Azozepam injection and preparation method thereof

Abstract

The invention discloses a preparation method of an azepam injection, the azepam injection comprises an azepam nanocrystal, a nonionic surfactant and purified water, the weight ratio of the azepam nanocrystal to the nonionic surfactant is 1: (0.05-0.2), and the weight ratio of the azepam nanocrystal to the nonionic surfactant is 1: (0.05-0.2). The azepine nanocrystal is prepared by the following process: taking a raw material medicine azepine, a surfactant and an organic solvent as solvents, and the preparation method comprises the following specific steps: a, dissolving azepine in the organic solvent to form a medicine solution; b, dissolving a surfactant in water to form a water phase solution; c, slowly dropwise adding the medicine solution into the water-phase solution at normal temperature and normal pressure, and stirring to form an oil / water type emulsion; d, crystallizing: heating the emulsion to 53-60 DEG C, increasing the pressure to 2.38 atm, evaporating for 30 minutes to remove the organic solvent, and precipitating the azepine to form nanocrystals; and e, filtering and washing. According to the invention, the problem of poor water solubility of the azepam is solved, and the prepared azepam injection is safe, stable and small in side effect.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparation technology, and particularly relates to an arbutin injection and its preparation method. Background Technology

[0002] Argatropan, also known as argatropan, was developed and synthesized by Mitsubishi Pharmaceutical Works Co., Ltd. (now known as Tanabe Mitsubishi Pharmaceutical) and was first launched in Japan in February 1990. The drug was initially developed to treat peripheral arterial occlusive disease, and its applications have since expanded to include chronic arterial occlusive disease, acute cerebral thrombosis, adjunctive therapy for thrombolysis in myocardial infarction, and anticoagulation in hemodialysis.

[0003] Poor water solubility remains a major challenge in the preparation of arcropan injection. According to the United States Pharmacopeia solute classification, arcropan, with a solubility of approximately 0.8-0.9 mg / mL, is considered slightly to very slightly soluble in water. Chinese patent CN101257890A discloses a sterile pharmaceutical composition containing an acid as a solubilizer, and Chinese patent CN101516370A discloses a pharmaceutical composition containing amino acids, lactobionic acid, and other solubilizers and stabilizers. Although these two inventions' pharmaceutical compositions do not contain organic solvents such as ethanol and glycerol, they include amino acids and lactobionic acid, making the preparation methods complex and unsuitable for large-scale industrial production. Furthermore, CN113521244B adds surfactants and glacial acetic acid, simplifying the preparation process, but still introduces glacial acetic acid. Although low concentrations of glacial acetic acid are of low toxicity, long-term use can still cause skin corrosion.

[0004] Therefore, the preparation of an arzopan injection with good water solubility, few side effects, and high safety and stability remains an urgent problem to be solved. Summary of the Invention

[0005] This application provides a method for preparing arcozopan injection, which solves the problem of poor water solubility of arcozopan, while reducing the addition of excipients, having fewer side effects, and high stability.

[0006] This application provides a method for preparing arcozopan injection, comprising arcozopan nanocrystals, nonionic surfactant, and purified water.

[0007] Preferably, the ratio of Azopan nanocrystals to nonionic surfactant is 1:(0.05-0.2), and more preferably 1:0.15.

[0008] Preferably, the nonionic surfactant may be poloxamer 188, polysorbate 80, or polyvinylpyrrolidone.

[0009] Preferably, the preparation of Agzopan nanocrystals uses an emulsification method.

[0010] Preferably, an organic solvent, such as dimethyl sulfoxide, is used in the process of preparing argozopan nanocrystals using the emulsification method.

[0011] Preferably, in the process of preparing argozopan nanocrystals using the emulsification method, the atmospheric pressure set for the evaporation of the organic solvent dimethyl sulfoxide is 2.38 atm, and the temperature rise is 53-60℃.

[0012] Preferably, the evaporation time of the organic solvent dimethyl sulfoxide can be 25-35 min.

[0013] Preferably, in the preparation of arcozopan nanocrystals, the ratio of arcozopan to dimethyl sulfoxide is 40-60 g / L, more preferably 50 g / L.

[0014] Preferably, in the process of preparing argotropane nanocrystals by emulsification, the weight ratio of the surfactant used to the argotropane raw material is 4%-6%.

[0015] This application also provides an arbutin injection prepared according to any of the above methods.

[0016] Beneficial effects:

[0017] 1) Solved the problem of poor water solubility of arcozopan: By emulsification, the arcozopan particles are reduced to the nanoscale, increasing the specific surface area of ​​the poorly soluble arcozopan particles, improving solubility and dissolution rate, and greatly increasing the solubility of arcozopan in the aqueous phase.

[0018] 2) High stability: After processing, the raw material of arbutin is mixed with nonionic surfactant in water. The pH value is relatively stable before and after sterilization. Furthermore, no solids are precipitated after arbutin injection is exposed to the sun for a long time. The content of active ingredients and pH value are relatively stable, thus achieving a stable effect.

[0019] 3) Enhanced safety: The preparation of atorzopan injection using atorzopan nanocrystals requires only a small amount of surfactant, resulting in fewer adverse reactions caused by surfactants and higher safety, which can overcome the aforementioned adverse reactions; furthermore, atorzopan nanocrystals have greater surface adhesion, prolonging the drug's action time in the mucus layer, limiting diffusion, increasing local drug concentration, and promoting drug absorption in the gastrointestinal tract. Detailed Implementation

[0021] The technical solutions in the embodiments of this application will be clearly described below with reference to the embodiments of this application. Obviously, the described embodiments are only some embodiments of this application, and not all embodiments. All other embodiments obtained by those skilled in the art based on the embodiments of this application are within the scope of protection of this application.

[0024] 1) Preparation of Agzopan nanocrystals:

[0025] Raw materials weighing: arcozopam, surfactant, organic solvent, and water. The organic solvent can be dimethyl sulfoxide (DMSO); the ratio of arcozopam to DMSO is 40-60 g / L, preferably 50 g / L, 50 g / L, or 60 g / L; the surfactant used is preferably 4%-6% by weight of the arcozopam raw material, preferably 5%.

[0026] Argozopan nanocrystals were prepared using an emulsification method, and the specific steps are as follows:

[0027] a. Dissolve the arbutin active pharmaceutical ingredient in dimethyl sulfoxide to form a drug solution;

[0028] b. Dissolve poloxamer 188 in water to form an aqueous solution;

[0029] c. At room temperature and pressure, slowly add the drug solution dropwise to the aqueous phase solution while stirring vigorously at a speed of 500 rpm for 20 minutes to form an "oil / water" emulsion.

[0030] d. Crystallization: The emulsion is heated to 53-60℃ and the pressure is increased to 2.38 atm. It is evaporated for 25-35 minutes to remove the organic solvent DMSO. As the solvent evaporates, argozopan gradually precipitates to form nanocrystals.

[0031] e. Filtration to separate the nanocrystals from the emulsion, washing to remove residual surfactants and impurities, and drying to obtain Agzopan nanocrystals.

[0032] 2) Preparation of Argiopan Injection:

[0033] Take the prepared arcozopan nanocrystals, nonionic surfactant, and purified water, mix and stir evenly, add 10% sodium hydroxide solution to adjust the pH value to 5.5-6.8, and measure the pH value at this time; the nonionic surfactant can be poloxamer 188, polysorbate 80, or polyvinylpyrrolidone, and the ratio of arcozopan nanocrystals to nonionic surfactant is 1:(0.05-0.2); it can be 1:0.05, 1:0.10, 1:0.15, or 1:0.2, preferably 1:0.15. The preferred ratio of arcozopan nanocrystals to purified water is 5 mg / ml.

[0034] 3) Before filling, purge the empty bottle with nitrogen gas, fill with 2ml of liquid medicine, and then seal it.

[0035] 4) The sealed sample was subjected to moist heat sterilization at 121℃ for 15 minutes to obtain the sample azithromycin injection.

[0036] Example 1

[0037] 1) Preparation of Arcozopan Nanocrystals: 100g of arcozopan, 5g of poloxamer 188, and 2L of organic solvent DMSO were used as solvents to prepare arcozopan nanocrystals using an emulsification method. The specific steps are as follows:

[0038] a. Dissolve the arbutin active pharmaceutical ingredient in dimethyl sulfoxide to form a drug solution;

[0039] b. Dissolve poloxamer 188 in 1L of water to form an aqueous solution;

[0040] c. At room temperature and pressure, slowly add the drug solution dropwise to the aqueous phase solution while stirring vigorously at a speed of 500 rpm for 20 minutes to form an "oil / water" emulsion.

[0041] d. Crystallization: The emulsion was heated to 55°C and the pressure was increased to 2.38 atm. It was evaporated for 30 min to remove the organic solvent DMSO. As the solvent evaporated, argozopan gradually precipitated to form nanocrystals.

[0042] e. Filtration to separate the nanocrystals from the emulsion, washing to remove residual surfactants and impurities, and drying to obtain Agzopan nanocrystals.

[0043] 2) Preparation of Argiopan Injection:

[0044] Take 10.0g of the above-prepared azopan nanocrystals, add 1.5g of poloxamer 188 and pure water to 2L, mix and stir evenly, add 10% sodium hydroxide solution to adjust the pH value to 5.5-6.8, and measure the pH value at this time.

[0045] 3) Before filling, purge the empty bottle with nitrogen gas, fill with 2ml of liquid medicine, and then seal it.

[0046] 4) The sealed sample was subjected to moist heat sterilization at 121℃ for 15 minutes to obtain sample 1.

[0047] Example 2

[0048] 1) Preparation of Arcozopan Nanocrystals: Take 100g of arcozopan, 5g of polysorbate 80, and 2L of dimethyl sulfoxide (DMSO) as the solvent. Prepare arcozopan nanocrystals using an emulsification method. The specific steps are as follows:

[0049] a. Dissolve the arbutin active pharmaceutical ingredient in dimethyl sulfoxide to form a drug solution;

[0050] b. Dissolve poloxamer 188 in 1L of water to form an aqueous solution;

[0051] c. At room temperature and pressure, slowly add the drug solution dropwise to the aqueous phase solution while stirring vigorously at a speed of 500 rpm for 20 minutes to form an "oil / water" emulsion.

[0052] d. Crystallization: The emulsion was heated to 55°C and the pressure was increased to 2.38 atm. It was evaporated for 30 min to remove the organic solvent DMSO. As the solvent evaporated, argozopan gradually precipitated to form nanocrystals.

[0053] e. Filtration to separate the nanocrystals from the emulsion, washing to remove residual surfactants and impurities, and drying to obtain Agzopan nanocrystals.

[0054] 2) Preparation of Argiopan Injection:

[0055] Take 10g of the above-prepared arbutin nanocrystals, add 1.5g of polysorbate 80 and pure water to 2L, mix and stir evenly, add 10% sodium hydroxide solution to adjust the pH value to 5.5-6.8, and record the pH value at this time.

[0056] 3) Before filling, purge the empty bottle with nitrogen gas, fill with 2ml of liquid medicine, and then seal it.

[0057] 4) The sealed sample was subjected to moist heat sterilization at 121℃ for 15 minutes to obtain sample 2.

[0058] Example 3

[0059] 1) Preparation of Arcozopan Nanocrystals: Take 100g of arcozopan, 5g of polyvinylpyrrolidone, and 2L of dimethyl sulfoxide (DMSO) as the solvent, and prepare arcozopan nanocrystals using an emulsification method. The specific steps are as follows:

[0060] a. Dissolve the arbutin active pharmaceutical ingredient in dimethyl sulfoxide to form a drug solution;

[0061] b. Dissolve poloxamer 188 in 1L of water to form an aqueous solution;

[0062] c. At room temperature and pressure, slowly add the drug solution dropwise to the aqueous phase solution while stirring vigorously at a speed of 500 rpm for 20 minutes to form an "oil / water" emulsion.

[0063] d. Crystallization: The emulsion was heated to 55°C and the pressure was increased to 2.38 atm. It was evaporated for 30 min to remove the organic solvent DMSO. As the solvent evaporated, argozopan gradually precipitated to form nanocrystals.

[0064] e. Filtration to separate the nanocrystals from the emulsion, washing to remove residual surfactants and impurities, and drying to obtain Agzopan nanocrystals.

[0065] 2) Preparation of Argiopan Injection:

[0066] Take 10g of the above-prepared arbutin nanocrystals, add 1.5g of polyvinylpyrrolidone and pure water to 2L, mix and stir evenly, add 10% sodium hydroxide solution to adjust the pH value to 5.5-6.8, and measure the pH value at this time.

[0067] 3) Before filling, purge the empty bottle with nitrogen gas, fill with 2ml of liquid medicine, and then seal it.

[0068] 4) The sealed sample was subjected to moist heat sterilization at 121℃ for 15 minutes to obtain sample 3.

[0069] Example 4

[0070] 1) Preparation of Arcozopan Nanocrystals: Take 100g of arcozopan, 5g of poloxamer 188, and 2L of dimethyl sulfoxide (DMSO) as the solvent, and prepare arcozopan nanocrystals using an emulsification method. The specific steps are as follows:

[0071] a. Dissolve the arbutin active pharmaceutical ingredient in dimethyl sulfoxide to form a drug solution;

[0072] b. Dissolve poloxamer 188 in 1L of water to form an aqueous solution;

[0073] c. At room temperature and pressure, slowly add the drug solution dropwise to the aqueous phase solution while stirring vigorously at a speed of 500 rpm for 20 minutes to form an "oil / water" emulsion.

[0074] d. Crystallization: The emulsion was heated to 55°C and the pressure was increased to 2.38 atm. It was evaporated for 30 min to remove the organic solvent DMSO. As the solvent evaporated, argozopan gradually precipitated to form nanocrystals.

[0075] e. Filtration to separate the nanocrystals from the emulsion, washing to remove residual surfactants and impurities, and drying to obtain Agzopan nanocrystals.

[0076] 2) Preparation of Argiopan Injection:

[0077] Take 10g of the above-prepared azopan nanocrystals, add 0.5g of poloxamer 188 and pure water to 2L, mix and stir evenly, add 10% sodium hydroxide solution to adjust the pH value to 5.5-6.8, and measure the pH value at this time.

[0078] 3) Before filling, purge the empty bottle with nitrogen gas, fill with 2ml of liquid medicine, and then seal it.

[0079] 4) The sealed sample was subjected to moist heat sterilization at 121℃ for 15 min to obtain sample 4.

[0080] Example 5

[0081] 1) Preparation of Arcozopan Nanocrystals: Take 100g of arcozopan, 5g of poloxamer 188, and 2L of dimethyl sulfoxide (DMSO) as the solvent, and prepare arcozopan nanocrystals using an emulsification method. The specific steps are as follows:

[0082] a. Dissolve the arbutin active pharmaceutical ingredient in dimethyl sulfoxide to form a drug solution;

[0083] b. Dissolve poloxamer 188 in 1L of water to form an aqueous solution;

[0084] c. At room temperature and pressure, slowly add the drug solution dropwise to the aqueous phase solution while stirring vigorously at a speed of 500 rpm for 20 minutes to form an "oil / water" emulsion.

[0085] d. Crystallization: The emulsion was heated to 55°C and the pressure was increased to 2.38 atm. It was evaporated for 30 min to remove the organic solvent DMSO. As the solvent evaporated, argozopan gradually precipitated to form nanocrystals.

[0086] e. Filtration to separate the nanocrystals from the emulsion, washing to remove residual surfactants and impurities, and drying to obtain Agzopan nanocrystals.

[0087] 2) Preparation of Argiopan Injection:

[0088] Take 10g of the above-prepared azopan nanocrystals, add 1.0g of poloxamer 188 and pure water to 2L, mix and stir evenly, add 10% sodium hydroxide solution to adjust the pH value to 5.5-6.8, and measure the pH value at this time.

[0089] 3) Before filling, purge the empty bottle with nitrogen gas, fill with 2ml of liquid medicine, and then seal it.

[0090] 4) The sealed sample was subjected to moist heat sterilization at 121℃ for 15 min to obtain sample 5.

[0091] Example 6

[0092] 1) Preparation of Arcozopan Nanocrystals: Take 100g of arcozopan, 5g of poloxamer 188, and 2L of dimethyl sulfoxide (DMSO) as the solvent, and prepare arcozopan nanocrystals using an emulsification method. The specific steps are as follows:

[0093] a. Dissolve the arbutin active pharmaceutical ingredient in dimethyl sulfoxide to form a drug solution;

[0094] b. Dissolve poloxamer 188 in 1L of water to form an aqueous solution;

[0095] c. At room temperature and pressure, slowly add the drug solution dropwise to the aqueous phase solution while stirring vigorously at a speed of 500 rpm for 20 minutes to form an "oil / water" emulsion.

[0096] d. Crystallization: The emulsion was heated to 55°C and the pressure was increased to 2.38 atm. It was evaporated for 30 min to remove the organic solvent DMSO. As the solvent evaporated, argozopan gradually precipitated to form nanocrystals.

[0097] e. Filtration to separate the nanocrystals from the emulsion, washing to remove residual surfactants and impurities, and drying to obtain Agzopan nanocrystals.

[0098] 2) Preparation of Argiopan Injection:

[0099] Take 10g of the above-prepared azopan nanocrystals, add 2.0g of poloxamer 188 and pure water to 2L, mix and stir evenly, add 10% sodium hydroxide solution to adjust the pH value to 5.5-6.8, and measure the pH value at this time.

[0100] 3) Before filling, purge the empty bottle with nitrogen gas, fill with 2ml of liquid medicine, and then seal it.

[0101] 4) The sealed sample was subjected to moist heat sterilization at 121℃ for 15 minutes to obtain sample 6.

[0102] Example 7

[0103] 1) Preparation of Arcozopan Nanocrystals: Take 100g of arcozopan, 5g of poloxamer 188, and 2L of dimethyl sulfoxide (DMSO) as the solvent, and prepare arcozopan nanocrystals using an emulsification method. The specific steps are as follows:

[0104] a. Dissolve the arbutin active pharmaceutical ingredient in dimethyl sulfoxide to form a drug solution;

[0105] b. Dissolve poloxamer 188 in 1L of water to form an aqueous solution;

[0106] c. At room temperature and pressure, slowly add the drug solution dropwise to the aqueous phase solution while stirring vigorously at a speed of 500 rpm for 20 minutes to form an "oil / water" emulsion.

[0107] d. Crystallization: The emulsion was heated to 53°C and the pressure was increased to 2.38 atm. It was evaporated for 30 min to remove the organic solvent DMSO. As the solvent evaporated, argozopan gradually precipitated to form nanocrystals.

[0108] e. Filtration to separate the nanocrystals from the emulsion, washing to remove residual surfactants and impurities, and drying to obtain Agzopan nanocrystals.

[0109] 2) Preparation of Argiopan Injection:

[0110] Take 10g of the above-prepared azopan nanocrystals, add 1.5g of poloxamer 188 and pure water to 2L, mix and stir evenly, add 10% sodium hydroxide solution to adjust the pH value to 5.5-6.8, and measure the pH value at this time.

[0111] 3) Before filling, purge the empty bottle with nitrogen gas, fill with 2ml of liquid medicine, and then seal it.

[0112] 4) The sealed sample was subjected to moist heat sterilization at 121℃ for 15 minutes to obtain sample 7.

[0113] Example 8

[0114] 1) Preparation of Arcozopan Nanocrystals: Take 100g of arcozopan, 5g of poloxamer 188, and 2L of dimethyl sulfoxide (DMSO) as the solvent, and prepare arcozopan nanocrystals using an emulsification method. The specific steps are as follows:

[0115] a. Dissolve the arbutin active pharmaceutical ingredient in dimethyl sulfoxide to form a drug solution;

[0116] b. Dissolve poloxamer 188 in 1L of water to form an aqueous solution;

[0117] c. At room temperature and pressure, slowly add the drug solution dropwise to the aqueous phase solution while stirring vigorously at a speed of 500 rpm for 20 minutes to form an "oil / water" emulsion.

[0118] d. Crystallization: The emulsion was heated to 58°C and the pressure was increased to 2.38 atm. It was evaporated for 30 min to remove the organic solvent DMSO. As the solvent evaporated, argotron gradually precipitated to form nanocrystals.

[0119] e. Filtration to separate the nanocrystals from the emulsion, washing to remove residual surfactants and impurities, and drying to obtain Agzopan nanocrystals.

[0120] 2) Preparation of Argiopan Injection:

[0121] Take 10g of the above-prepared azopan nanocrystals, add 1.5g of poloxamer 188 and pure water to 2L, mix and stir evenly, add 10% sodium hydroxide solution to adjust the pH value to 5.5-6.8, and measure the pH value at this time.

[0122] 3) Before filling, purge the empty bottle with nitrogen gas, fill with 2ml of liquid medicine, and then seal it.

[0123] 4) The sealed sample was subjected to moist heat sterilization at 121℃ for 15 minutes to obtain sample 8.

[0124] Example 9

[0125] 1) Preparation of Arcozopan Nanocrystals: Take 100g of arcozopan, 5g of poloxamer 188, and 2L of dimethyl sulfoxide (DMSO) as the solvent, and prepare arcozopan nanocrystals using an emulsification method. The specific steps are as follows:

[0126] a. Dissolve the arbutin active pharmaceutical ingredient in dimethyl sulfoxide to form a drug solution;

[0127] b. Dissolve poloxamer 188 in 1L of water to form an aqueous solution;

[0128] c. At room temperature and pressure, slowly add the drug solution dropwise to the aqueous phase solution while stirring vigorously at a speed of 500 rpm for 20 minutes to form an "oil / water" emulsion.

[0129] d. Crystallization: The emulsion was heated to 60°C and the pressure was increased to 2.38 atm. It was evaporated for 30 min to remove the organic solvent DMSO. As the solvent evaporated, argozopan gradually precipitated to form nanocrystals.

[0130] e. Filtration to separate the nanocrystals from the emulsion, washing to remove residual surfactants and impurities, and drying to obtain Agzopan nanocrystals.

[0131] 2) Preparation of Argiopan Injection:

[0132] Take 10g of the above-prepared azopan nanocrystals, add 1.5g of poloxamer 188 and pure water to 2L, mix and stir evenly, add 10% sodium hydroxide solution to adjust the pH value to 5.5-6.8, and measure the pH value at this time.

[0133] 3) Before filling, purge the empty bottle with nitrogen gas, fill with 2ml of liquid medicine, and then seal it.

[0134] 4) The sealed sample was subjected to moist heat sterilization at 121℃ for 15 minutes to obtain sample 9.

[0135] Example 10

[0136] 1) Preparation of Arcozopan Nanocrystals: Take 100g of arcozopan, 5g of poloxamer 188, and 2L of dimethyl sulfoxide (DMSO) as the solvent, and prepare arcozopan nanocrystals using an emulsification method. The specific steps are as follows:

[0137] a. Dissolve the arbutin active pharmaceutical ingredient in dimethyl sulfoxide to form a drug solution;

[0138] b. Dissolve poloxamer 188 in 1L of water to form an aqueous solution;

[0139] c. At room temperature and pressure, slowly add the drug solution dropwise to the aqueous phase solution while stirring vigorously at a speed of 500 rpm for 20 minutes to form an "oil / water" emulsion.

[0140] d. Crystallization: The emulsion was heated to 55°C and the pressure was increased to 2.38 atm. It was evaporated for 25 min to remove the organic solvent DMSO. As the solvent evaporated, argotron gradually precipitated to form nanocrystals.

[0141] e. Filtration to separate the nanocrystals from the emulsion, washing to remove residual surfactants and impurities, and drying to obtain Agzopan nanocrystals.

[0142] 2) Preparation of Argiopan Injection:

[0143] Take 10g of the above-prepared azopan nanocrystals, add 1.5g of poloxamer 188 and pure water to 2L, mix and stir evenly, add 10% sodium hydroxide solution to adjust the pH value to 5.5-6.8, and measure the pH value at this time.

[0144] 3) Before filling, purge the empty bottle with nitrogen gas, fill with 2ml of liquid medicine, and then seal it.

[0145] 4) The sealed sample was subjected to moist heat sterilization at 121℃ for 15 min to obtain sample 10.

[0146] Example 11

[0147] 1) Preparation of Arcozopan Nanocrystals: Take 100g of arcozopan, 5g of poloxamer 188, and 2L of dimethyl sulfoxide (DMSO) as the solvent, and prepare arcozopan nanocrystals using an emulsification method. The specific steps are as follows:

[0148] a. Dissolve the arbutin active pharmaceutical ingredient in dimethyl sulfoxide to form a drug solution;

[0149] b. Dissolve poloxamer 188 in 1L of water to form an aqueous solution;

[0150] c. At room temperature and pressure, slowly add the drug solution dropwise to the aqueous phase solution while stirring vigorously at a speed of 500 rpm for 20 minutes to form an "oil / water" emulsion.

[0151] d. Crystallization: The emulsion was heated to 55°C and the pressure was increased to 2.38 atm. It was evaporated for 35 min to remove the organic solvent DMSO. As the solvent evaporated, argotron gradually precipitated to form nanocrystals.

[0152] e. Filtration to separate the nanocrystals from the emulsion, washing to remove residual surfactants and impurities, and drying to obtain Agzopan nanocrystals.

[0153] 2) Preparation of Argiopan Injection:

[0154] Take 10g of the above-prepared azopan nanocrystals, add 1.5g of poloxamer 188 and pure water to 2L, mix and stir evenly, add 10% sodium hydroxide solution to adjust the pH value to 5.5-6.8, and measure the pH value at this time.

[0155] 3) Before filling, purge the empty bottle with nitrogen gas, fill with 2ml of liquid medicine, and then seal it.

[0156] 4) The sealed sample was subjected to moist heat sterilization at 121℃ for 15 min to obtain sample 11.

[0157] Comparative Example 1

[0158] 1) Preparation of Arcozopan Nanocrystals: Take 100g of arcozopan, 5g of poloxamer 188, and 2L of dimethyl sulfoxide (DMSO) as the solvent, and prepare arcozopan nanocrystals using an emulsification method. The specific steps are as follows:

[0159] a. Dissolve the arbutin active pharmaceutical ingredient in dimethyl sulfoxide to form a drug solution;

[0160] b. Dissolve poloxamer 188 in 1L of water to form an aqueous solution;

[0161] c. At room temperature and pressure, slowly add the drug solution dropwise to the aqueous phase solution while stirring vigorously at a speed of 500 rpm for 20 minutes to form an "oil / water" emulsion.

[0162] d. Crystallization: The emulsion was heated to 55°C and the pressure was increased to 2.38 atm. It was evaporated for 30 min to remove the organic solvent DMSO. As the solvent evaporated, argozopan gradually precipitated to form nanocrystals.

[0163] e. Filtration to separate the nanocrystals from the emulsion, washing to remove residual surfactants and impurities, and drying to obtain Agzopan nanocrystals.

[0164] 2) Preparation of Argiopan Injection:

[0165] Take 10g of the above-prepared azopan nanocrystals, add 0.3g of poloxamer 188 and pure water to 2L, mix and stir evenly, add 10% sodium hydroxide solution to adjust the pH value to 5.5-6.8, and measure the pH value at this time.

[0166] 3) Before filling, purge the empty bottle with nitrogen gas, fill with 2ml of liquid medicine, and then seal it.

[0167] 4) The sealed sample was subjected to moist heat sterilization at 121℃ for 15 minutes to obtain sample 12.

[0168] Comparative Example 2

[0169] 1) Preparation of Arcozopan Nanocrystals: Take 100g of arcozopan, 5g of poloxamer 188, and 2L of dimethyl sulfoxide (DMSO) as the solvent, and prepare arcozopan nanocrystals using an emulsification method. The specific steps are as follows:

[0170] a. Dissolve the arbutin active pharmaceutical ingredient in dimethyl sulfoxide to form a drug solution;

[0171] b. Dissolve poloxamer 188 in 1L of water to form an aqueous solution;

[0172] c. At room temperature and pressure, slowly add the drug solution dropwise to the aqueous phase solution while stirring vigorously at a speed of 500 rpm for 20 minutes to form an "oil / water" emulsion.

[0173] d. Crystallization: The emulsion was heated to 55°C and the pressure was increased to 2.38 atm. It was evaporated for 30 min to remove the organic solvent DMSO. As the solvent evaporated, argozopan gradually precipitated to form nanocrystals.

[0174] e. Filtration to separate the nanocrystals from the emulsion, washing to remove residual surfactants and impurities, and drying to obtain Agzopan nanocrystals.

[0175] 2) Preparation of Argiopan Injection:

[0176] Take 10g of the above-prepared azopan nanocrystals, add 2.5g of poloxamer 188 and pure water to 2L, mix and stir evenly, add 10% sodium hydroxide solution to adjust the pH value to 5.5-6.8, and measure the pH value at this time.

[0177] 3) Before filling, purge the empty bottle with nitrogen gas, fill with 2ml of liquid medicine, and then seal it.

[0178] 4) The sealed sample was subjected to moist heat sterilization at 121℃ for 15 min to obtain sample 13.

[0179] Comparative Example 3

[0180] 1) Preparation of Arcozopan Nanocrystals: Take 100g of arcozopan, 5g of poloxamer 188, and 2L of dimethyl sulfoxide (DMSO) as the solvent, and prepare arcozopan nanocrystals using an emulsification method. The specific steps are as follows:

[0181] a. Dissolve the arbutin active pharmaceutical ingredient in dimethyl sulfoxide to form a drug solution;

[0182] b. Dissolve poloxamer 188 in 1L of water to form an aqueous solution;

[0183] c. At room temperature and pressure, slowly add the drug solution dropwise to the aqueous phase solution while stirring vigorously at a speed of 500 rpm for 20 minutes to form an "oil / water" emulsion.

[0184] d. Crystallization: The emulsion was heated to 50°C and the pressure was increased to 2.38 atm. It was evaporated for 30 min to remove the organic solvent DMSO. As the solvent evaporated, argotron gradually precipitated to form nanocrystals.

[0185] e. Filtration to separate the nanocrystals from the emulsion, washing to remove residual surfactants and impurities, and drying to obtain Agzopan nanocrystals.

[0186] 2) Preparation of Argiopan Injection:

[0187] Take 10g of the above-prepared azopan nanocrystals, add 1.5g of poloxamer 188 and pure water to 2L, mix and stir evenly, add 10% sodium hydroxide solution to adjust the pH value to 5.5-6.8, and measure the pH value at this time.

[0188] 3) Before filling, purge the empty bottle with nitrogen gas, fill with 2ml of liquid medicine, and then seal it.

[0189] 4) The sealed sample was subjected to moist heat sterilization at 121℃ for 15 min to obtain sample 14.

[0190] Comparative Example 4

[0191] 1) Preparation of Arcozopan Nanocrystals: Take 100g of arcozopan, 5g of poloxamer 188, and 2L of dimethyl sulfoxide (DMSO) as the solvent, and prepare arcozopan nanocrystals using an emulsification method. The specific steps are as follows:

[0192] a. Dissolve the arbutin active pharmaceutical ingredient in dimethyl sulfoxide to form a drug solution;

[0193] b. Dissolve poloxamer 188 in 1L of water to form an aqueous solution;

[0194] c. At room temperature and pressure, slowly add the drug solution dropwise to the aqueous phase solution while stirring vigorously at a speed of 500 rpm for 20 minutes to form an "oil / water" emulsion.

[0195] d. Crystallization: The emulsion was heated to 65°C and the pressure was increased to 2.38 atm. It was evaporated for 30 min to remove the organic solvent DMSO. As the solvent evaporated, argotron gradually precipitated to form nanocrystals.

[0196] e. Filtration to separate the nanocrystals from the emulsion, washing to remove residual surfactants and impurities, and drying to obtain Agzopan nanocrystals.

[0197] 2) Preparation of Argiopan Injection:

[0198] Take 10g of the above-prepared azopan nanocrystals, add 1.5g of poloxamer 188 and pure water to 2L, mix and stir evenly, add 10% sodium hydroxide solution to adjust the pH value to 5.5-6.8, and measure the pH value at this time.

[0199] 3) Before filling, purge the empty bottle with nitrogen gas, fill with 2ml of liquid medicine, and then seal it.

[0200] 4) The sealed sample was subjected to moist heat sterilization at 121℃ for 15 minutes to obtain sample 15.

[0201] Comparative Example 5

[0202] 1) Preparation of Arcozopan Nanocrystals: Take 100g of arcozopan, 5g of poloxamer 188, and 2L of dimethyl sulfoxide (DMSO) as the solvent, and prepare arcozopan nanocrystals using an emulsification method. The specific steps are as follows:

[0203] a. Dissolve the arbutin active pharmaceutical ingredient in dimethyl sulfoxide to form a drug solution;

[0204] b. Dissolve poloxamer 188 in 1L of water to form an aqueous solution;

[0205] c. At room temperature and pressure, slowly add the drug solution dropwise to the aqueous phase solution while stirring vigorously at a speed of 500 rpm for 20 minutes to form an "oil / water" emulsion.

[0206] d. Crystallization: The emulsion was heated to 55°C and the pressure was increased to 2.38 atm. It was evaporated for 20 min to remove the organic solvent DMSO. As the solvent evaporated, argozopan gradually precipitated to form nanocrystals.

[0207] e. Filtration to separate the nanocrystals from the emulsion, washing to remove residual surfactants and impurities, and drying to obtain Agzopan nanocrystals.

[0208] 2) Preparation of Argiopan Injection:

[0209] Take 10g of the above-prepared azopan nanocrystals, add 1.5g of poloxamer 188 and pure water to 2L, mix and stir evenly, add 10% sodium hydroxide solution to adjust the pH value to 5.5-6.8, and measure the pH value at this time.

[0210] 3) Before filling, purge the empty bottle with nitrogen gas, fill with 2ml of liquid medicine, and then seal it.

[0211] 4) The sealed sample was subjected to moist heat sterilization at 121℃ for 15 min to obtain sample 16.

[0212] Comparative Example 6

[0213] 1) Preparation of Arcozopan Nanocrystals: Take 100g of arcozopan, 5g of poloxamer 188, and 2L of dimethyl sulfoxide (DMSO) as the solvent, and prepare arcozopan nanocrystals using an emulsification method. The specific steps are as follows:

[0214] a. Dissolve the arbutin active pharmaceutical ingredient in dimethyl sulfoxide to form a drug solution;

[0215] b. Dissolve poloxamer 188 in 1L of water to form an aqueous solution;

[0216] c. At room temperature and pressure, slowly add the drug solution dropwise to the aqueous phase solution while stirring vigorously at a speed of 500 rpm for 20 minutes to form an "oil / water" emulsion.

[0217] d. Crystallization: The emulsion was heated to 55°C and the pressure was increased to 2.38 atm. It was evaporated for 40 min to remove the organic solvent DMSO. As the solvent evaporated, argozopan gradually precipitated to form nanocrystals.

[0218] e. Filtration to separate the nanocrystals from the emulsion, washing to remove residual surfactants and impurities, and drying to obtain Agzopan nanocrystals.

[0219] 2) Preparation of Argiopan Injection:

[0220] Take 10g of the above-prepared azopan nanocrystals, add 1.5g of poloxamer 188 and pure water to 2L, mix and stir evenly, add 10% sodium hydroxide solution to adjust the pH value to 5.5-6.8, and measure the pH value at this time.

[0221] 3) Before filling, purge the empty bottle with nitrogen gas, fill with 2ml of liquid medicine, and then seal it.

[0222] 4) The sealed sample was subjected to moist heat sterilization at 121℃ for 15 min to obtain sample 17.

[0223] Comparative Example 7

[0224] 1) Preparation of Arcozopan Nanocrystals: Take 100g of arcozopan, 5g of sodium dodecyl sulfate, and 2L of dimethyl sulfoxide (DMSO) as the solvent, and prepare arcozopan nanocrystals by emulsification. The specific steps are as follows:

[0225] a. Dissolve the arbutin active pharmaceutical ingredient in dimethyl sulfoxide to form a drug solution;

[0226] b. Dissolve poloxamer 188 in 1L of water to form an aqueous solution;

[0227] c. At room temperature and pressure, slowly add the drug solution dropwise to the aqueous phase solution while stirring vigorously at a speed of 500 rpm for 20 minutes to form an "oil / water" emulsion.

[0228] d. Crystallization: The emulsion was heated to 55°C and the pressure was increased to 2.38 atm. It was evaporated for 30 min to remove the organic solvent DMSO. As the solvent evaporated, argozopan gradually precipitated to form nanocrystals.

[0229] e. Filtration to separate the nanocrystals from the emulsion, washing to remove residual surfactants and impurities, and drying to obtain Agzopan nanocrystals.

[0230] 2) Preparation of Argiopan Injection:

[0231] Take 10g of the above-prepared argozopan nanocrystals, add 1.5g of sodium dodecyl sulfate and pure water to 2L, mix and stir evenly, add 10% sodium hydroxide solution to adjust the pH value to 5.5-6.8, and measure the pH value at this time.

[0232] 3) Before filling, purge the empty bottle with nitrogen gas, fill with 2ml of liquid medicine, and then seal it.

[0233] 4) The sealed sample was subjected to moist heat sterilization at 121℃ for 15 min to obtain sample 18.

[0234] Table 1. Summary of the types and amounts of surfactants used in Examples 1-11 and Comparative Examples 1-7, as well as the evaporation temperatures and times during the preparation stages of arcozopan nanocrystals.

[0235]

[0236]

[0237] The stability of the active ingredients in samples 1-18 was tested.

[0238] I. The pH values ​​of samples 1-18 before and after sterilization were measured. The results are shown in Table 2.

[0239] Table 2. pH values ​​of samples 1-18 before and after sterilization.

[0240]

[0241]

[0242] Comparing samples 1-3 and 18, it was found that the pH value of samples 1-3 changed very little before and after sterilization, while the pH value of sample 18 changed significantly before and after sterilization. This indicates that, under the same conditions, arbutin injection prepared using sodium dodecyl sulfate, an ionic surfactant, showed a larger pH change before and after sterilization, indicating poor drug stability. In contrast, arbutin injection prepared using a nonionic surfactant showed a smaller pH change before and after sterilization, indicating better drug stability and higher safety.

[0243] Comparing samples 1, 4-6, 12, and 13, it can be seen that the pH value of samples 1 and 4-6 changed less before and after sterilization, while the pH value of samples 12 and 13 changed more before and after sterilization. Therefore, under the condition that other conditions remain unchanged, when the ratio of nonionic surfactant to arbutin raw material is (0.5-2):10, the prepared arbutin injection has better stability and higher safety.

[0244] Comparing samples 1, 7-9, 14, and 15, it can be seen that the pH value of samples 1 and 7-9 changed less before and after sterilization, while the pH value of samples 14 and 15 changed more before and after sterilization. Therefore, under the condition that other conditions remain unchanged, in the process of preparing arcozopan nanocrystals, setting the temperature for heating the emulsifier to allow the organic solvent DMSO to evaporate to 53-60℃ will result in arcozopan injection with better stability and higher safety.

[0245] Comparing samples 1, 10, 11, 16, and 17, it can be seen that the pH value of samples 1, 10, and 11 changed little before and after sterilization, while the pH value of samples 14 and 15 changed significantly before and after sterilization. Therefore, under the condition that other conditions remain unchanged, when the evaporation time of the organic solvent DMSO to be volatilized by heating the emulsifier in the preparation of arcozopan nanocrystals is 25-35 min, the prepared arcozopan injection solution has better stability and higher safety.

[0246] II. Stability of active ingredients in samples 1-18 was tested.

[0247] Samples 1-18 were placed under the influencing factors of high temperature (60℃±2℃) and light intensity of 4500Lx±500Lx for 10 days. Samples were taken on the 10th day to detect appearance, pH value, content, related substances (single impurities, total impurities), and visible foreign matter, and the results were compared with the data from day 0. The content of arbutin and related substances in arbutin injection was determined by high performance liquid chromatography (2015 edition, Part IV, 0512), and the detection data are shown in Table 3.

[0248] Table 3. Summary of performance parameter measurements for samples 1-18 after 0 days and 10 days of light exposure.

[0249]

[0250]

[0251]

[0252]

[0253]

[0254]

[0255]

[0256]

[0257]

[0258] The standard limits for arbutin injection are known to be: colorless, clear, and transparent liquid; pH value of 5.5-6.8; content of 95%-105%; single impurity ≤0.2%; and total impurity ≤0.3%.

[0259] Comparing samples 1-3 and sample 18, it was found that after 10 days of storage at high temperature (60℃±2℃) and light exposure of 4500Lx±500Lx, samples 1-3 remained a colorless, clear, and transparent liquid with a pH value between 5.5 and 6.8, a content between 95% and 105%, and total impurities ≤0.3%. However, sample 18, after 10 days under the same conditions, turned into a pale yellow, clear, and transparent liquid with a pH value less than 5.5, a content less than 95%, a single impurity greater than 0.2%, a total impurity greater than 0.3%, and solid precipitation. Therefore, under the same conditions, arzopan injection prepared using sodium dodecyl sulfate, an ionic surfactant, exhibits poorer drug stability, while arzopan injection prepared using a nonionic surfactant shows stronger drug stability.

[0260] Comparing samples 1, 4-6, 12, and 13, it was found that samples 1 and 4-6, after being placed under high temperature (60℃±2℃) and light irradiation of 4500Lx±500Lx for 10 days, remained colorless, clear, and transparent liquids with a pH value between 5.5 and 6.8, a content between 95% and 105%, single impurities ≤0.2%, and total impurities ≤0.3%, with solid precipitation. Samples 12 and 13, however, after being placed under the same conditions for 10 days, turned into pale yellow, clear, and transparent liquids with a pH value less than 5.5, a content less than 95%, single impurities greater than 0.2%, total impurities greater than 0.3%, and solid precipitation. Therefore, under the same conditions, when the ratio of nonionic surfactant to arbutin raw material is (0.5-2):10, the prepared arbutin injection exhibits better stability and higher safety.

[0261] Comparing samples 1, 7-9, 14, and 15, it is evident that samples 1 and 7-9, after being placed under high temperature (60℃±2℃) and light irradiation of 4500Lx±500Lx for 10 days, remained colorless, clear, and transparent liquids with a pH value between 5.5 and 6.8, a content of 95%-105%, single impurities ≤0.2%, and total impurities ≤0.3%. In contrast, samples 14 and 15, after being placed under the same conditions for 10 days, turned into pale yellow, clear, and transparent liquids with a pH value less than 5.5, a content less than 95%, single impurities greater than 0.2%, total impurities greater than 0.3%, and solid precipitation. Therefore, under the same conditions, setting the temperature for heating the emulsifier to allow the organic solvent DMSO to evaporate to 53-60℃ during the preparation of argotropane nanocrystals resulted in a argotropane injection solution with better stability and higher safety.

[0262] Comparing samples 1, 10, 11, 16, and 17, it is evident that samples 1, 10, and 11, after being placed under high temperature (60℃±2℃) and light irradiation of 4500Lx±500Lx for 10 days, remained colorless, clear, and transparent liquids with a pH value between 5.5 and 6.8, a content of 95%-105%, single impurities ≤0.2%, and total impurities ≤0.3%. In contrast, samples 16 and 17, after being placed under the same conditions for 10 days, turned into pale yellow, clear, and transparent liquids with a pH value less than 5.5, a content less than 95%, single impurities greater than 0.2%, total impurities greater than 0.3%, and solid precipitation. Therefore, under otherwise unchanged conditions, when the evaporation time of the organic solvent DMSO during the heating of the emulsifier in the preparation of argotropane nanocrystals is 25-35 min, the resulting argotropane injection exhibits better stability and higher safety.

[0263] It is understood that the above embodiments are merely exemplary embodiments used to illustrate the principles of this application, and this application is not limited thereto. For those skilled in the art, various modifications and improvements can be made without departing from the spirit and substance of this application, and these modifications and improvements are also considered to be within the scope of protection of this invention.

Claims

1. A method for preparing arbutin injection, characterized in that, It contains Agzopan nanocrystals, nonionic surfactants, and purified water.

2. The method for preparing arzopanic acid injection according to claim 1, characterized in that, The weight ratio of the argozopan nanocrystals to the nonionic surfactant is 1:(0.05-0.2), preferably 1:0.

15.

3. The method for preparing arbutin injection according to claim 1, characterized in that, The nonionic surfactant may be poloxamer 188, polysorbate 80, or polyvinylpyrrolidone.

4. The method for preparing arbutin injection according to claim 1, characterized in that, The Agozopan nanocrystals were prepared using an emulsification method.

5. The method for preparing arzopanic acid injection according to claim 4, characterized in that, In the emulsification method, an organic solvent is used, which may be dimethyl sulfoxide.

6. The method for preparing arzopanic acid injection according to claim 5, characterized in that, In the emulsification method, the evaporation pressure of the organic solvent dimethyl sulfoxide is set at 2.38 atm, and the temperature is raised to 50-65°C, preferably 55°C.

7. The method for preparing arbutin injection according to claim 6, characterized in that, The evaporation time of the organic solvent dimethyl sulfoxide can be 25-35 min, preferably 30 min.

8. The method for preparing arbutin injection according to claim 5, characterized in that, In the emulsification method, the ratio of arbutin to dimethyl sulfoxide is 40-60 g / L, preferably 50 g / L.

9. The method for preparing arbutin injection according to claim 4, characterized in that, In the emulsification process, a surfactant is used, and the weight ratio of the surfactant to the arbutin raw material is 4%-6%.

10. An arbutin injection, characterized in that, The anotropin injection is prepared according to any one of claims 1-9.

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