in Agitation Tank equal
One solution, the liquid filling obtained in Agitation Tank is penetrated is settled to 100L with water;
Solution obtains filling liquid through 0.22 μm of membrane filtration after above-mentioned constant volume;
Step 2:It is filling,
Step 3:It is lyophilized:
Freeze drier is opened, the Angiomax semi-finished product dispensed is put into, is freezed by the freeze-drying curve of setting:-40
DEG C pre-freeze 6 hours, is evacuated to 10 to 50Pa, and trunk is dry to be warming up to -5 DEG C and kept for 28 hours, pays attention to that the ice crystal of observation product disappears
Mistake situation, ice crystal disappear after be warming up to 25 DEG C keep 4 hours, then be warming up to 30 DEG C keep 22 hours after outlet, produce.
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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 |
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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 |
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