CN101007007A - Cefquinome medicinal composition for injection capable of being stored stably and dissolved easily in water - Google Patents
Cefquinome medicinal composition for injection capable of being stored stably and dissolved easily in water Download PDFInfo
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- CN101007007A CN101007007A CN 200610001875 CN200610001875A CN101007007A CN 101007007 A CN101007007 A CN 101007007A CN 200610001875 CN200610001875 CN 200610001875 CN 200610001875 A CN200610001875 A CN 200610001875A CN 101007007 A CN101007007 A CN 101007007A
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- cefquinome
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Abstract
The invention relates to the water soluble Cefquinome compounds which are used for injection. The compounds include Cefquinome (the active ingredient) and/or added salt with acid, one kind or many kinds of auxiliary solvent which can be used in medicine, and one kind or many kinds of additives commonly used for injections. The preparing method of the compounds is also mentioned in the invention. The product in the invention has a steady quality and can be dissolved in water easily.
Description
Technical field
The present invention relates to the cefquinome of injection and/or pharmaceutical composition of its officinal salt and preparation method thereof.
Background technology
Cefquinome (cefquinome) be the 4th generation the animal specific cephalosporins, its structure is formula (I) as follows, chemical name is (6R, 7R)-7-[(2Z)-(thiazolamine-4-yl)-2-methoxyimino acetylamino]-3-(5,6,7,8-tetrahydroquinoline-1-ylmethyl)-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxyl inner salt.
Cefquinome has overcome that first three is strong to gram positive bacteria usefulness for cephalosporins, to negative bacterium effect more weak shortcoming relatively, Gram-negative and positive bacteria is all had very strong killing action.When low concentration, can stronger inhibitory action be arranged to staphylococcus aureus, streptococcus, pasteurellosis bacillus, Salmonella, Actinobacillus and most of intestinal.Compare with other cephalosporins medicines, have has a broad antifungal spectrum, highly stable to beta-lactamase, consumption little (1～2mg/kg body weight) absorbs characteristics such as rapid, evident in efficacy.General clinically normal employing cefquinome sulfate is made into Emulsion or suspensoid, through subcutaneous, intramuscular injection or breast perfusion, in order to various bacterial respiratory tract infections or the mastitis of animals such as treatment cattle, pig.
Because the unstability of Cefquinome sulfate structure is met the water capacity and is easily degraded, again because its dissolubility in water is less, so often make Emulsion or suspensoid use.But Emulsion or suspensoid preparation technology have relatively high expectations, infiltration rate slow, it is inconvenient to use.
Summary of the invention
At the variety of issue that cefquinome preparation in the prior art exists, the inventor is devoted to study with the cefquinome pharmaceutical composition soluble in water of the injection that is active component, and has obtained ideal effect, thereby has finished the present invention.
Therefore, one aspect of the present invention relates to a kind of cefquinome pharmaceutical composition soluble in water of injection, wherein comprise as the cefquinome of active component and/or its officinal salt, one or more pharmaceutically acceptable cosolvents, and one or more injections additive commonly used randomly.
Another aspect of the present invention relates to the cefquinome preparation of drug combination method of described injection, this method comprises cefquinome and/or its pharmaceutical salts and cosolvent dissolving and lyophilizing after aseptic filtration, perhaps uniform mixing aseptic cefquinome and/or the drug particles of its pharmaceutical salts and aseptic cosolvent particle in small, broken bits in small, broken bits obtains the tight and uniform Powdered physical mixture of medicine and cosolvent.
The pharmaceutical composition of the injection described in the present invention only is used for purposes for animals.
According to the present invention, the active component cefquinome in the described cefquinome pharmaceutical composition can be the officinal salt of cefquinome, cefquinome or both mixture.Described officinal salt is cefquinome and the organic acid of pharmaceutically acceptance or the acid-addition salts of mineral acid formation, include but not limited to sulphuric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, formic acid, acetic acid, tartaric acid, p-methyl benzenesulfonic acid etc., wherein the sulfate of preferred cefquinome.
According to the present invention, be selected from the following material one or more as the cosolvent of hydrotropy composition in the described cefquinome pharmaceutical composition: neutrality or basic amino acid and officinal salt thereof, alkali metal or alkaline earth metal hydroxide, the inorganic acid salt of alkali metal or alkaline-earth metal, the acylate of alkali metal or alkaline-earth metal, organic base, organic or inorganic ammonium salt, ammonia or ammonia solution.
Described neutrality or basic amino acid are arginine, histidine, lysine or other pharmaceutically acceptable neutrality or basic amino acid, and they can be D-isomer or L-isomer or DL-chemical compound.Also can use their officinal salt, the acid-addition salts of aminoacid and pharmaceutically acceptable mineral acid for example, it includes but not limited to arginine monohydrochloride, arginine sulfate, argininephosphoric acid salt, lysine hydrochloride, lysine sulfate, histidine hydrochloride, histidine phosphate etc.
Preferred neutrality or basic amino acid are L-arginine, L-lysine, L-histidine or L-cysteine.More preferably L-arginine.
Described alkali metal and alkaline-earth metal are alkali metal and alkaline-earth metal pharmaceutically commonly used, as lithium, sodium, potassium, calcium, magnesium etc.; The hydroxide of alkali metal or alkaline-earth metal generally is selected from Lithium hydrate, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide etc.
Described alkali metal or alkaline-earth metal inorganic acid salt can be carbonate or bicarbonate, phosphate or hydrophosphate or dihydric phosphate.Carbonate or bicarbonate include but not limited to lithium carbonate, sodium carbonate, potassium carbonate, lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, calcium carbonate, magnesium carbonate, calcium bicarbonate, magnesium bicarbonate etc.; Phosphate or hydrophosphate or dihydric phosphate include but not limited to lithium phosphate, lithium hydrogen phosphate, lithium dihydrogen phosphate, sodium phosphate, dibastic sodium phosphate, sodium dihydrogen phosphate, potassium phosphate, potassium hydrogen phosphate, potassium dihydrogen phosphate; Calcium phosphate, calcium hydrogen phosphate, magnesium phosphate, magnesium hydrogen phosphate etc.
Preferred alkali metal or alkaline-earth metal inorganic acid salt are sodium carbonate.
The acylate of alkali metal or alkaline-earth metal can be formates, acetate, the benzoate of alkali metal or alkaline-earth metal; Described organic base can be trimethylamine, triethylamine, N-methylmorpholine, N-methyl piperidine, pyridine; The organic or inorganic ammonium salt can be ammonium acetate, ammonium carbonate, ammonium bicarbonate, ammonium phosphate, ammonium hydrogen phosphate, ammonium chloride, ammonium sulfate, ammonium hydrogen sulfate; Ammonia solution is an ammonia.
Preferred alkali metal or alkaline-earth metal acylate are sodium acetate, sodium benzoate.
According to the present invention, in described cefquinome pharmaceutical composition, cefquinome and/or its officinal salt and cosolvent need to make up by certain mol proportion, otherwise cefquinome and/or its officinal salt can not dissolve in cosolvent fully.The inventor is through discovering repeatedly, proportioning between cefquinome and/or its officinal salt and the cosolvent counts in molar ratio and generally should be 1: 0.01～and 10, more preferably, the mol ratio between cefquinome and/or its officinal salt and the cosolvent is 1: 0.02～5.
According to the present invention, can choose the additive that other injection below adding is used always in the cefquinome pharmaceutical composition of described injection as required wantonly: as the pH regulator agent, example hydrochloric acid or sodium hydrate aqueous solution; Buffer agent is as dipotassium hydrogen phosphate etc.; Isotonic agent is as sodium chloride etc.; Excipient, as water miscible mannitol, lactose, glucose etc., preferred mannitol.Can adopt described additive and combination in any thereof, the addition of additive and proportional quantity each other are within those skilled in the art's determination range.
According to the present invention, the active component cefquinome in the described cefquinome pharmaceutical composition and/or the amount of its pharmaceutically acceptable acid addition salts should make the cefquinome after the dissolving reach clinical desired drug level.Generally speaking, the concentration of active component is 0.5%-10% in the injection solution.
The cefquinome pharmaceutical composition of injection of the present invention is dissolved in the aqueous solution for injection that water for injection is made into, and its pH is preferably between 3～8.
The cefquinome pharmaceutical composition of injection of the present invention can be made lyophilized formulations, drying under reduced pressure preparation or injectable powder form, and uses with lyophilized formulations, drying under reduced pressure preparation or injectable powder form.
Described preparation can prepare by the following method: will meet the cefquinome of aforementioned proportion and/or its officinal salt and mix with cosolvent and be dissolved in water for injection after after the aseptic filtration, again through lyophilization or drying under reduced pressure, perhaps, obtain pulverulent product by the mixing of subdivided solids direct physical.Described preparation technology is simple, and cost is lower and be convenient to suitability for industrialized production.During clinical practice, above-mentioned pulverulent product can be dissolved in sterilized water for injection or normal saline wiring solution-forming and use.
Specifically, cefquinome lyophilized formulations of the present invention can prepare by following process: under cleaning condition, after cefquinome and/or its pharmaceutical salts and cosolvent be dissolved in water for injection, with dilute sodium hydroxide aqueous solution or diluted hydrochloric acid aqueous solution regulator solution to pH3-8, decolour with proper amount of active carbon, aseptic filtration is sub-packed in this aseptic apyrogenic clear and bright filtrate in the aseptic cillin bottle, and the freeze-dry process lyophilizing promptly gets product routinely.
Injection cefquinome injectable powder of the present invention can prepare by following process: under cleaning condition, the aseptic cefquinome that uniform mixing is in small, broken bits and/or the drug particles of its pharmaceutical salts and aseptic cosolvent particle in small, broken bits are so that obtain cefquinome as the medicine of active component and the tight and uniform Powdered physical mixture of cosolvent.
The above-mentioned ejection preparation of the present invention can be made into the specification that contains cefquinome 0.05g-10g, and for example specification is 0.05g, 0.1g, 0.2g, 0.5g, 1g, 2g, 4g, 10g etc.
Need control the lyophilized formulations of cefquinome pharmaceutical composition of the present invention or the moisture in the injectable powder, the content of moisture should be less than 5%, and preferably, water content is between 0.5%-3%.
Adopt the advantage of the cefquinome ejection preparation that the cefquinome pharmaceutical composition of injection of the present invention makes to be: through the long preservation steady quality, dissolving is rapidly in aqueous solution during clinical use.
The specific embodiment
Following examples and reference example will further specify the present invention, but not limit the present invention.
Embodiment 1:
Get the 10g Cefquinome sulfate, add the cold water for injection of 100ml prepared fresh, stir adding 4gL-arginine down, 0.6g mannitol transfers to pH6.5 with 0.1N sodium hydrate aqueous solution or 0.1N aqueous hydrochloric acid solution, adds the 0.1g active carbon and stirs 20 minutes, takes off charcoal.Under aseptic condition, 0.22 micron microporous membrane filter of reuse filtration sterilization after coarse filtration, in the cillin bottle of packing into filtrate branch, lyophilization gets freeze-dried powder injection, and is made into the specification that contains cefquinome 0.1g/ bottle.
The test specimen of embodiment 1 was preserved 6 months in 4 ℃ ± 2 ℃, in storing the detection dissolubility that uses the same method before and afterwards, the result shows, 0.2g sample before and after storing all can be dissolved in the 3ml room temperature water for injection in 10 seconds, and do not stay any water-insoluble solid material, satisfy the injecting drug use needs.
The test specimen of embodiment 1 was preserved 6 months in 4 ℃ ± 2 ℃, respectively at 0 month, 3 months, measure the related physical chemical property in the time of 6 months, as shown in table 1:
Table 1. injection Cefquinome sulfate lyophilized injectable powder stability data.
| Time (moon) | Character | Moisture (%) | Acidity (pH) | Solution | Total impurities (%) | |
| Clarity | Color | |||||
| 0 | The off-white color crystalline powder | 1.31 | 6.42 | Clarification | Yellow No. 2 | 1.51 |
| 3 | The off-white color crystalline powder | 1.33 | 6.40 | Clarification | Yellow No. 2 | 1.59 |
| 6 | The off-white color crystalline powder | 1.42 | 6.40 | Clarification | Yellow No. 2 | 1.84 |
The detection method high effective liquid chromatography for measuring of total impurities in the table 1.Concrete chromatographic condition is as follows: with octadecylsilane chemically bonded silica is filler; (get ammonium acetate 2.9g, be dissolved in water and be diluted to 1000ml, regulate pH value to 3.3 with glacial acetic acid)-acetonitrile (80: 10) is a mobile phase with ammonium acetate solution; Detect wavelength 270nm.It is an amount of to get test specimen, add the mobile phase dissolving and make the solution that contains cefquinome 0.5mg among every 1ml approximately, shake up, get 20 μ l and inject chromatograph of liquid, the record chromatogram is to three times of the main constituent retention time, calculate the percentage composition sum of all impurity peak area by area normalization method, be the percentage composition of total impurities.
Table 1 data show that embodiment 1 sample is stored no significant change in 6 months under above-mentioned storage requirement, and sample is stable.
Embodiment 2:
Under aseptic environments, with 100g Cefquinome sulfate aseptic powder and 24gNa
2CO
3The sterilized powder mixing ground sieve No. six, and aseptic subpackaged then one-tenth bottle promptly gets injection cefquinome injectable powder, is made into the specification that contains cefquinome 1g/ bottle.
The test specimen of embodiment 2 was preserved 6 months in 4 ℃ ± 2 ℃, in storing the detection dissolubility that uses the same method before and afterwards, the result shows, 0.2g sample before and after storing all can be dissolved in the 3ml room temperature water for injection in 20 seconds, and do not stay any water-insoluble solid material, satisfy the injecting drug use needs.
The test specimen of getting embodiment 2 was in 4 ℃ ± 2 ℃ preservations 6 months, and respectively at 0 month, 3 months, mensuration related physical chemical property was as shown in table 2 in the time of 6 months.
Table 2. injection Cefquinome sulfate injectable powder stability data.
| Time | Character | Moisture (%) | Acidity (pH) | Solution | Total impurities (%) | |
| Clarity | Color | |||||
| 0 | The off-white color crystalline powder | 1.92 | 6.25 | Clarification | Yellow No. 2 | 1.68 |
| 3 | The off-white color crystalline powder | 1.98 | 6.29 | Clarification | Yellow No. 2 | 1.79 |
| 6 | The off-white color crystalline powder | 2.08 | 6.20 | Clarification | Yellow No. 2 | 1.95 |
By table 2 test data as can be seen, the sample of embodiment 2 is stored no significant change in 6 months under described storage requirement, and sample is stable.
Claims (10)
1. cefquinome pharmaceutical composition, wherein comprise following formula (I) expression as the cefquinome of active component and/or its pharmaceutically acceptable acid addition salts, one or more pharmaceutically acceptable cosolvents, and one or more injections additive commonly used randomly:
Wherein, the proportioning between cefquinome and/or its officinal salt and the cosolvent is calculated in molar ratio as 1: 0.01～10.
2. the pharmaceutical composition of claim 1, the acid-addition salts of described cefquinome is a Cefquinome sulfate.
3. the pharmaceutical composition of claim 1, described cosolvent is selected from one or more in the following material: neutrality or basic amino acid and officinal salt thereof, alkali metal or alkaline earth metal hydroxide, the inorganic acid salt of alkali metal or alkaline-earth metal, the acylate of alkali metal or alkaline-earth metal, organic base, organic or inorganic ammonium salt, ammonia or ammonia solution.
4. the pharmaceutical composition of claim 3, described neutrality or basic amino acid are L-arginine, L-lysine, L-histidine or L-cysteine.
5. the pharmaceutical composition of claim 4, described neutrality or basic amino acid are the L-arginine.
6. the pharmaceutical composition of claim 3, described alkali metal inorganic acid salt is a sodium carbonate.
7. the pharmaceutical composition of claim 1, wherein the proportioning between cefquinome and/or its officinal salt and the cosolvent is calculated in molar ratio as 1: 0.02～5 in the compositions.
8. each pharmaceutical composition of claim 1-7, it is freeze-dried powder, drying under reduced pressure powder or injection powder injection formulation form.
9. the pharmaceutical composition of claim 8, the content of cefquinome is respectively the specification of 0.05g, 0.1g, 0.2g, 0.5g, 1g, 2g, 4g, 10g in the described preparation.
10. the method for pharmaceutical composition of preparation claim 1, it comprise cefquinome and/or its pharmaceutical salts and cosolvent be dissolved in water for injection after, regulator solution is to pH 3-8, after the aseptic filtration, lyophilizing or drying under reduced pressure; Perhaps under cleaning condition, the aseptic cefquinome that uniform mixing is in small, broken bits and/or the drug particles of its pharmaceutical salts and aseptic cosolvent particle in small, broken bits obtain the tight and uniform Powdered physical mixture of medicine and cosolvent.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200610001875 CN101007007A (en) | 2006-01-25 | 2006-01-25 | Cefquinome medicinal composition for injection capable of being stored stably and dissolved easily in water |
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| CN 200610001875 CN101007007A (en) | 2006-01-25 | 2006-01-25 | Cefquinome medicinal composition for injection capable of being stored stably and dissolved easily in water |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102349872A (en) * | 2011-10-14 | 2012-02-15 | 南京威泰珐玛兽药研究所有限公司 | Sulfuric acid cefquinome frozen powder injection and preparation method thereof |
| CN102406599A (en) * | 2011-09-30 | 2012-04-11 | 上海恒丰强动物药业有限公司 | Cefquinome solution and preparation method thereof |
| CN110559264A (en) * | 2019-09-24 | 2019-12-13 | 李会芳 | Composition for preparing cefquinome drug sensitive tablets |
-
2006
- 2006-01-25 CN CN 200610001875 patent/CN101007007A/en active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102406599A (en) * | 2011-09-30 | 2012-04-11 | 上海恒丰强动物药业有限公司 | Cefquinome solution and preparation method thereof |
| CN102349872A (en) * | 2011-10-14 | 2012-02-15 | 南京威泰珐玛兽药研究所有限公司 | Sulfuric acid cefquinome frozen powder injection and preparation method thereof |
| CN102349872B (en) * | 2011-10-14 | 2013-05-22 | 南京威泰珐玛兽药研究所有限公司 | Sulfuric acid cefquinome frozen powder injection and preparation method thereof |
| CN110559264A (en) * | 2019-09-24 | 2019-12-13 | 李会芳 | Composition for preparing cefquinome drug sensitive tablets |
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Open date: 20070801 |