A tedizolid injection and a preparation method and application thereof

Abstract

The application provides a tediroxine injection as well as a preparation method and application thereof, and belongs to the technical field of animal medicine. The tediroxine injection provided by the application comprises tediroxine, poloxamer, polyhydric alcohol, a pH regulator and water, the concentration of the tediroxine in the tediroxine injection is 0.04-0.18 g / mL, and the mass ratio of the tediroxine, the poloxamer and the polyhydric alcohol is 4-18:0.4-1.8:50. The polyhydric alcohol and the poloxamer are compounded in the application, the slow release of the tediroxine is realized, the further enrichment of the tediroxine in the respiratory tract is realized, the stimulation problem caused by the tediroxine is solved, the curative effect is improved, and the drug dosage can be reduced.

Description

Technical Field

[0001] This invention relates to the field of animal medicine technology, and in particular to a tylosin injection, its preparation method, and its application. Background Technology

[0002] Currently, the high incidence and mortality rates of respiratory diseases are the primary problems facing the global livestock and poultry farming industry. These diseases not only cause enormous economic losses but also constitute a significant factor hindering the industry's development. Because of the diverse types of pathogens, the frequent occurrence of mixed infections, and the wide age range of susceptibility (from calves to adults), the prevention and control of respiratory diseases present considerable challenges.

[0003] Tedirocin is a new semi-synthetic macrolide antibiotic developed by Intervet for animal use. Its sterile injection (trade name Zuprevo) has a significant therapeutic effect on respiratory diseases in pigs and cattle, and boasts advantages such as being animal-specific, having a broad antibacterial spectrum, requiring low dosage, and having a long-lasting effect, meeting the needs of respiratory disease prevention and treatment. However, tedirocin contains a double bond structure in its molecular formula, making it sensitive to light and temperature, which greatly limits its clinical application. Furthermore, this drug has the disadvantage of causing significant irritation during clinical use, such as pain and swelling at the injection site in animals. When using Zuprevo, a single injection of no more than 5 mL is required; this irritation is mainly caused by the drug itself and is difficult to avoid, while multiple injection sites would bring additional workload and stress. The tedirocin injection solutions provided by patents CN201610414404.4 and CN202110495550.5 have better stability, but the problem of significant irritation still exists. Summary of the Invention

[0004] The purpose of this invention is to provide a teldroxine injection, its preparation method, and its application. The teldroxine injection provided by this invention not only solves the irritation problem caused by teldroxine but also improves the efficacy and allows for reduced dosage.

[0005] To achieve the above-mentioned objectives, the present invention provides the following technical solution:

[0006] This invention provides a teldrone injection solution, comprising teldrone, poloxamer, polyol, pH adjuster and water, wherein the concentration of teldrone in the teldrone injection solution is 0.04-0.18 g / mL, and the mass ratio of teldrone, poloxamer and polyol is 4-18:0.4-1.8:50.

[0007] Preferably, the polyol includes propylene glycol and / or polyethylene glycol.

[0008] Preferably, the weight-average molecular weight of the polyethylene glycol is 200 to 600.

[0009] Preferably, the polyethylene glycol includes polyethylene glycol 200 and / or polyethylene glycol 400.

[0010] Preferably, the poloxamer includes poloxamer 407 and / or poloxamer 188.

[0011] Preferably, the pH value of the teldrone injection is 5.0 to 6.0.

[0012] Preferably, the pH adjuster includes an acidic reagent or an alkaline reagent.

[0013] Preferably, the acidic reagent includes citric acid and / or hydrochloric acid; the alkaline reagent includes sodium hydroxide.

[0014] This invention provides a method for preparing the sediloxine injection described above, comprising the following steps:

[0015] Poloxamer was mixed with a polyol to obtain solution A;

[0016] Solution B is obtained by mixing tylosin, pH adjuster, and some water;

[0017] The solutions A and B are mixed with the remaining water to obtain the teldrolidine injection.

[0018] This invention provides the application of the tadalafil injection described in the above technical solution or the tadalafil injection prepared by the preparation method described in the above technical solution in the preparation of drugs for the prevention and control of respiratory diseases in livestock and poultry.

[0019] This invention provides a teldroxine injection, comprising teldroxine, poloxamer, a polyol, a pH adjuster, and water. The concentration of teldroxine in the injection is 0.04–0.18 g / mL, and the mass ratio of teldroxine, poloxamer, and polyol is 4–18:0.4–1.8:50. This invention, through the combination of polyol and poloxamer, not only achieves sustained release of teldroxine, avoiding the irritation caused by sudden release, but also achieves further enrichment of teldroxine in the respiratory tract, improving efficacy and allowing for dosage reduction. Specifically, the teldroxine injection provided by this invention allows for single-point administration, reducing stress; it has good efficacy and allows for dosage reduction. For example, test results show that, compared with the control group in clinical stimulation, the increased dose of the teldroxine injection provided by this invention did not cause irritation; compared with the control group in clinical efficacy, the reduced dose of the teldroxine injection provided by this invention also has good efficacy, with a higher concentration ratio of teldroxine in the alveoli and plasma. Attached Figure Description

[0020] Figure 1 This is a graph showing the results of an in vitro release test.

[0021] Figure 2 The diagram shows the results of the pharmacokinetic experiment. Detailed Implementation

[0022] This invention provides a teldroxine injection solution, comprising teldroxine, poloxamer, a polyol, a pH adjuster, and water. In this invention, the concentration of teldroxine in the teldroxine injection solution is 0.04–0.18 g / mL, specifically 0.04 g / mL, 0.06 g / mL, 0.08 g / mL, 0.10 g / mL, 0.12 g / mL, 0.14 g / mL, 0.16 g / mL, or 0.18 g / mL. In this invention, the preferred mass ratio of teldroxine, poloxamer, and polyol is 4–18:0.4–1.8:50, specifically 4:0.4:50, 8:0.8:50, 12:1.2:50, or 18:1.8:50.

[0023] In this invention, the polyol preferably includes propylene glycol and / or polyethylene glycol, specifically propylene glycol, polyethylene glycol, or a mixture of propylene glycol and polyethylene glycol. When the polyol is a mixture of propylene glycol and polyethylene glycol, the mass ratio of propylene glycol to polyethylene glycol is preferably 1:0.25 to 4, more preferably 1:1 to 3, and even more preferably 1:1.5. In this invention, the weight-average molecular weight of the polyethylene glycol is preferably 200 to 600, more preferably 200 to 400. Specifically, the polyethylene glycol preferably includes polyethylene glycol 200 and / or polyethylene glycol 400, more preferably polyethylene glycol 200 or polyethylene glycol 400.

[0024] In this invention, the poloxamer preferably includes poloxamer 407 and / or poloxamer 188, specifically poloxamer 407, poloxamer 188, or a combination of poloxamer 407 and poloxamer 188; when the poloxamer is poloxamer 407 and poloxamer 188, the mass ratio of poloxamer 407 to poloxamer 188 is preferably 1:0.3 to 3, more preferably 1:0.8 to 2, and even more preferably 1:1.

[0025] In this invention, the pH adjuster preferably includes an acidic or alkaline reagent; the acidic reagent preferably includes citric acid and / or hydrochloric acid, specifically citric acid, hydrochloric acid, or a combination of citric acid and hydrochloric acid; the alkaline reagent preferably includes sodium hydroxide. In this invention, the amount of pH adjuster added is sufficient to ensure that the teldroxine injection meets the predetermined pH requirement. Specifically, the pH of the teldroxine injection is preferably 5.0–6.0, more preferably 5.2–5.8, and even more preferably 5.5.

[0026] In this invention, the water is preferably water for injection.

[0027] In this invention, specifically, each 100 mL of the teldroxine injection preferably contains 4-18 g of teldroxine, a pH adjuster to adjust the pH of the teldroxine injection to 5.0-6.0, 0.4-1.8 g of poloxamer, 50 g of polyol, and the remainder is water.

[0028] The teldroxine injection provided by this invention can avoid the irritation caused by the sudden release of teldroxine, and can increase the enrichment of the target site, enhance the efficacy, and achieve the purpose of reducing the dosage.

[0029] This invention provides a method for preparing the sediloxine injection described above, comprising the following steps:

[0030] Poloxamer was mixed with a polyol to obtain solution A;

[0031] Solution B is obtained by mixing tylosin, pH adjuster, and some water;

[0032] The solutions A and B are mixed with the remaining water to obtain the teldrolidine injection.

[0033] This invention involves mixing poloxamer with a polyol to obtain solution A. Preferably, the poloxamer is added to the polyol and heated to dissolve, yielding solution A; the heating temperature is preferably 55–65°C, more preferably 60°C.

[0034] This invention involves mixing teldronexine, a pH adjuster, and a portion of water to obtain solution B. In this invention, the portion of water preferably comprises 75-85% of the total water mass, more preferably 80%. Preferably, the pH adjuster is added to the portion of water under stirring conditions, and after thorough mixing, teldronexine is added and dissolved under stirring conditions to obtain solution B.

[0035] After obtaining solutions A and B, the present invention mixes solutions A and B with the remaining water to obtain the teldrone injection. Preferably, solution B is added to solution A under stirring conditions, followed by the addition of the remaining water, and the mixture is stirred until homogeneous.

[0036] After mixing the solutions A and B with the remaining water, the present invention preferably filters the resulting liquid through a 0.22μm microporous membrane to obtain tadalafil injection.

[0037] This invention provides the application of the teldroxine injection described in the above-described technical solution or the teldroxine injection prepared by the preparation method described in the above-described technical solution in the preparation of drugs for the prevention and control of respiratory diseases in livestock and poultry. In this invention, the livestock preferably includes pigs, cattle, or sheep; the poultry preferably includes chickens, ducks, or geese.

[0038] The technical solutions of this invention will be clearly and completely described below with reference to the embodiments thereof. Obviously, the described embodiments are only a part of the embodiments of this invention, and not all of them. All other embodiments obtained by those skilled in the art based on the embodiments of this invention without creative effort are within the scope of protection of this invention.

[0039] Example 1

[0040] In this embodiment, the formulation of 100mL of teldroxil injection is as follows: teldroxil 4g; citric acid 1.8g; poloxamer 4070.4g; propylene glycol 50g; appropriate amount of hydrochloric acid to make the pH value of teldroxil injection 5.5; the remainder is water for injection.

[0041] The preparation method of the tadalafil injection is as follows:

[0042] Poloxamer 407 was added to propylene glycol and heated to 60°C to dissolve, yielding solution A;

[0043] Citric acid and hydrochloric acid were added to 80% water for injection under stirring conditions, and after mixing evenly, tebuconazole was added and dissolved under stirring conditions to obtain solution B.

[0044] Under stirring conditions, solution B is added to solution A, and then the remaining water for injection is added to make up the volume. After mixing evenly, the mixture is filtered through a 0.22 μm microporous membrane to obtain tadalafil injection.

[0045] Example 2

[0046] The teldroxil injection was prepared according to the method in Example 1, except that the formulation of teldroxil injection per 100 mL in this example is as follows: teldroxil 18 g; citric acid 8 g; poloxamer 407 1.8 g; polyethylene glycol 400 50 g; appropriate amount of hydrochloric acid to make the pH value of teldroxil injection 5.5; the remainder is water for injection.

[0047] Example 3

[0048] The teldroxil injection was prepared according to the method in Example 1, except that the formulation of teldroxil injection per 100 mL in this example is as follows: teldroxil 4 g; poloxamer 407 0.2 g; poloxamer 188 0.2 g; propylene glycol 20 g; polyethylene glycol 200 30 g; appropriate amount of hydrochloric acid to make the pH value of teldroxil injection 5.5; the remainder is water for injection.

[0049] Comparative Example 1

[0050] The teldroxine injection was prepared according to the method in Example 1, except that the formulation of teldroxine injection per 100 mL in this comparative example was: 4 g teldroxine; 1.8 g citric acid; 50 g propylene glycol; appropriate amount of hydrochloric acid to make the pH value of teldroxine injection 5.5; the remainder was water for injection.

[0051] Comparative Example 2

[0052] The teldroxil injection was prepared according to the method in Example 1, except that the formulation of teldroxil injection per 100 mL in this comparative example is as follows: teldroxil 4 g; citric acid 1.8 g; poloxamer 407 0.4 g; appropriate amount of hydrochloric acid to make the pH value of teldroxil injection 5.5; the remainder is water for injection.

[0053] Test Example 1

[0054] This test used dynamic membrane dialysis to determine the extracellular release of teldrolidine injection, as detailed below:

[0055] Cut the dialysis bag into small segments of appropriate length (10-20cm), put them into 1000mL of solution containing 2wt% sodium bicarbonate and 1mmol / L EDTA (pH=8.0) and boil for 10min. Then rinse the dialysis bag thoroughly with distilled water to obtain the pretreated dialysis bag.

[0056] Take 5 mL of teldroxine injection prepared in Examples 1, 3, and Comparative Examples 1-2, and 1.2 mL of teldroxine injection prepared in Example 2 (n=5), and add them to the pretreatment dialysis bags respectively. Place them in a dissolution apparatus and take samples at predetermined time points (0.5h, 1h, 2h, 4h, 8h, 12h, 24h). After filtration through a 0.22μm microporous membrane, determine the content by HPLC. After each sampling, add an equal amount of fresh phosphate buffer (pH=7.4, specifically obtained by diluting 1.36g (20.4g) of potassium dihydrogen phosphate and 0.316g (4.74g) of sodium hydroxide with water to 200mL (3000mL).

[0057] Figure 1 The results of the in vitro release assay are shown in Table 1. Figure 1 As shown in Table 1, compared with the teldrolidine injection prepared in the comparative example, the teldrolidine injection prepared in the example effectively avoids the burst release effect, which helps to reduce the irritation caused by teldrolidine.

[0058] Table 1 In vitro release test data

[0059]

[0060] Test Example 2

[0061] In this embodiment, 140 fattening pigs weighing approximately 50 kg were randomly divided into 7 groups of 20 pigs each. The pain and swelling at the injection site before and after medication were observed to determine the irritation at the injection site. The results are shown in Table 2. Table 2 shows that compared to the low-dose comparative example of teldroxine injection, the low-dose teldroxine injection in this embodiment caused no pain or swelling. Even with increased dosage and single-point injection volume, the pain and swelling of the teldroxine injection in this embodiment were still superior to those of the low-dose comparative example, indicating that the irritation of the teldroxine injection prepared in this embodiment of the invention has been significantly improved.

[0062] Table 2. Data on irritation at the injection site.

[0063]

[0064] Note: Screaming, ruffling, agitation, and abdominal breathing in animals after injection are all considered signs of pain.

[0065] Test Example 3

[0066] One hundred and twenty mice weighing approximately 20g were randomly divided into two groups of sixty mice each: the test group (4mg / kg, specifically the tadalafil injection prepared in Example 1) and the control group (4mg / kg, specifically the tadalafil injection prepared in Comparative Example 1). Each mouse received a single subcutaneous injection. Plasma and alveolar samples were collected before and after administration to determine the concentration of tadalafil in the plasma and alveoli.

[0067] Figure 2 The pharmacokinetic experimental results are shown in the graph; specific data are listed in Table 3. Figure 2 As shown in Table 3, compared with the comparative group, the plasma concentration of teldroxine in the example group was slightly lower, but the concentration of teldroxine in the target organ alveoli was significantly increased. This indicates that the teldroxine injection prepared in the examples of the present invention significantly enhanced the enrichment of teldroxine in the target organ alveoli and enhanced its therapeutic effect.

[0068] Table 3 Pharmacokinetic Experimental Data

[0069]

[0070] Test Example 4

[0071] This test case conducted a clinical efficacy trial on the tylosin injection prepared in the examples and comparative examples. Specifically, it investigated the efficacy of tylosin injection in treating post-weaning respiratory syndrome in pigs under pressure from Pasteurella multocida, Bordetella bronchiseptica, Haemophilus parasuis, and Streptococcus suis. The steps were as follows: 90 piglets were selected and randomly divided into 3 groups of 30 piglets each. The piglets were given the medication at weaning, and the study period was five weeks after weaning. The efficacy was determined by observing the clinical symptoms of the piglets before and after medication. The medication administration details for each group are as follows:

[0072] High-dose group of test substance: Tedirocin injection prepared in Example 1, 4 mg / kg intramuscular injection;

[0073] Low-dose group of test substance: Tedirocin injection prepared in Example 1, 2 mg / kg intramuscular injection;

[0074] High-dose comparative group: 4 mg / kg of teldrone injection prepared in comparative example 1 was administered intramuscularly.

[0075] Table 4 shows the clinical efficacy trial data. As can be seen from Table 4, the high-dose group of the test substance had the best clinical efficacy. The daily weight gain, mortality rate, piglet culling rate, and recurrence rate of the low-dose group of the test substance were also better than those of the high-dose group of the control group. This indicates that the tylosin injection prepared in the embodiments of the present invention significantly improves the clinical efficacy of tylosin and can be used at low doses.

[0076] Table 4 Clinical efficacy trial data

[0077]

[0078] Note: Piglets that die, suffer from prolonged illness, recur frequently, or experience slow growth after recovery, thus severely impacting their growth, development, and feed efficiency, shall be culled.

[0079] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A tedipriloxin injection, consisting of tedipriloxin, poloxamer, polyhydric alcohol, pH regulator and water, wherein the concentration of tedipriloxin in the tedipriloxin injection is 0.04-0.18 g / mL, the mass ratio of tedipriloxin, poloxamer and polyhydric alcohol is 4-18:0.4-1.8:

50. The polyhydric alcohol is propylene glycol and / or polyethylene glycol; the weight average molecular weight of the polyethylene glycol is 200-600. The poloxamer is poloxamer 407 and poloxamer 188, or poloxamer 407.

2. The tedizolid injection of claim 1, wherein, The polyethylene glycol is polyethylene glycol 200 and / or polyethylene glycol 400.

3. The tedizolid injection of claim 1, wherein, The pH of the tedipriloxin injection is 5.0-6.

0.

4. The tedizolid injection of claim 1, wherein, The pH regulator is an acidic agent or a basic agent.

5. The tedizolid injection of claim 4, wherein, The acidic agent is citric acid and / or hydrochloric acid; the basic agent is sodium hydroxide. 6.A preparation method of the tedipriloxin injection according to any one of claims 1-5, comprising the following steps: mixing poloxamer and polyhydric alcohol to obtain solution A; mixing tedipriloxin, pH regulator and part of water to obtain solution B; mixing the solution A, solution B and the rest of water to obtain the tedipriloxin injection. 7.Use of the tedipriloxin injection according to any one of claims 1-5 or prepared by the preparation method of claim 6 in the preparation of a medicine for preventing and controlling respiratory diseases of livestock and poultry.

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