CN103230364B - Preparation method of ceftiofur acid long-acting injection - Google Patents
Preparation method of ceftiofur acid long-acting injection Download PDFInfo
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- CN103230364B CN103230364B CN201310174936.1A CN201310174936A CN103230364B CN 103230364 B CN103230364 B CN 103230364B CN 201310174936 A CN201310174936 A CN 201310174936A CN 103230364 B CN103230364 B CN 103230364B
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Abstract
The invention belongs to the technical field of preparation of medicines and in particular relates to a preparation method of ceftiofur acid long-acting injection. The preparation method comprises the followings steps of: adding ceftiofur acid and 2-hydroxypropyl-beta-cyclodextrin in a molar ratio of 1:(1-2) to a ball mill for uniformly mixing; sufficiently grinding under the room temperature, and sufficiently uniformly and sieving to obtain a ceftiofur acid clathrate compound; dissolving sodium alginate in sterile water and adding poloxamer 407 and poloxamer 188, storing for 12-24 hours under the temperature condition of 4 DEG C, so that the poloxamer 407 and the poloxamer 188 are completely dissolved and sterilized under the temperature of 121 DEG C, carrying out ice-bath cooling to obtain a transparent solution; magnetically stirring under the temperature condition of 4 DEG C and the rotation speed condition of 150r/min; adding the ceftiofur acid clathrate compound in a weight ratio of the sodium alginate to the ceftiofur acid clathrate compound of (0.1-0.3):(5-10), so that the ceftiofur acid clathrate compound is sufficiently dispersed uniformly to obtain the ceftiofur acid long-acting injection. According to the preparation method of the ceftiofur acid long-acting injection, the preparation process is simple, the product intramuscular injection half-life period is long, the dissolution degree of the ceftiofur acid is high, the production and treatment cost is low, the cure rate is high and the environment is friendly.
Description
Technical field:
The invention belongs to medical preparing technical field, relate to a kind of preparation method of Ceftiofur acid long-acting injection, adopt cyclodextrin inclusion technique to combine with temperature sensitive type in-situ gel slow release method, a kind of production technology of novel ceftiofur long-acting injection is provided.
Background technology:
Ceftiofur is animal specific third generation antibiotic, and ceftiofur medicine original shape is Ceftiofur acid, water insoluble, ceftiofur sodium salt is that ceftiofur sodium is soluble in water, dissolves rear stability poor, and injection needs matching while using, and the rear half-life of injection is short, needs frequent drug administration; Ceftiofur hydrochloride is that Ceftiofur Hydrochloride is insoluble in water, is usually used in preparing the long-acting suspension injection of Ceftiofur Hydrochloride.Routine clinical preparation mainly contains Ceftiofur sodium for injection, and drug administration by injection needs once a day, and stress having a certain impact to therapeutic effect of drug administration by injection generation, and growth of animal is frequently subject to inhibition in various degree, causes economic benefit to reduce; Existing domestic ceftiofur long-acting suspension injection
adopt solid dispersion technology taking castor oil hydrogenated as slow-released carrier, prepare Ceftiofur Hydrochloride durative action preparation by organic reagent emulsifying, the interpolation of organic reagent strengthens preparation toxicity, and preparation layering, needs to shake up before use, easily causes injection uneven; What the ceftiofur long-acting formulation application of import was more is Pfizer animal health company
this product is prepared the acid of ceftiofur crystal detachment with Ceftiofur acid, though overcome short deficiency of ceftiofur intramuscular injection half-life, but preparation has local irritation, single-point injection can not exceed 2mL, before use, need to shake up, preparation viscosity is large, and injection is difficulty relatively, and its price is high, reduce the economic benefit of producing.Therefore the preparation method of, researching and developing a kind of novel Ceftiofur acid long-acting injection has important clinical meaning.
Summary of the invention:
The object of the invention is to overcome the shortcoming that prior art exists, seeking design provides a kind of preparation method of novel Ceftiofur acid long-acting injection, adopt inclusion technique to combine with in-situ gel sustained-release technology and prepare the Ceftiofur acid long-acting injection that can be deformed into mutually in vivo situ-gel after intramuscular injection, overcome short deficiency of half-life after Ceftiofur acid poor solubility and Ceftiofur acid intramuscular injection, solve toxicity, injection site zest and the preparation lamination problem of existing ceftiofur long-acting preparation.
To achieve these goals, concrete technology step of the present invention is:
(1), the ratio that is 1:1～2 by Ceftiofur acid and 2-HP-BETA-CD in mole mass ratio puts into ball mill and mixes, and under room temperature, fully grinds, fully mixing sieves obtains Ceftiofur acid clathrate;
(2), add poloxamer188 and PLURONICS F87 after sodium alginate being dissolved in to sterilized water, under 4 DEG C of temperature conditions, store 12～24h, sterilizing at 121 DEG C of temperature after poloxamer188 and PLURONICS F87 are dissolved completely, the cooling clear solution that obtains of ice bath;
(3), step (2) make by clear solution after 4 DEG C of temperature and 150r/min speed conditions lower magnetic force stir, by sodium alginate: the weight proportion of Ceftiofur acid=0.1～0.3:5～10 adds Ceftiofur acid clathrate, after being fully uniformly dispersed, Ceftiofur acid clathrate obtains Ceftiofur acid long-acting injection.
The percentage by weight of the each component of Ceftiofur acid long-acting injection prepared by the present invention is respectively: Ceftiofur acid is 5～10%, 2-HP-BETA-CD is 13～28%, poloxamer188 is 20～30%, PLURONICS F87 is 2～5%, sodium alginate is 0.1～0.3%, all the other are sterilized water, and total amount is 100%.
Compared with prior art, its preparation technology is simple in the present invention, product intramuscular injection long half time, the dissolubility of Ceftiofur acid is high, has solved toxicity, injection site zest and the preparation lamination problem of existing ceftiofur long-acting preparation, and production and treatment cost are low, cure rate is high, environmental friendliness.
Detailed description of the invention:
Below by embodiment, the invention will be further described.
Embodiment 1:
The concrete technology step that the present embodiment is prepared Ceftiofur acid long-acting injection is:
(1), Ceftiofur acid 0.50g and 1.40g 2-HP-BETA-CD put into ball mill mix, under room temperature, grind 15min, fully mixing sieves obtains Ceftiofur acid clathrate;
(2), add 2.00g poloxamer188 and 0.25g PLURONICS F87 after 0.01g sodium alginate is dissolved in to 6g sterilized water, 4 DEG C of refrigerator storage 24h make it dissolve rear 121 DEG C of autoclavings completely, the cooling clear solution that obtains of ice bath;
(3), clear solution is stirred at 4 DEG C and 150r/min condition lower magnetic force, add 1.90g Ceftiofur acid clathrate, Ceftiofur acid clathrate is fully disperseed, after being uniformly dispersed, add sterilized water and be settled to 10mL.
The percentage by weight of each component of ceftiofur acid injection prepared by the present embodiment is: Ceftiofur acid is 5.0%, and 2-HP-BETA-CD is 14.0%, and poloxamer188 is 20%, PLURONICS F87 is 2.5%, sodium alginate is 0.1%, and all the other are sterilized water, and total amount is 100%.
Embodiment 2:
The preparation technology of the present embodiment is with embodiment 1, and in its product injection, the percentage by weight of each composition is respectively that Ceftiofur acid is 10%, and 2-HP-BETA-CD is 20%, poloxamer188 is 25%, and PLURONICS F87 is 4%, and sodium alginate is 0.3%, all the other are sterilized water, and total amount is 100%.
Ceftiofur acid long-acting injection prepared by the present embodiment respectively after the trigonum intramuscular injection of Laoshan dairy goat cervical region pharmacokinetic show, with 5mg/kg body weight intramuscular injection Ceftiofur acid long-acting injection, drug eliminated half life is 17.13h, the minimum bactericidal blood drug level of 0.2 μ g/mL at least can maintain 48h, Ceftiofur acid long-acting injection is eliminated half-life and the sterilization length of holding time, and bioavailability is high; The pharmacodynamics test of clinical piglet pujos blancos is shown, the Ceftiofur acid long-acting injection 5mg/kg of preparation is administered once for every three days, and compared with within one day, being administered once with same dosage ceftiofur sodium, after 6 days, cure rate is respectively 87.5% and 72.5%.
The present embodiment adopts high performance liquid chromatography (HPLC), and to record dissolubility in ceftiofur sour water be 0.03mg/mL, and being prepared into dissolubility after Ceftiofur acid clathrate is 2.18mg/mL, 72.7 times of solubilisings.
Ceftiofur acid long-acting injection phase transition temperature prepared by the present embodiment is 35.5 DEG C, and steady-state viscosity is 0.28Pas, after injection, easily raises and forms situ-gel with temperature in vivo, injection viscosity is less, room temperature is placed for a long time character and is investigated result demonstration, and medicine good dispersion, without obvious lamination.
Ceftiofur acid long-acting injection prepared by the present embodiment shows the Local irritation study of rabbit intramuscular injection, injection site muscle compared with normal saline matched group outward appearance without significant change, histology investigates muscle without necrosis, only there is few inflammatory cell infiltration, local injection nonirritant is described.
Claims (2)
1. a preparation method for Ceftiofur acid long-acting injection, is characterized in that concrete technology step is:
(1), the ratio that is 1:1～2 by Ceftiofur acid and 2-HP-BETA-CD in mole mass ratio puts into ball mill and mixes, and under room temperature, fully grinds, fully mixing sieves obtains Ceftiofur acid clathrate;
(2), add poloxamer188 and PLURONICS F87 after sodium alginate being dissolved in to sterilized water, under 4 DEG C of temperature conditions, store 12～24h, sterilizing at 121 DEG C of temperature after poloxamer188 and PLURONICS F87 are dissolved completely, the cooling clear solution that obtains of ice bath;
(3), step (2) make by clear solution after 4 DEG C of temperature and 150r/min speed conditions lower magnetic force stir, by sodium alginate: the weight proportion of Ceftiofur acid=0.1～0.3:5～10 adds Ceftiofur acid clathrate, after being fully uniformly dispersed, Ceftiofur acid clathrate obtains Ceftiofur acid long-acting injection.
2. the preparation method of Ceftiofur acid long-acting injection according to claim 1, the percentage by weight that it is characterized in that the each component of Ceftiofur acid long-acting injection of preparation is respectively: Ceftiofur acid is 5～10%, 2-HP-BETA-CD is 13～28%, poloxamer188 is 20～30%, PLURONICS F87 is 2～5%, sodium alginate is 0.1～0.3%, and all the other are sterilized water, and total amount is 100%.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| AU2016222532B2 (en) * | 2015-02-26 | 2018-07-12 | Boehringer Ingelheim Animal Health USA Inc. | Long-acting injectable formulations comprising an isoxazoline active agent, methods and uses thereof |
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| 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 |
| CN103751196B (en) * | 2014-01-08 | 2016-08-17 | 中国农业科学院兰州畜牧与兽药研究所 | Ceftiofur hydroxypropyl-beta-cyclodextrin inclusion and preparation method thereof |
| CN105232450B (en) * | 2015-11-17 | 2018-08-17 | 南京多普特兽药研发有限公司 | Breast injection situ-gel containing rifaximin and preparation method thereof |
| CN112516076B (en) * | 2020-12-16 | 2024-05-03 | 郑州百瑞动物药业有限公司 | In-situ gel for ceftiofur injection and preparation method thereof |
| CN115969772A (en) * | 2022-12-16 | 2023-04-18 | 湖南创健医疗器械有限公司 | Preparation method and application of temperature-sensitive hydrogel |
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| AU6701101A (en) * | 2000-06-21 | 2002-01-02 | Cubist Pharm Inc | Compositions and methods to improve the oral absorption of antimicrobial agents |
| CN101780035B (en) * | 2010-03-22 | 2011-09-14 | 海南永田药物研究院有限公司 | Cefmenoxime hydrochloride suspended preparation and novel application thereof |
| CN102462686A (en) * | 2010-11-05 | 2012-05-23 | 天津瑞普生物技术股份有限公司 | Pharmaceutical composition used for preventing and treating colibacillosis in livestock and poultry |
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| AU2016222532B2 (en) * | 2015-02-26 | 2018-07-12 | Boehringer Ingelheim Animal Health USA Inc. | Long-acting injectable formulations comprising an isoxazoline active agent, methods and uses thereof |
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