CN111249227A - Preparation method of fondaparinux sodium injection - Google Patents
Preparation method of fondaparinux sodium injection Download PDFInfo
- Publication number
- CN111249227A CN111249227A CN201811492043.0A CN201811492043A CN111249227A CN 111249227 A CN111249227 A CN 111249227A CN 201811492043 A CN201811492043 A CN 201811492043A CN 111249227 A CN111249227 A CN 111249227A
- Authority
- CN
- China
- Prior art keywords
- injection
- fondaparinux sodium
- water
- regulator
- fondaparinux
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 229960003661 fondaparinux sodium Drugs 0.000 title claims abstract description 83
- 238000002347 injection Methods 0.000 title claims abstract description 70
- 239000007924 injection Substances 0.000 title claims abstract description 70
- 238000002360 preparation method Methods 0.000 title claims abstract description 24
- XEKSTYNIJLDDAZ-JASSWCPGSA-F fondaparinux sodium Chemical compound [Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].O[C@@H]1[C@@H](NS([O-])(=O)=O)[C@@H](OC)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]2[C@@H]([C@@H](OS([O-])(=O)=O)[C@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O[C@@H]4[C@@H]([C@@H](O)[C@H](O)[C@@H](COS([O-])(=O)=O)O4)NS([O-])(=O)=O)[C@H](O3)C(O)=O)O)[C@@H](COS([O-])(=O)=O)O2)NS([O-])(=O)=O)[C@H](C(O)=O)O1 XEKSTYNIJLDDAZ-JASSWCPGSA-F 0.000 title abstract description 76
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 43
- 230000001954 sterilising effect Effects 0.000 claims abstract description 39
- 238000004659 sterilization and disinfection Methods 0.000 claims abstract description 37
- 239000008215 water for injection Substances 0.000 claims abstract description 34
- 239000003814 drug Substances 0.000 claims abstract description 27
- 239000007788 liquid Substances 0.000 claims abstract description 23
- 239000000243 solution Substances 0.000 claims abstract description 19
- 239000004480 active ingredient Substances 0.000 claims abstract description 12
- 238000011049 filling Methods 0.000 claims abstract description 12
- 238000003756 stirring Methods 0.000 claims abstract description 12
- 238000010438 heat treatment Methods 0.000 claims abstract description 9
- 238000001816 cooling Methods 0.000 claims abstract description 8
- 238000001914 filtration Methods 0.000 claims abstract description 7
- 239000012528 membrane Substances 0.000 claims abstract description 7
- 229940071643 prefilled syringe Drugs 0.000 claims abstract description 7
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 66
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 42
- 239000011780 sodium chloride Substances 0.000 claims description 21
- 238000000034 method Methods 0.000 claims description 17
- 239000000203 mixture Substances 0.000 claims description 15
- 238000004519 manufacturing process Methods 0.000 claims description 13
- 239000000337 buffer salt Substances 0.000 claims description 3
- 150000002500 ions Chemical class 0.000 claims description 2
- 238000010979 pH adjustment Methods 0.000 claims description 2
- XEKSTYNIJLDDAZ-JASSWCPGSA-D decasodium;(2s,3s,4r,5r,6r)-6-[(2r,3r,4r,5r,6r)-6-[(2r,3s,4s,5r,6r)-2-carboxylato-4-hydroxy-6-[(2r,3s,4r,5r,6s)-4-hydroxy-6-methoxy-5-(sulfonatoamino)-2-(sulfonatooxymethyl)oxan-3-yl]oxy-5-sulfonatooxyoxan-3-yl]oxy-5-(sulfonatoamino)-4-sulfonatooxy-2-(sul Chemical compound [Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].O[C@@H]1[C@@H](NS([O-])(=O)=O)[C@@H](OC)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]2[C@@H]([C@@H](OS([O-])(=O)=O)[C@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O[C@@H]4[C@@H]([C@@H](O)[C@H](O)[C@@H](COS([O-])(=O)=O)O4)NS([O-])(=O)=O)[C@H](O3)C([O-])=O)O)[C@@H](COS([O-])(=O)=O)O2)NS([O-])(=O)=O)[C@H](C([O-])=O)O1 XEKSTYNIJLDDAZ-JASSWCPGSA-D 0.000 claims 8
- 238000009472 formulation Methods 0.000 claims 1
- 238000007689 inspection Methods 0.000 abstract description 12
- 239000012535 impurity Substances 0.000 abstract description 11
- 238000004806 packaging method and process Methods 0.000 abstract description 8
- 238000005303 weighing Methods 0.000 abstract description 8
- 229940079593 drug Drugs 0.000 abstract description 5
- 238000009776 industrial production Methods 0.000 abstract description 5
- 230000036512 infertility Effects 0.000 abstract description 5
- 239000000463 material Substances 0.000 abstract description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 14
- 230000003204 osmotic effect Effects 0.000 description 13
- 230000000052 comparative effect Effects 0.000 description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- 229910052757 nitrogen Inorganic materials 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 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 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 4
- 229960002897 heparin Drugs 0.000 description 4
- 229920000669 heparin Polymers 0.000 description 4
- 239000003055 low molecular weight heparin Substances 0.000 description 4
- 239000001301 oxygen Substances 0.000 description 4
- 229910052760 oxygen Inorganic materials 0.000 description 4
- 206010018910 Haemolysis Diseases 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 230000008588 hemolysis Effects 0.000 description 3
- 125000001805 pentosyl group Chemical group 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 208000032843 Hemorrhage Diseases 0.000 description 2
- 206010020751 Hypersensitivity Diseases 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 208000026935 allergic disease Diseases 0.000 description 2
- 230000007815 allergy Effects 0.000 description 2
- WQZGKKKJIJFFOK-UHFFFAOYSA-N alpha-D-glucopyranose Natural products OCC1OC(O)C(O)C(O)C1O WQZGKKKJIJFFOK-UHFFFAOYSA-N 0.000 description 2
- 150000001450 anions Chemical class 0.000 description 2
- 239000003146 anticoagulant agent Substances 0.000 description 2
- 230000010100 anticoagulation Effects 0.000 description 2
- 239000004019 antithrombin Substances 0.000 description 2
- 208000034158 bleeding Diseases 0.000 description 2
- 230000000740 bleeding effect Effects 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 229910001873 dinitrogen Inorganic materials 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- HNSDLXPSAYFUHK-UHFFFAOYSA-N 1,4-bis(2-ethylhexyl) sulfosuccinate Chemical compound CCCCC(CC)COC(=O)CC(S(O)(=O)=O)C(=O)OCC(CC)CCCC HNSDLXPSAYFUHK-UHFFFAOYSA-N 0.000 description 1
- 208000004476 Acute Coronary Syndrome Diseases 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 108010074860 Factor Xa Proteins 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- 102100027378 Prothrombin Human genes 0.000 description 1
- 108010094028 Prothrombin Proteins 0.000 description 1
- 208000010378 Pulmonary Embolism Diseases 0.000 description 1
- 229940124639 Selective inhibitor Drugs 0.000 description 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 230000002785 anti-thrombosis Effects 0.000 description 1
- 229940127219 anticoagulant drug Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- AEMOLEFTQBMNLQ-QIUUJYRFSA-N beta-D-glucuronic acid Chemical compound O[C@@H]1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O AEMOLEFTQBMNLQ-QIUUJYRFSA-N 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 238000010523 cascade reaction Methods 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 230000015271 coagulation Effects 0.000 description 1
- 238000005345 coagulation Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- HDFXRQJQZBPDLF-UHFFFAOYSA-L disodium hydrogen carbonate Chemical compound [Na+].[Na+].OC([O-])=O.OC([O-])=O HDFXRQJQZBPDLF-UHFFFAOYSA-L 0.000 description 1
- 229960005153 enoxaparin sodium Drugs 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000000815 hypotonic solution Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 239000000644 isotonic solution Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000000399 orthopedic effect Effects 0.000 description 1
- 229920000193 polymethacrylate Polymers 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 229940039716 prothrombin Drugs 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 230000008929 regeneration Effects 0.000 description 1
- 238000011069 regeneration method Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 229910052709 silver Inorganic materials 0.000 description 1
- 239000004332 silver Substances 0.000 description 1
- -1 silver ions Chemical class 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 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 description 1
- 239000003643 water by type Substances 0.000 description 1
Classifications
-
- 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
- A61K9/08—Solutions
-
- 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
- A61K31/702—Oligosaccharides, i.e. having three to five saccharide radicals attached to each other by glycosidic linkages
-
- 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
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2/00—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor
- A61L2/0005—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor for pharmaceuticals, biologicals or living parts
- A61L2/0011—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor for pharmaceuticals, biologicals or living parts using physical methods
- A61L2/0023—Heat
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2202/00—Aspects relating to methods or apparatus for disinfecting or sterilising materials or objects
- A61L2202/20—Targets to be treated
- A61L2202/21—Pharmaceuticals, e.g. medicaments, artificial body parts
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Molecular Biology (AREA)
- Engineering & Computer Science (AREA)
- Biomedical Technology (AREA)
- Inorganic Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Dermatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention discloses a preparation method of fondaparinux sodium injection, which comprises the following steps: (1) weighing the raw and auxiliary materials according to the prescription of the fondaparinux sodium injection. (2) Adding part of water for injection into a solution preparation container, heating to 100 ℃, cooling to room temperature, adding active ingredients and an isoosmotic adjusting agent, and stirring for dissolving; (3) adjusting the pH value of the solution obtained in the step (2) to 6.5-7.5 by adopting a pH regulator, and adding the rest water for injection to fix the volume; (4) filtering the liquid medicine with 0.22 micron microporous filter membrane or filter element; (5) filling the filtered liquid medicine into a prefilled syringe, and carrying out damp-heat sterilization at the temperature of 121-. (6) And (5) after sterilization, performing light inspection, packaging and inspection to obtain the fondaparinux sodium injection. The preparation method of the invention conforms to the requirements of drug registration regulations, has less impurities, good stability and high sterility assurance level, and is suitable for industrial production.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a production and preparation method of fondaparinux sodium injection.
Background
Fondaparinux sodium is a single compound that is chemically synthesized, structurally defined, and of defined molecular weight. It is currently the most potent factor Xa selective inhibitor. Compared with heparin and low molecular heparin derived from animals, fondaparinux sodium is a single compound with a definite structure, and heparin and low molecular heparin are complex compounds with structures which cannot be clearly characterized. The fondaparinux sodium is an analogue of anticoagulant characteristic pentose fragment at an active site of low-molecular heparin, can be reversibly combined with antithrombin, and increases the activity of the antithrombin for inhibiting Xa by about 300 times, thereby effectively inhibiting the coagulation cascade reaction.
The fondaparinux sodium is not combined with the platelet, and does not influence the function of the platelet, the aggregation and prothrombin time of the platelet, thereby reducing the bleeding risk of low molecular heparin. Clinical data show that the curative effect of fondaparinux sodium in antithrombotic treatment of orthopedic surgery, pulmonary embolism, acute coronary syndrome and the like is not lower than that of enoxaparin sodium, and the relative risk of bleeding is reduced by 50%.
When people research the anti-coagulation structure of heparin, a pentose sequence is found to be the real anti-coagulation function in heparin molecules, the molecular structure of the pentose sequence is determined, and then people synthesize the active ingredient fondaparinux sodium of the structure.
Fondaparinux sodium has the chemical name methyl O- (2-deoxy-6-O-sulfonic-2-sulfonamide- α -D-glucopyranose) - (1 → 4) -O- (β -D-glucopyranose-uronic acid) - (1 → 4) -O- (2-deoxy-3, 6-O-disulfonic-2-sulfonamide- α -D-glucopyranose) - (1 → 4) -O- (2-O-sulfonic- α -L-iduronic acid) - (1 → 4) -2-deoxy-6-O-sulfonic-2-sulfonamide- α -D-glucopyranoside decasodium salt.
Fondaparinux sodium injection, common name: fondaparinux sodium injection, english name: fondaparinux Sodium Injection.
The molecular formula is as follows: c31H43N3Na10O49S8Molecular weight: 1728.
CN 105596291 a discloses a fondaparinux sodium injection composition, which contains 50-120ppm of silver ions to reduce the degradation of fondaparinux sodium, but the method does not meet the safety requirement of injection due to the addition of metal ions, is not suitable for quality control of the current quality standard, and cannot ensure safety and effectiveness.
The stability of the fondaparinux sodium injection is improved by adding a buffer solution into the composition described in CN 106727289A, but the osmotic pressure of the liquid medicine is increased by adopting buffer salt, which exceeds the normal osmotic pressure range, so that the problems of hemolysis, pain and the like are easily caused; the active carbon adsorption operation is introduced in the process, and the operation is not recommended to be used in the current injection production process; the method is stirred and dissolved at the controlled temperature, and the operation is complicated; 110 ℃ and 116 ℃ (6-20min) are adopted for sterilization, which does not meet the requirement of aseptic guarantee of injection production.
CN 107595769A discloses a preparation method of fondaparinux sodium injection composition, and although the invention is more in line with the requirements of drug registration regulations and industrial production than the previous invention, the impurity content is higher, and the process problem cannot be actually solved.
CN 108451899A discloses a production method of fondaparinux sodium injection, but the method adopts circulating steam sterilization at the temperature of 125-126 ℃ for 5-10min, which is difficult to realize in production, and the method has higher impurity content than CN 107595769A and low practical application value.
Disclosure of Invention
The invention provides a preparation method of fondaparinux sodium injection on the basis of the prior art. By optimizing the process, the prepared fondaparinux sodium injection has low impurity content and good stability, meets the requirements of drug registration regulations on quality, and is suitable for industrial production.
In order to achieve the purpose, the invention provides the following technical scheme:
a preparation method of fondaparinux sodium injection comprises the following steps:
(1) weighing various raw and auxiliary materials according to the prescription of the fondaparinux sodium injection, wherein the fondaparinux sodium injection consists of the following raw and auxiliary materials: fondaparinux sodium, sodium chloride, sodium hydroxide and water for injection;
(2) adding part of water for injection into a solution preparation container, heating to 100 ℃, cooling to room temperature, adding active ingredients and an isoosmotic adjusting agent, and stirring for dissolving;
(3) adjusting the pH value of the solution obtained in the step (2) to 6.5-7.5 by adopting a pH regulator, and adding the rest water for injection to fix the volume;
(4) filtering the liquid medicine with 0.22 micron microporous filter membrane or filter element;
(5) filling the filtered liquid medicine into a prefilled syringe, and carrying out damp-heat sterilization at the temperature of 121-.
(6) And (5) after sterilization, performing light inspection, packaging and inspection to obtain the fondaparinux sodium injection.
In the preparation method of the fondaparinux sodium injection, the product prescription in the step (1) only contains active ingredients, an isotonic regulator, a pH regulator and water for injection, and buffer salt and other ions are not added; every 1000M of fondaparinux sodium injection contains the following components in dosage: 2.5g of fondaparinux sodium, 4.2g of sodium chloride, pH adjustment to 6.5-7.5 by a pH regulator, and the balance of water for injection to 500 ml.
In a preferred embodiment, the injection water is added in the step (2) in an amount of 90-95%, preferably 90%, of the total amount thereof; the water for injection is warmed to 100 ℃ and held for a period of 0 to 10 minutes, preferably 5 minutes.
In a preferred embodiment, the pH regulator in step (3) is 0.1mol/L to 0.5mol/L sodium hydroxide, preferably 0.1mol/L sodium hydroxide, and the pH is adjusted to 6.5 to 7.5, preferably 7.5.
In a preferred embodiment, the sterilization mode in the step (5) is moist heat sterilization, the sterilization temperature is 121-125 ℃, preferably 121 ℃, and the sterilization time is 12-15 minutes, preferably 15 minutes.
Compared with the prior art, the invention has the beneficial effects that:
1. the fondaparinux sodium injection prepared by the invention removes oxygen contained in the solution and reduces the oxygen content by heating the water for injection to 100 ℃ so as to improve the stability of the product. Compared with nitrogen filling, the method is simpler and easier to implement, does not need to be provided with a nitrogen generating device, is not influenced by the quality of nitrogen, and has good effect.
2. The pH regulator sodium hydroxide used in the invention can effectively regulate the pH of the solution, the pH of the fondaparinux sodium injection is regulated to 6.5-7.5, the clarity of the obtained solution is good, the detection requirements of various items under the Chinese pharmacopoeia injection item are met, and the stability of the product quality is greatly improved. Through studies in the pH range of 4 to 9, the inventors have found that moist heat sterilization can be tolerated up to 125 ℃ for at least 15 minutes in the range of 6.5 to 7.5. The inventor researches and discovers that the product impurities are greatly increased after high-humidity sterilization below the pH value.
3. The fondaparinux sodium injection adopts a damp-heat sterilization method, and ensures that the sterility assurance level is not higher than 10 under the conditions of increasing the sterilization temperature and prolonging the sterilization time-6And the sterility of the injection is ensured. Meanwhile, through reasonable process parameters, the generation of various impurities is reduced, and the stability of the product quality is ensured.
4. The preparation method of the invention meets the requirements of drug registration regulations, is suitable for industrial production, the product quality meets the USP current quality standard, and the prepared product is safe and effective after allergy, hemolysis and irritation experiments.
Detailed Description
The production process of the present invention is further illustrated by the following examples, which are not intended to limit the present invention in any way.
Example 1
| Composition of matter | Dosage of | Function of |
| Fondaparinux sodium | 2.5g | Active ingredient |
| Sodium chloride | 4.2g | Osmotic pressure regulator |
| Sodium hydroxide | Proper amount of | pH regulator |
| Water for injection | Adding to 500ml | Solvent(s) |
In this embodiment, the preparation method of fondaparinux sodium injection includes the following steps:
(1) according to the prescription of the fondaparinux sodium injection, weighing fondaparinux sodium, sodium chloride, sodium hydroxide and water for injection according to the prescription amount;
(2) adding 90% of water for injection into the solution preparation container, heating to 100 deg.C, cooling to room temperature, adding fondaparinux sodium and sodium chloride, stirring and dissolving;
(3) adjusting pH to 7.0 with sodium hydroxide solution, adding the rest water for injection to constant volume;
(4) filtering the liquid medicine with 0.22 micron microporous filter membrane or filter element;
(5) filling the filtered liquid medicine into a prefilled syringe, and performing damp-heat sterilization at 121 ℃ for 12 minutes to obtain the liquid medicine;
(6) and (5) after sterilization, performing light inspection, packaging and inspection to obtain the fondaparinux sodium injection.
Example 2
| Composition of matter | Dosage of | Function of |
| Fondaparinux sodium | 2.5g | Active ingredient |
| Sodium chloride | 4.2g | Osmotic pressure regulator |
| Sodium hydroxide | Proper amount of | pH regulator |
| Water for injection | Adding to 500ml | Solvent(s) |
In this embodiment, the preparation method of fondaparinux sodium injection includes the following steps:
(1) according to the prescription of the fondaparinux sodium injection, weighing fondaparinux sodium, sodium chloride, sodium hydroxide and water for injection according to the prescription amount;
(2) adding injection water accounting for 95% of the total amount into a solution preparation container, heating to 100 ℃, keeping for 10 minutes, cooling to room temperature, adding fondaparinux sodium and sodium chloride, and stirring for dissolving;
(3) adjusting pH to 6.5 with sodium hydroxide solution, adding the rest water for injection to constant volume;
(4) filtering the liquid medicine with 0.22 micron microporous filter membrane or filter element;
(5) filling the filtered liquid medicine into a prefilled syringe, and performing damp-heat sterilization at 125 ℃ for 12 minutes to obtain the liquid medicine;
(6) sterilizing, inspecting under light, packaging, and inspecting to obtain Fondaparinux sodium injection
Example 3
| Composition of matter | Dosage of | Function of |
| Fondaparinux sodium | 2.5g | Active ingredient |
| Sodium chloride | 4.2g | Osmotic pressure regulator |
| Sodium hydroxide | Proper amount of | pH regulator |
| Water for injection | Adding to 500ml | Solvent(s) |
In this embodiment, the preparation method of fondaparinux sodium injection includes the following steps:
(1) according to the prescription of the fondaparinux sodium injection, weighing fondaparinux sodium, sodium chloride, sodium hydroxide and water for injection according to the prescription amount;
(2) adding 90% of water for injection into a solution preparation container, heating to 100 deg.C, maintaining for 5min, cooling to room temperature, adding fondaparinux sodium and sodium chloride, stirring and dissolving;
(3) adjusting pH to 7.0 with sodium hydroxide solution, adding the rest water for injection to constant volume;
(4) filtering the liquid medicine with 0.22 micron microporous filter membrane or filter element;
(5) filling the filtered liquid medicine into a prefilled syringe, and performing damp-heat sterilization at 121 ℃ for 15 minutes to obtain the liquid medicine;
(6) sterilizing, inspecting under light, packaging, and inspecting to obtain Fondaparinux sodium injection
Example 4
| Composition of matter | Dosage of | Function of |
| Fondaparinux sodium | 2.5g | Active ingredient |
| Sodium chloride | 4.2g | Osmotic pressure regulator |
| Sodium hydroxide | Proper amount of | pH regulator |
| Water for injection | Adding to 500ml | Solvent(s) |
In this embodiment, the preparation method of fondaparinux sodium injection includes the following steps:
(1) according to the prescription of the fondaparinux sodium injection, weighing fondaparinux sodium, sodium chloride, sodium hydroxide and water for injection according to the prescription amount;
(2) adding injection water accounting for 95% of the total amount into a solution preparation container, heating to 100 ℃, keeping for 5 minutes, cooling to room temperature, adding fondaparinux sodium and sodium chloride, and stirring for dissolving;
(3) adjusting pH to 7.5 with sodium hydroxide solution, adding the rest water for injection to constant volume;
(4) filtering the liquid medicine with 0.22 micron microporous filter membrane or filter element;
(5) filling the filtered liquid medicine into a prefilled syringe, and performing damp-heat sterilization at 125 ℃ for 15 minutes to obtain the liquid medicine;
(6) and (5) after sterilization, performing light inspection, packaging and inspection to obtain the fondaparinux sodium injection.
Comparative example 1
See patent CN 107595769A for example 1 sample production method for preparing sample and detecting osmotic pressure and impurity content
| Composition of matter | Dosage of | Function of |
| Fondaparinux sodium | 5g | Active ingredient |
| Sodium chloride | 9g | Isotonic regulator |
| Sodium hydroxide | Adjusting the pH to 7-8 | pH value regulator |
| Hydrochloric acid | Adjusting the pH to 7-8 | pH value regulator |
| Water for injection | Is added to 2000ml | Solvent(s) |
| Is made into | 4000 pieces of | —— |
In this comparative example, the preparation method of the fondaparinux sodium injection composition includes the following steps:
(1) weighing the raw materials according to the prescription of the fondaparinux sodium injection composition, wherein the fondaparinux sodium injection composition is prepared from the following raw materials: fondaparinux sodium, sodium chloride, a pH regulator and water for injection, wherein the pH regulator is sodium hydroxide or hydrochloric acid;
(2) mixing fondaparinux sodium and sodium chloride, adding injection water accounting for 75% of the total amount, stirring to dissolve, adjusting the pH to 7-8 by using a pH regulator, adding the rest injection water, and uniformly stirring to obtain a liquid medicine, wherein the stirring is performed at 10 ℃;
(3) filling the prepared liquid medicine, and performing high-temperature sterilization, cooling, light inspection, packaging and inspection to obtain the fondaparinux sodium injection composition, wherein the high-temperature sterilization is performed for 20min at 121 ℃.
The results of the osmotic pressure test performed on example 1, example 2, example 3, example 4 and comparative example 1 are shown in the following table:
TABLE 1 comparison of osmotic pressure results for the examples and comparative example 1
| Sample (I) | Osmotic pressure |
| Example 1 | 312mOsm/kg |
| Example 2 | 305mOsm/kg |
| Example 3 | 310mOsm/kg |
| Example 4 | 308mOsm/kg |
| Comparative example 1 | 215mOsm/kg |
According to the original research instruction of fondaparinux sodium injection, the fondaparinux sodium injection is an isotonic solution. As can be seen from the results in Table 1, the osmotic pressure in the comparative example is much lower than the isotonic requirement specified in the Chinese pharmacopoeia and the United states pharmacopoeia: 285 and 310mOsm/kg, which is a hypotonic solution, does not meet the quality requirement of the injection product. In the embodiment, the osmotic pressure is in the range of 285-310mOsm/kg, so that the application problems of edema, pain and the like caused by hypotonic can be avoided, and the standard of Chinese and United states pharmacopoeia is met.
Comparative example 2
See patent CN 108451899 a for example 2 sample production method to prepare sample and test its impurity content.
| Composition of matter | Dosage of | Function of |
| Fondaparinux sodium | 2.5g | Active ingredientIs divided into |
| Sodium chloride | 8.5-9g | Isotonic regulator |
| Sodium hydroxide | Adjusting the pH to 5.5-5.7 | pH regulator |
| Hydrochloric acid | Adjusting the pH to 5.5-5.7 | pH regulator |
| Water for injection | Adding to 1000ml | Solvent(s) |
| Nitrogen gas | Proper amount of | Insulating oxygen |
In the comparative example, the production method of the fondaparinux sodium injection comprises the following steps:
(1) weighing the materials according to the formula of the fondaparinux sodium injection, wherein the materials comprise the following components in percentage by weight: fondaparinux sodium, sodium chloride, sodium hydroxide, hydrochloric acid and water for injection;
(2) adding 60% of water for injection, introducing nitrogen gas to control dissolved oxygen amount not higher than 10ppm, adding sodium chloride and fondaparinux sodium respectively, and stirring and charging nitrogen continuously during charging process.
(3) Adjusting pH to 5.5-5.7 with pH regulator, adding the rest injectable water to desired volume, charging nitrogen, and stirring to obtain medicinal liquid.
(4) Filling with a prefilled needle filling machine, introducing nitrogen for protection during filling, allowing the filled liquid medicine to circulate steam at 125-126 deg.C, sterilizing at high temperature for 10min, and performing light inspection, packaging and inspection.
In the comparative example preparation process, flow-through steam sterilization at 125 ℃ -126 ℃ was found to be difficult to achieve, according to the definition in pharmacy for flow-through steam: it is a method for killing microorganisms by heating circulating steam at 100 ℃ under normal pressure. The sterilization time is usually 30 to 60 minutes. The method is suitable for disinfection and sterilization of high-temperature-intolerant preparations, but cannot guarantee that all spores are killed, and is an unreliable sterilization method. As the operation mode of 'steam circulation at 125-126 ℃ and high-temperature sterilization for 10 min' of the original inventor does not conform to the conventional expression of the professional field, the steam circulation at 125-126 ℃ cannot be realized, and the production feasibility is not realized.
The sample described in example 2 of CN 108451899A according to the invention was prepared by autoclaving at 125 ℃ for 10min as described by the inventors.
The impurity contents of the examples and comparative examples were measured according to the chromatographic conditions disclosed in patent CN 107595769 a:
chromatographic conditions are as follows: using polymethacrylate resin with tetra-ammonium functional group as filling agent (Waters ICPak Anion Colum, 4.6X 50mm is suitable); the detector is a conductivity detector, an anion automatic regeneration inhibitor (Dionex ASRS-5004 mm can be used), and a sodium carbonate-sodium bicarbonate solution (0.106 g of anhydrous sodium carbonate and 0.168g of sodium bicarbonate are taken and put in a 1000ml measuring flask, dissolved and diluted to a scale by water, shaken up and filtered) is taken as a mobile phase, and the flow rate is 1ml per minute.
The results are given in the following table:
table 2 comparison of the results of the measurement of impurity content in examples and comparative example 1
The influencing factors of the product of example 3 and example 4 are tested, and the results of the relevant substances are shown in the following table:
table 3 example 3 influencing factors experimental results
Table 4 example 4 influencing factors experimental results
The fondaparinux sodium injection prepared by the invention has the advantages that the injection water is boiled, the pH value is controlled within a reasonable range, the proper sterilization temperature and time are adopted, the osmotic pressure of the obtained solution meets the isotonic requirement, the clarity is good, the related substances are obviously less than the known invention cases, the detection requirements under the Chinese pharmacopoeia injection item are met, the product quality standard in USP is also met, and the stability of the product quality is greatly improved.
The fondaparinux sodium injection adopts a damp-heat sterilization method, the sterilization temperature and time meet the requirements of Chinese pharmacopoeia on injection, the sterility of the injection is ensured, and the sterility guarantee level is not higher than 10-6。
The fondaparinux sodium injection strictly controls the conditions of all process parameters, further ensures the stability of product quality, has no crystallization and turbidity of solution, obviously reduces the generation of impurities, is suitable for industrial production, and is safe and effective after being proved by allergy, hemolysis and stimulation experiments.
While the preferred embodiments of the present invention have been described in detail, the present invention is not limited to the above embodiments, and various changes can be made without departing from the spirit of the present invention within the knowledge of those skilled in the art.
Claims (5)
1. A preparation method of fondaparinux sodium injection is characterized by comprising the following steps:
(1) the fondaparinux sodium injection of the invention has the following prescription composition: active ingredients, isotonic regulator, pH regulator and water for injection;
(2) adding part of water for injection into a container, heating to 100 deg.C, cooling to room temperature, adding active ingredient and isoosmotic adjusting agent, stirring and dissolving;
(3) adjusting the pH value of the solution obtained in the step (2) to 6.5-7.5 by adopting a pH regulator, and adding the rest water for injection to fix the volume;
(4) filtering the liquid medicine with 0.22 micron microporous filter membrane or filter element;
(5) filling the filtered liquid medicine into a prefilled syringe, and carrying out damp-heat sterilization at the temperature of 121-.
2. The method for preparing fondaparinux sodium injection according to claim 1, wherein the formulation of the product in step (1) only contains active ingredients, isotonic regulator, pH regulator and water for injection, and no buffer salt or other ions are added; every 1000M of fondaparinux sodium injection contains the following components in dosage: 2.5g of fondaparinux sodium, 4.2g of sodium chloride, pH adjustment to 6.5-7.5 by a pH regulator, and the balance of water for injection to 500 ml.
3. The method for producing fondaparinux sodium injection according to claim 1, wherein the injection water is added in an amount of 90-95%, preferably 90%, of the total amount in step (2); the water for injection is warmed to 100 ℃ and held for a period of 0 to 10 minutes, preferably 5 minutes.
4. The method for producing fondaparinux sodium injection according to claim 1, wherein the pH regulator in step (3) is 0.1mol/L to 0.5mol/L NaOH, preferably 0.1mol/L NaOH, and the pH is adjusted to 6.5 to 7.5, preferably 7.5.
5. The method for producing fondaparinux sodium injection according to claim 1, wherein the sterilization manner in step (5) is moist heat sterilization, the sterilization temperature is 121-125 ℃, preferably 121 ℃, and the sterilization time is 12-15 minutes, preferably 15 minutes.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811492043.0A CN111249227A (en) | 2018-11-30 | 2018-11-30 | Preparation method of fondaparinux sodium injection |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811492043.0A CN111249227A (en) | 2018-11-30 | 2018-11-30 | Preparation method of fondaparinux sodium injection |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN111249227A true CN111249227A (en) | 2020-06-09 |
Family
ID=70942948
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201811492043.0A Pending CN111249227A (en) | 2018-11-30 | 2018-11-30 | Preparation method of fondaparinux sodium injection |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN111249227A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113813228A (en) * | 2021-10-11 | 2021-12-21 | 北京鑫开元医药科技有限公司 | Injection with JAK kinase inhibitory activity and preparation method and application thereof |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101518512A (en) * | 2009-03-24 | 2009-09-02 | 河北天成药业有限公司 | Calcium gluconate injection and preparation method thereof |
| WO2013108180A1 (en) * | 2012-01-16 | 2013-07-25 | Novocat Farma, S. A. | Aqueous paracetamol composition for injection |
| CN105267143A (en) * | 2015-11-09 | 2016-01-27 | 上海金苇子生物技术有限公司 | Injection solvent and preparation method and application thereof |
| CN107595769A (en) * | 2017-10-23 | 2018-01-19 | 上海博悦生物科技有限公司 | A kind of preparation method of Fondaparinux sodium injecta composition |
| CN108324683A (en) * | 2017-01-18 | 2018-07-27 | 江苏正大丰海制药有限公司 | A kind of big infusion Edaravone Injection and its preparation process of stabilization |
-
2018
- 2018-11-30 CN CN201811492043.0A patent/CN111249227A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101518512A (en) * | 2009-03-24 | 2009-09-02 | 河北天成药业有限公司 | Calcium gluconate injection and preparation method thereof |
| WO2013108180A1 (en) * | 2012-01-16 | 2013-07-25 | Novocat Farma, S. A. | Aqueous paracetamol composition for injection |
| CN105267143A (en) * | 2015-11-09 | 2016-01-27 | 上海金苇子生物技术有限公司 | Injection solvent and preparation method and application thereof |
| CN108324683A (en) * | 2017-01-18 | 2018-07-27 | 江苏正大丰海制药有限公司 | A kind of big infusion Edaravone Injection and its preparation process of stabilization |
| CN107595769A (en) * | 2017-10-23 | 2018-01-19 | 上海博悦生物科技有限公司 | A kind of preparation method of Fondaparinux sodium injecta composition |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113813228A (en) * | 2021-10-11 | 2021-12-21 | 北京鑫开元医药科技有限公司 | Injection with JAK kinase inhibitory activity and preparation method and application thereof |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102008727B (en) | Injection-purpose medicine composition for improving stability of ligustrazine medicine injection formulation | |
| CN102166360B (en) | Ibuprofen intravenously administrable preparation and preparation method thereof | |
| CN102552127A (en) | Ornidazole injection | |
| CN109432123B (en) | Compound electrolyte glucose injection and preparation method thereof | |
| JP2017506632A (en) | Method for producing a stable low concentration injectable solution of noradrenaline | |
| CN102335123A (en) | Noradrenaline bitartrate injection and preparation technology thereof | |
| CN112088898B (en) | Composition containing oxidation-reduction potential water and preparation method thereof | |
| JPH05105633A (en) | Glucose preparation and its production | |
| CN104146953A (en) | Vortioxetine hydrobromide injection | |
| CN114126583A (en) | Ornidazole injection and S-ornidazole injection | |
| CN102836171A (en) | Solution for surgery and endoscope washing and preparation method thereof | |
| CN111249227A (en) | Preparation method of fondaparinux sodium injection | |
| CN108324683A (en) | A kind of big infusion Edaravone Injection and its preparation process of stabilization | |
| CN105125480B (en) | A kind of liquid preparation of lipoic acid and preparation method thereof | |
| CN104856946B (en) | A kind of dexamethasone sodium phosphate injection and its preparation technology | |
| CN113476398B (en) | Stable and safe argatroban injection and preparation method thereof | |
| CN105769756B (en) | A kind of fumaric acid Sitafloxacin hydrate injection and preparation method thereof | |
| CN102283804A (en) | Meglumine adenosine cyclophosphate injection and preparation method thereof | |
| JPH02304026A (en) | Liquid for peritoneal lavage | |
| CN113813228B (en) | Injection with JAK kinase inhibitory activity and preparation method and application thereof | |
| CN104784113A (en) | Linezolid-containing composition and preparation method thereof | |
| CN108904529A (en) | A kind of oral rehydration salts and preparation method thereof | |
| CN108451899B (en) | Production method of fondaparinux sodium injection | |
| CN116251057B (en) | Isosorbide dinitrate injection and preparation method thereof | |
| CN102895220A (en) | Ketoprofen intravenous administration preparation and preparation method thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20200609 |
|
| WD01 | Invention patent application deemed withdrawn after publication |