CN104367636A - Oil-in-water type compound ceftriaxone nanoemulsion antimicrobial medicine - Google Patents
Oil-in-water type compound ceftriaxone nanoemulsion antimicrobial medicine Download PDFInfo
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- CN104367636A CN104367636A CN201410561144.4A CN201410561144A CN104367636A CN 104367636 A CN104367636 A CN 104367636A CN 201410561144 A CN201410561144 A CN 201410561144A CN 104367636 A CN104367636 A CN 104367636A
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Abstract
The invention relates to an oil-in-water type compound ceftriaxone nanoemulsion antimicrobial medicine which is a nanoemulsion preparation taking ceftriaxone and an aqueous extract of lotus leaves as effective components. The medicine is prepared from the following components in parts by weight: 1 to 25 parts of ceftriaxone, 15 to 35 parts of surfactant, 0 to 20 parts of cosurfactant, 1 to 20 parts of aqueous extract of lotus leaves, 1 to 20 parts of oil and 20 to 70 parts of distilled water. The medicine is good in pharmacological action and excellent in antimicrobial effect via combination of the ceftriaxone and the aqueous extract of lotus leaves, and is very simple in preparation method and easy to popularize.
Description
Technical field
The invention belongs to field of medicaments, particularly relate to a kind of compound recipe ceftriaxone antibacterials, be specially a kind of oil-in-water type compound ceftriaxone nanometer breast antibacterials.
Background technology
Ceftriaxone refers generally to ceftriaxone sodium, ceftriaxone sodium (Ceftriaxone Sodium), have another name called rocephin, chemical name is (6R, 7R)-7-[[(2-amino-4-thiazolyl) (methoxyimino) acetyl] is amino]-8-oxo-3-[[1, 2, 5, 6-tetrahydrochysene-2-methyl-5, 6-dioxo-1, 2, 4-triazine-3-base) sulfo-] methyl]-5-sulfo--1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid disodium salt, it is Third generation Cephalosporins antibiotic, to many gram positive bacterias, negative bacterium and anaerobe have bactericidal action.The structure of methoxyl group imines can improve the stability be the beta lactamase secreted by gram negative bacteria, and this special stability increases ceftriaxone to the resistance of against gram-negative bacteria; Replace the acetyl that cefotaxime is easy to be hydrolyzed, there is the azo ion ketone of metabolic stability one end of ceftriaxone.Be widely used in the respiratory tract infection to ceftriaxone sensitivity, urinary system infection clinically, comprise pyelonephritis and drench inflammation, meningitis, burn infection, postoperative infection, osteoarthrosis, soft tissue, skin and wound infection, abdominal infection etc. and average of operation periods infection mitigation, at present as the First Line medicine for the treatment of gonorrhea.
Ceftriaxone is a kind of orange-yellow crystal powder, and water soluble is only soluble in methanol and is dissolved in ethanol very less.Medicine mostly is intravenous administration or intramuscular injection, and after intravenous administration, local response has phlebitis, and intramuscular injection then can cause having an intense pain, and also may have the anaphylaxiss such as erythra, pruritus, heating, bronchospasm and serum sickness; Oral ceftriaxone can from gastrointestinal absorption, but absorb not exclusively, drug-eluting speed is slow, biological rate rate variance, time oral, ptyalin makes pharmaceutical agent moiety degraded inactivation, meanwhile, there is the untoward reaction of the digestive tract reactions such as diarrhoea, Nausea and vomiting, stomachache, colitis, jaundice, flatulence, dysgeusia and dyspepsia.In addition, antibiotic a large amount of use is also the immediate cause causing drug tolerance of strain to increase.Based on above-mentioned various problems, the present invention is intended to improve the peanut ability of body to this medicine by changing dosage form, reduces untoward reaction rate, improves its therapeutic effect.
Summary of the invention
The object of the present invention is to provide a kind of oil-in-water type compound ceftriaxone nanometer breast.
For achieving the above object, the technical scheme that the present invention proposes is:
Oil-in-water type compound ceftriaxone nanometer breast antibacterials, its effective ingredient is ceftriaxone and Folium Nelumbinis water extract.
The parts by weight of described oil-in-water type compound ceftriaxone nanometer breast antibacterials effective ingredient consist of: ceftriaxone 1 ~ 25 part, Folium Nelumbinis water extract 1 ~ 20 part.
The parts by weight of described oil-in-water type compound ceftriaxone nanometer breast antibacterials consist of: ceftriaxone 1 ~ 25 part, 15 ~ 35 parts, surfactant, cosurfactant 0 ~ 20 part, Folium Nelumbinis water extract 1 ~ 20 part, oil 1 ~ 20 part, distilled water 20 ~ 70 parts.
Preferably, the parts by weight of described oil-in-water type compound ceftriaxone nanometer breast antibacterials consist of: ceftriaxone 5 ~ 15 parts, 20 ~ 30 parts, surfactant, cosurfactant 1 ~ 12 part, Folium Nelumbinis water extract 1 ~ 15 part, oil 5 ~ 20 parts, distilled water 25 ~ 65 parts.
Preferably, the parts by weight of described oil-in-water type compound ceftriaxone nanometer breast antibacterials consist of: ceftriaxone 5.1 parts, 28 parts, surfactant, cosurfactant 4 parts, Folium Nelumbinis water extract 7.6 parts, oil 15 parts, distilled water 40.3 parts.
In the present invention, described surfactant is polyoxyl 40 hydrogenated castor oil (RH-40), castor oil polyoxyethylene ether 40(EL-40), in Tween 80 or PLURONICS F87 any one or with the mixture of span80.
In the present invention, described cosurfactant is any one or a few the mixture in dehydrated alcohol, 1,2-PD, PEG400 or glycerol.
In the present invention, described oil is any one in soybean oil, cinnamic aldehyde, Ethyl formate, ethyl oleate, fatty glyceride, Oleum Ricini, Oleum Brassicae campestris, linoleic acid, ethyl n-butyrate., isopropyl myristate, ethyl acetate or oleic acid.
Preferably, described oil is ethyl n-butyrate..
Based on the oil-in-water type compound ceftriaxone nanometer breast antibacterials of above-mentioned formula, its preparation method is: accurately take ceftriaxone, surfactant and cosurfactant, stir under room temperature (25 DEG C) condition, then slowly the distilled water of Folium Nelumbinis water extract has been dissolved in instillation wherein; Along with the increase of the distillation water yield, system stickiness increases, when the amount adding distilled water makes system become oil-in-water type nano-emulsion from Water-In-Oil, system viscosity is thinning from the state of most thickness, and namely what now produce is water white compound recipe ceftriaxone nanometer milk product.
In the said goods, the diameter of aspirin particle of Folium Nelumbinis water extract, ceftriaxone antimicrobial nano breast is between 35.7 ~ 74.1nm, and mean diameter is 52.6nm, can directly take, also can through encapsulated or through process such as lyophilized powder technology.
Nano-emulsion (nanoemulsion), also known as microemulsion (microemulsion), is by spontaneous transparent or semitransparent homodisperse systems formed such as water, oil, surfactant and cosurfactants.In general, nano-emulsion is divided into three types, i.e. oil-in-water type nano-emulsion (O/W), water-in-oil type nanoemulsion (W/O) and bicontinuous nano-emulsion (B.C).Nano-emulsion has the unrivaled advantage of other preparations many: 1. for isotropic transparency liquid, belongs to thermodynamically metastable fixed system, through pressure sterilizing or centrifugally can not make it layering; 2. technique is simple, and preparation process does not need special installation, can spontaneously be formed, and nano-emulsion particle diameter is generally 1 ~ 100nm; 3. viscosity is low, can reduce pain during injection; 4. there is slow release and targeting; 5. improve the dissolubility of medicine, reduce medicine enzymolysis in vivo, can be formed the protective effect of medicine and improve the absorption of gastrointestinal tract to medicine, improving the bioavailability of medicine.
In the present invention, human body is to the transhipment of ceftriaxone medicine and absorb extremely difficult, nano-emulsion substrate provides good dissolving environment for ceftriaxone, can through Lymphatic time oral, overcome first pass effect and molecule by barrier during gastrointestinal tract, greatly improve the dissolubility of ceftriaxone, reduce medicine first pass effect in vivo, promote ceftriaxone gastrointestinal absorption; In addition, the combination of fat-soluble ceftriaxone and water solublity Folium Nelumbinis water extract, while maintaining ceftriaxone drug effect, also improves the antibacterial ability of Folium Nelumbinis water extract, makes antibacterial more stable, better effects if.
In Folium Nelumbinis water extract, the English name of nuciferine: lotus leaf p.e. latin name: Nelumbo Nucifera Gaern. molecular formula: C
19h
21o
2, molecular weight: 295.376, CAS No.:475-83-2.Effective ingredient: the main chemical compositions of Folium Nelumbinis water extract has lotus leaf alkaloid, lotus flavone, citric acid, oxalic acid etc.There is clearing away summer-heat, sending up the lucid YANG, effect of cooling blood for hemostasis, be usually used in summer-heat excessive thirst, diarrhea due to summer heat and dampness, insufficiency of the spleen, metrorrhagia of having blood in stool; Burnt FOLIUM NELUMBINIS astringent therapy removing stasis to stop bleeding, is usually used in hemorrhage and puerperal blood faints.Pharmacological research shows, Folium Nelumbinis has the effects such as diuresis relieving constipation, logical intestinal poison, blood fat reducing oil removing, clearing away summer-heat be antipyretic, obviously can reduce triglyceride and cholesterol level in serum, have the health-care effect of adjusting blood lipid.Folium Nelumbinis water extract has good killing action to staphylococcus aureus, bacillus subtilis and escherichia coli etc.
Folium Nelumbinis water extract extracts by following means: to shine the Folium Nelumbinis of dry grinding for raw material, adopts cellulase pretreatment, dilute hydrochloric acid lixiviate, ultrasonic assistant extraction, merge extractive liquid, alkalization adjust pH, concentration and evaporation water is to the extractum of proportion D=1.15, cool, 10 times amount chloroforms stir, stratification, aqueous phase continuous extraction three times, combined chloroform phase also reclaims chloroform, and extractum dusts, and pulverizes, mixing, packs and obtains Folium Nelumbinis water extract.
The present invention adds bland cosurfactant as ethanol, 1 in medicine, 2-propylene glycol, glycerol or PEG400, except hydrotropy effect, more can the hydrophile-lipophile balance value (HLB) of adjustment form surface-active agent, oil water interfacial tension is reduced further, increases profit and the rigidity of limitans.Cosurfactant is incorporated in interfacial film, promotes the formation of radius of curvature very membranelle, expands the newborn district area of nano-emulsion, improves the activity of nano-emulsion further, improves the effect that water soluble drug is combined with fat-soluble medicine.
Compared with prior art, the invention has the advantages that:
(1) compound recipe ceftriaxone nanometer breast emulsion particle diameter narrow distribution of the present invention, system is transparent, good stability; There is lower surface tension, there is good mobility, taking convenience;
(2) ceftriaxone and Folium Nelumbinis water extract compound, fungistatic effect is better;
(3) first pass effect can be overcome after oral administration, promote the gastrointestinal absorption of medicine, Folium Nelumbinis water extract and ceftriaxone nano-particle can be engulfed by reticuloendothelial cell rapidly, medicine rapid-onset can be made, and maintain constant blood drug level and pharmacodynamics effect, improve the bioavailability of medicine, strengthen drug effect, the consumption reducing medicine and access times, curative effect is better, drug effect is more stable;
(4) preparation method of nano-emulsion is very simple, consumes energy low, impels medicine to be easier to promote;
(5) preparation has good mobility, and can directly use as oral liquid, also can utilize encapsulated or be lyophilized into powder through lyophilized powder technology, application mode is enriched flexibly.
Accompanying drawing explanation
Fig. 1 is the transmission electron microscope photo of oil-in-water type compound ceftriaxone nanometer breast antibacterials in embodiment 1;
Fig. 2 is the grain size distribution of oil-in-water type compound ceftriaxone nanometer breast antibacterials in embodiment 1.
Detailed description of the invention
Below in conjunction with concrete preferred embodiment, the invention will be further described, but protection domain not thereby limiting the invention.
Case study on implementation
Table 1 case study on implementation formula
| Embodiment | Ceftriaxone/g | Folium Nelumbinis water extract/g | Surfactant/g | Cosurfactant/g | Oil/g | Water/g |
| 1 | 5.1 | 7.6 | 28（EL-40） | 4(ethanol) | 15(ethyl n-butyrate .) | 40.3 |
| 2 | 7.5 | 6.9 | 27（EL-40） | 3(1,2-propylene glycol) | 14(fatty glyceride) | 41.6 |
| 3 | 4.5 | 6.5 | 28（RH-40） | 5(glycerol) | 16(linoleic acid) | 40 |
| 4 | 7.2 | 2.2 | 32（RH-40） | 4(ethanol) | 14(oleic acid) | 40.6 |
| 5 | 7.5 | 2.5 | 25(Tween 80) | 12(glycerol) | 15(Ethyl formate) | 38 |
| 6 | 6.5 | 9.8 | 20(Tween 80) | 4(PEG400) | 10(ethyl acetate) | 49.7 |
Preparation method: accurately take ceftriaxone, surfactant and cosurfactant, stirs under room temperature (25 DEG C) condition, and then slowly the distilled water of Folium Nelumbinis water extract has been dissolved in instillation wherein; Along with the increase of the distillation water yield, system stickiness increases, when the amount adding distilled water makes system become oil-in-water type nano-emulsion from Water-In-Oil, system viscosity is thinning from the state of most thickness, and namely what now produce is water white compound recipe ceftriaxone nanometer milk product.
Analysis of cases
(1) particle diameter is observed
Observe the nano-emulsion product of embodiment 1 ~ 6 under transmission electron microscope, find that drop is that class is spherical, good dispersion, without adhesion.Fig. 1 is the transmission electron microscope photo of embodiment 1 product.Utilize the nano-emulsion of Malvern Particle Size Analyzer to embodiment 1 to detect, testing result as shown in Figure 2.As can be seen from Figure 2, nano-emulsion diameter Distribution is between 35.7 ~ 74.1nm, and mean diameter is 52.6nm.
(2) stability test
The nano-emulsion product of Example 1 ~ 6 carries out high speed centrifugation test, photo-stability testing, temperature stability test etc. respectively, observes the stability of product nano-emulsion of the present invention, has been confirmed whether that the wild effects such as layering, muddiness or crystal precipitation occur.
1. high speed centrifugation test: get the outturn sample for preparing in right amount in centrifuge tube, with centrifugal 10 min of the rotating speed of 15 000r/min, after centrifugal test, sample still keep centrifugal before clear, have no the wild effects such as layering, muddiness or crystal precipitation.
2. photo-stability testing: the outturn sample for preparing in right amount loaded in transparent good colourless, transparent vial, sealing, is positioned over 10d under normal lighting conditions, observes respectively at 1d, 2d, 4d, 6d, 8d, 10d sampling.Result shows that the every increment product of sample all keep clear, has no the wild effects such as layering, muddiness or crystal precipitation.
3. temperature stability test: the outturn sample for preparing in right amount loaded in the good flint glass bottle of transparency, sealing, is positioned over 4 DEG C, keeps sample in room temperature (25 DEG C) and 40 DEG C three and investigate each 30d, every 5d sampling observation under temperature conditions.Result shows, sample all keeps clear under these three kinds of temperature conditions, has no the wild effects such as layering, muddiness or crystal precipitation.
4. long-term stable experiment: 3 batches of nano-emulsions are sealed in Brown Glass Brown glass bottles and jars only, be placed in (25 ± 2) DEG C, relative humidity (60 ± 5) % condition lower 12 months, sample respectively at when 0,3,6,9 and 12 months, investigate character and the changes of contents of nano-emulsion, and list of references statistical analysis technique, the effect duration of calculation sample.Result of the test shows under long term test condition, and the outward appearance of sample keeps clear and bright, homogeneous always, has no the phenomenons such as layering, complexion changed, flocculation and breakdown of emulsion; Folium Nelumbinis water extract in system and ceftriaxone content extend in time and reduce gradually, the equation of linear regression that its content-time changing curve provides, and the effect duration calculating sample is 37.15 months (with time short person for standard).
(3) toxicity test
With commercially available Folium Nelumbinis water extract tablet (USP nuciferine) for contrast agents, carry out acute toxicity test according to new drug nonphosphorylated neurofilament H method: repeated dose toxicity test, genetic toxicity test (comprising Ames test, Micronuclei In The Mouse Bone Marrow test, the test of In vitro culture mammalian cell chromosome mutation), reproductive toxicity test (General Reproductiv e Toxicity Assessment, sensitive period to teratogenic agent toxicity test, perinatal toxicity are tested), carcinogenic test, immunotoxicity test and Local irritation study, result of the test is as follows:
To Mouse Acute Toxicity experiment conclusion: contrast with commercially available Folium Nelumbinis water extract tablet, compound recipe ceftriaxone nanometer breast does not occur measuring interior untoward reaction and death.
The result of the genetic toxicity tests such as Salmonella reversion test, mouse inbred strain and testis chromosomal aberration test is feminine gender.
The result that rat 30d feeds product of the present invention shows: contrast with commercially available Folium Nelumbinis water extract tablet, within experimental period, in the metering of compound recipe ceftriaxone nanometer breast, each test group of animals growth promoter is good, the indexs such as body weight, food ration, routine blood test, blood biochemistry, organ coefficient are all within normal range, and histopathologic examination is no abnormality seen also.
Long term toxicity test conclusion: contrast with commercially available Folium Nelumbinis water extract tablet, within experimental period, in the metering of compound recipe ceftriaxone nanometer breast, this medicine has no rat untoward reaction for three months at continuous gastric infusion, every Index for examination is all within normal range, and its main organs of pathologic finding and target organ are showed no the toxic pathological change that this guiding drug rises.
With commercially available ceftriaxone tablet (Ceftriaxone) for contrast agents, carry out acute toxicity test according to new drug nonphosphorylated neurofilament H method: repeated dose toxicity test, genetic toxicity test (comprising Ames test, Micronuclei In The Mouse Bone Marrow test, the test of In vitro culture mammalian cell chromosome mutation), reproductive toxicity test (General Reproductiv e Toxicity Assessment, sensitive period to teratogenic agent toxicity test, perinatal toxicity are tested), carcinogenic test, immunotoxicity test and Local irritation study, result of the test is as follows:
To Mouse Acute Toxicity experiment conclusion: contrast with commercially available ceftriaxone tablet, compound recipe ceftriaxone nanometer breast does not occur measuring interior untoward reaction and death.
The result of the genetic toxicity tests such as Salmonella reversion test, mouse inbred strain and testis chromosomal aberration test is feminine gender.
The result that rat 30d feeds product of the present invention shows: contrast with commercially available ceftriaxone tablet, within experimental period, in the metering of compound recipe ceftriaxone nanometer breast, each test group of animals growth promoter is good, the indexs such as body weight, food ration, routine blood test, blood biochemistry, organ coefficient are all within normal range, and histopathologic examination is no abnormality seen also.
Long term toxicity test conclusion: contrast with commercially available ceftriaxone tablet, within experimental period, in the metering of compound recipe ceftriaxone nanometer breast, this medicine has no rat untoward reaction for three months at continuous gastric infusion, every Index for examination is all within normal range, and its main organs of pathologic finding and target organ are showed no the toxic pathological change that this guiding drug rises.
(4) pharmacokinetics
Result of the test shows, Folium Nelumbinis water extract, ceftriaxone antimicrobial nano breast absorbed following oral administration about 79%, absorbs not by the impact of food in gastrointestinal tract.After oral this product, about 1 hour blood drug level reaches peak, and effective half-life is 12 hours.After oral this product, antibacterial action was in 1 hour, and within 4 hours, reach peak, antibacterial action can maintain more than 24 hours; Through renal excretion, oral dose about 94% with this product or Folium Nelumbinis water extract draw be present in urine and feces in, without other metabolites; When glomerular filtration rate reduces to below 30ml per minute, peak time, reach steady state time and all postpone; The administration of this nano-emulsion was distributed widely in whole body after 20 minutes, and liver, kidney, harmonization of the stomach small intestinal drug level are the highest, and after 24h, this nano-emulsion is combined with Angiotensin-Converting and reaches stable state, and final Increased Plasma Half-life is 35 hours, primarily of renal excretion.
(5) test of pesticide effectiveness
Table 2 extracorporeal bacteria inhibitor test
In this test, get the escherichia coli (be labeled as respectively and mix sense bacterium source A, B, C, D) of separate sources respectively, be inoculated in ordinary nutritional meat soup and carry out cellar culture, get broth culture and carry out bacteriostatic test with test group medicinal liquid respectively, observe antibacterial situation and measure the size of inhibition zone.Result shows, composite nano-emulsion of the present invention has better fungistatic effect than ceftriaxone, Folium Nelumbinis water extract and their simple mixtures.
Claims (9)
1. oil-in-water type compound ceftriaxone nanometer breast antibacterials, it is characterized in that, effective ingredient is ceftriaxone and Folium Nelumbinis water extract.
2. oil-in-water type compound ceftriaxone nanometer breast antibacterials according to claim 1, it is characterized in that, the parts by weight of described effective ingredient consist of: ceftriaxone 1 ~ 25 part, Folium Nelumbinis water extract 1 ~ 20 part.
3. oil-in-water type compound ceftriaxone nanometer breast antibacterials according to claim 2, it is characterized in that, the parts by weight of described nano-emulsion antibacterial drug consist of: ceftriaxone 1 ~ 25 part, 15 ~ 35 parts, surfactant, cosurfactant 0 ~ 20 part, Folium Nelumbinis water extract 1 ~ 20 part, oil 1 ~ 20 part, distilled water 20 ~ 70 parts.
4. oil-in-water type compound ceftriaxone nanometer breast antibacterials according to claim 3, it is characterized in that, the parts by weight of described nano-emulsion antibacterial drug consist of: ceftriaxone 5 ~ 15 parts, 20 ~ 30 parts, surfactant, cosurfactant 1 ~ 12 part, Folium Nelumbinis water extract 1 ~ 15 part, oil 5 ~ 20 parts, distilled water 25 ~ 65 parts.
5. oil-in-water type compound ceftriaxone nanometer breast antibacterials according to claim 4, it is characterized in that, the parts by weight of described nano-emulsion antibacterial drug consist of: ceftriaxone 5.1 parts, 28 parts, surfactant, cosurfactant 4 parts, Folium Nelumbinis water extract 7.6 parts, oil 15 parts, distilled water 40.3 parts.
6. according to claim 3 ~ 5 arbitrary described oil-in-water type compound ceftriaxone nanometer breast antibacterials, it is characterized in that, described surfactant be in polyoxyl 40 hydrogenated castor oil, castor oil polyoxyethylene ether 40, Tween 80 or PLURONICS F87 any one or with the mixture of span80.
7. according to claim 3 ~ 5 arbitrary described oil-in-water type compound ceftriaxone nanometer breast antibacterials, it is characterized in that, described cosurfactant is one in ethanol, 1,2-PD, PEG400 or glycerol or combination in any.
8. according to claim 3 ~ 5 arbitrary described oil-in-water type compound ceftriaxone nanometer breast antibacterials, it is characterized in that, described grease separation is from soybean oil, cinnamic aldehyde, Ethyl formate, ethyl oleate, fatty glyceride, Oleum Ricini, Oleum Brassicae campestris, linoleic acid, ethyl n-butyrate., isopropyl myristate, ethyl acetate and oleic acid.
9. oil-in-water type compound ceftriaxone nanometer breast antibacterials according to claim 8, it is characterized in that, described oil is ethyl n-butyrate..
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106420612A (en) * | 2016-11-30 | 2017-02-22 | 河南牧翔动物药业有限公司 | Cefovecin microemulsion and preparation method thereof |
| CN113855680A (en) * | 2021-09-02 | 2021-12-31 | 四川农业大学 | Application of cinnamic aldehyde combined with ceftriaxone sodium |
-
2014
- 2014-10-21 CN CN201410561144.4A patent/CN104367636A/en active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106420612A (en) * | 2016-11-30 | 2017-02-22 | 河南牧翔动物药业有限公司 | Cefovecin microemulsion and preparation method thereof |
| CN106420612B (en) * | 2016-11-30 | 2019-07-26 | 河南牧翔动物药业有限公司 | A kind of cephalo dimension star micro emulsion and preparation method thereof |
| CN113855680A (en) * | 2021-09-02 | 2021-12-31 | 四川农业大学 | Application of cinnamic aldehyde combined with ceftriaxone sodium |
| CN113855680B (en) * | 2021-09-02 | 2023-11-03 | 四川农业大学 | Application of cinnamaldehyde combined with ceftriaxone sodium |
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Application publication date: 20150225 |