A composition for inducing dissolution of injection of DABPU and derivatives thereof

Abstract

The present invention relates to a composition for dissolving a DABPU injectable derivative of the poorly soluble DABPU (3-(4'-(dimethylamino)-[1,1'-biphenyl-3-yl)urea) and a method for preparing the same. According to the composition for dissolving a DABPU injectable of the present invention, the solubility and stability of DABPU in liquid formulations can be significantly improved. Furthermore, in the case of a DABPU injectable to which the composition of the present invention is applied, the solubility of DABPU is excellently improved, and it can be used directly for intramuscular injection (IM) or intravenous administration (IV), and the method for preparing the said injectable is also simple.

Description

Technology Field

[0001] The present invention relates to a composition for dissolving an injectable derivative of water-insoluble DABPU (3-(4'-(dimethylamino)-[1,1'-biphenyl-3-yl)urea) and a method for preparing the same. Background Technology

[0002] Influenza is an acute respiratory disease caused by the influenza virus. It is accompanied by respiratory symptoms, such as a sore throat and cough, accompanied by the sudden onset of systemic symptoms like headache, fever, chills, and muscle pain. Although there are four types of influenza viruses—A, B, C, and D—types A and B are the ones that cause illness in humans. Type A exists in various forms depending on the types of H and N antigens on the surface of the virus (currently, 18 types of H antigens and 11 types of N antigens are known). Type B has milder symptoms and exists in only two forms (Yamagata and Victoria), while Type C causes only general cold symptoms, and there have been no reported cases of Type D transmission to humans. Generally, influenza affects the upper respiratory system (nose and throat) or the lower respiratory system (lungs) and is accompanied by general physical symptoms such as sudden high fever, headache, muscle pain, and general fatigue. Influenza is a clear challenge for humanity and one of the infectious diseases that has plagued humankind for a longer period than any other disease to date; even now, it continues to cause hundreds of thousands of deaths and property damage worldwide every year like an annual event. Influenza is significant because it is highly contagious, and if the elderly, children, or those with underlying conditions contract the virus, mortality rates and the incidence of complications increase. Furthermore, if a new type of influenza virus spreads rapidly across a wide area rather than remaining confined to a specific region, it can cause significant deaths even among young people. The emergence of such new influenza viruses, to which humans have no prior immunity, can trigger a global pandemic. For this reason, it is a candidate for a pandemic that numerous virology experts continuously predict.

[0003] Atglistatin is a representative treatment for such influenza. Its chemical name is DABPU-DM (3-(4'-(Dimethylamino)-[1,1'-biphenyl]-3-yl)-1,1-dimethylurea), and as an adipose triglyceride lipase inhibitor, it is also abbreviated as an ATGL inhibitor. However, DABPU-DE has recently been attracting attention; it is a drug exhibiting similar function to Atglistatin, and its molecular formula is C 19 H 25 It is N3O, has a molecular weight of 311.429, and its chemical name is 3-(4'-(dimethylamino)-[1,1'-biphenyl-3-yl)-1,1-diethylurea(3-(4'-(Dimethylamino)biphenyl-3-yl)-1,1-diethylurea), abbreviated as DABPU-DE. The above compound has the following chemical structural formula.

[0004]

[0005] Although DABPU-DE can be considered superior to Atglistatin in terms of antiviral activity, its solubility in water at 25°C is 0.00 mg / mL, making it practically insoluble in water; consequently, its application as an intramuscular or intravenous injection is difficult. In other words, the low water solubility of DABPU-DE is a major factor that makes the development of intramuscular and intravenous formulations very difficult. In the case of water-insoluble drugs, new formulations can generally be created or solubility improved by altering the drug's physicochemical properties or using mixed solvents, thereby enabling their application to existing formulations.

[0006] Meanwhile, regarding an injectable for the treatment of influenza virus, Patent Document 1 discloses a pharmaceutical composition in the form of a premix formulation containing a peramivir compound. However, in this case, not only is the active substance itself different from the derivative of DABPU (3-(4'-(dimethylamino)-[1,1'-biphenyl-3-yl)-1,1-dimethylurea) of the present invention, but the active substance is merely formulated into a hydrate and contained in a sealed container as a liquid premix formulation for parenteral administration.

[0007] In addition, Patent Document 2 is similar to the present invention in that it employs a co-solvent to utilize water-insoluble chemical substances as injectables. However, Patent Document 2 discloses a composition containing meloxicam, an enol non-steroidal anti-inflammatory drug, as a co-solvent. Yet, meloxicam is completely different from the present invention in terms of its efficacy as well as its chemical properties, as well as its derivatives, DABPU (3-(4'-(dimethylamino)-[1,1'-biphenyl-3-yl)urea) or its derivatives. Therefore, the technical concept differs from the present invention in that a composition involving mixing an alkaline aqueous solution and an organic solvent is essential.

[0008] Consequently, a water-soluble DABPU-DE solution for injectables that dissolves well in water has not yet been developed. Therefore, there is a need for a composition for dissolving injectables that improves the solubility of DABPU, particularly DABPU-DE injectables, while offering high potential for quality control, stability, and safety. Prior art literature

[0009] Patent Document 1: Patent Publication No. 10-2022-0033561 Patent Document 2: Patent Publication No. 10-2021-007951 The problem to be solved

[0010] In order to solve the problem of water insolubility of DABPU as described above, the present invention provides a composition for dissolving injectables of DABPU and its derivatives.

[0011] That is, according to one embodiment of the present invention, a composition for dissolving a DABPU injectable is provided, wherein the composition comprises DABPU-DE, a mixed solvent, and a buffer, and the mixed solvent is a mixed solvent comprising water and an organic solvent. Additionally, a pH adjuster may be provided, and the pH adjuster may be an acidic pH adjuster, a basic pH adjuster, or a buffer.

[0012] In other words, when administering DABPU to treat an influenza virus infection to a person who may come into contact with a person suffering from the influenza virus infection or to a person who already suffers from the influenza virus infection, an injectable agent incorporating the composition for dissolving DABPU injectable agents of the present invention may be administered. In some embodiments, an injectable agent incorporating the composition of the present invention may be administered prophylactically to a person who comes into contact with a person suffering from the influenza virus infection. In some embodiments, an injectable agent incorporating the composition of the present invention may be administered to an individual who has shown a positive reaction for influenza infection but has not yet shown symptoms of influenza infection. In some embodiments, an injectable agent incorporating the composition of the present invention may be administered to the individual when symptoms of influenza infection begin. means of solving the problem

[0013] To solve the above problem, the present invention provides the following inventive means.

[0014] (1) A composition for dissolving DABPU injectable, comprising a derivative of DABPU (3-(4'-(dimethylamino)-[1,1'-biphenyl-3-yl)urea), a mixed solvent, and a buffer.

[0015] (2) In the above (1), the derivative is DABPU-DM(3-(4'-(Dimethylamino)-[1,1'-biphenyl]-3-yl)-1,1-dimethylurea), DABPU-EM(3-(4'-(Dimethylamino)-[1,1'-biphenyl]-3-yl)-1-ethyl-1-methylurea), DABPU-Dph(3-(4'-(Dimethylamino)-[1,1'-biphenyl]-3-yl)-1,1-diphenylurea), DABPU-pyrrol( N -(4'-(Dimethylamino)-[1,1'-biphenyl]-3-yl)pyrrolidine-1-carboxamide), DABPU-Morph( N A composition selected from the group consisting of -(4'-(Dimethylamino)-[1,1'-biphenyl]-3-yl)morpholine-4-carboxamide) and DABPU-DE(3-(4'-(Dimethylamino)-[1,1'-biphenyl]-3-yl)-1,1-diethylurea).

[0016] (3) A composition according to (1) above, further comprising a pH adjuster.

[0017] (4) In the above (1), the mixed solvent is a composition selected from two or more of the group consisting of ethanol, propylene glycol, butylene glycol, 1-methyl-2-pyrrolidone (NMP), 1,3-dimethyl-2-imidazolidinone, dimethyl sulfoxide (DMSO), acetone, isopropanol, tetrahydrofurfuryl alcohol, tetrahydrofuran polyethylene glycol ether, 1,4-dioxane, acetonitrile (ACN), dimethylformamide (DMF), propylene carbonate, glycerin, dimethylacetamide (DMA), and polyethylene glycol.

[0018] (5) In the above (3), the pH adjuster is a composition selected from one or more of the group consisting of inorganic acid, organic acid, and alkaline components.

[0019] (6) A composition in which the inorganic acid in (5) above is selected from the group consisting of hydrochloric acid, sulfuric acid, nitric acid, brominated acid, sulfamic acid, and phosphoric acid.

[0020] (7) In the above (5), the organic acid is ascorbic acid, lactic acid, acetic acid, propionic acid, glycolic acid, pyruvate, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, gluconic acid, isethionic acid, lactobionic acid, tannic acid, palmitic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, polygalacturonic acid, sulfosalicylic acid, glycolic acid, 2-hydroxy-3-naphthoate, pamoate, stearic acid, phthalic acid, ethanesulfonic acid, A composition comprising one or more selected from the group consisting of glutamic acid, serine, threonine, hydrochloric acid, sulfuric acid, nitric acid, bromic acid, sulfamic acid, and phosphoric acid.

[0021] (8) A composition in which the alkali component of (5) above is selected from one or more of the group consisting of potassium hydroxide, sodium hydroxide, sodium carbonate, sodium bicarbonate, triethylamine, diethanolamine, sodium phosphate, disodium hydrogen phosphate, sodium dihydrogen phosphate, trihydroxymethylaminomethane, arginine, lysine, histidine and glycine.

[0022] (9) The above (1) wherein the buffer is a composition selected from one or more of the group consisting of Tris, MOPS, acetate, phosphate, PBS, citrate, HEPES, MES (2-(N-Morpholino)ethanesulfonic acid), succinate, SSC (saline sodium citrate), and Tricine.

[0023] (10) In the above (1), the mixed solvent is a composition in which the amount of the solvent is 1% to 95% based on 100% volume of the composition for dissolving DABPU injection.

[0024] (11) A composition according to (1), wherein the content of DABPU (3-(4'-(dimethylamino)-[1,1'-biphenyl-3-yl)urea) or its derivative is 0.01 to 50.0 mg / mL.

[0025] (12) A composition in which one or more of the solubilizing agent and surfactant are not included in the above (1).

[0026] (13) A composition according to (1) further comprising a diluent, an auxiliary agent, an excipient, a dispersant or a vehicle.

[0027] (14) A composition in which the injectable agent in (1) above is a intramuscular injection or an intravenous injection.

[0028] (15) A method for preparing a composition for dissolving DABPU injectables comprising the step of mixing a mixed solvent with DABPU (3-(4'-(dimethylamino)-[1,1'-biphenyl-3-yl)urea) or a derivative thereof.

[0029] (16) A manufacturing method further comprising the step of mixing a first pH adjuster with water to lower the pH of the water to 7.0 or lower to obtain an acidic aqueous solution, and then mixing the acidic aqueous solution with a solvent to obtain the mixed solvent.

[0030] (17) A manufacturing method comprising the step of further adjusting the pH value of the composition by mixing a second pH adjuster with the composition for dissolving the DABPU injection obtained in (15).

[0031] (18) A manufacturing method comprising the step of further sterilizing the obtained DABPU injection dissolving composition in (15) above.

[0032] (19) The composition of (1) above is administered intravenously, intramuscularly, subcutaneously, epidurally, or through a needle or catheter inserted into the spinal canal by an IV bolus (temporary injection) method.

[0033] (20) The composition of (1) above is a composition that is administered by drip infusion by mixing it with a fluid selected from the group consisting of physiological saline, glucose injection solution, glucose physiological saline solution, Hartmann's solution (HOTSOL), and plasma solution injection by an intravenous (IV) infusion (continuous infusion) method.

[0034] (21) Use of the composition of (1) for use as an intramuscular injection or intravenous injection. Effects of the invention

[0035] According to the composition for dissolving DABPU derivative injectables of the present invention, the solubility and stability of DABPU in liquid formulations can be significantly improved. Furthermore, in the case of a DABPU injectable to which the composition of the present invention is applied, the solubility of DABPU is excellently improved, and it can be used directly for intramuscular injection (IM) or intravenous administration (IV), and the method of manufacturing said injectable is also simple. Brief explanation of the drawing

[0036] Figure 1 is a photograph showing the condition of the lungs, liver, heart, kidneys, spleen, and muscle (injection site) after injecting DABPU-DE injectables, i.e., the injectables of Preparation Examples 1 to 3, dissolved in three mixed solvents composed of different compositions, into the muscle of rats (Biceps Femoris), with 5 rats in each of the vehicle treatment group and experimental groups 1 to 3. Figure 2 is a photograph showing the condition of the liver, lungs, kidneys, heart, and spleen after injecting DABPU-DE injectables, i.e., the injectables of Preparation Examples 1 to 3, dissolved in three mixed solvents composed of different compositions, into the tail veins of five rats per group. Figure 3 is a photograph showing the results of histopathological staining of the lungs, liver, heart, kidneys, spleen, and muscle (injection site) after injecting DABPU-DE injectables, i.e., the injectables of Preparation Examples 1 to 3, dissolved in three mixed solvents composed of different compositions, into the muscle (Biceps Femoris) of five rats in each of the vehicle treatment group and experimental groups 1 to 3. Figure 4 is a photograph showing the results of histopathological staining of the liver, lungs, kidneys, heart, and spleen after injecting DABPU-DE injectables, i.e., the injectables of Preparation Examples 1 to 3, dissolved in three mixed solvents composed of different compositions, into the tail veins of five rats per group. Figure 5 is a photograph showing the results of histopathological staining of the liver, lungs, kidneys, heart, and spleen after injecting the injectable preparation of Example 5 into the tail veins of five rats per group. (Originally, it was the data from Preparation Example 6 (now Comparative Preparation Example 16), but it was modified to use that of Preparation Example 5 to enrich the experimental examples.) Figure 6 is a photograph showing the results of injecting the water-soluble DABPU-DE injectable (containing NMP) prepared in Comparative Example 16 and the control injectable (identical ingredients except for the absence of DABPU-DE, labeled as Vehicle-treated) into the muscles of rats at high doses of 1.0 mg / kg, 5.0 mg / kg, and 10.0 mg / kg daily for 5 days and then extracting the organs. Figure 7 is a photograph showing the leg muscles of rats incised after injecting the water-soluble DABPU-DE injectable (containing NMP) prepared in Comparative Preparation Example 16 and the control injectable (identical ingredients except for the absence of DABPU-DE, labeled as Vehicle-treated) into the muscles of rats at high doses of 1.0 mg / kg, 5.0 mg / kg, and 10.0 mg / kg daily for 5 days. Specific details for implementing the invention

[0037] A first aspect of the present invention is a composition for dissolving DABPU injectable, comprising DABPU (3-(4'-(dimethylamino)-[1,1'-biphenyl-3-yl)urea) or a derivative thereof, a mixed solvent, and a buffer. Examples of derivatives include DABPU-DM, DABPU-EM, DABPU-Dph, DABPU-pyrrol, DABPU-Morph, and DABPU-DE, but preferably DABPU-DM, DABPU-EM, DABPU-DE, and most preferably DABPU-DE, for the sake of antiviral efficacy.

[0038]

[0039] That is, the pharmaceutical composition to which the composition for dissolving DABPU injectable of the present invention, comprising the above-mentioned compound, is applied is a water-soluble composition in the form of a sterile injectable, for example, comprising the active compound DABPU-DE and composed of 1 to 95% of a mixed solvent.

[0040] The above mixed solvent comprises a mixture that may be one, two, or more of various organic solvents, such as ethanol, isopropanol, acetone, propylene glycol, butylene glycol, 1-methyl-2-pyrrolidone (NMP), 1,3-dimethyl-2-imidazolidinone, dimethyl sulfoxide (DMSO), tetrahydrofurfuryl alcohol, tetrahydrofuran polyethylene glycol ether, 1,4-dioxane, acetonitrile (ACN), dimethylformamide (DMF), propylene carbonate, glycerin, dimethylacetamide (DMA), polyethylene glycol, such as PEG300, PEG400, PEG600, etc. More preferably, the organic solvent is a mixture of two or more selected from the group consisting of dimethyl sulfoxide (DMSO), dimethylacetamide (DMA), PEG300 and / or PEG400. Or, the mixed solvent of the present invention is a mixture of, for example, 2 components, 3 components, 4 components, 5 components, 6 components, 7 components, 8 components, 9 components, 10 components, 11 components, 12 components, 13 components, 14 components, 15 components, 16 components, and 17 components among the solvents listed above.

[0041] Meanwhile, water may be mixed into the above mixed solvent, and the water may be water suitable for medicinal use, such as purified water, physiological saline solution, buffer, and water for injection.

[0042] According to one embodiment of the present invention, the concentration of the mixed solvent containing the organic solvent is 1% to 95% on a volume (v / v) basis, preferably 3% to 90%, more preferably 5% to 85%, and most preferably 10% to 80%. For example, it may be 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 95%.

[0043] It is preferable that the composition of the present invention has a pH value suitable for use as an injectable, particularly as an intramuscular or intravenous injection. The composition of the present invention may further include a pH adjuster as needed.

[0044] According to one embodiment of the present invention, the pH adjuster may be selected from basic pH adjusters and / or acidic pH adjusters. Of course, it may also include a buffer.

[0045] The above basic pH adjuster may be selected from one, two, or more of potassium hydroxide, sodium hydroxide, sodium carbonate, sodium bicarbonate, triethylamine, diethanolamine, sodium phosphate, disodium hydrogen phosphate, sodium dihydrogen phosphate, Tris (trihydroxymethylaminomethane), arginine, lysine, histidine, and glycine; preferably, it may be selected from one, two, or more of potassium hydroxide, sodium hydroxide, sodium carbonate, sodium bicarbonate, Tris, arginine, lysine, glycine, and triethylamine; more preferably, it is selected from potassium hydroxide, sodium hydroxide, sodium carbonate, Tris, or lysine; and most preferably, it is selected from potassium hydroxide, sodium hydroxide, or sodium carbonate.

[0046] The above acidic pH regulator may be selected from one, two, or more of hydrochloric acid, sulfuric acid, nitric acid, brominated acid, sulfamic acid, and phosphoric acid as inorganic acids. Organic acids among acidic pH adjusters include ascorbic acid, lactic acid, acetic acid, propionic acid, glycolic acid, pyruvate, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, gluconic acid, isethionic acid, lactobionic acid, tannic acid, palmitic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, polygalacturonic acid, sulfosalicylic acid, glycolic acid, 2-hydroxy-3-naphthoate, pamoate, stearic acid, phthalic acid, ethanesulfonic acid, glutamic acid, The acidic pH adjuster may be selected from one, two, or more selected from the group consisting of lysine, arginine, glycine, serine, and threonine. The acidic pH adjuster is preferably selected from one, two, or more of lactic acid, malic acid, tartaric acid, citric acid, hydrochloric acid, phosphoric acid, and acetic acid, more preferably selected from one, two, or more of lactic acid, tartaric acid, citric acid, hydrochloric acid, phosphoric acid, and acetic acid, and even more preferably selected from one, two, or more of lactic acid, phosphoric acid, and acetic acid.

[0047] According to one embodiment of the present invention, the pH adjuster may include a buffer, such as Tris buffer, MOPS buffer, acetate buffer, phosphate buffer, PBS buffer, citric acid buffer, HEPES buffer, MES buffer (2-(N-morpholino)ethanesulfonic acid), succinic acid buffer, SSC (saline sodium citrate) buffer, and Tricine buffer, but is not limited thereto.

[0048] In the composition of the present invention, the mixed solvent may be 1% to 95% (v / v) based on 100 volume% of the composition.

[0049] In addition, in the composition of the present invention, the effective dose of the active ingredient depends at least on the characteristics of the condition being treated, toxicity, whether the compound is used prophylactically (at a low dose) or for an active viral infection, the method of delivery, and the pharmaceutical formulation, and will be determined by a clinician using conventional dose escalation studies. This can be expected to be about 0.0001 to about 100 mg / kg body weight / day; generally about 0.01 to about 30 mg / kg body weight / day; more generally about 0.1 to about 20 mg / kg body weight / day; most generally about 0.5 to about 0.10 mg / kg body weight / day. For example, for an adult weighing about 70 kg, the daily candidate dose is between 1 mg and 1000 mg, preferably between 5 mg and 500 mg, and may take the form of a single or multiple doses.

[0050] However, according to one embodiment of the present invention, the effective dose of the active ingredient in the composition of the present invention may be about 0.0001 to about 10 mg / kg, preferably about 0.001 to about 5 mg / kg, more preferably about 0.01 to about 3 mg / kg, even more preferably about 0.5 to about 2 mg / kg, and most preferably about 1 mg / kg, based on work for the active ingredient DABPU (3-(4'-(dimethylamino)-[1,1'-biphenyl-3-yl)urea).

[0051] Meanwhile, the content of the derivative of the above DABPU (3-(4'-(dimethylamino)-[1,1'-biphenyl-3-yl)urea) may be 0.01 to 50.0 mg / mL.

[0052] According to one embodiment of the present invention, the mass / volume ratio of the DABPU and the mixed solvent in the composition of the present invention, i.e., the concentration of DABPU, is 0.01 to 50.0 mg / mL, preferably 0.1 to 45 mg / mL, more preferably 1 to 40 mg / mL, even more preferably 3 to 35 mg / mL, and most preferably 5 to 30 mg / mL.

[0053] In the composition according to the present invention, the amount of DABPU in the total composition is not specifically limited, and considering mass production, it may be, for example, 1.0 g or more, 10 g or more, 50 g or more, 100 g or more, or 500 g or more.

[0054] In the composition of the present invention, the volume of the mixed solvent in the total composition is not specifically limited, and considering mass production, it may be, for example, 0.1 L or more, 1 L or more, 10 L or more, 20 L or more, or 100 L or more.

[0055] Furthermore, the composition of the present invention may not include one or more of a solubilizing agent and a surfactant.

[0056] In addition, the composition of the present invention may further include a diluent, an auxiliary agent, an excipient, a dispersant, or a vehicle.

[0057] According to a second aspect of the present invention, the present invention provides a method for preparing a composition for dissolving an injectable drug, comprising the step of mixing a mixed solvent with DABPU (3-(4'-(dimethylamino)-[1,1'-biphenyl-3-yl)urea) or a derivative thereof.

[0058] The above mixed solvent may optionally include water.

[0059] A pH adjuster may be further mixed in the above mixing step.

[0060] If the composition of the present invention includes a pH adjuster, for example, the method further includes the step of first mixing water with a first pH adjuster and then further mixing with an organic solvent to obtain a mixed solution, and then mixing with a second pH adjuster and then further mixing with an organic solvent. The first pH adjuster and the second pH adjuster are different and are selected independently from the definitions of pH adjusters described above. Preferably, the first pH adjuster is an acidic adjuster and the second pH adjuster is a basic adjuster. That is, in the method for preparing the composition of the present invention, the method may further include the step of mixing the first pH adjuster with water to lower the pH of the water to 7.0 or lower to obtain an acidic aqueous solution, and then mixing the acidic aqueous solution with the solvent to obtain the mixed solvent, separately from the step of mixing the mixed solvent. Optionally, the method may further include the step of mixing the second pH adjuster with the obtained composition for dissolving DABPU injectables to further adjust the pH value of the composition.

[0061] Optionally, the step of sterilizing the obtained DABPU injectable dissolving composition may be further included.

[0062] According to one embodiment of the present invention, when, for example, DABPU-DE is used as an active ingredient, the method for manufacturing the composition of the present invention may include the following steps:

[0063] 1) A step of adding DABPU-DE to an organic solvent to obtain a mixed solution containing DABPU-DE,

[0064] 2) A step of obtaining an acidic aqueous solution by mixing a first pH adjuster with water as an acidity adjuster to make the pH of the water 7.0 or lower, for example, pH ≤5.0, pH ≤3.0, or pH ≤1.0;

[0065] 3) A step of obtaining a mixed solution by mixing the mixed solution obtained in Step 1) with the acidic aqueous solution obtained in Step 2); and

[0066] 4) A step of obtaining a DABPU-DE composition by adding a buffer to adjust the pH value of the solution obtained in step 3).

[0067] According to another embodiment of the present invention, for example, when DABPU-DE is used as an active ingredient, the method for manufacturing the composition of the present invention may include the following steps:

[0068] 1) A step of obtaining an acidic aqueous solution by mixing a first pH adjuster and water as an acidity adjuster so that the pH of the water becomes ≤7.0, e.g., pH ≤5.0, pH ≤3.0, or pH ≤1.0;

[0069] 2) A step of mixing an organic solvent with the acidic aqueous solution obtained in step 1) to obtain a mixed solution;

[0070] 3) a step of adding DABPU-DE to the mixed solution obtained in step 2) to obtain a mixed solution containing DABPU-DE; and

[0071] 4) A step of obtaining a DABPU-DE composition by adjusting the pH value of the solution obtained in step 3) using a second pH adjuster as a basic adjuster.

[0072] According to another additional embodiment of the present invention, when, for example, DABPU-DE is used as an active ingredient, the method for preparing the composition of the present invention may include the following steps:

[0073] 1) A step of obtaining an acidic aqueous solution by mixing a first pH adjuster and water as an acidity adjuster so that the pH of the water becomes ≤7.0, e.g., pH ≤5.0, pH ≤3.0, or pH ≤1.0,

[0074] 2) A step of adding an organic solvent and DABPU-DE to obtain a mixed solution containing DABPU-DE,

[0075] 3) a step of mixing the acidic aqueous solution obtained in step 1) with the mixed solution obtained in step 2) to obtain another mixed solution; and

[0076] 4) A step of obtaining a DABPU-DE composition by adjusting the pH value of the solution obtained in step 3) using a buffer.

[0077] In the different embodiments above, at each step such as step 1), 2), 3), or 4), stirring may be performed to promote mixing, and the stirring time may be 10 minutes or more, and may be, for example, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 60 minutes or more.

[0078] Generally, the mixing temperature of each solution in the above manufacturing method is not specifically limited. In addition, an organic solvent can be added and stirred without waiting for the acidic aqueous solution to cool. For example, the temperature of step 1), 2), 3), or 4) is 5°C to 80°C, preferably 10°C to 70°C, more preferably 20°C to 40°C; as a specific example, the temperature may be 20°C, 25°C, or 50°C.

[0079] Meanwhile, general commercial storage conditions for the composition of the present invention include a temperature of about 23°C (ambient room temperature) and a refrigerated temperature lower than ambient room temperature, for example, about 5°C. Preferably, the liquid formulation of the composition of the present invention is stored at a refrigerated temperature.

[0080] The present invention further provides liquid formulations, such as injectables, preferably intramuscular or intravenous injections, said injectables comprising the composition of said DABPU. Such injectables may be contained, for example, in ampoules, vials, or multi-dose containers. Alternatively, injectables according to the present invention may be provided in the form of jars, pre-loaded syringes, blister packs, tins, cans, bottles, boxes, or intravenous injection bags.

[0081] The injectable according to the present invention may include a small-volume injectable (20 mL or less, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, or 20 mL) or a large-volume injectable (50 mL or more and 1000 mL or less, e.g., 50, 60, 70, 75, 80, 90, 100, 250, 500, or 1000 mL).

[0082] The present invention further comprises the step of placing the composition of the present invention into a container; preferably, sterilization treatment may be performed on the composition before or after placing it into the container. The sterilization may be moist heat sterilization or filter sterilization.

[0083] In one embodiment of the present invention, the use of the composition of the present invention for treating a disease (viral inflammation) is also provided. Preferably, the composition of the present invention is an injectable, particularly an intramuscular injection or an intravenous injection.

[0084] If the composition of the present invention is in the form of an injectable formulation, a parenterally acceptable diluent and / or solvent may be added. Acceptable vehicles or solvents that may be used include water, Ringer's solution, PBS, and isotonic sodium chloride solution.

[0085] Formulations of the compositions of the present invention can be conveniently provided in unit dosage forms and can be prepared by methods well known in the pharmaceutical field. One or more compounds of the present invention (hereinafter referred to as active ingredients) are administered by any route suitable for the condition to be treated. Suitable routes include oral, rectal, nasal, pulmonary, topical (including buccal and sublingual), vaginal, and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal, and epidural), etc.

[0086] Formulations suitable for parenteral administration include water-soluble and water-insoluble injectables, which may include antioxidants, buffers, bacteriostatic agents, and solutes that make the formulation isotonic with the blood of the intended recipient.

[0087] In addition, the composition of the present invention may be combined with one or more additional active therapeutic agents in a single-dose form and administered to a patient simultaneously or sequentially. The combination therapy may be administered as a simultaneous or sequential therapy. When administered sequentially, the combination may be administered in two or more doses. Co-administration of the composition of the present invention with one or more other active therapeutic agents generally refers to administering the composition of the present invention and one or more other active therapeutic agents simultaneously or sequentially, wherein therapeutically effective amounts of both the composition of the present invention and one or more other active therapeutic agents are present in the patient's body.

[0088] In addition, the scope of the present invention includes in vivo metabolites of the compounds described herein, and such products may be generated primarily by enzymes, such as oxidation, reduction, hydrolysis, amidation, and esterification of the administered compounds. Accordingly, the present invention comprises compounds produced by a process of maintaining the compounds of the present invention for a sufficient time to generate metabolites in mammals or birds.

[0089] Since it is not possible to administer the active ingredient alone, it is more desirable to provide it in a pharmaceutical formulation. The formulations of the present invention for veterinary and human use comprise one or more acceptable carriers together with at least one active ingredient as defined above, but may optionally comprise other therapeutic ingredients, particularly additional therapeutic ingredients as discussed herein. The carriers must be "acceptable" in the sense that they are compatible with other ingredients of the formulation and are physiologically harmless to the recipient.

[0090] The composition of the present invention allows the active ingredient, such as DABPU, to mix well with an aqueous solution while significantly improving the solubility of the active ingredient in a liquid formulation. For example, if the pH of the solution system is adjusted to 1.0 or higher before DABPU-DE is dissolved and the volume ratio of the organic solvent in the mixed solvent is ≥5%, the concentration of DABPU-DE can reach 30 mg / mL or even higher, which significantly improves the solubility of the drug.

[0091] The inventors of the present invention have also unexpectedly discovered that the composition of the present invention possesses excellent stability. For example, when the organic solvent used occupies an equal proportion in the mixed solvent, and polyethylene glycol (e.g., PEG300 or PEG400, etc.) is used as one of the components of the mixed solvent, stability is significantly improved, no precipitation occurs during long-term storage, the content of impurities such as decomposition products does not increase, and a stable water-soluble liquid composition is obtained under injectable conditions (particularly under intramuscular and intravenous injection conditions). In other words, the mixed solvent selected in the present invention significantly improves the solubility of the drug while simultaneously significantly enhancing the stability of the drug.

[0092] Since the composition of the present invention does not contain auxiliary components such as solubilizers or surfactants, the irritancy of the composition is reduced, and it is made safer. The DABPU-DE composition provided in the present invention can even be used directly for intramuscular injection or intravenous administration, allowing for the rapid attainment of an effective therapeutic concentration.

[0093] In addition, the manufacturing method of the composition of the present invention is simple, and since stirring, dispersion, and dissolution can be easily completed within a short time at room temperature, it is easy to expand to mass production.

[0094] The present invention significantly improves the stability of the composition and, in particular, significantly enhances the safety of liquid formulations by using phosphoric acid as an acidic pH regulator to effectively increase solubility, and also prevents precipitation from occurring during prolonged storage. This is highly advantageous for the application of DABPU-DE as an injectable (especially an intravenous injectable).

[0095] Examples

[0096] The technical solution means of the present invention is described in more detail below based on specific embodiments. The following embodiments are merely illustrative for explaining and interpreting the present invention and should not be interpreted as limiting the scope of protection of the present invention. All technologies implemented based on the present invention are included within the scope of protection of the present invention.

[0097] Unless otherwise stated, the raw materials and reagents used in the following examples are all commercially available products or can be easily manufactured by conventional methods.

[0098] Meanwhile, in the following examples and comparative examples, the content of the DABPU-DE raw material is 99.9 wt% in all cases, and the total impurity is 0.05 wt% or less. The method for measuring the DABPU-DE content described in the examples and comparative examples of the present invention was measured by 1H NMR.

[0099] Preparation Example 1. Preparation of DABPU-DE injectable composition

[0100] (1) Ingredients

[0101] DABPU-DE 1.0 ~ 2.0 g

[0102] 10 mL of dimethylacetamide (DMA)

[0103] PEG400 30 mL

[0104] 2% phosphoric acid

[0105] PBS 10%

[0106] water Add until the total volume of the composition reaches 50 mL.

[0107] (2) Manufacturing method

[0108] DABPU-DE of the above amount was added to dimethylacetamide (DMA) and stirred uniformly at room temperature, then PEG400 was added and stirred uniformly at room temperature again, then phosphoric acid was added to a concentration of 2%, and PBS and water were added to make the total volume 50 mL (defined as 100%). After complete dissolution, when placed at room temperature, it became a colorless transparent or slightly light brown transparent liquid, and no foreign substances such as insoluble fine particles were visible. As a result of observation at -20°C and 2 to 8°C for more than 90 days, no insoluble particles or visible foreign substances appeared in the solution, and there was no change in the color of the solution.

[0110] Preparation Example 2. Preparation of DABPU-DE injectable composition

[0111] (1) Ingredients

[0112] DABPU-DE 1.0 ~ 2.0 g

[0113] 10 mL of dimethylacetamide (DMA)

[0114] PEG400 30 mL

[0115] 1.5% phosphoric acid

[0116] PBS 10%

[0117] water Add until the total volume of the composition reaches 50 mL.

[0118] (2) Manufacturing method

[0119] DABPU-DE of the above amount was added to dimethylacetamide (DMA) and stirred uniformly at room temperature, then PEG400 was added and stirred uniformly again at room temperature, phosphoric acid was added to a concentration of 1.50%, and PBS and water were added to make the total volume 50 mL (defined as 100%). After complete dissolution, when placed at room temperature, it became a colorless transparent or slightly light brown transparent liquid, and no foreign substances such as insoluble fine particles were visible. As a result of observation at -20°C and 2 to 8°C for more than 90 days, no insoluble particles or visible foreign substances appeared in the solution, and there was no change in the color of the solution.

[0121] Preparation Example 3. Preparation of DABPU-DE injectable composition

[0122] (1) Ingredients

[0123] DABPU-DE 1.0 ~ 2.0 g

[0124] 10 mL of dimethylacetamide (DMA)

[0125] PEG400 30 mL

[0126] Phosphoric acid 1.0%

[0127] PBS 10%

[0128] water Add until the total volume of the composition reaches 50 mL.

[0129] (2) Manufacturing method

[0130] DABPU-DE of the above amount was added to dimethylacetamide (DMA) and stirred uniformly at room temperature, then PEG400 was added and stirred uniformly at room temperature again, then phosphoric acid was added to a concentration of 1.0%, and PBS and water were added to make the total volume 50 mL (defined as 100%). After complete dissolution, when placed at room temperature, it became a colorless transparent or slightly light brown transparent liquid, and no foreign substances such as insoluble fine particles were visible. As a result of observation at -20°C and 2 to 8°C for more than 90 days, no insoluble particles or visible foreign substances appeared in the solution, and there was no change in the color of the solution.

[0132] Preparation Example 4. Preparation of DABPU-DE composition

[0133] (1) Ingredients

[0134] DABPU-DE 1.0 ~ 2.0 g

[0135] 10 mL of dimethylacetamide (DMA)

[0136] PEG400 30 mL

[0137] 2% phosphoric acid

[0138] PBS 10%

[0139] Add until the total volume of the water composition reaches 50 mL.

[0140] (2) Manufacturing method

[0141] PEG400 was added to dimethylacetamide (DMA) to a concentration of 2%, phosphoric acid was added, PBS and water were added to a total volume of 50 mL (defined as 100%), and then uniformly stirred at room temperature. Afterward, DABPU-DE in the above amount was added and uniformly stirred at room temperature. That is, unlike Preparation Example 1, in this preparation example, DABPU-DE was added after the mixed solvent was prepared in advance.

[0142] When completely dissolved and placed at room temperature, it became a colorless, transparent or slightly light brown transparent liquid with no foreign substances such as insoluble fine particles. When observed for more than 90 days at -20℃ and 2 to 8℃, no insoluble particles or visible foreign substances appeared in the solution, and there was no change in the color of the solution.

[0144] Preparation Example 5. Preparation of DABPU-DE composition

[0145] (1) Ingredients

[0146] DABPU-DE 1.0 ~ 2.0 g

[0147] 10 mL of dimethylacetamide (DMA)

[0148] PEG400 30 mL

[0149] Citric acid 0.1 M

[0150] PBS 10%

[0151] water Add until the total volume of the composition reaches 50 mL.

[0152] (2) Manufacturing method

[0153] PEG400 is added to dimethylacetamide (DMA), citric acid is added to a concentration of 0.1 M, PBS and water are added to a total volume of 50 mL (defined as 100%), and then uniformly stirred at room temperature. After that, DABPU-DE of the above amount is added and uniformly stirred at room temperature. That is, the difference here is that citric acid is used instead of phosphoric acid in the preceding Preparation Example 4.

[0154] When completely dissolved and placed at room temperature, it became a colorless, transparent or slightly light brown transparent liquid with no foreign substances such as insoluble fine particles. When observed for more than 90 days at -20℃ and 2 to 8℃, no insoluble particles or visible foreign substances appeared in the solution, and there was no change in the color of the solution.

[0156] Example 1. Intramuscular injection of DABPU-DE, a water-soluble liquid.

[0157] The water-soluble DABPU-DE injectable prepared in Preparation Examples 1 to 3 above and the control group injectable (identical composition except for the absence of DABPU-DE, labeled as Vehicle-treated) were injected into the biceps femoris of rats at a concentration of 20 mg / kg for 5 days, and the organs were observed visually. Here, they were labeled as the control group, experimental group 1, experimental group 2, and experimental group 3, respectively. Specifically, the lungs, liver, heart, kidneys, spleen, and muscles were excised to observe for abnormalities, and the results are shown in Fig. 1.

[0158] As shown in the photo, no pathological changes were observed in any of the experimental groups compared to the control group.

[0160] Example 2. Intravenous injection of DABPU-DE, a water-soluble liquid.

[0161] The water-soluble DABPU-DE injectable prepared in Preparation Examples 1 to 3 above and the control group injectable (identical ingredients except for the absence of DABPU-DE, labeled as Vehicle-treated) were injected into the tail veins of rats at a concentration of 20 mg / kg for 5 days, and the organs were observed visually. Here, they were labeled as the control group, experimental group 1, experimental group 2, and experimental group 3, respectively. Specifically, the lungs, liver, heart, kidneys, and spleen were removed to observe for abnormalities, and the results are shown in Fig. 2.

[0162] As shown in the photo, no pathological changes were observed in any of the experimental groups compared to the control group.

[0164] Example 3. Tissue examination after intramuscular injection of DABPU-DE, a water-soluble liquid injection

[0165] The water-soluble DABPU-DE injectable prepared in Preparation Examples 1 to 3 above and the control injectable (identical ingredients except for the absence of DABPU-DE, labeled as Vehicle-treated) were injected into the muscle (Biceps Femoris) of rats at a concentration of 20 mg / kg for 5 days, and the organs were stained and observed by histological methods. That is, the sample itself is identical to that of Example 1 above.

[0166] Here, they were labeled as the control group, experimental group 1, experimental group 2, and experimental group 3, respectively. That is, the lungs, liver, heart, kidneys, spleen, and muscles were excised and examined for abnormalities using microscopic photographs, and the results are shown in Figure 3.

[0167] As shown in the photo, no pathological changes were observed in any of the experimental groups compared to the control group.

[0169] Example 4. Tissue examination after intravenous injection of DABPU-DE, a water-soluble liquid.

[0170] The water-soluble DABPU-DE injectable prepared in Preparation Examples 1 to 3 above and the control injectable (identical ingredients except for the absence of DABPU-DE, labeled as Vehicle-treated) were injected into the tail veins of rats at a concentration of 20 mg / kg for 5 days, and the organs were stained and observed by histological methods. That is, the sample itself is the same as that in Example 2 above.

[0171] Here, they were labeled as the control group, experimental group 1, experimental group 2, and experimental group 3, respectively. Specifically, the organs were the lungs, liver, heart, kidneys, and spleen, and the presence of abnormalities was observed using microscopic photographs, and the results are shown in Figure 4.

[0172] As shown in the photo, no pathological changes were observed in any of the experimental groups compared to the control group.

[0174] Example 5. Intravenous injection of DABPU-DE, a water-soluble liquid.

[0175] The water-soluble DABPU-DE injectable prepared in Preparation Example 6 above and the control injectable (identical composition except for the absence of DABPU-DE, labeled as Vehicle-treated) were injected into the tail veins of rats daily for 5 days, and organs were excised and observed visually. DABPU-DE was injected at concentrations of 1.0 mg / kg, 5.0 mg / kg, and 10.0 mg / kg. The liver, lungs, kidneys, heart, and spleen were excised to check for abnormalities, and the results are shown in Fig. 5. The injectable of this example is characterized by the use of 1-methyl-2-pyrrolidone (NMP) instead of dimethylacetamide (DMA) as a solvent.

[0176] As shown in the photograph in Fig. 5, no pathological changes were observed in any of the experimental groups compared to the control group.

[0178] Comparative Manufacturing Example 1

[0179] Attempted to dissolve 10 mg of DABPU-DM in 10% polyethylene glycol 400 (PEG400) (v / v) water, but the liquid became cloudy rather than clear. This indicates that it was not dissolved.

[0180] Comparative Manufacturing Example 2

[0181] Attempted to dissolve 80 mg of DABPU-DM in 50% polyethylene glycol 400 (PEG400) (v / v) water, but the liquid became cloudy rather than clear. This indicates that it was not dissolved.

[0182] Comparative Manufacturing Example 3

[0183] 30 mg of DABPU-DM was first dissolved in 500 μL of the organic solvent 1-methyl-2-pyrrolidone (NMP), and then mixed with 4% phosphoric acid, 150 μL of PBS, and 150 μL of water, but a precipitation reaction occurred. In other words, it did not ultimately become an aqueous solution.

[0184] Comparative Manufacturing Example 4

[0185] 30 mg of DABPU-DM was first dissolved in 500 μL of the organic solvent NMP, and then mixed with 4% acetic acid, 50 μL of PBS, and 300 μL of water, but a precipitation reaction occurred. In other words, it did not ultimately become an aqueous solution.

[0186] Comparative Manufacturing Example 5

[0187] 30 mg of DABPU-DM was first dissolved in 500 μL of the organic solvent NMP, and then mixed with 1% acetic acid, 50 μL of PBS, and 400 μL of water, but a precipitation reaction occurred. In other words, it did not ultimately become an aqueous solution.

[0188] Comparative Manufacturing Example 6

[0189] 30 mg of DABPU-DM was first dissolved in 500 μL of the organic solvent NMP, and then mixed with 4% acetic acid and 300 μL of PBS, but a precipitation reaction occurred. In other words, it did not ultimately become an aqueous solution.

[0190] Comparative Manufacturing Example 7

[0191] 30 mg of DABPU-DM was first dissolved in 500 μL of the organic solvent NMP, and then mixed with 4% acetic acid, 100 μL of PBS, and 200 μL of water, but a precipitation reaction occurred. In other words, it did not ultimately become an aqueous solution.

[0192] Comparative Manufacturing Example 8

[0193] 25 mg of DABPU-DM was dissolved in 2% hydrochloric acid and mixed with 600 μL of 1.5 M Tris buffer solution, but a precipitation reaction occurred. In other words, it did not ultimately become an aqueous solution.

[0194] Comparative Manufacturing Example 9

[0195] 10 mg of DABPU-DM was dissolved in 1.8% hydrochloric acid and mixed with 750 μL of 1.5 M Tris buffer solution, but a precipitation reaction occurred. In other words, it did not ultimately become an aqueous solution.

[0196] Comparative Manufacturing Example 10

[0197] 3.2 mg of DABPU-DM was dissolved in 9 μL of phosphoric acid and mixed with 910 μL of 1.5 M Tris buffer solution, but a precipitation reaction occurred. In other words, it did not ultimately become an aqueous solution.

[0198] Comparative Manufacturing Example 11

[0199] 16 mg of DABPU-DM was dissolved in 400 μL of acetic acid and mixed with 600 μL of 1.5 M Tris buffer solution, but a precipitation reaction occurred. In other words, it did not ultimately become an aqueous solution.

[0200] Comparative Manufacturing Example 12

[0201] 10 mg of DABPU-DE was first dissolved in 500 μL of the organic solvent NMP, and then mixed with 5% phosphoric acid and 160 μL of 4N sodium hydroxide solution, but a precipitation reaction occurred. In other words, it did not ultimately become an aqueous solution.

[0202] Comparative Manufacturing Example 13

[0203] 10 mg of DABPU-DE was first dissolved in 500 μL of the organic solvent NMP, and then mixed with 2.5% phosphoric acid and 160 μL of 4N sodium hydroxide solution, but a precipitation reaction occurred. In other words, it did not ultimately become an aqueous solution.

[0204] Comparative Manufacturing Example 14

[0205] 10 mg of DABPU-DE was first dissolved in 100 μL of the organic solvent NMP, and then mixed with 100 μL of 5% phosphoric acid and 160 μL of 4N sodium hydroxide solution, but a precipitation reaction occurred. In other words, it did not ultimately become an aqueous solution.

[0206] Comparative Manufacturing Example 15

[0207] 10 mg of DABPU-DE was first dissolved in 270 μL of the organic solvent NMP, and then mixed with 350 μL of 10% phosphoric acid and 200 μL of 4N sodium hydroxide solution, but a precipitation reaction occurred. In other words, it did not ultimately become an aqueous solution.

[0208] Comparative Manufacturing Example 16

[0209] (1) Ingredients

[0210] DABPU-DE 0.75 g

[0211] 1-Methyl-2-pyrrolidone (NMP) 5.335 mL

[0212] 2.4% phosphoric acid

[0213] 1N KOH 1.33 mL

[0214] Add until the total volume of the PBS composition reaches 50 mL.

[0215] (2) Manufacturing method

[0216] DABPU-DE was added to 1-methyl-2-pyrrolidone (NMP) and dissolved thoroughly, phosphoric acid was added and mixed well, KOH was added, and PBS was added to adjust the volume while stirring uniformly at room temperature. When left at room temperature, it became a colorless or transparent liquid with a slightly light brown tint, and there were no foreign substances such as insoluble particulates.

[0218] Comparative Example 1. Intramuscular injection of DABPU-DE injection, a water-soluble liquid.

[0219] The water-soluble DABPU-DE injectable (containing NMP) prepared in Comparative Preparation Example 16 above and the control injectable (identical ingredients except for the absence of DABPU-DE, labeled as Vehicle-treated) were injected into the muscles of rats at high doses of 1.0 mg / kg, 5.0 mg / kg, and 10.0 mg / kg daily for 5 days, and the organs were excised and observed visually.

[0220] In the above negative control group, no abnormal findings were observed in any organs or tissues, including the muscle area. The liver, lungs, kidneys, heart, and spleen were removed to check for abnormalities, and the results are shown in Fig. 6. No particular abnormal findings were observed in the above organs. However, among the experimental groups administered the water-soluble DABPU-DE injection of Comparative Example 16, mild granulomatous inflammation (red arrow) was observed in the muscle area in the 5.0 mg / kg dose group, while relatively strong granulomatous inflammation (red arrow) was observed in the muscle area of ​​all rats in the 10.0 mg / kg dose group (Fig. 7).

[0222] In the above Comparative Manufacturing Examples 1 to 15, only one type of solvent was used, so it can be interpreted that dissolution did not occur. Additionally, in the above Comparative Manufacturing Example 16, phosphoric acid acted as part of the solvent and exhibited an effect similar to a mixed solvent, so there appeared to be no problem in the preparation of the injectable drug. However, when this was actually injected, problems occurred in the body, which is thought to be due to the incomplete solubility of the active ingredient.

[0224] The embodiments of the present invention have been described above. However, the present invention is not limited to the above embodiments. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention shall be included within the scope of protection of the present invention.

Claims

Claim 1 A composition for dissolving DABPU injectables comprising a derivative of DABPU (3-(4'-(dimethylamino)-[1,1'-biphenyl-3-yl)urea), a mixed solvent, and a buffer. Claim 2 In claim 1, the derivative of DABPU (3-(4'-(dimethylamino)-[1,1'-biphenyl-3-yl)urea) is DABPU-DM (3-(4'-(Dimethylamino)-[1,1'-biphenyl]-3-yl)-1,1-dimethylurea), DABPU-EM (3-(4'-(Dimethylamino)-[1,1'-biphenyl]-3-yl)-1-ethyl-1-methylurea), DABPU-Dph (3-(4'-(Dimethylamino)-[1,1'-biphenyl]-3-yl)-1,1-diphenylurea), DABPU-pyrrol ( N -(4'-(Dimethylamino)-[1,1'-biphenyl]-3-yl)pyrrolidine-1-carboxamide), DABPU-Morph( N A composition selected from the group consisting of -(4'-(Dimethylamino)-[1,1'-biphenyl]-3-yl)morpholine-4-carboxamide) and DABPU-DE(3-(4'-(Dimethylamino)-[1,1'-biphenyl]-3-yl)-1,1-diethylurea). Claim 3 A composition according to claim 1, further comprising a pH adjuster. Claim 4 A composition according to claim 1, wherein the mixed solvent is two or more selected from the group consisting of ethanol, propylene glycol, butylene glycol, 1-methyl-2-pyrrolidone (NMP), 1,3-dimethyl-2-imidazolidinone, dimethyl sulfoxide (DMSO), acetone, isopropanol, tetrahydrofurfuryl alcohol, tetrahydrofuran polyethylene glycol ether, 1,4-dioxane, acetonitrile (ACN), dimethylformamide (DMF), propylene carbonate, glycerin, dimethylacetamide (DMA), and polyethylene glycol. Claim 5 A composition according to claim 3, wherein the pH adjuster is one or more selected from the group consisting of inorganic acid, organic acid, and alkaline component. Claim 6 A composition according to claim 1, wherein the mixed solvent is 1% to 95% based on 100% by volume of the composition for dissolving DABPU injectable, and the content of DABPU (3-(4'-(dimethylamino)-[1,1'-biphenyl-3-yl)urea) or its derivative is 0.01 to 50.0 mg / mL. Claim 7 A composition according to claim 1, wherein one or more of a solubilizing agent and a surfactant are not included. Claim 8 A composition according to claim 1, further comprising a diluent, an auxiliary agent, an excipient, a dispersant, or a vehicle. Claim 9 A composition according to claim 1, wherein the injectable is an intramuscular injection or an intravenous injection. Claim 10 A method for preparing a composition for dissolving DABPU injectables, comprising the step of mixing a mixed solvent with a derivative of DABPU (3-(4'-(dimethylamino)-[1,1'-biphenyl-3-yl)urea). Claim 11 A manufacturing method according to claim 10, further comprising the step of mixing a first pH adjuster with water to lower the pH of the water to 7.0 or lower to obtain an acidic aqueous solution, and then mixing the acidic aqueous solution with the mixed solvent to obtain the mixed solvent. Claim 12 A manufacturing method according to claim 11, further comprising the step of mixing a second pH adjuster with the obtained DABPU injection dissolving composition to further adjust the pH value of the composition.

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