CN112137969A - Enoxaparin sodium for injection containing enoxaparin sodium and preparation method thereof - Google Patents
Enoxaparin sodium for injection containing enoxaparin sodium and preparation method thereof Download PDFInfo
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- CN112137969A CN112137969A CN202011078701.9A CN202011078701A CN112137969A CN 112137969 A CN112137969 A CN 112137969A CN 202011078701 A CN202011078701 A CN 202011078701A CN 112137969 A CN112137969 A CN 112137969A
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- 229960005153 enoxaparin sodium Drugs 0.000 title claims abstract description 97
- CIJQTPFWFXOSEO-NDMITSJXSA-J tetrasodium;(2r,3r,4s)-2-[(2r,3s,4r,5r,6s)-5-acetamido-6-[(1r,2r,3r,4r)-4-[(2r,3s,4r,5r,6r)-5-acetamido-6-[(4r,5r,6r)-2-carboxylato-4,5-dihydroxy-6-[[(1r,3r,4r,5r)-3-hydroxy-4-(sulfonatoamino)-6,8-dioxabicyclo[3.2.1]octan-2-yl]oxy]oxan-3-yl]oxy-2-(hydroxy Chemical compound [Na+].[Na+].[Na+].[Na+].O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1O)NC(C)=O)O[C@@H]1C(C[C@H]([C@@H]([C@H]1O)O)O[C@@H]1[C@@H](CO)O[C@H](OC2C(O[C@@H](OC3[C@@H]([C@@H](NS([O-])(=O)=O)[C@@H]4OC[C@H]3O4)O)[C@H](O)[C@H]2O)C([O-])=O)[C@H](NC(C)=O)[C@H]1C)C([O-])=O)[C@@H]1OC(C([O-])=O)=C[C@H](O)[C@H]1O CIJQTPFWFXOSEO-NDMITSJXSA-J 0.000 title claims abstract description 97
- 238000002347 injection Methods 0.000 title claims abstract description 55
- 239000007924 injection Substances 0.000 title claims abstract description 55
- 238000002360 preparation method Methods 0.000 title claims abstract description 25
- 239000000243 solution Substances 0.000 claims description 38
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 36
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 24
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 19
- 239000008215 water for injection Substances 0.000 claims description 17
- 238000001035 drying Methods 0.000 claims description 13
- 238000001816 cooling Methods 0.000 claims description 12
- 238000011049 filling Methods 0.000 claims description 10
- 229910052757 nitrogen Inorganic materials 0.000 claims description 10
- 238000001914 filtration Methods 0.000 claims description 9
- 238000010438 heat treatment Methods 0.000 claims description 9
- 238000005192 partition Methods 0.000 claims description 9
- 239000002033 PVDF binder Substances 0.000 claims description 8
- 238000002156 mixing Methods 0.000 claims description 8
- 229920002981 polyvinylidene fluoride Polymers 0.000 claims description 8
- 238000005303 weighing Methods 0.000 claims description 8
- 239000003814 drug Substances 0.000 claims description 7
- 238000000859 sublimation Methods 0.000 claims description 7
- 230000008022 sublimation Effects 0.000 claims description 7
- 229940079593 drug Drugs 0.000 claims description 4
- 238000007710 freezing Methods 0.000 claims description 3
- 230000008014 freezing Effects 0.000 claims description 3
- 239000002158 endotoxin Substances 0.000 claims description 2
- 238000012792 lyophilization process Methods 0.000 claims 1
- 125000006850 spacer group Chemical group 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 22
- 230000008569 process Effects 0.000 abstract description 21
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- 238000004108 freeze drying Methods 0.000 description 17
- 230000000694 effects Effects 0.000 description 7
- 238000004458 analytical method Methods 0.000 description 6
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 4
- 230000008859 change Effects 0.000 description 4
- 229920000669 heparin Polymers 0.000 description 4
- 206010051055 Deep vein thrombosis Diseases 0.000 description 3
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 3
- 206010047249 Venous thrombosis Diseases 0.000 description 3
- 230000001133 acceleration Effects 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 229960002897 heparin Drugs 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- ZZZCUOFIHGPKAK-UHFFFAOYSA-N D-erythro-ascorbic acid Natural products OCC1OC(=O)C(O)=C1O ZZZCUOFIHGPKAK-UHFFFAOYSA-N 0.000 description 2
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 2
- 208000002193 Pain Diseases 0.000 description 2
- 229930003268 Vitamin C Natural products 0.000 description 2
- 230000010100 anticoagulation Effects 0.000 description 2
- 238000003795 desorption Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000003825 pressing Methods 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 235000019154 vitamin C Nutrition 0.000 description 2
- 239000011718 vitamin C Substances 0.000 description 2
- PWKSKIMOESPYIA-UHFFFAOYSA-N 2-acetamido-3-sulfanylpropanoic acid Chemical compound CC(=O)NC(CS)C(O)=O PWKSKIMOESPYIA-UHFFFAOYSA-N 0.000 description 1
- 206010002388 Angina unstable Diseases 0.000 description 1
- 206010003178 Arterial thrombosis Diseases 0.000 description 1
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
- 108010074860 Factor Xa Proteins 0.000 description 1
- 208000032843 Hemorrhage Diseases 0.000 description 1
- OHJKXVLJWUPWQG-PNRHKHKDSA-N Heparinsodiumsalt Chemical compound O[C@@H]1[C@@H](NS(O)(=O)=O)[C@@H](O)O[C@H](COS(O)(=O)=O)[C@H]1O[C@H]1[C@H](OS(O)(=O)=O)[C@@H](O)[C@H](O)[C@H](C(O)=O)O1 OHJKXVLJWUPWQG-PNRHKHKDSA-N 0.000 description 1
- 235000013878 L-cysteine Nutrition 0.000 description 1
- 239000004201 L-cysteine Substances 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 208000010378 Pulmonary Embolism Diseases 0.000 description 1
- 208000007814 Unstable Angina Diseases 0.000 description 1
- 230000003187 abdominal effect Effects 0.000 description 1
- 229960001138 acetylsalicylic acid Drugs 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 230000001858 anti-Xa Effects 0.000 description 1
- 230000002785 anti-thrombosis Effects 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 229940127219 anticoagulant drug Drugs 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 239000004019 antithrombin Substances 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 230000000740 bleeding effect Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 208000009190 disseminated intravascular coagulation Diseases 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- 238000001631 haemodialysis Methods 0.000 description 1
- 150000002373 hemiacetals Chemical group 0.000 description 1
- 230000000322 hemodialysis Effects 0.000 description 1
- ZFGMDIBRIDKWMY-PASTXAENSA-N heparin Chemical compound CC(O)=N[C@@H]1[C@@H](O)[C@H](O)[C@@H](COS(O)(=O)=O)O[C@@H]1O[C@@H]1[C@@H](C(O)=O)O[C@@H](O[C@H]2[C@@H]([C@@H](OS(O)(=O)=O)[C@@H](O[C@@H]3[C@@H](OC(O)[C@H](OS(O)(=O)=O)[C@H]3O)C(O)=O)O[C@@H]2O)CS(O)(=O)=O)[C@H](O)[C@H]1O ZFGMDIBRIDKWMY-PASTXAENSA-N 0.000 description 1
- 229960001008 heparin sodium Drugs 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 201000004332 intermediate coronary syndrome Diseases 0.000 description 1
- 210000004347 intestinal mucosa Anatomy 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000003055 low molecular weight heparin Substances 0.000 description 1
- 229940127215 low-molecular weight heparin Drugs 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 238000010979 pH adjustment Methods 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L sulfate group Chemical group S(=O)(=O)([O-])[O-] QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 238000011287 therapeutic dose Methods 0.000 description 1
- 230000009424 thromboembolic effect Effects 0.000 description 1
- PJVWKTKQMONHTI-UHFFFAOYSA-N warfarin Chemical compound OC=1C2=CC=CC=C2OC(=O)C=1C(CC(=O)C)C1=CC=CC=C1 PJVWKTKQMONHTI-UHFFFAOYSA-N 0.000 description 1
- 229960005080 warfarin Drugs 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
- A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
- A61K31/727—Heparin; Heparan
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- Dermatology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Molecular Biology (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Inorganic Chemistry (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses enoxaparin sodium containing enoxaparin sodium for injection and a preparation method thereof. The invention also provides a preparation method of the enoxaparin sodium for injection, which has the advantages of simple process and lower cost and is suitable for commercial production.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to enoxaparin sodium containing injection enoxaparin sodium and a preparation method thereof.
Background
Enoxaparin Sodium (Enoxaparin Sodium) is a low molecular weight heparin Sodium salt, which is Sodium salt of aminodextran sulfate fragment obtained by alkali degradation after benzyl esterification of heparin extracted from porcine small intestinal mucosa, and is a polysaccharide mixture with average molecular weight of about 4500 daltons. FDA approval was obtained in 1933 and marketed in the united states, the main mechanism of action of which is inhibition of factor Xa and factor iia activity by binding to antithrombin and complexes thereof, and its major indications include: the composition can be used for preventing deep venous thrombosis of patients with limited activity, preventing deep venous thrombosis of patients with thromboembolic complications in abdominal operations, preventing arterial thrombosis of patients with unstable angina and patients without Q-wave myocardial infarction by combining with aspirin, preventing acute deep venous thrombosis without pulmonary embolism by combining with warfarin, preventing disseminated intravascular coagulation caused by various reasons, and also being used in operations such as hemodialysis, extracorporeal circulation, catheter operation, microvascular operation and the like and anticoagulation treatment of certain blood specimens or instruments.
Enoxaparin sodium has strong anti-Xa activity and low anti-IIa activity, and thus has the advantages of low anticoagulation, high antithrombotic activity, high bioavailability, long action time, convenient use and less bleeding compared with common heparin. Because of the inconvenience and great side effect of common heparin in clinical use, the clinical use amount of enoxaparin sodium is far greater than that of heparin sodium.
Analysis on the structure and physicochemical properties of the enoxaparin sodium shows that the unsaturated hemiacetal structure on the main chain makes the enoxaparin sodium extremely unstable to heat and oxidizing agents, so that the enoxaparin sodium preparation is deteriorated during the placement process.
The enoxaparin sodium injection is prepared by the following general production process: dissolving enoxaparin sodium in cooled water for injection, sterile filtering, bottling, inspecting, and packaging. The enoxaparin sodium injection produced by the process has poor stability in pH, color and activity, and particularly in the process of accelerated experiment, the medicament has poor stability in the later period of accelerated experiment, including large reduction of pH, obvious change of color, reduction of potency of liquid medicine and the like, so the injection produced by the common sterile process has certain quality problems.
The patent CN102085178A increases the stability of the solution through nitrogen protection and pH adjustment processes, but the actual operation is complicated, the problem of oxygen content in water cannot be fundamentally solved while the production is not changed, the color of the solution is gradually deepened in long-term storage and acceleration tests, and the activity is reduced.
Patent CN104013570B discloses a prescription of enoxaparin sodium injection, wherein the prescription is applied to the preparation of enoxaparin sodium injection by adding an antioxidant of a specified type and adjusting the pH. The injection is prepared from enoxaparin sodium, vitamin C, L-cysteine and water for injection, and the pH value of the injection is adjusted to 5.5-7.5 by a pH regulator. Compared with the prior art, the stability of the enoxaparin sodium injection is greatly improved, but the risk of safety and effectiveness of the product in the clinical use process can be increased by adding two auxiliary materials, namely vitamin C and L-cysteine, which are not contained in the original research into the prescription.
The method is poor in pH, color and potency stability of the enoxaparin sodium injection, and particularly has poor drug stability in the accelerated experiment process, including the large decrease of pH, color change, the decrease of potency of liquid medicine and the like. Therefore, it is still necessary to provide a stable enoxaparin sodium preparation, which has better stability and is convenient for clinical administration.
Disclosure of Invention
The invention provides enoxaparin sodium for injection and a preparation method thereof, wherein the enoxaparin sodium for injection contains enoxaparin sodium and hydrochloric acid or sodium hydroxide serving as a pH regulator, and the preparation method comprises the following steps:
a. weighing 60% of water for injection below 25 ℃, adding enoxaparin sodium to dissolve, uniformly mixing, and adjusting the pH value of the solution to 6.5-7.5 by using a pH regulator hydrochloric acid or sodium hydroxide;
b. adding water for injection into the solution to the amount of the prescription;
c. filtering with 0.22 μm PVDF filter element to obtain per 1ml filter element containing enoxaparin sodium 10000 AXaIU;
d. filling to obtain bottles containing enoxaparin sodium with concentration of 3000AXaIU 0.3ml, 4000AXaIU 0.4ml, 6000AXaIU 0.6ml, 8000AXaIU 0.8 ml.
According to the enoxaparin sodium for injection and the preparation method thereof, the amount of bacterial endotoxin of the raw material drug enoxaparin sodium is less than 0.008 EU/IU.
According to the enoxaparin sodium for injection and the preparation method thereof, hydrochloric acid or sodium hydroxide is used as a pH regulator, and the pH value of the solution is regulated to 6.5-7.5.
According to the enoxaparin sodium for injection and the preparation method thereof, the freeze-drying process comprises three steps of pre-freezing, primary drying and analytic drying.
According to the enoxaparin sodium for injection and the preparation method thereof, the prefreezing comprises the following steps of reducing the temperature of a product to-20 ℃, then preserving heat for 1 hour, then reducing the temperature of a clapboard to-40 ℃, and preserving heat for 2 hours.
According to the enoxaparin sodium for injection and the preparation method thereof, the temperature of the partition plate is raised to-25 ℃ in one sublimation step and is kept for about 9-13 hours.
According to the enoxaparin sodium for injection and the preparation method thereof, the temperature of the clapboard is raised to 0 ℃ in the desorption drying step and is kept for about 1-3 hours. And raising the temperature of the rear partition plate to 20 ℃, closing and heating the sample to about 10 ℃, filling nitrogen and pressing a plug.
The inventor finds that the enoxaparin sodium injection prepared into the enoxaparin sodium for injection has the following advantages: 1) the enoxaparin sodium for injection is more stable than the enoxaparin sodium injection, the enoxaparin sodium injection is greatly influenced by external temperature, the color of the enoxaparin sodium injection solution can obviously change under the high-temperature condition, and the color of the enoxaparin sodium injection is changed from yellow No. 1 to be more than yellow No. 8 in an accelerated test of 6 months, so that the color of the enoxaparin sodium injection is far out of standard. In an accelerated test, the enoxaparin sodium for injection produced by the invention has no obvious change in each index, even after a high-temperature test at 60 ℃ for 30 days, each index is kept stable, and the color is less than yellow No. 1. 2) Better administration convenience, convenient use for injecting 40mg enoxaparin sodium for patients with large dose, reduced administration times, reduced infection risk and reduced pain. For example, 75kg of patients with 100IU per kg of therapeutic dose need to take 7500IU and 4000IU of enoxaparin sodium injection into two branches, and 4000IU of enoxaparin sodium for injection can be dissolved together and a needle is used, so that the pain of the patients caused by the injection is reduced. The enoxaparin sodium for injection is more convenient to administer than the enoxaparin sodium injection. 3) Convenience of transportation. The enoxaparin sodium for injection is packaged in 2ml penicillin bottles with 10 capsules, occupies small space and is convenient to deliver. And the enoxaparin sodium injection is only contained in 2 boxes with the same size, occupies clinical use space and is inconvenient to transport.
The inventor researches and discovers that the enoxaparin sodium for injection has better stability when the pH value of the enoxaparin sodium for injection is controlled to be 6.5-7.5. When the pH value is less than 6.5 or more than 7.5, it is found that the prepared enoxaparin sodium for injection has the phenomena of darkening of color and lowering of titer.
The inventor researches and discovers that the temperature of the clapboard for primary drying of the enoxaparin sodium for injection is controlled to be-25 ℃ and kept for about 9-13 h, and the temperature of the clapboard for desorption drying is controlled to be 0 ℃ and kept for about 1-3 h. And raising the temperature of the rear partition plate to 20 ℃, closing and heating the sample to about 10 ℃, filling nitrogen and pressing a plug. The product has better turbidity and appearance.
According to the present invention, a more stable anticoagulant preparation containing enoxaparin sodium can be obtained. The invention adopts the freeze-drying process to prepare the enoxaparin sodium for injection, has simple process and cost saving, and is more suitable for commercial production.
Detailed Description
In order to make those skilled in the art better understand the technical solution of the present invention, the following specific examples are given, but the present invention is not limited to the following examples.
Example 1:
remarking: represents removal in the freeze-drying process.
The preparation method of the formula 1 comprises the following steps: weighing 60% of water for injection below 25 ℃, adding enoxaparin sodium, dissolving, mixing uniformly, and adjusting the pH value of the solution to 7.0 by using a pH regulator hydrochloric acid or sodium hydroxide; adding water for injection into the solution to the amount of the prescription; filtering with 0.22 μm PVDF filter element to obtain per 1ml filter element containing enoxaparin sodium 10000 AXaIU; filling to obtain a solution (nitrogen-filled) containing enoxaparin sodium with concentration of 4000AXaIU:0.4ml in each bottle.
The preparation method of the formula 2 comprises the following steps: weighing 60% of water for injection below 25 ℃, adding enoxaparin sodium, dissolving, mixing uniformly, and adjusting the pH value of the solution to 7.0 by using a pH regulator hydrochloric acid or sodium hydroxide; adding water for injection into the solution to the amount of the prescription; filtering with 0.22 μm PVDF filter element to obtain per 1ml filter element containing enoxaparin sodium 10000 AXaIU; filling to obtain a solution containing enoxaparin sodium with the concentration of 4000AXaIU:0.4ml in each bottle. Then freeze-drying the obtained solution, wherein the freeze-drying process comprises the following steps of cooling the pre-frozen product to-20 ℃, then preserving heat for 1h, cooling the temperature of the partition plate to-40 ℃, and preserving heat for 2 h; in the primary sublimation step, the temperature of the clapboard is raised to-25 ℃ and kept for about 11 hours; and in the analysis drying step, the temperature of the clapboard is increased to 0 ℃, the temperature of the clapboard is increased to 20 ℃ after the temperature is maintained for about 2 hours, the heating is closed when the temperature of the sample is about 10 ℃, nitrogen is filled, and the plug is pressed.
The stability of reference formulation 8S275, recipe 1 and recipe 2 were examined separately under accelerated conditions (40 ℃ C., 75% RH), and the results are shown in Table 1 for stability under accelerated conditions.
Table 1: stability under accelerated conditions
| Batch number | Test item | Acceleration of 0 month | Accelerated for 6 months |
| 8S275 | Color of solution | Yellow No. 1 | Yellow No. 8 |
| Prescription 1 | Color of solution | Yellow No. 1 | Yellow No. 8 |
| Prescription 2 | Color of solution | Less than yellow No. 1 | Less than yellow No. 1 |
And (4) analyzing results: the color of the solution changes from yellow No. 1 accelerated for 0 month to yellow No. 8 accelerated for 6 months under the acceleration condition of the originally-researched enoxaparin sodium injection and the home-made enoxaparin sodium injection, and the color becomes darker along with the increase of the stability time; the enoxaparin sodium for injection has no obvious deepening phenomenon, and is less than yellow No. 1 in both 0 month and 6 months.
Example 2:
remarking: represents removal in the freeze-drying process.
The preparation method comprises the following steps: weighing 60% of water for injection below 25 ℃, adding enoxaparin sodium, dissolving, mixing uniformly, and adjusting the pH value of the solution to a target pH value by using a pH regulator hydrochloric acid or sodium hydroxide; adding water for injection into the solution to the amount of the prescription; filtering with 0.22 μm PVDF filter element to obtain per 1ml filter element containing enoxaparin sodium 10000 AXaIU; filling to obtain a solution containing enoxaparin sodium with the concentration of 4000AXaIU:0.4ml in each bottle. Then freeze-drying the obtained solution, wherein the freeze-drying process comprises the following steps of cooling the pre-frozen product to-20 ℃, then preserving heat for 1h, cooling the temperature of the partition plate to-40 ℃, and preserving heat for 2 h; in the primary sublimation step, the temperature of the clapboard is raised to-25 ℃ and kept for about 11 hours; and in the analysis drying step, the temperature of the clapboard is increased to 0 ℃, the temperature of the clapboard is increased to 20 ℃ after the temperature is maintained for about 2 hours, the heating is closed when the temperature of the sample is about 10 ℃, nitrogen is filled, and the plug is pressed.
Example 3:
remarking: represents removal in the freeze-drying process.
The preparation method comprises the following steps: weighing 60% of water for injection below 25 ℃, adding enoxaparin sodium, dissolving, mixing uniformly, and adjusting the pH value of the solution to a target pH value by using a pH regulator hydrochloric acid or sodium hydroxide; adding water for injection into the solution to the amount of the prescription; filtering with 0.22 μm PVDF filter element to obtain per 1ml filter element containing enoxaparin sodium 10000 AXaIU; filling to obtain a solution containing enoxaparin sodium in each bottle, wherein the concentration of enoxaparin sodium is 3000AXaIU:0.3 ml. Then freeze-drying the obtained solution, wherein the freeze-drying process comprises the following steps of cooling the pre-frozen product to-20 ℃, then preserving heat for 1h, cooling the temperature of the partition plate to-40 ℃, and preserving heat for 2 h; in the primary sublimation step, the temperature of the clapboard is raised to-25 ℃ and kept for about 9 hours; and in the analysis drying step, the temperature of the clapboard is increased to 0 ℃, the temperature of the clapboard is increased to 20 ℃ after the temperature is maintained for about 2 hours, the heating is closed when the temperature of the sample is about 10 ℃, nitrogen is filled, and the plug is pressed.
Example 4:
remarking: represents removal in the freeze-drying process.
The preparation method comprises the following steps: weighing 60% of water for injection below 25 ℃, adding enoxaparin sodium, dissolving, mixing uniformly, and adjusting the pH value of the solution to a target pH value by using a pH regulator hydrochloric acid or sodium hydroxide; adding water for injection into the solution to the amount of the prescription; filtering with 0.22 μm PVDF filter element to obtain per 1ml filter element containing enoxaparin sodium 10000 AXaIU; filling to obtain a solution containing enoxaparin sodium with concentration of 6000AXaIU:0.6ml in each bottle. Then freeze-drying the obtained solution, wherein the freeze-drying process comprises the following steps of cooling the pre-frozen product to-20 ℃, then preserving heat for 1h, cooling the temperature of the partition plate to-40 ℃, and preserving heat for 2 h; in the primary sublimation step, the temperature of the clapboard is raised to-25 ℃ and kept for about 13 hours; and in the analysis drying step, the temperature of the clapboard is increased to 0 ℃, the temperature of the clapboard is increased to 20 ℃ after the temperature is maintained for about 1h, the heating is closed when the temperature of the sample is about 10 ℃, nitrogen is filled, and the plug is pressed.
Example 5:
remarking: represents removal in the freeze-drying process.
The preparation method comprises the following steps: weighing 60% of water for injection below 25 ℃, adding enoxaparin sodium, dissolving, mixing uniformly, and adjusting the pH value of the solution to a target pH value by using a pH regulator hydrochloric acid or sodium hydroxide; adding water for injection into the solution to the amount of the prescription; filtering with 0.22 μm PVDF filter element to obtain per 1ml filter element containing enoxaparin sodium 10000 AXaIU; filling to obtain a solution containing enoxaparin sodium in each bottle and having a concentration of 10000AXaIU:1.0 ml. Then freeze-drying the obtained solution, wherein the freeze-drying process comprises the following steps of cooling the pre-frozen product to-20 ℃, then preserving heat for 1h, cooling the temperature of the partition plate to-40 ℃, and preserving heat for 2 h; in the primary sublimation step, the temperature of the clapboard is raised to-25 ℃ and kept for about 9 hours; and in the analysis drying step, the temperature of the clapboard is increased to 0 ℃, the temperature of the clapboard is increased to 20 ℃ after the temperature is maintained for about 3 hours, the heating is closed when the temperature of the sample is about 10 ℃, nitrogen is filled, and the plug is pressed.
Claims (7)
1. Enoxaparin sodium for injection containing enoxaparin sodium and its preparation method, contain enoxaparin sodium and pH regulator hydrochloric acid or sodium hydroxide in the enoxaparin sodium for injection, characterized by, the preparation method includes the following steps:
a. weighing 60% of water for injection below 25 ℃, adding enoxaparin sodium to dissolve, uniformly mixing, and adjusting the pH value of the solution to 6.5-7.5 by using a pH regulator hydrochloric acid or sodium hydroxide;
b. adding water for injection into the solution to the amount of the prescription;
c. filtering with 0.22 μm PVDF filter element to obtain per 1ml filter element containing enoxaparin sodium 10000 AXaIU;
d. filling to obtain a bottle containing enoxaparin sodium with concentration of 3000AXaIU of 0.3ml, 4000AXaIU of 0.4ml, 6000AXaIU of 0.6ml and 8000AXaIU of 0.8 ml;
e. the solution is frozen and dried to obtain the enoxaparin sodium for injection.
2. The enoxaparin sodium for injection according to claim 1, wherein the amount of bacterial endotoxin in the drug enoxaparin sodium is less than 0.008 EU/IU.
3. The enoxaparin sodium for injection according to claim 1, wherein the pH regulator is hydrochloric acid or sodium hydroxide, and the pH of the solution is adjusted to 6.5-7.5.
4. The enoxaparin sodium for injection according to claim 1, wherein the lyophilization process comprises three steps of pre-freezing, primary drying and analytical drying.
5. The enoxaparin sodium for injection according to claim 4, wherein the pre-freezing step comprises the steps of cooling the product to-20 ℃, maintaining the temperature for 1 hour, cooling the spacer to-40 ℃, and maintaining the temperature for 2 hours.
6. The enoxaparin sodium for injection according to claim 4, wherein the temperature of the partition is raised to-25 ℃ in one sublimation step and maintained for about 9-13 hours.
7. The enoxaparin sodium for injection according to claim 4, wherein the drying step is performed by heating the separator to 0 ℃ for about 1-3 hours; then the temperature of the clapboard is raised to 20 ℃, the heating is closed when the temperature of the sample is about 10 ℃, nitrogen is filled, the plug is pressed, and the sample is taken out of the box.
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| CN112656767A (en) * | 2021-01-22 | 2021-04-16 | 烟台东诚药业集团股份有限公司 | Enoxaparin sodium injection and preparation method thereof |
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