CN113171337B - Veterinary cefquinome nanogel and preparation method thereof - Google Patents
Veterinary cefquinome nanogel and preparation method thereof Download PDFInfo
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- CN113171337B CN113171337B CN202110458056.1A CN202110458056A CN113171337B CN 113171337 B CN113171337 B CN 113171337B CN 202110458056 A CN202110458056 A CN 202110458056A CN 113171337 B CN113171337 B CN 113171337B
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
- A61K31/545—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine
- A61K31/546—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine containing further heterocyclic rings, e.g. cephalothin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0041—Mammary glands, e.g. breasts, udder; Intramammary administration
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/14—Drugs for genital or sexual disorders; Contraceptives for lactation disorders, e.g. galactorrhoea
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y40/00—Manufacture or treatment of nanostructures
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
The invention discloses a veterinary cefquinome nanogel and a preparation method thereof, wherein the veterinary cefquinome nanogel is composed of the following raw materials in parts by mass: 3-10 parts of a cationic drug carrier; 5-15 parts of an anionic drug carrier; 0.25-2 parts of an ionic crosslinking agent; 40-95 parts of distilled water; 0.5-3 parts of cefquinome. Has the advantages that: by combining the advantages of the nanotechnology and the gel technology, the intracellular transport capacity of the antibacterial agent is enhanced, and the antibacterial activity to pathogenic bacteria is enhanced; the manufacturing process is simple and convenient for production; can reduce the clinical use amount of the cefquinome, thereby reducing the treatment cost of the mastitis of the dairy cattle.
Description
Technical Field
The invention relates to the technical field of veterinary drug preparation, and in particular relates to a veterinary cefquinome nano gel and a preparation method thereof.
Background
Cefquinome as the fourth generation cephalosporin antibiotics has wide antibacterial spectrum and strong antibacterial activity, is suitable for parenteral administration, is particularly suitable for treating mastitis of dairy cows, and can be used for inhibiting common gram-positive and gram-negative bacteria, such as escherichia coli, klebsiella, pasteurella, proteus, salmonella, staphylococcus aureus, streptococcus, erysipelothrix rhusiopathiae and the like.
Staphylococcus aureus is an important pathogenic bacterium causing mastitis of dairy cows, is a facultative intracellular parasitic bacterium, is more easily taken by cells after being developed into a microcolony variant strain from a normal state under the action of an antibacterial medicament, and survives in host cells in the mode of the microcolony variant strain to form a bacterial storage place. However, the antibacterial agent is difficult to remove the bacteria due to the biological barrier effect of the cell membrane. Meanwhile, the sub-therapeutic dosage of the antibacterial drug is easier to enable the microcolony variant to generate drug resistance. More importantly, the microcolony variant, as a persistent pathogen pool, may cause long-term and repeated infections in cows, often resulting in clinical failure in treatment of mastitis in cows.
Disclosure of Invention
The invention aims to solve the problems and provide a veterinary cefquinome nanogel, and a preferable technical scheme in various technical schemes provided by the invention comprises the following steps: reasonable formula, simple preparation process, stable and safe quality and other technical effects, which are explained in detail below.
In order to achieve the purpose, the invention provides the following technical scheme:
the invention provides a veterinary cefquinome nanogel which is prepared from the following raw materials in parts by weight:
3-10 parts of a cationic drug carrier;
5-15 parts of an anionic drug carrier;
0.25-2 parts of an ionic crosslinking agent;
40-95 parts of distilled water;
0.5-3 parts of cefquinome.
Preferably, the cationic drug carrier is one or a combination of two or more of chitosan, gelatin, dimethyl diallyl ammonium chloride, ethylene imine, acryloyloxyethyl trimethyl ammonium chloride and vinyl pyrrolidone.
Preferably, the anionic drug carrier is one or a combination of two or more of carboxymethyl chitosan, carbomer, sodium alginate, acrylic acid, methacrylic acid and styrene sulfonic acid.
Preferably, the ionic crosslinking agent is CaCl2One or a combination of two or more of EDTA-Ca, glutaraldehyde, sodium tripolyphosphate and NaCl.
Preferably, the feed consists of the following raw materials in parts by mass:
4-8 parts of a cationic drug carrier;
6-10 parts of an anionic drug carrier;
0.4-1 part of ionic crosslinking agent;
60-90 parts of distilled water;
0.8-2 parts of cefquinome.
Preferably, the feed consists of the following raw materials in parts by mass:
6 parts of a cationic drug carrier;
6 parts of an anionic drug carrier;
0.8 part of ionic crosslinking agent;
86 parts of distilled water;
1.2 parts of cefquinome.
A preparation method of cefquinome nanogel for livestock comprises the following steps:
s110, dividing distilled water into two parts, namely distilled water 1 and distilled water 2, adding a cationic drug carrier into the distilled water 1, and heating to dissolve the cationic drug carrier to obtain a solution 1;
s120, adding cefquinome into the solution 1, and uniformly mixing to obtain a solution 2;
s130, adding an ionic cross-linking agent into the solution 2, and uniformly mixing to obtain a solution 3;
s140, adding the anionic drug carrier into distilled water 2, and heating for dissolving to obtain a solution 4;
s150, dropwise adding the solution 3 into the solution 4, stirring simultaneously to uniformly mix the two solutions to obtain a premixed solution, and continuously stirring the premixed solution to spontaneously form the nano gel to obtain the cefquinome nano gel.
Preferably, in step S120, the cefquinome is added to the solution 1 in a dropwise manner, and stirring is performed while the cefquinome is added dropwise.
Preferably, in step S130, the ionic crosslinking agent is added to the solution 2 in a dropwise manner, and stirring is performed while the ionic crosslinking agent is added dropwise.
Preferably, the cationic drug carrier is one or the combination of two of gelatin and chitosan; the anionic drug carrier is one or the combination of two of sodium alginate and carboxymethyl chitosan; the ionic crosslinking agent is CaCl2Or one or the combination of two of the sodium tripolyphosphate.
The invention has the beneficial effects that: 1. by combining the advantages of the nanotechnology and the gel technology, the intracellular transport capacity of the antibacterial agent is enhanced, and the antibacterial activity to pathogenic bacteria is enhanced;
2. the manufacturing process is simple and convenient for production;
3. can reduce the clinical use amount of the cefquinome, thereby reducing the treatment cost of the mastitis of the dairy cattle.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below, it is obvious that the drawings in the following description are only some embodiments of the present invention, and for those skilled in the art, other drawings can be obtained according to the drawings without creative efforts.
Fig. 1 is a schematic diagram of appearance characteristics of the veterinary cefquinome nanogel in example 3;
fig. 2 is a schematic diagram of Zeta potential of cefquinome nanogel for veterinary use in example 3;
fig. 3 is a schematic diagram of the particle size distribution of the cefquinome nanogel for veterinary use in example 3;
fig. 4 is a schematic scanning electron microscope of the cefquinome nanogel for veterinary use in example 3;
fig. 5 is a schematic diagram of PCR of veterinary cefquinome nanogel for treatment of infected mouse model in therapeutic trials of mouse model.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the technical solutions of the present invention will be described in detail below. It is to be understood that the described embodiments are merely exemplary of the invention, and not restrictive of the full scope of the invention. All other embodiments, which can be derived by a person skilled in the art from the examples given herein without any inventive step, are within the scope of the present invention.
The invention provides veterinary cefquinome nanogel which is prepared from the following raw materials in parts by weight: 3-10 parts of a cationic drug carrier; 5-15 parts of an anionic drug carrier; 0.25-2 parts of an ionic crosslinking agent; 40-95 parts of distilled water; 0.5-3 parts of cefquinome. The cationic drug carrier is one or a combination of two or more of chitosan, gelatin, dimethyl diallyl ammonium chloride, ethylene imine, acryloyloxyethyl trimethyl ammonium chloride and vinyl pyrrolidone; the anion drug carrier is carboxymethyl chitosan,One or a combination of two or more of carbomer, sodium alginate, acrylic acid, methacrylic acid and styrene sulfonic acid; the ionic crosslinking agent is CaCl2One or a combination of two or more of EDTA-Ca, glutaraldehyde, sodium tripolyphosphate and NaCl.
A preparation method of cefquinome nanogel for livestock comprises the following steps:
s110, dividing distilled water into two parts, namely distilled water 1 and distilled water 2, adding a cationic drug carrier into the distilled water 1, and heating to dissolve the cationic drug carrier to obtain a solution 1;
s120, dripping cefquinome into the solution 1, stirring at a high speed while dripping, and uniformly mixing to obtain a solution 2;
s130, dropwise adding the ionic crosslinking agent into the solution 2, stirring at a high speed while dropwise adding, and uniformly mixing to obtain a solution 3;
s140, adding the anionic drug carrier into distilled water 2, and heating for dissolving to obtain a solution 4;
s150, dropwise adding the solution 3 into the solution 4, stirring simultaneously to uniformly mix the two solutions to obtain a premixed solution, and continuously stirring the premixed solution to spontaneously form the nano gel to obtain the cefquinome nano gel.
The cationic drug carrier is one or the combination of two of gelatin and chitosan; the anionic drug carrier is one or the combination of two of sodium alginate and carboxymethyl chitosan; the ionic crosslinking agent is CaCl2Or sodium tripolyphosphate or a combination of the two.
By combining the nanotechnology and the gel technology, the medicine has good transmembrane and intracellular accumulation capacity, and the intracellular transport capacity and the antibacterial activity to pathogenic bacteria of the antibacterial medicine are enhanced;
the gel material has good biocompatibility and mucosa adhesion, so that the permeability of mammary epithelial cells can be improved, the cefquinome nanogel can be further improved to enter the mammary epithelial cells, the intracellular drug concentration is improved, and the inhibition effect on intracellular staphylococcus aureus microcolony variant strains is hopeful to be improved;
the novel dosage form of nanogel has multiple bacteriostatic mechanisms endowed by antibacterial drugs, nanoparticles, gel materials and the like, and is also favorable for relieving the occurrence of clinical staphylococcus aureus drug resistance.
The specific embodiment is as follows:
example 1:
the composite material consists of the following raw materials in parts by mass: 2.5 parts of chitosan;
5.5 parts of dimethyl diallyl ammonium chloride;
4 parts of carboxymethyl chitosan;
5 parts of carbomer;
CaCl20.4 part;
0.6 part of EDTA-Ca;
80 parts of distilled water;
and 2 parts of cefquinome.
Example 2:
the composite material consists of the following raw materials in parts by mass: 2 parts of chitosan;
5 parts of vinyl pyrrolidone;
3 parts of carboxymethyl chitosan;
4 parts of acrylic acid;
CaCl20.3 part;
0.5 part of NaCl;
84 parts of distilled water;
1.2 parts of cefquinome.
Example 3:
the composite material consists of the following raw materials in parts by mass: 2 parts of chitosan;
4 parts of gelatin;
3 parts of carboxymethyl chitosan;
3 parts of sodium alginate;
CaCl20.3 part;
0.5 part of sodium tripolyphosphate;
86 parts of distilled water;
1.2 parts of cefquinome.
An appropriate amount of the cefquinome nanogel in the embodiments 1 to 3 is taken, and an eye observation is carried out to see whether the gel formed by the gel material and the cross-linking agent generates particles or bubbles with uneven sizes, as shown in table 1, wherein the cefquinome nanogel prepared from the components in the embodiment 3 has good uniformity and is used as a subsequent therapeutic test medicament for a mouse model.
Table 1:
| sample (I) | Uniformity of |
| Example 1 | Non-uniform and varying sized particles |
| Example 2 | Non-uniform, with particles and bubbles of varying sizes |
| Example 3 | Uniform, no particles and bubbles of different sizes |
Treatment trials of mouse models:
1. materials and methods
1.1 medicine cefquinome sulfate injection (10%), cefquinome nanogel (1.2%).
1.2 test animals 120 clean-grade (ICR) Kunming mice, purchased from the animal laboratory site at Tarim university.
1.3 instruments of a laser nanometer particle size analyzer, a heat collection type constant temperature magnetic stirrer, a heating magnetic stirrer, a PCR instrument, a gel imaging system and an electrophoresis instrument.
1.4 test methods
1.4.1 construction of Staphylococcus aureus microcolony variant infected mouse model
Mixing golden yellow grapeAfter the recovery and passage of the microcolony variant strains of the cocci, inoculating 100 mu L of log phase strain in LB broth culture medium of 2mL, incubating for 24h at 37 ℃ to obtain experimental stock solution, and diluting the experimental stock solution to 1.0X 10 by using normal saline9CFU/mL was used as a stock solution. 120 mice (18-22 g) were randomly divided into 4 groups (cefquinome nanogel treatment group, cefquinome injection treatment group, positive control group, negative control group) of 30 mice each. Wherein 0.4mL of standby bacterial liquid is inoculated to each of 1-3 groups of mice respectively for continuous infection for 3 days, and a staphylococcus aureus microcolony variant infected mouse model is constructed. Group 4 mice were not infected (negative control group). Mice infected with the staphylococcus aureus microcolony variant are poor in mental state, less in activity, less in drinking water and diet, shrugging, more in dirt around the anus and high in viscosity, and eyes are closed by cheese-like substances. In the later period of disease, the sick rats are curled into a ball, extremely weak, crowded together and unwilling to move, the perianal area is red and swollen, and the severe sick rats are exhausted and die. And (4) if the control group mice drink normal water and have no symptoms, successfully establishing a staphylococcus aureus microcolony variant infected mouse model.
1.4.2 therapeutic experiments
The group 1 uses cefquinome nanogel to treat infected mice, the group 2 uses cefquinome injection to treat infected mice, the group 3 does not carry out any treatment after infecting the mice with staphylococcus aureus microcolony variant strains, and the group 4 does not carry out any treatment. And observed for treatment. The cefquinome nano gel and the cefquinome injection are used for treating infected mice through intramuscular injection, the treatment is continuously carried out for 3 days, and the treatment condition of the mice within 5 days is observed and recorded.
1.4.3 determination of results
And (3) judging clinical symptoms: after confirming the success of the infection of the mice, the mice were observed 1 time every 3h, during which the mental status of the mice was observed, and the disease and treatment of the mice were recorded. After treatment, the infected mice have less spirit, activity, diet and drinking water and recover to normal, and then the treatment is judged to be successful.
And (3) PCR judgment: taking mouse tissue, culturing bacteria, extracting bacteria by using bacterial genome DNA extraction kitAfter the DNA, PCR amplification was performed. The assay employs a 50 μ L PCR amplification system: ddH2O (40.7. mu.l), Easy Taq enzyme (0.3. mu.l), Easy Taq buffer (5. mu.l), dNTP (1. mu.l), primers nucF and nucR each 1. mu.l. nuc gene amplification procedure: pre-denaturation at 94 deg.C for 5min, denaturation at 94 deg.C for 1min, annealing at 55 deg.C for 30s, extension at 72 deg.C for 1.5min, and performing 30 cycles, and total extension at 72 deg.C for 3.5 min.
1.5 test results
Infected mice have poor mental status, less activity, less drinking water, shrugging on the back, more dirt and greater viscosity around the anus, and cheese-like closed eyes. The sick mice in the later period of the disease are curled into a ball, extremely weak, crowded together and unwilling to move, red and swollen around the anus, exhaustion and death of the severe mice and the like, and then a staphylococcus aureus microcolony variant infected mouse model is successfully established.
After a staphylococcus aureus microcolony variant infected mouse model is treated by cefquinome nanogel and a cefquinome injection, the mouse model has less spirit, activity, diet and drinking water and is recovered to be normal, and the mouse model is judged to be successfully treated from the aspect of clinical symptoms. After PCR amplification, if a 279bp band is not amplified, the treatment is judged to be successful from the PCR perspective.
The above description is only for the specific embodiments of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art can easily conceive of the changes or substitutions within the technical scope of the present invention, and all the changes or substitutions should be covered within the scope of the present invention. Therefore, the protection scope of the present invention shall be subject to the protection scope of the appended claims.
Claims (4)
1. The veterinary cefquinome nanogel is characterized by comprising the following raw materials in parts by weight:
6 parts of a cationic drug carrier;
6 parts of an anionic drug carrier;
0.8 part of ionic crosslinking agent;
86 parts of distilled water;
1.2 parts of cefquinome;
the cationic drug carrier comprises 2 parts of chitosan and 4 parts of gelatin;
the anionic drug carrier comprises 3 parts of carboxymethyl chitosan and sodium alginate respectively;
the ionic crosslinking agent comprises CaCl2 0.3 part and 0.5 part of sodium tripolyphosphate.
2. The preparation method of cefquinome nanogel for veterinary use as claimed in claim 1, which is characterized by comprising the following steps:
s110, dividing distilled water into two parts, namely distilled water 1 and distilled water 2, adding a cationic drug carrier into the distilled water 1, and heating to dissolve to obtain a solution 1;
s120, adding cefquinome into the solution 1, and uniformly mixing to obtain a solution 2;
s130, adding an ionic cross-linking agent into the solution 2, and uniformly mixing to obtain a solution 3;
s140, adding the anionic drug carrier into distilled water 2, and heating and dissolving to obtain a solution 4;
s150, dropwise adding the solution 3 into the solution 4, stirring simultaneously to uniformly mix the two solutions to obtain a premixed solution, and continuously stirring the premixed solution to spontaneously form the nano gel to obtain the cefquinome nano gel.
3. The preparation method of the cefquinome nanogel for veterinary use according to claim 2, wherein the preparation method comprises the following steps: in the step S120, the cefquinome is added to the solution 1 in a dropwise manner, and the cefquinome is stirred while being added dropwise.
4. The preparation method of the cefquinome nanogel for veterinary use according to claim 2, wherein the preparation method comprises the following steps: in the step S130, the ionic cross-linking agent is added to the solution 2 in a dropwise manner, and the solution is stirred while being added dropwise.
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Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6911441B2 (en) * | 2002-12-16 | 2005-06-28 | Akzo Nobel N.V. | Prolonged release pharmaceutical composition |
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Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1686560A (en) * | 2005-04-08 | 2005-10-26 | 武汉大学 | Chitin tetra ammonium salt nano-particle, its preparation method and use |
| CN1793209A (en) * | 2005-12-20 | 2006-06-28 | 武汉大学 | Polyelectrolyte polysaccharose nano paticle and preparation process thereof |
| CN104958251A (en) * | 2015-06-10 | 2015-10-07 | 杨甫进 | Preparation method of hyaluronic acid nanogel |
| CN108778257A (en) * | 2017-01-19 | 2018-11-09 | 中山大学 | Load the nanoparticle and preparation method thereof of therapeutic protein |
| CN109044970A (en) * | 2018-11-08 | 2018-12-21 | 遂宁市中通实业集团动物药业有限公司 | A kind of cefquinome sulfate injection and preparation method thereof |
| CN110693814A (en) * | 2019-10-09 | 2020-01-17 | 华中农业大学 | Veterinary tilmicosin nano-gel breast perfusion agent and preparation method thereof |
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