A tilmicosin injection and a preparation method thereof

Abstract

The present application provides a tilmicosin injection, comprising tilmicosin, a pharmaceutically acceptable organic solvent; wherein the pharmaceutically acceptable organic solvent is selected from one or more of alpha-pyrrolidone, ethanol, propylene glycol, dimethylformamide, benzyl alcohol. In addition, a preparation method thereof is also provided. The tilmicosin injection of the present application can be produced by using tilmicosin with a content greater than 98% as raw material, which greatly reduces the use amount of raw material in the liquid medicine compared with using tilmicosin phosphate (with a content less than 77%), and greatly reduces the viscosity of the liquid medicine to a certain extent.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical formulation technology, specifically to a tilmicosin injection and its preparation method. Background Technology

[0002] Tilmicosin is a semi-synthetic macrolide antibiotic for animals, derived from tylosin. It possesses broad-spectrum antipathogenic activity, exhibiting good inhibitory effects against Gram-positive bacteria, certain Gram-negative bacteria, mycoplasma, and spirochetes. It shows strong activity against *Actinobacillus pleuropneumoniae*, *Pasteurella multocida*, and mycoplasma in pigs, and is widely used for the prevention and treatment of bovine mastitis, porcine mycoplasmal pneumonia, and mycoplasma infections in livestock and poultry. Its antibacterial mechanism involves reversibly binding to the 50S subunit of bacterial ribosomes, blocking transpeptidation and mRNA translocation, thereby inhibiting bacterial protein synthesis and thus inhibiting bacterial reproduction. Sensitive Gram-positive bacteria include *Staphylococcus aureus* (including penicillin-resistant *Staphylococcus aureus*), *Streptococcus pneumoniae*, *Bacillus anthracis*, *Erysipelothrix rhusiopathiae*, *Listeria monocytogenes*, *Clostridium putrefactiveum*, and *Clostridium emphysematous*. Sensitive Gram-negative bacteria include *Haemophilus influenzae*, *Neisseria meningitidis*, and *Pasteurella multocida*. 95% of hemolytic *Pasteurella multocida* strains are sensitive to tilmicosin.

[0003] Tilmicosin raw materials are divided into two types: water-insoluble tilmicosin and water-soluble tilmicosin salts (tartrates, phosphates). Due to their physicochemical properties, most injectable products currently on the market use phosphates as raw materials. The quality standard for "Tilmicosin Injection" on page 334 of the 2020 edition of the Chinese Veterinary Pharmacopoeia (CVP2020-1) stipulates that "this product is a sterile solution prepared from tilmicosin and propylene glycol, etc. The content of tilmicosin should be 90%–110% of the labeled amount," and the quality standard only lists one specification: "10mL: 3g." Tilmicosin phosphate contains approximately 74%–76% tilmicosin. If 100% tilmicosin is used, then 39.4g–40.5g of tilmicosin phosphate is required per 100mL. Dissolving such a large amount of raw material in a solvent increases the difficulty of dissolution. Even when heated to 50℃–60℃, the dissolution process is slow. Furthermore, the dissolved and cooled solution is very viscous. In large-scale production, problems such as viscous solution that cannot be filtered, uneven filling, and excessive carbon residue (generated during flame drawing and filling) exist. In clinical use, it is difficult to draw the solution with a syringe.

[0004] Currently, most products on the market tend to darken in color after the summer heat, which is actually due to the degradation of tilmicosin at high temperatures and the instability of the product. Summary of the Invention

[0005] To solve the above-mentioned technical problems, the present invention provides a tilmicosin injection solution with relatively low viscosity and high stability; the pH is always within the qualified range.

[0006] Specifically:

[0007] In a first aspect, the present invention provides a tilmicosin injection, comprising tilmicosin and a pharmaceutically acceptable organic solvent; wherein the pharmaceutically acceptable organic solvent is selected from one or more of α-pyrrolidone, ethanol, propylene glycol, dimethylformamide, and benzyl alcohol.

[0008] In some embodiments of the first aspect, the medicament-acceptable organic solvent is selected from one or more of dimethylformamide, propylene glycol, and ethanol.

[0009] In some embodiments of the first aspect, the medicament-acceptable organic solvent is selected from combinations of dimethylformamide, propylene glycol, and ethanol.

[0010] In some embodiments of the first aspect, the volume percentage of propylene glycol in the pharmaceutically acceptable organic solvent is not higher than 15%.

[0011] In some embodiments of the first aspect, the volume percentage of propylene glycol in the pharmaceutically acceptable organic solvent is not higher than 10%.

[0012] In some embodiments of the first aspect, the volume percentage of propylene glycol in the medicament-acceptable organic solvent is 3-10%.

[0013] In some embodiments of the first aspect, the volume percentage of propylene glycol in the medicament-acceptable organic solvent is 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10%.

[0014] In some embodiments of the first aspect, the volume percentage of ethanol in the medicament-acceptable organic solvent is 20-50%.

[0015] In some embodiments of the first aspect, the volume percentage of ethanol in the organic solvent acceptable for the drug is 30-45%.

[0016] In some embodiments of the first aspect, the volume percentage of ethanol in the pharmaceutically acceptable organic solvent is 20%, 25%, 30%, 35%, 40%, 45%, or 50%.

[0017] In some embodiments of the first aspect, the volume percentage of dimethylformamide in the pharmaceutically acceptable organic solvent is 30%-70%.

[0018] In some embodiments of the first aspect, the volume percentage of dimethylformamide in the pharmaceutically acceptable organic solvent is 40%-60%.

[0019] In some embodiments of the first aspect, the volume percentage of dimethylformamide in the pharmaceutically acceptable organic solvent is 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, or 70%.

[0020] In some embodiments of the first aspect, the ratio of the mass of tilmicosin to the volume of the pharmaceutically acceptable organic solvent is 30 g : (90-100) mL.

[0021] In some embodiments of the first aspect, the tilmicosin injection of the present invention further includes an antioxidant and / or an acidity regulator.

[0022] In some embodiments of the first aspect, the mass ratio of tilmicosin to antioxidant is 30:(0.1-0.2).

[0023] In some embodiments of the first aspect, the acidity adjuster adjusts the pH value to 5.6-6.0.

[0024] In some embodiments of the first aspect, the antioxidant is selected from one or more of sodium thiosulfate, 2,6-di-tert-butyl-p-cresol, and anhydrous sodium sulfite.

[0025] In some embodiments of the first aspect, the antioxidant is a combination of sodium thiosulfate and 2,6-di-tert-butyl-p-cresol.

[0026] In some embodiments of the first aspect, the antioxidant is sodium thiosulfate and 2,6-di-tert-butyl-p-cresol in a mass ratio of (0.3-0.8):1.

[0027] In some embodiments of the first aspect, the antioxidant is sodium thiosulfate and 2,6-di-tert-butyl-p-cresol in a mass ratio of 0.4:1, 0.5:1, 0.6:1, 0.7:1 or 0.8:1.

[0028] In some embodiments of the first aspect, the antioxidant is sodium thiosulfate and 2,6-di-tert-butyl-p-cresol in a mass ratio of 0.5:1.

[0029] In some embodiments of the first aspect, the acidity regulator is selected from one or more of hydrochloric acid, lactic acid, and dilute sulfuric acid.

[0030] In some embodiments of the first aspect, the acidity regulator is lactic acid and hydrochloric acid.

[0031] In some embodiments of the first aspect, the volume ratio of lactic acid to hydrochloric acid is 1:(3-5).

[0032] In some embodiments of the first aspect, the volume ratio of lactic acid to hydrochloric acid is 1:3, 1:4 or 1:5, preferably 1:4.

[0033] Secondly, the present invention also provides a method for preparing tilmicosin injection, comprising the following steps:

[0034] (1) Add tilmicosin to an organic solvent solution acceptable to the drug and heat and stir to dissolve it;

[0035] (2) Add water for injection to the total volume;

[0036] Preferably, the temperature is raised to 60°C to 70°C.

[0037] In some embodiments of the second aspect, the medicament-acceptable organic solvent is selected from one or more of α-pyrrolidone, ethanol, propylene glycol, dimethylformamide, and benzyl alcohol.

[0038] In some embodiments of the second aspect, the medicament-acceptable organic solvent is selected from one or more of dimethylformamide, propylene glycol, and ethanol.

[0039] In some embodiments of the second aspect, the medicament-acceptable organic solvent is selected from combinations of dimethylformamide, propylene glycol, and ethanol.

[0040] In some embodiments of the second aspect, the volume percentage of propylene glycol in the pharmaceutically acceptable organic solvent is not higher than 15%.

[0041] In some embodiments of the second aspect, the volume percentage of propylene glycol in the pharmaceutically acceptable organic solvent is not higher than 10%.

[0042] In some embodiments of the second aspect, the volume percentage of propylene glycol in the medicament-acceptable organic solvent is 3-10%.

[0043] In some embodiments of the second aspect, the volume percentage of propylene glycol in the medicament-acceptable organic solvent is 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10%.

[0044] In some embodiments of the second aspect, the volume percentage of ethanol in the medicament-acceptable organic solvent is 20-50%.

[0045] In some embodiments of the second aspect, the volume percentage of ethanol in the organic solvent acceptable for the drug is 30-45%.

[0046] In some embodiments of the second aspect, the volume percentage of ethanol in the medicament-acceptable organic solvent is 20%, 25%, 30%, 35%, 40%, 45%, or 50%.

[0047] In some embodiments of the second aspect, the volume percentage of dimethylformamide in the pharmaceutically acceptable organic solvent is 30%-70%.

[0048] In some embodiments of the second aspect, the volume percentage of dimethylformamide in the pharmaceutically acceptable organic solvent is 40%-60%.

[0049] In some embodiments of the second aspect, the volume percentage of dimethylformamide in the pharmaceutically acceptable organic solvent is 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, or 70%.

[0050] In some embodiments of the second aspect, the ratio of the mass of tilmicosin to the volume of the pharmaceutically acceptable organic solvent is 30 g : (90-100) mL.

[0051] Thirdly, the present invention also provides a method for preparing tilmicosin injection, comprising the following steps:

[0052] (1) Dissolve the antioxidant by heating and stirring in an organic solvent acceptable to the drug;

[0053] (2) Add tilmicosin to the solution in (1) and stir to dissolve;

[0054] (3) Adjust the pH value to 5.6-6.0 with an acidity regulator, add dimethylformamide to the total volume, filter, and sterilize to obtain the product;

[0055] Preferably, the temperature is raised to 60°C to 70°C.

[0056] In some embodiments of the third aspect, the medicament-acceptable organic solvent is selected from one or more of α-pyrrolidone, ethanol, propylene glycol, dimethylformamide, and benzyl alcohol.

[0057] In some embodiments of the third aspect, the medicament-acceptable organic solvent is selected from one or more of dimethylformamide, propylene glycol, and ethanol.

[0058] In some embodiments of the third aspect, the medicament-acceptable organic solvent is selected from combinations of dimethylformamide, propylene glycol, and ethanol.

[0059] In some embodiments of the third aspect, the volume percentage of propylene glycol in the pharmaceutically acceptable organic solvent is not higher than 15%.

[0060] In some embodiments of the third aspect, the volume percentage of propylene glycol in the pharmaceutically acceptable organic solvent is not higher than 10%.

[0061] In some embodiments of the third aspect, the volume percentage of propylene glycol in the medicament-acceptable organic solvent is 3-10%.

[0062] In some embodiments of the third aspect, the volume percentage of propylene glycol in the pharmaceutically acceptable organic solvent is 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10%.

[0063] In some embodiments of the third aspect, the volume percentage of ethanol in the pharmaceutically acceptable organic solvent is 20-50%.

[0064] In some embodiments of the third aspect, the volume percentage of ethanol in the pharmaceutically acceptable organic solvent is 30-45%.

[0065] In some embodiments of the third aspect, the volume percentage of ethanol in the pharmaceutically acceptable organic solvent is 20%, 25%, 30%, 35%, 40%, 45%, or 50%.

[0066] In some embodiments of the third aspect, the volume percentage of dimethylformamide in the pharmaceutically acceptable organic solvent is 40%-70%.

[0067] In some embodiments of the third aspect, the volume percentage of dimethylformamide in the pharmaceutically acceptable organic solvent is 40%-60%.

[0068] In some embodiments of the third aspect, the volume percentage of dimethylformamide in the pharmaceutically acceptable organic solvent is 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, or 70%.

[0069] In some implementations of the third aspect, the ratio of the mass of tilmicosin to the volume of the pharmaceutically acceptable organic solvent is 30 g: (90-100) mL.

[0070] In some embodiments of the third aspect, the tilmicosin injection of the present invention further includes an antioxidant and / or an acidity regulator.

[0071] In some embodiments of the third aspect, the mass ratio of tilmicosin to antioxidant is 30:(0.1-0.2).

[0072] In some embodiments of the third aspect, the acidity regulator adjusts the pH value to 5.6-6.0.

[0073] In some embodiments of the third aspect, the antioxidant is selected from one or more of sodium thiosulfate, 2,6-di-tert-butyl-p-cresol, and anhydrous sodium sulfite.

[0074] In some embodiments of the third aspect, the antioxidant is a combination of sodium thiosulfate and 2,6-di-tert-butyl-p-cresol.

[0075] In some embodiments of the third aspect, the antioxidant is sodium thiosulfate and 2,6-di-tert-butyl-p-cresol in a mass ratio of (0.3-0.8):1.

[0076] In some embodiments of the third aspect, the antioxidant is sodium thiosulfate and 2,6-di-tert-butyl-p-cresol in a mass ratio of 0.5:1.

[0077] In some embodiments of the third aspect, the acidity regulator is selected from one or more of hydrochloric acid, lactic acid, and dilute sulfuric acid.

[0078] In some embodiments of the third aspect, the acidity regulator is lactic acid and hydrochloric acid.

[0079] In some embodiments of the third aspect, the volume ratio of lactic acid to hydrochloric acid is 1:(3-5).

[0080] In some embodiments of the third aspect, the volume ratio of lactic acid to hydrochloric acid is 1:3, 1:4 or 1:5, preferably 1:4.

[0081] In some embodiments of the third aspect, the present invention provides a method for preparing tilmicosin injection, comprising the following steps:

[0082] (1) Dissolve BHT and sodium thiosulfate by heating and stirring in an organic solvent acceptable to the drug.

[0083] (2) Add tilmicosin to the solution in (1) and stir to dissolve;

[0084] (3) Adjust the pH value to 5.6-6.0 with an acidity regulator, add dimethylformamide to the full volume, filter, and sterilize to obtain the product.

[0085] Furthermore, during the stirring process in step (1), the temperature is slowly heated and controlled at 50-60°C.

[0086] Beneficial effects

[0087] This invention provides a tilmicosin injection solution that can be produced using tilmicosin with a content greater than 98% as a raw material. Compared to using tilmicosin phosphate (with a content less than 77%), this significantly reduces the amount of raw material used in the solution, thereby greatly reducing the viscosity of the solution. Furthermore, this invention uses a combination of food-grade antioxidants 2,6-di-tert-butyl-p-cresol and sodium thiosulfate to enhance the stability of tilmicosin; and employs an acidity regulator composed of lactic acid and hydrochloric acid to ensure that the pH of the solution remains within the acceptable range. Under normal temperature storage conditions, if the tilmicosin injection solution is opened and then resealed before complete use, the content decreases by no more than 3% within the shelf life, and the color and properties of the solution remain unchanged, remaining a clear yellow liquid.

[0088] Terminology Explanation

[0089] In the description of this specification, the references to terms such as "one embodiment," "some embodiments," "example," "specific example," or "some examples," etc., indicate that a specific feature, structure, material, or characteristic described in connection with that embodiment or example is included in at least one embodiment or example of the present invention. In this specification, the illustrative expressions of the above terms do not necessarily refer to the same embodiment or example. Furthermore, the specific features, structures, materials, or characteristics described may be combined in any suitable manner in one or more embodiments or examples. Moreover, without contradiction, those skilled in the art can combine and integrate the different embodiments or examples described in this specification, as well as the features of different embodiments or examples.

[0090] In the following content, all figures disclosed herein, whether or not they use words such as "approximately" or "about," are approximate values. The value of each figure may vary by 1%, 2%, 5%, 7%, 8%, 10%, 15%, or 20%, etc. Whenever a figure with a value of N is disclosed, any figure with a value of N+ / -1%, N+ / -2%, N+ / -3%, N+ / -5%, N+ / -7%, N+ / -8%, N+ / -10%, N+ / -15%, or N+ / -20% will be explicitly disclosed, where "+ / -" indicates addition or subtraction.

[0091] The dilute sulfuric acid (1→2) used in this invention is prepared by mixing 1 volume part of concentrated sulfuric acid with 1 volume part of water.

[0092] The hydrochloric acid solution (1→2) used in this invention is prepared by mixing 1 volume part of concentrated hydrochloric acid with 1 volume part of water.

[0093] The acidity regulator used in this invention, also known as a pH adjuster, is used to control the acidifier, alkali, and buffering salt required for this injection solution. The acidifier includes organic or inorganic acids. Organic acids include fumaric acid, metatartaric acid, citric acid, lactic acid, malic acid, L(+)-tartaric acid and tartaric acid, glacial acetic acid and acetic acid, adipic acid, etc.; inorganic acids include phosphoric acid, hydrochloric acid, sulfuric acid, etc. Salts include monosodium fumarate, sodium citrate, potassium citrate, monosodium citrate, phosphates, calcium sulfate, calcium lactate, sodium acetate, etc. Alkalis include calcium hydroxide, potassium hydroxide, sodium hydroxide. In some embodiments, the acidity regulator of this invention is selected from one or more of hydrochloric acid, lactic acid, and dilute sulfuric acid; preferably, the acidity regulator is lactic acid and hydrochloric acid; more preferably, the volume ratio of lactic acid to hydrochloric acid is 1:(3-5); even more preferably, the volume ratio of lactic acid to hydrochloric acid is 1:4.

[0094] The antioxidants used in this invention are substances that prevent the adverse effects of oxygen. Antioxidants can be classified as follows: (1) Antioxidants can be classified by source into synthetic antioxidants (such as BHA, BHT, PG, etc.) and natural antioxidants (such as tea polyphenols, phytic acid, etc.). (2) Antioxidants can be classified by solubility into three categories: oil-soluble, water-soluble, and compatible. Oil-soluble antioxidants include BHA, BHT, etc.; water-soluble antioxidants include ascorbic acid, tea polyphenols, etc.; compatible antioxidants include ascorbate palmitate, etc. (3) Antioxidants can be classified by mode of action into free radical absorbers, metal ion chelators, oxygen scavengers, peroxide decomposers, enzyme antioxidants, ultraviolet absorbers, or singlet oxygen quenchers, etc. Commonly used antioxidants include tea polyphenols (TP), tocopherols, flavonoids, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), tert-butylhydroquinone (TBHQ), etc. In some embodiments, the antioxidant of the present invention is selected from one or more of sodium thiosulfate, 2,6-di-tert-butyl-p-cresol, and anhydrous sodium sulfite; preferably, the antioxidant is a combination of sodium thiosulfate and 2,6-di-tert-butyl-p-cresol; more preferably, the antioxidant is sodium thiosulfate and 2,6-di-tert-butyl-p-cresol in a mass ratio of (0.3-0.8):1; even more preferably, the antioxidant is sodium thiosulfate and 2,6-di-tert-butyl-p-cresol in a mass ratio of 0.5:1.

[0095] The organic solvent used in this invention refers to a pharmaceutically acceptable organic solvent. That is, the target drug is also acceptable to the organic solvent within the dosage range of the drug being used, and the organic solvent is inert to the drug and will not interact with it. In some embodiments, the pharmaceutically acceptable organic solvent is selected from one or more of α-pyrrolidone, ethanol, propylene glycol, dimethylformamide, and benzyl alcohol; preferably, the pharmaceutically acceptable organic solvent is selected from one or more of dimethylformamide, propylene glycol, and ethanol; more preferably, the pharmaceutically acceptable organic solvent is selected from a combination of dimethylformamide, propylene glycol, and ethanol. Detailed Implementation

[0096] To enable those skilled in the art to better understand the technical solutions of the present invention, some non-limiting embodiments are further disclosed below to provide a more detailed description of the present invention.

[0097] All reagents used in this invention can be purchased commercially or prepared by the methods described in this invention.

[0098] I. Preparation of Tilmicosin Injection

[0099] Example 1

[0100] A tilmicosin injection is composed of tilmicosin and an organic solvent. Each 100 mL solution contains 30 g of tilmicosin, 30 mL of propylene glycol, 20 mL of ethanol, and 10 mL of benzyl alcohol. Dimethylformamide is added to bring the total volume to 100 mL, with a volume of approximately 20 mL.

[0101] Its preparation method is as follows:

[0102] (1) Mix propylene glycol, ethanol and benzyl alcohol and heat to 60℃~70℃, add tilmicosin and stir until dissolved;

[0103] (2) After cooling, add dimethylformamide to 100 mL.

[0104] In this embodiment, the tilmicosin injection contains 30% tilmicosin by weight or volume.

[0105] Example 2

[0106] A tilmicosin injection is composed of tilmicosin and an organic solvent. Each 100 mL solution contains 30 g of tilmicosin, 20 mL of propylene glycol, 20 mL of ethanol, and 20 mL of benzyl alcohol. Dimethylformamide is added to bring the total volume to 100 mL, with a volume of approximately 20 mL.

[0107] Its preparation method is as follows:

[0108] (1) Mix propylene glycol, ethanol and benzyl alcohol and heat to 60℃~70℃, add tilmicosin and stir until dissolved;

[0109] (2) After cooling, add dimethylformamide to 100 mL.

[0110] In this embodiment, the tilmicosin injection contains 30% tilmicosin by weight or volume.

[0111] Example 3

[0112] A tilmicosin injection is composed of tilmicosin and an organic solvent, wherein each 100 mL of the solution contains 30 g of tilmicosin, 10 mL of propylene glycol, 20 mL of ethanol, and dimethylformamide to make up to a total volume of 100 mL, the amount of which is about 50 mL.

[0113] Its preparation method is as follows:

[0114] (1) Mix propylene glycol, ethanol, and dimethylformamide (30 mL) and heat to 60℃~70℃. Add tilmicosin and stir until dissolved.

[0115] (3) After cooling, add dimethylformamide to 100 mL.

[0116] (4) In this embodiment, the tilmicosin injection contains 30% tilmicosin by mass and volume.

[0117] Example 4

[0118] A tilmicosin injection solution is composed of tilmicosin and an organic solvent, wherein each 100 mL of solution contains 30 g of tilmicosin, 5 mL of propylene glycol, and 25 mL of ethanol. Dimethylformamide is added to bring the total volume to 100 mL, approximately 55 mL in volume.

[0119] Its preparation method is as follows:

[0120] (1) Mix propylene glycol, ethanol, and dimethylformamide (30 mL) and heat to 60℃~70℃. Add tilmicosin and stir until dissolved.

[0121] (2) After cooling, add dimethylformamide to 100 mL.

[0122] In this embodiment, the tilmicosin injection contains 30% tilmicosin by weight or volume.

[0123] Example 5

[0124] A tilmicosin injection solution is composed of tilmicosin, an organic solvent, and an acidity regulator. Each 100 mL solution contains 30 g of tilmicosin, 5 mL of propylene glycol, 25 mL of ethanol, 5 mL of lactic acid, and dimethylformamide to bring the total volume to 100 mL, with a volume of approximately 50 mL.

[0125] Its preparation method is as follows:

[0126] (1) Mix propylene glycol, ethanol, and dimethylformamide (30 mL) and heat to 60℃~70℃. Add tilmicosin and stir until dissolved.

[0127] (2) After cooling, adjust the pH to 5.8 with lactic acid;

[0128] (3) Add dimethylformamide to 100 mL.

[0129] In this embodiment, the tilmicosin injection contains 30% tilmicosin by weight or volume.

[0130] Example 6

[0131] A tilmicosin injection is composed of tilmicosin, an organic solvent, and an acidity regulator. Each 100 mL solution contains 30 g of tilmicosin, 5 mL of propylene glycol, 25 mL of ethanol, 4 mL of dilute sulfuric acid (1→2), and dimethylformamide to make up to a total volume of 100 mL, with a volume of approximately 55 mL.

[0132] Its preparation method is as follows:

[0133] (1) Mix propylene glycol, ethanol, and dimethylformamide (30 mL) and heat to 60℃~70℃. Add tilmicosin and stir until dissolved.

[0134] (2) After cooling, adjust the pH to 5.9 with dilute sulfuric acid (1→2);

[0135] (3) Add dimethylformamide to 100 mL.

[0136] In this embodiment, the tilmicosin injection contains 30% tilmicosin by weight or volume.

[0137] Example 7

[0138] A tilmicosin injection is composed of tilmicosin, an organic solvent, and an acidity regulator. Each 100 mL solution contains 30 g of tilmicosin, 5 mL of propylene glycol, 25 mL of ethanol, 4 mL of hydrochloric acid solution (1→2), 1 mL of lactic acid, and dimethylformamide to bring the total volume to 100 mL, with a volume of approximately 55 mL.

[0139] Its preparation method is as follows:

[0140] (1) Mix propylene glycol, ethanol, and dimethylformamide (30 mL) and heat to 60℃~70℃. Add tilmicosin and stir until dissolved.

[0141] (2) After cooling, adjust the pH to 5.8 using hydrochloric acid solution (1→2) and lactic acid;

[0142] (3) Add dimethylformamide to 100 mL.

[0143] In this embodiment, the tilmicosin injection contains 30% tilmicosin by weight or volume.

[0144] Example 8

[0145] A tilmicosin injection solution is composed of tilmicosin, an organic solvent, an acidity regulator, and an antioxidant. Each 100 mL solution contains 30 g of tilmicosin, 5 mL of propylene glycol, 25 mL of ethanol, 4 mL of hydrochloric acid solution (1→2), 1 mL of lactic acid, 0.1 g of sodium thiosulfate, 0.05 g of anhydrous sodium sulfite, and dimethylformamide to bring the total volume to 100 mL, with a volume of approximately 55 mL.

[0146] Its preparation method is as follows:

[0147] (1) Mix propylene glycol, ethanol, and dimethylformamide (30 mL) and heat to 60℃~70℃. Add sodium thiosulfate and anhydrous sodium sulfite and stir to dissolve.

[0148] (2) Continue adding tilmicosin and stir to dissolve;

[0149] (3) After cooling, adjust the pH to 5.8 using hydrochloric acid solution (1→2) and lactic acid;

[0150] (4) Add dimethylformamide to 100 mL.

[0151] In this embodiment, the tilmicosin injection contains 30% tilmicosin by weight or volume.

[0152] Example 9

[0153] A tilmicosin injection solution is composed of tilmicosin, an organic solvent, an acidity regulator, and an antioxidant. Each 100 mL solution contains 30 g of tilmicosin, 5 mL of propylene glycol, 25 mL of ethanol, 4 mL of hydrochloric acid solution (1→2), 1 mL of lactic acid, 0.05 g of anhydrous sodium sulfite, 0.1 g of BHT, and dimethylformamide to bring the total volume to 100 mL, with a volume of approximately 55 mL.

[0154] Its preparation method is as follows:

[0155] (1) Mix propylene glycol, ethanol, and dimethylformamide (30 mL) and heat to 60℃~70℃. Add 2,6-di-tert-butyl-p-cresol (BHT) and anhydrous sodium sulfite and stir to dissolve.

[0156] (2) Continue adding tilmicosin and stir to dissolve;

[0157] (3) After cooling, adjust the pH to 5.8 using hydrochloric acid solution (1→2) and lactic acid;

[0158] (4) Add dimethylformamide to 100 mL.

[0159] In this embodiment, the tilmicosin injection contains 30% tilmicosin by weight or volume.

[0160] Example 10

[0161] A tilmicosin injection solution is composed of tilmicosin, an organic solvent, an acidity regulator, and an antioxidant. Each 100 mL solution contains 30 g of tilmicosin, 5 mL of propylene glycol, 25 mL of ethanol, 4 mL of hydrochloric acid solution (1→2), 1 mL of lactic acid, 0.05 g of sodium thiosulfate, 0.1 g of BHT, and dimethylformamide to bring the total volume to 100 mL, with a volume of approximately 60 mL.

[0162] Its preparation method is as follows:

[0163] (1) Mix propylene glycol, ethanol, and dimethylformamide (30 mL) and heat to 60℃~70℃. Add BHT and sodium thiosulfate and stir to dissolve.

[0164] (2) Continue adding tilmicosin and stir to dissolve;

[0165] (3) After cooling, adjust the pH to 5.8 using hydrochloric acid solution (1→2) and lactic acid;

[0166] (4) Add dimethylformamide to 100 mL.

[0167] In this embodiment, the tilmicosin injection contains 30% tilmicosin by weight or volume.

[0168] II. Viscosity Comparison Test

[0169] The viscosity of the four examples (Example 1, Example 2, Example 3, and Example 4) prepared in this invention was measured using a rotational viscometer. By comparison, the example with the lowest viscosity was identified, and the type and proportion of solvent were determined.

[0170] 1. Experimental basis: Viscosity is measured by the resistance encountered by an object moving inside a liquid (rotational viscometer). If the resistance encountered by an object moving at a certain speed inside a liquid is large, the viscosity of the liquid is relatively large, and the number of rotations will be smaller, and vice versa.

[0171] 2. Testing instrument: Rotational viscometer (Shanghai Lichen, NDJ-9S, with temperature sensor).

[0172] 3. Test conditions: (1) Same room temperature (25.5℃); (2) Same volume of solution (100mL); (3) Same rotation speed (120r / min) and rotor (No. 3); (4) Same rotation time (1 minute).

[0173] 4. Result Judgment Criteria:

[0174] Under the same conditions, the average of three rotor speeds in each solution is used as the criterion. The more times the rotor rotates, the lower the viscosity of the liquid, and vice versa. If the rotor rotates more than 90 times per minute, it is considered qualified.

[0175] 5. The test results are shown in Table 1:

[0176] Table 1

[0177]

[0178] 6. Results and Analysis

[0179] Viscosity comparison experiments showed that propylene glycol affects the viscosity of the solution; the more propylene glycol, the higher the viscosity.

[0180] Data comparison showed that Examples 2, 3, and 4 all met expectations.

[0181] III. The Impact of Viscosity on the Production Process

[0182] According to Examples 2, 3, and 4 of this invention, 10,000 mL of drug solution was prepared respectively. Using filter membranes with the same pore size, the time it took for all the drug solution to pass through the filter membrane under the same pressure was recorded. During filling, the number of tubes that met the requirements after filling was recorded at the same filling speed. After filling, the tubes were inspected by light and the number of tubes with charred heads at the seal was calculated.

[0183] filter:

[0184] 3.1.1 Test Basis: The higher the viscosity of the drug solution, the longer it takes to pass through the same pore size filter membrane under the same pressure, and vice versa. The filling machine fills at the same filling speed (10mL / ampoule). If the drug solution has high viscosity, uneven drug absorption will occur during filling. The higher the viscosity, the more uneven it will be. Moreover, due to the viscosity of the drug solution, the filling needle will exhibit drug stringing. When the needle is withdrawn from the ampoule, the drug solution will stick to the neck of the ampoule. During the stringing and sealing stage, after being heated by high temperature with a flame, the drug solution stuck to the neck will burn into black charcoal, affecting the inspection of visible foreign matter in the drug solution.

[0185] 3.1.2 Test instrument: Plate and frame filter.

[0186] 3.1.3 Test conditions: The drug solution temperature was kept the same (26.4℃), and the filter membrane pore size was the same (0.22um).

[0187] 3.1.4 Result Judgment Criteria:

[0188] Under the same conditions, it is advisable that the time for all the medicine to pass through the filter membrane is less than 15 minutes.

[0189] 3.1.5 Results and Analysis: The results are shown in Table 2.

[0190] Table 2

[0191]

[0192]

[0193] Based on the data in Table 2, Examples 3 and 4 are as expected.

[0194] Canned:

[0195] 3.2.1 Test instrument: wire drawing and filling machine.

[0196] 3.2.2 Test conditions: The machine filling speed is the same, and the flame temperature is under the same conditions (same pressure of liquefied gas and oxygen).

[0197] 3.2.3 Result Judgment Criteria:

[0198] The filling quantity qualification rate is greater than 98.0%.

[0199] 3.2.4 Results and Analysis: The results are shown in Table 3.

[0200] Table 3

[0201] Sample number Total number of bottles filled Number of qualified pieces pass rate Example 2 901 671 74.5％ Example 3 841 674 80.1％ Example 4 813 801 98.5％

[0202] As shown in Table 3, Example 4 is in line with expectations.

[0203] Light inspection:

[0204] 3.3.1 Test instrument: wire drawing and filling machine.

[0205] 3.3.2 Test conditions: The machine filling speed is the same, and the flame temperature is under the same conditions (same pressure of liquefied gas and oxygen).

[0206] 3.3.3 Result Judgment Criteria:

[0207] The rate of no burnt head is greater than 98.0%.

[0208] 3.3.4 Results and Analysis: The results are shown in Table 4.

[0209] Table 4

[0210] Sample number Total number of bottles filled lamp inspection for the number of burnt heads pass rate Example 2 901 632 70.1％ Example 3 841 765 91.0％ Example 4 812 797 98.3％

[0211] According to Table 4, Example 4 meets the expectations.

[0212] In summary, through Examples 1, Example 2, Example 3, and Example 4, after verification and comparison of the four examples, Example 4 is preferably selected as the best example, and the organic solvent and ratio selected in Example 4 are the best solutions.

[0213] IV. Effect Test of Acid Regulators

[0214] On the basis of Example 4, Examples 5, Example 6, and Example 7 are set up for "screening of acid regulators".

[0215] 20 mL of tilmicosin injection of Examples 5, Example 6, and Example 7 prepared in the present invention are respectively filled into 5 20-mL vials, stoppered and crimped, and placed in a water bath at 100 °C and boiled for 30 minutes.

[0216] 1. Screening basis: (1) During the process of adjusting the pH, it should not affect the color of the liquid medicine, not deepen the color or change the color; (2) After the pH value of the liquid medicine is adjusted, after high-temperature sterilization of the liquid medicine, the pH value should not change by more than 0.2; (3) On the premise of ensuring both of the above two points, it is also necessary to ensure safety and convenience during the production process.

[0217] 2. Test instruments: adjustable electric furnace, beaker, pH meter, etc.

[0218] 3. Result judgment standard:

[0219] After boiling for the 30 minutes, if the change in pH value does not exceed 0.2, it is judged as qualified.

[0220] 3. The test results are shown in Table 5

[0221] Table 5

[0222]

[0223] 4. Result analysis

[0224] During the preparation process, there is no change in the color during the pH adjustment process in Examples 5, Example 6, and Example 7; and through Table 5, the pH changes in Examples 6 and Example 7 are less than 0.2, meeting the expectations; due to its danger, sulfuric acid is only suitable for small-scale preparation in the laboratory.

[0225] V. Antioxidant Effect Test

[0226] Based on Example 7, Examples 8, 9, and 10 were set up to investigate and analyze the effect of the antioxidant. 10 mL of each tilmicosin injection solution was filled into 10 mL ampoules, and the seal integrity was verified after string sealing. The ampoules were then sterilized in a water bath for 30 minutes, and the change in content was measured.

[0227] In Examples 8, 9, and 10, tilmicosin was converted to 100% concentration based on its content.

[0228] 1. Experimental basis: Based on the 2020 edition of the Chinese Veterinary Pharmacopoeia.

[0229] 2. Test instrument: High performance liquid chromatograph (Shimadzu LC-16C, Japan).

[0230] 3. Result Judgment Criteria:

[0231] In Examples 8, 9, and 10, samples were taken before sterilization to determine the tilmicosin content and pH value; samples were taken after sterilization, and the content and pH value were determined under the same conditions and methods. If the content change before and after sterilization did not exceed 2%, and the pH value change did not exceed 0.2, it was considered optimal.

[0232] 4. Results and analysis: The results are shown in Table 6.

[0233] Table 6

[0234]

[0235] As can be clearly seen from Table 6, the pH values ​​of Examples 8, 9, and 10 are very stable. After sterilization, the content of Tilmicosin in Example 8 decreased by 4.6%, which is not as expected. After sterilization, the content of Tilmicosin in Example 9 decreased by 1.9%, and in Example 10, the content of Tilmicosin decreased by 1.2%, all of which are as expected.

[0236] This experiment confirms that Examples 9 and 10 achieved the expected results, which are in line with expectations.

[0237] VI. Stability Testing and Verification

[0238] The injection solutions prepared in Examples 9 and 10 were placed at (60±2)℃ for a 6-month test. Samples were taken at the end of months 0, 1, 2, 3, and 6 during the test period to check for significant differences in content, pH value, and drug properties.

[0239] 1. Experimental basis: Based on the 2020 edition of the Chinese Veterinary Pharmacopoeia.

[0240] 2. Test instruments: High performance liquid chromatograph (Shimadzu LC-16C, Japan), drug stability test chamber (Guangdong Taihongjun, LHH-SD), etc.

[0241] 3. Result Judgment Criteria:

[0242] If, after 6 months of accelerated treatment, the content changes by no more than 5%, the pH value changes by no more than 0.3, and the color of the solution changes by no more than brownish-yellow, then it is considered qualified.

[0243] 4. Experimental results, as shown in Tables 7, 8, and 9:

[0244] Table 7 Content Determination

[0245]

[0246] Table 8 pH value determination

[0247]

[0248] Table 9 Properties of the Liquid

[0249]

[0250] 5. Results Analysis

[0251] Comparing Tables 7, 8, and 9 above, Example 10 is superior to Example 9 in terms of content, pH value, and stability of properties, and the changes in each parameter are in line with expectations.

[0252] In summary, through the above embodiments, a tilmicosin injection solution with stable quality, low viscosity, and good flowability was selected using the following production formula and process.

[0253] The method of this invention has been described through preferred embodiments. Those skilled in the art will readily be able to modify or appropriately alter and combine the methods and applications described herein within the scope, spirit, and context of this invention to implement and apply the technology of this invention. Those skilled in the art can refer to the content herein to appropriately improve process parameters. It should be particularly noted that all similar substitutions and modifications are obvious to those skilled in the art and are considered to be included within the scope of this invention.

Claims

1. A tilmicosin injection, comprising tilmicosin, a pharmaceutically acceptable organic solvent, an antioxidant, and an acidity regulator; wherein the pharmaceutically acceptable organic solvent is selected from a combination of dimethylformamide, propylene glycol, and ethanol. in, The volume percentage of propylene glycol is 3-9%. The volume percentage of ethanol is 25-40%; The volume percentage of dimethylformamide is 55%-60%; The mass ratio of tilmicosin to antioxidant is 30:(0.1-0.2). The antioxidant is a combination of sodium thiosulfate and 2,6-di-tert-butyl-p-cresol; wherein the mass ratio of sodium thiosulfate to 2,6-di-tert-butyl-p-cresol is (0.3-0.8):1; The acidity regulator is lactic acid and hydrochloric acid, and the acidity regulator adjusts the pH of the tilmicosin injection to 5.6-6.0; The mass ratio of tilmicosin to the volume of the pharmaceutically acceptable organic solvent is 30 g : (90~100) mL.

2. The tilmicosin injection solution according to claim 1, characterized in that, The mass ratio of sodium thiosulfate to 2,6-di-tert-butyl-p-cresol is 0.5:

1.

3. The tilmicosin injection solution according to claim 1, characterized in that, The volume ratio of lactic acid to hydrochloric acid is 1:(3-5).

4. The tilmicosin injection solution according to claim 1, characterized in that, The volume ratio of lactic acid to hydrochloric acid is 1:

4.

5. A method for preparing tilmicosin injection, comprising the following steps: (1) Add tilmicosin and antioxidant to a drug-acceptable organic solvent solution and heat and stir to dissolve; (2) Adjust the pH of the tilmicosin injection to 5.6-6.0 with an acidity adjuster, and add dimethylformamide to the total volume; The organic solvent acceptable for the drug is selected from combinations of dimethylformamide, propylene glycol, and ethanol. The volume percentage of propylene glycol is 3-9%. The volume percentage of ethanol is 25-40%; The volume percentage of dimethylformamide is 55%-60%; The mass ratio of tilmicosin to antioxidant is 30:(0.1-0.2). The antioxidant is a combination of sodium thiosulfate and 2,6-di-tert-butyl-p-cresol; wherein the mass ratio of sodium thiosulfate to 2,6-di-tert-butyl-p-cresol is (0.3-0.8):1; The acidity regulator is lactic acid and hydrochloric acid; The mass ratio of tilmicosin to the volume of the pharmaceutically acceptable organic solvent is 30 g : (90~100) mL.

6. The preparation method according to claim 5, wherein, Heat to 60℃~70℃.

7. A method for preparing tilmicosin injection, comprising the following steps: (1) Dissolve the antioxidant by heating and stirring in an organic solvent acceptable to the drug; (2) Add tilmicosin to the solution in (1) and stir to dissolve; (3) Adjust the pH of the tilmicosin injection to 5.6-6.0 with an acidity regulator, add dimethylformamide to the total volume, filter, and sterilize to obtain the product; The organic solvent acceptable for the drug is selected from combinations of dimethylformamide, propylene glycol, and ethanol. The volume percentage of propylene glycol is 3-9%. The volume percentage of ethanol is 25-40%; The volume percentage of dimethylformamide is 55%-60%; The mass ratio of tilmicosin to antioxidant is 30:(0.1-0.2). The antioxidant is a combination of sodium thiosulfate and 2,6-di-tert-butyl-p-cresol; wherein the mass ratio of sodium thiosulfate to 2,6-di-tert-butyl-p-cresol is (0.3-0.8):1; The acidity regulator is lactic acid and hydrochloric acid; The mass ratio of tilmicosin to the volume of the pharmaceutically acceptable organic solvent is 30 g : (90~100) mL.

8. The preparation method according to claim 7, wherein, Heat to 60℃~70℃.

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