CN103230364A - Preparation method of ceftiofur acid long-acting injection - Google Patents

Abstract

The invention belongs to the technical field of medicine preparation, and relates to a preparation method of ceftiofuric acid long-acting injection. Firstly, the molar mass ratio of ceftiofuric acid and 2-hydroxypropyl-β-cyclodextrin is 1:1~ 2 in a ball mill and mix well, fully grind at room temperature, fully mix and sieve to obtain ceftiofur acid inclusion complex; dissolve sodium alginate in sterile water and add Poloxamer 407 and Poloxamer 188, stored at 4°C for 12 to 24 hours, completely dissolved Poloxamer 407 and Poloxamer 188 and then sterilized at 121°C, cooled in an ice bath to obtain a transparent solution, then sterilized at 4°C and 150r/min Stir with magnetic force under the condition of rotating speed, add ceftiofur acid inclusion compound according to the weight ratio of sodium alginate: ceftiofuric acid = 0.1-0.3: 5-10, so that the ceftiofur acid inclusion compound is fully dispersed and uniform to obtain cephalosporin Thiofuroxime long-acting injection; the preparation process is simple, the intramuscular injection of the product has a long half-life, the solubility of ceftiofuric acid is high, the production and treatment costs are low, the cure rate is high, and the environment is friendly.

Description

A kind of preparation method of ceftiofur acid long-acting injection

Technical field:

The invention belongs to the technical field of medicine preparation, and relates to a preparation method of ceftiofuric acid long-acting injection, which adopts the combination of cyclodextrin inclusion technology and temperature-sensitive in-situ gel slow-release technology to provide a new type of cefotaxime The production process of Fu long-acting injection.

Background technique:

采用固体分散技术以氢化蓖麻油为缓释载体，通过有机试剂乳化制备盐酸头孢噻呋长效制剂，有机试剂的添加增强制剂毒性，且制剂分层，使用前需摇匀，易导致注射不均；进口的头孢噻呋长效制剂应用较多的是美国辉瑞动物保健公司的

该产品以头孢噻呋酸制备头孢噻呋晶体游离酸，虽克服头孢噻呋肌肉注射半衰期短的不足，但制剂有局部刺激性，单点注射不能超过2mL，使用前需摇匀，制剂粘度大，注射相对困难，且其价格高昂，降低生产的经济效益。因此，研究开发一种新型头孢噻呋酸长效注射液的制备方法具有重要的临床意义。Ceftiofur is the third-generation antibiotic for animals. The prototype of ceftiofur is ceftiofur acid, which is insoluble in water. Ceftiofur sodium salt is ceftiofur sodium, which is easily soluble in water and has poor stability after dissolution. It needs to be used immediately It is prepared now and has a short half-life after injection, so frequent administration is required; ceftiofur hydrochloride, namely ceftiofur hydrochloride, is insoluble in water and is often used to prepare ceftiofur hydrochloride long-acting suspension injection. Clinical routine preparations mainly include ceftiofur sodium freeze-dried powder, which needs to be injected once a day. The stress caused by frequent injections has a certain impact on the therapeutic effect, and the growth of animals is inhibited to varying degrees, resulting in economic benefits. Reduced; the existing domestic ceftiofur long-acting suspension injection

Using solid dispersion technology and using hydrogenated castor oil as a slow-release carrier, the long-acting preparation of ceftiofur hydrochloride was prepared by emulsification of organic reagents. The addition of organic reagents enhances the toxicity of the preparation, and the preparation is layered. Shake well before use, which may easily lead to uneven injection ; Imported ceftiofur long-acting preparations are mostly used by Pfizer Animal Health of the United States

This product uses ceftiofur acid to prepare ceftiofur crystalline free acid. Although it overcomes the short half-life of ceftiofur intramuscular injection, the preparation has local irritation, and the single point injection should not exceed 2mL. Shake well before use, and the preparation has a high viscosity , injection is relatively difficult, and its price is high, which reduces the economic benefits of production. Therefore, researching and developing a preparation method of a novel ceftiofuric acid long-acting injection has important clinical significance.

Invention content:

The purpose of the present invention is to overcome the shortcomings of the prior art, seek to design and provide a preparation method for a novel ceftiofuric acid long-acting injection, and adopt inclusion technology combined with in situ gel slow-release technology to prepare intramuscular injection. The long-acting ceftiofur injection that forms an in situ gel through phase transition in vivo overcomes the shortcomings of poor solubility of ceftiofur and short half-life after intramuscular injection of ceftiofur, and solves the toxicity of existing long-acting ceftiofur preparations , Injection local irritation and preparation layering problems.

In order to achieve the above object, the concrete processing steps of the present invention are:

(1) Put ceftiofuric acid and 2-hydroxypropyl-β-cyclodextrin in a molar mass ratio of 1:1 to 2 and mix them in a ball mill, grind them thoroughly at room temperature, mix well and sieve Obtain ceftiofur acid inclusion compound;

(2) Dissolve sodium alginate in sterile water, add Poloxamer 407 and Poloxamer 188, and store at 4°C for 12-24 hours to completely dissolve Poloxamer 407 and Poloxamer 188 Afterwards, sterilize at a temperature of 121° C., and cool in an ice bath to obtain a transparent solution;

(3) After magnetically stirring the transparent solution prepared in step (2) at a temperature of 4°C and a rotational speed of 150r/min, the weight ratio of sodium alginate:ceftiofuric acid=0.1～0.3:5～10 The ceftiofur acid inclusion compound is added to fully disperse the ceftiofur acid inclusion compound to obtain a ceftiofur acid long-acting injection.

The percentages by weight of the components of the ceftiofuric acid long-acting injection prepared by the present invention are respectively: 5-10% for ceftiofuric acid, 13-28% for 2-hydroxypropyl-β-cyclodextrin, 13-28% for porol Sham 407 is 20-30%, poloxamer 188 is 2-5%, sodium alginate is 0.1-0.3%, the rest is sterile water, the total is 100%.

Compared with the prior art, the present invention has simple preparation process, long half-life of product intramuscular injection, high solubility of ceftiofur, and solves the problems of toxicity, injection local irritation and preparation layering of existing ceftiofur long-acting preparations , low production and treatment costs, high cure rate, and environmentally friendly.

Detailed ways:

Below by embodiment the present invention will be further described.

Example 1:

The concrete process steps of present embodiment preparation ceftiofuric acid long-acting injection are:

(1) Put 0.50 g of ceftiofur acid and 1.40 g of 2-hydroxypropyl-β-cyclodextrin into a ball mill and mix them evenly, grind them at room temperature for 15 minutes, mix well and sieve to obtain ceftiofur acid inclusion compound ;

(2) Dissolve 0.01g of sodium alginate in 6g of sterile water, add 2.00g of poloxamer 407 and 0.25g of poloxamer 188, store in a refrigerator at 4°C for 24 hours to completely dissolve, and then autoclave at 121°C. Cool in an ice bath to obtain a transparent solution;

(3) Magnetically stir the transparent solution at 4°C and 150r/min, add 1.90g of ceftiofur acid inclusion compound to fully disperse the ceftiofur acid inclusion compound, and add sterile water after the dispersion is uniform. Make up to 10mL.

The percentage by weight of each component of the ceftiofuric acid injection prepared in this example is: 5.0% for ceftiofuric acid, 14.0% for 2-hydroxypropyl-β-cyclodextrin, and 20% for poloxamer 407 %, poloxamer 188 is 2.5%, sodium alginate is 0.1%, the rest is sterile water, the total is 100%.

Example 2:

The preparation process of this embodiment is the same as that of Example 1, and the weight percentages of each component in the product injection are 10% for ceftiofuric acid, 20% for 2-hydroxypropyl-β-cyclodextrin, and 20% for poloxamer. 407 is 25%, poloxamer 188 is 4%, sodium alginate is 0.3%, and the rest is sterile water, the total is 100%.

Pharmacokinetic studies of the ceftiofuric acid long-acting injection prepared in this example after intramuscular injection in the neck triangle of Laoshan dairy goats showed that, with 5 mg/kg body weight of ceftiofuric acid long-acting injection The half-life is 17.13h, and the minimum bactericidal blood concentration of 0.2μg/mL can be maintained for at least 48h. Ceftiofuric acid long-acting injection has a long elimination half-life and bactericidal maintenance time, and high bioavailability; pharmacodynamic test on clinical pullorum of piglets It shows that the prepared ceftiofur acid long-acting injection 5mg/kg is administered once every three days, compared with the same dose of ceftiofur sodium administered once a day, the cure rates after 6 days are 87.5% and 72.5%, respectively.

In this example, the solubility of ceftiofuric acid in water measured by high performance liquid chromatography (HPLC) is 0.03 mg/mL, and the solubility after preparation of ceftiofuric acid inclusion compound is 2.18 mg/mL, and the solubility is 72.7 times.

The ceftiofuric acid long-acting injection prepared in this example has a phase transition temperature of 35.5°C and a steady-state viscosity of 0.28 Pa·s. The results of long-term storage properties showed that the drug was dispersed well without obvious stratification.

The local irritation test of the ceftiofuric acid long-acting injection prepared in this embodiment to the intramuscular injection of rabbits showed that there was no obvious change in the appearance of the injected local muscle compared with the normal saline control group, and there was no necrosis in the muscle in histological examination, with only a very small amount. Less inflammatory cell infiltration, indicating that local injection is non-irritating.

Claims (2)

1. the preparation method of ceftiofur acid long-acting injection is characterized in that concrete processing step is:

(1), be that the ratio of 1:1～2 is put into the ball mill mixing with ceftiofur acid and 2-HP-in the mole mass ratio, fully grind under the room temperature, fully mixing sieves and obtains ceftiofur acid clathrate;

(2), sodium alginate is dissolved in adds poloxamer 407 and poloxamer 188 behind the sterilized water, under 4 ℃ of temperature conditions, store 12～24h, make poloxamer 407 and poloxamer 188 dissolve the back fully and sterilize under 121 ℃ of temperature, the ice bath cooling obtains clear solution;

(3), step (2) make with clear solution after 4 ℃ of temperature and 150r/min speed conditions lower magnetic force stir, press sodium alginate: the weight proportion of ceftiofur acid=0.1～0.3:5～10 adds ceftiofur acid clathrate, obtains ceftiofur acid long-acting injection after ceftiofur acid clathrate fully is uniformly dispersed.

2. the preparation method of ceftiofur according to claim 1 acid long-acting injection, the percentage by weight of each component of ceftiofur acid long-acting injection that it is characterized in that preparing is respectively: ceftiofur acid is 5～10%, the 2-HP-is 13～28%, poloxamer 407 is 20～30%, poloxamer 188 is 2～5%, sodium alginate is 0.1～0.3%, and all the other are sterilized water, and total amount is 100%.