CN116983258B - Preparation process of mannitol injection not easy to crystallize - Google Patents
Preparation process of mannitol injection not easy to crystallize Download PDFInfo
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- CN116983258B CN116983258B CN202310918026.3A CN202310918026A CN116983258B CN 116983258 B CN116983258 B CN 116983258B CN 202310918026 A CN202310918026 A CN 202310918026A CN 116983258 B CN116983258 B CN 116983258B
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- mannitol
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- aqueous solution
- filling
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- 229940080526 mannitol injection Drugs 0.000 title claims abstract description 37
- 238000002360 preparation method Methods 0.000 title claims abstract description 32
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims abstract description 162
- 229930195725 Mannitol Natural products 0.000 claims abstract description 162
- 239000000594 mannitol Substances 0.000 claims abstract description 162
- 235000010355 mannitol Nutrition 0.000 claims abstract description 162
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 70
- 238000011049 filling Methods 0.000 claims abstract description 52
- 239000007864 aqueous solution Substances 0.000 claims abstract description 50
- 238000002425 crystallisation Methods 0.000 claims abstract description 45
- 230000008025 crystallization Effects 0.000 claims abstract description 45
- 239000008215 water for injection Substances 0.000 claims abstract description 43
- 239000012528 membrane Substances 0.000 claims abstract description 28
- 239000002994 raw material Substances 0.000 claims abstract description 28
- 230000001954 sterilising effect Effects 0.000 claims abstract description 25
- 238000000108 ultra-filtration Methods 0.000 claims abstract description 24
- 238000001914 filtration Methods 0.000 claims abstract description 19
- 239000013078 crystal Substances 0.000 claims abstract description 16
- 238000000034 method Methods 0.000 claims abstract description 12
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 88
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 72
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 44
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 43
- 239000011780 sodium chloride Substances 0.000 claims description 36
- 238000004140 cleaning Methods 0.000 claims description 31
- 229910052799 carbon Inorganic materials 0.000 claims description 30
- 239000007924 injection Substances 0.000 claims description 27
- 238000002347 injection Methods 0.000 claims description 27
- 229940090044 injection Drugs 0.000 claims description 25
- 239000007788 liquid Substances 0.000 claims description 21
- 239000011521 glass Substances 0.000 claims description 17
- 238000004659 sterilization and disinfection Methods 0.000 claims description 13
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 12
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 12
- 239000012459 cleaning agent Substances 0.000 claims description 9
- 238000010438 heat treatment Methods 0.000 claims description 9
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 claims description 8
- 238000002791 soaking Methods 0.000 claims description 8
- -1 polypropylene Polymers 0.000 claims description 7
- 238000001816 cooling Methods 0.000 claims description 6
- 238000007865 diluting Methods 0.000 claims description 6
- 238000001035 drying Methods 0.000 claims description 6
- 238000002156 mixing Methods 0.000 claims description 6
- 239000000203 mixture Substances 0.000 claims description 6
- 239000004743 Polypropylene Substances 0.000 claims description 5
- 229920001155 polypropylene Polymers 0.000 claims description 5
- 238000003756 stirring Methods 0.000 claims description 5
- WQZGKKKJIJFFOK-QTVWNMPRSA-N D-mannopyranose Chemical compound OC[C@H]1OC(O)[C@@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-QTVWNMPRSA-N 0.000 claims description 4
- 239000001103 potassium chloride Substances 0.000 claims description 4
- 235000011164 potassium chloride Nutrition 0.000 claims description 4
- 238000000967 suction filtration Methods 0.000 claims description 2
- 239000000243 solution Substances 0.000 abstract description 13
- 239000000825 pharmaceutical preparation Substances 0.000 abstract description 2
- 239000002245 particle Substances 0.000 description 30
- 239000000047 product Substances 0.000 description 13
- 230000000052 comparative effect Effects 0.000 description 10
- 238000005406 washing Methods 0.000 description 9
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 8
- 239000003814 drug Substances 0.000 description 7
- 239000008187 granular material Substances 0.000 description 7
- 239000002158 endotoxin Substances 0.000 description 6
- 230000008569 process Effects 0.000 description 6
- 238000001514 detection method Methods 0.000 description 5
- 238000005429 filling process Methods 0.000 description 5
- 238000011068 loading method Methods 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- 238000004031 devitrification Methods 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 235000011187 glycerol Nutrition 0.000 description 4
- 238000007689 inspection Methods 0.000 description 4
- 238000002372 labelling Methods 0.000 description 4
- 238000005374 membrane filtration Methods 0.000 description 4
- 238000004806 packaging method and process Methods 0.000 description 4
- 229920003023 plastic Polymers 0.000 description 4
- 239000004033 plastic Substances 0.000 description 4
- 230000001105 regulatory effect Effects 0.000 description 4
- 238000001179 sorption measurement Methods 0.000 description 4
- 239000007921 spray Substances 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 3
- 239000013618 particulate matter Substances 0.000 description 3
- 238000012797 qualification Methods 0.000 description 3
- 238000003860 storage Methods 0.000 description 3
- 239000002699 waste material Substances 0.000 description 3
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- 206010048962 Brain oedema Diseases 0.000 description 2
- 239000004698 Polyethylene Substances 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- 239000004372 Polyvinyl alcohol Substances 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 2
- 229910052782 aluminium Inorganic materials 0.000 description 2
- 208000006752 brain edema Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 229940075529 glyceryl stearate Drugs 0.000 description 2
- 238000007917 intracranial administration Methods 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 229920000573 polyethylene Polymers 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 229920002451 polyvinyl alcohol Polymers 0.000 description 2
- 229920000915 polyvinyl chloride Polymers 0.000 description 2
- 239000004800 polyvinyl chloride Substances 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 238000005096 rolling process Methods 0.000 description 2
- 235000002639 sodium chloride Nutrition 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 230000003727 cerebral blood flow Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 239000000498 cooling water Substances 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000005611 electricity Effects 0.000 description 1
- 239000003792 electrolyte Substances 0.000 description 1
- 239000012943 hotmelt Substances 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 239000013072 incoming material Substances 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 210000002977 intracellular fluid Anatomy 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 230000010412 perfusion Effects 0.000 description 1
- 230000004526 pharmaceutical effect Effects 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 230000003068 static effect Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000003466 welding Methods 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
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
- A61K31/047—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates having two or more hydroxy groups, e.g. sorbitol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
- A61J3/00—Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- 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
- A61P7/10—Antioedematous agents; Diuretics
-
- 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
- A61P9/12—Antihypertensives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
- C07C29/74—Separation; Purification; Use of additives, e.g. for stabilisation
- C07C29/76—Separation; Purification; Use of additives, e.g. for stabilisation by physical treatment
- C07C29/78—Separation; Purification; Use of additives, e.g. for stabilisation by physical treatment by condensation or crystallisation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C31/00—Saturated compounds having hydroxy or O-metal groups bound to acyclic carbon atoms
- C07C31/18—Polyhydroxylic acyclic alcohols
- C07C31/26—Hexahydroxylic alcohols
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Dermatology (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Crystallography & Structural Chemistry (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention discloses a preparation process of mannitol injection which is not easy to crystallize, belonging to the technical field of pharmaceutical preparations. The method comprises the following steps: (1) preparing a raw material; (2) preparing mannitol aqueous solution; (3) adjusting the pH value; (4) filtering; (5) filling; (6) sterilizing; in step (1), the starting mannitol is recrystallized: mannitol is added into water for injection to prepare mannitol aqueous solution, the mannitol aqueous solution is filtered by an ultrafiltration membrane, then crystallization nucleus is added, mannitol is recrystallized, mannitol crystals are obtained by filtration, and the mannitol crystals are dried for later use. In the invention, the method is improved from a plurality of links such as raw material treatment, temperature regulation and control, solution filtration treatment and the like, and the possibility of crystallization of mannitol injection is greatly reduced.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a preparation process of mannitol injection which is not easy to crystallize.
Background
Mannitol injection is a commonly used medical chemical, and the main component is mannitol, which can be used for treating diseases such as high cranium pressure, cerebral edema and the like, and the mannitol reduces the intracellular fluid volume by adjusting the osmotic pressure in the body, thereby reducing the cerebral edema, reducing the intracranial pressure, improving cerebral blood flow perfusion and promoting the recovery of nerve functions.
However, mannitol injection is easy to crystallize, is inconvenient in clinical use, and meanwhile, the crystallized mannitol is harmful to human bodies after being input into the human bodies in a mode of intravenous infusion, and potential safety hazards exist, so that in order to ensure medication safety, reduce risks to human bodies, the crystallization problem of the mannitol injection needs to be solved, and the quality of the mannitol injection on the market is ensured.
For example, in Chinese patent No. CN105147600B (a compound mannitol injection), mannitol, sorbitol, tween, olive oil, sodium chloride, water for injection and the like are adopted as raw materials to prepare the compound mannitol injection, so that the compound mannitol injection has good curative effect, no crystallization at low temperature and high use safety. In Chinese patent No. CN101732287B (mannitol and glycerin injection and its preparation process), mannitol, glycerin and water for injection are added, and then active carbon is added for boiling and filtering to obtain mannitol and glycerin injection. Mannitol and glycerin are used for compatibility, so that the effect of reducing intracranial pressure can be achieved cooperatively, and the crystallization phenomenon caused by temperature change or storage and transportation process is eliminated. However, in the above-mentioned patent technology, mannitol injection is obtained by designing the types of raw materials, and the added raw materials also have corresponding pharmaceutical effects, which limits the practical application scenarios thereof.
Therefore, starting from the preparation process, a preparation process capable of reducing crystallization of mannitol injection is designed, and other medicinal components with therapeutic effects are not added at the same time, so that the application of mannitol injection is ensured.
Disclosure of Invention
The invention aims to provide a preparation process of mannitol injection which is not easy to crystallize, so as to solve the technical problems in the background technology.
In order to achieve the above purpose, the invention discloses a preparation process of mannitol injection which is not easy to crystallize, comprising the following steps: (1) preparing a raw material; (2) preparing mannitol aqueous solution; (3) adjusting the pH value; (4) filtering; (5) filling; (6) sterilizing;
in step (1), the starting mannitol is recrystallized: mannitol is added into water for injection to prepare mannitol aqueous solution, the mannitol aqueous solution is filtered by an ultrafiltration membrane, then crystallization nucleus is added, mannitol is recrystallized, mannitol crystals are obtained by filtration, and the mannitol crystals are dried for later use.
And all liquid raw materials, including water for injection, hydrochloric acid, ethanol and the like, need to be filtered by an ultrafiltration membrane of 2-50nm before being used.
Further, the crystallization nucleus comprises an inorganic crystallization nucleus and an organic crystallization nucleus, the inorganic crystallization nucleus comprises one or more of sodium chloride, potassium chloride and sodium sulfate, and the organic crystallization nucleus comprises one or more of mannose, ethylene glycol, propylene glycol, glyceryl stearate, polyvinyl alcohol and polyethylene glycol.
Further, in the steps (2) to (5), the temperature of the aqueous mannitol solution is maintained at 40 to 60 ℃.
Further, in the step (2), in the mannitol aqueous solution, the solute includes mannitol and sodium chloride.
Further, in the step (3), hydrochloric acid is adopted to adjust the pH value of the mannitol aqueous solution, and the pH value of the mannitol aqueous solution is adjusted to be 4.5-5.5.
In the step (4), active carbon is added into the mannitol aqueous solution to adsorb impurities, and then an ultrafiltration membrane is adopted to filter the mannitol aqueous solution, so that the steps are circulated for a plurality of times until no particles exist in the mannitol aqueous solution under a microscope.
Further, before the activated carbon is used, the activated carbon is cleaned by adopting a mixed solution of ethanol and hydrochloric acid.
Further, in the step (5), before filling, the filling equipment and the filling container are cleaned in advance, and injection water with the temperature of 40-60 ℃ is adopted to perform multiple cleaning under the water pressure of 0.1-0.3 MPa.
Furthermore, during filling, the filling container is made of glass, polyethylene, polypropylene or polyvinyl chloride, and the liquid is ensured not to contact the mouth of the filling container during filling.
Further, in the step (6), a steam sterilization method is adopted: sterilizing at 121deg.C and 0.1MPa for 20-60min.
Compared with the prior art, the preparation process of the mannitol injection which is not easy to crystallize has the following beneficial effects:
(1) In the invention, mannitol is recrystallized before mannitol injection is prepared, and the liquid raw material is filtered by adopting an ultrafiltration membrane, so that the possibility of crystallization of mannitol injection caused by particles is reduced from the incoming material.
(2) In the invention, when mannitol is recrystallized, the inorganic crystallization nucleus and the organic crystallization nucleus are selected to be used together, and recrystallized mannitol crystals are modified, so that the mannitol recrystallized crystals can be controlled, the solubility of mannitol in water can be improved, and the crystallization phenomenon of mannitol injection can be further prevented.
(3) In the invention, in the steps of preparing mannitol solution, regulating pH value, filtering, filling and the like, the temperature of the mannitol aqueous solution is set to 40-60 ℃, rapid heating or cooling is avoided, the stability of the mannitol injection is improved, and the crystallization probability of the mannitol injection is further reduced.
(4) In the invention, in the prepared mannitol solution, the method of alternately and circularly carrying out activated carbon adsorption and ultrafiltration membrane filtration is adopted, so that the particles in the mannitol solution are sufficiently removed, and the crystallization phenomenon caused by the particles is further reduced.
Detailed Description
Embodiments of the present invention will now be described in detail with reference to the following examples, which are provided for illustration only and are not to be construed as limiting the scope of the invention. The specific conditions are not noted in the examples and are carried out according to conventional conditions or conditions recommended by the manufacturer.
A preparation process of mannitol injection which is not easy to crystallize comprises the following steps:
(1) Preparing raw materials: mannitol (injection grade), sodium chloride (injection grade), water for injection, active carbon (medicinal grade, injection active carbon), hydrochloric acid (medicinal grade), ethanol (medicinal grade);
pretreatment of raw materials: all liquid raw materials, including water for injection, hydrochloric acid and ethanol, are filtered by an ultrafiltration membrane of 2-50nm before use.
In addition, the pretreatment of mannitol and active carbon is also included, and specifically:
(a) Pretreatment of mannitol: and recrystallizing mannitol to further improve the purity of mannitol raw materials.
Mannitol is added into water for injection at 60-80 ℃ to prepare 50-70% mannitol aqueous solution, the mannitol aqueous solution is filtered by an ultrafiltration membrane of 2-50nm, then crystallization nuclei are added, the temperature is slowly reduced, the temperature reduction speed is controlled to be 1.5-2 ℃/min, the mannitol is cooled to 10-15 ℃, the mannitol is recrystallized, the recrystallized system is subjected to suction filtration by a 0.1 micron filter membrane, and the obtained mannitol crystals are dried for later use.
The filtered filtrate can be evaporated, condensed and recycled.
The crystallization nucleus comprises inorganic crystallization nucleus and organic crystallization nucleus, wherein the inorganic crystallization nucleus comprises one or more of sodium chloride, potassium chloride and sodium sulfate, and the organic crystallization nucleus comprises one or more of mannose, ethylene glycol, propylene glycol, glyceryl stearate, polyvinyl alcohol and polyethylene glycol.
In the process of mannitol recrystallization, the inorganic crystallization core can form a uniform crystal mixture with mannitol crystals, so that the stability of mannitol crystals is improved, the organic crystallization core can be adsorbed on the surface of the crystal mixture, and the crystallization tendency of mannitol injection can be reduced under the combined action of the inorganic crystallization core and the mannitol crystals.
The adding mass of the crystallization nucleus is 1-5% of the adding mass of mannitol, wherein the mass ratio of the inorganic crystallization nucleus to the organic crystallization nucleus is 1:1-3.
(b) Pretreatment of activated carbon: mixing ethanol and dilute hydrochloric acid (0.5-2.0 mol/L) as a cleaning agent, wherein the volume ratio of the ethanol to the dilute hydrochloric acid is 1:2-5; soaking and cleaning the activated carbon at 50-70 ℃ with the dosage of the cleaning agent of 5-15mL/g of activated carbon for 12-36h, taking out the activated carbon, cleaning with water for injection, and drying for later use.
(2) Preparing mannitol aqueous solution: mannitol and sodium chloride are dissolved in water for injection to be mixed, and are firstly concentrated and then diluted, and the mass concentration of mannitol in the final mannitol aqueous solution is 15% and the mass concentration of sodium chloride is 5%.
Sodium chloride is added into mannitol solution, so that the dosage of mannitol can be reduced, the crystallization probability of mannitol injection is reduced, and meanwhile, the possibility of excessive dehydration and electrolyte disorder caused in the use process of mannitol can be reduced by adding sodium chloride.
(3) Adjusting the pH value: the pH value is regulated to 4.5-5.5 by adopting 0.5-2.0mol/L dilute hydrochloric acid.
(4) And (3) filtering: adding active carbon into mannitol aqueous solution, filtering with 2-50nm ultrafiltration membrane, and repeating the steps of adding active carbon for adsorption and ultrafiltration membrane filtration repeatedly until no particulate matter exists in mannitol aqueous solution under microscope. The ratio of the total added mass of the activated carbon to the volume of the mannitol aqueous solution is controlled to be 0.001-0.005:1.
(5) And (3) filling: before filling, filling equipment and a filling container are cleaned in advance, and injection water with the temperature of 40-60 ℃ is adopted to perform multiple times of cleaning under the water pressure of 0.1-0.3MPa, including bottle external cleaning, rough cleaning, fine cleaning and the like.
In the filling process, the liquid is ensured not to touch the mouth part of the filling container, and the filling container is selected to be made of glass, polyethylene, polypropylene or polyvinyl chloride.
Wherein, in the steps (2) - (5), the temperature of the mannitol aqueous solution is equal, and the temperature is controlled to be 40-60 ℃.
(6) And (3) sterilization: hot press sterilizing at 121deg.C for 20-60min, and spray sterilizing with hot water.
And then carrying out lamp inspection, labeling and film-covered packaging on the product after filling and sterilization, and warehousing.
The mannitol injection obtained by the preparation process of the mannitol injection is not easy to crystallize in the use process, and the technical problem that the mannitol injection is easy to crystallize is solved.
Example 1
(1) Preparing raw materials: mannitol (injection grade), sodium chloride (injection grade), water for injection, active carbon (medicinal grade, injection active carbon), hydrochloric acid (medicinal grade), ethanol (medicinal grade);
pretreatment of raw materials: all liquid raw materials, including water for injection, hydrochloric acid and ethanol, are filtered by an ultrafiltration membrane of 20nm before use.
In addition, the pretreatment of mannitol and active carbon is also included, and specifically:
(a) Pretreatment of mannitol: and recrystallizing mannitol to further improve the purity of mannitol raw materials.
Mannitol is added into water for injection at 65 ℃ to prepare mannitol water solution with 55% mass concentration, the mannitol water solution is filtered by an ultrafiltration membrane of 20nm, then crystallization nucleus (sodium chloride and ethylene glycol with the mass ratio of 1:1) with the weight of 5% of mannitol is added, the temperature is slowly reduced, the cooling speed is controlled to be 1.6 ℃/min, the mannitol is cooled to 10 ℃, the mannitol is recrystallized, the recrystallized system is filtered by a 0.1 micron filter membrane, and the mannitol crystal is dried for standby. The filtered filtrate can be evaporated, condensed and recycled.
(b) Pretreatment of activated carbon: mixing ethanol and dilute hydrochloric acid (1.0 mol/L) as a cleaning agent, wherein the volume ratio of the ethanol to the dilute hydrochloric acid is 1:5; and (3) soaking and cleaning the activated carbon at 65 ℃, wherein the dosage of the cleaning agent is 10mL/g of the activated carbon, the soaking and cleaning time is 30 hours, and then taking out the activated carbon, cleaning the activated carbon by using water for injection and drying for later use.
(2) Preparing mannitol aqueous solution: mannitol and sodium chloride are dissolved in water for injection to be mixed, and are firstly concentrated and then diluted, and the mass concentration of mannitol in the final mannitol aqueous solution is 15% and the mass concentration of sodium chloride is 5%.
When in concentration, adding a proper amount of water for injection into a concentration preparation tank, heating to 50 ℃ by using steam, adding mannitol and sodium chloride according to the formula amount, and stirring to dissolve the mannitol and sodium chloride; then the mixture is led into a diluting preparation tank, and the rest water for injection is added for constant volume.
(3) Adjusting the pH value: the pH value is regulated to be between 4.5 and 5.0 by adopting 1.5mol/L dilute hydrochloric acid.
(4) And (3) filtering: adding active carbon into mannitol aqueous solution, filtering with 20nm ultrafiltration membrane, and repeating the steps of adding active carbon for adsorption and ultrafiltration membrane filtration repeatedly until no particulate matter exists in mannitol aqueous solution under microscope. The ratio of the total added mass of the activated carbon to the volume of the mannitol aqueous solution is controlled to be 0.001-0.003:1.
The detection steps are as follows: and sucking a proper amount of mannitol aqueous solution, placing the mannitol aqueous solution under an optical microscope for particle detection, and observing no particles in a field of view of 1000 times magnification.
(5) And (3) filling: before filling, the filling pipeline is cleaned in advance, and the filling pipeline is cleaned for a plurality of times by using water for injection at the temperature of 50 ℃ under the water pressure of 0.2 MPa.
And (3) filling the glass bottles, cleaning the glass bottles from a storage room, sending the glass bottles into a large transfusion production linkage line, cleaning the glass bottles, and sending the glass bottles to the filling room after rough cleaning and fine cleaning. The fine washing step adopts water for injection at 50 ℃, part of the water can be recycled to the rough washing step after being collected, and the rough washing ring can be recycled to the bottle outside for washing in a water-saving way.
The filling line is automatic production, and qualified liquid medicine which is prepared is metered and filled in a glass bottle. And (3) covering the cleaned rubber plug and aluminum cover, and rolling the cover for loading, so that the liquid medicine is ensured not to touch the mouth part of the glass bottle in the filling process.
Wherein, in the steps (2) - (5), the temperature of the mannitol aqueous solution is equal, and the temperature of the mannitol aqueous solution is controlled to be 50 ℃.
(6) And (3) sterilization: and (3) carrying out hot press sterilization for 45min at the temperature of 121 ℃ and carrying out hot water spray sterilization.
And then carrying out lamp inspection, labeling and film-covered packaging on the product after filling and sterilization, and warehousing. The reject is disposed of as waste by a qualification unit.
Example 2
(1) Preparing raw materials: mannitol (injection grade), sodium chloride (injection grade), water for injection, active carbon (medicinal grade, injection active carbon), hydrochloric acid (medicinal grade), ethanol (medicinal grade);
pretreatment of raw materials: all liquid raw materials, including water for injection, hydrochloric acid and ethanol, are filtered by an ultrafiltration membrane of 10nm before use.
In addition, the pretreatment of mannitol and active carbon is also included, and specifically:
(a) Pretreatment of mannitol: and recrystallizing mannitol to further improve the purity of mannitol raw materials.
Mannitol is added into water for injection at 70 ℃ to prepare mannitol water solution with the mass concentration of 60%, the mannitol water solution is filtered by an ultrafiltration membrane of 10nm, then crystallization nuclei (sodium chloride and mannose with the mass ratio of 1:2) with the mass of 2% of mannitol are added, the temperature is slowly reduced, the cooling speed is controlled to be 1.5 ℃/min, the mannitol is cooled to 10 ℃, the mannitol is recrystallized, the recrystallized system is filtered by a filter membrane of 0.1 micron, and the mannitol crystals obtained are dried for standby. The filtered filtrate can be evaporated, condensed and recycled.
(b) Pretreatment of activated carbon: mixing ethanol and dilute hydrochloric acid (2.0 mol/L) as a cleaning agent, wherein the volume ratio of the ethanol to the dilute hydrochloric acid is 1:2; and (3) soaking and cleaning the activated carbon at 70 ℃, wherein the dosage of the cleaning agent is 15mL/g of the activated carbon, the soaking and cleaning time is 36h, and then taking out the activated carbon, cleaning the activated carbon by using water for injection and drying for later use.
(2) Preparing mannitol aqueous solution: mannitol and sodium chloride are dissolved in water for injection to be mixed, and are firstly concentrated and then diluted, and the mass concentration of mannitol in the final mannitol aqueous solution is 15% and the mass concentration of sodium chloride is 5%.
When in concentration, adding a proper amount of water for injection into a concentration preparation tank, heating to 55 ℃ by using steam, adding mannitol and sodium chloride according to the formula amount, and stirring to dissolve the mannitol and sodium chloride; then the mixture is led into a diluting preparation tank, and the rest water for injection is added for constant volume.
(3) Adjusting the pH value: the pH value is regulated to be between 4.5 and 5.0 by adopting 2.0mol/L dilute hydrochloric acid.
(4) And (3) filtering: adding active carbon into mannitol aqueous solution, filtering with 10nm ultrafiltration membrane, and repeating the steps of adding active carbon for adsorption and ultrafiltration membrane filtration repeatedly until no particulate matter exists in mannitol aqueous solution under microscope. The ratio of the total added mass of the activated carbon to the volume of the mannitol aqueous solution is controlled to be 0.002-0.003:1.
And sucking a proper amount of mannitol aqueous solution, placing the mannitol aqueous solution under an optical microscope for particle detection, and observing no particles in a field of view of 1000 times magnification.
(5) And (3) filling: before filling, the filling pipeline is cleaned in advance, and the filling pipeline is cleaned for a plurality of times by using water for injection at the temperature of 55 ℃ under the water pressure of 0.15 MPa.
And (3) filling the glass bottles, cleaning the glass bottles from a storage room, sending the glass bottles into a large transfusion production linkage line, cleaning the glass bottles, and sending the glass bottles to the filling room after rough cleaning and fine cleaning. The fine washing step adopts injection water at 55 ℃, part of the water can be recycled to the rough washing step after being collected, and the rough washing ring can be recycled to the bottle outside for washing in a water-saving way.
The filling line is automatic production, and qualified liquid medicine which is prepared is metered and filled in a glass bottle. And (3) covering the cleaned rubber plug and aluminum cover, and rolling the cover for loading, so that the liquid medicine is ensured not to touch the mouth part of the glass bottle in the filling process.
Wherein, in the steps (2) - (5), the temperature of the mannitol aqueous solution is equal, and the temperature is controlled to be 55 ℃.
(6) And (3) sterilization: and hot-press sterilizing at 121deg.C for 55min, and spray sterilizing with hot water.
And then carrying out lamp inspection, labeling and film-covered packaging on the product after filling and sterilization, and warehousing. The reject is disposed of as waste by a qualification unit.
Example 3
(1) Preparing raw materials: mannitol (injection grade), sodium chloride (injection grade), water for injection, active carbon (medicinal grade, injection active carbon), hydrochloric acid (medicinal grade), ethanol (medicinal grade);
pretreatment of raw materials: all liquid raw materials, including water for injection, hydrochloric acid and ethanol, are filtered by an ultrafiltration membrane of 10nm before use.
In addition, the pretreatment of mannitol and active carbon is also included, and specifically:
(a) Pretreatment of mannitol: and recrystallizing mannitol to further improve the purity of mannitol raw materials.
Mannitol is added into water for injection at 70 ℃ to prepare a mannitol water solution with 65% mass concentration, the mannitol water solution is filtered by an ultrafiltration membrane of 10nm, then crystallization nuclei (potassium chloride and propylene glycol with the mass ratio of 1:1.5) with the weight of 1% of mannitol are added, the temperature is slowly reduced, the temperature reduction speed is controlled to be 1.8 ℃/min, the mannitol is cooled to 10 ℃, mannitol is recrystallized, the recrystallized system is filtered by a filter membrane of 0.1 micron, and the obtained mannitol crystals are dried for standby. The filtered filtrate can be evaporated, condensed and recycled.
(b) Pretreatment of activated carbon: mixing ethanol and dilute hydrochloric acid (1.5 mol/L) as a cleaning agent, wherein the volume ratio of the ethanol to the dilute hydrochloric acid is 1:3; and (3) soaking and cleaning the activated carbon at 65 ℃, wherein the dosage of the cleaning agent is 10mL/g of the activated carbon, the soaking and cleaning time is 36h, and then taking out the activated carbon, cleaning the activated carbon by using water for injection and drying for later use.
(2) Preparing mannitol aqueous solution: mannitol and sodium chloride are dissolved in water for injection to be mixed, and are firstly concentrated and then diluted, and the mass concentration of mannitol in the final mannitol aqueous solution is 15% and the mass concentration of sodium chloride is 5%.
When in concentration, adding a proper amount of water for injection into a concentration preparation tank, heating to 55 ℃ by using steam, adding mannitol and sodium chloride according to the formula amount, and stirring to dissolve the mannitol and sodium chloride; then the mixture is led into a diluting preparation tank, and the rest water for injection is added for constant volume.
(3) Adjusting the pH value: the pH value is adjusted to be between 5.0 and 5.5 by adopting 1.0mol/L dilute hydrochloric acid.
(4) And (3) filtering: adding the formula amount of active carbon into the mannitol aqueous solution at one time, filtering by using a 10nm ultrafiltration membrane, and controlling the ratio of the total added mass of the active carbon to the volume of the mannitol aqueous solution to be 0.002-0.003:1.
(5) And (3) filling: before filling, the filling pipeline is cleaned in advance, and the filling pipeline is cleaned for a plurality of times by using water for injection at the temperature of 55 ℃ under the water pressure of 0.25 MPa.
The polypropylene plastic bottle is selected for filling, an ion wind air washing process is adopted for cleaning, the cleaning medium is sterile compressed air with anions, and the sterile compressed air is filtered through a filter membrane with the diameter of 0.1 micrometer, so that foreign matters in the plastic bottle can be cleaned, and static electricity on the bottle wall can be eliminated.
The filling line is automatic production, and qualified liquid medicine is metered and filled through a pneumatic valve. The plastic bottle and the cover are purchased externally, the automatic cover loading station is provided with an automatic cover loading hopper which is matched with the oscillating disc, and automatic material level detection and cover loading can be realized. The bottle cap and the bottle body are automatically welded by adopting hot melt welding.
In the filling process, the liquid medicine is ensured not to touch the mouth part of the polypropylene plastic bottle.
Wherein, in the steps (2) - (5), the temperature of the mannitol aqueous solution is equal, and the temperature is controlled to be 55 ℃.
(6) And (3) sterilization: hot press sterilizing at 121deg.C for 60min, and spray sterilizing with hot water.
And then carrying out lamp inspection, labeling and film-covered packaging on the product after filling and sterilization, and warehousing. The reject is disposed of as waste by a qualification unit.
Comparative example 1
(1) Preparing raw materials including mannitol (injection grade), sodium chloride (injection grade), water for injection, active carbon (medicinal grade, injection active carbon), hydrochloric acid (medicinal grade), and ethanol (medicinal grade);
(2) Preheating a circulating pipeline by using high-temperature injection water at 90 ℃, respectively adding mannitol, sodium chloride and injection water into a concentrated preparation tank, heating to 80 ℃, stirring until the mannitol, the sodium chloride and the injection water are completely dissolved, then adding active carbon into the concentrated preparation tank, continuously heating until the active carbon is boiled, preserving heat for 30min, and introducing the aqueous solution in the concentrated preparation tank into a dilute preparation tank through a 0.22 micron filter membrane after stopping heating;
(3) Adding water for injection into a diluting preparation tank to fix volume, then adjusting the pH value to be between 4.5 and 5.0 by using 2mol/L dilute hydrochloric acid to obtain diluted preparation liquid, then opening process cooling water, heating and refluxing the diluted preparation liquid for 30min, keeping the temperature of the diluted preparation liquid at 50 ℃, and then filtering the diluted preparation liquid through a 0.22 micrometer filter membrane in sequence until the diluted preparation liquid is clear and transparent to obtain mannitol injection; the mass concentration of mannitol is 15% and the mass concentration of sodium chloride is 5%.
(4) And then filling and sterilizing the mannitol injection, wherein in the filling process, the filling pipeline is preheated by high-temperature injection water at 90 ℃ in advance, and the cleaning, filling and sterilizing processes of the filling container are the same as those in the embodiment 1.
The mannitol injections obtained in examples 1 to 3 and comparative example 1 were subjected to performance measurement. Several mannitol injection samples were taken from each group, and placed at 4℃for several days, and the crystallization results, insoluble particles and bacterial endotoxin content were observed, and the results are shown in Table 1.
TABLE 1 results of Performance measurements of mannitol injections of examples 1-3 and comparative example 1, which were left for 0 days at 4℃
| Numbering device | With or without devitrification | The average value (granule) of insoluble particles with the particle size of more than or equal to 10 microns in per milliliter of the product | The average value (granule) of insoluble particles with the particle size of more than or equal to 25 microns in per milliliter of the product | Bacterial endotoxin content (EU) |
| Example 1 | Without any means for | 5 | 0.1 | 0.30 |
| Example 2 | Without any means for | 6 | 0.3 | 0.46 |
| Example 3 | Without any means for | 6 | 0.5 | 0.42 |
| Comparative example 1 | Without any means for | 17 | 1.8 | 1.20 |
TABLE 2 determination of the Property of mannitol injection of examples 1-3 and comparative example 1 left standing at 4℃for 3 days
| Numbering device | With or without devitrification | The average value (granule) of insoluble particles with the particle size of more than or equal to 10 microns in per milliliter of the product | Every milliliter of the productAverage value (particles) of insoluble particles with particle diameter of more than or equal to 25 microns | Bacterial endotoxin content (EU) |
| Example 1 | Without any means for | 7 | 0.3 | 0.40 |
| Example 2 | Without any means for | 9 | 0.6 | 0.53 |
| Example 3 | Without any means for | 8 | 0.7 | 0.52 |
| Comparative example 1 | Has the following components | 19 | 2.4 | 1.38 |
TABLE 3 determination of the Property of mannitol injection of examples 1-3 and comparative example 1 left standing at 4℃for 5 days
| Numbering device | With or without devitrification | The average value (granule) of insoluble particles with the particle size of more than or equal to 10 microns in per milliliter of the product | The average value (granule) of insoluble particles with the particle size of more than or equal to 25 microns in per milliliter of the product | Bacterial endotoxin content (EU) |
| Example 1 | Without any means for | 10 | 0.7 | 0.51 |
| Example 2 | Without any means for | 13 | 0.8 | 0.62 |
| Example 3 | Without any means for | 11 | 0.9 | 0.64 |
| Comparative example 1 | Has the following components | 21 | 2.8 | 1.43 |
TABLE 4 determination of the Performance of mannitol injection solutions of examples 1-3 and comparative example 1, which were left at 4℃for 10 days
| Numbering device | With or without devitrification | The average value (granule) of insoluble particles with the particle size of more than or equal to 10 microns in per milliliter of the product | The average value (granule) of insoluble particles with the particle size of more than or equal to 25 microns in per milliliter of the product | Bacterial endotoxin content (EU) |
| Example 1 | Without any means for | 15 | 1.1 | 0.80 |
| Example 2 | Without any means for | 17 | 1.3 | 0.95 |
| Example 3 | Without any means for | 16 | 1.4 | 0.92 |
| Comparative example 1 | Has the following components | 26 | 3.2 | 1.68 |
Therefore, the mannitol injection obtained by the preparation process is not easy to crystallize, and has no crystallization after being placed for a plurality of days at a low temperature, and the detection results of the average value of insoluble particles with the particle size of more than or equal to 10 microns per milliliter of the product, the average value of insoluble particles with the particle size of more than or equal to 25 microns per milliliter of the product, the bacterial endotoxin content and the like are far better than the indexes required by national formulary.
The above description is only of the preferred embodiments of the present invention, and is not intended to limit the invention, but any modifications, equivalent substitutions, improvements, etc. within the design concept of the present invention should be included in the scope of the present invention.
Claims (1)
1. A preparation process of mannitol injection which is not easy to crystallize is characterized in that: the method comprises the following steps:
(1) Preparing raw materials: mannitol, sodium chloride, water for injection, active carbon, hydrochloric acid and ethanol;
pretreatment of raw materials: all liquid raw materials are filtered by an ultrafiltration membrane of 10-20nm before use and then are used;
in addition, the pretreatment of mannitol and active carbon is also included, and specifically:
(a) Pretreatment of mannitol: recrystallizing mannitol, adding mannitol into water for injection at 65-70 ℃ to prepare mannitol aqueous solution with the mass concentration of 55-65%, filtering by an ultrafiltration membrane of 10-20nm, adding crystallization nucleus with the weight of 1-5% of mannitol, cooling, controlling the cooling speed to be 1.5-1.8 ℃/min, cooling to 10 ℃, recrystallizing mannitol, carrying out suction filtration on the recrystallized system by a filter membrane of 0.1 micrometer, and drying the obtained mannitol crystal for later use;
the crystallization nucleus comprises an inorganic crystallization nucleus and an organic crystallization nucleus, wherein the inorganic crystallization nucleus comprises one or two of sodium chloride and potassium chloride, and the organic crystallization nucleus comprises one or more of mannose, ethylene glycol and propylene glycol, and the mass ratio of the inorganic crystallization nucleus to the organic crystallization nucleus is 1:1-2;
(b) Pretreatment of activated carbon: mixing ethanol and dilute hydrochloric acid with the concentration of 1.0-1.5mol/L, wherein the volume ratio of the ethanol to the dilute hydrochloric acid is 1:2-5; soaking and cleaning the activated carbon at 65-70 ℃ with the dosage of the cleaning agent of 10-15mL/g of activated carbon for 30-36h, taking out the activated carbon, cleaning with water for injection, and drying for later use;
(2) Preparing mannitol aqueous solution: dissolving mannitol and sodium chloride in water for injection for mixing, firstly concentrating, then diluting, wherein the mass concentration of mannitol in the final mannitol aqueous solution is 15%, and the mass concentration of sodium chloride is 5%;
when in concentration, adding a proper amount of water for injection into a concentration preparation tank, heating to 50-55 ℃ by using steam, adding mannitol and sodium chloride according to the formula amount, and stirring to dissolve the mannitol and sodium chloride; then the mixture is led into a diluting preparation tank, and the rest water for injection is added for constant volume;
(3) Adjusting the pH value: adjusting the pH value of the mannitol aqueous solution to be between 4.5 and 5.5 by adopting hydrochloric acid;
(4) And (3) filtering: adding active carbon into mannitol aqueous solution, filtering with 10-20nm ultrafiltration membrane, repeating the cycle for several times, and controlling the ratio of the total added mass of active carbon to the volume of mannitol aqueous solution to be 0.001-0.003:1;
(5) And (3) filling: before filling, cleaning filling equipment and a filling container in advance, and cleaning for a plurality of times by adopting injection water with the temperature of 40-60 ℃ under the water pressure of 0.1-0.3 MPa; during filling, the filling container is made of glass or polypropylene, and the liquid is ensured not to contact the mouth part of the filling container during filling;
(6) And (3) sterilization: adopts a steam sterilization method: sterilizing at 121deg.C and 0.1MPa for 20-60min.
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