CN101822686B - Cefpirome sulfate combined drug - Google Patents
Cefpirome sulfate combined drug Download PDFInfo
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- CN101822686B CN101822686B CN2010101038489A CN201010103848A CN101822686B CN 101822686 B CN101822686 B CN 101822686B CN 2010101038489 A CN2010101038489 A CN 2010101038489A CN 201010103848 A CN201010103848 A CN 201010103848A CN 101822686 B CN101822686 B CN 101822686B
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- cefpirome sulfate
- combined drug
- cefpirome
- sulfate combined
- medicinal liquid
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- RKTNPKZEPLCLSF-GNERTXCBSA-N OS([O-])(=O)=O.N([C@@H]1C(N2C(=C(C[N+]=3C=4CCCC=4C=CC=3)CS[C@@H]21)C(O)=O)=O)C(=O)/C(=N/OC)C1=CSC(N)=N1 Chemical compound OS([O-])(=O)=O.N([C@@H]1C(N2C(=C(C[N+]=3C=4CCCC=4C=CC=3)CS[C@@H]21)C(O)=O)=O)C(=O)/C(=N/OC)C1=CSC(N)=N1 RKTNPKZEPLCLSF-GNERTXCBSA-N 0.000 title claims abstract description 125
- 229960002838 cefpirome sulfate Drugs 0.000 title claims abstract description 125
- 239000003814 drug Substances 0.000 title claims abstract description 71
- 229940079593 drug Drugs 0.000 title claims abstract description 58
- 238000002360 preparation method Methods 0.000 claims abstract description 38
- 238000002347 injection Methods 0.000 claims abstract description 28
- 239000007924 injection Substances 0.000 claims abstract description 28
- 239000007788 liquid Substances 0.000 claims description 35
- 206010035664 Pneumonia Diseases 0.000 claims description 21
- 238000005516 engineering process Methods 0.000 claims description 21
- 238000000034 method Methods 0.000 claims description 20
- 230000008569 process Effects 0.000 claims description 20
- ILRKKHJEINIICQ-OOFFSTKBSA-N Monoammonium glycyrrhizinate Chemical compound N.O([C@@H]1[C@@H](O)[C@H](O)[C@H](O[C@@H]1O[C@H]1CC[C@]2(C)[C@H]3C(=O)C=C4[C@@H]5C[C@](C)(CC[C@@]5(CC[C@@]4(C)[C@]3(C)CC[C@H]2C1(C)C)C)C(O)=O)C(O)=O)[C@@H]1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O ILRKKHJEINIICQ-OOFFSTKBSA-N 0.000 claims description 17
- YTGJWQPHMWSCST-UHFFFAOYSA-N Tiopronin Chemical compound CC(S)C(=O)NCC(O)=O YTGJWQPHMWSCST-UHFFFAOYSA-N 0.000 claims description 17
- 108010058907 Tiopronin Proteins 0.000 claims description 17
- 229960004402 tiopronin Drugs 0.000 claims description 17
- 238000000108 ultra-filtration Methods 0.000 claims description 17
- NNJVILVZKWQKPM-UHFFFAOYSA-N Lidocaine Chemical compound CCN(CC)CC(=O)NC1=C(C)C=CC=C1C NNJVILVZKWQKPM-UHFFFAOYSA-N 0.000 claims description 16
- 229960004194 lidocaine Drugs 0.000 claims description 16
- 239000012528 membrane Substances 0.000 claims description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 14
- 206010022000 influenza Diseases 0.000 claims description 11
- 238000005374 membrane filtration Methods 0.000 claims description 8
- JGSARLDLIJGVTE-UHFFFAOYSA-N 3,3-dimethyl-7-oxo-6-[(2-phenylacetyl)amino]-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid Chemical compound O=C1N2C(C(O)=O)C(C)(C)SC2C1NC(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-UHFFFAOYSA-N 0.000 claims description 7
- 239000004480 active ingredient Substances 0.000 claims description 7
- 238000004108 freeze drying Methods 0.000 claims description 7
- 239000007787 solid Substances 0.000 claims description 7
- 239000000243 solution Substances 0.000 claims description 7
- 238000003756 stirring Methods 0.000 claims description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 7
- 239000008215 water for injection Substances 0.000 claims description 7
- 238000001035 drying Methods 0.000 claims description 3
- 239000002552 dosage form Substances 0.000 claims 1
- 230000001105 regulatory effect Effects 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 abstract description 19
- 210000004185 liver Anatomy 0.000 abstract description 9
- 206010037660 Pyrexia Diseases 0.000 abstract description 7
- 208000001297 phlebitis Diseases 0.000 abstract description 2
- 206010002198 Anaphylactic reaction Diseases 0.000 abstract 1
- 208000003455 anaphylaxis Diseases 0.000 abstract 1
- 230000000694 effects Effects 0.000 abstract 1
- 241001465754 Metazoa Species 0.000 description 25
- 208000015181 infectious disease Diseases 0.000 description 25
- 238000010172 mouse model Methods 0.000 description 20
- 241000894006 Bacteria Species 0.000 description 11
- 241000699670 Mus sp. Species 0.000 description 10
- 241000191967 Staphylococcus aureus Species 0.000 description 10
- 241000193998 Streptococcus pneumoniae Species 0.000 description 10
- 229940031000 streptococcus pneumoniae Drugs 0.000 description 10
- 238000012360 testing method Methods 0.000 description 10
- 229960000466 cefpirome Drugs 0.000 description 8
- DKOQGJHPHLTOJR-WHRDSVKCSA-N cefpirome Chemical compound N([C@@H]1C(N2C(=C(C[N+]=3C=4CCCC=4C=CC=3)CS[C@@H]21)C([O-])=O)=O)C(=O)\C(=N/OC)C1=CSC(N)=N1 DKOQGJHPHLTOJR-WHRDSVKCSA-N 0.000 description 8
- 239000000203 mixture Substances 0.000 description 7
- 102000009338 Gastric Mucins Human genes 0.000 description 6
- 108010009066 Gastric Mucins Proteins 0.000 description 6
- PQMWYJDJHJQZDE-UHFFFAOYSA-M Methantheline bromide Chemical compound [Br-].C1=CC=C2C(C(=O)OCC[N+](C)(CC)CC)C3=CC=CC=C3OC2=C1 PQMWYJDJHJQZDE-UHFFFAOYSA-M 0.000 description 6
- 238000013459 approach Methods 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 6
- 238000011082 depyrogenation Methods 0.000 description 6
- 238000009472 formulation Methods 0.000 description 6
- 239000007921 spray Substances 0.000 description 6
- 239000011550 stock solution Substances 0.000 description 6
- 210000003462 vein Anatomy 0.000 description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 5
- 241000699666 Mus <mouse, genus> Species 0.000 description 5
- 230000001580 bacterial effect Effects 0.000 description 5
- 230000037396 body weight Effects 0.000 description 5
- 231100000668 minimum lethal dose Toxicity 0.000 description 5
- 230000003285 pharmacodynamic effect Effects 0.000 description 5
- 230000009467 reduction Effects 0.000 description 5
- 230000004044 response Effects 0.000 description 5
- 238000013112 stability test Methods 0.000 description 5
- 210000002784 stomach Anatomy 0.000 description 5
- 238000010998 test method Methods 0.000 description 5
- 229910052799 carbon Inorganic materials 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- 239000002510 pyrogen Substances 0.000 description 3
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 239000003963 antioxidant agent Substances 0.000 description 2
- 230000003078 antioxidant effect Effects 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 210000003734 kidney Anatomy 0.000 description 2
- 229910021645 metal ion Inorganic materials 0.000 description 2
- 241000894007 species Species 0.000 description 2
- 239000001117 sulphuric acid Substances 0.000 description 2
- 235000011149 sulphuric acid Nutrition 0.000 description 2
- 229930186147 Cephalosporin Natural products 0.000 description 1
- 206010013700 Drug hypersensitivity Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000000843 anti-fungal effect Effects 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- LRAJHPGSGBRUJN-OMIVUECESA-N cefepime hydrochloride Chemical compound O.Cl.[Cl-].S([C@@H]1[C@@H](C(N1C=1C(O)=O)=O)NC(=O)\C(=N/OC)C=2N=C(N)SC=2)CC=1C[N+]1(C)CCCC1 LRAJHPGSGBRUJN-OMIVUECESA-N 0.000 description 1
- 229960000927 cefepime hydrochloride Drugs 0.000 description 1
- GPRBEKHLDVQUJE-VINNURBNSA-N cefotaxime Chemical compound N([C@@H]1C(N2C(=C(COC(C)=O)CS[C@@H]21)C(O)=O)=O)C(=O)/C(=N/OC)C1=CSC(N)=N1 GPRBEKHLDVQUJE-VINNURBNSA-N 0.000 description 1
- 229960004261 cefotaxime Drugs 0.000 description 1
- 229940124587 cephalosporin Drugs 0.000 description 1
- 150000001780 cephalosporins Chemical class 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 230000001627 detrimental effect Effects 0.000 description 1
- 201000005311 drug allergy Diseases 0.000 description 1
- 239000010419 fine particle Substances 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- -1 group is new Chemical compound 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a cefpirome sulfate combined drug, overcoming cefpirome sulfate fever reaction, anaphylactic reaction, harm to liver, injection pain, phlebitis caused by injection and other untoward reactions in the prior art. The cefpirome sulfate combined drug is safe to use, stable in quality and reliable in curative effect. The preparation process is energy-saving, environment-friendly and pollution-free.
Description
Technical field
The present invention relates to cefpirome sulfate combined drug and preparation technology thereof.
Background technology
Cefpirome Sulfate, other titles have: cefpirome, cefrom see cefpirome, cefrom see cefpirome, group is new, cefotaxime pyrrole penta cephalo.Be the 4th generation cephalosporin.English name Cefpirome Culfate, main component is a Cefpirome Sulfate.Its has a broad antifungal spectrum, antibacterial action is strong, oral absorption hardly, vein and administered intramuscular absorb rapidly, and absolute bioavailability is greater than 90%.Cefpirome Sulfate not metabolism of 80-90% in vivo.Existing Cefpirome Sulfate injection is at room temperature preserved also unstable, has drug allergy to reach untoward reaction such as gastrointestinal tract, liver, kidney, blood systems, the untoward reaction that also has drug fever reaction, intravenous drip pain and have phlebitis to produce.
Summary of the invention
In order to overcome prior art for preparing Cefpirome Sulfate injection defective, the present invention provides a kind of cefpirome sulfate combined drug and preparation technology thereof.
One. cefpirome sulfate combined drug provided by the invention, form by following active ingredient weight proportion:
Cefpirome Sulfate 500-2000
Lignocaine 100-200
Tiopronin 50-120
Monoammonium glycyrrhizinate 200-500
Two. preparation technology of the present invention: technology of the present invention aseptic, 18 ℃ to 20 ℃, by national GMP enforcement of regulations.
1. stir down in normal speed with the 50-200 of Cefpirome Sulfate weight water for injection doubly, complete Cefpirome Sulfate, lignocaine, tiopronin, monoammonium glycyrrhizinate dissolving respectively, make the cefpirome sulfate combined drug medicinal liquid;
2. the membrane ultrafiltration of the combination of Cefpirome Sulfate medicine medicinal liquid elder generation of the 1st step preparation, get filtrating, get filtrating, with 8% hydrochloric acid solution liquid adjust pH 4.0-6.0 again through the membrane ultrafiltration of the molecular weight 2000D that dams through molecular cut off 8000D;
3. the membrane filtration mistake of the cefpirome sulfate combined drug medicinal liquid reuse 0.22 μ m of the 3rd step preparation;
4. measure the cefpirome sulfate combined drug medicinal liquid of the 4th step preparation the content of Cefpirome Sulfate; Press the Cefpirome Sulfate dosage that pharmaceutics allows; Aseptic subpackaged in cillin bottle; Well-established law lyophilization in freezer dryer makes in the lyophilized solid moisture below 2%, can process the lyophilized injection or the spray of the cefpirome sulfate combined drug that pharmaceutics allows by well-established law.
Because the aqueous solution of Cefpirome Sulfate is unstable,, do not absorb owing to oral Cefpirome Sulfate again, so can not process its oral formulations so can not process aqueous injection.
One. advantage of the present invention:
1. the present invention's research can be known; Protect Cefpirome Sulfate in manufacturing, storage, transportation, use, intravital oxidation and peroxidating with the antioxidant tiopronin; Untoward reaction is alleviated greatly, and tiopronin and monoammonium glycyrrhizinate have protection liver, kidney again not by the Cefpirome Sulfate detrimental effect;
2. the present invention's research can know that lignocaine and monoammonium glycyrrhizinate are the excipient of combination, the pain untoward reaction when lignocaine can alleviate intravenous drip again;
3. the present invention research can be known, but monoammonium glycyrrhizinate sulfuric-resisting cefpirome to liver, renal damage untoward reaction;
4. but among the preparation technology of research knowledge capital invention of the present invention; Remove pyrogen and the pyrogen segment of molecular weight with the ultrafilter membrane continuous ultrafiltration of molecular cut off 8000D and molecular cut off 2000D greater than 2000D; Depyrogenation of the present invention technology is than the active carbon depyrogenation of prior art with only alleviate greatly with the technical agent pyrogen reaction of the molecular weight 10000D ultrafiltration depyrogenation that dams;
5. the present invention is after ultrafiltration, adjust pH 4.0-6.0, and, make composition of medicine quality of the present invention more stable again through the membrane filtration degerming of 0.22 μ m.
6. because the present invention has added antioxidant tiopronin, depyrogenation, degerming at normal temperatures at normal temperatures, that avoids prior art adds the active carbon high-temp depyrogenation, avoids metal ion species that activated carbon process is brought into and active carbon fine particle in medicinal liquid; The present invention makes medicine its chemistry of maintenance and physical property constant with the spraying drying of freezing drying replacement prior art; It is thorough that the present invention removes metal ion species, depyrogenation, degerming, and messenger drug article matter is high, steady quality;
7. technology of the present invention be low-carbon (LC) technology be again energy-conserving and environment-protective technology.
The specific embodiment:
Embodiment 1
Cefpirome sulfate combined drug provided by the invention, form by following active ingredient weight proportion:
Cefpirome Sulfate 500
Lignocaine 100
Tiopronin 50
Monoammonium glycyrrhizinate 200
Preparation technology of the present invention: technology of the present invention aseptic, 18 ℃ to 20 ℃, by national GMP enforcement of regulations.
1. stir down in normal speed with the 50-200 of Cefpirome Sulfate weight water for injection doubly, complete Cefpirome Sulfate, lignocaine, tiopronin, monoammonium glycyrrhizinate dissolving respectively, make the cefpirome sulfate combined drug medicinal liquid;
2. the membrane ultrafiltration of the combination of Cefpirome Sulfate medicine medicinal liquid elder generation of the 1st step preparation, get filtrating, get filtrating, with 8% hydrochloric acid solution liquid adjust pH 4.0-6.0 again through the membrane ultrafiltration of the molecular weight 2000D that dams through molecular cut off 8000D;
3. the membrane filtration mistake of the cefpirome sulfate combined drug medicinal liquid reuse 0.22 μ m of the 3rd step preparation;
4. measure the cefpirome sulfate combined drug medicinal liquid of the 4th step preparation the content of Cefpirome Sulfate; Press the Cefpirome Sulfate dosage that pharmaceutics allows; Aseptic subpackaged in cillin bottle; Well-established law lyophilization in freezer dryer makes in the lyophilized solid moisture below 2%, can process the lyophilized injection or the spray of the cefpirome sulfate combined drug that pharmaceutics allows by well-established law.
Because the aqueous solution of Cefpirome Sulfate is unstable,, do not absorb owing to oral Cefpirome Sulfate again, so can not process its oral formulations so can not process aqueous injection.
Stability test: under 20 ℃-22 ℃, Cefpirome Sulfate was deposited 360 days, measured Cefpirome Sulfate content, calculated the content reduction rate.
The pharmacodynamics demonstration test:
(1) animal is selected: select the mice by the infection animal experimental model of Experimental Animal Center preparation, body weight 18-22g, male and female half and half, random packet, 10 of every treated animals.
(2) infection bacteria species: staphylococcus aureus causes the model mice of pneumonia, four groups of model mice, Ke Shi pneumobacillus, hemophilus influenza that streptococcus pneumoniae causes pneumonia.
(3) infection dosage: measure 100% minimum lethal dose (100%MLD) of the bacterial strain that tries by Experimental Animal Center, as infection dosage.
(4) approach is dyed in sense 2: bacterium stock solution is diluted to desired concn (Experimental Animal Center is confirmed) with 5% gastric Mucin, through tail vein injection.
(5) test method: with the mice branch: the A. staphylococcus aureus causes the model mice group of pneumonia, model mice group, C. Ke Shi pneumobacillus group, four groups of D. hemophilus influenza group that the B. streptococcus pneumoniae causes pneumonia.Carry out the contrast of injection sulphuric acid acid cefpirome, the medicine of the present invention contrast of not administration contrast, prior art for preparing.10 of every group model animals.Quiet immediately notes administration after the infection whenever was administered once at a distance from 6 hours again.Note observing the reaction of animal thing, continuous 7 days, record dead mouse number.
The result of the test contrast:
| Project | A strain infected group mortality rate % | B strain infected group mortality rate % | C strain infected group mortality rate % | D strain infected group mortality rate % | Drug fever response rate % | Deposit 1 year content rate of descent % for 20 ℃-22 ℃ | Stomach and liver untoward reaction rate % |
| Drug treatment not | 100 | ?100 | 100 | 100 | -- | -- | -- |
| The administration of 20mg/kg injection Cefpirome Sulfate | 70 | ?60 | 60 | 50 | 20 | 36 | 10 |
| Medicine 20mk/kg of the present invention administration | 20 | ?30 | 20 | 10 | 0 | 10 | 0 |
| Remarks |
Embodiment 2
Cefpirome sulfate combined drug provided by the invention, form by following active ingredient weight proportion:
Cefpirome Sulfate 2000
Lignocaine 200
Tiopronin 120
Monoammonium glycyrrhizinate 500
Two. preparation technology of the present invention: technology of the present invention aseptic, 18 ℃ to 20 ℃, by national GMP enforcement of regulations.
1. stir down in normal speed with the 50-200 of Cefpirome Sulfate weight water for injection doubly, complete Cefpirome Sulfate, lignocaine, tiopronin, monoammonium glycyrrhizinate dissolving respectively, make the cefpirome sulfate combined drug medicinal liquid;
2. the membrane ultrafiltration of the combination of Cefpirome Sulfate medicine medicinal liquid elder generation of the 1st step preparation, get filtrating, get filtrating, with 8% hydrochloric acid solution liquid adjust pH 4.0-6.0 again through the membrane ultrafiltration of the molecular weight 2000D that dams through molecular cut off 8000D;
3. the membrane filtration mistake of the cefpirome sulfate combined drug medicinal liquid reuse 0.22 μ m of the 3rd step preparation;
4. measure the cefpirome sulfate combined drug medicinal liquid of the 4th step preparation the content of Cefpirome Sulfate; Press the Cefpirome Sulfate dosage that pharmaceutics allows; Aseptic subpackaged in cillin bottle; Well-established law lyophilization in freezer dryer makes in the lyophilized solid moisture below 2%, can process the lyophilized injection or the spray of the cefpirome sulfate combined drug that pharmaceutics allows by well-established law.
Because the aqueous solution of Cefpirome Sulfate is unstable,, do not absorb owing to oral Cefpirome Sulfate again, so can not process its oral formulations so can not process aqueous injection.
Stability test: under 20 ℃ of-22 ℃ of temperature, Cefpirome Sulfate was deposited 360 days, measured Cefpirome Sulfate content, calculated the content reduction rate.
The pharmacodynamics demonstration test:
(1) animal is selected: select the mice by the infection animal experimental model of Experimental Animal Center preparation, body weight 18-22g, male and female half and half, random packet, 10 of every treated animals.
(2) infection bacteria species: staphylococcus aureus causes the model mice of pneumonia, four groups of model mice, Ke Shi pneumobacillus, hemophilus influenza that streptococcus pneumoniae causes pneumonia.
(3) infection dosage: measure 100% minimum lethal dose (100%MLD) of the bacterial strain that tries by Experimental Animal Center, as infection dosage.
(4) approach is dyed in sense 2: bacterium stock solution is diluted to desired concn (Experimental Animal Center is confirmed) with 5% gastric Mucin, and is quiet through tail
(4) approach is dyed in sense 2: bacterium stock solution is diluted to desired concn (Experimental Animal Center is confirmed) with 5% gastric Mucin, through tail vein injection.
(5) test method: with the mice branch: the A. staphylococcus aureus causes the model mice group of pneumonia, model mice group, C. Ke Shi pneumobacillus group, four groups of D. hemophilus influenza group that the B. streptococcus pneumoniae causes pneumonia.Carry out the injection Cefpirome Sulfate contrast of not administration contrast, prior art for preparing, medicine of the present invention contrast.10 of every group model animals.Quiet immediately notes administration after the infection whenever was administered once at a distance from 6 hours again.Note observing the reaction of animal thing, continuous 7 days, record dead mouse number.
The result of the test contrast:
| Project | A strain infected group mortality rate % | B strain infected group mortality rate % | C strain infected group mortality rate % | D strain infected group mortality rate % | Drug fever response rate % | Deposit 1 year content rate of descent % for 20 ℃-22 ℃ | Stomach and liver untoward reaction rate % |
| Drug treatment not | 100 | ?100 | ?100 | ?100 | -- | -- | -- |
| The administration of 20mg/kg Cefpirome Sulfate | 60 | ?60 | ?60 | ?50 | 20 | 32 | 10 |
| Medicine 20mk/kg of the present invention administration | 20 | ?30 | ?20 | ?10 | 0 | 6 | 0 |
| Remarks |
Embodiment 3
Cefpirome sulfate combined drug provided by the invention, form by following active ingredient weight proportion:
Cefpirome Sulfate 893
Lignocaine 148
Tiopronin 79
Monoammonium glycyrrhizinate 321
Two. preparation technology of the present invention: technology of the present invention aseptic, 18 ℃ to 20 ℃, by national GMP enforcement of regulations.
1. stir down in normal speed with the 50-200 of Cefpirome Sulfate weight water for injection doubly, complete Cefpirome Sulfate, lignocaine, tiopronin, monoammonium glycyrrhizinate dissolving respectively, make the cefpirome sulfate combined drug medicinal liquid;
2. the membrane ultrafiltration of the combination of Cefpirome Sulfate medicine medicinal liquid elder generation of the 1st step preparation, get filtrating, get filtrating, with 8% hydrochloric acid solution liquid adjust pH 4.0-6.0 again through the membrane ultrafiltration of the molecular weight 2000D that dams through molecular cut off 8000D;
3. the membrane filtration mistake of the cefpirome sulfate combined drug medicinal liquid reuse 0.22 μ m of the 3rd step preparation;
4. measure the cefpirome sulfate combined drug medicinal liquid of the 4th step preparation the content of Cefpirome Sulfate; Press the Cefpirome Sulfate dosage that pharmaceutics allows; Aseptic subpackaged in cillin bottle; Well-established law lyophilization in freezer dryer makes in the lyophilized solid moisture below 2%, can process the lyophilized injection or the spray of the cefpirome sulfate combined drug that pharmaceutics allows by well-established law.
Because the aqueous solution of Cefpirome Sulfate is unstable,, do not absorb owing to oral Cefpirome Sulfate again, so can not process its oral formulations so can not process aqueous injection.
Stability test: under 20 ℃ of-22 ℃ of temperature, Cefpirome Sulfate was deposited 360 days, measured Cefpirome Sulfate content, calculated the content reduction rate.
The pharmacodynamics demonstration test:
(1) animal is selected: select the mice by the infection animal experimental model of Experimental Animal Center preparation, body weight 18-22g, male and female half and half, random packet, 10 of every treated animals.
(2) infection bacteria species: staphylococcus aureus causes the model mice of pneumonia, four groups of model mice, Ke Shi pneumobacillus, hemophilus influenza that streptococcus pneumoniae causes pneumonia.
(3) infection dosage: measure 100% minimum lethal dose (100%MLD) of the bacterial strain that tries by Experimental Animal Center, as infection dosage.
(4) approach is dyed in sense 2: bacterium stock solution is diluted to desired concn (Experimental Animal Center is confirmed) with 5% gastric Mucin, through tail vein injection.
(5) test method: with the mice branch: the A. staphylococcus aureus causes the model mice group of pneumonia, model mice group, C. Ke Shi pneumobacillus group, four groups of D. hemophilus influenza group that the B. streptococcus pneumoniae causes pneumonia.Carry out the injection Cefpirome Sulfate contrast of not administration contrast, prior art for preparing, medicine of the present invention contrast.10 of every group model animals.Quiet immediately notes administration after the infection whenever was administered once at a distance from 6 hours again.Note observing the reaction of animal thing, continuous 7 days, record dead mouse number.
The result of the test contrast:
| Project | A strain infected group mortality rate % | B strain infected group mortality rate % | C strain infected group mortality rate % | D strain infected group mortality rate % | Drug fever response rate % | Deposit 1 year content rate of descent % for 20 ℃-22 ℃ | Stomach and liver untoward reaction rate % |
| Drug treatment not | 100 | ?100 | ?100 | ?100 | -- | -- | -- |
| The administration of 20mg/kg cefepime hydrochloride | 60 | ?50 | ?50 | ?60 | 20 | 25 | 10 |
| Medicine 20mk/kg of the present invention administration | 20 | ?30 | ?20 | ?10 | 0 | 4 | 0 |
| Remarks |
Embodiment 4:
Cefpirome sulfate combined drug provided by the invention, form by following active ingredient weight proportion:
Cefpirome Sulfate 500
Lignocaine 200
Tiopronin 50
Monoammonium glycyrrhizinate 500
Two. preparation technology of the present invention: technology of the present invention aseptic, 18 ℃ to 20 ℃, by national GMP enforcement of regulations.
1. stir down in normal speed with the 50-200 of Cefpirome Sulfate weight water for injection doubly, complete Cefpirome Sulfate, lignocaine, tiopronin, monoammonium glycyrrhizinate dissolving respectively, make the cefpirome sulfate combined drug medicinal liquid;
2. the membrane ultrafiltration of the combination of Cefpirome Sulfate medicine medicinal liquid elder generation of the 1st step preparation, get filtrating, get filtrating, with 8% hydrochloric acid solution liquid adjust pH 4.0-6.0 again through the membrane ultrafiltration of the molecular weight 2000D that dams through molecular cut off 8000D;
3. the membrane filtration mistake of the cefpirome sulfate combined drug medicinal liquid reuse 0.22 μ m of the 3rd step preparation;
4. measure the cefpirome sulfate combined drug medicinal liquid of the 4th step preparation the content of Cefpirome Sulfate; Press the Cefpirome Sulfate dosage that pharmaceutics allows; Aseptic subpackaged in cillin bottle; Well-established law lyophilization in freezer dryer makes in the lyophilized solid moisture below 2%, can process the lyophilized injection or the spray of the cefpirome sulfate combined drug that pharmaceutics allows by well-established law.
Because the aqueous solution of Cefpirome Sulfate is unstable,, do not absorb owing to oral Cefpirome Sulfate again, so can not process its oral formulations so can not process aqueous injection.
Stability test: under 20 ℃-22 ℃, Cefpirome Sulfate was deposited 360 days, measured Cefpirome Sulfate content, calculated the content reduction rate.
The pharmacodynamics demonstration test:
(1) animal is selected: select the mice by the infection animal experimental model of Experimental Animal Center preparation, body weight 18-22g, male and female half and half, random packet, 10 of every treated animals.
(2) infection bacteria species: staphylococcus aureus causes the model mice of pneumonia, four groups of model mice, Ke Shi pneumobacillus, hemophilus influenza that streptococcus pneumoniae causes pneumonia.
(3) infection dosage: measure 100% minimum lethal dose (100%MLD) of the bacterial strain that tries by Experimental Animal Center, as infection dosage.
(4) approach is dyed in sense 2: bacterium stock solution is diluted to desired concn (Experimental Animal Center is confirmed) with 5% gastric Mucin, through tail vein injection.
(5) test method: with the mice branch: the A. staphylococcus aureus causes the model mice group of pneumonia, model mice group, C. Ke Shi pneumobacillus group, four groups of D. hemophilus influenza group that the B. streptococcus pneumoniae causes pneumonia.Carry out the injection Cefpirome Sulfate contrast of not administration contrast, prior art for preparing, medicine of the present invention contrast.10 of every group model animals.Quiet immediately notes administration after the infection whenever was administered once at a distance from 6 hours again.Note observing the reaction of animal thing, continuous 7 days, record dead mouse number.
Result of the test:
| Project | A strain infected group mortality rate % | B strain infected group mortality rate % | C strain infected group mortality rate % | D strain infected group mortality rate % | Drug fever response rate % | Deposit 1 year content rate of descent % for 20 ℃-22 ℃ | Stomach and liver untoward reaction rate % |
| Drug treatment not | 100 | ?100 | ?100 | ?100 | -- | -- | -- |
| The administration of 20mg/kg Cefpirome Sulfate | 60 | ?70 | ?60 | ?50 | 20 | 27 | 10 |
| Medicine 20mk/kg of the present invention administration | 20 | ?30 | ?20 | ?10 | 0 | 5 | 0 |
| Remarks |
Embodiment 5
Cefpirome sulfate combined drug provided by the invention, form by following active ingredient weight proportion:
Cefpirome Sulfate 2000
Lignocaine 100
Tiopronin 120
Monoammonium glycyrrhizinate 200
Two. preparation technology of the present invention: technology of the present invention aseptic, 18 ℃ to 20 ℃, by national GMP enforcement of regulations.
1. stir down in normal speed with the 50-200 of Cefpirome Sulfate weight water for injection doubly, complete Cefpirome Sulfate, lignocaine, tiopronin, monoammonium glycyrrhizinate dissolving respectively, make the cefpirome sulfate combined drug medicinal liquid;
2. the membrane ultrafiltration of the combination of Cefpirome Sulfate medicine medicinal liquid elder generation of the 1st step preparation, get filtrating, get filtrating, with 8% hydrochloric acid solution liquid adjust pH 4.0-6.0 again through the membrane ultrafiltration of the molecular weight 2000D that dams through molecular cut off 8000D;
3. the membrane filtration mistake of the cefpirome sulfate combined drug medicinal liquid reuse 0.22 μ m of the 3rd step preparation;
4. measure the cefpirome sulfate combined drug medicinal liquid of the 4th step preparation the content of Cefpirome Sulfate; Press the Cefpirome Sulfate dosage that pharmaceutics allows; Aseptic subpackaged in cillin bottle; Well-established law lyophilization in freezer dryer makes in the lyophilized solid moisture below 2%, can process the lyophilized injection or the spray of the cefpirome sulfate combined drug that pharmaceutics allows by well-established law.
Because the aqueous solution of Cefpirome Sulfate is unstable,, do not absorb owing to oral Cefpirome Sulfate again, so can not process its oral formulations so can not process aqueous injection.
Stability test: under 20 ℃ of-22 ℃ of temperature, Cefpirome Sulfate was deposited 360 days, measured the sulphuric acid head
A spore Luo Hanliang calculates the content reduction rate.
The pharmacodynamics demonstration test:
(1) animal is selected: select the mice by the infection animal experimental model of Experimental Animal Center preparation, body weight 18-22g, male and female half and half, random packet, 10 of every treated animals.
(2) infection bacteria species: staphylococcus aureus causes the model mice of pneumonia, four groups of model mice, Ke Shi pneumobacillus, hemophilus influenza that streptococcus pneumoniae causes pneumonia.
(3) infection dosage: measure 100% minimum lethal dose (100%MLD) of the bacterial strain that tries by Experimental Animal Center, as infection dosage.
(4) approach is dyed in sense 2: bacterium stock solution is diluted to desired concn (Experimental Animal Center is confirmed) with 5% gastric Mucin, through tail vein injection.
(5) test method: with the mice branch: the A. staphylococcus aureus causes the model mice group of pneumonia, model mice group, C. Ke Shi pneumobacillus group, four groups of D. hemophilus influenza group that the B. streptococcus pneumoniae causes pneumonia.Carry out the injection Cefpirome Sulfate contrast of not administration contrast, prior art for preparing, medicine of the present invention contrast.10 of every group model animals.Quiet immediately notes administration after the infection whenever was administered once at a distance from 6 hours again.Note observing the reaction of animal thing, continuous 7 days, record dead mouse number.
The result of the test contrast:
| Project | A strain infected group mortality rate % | B strain infected group mortality rate % | C strain infected group mortality rate % | D strain infected group mortality rate % | Drug fever response rate % | Deposit 1 year content rate of descent % for 20 ℃-22 ℃ | Stomach and liver untoward reaction rate % |
| Drug treatment not | 100 | ?100 | ?100 | ?100 | -- | -- | -- |
| The administration of 20mg/kg Cefpirome Sulfate | 60 | ?60 | ?60 | ?50 | 20 | 30 | 10 |
| Medicine 20mk/kg of the present invention administration | 20 | ?30 | ?20 | ?10 | 0 | 10 | 0 |
| Remarks |
The present invention is described according to preferred embodiment.The description and the embodiment that should be understood that the front only are for the present invention is described; Under prerequisite without departing from the spirit and scope of the present invention; Those skilled in the art can design multiple replacement scheme of the present invention, and it all should be understood to be within protection scope of the present invention.
Claims (2)
1. cefpirome sulfate combined drug is characterized in that, is processed by effective active ingredient of following parts by weight:
Cefpirome Sulfate 500-1500
Lignocaine 100-200
Tiopronin 50-120
Monoammonium glycyrrhizinate 200-500
The preparation technology of said cefpirome sulfate combined drug is under aseptic, 18 ℃ to 20 ℃ conditions, by national GMP enforcement of regulations, and its preparation process is following:
(1). stir down in normal speed with the water for injection of 50-200 times of Cefpirome Sulfate weight, complete described Cefpirome Sulfate, lignocaine, tiopronin, monoammonium glycyrrhizinate dissolving respectively, obtain the cefpirome sulfate combined drug medicinal liquid;
(2). is the cefpirome sulfate combined drug medicinal liquid of step (1) preparation the ultrafiltration of 8000D ultrafilter membrane through molecular cut off earlier, and getting filtrating is the membrane ultrafiltration of 2000D through molecular cut off again, gets filtrating, and the hydrochloric acid solution with 8% is regulated pH value to 4.0-6.0;
(3). the cefpirome sulfate combined drug medicinal liquid of step (2) preparation, again through the membrane filtration of 0.22 μ m;
(4). measure the cefpirome sulfate combined drug medicinal liquid of step (3) preparation the content of Cefpirome Sulfate; Press the dosage of the Cefpirome Sulfate of pharmaceutics permission; Aseptic subpackaged in cillin bottle; Well-established law lyophilization in the cool drying machine makes the lyophilized solid moisture below 2%, processes the cefpirome sulfate combined drug that pharmaceutics allows by well-established law.
2. cefpirome sulfate combined drug according to claim 1 is characterized in that, the dosage form of the cefpirome sulfate combined drug that said pharmaceutics allows is a lyophilized injection.
3.According to the said cefpirome sulfate combined drug of claim 1, it is characterized in that the cefpirome sulfate combined drug that said pharmaceutics allows is used to treat pneumonia and influenza.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1660116A (en) * | 2004-12-24 | 2005-08-31 | 邢为藩 | New combination of Cefpirome Sulfate and preparation method |
| CN1839899A (en) * | 2006-01-19 | 2006-10-04 | 四川大华亿信药物科技有限公司 | Liver disease-treating medicine |
| CN101049294A (en) * | 2006-04-07 | 2007-10-10 | 黄振华 | Medication composition in use for treating liver disease |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1660116A (en) * | 2004-12-24 | 2005-08-31 | 邢为藩 | New combination of Cefpirome Sulfate and preparation method |
| CN1839899A (en) * | 2006-01-19 | 2006-10-04 | 四川大华亿信药物科技有限公司 | Liver disease-treating medicine |
| CN101049294A (en) * | 2006-04-07 | 2007-10-10 | 黄振华 | Medication composition in use for treating liver disease |
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