CN108158987A - A kind of edrophonium chloride injection and preparation method thereof - Google Patents
A kind of edrophonium chloride injection and preparation method thereof Download PDFInfo
- Publication number
- CN108158987A CN108158987A CN201810137339.4A CN201810137339A CN108158987A CN 108158987 A CN108158987 A CN 108158987A CN 201810137339 A CN201810137339 A CN 201810137339A CN 108158987 A CN108158987 A CN 108158987A
- Authority
- CN
- China
- Prior art keywords
- edrophonium chloride
- preparation
- calcium alginate
- titanium dioxide
- water
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- BXKDSDJJOVIHMX-UHFFFAOYSA-N edrophonium chloride Chemical compound [Cl-].CC[N+](C)(C)C1=CC=CC(O)=C1 BXKDSDJJOVIHMX-UHFFFAOYSA-N 0.000 title claims abstract description 61
- 229960002406 edrophonium chloride Drugs 0.000 title claims abstract description 57
- 238000002347 injection Methods 0.000 title claims abstract description 35
- 239000007924 injection Substances 0.000 title claims abstract description 35
- 238000002360 preparation method Methods 0.000 title claims abstract description 28
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 39
- 239000000648 calcium alginate Substances 0.000 claims abstract description 36
- 229960002681 calcium alginate Drugs 0.000 claims abstract description 36
- 239000000243 solution Substances 0.000 claims abstract description 26
- 239000003002 pH adjusting agent Substances 0.000 claims abstract description 21
- 239000012982 microporous membrane Substances 0.000 claims abstract description 18
- 238000001914 filtration Methods 0.000 claims abstract description 15
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 14
- 229940101006 anhydrous sodium sulfite Drugs 0.000 claims abstract description 14
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 claims abstract description 14
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid group Chemical class C(CC(O)(C(=O)O)CC(=O)O)(=O)O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims abstract description 13
- 235000010410 calcium alginate Nutrition 0.000 claims abstract description 12
- 239000008215 water for injection Substances 0.000 claims abstract description 12
- OKHHGHGGPDJQHR-YMOPUZKJSA-L calcium;(2s,3s,4s,5s,6r)-6-[(2r,3s,4r,5s,6r)-2-carboxy-6-[(2r,3s,4r,5s,6r)-2-carboxylato-4,5,6-trihydroxyoxan-3-yl]oxy-4,5-dihydroxyoxan-3-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylate Chemical compound [Ca+2].O[C@@H]1[C@H](O)[C@H](O)O[C@@H](C([O-])=O)[C@H]1O[C@H]1[C@@H](O)[C@@H](O)[C@H](O[C@H]2[C@H]([C@@H](O)[C@H](O)[C@H](O2)C([O-])=O)O)[C@H](C(O)=O)O1 OKHHGHGGPDJQHR-YMOPUZKJSA-L 0.000 claims abstract description 11
- 238000001514 detection method Methods 0.000 claims abstract description 11
- SOQBVABWOPYFQZ-UHFFFAOYSA-N oxygen(2-);titanium(4+) Chemical compound [O-2].[O-2].[Ti+4] SOQBVABWOPYFQZ-UHFFFAOYSA-N 0.000 claims abstract description 9
- 239000000203 mixture Substances 0.000 claims abstract description 8
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 8
- 238000007689 inspection Methods 0.000 claims abstract description 7
- 238000004806 packaging method and process Methods 0.000 claims abstract description 7
- 230000001954 sterilising effect Effects 0.000 claims abstract description 7
- 239000001509 sodium citrate Substances 0.000 claims abstract description 5
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 claims abstract description 5
- 239000012528 membrane Substances 0.000 claims description 28
- 238000003756 stirring Methods 0.000 claims description 24
- 229910052719 titanium Inorganic materials 0.000 claims description 18
- 239000010936 titanium Substances 0.000 claims description 18
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 10
- 239000007788 liquid Substances 0.000 claims description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 8
- 239000003431 cross linking reagent Substances 0.000 claims description 8
- 239000008367 deionised water Substances 0.000 claims description 8
- 229910021641 deionized water Inorganic materials 0.000 claims description 8
- 238000004132 cross linking Methods 0.000 claims description 6
- 239000004695 Polyether sulfone Substances 0.000 claims description 5
- 229960000583 acetic acid Drugs 0.000 claims description 5
- 239000002253 acid Substances 0.000 claims description 5
- 229920000615 alginic acid Polymers 0.000 claims description 5
- 239000012362 glacial acetic acid Substances 0.000 claims description 5
- 229920002492 poly(sulfone) Polymers 0.000 claims description 5
- 229920006393 polyether sulfone Polymers 0.000 claims description 5
- 239000000843 powder Substances 0.000 claims description 5
- 239000004677 Nylon Substances 0.000 claims description 4
- 235000010443 alginic acid Nutrition 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- 229920001778 nylon Polymers 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 4
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 claims description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 3
- FPCJKVGGYOAWIZ-UHFFFAOYSA-N butan-1-ol;titanium Chemical compound [Ti].CCCCO.CCCCO.CCCCO.CCCCO FPCJKVGGYOAWIZ-UHFFFAOYSA-N 0.000 claims description 3
- 239000001110 calcium chloride Substances 0.000 claims description 3
- 229910001628 calcium chloride Inorganic materials 0.000 claims description 3
- 239000011734 sodium Substances 0.000 claims description 3
- 229910052708 sodium Inorganic materials 0.000 claims description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 3
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 2
- 239000002033 PVDF binder Substances 0.000 claims description 2
- 239000000783 alginic acid Substances 0.000 claims description 2
- 229960001126 alginic acid Drugs 0.000 claims description 2
- 239000011575 calcium Substances 0.000 claims description 2
- 229910052791 calcium Inorganic materials 0.000 claims description 2
- 239000001913 cellulose Substances 0.000 claims description 2
- 229920002678 cellulose Polymers 0.000 claims description 2
- 230000007935 neutral effect Effects 0.000 claims description 2
- 229920002981 polyvinylidene fluoride Polymers 0.000 claims description 2
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 claims 2
- 240000007594 Oryza sativa Species 0.000 claims 1
- 235000007164 Oryza sativa Nutrition 0.000 claims 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-N Sulfurous acid Chemical compound OS(O)=O LSNNMFCWUKXFEE-UHFFFAOYSA-N 0.000 claims 1
- JTCFNJXQEFODHE-UHFFFAOYSA-N [Ca].[Ti] Chemical compound [Ca].[Ti] JTCFNJXQEFODHE-UHFFFAOYSA-N 0.000 claims 1
- 150000004781 alginic acids Chemical class 0.000 claims 1
- UDUSKVQRFMRRGV-UHFFFAOYSA-N calcium oxygen(2-) titanium(4+) Chemical compound [Ca+2].[Ti+4].[O-2].[O-2].[Ti+4] UDUSKVQRFMRRGV-UHFFFAOYSA-N 0.000 claims 1
- WMMAJCFFFQQZGX-UHFFFAOYSA-N calcium;oxygen(2-);titanium(4+) Chemical compound [O-2].[O-2].[Ca+2].[Ti+4] WMMAJCFFFQQZGX-UHFFFAOYSA-N 0.000 claims 1
- 235000009566 rice Nutrition 0.000 claims 1
- 239000004408 titanium dioxide Substances 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 7
- 230000000844 anti-bacterial effect Effects 0.000 abstract 1
- 239000003963 antioxidant agent Substances 0.000 abstract 1
- 230000003078 antioxidant effect Effects 0.000 abstract 1
- 235000006708 antioxidants Nutrition 0.000 abstract 1
- 235000015165 citric acid Nutrition 0.000 abstract 1
- 238000005260 corrosion Methods 0.000 abstract 1
- 239000000047 product Substances 0.000 description 10
- 239000003182 parenteral nutrition solution Substances 0.000 description 7
- 229920001661 Chitosan Polymers 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 210000004379 membrane Anatomy 0.000 description 6
- 210000002469 basement membrane Anatomy 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 239000002158 endotoxin Substances 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 241000894006 Bacteria Species 0.000 description 3
- 240000002853 Nelumbo nucifera Species 0.000 description 3
- 235000006508 Nelumbo nucifera Nutrition 0.000 description 3
- 235000006510 Nelumbo pentapetala Nutrition 0.000 description 3
- 238000003618 dip coating Methods 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 235000019441 ethanol Nutrition 0.000 description 3
- 239000012535 impurity Substances 0.000 description 3
- 210000002027 skeletal muscle Anatomy 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 2
- 241000512259 Ascophyllum nodosum Species 0.000 description 2
- 206010013786 Dry skin Diseases 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 241000700605 Viruses Species 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 230000000996 additive effect Effects 0.000 description 2
- 229940072056 alginate Drugs 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 239000005557 antagonist Substances 0.000 description 2
- 238000005266 casting Methods 0.000 description 2
- 239000003610 charcoal Substances 0.000 description 2
- 239000011248 coating agent Substances 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- 239000000084 colloidal system Substances 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 230000003750 conditioning effect Effects 0.000 description 2
- 230000005611 electricity Effects 0.000 description 2
- 125000005909 ethyl alcohol group Chemical group 0.000 description 2
- 239000008236 heating water Substances 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 239000002086 nanomaterial Substances 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 230000006641 stabilisation Effects 0.000 description 2
- 238000011105 stabilization Methods 0.000 description 2
- 238000013268 sustained release Methods 0.000 description 2
- 239000012730 sustained-release form Substances 0.000 description 2
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- 229940122601 Esterase inhibitor Drugs 0.000 description 1
- 108090000371 Esterases Proteins 0.000 description 1
- SXRSQZLOMIGNAQ-UHFFFAOYSA-N Glutaraldehyde Chemical compound O=CCCCC=O SXRSQZLOMIGNAQ-UHFFFAOYSA-N 0.000 description 1
- 206010021118 Hypotonia Diseases 0.000 description 1
- 206010028372 Muscular weakness Diseases 0.000 description 1
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N N-phenyl amine Natural products NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 1
- 239000004952 Polyamide Substances 0.000 description 1
- 229920000388 Polyphosphate Polymers 0.000 description 1
- 241000195474 Sargassum Species 0.000 description 1
- RTAQQCXQSZGOHL-UHFFFAOYSA-N Titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 150000001412 amines Chemical group 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 210000000481 breast Anatomy 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000002801 charged material Substances 0.000 description 1
- 238000007385 chemical modification Methods 0.000 description 1
- 239000000544 cholinesterase inhibitor Substances 0.000 description 1
- 230000003153 cholinolytic effect Effects 0.000 description 1
- 230000000718 cholinopositive effect Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000002242 deionisation method Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000004945 emulsification Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 229940072357 enlon Drugs 0.000 description 1
- 239000002389 essential drug Substances 0.000 description 1
- 239000002329 esterase inhibitor Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000010419 fine particle Substances 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 238000002386 leaching Methods 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000036640 muscle relaxation Effects 0.000 description 1
- 230000036473 myasthenia Effects 0.000 description 1
- 206010028417 myasthenia gravis Diseases 0.000 description 1
- 239000003158 myorelaxant agent Substances 0.000 description 1
- 229960002362 neostigmine Drugs 0.000 description 1
- LULNWZDBKTWDGK-UHFFFAOYSA-M neostigmine bromide Chemical compound [Br-].CN(C)C(=O)OC1=CC=CC([N+](C)(C)C)=C1 LULNWZDBKTWDGK-UHFFFAOYSA-M 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 210000000715 neuromuscular junction Anatomy 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- -1 physics Substances 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 229920002647 polyamide Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 239000001205 polyphosphate Substances 0.000 description 1
- 235000011176 polyphosphates Nutrition 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 150000004804 polysaccharides Chemical class 0.000 description 1
- 238000012805 post-processing Methods 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000009288 screen filtration Methods 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical compound CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000000052 vinegar Substances 0.000 description 1
- 235000021419 vinegar Nutrition 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/14—Quaternary ammonium compounds, e.g. edrophonium, choline
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D61/00—Processes of separation using semi-permeable membranes, e.g. dialysis, osmosis or ultrafiltration; Apparatus, accessories or auxiliary operations specially adapted therefor
- B01D61/14—Ultrafiltration; Microfiltration
- B01D61/147—Microfiltration
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D67/00—Processes specially adapted for manufacturing semi-permeable membranes for separation processes or apparatus
- B01D67/0002—Organic membrane manufacture
- B01D67/0006—Organic membrane manufacture by chemical reactions
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D69/00—Semi-permeable membranes for separation processes or apparatus characterised by their form, structure or properties; Manufacturing processes specially adapted therefor
- B01D69/02—Semi-permeable membranes for separation processes or apparatus characterised by their form, structure or properties; Manufacturing processes specially adapted therefor characterised by their properties
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D71/00—Semi-permeable membranes for separation processes or apparatus characterised by the material; Manufacturing processes specially adapted therefor
- B01D71/06—Organic material
- B01D71/76—Macromolecular material not specifically provided for in a single one of groups B01D71/08 - B01D71/74
- B01D71/82—Macromolecular material not specifically provided for in a single one of groups B01D71/08 - B01D71/74 characterised by the presence of specified groups, e.g. introduced by chemical after-treatment
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D2325/00—Details relating to properties of membranes
- B01D2325/24—Mechanical properties, e.g. strength
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Engineering & Computer Science (AREA)
- Water Supply & Treatment (AREA)
- Manufacturing & Machinery (AREA)
- Inorganic Chemistry (AREA)
- Dermatology (AREA)
- Separation Using Semi-Permeable Membranes (AREA)
- Cosmetics (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention discloses a kind of edrophonium chloride injection and preparation method thereof, edrophonium chloride injection is by as follows into being grouped as：8~12g of Edrophonium Chloride, 1~4g of anhydrous sodium sulfite, water for injection add to 1000ml, and it is 4.0~7.0 to adjust pH with pH adjusting agent；PH adjusting agent is the mixture that weight ratio is 1: 2~1: 5 citric acids and sodium citrate.The present invention also provides a kind of preparation methods of edrophonium chloride injection, include the following steps：A) anhydrous sodium sulfite solution is prepared, adjusts pH, Edrophonium Chloride is added in, is stirred to dissolve；B) it is filtered with nano-titanium dioxide calcium alginate charged microporous membrane to clear and bright, adjusting pH；C) nitrogen charging embedding, sterilizing, leak detection, lamp inspection, packaging.It is according to the invention formula and method prepare edrophonium chloride injection, reduce filtration step, can anti-oxidant, antibacterial, anti-corrosion, product is avoided to degrade, storage stability is good.
Description
Technical field
The invention belongs to pharmaceutical technology fields, and in particular to a kind of edrophonium chloride injection and preparation method thereof.
Technical background
Edrophonium Chloride also known as edrophonium chloride, edrophonium chloride, edrophonium chloride, edrophone chloride belong to quaternary amines easily against property cholinolytic
Esterase medicine acts on same neostigmine.Cholinomimetic Edrophonium Chloride is classical short-acting anticholinesterase, is clinically used as weight
Disease myasthenia diagnosticum and skeletal muscle relaxant antagonist, feature are to nerve and neuromuscular junction high selectivity, are worked rapid,
Duration is short, Small side effects.Edrophonium Chloride at home and abroad has commonly used, bulk pharmaceutical chemicals and its loaded U.S. of injection
State, Britain, Japan and other countries pharmacopeia, China are included in for 1996《National essential drugs list》.
Edrophonium Chloride (I), also referred to as edrophonium chloride, its chemical name is N, N- dimethyl-N-ethyls-hydroxy chloride aniline, states
Border medicament universal entitled Edrophonium Chloride, trade name Tensilon, Enlon, Reversol etc., are short-acting courages
Alkali esterase inhibitor has special role to skeletal muscle, diagnosticum and nondepolarizing type skeletal muscle relaxation as myasthenia gravis
The antagonist of medicine.
In order to ensure the quality of parenteral solution, usually require to carry out the filtering to four times twice in preparation process.Pharmacy is looked forward to
The batch micro operations that most of nuclepore membrane filter that industry uses is provided for equipment supplier, there are effective mistakes for filter membrane used
Filtering surface product is small, filter efficiency is low, service life is short, mechanical strength is low leads to the defects of easily breakdown.
There are two types of the mechanism of filtering with microporous membrane purification, first, mechanical retention acts on, i.e., by the screening of film porous structure
Effect, filters out the particle more than miillpore filter aperture；Second is that electrical property suction-operated, i.e., carry electrical by film surfaces externally and internally
Can, the impurity absorption of oppositely charged in filtering solution is removed.Some naturally occurring impurity such as bacterium, bacterium in general water
Endotoxin, virus, colloid and certain pigments are negatively charged, thus it is miscellaneous to remove these using positively charged miillpore filter
Matter.
Alginate is a kind of natural polysaccharide extracted from the brown algas such as kelp, sargassum, bulk kelp, and common alginate is
The water-soluble algin such as sodium alginate, calcium alginate.Calcium alginate is not soluble in water, is insoluble in the organic solvents such as ethyl alcohol, slowly
It is dissolved in the solution of polyphosphate sodium, sodium carbonate liquor and sodium chloride.The spy that moisture dissipates plus alkali or salt dissolve is met using calcium alginate
Property, the functions such as suspending, thick stabilization, emulsification, film forming, sustained release can be played.In addition, nano material has, particle size is small, compares table
Many characteristics such as area is big, surface-active is high.In recent years, people start with nano material and original material are modified, can
Make resulting materials that there are the excellent properties different from raw material.
Certain Polymer Surfaces can be made positively charged by chemical modification, it therefore, can be uncharged common with certain
Miillpore filter makees basement membrane, through suitably post-processing, is allowed to positive charge.As USP5,151,189 uses uncharged polyether sulfone
Film makees basement membrane, charged with the first charger and the second charger and two kinds respectively using non-leaching polymeric additive therein
The effect of being cross-linked with each other between agent prepares the miillpore filter of lotus positive electricity.Also have using positively charged material with it is other into membrane material
Material is made into casting solution, and charged membrane is directly prepared using phase inversion.Such as JP88287503, chitosan and polyamide are compared as certain
Example is dissolved in formic acid, adds in other additive composition casting solutions, the micropore that can remove bacterial endotoxin has been made through phase inversion
Filter membrane.The miillpore filter made from the method, electrical property are weaker.
Invention content
The purpose of the present invention is to provide a kind of edrophonium chloride injections and preparation method thereof, miillpore filter are added in certain
Charged microporous membrane is made in the nano-titanium dioxide and calcium alginate of amount, to improve the machinery of filter membrane, physics, chemical property, prolongs
Its long service life.The preparation method of edrophonium chloride injection provided by the invention reduces the filtering in parenteral solution preparation process
Step, technological operation is simple, and filter efficiency is high, can improve product quality, reduces production cost, improves production efficiency.
The present invention provides a kind of edrophonium chloride injection, by as follows into being grouped as：8~12g of Edrophonium Chloride, anhydrous sulfurous
Sour 1~4g of sodium, water for injection add to 1000ml, and it is 4~7 to adjust pH with pH adjusting agent.
Preferably, the edrophonium chloride injection, by as follows into being grouped as：Edrophonium Chloride 10g, anhydrous sodium sulfite
2.0g, water for injection add to 1000ml, and it is 5.0 to adjust pH with pH adjusting agent.
Mixture of the pH adjusting agent of the present invention for citric acid and sodium citrate, citric acid: the weight ratio of sodium citrate
It is 1: 2~1: 5.
The present invention also provides a kind of preparation methods of edrophonium chloride injection, include the following steps：
S1, the water for injection of recipe quantity 60%-90% is added in liquid dispensing container, then adds in anhydrous sodium sulfite stirring
To dissolving, add in pH adjusting agent and adjust pH value 4.0~7.0, obtain mixed liquor I；
S2, Edrophonium Chloride is added in mixed liquor I obtained by S1, to dissolving, filtering injects water to for stirring
1000ml is stirred evenly, and obtains mixed liquor I I；
S3, it is filtered with the nano-titanium dioxide that aperture is 0.01~0.45 μm-calcium alginate charged microporous membrane, adds in pH
Conditioning agent adjusts pH value 4.0~7.0, nitrogen charging embedding, sterilizing, leak detection, inspection, packaging on embedding interlocking equipment.
Nano-titanium dioxide-calcium alginate charged microporous membrane preparation method in step S3 of the present invention is：
Using hydrophilic neutral miillpore filter as carrier, 1~2h in the concentrated sulfuric acid is immersed, is then rinsed with deionized water
Totally, 5~20min in nano-titanium dioxide-calcium alginate colloidal sol is immersed, is rinsed with deionized water, is handed over after dry with crosslinking agent
Connection is to get nano-titanium dioxide-calcium alginate charged microporous membrane.
Filter membrane carrier of the present invention includes polysulfones filter membrane, polyethersulfone membranes, polysulfones/polyether sulfone mixture filter membrane, Buddhist nun
Imperial 6 filter membranes, 6/6 filter membrane of nylon, 4/6 filter membrane of nylon, polyvinylidene fluoride filter membrane, cellulose mixture filter membrane and this hair can be adsorbed
Other filter membranes of the bright nano-titanium dioxide-calcium alginate colloidal sol.It is hydrophilic that its premise important document is that this filter membrane carrier must have
Property, it can easily be soaked by pure water.The filter sizes that the present invention is covered belong to miillpore filter at 0.01 micron to 0.45 micron
Aperture covering scope, but also can be used and invent other porous filtration membranes except the covering scope of aperture in the present invention.
Crosslinking agent of the present invention is the calcium chloride water that mass fraction is 2.5%, crosslinking time for 20~
60min。
Nano-titanium dioxide of the present invention-calcium alginate colloidal sol is prepared in accordance with the following steps：Metatitanic acid is taken at room temperature
Butyl ester is dissolved in absolute ethyl alcohol, forms solution A；It is another that absolute ethyl alcohol is taken to add in deionized water, it adds glacial acetic acid and is uniformly mixed shape
Into solution B；Solution A is poured into beaker, solution B is added dropwise in 35~50 DEG C of heating water bath while stirring, with salt acid for adjusting pH
Between 1.0~3.5, calcium alginate powder is subsequently added into, stirring makes it fully dissolve to get nano-titanium dioxide-alginic acid
Calcium sol.
Butyl titanate in nano-titanium dioxide of the present invention-calcium alginate colloidal sol preparation method: it absolute ethyl alcohol: goes
Ionized water: the volume ratio of glacial acetic acid is 1: 15: 3: 2, calcium alginate powder is 0.5~1g.
The present invention using nano-titanium dioxide-calcium alginate charged microporous membrane, improve miillpore filter mechanical strength,
Strainability, so as to improve the filter efficiency of edrophonium chloride injection.The effect of nano-titanium dioxide shielding ultraviolet rays is strong, has good
Dispersibility and weatherability, there are the performances such as high specific surface area, high activity.Calcium alginate has suspending, thick stabilization, breast
The functions such as change, film forming, sustained release, and nontoxic, good biocompatibility.Calcium alginate is supported on miillpore filter as charger,
The negatively charged impurity such as adsorbable bacterium, bacterial endotoxin, virus, colloid, it is sol-gel modified with nano-titanium dioxide-calcium alginate
Charged microporous membrane obtained changes its micro-property.
Compared with prior art, the beneficial effects of the present invention are：
(1) nano-titanium dioxide-calcium alginate charged microporous membrane that the present invention uses so that the specific surface of miillpore filter
Product increase, adsorptivity and polarity increase, and tensile strength is big, high mechanical strength, and the rejection of fine particle is greatly improved, is carried
The high filter effect of parenteral solution.
(2) preparation method of nano-titanium dioxide-calcium alginate charged microporous membrane that the present invention uses, processing step letter
It is single, it is easy to grasp, production cost is low, can be widely applied to the fields such as drug, water process.
(3) preparation method of edrophonium chloride injection that the present invention uses, it is ensured that Edrophonium Chloride is non-degradable, may be such that production
The endotoxin of product meets regulation, and does not have suction-operated to product, ensures product quality.
Specific embodiment
The following describes the present invention further through the description of specific embodiments, but this is not the limit to the present invention
System, those skilled in the art's basic thought according to the present invention can make various modifications or improvements, but without departing from this
The basic thought of invention, is all within the scope of the present invention.
The preparation method of embodiment 1, nano-titanium dioxide-calcium alginate charged microporous membrane
Include the following steps：
Using the polysulfones filter membrane filter membrane that aperture is 0.22 μm as carrier, 1.5h in the concentrated sulfuric acid is immersed, then uses deionization
Water is rinsed well, is immersed 15min in nano-titanium dioxide-calcium alginate colloidal sol, is rinsed with deionized water, is divided after dry with quality
The calcium chloride water that number is 2.5% is as crosslinking agent, crosslinking time 30min.Up to nano-titanium dioxide-calcium alginate lotus
Electric miillpore filter.
Wherein, nano-titanium dioxide-calcium alginate colloidal sol is prepared according to following steps：100mL metatitanic acid fourths are taken at room temperature
Ester is dissolved in 100mL absolute ethyl alcohols, forms solution A；It is another that the addition of 50mL absolute ethyl alcohols is taken to remove 300mL ionized waters, add 200mL
Glacial acetic acid is uniformly mixed to form solution B；Solution A is poured into beaker, solution is added dropwise to 40 DEG C in heating water bath while stirring
B with salt acid for adjusting pH to 3.0, is subsequently added into 1g calcium alginate powder, stirring it is made fully to dissolve to get nano-titanium dioxide-
Calcium alginate colloidal sol.
Embodiment 2, a kind of edrophonium chloride injection
The edrophonium chloride injection is by as follows into being grouped as：Edrophonium Chloride 10g, anhydrous sodium sulfite 2.0g, injection
Water adds to 1000mL, and it is 5.0 to adjust pH with pH adjusting agent.
The preparation method of the parenteral solution includes the following steps：
S1, the water for injection of recipe quantity 60% is added in liquid dispensing container, then adds in anhydrous sodium sulfite and stir to molten
Solution, it is 5.0 to add in pH adjusting agent and adjust pH value, obtains mixed liquor I；
S2, Edrophonium Chloride is added in S1 acquired solutions, to dissolving, filtering injects water to 1000ml, stirs for stirring
It mixes uniformly, obtains mixed liquor I I；
S3, mixed liquor I I are filtered through nano-titanium dioxide made from embodiment 1-calcium alginate charged microporous membrane, are added in
PH adjusting agent adjusts pH value 5.0, nitrogen charging embedding, sterilizing, leak detection, inspection, packaging on embedding interlocking equipment.
The method detection that this product is taken to be recorded according to Chinese Pharmacopoeia, obtains following result：
Embodiment 3, a kind of edrophonium chloride injection
The edrophonium chloride injection is by as follows into being grouped as：Edrophonium Chloride 10g, anhydrous sodium sulfite 2g, water for injection
1000ml is added to, it is 6.0 to adjust pH with pH adjusting agent.
The preparation method of the parenteral solution includes the following steps：
S1, the water for injection of recipe quantity 90% is added in liquid dispensing container, then adds in anhydrous sodium sulfite and stir to molten
Solution, it is 6.0 to add in pH adjusting agent and adjust pH value, obtains mixed liquor I；
S2, Edrophonium Chloride is added in S1 acquired solutions, to dissolving, filtering injects water to 1000ml, stirs for stirring
It mixes uniformly, obtains mixed liquor I I；
S3, mixed liquor I I are filtered through nano-titanium dioxide made from embodiment 1-calcium alginate charged microporous membrane, are added in
PH adjusting agent adjusts pH value 6.0, nitrogen charging embedding, sterilizing, leak detection, inspection, packaging on embedding interlocking equipment.
The method detection that this product is taken to be recorded according to Chinese Pharmacopoeia, obtains following result：
Comparative example 1, a kind of edrophonium chloride injection
The edrophonium chloride injection is by as follows into being grouped as：Edrophonium Chloride 10g, anhydrous sodium sulfite 2.0g, injection
Water adds to 1000ml, and it is 5.0 to adjust pH with pH adjusting agent.
The preparation method of the parenteral solution includes the following steps：
S1, the water for injection of recipe quantity 60% is added in liquid dispensing container, then adds in anhydrous sodium sulfite and stir to molten
Solution, it is 5.0 to add in pH adjusting agent and adjust pH value, obtains mixed liquor I；
S2, Edrophonium Chloride is added in S1 acquired solutions, to dissolving, filtering injects water to 1000ml, stirs for stirring
It mixes uniformly, obtains mixed liquor I I；
The medical charcoal stirring and adsorbing of S3, then warp containing 0.1% that weight is mixed liquor I I total weights 20 minutes, adds in pH
It is 5.0 that conditioning agent, which adjusts pH value,；
S4, charcoal first is taken off with titanium filter stick, then with 0.45 μm of filter element filtering, filtrate is again with≤0.22 μm of filter element filtering.It is filling
Seal nitrogen charging embedding, sterilizing, leak detection, inspection, packaging on interlocking equipment.
The method detection that this product is taken to be recorded according to Chinese Pharmacopoeia, obtains following result：
Comparative example 2, a kind of edrophonium chloride injection
The edrophonium chloride injection is by as follows into being grouped as：Edrophonium Chloride 10g, anhydrous sodium sulfite 2.0g, injection
Water adds to 1000ml, and it is 5.0 to adjust pH with pH adjusting agent.
The preparation method of the parenteral solution includes the following steps：
S1, the water for injection of recipe quantity 60% is added in liquid dispensing container, then adds in anhydrous sodium sulfite and stir to molten
Solution, obtains mixed liquor I；
S2, Edrophonium Chloride is added in S1 acquired solutions, to dissolving, filtering injects water to 1000ml, stirs for stirring
It mixes uniformly, it is 5.0 to add in pH adjusting agent and adjust pH value, obtains mixed liquor I I；
S3, mixed liquor I I are filtered through chitosan charged microporous membrane to clear and bright, and it is 5.0 to add in pH adjusting agent and adjust pH value,
Nitrogen charging embedding, sterilizing, leak detection, inspection, packaging on embedding interlocking equipment.
The preparation method of the chitosan charged microporous membrane is as follows：
Using PA membrane basement membrane, charger is made with chitosan, lotus is prepared by dip-coating, crosslinking, washing, drying and other steps
The miillpore filter of positive electricity, is as follows：Chitosan is dissolved in 3% (W/V) spirit of vinegar, it is molten to be made into 0.4% (W/V) chitosan
Liquid with the screen filtration of aperture 150 ± 6.6 μm (120 mesh), obtains coating liquid.Basement membrane is immersed into coating liquid, after dip-coating 60min
Taking-up drains, 120 DEG C of dryings.The dried film of dip-coating is dipped in crosslinking agent and is crosslinked, crosslinking agent selects 3% (W/V) glutaraldehyde,
Crosslinking temperature is 50 DEG C.The coated film after crosslinking is rinsed repeatedly with distilled water, removes remaining lotion and crosslinking agent, 100
~120 DEG C of dryings.
The method detection that this product is taken to be recorded according to Chinese Pharmacopoeia, obtains following result：
Claims (9)
1. a kind of edrophonium chloride injection, which is characterized in that by as follows into being grouped as：8~12g of Edrophonium Chloride, anhydrous sulfurous acid
1~4g of sodium, water for injection add to 1000ml, and it is 4~7 to adjust pH with pH adjusting agent.
2. edrophonium chloride injection according to claim 1, which is characterized in that by as follows into being grouped as：Edrophonium Chloride
10g, anhydrous sodium sulfite 2.0g, water for injection add to 1000ml, and it is 5.0 to adjust pH with pH adjusting agent.
3. edrophonium chloride injection according to claim 1 or 2, which is characterized in that the pH adjusting agent for citric acid and
The mixture of sodium citrate, the citric acid: the weight ratio of sodium citrate is 1:2~1:5.
4. according to the preparation method of any edrophonium chloride injections of claim 1-3, which is characterized in that including walking as follows
Suddenly：
S1, the water for injection of recipe quantity 60-90% is added in liquid dispensing container, then adds in anhydrous sodium sulfite and stir to molten
Solution adds in pH adjusting agent and adjusts pH value 4.0~7.0, obtains mixed liquor I；
S2, Edrophonium Chloride is added in mixed liquor I obtained by S1, to dissolving, filtering injects water to 1000ml, stirs for stirring
It mixes uniformly, obtains mixed liquor I I；
S3, it is filtered with the nano-titanium dioxide that aperture is 0.01~0.45 μm-calcium alginate charged microporous membrane, adds in pH and adjust
Agent adjusts pH value 4.0~7.0, nitrogen charging embedding, sterilizing, leak detection, inspection, packaging on embedding interlocking equipment.
5. the preparation method of edrophonium chloride injection according to claim 4, which is characterized in that receiving in the step S4
Rice titanium dioxide-calcium alginate charged microporous membrane preparation method be：
Using hydrophilic neutral miillpore filter as carrier, 1~2h in the concentrated sulfuric acid is immersed, is then rinsed with deionized water dry
Only, 5~20min in nano-titanium dioxide-calcium alginate colloidal sol is immersed, is rinsed with deionized water, cross-linking agents are used after dry,
Up to nano-titanium dioxide-calcium alginate charged microporous membrane.
6. the preparation method of edrophonium chloride injection according to claim 5, which is characterized in that the hydrophilic neutrality
Miillpore filter is polysulfones filter membrane, polyethersulfone membranes, polysulfones/polyether sulfone mixture filter membrane, 6 filter membrane of nylon, 6/6 filter membrane of nylon, Buddhist nun
Imperial 4/6 filter membrane, polyvinylidene fluoride filter membrane, cellulose mixture filter membrane.
7. the preparation method of edrophonium chloride injection according to claim 5, which is characterized in that the crosslinking agent is quality
Score is 2.5% calcium chloride water, and crosslinking time is 20~60min.
8. the preparation method of edrophonium chloride injection according to claim 5, which is characterized in that the nanometer titanium dioxide
Titanium-calcium alginate colloidal sol is prepared in accordance with the following steps：Butyl titanate is taken to be dissolved in absolute ethyl alcohol at room temperature, form solution A；Separately
Absolute ethyl alcohol is taken to add in deionized water, glacial acetic acid is added and is uniformly mixed to form solution B；Solution A is poured into beaker, water-bath adds
35~50 DEG C of heat, is added dropwise solution B, with salt acid for adjusting pH value between 1.0~3.5, is subsequently added into alginic acid while stirring
Calcium powder, stirring make it fully dissolve to get nano-titanium dioxide-calcium alginate colloidal sol.
9. the preparation method of edrophonium chloride injection according to claim 8, which is characterized in that the nanometer titanium dioxide
Butyl titanate in titanium-calcium alginate colloidal sol preparation method: absolute ethyl alcohol: deionized water: the volume ratio of glacial acetic acid is 1: 15: 3:
2, calcium alginate powder is 0.5~1g.
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Denomination of invention: A kind of ephalamide chloride injection and preparation method thereof Effective date of registration: 20220829 Granted publication date: 20210205 Pledgee: Industrial and Commercial Bank of China Co.,Ltd. Qingyuan Economic Development Zone Sub branch Pledgor: GUANGDONG JIABO PHARMACEUTICAL Co.,Ltd. Registration number: Y2022980013893 |
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