CN100516071C - Amino butanetriol salt of cephalosporin compounds and preparing method - Google Patents
Amino butanetriol salt of cephalosporin compounds and preparing method Download PDFInfo
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- CN100516071C CN100516071C CNB2007100263204A CN200710026320A CN100516071C CN 100516071 C CN100516071 C CN 100516071C CN B2007100263204 A CNB2007100263204 A CN B2007100263204A CN 200710026320 A CN200710026320 A CN 200710026320A CN 100516071 C CN100516071 C CN 100516071C
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Abstract
The invention discloses a pehanorm salt or hydrate with chemical formula as picture (1) and drug composition and application to treat bacterial infection, which comprises the following parts: cefuroxime oxtatromethane, cepham qusong tromethane, cepham thiotepa tromethane, cefoperazone tromethane, cephalothin tromethane, cefotaxime tromethane, cefolading tromethane, cefonixin tromethane, cefameizin tromethane, cefadizine tromethane, cefuroxime tromethane, cefazolin tromethane, cefapamine tromethane, cefazoline tromethane, cefaadid tromethane, cefaoxofluoride tromethane, cefaminol tromethane and their hydrate.
Description
Technical field:
The invention belongs to the field of medicaments of compound, relate to derivative of cephalosporin compound and preparation method thereof.
Background technology:
Cephalosporins (Ce.pha) osporkr) is gang's beta-lactam wide spectrum semisynthetic antibiotics, antibiotic position is its parent nucleus 7-amino-cephalosporanic acid (7ACA), and side chain substituents and its antimicrobial spectrum, anti-microbial activity, relevant to stability and some pharmacokinetics of β-Nei Xiananmei.First generation cephalosporin is widely used in that China is clinical, second and third in generation cynnematin begun to introduce, also can produce individually.The 4th generation cynnematin research and development energetically abroad will be introduced China soon and promoted the use of.
All can produce resistance in most cynnematin uses, and toxic side effect.Exist more problem in the use, for example: 1) have blood vessel irritation, life-time service easily causes symptoms such as vasculitis; 2) major part is that form with sodium salt exists, sodium ion is so a large amount of enters human body, very high for crowd's risks such as infull person of diabetes bacterial infection patients, Neurological Surgery patient with severe symptoms, cardiorenal function or hyperpietics, easily cause hypernatremia, cause untoward reaction; 3) there is incompatibility in the part kind, uses inconvenience; 4) muscle irritation is arranged during intramuscular injection; Or the like problem.With existing cephalosporin compound is that the foundational development new antibiotic is very significant.
In order to address the above problem, we are prepared into tromethamine salt with such cepham compound, obtain brand-new compound.Pharmacological evaluation proves, the tromethamine salt intramuscular injection of cephalosporin compound and quiet all do not find pungency, have avoided the absorption of sodium ion, and this is highly significant when clinical use.
Summary of the invention:
The objective of the invention is to solve the problem that exists in the clinical use of cynnematin injection formulations.
To achieve these goals, the present invention has adopted following technical scheme:
We provide tromethamine salt or its hydrate by the cephalosporin compound of following general formula (1) expression:
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Work as R
1=-CH
3The time
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Work as R
1During=H
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Can be the cephalofruxin tromethamine salt, chemical formula as the formula (2):
Can be the ceftriaxone tromethamine salt, chemical formula as the formula (3):
Can be the ceftezole tromethamine salt, chemical formula as the formula (4):
Can be the cefoperazone tromethamine salt, chemical formula as the formula (5):
Can be the cefoxitin tromethamine salt, chemical formula as the formula (6):
Can be to be the cefotaxime tromethamine salt, chemical formula as the formula (7):
Can be to be the Cephradine tromethamine salt, chemical formula as the formula (8):
Can be the cefonicid tromethamine salt, chemical formula as the formula (9):
Can be the cefmetazole tromethamine salt, chemical formula as the formula (10):
Can be the Cefodizime tromethamine salt, chemical formula as the formula (11):
Can be the cefmenoxime tromethamine salt, chemical formula as the formula (12):
Can be the ceftizoxime tromethamine salt, chemical formula as the formula (13):
Can be the cefpiramide tromethamine salt, chemical formula as the formula (14):
Can be the Kefzol tromethamine salt, chemical formula as the formula (15):
Can be the cefoxitin tromethamine salt, chemical formula as the formula (16):
Can be the flomoxef tromethamine salt, chemical formula as the formula (17):
Can be the cefminox tromethamine salt, structural formula as the formula (18):
We have also found the synthetic method of cephalosporin compound tromethamine salt, are by cephalosporin compound and the Trometamol mixed with the corresponding moles of ammonia trihydroxybutane of one mole of carboxyl, under the condition that can react below 20 ℃, synthesize in the non-aqueous system.Find in the experiment, the cephalosporin compound less stable, temperature influence is bigger in the building-up process, proves below 20 ℃ it is stable.
We also provide pharmaceutical composition, wherein contain the tromethamine salt of cephalosporin compound or its hydrate as activeconstituents, and contain conventional injection formulations pharmaceutical carrier.Can be prepared into injection formulationss such as little pin, infusion solutions, injection lyophilized powder or injection powder pin by the pharmacy field routine techniques.
We also provide the application of tromethamine salt in preparation treatment infectation of bacteria injection formulations of cephalosporin compound.
Be particularly useful for strictly to control sodium ion intake patient's the full patient's infectation of bacteria of infectation of bacteria, fire victim's severe infection, cardiorenal function, hyperpietic's infectation of bacteria or diabetic subject's infectation of bacteria.
The present invention successfully synthesizes the tromethamine salt of cephalosporin compound, and further makes injection formulations, comprises injection liquid, injection lyophilized powder and sterile powder for injection.Filled up the blank of this compounds tromethamine salt, the problems that existing cephalosporin compound exists have been solved: 1) with behind the Trometamol salify reduced the intake of sodium ion, evaded the hypernatremia risk that needs such as full person of diabetes bacterial infection patients, Neurological Surgery patient with severe symptoms, cardiorenal function or hyperpietic are controlled the infectation of bacteria crowd of sodium ion intakes; 2) experimental results show that do not have blood vessel irritation and muscle irritation.
Further specify the present invention below by specific embodiment, but can not be used to be interpreted as unique qualification the present invention.
Specific embodiment:
Embodiment 1: the preparation of cephalofruxin Trometamol
In the 250ml there-necked flask, add 12.1g (0.1mol) Trometamol and 60% ethanol 20ml, splash into the 20ml80% ethanolic soln that contains cefuroxime acid 42.4g (0.1mol) under the high-temperature stirring, splashing into finishes is stirred to the mixture clarification, stirring at room is 2 hours again, the blended reactant is splashed in 300ml (5-10 ℃) acetone soln, get the white powder crystallization, the suction filtration pressed powder washs solid with small amount of acetone, vacuum-drying 24 hours under the Vanadium Pentoxide in FLAKES condition at high temperature, promptly get the 48g pulverulent solids, yield 88%, mp:121-123 ℃, content analysis: (HPLC method) contains cefuroxime acid 77.6-77.8%.Product is through ultimate analysis (theoretical value: C 44.0%H 5.0%N 12.8%O 32.3%S 5.9%; Measured value: C 44.9%H 5.2%N 12.6%O 32.0%S 5.3%), NMR, MS, UV, IR and HPLC analyze, and product is the cephalofruxin tromethamine salt, is 99.5% in cephalofruxin Trometamol purity.
Embodiment 2: the preparation of ceftriaxone Trometamol
In the what 250ml there-necked flask, add 12.1g (0.1mol) Trometamol and methyl alcohol 4ml, water 2ml, high-temperature stirring, add 57.7g (0.1mol) ceftriaxone, stirring made behind the CL restir 2 hours, and mixture is at high temperature splashed in the 500ml acetone, separated out a large amount of white crystalline powders, the suction filtration solid washs with small amount of acetone, and high temperature drying promptly got white crystalline ceftriaxone tromethamine salt 62.3g in 24 hours under the Vanadium Pentoxide in FLAKES.Yield: 89.2%, mp:93-95 ℃, content analysis (HPLC method): contain ceftriaxone acid 82.1-84.1%.Product is through ultimate analysis (theoretical value: C 37.8%H 4.0%N 18.1%O 22.9%S 13.8%Na 3.4%; Measured value: C 38.0%H 4.2%N 17.9%O 22.7%S 13.7%Na 3.5%), NMR, MS, UV, IR and HPLC analyze, and product is the ceftriaxone tromethamine salt, is 99.1% in ceftriaxone Trometamol purity.
Embodiment 3: the preparation of ceftezole Trometamol
In the what 250ml there-necked flask, add 12.1g (0.1mol) Trometamol and methyl alcohol 4ml, water 2ml, high-temperature stirring, add 44g (0.1mol) ceftezole, stirring made behind the CL restir 1 hour, and mixture is at high temperature splashed in the 500ml acetone, separated out a large amount of white crystalline powders, the suction filtration solid washs with small amount of acetone, and high temperature drying promptly got white crystalline ceftezole tromethamine salt 49.8g in 24 hours under the Vanadium Pentoxide in FLAKES.Yield: 88.8%, content analysis (HPLC method): contain ceftezole acid 77.8-79.0%.Product is through ultimate analysis (theoretical value: C 36.4%H 4.1%N 22.5%O 20.0%S 17.0%; Measured value: C 36.2%H 4.3%N 22.3%O 20.2%S 17.0%), NMR, MS, UV, IR and HPLC analyze, and product is the ceftezole tromethamine salt, is 99.0% in ceftizoxime Trometamol purity.
Embodiment 4: the preparation of cefoperazone Trometamol
In the what 250ml there-necked flask, add 12.1g (0.1mol) Trometamol and methyl alcohol 4ml, water 2ml, high-temperature stirring, add 64.6g (0.1mol) cefoperazone, stirring made behind the CL restir 1 hour, and mixture is at high temperature splashed in the 500ml acetone, separated out a large amount of white crystalline powders, the suction filtration solid washs with small amount of acetone, and high temperature drying promptly got white crystalline cefoperazone tromethamine salt 67.4g in 24 hours under the Vanadium Pentoxide in FLAKES.Yield: 87.9%, content analysis (HPLC method): contain cefoperazone acid 83.8-84.5%.Product is through ultimate analysis (theoretical value: C 45.4%H 5.0%N 18.3%O 22.9%S 8.4%; Measured value: C 45.5%H 4.9%N 18.5%O 22.8%S 8.3%), NMR, MS, UV, IR and HPLC analyze, and product is the cefoperazone tromethamine salt, is 99.4% in cefoperazone Trometamol purity.
Embodiment 5: the preparation of cefoxitin Trometamol
In the what 250ml there-necked flask, add 12.1g (0.1mol) Trometamol and methyl alcohol 4ml, water 2ml, high-temperature stirring, add 39.6g (0.1mol) cefoxitin, stirring made behind the CL restir 2 hours, and mixture is at high temperature splashed in the 500ml acetone, separated out a large amount of white crystalline powders, the suction filtration solid washs with small amount of acetone, and high temperature drying promptly got white crystalline cefoxitin tromethamine salt 45.7g in 24 hours under the Vanadium Pentoxide in FLAKES.Yield: 88.4%, content analysis (HPLC method): contain cephalothin acid 76.0-77.1%.Product is through ultimate analysis (theoretical value: C 46.4%H 5.2%N 8.1%O 27.9%S 12.4%; Measured value: C 46.2%H 5.4%N 8.0%O 28.0%S 12.4%), NMR, MS, UV, IR and HPLC analyze, and product is the cefoxitin tromethamine salt, is 99.3% in cefoxitin Trometamol purity.
Embodiment 6: the preparation of cefotaxime Trometamol
In the what 250ml there-necked flask, add 12.1g (0.1mol) Trometamol and methyl alcohol 4ml, water 2ml, high-temperature stirring, add 45.6g (0.1mol) cefotaxime, stirring made behind the CL restir 1 hour, and mixture is at high temperature splashed in the 500ml acetone, separated out a large amount of white crystalline powders, the suction filtration solid washs with small amount of acetone, and high temperature drying promptly got white crystalline cefotaxime tromethamine salt 51g in 24 hours under the Vanadium Pentoxide in FLAKES.Yield: 88.4%, content analysis (HPLC method): contain cefotaxime acid 78.2-79.3%.Product is through ultimate analysis (theoretical value: C 41.7%H 4.9%N 14.6%O 27.7%S 11.1%; Measured value: C 41.6%H 4.8%N 14.3%O 27.8%S 11.3%), NMR, MS, UV, IR and HPLC analyze, and product is the cefotaxime tromethamine salt, is 99.6% in cefotaxime Trometamol purity.
Embodiment 7: the preparation of Cephradine Trometamol
In the what 250ml there-necked flask, add 12.1g (0.1mol) Trometamol and methyl alcohol 4ml, water 2ml, high-temperature stirring, add 34.9 (0.1mol) Cephradine, stirring made behind the CL restir 1 hour, and mixture is at high temperature splashed in the 500ml acetone, separated out a large amount of white crystalline powders, the suction filtration solid washs with small amount of acetone, and high temperature drying promptly got white crystalline Cephradine tromethamine salt 42.3g in 24 hours under the Vanadium Pentoxide in FLAKES.Yield: 90.1%, content analysis (HPLC method): contain Cephradine acid 73.8-74.9%.Product is through ultimate analysis (theoretical value: C 51.1%H 6.4%N 11.9%O 23.8%S 6.8%; Measured value: C 50.8%H 6.6%N 12.0%O 24.0%S 6.6%), NMR, MS, UV, IR and HPLC analyze, and product is the Cephradine tromethamine salt, is 99.7% in Cephradine Trometamol purity.
Embodiment 8: the preparation of cefonicid Trometamol
In the what 250ml there-necked flask, add 12.1g (0.1mol) Trometamol and methyl alcohol 4ml, water 2ml, high-temperature stirring, add 56.4g (0.1mol) cefonicid, stirring made behind the CL restir 1 hour, and mixture is at high temperature splashed in the 500ml acetone, separated out a large amount of white crystalline powders, the suction filtration solid washs with small amount of acetone, and high temperature drying promptly got white crystalline cefonicid tromethamine salt 62.5g in 24 hours under the Vanadium Pentoxide in FLAKES.Yield: 91.2%, content analysis (HPLC method): contain cefonicid acid 82.2-83.3%.Product is through ultimate analysis (theoretical value: C 38.6%H 4.1%N 14.3%O 25.7%S 14.1%Na 3.2%; Measured value: C 38.8%H 4.0%N 14.2%O 25.9%S 14.0%Na 3.1%), NMR, MS, UV, IR and HPLC analyze, and product is the cefonicid tromethamine salt, is 99.7% in cefonicid Trometamol purity.
Embodiment 9: the preparation of cefmetazole Trometamol
In the what 250ml there-necked flask, add 12.1g (0.1mol) Trometamol and methyl alcohol 4ml, water 2ml, high-temperature stirring, add 47.2g (0.1mol) cefmetazole, stirring made behind the CL restir 1 hour, and mixture is at high temperature splashed in the 500ml acetone, separated out a large amount of white crystalline powders, the suction filtration solid washs with small amount of acetone, and high temperature drying promptly got white crystalline cefmetazole tromethamine salt 53.5g in 24 hours under the Vanadium Pentoxide in FLAKES.Yield: 90.2%, content analysis (HPLC method): contain cefmetazole acid 78.9-80.4%.Product is through ultimate analysis (theoretical value: C 38.5%H 4.7%N 18.9%O 21.6%S 16.3%; Measured value: C 38.8%H 4.6%N 18.7%O 21.4%S 16.5%), NMR, MS, UV, IR and HPLC analyze, and product is the cefmetazole tromethamine salt, is 99.5% in cefmetazole Trometamol purity.
Embodiment 10: the preparation of Cefodizime Trometamol
In the what 250ml there-necked flask, add 24.2g (0.1mol) Trometamol and methyl alcohol 4ml, water 2ml, high-temperature stirring, add 58.5g (0.1mol) Cefodizime, stirring made behind the CL restir 1 hour, and mixture is at high temperature splashed in the 500ml acetone, separated out a large amount of white crystalline powders, the suction filtration solid washs with small amount of acetone, and high temperature drying promptly got white crystalline Cefodizime tromethamine salt 73.9g in 24 hours under the Vanadium Pentoxide in FLAKES.Yield: 89.4%, content analysis (HPLC method): contain Cefodizime acid 69.8-71.0%.Product is through ultimate analysis (theoretical value: C 40.6%H 5.1%N 13.5%O 25.2%S 15.6%; Measured value: C 40.8%H 5.2%N 13.2%O 25.0%S 15.8%), NMR, MS, UV, IR and HPLC analyze, and product is the Cefodizime tromethamine salt, is 99.4% in Cefodizime Trometamol purity.
Embodiment 11: the preparation of cefmenoxime Trometamol
In the what 250ml there-necked flask, add 12.1g (0.1mol) Trometamol and methyl alcohol 4ml, water 2ml, high-temperature stirring, add 51.2g (0.1mol) cefmenoxime, stirring makes behind the CL restir l hour, and mixture is at high temperature splashed in the 500ml acetone, separates out a large amount of white crystalline powders, the suction filtration solid washs with small amount of acetone, and high temperature drying promptly got white crystalline cefmenoxime tromethamine salt 56.9g in 24 hours under the Vanadium Pentoxide in FLAKES.Yield: 89.9%, content analysis (HPLC method): contain cefmenoxime acid 80.2-82.1%.Product is through ultimate analysis (theoretical value: C 37.9%H 4.4%N 22.1%O 20.2%S 15.2%; Measured value: C 37.7%H 4.2%N 22.5%O 20.1%S 15.3%), NMR, MS, UV, IR and HPLC analyze, and product is the cefmenoxime tromethamine salt, is 99.2% in cefmenoxime Trometamol purity.
Embodiment 12: the preparation of ceftizoxime Trometamol
In the what 250ml there-necked flask, add 12.1g (0.1mol) Trometamol and methyl alcohol 4ml, water 2ml, high-temperature stirring, add 38.3g (0.1mol) ceftizoxime, stirring made behind the CL restir 1 hour, and mixture is at high temperature splashed in the 500ml acetone, separated out a large amount of white crystalline powders, the suction filtration solid washs with small amount of acetone, and high temperature drying promptly got white crystalline ceftizoxime tromethamine salt 44.7g in 24 hours under the Vanadium Pentoxide in FLAKES.Yield: 88.7%, content analysis (HPLC method): contain ceftizoxime acid 75.9-76.5%.Product is through ultimate analysis (theoretical value: C 40.5%H 4.8%N 16.7%O 25.4%S 12.6%; Measured value: C 40.7%H 5.0%N 16.8%O 25.1%S 12.4%), NMR, MS, UV, IR and HPLC analyze, and product is the ceftizoxime tromethamine salt, is 99.0% in ceftizoxime Trometamol purity.
Embodiment 13: the preparation of cefpiramide Trometamol
In the what 250ml there-necked flask, add 12.1g (0.1mol) Trometamol and methyl alcohol 4ml, water 2ml, high-temperature stirring, add 61.3g (0.1mol) cefpiramide, stirring made behind the CL restir 1 hour, and mixture is at high temperature splashed in the 500ml acetone, separated out a large amount of white crystalline powders, the suction filtration solid washs with small amount of acetone, and high temperature drying promptly got white crystalline cefpiramide tromethamine salt 51g in 24 hours under the Vanadium Pentoxide in FLAKES.Yield: 89.4%, content analysis (HPLC method): contain Cefpiramide Acid 78.2-79.3%.Product is through ultimate analysis (theoretical value: C 47.5%H 4.7%N 17.3%O 21.8%S 8.7%; Measured value: C 47.6%H 4.8%N 17.4%O 21.6%S 8.6%), NMR, MS, UV, IR and HPLC analyze, and product is the cefpiramide tromethamine salt, is 99.1% in cefpiramide Trometamol purity.
Embodiment 14: the preparation of Kefzol Trometamol
In the what 250ml there-necked flask, add 12.1g (0.1mol) Trometamol and methyl alcohol 4ml, water 2ml, high-temperature stirring, add 45.4g (0.1mol) Kefzol, stirring made behind the CL restir 1 hour, and mixture is at high temperature splashed in the 500ml acetone, separated out a large amount of white crystalline powders, the suction filtration solid washs with small amount of acetone, and high temperature drying promptly got white crystalline Kefzol tromethamine salt 51.2g in 24 hours under the Vanadium Pentoxide in FLAKES.Yield: 89.1%, content analysis (HPLC method): contain Kefzol acid 78.4-79.5%.Product is through ultimate analysis (theoretical value: C 37.6%H 4.3%N 21.9%O 19.5%S 16.7%; Measured value: C 37.8%H 4.2%N 21.8%O 19.3%S 16.9%), NMR, MS, UV, IR and HPLC analyze, and product is the Kefzol tromethamine salt, is 99.5% in Kefzol Trometamol purity.
Embodiment 15: the preparation of cefoxitin Trometamol
In the what 250ml there-necked flask, add 12.1g (0.1mol) Trometamol and methyl alcohol 4ml, water 2ml, high-temperature stirring, add 42.7g (0.1mol) cefoxitin, stirring made behind the CL restir 1 hour, and mixture is at high temperature splashed in the 500ml acetone, separated out a large amount of white crystalline powders, the suction filtration solid washs with small amount of acetone, and high temperature drying promptly got white crystalline cefoxitin tromethamine salt 49.1g in 24 hours under the Vanadium Pentoxide in FLAKES.Yield: 89.6%, content analysis (HPLC method): contain cefoxitin acid 77.6-78.8%.Product is through ultimate analysis (theoretical value: C 43.8%H 5.1%N 10.2%O 29.2%S 11.7%; Measured value: C 43.6%H 4.9%N 10.3%O 29.3%S 11.9%), NMR, MS, UV, IR and HPLC analyze, and product is the cefoxitin tromethamine salt, is 99.3% in cefoxitin Trometamol purity.
Embodiment 16: the preparation of flomoxef Trometamol
In the what 250ml there-necked flask, add 12.1g (0.1mol) Trometamol and methyl alcohol 4ml, water 2ml, high-temperature stirring, add 49.6g (0.1mol) flomoxef, stirring made behind the CL restir 1 hour, and mixture is at high temperature splashed in the 500ml acetone, separated out a large amount of white crystalline powders, the suction filtration solid washs with small amount of acetone, and high temperature drying promptly got white crystalline flomoxef tromethamine salt 55.1g in 24 hours under the Vanadium Pentoxide in FLAKES.Yield: 89.3%, content analysis (HPLC method): fluorine-containing oxygen cephalo acid 79.2-80.6%.Product is through ultimate analysis (theoretical value: C 37.0%H 4.7%N 15.9%O 25.9%S 10.4%F 6.2; Measured value: C 37.2%H 4.8%N 16.0%O 25.8%S 10.3%F6.0%; ), NMR, MS, UV, IR and HPLC analyze, and product is the flomoxef tromethamine salt, is 99.4% in flomoxef Trometamol purity.
Embodiment 16: the preparation of cefminox Trometamol
In the what 250ml there-necked flask, add 12.1g (0.1mol) Trometamol and methyl alcohol 4ml, water 2ml, high-temperature stirring, add 54.2g (0.1mol) cefminox, stirring made behind the CL restir 1 hour, and mixture is at high temperature splashed in the 500ml acetone, separated out a large amount of white crystalline powders, the suction filtration solid washs with small amount of acetone, and high temperature drying promptly got white crystalline cefminox tromethamine salt 59.3g in 24 hours under the Vanadium Pentoxide in FLAKES.Yield: 89.4%, content analysis (HPLC method): contain cefminox acid 81.2-82.3%.Product is through ultimate analysis (theoretical value: C 37.5%H 5.0%N 17.5%O 25.0%S 15.0%; Measured value: C 37.3%H 4.9%N 17.4%O 25.2%S 15.2%), NMR, MS, UV, IR and HPLC analyze, and product is the cefminox tromethamine salt, is 99.3% in cefminox Trometamol purity.
Embodiment 17: the preparation of cefuroxime for inj Trometamol lyophilized powder
Get the cephalofruxin Trometamol 31g (containing cefuroxime acid 25g) of embodiment 1 preparation, add 120ml water for injection, dissolving, add N.F,USP MANNITOL 4.5g again, fully after the dissolving, add water for injection, cross millipore filtration after the gac decarburization to 150ml, be sub-packed in the 7ml cillin bottle, every bottle of 3ml jumps a queue, freeze-drying, gland, promptly.Specification: 0.5g/ bottle.
Embodiment 17: the preparation of cefotaxime for inj Trometamol lyophilized powder
Get the cefotaxime Trometamol 30.6g (containing cefotaxime acid 25g) of embodiment 6 preparations, add 80ml water for injection, dissolving, add N.F,USP MANNITOL 3.0g again, fully after the dissolving, add water for injection, cross millipore filtration after the gac decarburization to 100ml, be sub-packed in the 7ml cillin bottle, every bottle of 4ml jumps a queue, freeze-drying, gland, promptly.Specification: 1.0g/ bottle.
Embodiment 18: pharmacological testing
Experimental strain:
Escherichia coli.
Laboratory animal:
Kunming kind small white mouse, body weight 18 ~ 22g, male and female half and half.
Experimental technique:
To test with bacterial strain 37 ℃ of cultivations overnight in the fresh meat soup of 3ml, sterilizing with 0.5%, to carry out doubling dilution standby for dry yeast liquid.Be mixed with the required bacterium liquid of infection animal with 0.5% sterilization dry yeast liquid, the same day, fresh preparation was used for experiment.
Before the test mouse is stopped eating, supplies water.Mouse is divided into three groups at random, 10 every group.1. blank group: every mouse all gives the blank bacterium liquid of abdominal injection 0.5ml (0.5% sterilization dry yeast liquid), at once respectively at caudal vein injecting normal saline 0.5ml; 2. Cefuroxime sodium group: every mouse all gives abdominal cavity infection test organisms liquid 0.5ml, after the infection at once respectively at caudal vein injection cephalofruxin sodium solution 0.5ml (by cephalofruxin, dosage is 450.5mg/kg); 3. cephalofruxin Trometamol group: every mouse all gives abdominal cavity infection test organisms liquid 0.5ml, after the infection at once respectively at caudal vein injection cephalofruxin Trometamol solution 0.5ml (by cephalofruxin, dosage is 450.5mg/kg).Observe and record mouse survival number, continuous 14 days, during off-test, the mouse of survival broken end was got blood, measures plasma osmolarity, blood sugar, blood sodium.
Experimental result
Cephalofruxin Trometamol group mouse survival number approaches the blank group than Cefuroxime sodium group height, sees Table 1.The blood sodium level of Cefuroxime sodium group mouse is apparently higher than blank group and cephalofruxin Trometamol group, P＜0.01, and there was no significant difference between three groups in the blood sugar, plasma osmolarity sees Table 2.
Table 1 mouse survival rate
Table 2 blood results of biochemical (x ± s)
Compare with control group
*P＜0.01
Discuss: all with the form performance pharmacological action of cefuroxime acid, the sodium amount that contains of Cefuroxime sodium is about 25%, in the 1g medicine, contains sodium and is about 11mmol in vivo for Cefuroxime sodium and cephalofruxin Trometamol.The survival rate of Cefuroxime sodium sodium group mouse is low than other two groups in this test, may be higher relevant with its blood sodium level.
Embodiment 19: irritation test
The test of the local irritation of cephalofruxin Trometamol is as the part of its safety research, carries out in that rabbit is following on one's body: subcutaneous injection (single), eye conjunctival sac medication (single), intramuscular injection (single repeats 7 days) and intravenous injection (repeating 8 days).In addition, adopt people's blood to carry out hemolytic test.When with the cephalofruxin Trometamol subcutaneous injection administration of 20% concentration, the pungency that the pungency of generation is equal to or produces a little less than water or Trometamol injection of solution.When being used for conjunctival sac, eyes almost there is not pungency with the cephalofruxin Trometamol solution of concentration.In the test of single administered intramuscular, it is suitable with 0.75% acetum that the muscle that the cephalofruxin Trometamol of 10% concentration causes changes, and slightly seriously in physiological saline, administration is after 2 days, and its caused muscle changes the acetum far below 6%.But in the time of the 7th day, its caused muscle changes the acetum far below 0.75%.Intramuscular injection repeat administration test-results is as follows: in the time of 7 days, the muscle that 10% cephalofruxin Trometamol injection causes changes slightly seriously in physiological saline, still far below other contrast solution in administration.In the blood vessel irritation test, 10% cephalofruxin Trometamol solution administration macroscopic thrombus can occur on the 5th day, and when administration finished on the 8th day, microscope can be observed thrombus and organize bolt.In hemolytic test, adopt and divide the inspection of tube photometer method, the result shows that 10% cephalofruxin Trometamol solution hemolytic reaction can not occur after joining in fresh adult's blood.
Embodiment 20: the stability test of cefotaxime Trometamol
Press the new drug requirements of customs declaration, cefotaxime for inj Trometamol lyophilized powder sample is being intended under the listing terms of packing, place the climatic chamber of 40 ℃ of relative humidity 75% of temperature, respectively 0,1,2,3, the sampling in June investigates proterties, pH value, solution clarity and color, particulate matter, weight loss on drying, aseptic, bacterial endotoxin, related substance and content.The results are shown in Table 3:
The accelerated test result of table 3 cefotaxime for inj tromethamine salt
Through quickening (40 ℃) test 6 months, sampling detected every index to the brief summary trial-product respectively in 1,2,3,6 month under simulation commercially available back state, and the result shows that every index do not have considerable change.
Claims (6)
1, by the tromethamine salt of the cephalosporin compound of following general formula (1) expression:
When
The time
Work as R
1=
The time
When
The time
When
The time
When
The time
Work as R
1=-CH
3The time
When
When
The time
When
When
The time
Work as R
1During=H
When
The time
When
The time
When
The time
When
The time
The time
2, pharmaceutical composition, the tromethamine salt of cephalosporin compound that wherein contains claim 1 be as activeconstituents, and contain conventional injection formulations pharmaceutical carrier.
3, the application of the described compound of claim 1 in preparation treatment infectation of bacteria injection agent medicine.
4, the application of the tromethamine salt of cephalosporin compound as claimed in claim 3 in preparation treatment infectation of bacteria injection formulations, it is characterized in that being applicable to must the strict infectation of bacteria of controlling the patient of sodium ion intake.
5, the tromethamine salt of cephalosporin compound as claimed in claim 3 is preparing the application for the treatment of in the infectation of bacteria injection formulations, it is characterized in that being applicable to fire victim's severe infection or diabetic subject's infectation of bacteria.
6, the application of the tromethamine salt of cephalosporin compound as claimed in claim 3 in preparation treatment infectation of bacteria injection formulations is characterized in that being applicable to the complete or hyperpietic's of cardiorenal function infectation of bacteria.
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