CN101693014A - Process for preparing coenzyme A medicament freeze drying preparation - Google Patents
Process for preparing coenzyme A medicament freeze drying preparation Download PDFInfo
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- CN101693014A CN101693014A CN200910210056A CN200910210056A CN101693014A CN 101693014 A CN101693014 A CN 101693014A CN 200910210056 A CN200910210056 A CN 200910210056A CN 200910210056 A CN200910210056 A CN 200910210056A CN 101693014 A CN101693014 A CN 101693014A
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Abstract
The invention discloses a process for preparing a coenzyme A medicament freeze drying preparation, which comprises steps of preparing medical liquor, removing bacteria, filtering, filling and freeze drying, wherein the freeze drying step includes pre-freezing, primary drying and secondary drying. The invention shortens freezing time from more than 20 hours to hours between 13 and 16, reduces 20%-35% of energy consumption, simultaneously improves 20%-35% of production capacity under the circumstance of no increase of hardware investment owing to shortened freeze drying time, thereby saving energy, increasing production and greatly lowering production cost.
Description
Technical field
The present invention relates to medical technical field, particularly relate to a kind of preparation method of coenzyme A medicament freeze-drying preparation.
Background technology
Coenzyme A is a nucleoside acids coenzyme, forms molecular formula by pantothenic acid, gland glycoside, phosphoric acid and aminoothyl mercaptan: C
21H
36N
7O
16P
3S; Molecular weight: 767.54.Molecular structure is formula as follows:
It is the coenzyme of acetylase in the body, plays a part to transmit acetyl group, and the metabolism to sugar, protein and lipid in human physiological metabolism's process tricarboxylic acid cycle (tricarboxylic acid cycle) has played important function.The 1950's, its chemical constitution was illustrated, and introduce clinic study by preclinical medicine the sixties, and the seventies begins to be used for clinical, and safety is extensively verified.
Injection coenzyme A (Coenzyme A for injection): be the aseptic freeze-dried product that CoA adds proper excipient, be the lyophilizing bulk or the powder of white or off-white color.The clinical auxiliary treatment that is used for leukopenia, idiopathic thrombocytopenic purpura and functional low grade fever.
Coenzyme A is unstable in aqueous solution, its lyophilized formulations commonly used clinically, and the production procedure of lyophilized formulations is: lid-visual inspection-packing is rolled in medicinal liquid preparation-fill false add plug-lyophilization-tamponade.Existing manufacturing technique roughly has following several:
One, forms: coenzyme A; Mannitol; Lactose; Cysteine hydrochloride.Production technology operating process: will claim fixed mannitol, lactose, cysteine hydrochloride to add in an amount of water for injection, and be stirred to dissolving fully, and add the medicinal charcoal of dose volume 0.3%, and boil 30min.After taking off the charcoal processing after filtration, add the water for injection of dose volume 50%, coenzyme A is dissolved wherein fully, adjust pH 4.0～5.0, benefit adds to the full amount of water for injection, and is filtered to basin through germ tight filter, after the inspection of semifinished product is qualified, fill, lyophilizing, roll lid, lamp inspection.
Two, form: coenzyme A; Dextran; Mannitol; Calcium gluconate; Sodium sulfite.Production technology operating process: will claim fixed dextran, mannitol, calcium gluconate and sodium sulfite to add in an amount of water for injection, be stirred to dissolving fully, again coenzyme A added preparing tank, be stirred to dissolving fully, adjust pH 4.3～4.5, benefit adds to the full amount of water for injection.Add the medicinal charcoal of dose volume 0.3%, leave standstill 30min.Take off charcoal, germ tight filter through the titanium rod and filter, after the inspection of semifinished product is qualified, fill, lyophilizing, roll lid, lamp inspection.
Three, form: coenzyme A; Dextran; Mannitol; Calcium gluconate; Sodium sulfite.Production technology operating process: will claim fixed dextran, mannitol, calcium gluconate and sodium sulfite to add in an amount of water for injection, and be stirred to dissolving fully, and add the medicinal charcoal of dose volume 0.3%, and boil 30min.After the titanium rod takes off the charcoal processing, the water for injection that adds dose volume 80%, coenzyme A is dissolved wherein fully, adjust pH 4.3～4.5, benefit adds to the full amount of water for injection, and to basin, tank bottom connects Hollow Fiber Ultrafiltration equipment through the degerming filter element filtering, after the inspection of semifinished product is qualified, fill, lyophilizing, roll lid, lamp inspection.
Four, form: coenzyme A; Dextran; Mannitol; Calcium gluconate; Cysteine hydrochloride.Production technology operating process: will claim fixed mannitol, calcium gluconate, cysteine hydrochloride to add in an amount of water for injection, and be stirred to dissolving fully, and add the medicinal charcoal of dose volume 0.3%, and boil 30min.After taking off the charcoal processing after filtration, add the water for injection of dose volume about 50%, again coenzyme A is dissolved wherein fully, benefit adds to the full amount of water for injection, and control and adjust pH 4.2-4.6 are filtered to basin through germ tight filter, intermediate products fill, lyophilizing, roll lid, lamp inspection after the assay was approved.
Above-mentioned operational process of craft, coenzyme A lyophilized formulations in process of production owing to will be mixed with aqueous solution earlier, process fill false add plug is before lyophilization finishes again, coenzyme A is in non-drying regime always, the reduction of degrading easily, tire, and unstable product quality:
(1) prepare, be filled to before lyophilizing begins: find by study on the stability: coenzyme A in preparation, be filled in the aqueous solution before lyophilizing begins degradation speed and be 0.7%-0.8% per hour; And (pH value＞7.0) degraded is faster in meta-acid or meta-alkalescence solution, and degradation speed per hour can reach more than 0.8%, coenzyme A through preparation, be filled to lyophilizing when beginning, coenzyme A (sign content) the decline 5.0%-8.0% that tires.
(2) in freezing dry process: coenzyme A still is in non-drying regime, coenzyme A tire (sign content) still unstable, continue degraded, the freeze-drying process time is long more, the decline of tiring of coenzyme A is obvious more, and injection coenzyme A sublimation drying is generally more than 20 hours, behind the experience freezing dry process at present, coenzyme A is tired and is generally descended more than 5.0%, so improve freeze-dry process, shorten freeze-drying time and help improving the quality of products.
(3) variation of pH value is to the influence of injection coenzyme A: present production technology, the injection coenzyme A finishes through preparing, be filled to lyophilizing, arrive clinical use again when redissolving, pH value changes greatly, often at the qualified product of when preparation pH value, when the experience lyophilizing was redissolved again, the variation of pH value was bigger, reach ± 0.8, easily exceed the internal control scope.
According to existing production technology, through a production cycle, tire (sign content) general specific inventory of coenzyme A reduces 10-13% in the injection coenzyme A, so during batching, inventory is generally 110-113%, the degraded of coenzyme A, must increase other relative substance, influence product quality; Owing to the increase of inventory, production cost increases more than 10% simultaneously.
Summary of the invention
The purpose of this invention is to provide a kind of preparation method of having improved the coenzyme A medicament freeze-drying preparation of freeze drying process condition, by foreshortening to 13-16 hour more than 20 hours, 20%-35% cuts down the consumption of energy with freeze-drying time for it; Owing to shorten freeze-drying time, under the situation that does not increase the hardware input, improved production production capacity 20%-35% simultaneously, energy-saving and production-increase has reduced production cost.
A kind of preparation method of coenzyme A medicament freeze-drying preparation comprises preparating liquid, aseptic filtration, fill and step of freeze drying, and wherein step of freeze drying is:
(1) pre-freeze: at first condenser temperature is reduced in advance below-40 ℃, in 0.5-1 hour, the flaggy temperature is reduced to below-30 ℃ behind the product inlet, kept low temperature state 2 hours;
(2) primary drying: open vacuum pump, keep being warming up to 5 ℃ in 0.5 hour below the vacuum 20Pa, be incubated 2.5-3 hour, carry out primary drying;
(3) redrying: behind the goods primary drying, flaggy was warming up to 15 ℃ in 0.5 hour, vacuum degree control is incubated 1.5-2 hour at 10-20Pa, is warming up to 35 ℃ in 0.5-1 hour, is incubated 5-6 hour.
Preparation method of the present invention is applicable to the coenzyme A medicament freeze-drying preparation of known various prescriptions.More preferably be used for following prescription: the supplementary material of medicinal liquid is: coenzyme A; Mannitol; Calcium gluconate; Cysteine hydrochloride; Phosphate-buffered salt; And water for injection.Concrete consumption is preferably: coenzyme A: 90.0-110.0 unit/mL; Mannitol: 10-60mg/mL; Calcium gluconate: 0.5-2.0mg/mL; Cysteine hydrochloride: 0.5-2.0mg/mL; Phosphate-buffered salt: 1.0-6.0mg/mL; Supply total amount with water for injection.The phosphate-buffered salt that the present invention adopts is commercially available pharmaceutical grade phosphate-buffered salt, and wherein the weight ratio of sodium hydrogen phosphate and sodium dihydrogen phosphate is 1: 6.Medicinal liquid pH value after the preparation also can adopt diluted acid or diluted alkaline to regulate generally at pH5.2-5.8.
The preparation method of above-mentioned optimization formula may further comprise the steps:
(1) preparation of medicinal liquid: in mannitol, calcium gluconate, the cysteine hydrochloride adding water for injection, be stirred to dissolving fully, add active carbon and stirred 15-30 minute, filtering decarbonization is handled then, gets solution 1.; Phosphate-buffered salt adds in the water for injection, is stirred to dissolving fully, coenzyme A is dissolved wherein fully again, gets solution 2.; Merge solution 1., solution 2., amalgamation liquid is added water for injection to total amount, control and adjust pH 5.2-5.8;
(2) aseptic filtration: through filter, fill after the pressurization filter pressing;
(3) lyophilization:
A. pre-freeze: at first condenser temperature is reduced in advance below-40 ℃, in 0.5-1 hour, the flaggy temperature is reduced to below-30 ℃ behind the product inlet, kept low temperature state 2 hours;
B. primary drying: open vacuum pump, keep being warming up to 5 ℃ in 0.5 hour below the vacuum 20Pa, be incubated 2.5-3 hour, carry out primary drying;
C. redrying: behind the goods primary drying, flaggy was warming up to 15 ℃ in 0.5 hour, vacuum degree control is incubated 1.5-2 hour at 10-20Pa, is warming up to 35 ℃ in 0.5-1 hour, is incubated 5-6 hour; Lyophilizing is carried out hydraulic pressure and is jumped a queue after finishing.
Preparation method provided by the invention has been improved freeze drying process, and shorten freeze-drying time and can make coenzyme A break away from non-drying regime as early as possible, the freeze-dry process that the present invention adopts, by foreshortening to 13-16 hour more than 20 hours, 20%-35% cuts down the consumption of energy with freeze-drying time; Owing to shorten freeze-drying time, under the situation that does not increase the hardware input, improved production production capacity 20%-35% simultaneously, energy-saving and production-increase has reduced production cost.
Preparation method of the present invention is in conjunction with preferred liquid formula owing to contain phosphate-buffered salt, after the lyophilizing product redissolve the variation of pH value be no more than ± 0.3, thereby the stability of coenzyme A further is guaranteed.Through the whole freezing dry run, the coenzyme A degraded is no more than 1.5%.The results are shown in following table:
The variation of injection coenzyme A pH value, sign content before and after lyophilizing
| The sample lot number | The preparating liquid pH value | Lyophilizing begins preceding pH value | Redissolution pH value after the lyophilizing | Feed intake and indicate content (%) | Content (%) before the lyophilizing | Finished product redissolution content (%) | Loss on drying (%) |
| ??1 | ??5.26 | ??5.22 | ??5.50 | ??100 | ??97.82 | ??96.28 | ??1.0 |
| ??2 | ??5.28 | ??5.25 | ??5.44 | ??100 | ??98.22 | ??97.36 | ??1.1 |
| ??3 | ??5.22 | ??5.26 | ??5.46 | ??100 | ??98.68 | ??97.52 | ??1.1 |
The specific embodiment
Below in conjunction with embodiment, the specific embodiment of the present invention is described in further detail.Following examples are used to illustrate the present invention, but are not used for limiting the scope of the invention.
Embodiment 1:
One, supplementary material: coenzyme A 1,000,000 units; Mannitol 100g; Cysteine hydrochloride 5g; Calcium gluconate 10g; Phosphate-buffered salt 20g; Add the injection water to 10000mL
Two, preparation process:
1. the preparation of medicinal liquid
1.1 treatment with mannitol: take by weighing mannitol, in stainless steel cask, add 2000mL water for injection dissolve solution 1..
1.2 cysteine hydrochloride, calcium gluconate are handled: take by weighing cysteine hydrochloride in beaker, add water for injection 1000mL dissolve solution 2.; Take by weighing calcium gluconate in beaker, add injection water 500mL, boil dissolve solution 3..
1.3 merge solution 1., solution 2., solution 3., add 0.2% (percent weight in volume) active carbon and stirred 20 minutes, filtering decarbonization is handled then, filtrate 4.
1.4 raw material is handled: take by weighing phosphate-buffered salt, add 2000 milliliters of waters for injection, dissolving, precision takes by weighing in the former powder adding of the coenzyme A phosphate buffered saline(PBS) and dissolves again, gets solution 5..
1.5 with filtrate 4., 5. solution successively slowly pour in the material-compound tank, reuse water for injection is supplied volume to total amount, stirs evenly.
1.6 adjusting pH value: survey the original liquid pH value earlier, as exceed the internal control scope, then regulate pH value to internal control scope (pH5.2-5.8) with the pH regulator agent.The pH regulator agent is the HCl solution of 5%NaOH solution or 5%.
1.7 filter: medicinal liquid is through coarse filter (aperture 0.45 μ m), fine filter (aperture 0.22 μ m), and is to the fill non-conservation tank, to be filled by the nitrogen pressure filter pressing.
2. fill: check feed liquid clarity, color and luster, carry out fill after qualified, the 2mL cillin bottle (loading amount 1mL) of packing into, the intermediate products that install are sent into and are treated lyophilizing in the freeze drying box.
3. lyophilization (13-16 hour lyophilizing total time)
3.1 pre-freeze: at first condenser temperature is reduced in advance below-40 ℃, in 0.5-1 hour, the flaggy temperature is reduced to below-30 ℃ fast behind the product inlet, kept low temperature state 2 hours.
3.2 primary drying: open vacuum pump, keep being warming up to 5 ℃ in 0.5 hour below the vacuum 20Pa, be incubated 2.5-3 hour, carry out primary drying.
3.3 redrying: behind the goods primary drying, 0.5 hour with flaggy be warming up to 15 ℃ (vacuum degree control is at 10-20Pa) insulation 1.5-2 hour, be warming up to 35 ℃ in 0.5-1 hour, be incubated 5-6 hour.
Concrete parameter sees the following form 1.
Table 1 product parameters of freeze-drying process
| Time (h) | Condenser temperature (℃) | Products temperature (℃) | The flaggy temperature (℃) | Vacuum (Pa) |
| ??0 | ??-40 | ??25 | ??25 | |
| ??2 | ??-50 | ??-25 | ??-39 | |
| ??3 | ??-58 | ??-30 | ??-40 | ??14 |
| Time (h) | Condenser temperature (℃) | Products temperature (℃) | The flaggy temperature (℃) | Vacuum (Pa) |
| ??4 | ??-57 | ??-25 | ??3 | ??17 |
| ??5 | ??-57 | ??-20 | ??5 | ??17 |
| ??6 | ??-57 | ??-15 | ??5 | ??17 |
| ??8 | ??-55 | ??-5 | ??15 | ??18 |
| ??10 | ??-60 | ??15 | ??30 | ??13 |
| ??12 | ??-58 | ??25 | ??35 | ??12 |
| ??14 | ??-58 | ??30 | ??35 | ??9 |
3.4 in the freeze-drying process, check flaggy temperature, products temperature, condenser temperature etc., lyophilizing is carried out hydraulic pressure and is jumped a queue after finishing.
4. roll lid, visual inspection
5. pack: 100 units: 10 bottle/boxes * 200 boxes/part.
6. complete of product detects, and the results are shown in Table 2
Complete testing result of table 2
Three, study on the stability
1, stable accelerated test
The coenzyme A lyophilized formulations of making put in 40 ± 2 ℃ the calorstat, respectively at checking character, pH value, moisture, clarity, six investigation projects of content in 0,1,3,6 month.
After 6 months accelerated tests, character, pH value, moisture, clarity, six indexs of investigating project of content do not have significant change as shown in Table 3, all meet the regulation in the national drug standards of injection coenzyme A.The result shows the new production technology injection coenzyme A lyophilized formulations stability of employing better.
The stable accelerated test result of table 3
2, stable content analysis
Detect the sample that keeps sample after six months stable accelerated tests, every index all meets the national drug standards, the 6th the end of month sample changes of contents be respectively 1.48%, 1.52%, 1.46%, average out to (1.49 ± 0.03) %, RSD=2.01.Further verified the reliability of preparation method.
The above only is a preferred implementation of the present invention; should be pointed out that for those skilled in the art, under the prerequisite that does not break away from the technology of the present invention principle; can also make some improvements and modifications, these improvements and modifications also should be considered as protection scope of the present invention.
Claims (4)
1. the preparation method of a coenzyme A medicament freeze-drying preparation comprises preparating liquid, aseptic filtration, fill and step of freeze drying, it is characterized in that, wherein step of freeze drying is:
(1) pre-freeze: at first condenser temperature is reduced in advance below-40 ℃, in 0.5-1 hour, the flaggy temperature is reduced to below-30 ℃ behind the product inlet, kept low temperature state 2 hours;
(2) primary drying: open vacuum pump, keep being warming up to 5 ℃ in 0.5 hour below the vacuum 20Pa, be incubated 2.5-3 hour, carry out primary drying;
(3) redrying: behind the goods primary drying, flaggy was warming up to 15 ℃ in 0.5 hour, vacuum degree control is incubated 1.5-2 hour at 10-20Pa, is warming up to 35 ℃ in 0.5-1 hour, is incubated 5-6 hour.
2. preparation method as claimed in claim 1 is characterized in that the supplementary material of described medicinal liquid is: coenzyme A; Mannitol; Calcium gluconate; Cysteine hydrochloride; Sodium hydrogen phosphate and sodium dihydrogen phosphate buffer salt; Water for injection.
3. preparation method as claimed in claim 2 is characterized in that, the supplementary material of described medicinal liquid is: coenzyme A: 90.0-110.0 unit/mL; Mannitol: 10-60mg/mL; Calcium gluconate: 0.5-2.0mg/mL; Cysteine hydrochloride: 0.5-2.0mg/mL; Phosphate-buffered salt: 1.0-6.0mg/mL; Supply total amount with water for injection.
4. as claim 2 or 3 described preparation methoies, it is characterized in that, may further comprise the steps:
(1) preparation of medicinal liquid: in mannitol, calcium gluconate, the cysteine hydrochloride adding water for injection, be stirred to dissolving fully, add active carbon and stirred 15-30 minute, filtering decarbonization is handled then, gets solution 1.; Phosphate-buffered salt adds in the water for injection, is stirred to dissolving fully, coenzyme A is dissolved wherein fully again, gets solution 2.; Merge solution 1., solution 2., amalgamation liquid is added water for injection to total amount, control and adjust pH 5.2-5.8;
(2) aseptic filtration: through filter, fill after the pressurization filter pressing;
(3) lyophilization:
A. pre-freeze: at first condenser temperature is reduced in advance below-40 ℃, in 0.5-1 hour, the flaggy temperature is reduced to below-30 ℃ behind the product inlet, kept low temperature state 2 hours;
B. primary drying: open vacuum pump, keep being warming up to 5 ℃ in 0.5 hour below the vacuum 20Pa, be incubated 2.5-3 hour, carry out primary drying;
C. redrying: behind the goods primary drying, flaggy was warming up to 15 ℃ in 0.5 hour, vacuum degree control is incubated 1.5-2 hour at 10-20Pa, is warming up to 35 ℃ in 0.5-1 hour, is incubated 5-6 hour; Lyophilizing is carried out hydraulic pressure and is jumped a queue after finishing.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102397259A (en) * | 2011-09-28 | 2012-04-04 | 河南辅仁怀庆堂制药有限公司 | Coenzyme A for injection and production process thereof |
| CN103341155A (en) * | 2013-07-17 | 2013-10-09 | 北京双鹭药业股份有限公司 | Stable compound coenzyme preparation and preparation method as well as application thereof |
| CN104623626A (en) * | 2013-07-17 | 2015-05-20 | 北京双鹭药业股份有限公司 | Stable compound coenzyme preparation as well as preparation method and applications thereof |
| CN104644569A (en) * | 2013-11-25 | 2015-05-27 | 蚌埠丰原涂山制药有限公司 | Tiopronin freeze-dried powder injection and preparation method thereof |
| CN105055344A (en) * | 2015-08-31 | 2015-11-18 | 济南维尔康生化制药有限公司 | Coenzyme A freeze drying agent and preparation method thereof |
Family Cites Families (4)
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| GB9606187D0 (en) * | 1996-03-23 | 1996-05-29 | Inst Of Food Research | Production of vanillin |
| CN1092986C (en) * | 1999-08-16 | 2002-10-23 | 上海本草生物医学工程研究所 | CoA oral preparation for reducing blood fat and its preparation method |
| CN1676133A (en) * | 2004-06-15 | 2005-10-05 | 天津市铭泰医药科技有限公司 | Doxufylline for injection and its preparing method |
| CN1331476C (en) * | 2005-07-05 | 2007-08-15 | 凌沛学 | Method for preparing coenzyme-A sublingual lozenge |
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| CN102397259A (en) * | 2011-09-28 | 2012-04-04 | 河南辅仁怀庆堂制药有限公司 | Coenzyme A for injection and production process thereof |
| CN103341155A (en) * | 2013-07-17 | 2013-10-09 | 北京双鹭药业股份有限公司 | Stable compound coenzyme preparation and preparation method as well as application thereof |
| CN103341155B (en) * | 2013-07-17 | 2015-03-11 | 北京双鹭药业股份有限公司 | Stable compound coenzyme preparation and preparation method as well as application thereof |
| CN104623626A (en) * | 2013-07-17 | 2015-05-20 | 北京双鹭药业股份有限公司 | Stable compound coenzyme preparation as well as preparation method and applications thereof |
| CN104644569A (en) * | 2013-11-25 | 2015-05-27 | 蚌埠丰原涂山制药有限公司 | Tiopronin freeze-dried powder injection and preparation method thereof |
| CN104644569B (en) * | 2013-11-25 | 2018-01-02 | 马鞍山丰原制药有限公司 | A kind of tiopronin freeze-dried powder injection and preparation method thereof |
| CN105055344A (en) * | 2015-08-31 | 2015-11-18 | 济南维尔康生化制药有限公司 | Coenzyme A freeze drying agent and preparation method thereof |
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