CN103315951B - Low-molecular-weight heparin calcium injection - Google Patents
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Abstract
The invention belongs to the technical field of medicinal preparation dosage forms and specifically relates to a low-molecular-weight heparin calcium injection, including hydro-acupuncture, powder injection and transfusion. The invention aims to provide low-molecular-weight heparin calcium and a low-molecular-weight heparin calcium product so as to overcome defects in the prior art. The invention provides the low-molecular-weight heparin calcium and the low-molecular-weight heparin calcium product which have advantages of high activity, low sodium and nitrate and simple technology. The low-molecular-weight heparin calcium injection provided by the invention is prepared by the following process: acidic resin acidification, sodium nitrite cracking, calcium oxide neutralization, alcohol precipitation of an anhydrous calcium chloride ethanol solution, filtration and drying. The invention provides the low-molecular-weight heparin calcium injection which is safe, effective, stable and quality-controllable.
Description
Technical field
The invention belongs to the technical field of medicament form of pharmaceutical preparation, be specifically related to a kind of high-quality Low molecular heparin calcium injection, comprise liquid drugs injection, powder pin and transfusion.
Background technology
Biological activity heparin has last 100 years history in clinical practice from being found, it is thrombosis and the choice drug for the treatment of Acute Venous thrombosis after prevention operation, in addition, heparin and derivant thereof are also widely used in adjusts blood fat, antiinflammatory, antiallergic and immunomodulating etc., it is still one of most important biochemical drug up till now, Ye Shi China main exit one of medicine of earning foreign exchange.
Heparin is a kind of mucopolysaccharide class material, is extensively present in the animal organ such as intestinal mucosa and lung and tissue, becomes pharmaceutical heparin sodium after the PROCESS FOR TREATMENT such as degrease and Deproteinization.It has anticoagulation, adjusts the function such as blood fat, has been widely used in Prevention of cardiovascular disease field, however heparin hemorrhage side effect is more serious clinically, clinical practice is restricted.Low molecular heparin (low molecular weight heparin, LMWH) be the anticoagulation developing the eighties in 20th century, it is to be obtained by unfractionated heparin (also claiming unfraction heparin, un fractionated heparin, UFH) cracking.Because LMWH can produce good and lasting anti thrombotic action compared with UFH when the low-level anticoagulation, side effect is less, can be used for preventing and treating the diseases such as dvt, pulmonary infarction, disseminated inravascular coagulation, therefore Low molecular heparin becomes the study hotspot of cardiovascular drugs.
Low molecular heparin calcium (LMWH) is the class novel biochemical medicine growing up in the time of research Heprin heparin (Hep) molecule structure effect the 1980s, low-molecular-weight component or the fragment being formed with different technical gradings or degraded by Hep, the basic structure with Hep, molecular weight is generally 4kD ~ 6kD.Compared with Hep, LMWH has that little, the easy absorption of molecule, bioavailability are high, long half time, clear and definite, the low anticoagulant of dose-effect relationship, high thromboembolism preventing and the advantage such as hemorrhage side effect is few.In May, 1993, LMWH is applied to common anticoagulation therapy in the U.S. first.In most of European countries and Canada, LMWH has become the standard drug of prevention venous thromboembolism (VTE).The structure of Low molecular heparin, because LMWH is the component of the lower molecular weight that obtained through chemical degradation or enzymatic degradation by Hep, LMWH has the precursor structure identical with Hep, is a kind of mucopolysaccharide sulfuric acid ester being alternately made up of glucamine, L-idose aldehyde glycosides, NAG and D-glucuronic acid.
At present, oneself has more than ten kind of low molecular heparin calcium Related product to come out both at home and abroad.The nadroparin calcium (trade name: fast green woods) that the low molecular heparin calcium of existing clinical use has GlaxoSmithKline PLC group of Britain to produce, the Enoxaparin Sodium (trade name: Ke Sai) of Zhejiang Hangzhou Sano-Synth labo people's livelihood pharmaceutical manufacturing, the low molecular weight calcium heparin that Tianjin Chasesun Pharmaceutical Co., Ltd produces, the LMWH-Ca (trade name: You Nishu) that the dalteparin sodium (trade name: Fragmin) that Pharmacia & Upjohn company of Sweden produces and Hainan pharmaceutical Co. Ltd of general alliance produce etc.In recent years, along with LMWH anticoagulant therapy is more and more extensive in the application of cardiovascular field, domestic market progressively replaces taking nadroparin calcium, Enoxaparin Sodium as the LMWH series products of representative, and the market share of Hep is declining gradually.
Calciparine all can delay or stop blood coagulation in vivo and in vitro, its anticoagulant complicated mechanism, the links of blood coagulation is all had to effect, comprise that proenzyme changed thrombin, anticoagulant enzymatic activity into, hindered Fibrinogen to change fibrin into, prevent platelet aggregation anticoagulant.Calciparine also can reduce blood fat, reduces LDL and VLDL, and rising HDL changes blood viscosity, protection vascular endothelial cell, and prevention of arterial is atherosis, and promoting blood flow improves the effects such as coronary artery circulation.Because it is to play a role in vivo with calcium salt forms, after subcutaneous injection, slowly diffusion in blood circulation, can not reduce the calcium colloid of blood capillary between local cells, do not change vascular permeability, almost cause the side effect of local hemorrhage without heparin sodium subcutaneous injection, be applicable to prevention and treatment thrombosis-thrombotic disease and thrombosis yet, calciparine also has obvious anti-feritin and aldosterone antagonist activity, thereby also can be used for artificial kidney, artificial liver and extracorporeal circulation use.But in clinical use, find, after the unassorted heparin of common molecular weight and derivant life-time service thereof, there will be many negative effects, as hemorrhage, cause osteoporosis, induced platelet minimizing etc., and need detect platelet count in the time of application.
CN101649008A discloses a kind of production technology of low molecular weight heparin sodium salt, it is by the technique taking low molecular weight heparin sodium crude product as raw material production low molecular sodium heparin, comprising: prepare the processing steps such as heparin sodium aqua, degradation solution, neutralizer, collecting precipitation thing, low molecular sodium heparin crude product processed, low molecular sodium heparin fine work processed.But this manufacturing process is conventional subtractive process, effect is not fine.
CN101519459A discloses the production technology of a kind of low molecular weight heparin sodium (calcium), comprising: taking heparin sodium solution, add sodium nitrite solution, and carry out cracking; Alkali regulates lysate, then adsorbs impurity with anion-exchange column; Washing, obtains ultra-low molecular heparin sodium (calcium); With ultrafiltration membrance filter, then be precipitated thing with ethanol; Through desalination, after dehydration, then precipitate, after lyophilization, make finished product ultra-low molecular heparin sodium (calcium).
CN101012289A discloses a kind of calciparine production technology.It is to be changed by low molecular sodium heparin, comprises depolymerization, reduces, turns calcium, the step such as filters, concentrated.But these preparation method processes are all too loaded down with trivial details, fabrication cycle is longer, is not suitable for suitability for industrialized production.
Because calciparine easily destroys under strong alkali environment and hot environment, be more easily hydrolyzed.Therefore, need especially a kind of simple, stable, preparation technology of Low molecular heparin efficiently, also can effectively improve the quality of formulation products simultaneously.
Summary of the invention
The present invention aims to provide a kind of low molecular heparin calcium and Low molecular heparin calcium product, the defect existing to overcome prior art.A kind of active high and low sodium and nitrate and the simple low molecular heparin calcium of technique and Low molecular heparin calcium product are provided.
A kind of Low molecular heparin calcium injection, is characterized in that: comprise low molecular weight calcium heparin, water for injection and regulate hydrochloric acid or the NaOH of pH value to make;
Wherein, the preparation method of low molecular heparin calcium raw material is: acidic resins acidify, sodium nitrite cracking, calcium oxide neutralization, anhydrous calcium chloride alcoholic solution precipitate with ethanol, filtration drying; In described acidic resins acidify, regulating the pH value of heparin sodium aqua with acidic resins is 2.5 ~ 2.7; In described sodium nitrite cracking, the consumption of Chile saltpeter is 1/20 ~ 1/10 of heparin sodium consumption; In described calcium oxide neutralization, slowly add calcium oxide, regulator solution pH value is 6.0-6.5; Described calcium chloride alcoholic solution precipitate with ethanol: add 8-12% anhydrous calcium chloride alcoholic solution.
Dosage form is selected from liquid drugs injection, powder pin or transfusion.
Described liquid drugs injection prescription (specification 1ml:5000IU): low molecular weight calcium heparin 5000000anti-XaIU, water for injection add to 1000ml, hydrochloric acid or NaOH appropriate, be distributed into 1000 bottles.
Described acidic resins are strong cation acidic resins.
Described calcium oxide neutralization, before neutralizing, to add acidic resins again to regulate pH value be 2.5 ~ 2.7 and add cysteine.
A kind of Low molecular heparin calcium injection, is characterized in that: comprise low molecular weight calcium heparin, water for injection and regulate hydrochloric acid or the NaOH of pH value to make;
(1) acidify: the water for injection of getting 30.0 ㎏ joins 50L in the clean stainless steel cask of sterilization treatment, then takes the heparin sodium of 5.0 ㎏ through being up to the standards, adds under stirring and in stainless steel cask, makes its dissolving.After all dissolving, add treated qualified acidic resins (pH value of strengthening the acid resin moderated solution of cation is 2.5 ~ 2.7), pH is qualified, and rear continuation is stirred 0.5 hour.Remove by filter resin; (2) cracking: under agitation, take the gradation of 50g sodium nitrite and add in the solution of removing resin and (add for approximately 0.5 hour), finish and continue stirring reaction 2 hours, then stop stirring, put into refrigerator low temperature and continue cracking 48 hours; (3) neutralization: lysate is taken out in refrigerator, slowly add calcium oxide, regulator solution pH value is to filter after 6.0-6.5; (4) precipitate with ethanol: add 10% anhydrous calcium chloride alcoholic solution in magnetic agitation tank.Weight is equivalent to 3 times of lysate, slowly adds step lysate under stirring, adds rear continuation and stirs 1 hour, stops stirring leaving standstill 10 hours; (5) rejection filter, oven dry: supernatant is extracted out, then precipitate is added centrifuge to carry out rejection filter, after rejection filter finishes, vacuum drying, temperature 60 C, vacuum 0.08Mpa; Approximately 5 hours time; Gained white crystalline powder is low molecular weight calcium heparin.
Step (2) cracking, after 48 hours, further comprises, at low temperature, to add strong cation acidic resins again to regulate pH value be 2.5 ~ 2.7 and add 5 grams of cysteine, stirs 30 minutes; Then carry out the alcohol precipitation of step (4).
Detailed description of the invention
1, the touchstone of low molecular heparin calcium raw material and preparation: the national drug standards WS1-of State Food and Drug Administration (X-147)-2005Z, low molecular weight calcium heparin.This strain with heparin sodium through nitrous acid cracking, refining and the calcium salt of CSSO3.Its weight average molecular weight is less than 8000, and molecular weight is less than 8000 component and is no less than 60% of total amount, calculates by dry product, and in every 1mg, anti-Xa factor must not tire and is less than 70IU; Anti-Xa factor is tired and must not be less than 1.5 with the anti-IIa factor ratio of tiring.Wherein, anti-Xa factor titration method is as follows:
Solution preparation: Tris-sodium chloride buffer [Tris-NaCl(pH7.4)], get Tris 6.08 g, sodium chloride 8.77 g, 500 ml that add water make to dissolve, add bovine serum albumin 10 g, with salt acid for adjusting pH value to 7.4, be diluted with water to 1 000 ml, for subsequent use.Tris-Calcium Disodium Versenate buffer [Tris-EDTA(pH8.4)] is got sodium chloride 5.12 g, Tris 3.03 g and Calcium Disodium Versenate 1.4 g, 250 ml that add water make to dissolve, with salt acid for adjusting pH value to 8.4, be diluted with water to 500 ml, for subsequent use.Tris-Nacl buffer for the preparation of standard substance and need testing solution (pH7.4) is diluted to standard substance (S) and test sample (T) respectively the solution of 4 variable concentrations, agent distance between each dosage is than being generally 1:0.7～1:0.6, this concentration should be in the range of linearity of 1og dose-response, is generally in 1 ml containing 0.025IU～0.21 IU.Antithrombase (AT III) solution, makes in 1 ml with Tris-sodium chloride buffer (pH7.4)
Containing the solution [1] of 1 IU AT III, for subsequent use.Chromophoric substrate S2765 solution with water is made the solution of 0.003 mol/L, adds before use Tris-Calcium Disodium Versenate buffer (pH8.4) and is diluted to 0.0005 mol/L, for subsequent use.(F X is Tris-sodium chloride buffer (pH7.4) for solution a), preparation FXa for Sanguis Bovis seu Bubali X a solution
Solution, debugs its concentration, makes it replacing in the anti-Xa factorial experiment of standard substance with 0.9% sodium chloride solution, 0.6～0.7, for subsequent use in the absorption value at the wavelength place of 405 nm.
Algoscopy: get 16 of small test tubes, respectively labelling T1, T2, T3, T4 and S1, S2, S3, S4.Parallel two pipes that do of each concentration.Every pipe adds respectively test sample (T) or standard substance (S) diluent 50 microlitres of 4 kinds of concentration, and antithrombase solution 50 microlitres, mixes, and must not produce bubble.Arrange according to S1, S2, S3, S4, T1, T2, T3, T4, T1, T2, T3, T4, S1, S2, S3, S4 order, 37 DEG C of balances 1 minute, add chromophoric substrate solution 250 microlitres, mix 37 DEG C of accurate insulations after 4 minutes, respectively add 30% acetum 375 microlitre cessation reactions.With the semimicro colorimetric pool of 1cm light path, taking Tris-sodium chloride buffer (pH7.4) as blank, measure the absorbance of every pipe at the wavelength of 405nm.Replace need testing solution (parallel two pipes that do) to operate as blank pipe with method using Tris-sodium chloride buffer (pH7.4), in the time that 16 arms start and end up, measure respectively the absorbance of blank pipe.Both absorbances must not have significant difference.Taking absorbance as vertical coordinate, the logarithm value of standard solution (or need testing solution) concentration is that abscissa does respectively line style recurrence, press parallel line analysis principle 4 × 4 method experimental designs in biologic assay (2005 editions two annex XIV of Chinese Pharmacopoeia), calculate and tire and experimental error.Average Reliable limit rate (FL%) must not be greater than 15%.
2, the mensuration of nitrite: get sodium nitrite 0.750g (calculating by dry product), be dissolved in water, be diluted to 100ml, shake up, precision measures 1ml, thin up becomes 100ml, shake up, then precision measures 1ml, thin up becomes 50ml, shake up, obtain standard nitrite solution, every 1ml is equivalent to the NO2-of 1 μ g.Get low molecular weight calcium heparin 0.20g, the 10ml that adds water dissolves in rearmounted nessler colorimetric tube, add the dilute hydrochloric acid solution (1 → 100 of P-aminobenzene-sulfonamide, 1 gram joins 100ml, lower same) 1ml and hydrochloride naphthodiamide solution (0.1 → 100) 1ml, the pink producing is than 10ml standard nitrite solution (0.2ml standard nitrite solution, add the water of 9.8ml without nitrite) more shallow by the color producing after Same Way processing, illustrate that the content of nitrite of low molecular weight calcium heparin is less than 2ppm.Same method, can measure according to the difference of extension rate, the situation of 1,4,6,8,10 ppm.
3,
calciumget the about 0.4g of this product, accurately weighed, the 100ml that adds water makes to dissolve, and hydro-oxidation sodium test solution 15ml and calconum indicator 0.1g, be titrated to solution with Calcium Disodium Versenate volumetric solution (0.05mol/L) and become pure blue from aubergine.Every 1ml Calcium Disodium Versenate volumetric solution (0.05mol/L) is equivalent to the Ca of 2.004mg, calculates by dry product, and this product calcium content should be 9.5%～11.5%.
4, sodium ions content is measured: adopt flame spectrophotometric determination.
Embodiment 1, raw material preparation technology
1, acidify: the water for injection of getting 30.0 ㎏ joins 50L in the clean stainless steel cask of sterilization treatment, then takes the heparin sodium of 5.0 ㎏ through being up to the standards, adds under stirring and in stainless steel cask, makes its dissolving.After all dissolving, add treated qualified acidic resins (pH value that adds acid resin moderated solution is 2.5 ~ 2.7), pH is qualified, and rear continuation is stirred 0.5 hour.Remove by filter resin.2, cracking: under agitation, take the gradation of 50g sodium nitrite and add in the solution of removing resin and (add for approximately 0.5 hour), finish and continue stirring reaction 2 hours, then stop stirring, put into refrigerator low temperature and continue cracking 48 hours.3, neutralization: lysate is taken out in refrigerator, slowly add calcium oxide, regulator solution pH value is to filter after 6.0-6.5.4, precipitate with ethanol: add 10% anhydrous calcium chloride alcoholic solution in magnetic agitation tank.Weight is equivalent to 3 times of lysate, slowly adds step lysate under stirring, adds rear continuation and stirs 1 hour, stops stirring leaving standstill 10 hours.5, rejection filter, oven dry: supernatant is extracted out, then precipitate is added centrifuge to carry out rejection filter, after rejection filter finishes, vacuum drying, temperature 60 C, vacuum 0.08Mpa.Approximately 5 hours time.Gained white crystalline powder is low molecular weight calcium heparin.Obtain 3020 grams of low molecular heparin calcium.
Embodiment 2, raw material preparation technology
With the method for embodiment 1, step (2) cracking, after 48 hours, further comprises, at low temperature, to add acidic resins again to regulate pH value be 2.5 ~ 2.7 and add 5 grams of cysteine, stirs 30 minutes; Then carry out the alcohol precipitation of step (4).Finally obtain 3050 grams of low molecular heparin calcium.
Embodiment 3, raw material preparation technology
1, acidify: the water for injection of getting 30.0 ㎏ joins 50L in the clean stainless steel cask of sterilization treatment, then takes the heparin sodium of 5.0 ㎏ through being up to the standards, adds under stirring and in stainless steel cask, makes its dissolving.After all dissolving, add glacial acetic acid, regulating pH value is that the qualified rear continuation of 3.0, pH is stirred 0.5 hour.2, cracking: under agitation, take the gradation of 50g sodium nitrite and add in the solution of removing resin and (add for approximately 0.5 hour), finish and continue stirring reaction 2 hours, then stop stirring, put into refrigerator low temperature and continue cracking 48 hours.3, neutralization: lysate is taken out in refrigerator, slowly add calcium oxide, regulator solution pH value is to filter after 6.0-6.5.4, precipitate with ethanol: add 10% anhydrous calcium chloride alcoholic solution in magnetic agitation tank.Weight is equivalent to 3 times of lysate, slowly adds step lysate under stirring, adds rear continuation and stirs 1 hour, stops stirring leaving standstill 10 hours.5, rejection filter, oven dry: supernatant is extracted out, then precipitate is added centrifuge to carry out rejection filter, after rejection filter finishes, vacuum drying, temperature 60 C, vacuum 0.08Mpa.Approximately 5 hours time.Gained white crystalline powder is low molecular weight calcium heparin.Obtain 3250 grams of low molecular heparin calcium.
Sample presentation, tests to the sample of embodiment 1-3, and result is as follows.
| Sample title | The anti-Xa factor | Nitrite | Sodium/calcium ion content is than (wt%) |
| Embodiment 1 | 140 IU/mg | <4ppm | 1.3 |
| Embodiment 2 | 143 IU/mg | <1ppm | 1.0 |
| Embodiment 3 | 98 IU/mg | .>10ppm | 7.5 |
Obviously, embodiment 1 and 2, especially embodiment 2 can obtain unexpected technique effect.This may be that application, the cysteine etc. of acidic resins, technique obtained
Embodiment 4: injection prescription and preparation technology
Prescription (specification 1ml:5000IU): low molecular weight calcium heparin 5000000anti-XaIU, water for injection add to 1000ml, hydrochloric acid or NaOH appropriate, be distributed into 1000 bottles.
This is the formula of injection, does not contain other adjuvant.In production, finding, there is good buffer capacity in low molecular heparin calcium itself, therefore need not select other pH buffer agent.
Preparation technology: the washing of 1.1 ampoules, ampoule, through ultrasonic waves for cleaning water for injection shower, after compressed air dries up, enters tunnel oven sterilizing, for subsequent use.1.2 dosings, take the low molecular heparin calcium of recipe quantity, add the water for injection of recipe quantity, stir it is dissolved completely, regulate pH value 5.0～8.0 with hydrochloric acid or the sodium hydroxide of 0.5M, through with 0.45 μ m microporous filter membrane fine straining; The filter membrane aseptic filtration of 0.22um, gets filtrate censorship, qualified rear stand-by.1.3 subpackages, import the empty ampoule after cleaning sterilizing and the medicinal liquid being up to the standards between subpackage into, after debugging racking machine is normal, carry out subpackage by the subpackage code of injection, and subpackage is sealing by fusing simultaneously.1.4 leak detections: damaged defective work is rejected in leak detection.
Claims (2)
1. a low molecular weight calcium heparin injection, is characterized in that: hydrochloric acid or NaOH by low molecular weight calcium heparin, water for injection and adjusting pH value make;
Wherein, the preparation method of the raw material of low molecular weight calcium heparin is: (1) acidify: the water for injection of getting 30.0 ㎏ joins 50L in the clean stainless steel cask of sterilization treatment, then take the heparin sodium of 5.0 ㎏ through being up to the standards, under stirring, add and in stainless steel cask, make its dissolving; The pH value of strengthening the acid resin moderated solution of cation after all dissolving is 2.5-2.7, and pH is qualified, and rear continuation is stirred 0.5 hour; Remove by filter resin; (2) cracking: under agitation, take the gradation of 50g sodium nitrite and join in the solution of removing resin, finish and continue stirring reaction 2 hours, then stop stirring, put into refrigerator low temperature and continue cracking 48 hours; (3) neutralization: lysate is taken out in refrigerator, slowly add calcium oxide, regulator solution pH value is to filter after 6.0-6.5; (4) precipitate with ethanol: add 10% anhydrous calcium chloride alcoholic solution in magnetic agitation tank, weight is equivalent to 3 times of lysate, slowly adds step lysate under stirring, adds rear continuation and stirs 1 hour, stops stirring leaving standstill 10 hours; (5) rejection filter, oven dry: supernatant is extracted out, then precipitate is added centrifuge to carry out rejection filter, after rejection filter finishes, vacuum drying, temperature 60 C, vacuum 0.08Mpa, approximately 5 hours time; Gained white crystalline powder is low molecular weight calcium heparin.
2. low molecular weight calcium heparin injection as claimed in claim 1, is characterized in that, described injection is liquid drugs injection, powder pin or transfusion.
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| CN104072637B (en) * | 2014-07-07 | 2017-02-08 | 兆科药业（合肥）有限公司 | Preparation method for low-molecular-weight heparin calcium |
| CN104804110B (en) * | 2015-05-08 | 2017-04-12 | 深圳赛保尔生物药业有限公司 | High-purity nadroparin calcium |
| CN106749769B (en) * | 2016-12-26 | 2021-08-24 | 海南通用同盟药业有限公司 | Improved low molecular weight heparin calcium bulk drug and preparation thereof |
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| WO1981003276A1 (en) * | 1980-05-19 | 1981-11-26 | Riker Laboratories Inc | Improved anticoagulant substance |
| CN101012289A (en) * | 2007-02-01 | 2007-08-08 | 高树华 | Producing process for low molecular weight calcium heparin |
| CN101519459A (en) * | 2008-02-26 | 2009-09-02 | 苏州法思特生物制药科技有限公司 | Technique for producing ultra-low molecular heparin sodium (calcium) |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO1981003276A1 (en) * | 1980-05-19 | 1981-11-26 | Riker Laboratories Inc | Improved anticoagulant substance |
| CN101012289A (en) * | 2007-02-01 | 2007-08-08 | 高树华 | Producing process for low molecular weight calcium heparin |
| CN101519459A (en) * | 2008-02-26 | 2009-09-02 | 苏州法思特生物制药科技有限公司 | Technique for producing ultra-low molecular heparin sodium (calcium) |
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| 张万忠，等.低分子量肝素的制备与纯化.《沈阳化工学院学报》.2003,第17卷(第2期),114-117. * |
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Effective date of registration: 20160822 Address after: 101 room 70 (medical city), No. 803, 225300 health Avenue, Jiangsu, Taizhou Patentee after: Jiangsu Grand Alliance Pharmaceutical Co., Ltd. Address before: 570312 Hainan province Haikou City Xiuying Yong GUI Industrial Zone Haililu (no doorplates) Patentee before: General Tongmeng Pharmacy Industry Co., Ltd., Hainan |