CN103054816A - Aprotinin freeze-dried powder and preparation method thereof - Google Patents
Aprotinin freeze-dried powder and preparation method thereof Download PDFInfo
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- CN103054816A CN103054816A CN 201210578632 CN201210578632A CN103054816A CN 103054816 A CN103054816 A CN 103054816A CN 201210578632 CN201210578632 CN 201210578632 CN 201210578632 A CN201210578632 A CN 201210578632A CN 103054816 A CN103054816 A CN 103054816A
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Abstract
The invention provides an aprotinin freeze-dried powder injection and a preparation method thereof. The freeze-dried powder injection is composed of the following substances: 28-556 million units of aprotinin, 10-20g arginine, 5-20g human serum albumin, and 100g mannitol. In aprotinin freeze-dried powder injection production process of the present invention, rginine and human serum albumin are selected to be excipients which mainly play the roles of protecting the active ingredient aprotinin; and mannitol is selected to be a freeze-drying excipient to enable the shape-forming by freeze drying. A 5% phosphoric acid solution or a 5% sodium phosphate solution is selected as a pH adjusting agent which enables the pH of a prepared liquid medicine to be maintained consistent with the pH of the liquid medicine which is redissolved after the powder is freeze dried, so that the product quality is more stable. According to the invention, an improved freeze-drying process is adopted, thus shortening the freeze-drying time and helping to improve product quality and save energy and reduce cost.
Description
Technical field
The invention belongs to field of medicaments, specifically, relate to a kind of aprotinin lyophilized injectable powder and preparation method thereof.
Background technology
Aprotinin is the broad-spectrum protease inhibitor, and it is C that plasmin etc. is all had inhibitory action, molecular formula
284H
432N
84O
79S
7, molecular weight 6511.44.Can be used for extracorporeal circulation or other operation, to reduce in the art or the postoperative oozing of blood; It is hemorrhage that fibrinolysis causes; Prevent hemorrhage; Prevent postoperative intestinal adhesion; Acute pancreatitis; Traumatic or hemorrhagic shock.Existing aprotinin lyophilized injectable powder is the aseptic freeze-dried product that aprotinin adds an amount of freeze drying protectant, is white or off-white color lyophilizing block or powder.Production technology is: medicinal liquid preparation-fill partly jumps a queue-lyophilization, tamponade-roll lid-visual inspection-packing.The problem that exists in the existing production technology comprises: (1) aprotinin is Enzyme Drugs, less stable in aqueous solution, according to existing formulation and technology aprotinin the experience whole production process after, before the deadline, product quality presents unstability, and tiring descends reaches more than 10%.(2) adopt 5%HCl solution or 5%NaOH solution as pH adjusting agent, the pH value fluctuation of redissolution medicinal liquid is larger after the pH value of the front medicinal liquid of lyophilizing and the lyophilizing.(3) freeze-drying time surpasses 22 hours in freezing dry process, and freeze-drying time is longer, and aprotinin is in that the non-drying regime time is longer, and product quality is more unstable, and energy consumption is larger, and production cost is higher.
Summary of the invention
The purpose of this invention is to provide a kind of aprotinin lyophilized injectable powder and preparation method thereof.
In order to realize the object of the invention, the described lyophilized injectable powder of a kind of aprotinin lyophilized injectable powder of the present invention composed as follows:
The preparation method of described lyophilized injectable powder may further comprise the steps:
1) mannitol with recipe quantity is dissolved in water, and adds 2 ‰ active carbons, boils, and is incubated 15 minutes after (preferred 15 minutes), and 1. filtering decarbonization gets solution;
2) arginine, the human albumin with recipe quantity mixes, and is dissolved in water, and gets solution 2.;
3) with the powdery aprotinin of recipe quantity, get solution 3. with the water dissolution below 25 ℃;
4) with solution 1., solution 2., 3. solution mix, the water that adds below 25 ℃ complements to the 10L cumulative volume, adjust pH 5～7, after the filtration sterilization, lyophilization.
The pH adjusting agent that adjust pH preferably uses in the step 4) is 5% phosphoric acid solution or 5% sodium radio-phosphate,P-32 solution.
Filter the preferred filter membrane that uses 0.22 μ m aperture in the step 4).
The lyophilization concrete operations are in the step 4):
A. pre-freeze: with in the step 4) after filtration the filtrate that obtains of degerming placing 2 hours below-35 ℃;
B. primary drying: below the vacuum 20Pa, be warming up to 6 ℃ in 1 hour, be incubated 3 hours;
C. redrying: vacuum degree control was warming up to 12 ℃ in 1 hour at 10-20Pa, was incubated 2 hours, then was warming up to 35-38 ℃ in 1 hour, was incubated 5 hours, lyophilizing 16 hours.
The invention has the advantages that:
(1) in aprotinin freeze-dried powder agent producing process of the present invention, adjuvant selects arginine and human albumin mainly to play the aprotinin of protection effective ingredient; Select mannitol to make freeze-dried excipient, lyophilizing is shaped.
(2) pH adjusting agent selects 5% phosphoric acid solution or 5% sodium radio-phosphate,P-32 solution that the medicinal liquid pH value that redissolves again after the pH value of preparating liquid and the product lyophilizing is consistent, thereby makes product quality more stable.
(3) the present invention adopts improved freeze drying process: because aprotinin easily degraded under solution state, shortening freeze-drying time can make aprotinin break away from as early as possible non-drying regime, adopt freeze-dry process of the present invention, freeze-drying time was foreshortened to 15-17 hour by about 22 hours, the stability of aprotinin further is guaranteed.Before the deadline, constant product quality, tiring descends is controlled in 5%.Simultaneously, owing to shortening freeze-drying time, reduce energy consumption and reach 20%, drop in the situation that do not increase hardware device, can improve production capacity about 20%, significantly reduced production cost.
(4) product stability is good, meets the regulation in the national drug standards.
The specific embodiment
Following examples are used for explanation the present invention, but are not used for limiting the scope of the invention.If do not specialize, the conventional means that used technological means is well known to those skilled in the art among the embodiment, the raw materials used commercial goods that is.
The preparation of embodiment 1 aprotinin lyophilized injectable powder
Specification 28 units; Lot number 081112; 10000 bottles of output.
(1) prescription: aprotinin 280,000 units; Arginine 10g; Human albumin 5g; Mannitol 100g, water for injection adds to 10000ml.
(2) preparation:
The mannitol of recipe quantity in stainless steel cask, is added the water for injection dissolving of 5000ml, add 2 ‰ active carbons, boil, be incubated after 15 minutes, 1. filtering decarbonization gets solution; Take by weighing arginine, the human albumin of recipe quantity, add 2000mL water for injection dissolve solution 2.; Precision takes by weighing the former powder of aprotinin of recipe quantity, add 1000 milliliters of cold waters for injection below 25 ℃ dissolve solution 3..With solution 1., solution 2., 3. solution slowly pour in the material-compound tank, supply volume to total amount with cold water for injection again, adjust pH 5～7(pH regulator is 5% phosphoric acid solution or 5% sodium radio-phosphate,P-32 solution), after 0.22 μ m aperture germ tight filter filters, be sub-packed in the 2ml glass tube vial by every bottle of 1ml, place freezer dryer, treat lyophilization.
(3) freeze drying process:
A. pre-freeze: at first condenser temperature is down in advance below-40 ℃, in 1 hour, the flaggy temperature is down to below-35 ℃ fast behind the product inlet, kept low temperature state 2 hours.
B. primary drying: open vacuum pump, keep being warming up to 6 ℃ in 1 hour below the vacuum 20Pa, be incubated 3 hours, carry out primary drying.
C. redrying: behind the goods primary drying, flaggy was warming up to 12 ℃ (vacuum degree control is at 10-20Pa) insulation 2 hours in 1 hour, heated up again 1 hour to 36 ℃, be incubated 5 hours (16 hours lyophilizing total times).
In the freeze-drying process, check flaggy temperature, products temperature, condenser temperature etc.
After lyophilizing finished, carry out hydraulic pressure and jump a queue, roll lid: the intermediate products that the lyophilizing tamponade is good were delivered to Cover-rolling machine, roll lid, visual inspection.
Packing: 10 bottle/boxes * 30 boxes/part.The product testing result is as shown in table 1.
081112 complete testing result of table 1 lot number
The preparation of embodiment 2 aprotinin lyophilized injectable powders
Specification 112 units; Lot number 081114; 10000 bottles of output.
(1) prescription: aprotinin 1,120,000 units; Arginine 10g; Human albumin 10g; Mannitol 100g, water for injection adds to 10000ml.
(2) preparation:
The mannitol of recipe quantity in stainless steel cask, is added the water for injection dissolving of 5000ml, add 2 ‰ active carbons, boil, be incubated after 15 minutes, 1. filtering decarbonization gets solution; Take by weighing arginine, the human albumin of recipe quantity, add 2000mL water for injection dissolve solution 2.; Precision takes by weighing the former powder of aprotinin of recipe quantity, add 1000 milliliters of cold waters for injection below 25 ℃ dissolve solution 3..With solution 1., solution 2., 3. solution slowly pour in the material-compound tank, supply volume to total amount with cold water for injection again, adjust pH 5～7(pH regulator is 5% phosphoric acid solution or 5% sodium radio-phosphate,P-32 solution), after 0.22 μ m aperture germ tight filter filters, be sub-packed in the 2ml glass tube vial by every bottle of 1ml, place freezer dryer, treat lyophilization.
(3) freeze drying process:
A. pre-freeze: at first condenser temperature is down in advance below-40 ℃, in 1 hour, the flaggy temperature is down to below-35 ℃ fast behind the product inlet, kept low temperature state 2 hours.
B. primary drying: open vacuum pump, keep being warming up to 6 ℃ in 1 hour below the vacuum 20Pa, be incubated 3 hours, carry out primary drying.
C. redrying: behind the goods primary drying, flaggy was warming up to 12 ℃ (vacuum degree control is at 10-20Pa) insulation 2 hours in 1 hour, heated up again 1 hour to 36 ℃, be incubated 5 hours (16 hours lyophilizing total times).
In the freeze-drying process, check flaggy temperature, products temperature, condenser temperature etc.
After lyophilizing finished, carry out hydraulic pressure and jump a queue, roll lid: the intermediate products that the lyophilizing tamponade is good were delivered to Cover-rolling machine, roll lid, visual inspection.
Packing: 10 bottle/boxes * 30 boxes/part.The product testing result is as shown in table 2.
081114 complete testing result of table 2 lot number
The preparation of embodiment 3 aprotinin lyophilized injectable powders
Specification 278 units; Lot number 081116; 10000 bottles of output.
(1) prescription: aprotinin 2,780,000 units; Arginine 15g; Human albumin 15g; Mannitol 100g, water for injection adds to 10000ml.
(2) preparation:
The mannitol of recipe quantity in stainless steel cask, is added the water for injection dissolving of 5000ml, add 2 ‰ active carbons, boil, be incubated after 15 minutes, 1. filtering decarbonization gets solution; Take by weighing arginine, the human albumin of recipe quantity, add 2000mL water for injection dissolve solution 2.; Precision takes by weighing the former powder of aprotinin of recipe quantity, add 1000 milliliters of cold waters for injection below 25 ℃ dissolve solution 3..With solution 1., solution 2., 3. solution slowly pour in the material-compound tank, supply volume to total amount with cold water for injection again, adjust pH 5～7(pH regulator is 5% phosphoric acid solution or 5% sodium radio-phosphate,P-32 solution), after 0.22 μ m aperture germ tight filter filters, be sub-packed in the 2ml glass tube vial by every bottle of 1ml, place freezer dryer, treat lyophilization.
(3) freeze drying process:
A. pre-freeze: at first condenser temperature is down in advance below-40 ℃, in 1 hour, the flaggy temperature is down to below-35 ℃ fast behind the product inlet, kept low temperature state 2 hours.
B. primary drying: open vacuum pump, keep being warming up to 6 ℃ in 1 hour below the vacuum 20Pa, be incubated 4 hours, carry out primary drying.
C. redrying: behind the goods primary drying, flaggy was warming up to 12 ℃ (vacuum degree control is at 10-20Pa) insulation 2 hours in 1 hour, heated up again 1 hour to 35-38 ℃, be incubated 5 hours (16 hours lyophilizing total times).
In the freeze-drying process, check flaggy temperature, products temperature, condenser temperature etc.
After lyophilizing finished, carry out hydraulic pressure and jump a queue, roll lid: the intermediate products that the lyophilizing tamponade is good were delivered to Cover-rolling machine, roll lid, visual inspection.
Packing: 10 bottle/boxes * 30 boxes/part.The product testing result is as shown in table 3.
081116 complete testing result of table 3 lot number
The preparation of embodiment 4 aprotinin lyophilized injectable powders
Specification 556 units; Lot number 081118; 10000 bottles of output.
(1) prescription: aprotinin 5,560,000 units; Arginase 12 0g; Human albumin 20g; Mannitol 100g, water for injection adds to 10000ml.
(2) preparation:
The mannitol of recipe quantity in stainless steel cask, is added the water for injection dissolving of 5000ml, add 2 ‰ active carbons, boil, be incubated after 15 minutes, 1. filtering decarbonization gets solution; Take by weighing arginine, the human albumin of recipe quantity, add 2000mL water for injection dissolve solution 2.; Precision takes by weighing the former powder of aprotinin of recipe quantity, add 1000 milliliters of cold waters for injection below 25 ℃ dissolve solution 3..With solution 1., solution 2., 3. solution slowly pour in the material-compound tank, supply volume to total amount with cold water for injection again, adjust pH 5～7(pH regulator is 5% phosphoric acid solution or 5% sodium radio-phosphate,P-32 solution), after 0.22 μ m aperture germ tight filter filters, be sub-packed in the 2ml glass tube vial by every bottle of 1ml, place freezer dryer, treat lyophilization.
(3) freeze drying process:
A. pre-freeze: at first condenser temperature is down in advance below-40 ℃, in 1 hour, the flaggy temperature is down to below-35 ℃ fast behind the product inlet, kept low temperature state 2 hours.
B. primary drying: open vacuum pump, keep being warming up to 6 ℃ in 1 hour below the vacuum 20Pa, be incubated 4 hours, carry out primary drying.
C. redrying: behind the goods primary drying, flaggy was warming up to 12 ℃ (vacuum degree control is at 10-20Pa) insulation 2 hours in 1 hour, heated up again 1 hour to 35-38 ℃, be incubated 5 hours (16 hours lyophilizing total times).
In the freeze-drying process, check flaggy temperature, products temperature, condenser temperature etc.
After lyophilizing finished, carry out hydraulic pressure and jump a queue, roll lid: the intermediate products that the lyophilizing tamponade is good were delivered to Cover-rolling machine, roll lid, visual inspection.
Packing: 10 bottle/boxes * 30 boxes/part.The product testing result is as shown in table 4.
081118 complete testing result of table 4 lot number
The study on the stability of embodiment 5 aprotinin lyophilized injectable powders
Respectively to four batch samples that prepare among the embodiment 1-4 line stabilization accelerated test of going forward side by side, as shown in Table 5 after 6 months accelerated tests, character, acidity, content uniformity, moisture, five indexs of investigating project of tiring are without significant change, all meet the regulation in the national drug standards of Aprotinin.The result shows the new production technology Aprotinin stability of employing better.
Table 5 Accelerated stability test result
Stable content analysis: detect the sample that keeps sample behind six months Accelerated stability tests, indices all meets the national drug standards, the 6th the end of month sample changes of contents be respectively 4.31%, 4.24%, 4.41%, 4.35%, average out to (4.33 ± 0.07) %, RSD=1.62 has further verified the reliability of manufacturing condition.
Although above the present invention is described in detail with a general description of the specific embodiments, on basis of the present invention, can make some modifications or improvements it, this will be apparent to those skilled in the art.Therefore, these modifications or improvements all belong to the scope of protection of present invention without departing from theon the basis of the spirit of the present invention.
Claims (5)
1. an aprotinin lyophilized injectable powder is characterized in that, described lyophilized injectable powder composed as follows:
2. the preparation method of the described lyophilized injectable powder of claim 1 is characterized in that, may further comprise the steps:
1) mannitol with recipe quantity is dissolved in water, and adds 2 ‰ active carbons, boils, and is incubated after 15 minutes, and 1. filtering decarbonization gets solution;
2) arginine, the human albumin with recipe quantity mixes, and is dissolved in water, and gets solution 2.;
3) with the powdery aprotinin of recipe quantity, get solution 3. with the water dissolution below 25 ℃;
4) with solution 1., solution 2., 3. solution mix, the water that adds below 25 ℃ complements to the 10L cumulative volume, adjust pH 5～7, after the filtration sterilization, lyophilization.
3. preparation method according to claim 2 is characterized in that, the pH adjusting agent that adjust pH uses in the step 4) is 5% phosphoric acid solution or 5% sodium radio-phosphate,P-32 solution.
4. preparation method according to claim 2 is characterized in that, filters the filter membrane that uses 0.22 μ m aperture in the step 4).
5. preparation method according to claim 2 is characterized in that, the lyophilization concrete operations are in the step 4):
A. pre-freeze: with in the step 4) after filtration the filtrate that obtains of degerming placing 2 hours below-35 ℃;
B. primary drying: below the vacuum 20Pa, be warming up to 6 ℃ in 1 hour, be incubated 3 hours;
C. redrying: vacuum degree control was warming up to 12 ℃ in 1 hour at 10-20Pa, was incubated 2 hours, then was warming up to 35-38 ℃ in 1 hour, was incubated 5 hours, lyophilizing 16 hours.
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| CN 201210578632 CN103054816A (en) | 2012-12-27 | 2012-12-27 | Aprotinin freeze-dried powder and preparation method thereof |
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| CN 201210578632 CN103054816A (en) | 2012-12-27 | 2012-12-27 | Aprotinin freeze-dried powder and preparation method thereof |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11604026B2 (en) | 2019-03-14 | 2023-03-14 | Terumo Bct Biotechnologies, Llc | Lyophilization loading tray assembly and system |
| US11634257B2 (en) | 2017-10-09 | 2023-04-25 | Terumo Bct Biotechnologies, Llc | Lyophilization container and method of using same |
-
2012
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11634257B2 (en) | 2017-10-09 | 2023-04-25 | Terumo Bct Biotechnologies, Llc | Lyophilization container and method of using same |
| US11604026B2 (en) | 2019-03-14 | 2023-03-14 | Terumo Bct Biotechnologies, Llc | Lyophilization loading tray assembly and system |
| US11609043B2 (en) | 2019-03-14 | 2023-03-21 | Terumo Bct Biotechnologies, Llc | Lyophilization container fill fixture, system and method of use |
| US11609042B2 (en) | 2019-03-14 | 2023-03-21 | Terumo Bct Biotechnologies, Llc | Multi-part lyophilization container and method of use |
| US11740019B2 (en) | 2019-03-14 | 2023-08-29 | Terumo Bct Biotechnologies, Llc | Lyophilization loading tray assembly and system |
| US11747082B2 (en) | 2019-03-14 | 2023-09-05 | Terumo Bct Biotechnologies, Llc | Multi-part lyophilization container and method of use |
| US11815311B2 (en) | 2019-03-14 | 2023-11-14 | Terumo Bct Biotechnologies, Llc | Lyophilization container fill fixture, system and method of use |
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Application publication date: 20130424 |