CN102657606B - Lipoic acid injection for intravenous administration - Google Patents
Lipoic acid injection for intravenous administration Download PDFInfo
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- CN102657606B CN102657606B CN201210167054.8A CN201210167054A CN102657606B CN 102657606 B CN102657606 B CN 102657606B CN 201210167054 A CN201210167054 A CN 201210167054A CN 102657606 B CN102657606 B CN 102657606B
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- thioctic acid
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- meglumine
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- 235000019136 lipoic acid Nutrition 0.000 title claims abstract description 71
- 229960002663 thioctic acid Drugs 0.000 title claims abstract description 71
- 238000002347 injection Methods 0.000 title claims abstract description 48
- 239000007924 injection Substances 0.000 title claims abstract description 48
- AGBQKNBQESQNJD-UHFFFAOYSA-M lipoate Chemical compound [O-]C(=O)CCCCC1CCSS1 AGBQKNBQESQNJD-UHFFFAOYSA-M 0.000 title abstract 4
- 238000001990 intravenous administration Methods 0.000 title abstract 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 29
- 238000000034 method Methods 0.000 claims abstract description 24
- 238000002360 preparation method Methods 0.000 claims abstract description 23
- 230000001954 sterilising effect Effects 0.000 claims abstract description 21
- 239000006184 cosolvent Substances 0.000 claims abstract description 15
- AGBQKNBQESQNJD-SSDOTTSWSA-N (R)-lipoic acid Chemical compound OC(=O)CCCC[C@@H]1CCSS1 AGBQKNBQESQNJD-SSDOTTSWSA-N 0.000 claims description 67
- AGBQKNBQESQNJD-UHFFFAOYSA-N alpha-Lipoic acid Natural products OC(=O)CCCCC1CCSS1 AGBQKNBQESQNJD-UHFFFAOYSA-N 0.000 claims description 67
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical group CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 claims description 26
- 229960003194 meglumine Drugs 0.000 claims description 25
- 239000008215 water for injection Substances 0.000 claims description 22
- 238000001914 filtration Methods 0.000 claims description 15
- 239000000243 solution Substances 0.000 claims description 12
- 239000012982 microporous membrane Substances 0.000 claims description 11
- 238000003756 stirring Methods 0.000 claims description 8
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 7
- 229910052799 carbon Inorganic materials 0.000 claims description 7
- 238000005262 decarbonization Methods 0.000 claims description 4
- 238000005352 clarification Methods 0.000 claims description 2
- 230000001186 cumulative effect Effects 0.000 claims description 2
- 238000004659 sterilization and disinfection Methods 0.000 abstract description 5
- 229940090044 injection Drugs 0.000 description 32
- 238000012360 testing method Methods 0.000 description 12
- 230000000694 effects Effects 0.000 description 8
- 238000004519 manufacturing process Methods 0.000 description 7
- 238000012216 screening Methods 0.000 description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000012535 impurity Substances 0.000 description 5
- 150000007530 organic bases Chemical class 0.000 description 5
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 239000003610 charcoal Substances 0.000 description 4
- 230000036512 infertility Effects 0.000 description 4
- 150000007529 inorganic bases Chemical class 0.000 description 4
- 238000013112 stability test Methods 0.000 description 4
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 239000008103 glucose Substances 0.000 description 3
- 238000011835 investigation Methods 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 230000008676 import Effects 0.000 description 2
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- 230000007774 longterm Effects 0.000 description 2
- 244000005700 microbiome Species 0.000 description 2
- 238000005070 sampling Methods 0.000 description 2
- 239000001632 sodium acetate Substances 0.000 description 2
- 235000017281 sodium acetate Nutrition 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 239000001509 sodium citrate Substances 0.000 description 2
- 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 description 2
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 2
- OBSLWIKITOYASJ-AZEWMMITSA-N (2r,3s,4s,5r,6s)-6-(hydroxymethyl)-3-(methylamino)oxane-2,4,5-triol Chemical compound CN[C@@H]1[C@H](O)O[C@@H](CO)[C@H](O)[C@H]1O OBSLWIKITOYASJ-AZEWMMITSA-N 0.000 description 1
- 101710088194 Dehydrogenase Proteins 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- YPZRHBJKEMOYQH-UYBVJOGSSA-N FADH2 Chemical compound C1=NC2=C(N)N=CN=C2N1[C@@H]([C@H](O)[C@@H]1O)O[C@@H]1COP(O)(=O)OP(O)(=O)OC[C@@H](O)[C@@H](O)[C@@H](O)CN1C(NC(=O)NC2=O)=C2NC2=C1C=C(C)C(C)=C2 YPZRHBJKEMOYQH-UYBVJOGSSA-N 0.000 description 1
- 102000004877 Insulin Human genes 0.000 description 1
- 108090001061 Insulin Proteins 0.000 description 1
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- ZSLZBFCDCINBPY-ZSJPKINUSA-N acetyl-CoA Chemical compound O[C@@H]1[C@H](OP(O)(O)=O)[C@@H](COP(O)(=O)OP(O)(=O)OCC(C)(C)[C@@H](O)C(=O)NCCC(=O)NCCSC(=O)C)O[C@H]1N1C2=NC=NC(N)=C2N=C1 ZSLZBFCDCINBPY-ZSJPKINUSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- STIAPHVBRDNOAJ-UHFFFAOYSA-N carbamimidoylazanium;carbonate Chemical compound NC(N)=N.NC(N)=N.OC(O)=O STIAPHVBRDNOAJ-UHFFFAOYSA-N 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 229940004223 digoxin injection Drugs 0.000 description 1
- 229940043279 diisopropylamine Drugs 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 230000037149 energy metabolism Effects 0.000 description 1
- 229940125396 insulin Drugs 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 229910052755 nonmetal Inorganic materials 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 239000013618 particulate matter Substances 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 239000002510 pyrogen Substances 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- -1 salt compound Chemical class 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 235000011083 sodium citrates Nutrition 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 230000004102 tricarboxylic acid cycle Effects 0.000 description 1
- 229940005605 valeric acid Drugs 0.000 description 1
Abstract
The invention discloses a lipoic acid injection for intravenous administration and a preparation method thereof. Per 1000ml of the injection comprises the following components: 25g of lipoic acid, 7.5 to 12.5g of cosolvent, and the balance of injection water. The lipoic acid injection has the advantages of stable quality, hot-press resistance, sterilization and high aseptic guarantee level. The invention also provides a prescription and a process preparation method of the injection, and the process has the advantages of convenience, high efficiency and controllable quality.
Description
Technical field
The present invention relates to the pharmaceutical technology field, be specifically related to a kind of injection of the thioctic acid for intravenously administrable and preparation method thereof.
Background technology
Thioctic acid (Thioctic Acid) chemistry 5-(1,2 dithiode alkyl-3-) valeric acid by name
Chemical structural formula:
Molecular formula: C
8h
14o
2s
2
Molecular weight: 206.33
Thioctic acid is a kind of biostearin of separating from pig liver the earliest, can obtain by chemosynthesis at present.Thioctic acid is the cofactor of pyruvic dehydrogenase, is present in liver kidney and heart more, and it changes S-acetyl-coenzyme-A at acetone acid, generates FADH, and participating in the tricarboxylic acid cycle process is indispensable material, aspect energy metabolism, plays a very important role.Research in recent years shows, thioctic acid not only participates in the metabolic process of glucose, and directly mediating the distribution of glucose in peripheral tissues that insulin is regulated, it also has the effect of removing free radical simultaneously, therefore chronic complicating diseases of diabetes is had to good preventive and therapeutic effect.Thioctic acid extensive use at home and abroad at present, be developed to various medicines and health product, and dosage form has injection, tablet, capsule etc.
In thioctic acid water, dissolubility is little, and thioctic acid has thermal instability, during excess Temperature, may be thermal decomposited, and produces higher impurity, thereby affects its biological activity and safety in utilization.Due to this characteristic, the thioctic acid injection is difficult to accept pressure sterilizing usually.Thioctic acid injection (the power difficult to understand of Germany's import
) and more domestic thioctic acid injection and lyophilized formulations of national drug food Surveillance Authority (SFDA) approval, all adopted sterile production technique, can't carry out final sterilization to preparation, the sterility assurance level of preparation is relatively low.
In the industry cycle, " sterility assurance level " (Sterility Assurance Level, SAL) concept commonly used is estimated the effect of sterilizing (aseptic) technique, and SAL is defined as the remaining probability of product microorganism after sterilizing/degerming.This value is less, shows that the probability that in product, microorganism exists is less.Unanimously stipulate in the world, adopt the SAL of moist hear heat test must not be greater than 10
-6, after sterilizing the probability of microbial survival must not be greater than 1,000,000/; And the product of employing sterile production technique, its SAL generally can only reach 10
-3therefore, only limit to clinical must drug administration by injection and really can't tolerate the product of terminal sterilization.Sterile production technique is only applicable to injectable powder or part small-volume injection.
Aseptic requirement according to national drug food Surveillance Authority (SFDA) to injection, injection needs the preferential final sterilization method that adopts, and guarantees that the SAL value reaches 10
-6, usually adopt 115 ℃ in China, the pressure sterilizing technique of 30 minutes.Therefore, we need a kind of prescription that can overcome the thioctic acid thermal instability to form, and the attainable preparation method of relative simple, improve the heat stability of thioctic acid injection, can tolerate 115 ℃, the pressure sterilizing technique of 30 minutes, final production goes out steady quality, aseptic guarantee value is high, and safety is better than other similar thioctic acid injections.
Summary of the invention
Main purpose of the present invention is to overcome the weak point of thioctic acid, provides a kind of sterility assurance level high, stay-in-grade thioctic acid injection.The present invention also provides prescription and its preparation process of this injection, and this simple process is efficient, be easy to large-scale production.
The objective of the invention is to realize in the following manner:
A kind of injection of the thioctic acid for intravenously administrable is characterized in that the raw material prescription of every 1000ml injection is: thioctic acid 25g, and cosolvent 7.5-12.5g, all the other are water for injection.
The raw material prescription of preferred every 1000ml injection is: thioctic acid 25g, and cosolvent 8.75-10g, all the other are water for injection.
Most preferably the raw material prescription of every 1000ml injection is: thioctic acid 25g, and cosolvent 8.75g, all the other are water for injection.
Above-mentioned preferred co-solvents is meglumine.
The preparation method of thioctic acid injection of the present invention comprises the steps:
Thioctic acid is joined in the 90-96% of water for injection cumulative volume, stir, add meglumine in continuing whipping process, to the solution clarification, add the active carbon (being to add the 0.05-0.06g active carbon in every 100ml solution) of overall solution volume 0.05-0.06%, stir 20-25 minute, filtering decarbonization, add remaining water for injection, filters, 115 ℃ of pressure sterilizing 30min, obtain.
The described filtering decarbonization of the method can adopt 0.80 μ m microporous filter membrane.Adopt 0.22 μ m filtering with microporous membrane described adding after remaining water for injection.
Above-mentioned cosolvent meglumine is applied in product of the present invention, can effectively increase the dissolubility of thioctic acid, uses meglumine hydrotropy and scalable pH value of solution to certain limit, has also obtained unexpectedly the effect that improves thioctic acid injection heat stability.The preparation technology's equipment needed thereby the present invention relates to is injection manufacturer basic equipment, simple process.
Percentage composition of the present invention is weight percentage, and equal commercially available the obtaining of thioctic acid used and meglumine.
Meglumine (N-METHYL-ALPHA-L-GLUCOSAMINE) be methylamine and glucose under raney ni catalysis, react and organic base.Having basic group in the meglumine molecule, is a kind of safe, nontoxic free alkali compounds.The present invention is when using the meglumine hydrotropy, unexpected discovery meglumine is under certain pH conditions, the non-metal salt compound stability that thioctic acid and meglumine form increases significantly, and can tolerate the pressure sterilizing of 115 ℃, makes thioctic acid injection terminal sterilization become possibility.
Below, with regard to the process of groping of thinking of the present invention and cosolvent kind, pH scope etc., briefly be described.
One, the screening of additives kind
1, the screening of inorganic base
The official preparation specification of thioctic acid injection is 0.3g:12ml, in 12ml thioctic acid injection, contains the 0.3g thioctic acid.Under normal condition, the dissolubility of thioctic acid far can not reach this concentration requirement.Therefore at first the not good characteristics for the thioctic acid water solublity, in order to make it to become preparation, select inorganic base salify with it, increases its water-soluble, carries out screening test.Investigate respectively highly basic sodium hydroxide, inorganic weak bases sodium carbonate, sodium bicarbonate, sodium acetate, sodium citrate and thioctic acid compatibility, investigated dissolubility and stability.The experimental result summary is in Table 1.
Table 1 inorganic base compatibility the selection result
Result is visible, and inorganic strong alkali, as sodium hydroxide has larger destruction to thioctic acid, causes content to descend serious, impurity also increases greatly, and weak sodium bicarbonate and the sodium citrate of alkalescence can't play enough hydrotropy effects, thioctic acid can not dissolve fully.Although the moderate sodium acetate of alkalescence, sodium carbonate can hydrotropies, after 115 ℃ of 30min sterilizings, the content of product descends, and impurity exceeds standard (the standard limit is 1%), therefore do not have qualified inorganic base to meet desired requirement.
2, the screening of organic base
Select organic base and thioctic acid salify, increase its water-soluble, carry out screening test.Manufacture experimently a plurality of schemes, respectively ethylenediamine, triethylamine, meglumine, guanidine carbonate and diisopropylamine are investigated, after lot of experiments, find that meglumine has unexpected effect to thioctic acid stable, part experiment summary is in Table 2.
Table 2 organic base compatibility the selection result
Result of the test shows, uses organic base as cosolvent, and the stability of thioctic acid is improved, and the effect of meglumine is particularly outstanding, and product is after the pressure sterilizing of 115 ℃ of 30min, and the testing result of content and impurity is all up to specification.
Two, the screening of best pH scope
By a large amount of cosolvent screening experiment, optimizing meglumine is best cosolvent, and it had both had the hydrotropy effect, increased in addition the effect of stability.In order to obtain the pH scope of the optimal consumption of meglumine and this case the best, further to manufacture experimently a plurality of schemes and screened, the part test result is sketched in Table 3.
Table 3 additives consumption, optimum pH scope the selection result
Result of the test shows, meglumine is applied in sulfur digoxin injection liquid, can effectively increase the dissolubility of thioctic acid, particularly in scheme 2,3,4, in every 1000ml injection, contain thioctic acid 25g, cosolvent 7.5-10g, all the other are water for injection, injection pH value scope, at 8.0-8.25, can obtain the better thermal stability result of thioctic acid injection, and wherein optimal case is to contain thioctic acid 25g in every 1000ml injection, cosolvent 8.75g, all the other are water for injection.
The specific embodiment
By embodiments of the invention given below, further set forth content of the present invention, but the present invention is not subject to the restriction of embodiment.
Embodiment 1
Prescription (1000 preparation units):
Thioctic acid 300g
Meglumine 90g
Water for injection adds to 12000ml
Preparation technology: thioctic acid is joined in water for injection 11500ml, continue to add meglumine in whipping process, after clarifying to solution, pH value is 8.02, adds the active carbon of 6g, stirs 20 minutes, with the de-charcoal of 0.80 μ m filtering with microporous membrane, inject water to 12000ml, 0.22 μ m filtering with microporous membrane, embedding, 115 ℃ of pressure sterilizing 30min, obtain.
Embodiment 2
Prescription (1000 preparation units):
Thioctic acid 300g
Meglumine 105g
Water for injection adds to 12000ml
Preparation technology: thioctic acid is joined in water for injection 11000ml, continue to add meglumine in whipping process, after clarifying to solution, pH value is 8.13, adds the active carbon of 5.5g, stirs 20 minutes, with the de-charcoal of 0.80 μ m filtering with microporous membrane, inject water to 12000ml, 0.22 μ m filtering with microporous membrane, embedding, 115 ℃ of pressure sterilizing 30min, obtain.
Embodiment 3
Prescription (1000 preparation units):
Thioctic acid 300g
Meglumine 120g
Water for injection adds to 12000ml
Preparation technology: thioctic acid is joined in water for injection 11500ml, continue to add meglumine in whipping process, after clarifying to solution, pH value is 8.22, adds the active carbon of 6g, stirs 20 minutes, with the de-charcoal of 0.80 μ m filtering with microporous membrane, inject water to 12000ml, 0.22 μ m filtering with microporous membrane, embedding, 115 ℃ of pressure sterilizing 30min, obtain.
Embodiment 4
Prescription (1000 preparation units):
Thioctic acid 300g
Meglumine 150g
Water for injection adds to 12000ml
Preparation technology: thioctic acid is joined in water for injection 11500ml, continue to add meglumine in whipping process, after clarifying to solution, pH value is 8.43, adds the active carbon of 6g, stirs 25 minutes, with the de-charcoal of 0.80 μ m filtering with microporous membrane, inject water to 12000ml, 0.22 μ m filtering with microporous membrane, embedding, 115 ℃ of pressure sterilizing 30min, obtain.
Adopt the formulation and technology of technical scheme embodiment 1-4 of the present invention, the product of preparation, after 115 ℃ of 30min pressure sterilizings, every quality index is all up to specification, and the import that quality goes out with the sterile production explained hereafter contrasts thioctic acid injection (power difficult to understand
german History reaches the large pharmaceutical factory of moral lot number 90629) similar, but aseptic assurance ability greatly improves.Measurement result is in Table 4 in detail.
Each embodiment of table 4 prepares the quality investigation result of sample
Annotate: the present invention's " visible foreign matters ", " particulate matter ", " solution colour ", " pH ", " pyrogen " and " aseptic " assay method adopt " method mensuration in two appendix of Chinese pharmacopoeia version in 2010, " content " and " impurity " employing thioctic acid injection quality standard (standard No.: YBH39222005) measure under the continuous item.
Embodiment 5
According to " two appendix XIX C stability test guidelines of Chinese pharmacopoeia version in 2010 make sample to the embodiment 2 of optimum combination and carry out the stability test investigation:
Accelerated test: by lot number 100704 samples, be placed in the climatic chamber of 40 ℃ of temperature, relative humidity 75%, place 6 months, during respectively at the 1st, 2,3,6 months, sampling, detected according to the study on the stability project, and compared with the data of 0 month.
Long term test: by lot number 100704 samples, be placed under the condition of 25 ℃ of temperature, relative humidity 60% and place, during respectively at the 6th, 12,18 months, sampling, detected according to the investigation project, and compared with the data of 0 month.Stability test the results are shown in Table 5.
The stability test result shows, thioctic acid injection accelerated test June and long term test are after 24 months, and every quality is all up to specification, and thioctic acid injection prepared by technical solution of the present invention is stable and controllable for quality.
Table 5 thioctic acid injection study on the stability result of the test
Claims (6)
1. the injection of the thioctic acid for intravenously administrable is characterized in that the prescription of every 1000ml injection is: thioctic acid 25g, and cosolvent 7.5-12.5g, all the other are water for injection; Described cosolvent is meglumine.
2. the injection of the thioctic acid for intravenously administrable according to claim 1 is characterized in that the prescription of every 1000ml injection is: thioctic acid 25g, and cosolvent 8.75-10g, all the other are water for injection.
3. thioctic acid injection according to claim 2 is characterized in that the prescription of every 1000ml injection is: thioctic acid 25g, and cosolvent 8.75g, all the other are water for injection.
4. the preparation method of a thioctic acid injection claimed in claim 1, is characterized in that the method comprises the steps:
Thioctic acid is joined in the 90-96% of water for injection cumulative volume, stir, add meglumine in continuing whipping process, to the solution clarification, add overall solution volume 0.05-0.06%(g/ml) active carbon, stir 20-25 minute, filtering decarbonization, add remaining water for injection, filters, 115 ℃ of pressure sterilizing 30min, obtain.
5. the preparation method of thioctic acid injection according to claim 4, is characterized in that the described filtering decarbonization of the method adopts 0.80 μ m filtering with microporous membrane.
6. the preparation method of thioctic acid injection according to claim 4, adopt 0.22 μ m filtering with microporous membrane after it is characterized in that the method is described and adding remaining water for injection.
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| CN105125480B (en) * | 2015-08-14 | 2018-04-13 | 南京海融制药有限公司 | A kind of liquid preparation of lipoic acid and preparation method thereof |
| CN105342998A (en) * | 2015-12-15 | 2016-02-24 | 山东齐都药业有限公司 | Lipoic acid transfusion preparation and preparing method thereof |
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| Title |
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| Antioxidant properties of alpha-lipoic acid: effects on red blood membrane permeability and adaptation of isolated rat heart to reversible ischemia;S. Ghibu etal;《Mol Cell Biochem》;20081007(第320期);第141–148页 * |
| S. Ghibu etal.Antioxidant properties of alpha-lipoic acid: effects on red blood membrane permeability and adaptation of isolated rat heart to reversible ischemia.《Mol Cell Biochem》.2008,(第320期),第141–148页. |
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