CN113384525A - Preparation method and application of edaravone sodium chloride injection - Google Patents
Preparation method and application of edaravone sodium chloride injection Download PDFInfo
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- CN113384525A CN113384525A CN202110771570.0A CN202110771570A CN113384525A CN 113384525 A CN113384525 A CN 113384525A CN 202110771570 A CN202110771570 A CN 202110771570A CN 113384525 A CN113384525 A CN 113384525A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 106
- QELUYTUMUWHWMC-UHFFFAOYSA-N edaravone Chemical compound O=C1CC(C)=NN1C1=CC=CC=C1 QELUYTUMUWHWMC-UHFFFAOYSA-N 0.000 title claims abstract description 87
- 229950009041 edaravone Drugs 0.000 title claims abstract description 87
- 239000008354 sodium chloride injection Substances 0.000 title claims abstract description 56
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 103
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 50
- 238000011049 filling Methods 0.000 claims abstract description 48
- 230000001954 sterilising effect Effects 0.000 claims abstract description 41
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims abstract description 34
- 239000001301 oxygen Substances 0.000 claims abstract description 34
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 34
- 238000004659 sterilization and disinfection Methods 0.000 claims abstract description 31
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 31
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims abstract description 26
- 239000007924 injection Substances 0.000 claims abstract description 24
- 238000002347 injection Methods 0.000 claims abstract description 24
- 238000001816 cooling Methods 0.000 claims abstract description 19
- 239000008215 water for injection Substances 0.000 claims abstract description 19
- 238000003756 stirring Methods 0.000 claims abstract description 16
- QIJRTFXNRTXDIP-UHFFFAOYSA-N (1-carboxy-2-sulfanylethyl)azanium;chloride;hydrate Chemical compound O.Cl.SCC(N)C(O)=O QIJRTFXNRTXDIP-UHFFFAOYSA-N 0.000 claims abstract description 14
- 229960001305 cysteine hydrochloride Drugs 0.000 claims abstract description 14
- 239000000203 mixture Substances 0.000 claims abstract description 13
- 239000011780 sodium chloride Substances 0.000 claims abstract description 13
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 claims abstract description 12
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 claims abstract description 12
- 229960002668 sodium chloride Drugs 0.000 claims abstract description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 21
- 238000005538 encapsulation Methods 0.000 claims description 20
- 239000012528 membrane Substances 0.000 claims description 17
- 238000007689 inspection Methods 0.000 claims description 13
- 238000000034 method Methods 0.000 claims description 11
- 238000007789 sealing Methods 0.000 claims description 10
- 238000004806 packaging method and process Methods 0.000 claims description 9
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 8
- 230000004888 barrier function Effects 0.000 claims description 8
- 238000001802 infusion Methods 0.000 claims description 8
- 238000001125 extrusion Methods 0.000 claims description 6
- 230000008569 process Effects 0.000 claims description 5
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 4
- 238000009472 formulation Methods 0.000 claims 1
- 230000000052 comparative effect Effects 0.000 description 22
- 239000000047 product Substances 0.000 description 20
- 239000003814 drug Substances 0.000 description 16
- 239000007788 liquid Substances 0.000 description 14
- 239000000243 solution Substances 0.000 description 10
- 238000001514 detection method Methods 0.000 description 9
- 238000001914 filtration Methods 0.000 description 8
- 238000005507 spraying Methods 0.000 description 6
- 238000005429 filling process Methods 0.000 description 5
- 230000007774 longterm Effects 0.000 description 5
- 239000012535 impurity Substances 0.000 description 4
- 239000011265 semifinished product Substances 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- 230000002490 cerebral effect Effects 0.000 description 3
- 206010008118 cerebral infarction Diseases 0.000 description 3
- 229910001873 dinitrogen Inorganic materials 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000005286 illumination Methods 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- 229910001220 stainless steel Inorganic materials 0.000 description 3
- 239000010935 stainless steel Substances 0.000 description 3
- 238000003860 storage Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 238000009736 wetting Methods 0.000 description 3
- 201000006474 Brain Ischemia Diseases 0.000 description 2
- 206010048962 Brain oedema Diseases 0.000 description 2
- 206010008120 Cerebral ischaemia Diseases 0.000 description 2
- 208000012322 Raynaud phenomenon Diseases 0.000 description 2
- 239000003963 antioxidant agent Substances 0.000 description 2
- 208000006752 brain edema Diseases 0.000 description 2
- 208000026106 cerebrovascular disease Diseases 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 238000011031 large-scale manufacturing process Methods 0.000 description 2
- -1 lipid peroxides Chemical class 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 239000000523 sample Substances 0.000 description 2
- 238000001179 sorption measurement Methods 0.000 description 2
- 208000002381 Brain Hypoxia Diseases 0.000 description 1
- 229940123457 Free radical scavenger Drugs 0.000 description 1
- 206010061216 Infarction Diseases 0.000 description 1
- VLSOAXRVHARBEQ-UHFFFAOYSA-N [4-fluoro-2-(hydroxymethyl)phenyl]methanol Chemical compound OCC1=CC=C(F)C=C1CO VLSOAXRVHARBEQ-UHFFFAOYSA-N 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 210000005013 brain tissue Anatomy 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000005520 cutting process Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 230000006866 deterioration Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000000428 dust Substances 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000007954 hypoxia Effects 0.000 description 1
- 230000007574 infarction Effects 0.000 description 1
- 230000000302 ischemic effect Effects 0.000 description 1
- 150000002617 leukotrienes Chemical class 0.000 description 1
- 230000003859 lipid peroxidation Effects 0.000 description 1
- 210000000944 nerve tissue Anatomy 0.000 description 1
- 210000002569 neuron Anatomy 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 238000010979 pH adjustment Methods 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 238000012805 post-processing Methods 0.000 description 1
- 238000004382 potting Methods 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 239000002516 radical scavenger Substances 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 230000010410 reperfusion Effects 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 229940079827 sodium hydrogen sulfite Drugs 0.000 description 1
- 238000012430 stability testing Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 208000037816 tissue injury Diseases 0.000 description 1
- 210000003556 vascular endothelial cell Anatomy 0.000 description 1
Classifications
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- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
- A61K31/4152—1,2-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. antipyrine, phenylbutazone, sulfinpyrazone
-
- 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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
- A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P39/00—General protective or antinoxious agents
- A61P39/06—Free radical scavengers or antioxidants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- Pharmacology & Pharmacy (AREA)
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- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Organic Chemistry (AREA)
- Dermatology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Biochemistry (AREA)
- Toxicology (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
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- Heart & Thoracic Surgery (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a preparation method and application of edaravone sodium chloride injection, wherein the preparation method comprises the following steps: (1) preparation: adding water for injection into a preparation tank, vacuumizing, introducing nitrogen for cooling, adding sodium chloride, cysteine hydrochloride and edaravone, stirring, adding sodium bisulfite and water for injection, stirring for cooling, and adjusting pH to obtain a mixture A; (2) encapsulating: feeding the mixture A obtained in the step (1) into a filling machine from a preparation tank for filling to obtain a filled injection bag; (3) and (3) sterilization: and (3) sterilizing and post-treating the filled injection bag obtained in the step (2) to obtain the edaravone sodium chloride injection. The edaravone sodium chloride injection provided by the invention has the advantages of low dissolved oxygen and residual oxygen, good stability and small influence of sterilization on the edaravone content.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a preparation method and application of an edaravone sodium chloride injection, in particular to a preparation method and application of an edaravone sodium chloride injection with low dissolved oxygen and residual oxygen.
Background
The edaravone sodium chloride injection is a novel strong free radical scavenger, can inhibit the generation of a large number of free radicals and lipid peroxides caused by reperfusion after cerebral ischemia and hypoxia, can effectively clear harmful hydroxyl free radical lipid peroxidation paths increased after cerebral ischemia, inhibit cerebral edema and cerebral nerve tissue injury, inhibit the synthesis of leukotriene in brain, improve vascular endothelial cell dysfunction, act on the early stage of cerebral infarction, inhibit cerebral edema, shrink infarction area, relieve the attack of neurosism, inhibit the death of delayed cerebral nerve cells and the occurrence and development (namely deterioration) of cerebral ischemic cerebrovascular disorder, and protect the structure and function of brain tissue.
Most of the existing edaravone new preparations have complicated preparation processes, low possibility of large-scale production and high difficulty, the treatment effect needs to be further verified, the physicochemical quality of the medicine can be properly improved by changing the prescription, but certain potential safety hazards exist compared with the original preparation for long-term use.
CN103083232B discloses an edaravone injection without antioxidant and a preparation method thereof, which comprises the following components: edaravone, pH value regulator and water for injection; the preparation method comprises the following steps: A. preparing a liquid; B. filtering; C. filling; D. sterilizing; and in the first 3 steps, nitrogen is filled for protection, and the residual oxygen content in water and the impurity content of the product are strictly controlled, so that the safety and effectiveness of the product in clinical use are ensured.
CN108324683A discloses a stable edaravone injection for large infusion and a preparation process thereof, belonging to the field of pharmaceutical preparations. The edaravone sodium chloride injection comprises edaravone raw materials as effective components for treatment, sodium chloride as an osmotic pressure regulator and a pH regulator: phosphate buffer composed of phosphoric acid and sodium hydroxide, wherein sodium hydroxide is also a dissolution assistant, and antioxidants L-cysteine hydrochloride and sodium bisulfite. The specification of the edaravone sodium chloride injection for large infusion is 100 mL: 0.03 g of edaravone and 0.855 g of sodium chloride. The preparation method comprises the following steps: preparing liquid; filtering; filling; fourthly, sterilizing; the first three steps are all filled with high-purity nitrogen for protection, the water for injection is boiled to remove oxygen, and the residual oxygen content in the liquid medicine and the content of related substances of the product are strictly controlled to ensure the safety and effectiveness of the liquid medicine in clinic. Influence factor experiments show that related substances are relatively less generated, and the product quality is stable and safe.
The preparation process of the existing edaravone new preparation is complex and is difficult to be applied to large-scale production. Therefore, how to provide an edaravone preparation which is simple to prepare, good in effect and good in stability becomes a problem to be solved urgently.
Disclosure of Invention
Aiming at the defects of the prior art, the invention aims to provide a preparation method and application of an edaravone sodium chloride injection, and particularly provides a preparation method and application of an edaravone sodium chloride injection with low dissolved oxygen and residual oxygen. The edaravone sodium chloride injection provided by the invention has the advantages of low dissolved oxygen and residual oxygen, good stability and small influence of sterilization on the edaravone content.
In order to achieve the purpose, the invention adopts the following technical scheme:
on one hand, the invention provides a preparation method of edaravone sodium chloride injection, which comprises the following steps:
(1) preparation: adding water for injection into a preparation tank, vacuumizing, introducing nitrogen for cooling, adding sodium chloride, cysteine hydrochloride and edaravone, stirring, adding sodium bisulfite and water for injection, stirring for cooling, and adjusting pH to obtain a mixture A;
(2) encapsulating: feeding the mixture A obtained in the step (1) into a filling machine from a preparation tank for filling to obtain a filled injection bag;
(3) and (3) sterilization: and (3) sterilizing and post-treating the filled injection bag obtained in the step (2) to obtain the edaravone sodium chloride injection.
The preparation and encapsulation are carried out under the condition of filling nitrogen, the nitrogen pressure in the preparation tank is not less than 0.02 MPa before the pH is adjusted in the preparation process, the nitrogen pressure in the preparation tank is not more than 0.02 MPa after the pH is adjusted, the nitrogen pressure in the preparation tank is not more than 0.02 MPa in the encapsulation process, and the nitrogen pressure of an filling needle head is not less than 0.2 bar.
The nitrogen pressure in the preparation tank before the adjustment of the pH may be 0.02 MPa, 0.022 MPa, 0.024 MPa, 0.026 MPa, 0.028 MPa or 0.03 MPa, the nitrogen pressure in the preparation tank after the adjustment of the pH may be 0.02 MPa, 0.018 MPa, 0.016 MPa, 0.014 MPa, 0.012 MPa or 0.01 MPa, the nitrogen pressure in the preparation tank during the filling process may be 0.02 MPa, 0.018 MPa, 0.016 MPa, 0.014 MPa, 0.012 MPa or 0.01 MPa, the nitrogen pressure in the filling needle may be 0.2 bar, 0.22 bar, 0.24 bar, 0.26 bar, 0.28 bar or 0.3 bar, but not limited to the above-mentioned values, and other values not listed in the above-mentioned value range may be applied similarly.
The preparation method adopting the specific steps and the specific nitrogen filling process can reduce the content of dissolved oxygen and residual oxygen in the product, further reduce the content of impurities, ensure the quality of the product, and simultaneously has the advantages of simple and controllable preparation process and good reproducibility.
Preferably, the amount of sodium chloride added in step (1) is a prescribed amount.
Preferably, the cysteine hydrochloride in the step (1) is added in a prescribed amount.
Preferably, the edaravone is added in the prescribed amount in the step (1).
Preferably, the amount of sodium bisulfite added in step (1) is a prescribed amount.
Preferably, the pH regulator in step (1) is NaOH and/or phosphoric acid.
Preferably, the pH adjustment in step (1) is to 3.9-5.0, such as 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9 or 5.0, but not limited to the above-listed values, and other values not listed within the above-mentioned range of values are equally applicable.
Preferably, the filled membrane for encapsulation in the step (2) is a five-layer co-extrusion membrane for infusion, and the model of the five-layer co-extrusion membrane for infusion is MF 518H.
The specific encapsulating membrane can reduce the edaravone content reduction caused by the adsorption of edaravone on the encapsulating membrane due to sterilization, and improve the content of products.
Preferably, the temperature for the sterilization in the step (3) is 120-122 ℃, and the time is 14-16 min.
Preferably, F of the injection solution in the sterilized filled injection bag of the step (3)0Not less than 12.
Wherein the sterilization temperature can be 120 deg.C, 120.5 deg.C, 121 deg.C, 121.5 deg.C or 122 deg.C, the time can be 14 min, 14.5 min, 15 min, 15.5 min or 16 min, F0The above-mentioned range may include 12, 12.5, 13, 13.5, 14, etc., but is not limited to the above-mentioned values, and other values not listed in the above-mentioned range are also applicable.
Preferably, the post-processing of step (3) includes light inspection and packaging.
Preferably, the packaging comprises the steps of: putting the filled injection bag into a high barrier bag, and putting a deoxidizer and an oxygen indicator into the high barrier bag;
preferably, the high barrier bag is model number RG22002 or M712.
The specific high-barrier bag can fully isolate oxygen in the external environment from entering the bag, and the stability of the edaravone sodium chloride injection is improved.
As a preferred technical scheme of the invention, the preparation method comprises the following steps:
(1) preparation: adding water for injection into a preparation tank, vacuumizing, introducing nitrogen for cooling, adding a prescribed amount of sodium chloride, a prescribed amount of cysteine hydrochloride and a prescribed amount of edaravone, stirring, adding a prescribed amount of sodium bisulfite and water for injection, stirring for cooling, and then adjusting the pH value to 3.9-5.0 to obtain a mixture A;
(2) encapsulating: conveying the mixture A obtained in the step (1) into a filling machine from a preparation tank, and filling the mixture A with an MF518H five-layer co-extrusion film for infusion to obtain a filled injection bag;
(3) and (3) sterilization: and (3) sterilizing the filled injection bag obtained in the step (2), performing light inspection and packaging to obtain the edaravone sodium chloride injection.
On the other hand, the invention also provides the application of the preparation method of the edaravone sodium chloride injection in preparing the edaravone preparation.
Compared with the prior art, the invention has the following beneficial effects:
the preparation method of the edaravone sodium chloride injection is obtained through the specific steps of screening and the specific nitrogen charging process, the content of dissolved oxygen and residual oxygen in the product can be reduced, the content of impurities is further reduced, the quality of the product is ensured, and meanwhile, the preparation process is simple and controllable and has good reproducibility; the content reduction of edaravone caused by the adsorption of edaravone on the encapsulation membrane due to sterilization can be reduced by selecting the specific encapsulation membrane, and the content of the product is improved; the specific high-barrier bag is selected, so that oxygen in the external environment can be fully isolated from entering the bag, and the stability of the edaravone sodium chloride injection is improved.
Detailed Description
To further illustrate the technical means and effects of the present invention, the following further describes the technical solution of the present invention with reference to the preferred embodiments of the present invention, but the present invention is not limited to the scope of the embodiments.
In the following comparative examples, edaravone was used in an amount of 30 mg, sodium chloride was used in an amount of 855 mg, cysteine hydrochloride was used in an amount of 10 mg, sodium hydrogen sulfite was used in an amount of 20 mg, and water for injection was added to 100 mL.
Membranes MF518H, MF518 were from raynaud, M312C was from hill, APP114 was from boli.
High barrier bag RG22002 was purchased from raynaud, M712 was purchased from hilgler, and a non-functional dust bag was produced by shanghai ni pharmaceutical company ltd.
Example 1
The embodiment provides a preparation method of an edaravone sodium chloride injection, which comprises the following specific steps:
1. preparation of
Adding 85% of water for injection into a preparation tank, vacuumizing, introducing nitrogen, cooling to 40 ℃, and introducing nitrogen for 30 minutes under the pressure of 0.22 MPa. Adding the pre-dissolved sodium chloride, pre-dissolving cysteine hydrochloride with injection water in a preparation tank, adding edaravone into cysteine hydrochloride solution, wetting, adding into the preparation tank, spraying with injection water, and stirring to completely dissolve. Adding the pre-dissolved sodium bisulfite into a preparation tank, and adding the water for injection into the preparation tank in batches.
Stirring and cooling for 15 min, circularly filtering the medicinal liquid with 0.45 μm and 0.2 μm cylindrical filters for 20 min, cooling to 40 deg.C, adjusting pH to 4.5 with 10% NaOH solution, and introducing nitrogen gas for protection. The positive pressure in the preparation tank is maintained by nitrogen, and the pressure is 0.02 MPa. Sterilizing and filtering the medicinal liquid with 0.2 μm cylindrical filter, and filling into the filling station for filling.
2. Encapsulation (encapsulation)
The filling machine was adjusted to a filling volume of 106 mL. Filling nitrogen into the liquid medicine pumped from the target preparation tank for encapsulation: upper film → printing → bag making → interface adding → filling → capping and sealing. And filling nitrogen in the whole filling process, wherein the nitrogen pressure in the preparation tank is 0.18 MPa, the nitrogen pressure of a filling needle is 0.21 bar, and the membrane for filling is MF 518H.
3. Sterilization
Conveying the sealed bagged semi-finished product to a superheated water spraying back pressure type sterilization cabinet through a conveyor belt for sterilization, wherein the sterilization temperature is as follows: 121.0 ℃, sterilization time: 15.0 min, F0Is greater than 12. And conveying the sterilized medicine bag to a soft bag dryer for drying, and conveying the dried medicine bag to a lamp inspection station through a conveying belt.
4. Lamp inspection
And adjusting the illumination of the clarity detector to 1500 Lx, checking the conditions of visible foreign matters, printing quality, appearance and the like, and conveying qualified products after lamp inspection to a packaging post through a conveyor belt.
5. Package (I)
When an HDK-4 type high-voltage discharge leak detector is used for leak detection, setting high-voltage values of channels of the high-voltage discharge leak detector; and detecting leakage of the medicine bags one by one according to the operating specification of the leakage detector. And (3) sealing the high-barrier bag (RG 22002) by using an SF-150 type stainless steel automatic sealing machine, and putting 1 deoxidizer and 1 oxygen indicator into the high-barrier bag respectively to obtain the edaravone sodium chloride injection.
Example 2
The embodiment provides a preparation method of an edaravone sodium chloride injection, which comprises the following specific steps:
1. preparation of
Adding 85% of water for injection into a preparation tank, vacuumizing, introducing nitrogen, cooling to 40 ℃, and introducing nitrogen for 30 minutes under the pressure of 0.025 MPa. Adding the pre-dissolved sodium chloride, pre-dissolving cysteine hydrochloride with injection water in a preparation tank, adding edaravone into cysteine hydrochloride solution, wetting, adding into the preparation tank, spraying with injection water, and stirring to completely dissolve. Adding the pre-dissolved sodium bisulfite into a preparation tank, and adding the water for injection into the preparation tank in batches.
Stirring and cooling for 15 min, circularly filtering the medicinal liquid with 0.45 μm and 0.2 μm cylindrical filters for 20 min, cooling to 40 deg.C, adjusting pH to 3.9 with 10% NaOH solution and 10% phosphoric acid solution, and introducing nitrogen gas for protection. The positive pressure in the preparation tank is maintained by nitrogen, and the pressure is 0.015 MPa. Sterilizing and filtering the medicinal liquid with 0.2 μm cylindrical filter, and filling into the filling station for filling.
2. Encapsulation (encapsulation)
The filling machine was adjusted to a filling volume of 106 mL. Filling nitrogen into the liquid medicine pumped from the target preparation tank for encapsulation: upper film → printing → bag making → interface adding → filling → capping and sealing. The filling process is carried out by filling nitrogen, the nitrogen pressure in the preparation tank is 0.015 MPa, the nitrogen pressure of a filling needle is 0.25 bar, and the filling membrane is MF 518H.
3. Sterilization
Conveying the sealed bagged semi-finished product to a superheated water spraying back pressure type sterilization cabinet through a conveyor belt for sterilization, wherein the sterilization temperature is as follows: 121.0 ℃, sterilization time: 15.0 min, F0Is greater than 12. And conveying the sterilized medicine bag to a soft bag dryer for drying, and conveying the dried medicine bag to a lamp inspection station through a conveying belt.
4. Lamp inspection
And adjusting the illumination of the clarity detector to 1500 Lx, checking the conditions of visible foreign matters, printing quality, appearance and the like, and conveying qualified products after lamp inspection to a packaging post through a conveyor belt.
5. Package (I)
When an HDK-4 type high-voltage discharge leak detector is used for leak detection, setting high-voltage values of channels of the high-voltage discharge leak detector; and detecting leakage of the medicine bags one by one according to the operating specification of the leakage detector. And (3) sealing the high-barrier bag (M712) by using an SF-150 type stainless steel automatic sealing machine, and putting 1 deoxidizer and 1 oxygen indicator into the high-barrier bag respectively to obtain the edaravone sodium chloride injection.
Example 3
The embodiment provides a preparation method of an edaravone sodium chloride injection, which comprises the following specific steps:
1. preparation of
Adding 85% of water for injection into a preparation tank, vacuumizing, introducing nitrogen, cooling to 40 ℃, and introducing nitrogen for 30 minutes under the pressure of 0.023 MPa. Adding the pre-dissolved sodium chloride, pre-dissolving cysteine hydrochloride with injection water in a preparation tank, adding edaravone into cysteine hydrochloride solution, wetting, adding into the preparation tank, spraying with injection water, and stirring to completely dissolve. Adding the pre-dissolved sodium bisulfite into a preparation tank, and adding the water for injection into the preparation tank in batches.
Stirring and cooling for 15 min, circularly filtering the medicinal liquid with 0.45 μm and 0.2 μm cylindrical filters for 20 min, cooling to 40 deg.C, adjusting pH to 5.0 with 10% NaOH solution, and introducing nitrogen gas for protection. The positive pressure in the preparation tank is maintained by nitrogen, and the pressure is 0.017 MPa. Sterilizing and filtering the medicinal liquid with 0.2 μm cylindrical filter, and filling into the filling station for filling.
2. Encapsulation (encapsulation)
The filling machine was adjusted to a filling volume of 106 mL. Filling nitrogen into the liquid medicine pumped from the target preparation tank for encapsulation: upper film → printing → bag making → interface adding → filling → capping and sealing. And filling nitrogen in the whole filling process, wherein the nitrogen pressure in the preparation tank is 0.019 MPa, the nitrogen pressure of a filling needle is 0.22 bar, and the film for filling is MF 518H.
3. Sterilization
Conveying the sealed bagged semi-finished product to a superheated water spraying back pressure type sterilization cabinet through a conveyor belt for sterilization, wherein the sterilization temperature is as follows: 121.0 ℃, sterilization time: 15.0 min, F0Is greater than 12. And conveying the sterilized medicine bag to a soft bag dryer for drying, and conveying the dried medicine bag to a lamp inspection station through a conveying belt.
4. Lamp inspection
And adjusting the illumination of the clarity detector to 1500 Lx, checking the conditions of visible foreign matters, printing quality, appearance and the like, and conveying qualified products after lamp inspection to a packaging post through a conveyor belt.
5. Package (I)
When an HDK-4 type high-voltage discharge leak detector is used for leak detection, setting high-voltage values of channels of the high-voltage discharge leak detector; and detecting leakage of the medicine bags one by one according to the operating specification of the leakage detector. And (3) sealing the high-barrier bag (RG 22002) by using an SF-150 type stainless steel automatic sealing machine, and putting 1 deoxidizer and 1 oxygen indicator into the high-barrier bag respectively to obtain the edaravone sodium chloride injection.
Example 4
This example provides a method for preparing edaravone sodium chloride injection, which is the same as that in example 1 except that the high barrier bag RG22002 is replaced with M712.
Comparative example 1
The comparative example provides a preparation method of edaravone sodium chloride injection, and the preparation method is the same as the embodiment 1 except that the nitrogen pressure is different from the embodiment 1.
Comparative example 1 the nitrogen pressure in each step was as follows:
comparative example 2
The comparative example provides a preparation method of edaravone sodium chloride injection, and the preparation method is the same as the embodiment 1 except that the nitrogen pressure is different from the embodiment 1.
Comparative example 2 the nitrogen pressure in each step was as follows:
comparative example 3
The comparative example provides a preparation method of edaravone sodium chloride injection, which is the same as that in example 1 except that the membrane for encapsulation MF518H is replaced by M312C.
Comparative example 4
The comparative example provides a preparation method of edaravone sodium chloride injection, which is the same as that in example 1 except that APP114 is replaced by a membrane MF518H for encapsulation.
Comparative example 5
The comparative example provides a preparation method of edaravone sodium chloride injection, which is consistent with example 1 except that the membrane for encapsulation MF518H is replaced by MF 518.
Comparative example 6
The embodiment provides a preparation method of an edaravone sodium chloride injection, which is the same as that in embodiment 1 except that a high-barrier bag RG22002 is replaced by a non-functional dustproof bag.
Comparing different nitrogen charging processes:
dissolved oxygen and residual oxygen content detection and product key quality attribute (CQAs) detection are carried out on the edaravone sodium chloride injection provided by the example 1 and the comparative examples 1-2:
a detection instrument:
| name of instrument | Model number | Manufacturer of the product |
| Dissolved oxygen tester | Seven2GoTM pro S9 | METTLER |
| Oxygen analyzer | MAP TEK 200 | METTLER |
The detection method comprises the following steps:
dissolving oxygen: and inserting the probe of the dissolved oxygen meter into the liquid medicine, and recording the numerical value after the reading is stable.
Residual oxygen: and (3) placing the funnel for gas collection in water, emptying the air at one end with the rubber plug, cutting a sample in the water, collecting the gas into the funnel, and detecting by using a residual oxygen meter.
The results are as follows:
| group of | Dissolved oxygen content (mg/L) | Residual oxygen content (%) |
| Example 1 | 4.62 | 14.5 |
| Comparative example 1 | 5.88 | 16.3 |
| Comparative example 2 | 8.16 | 19.5 |
Note: n.d indicates no detection, as follows.
From the results, the specific nitrogen charging process in the preparation method of the edaravone sodium chloride injection provided by the invention can reduce the content of dissolved oxygen and residual oxygen in the product, reduce the content of impurities and improve the product quality.
Comparison of different membranes for potting:
the edaravone sodium chloride injection provided in example 1 and comparative examples 3 to 5 was tested for edaravone content in the semi-finished product before and after sterilization, and the results were as follows:
| group of | Content before sterilization | Content after sterilization | Amount of change |
| Example 1 | 100.9% | 100.2% | 0.7% |
| Comparative example 3 | 100.5% | 82.9% | 17.6% |
| Comparative example 4 | 97.8% | 91.0% | 6.8% |
| Comparative example 5 | 97.8% | 91.6% | 6.2% |
The data show that the content reduction of edaravone caused by sterilization is obviously reduced, the consumption of edaravone is reduced, the content of the product is increased, and the loss is reduced by selecting the specific film for encapsulation.
Comparison of different high barrier bags:
the edaravone sodium chloride injection provided by examples 1 and 4 and comparative example 6 is placed in an environment at 60 ℃, and the detection is carried out on the CQAs of the product on the tenth day and the thirty day respectively, and the results are as follows:
the above results show that the use of the high barrier pouch according to the present invention can reduce the content of the relevant substances, and that the edaravone content changes little, thereby enabling long-term storage.
And (3) stability testing:
the edaravone sodium chloride injection provided in examples 1 to 4 was subjected to an accelerated test at 40 ℃ and a long-term test at 25 ℃ respectively, and periodically detected, and the results were as follows:
(1) accelerated test
Example 1:
example 2:
example 3:
example 4:
(2) long term test
Example 1:
example 2:
example 3:
example 4:
the data show that all indexes of the edaravone sodium chloride injection provided by the invention meet the standards after high-temperature accelerated storage and long-term storage, and excellent stability is embodied.
The applicant states that the preparation method and application of the edaravone sodium chloride injection of the present invention are illustrated by the above examples, but the present invention is not limited to the above examples, i.e. the present invention is not limited to the above examples. It should be understood by those skilled in the art that any modification of the present invention, equivalent substitutions of the raw materials of the product of the present invention, addition of auxiliary components, selection of specific modes, etc., are within the scope and disclosure of the present invention.
The preferred embodiments of the present invention have been described in detail, however, the present invention is not limited to the specific details of the above embodiments, and various simple modifications may be made to the technical solution of the present invention within the technical idea of the present invention, and these simple modifications are within the protective scope of the present invention.
It should be noted that the various technical features described in the above embodiments can be combined in any suitable manner without contradiction, and the invention is not described in any way for the possible combinations in order to avoid unnecessary repetition.
Claims (14)
1. A preparation method of edaravone sodium chloride injection is characterized by comprising the following steps:
(1) preparation: adding water for injection into a preparation tank, vacuumizing, introducing nitrogen for cooling, adding sodium chloride, cysteine hydrochloride and edaravone, stirring, adding sodium bisulfite and water for injection, stirring for cooling, and adjusting pH to obtain a mixture A;
(2) encapsulating: feeding the mixture A obtained in the step (1) into a filling machine from a preparation tank for filling to obtain a filled injection bag;
(3) and (3) sterilization: sterilizing and post-treating the filled injection bag obtained in the step (2) to obtain the edaravone sodium chloride injection;
wherein, the preparation and encapsulation are carried out under the condition of nitrogen filling, the nitrogen pressure in the preparation tank is not less than 0.02 MPa before the pH is adjusted in the preparation process, the nitrogen pressure in the preparation tank is not more than 0.02 MPa after the pH is adjusted, the nitrogen pressure in the preparation tank is not more than 0.02 MPa in the encapsulation process, and the nitrogen pressure of the filling needle head is not less than 0.2 bar;
the filling and sealing membrane in the step (2) is a five-layer co-extrusion infusion membrane, and the model of the five-layer co-extrusion infusion membrane is MF 518H.
2. The preparation method of edaravone sodium chloride injection as claimed in claim 1, wherein the amount of sodium chloride added in step (1) is a prescribed amount.
3. The preparation method of edaravone sodium chloride injection as claimed in claim 1, wherein the amount of cysteine hydrochloride added in step (1) is a prescribed amount.
4. The preparation method of edaravone sodium chloride injection as claimed in claim 1, wherein the edaravone is added in the prescribed amount in step (1).
5. The preparation method of edaravone sodium chloride injection as claimed in claim 1, wherein the amount of sodium bisulfite added in step (1) is a prescribed amount.
6. The preparation method of edaravone sodium chloride injection as claimed in claim 1, wherein the pH regulator in step (1) is NaOH and/or phosphoric acid.
7. The preparation method of edaravone sodium chloride injection as claimed in claim 1, wherein the pH is adjusted to 3.9-5.0 in step (1).
8. The method for preparing edaravone sodium chloride injection as claimed in claim 1, wherein the temperature for sterilization in step (3) is 120-122 ℃, and the time is 14-16 min.
9. The method for preparing edaravone sodium chloride injection as claimed in claim 1, wherein F of the injection in the sterilized filled injection bag in step (3)0Not less than 12.
10. The preparation method of edaravone sodium chloride injection as claimed in claim 1, wherein the post-treatment in step (3) comprises light inspection and packaging.
11. The method for preparing edaravone sodium chloride injection as claimed in claim 10, wherein the packaging comprises the following steps: and (3) putting the filled injection bag into a high-barrier bag, and putting a deoxidizer and an oxygen indicator into the high-barrier bag.
12. The method for preparing edaravone sodium chloride injection as claimed in claim 11, wherein the high barrier bag is RG22002 or M712.
13. The preparation method of edaravone sodium chloride injection as claimed in claim 1, wherein the preparation method comprises the following steps:
(1) preparation: adding water for injection into a preparation tank, vacuumizing, introducing nitrogen for cooling, adding a prescribed amount of sodium chloride, a prescribed amount of cysteine hydrochloride and a prescribed amount of edaravone, stirring, adding a prescribed amount of sodium bisulfite and water for injection, stirring for cooling, and then adjusting the pH value to 3.9-5.0 to obtain a mixture A;
(2) encapsulating: conveying the mixture A obtained in the step (1) into a filling machine from a preparation tank, and filling the mixture A with an MF518H five-layer co-extrusion film for infusion to obtain a filled injection bag;
(3) and (3) sterilization: and (3) sterilizing the filled injection bag obtained in the step (2), performing light inspection and packaging to obtain the edaravone sodium chloride injection.
14. Use of a method of preparation of edaravone sodium chloride injection as claimed in any one of claims 1 to 13 in the preparation of an edaravone formulation.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2010077104A (en) * | 2008-08-29 | 2010-04-08 | Nihon Pharmaceutical Co Ltd | Aqueous injection solution of 3-methyl-1-phenyl-2-pyrazoline-5-one |
| CN107823128A (en) * | 2017-11-21 | 2018-03-23 | 扬子江药业集团上海海尼药业有限公司 | A kind of preparation method of Edaravone Injection |
| WO2019119720A1 (en) * | 2017-12-19 | 2019-06-27 | 北京盈科瑞创新药物研究有限公司 | Fudosteine solution preparation for aerosol inhalation, and preparation method therefor |
| CN110478315A (en) * | 2019-10-08 | 2019-11-22 | 四川太平洋药业有限责任公司 | A kind of Edaravone sodium chloride injection and preparation process |
-
2021
- 2021-07-08 CN CN202110771570.0A patent/CN113384525A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2010077104A (en) * | 2008-08-29 | 2010-04-08 | Nihon Pharmaceutical Co Ltd | Aqueous injection solution of 3-methyl-1-phenyl-2-pyrazoline-5-one |
| CN107823128A (en) * | 2017-11-21 | 2018-03-23 | 扬子江药业集团上海海尼药业有限公司 | A kind of preparation method of Edaravone Injection |
| WO2019119720A1 (en) * | 2017-12-19 | 2019-06-27 | 北京盈科瑞创新药物研究有限公司 | Fudosteine solution preparation for aerosol inhalation, and preparation method therefor |
| CN110478315A (en) * | 2019-10-08 | 2019-11-22 | 四川太平洋药业有限责任公司 | A kind of Edaravone sodium chloride injection and preparation process |
Non-Patent Citations (2)
| Title |
|---|
| 方国民等: "依达拉奉注射液的制备工艺研究", 《中国药业》 * |
| 李禄辉等: "依达拉奉注射液处方筛选与工艺研究", 《河南大学学报( 医学版) 》 * |
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