CN102657607A - Tilmicosin stabilizing agent and preparation method thereof - Google Patents
Tilmicosin stabilizing agent and preparation method thereof Download PDFInfo
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- CN102657607A CN102657607A CN201210167702XA CN201210167702A CN102657607A CN 102657607 A CN102657607 A CN 102657607A CN 201210167702X A CN201210167702X A CN 201210167702XA CN 201210167702 A CN201210167702 A CN 201210167702A CN 102657607 A CN102657607 A CN 102657607A
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Abstract
The invention relates to a tilmicosin stabilizing preparation. The preparation is neutral and comprises the following components in each 100 ml: 20-50 g of tilmicosin, 30-50 g of penetration cosolvent, 0.2-0.4 g of antioxidant and 0.2 g of chelating agent. According to the invention, the tilmicosin, the penetration cosolvent, the antioxidant and the chelating agent are integrated together to form a faint yellow homogeneous solution, and the pH (Potential of Hydrogen) is 7; when the tilmicosin stabilizing preparation is stored, the character is stable; when the tilmicosin stabilizing preparation is used, an animal organism does not have adverse reactions; the time of reaching a blood concentration peak is much shorter than that of a traditional injection solution, and a tissue seepage force is 4-5 times as much as that of the traditional injection solution, so that the tilmicosin stabilizing preparation is one stable preparation with good curative effects.
Description
Technical field
The present invention relates to tilmicosin preparation of medicaments technical field, especially a kind of tilmicosin stabilization formulations and preparation method thereof.
Background technology
Tilmicosin belongs to the animal specific macrolide antibiotics; Gram positive bacteria, gram negative bacteria, anaerobic cocci, legionella, mycoplasma, chlamydia etc. had good bacteriostatic activity; Activity to pleura unwrapping wire property bacillus, pasteurellosis bacillus and the livestock and poultry mycoplasma of pig is stronger; The prophylactic treatment that is widely used in diseases such as Mammitis of cattle, mycoplasmal pneumonia of swine and livestock and poultry mycoplasma infection; It is responsive to the pasteurella haemolytica more than 95%, and pharmacological action exceeds 3～5 times than medicines such as tylosin, erythromycin thiocyanates.
Because tilmicosin do not dissolve in water, so during clinical use, people use cosolvent to strengthen the dissolubility of tilmicosin, the effective ingredient of the tilmicosin injection of making thus accounts for 10%, and its pH value is 5.5～6.5, is faintly acid.But, in the sour environment, the less stable of tilmicosin injection; So the shelf-life of this injection is shorter, be unfavorable for clinical use, and this injection active constituent content is lower; Need large bolus injection during use, operation inconvenience is bigger to the animal body zest.
Summary of the invention
The objective of the invention is to overcome the deficiency of prior art, stable in properties, a kind of tilmicosin stabilization formulations that penetration is high are provided.
The technical scheme that the present invention takes is:
A kind of tilmicosin stabilization formulations is characterized in that: said preparation for neutral and per 100 milliliters in comprise following component:
And, the mixture of the mixture that said infiltration cosolvent is p-phthalic acid and sodium lauryl sulphate or the mixture of Span-80 and cholesterol or alpha-tocopherol and cholesterol.
And said antioxidant is sodium thiosulfate or sodium sulfite.
And said chelating agen is an ethylenediaminetetraacetic acid.
Another object of the present invention provides a kind of method for preparing of tilmicosin stabilization formulations, it is characterized in that: may further comprise the steps:
(1) tilmicosin is added to forms suspension in the solvent;
(2) in the suspension of step (1), add the infiltration cosolvent, form faint yellow translucent suspension;
(3) continue to add the infiltration cosolvent, under the condition of 30～60 degrees centigrade of temperature, carry out ultrasound bath, obtain light yellow transparent solution;
(4) adding alkali liquor and acid solution adjust pH are 7 in the yellow solution of step (3);
(5) add antioxidant;
(6) add chelating agen;
(7) the adding purified water is settled to 100 milliliters and promptly makes finished product.
And, carry out 0.22 micron filter membrane aseptic filtration between step (6) and the step (7).
And solvent described in the step (1) is one or more the mixture in purified water, dehydrated alcohol, ethyl acetate or the propylene glycol.
Advantage of the present invention and good effect are:
Among the present invention, tilmicosin, infiltration cosolvent, antioxidant and chelating agen are combined, form faint yellow homogeneous solution; Its pH value is 7, and when depositing, character is stable; Animal body has no adverse reaction during use, and the traditional injection of the time ratio that arrives of blood drug level peak is short a lot, and tissue penetration power is higher than 4～5 times of conventional injection liquid; It is thus clear that it is a kind of good effect, stable formulation.
The specific embodiment
Below in conjunction with embodiment, the present invention is further specified, following embodiment is illustrative, is not determinate, can not limit protection scope of the present invention with following embodiment.
A kind of tilmicosin stabilization formulations, said preparation for neutral and per 100 milliliters in comprise following component:
Wherein, the infiltration cosolvent is mixture or the mixture of Span-80 and cholesterol or the mixture of alpha-tocopherol and cholesterol of p-phthalic acid and sodium lauryl sulphate.Antioxidant is sodium thiosulfate or sodium sulfite.Chelating agen is an ethylenediaminetetraacetic acid.
The method for preparing of above-mentioned tilmicosin stabilization formulations may further comprise the steps:
(1) tilmicosin is added to forms suspension in the solvent;
Solvent is one or more the mixture in purified water, dehydrated alcohol, ethyl acetate or the propylene glycol.
(2) in the suspension of step (1), add the infiltration cosolvent, form faint yellow translucent suspension;
(3) continue to add the infiltration cosolvent, under the condition of 30～60 degrees centigrade of temperature, carry out ultrasound bath, obtain light yellow transparent solution;
(4) adding alkali liquor and acid solution adjust pH are 7 in the yellow solution of step (3);
(5) add antioxidant;
(6) add chelating agen;
(7) carry out 0.22 micron filter membrane aseptic filtration;
(8) the adding purified water is settled to 100 milliliters and promptly makes finished product.
Embodiment 1
(1) 30 gram tilmicosins is added in 50 milliliters of solvents and forms suspension;
Solvent is the mixture of 20 milliliters of propylene glycol, 10 milliliters of ethyl acetate and 20 milliliters of purified water.
(2) in the suspension of step (1), add 5g p-phthalic acid and 10g sodium lauryl sulphate, form faint yellow translucent suspension;
(3) continue to add 12g p-phthalic acid and 8g sodium lauryl sulphate, under the condition of 30 degrees centigrade of temperature, carry out ultrasound bath, obtain light yellow transparent solution;
(4) in the yellow solution of step (3), adding concentration is that 7 milliliters of sodium hydroxide solutions and the concentration of 0.01mol/l is 3 milliliters of the arginine solution of 0.2mol/l, and adjust pH is 7;
(5) sodium thiosulfate of adding 0.4 gram;
(6) ethylenediaminetetraacetic acid of adding 0.2 gram;
(7) carry out 0.22 micron filter membrane aseptic filtration;
(8) the adding purified water is settled to 100 milliliters and promptly makes finished product.
The tilmicosin active constituent content is: 30%.
The pH value of yellow solution is 7.
Embodiment 2
(1) 50 gram tilmicosins is added in 50 milliliters of solvents and forms suspension;
Solvent is the mixture of 30 milliliters of propylene glycol, 10 milliliters of ethyl acetate and 10 milliliters of purified water.
(2) Span-80 and the 5g cholesterol of adding 20g in the suspension of step (1) form faint yellow translucent suspension;
(3) continuation adds the Span-8 of 10g, under the condition of 45 degrees centigrade of temperature, carries out ultrasound bath, obtains light yellow transparent solution;
(4) in the yellow solution of step (3), adding concentration is that 5 milliliters of adjust pHs of sodium hydroxide solution of 0.01mol/l are 7;
(5) sodium thiosulfate of adding 0.4 gram;
(6) ethylenediaminetetraacetic acid of adding 0.2 gram;
(7) carry out 0.22 micron filter membrane aseptic filtration;
(8) the adding purified water is settled to 100 milliliters and promptly makes finished product.
The tilmicosin active constituent content is: 50%.
The pH value of yellow solution is 7.
Embodiment 3
(1) 40 gram tilmicosins is added in 50 milliliters of solvents and forms suspension;
Solvent is the mixture of 20 milliliters of propylene glycol, 10 milliliters of ethyl acetate and 20 milliliters of purified water.
(2) alpha-tocopherol and the 5g cholesterol of adding 10g in the suspension of step (1) form faint yellow translucent suspension;
(3) continue to add the 15g cholesterol, under the condition of 50 degrees centigrade of temperature, carry out ultrasound bath, obtain light yellow transparent solution;
(4) in the yellow solution of step (3), adding concentration is that 5 milliliters of adjust pHs of sodium hydroxide solution of 0.01mol/l are 7;
(5) sodium thiosulfate of adding 0.4 gram;
(6) ethylenediaminetetraacetic acid of adding 0.2 gram;
(7) carry out 0.22 micron filter membrane aseptic filtration;
(8) the adding purified water is settled to 100 milliliters and promptly makes finished product.
The tilmicosin active constituent content is: 40%.
The pH value of yellow solution is 7.
The stability test of embodiment 1～3, the result sees table 1:
Table 1: stability test
Can know that by table 1 after embodiment 1～3 deposited 24 months, character was stable.
The toxicity test of embodiment 1～3, the result sees table 2:
Can know by table 2, after embodiment 1～3 injects, all have no adverse reaction.
The medicine of embodiment 1～3 is for test, and the result sees table 3:
Can be known that by table 3 time that the blood drug level peak arrives is shorter, conventional injection liquid needs about 1.2 hours, and half-life and conventional injection liquid phase are near, and the tissue penetration ability is higher than 4～5 times of conventional injection liquid.
Among the present invention, tilmicosin, infiltration cosolvent, antioxidant and chelating agen are combined, form faint yellow homogeneous solution, its pH value is 7, and when depositing, character is stable, avirulence, and tissue penetration is strong, is a kind of good effect, stable formulation.
Claims (7)
1. tilmicosin stabilization formulations is characterized in that: said preparation for neutral and per 100 milliliters in comprise following component:
2. a kind of tilmicosin stabilization formulations according to claim 1 is characterized in that: the mixture of the mixture that said infiltration cosolvent is p-phthalic acid and sodium lauryl sulphate or the mixture of Span-80 and cholesterol or alpha-tocopherol and cholesterol.
3. a kind of tilmicosin stabilization formulations according to claim 1 is characterized in that: said antioxidant is sodium thiosulfate or sodium sulfite.
4. a kind of tilmicosin stabilization formulations according to claim 1 is characterized in that: said chelating agen is an ethylenediaminetetraacetic acid.
5. one kind like claim 1 or 2 or the method for preparing of 3 or 4 described tilmicosin stabilization formulations, it is characterized in that: may further comprise the steps:
(1) tilmicosin is added to forms suspension in the solvent;
(2) in the suspension of step (1), add the infiltration cosolvent, form faint yellow translucent suspension;
(3) continue to add the infiltration cosolvent, under the condition of 30～60 degrees centigrade of temperature, carry out ultrasound bath, obtain light yellow transparent solution;
(4) adding alkali liquor and acid solution adjust pH are 7 in the yellow solution of step (3);
(5) add antioxidant;
(6) add chelating agen;
(7) the adding purified water is settled to 100 milliliters and promptly makes finished product.
6. a kind of tilmicosin stabilization formulations according to claim 5 is characterized in that: carry out 0.22 micron filter membrane aseptic filtration between step (6) and the step (7).
7. a kind of tilmicosin stabilization formulations according to claim 5 is characterized in that: solvent described in the step (1) is one or more the mixture in purified water, dehydrated alcohol, ethyl acetate or the propylene glycol.
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| CN201210167702.XA CN102657607B (en) | 2012-05-25 | 2012-05-25 | Tilmicosin stabilizing agent and preparation method thereof |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103301057A (en) * | 2013-06-09 | 2013-09-18 | 江西英特科胜动保科技有限公司 | Tilmicosin injection capable of improving low-temperature freezing resistance and preparation method of tilmicosin injection |
| CN103860579A (en) * | 2014-03-05 | 2014-06-18 | 四川天定生物科技有限公司 | Compound tilmicosin injection and preparation method thereof |
| CN104161768A (en) * | 2013-08-30 | 2014-11-26 | 郑州后羿制药有限公司 | Veterinary compound tilmicosin injection and preparation method thereof |
| CN107308110A (en) * | 2017-06-14 | 2017-11-03 | 王荻 | A kind of anhydrous micellar solution of Tilmicosin and preparation method thereof |
| CN109953997A (en) * | 2019-04-22 | 2019-07-02 | 佛山科学技术学院 | A kind of preparation method of tilmicosin micro-capsule preparation |
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| CN103301057A (en) * | 2013-06-09 | 2013-09-18 | 江西英特科胜动保科技有限公司 | Tilmicosin injection capable of improving low-temperature freezing resistance and preparation method of tilmicosin injection |
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| CN103860579A (en) * | 2014-03-05 | 2014-06-18 | 四川天定生物科技有限公司 | Compound tilmicosin injection and preparation method thereof |
| CN103860579B (en) * | 2014-03-05 | 2016-06-01 | 四川天定生物科技有限公司 | A kind of compound tilmicosin injection liquid and its preparation method |
| CN107308110A (en) * | 2017-06-14 | 2017-11-03 | 王荻 | A kind of anhydrous micellar solution of Tilmicosin and preparation method thereof |
| CN107308110B (en) * | 2017-06-14 | 2020-07-07 | 王荻 | Tilmicosin anhydrous micelle solution and preparation method thereof |
| CN109953997A (en) * | 2019-04-22 | 2019-07-02 | 佛山科学技术学院 | A kind of preparation method of tilmicosin micro-capsule preparation |
| CN109953997B (en) * | 2019-04-22 | 2021-06-29 | 佛山科学技术学院 | Preparation method of tilmicosin preparation |
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Inventor after: Zhao Yunying Inventor after: Liu Dingkuo Inventor after: Dong Huifeng Inventor after: Zhang Junxia Inventor after: Zhang Yong Inventor after: Wang Lihong Inventor after: Zhang Fenghong Inventor before: Liu Dingkuo Inventor before: Dong Huifeng Inventor before: Zhang Junxia Inventor before: Zhang Yong Inventor before: Wang Lihong Inventor before: Zhang Fenghong |
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Denomination of invention: Tilmicosin stabilizing agent and preparation method thereof Effective date of registration: 20140923 Granted publication date: 20140212 Pledgee: China Co truction Bank Corp Tianjin Xiqing branch Pledgor: Dingzheng Animal Pharmaceutical (Tianjin) Co., Ltd. Registration number: 2014120000050 |
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Date of cancellation: 20141215 Granted publication date: 20140212 Pledgee: China Co truction Bank Corp Tianjin Xiqing branch Pledgor: Dingzheng Animal Pharmaceutical (Tianjin) Co., Ltd. Registration number: 2014120000050 |
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Owner name: DINGZHENG XINXING BIOTECHNOLOGY (TIANJIN) CO., LTD Free format text: FORMER OWNER: DING IS ANIMAL MEDICINE (TIANJIN) CO., LTD. Effective date: 20150320 |
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Effective date of registration: 20150320 Address after: 300000 Taifeng Tianjin economic and Technological Development Zone, Road No. 81 building two building 201 A1 Patentee after: Ding is emerging biotechnology (Tianjin) Co., Ltd. Address before: 300402 Tianjin Road, Beichen District, Tianjin Road, Beichen science and Technology Park Road, No. 1 Patentee before: Dingzheng Animal Pharmaceutical (Tianjin) Co., Ltd. |