CN103655460A - Injection medicinal composition containing aztreonam, as well as preparation method and application thereof - Google Patents
Injection medicinal composition containing aztreonam, as well as preparation method and application thereof Download PDFInfo
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- CN103655460A CN103655460A CN201210344967.2A CN201210344967A CN103655460A CN 103655460 A CN103655460 A CN 103655460A CN 201210344967 A CN201210344967 A CN 201210344967A CN 103655460 A CN103655460 A CN 103655460A
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Abstract
The invention provides an injection medicinal composition containing aztreonam as well as a preparation method and an application of the medicinal composition, and the composition consists of beta crystal-form aztreonam, L-arginine and anhydrous sodium carbonate. According to the composition, use of arginine is reduced to a certain extent, and the possibility of potential adverse response can be reduced; the medicinal composition is simple in prescription, good in dissolubility and high in stability, can be stored for a long time, and is suitable for industrial production. Special safety testing researches prove that the solution does not irritate blood vessels, does not have allergic responses or hemolysis phenomenon, can guarantee human body administration safety, and is worthy of clinical popularization and application.
Description
Technical field
The invention belongs to field of medicaments, be specifically related to a kind of medicinal composition for injections that comprises antibiotic aztreonam and its production and use.
Background technology
The Bristol-Myers Squibb company of the aztreonam Shi You U.S. develops, early than 1984, in Italy, go on the market, within 1986, in Pakistan, go on the market, 1988 Nian Indonesia go on the market with trade name Azactam, 1987 in Japan's listing, simultaneously in listings such as Germany, Spain, France.Aztreonam raw material was in import China in 2002, and preparation You Shiguibao company produced at home in 1997.Aztreonam is that first is applied to clinical monocycle beta-lactam antibiotics, and it has the antibacterial activity of height to comprising the most of aerobic gram-negative bacteria of the enterobacteriaceae lactobacteriaceaes such as the pneumobacillus of escherichia coli, Klebsiella and OKCY holder bacterium, aerobacteria, bacillus cloacae, Proteus, Serratia, citric acid bacterium genus, Shigella and hemophilus influenza, gonococcus, meningococcus.Aztreonam is used for the treatment of the various infection due to responsive aerobic gram-negative bacteria in clinical, as: the skin soft-tissue infections such as urinary tract infection, lower respiratory infection, septicemia, intra-abdominal infection, gynecological infection, postoperative wound and burn, ulcer etc.
In beta-lactam antibiotic, the antimicrobial spectrum of aztreonam is very unique.Different from most beta-lactam antibiotics is aztreonam to gram positive bacteria (as staphylococcus, the anaerobe of streptococcus and propagation) almost or at all there is no activity, but aerobic, gram negative bacteria that inpatient is often run into have very strong antibacterial activity, and Pseudomonas aeruginosa is also had to good antibacterial action.Aztreonam is different from most of beta-lactam antibiotics, and it does not induce antibacterial to produce beta-lactamase, and bacteriogenic most beta-lactamase is had to high stability.
Molecular formula: C
13h
17n
5o
8s
2
Molecular weight: 435.43
Chemical structural formula:
Chemical name: [2S-[2 α, 3 β (Z)]]-2-[[[1-(2-amino-4-thiazolyl)-2-[(2-methyl-4-oxo-1-sulfo group-3-azetidinyl) amino]-2-oxo ethylidene] amino] oxo]-2 Methylpropionic acid.
Physicochemical property: this product be white to light yellow crystalline powder, odorless, have draw moist.This product can be dissolved in dimethyl formamide or dimethyl sulfoxide, slightly soluble in water or methanol, and soluble,very slightly in ethanol, almost insoluble in ethyl acetate, chloroform or toluene.
Aztreonam is as a kind of antibacterial, it is mainly by the bactericidal action of having synthesized of anti-bacteria cell wall, penicillin-binding protein 3 (PBP-3) on gram negative bacilli cell membrane is had to height affinity, make the division of bacterial cell be obstructed and form filamentous, thereby it is dead to cause bacterial body to dissolve; And to gram positive bacteria because of can not be a large amount of in conjunction with a little less than antibacterial action with the PBP of this bacterioid.
Interaction with beta-lactamase: the hydrolysis that aztreonam can resistance to beta-lactamase.Verified, the beta-lactamase of aztreonam to G-bacteria plasmid type, has stability highly, and to the chromosomal beta-lactamase of G-bacterium, aztreonam is inhibitor or lacks active zymolyte.Aztreonam can induced chromosome type beta-lactamase generation.
Aztreonam raw material has 4 kinds of crystal formations, is respectively α, β, γ, δ crystal formation, and alpha-crystal form is moisture crystal formation, soluble in water, the also easy moisture absorption, poor stability.In raw material production, often aztreonam is converted into beta crystal.Beta crystal aztreonam is anhydrous, is difficult for the moisture absorption, and density is large, good fluidity, stable in properties; But the aztreonam of aztreonam, especially beta crystal dissolubility in water is less, and dissolution velocity is slower.Therefore, aztreonam absorbs after oral hardly; And after intramuscular injection or intravenous injection, aztreonam can be distributed in interior each tissue of body and body fluid rapidly, widely, thereby reach therapeutic effect; Due to solution shape aztreonam poor stability, can not tolerate heat sterilization simultaneously, so its suitable injection that is developed to solid form, i.e. aztreonam for injection.
In actual production, aztreonam for injection adopts three kinds of methods to produce conventionally, and the first is dissolved in the water aztreonam and L-arginine according to certain ratio combination, carry out carrying out lyophilization after aseptic apyrogeneity processing; It two is to adopt aztreonam beta crystal to mix with L-arginine, direct aseptic subpackaged acquisition; It three is to adopt aztreonam and L-arginine salify in organic solvent, and the solid of recrystallization acquisition is directly aseptic subpackaged.First the effect of L-arginine in aztreonam preparation be to increase the dissolubility of aztreonam and dissolution velocity, adjusting pH; Next is promote aztreonam stable, reduces the open loop impurity of aztreonam.Ring-opening aztreonam is one of major impurity of aztreonam, it has reduced the content of medicine on the one hand, cause the reduction of tiring of medicine, easily there is self-polymerization formation high polymer (macromolecule impurity) in ring-opening aztreonam on the other hand, and the content of high polymer directly affects anaphylactoid incidence rate.
In the process of producing, aztreonam and arginic proportioning are generally: 1 part of aztreonam, 0.78 part of arginine; If reduce arginine proportioning, the pH value of solution is too low, and aztreonam dissolves not to be clarified, and increases arginine proportioning, and the pH value of solution is too high, and during injection, zest is larger.In addition; aztreonam and these the two kinds of easy layerings of composition of L-arginine in the vibration processes such as production, transportation, storage of aztreonam preparation; mix uneven; arginine can not comprehensive engagement and protection aztreonam; aztreonam pH value between causing every bottle, dissolubility, dissolution velocity, stability etc. are inconsistent, the prescription that can not satisfy the prescriptive period.Appropriate arginine can improve the immunologic function of cell, improves anti-infection ability.But have report to show, critically ill patient is used containing after arginic preparation, can not reduce infection rate, can not reduce mortality rate, can cause that on the contrary the damage of cardiovascular system or other system causes death, and mortality rate is increased.Therefore, the increase of L-arginine use amount in medicine, will cause the dangerous increase of medication.Therefore, developing the aztreonam preparation that arginine content is low, stability is high, safe is current urgent needs.
Aztreonam, L-arginine are mixed by a certain percentage with natrium carbonicum calcinatum, yet there are no up to now any relevant report.
Summary of the invention
One object of the present invention is to provide a kind of medicinal composition for injections containing aztreonam, this pharmaceutical composition has reduced arginic use to a certain extent, reduced the probability that potential adverse effect occurs, and dissolubility is good, stability is high, effect duration is long.
Another object of the present invention is to provide the preparation method of aforementioned pharmaceutical compositions.
Another object of the present invention is to provide the purposes of aforementioned pharmaceutical compositions.
The object of the invention is to be achieved through the following technical solutions:
On the one hand, the invention provides a kind of medicinal composition for injections containing aztreonam, described compositions is comprised of beta crystal aztreonam, L-arginine and natrium carbonicum calcinatum.
Preferably, described compositions is comprised of 1 weight portion beta crystal aztreonam, 0.4 ~ 0.6 weight portion L-arginine and 0.05 ~ 0.08 weight portion natrium carbonicum calcinatum.
Preferably, described compositions is comprised of 1 weight portion beta crystal aztreonam, 0.6 weight portion L-arginine and 0.05 weight portion natrium carbonicum calcinatum.
More preferably, described compositions is comprised of 1 weight portion beta crystal aztreonam, 0.5 weight portion L-arginine and 0.065 weight portion natrium carbonicum calcinatum.
Preferably, described compositions is comprised of 1 weight portion beta crystal aztreonam, 0.4 weight portion L-arginine and 0.08 weight portion natrium carbonicum calcinatum.
On the other hand, the invention provides a kind of method of preparing above-mentioned pharmaceutical composition, comprise and be prepared as follows technique:
A. beta crystal aztreonam and L-arginine are joined in the mixer in Bai Ji toilet and mixed homogeneously;
B. natrium carbonicum calcinatum is joined in the mixture of step a to mix homogeneously in the mixer in Bai Ji toilet;
C. mixed qualified by intermediate check content after, carry out aseptic subpackaged, tamponade, roll lid, lamp inspection and packing, obtain.
Preferably, the incorporation time in described step a and/or step b is 3 hours.
Preferably, described step c adopts secondary to fill nitrogen technique in aseptic subpackaged process, the remaining oxygen content in medicine bottle is controlled at below 1%v/v, to improve product stability.
Another aspect, the invention provides the purposes of above-mentioned pharmaceutical composition in the medicine of preparation treatment infection due to aerobic gram-negative bacteria by sensitivity.
Preferably, describedly by the infection due to the aerobic gram-negative bacteria of sensitivity, comprise one or more in the skin soft-tissue infections such as urinary tract infection, lower respiratory infection, septicemia, intra-abdominal infection, gynecological infection and postoperative wound and burn, ulcer.
The invention solves the difficult problems such as aztreonam drug solubility is low, poor stability.Pharmaceutical composition of the present invention reduced arginic use, reduced the probability that potential adverse effect occurs, and prescription is simple, dissolubility and have good stability, can long term storage, be applicable to industrialization and produce.Through specific safety experimental study, confirm, the solution of this product is non-stimulated to blood vessel, without anaphylaxis, also without haemolysis, can guarantee the drug safety of human body, and clinic is applied.Preparation method of the present invention is on the basis of mixing subpackage, to prepare a kind of new medicinal composition for injections containing aztreonam, this pharmaceutical composition not only has general subpackage can guarantee that aztreonam for injection and raw material have mutually isomorphous advantage, also can reduce the shortcoming of each composition layering in production, transportation, storage process.
The specific embodiment
The present invention can be described further by following examples and test example, but the present invention is not limited in following examples and test example.
embodiment 1
Produce prescription:
Get the beta crystal aztreonam of 1 weight portion and the L-arginine of 0.6 weight portion, material is placed in to hundred grades of V-Mixers in clean area, mix 3 hours; The natrium carbonicum calcinatum of getting 0.05 weight portion adds in said mixture, in the V-Mixer in hundred grades of clean area, mixes 3 hours; To mix powder and be loaded in aseptic tank, sternly envelope.Check again the content of active component in intermediate, carry out full-automatic sterile subpackage, tamponade after qualified, roll lid, lamp inspection.In aseptic subpackaged process, adopt secondary to fill nitrogen technique, reduce the oxygen content in medicine bottle as far as possible, be controlled at below 1%v/v, to improve product stability.
embodiment 2
Produce prescription:
Get the beta crystal aztreonam of 1 weight portion and the L-arginine of 0.5 weight portion, material is placed in to hundred grades of V-Mixers in clean area, mix 3 hours; The natrium carbonicum calcinatum of getting 0.065 weight portion adds in said mixture, in the V-Mixer in hundred grades of clean area, mixes 3 hours; To mix powder and be loaded in aseptic tank, sternly envelope.Check again the content of active component in intermediate, carry out full-automatic sterile subpackage, tamponade after qualified, roll lid, lamp inspection.In aseptic subpackaged process, adopt secondary to fill nitrogen technique, reduce the oxygen content in medicine bottle as far as possible, be controlled at below 1%v/v, to improve product stability.
embodiment 3
Produce prescription:
Get the beta crystal aztreonam of 1 weight portion and the L-arginine of 0.4 weight portion, material is placed in to hundred grades of V-Mixers in clean area, mix 3 hours; The natrium carbonicum calcinatum of getting 0.08 weight portion adds in said mixture, in the V-Mixer in hundred grades of clean area, mixes 3 hours; To mix powder and be loaded in aseptic tank, sternly envelope.Check again the content of active component in intermediate, carry out full-automatic sterile subpackage, tamponade after qualified, roll lid, lamp inspection.In aseptic subpackaged process, adopt secondary to fill nitrogen technique, reduce the oxygen content in medicine bottle as far as possible, be controlled at below 1%v/v, to improve product stability.
comparative example 1
Existing prescription:
Get the beta crystal aztreonam of 1 weight portion and the L-arginine of 0.78 weight portion, material is placed in to hundred grades of V-Mixers in clean area, mix 3 hours; To mix powder and be loaded in aseptic tank, sternly envelope.Check again the content of active component in intermediate, carry out full-automatic sterile subpackage, tamponade after qualified, roll lid, lamp inspection.In aseptic subpackaged process, adopt secondary to fill nitrogen technique, reduce the oxygen content in medicine bottle as far as possible, be controlled at below 1%v/v, to improve product stability.
test example 1
The ratio that compares each component in comparative example 1 and embodiment 1-3, in Table 1.
Table 1
| Comparative example 1 | Embodiment 1 | Embodiment 2 | Embodiment 3 | |
| Beta crystal aztreonam | 1 weight portion | 1 weight portion | 1 weight portion | 1 weight portion |
| L-arginine | 0.78 weight portion | 0.6 weight portion | 0.5 weight portion | 0.4 weight portion |
| Natrium carbonicum calcinatum | - | 0.05 weight portion | 0.065 weight portion | 0.08 weight portion |
In existing prescription (comparative example 1), the ratio of adjuvant (being L-arginine) in 1 weight portion preparation is about 43.8%; In embodiment 1, the ratio of adjuvant (L-arginine and natrium carbonicum calcinatum) in 1 weight portion preparation is about 39.4%; In embodiment 2, the ratio of adjuvant (L-arginine and natrium carbonicum calcinatum) in 1 weight portion preparation is about 36.1%; In embodiment 3, the ratio of adjuvant (L-arginine and natrium carbonicum calcinatum) in 1 weight portion preparation is about 32.4%.From above-mentioned data, can find out, the ratio of embodiment 1, embodiment 2 and embodiment 3 adjuvant in having reduced in varying degrees every weight portion, improved the content of aztreonam in every weight portion, the present invention simultaneously has all reduced the consumption of L-arginine, has reduced the probability that untoward reaction occurs.
test example 2
Observe the mixed-powder that comparative example 1 and embodiment 1-3 obtain, investigate appearance character, pH, angle of repose and dissolubility, the results are shown in Table 2.
Table 2
| Inspection item | Comparative example 1 | Embodiment 1 | Embodiment 2 | Embodiment 3 |
| Character | Off-white powder | Off-white powder | Off-white powder | Off-white powder |
| pH | 5.1 | 4.6 | 5.3 | 6.5 |
| Angle of repose | 36.7° | 36.4° | 33.8° | 35.7° |
| Dissolubility | Yi Rong | Solvable | Yi Rong | Yi Rong |
It is acid that aztreonam crude drug is, and adds basic auxiliary can increase its dissolubility and stability, and alkalescence and the arginine of sodium carbonate are suitable, can reduce arginic consumption in prescription; The angle of repose of embodiment 1-3 gained powder is smaller compared with comparative example 1, illustrates that the mobility of embodiment 1-3 gained powder is better, can guarantee that subpackage loading amount is stable.
test example 3
Getting the mixed powder sample that comparative example 1 and embodiment 1-3 obtain is positioned over respectively in 10L pharmaceutical powder Aluminum Drum, inflated with nitrogen is preserved, after jolting, in 0 month, December with get respectively two points at San Ge position, upper, middle and lower in 24 months, measure respectively the situation of change of each pH value and content, the results are shown in Table 3.
Table 3
By above test data, can be found out, 25 ± 2 ℃ of temperature, under relative humidity RH 60 ± 10% conditions, in 24 months of having investigated, in the product of embodiment of the present invention 1-3, the distribution of aztreonam in upper, middle and lower-ranking is all comparatively stable, quality is better than existing prescription (comparative example 1), wherein the prescription of the preferred embodiment of the present invention 2.
Test example 4 accelerated stability tests
Get the sample that comparative example 1 and embodiment 1-3 obtain, be placed in 40 ± 2 ℃ of temperature, under relative humidity RH 75 ± 5% conditions, place and within 6 months, carry out accelerated test investigation.In each sampling at the 0th, 1,2,3,6 the end of month once, according to investigation method, every investigation project is detected result and comparison in 0 month.The results are shown in Table 4.
Table 4
By above test data, can be found out, 40 ± 2 ℃ of temperature, under relative humidity RH 75 ± 5% conditions, in 6 months of having investigated, the every investigation index of product of embodiment of the present invention 1-3 all, without significantly changing and all meet the regulation of version < < Chinese Pharmacopoeia > > in 2010, has good stability.Aforementioned stable test data also shows, the product of embodiment of the present invention 1-3 is more stable with respect to the product of comparative example 1, and quality is better than existing prescription (comparative example 1).The preferred prescription of the embodiment of the present invention 2 wherein.
test example 5 long-term stable experiments
Get the sample that comparative example 1 and embodiment 1-3 obtain, 25 ± 2 ℃ of temperature, under the condition of relative humidity RH60 ± 10%, place and carry out long term test.In each sampling at the 0th, 3,6,9,12 the end of month once, according to investigation method, every investigation project is detected, with result comparison in 0 month.The results are shown in Table 5.
Table 5
By above test data, can be found out, 25 ± 2 ℃ of temperature, under relative humidity RH 60 ± 10% conditions, in 12 months of having investigated, the every investigation index of product of embodiment of the present invention 1-3 all, without significantly changing and all meet the regulation of version < < Chinese Pharmacopoeia > > in 2010, has good stability.Aforementioned stable test data also shows, the product of embodiment of the present invention 1-3 is more stable with respect to the product of comparative example 1, and quality is better than existing prescription (comparative example 1).The preferred prescription of the embodiment of the present invention 2 wherein.
Test example 6 anaphylaxis, zest and hemolytic test
1, material
Experimental animal:
New zealand rabbit, body weight 1.9～2.1kg, purchased from Hainan Province's medical experiment animal center, the quality certification number: No. 30-041st, the moving word of doctor;
Albino guinea pig, male and female dual-purpose (female without pregnant), body weight 250-340g, purchased from Hubei Province's Experimental Animal Center, the quality certification number: No. 19-101, the moving word of doctor.
Need testing solution:
Aztreonam for injection compositions in embodiment 1 is dissolved in to 0.9% sodium chloride injection (purchased from Hainan Dong Lianchangfu pharmaceutical factory), the need testing solution 3 that the need testing solution 2 that the need testing solution 1 that compound concentration is 13.3mg/mL respectively, concentration are 4.0mg/ml and concentration are 40.0mg/mL.
10% bovine serum albumin: appropriate bovine serum albumin powder is prepared in proportion with 0.9% sodium chloride injection.
2, method
Vein blood vessel irritation test, muscle irritation test, hemolytic test and systemic allergy test test method are with reference to < < herbal pharmacology experimental methodology > > [M], Qi Chen chief editor, Beijing people's health 1993:163-168 of publishing house, and < < pharmacological experimental methodology > > [M], Xu Shuyun etc. write, Beijing people's health publishing house, 1994:223-224.
3, result
1) vein blood vessel irritation test
3 new zealand rabbits are auricular vein instillation every day need testing solution 2 for three days on end, and dropped amount is that 40.3mg/kg(is clinical application amount rabbit dose,equivalent), by the naked eye, its left side ear is showed no obvious hyperemia and edema, and vessel boundary is clear.Microscopy result shows, auricular vein inner membrance is complete, smooth, and wall of vein and inner membrance have no inflammatory reaction, and tube chamber is without thrombosis.
2) muscular irritation test
3 new zealand rabbit quadriceps femoris injection need testing solutions 3, injection volume is 1mL/ pleural muscle meat, and perusal has no the irritant reaction such as hyperemia, edema, degeneration or necrosis, and reaction score value summation is 0, and microscopy result is there are no pathologic reactions such as inflammation.
3) hemolytic test
Get Rabbit Heart blood 10mL, with bead, remove fibrin, make into defibrinated blood, in immigration graduated centrifuge tube, add normal saline, shake up, centrifugal 10min(1500r/min), supernatant inclines, add again normal saline, centrifugal, till being repeatedly washed till supernatant and being water white transparency, take out hemocyte, with normal saline dilution, become 2% Sanguis Leporis seu oryctolagi cell suspension.Erythrocyte is placed in to the sucrose solution of low ion concns, is distributed in 7 test tubes, each manages solution in 37 ℃ of insulations 4 hours.Wherein 5 test tubes add respectively 0.1,0.2,0.3,0.4, the need testing solution 1 of 0.5mL, one in another two adds distilled water.Through observing, positive control pipe (adding distilled water) becomes red clear solution, and showing has haemolysis; Each pipe of blank pipe and dosing is showed no haemolysis, and erythrocyte all sinks, and supernatant achromatism and clarity, has no flocculent deposit, shows that need testing solution 1 is 0.1,0.2,0.3,0.4, during 0.5mL dosage, to erythrocyte without haemolysis and agglutination.
4) systemic allergy test
Albino guinea pig, after lumbar injection need testing solution 3 sensitization, excited in the 14th day, and that Cavia porcellus is showed no is excited uneasy, grab nose, perpendicular hair, cough, dyspnea, tremble and the obvious symptoms of allergic such as dead, and anaphylaxis progression is 0.After Albino guinea pig (injection 10% bovine serum albumin solution) sensitization as positive control, excite animal dead.The above results shows that concentration is that need testing solution 3 does not produce obvious systemic anaphylaxis.
As can be seen here, aztreonam for injection aseptic composite provided by the invention to rabbit auricular vein blood vessel and quadriceps femoris all without obvious stimulation effect, can not cause erythrocyte generation haemolysis and aggregation, and can not produce systemic anaphylaxis to Albino guinea pig, therefore can use safely clinically.
Claims (10)
1. containing a medicinal composition for injections for aztreonam, described compositions is comprised of beta crystal aztreonam, L-arginine and natrium carbonicum calcinatum.
2. pharmaceutical composition according to claim 1, wherein, described compositions is comprised of 1 weight portion beta crystal aztreonam, 0.4 ~ 0.6 weight portion L-arginine and 0.05 ~ 0.08 weight portion natrium carbonicum calcinatum.
3. pharmaceutical composition according to claim 1, wherein, described compositions is comprised of 1 weight portion beta crystal aztreonam, 0.6 weight portion L-arginine and 0.05 weight portion natrium carbonicum calcinatum.
4. pharmaceutical composition according to claim 1, wherein, described compositions is comprised of 1 weight portion beta crystal aztreonam, 0.5 weight portion L-arginine and 0.065 weight portion natrium carbonicum calcinatum.
5. pharmaceutical composition according to claim 1, wherein, described compositions is comprised of 1 weight portion beta crystal aztreonam, 0.4 weight portion L-arginine and 0.08 weight portion natrium carbonicum calcinatum.
6. a method of preparing the pharmaceutical composition described in any one in claim 1 to 5, comprises and is prepared as follows technique:
A. beta crystal aztreonam and L-arginine are joined in the mixer in Bai Ji toilet and mixed homogeneously;
B. natrium carbonicum calcinatum is joined in the mixture of step a to mix homogeneously in the mixer in Bai Ji toilet;
C. mixed qualified by intermediate check content after, carry out aseptic subpackaged, tamponade, roll lid, lamp inspection and packing, obtain.
7. method according to claim 6, wherein, the incorporation time in described step a and/or step b is 3 hours.
8. method according to claim 6, wherein, described step c adopts secondary to fill nitrogen technique in aseptic subpackaged process, and the remaining oxygen content in medicine bottle is controlled at below 1%v/v.
9. the purposes in the medicine for the treatment of the infection due to aerobic gram-negative bacteria by sensitivity according to the pharmaceutical composition described in any one in claim 1 to 5 in preparation.
10. purposes according to claim 9, wherein, one or more in the described skin soft-tissue infection that comprises urinary tract infection, lower respiratory infection, septicemia, intra-abdominal infection, gynecological infection and postoperative wound and burn, ulcer by the infection due to the aerobic gram-negative bacteria of sensitivity.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN105055407A (en) * | 2015-09-15 | 2015-11-18 | 青岛华之草医药科技有限公司 | Medicine aztreonam composition for curing infectious diseases |
| CN105125538A (en) * | 2015-08-05 | 2015-12-09 | 青岛蓝盛洋医药生物科技有限责任公司 | Medicinal aztreonam composition for treating bacterial infection |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN105125538A (en) * | 2015-08-05 | 2015-12-09 | 青岛蓝盛洋医药生物科技有限责任公司 | Medicinal aztreonam composition for treating bacterial infection |
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