CN101693015B - Coenzyme A medicament freeze-drying preparation and process for preparing same - Google Patents
Coenzyme A medicament freeze-drying preparation and process for preparing same Download PDFInfo
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- CN101693015B CN101693015B CN2009102100573A CN200910210057A CN101693015B CN 101693015 B CN101693015 B CN 101693015B CN 2009102100573 A CN2009102100573 A CN 2009102100573A CN 200910210057 A CN200910210057 A CN 200910210057A CN 101693015 B CN101693015 B CN 101693015B
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Abstract
The invention discloses a coenzyme A medicament freeze-drying preparation, which adopts disodium hydrogen phosphate and sodium dishydrogen phosphate buffered salt liquor to protect a coenzyme A in the process of preparing the freeze-drying preparation. The freeze-drying preparation selects phosphate buffered salt liquor in the process of preparing medical liquor to enable the coenzyme A to be in the liquor with relatively constant pH values. Simultaneously, the phosphate buffered salt liquor is favorable for stabilizing a coenzyme A molecular structure containing phosphate groups, a coenzyme A potency (marked content) is lowered by no more than 2.5% from the process of preparing and filling to the beginning of freeze-drying.
Description
Technical field
The present invention relates to medical technical field, particularly relate to a kind of coenzyme A medicament freeze-drying preparation and preparation method thereof.
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) 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 and a kind ofly be not easy degraded, tire that it is less to reduce, coenzyme A medicament freeze-drying preparation of constant product quality and preparation method thereof.
A kind of coenzyme A medicament freeze-drying preparation adopts phosphate buffered saline(PBS) to protect coenzyme A in preparation lyophilized formulations process.The present invention selects phosphate buffered saline(PBS) for use at the medicinal liquid process for preparation, coenzyme A is in the solution of relative constant pH, simultaneously phosphate-buffered salt helps containing coenzyme A molecular structure stable of phosphate group, through preparation, be filled to lyophilizing when beginning, coenzyme A tire (sign content) descend and be no more than 2.5%.
Coenzyme A medicament freeze-drying preparation of the present invention, the supplementary material that is used to prepare it is preferably: coenzyme A; Mannitol; Calcium gluconate; Cysteine hydrochloride; Phosphate-buffered salt; Water for injection.Concrete consumption can be 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 coenzyme A medicament freeze-drying preparation in mannitol, calcium gluconate, the cysteine hydrochloride adding water for injection, is stirred to dissolving fully, adds active carbon and stirs 15-30 minute, and 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, after the aseptic filtration, fill, lyophilizing.
Above-mentioned preparation method, wherein activated carbon dosage is the 0.2-0.3% of preparation total amount volume.
Coenzyme A medicament freeze-drying preparation provided by the invention, the medicinal liquid process for preparation is selected phosphate buffered saline(PBS) for use, coenzyme A is in the solution of relative constant pH, simultaneously phosphate-buffered salt helps containing coenzyme A molecular structure stable of phosphate group, through preparation, be filled to lyophilizing when beginning, coenzyme A tire (sign content) descend and be no more than 2.5%.Liquid formula of the present invention 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.The concrete outcome of the variation of pH value, sign content can see the following form when coenzyme A medicament freeze-drying preparation of the present invention began through preparing, be filled to lyophilizing:
| The sample lot number | The preparating liquid pH value | Lyophilizing begins preceding pH value | The border that feeds intake shows content (%) | Content (%) before the lyophilizing |
| 1 | 5.26 | 5.22 | 100 | 97.82 |
| 2 | 5.28 | 5.25 | 100 | 98.22 |
| 3 | 5.22 | 5.26 | 100 | 98.68 |
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, 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 1
Complete testing result of table 1
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 2, 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 2
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.
Embodiment 2: except that supplementary material consumption difference, all the other are all with embodiment 1.
Supplementary material: coenzyme A 1,100,000 units; Mannitol 600g; Cysteine hydrochloride 20g; Calcium gluconate 20g; Phosphate-buffered salt 60g; Add the injection water to 10000mL.
Embodiment 3: except that supplementary material consumption difference, all the other are all with embodiment 1.
Supplementary material: coenzyme A 900,000 units; Mannitol 200g; Cysteine hydrochloride 10g; Calcium gluconate 5g; Phosphate-buffered salt 10g; Add the injection water to 10000mL.
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 (1)
1. the preparation method of a coenzyme A medicament freeze-drying preparation is characterized in that, mannitol, calcium gluconate, cysteine hydrochloride add in the water for injection, is stirred to dissolving fully, adds charcoal treatment, and 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, after the aseptic filtration, fill, lyophilizing;
Wherein, each raw material consumption 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; Activated carbon dosage is the 0.2-0.3% of preparation total amount volume.
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| CN2009102100573A CN101693015B (en) | 2009-11-04 | 2009-11-04 | Coenzyme A medicament freeze-drying preparation and process for preparing same |
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| CN2009102100573A CN101693015B (en) | 2009-11-04 | 2009-11-04 | Coenzyme A medicament freeze-drying preparation and process for preparing same |
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| CN101693015A CN101693015A (en) | 2010-04-14 |
| CN101693015B true CN101693015B (en) | 2011-12-28 |
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Owner name: MAANSHAN FENGYUAN PHARMACEUTICAL CO., LTD. Free format text: FORMER OWNER: ANHUI BBCA PHARMACEUTICAL CO., LTD. Effective date: 20111013 |
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Free format text: CORRECT: ADDRESS; FROM: 233010 BENGBU, ANHUI PROVINCE TO: 243000 MAANSHAN, ANHUI PROVINCE |
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Effective date of registration: 20111013 Address after: 243000 No. 1503, Mei Shan Road, Ma'anshan economic and Technological Development Zone, Anhui Applicant after: Maanshan Fengyuan Pharmaceutical Co.,Ltd. Address before: 233010 No. 2001 Tu Shan Road, Anhui, Bengbu Applicant before: Anhui BBCA Pharmaceutical Co., Ltd. |
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