CN101874773B - Long-acting ceftiofur hydrochloride injection and preparation method thereof - Google Patents
Long-acting ceftiofur hydrochloride injection and preparation method thereof Download PDFInfo
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- CN101874773B CN101874773B CN2009100501269A CN200910050126A CN101874773B CN 101874773 B CN101874773 B CN 101874773B CN 2009100501269 A CN2009100501269 A CN 2009100501269A CN 200910050126 A CN200910050126 A CN 200910050126A CN 101874773 B CN101874773 B CN 101874773B
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Abstract
The invention discloses a long-acting ceftiofur hydrochloride injection and a preparation method thereof. The long-acting ceftiofur hydrochloride injection of the invention is prepared from the following raw materials in percentage by weight: 10.2%-10.8% of ceftiofur hydrochloride, 2.0%-6.5% of additive and balance of soybean oil for injection. The long-acting ceftiofur hydrochloride injection of the invention can slowly release drug effect; the duration time of the blood drug concentration of the long-acting ceftiofur hydrochloride injection is 72-84 hours, which is greatly longer than the duration time of the blood drug concentration of the current ceftiofur hydrochloride injection; and compared with the conventional injection which needs to be injected once per day, the long-acting ceftiofur hydrochloride injection only needs to be injected once every 3 days and has good stability.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, particularly, relate to a kind of long-acting ceftiofur hydrochloride injection and preparation method thereof.
Background technology
Ceftiofur (Ceftiofur) has another name called Sai Defu, is at first synthetic in 1984 by people such as Bernard Labeeuw the earliest, is the special-purpose third generation cephalosporin class antibiotic of first poultry; Thereafter the treatment that the lyophilized powder of sodium salt and the suspension of hydrochlorate (commodity are called Naxcel, Excenel) are used for Animal diseases is made with it by the strong company of Pharmacia-Pu (Pharmacia).
Ceftiofur absorbs rapidly, and bioavailability is high; High with body internal protein combination rate, form stock's sterilizing power, long half time, lasting medicine; Compare with other antibiotic, the unique distinction of this medicine is that the content of medicine in infected tissue than high 2～4 times in the non-infected tissue, is the concentrated distribution that target is arranged, the performance bactericidal action.
Ceftiofur is the kill bacteria through acting on the synthetic of transpeptidase blocking-up bacteria cell wall mainly; Various gram positive bacterias (like staphylococcus), gram negative bacteria (like escherichia coli, Salmonella, bacillus pyocyaneus) and some anaerobe all there is very strong antibacterial activity.Ceftiofur is residual low in tissue; Safety is good; Molecular structure stabilized and can not destroyed by beta-lactamase; Be difficult for producing drug resistance and cross resistance, is the strongest antibiotic of sterilizing power for animals on the market now, has the incomparable multiple superiority of other antibiotic of present veterinary drug market popularity.
The preparation of China's approval at present has ceftiofur soluble powder and suspension injection, and these products are the treatment Animal diseases and have brought into play due effect.Yet because the effective blood drug concentration of above-mentioned preparation was held time mostly between 24-32 hour, need the injection every day during clinical treatment, make troubles for veterinary's treatment work, also caused the inadaptability of treatment animal simultaneously.Durative action preparation about ceftiofur does not appear in the newspapers as yet at present.
Summary of the invention
Primary and foremost purpose of the present invention is to provide a kind of long-acting ceftiofur hydrochloride injection.
Second purpose of the present invention is to provide the method for preparing of said long-acting ceftiofur hydrochloride injection.
Long-acting ceftiofur hydrochloride injection of the present invention, formulated by following raw materials by weight percent:
Ceftiofur Hydrochloride 10.2%～10.8%;
Pharmaceutic adjuvant 2.0～6.5%;
Surplus is the injection soybean oil.
According to long-acting ceftiofur hydrochloride injection of the present invention, said additives comprise lecithin, span-80 and propylene glycol.
According to long-acting ceftiofur hydrochloride injection of the present invention, said lecithin content is 0.5～2.0%, is preferably 1.0%.
According to long-acting ceftiofur hydrochloride injection of the present invention, said span-80 content is 0.5～1.5%, is preferably 1.0%.
According to long-acting ceftiofur hydrochloride injection of the present invention, said content of propylene glycol is 1.0～3.0%, is preferably 2.0%.
Long-acting ceftiofur hydrochloride injection of the present invention, its preparation method may further comprise the steps:
With the injection soybean oil dissolving additives of heating, to sterilize behind the stirring and evenly mixing, the cooling back adds Ceftiofur Hydrochloride, uses homogenizer to mix the aseptic subpackaged injection finished product that obtains.
According to method of the present invention, used homogenizer is a high-shear homogenizing machine.
Long-acting ceftiofur hydrochloride injection of the present invention; Can slowly discharge drug effect, the blood drug level is held time more than 72 hours, is much higher than existing Ceftiofur Hydrochloride injecta; Injection every day by regular dosage form once reduces to injection in 3 days once, and good stability.
The method for preparing of long-acting ceftiofur hydrochloride injection of the present invention is simple, uses high-shear homogenizing machine to carry out the homogenate operation, obtains superfine granule medicinal liquid, has reduced the zest of medicinal liquid to the injection site.
The specific embodiment
Below in conjunction with specific embodiment, the present invention is described further.Should be understood that following examples only are used to the present invention is described but not are used to limit scope of the present invention.
In following examples, institute's medicament and reagent available from:
(Shandong, Shandong resists medical company limited to Ceftiofur Hydrochloride for moisture 2.2%, content 100.0%; Lot number 071103), lecithin (Shanghai is along thing Science and Technology Ltd. of Johnson & Johnson, lot number 070912); Injection soybean oil (Long Youxian field, Zhejiang Province rain Camellia oil development corporation, Ltd., lot number 07302).
In following examples, used testing equipment is:
GZJ type high-shear homogenizing machine (rich Buddhist nun's chemical industry equipment company limited), its operation principle is under the high-speed driving of motor, high-speed motion in the close clearance of material between multi-layer rotor and stator has formed intensive fluid power and has sheared and turbulent flow.
Embodiment 1-3, long-acting ceftiofur hydrochloride injection preparation
Press the formulated long-acting ceftiofur hydrochloride injection shown in the table 1, concrete operations are following:
The injection soybean oil in the vessel in heating to 90 ℃ through sterilization, is added additives span-80, propylene glycol, lecithin then, constantly stir it is mixed and dissolving; Continue to be heated to 150 ℃, sterilized 1 hour, the cooling back adds Ceftiofur Hydrochloride; Continue to stir 20min; Replenish injection soybean oil to 100% (1000ml), use GZJ type high-shear homogenizing machine to mix, suspension is imported 10,000 grades of toilet's fills; Use the packing of 10ml/50ml molded glass bottle, cover and pack after rolling lid, lamp inspection behind butyl rubber plug and the aluminium lid.
The purpose of using GZJ type high-shear homogenizing machine to carry out the homogenate operation in the process for preparation is that drug particle is beaten carefully, and medicinal liquid obtains the superfine granule through this equipment operation, can reduce the zest of medicinal liquid to the injection site.
Table 1
Embodiment 4, clinical experiment
Get 12 pigs (30～40 kilograms of body weight, public female half and half), be divided into three groups at random; Long-acting ceftiofur hydrochloride injection by per kilogram of body weight 5mg intramuscular injection embodiment 1～3 preparation; And as control Example, contrast as bioavailability with the quiet notes of Ceftiofur Hydrochloride with injection Ceftiofur Hydrochloride (Shandong, Shandong resists medical company limited, lot number 071103); The oxter venous blood collection detects blood drug level then, carries out the following and detects.
4.1, blood plasma Chinese medicine concentration detects
After giving the pig injectable drug, the oxter venous blood collection utilizes ion exchange-HPLC at each time point the ceftiofur concentration in the blood plasma to be detected, and the result sees table 2.
Table 2
ND: can not record (Not Detectable)
The result of table 2 shows, control Example intramuscular injection Ceftiofur Hydrochloride, and maximum duration point that can detected plasma drug level is 84h, but this moment, blood drug level was merely 0.06 μ g/ml.Intramuscular injection long-acting ceftiofur hydrochloride injection of the present invention, in back 84 hours of injection, effective blood drug concentration on average still can maintain 0.28 μ g/ml, and maximum duration point that can detected plasma drug level is 120h.Compare with existing Ceftiofur Hydrochloride, the valid density of blood drug level 0.28～0.30 μ g/m that long-acting ceftiofur hydrochloride injection of the present invention reaches in the pig body has prolonged about 24～36 hours.
4.2, pharmacokinetics detects
According to the mensuration result of blood drug level in the table 2, use the DAS2.0 of Medical University Of Anhui pharmacokinetics software analysis to draw long-acting ceftiofur hydrochloride injection of the present invention at the intravital pharmacokinetic parameter of pig, the result sees table 3.
Table 3
| Parameter | Unit | Embodiment 1 | Embodiment 2 | Embodiment 3 | Control Example | Quiet notes group |
| The AUC TG-AUC | mg/L*h | 110.71 | 115.38 | 121.11 | 117.99 | 142.78 |
| Absorb half-life t1/2 α | h | 0.70 | 1.60 | 1.91 | 0.39 | -- |
| Eliminate half-life t1/2 β | h | 21.12 | 29.32 | 23.73 | 13.61 | -- |
| Peak time tmax | h | 1.28 | 1.31 | 1.29 | 0.59 | -- |
| Reach peak concentration Cmax | mg/mL | 6.02 | 6.11 | 5.83 | 12.18 | -- |
Result by table 3 can know, compares with the regular hydrochloric acid ceftiofur, and long-acting ceftiofur hydrochloride injection soak time of the present invention prolonged with the elimination half-life; Peak time postpones, and reaches peak concentration and reduces, and has certain slow releasing function; And blood drug level is steady, obviously reaches the effect of long-acting treatment.
4.3, bioavailability detects
Calculate the bioavailability of Ceftiofur Hydrochloride and long-acting ceftiofur hydrochloride injection according to the AUC value in the table 3 and intravenous AUC value.The average bioavailability of long-acting ceftiofur hydrochloride injection is 79.0%; The bioavailability of Ceftiofur Hydrochloride is 82.9%; The bioavailability of the relative Ceftiofur Hydrochloride of long-acting ceftiofur hydrochloride injection is 95.3%, and both differ not remarkable, shows with Ceftiofur Hydrochloride and compares; The bioavailability of long-acting ceftiofur hydrochloride injection is equal to, and promptly the preparation process of long-acting ceftiofur hydrochloride injection does not have obvious influence to the bioavailability of Ceftiofur Hydrochloride.
Embodiment 5, product stability experiment
Embodiment 1～3 described long-acting ceftiofur hydrochloride injection is kept under 30 ℃ the ambient temperature, finds that through 6 months observations product keeps the milk yellow oil suspension, through strong illumination 10 days, product kept color constant.
According to pertinent regulations in the appendix of one one of " People's Republic of China's veterinary drug allusion quotation " version in 2005, the drug content of embodiment 1～3 described long-acting ceftiofur hydrochloride injection, settling volume are detected than, accelerated tests, specifically see table 4.
Table 4
| Embodiment 1 | Embodiment 2 | Embodiment 3 | |
| Drug content | 97.6％ | 97.9％ | 98.2％ |
| Aseptic | Qualified | Qualified | Qualified |
| The settling volume ratio | 0.97 | 0.97 | 0.98 |
| Accelerated test (6 months) | 92.5％ | 92.8％ | 93.3％ |
Can know that by table 4 drug content of long-acting ceftiofur hydrochloride injection of the present invention, settling volume ratio, release degree, accelerated tests etc. conform in every respect to the beastly officinal standard of China in 2005, good stability.
In sum, long-acting ceftiofur hydrochloride injection of the present invention can slowly discharge drug effect; The blood drug level was held time at 72～84 hours; Be much higher than existing Ceftiofur Hydrochloride injecta, once reduce to injection in 3 days once by injecting the every day of regular dosage form, and good stability.
In addition, the method for preparing of long-acting ceftiofur hydrochloride injection of the present invention is simple, uses high-shear homogenizing machine to carry out the homogenate operation, obtains superfine granule medicinal liquid, has reduced the zest of medicinal liquid to the injection site.
Claims (6)
1. a long-acting ceftiofur hydrochloride injection is characterized in that, and is formulated by following raw materials by weight percent:
Ceftiofur Hydrochloride 10.2%～10.8%;
Additives 2.0～6.5%;
Surplus is the injection soybean oil;
Said additives are lecithin, span-80 and propylene glycol;
Said lecithin content is 0.5～2.0%;
Said span-80 content is 0.5～1.5%;
Said content of propylene glycol is 1.0～3.0%.
2. injection as claimed in claim 1 is characterized in that, said lecithin content is 1.0%.
3. injection as claimed in claim 1 is characterized in that, said span-80 content is 1.0%.
4. injection as claimed in claim 1 is characterized in that, said content of propylene glycol is 2.0%.
5. the method for preparing of injection according to claim 1 is characterized in that, may further comprise the steps:
With the injection soybean oil dissolving additives of heating, said additives are lecithin, span-80 and propylene glycol, sterilize behind the stirring and evenly mixing, and the cooling back adds Ceftiofur Hydrochloride, uses homogenizer to mix the aseptic subpackaged injection finished product that obtains.
6. method as claimed in claim 5 is characterized in that, used homogenizer is a high-shear homogenizing machine.
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| CN2009100501269A CN101874773B (en) | 2009-04-28 | 2009-04-28 | Long-acting ceftiofur hydrochloride injection and preparation method thereof |
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| CN2009100501269A CN101874773B (en) | 2009-04-28 | 2009-04-28 | Long-acting ceftiofur hydrochloride injection and preparation method thereof |
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| CN101874773B true CN101874773B (en) | 2012-05-30 |
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Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102525915B (en) * | 2010-12-14 | 2016-09-28 | 江苏豪森药业集团有限公司 | A kind of ejection preparation of sustained release and its production and use |
| CN103705447B (en) * | 2013-12-24 | 2015-10-28 | 山东鲁抗立科药业有限公司 | A kind of long-acting ceftiofur hydrochloride injection and preparation method thereof |
| CN106309360B (en) * | 2016-09-13 | 2018-08-10 | 上海公谊药业有限公司 | A kind of preparation method of long-acting ceftiofur hydrochloride injection |
| CN113209015A (en) * | 2020-01-21 | 2021-08-06 | 江西邦诚动物药业有限公司 | Long-acting ceftiofur hydrochloride suspension injection and preparation process thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1813760A (en) * | 2005-12-12 | 2006-08-09 | 浙江升华拜克生物股份有限公司 | Ceftiofur-containing powder injection for beast |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1813760A (en) * | 2005-12-12 | 2006-08-09 | 浙江升华拜克生物股份有限公司 | Ceftiofur-containing powder injection for beast |
Non-Patent Citations (3)
| Title |
|---|
| 杨诗斌等.高剪切及高压均质机理研究及其在食品工业中的应用.《粮油加工与食品机械》.2002,(第4期),33-35. * |
| 肖俊等.长效头孢噻呋混悬注射液在猪体内的药物动力学试验.《中国兽医杂志》.2008,第44卷(第11期),62-63. * |
| 贾艳华等.兽用抗菌药缓释注射剂研究进展.《兽医导刊》.2007,(第4期),35-37. * |
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