CN111467310A - Cefquinome sustained-release colloidal powder injection for injection and preparation method thereof - Google Patents
Cefquinome sustained-release colloidal powder injection for injection and preparation method thereof Download PDFInfo
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- CN111467310A CN111467310A CN202010296806.5A CN202010296806A CN111467310A CN 111467310 A CN111467310 A CN 111467310A CN 202010296806 A CN202010296806 A CN 202010296806A CN 111467310 A CN111467310 A CN 111467310A
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- injection
- cefquinome
- sustained
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- colloidal powder
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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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
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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
-
- 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
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- 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
Abstract
The invention discloses a cefquinome sustained-release colloidal powder injection for injection and a preparation method thereof, belonging to the technical field of veterinary drug preparation and being prepared from the following components in percentage by mass: 0.05-20 parts of cefquinome, 0.05-3.0 parts of biodegradable sustained-release glue and 0.01-1.0 part of surfactant. The preparation method comprises the following steps: 1) weighing the components in proportion and mixing uniformly; 2) aseptically packaging the mixture obtained in the step 1) according to specifications to obtain the finished product. Compared with the common cefquinome for injection, the cefquinome for injection disclosed by the invention can be diluted by sterilized water for injection to quickly form a sustained-release colloidal liquid. After injection, a drug depot is formed at the injection site and slowly released into blood. The cefquinome sustained-release colloidal powder injection for injection provided by the invention can obviously prolong the effective blood concentration maintenance time, reduce the clinical medication times, reduce the animal stress and save the manpower, material resources and financial resources, and meanwhile, the cefquinome sustained-release colloidal powder injection is safe to use and is beneficial to clinical popularization and application.
Description
Technical Field
The invention relates to a cefquinome sustained-release colloidal powder injection for injection and a preparation method thereof, belonging to the technical field of veterinary drug preparation.
Background
The cefquinome is the only fourth-generation veterinary antibiotic special for cephalosporins, and has the characteristics of high stability to β -lactamase of ①, higher intrinsic antibacterial activity than the third-generation cephalosporins ceftiofur of ②, long plasma half-life period and no nephrotoxicity of the fourth-generation cephalosporins compared with the third-generation cephalosporins, very strong antibacterial activity of ③, and good killing effect on staphylococcus aureus, streptococcus, pseudomonas aeruginosa, enterobacteriaceae (escherichia coli, salmonella, klebsiella, citric acid bacteria and serratia marcescens), and also good killing effect on a plurality of methicillin-resistant staphylococcus and enterobacteria of ④, wide antibacterial spectrum, high antibacterial activity and suitability for parenteral administration.
At present, two cefquinome injection products exist in the market, one is a common cefquinome powder injection, a certain amount of sterilized injection water is used for dissolving before injection to form a cefquinome solution, intramuscular injection can be carried out, the cefquinome solution is directly absorbed into blood by an organism at the injection part, the slow release effect cannot occur, the intramuscular injection absorption is rapid, the blood concentration is rapidly increased, the peak reaching time is short by 0.28h-0.66h, the elimination half-life period is 1.41h-4.36h, and the bioavailability is 80%. Therefore, the half-life period of the common cefquinome powder injection is short, and the sterilization and bacteriostasis maintaining time is short. The other one is long-acting cefquinome injection which is a suspension oil solution (medicine and organic solvent) of fine particles, and when the injection is used, the cefquinome injection is directly pumped into an injector and is injected intramuscularly, so that the injection has a certain slow release effect, the effective blood concentration is relatively long, the content is between 2.5 and 5 percent, and more than 95 percent of the effective blood concentration is the organic solvent, so that the injection part is swollen and is not easy to dissipate. And the fine particles sink after standing, and the medicine is unevenly distributed, so that the cefquinome content is different when the injection with the same volume is sucked.
The common preparation needs to be administrated every day, which not only is inconvenient to use, but also causes the phenomenon of peak valley caused by great fluctuation of blood concentration. When the concentration of the medicine is in a peak, more side effects are caused when the concentration of the medicine exceeds the optimum treatment concentration; conversely, when the concentration of the drug is reduced to the low level, the drug is lower than the bactericidal or bacteriostatic concentration and is difficult to act. Clinically, the sustained-release preparation is needed to control the release speed of the medicament, reduce or avoid the peak-valley fluctuation of the blood concentration and ensure that the medicament can stably and continuously exert the curative effect.
Disclosure of Invention
The invention aims to overcome the technical defects, provides a cefquinome sustained-release colloidal powder injection for injection and a preparation method thereof, and solves the technical problems that the blood concentration fluctuation is large, the peak valley phenomenon appears, the sterilization or bacteriostasis concentration maintenance time is short, the daily administration is needed, the injection part is swollen and is not easy to dissipate and the like after the cefquinome is injected intramuscularly in the prior art. The invention has the characteristics of obviously prolonging the maintenance time of effective blood concentration, reducing the clinical medication times, reducing the stress of animals, saving manpower, material resources and financial resources, being safe to use, being beneficial to clinical popularization and application and the like.
The invention achieves the above object by the following technical scheme.
The invention provides a cefquinome sustained-release colloidal powder injection for injection, which is prepared from the following components in percentage by mass: 0.05-20 parts of cefquinome, 0.05-3.0 parts of biodegradable sustained-release glue and 0.01-1.0 part of surfactant.
The cefquinome is in the forms of sulfate, acetate and nitrate.
The biodegradable slow-release glue is polylactic acid, chitosan, gelatin, a chitosan-gelatin blend, chitosan, a hyaluronic acid blend, a chitosan collagen chondroitin sulfate blend, hydroxypropyl methyl cellulose or hydroxypropyl cellulose.
The surfactant is glycerol block polyether, rhamnolipid, sophorolipid, seaweed glycolipid or surface active peptide.
The preparation method of the cefquinome sustained-release colloidal powder injection for injection comprises the following steps: 1) weighing the components in proportion and mixing uniformly; 2) aseptically packaging the mixture obtained in the step 1) according to specifications to obtain the finished product.
Compared with the prior art, the invention has the beneficial effects that:
the synergistic effect among the components is obvious, a drug depot is formed after intramuscular injection, the slow release blood-entering effect is extremely obvious, the effective blood concentration maintaining time is obviously prolonged, and compared with the common cefquinome injection or cefquinome powder injection, the injection is performed for three times every two days, so that the stress influence of animals is greatly reduced, the labor, the material resources and the financial resources are saved, and meanwhile, the cefquinome injection is safe to use and is beneficial to clinical popularization and application.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail with reference to the following embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
The invention provides a cefquinome sustained-release colloidal powder injection for injection, which is prepared from the following components, by mass, 0.05-20 parts of cefquinome, 0.05-3.0 parts of biodegradable sustained-release glue and 0.01-1.0 part of a surfactant, wherein the cefquinome is in the forms of sulfate, acetate and nitrate, the biodegradable sustained-release glue is polylactic acid (P L A), chitosan, gelatin, a chitosan gelatin blend, a chitosan and hyaluronic acid blend, a chitosan collagen chondroitin sulfate blend, hydroxypropyl methyl cellulose and hydroxypropyl cellulose, preferably a polylactic acid, chitosan, gelatin and chitosan gelatin blend, and the surfactant is glycerol block polyether, rhamnolipid, sophorolipid, glycolipid seaweed and surface active peptide, preferably glycerol block polyether and surface active peptide.
Examples
The preparation method comprises the following steps: 1) weighing the components according to the formula and then uniformly mixing; 2) aseptically packaging the mixture obtained in the step 1) into penicillin bottles. Before use, the cefquinome is directly dissolved in sterile water for injection and is injected intramuscularly according to 4mg of cefquinome per kg of body weight, and the injection is performed once per 2 days. The following examples 1-9 and comparative examples 1-5 were prepared by the above-described method, as shown in Table 1.
TABLE 1
Safety test of application example
The sustained-release colloidal powder injection of cefquinome for injection prepared in example 1 is used as a sample for biological safety evaluation.
1) Safety evaluation of mice
64 Kunming mice with the weight of 20-30g are divided into a control group, a medium dose group, a high dose group and an ultrahigh dose group according to the sex of each half, each group comprises 16 mice, and the mice are raised under the same environmental condition by using the same feed and drinking water. In the control group, each mouse was injected with physiological saline intramuscularly into the thigh at a rate of 4mg/kg (0.1ml/kg) of body weight using a microinjector. The cefquinome sustained-release solution prepared in example 1 of the invention is injected in thigh muscle by a microinjector for each mouse in a medium-dose group according to 0.1ml/kg of body weight (1-fold recommended dose), a microinjector for each mouse in a high-dose group according to 8mg/kg (0.2ml/kg) of body weight (2-fold recommended dose), and a microinjector for each mouse in an ultrahigh-dose group according to 40mg/kg (1.0ml/kg) of body weight (10-fold recommended dose), and is injected once every two days for three times, then observing for another week, wherein the observation items comprise average weight change, mental state, red and swollen condition of injection part and death number of animals, if mice die during the experiment, and (3) performing autopsy within 2h after death, selecting 3 cervical vertebra luxations randomly from each group of mice to perform death after the experiment is ended if no death exists, and performing autopsy and observing the change of visceral tissues and organs.
The results of the experiment are shown in table 2.
TABLE 2
The experimental results show that: the average body weight of each group of mice before and after the experiment has no obvious change, the mental state is good, the injection part has no red swelling, no dead mice exist in the experimental period, and the visceral organs do not have abnormal changes after the experiment is finished.
2) Chick safety evaluation
40 healthy white feather broilers of 10 days old adapt to a new environment in an animal house for 10 days, are randomly divided into a control group, a medium-dose group, a high-dose group and an ultrahigh-dose group, and 10 broilers in each group are fed under the same environmental condition by using the same feed and drinking water. In the control group, each chick was injected with 0.1ml/kg body weight of physiological saline via breast muscle injection. The cefquinome sustained-release solution is injected into each chick in a medium-dose group according to 4mg/kg (0.1ml/kg) of body weight (1-time recommended dose), each chick in a high-dose group according to 8mg/kg (0.2ml/kg) of body weight (2-time recommended dose), each chick in an ultrahigh-dose group according to 40mg/kg (1.0ml/kg) of body weight (10-time recommended dose) through chest intramuscular injection once every two days, the injection is performed three times, then observation is performed for one week, the observation items are the average body weight change, the mental state, the red and swollen condition of an injection part and the death number of the animals, if the chickens die in the experiment period, the autopsy is performed within 2h after the death, if no death exists, 3 jugular vein bloodletting blood of each group of chickens are randomly selected for death, and the change of visceral organs is inspected and observed.
The results of the experiment are shown in table 3.
TABLE 3
The experimental results of table 3 show that: the average body weight of each group of chicks before and after the experiment has no obvious change, the mental state is good, the injection part has no red swelling, no dead chicks exist in the experimental period, and the visceral organs do not change abnormally after the experiment is finished.
The experimental result shows that the slow-release colloidal powder injection of cefquinome for injection has no risk of acute poisoning.
Application example stability test
Stability determination was performed using the cefquinome sustained-release colloidal powder injection for injection prepared in examples 1 to 9 and comparative examples 1 to 5 as a sample
1) High temperature test
2 samples of the examples 1 to 9 and the comparative examples 1 to 5 were respectively taken and placed in a closed sterile vial, and the vial was placed at 60 ℃ for 10 days, and 1 sample of the examples 1 to 3 was respectively taken on the 5 th day and the 10 th day, and the properties of the cefquinome sustained-release colloidal powder injection of the present invention were observed. The results showed that examples 1-9 and comparative examples 1-5 were white powders, uniform in appearance, free from caking on days 5 and 10, and well soluble in sterile water for injection. Determining the content of cefquinome by high performance liquid chromatography, wherein the chromatographic conditions are as follows: the chromatographic column is Welch XB-C18A column (250mm × 4.6.6 mm, 5 μm) with a mobile phase of 0.1 mol/L acetate buffer (ph4.0) -acetonitrile-methanol 85:7:8 at a flow rate of 1.0m L/min, a column temperature of 25 ℃, and a fluorescence detector excitation wavelength of 265nm, showing that the contents of cefquinome are not significantly changed: (no significant change in cefquinome content: (250mm 8978.6 mm, 5 μm))<95％)。
2) High humidity test
2 samples of the examples 1 to 9 and the comparative examples 1 to 5 are respectively taken and placed in a closed sterile vial, the vial is placed at the temperature of 25 ℃ and the relative humidity of 75% +/-5% for 10 days, 1 sample is respectively taken on the 5 th day and the 10 th day, and the properties of the cefquinome sustained-release colloidal powder injection are observed. The results show that the products of examples 1 to 9 and comparative examples 1 to 5 are white powders on the 5 th day and the 10 th day, have uniform appearance and no caking phenomenon, are well dissolved by sterilized water for injection, and have no obvious change (< 95%) in the contents of cefquinome, polylactic acid and glycerin block polyether determined by high performance liquid chromatography.
3) Light test
The results show that the samples of the examples 1 to 9 and the comparative examples 1 to 5 are white powder on the 5 th day and the 10 th day, have uniform appearance and no caking phenomenon, are well dissolved by using water for sterilization injection, and the contents of the cefquinome, the polylactic acid and the glycerol block polyether are not obviously changed (95%) by using a high performance liquid chromatography.
4) Accelerated test
Respectively taking 3 samples of examples 1-9 and comparative examples 1-5, placing the samples in a sealed sterile vial, placing the vial at 40 +/-2 ℃ and 75% +/-5% relative humidity for 6 months, respectively taking 1 sample at the end of the month of 2, 4 and 6 months, and observing the properties of the cefquinome sustained-release colloidal powder injection. The results show that examples 1-9 were all white powders at the end of months 2, 4 and 6, with uniform appearance and no caking, and were well soluble in sterile water for injection, as determined by high performance liquid chromatography. The contents of cefquinome, biodegradable sustained-release glue and surfactant in examples 1-9 are not significantly changed (< 95%); while the samples of comparative example 1, comparative example 2, comparative example 4 and comparative example 5 showed delamination after dissolution at month 6, and the sample of comparative example 3 showed blocking at month 6.
5) Long term test
7 samples of the embodiments 1-9 and the comparative examples 1-5 are respectively taken and placed in a closed sterile vial, 1 sample of the embodiments 1-3 is taken at the end of 3 months, 6 months, 9 months and 12 months respectively under the conditions of 25 +/-2 ℃ and 60% +/-5% relative humidity, and the properties of the cefquinome sustained-release colloidal powder injection are observed. The results showed that examples 1-3 were white powders at the end of months 3, 6, 9 and 12, uniform in appearance, free from caking, well soluble in sterile water for injection, and determined by high performance liquid chromatography. In examples 1 to 9, the contents of cefquinome, biodegradable sustained-release gel and surfactant are not significantly changed (< 95%), which indicates that the effective period of the cefquinome sustained-release colloidal powder injection of the invention is at least 12 months. While the samples of comparative example 1, comparative example 2, comparative example 4 and comparative example 5 showed delamination after dissolution at month 12 and blocking at month 9 in comparative example 3.
Application example sustained Release test
Sustained release tests were carried out using the sustained release colloidal powder injections of cefquinome for injection prepared in examples 1 to 9 and comparative example 5 as samples.
Randomly dividing 8 male and female half-China rural dogs into a control group and an experimental group, wherein the control group adopts commercially available long-acting cefquinome sulfate long-acting injection for thigh intramuscular injection, the experimental group adopts the slow-release colloidal powder injection of the cefquinome for injection to dissolve, the thigh intramuscular injection is carried out, the injection dosage is 4mg/kg of body weight, the forelimb is subjected to intravenous blood sampling 1h, 2h, 6h, 12h, 24h and 48h after the injection, the serum is separated, and the concentration of the cefquinome in the serum is measured by high performance liquid chromatography. The experimental results of example 2 (the working group) and comparative example 5 (the control group) are shown in table 4:
TABLE 4
The experimental results in table 4 show that the highest blood concentration values of the experimental group and the control group are both 8h, but the blood concentration of the experimental group before 8h is lower than that of the control group (comparative example 5), and after 8h, the blood concentration of the experimental group is higher than that of the control group, so that compared with the commercially available long-acting cefquinome sulfate long-acting injection, the cefquinome slow-release colloidal powder for injection has a remarkable slow-release effect, and the effective blood concentration time is obviously prolonged.
Finally, it should be noted that: although the present invention has been described in detail with reference to the foregoing embodiments, it will be apparent to those skilled in the art that changes may be made in the embodiments and/or equivalents thereof without departing from the spirit and scope of the invention. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (5)
1. The slow-release colloidal powder injection of cefquinome for injection is characterized by comprising the following components in percentage by mass: 0.05-20 parts of cefquinome, 0.05-3.0 parts of biodegradable sustained-release glue and 0.01-1.0 part of surfactant.
2. The cefquinome sustained-release colloidal powder injection for injection as claimed in claim 1, wherein the cefquinome is in the form of sulfate, acetate or nitrate.
3. The cefquinome sustained-release colloidal powder injection according to claim 1, wherein the biodegradable sustained-release gel is polylactic acid, chitosan, gelatin, chitosan-gelatin blend, chitosan, hyaluronic acid blend, chitosan collagen chondroitin sulfate blend, hydroxypropyl methylcellulose or hydroxypropyl cellulose.
4. The cefquinome sustained-release colloidal powder injection for injection as claimed in claim 1, wherein the surfactant is glycerol block polyether, rhamnolipid, sophorolipid, algal glycolipid or surfactant peptide.
5. The preparation method of the cefquinome sustained-release colloidal powder injection for injection according to any one of claims 1 to 4, which is characterized by comprising the following steps: 1) weighing the components in proportion and mixing uniformly; 2) aseptically packaging the mixture obtained in the step 1) according to specifications to obtain the finished product.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103751103A (en) * | 2014-02-21 | 2014-04-30 | 山东鲁抗立科药业有限公司 | Long-acting cefquinome sulfate injection and preparation method thereof |
| CN106361704A (en) * | 2016-08-30 | 2017-02-01 | 甘肃新天马制药股份有限公司 | Ceftiofur sodium drug sustained-release colloid powder injection for injection and preparation method thereof |
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2020
- 2020-04-15 CN CN202010296806.5A patent/CN111467310A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103751103A (en) * | 2014-02-21 | 2014-04-30 | 山东鲁抗立科药业有限公司 | Long-acting cefquinome sulfate injection and preparation method thereof |
| CN106361704A (en) * | 2016-08-30 | 2017-02-01 | 甘肃新天马制药股份有限公司 | Ceftiofur sodium drug sustained-release colloid powder injection for injection and preparation method thereof |
Non-Patent Citations (1)
| Title |
|---|
| 中国兽药典委员会，: "《中华人民共和国兽药典兽药使用指南 2005年版 化学药品卷》", 30 April 2006, 中国农业出版社 * |
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