CN101612130A - The preparation technology of low molecular weight sodium heparin used for injection - Google Patents
The preparation technology of low molecular weight sodium heparin used for injection Download PDFInfo
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- CN101612130A CN101612130A CN200910054910A CN200910054910A CN101612130A CN 101612130 A CN101612130 A CN 101612130A CN 200910054910 A CN200910054910 A CN 200910054910A CN 200910054910 A CN200910054910 A CN 200910054910A CN 101612130 A CN101612130 A CN 101612130A
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Abstract
The present invention relates to a kind of preparation technology of low molecular weight sodium heparin used for injection, carry out under aseptic condition, the low molecular sodium heparin with water for injection dissolving recipe quantity adds in the material-compound tank, adds water for injection to cumulative volume, and wiring solution-forming also stirs; Adjust pH value to 5.5～7.0 with diluted acid or dilute alkaline soln; Solution after the double-deck microporous filter membrane aseptic filtration of 0.2 μ m, feed liquid fill half tamponade; Feed liquid is refrigerated to-45～-40 ℃, be incubated after at least 3 hours, condenser temperature is controlled at-50～-45 ℃, open vacuum pump, be controlled at 18～20Pa distillation, the plate temperature control is warming up to 28～32 ℃ at 2～4 ℃/h, is incubated 3～4 hours, total head plug outlet is made white or off-white color lyophilizing block or powder.Advantage is: the aseptic freeze-dried injectable powder that adopts modern preparation technique to make, but room temperature transports, preserves the stability and the safety that have improved this product; Preparation technology is simple, and is scientific and reasonable, easily operation.
Description
Technical field
The present invention relates to field of medicine preparations, especially a kind of preparation technology of low molecular weight sodium heparin used for injection and using method can be made into the low molecular weight heparin sodium injection.
Background technology
Thrombotic disease is a kind of commonly encountered diseases, often shows as myocardial infarction, ischemic cerebral infarction, venous thromboembolism.Along with China's population aging degree is increasingly sharpened, the thrombotic disease incidence rate constantly rises, the rapid dilatation in antithrombotic reagent market, and the successful exploitation of the introduction of new product and novel antithrombotic reagent becomes the key factor of market development.Data computation according to the relevent statistics, China's antithrombotic reagent year market scale more than 1,800,000,000 yuan, the annual sales amount increasing degree is about 20%.
Comprise heparin class, non-heparin anti-platelet aggregation medicinal, enzyme and other 4 little subclass in the antithrombotic reagent, heparin class and enzyme are basically based on biochemical drug.The heparin class is occupied antithrombotic market lion's share, the first three quarters was about 50% in 2005, wherein, occupy an leading position with Low molecular heparin class medicine again, low molecular heparin calcium and low molecular sodium heparin account for the share of whole antithrombotic class pharmaceutical market 15% and 9% respectively.
Low molecular heparin is the anticoagulant new drug that develops the eighties in 20th century, is to be got by the unfractionated heparin depolymerization.Its anti thrombotic action is better than heparin, have characteristics such as long half time in the bioavailability height, body, bleeding tendency are little, oral easy absorption, because its effectiveness and safety all are better than unfractionated heparin, the domestic market is that the Low molecular heparin series products of representative has progressively replaced the unfractionated heparin product with low molecular heparin calcium, low molecular sodium heparin and Enoxaparin at present.
Low molecular heparin has become the clinical choice drug that prevents that acute thrombus from forming, and potential applicability in clinical practice is wide.
Low molecular weight heparin sodium has injection and two kinds of dosage forms of external.The former is main dosage form, the latter such as Low molecular heparin sodium gel and low molecular weight heparin sodium emulsifiable paste.Also has the heparinoid preparation in addition, receive the concern of researcher owing to its some special construction and biological activity, as Danaparoid Sodium (NV Organon production), sulfur acid heparin (84%), dermatan sulfate (12%) and chondroitin sulfate (4%) or the like.
In addition along with the going deep into of research, it is found that low molecular sodium heparin not only has anticoagulant, antithrombotic to form and the effect of blood lipid regulation, also have antiinflammatory, antiallergic, antiviral, function such as anticancer.
At home, the purposes of low molecular weight heparin sodium is not also well developed and is used, and in conjunction with clinical practice, the low molecular weight heparin that development desired molecular weight and desired molecular weight distribute and the production of ultra-low molecular weight heparin have vast potential for future development.Along with developing rapidly of pharmaceuticals industry, the succeeding in developing of the oral and exterior-applied formulation of low molecular weight heparin, the anticoagulant of low molecular weight heparin, anti thrombotic action can be more outstanding, and the clinical practice meeting is more extensive.
The low molecular weight sodium heparin used for injection raw material is a low molecular weight heparin sodium, and low molecular weight heparin sodium is the catabolite of heparin sodium, because heparin sodium so far still can't chemosynthesis, can only extract the leftover bits and pieces behind animal slaughtering, and market demand is very big, numerous European travelling traders news dish again and again in China's Guangzhou Export Commodities Fair in 1998 desires to buy in a large number the heparin sodium crude drug product that China produces.This situation causes the many enterprises of China erroneous judgement international market trend, and the numerous enterprises production heparin sodium of jumping on the bandwagon occurs.It is reported that China once had 500～600 tame enterprises to produce heparin sodium simultaneously the most for a long time.
Because the manufacturer is too many, product quality is very different naturally, causes heparin sodium injection poor quality after the processing, causes malpractice, particularly " heparin sodium " incident of appearance in 2008.This incident causes the great attention of State Food and Drug Administration, and to the supervision of medicinal chemicals as one of major tasks, low molecular weight sodium heparin used for injection raw material production situation obtains taking a turn for the better at present.
Summary of the invention
Technical problem to be solved by this invention is to provide that a kind of technology is simple, the low molecular weight sodium heparin used for injection and the preparation technology thereof of drug safety.
The present invention solves the problems of the technologies described above the technical scheme of being taked: a kind of preparation technology of low molecular weight sodium heparin used for injection, under aseptic condition, carry out, and comprise the steps:
The first step: the low molecular sodium heparin with water for injection dissolving recipe quantity, add in the material-compound tank, add water for injection to volume required (500ml water for injection about 25g of dissolving or 50g low molecular weight heparin sodium), wiring solution-forming also stirs;
Second step: adjust pH value to 5.5～7.0 with diluted acid or dilute alkaline soln;
The 3rd step: solution after the double-deck microporous filter membrane aseptic filtration of 0.2 μ m, feed liquid fill half tamponade;
The 4th step: lyophilization: feed liquid is refrigerated to-40～-45 ℃, be incubated after at least 3 hours, condenser temperature is controlled at-50～-45 ℃, open vacuum pump, be controlled at 18～20Pa distillation, the plate temperature control is warming up to 28～32 ℃ at 2～4 ℃/h, is incubated 3～4 hours, total head plug outlet, making character is the lyophilizing block or the powder of white or off-white color.
The pH value of regulator solution can be 5.5,5.6,5.8,6.0,6.2,6.5,6.8 or 7.0.
On the basis of such scheme, described diluted acid is 0.5～1.5mol/L hydrochloric acid, and diluted alkaline is 0.5～1.5mol/L sodium hydroxide, is preferably 1mol/L.
The above-mentioned injection that makes with the using method of low molecular weight heparin sodium is, white or off-white color lyophilizing block or powder is bottled with 2ml control, packing specification is that 2500AXaIU/ props up or 5000XaIU/ props up, before the use, dissolve with water for injection by every milliliter of 5000AXaIU, be made into the low molecular weight heparin sodium injection.
The invention has the beneficial effects as follows:
1, low molecular weight sodium heparin used for injection of the present invention is the aseptic freeze-dried injectable powder that adopts modern preparation technique to make, but room temperature transports, preserves the stability and the safety that have improved this product;
2, this product has good effect, and stay-in-grade characteristics are used for the hemodialysis extracorporeal circulation and prevent thrombosis, also can be used for preventing dvt to form;
3, the preparation technology of this product is simple, and is scientific and reasonable, easily operation.
The specific embodiment
Embodiment 1
A kind of preparation technology of low molecular weight sodium heparin used for injection takes by weighing recipe quantity between aseptic weighing, comprises the steps:
The first step: with the low molecular sodium heparin of a small amount of water for injection dissolving recipe quantity, add in the material-compound tank earlier, add water for injection to cumulative volume, wiring solution-forming stirs;
Second step: the pH value about 6.0 of adjusting solution with 1mol/L hydrochloric acid or 1mol/L sodium hydroxide solution;
The 3rd step: through behind the double-deck filtering with microporous membrane of 0.2 μ m between the input embedding, will feed liquid fill after aseptic filtration, half tamponade;
The 4th step: lyophilization: pre-freeze is to-40 ℃ behind the goods inlet, be incubated after 3 hours, condenser temperature is lower than-45 ℃, open vacuum pump, be controlled at 20Pa following about distillation, the plate temperature heats up about with 3 ℃/h, reaches 30 ℃ up to goods, plate Wen Jun, constant temperature keeps total head plug outlet after 3 hours, makes white or off-white color lyophilizing block or powder.
Using method: low molecular weight heparin sodium lyophilizing block or powder are bottled with 2ml control, and packing specification is that 2500AXaIU/ props up with 5000AXaIU/ and props up, face with before, by every milliliter of 5000AXaIU, add the injection water and make it dissolving.
Embodiment 2
A kind of preparation technology of low molecular weight sodium heparin used for injection takes by weighing recipe quantity between aseptic weighing, comprises the steps:
The first step: with the low molecular sodium heparin of a small amount of water for injection dissolving recipe quantity, add in the material-compound tank earlier, add water for injection to cumulative volume, wiring solution-forming stirs;
Second step: the pH value about 6.5 of adjusting solution with 1mol/L hydrochloric acid or 1mol/L sodium hydroxide solution;
The 3rd step: through behind the double-deck filtering with microporous membrane of 0.2 μ m between the input embedding, will feed liquid fill after aseptic filtration, half tamponade;
The 4th step: lyophilization: pre-freeze is to-40 ℃ behind the goods inlet, be incubated after 3 hours, condenser temperature-46 ℃, open vacuum pump, be controlled at the 20Pa distillation, the plate temperature heats up with 4 ℃/h, reaches 30 ℃ up to goods, plate Wen Jun, constant temperature keeps total head plug outlet after 4 hours, makes white or off-white color lyophilizing block or powder.
Using method: low molecular weight heparin sodium lyophilizing block or powder 2ml control are bottled, and packing specification is that 2500AXaIU/ props up or 5000AXaIU/ props up, face with before, by every milliliter of 5000AXaIU, add the injection water and make dissolving.
Embodiment 3
A kind of preparation technology of low molecular weight sodium heparin used for injection takes by weighing recipe quantity between aseptic weighing, comprises the steps:
The first step: with the low molecular sodium heparin of a small amount of water for injection dissolving recipe quantity, add in the material-compound tank earlier, add water for injection to cumulative volume, wiring solution-forming stirs;
Second step: the pH value about 6.9 of adjusting solution with 1mol/L hydrochloric acid or 1mol/L sodium hydroxide solution;
The 3rd step: after putting the double-deck filtering with microporous membrane of 0.2um between the input embedding, will feed liquid fill after aseptic filtration, half tamponade;
The 4th step: lyophilization: pre-freeze is to-40 ℃ behind the goods inlet, be incubated after 3 hours, condenser temperature-45.5 ℃, open vacuum pump, be controlled at 19Pa distillation, the plate temperature heats up about with 3 ℃/h, reaches 30 ℃ up to goods, plate Wen Jun, constant temperature keeps total head plug outlet after 3.5 hours, makes white or off-white color lyophilizing block or powder.
Using method: low molecular weight heparin sodium lyophilizing block or powder 2ml control are bottled, and packing specification is that 2500AXaIU/ props up or 5000AXaIU/ props up, face with before, by every milliliter of 5000AXaIU, add the injection water and make dissolving.
Claims (2)
1, a kind of preparation technology of low molecular weight sodium heparin used for injection carries out under aseptic condition, it is characterized in that comprising the steps:
The first step: the low molecular sodium heparin with water for injection dissolving recipe quantity, add in the material-compound tank, add water for injection to volume required, wiring solution-forming also stirs;
Second step: adjust pH value to 5.5～7.0 with diluted acid or dilute alkaline soln;
The 3rd step: solution after the double-deck microporous filter membrane aseptic filtration of 0.2 μ m, feed liquid fill half tamponade;
The 4th step: feed liquid is refrigerated to-45～-40 ℃, be incubated after at least 3 hours, condenser temperature is controlled at-50～-45 ℃, open vacuum pump, be controlled at 18～20Pa distillation, the plate temperature control is warming up to 28～32 ℃ at 2～4 ℃/h, is incubated 3～4 hours, total head plug outlet is made white or off-white color lyophilizing block or powder.
2, the preparation technology of low molecular weight sodium heparin used for injection according to claim 1 is characterized in that: described diluted acid is 0.5～1.5mol/L hydrochloric acid, and diluted alkaline is 0.5～1.5mol/L sodium hydroxide.
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| CN200910054910A CN101612130A (en) | 2009-07-16 | 2009-07-16 | The preparation technology of low molecular weight sodium heparin used for injection |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105030702A (en) * | 2015-07-15 | 2015-11-11 | 马鞍山丰原制药有限公司 | Pharmaceutical composition containing heparin sodium and preparation method thereof |
| CN105362238A (en) * | 2015-12-18 | 2016-03-02 | 成都百裕制药股份有限公司 | Enoxaparin injection preparation and industrial production method thereof |
| CN105832663A (en) * | 2016-06-03 | 2016-08-10 | 邱阳 | Injection for preventing phlebothrombosis after orthopedic or surgical operations and preparation method of injection |
| CN113069414A (en) * | 2021-04-06 | 2021-07-06 | 山东万邦赛诺康生化制药股份有限公司 | Preparation method of heparin sodium injection |
-
2009
- 2009-07-16 CN CN200910054910A patent/CN101612130A/en active Pending
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105030702A (en) * | 2015-07-15 | 2015-11-11 | 马鞍山丰原制药有限公司 | Pharmaceutical composition containing heparin sodium and preparation method thereof |
| CN105030702B (en) * | 2015-07-15 | 2019-01-18 | 马鞍山丰原制药有限公司 | One kind sodium pharmaceutical composition containing heparin and preparation method thereof |
| CN105362238A (en) * | 2015-12-18 | 2016-03-02 | 成都百裕制药股份有限公司 | Enoxaparin injection preparation and industrial production method thereof |
| CN105362238B (en) * | 2015-12-18 | 2019-03-19 | 成都百裕制药股份有限公司 | A kind of Enoxaparin ejection preparation and its industrialized preparing process |
| CN105832663A (en) * | 2016-06-03 | 2016-08-10 | 邱阳 | Injection for preventing phlebothrombosis after orthopedic or surgical operations and preparation method of injection |
| CN113069414A (en) * | 2021-04-06 | 2021-07-06 | 山东万邦赛诺康生化制药股份有限公司 | Preparation method of heparin sodium injection |
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Application publication date: 20091230 |