CN102038939B - Preparation method of adenosine triphosphate coenzyme insulin freeze-dried powder injection - Google Patents
Preparation method of adenosine triphosphate coenzyme insulin freeze-dried powder injection Download PDFInfo
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- CN102038939B CN102038939B CN 200910075772 CN200910075772A CN102038939B CN 102038939 B CN102038939 B CN 102038939B CN 200910075772 CN200910075772 CN 200910075772 CN 200910075772 A CN200910075772 A CN 200910075772A CN 102038939 B CN102038939 B CN 102038939B
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Abstract
The invention discloses a preparation method of an adenosine triphosphate coenzyme insulin freeze-dried powder injection, comprising the following steps of: adjusting injection water with diluted hydrochloric acid until the pH value is 2.5-3.5, adding insulin and uniformly mixing to obtain a solution I; adding L-arginine and disodium ethylene diamine tetraacetate in the injection water, uniformly stirring, adding carbon and stirring; after removing carbon, adding adenosine disodium triphosphate and uniformly stirring to obtain a solution II; adding calcium gluconate, low molecular weight dextran and cysteine hydrochloride in the injection water, adding carbon and removing the carbon and uniformly stirring to obtain a solution III; mixing three solutions, uniformly stirring, adjusting the pH value to be 5.7-6.2 with a 2-4 percent NaOH solution, adding coenzyme A and supplementing the balance of injection water; and sterilizing, measuring the content, subpackaging and freezing dry. The adenosine triphosphate coenzyme insulin freeze-dried powder injection prepared by the method has the advantages of favorable redissolution, clearness and quality stability of products and is saturated in appearance.
Description
Technical field:
The present invention relates to the method for preparing of medicine, specifically to the method for preparing of the ATP coenzyme insulin lyophilized injectable powder of saying so.
Background technology
ATP coenzyme insulin lyophilized injectable powder is by adenosine triphosphate disodium salt, and coenzyme A and insulin are the aseptic freeze-dried injectable powder that principal agent is processed.Adenosine triphosphate disodium salt in the medicine has the organism metabolism of improvement, participates in the generation of body fat protein, sugar, nucleic acid and nucleotide.The effect of thanking is again the source of energy i (in vivo) simultaneously.Coenzyme A is the coenzyme of internal metabolism acetyl reaction, and sugar, fat and proteinic metabolism are played an important role.The accumulating of synthetic, the hepatic glycogen of acetylcholine, the reduction of cholesterol amount and the adjusting of lipids contents all have substantial connection in itself and the body.Islets of langerhans have blood sugar lowering, suppresses glycogenolysis and gluconeogenesis, impels muscle and fatty tissue ingestion of glucose and aminoacid, impels effects such as VLDL decomposition.This medicine principal agent is used for the doing well,improving of diseases such as hepatitis, nephritis, liver cirrhosis, heart failure.
When preparing ATP coenzyme insulin lyophilized injectable powder at present, to add usually than strong dose and improve its dissolubility and the quality of product with adjuvant.Yet amount of excipient is too much, is not only the cost that increases product, and main is in product, to introduce unnecessary impurity, and then influences patient's drug safety.In addition, adopt traditional freeze-dry process to prepare ATP coenzyme insulin lyophilized injectable powder, its outward appearance subsides, it is poor to freeze type, and freeze-drying time is long, redissolve and clarity wayward, product stability is poor.
Summary of the invention
The object of the invention just provides a kind of new method for preparing ATP coenzyme insulin lyophilized injectable powder, to overcome the weak point of prior art.
The objective of the invention is to realize like this:
The method for preparing of ATP coenzyme insulin dry powder injection provided by the present invention may further comprise the steps:
(a) technical recipe: every injection contains
Adenosine triphosphate disodium salt 20mg
Coenzyme A 50 units
Insulin 4 units
L-arginine 6mg
Disodiumedetate 0.36mg
Low molecular dextran 5mg
Calcium gluconate 1mg
Cysteine hydrochloride 0.5mg
Water for injection 0.5ml;
(b) water for injection is transferred to pH value 2.5～3.5 with dilute hydrochloric acid, add insulin, stir, be prepared into solution I, subsequent use;
(c) in proper amount of water for injection, add L-arginine, disodiumedetate, stir, add 1～2% active carbon and stirred 20～30 minutes, remove active carbon after, add adenosine triphosphate disodium salt, stir, be prepared into solution II, subsequent use;
(d) add calcium gluconate, low molecular dextran, cysteine hydrochloride in an amount of water for injection, add 2% (g/ml) active carbon and stirred 30 minutes, remove active carbon after, stir, be prepared into solution III, subsequent use;
(e) above-mentioned three kinds of solution are mixed, stir, transfer pH value to 5.7～6.2, add coenzyme A, supply the water for injection of surplus with 2～4%NaOH solution; Sterilization is measured content, packing, lyophilizing; Freeze-dry process is:
Pre-freeze: the medicine that branch is installed places on the freeze drying box dividing plate, makes goods be chilled to-40 ℃, is incubated 2～4 hours;
Distillation: goods are warming up to-4 ℃ of insulations 2 hours, reduce to-40 ℃ of insulations 2 hours again; And condenser is cooled to below-45 ℃, evacuation, control vacuum is at 10～20pa;
Parsing-desiccation: heat up 5～8 ℃ with per 1 hour, with plate temperature rise to 0 ℃, this moment, products temperature was about-30 ℃, after this to heat up in per 1 hour 7～10 ℃ products temperature was risen to 20 ℃; Be incubated 2～4 hours.
The method for preparing of ATP coenzyme insulin dry powder injection according to the invention, preferred 4 hours of its described pre-freeze temperature retention time.
The preferred 10pa of distillation control vacuum;
The parsing-desiccation condition optimization is to heat up 8 ℃ with per 1 hour, with plate temperature rise to 0 ℃, after this to heat up in per 1 hour 7 ℃ products temperature is risen to 20 ℃.
Adopt the prepared ATP coenzyme insulin lyophilized injectable powder of the inventive method, outward appearance is full, and solubility, clarity are good, and constant product quality.
The specific embodiment
Below in conjunction with specific embodiment the inventive method is detailed further, but it is not to be limitation of the present invention.
Embodiment 1
Take by weighing principal agent and adjuvant according to following technical recipe:
Adenosine triphosphate disodium salt 20mg
Coenzyme A 50 units
Insulin 4 units
L-arginine 6mg
Disodiumedetate (EDTA) 0.36mg
Low molecular dextran 5mg
Calcium gluconate 1mg
Cysteine hydrochloride 0.5mg
Water for injection 0.5ml;
Concrete preparation process is:
(a) in stainless steel cask, add an amount of water for injection, the hydrochloric acid with 10% transfers to pH value about 2.5, adds insulin, stirs, and it is subsequent use to be prepared into solution I.
(b) in stainless steel cask, add an amount of water for injection, behind adding L-arginine, the EDTA, stir, add 2% (g/ml) active carbon and stirred 30 minutes, take off charcoal.Add adenosine triphosphate disodium salt, stir, it is subsequent use to be prepared into solution II.
(c) in stainless steel cask, add an amount of water for injection, add calcium gluconate, low molecular dextran, cysteine hydrochloride, add 2% (g/ml) active carbon and stirred 30 minutes, take off charcoal, it is subsequent use to be prepared into solution III.
(d) pour above-mentioned three kinds of solution into material-compound tank, open and stir, mix homogeneously is transferred about pH value to 5.7 with 4%NaOH, adds coenzyme A, supplies water for injection.PH value, content are surveyed in the laboratory sampling, and qualified back adds filter paper with filter press and is pressed into the packing chamber;
Medicinal liquid is carried out lyophilization:
(1) pre-freeze: the medicine that branch is installed places on the freeze drying box dividing plate, makes goods be chilled to-40 ℃, is incubated 4 hours.
(2) distillation: goods are warming up to-4 ℃ of insulations 2 hours, reduce to-40 ℃ of insulations 2 hours again.And condenser is cooled to below-45 ℃, evacuation, control vacuum is at 10pa.
(3) parsing-desiccation: heat up 5 ℃ with per 1 hour, with plate temperature rise to 0 ℃, this moment, products temperature was about-30 ℃, after this to heat up in per 1 hour 7 ℃ products temperature was risen to 20 ℃.This process is about 12 hours.20 ℃ of insulations 2 hours.After treating that above-mentioned steps is accomplished, outlet.Roll lid, lamp inspection, packing.
Prepare three batches of products according to the method described above, 5000 every batch, stipulate down to detect according to 2000 editions Chinese Pharmacopoeia medicine items, the result (sees table) as follows.
| Batch project | 090401 | 090402 | 090403 |
| Character | Be white or off-white color lyophilizing block or powder | Be white or off-white color lyophilizing block or powder | Be white or off-white color lyophilizing block or powder |
| Differentiate | Meet drug standard | Meet drug standard | Meet drug standard |
| Content (labelled amount) | Meet drug standard | Meet drug standard | Meet drug standard |
| PH | 5.7 | 5.8 | 5.9 |
| The clarity of solution | <=No. 1 | <=No. 1 | <=No. 1 |
| Color | <=No. 1 | <=No. 1 | <=No. 1 |
| Related substance | 0.20 | 0.21 | 0.20 |
| Moisture | 0.3 | 0.2 | 0.2 |
| Pyrogen | Up to specification | Up to specification | Up to specification |
| Aseptic | Up to specification | Up to specification | Up to specification |
| Content uniformity | Up to specification | Up to specification | Up to specification |
| Appearance yield | 99 | 98 | 99 |
Above-mentioned test shows: its outward appearance of ATP coenzyme insulin lyophilized injectable powder of the inventive method preparation is full, and solubility, clarity are good, and constant product quality property is good
Claims (4)
1. the method for preparing of an ATP coenzyme insulin dry powder injection is characterized in that it may further comprise the steps:
(a) technical recipe:
Adenosine triphosphate disodium salt 20mg
Coenzyme A 50 units
Insulin 4 units
L-arginine 6mg
Disodiumedetate 0.36mg
Low molecular dextran 5mg
Calcium gluconate 1mg
Cysteine hydrochloride 0.5mg
Water for injection 0.5ml;
(b) water for injection is transferred to pH value 2.5～3.5 with dilute hydrochloric acid, add insulin, stir, be prepared into solution I, subsequent use;
(c) in proper amount of water for injection, add L-arginine, disodiumedetate, stir, add 1～2% active carbon and stirred 20～30 minutes, remove active carbon after, add adenosine triphosphate disodium salt, stir, be prepared into solution II, subsequent use;
(d) in an amount of water for injection, adding calcium gluconate, low molecular dextran, cysteine hydrochloride, adding 2% active carbon and stirred 30 minutes, remove active carbon after, stir, be prepared into solution III, subsequent use;
(e) above-mentioned three kinds of solution are mixed, stir, transfer pH value to 5.7～6.2, add coenzyme A, supply the water for injection of surplus with 2-4%NaOH solution; Sterilization is measured content, packing, lyophilizing; Freeze-dry process is:
Pre-freeze: the medicine that branch is installed places on the freeze drying box dividing plate, makes goods be chilled to-40 ℃, is incubated 2-4 hour;
Distillation: goods are warming up to-4 ℃ of insulations 2 hours, reduce to-40 ℃ of insulations 2 hours again; And condenser is cooled to below-45 ℃, evacuation, control vacuum is at 10～20pa;
Parsing-desiccation: heat up 5～8 ℃ with per 1 hour,, after this heated up 7～10 ℃, products temperature is risen to 20 ℃ with per 1 hour with plate temperature rise to 0 ℃; Be incubated 2～4 hours.
2. the method for preparing of ATP coenzyme insulin dry powder injection according to claim 1 is characterized in that described pre-freeze temperature retention time is 4 hours.
3. the method for preparing of ATP coenzyme insulin dry powder injection according to claim 1 and 2 is characterized in that described distillation control vacuum is at 10pa.
4. the method for preparing of ATP coenzyme insulin dry powder injection according to claim 3 is characterized in that described parsing-desiccation is to heat up 8 ℃ with per 1 hour, with plate temperature rise to 0 ℃, after this to heat up in per 1 hour 7 ℃ products temperature is risen to 20 ℃.
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| CN 200910075772 CN102038939B (en) | 2009-10-23 | 2009-10-23 | Preparation method of adenosine triphosphate coenzyme insulin freeze-dried powder injection |
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| CN 200910075772 CN102038939B (en) | 2009-10-23 | 2009-10-23 | Preparation method of adenosine triphosphate coenzyme insulin freeze-dried powder injection |
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| CN102038939B true CN102038939B (en) | 2012-12-26 |
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Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102397536A (en) * | 2011-09-28 | 2012-04-04 | 河南辅仁怀庆堂制药有限公司 | Triphosadenine coenzyme insulin for injection and production technology thereof |
| CN102512668A (en) * | 2011-12-21 | 2012-06-27 | 蚌埠丰原涂山制药有限公司 | Lyophilized powder of adenosine disodium triphosphate, coenzyme A and insulin for injection and preparation method thereof |
| CN102698253B (en) * | 2012-06-08 | 2013-05-01 | 夏智红 | Adenosine disodium triphosphate composition |
| CN103512318B (en) * | 2012-06-20 | 2015-11-18 | 徐州万邦金桥制药有限公司 | The freeze-dry process of insulin |
| CN102895656B (en) * | 2012-09-24 | 2014-06-18 | 罗诚 | Adenosine triphosphate-coenzyme-insulin compound-containing pharmaceutical composition |
| CN103040765B (en) * | 2012-12-25 | 2014-10-15 | 马鞍山丰原制药有限公司 | Pharmaceutical composition containing adenosine disodium triphosphate and preparation method of pharmaceutical composition |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101125126A (en) * | 2006-08-16 | 2008-02-20 | 丛繁滋 | Method for preparing medical freeze-dried powder (injection) preparation |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101125126A (en) * | 2006-08-16 | 2008-02-20 | 丛繁滋 | Method for preparing medical freeze-dried powder (injection) preparation |
Non-Patent Citations (2)
| Title |
|---|
| 仲平 连莹.高效液相色谱法测定能量合剂中辅酶S的含量.《中国医院药学杂志》.2002,第22卷(第8期),471-472. * |
| 陆国庆 等.胰岛素与能量合剂配伍的稳定性.《中国医院药学杂志》.2005,第25卷(第12期),1185-1186. * |
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Owner name: HUABEI PHARMACEUTICAL CO., LTD. Free format text: FORMER OWNER: NORTH CHINA PHARMACEUTICAL GROUP PREPARATION CO., LTD. Effective date: 20150217 |
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Effective date of registration: 20150217 Address after: 050015 Heping East Road, Hebei, Shijiazhuang, No. 388 Patentee after: Huabei Pharmaceutical Co., Ltd. Address before: 050015 No. 135 North sports street, Hebei, Shijiazhuang Patentee before: North China Pharmaceutical Group Preparation Co., Ltd. |