CN117503698A - Taidi Luo Xintong profen injection and preparation method thereof - Google Patents

Taidi Luo Xintong profen injection and preparation method thereof Download PDF

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CN117503698A
CN117503698A CN202311676390.XA CN202311676390A CN117503698A CN 117503698 A CN117503698 A CN 117503698A CN 202311676390 A CN202311676390 A CN 202311676390A CN 117503698 A CN117503698 A CN 117503698A
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injection
tylosin
ketoprofen
luo
xintong
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刘漫
赵新祥
杨申永
李建国
方军
王玲
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Amicogen China Biopharm Co Ltd
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Amicogen China Biopharm Co Ltd
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
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    • A61K31/19—Carboxylic acids, e.g. valproic acid
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
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    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6949—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
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    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

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Abstract

The invention discloses a tylosin Luo Xintong profen injection and a preparation method thereof, and belongs to the technical field of veterinary injection. The invention provides a tylosin Luo Xintong ibuprofen injection which is characterized by comprising tylosin, ketoprofen, cyclohexyl six-membered melon ring, sorbitol and water for injection. The injection prepared by the invention is water-soluble injection, adopts cyclohexyl six-membered melon ring as a solubilizer, adopts sorbitol as an antifreezing agent and adopts water for injection as a solvent. Compared with the prior art, the invention uses the cyclohexyl six-membered melon ring to encapsulate the tylosin and the ketoprofen, improves the sustained and controlled release effect of the tylosin and the ketoprofen drug molecules in animal bodies, and has obvious curative effect on treating acute and chronic pneumonia of animals. The invention adds the anti-freezing agent sorbitol, can achieve the anti-freezing at minus 20 ℃ and provides great convenience for the use of winter samples.

Description

Taidi Luo Xintong profen injection and preparation method thereof
Technical Field
The invention relates to the field of veterinary injection, in particular to a tylosin Luo Xintong profen injection and a preparation method thereof.
Background
Tylosin (tilapirosin) is a novel animal-specific macrolide antibiotic, originally developed by intel-titewei international limited (Intervet International, BV), as a tylosin derivative. The Taidi Luo Xinwei broad-spectrum antibacterial agent is effective for gram-positive bacteria and partial gram-negative bacteria, and especially has strong antibacterial activity on pathogenic bacteria (such as Pasteurella multocida, actinobacillus pleuropneumoniae, bordetella bronchiseptica, haemophilus parasuis, and hemolytic Mannheim) causing respiratory diseases of pigs, cattle and sheep. Studies show that the antibacterial effect of the tylosin on haemophilus parasuis and bordetella bronchiseptica is stronger than that of the florfenicol, and the antibacterial effect of the tylosin on actinobacillus pleuropneumoniae and pasteurella multocida is weaker.
Ketoprofen (Ketoprofen) is a phenylpropionic acid derivative, which is a non-steroidal anti-inflammatory drug. Ketoprofen can selectively block the action link of cyclooxygenase in the metabolic process of arachidonic acid, block the synthesis path of prostaglandin E1 (PGE 1), and restore the body temperature of animals with fever to normal, without obvious influence on normal body temperature, and has antiinflammatory, analgesic and antipyretic effects. The nonsteroidal anti-inflammatory drug can relieve disease symptoms and plays a vital role in the progress of diseases after healing.
In recent years, the incidence rate of respiratory diseases of animals is gradually increased, and when the animals are ill, clinical symptoms are accompanied with inflammatory reactions (fever, pain, local red swelling and the like) in many cases, and a series of stress reactions are generated, so that the animals do not eat, grow slowly, the feed conversion rate is reduced, and even die, and the economic benefits of farms are seriously affected. Therefore, the prevention and control of animal respiratory diseases should use antibacterial and antiviral drugs, and at the same time, it is also necessary to diminish inflammation to relieve clinical symptoms (fever and pain). The technology provides a tylosin and ketoprofen compound injection, provides a veterinary compound pharmaceutical composition for efficiently treating animal respiratory diseases, solves the problems of large dosage, poor curative effect, large toxic and side effects and the like of single medicaments, and prepares the pharmaceutical composition into an injection solution, so that the medicament has quicker effect and more remarkable effect.
The patent with application number 202010463185.5 discloses a compound tylosin injection, which is prepared by clathrating flunixin meglumine and sinomenine by using hydroxypropyl beta cyclodextrin, spray drying to obtain a clathrate, and then mixing with auxiliary materials, solvents and tylosin for complete dissolution. The prescription of the patent uses a large amount of hydroxypropyl beta cyclodextrin, absolute ethyl alcohol and propylene glycol, and the hydroxypropyl beta cyclodextrin has obvious solubilization effect, but the FDA only approves itraconazole injection and long-acting subcutaneous implant of levonorgestrel up to the present(levunorgestral) Implants hydroxypropyl beta cyclodextrin was used. Adverse reactions of hydroxypropyl beta cyclodextrin injection are mainly concentrated in nephrotoxicity and hemolysis, and long-term injection can also cause cancerogenesis and mutation. The injection of organic solvents such as absolute ethyl alcohol and propylene glycol often causes animal stress problems such as injection pain and injection site swelling. The patent application number 202310108724.7 discloses a veterinary compound tylosin injection and a preparation method thereof, and the compound preparation not only uses a large amount of hydroxypropyl beta cyclodextrin, but also has a complex preparation process, and is difficult to be suitable for mass production.
Based on the above situation, the invention provides a tylosin Luo Xintong profen injection and a preparation method thereof, which can effectively overcome the problems in the background technology.
Disclosure of Invention
In view of the defects of the prior art, the invention uses the cyclohexyl six-membered cucurbituril as a solubilizer, takes a special hydrophobic cage-shaped structure to generate a hydrophobic cage-shaped effect with the tylosin and the ketoprofen to form a self-assembled host-object inclusion compound, increases the water solubility and the stability of the tylosin and the ketoprofen, and prepares the tylosin Luo Xintong-profen compound injection for efficiently treating animal respiratory diseases. The invention has simple prescription process, no need of adding a large amount of propylene glycol and absolute ethyl alcohol, small medicine irritation and high safety. The invention is a compound preparation, and solves the problems of large dosage, poor curative effect, large toxic and side effects and the like of single medicine. Meanwhile, the inclusion technology is adopted, so that the medicine has longer acting time, quicker acting and more obvious effect.
In order to achieve the above purpose, the technical scheme adopted by the application is as follows:
the tylosin Luo Xintong profen injection consists of the following components: tylosin, ketoprofen, an antifreezing agent, a solubilizer and a solvent for injection; the mass ratio of the tylosin to the ketoprofen is 1:0.5 to 1:1.5;
the invention relates to a compound preparation of tylosin and ketoprofen, wherein the tylosin is macrolide antibiotics, and when a body is invaded by bacteria and viruses, the tylosin can achieve the antibacterial effect by affecting the synthesis of bacterial proteins. At the same time, prostaglandins are synthesized and released by the action of cyclooxygenase. Prostaglandin has certain correlation with body inflammatory reaction and pain, and ketoprofen can achieve antipyretic, analgesic and anti-inflammatory effects by inhibiting prostaglandin. Ketoprofen can relieve clinical symptoms during treatment, so that animals can recover diet as soon as possible, normal physiological functions can be recovered, and the ketoprofen plays a good auxiliary role in treating tylosin. Meanwhile, the two are formed into a inclusion complex by the cyclohexyl six-membered melon ring, so that the activity of the antibiotics can be improved, and the treatment effect is far better than that of a single preparation.
Both the tylosin and the ketoprofen are indissolvable in water, the long-term storage content of the single preparation is reduced, the curative effect is reduced, and the generated degradation impurities have certain toxicity to organisms. The invention uses cyclohexyl six-membered melon ring as solubilizer, and the special cage structure with outer hydrophilic-inner hydrophobic can generate hydrophobic cage action with tylosin and ketoprofen to form self-assembled host-object inclusion compound. The inclusion complex not only increases the solubility of the drug in water, but also improves the stability of the tylosin and ketoprofen during the shelf life.
The mass ratio of the solubilizer to the tylosin is as follows: 1:1;
the mass ratio of the antifreezing agent to the tylosin is as follows: 1:10;
the mass ratio of the injection solvent to the tylosin is as follows: 1:8.3
The antifreezing agent is sorbitol; the solvent used in the injection is water for injection, sorbitol is an antifreezing agent, and organic solvents such as propylene glycol, absolute ethyl alcohol and the like are not required to be added, so that the injection is non-irritating, and the problems of injection pain, injection site swelling and the like caused during injection are solved. And the antifreeze is added into the sample, so that the antifreeze at-20 ℃ can be achieved, and convenience is brought to the use of the northern winter sample.
The solubilizer is cyclohexyl six-membered cucurbituril.
The solvent for injection is water for injection.
Preferably, the mass ratio of the tylosin to the ketoprofen is 1:1.
the preparation method of the tylosin Luo Xintong profen injection comprises the following specific steps:
step one: taking water for injection with the formula amount of 90%, adding a solubilizer, and stirring and dissolving completely;
step two: adding tylosin and ketoprofen, and stirring until the tylosin and ketoprofen are completely dissolved;
step three: sorbitol is added and stirred to dissolve completely.
Step four: adding the rest of water for injection, and stirring and mixing uniformly;
step five: filtering and sterilizing the solution obtained in the step four by a microporous filter membrane with the thickness of 0.22 mu m, thus obtaining the tylosin Luo Xintong profen injection.
The cyclohexyl six-membered melon ring can be metabolically degraded in vivo, is discharged out of the body along with urine, and has no hemolysis and no toxic or side effect. The invention uses the cyclohexyl six-membered cucurbituril as the solubilizer, and the cyclohexyl six-membered cucurbituril can be discharged from the body after entering the body to release the medicine, thereby having no toxic or side effect on the body. Avoiding toxic and side effects such as hemolysis and the like caused by using cyclodextrin as a cosolvent and improving the safety of the injection.
The tylosin Luo Xintong profen injection is applied to the preparation of medicines for treating acute and chronic pneumonia.
The beneficial effects of the invention are as follows:
(1) The invention uses the cyclohexyl six-membered cucurbituril as the solubilizer, the cyclohexyl six-membered cucurbituril, the tylosin and the ketoprofen form a stable inclusion compound, after the medicine enters the body, the tylosin and the ketoprofen can be rapidly released through the change of the pH value in the body, the blood concentration with therapeutic effect is achieved, and the tylosin can be released in a large amount at a constant speed for a long time through the balance process of the concentration difference of the medicine in the body and the outside, so that the medicine takes effect quickly, the medicine effect can be maintained for a long time, the injection times are reduced, the bioavailability is improved, and the medicine has remarkable curative effect on the treatment of acute and chronic pneumonia.
(2) The cyclohexyl six-membered melon ring has the special hydrophobic cage-shaped structure, increases the water solubility and stability of the tylosin and the ketoprofen, improves the antibacterial effect of the tylosin, makes up the defect of poor antibacterial effect on actinobacillus pleuropneumoniae and pasteurella multocida, and has obvious curative effect on acute and chronic pneumonia of animals.
(3) The invention uses the cyclohexyl six-membered cucurbituril as the solubilizer, and the cyclohexyl six-membered cucurbituril can be discharged from the body after entering the body to release the medicine, thereby having no toxic or side effect on the body. Avoiding toxic and side effects such as hemolysis and the like caused by using cyclodextrin as a cosolvent and improving the safety of the injection.
(4) Cucurbiturils, also known as cucurbiturils, are known by the structural name pumpkin-like, and are a further novel caged host compound following macrocyclic compounds such as crown ethers, calixarenes, and the like. From the structural point of view, the cucurbituril is provided with a hydrophobic cavity and a port formed by surrounding carbonyl oxygen atoms, the structure is favorable for the cucurbituril to form stable inclusion complex at the port by utilizing organic micromolecules, biological macromolecules or dipolar or ionic compounds with proper inclusion size through cage-shaped hydrophobic effect, hydrogen bond, van der Waals force, ion dipolar and other non-covalent weak interaction selectivity in a solution state, and the guest molecules can realize reversible inclusion release through the change of external conditions (such as pH value, concentration difference and the like); functionally, due to the specificity of the cucurbituril structure and the excellent binding property with the guest molecule, the cucurbituril has important significance in aspects of drug transportation, slow release control, drug stability increase and the like. The cyclohexyl six-membered cucurbituril is a cyclohexane full-substituted compound of the six-membered cucurbituril, the solubility of the cyclohexane full-substituted compound in water and an organic solvent is obviously improved compared with that of the common cucurbituril, the drug-carrying molecule can be rapidly metabolized after entering the body, and meanwhile, researches on the toxicity of the cucurbituril by researchers at home and abroad show that the cucurbituril is nontoxic, can be used as a safe drug carrier, and has wide application in the field of pharmacy.
The melon ring port is surrounded by carbonyl oxygen atoms and has rigid cavity for enclosing various guest molecules. The power of its interaction with the object is generally derived from: 1) Hydrophilic port effects, i.e., the interaction of host molecules (cucurbiturils) with guest molecules (metal ions, etc.) through hydrogen bonds, ion-dipoles, etc., form host-guest complexes with certain stability. 2) The hydrophobic cage effect, i.e. the melon ring with its special hydrophobic cage structure, can react with various organic matters to form various self-assembled host-guest inclusion complexes. 3) The size of the guest molecule is matched with that of the cucurbituril cage body space, namely the size effect. Melon rings with different polymerization degrees provide different port diameters and cage spaces, and can be suitable for guest substances with different sizes and properties.
Detailed Description
The invention is further illustrated by, but is not limited to, the following specific examples.
The cyclohexyl six-membered cucurbituril is purchased from: western security Ji Yue biotechnology limited, cat No.: 6241, purity: 99 percent of
Example 1:
taidi Luo Xintong profen injection
The preparation method comprises the following steps:
step one: taking 90% of water for injection, adding cyclohexyl six-membered melon ring, stirring and dissolving completely;
step two: adding tylosin and ketoprofen, and stirring until the tylosin and ketoprofen are completely dissolved;
step three: sorbitol is added and stirred to dissolve completely.
Step four: adding the rest of water for injection, and stirring and mixing uniformly;
step five: filtering and sterilizing the solution obtained in the step four by a microporous filter membrane with the thickness of 0.22 mu m, thus obtaining the tylosin Luo Xintong profen injection.
Example 2:
taidi Luo Xintong profen injection
The preparation method comprises the following steps:
step one: taking 90% of water for injection, adding cyclohexyl six-membered melon ring, stirring and dissolving completely;
step two: adding tylosin and ketoprofen, and stirring until the tylosin and ketoprofen are completely dissolved;
step three: sorbitol is added and stirred to dissolve completely.
Step four: adding the rest of water for injection, and stirring and mixing uniformly;
step five: filtering and sterilizing the solution obtained in the step four by a microporous filter membrane with the thickness of 0.22 mu m, thus obtaining the tylosin Luo Xintong profen injection.
Example 3:
taidi Luo Xintong profen injection
The preparation method comprises the following steps:
step one: taking 90% of water for injection, adding cyclohexyl six-membered melon ring, stirring and dissolving completely;
step two: adding tylosin and ketoprofen, and stirring until the tylosin and ketoprofen are completely dissolved;
step three: sorbitol is added and stirred to dissolve completely.
Step four: adding the rest of water for injection, and stirring and mixing uniformly;
step five: filtering and sterilizing the solution obtained in the step four by a microporous filter membrane with the thickness of 0.22 mu m, thus obtaining the tylosin Luo Xintong profen injection.
The tylosin Luo Xintong profen injection prepared in examples 1-3 was heated to 60 ℃ for 10 days, and the influence of the proportion of tylosin and ketoprofen on the quality of the sample was examined by taking the properties, the content, the related substances and the isomers as evaluation indexes. The detection results are shown in Table 1.
TABLE 1 sample detection results of examples 1-3
Experimental results show that under the condition of high temperature for 10 days, the ratio of tulathromycin to ketoprofen in the embodiment 1 is 1:0.5, a small amount of long needle-shaped crystals are separated out, and the content of the tulathromycin is obviously reduced; the ratio of tulathromycin to ketoprofen in example 2 was 1:1, with no significant change in quality for days 0 and 10 at high temperature; in example 3, the ratio of tulathromycin to ketoprofen is 1:1.5, and a small amount of white powder is precipitated under the condition of high temperature for 10 days, so that the content of ketoprofen is obviously reduced.
Example 4:
taidi Luo Xintong profen injection
The preparation method comprises the following steps:
step one: taking 90% of water for injection, adding cyclohexyl six-membered melon ring, stirring and dissolving completely;
step two: adding tylosin and ketoprofen, and stirring until the tylosin and ketoprofen are completely dissolved;
step three: sorbitol is added and stirred to dissolve completely.
Step four: adding the rest of water for injection, and stirring and mixing uniformly;
step five: filtering and sterilizing the solution obtained in the step four by a microporous filter membrane with the thickness of 0.22 mu m, thus obtaining the tylosin Luo Xintong profen injection.
Example 5:
taidi Luo Xintong profen injection
The preparation method comprises the following steps:
step one: taking 90% of water for injection, adding cyclohexyl six-membered melon ring, stirring and dissolving completely;
step two: adding tylosin and ketoprofen, and stirring until the tylosin and ketoprofen are completely dissolved;
step three: sorbitol is added and stirred to dissolve completely.
Step four: adding the rest of water for injection, and stirring and mixing uniformly;
step five: filtering and sterilizing the solution obtained in the step four by a microporous filter membrane with the thickness of 0.22 mu m, thus obtaining the tylosin Luo Xintong profen injection.
Example 6:
taidi Luo Xintong profen injection
The preparation method comprises the following steps:
step one: taking 90% of water for injection, adding cyclohexyl six-membered melon ring, stirring and dissolving completely;
step two: adding tylosin and ketoprofen, and stirring until the tylosin and ketoprofen are completely dissolved;
step three: sorbitol is added and stirred to dissolve completely.
Step four: adding the rest of water for injection, and stirring and mixing uniformly;
step five: filtering and sterilizing the solution obtained in the step four by a microporous filter membrane with the thickness of 0.22 mu m, thus obtaining the tylosin Luo Xintong profen injection.
The characteristics, contents, related substances and isomers of the tyldinocap Luo Xinluo injection prepared in examples 4-6 were detected, and the results are shown in the following table:
table 20 days sample test results
The experimental result shows that the mass ratio of the tylosin to the cyclohexyl six-membered melon ring in the example 4 is 1: at 0.5, the content of the tylosin and the ketoprofen is low, and the inclusion is incomplete. In example 6, the mass ratio of the cyclotamarind to the cyclohexyl hexagram is 1: at 2.0, the isomer is larger. In example 5, the mass ratio of the six-membered ring of the clomazone to the cyclohexyl is 1:1, the content of the tylosin and the ketoprofen is 100%, the inclusion is complete, and the isomer has no obvious change. Thus, it was determined that the mass ratio of tylosin, cyclohexyl six-membered cucurbituril ranges from 1:0.5 to 1:1.5, preferably 1:1.
Example 7:
taidi Luo Xintong profen injection
The preparation method comprises the following steps:
step one: taking 90% of water for injection, adding cyclohexyl six-membered melon ring, stirring and dissolving completely;
step two: adding tylosin and ketoprofen, and stirring until the tylosin and ketoprofen are completely dissolved;
step three: sorbitol is added and stirred to dissolve completely.
Step four: adding the rest of water for injection, and stirring and mixing uniformly;
step five: filtering and sterilizing the solution obtained in the step four by a microporous filter membrane with the thickness of 0.22 mu m, thus obtaining the tylosin Luo Xintong profen injection.
Example 8:
taidi Luo Xintong profen injection
The preparation method comprises the following steps:
step one: taking 90% of water for injection, adding cyclohexyl six-membered melon ring, stirring and dissolving completely;
step two: adding tylosin and ketoprofen, and stirring until the tylosin and ketoprofen are completely dissolved;
step three: sorbitol is added and stirred to dissolve completely.
Step four: adding the rest of water for injection, and stirring and mixing uniformly;
step five: filtering and sterilizing the solution obtained in the step four by a microporous filter membrane with the thickness of 0.22 mu m, thus obtaining the tylosin Luo Xintong profen injection.
Example 9:
taidi Luo Xintong profen injection
The preparation method comprises the following steps:
step one: taking 90% of water for injection, adding cyclohexyl six-membered melon ring, stirring and dissolving completely;
step two: adding tylosin and ketoprofen, and stirring until the tylosin and ketoprofen are completely dissolved;
step three: sorbitol is added and stirred to dissolve completely.
Step four: adding the rest of water for injection, and stirring and mixing uniformly;
step five: filtering and sterilizing the solution obtained in the step four by a microporous filter membrane with the thickness of 0.22 mu m, thus obtaining the tylosin Luo Xintong profen injection.
Examples 7 to 9 were subjected to 0 day of detection of properties, contents, substances and isomers, and then cooled (-20 ℃) and sampled at low temperatures for 1, 3 and 6 months, respectively, and the effects of the amount of antifreeze on the quality of the samples were examined by taking the properties, contents, substances and isomers of the samples as evaluation indexes.
Table 3 0 day test results
TABLE 4 antifreeze (-20 ℃ C.) experimental investigation results
Experimental results show that when the consumption of the anti-freezing agent sorbitol is 1%, the quality of the sample does not change obviously under the condition of low-temperature storage, and the anti-freezing agent sorbitol can achieve anti-freezing at minus 20 ℃, so that convenience is provided for the use of the winter sample on the premise of ensuring the curative effect.
Example 10:
taidi Luo Xintong profen injection
The preparation method comprises the following steps:
step one: taking 90% of water for injection according to the formula amount under the protection of nitrogen in the whole process, adding cyclohexyl six-membered melon ring, and stirring and dissolving completely;
step two: adding tylosin and ketoprofen, and stirring until the tylosin and ketoprofen are completely dissolved;
step three: sorbitol is added and stirred to dissolve completely.
Step four: adding the rest of water for injection, and stirring and mixing uniformly;
step five: filtering and sterilizing the solution obtained in the step four by a microporous filter membrane with the thickness of 0.22 mu m, thus obtaining the tylosin Luo Xintong profen injection.
Example 11:
taidi Luo Xintong profen injection
The preparation method comprises the following steps:
step one: taking 90% of water for injection, adding cyclohexyl six-membered melon ring, stirring and dissolving completely;
step two: adding tylosin and ketoprofen, and stirring until the tylosin and ketoprofen are completely dissolved;
step three: sorbitol is added and stirred to dissolve completely.
Step four: adding the rest of water for injection, and stirring and mixing uniformly;
step five: filtering and sterilizing the solution obtained in the step four by a microporous filter membrane with the thickness of 0.22 mu m, thus obtaining the tylosin Luo Xintong profen injection.
The invention uses cyclohexyl six-membered melon ring as inclusion compound, no antioxidant is needed, no nitrogen charging protection process is needed, the prepared sample is put at high temperature (60 ℃) and illuminated (5000+/-500 LUX), sampling is carried out respectively in 5 days and 10 days, and the property, content, related substances and isomers are taken as evaluation indexes to investigate the change of the sample quality.
TABLE 5 results of influencing factor experiments
Experimental results show that the quality of the tylosin Luo Xintong profen injection in the nitrogen charging protection process and the non-nitrogen charging protection process is not obviously different under the conditions of 10 days at high temperature and 10 days under illumination, the use of the cyclohexyl six-membered melon ring does not need the nitrogen charging protection process or the addition of an antioxidant, and the sample stability is high.
Example 12: taidi Luo Xintong profen injection
The preparation method comprises the following steps:
step one: taking 90% of water for injection, adding cyclohexyl six-membered melon ring, stirring and dissolving completely;
step two: adding tylosin and ketoprofen, and stirring until the tylosin and ketoprofen are completely dissolved;
step three: sorbitol is added and stirred to dissolve completely.
Step four: adding the rest of water for injection, and stirring and mixing uniformly;
step five: filtering and sterilizing the solution obtained in the step four by a microporous filter membrane with the thickness of 0.22 mu m, thus obtaining the tylosin Luo Xintong profen injection.
The samples prepared in example 12 were subjected to an acceleration test (40.+ -. 2 ℃ C., RH 75%.+ -. 5%) and a long-term test (25.+ -. 2 ℃ C., RH 60%.+ -. 5%) to examine the stability of the samples. And sampling and detecting quality indexes such as properties, content, related substances, isomers and the like of the samples, wherein the detection results are shown in the following tables (tables 5 and 6):
table 6 results of accelerated experiments
TABLE 7 long-term experimental investigation results
The acceleration test and long-term test result show that the characteristics, the content, related substances and isomers of the tylosin Luo Xintong profen injection disclosed by the invention are not obviously changed after the tylosin Luo Xintong profen injection is placed for 6 months under the acceleration condition (40+/-2 ℃ and RH75% +/-5%) and placed for 24 months under the long-term condition (25+/-2 ℃ and RH60% +/-5%), so that the quality stability of the tylosin Luo Xintong profen injection disclosed by the invention is controllable.
Example 12 clinical efficacy experiment of Tildi Luo Xintong profen injection
Test materials:
test drug: the injection of tylosin Luo Xintong prepared in example 12 was injected intramuscularly, once daily for 3 days at a dose of 0.025ml/kg.
Control drug 1: the commercial tylosin injection is injected intramuscularly, and is used for 3 days continuously, and the dosage is 0.03ml/kg.
Control drug 2: the commercial ketoprofen injection is injected intramuscularly, and is used for 3 days at the dosage of 0.03ml/kg.
1. Acute pneumonia: beef cattle show symptoms soon after they develop and it is possible that the population develops disease after 1-2, i.e. all cattle show symptoms. The main symptoms of the sick cattle are listlessness, inappetence, obvious reduction of feed intake, frequent cough, dyspnea, purulent secretion at eyes and nose, high fever sometimes, rise of body temperature to about 41 ℃, mental retardation and wet sweat on the body surface. Along with the gradual aggravation of the symptoms, the times of cough are obviously increased and are more serious, the cough is severe dry cough, and auscultation has high-intensity factor, such as howling and whistle.
The 90 beef cattle with acute pneumonia is treated and divided into three groups, namely, injection of tylosin Luo Xintong, commercial tylosin and commercial ketoprofen, clinical symptoms are observed and recorded before each administration, and the observation period is 5 days.
TABLE 7 clinical examination results of acute pneumonia
2. Chronic pneumonia: beef cattle generally do not show very obvious symptoms immediately after suffering from the illness, have no abnormality in visual observation, are normal to eat, and only have little mucous secretion or purulent secretion at the nose and eyes. In terms of body temperature, the sick cattle do not have obvious changes, a few of the sick cattle have slight rise, the pulse is basically normal, and the breathing frequency can be slightly increased. However, with the progress of the course of the disease, the sick cattle can develop single-shot dry cough, the auscultation chest has asthma-like sound and whistle, and the sound can be heard through expiration and inspiration.
The 90 beef cattle with acute pneumonia is treated and divided into three groups, namely, injection of tylosin Luo Xintong, commercial tylosin and commercial ketoprofen, clinical symptoms are observed and recorded before each administration, and the observation period is 5 days.
TABLE 8 clinical examination results of chronic pneumonia
The clinical experiment results of the acute and chronic pneumonia show that the curative effect of the experimental medicine is more remarkable, the clinical symptoms disappear more rapidly, and the mental state is better recovered, so that the curative effect of the compound preparation is far better than that of the single preparation.

Claims (5)

1. The tylosin Luo Xintong profen injection is characterized by comprising the following components: tylosin, ketoprofen, an antifreezing agent, a solubilizer and a solvent for injection; the mass ratio of the tylosin to the ketoprofen is 1:0.5 to 1:1.5;
the mass ratio of the solubilizer to the tylosin is as follows: 1:1;
the mass ratio of the antifreezing agent to the tylosin is as follows: 1:10;
the mass ratio of the injection solvent to the tylosin is as follows: 1:8.3.
2. The tyldinocap Luo Xintong ibuprofen injection according to claim 1, wherein the antifreeze is sorbitol;
the solubilizer is cyclohexyl six-membered melon ring; the solvent for injection is water for injection.
3. The tylosin Luo Xintong ibuprofen injection as claimed in claim 1, wherein the mass ratio of tylosin to ketoprofen is 1:1.
4. a method for preparing the tylosin Luo Xintong ibuprofen injection according to claim 1, which is characterized by comprising the following specific steps:
step one: taking water for injection with the formula amount of 90%, adding a solubilizer, and stirring and dissolving completely;
step two: adding tylosin and ketoprofen, and stirring until the tylosin and ketoprofen are completely dissolved;
step three: adding sorbitol, stirring and dissolving completely;
step four: adding the rest of water for injection, and stirring and mixing uniformly;
step five: filtering and sterilizing the solution obtained in the step four by a microporous filter membrane with the thickness of 0.22 mu m, thus obtaining the tylosin Luo Xintong profen injection.
5. The use of the tylosin Luo Xintong profen injection according to claim 1 for preparing medicines for treating acute and chronic pneumonia.
CN202311676390.XA 2023-12-07 2023-12-07 Taidi Luo Xintong profen injection and preparation method thereof Pending CN117503698A (en)

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