阅读说明：本技术 一种长效复方泰地罗新注射液及其制备方法 (Long-acting compound tylonolide injection and preparation method thereof ) 是由 方炳虎 谢孟娟 张桂君 梁劲康 于 2020-05-27 设计创作，主要内容包括：本发明公开了一种长效复方泰地罗新注射液,主要成分为泰地罗新、氟尼辛葡甲胺和青藤碱,为兽医临床提供一种动物专用的既可治疗敏感菌引起的呼吸系统感染性疾病,又可辅助治疗减轻患病动物应激的长效复方注射液,联合用药能够明显改善临床症状,并可以增强抗菌药物活性,减少药物使用量和给药次数,减少动物应激,增强动物顺应性,降低劳动强度,使用方便。(The invention discloses a long-acting compound tylonolide injection, which mainly comprises tylonolide, flunixin meglumine and sinomenine, and provides a long-acting compound injection which is special for animals and can treat respiratory infectious diseases caused by sensitive bacteria and can assist in treating and relieving the stress of sick animals for veterinary clinic.)

1. A compound Tildipirosin injection is characterized by comprising Tildipirosin, flunixin meglumine inclusion compound, sinomenine, polyvinylpyrrolidone, poloxamer and solvent; every 100ml of injection contains: 2-10 g of tildipirosin, 2-6 g of flunixin meglumine, 0.02-0.2 g of sinomenine, 1-20 g of polyvinylpyrrolidone, 1-20 g of poloxamer and the balance of solvent; wherein flunixin meglumine and sinomenine are added in the form of inclusion compound.

2. The compound tildipirosin injection according to claim 1, wherein each 100ml of the injection comprises the following components: 4-9 g of tildipirosin, 3-5g of flunixin meglumine, 0.05-0.1 g of sinomenine, 3-8 g of polyvinylpyrrolidone, 5-15 g of poloxamer and the balance of solvent.

3. The compound tildipirosin injection according to claim 1, wherein the polyvinylpyrrolidone is any one of polyvinylpyrrolidone K10, polyvinylpyrrolidone K15, polyvinylpyrrolidone K17, and polyvinylpyrrolidone K30; the poloxamer is any one of poloxamer 124, poloxamer 188, poloxamer 237, poloxamer 338 and poloxamer 407; more preferably, the poloxamer is poloxamer 407; the solvent is propylene glycol or a mixed solution of propylene glycol and one or more of the following solvents: ethanol, polyethylene glycol and glycerol formal.

4. The compound tildipirosin injection according to claim 3, wherein the solvent is a mixed solution of propylene glycol, polyethylene glycol and glycerol formal, and the volume ratio of the propylene glycol, the polyethylene glycol and the glycerol formal is (4-10): 0.8-1.0): 1; the polyethylene glycol comprises polyethylene glycol 300 or polyethylene glycol 600.

5. The compound tildipirosin injection according to claim 1, wherein flunixin meglumine and sinomenine are added in the form of cyclodextrin inclusion compound, wherein the cyclodextrin is β -cyclodextrin or hydroxypropyl- β -cyclodextrin, and the preparation method of the cyclodextrin inclusion compound is as follows: uniformly mixing flunixin meglumine and sinomenine to obtain a mixture a; adding cyclodextrin and the mixture a into a 70% ethanol water solution according to the mass ratio (1.1-2): 1, stirring and reacting for 4-6 hours to obtain a clear and transparent inclusion compound solution, and performing spray drying to obtain the cyclodextrin inclusion compound of flunixin meglumine and sinomenine.

6. The compound tildipirosin injection according to claim 5, wherein the preparation method of the cyclodextrin inclusion compound of flunixin meglumine and sinomenine comprises: dissolving flunixin meglumine and sinomenine in a small amount of 70% ethanol water solution, taking beta-cyclodextrin or hydroxypropyl-beta-cyclodextrin which is 1.1-2 times of the amount of the flunixin meglumine and sinomenine substances, adding the beta-cyclodextrin or the hydroxypropyl-beta-cyclodextrin into the 70% ethanol water solution, mixing the two solutions, stirring and reacting for 4-6 hours at 50 ℃, performing complete inclusion reaction, and performing spray drying to obtain the cyclodextrin inclusion compound of the flunixin meglumine and the sinomenine.

7. The preparation method of the compound tildipirosin injection of claim 1, which is characterized by mainly comprising the following steps:

1) mixing polyvinylpyrrolidone, poloxamer and 50-70% of a prescribed amount of solvent until the polyvinylpyrrolidone, the poloxamer and the solvent are dissolved, adding the tildipirosin, and stirring to obtain a solution A;

2) mixing and stirring 10-20% of a prescription amount of a solvent, flunixin meglumine and sinomenine to obtain a solution B;

3) mixing the solution A in the step 1) and the solution B in the step 2), mixing with the rest of solvent, and filtering for later use; and (4) inspecting the semi-finished product, filling nitrogen and encapsulating after the semi-finished product is qualified, and sterilizing at 100-121 ℃ for 15-20 min to obtain the long-acting compound tildipirosin injection.

8. The preparation method of claim 7, wherein the stirring in the step 1) is performed at a rotation speed of 50-70 r/min for 15-25 min; the stirring speed in the step 2) is 50-70 r/min, and the stirring time is 15-25 min; the aperture of the filter membrane for filtration is 0.20-0.24 μm.

9. The compound tildipirosin injection as claimed in any one of claims 1 to 6, for use in veterinary drug field.

Technical Field

The invention relates to the field of veterinary drugs, and in particular relates to a long-acting compound tildipirosin injection and a preparation method thereof.

Background

In recent years, with the highly intensive breeding industry, respiratory infectious diseases of pigs and cattle caused by sensitive bacteria such as actinobacillus pleuropneumoniae, haemophilus parasuis, pasteurella multocida, and mannheimia haemolytica have become more serious, and in many cases, clinical symptoms such as fever and pain are accompanied, which seriously affect the health of animals and cause serious economic loss. Therefore, a long-acting compound injection which can not only aim at pathogenic bacteria, but also can assist in treating and relieving the stress of the sick animals is developed to meet the clinical medication requirements of veterinarians at present and ensure and promote the healthy development of the breeding industry.

Tildipirosin is a new macrolide antibiotic specially used for animals, is approved to be on the market by FDA, EMEA and China at present, has antibacterial activity on gram-positive bacteria and gram-negative bacteria, and is used for treating respiratory diseases of pigs and cows caused by infection of bacteria, mycoplasma and the like. The tylonolide has excellent pharmacokinetic characteristics, and has the advantages of quick absorption, short peak reaching time, high concentration in lung tissues, high bioavailability, slow elimination, lasting drug effect, high safety and very wide application prospect after single intramuscular injection or subcutaneous injection administration.

Flunixin meglumine is a very effective non-steroidal anti-inflammatory drug with anti-inflammatory, antipyretic and analgesic effects, can obviously improve clinical symptoms when used alone or in combination with antibiotics, and can enhance the activity of antibacterial drugs, and the drug is widely applied clinically.

Sinomenine (SIN) is an alkaloid monomer separated from the root and stem of the Chinese medicinal caulis Sinomenii, is a main active ingredient of caulis Sinomenii playing a role in treatment, has unique pharmacological action, and can be used for treating inflammation, autoimmune diseases and the like. In recent years, researches show that sinomenine also has the effects of immunoregulation, anti-inflammatory, anti-tumor, protection after organ injury, analgesia and the like.

At present, the tylonolide injection on the market is a single preparation, and when the tylonolide injection is used for clinically treating respiratory system infectious diseases such as pigs, cows and the like, the injection needs medicines with excessive volume, has high irritation, and aggravates pain and stress response; although flunixin meglumine is rapidly absorbed, the excretion is fast, the elimination half-life is short, and the problems that the medicine is frequently taken, the labor intensity is increased and the sick animals are stressed for many times exist.

In 1950, the U.S. Food and Drug Administration (FDA) firstly approved antibiotics to be used as feed additives, so that the antibiotics are comprehensively popularized and applied to animal breeding industry and play an important role in preventing and treating infectious diseases of animals, promoting the growth of the animals, improving the feed conversion rate and the like. While almost as early as the first penicillin started to be used in the 40 th 20 th century, bacterial resistance to it appeared, scientists were also aware of the problem of antibiotic resistance. With the recent serious harm to human health from antibiotic resistance, scientists have begun to develop strategies to combat resistance. The strategies mainly comprise vigorously mining and screening novel antibiotics and antibacterial drugs, researching novel action targets, researching and developing antibiotic adjuvants and the like. The antibiotic adjuvant is a compound which does not have an antibacterial effect per se, but can act synergistically with the antibiotic to promote the bactericidal activity of the antibiotic on bacteria, particularly resistant bacteria. The antibiotic adjuvant can interact with the antibiotic to promote each other, so that the use amount of single antibiotic is reduced to the maximum, the treatment effect of the antibiotic is improved, and the occurrence of clinical drug resistance is reduced. Currently, antibiotic adjuvants of Changbai sword mainly comprise probiotics and the like. In China, the plant source natural product has abundant data, mainly comprises substances such as polysaccharide, terpenoids, lignin, coumarin, flavone, alkaloid and the like, and has good effects in the aspects of bacteriostasis, inflammation diminishing, cancer resistance, immunoregulation and the like. The search for natural products of plant origin as novel antibiotic adjuvants has been one of the research hotspots.

Disclosure of Invention

In order to meet the clinical requirement and overcome the defects of the prior art, the invention provides a long-acting compound injection containing tylosin, flunixin meglumine and sinomenine and a preparation method thereof.

In order to achieve the above object, the present invention provides the following technical solutions:

the invention provides a long-acting compound tylonolide injection, which comprises tylonolide, flunixin meglumine inclusion compound, sinomenine, polyvinylpyrrolidone, poloxamer and solvent; every 100ml of injection contains: 2-10 g of tildipirosin, 2-6 g of flunixin meglumine, 0.02-0.2 g of sinomenine, 1-20 g of polyvinylpyrrolidone, 1-20 g of poloxamer and the balance of solvent; wherein flunixin meglumine and sinomenine are added in the form of inclusion compound.

Sinomenine is an alkaloid, and has pharmacological effects including immunoregulation and antiinflammatory, anti-tumor, organ injury protecting, and analgesic effects. The long-acting compound tylonolide injection provided by the invention is added with sinomenine in an inclusion compound form, so that the sinomenine can be released slowly and durably. In the long-acting compound tildipirosin injection, sinomenine is used as an antibiotic adjuvant and has a synergistic effect with the antibiotic tildipirosin, so that the antibacterial activity of the tildipirosin is greatly improved, the use amount of the antibiotic tildipirosin is greatly reduced under the condition of the same antibacterial effect, the occurrence of bacterial drug resistance is delayed, and the antibacterial effect is higher than that of the single antibiotic, so that the antibacterial process is safe and efficient.

Preferably, each 100ml of injection comprises the following components: 4-9 g of tildipirosin, 3-5g of flunixin meglumine, 0.05-0.1 g of sinomenine, 3-8 g of polyvinylpyrrolidone, 5-15 g of poloxamer and the balance of solvent.

Preferably, the polyvinylpyrrolidone is any one of polyvinylpyrrolidone K10, polyvinylpyrrolidone K15, polyvinylpyrrolidone K17 and polyvinylpyrrolidone K30; more preferably, the polyvinylpyrrolidone is polyvinylpyrrolidone K30.

Preferably, the poloxamer is any one of poloxamer 124, poloxamer 188, poloxamer 237, poloxamer 338 and poloxamer 407; more preferably, the poloxamer is poloxamer 407.

Preferably, the solvent is propylene glycol or a mixture of propylene glycol and one or more of the following solvents: ethanol, polyethylene glycol and glycerol formal.

Preferably, the solvent is a mixed solution of propylene glycol, polyethylene glycol and glycerol formal, and the volume ratio of the propylene glycol, the polyethylene glycol and the glycerol formal is (4-10) to (0.8-1.0): 1.

preferably, the polyethylene glycol comprises polyethylene glycol 300 or polyethylene glycol 600.

Preferably, flunixin meglumine and sinomenine are added in the form of a cyclodextrin inclusion compound, wherein the cyclodextrin is preferably beta-cyclodextrin or hydroxypropyl-beta-cyclodextrin, and the cyclodextrin inclusion compound is prepared by the following steps: uniformly mixing flunixin meglumine and sinomenine to obtain a mixture a; adding cyclodextrin and the mixture a into a 70% ethanol water solution according to the mass ratio (1.1-2): 1, stirring and reacting for 4-6 hours to obtain a clear and transparent inclusion compound solution, and performing spray drying to obtain the cyclodextrin inclusion compound of flunixin meglumine and sinomenine.

Preferably, the preparation method of the cyclodextrin inclusion compound of flunixin meglumine and sinomenine comprises the following steps: dissolving flunixin meglumine and sinomenine in a small amount of 70% ethanol water solution, taking beta-cyclodextrin or hydroxypropyl-beta-cyclodextrin which is 1.1-2 times of the amount of the flunixin meglumine and sinomenine substances, adding the beta-cyclodextrin or the hydroxypropyl-beta-cyclodextrin into the 70% ethanol water solution, mixing the two solutions, stirring and reacting for 4-6 hours at 50 ℃, performing complete inclusion reaction, and performing spray drying to obtain the cyclodextrin inclusion compound of the flunixin meglumine and the sinomenine.

Flunixin meglumine and sinomenine are subjected to cyclodextrin inclusion in a mixture form, and compared with the method that flunixin meglumine and sinomenine are subjected to cyclodextrin inclusion separately and then are physically mixed, the mixing uniformity is higher, so that the flunixin meglumine and sinomenine inclusion compound are dispersed more uniformly, and when a subsequent preparation is used, the flunixin meglumine and sinomenine are dissolved out and released uniformly and durably.

The invention also aims to provide the long-acting compound tylonolide injection and the preparation method thereof, wherein the long-acting compound tylonolide injection comprises the following steps:

1) mixing polyvinylpyrrolidone, poloxamer and 50-70% of a prescribed amount of solvent until the polyvinylpyrrolidone, the poloxamer and the solvent are dissolved, adding the tildipirosin, and stirring to obtain a solution A;

2) mixing and stirring 10-20% of a prescription amount of a solvent, flunixin meglumine and sinomenine to obtain a solution B;

3) mixing the solution A in the step 1) and the solution B in the step 2), mixing with the rest of solvent, and filtering for later use; inspecting the semi-finished product, filling nitrogen gas for encapsulation after the semi-finished product is qualified, and sterilizing at 100-121 ℃ for 15-20 min to obtain the long-acting compound tildipirosin injection;

4) preferably, the rotating speed of stirring in the step 1) is 50-70 r/min, and the stirring time is 15-25 min.

5) Preferably, the rotating speed of stirring in the step 2) is 50-70 r/min, and the stirring time is 15-25 min.

6) Preferably, the pore diameter of the filter membrane for filtration is 0.20 to 0.24 μm.

The long-acting compound tylonolide injection provided by the invention is applied to the field of veterinary medicines.

Compared with the prior art, the invention has the beneficial effects that:

1) the invention provides a long-acting compound tylonolide injection, which mainly comprises tylonolide, flunixin meglumine and sinomenine, and provides a long-acting compound injection which is special for animals and can treat respiratory infectious diseases caused by sensitive bacteria and relieve the stress of sick animals in an auxiliary way for veterinary clinic.

2) In the long-acting compound tildipirosin injection provided by the invention, flunixin meglumine and sinomenine are added in a form of a cyclodextrin inclusion compound, the slow release effect is good, the bioavailability is obviously improved, and the sinomenine component is added to be used as an antibiotic adjuvant, so that the antibacterial activity of the tildipirosin is greatly enhanced, an excellent antibacterial effect can be achieved under a low dose, and the drug resistance of bacteria is effectively improved.

3) The solvent used by the long-acting compound tylonolide injection provided by the invention can be well dissolved with water, and part of the medicine can be immediately released and absorbed after injection administration, so that the long-acting compound tylonolide injection can quickly take effect.

4) The high molecular compound polyethylene used in the invention mainly plays the roles of long-acting slow release, cosolvent, stabilizer and the like in the preparation system than the pyrrolidone K30 and the poloxamer 407, so that the medicine is slowly released at the injection site, the medicine effect is more durable, the quality stability is higher, and the biocompatibility is good.

5) The injection provided by the invention can reduce the usage amount and administration times of medicines, reduce animal stress, enhance the animal compliance, reduce the labor intensity and is convenient to use.

6) The preparation method of the long-acting compound tildipirosin injection has the advantages of simple process and convenient operation, and is suitable for large-scale industrial production.

Detailed Description

It is to be understood that the following detailed description is exemplary and is intended to provide further explanation of the invention as claimed. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

It is noted that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of exemplary embodiments according to the invention. As used herein, the singular forms "a", "an" and "the" are intended to include the plural forms as well, and it should be understood that when the terms "comprises" and/or "comprising" are used in this specification, they specify the presence of stated features, steps, operations, devices, components, and/or combinations thereof, unless the context clearly indicates otherwise.

The reagents used in this example are commercially available.