Edaravone dextroborneol solution and its preparation process and application

Abstract

The present application belongs to the field of medical technology, and in particular, relates to an edaravone dexamethasone solution and its preparation process and application. The preparation process of the edaravone dexamethasone solution comprises the steps of: dissolving edaravone in a heated organic solvent under an inert atmosphere, cooling to no more than 30°C, adding dexamethasone to dissolve, and obtaining a mixed solution; adding water and an antioxidant to the mixed solution under an inert atmosphere for mixing treatment, adjusting the pH value of the solution to 4 to 4.5, and obtaining an edaravone dexamethasone solution. The order and conditions of adding each raw material component in the preparation process of the edaravone dexamethasone solution of the present application improve the solubility of edaravone and dexamethasone in water, solve the problem that edaravone is easily oxidized and dexamethasone is easily volatilized at room temperature, have low impurity content, good pH stability, high product quality and stability, and are conducive to the long-term preservation of the edaravone dexamethasone solution.

Description

Technical Field

[0001] The present application belongs to the field of medical technology, and in particular relates to an edaravone-dexborneol solution and a preparation process and application thereof. Background Art

[0002] Edaravone, with the chemical name 3-methyl-1-phenyl-2-pyrazol-5-one, is easily soluble in sodium hydroxide solution, soluble in ethanol, and very slightly soluble or almost insoluble in water. Edaravone is extremely unstable in water and is easily affected by external environments such as oxygen, temperature, light, and metal ions. Over time, edaravone will accelerate decomposition and oxidation to produce high-molecular impurities. Edaravone is a highly efficient free radical scavenger and antioxidant (scavenging hydroxyl radicals, nitric oxide radicals, and ONOO- ions). Its application in the treatment of stroke can effectively improve the prognosis of stroke patients. Based on its precise mechanism of scavenging free radicals and inhibiting oxidative stress damage, the application of edaravone in the rare disease amyotrophic lateral sclerosis (ALS) has also continued to develop rapidly.

[0003] Borneol ((+)-borneol), chemical name endo-(1R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ol, is unstable at room temperature and pressure, highly flammable, soluble in organic solvents such as ethanol, ether, petroleum ether, benzene, toluene, acetone, decalin, tetralin, etc., almost insoluble in water, vapor evaporates at room temperature, and evaporates rapidly at high temperature. Borneol (bicyclic monoterpenoid compound) is a new type of anti-inflammatory drug that can inhibit the expression of inflammatory cytokines TNF-α, IL-1β and the expression of inflammatory proteins COX-2 and iNOS in cerebral ischemia-reperfusion models. Borneol can effectively inhibit the expression of cytokines and inflammatory proteins caused by inflammatory response, and can activate GABAa receptors, blocking the above vicious cycle pathways, thereby reducing cell apoptosis and cell necrosis, protecting the blood-brain barrier, reducing brain edema, and thus reducing ischemia-reperfusion injury.

[0004] The combination of two active ingredients, edaravone and dexborneol, can significantly reduce the brain nerve damage caused by acute ischemic stroke through multiple mechanisms of action such as free radical scavenging, anti-inflammatory and blood-brain barrier protection. However, edaravone and dexborneol have low solubility in water, edaravone is easily oxidized, and dexborneol is easily volatilized at room temperature. Therefore, a new formulation process needs to be developed to solve the problems existing in the above-mentioned edaravone dexborneol solution and its preparation process. Summary of the invention

[0005] The purpose of the present application is to provide an edaravone and dextroborneol solution and its preparation process and application, aiming to solve to a certain extent the problems that the existing edaravone and dextroborneol have low solubility in water, edaravone is easily oxidized, and dextroborneol is easily volatilized at room temperature.

[0006] In order to achieve the above application purpose, the technical solution adopted in this application is as follows:

[0007] In a first aspect, the present application provides a process for preparing an edaravone-dexamethasone solution, comprising the following steps:

[0008] S10. Under an inert atmosphere, dissolving edaravone in a heated organic solvent, cooling the mixture to no more than 30° C., and adding dextroborneol to dissolve the mixture to obtain a mixed solution;

[0009] S20. Under an inert atmosphere, water and an antioxidant are added to the mixed solution for mixing, and the pH value of the solution is adjusted to 4-4.5 to obtain an edaravone-dexamethasone solution.

[0010] In some embodiments, in the preparation of the edaravone-dexborneol solution, the concentration of edaravone is 0.10% to 0.3%, the concentration of dexborneol is 0.025% to 0.1%, the concentration of the organic solvent is 4% to 12%, and the concentration of the antioxidant is 0.05% to 0.2%.

[0011] In some embodiments, the water is water for injection, and the prepared edaravone and dextroborneol solution is edaravone and dextroborneol injection.

[0012] In some embodiments, the edaravone-dexamethasone solution has a residual dissolved oxygen content of less than 2.0 ppm and a residual headspace oxygen content of less than 2.0%.

[0013] In some embodiments, the step of dissolving edaravone in a heated organic solvent comprises: adding the organic solvent into a liquid preparation tank, filling it with nitrogen and heating it to 55° C. to 65° C., and then adding the edaravone and stirring until it is dissolved.

[0014] In some embodiments, the water added to the mixed solution is water for injection with a temperature below 30° C. and filled with nitrogen for more than 30 minutes.

[0015] In some embodiments, the organic solvent includes at least one of propylene glycol, polyethylene glycol, and ethanol.

[0016] In some embodiments, the antioxidant includes at least one of sodium metabisulfite, sodium bisulfite, sodium thiosulfate, and cysteine.

[0017] In some embodiments, the pH adjuster used to adjust the pH value includes at least one of hydrochloric acid, phosphoric acid, sodium hydroxide, and potassium hydroxide.

[0018] In some embodiments, after adjusting the pH value, the process further includes volume fixing, filtration, filling and sterilization.

[0019] In some embodiments, the volume adjustment process comprises the steps of adding water for injection to adjust the volume, filling with nitrogen and stirring.

[0020] In some embodiments, the filtration process is performed at least twice using a filter element with a pore size no greater than 0.22 μm.

[0021] In some embodiments, the filling process comprises the steps of: filling the prepared solution with nitrogen and controlling the residual oxygen content in the headspace to be below 2.0%.

[0022] In some embodiments, the sterilization treatment is carried out at a temperature of 100° C. to 130° C. and for a duration of 12 min to 15 min.

[0023] In a second aspect, the present application provides an edaravone-dexamethasone solution prepared by the above method, comprising edaravone, dexamethasone, an organic solvent, an antioxidant, a pH adjuster and water, wherein the pH value of the edaravone-dexamethasone solution is 4 to 4.5.

[0024] In some embodiments, the edaravone and dextroborneol solution is an edaravone and dextroborneol injection, wherein the water is water for injection, the concentration of edaravone is 0.10% to 0.3%, the concentration of dextroborneol is 0.025% to 0.1%, the concentration of the organic solvent is 4% to 12%, and the concentration of the antioxidant is 0.05% to 0.2%.

[0025] In a third aspect, the present application provides an application of an edaravone-dextrocarbol solution, wherein the edaravone-dextrocarbol solution prepared by the above method or the above edaravone-dextrocarbol solution is applied to at least one drug for scavenging free radicals, anti-inflammation, and protecting the blood-brain barrier.

[0026] The preparation process of the edaravone dexamethasone solution provided in the first aspect of the present application is carried out in an inert atmosphere, and the oxygen in the preparation system and the product is removed, the residual oxygen content of the product is controlled, and the oxidative damage of oxygen to edaravone is effectively reduced, and the generation of impurities is reduced, and the quality and stability of the product are improved. After edaravone is dissolved in a heated organic solvent, it is cooled to not more than 30 ° C and dexamethasone is added for dissolution. According to the characteristics of edaravone and dexamethasone, it is dissolved under heating conditions and low temperature conditions, respectively, which fully ensures that edaravone and dexamethasone are fully dissolved, and dexamethasone is dissolved under low temperature conditions to avoid the volatilization of dexamethasone. Water and an antioxidant are added to the mixed solution for mixed treatment, and the pH value is adjusted to maintain the pH value of the edaravone dexamethasone solution at 4 to 4.5. Within the pH value range, the pH fluctuation is small, the pH value is easily controlled, and the product stability is good, which is conducive to long-term preservation. The order and conditions of adding each raw material component in the preparation process of the edaravone and dexamethasone solution of the present application improve the solubility of edaravone and dexamethasone in water, solve the problem that edaravone is easily oxidized and dexamethasone is easily volatilized at room temperature, have low impurity content, good pH stability, high product quality and stability, and are conducive to the long-term storage of the edaravone and dexamethasone solution. The preparation process of the edaravone and dexamethasone solution provided by the present application has low cost, simple operation and short process cycle.

[0027] The edaravone and dextroborneol solution provided in the second aspect of the present application is prepared by the above method, comprising edaravone, dextroborneol, an organic solvent, an antioxidant, a pH regulator and water, and the pH value of the edaravone and dextroborneol solution is 4 to 4.5. The solubility of edaravone and dextroborneol in water is improved, the problem that edaravone is easily oxidized and dextroborneol is easily volatilized at room temperature is solved, the impurity content is low, the pH value is stable, the product quality and stability are high, and it can be stored for a long time.

[0028] In the third aspect of the present application, the edaravone and dextroborneol solution has powerful antioxidant, anti-inflammatory, microcirculation improving, mitochondrial function protecting and nerve repair promoting effects. Therefore, the edaravone and dextroborneol solution can be applied to at least one of the drugs for scavenging free radicals, anti-inflammatory and protecting the blood-brain barrier to improve related symptoms. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] In order to more clearly illustrate the technical solutions in the embodiments of the present application, the drawings required for use in the embodiments or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present application. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying any creative work.

[0030] Figure 1 It is a schematic flow chart of the preparation process of the edaravone-dexamethasone solution provided in the examples of the present application. DETAILED DESCRIPTION

[0031] In order to make the technical problems, technical solutions and beneficial effects to be solved by the present application more clearly understood, the present application is further described in detail below in conjunction with the embodiments. It should be understood that the specific embodiments described herein are only used to explain the present application and are not used to limit the present application.

[0032] In this application, the term "and / or" describes the association relationship of associated objects, indicating that there may be three relationships. For example, A and / or B can mean: A exists alone, A and B exist at the same time, and B exists alone. A and B can be singular or plural. The character " / " generally indicates that the associated objects are in an "or" relationship.

[0033] In this application, "at least one" means one or more, and "plurality" means two or more. "At least one of the following" or similar expressions refers to any combination of these items, including any combination of single items or plural items. For example, "at least one of a, b or c", or "at least one of a, b and c", can all represent: a, b, c, ab (i.e. a and b), ac, bc, or abc, where a, b, c can be single or multiple, respectively.

[0034] It should be understood that in the various embodiments of the present application, the size of the serial numbers of the above-mentioned processes does not mean the order of execution, some or all of the steps can be executed in parallel or sequentially, and the execution order of each process should be determined by its function and internal logic, and should not constitute any limitation on the implementation process of the embodiments of the present application.

[0035] The terms used in the embodiments of the present application are only for the purpose of describing specific embodiments, and are not intended to limit the present application. The singular forms "a", "an" and "the" used in the embodiments of the present application and the appended claims are also intended to include plural forms, unless the context clearly indicates other meanings.

[0036] The weight of the relevant components mentioned in the embodiments of the present specification can not only refer to the specific content of each component, but also represent the proportional relationship between the weights of the components. Therefore, as long as the content of the relevant components in the embodiments of the present specification is proportionally enlarged or reduced, it is within the scope disclosed in the embodiments of the present specification. Specifically, the mass described in the embodiments of the present specification can be μg, mg, g, kg and other mass units known in the chemical industry.

[0037] The terms "first" and "second" are used only for descriptive purposes to distinguish objects such as substances from each other, and should not be understood as indicating or implying relative importance or implicitly indicating the number of indicated technical features. For example, without departing from the scope of the embodiments of the present application, the first XX may also be referred to as the second XX, and similarly, the second XX may also be referred to as the first XX. Thus, the features defined as "first" and "second" may explicitly or implicitly include one or more of the features.

[0038] In a first aspect, the present application provides a process for preparing an edaravone-dexamethasone solution, as shown in the attached Figure 1 As shown, the following steps are included:

[0039] S10. Under an inert atmosphere, dissolving edaravone in a heated organic solvent, cooling the mixture to no more than 30° C., and adding dextroborneol to dissolve the mixture to obtain a mixed solution;

[0040] S20. Under an inert atmosphere, water and an antioxidant are added to the mixed solution for mixing, and the pH value of the solution is adjusted to 4-4.5 to obtain an edaravone-dexamethasone solution.

[0041] The preparation process of the edaravone dexamethasone solution provided in the first aspect of the embodiment of the present application, the preparation process is carried out in an inert atmosphere, the oxygen in the preparation system and the product is removed, the residual oxygen content of the product is controlled, the oxidative damage of oxygen to edaravone is effectively reduced, the generation of impurities is reduced, and the quality and stability of the product are improved. After edaravone is dissolved in a heated organic solvent, it is cooled to not more than 30 ° C and dexamethasone is added for dissolution. According to the characteristics of edaravone and dexamethasone, it is dissolved under heating conditions and low temperature conditions respectively, which fully ensures that edaravone and dexamethasone are fully dissolved, and dexamethasone is dissolved under low temperature conditions to avoid the volatilization of dexamethasone. Water and an antioxidant are added to the mixed solution for mixed treatment, and the pH value is adjusted so that the pH value of the edaravone dexamethasone solution is maintained at 4 to 4.5. Within the pH value range, the pH fluctuation amplitude is small, the pH value is easily controlled, and the product stability is good, which is conducive to long-term preservation. The order and conditions of adding each raw material component in the preparation process of the edaravone and dexamethasone solution of the embodiment of the present application improve the solubility of edaravone and dexamethasone in water, solve the problem that edaravone is easily oxidized and dexamethasone is easily volatilized at room temperature, have low impurity content, good pH stability, high product quality and stability, and are conducive to the long-term preservation of the edaravone and dexamethasone solution. The preparation process of the edaravone and dexamethasone solution provided in the embodiment of the present application has low cost, simple operation and short process cycle.

[0042] In some embodiments, the pH value of the edaravone-dexamethasone solution can be any typical but non-limiting value such as 4, 4.1, 4.2, 4.3, 4.4, 4.5, or an interval value between any two values.

[0043] In some possible implementations, in the preparation of edaravone and dexamethasone solution, the concentration of edaravone is 0.10% to 0.3%, the concentration of dexamethasone is 0.025% to 0.1%, the concentration of organic solvent is 4% to 12%, and the concentration of antioxidant is 0.05% to 0.2%. In this case, the concentration of edaravone and dexamethasone in the edaravone and dexamethasone solution fully ensures the dissolution efficiency and the application efficacy of the edaravone and dexamethasone solution, avoiding precipitation during the preparation of the product due to excessive concentration, and also avoiding the effect of the application efficacy of the edaravone and dexamethasone solution due to too low concentration. Among them, the concentration of the organic solvent ensures the dissolution of the edaravone and dexamethasone raw materials, reduces the risk of precipitation of edaravone and dexamethasone during the dilution of the product, and also reduces the high osmotic pressure of the product due to excessive content, affecting the safety performance of the product. The concentration of the antioxidant fully ensures the improvement of the stability of the edaravone and dexamethasone solution.

[0044] Exemplarily, in the edaravone-dexborneol solution, the concentration of edaravone can be 0.10%, 0.2%, 0.3%, etc., typical but non-limiting arbitrary point values ​​or interval values ​​between any two point values; the concentration of dexamethasone can be 0.025%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%, etc., typical but non-limiting arbitrary point values ​​or interval values ​​between any two point values; the concentration of the organic solvent can be 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, etc., typical but non-limiting arbitrary point values ​​or interval values ​​between any two point values; the concentration of the antioxidant can be 0.05%, 0.1%, 0.15%, 0.2%, etc., typical but non-limiting arbitrary point values ​​or interval values ​​between any two point values.

[0045] In some possible implementations, water is used as water for injection, and the prepared edaravone dexamethasone solution is edaravone dexamethasone injection. In this case, edaravone dexamethasone injection has higher stability, can maintain the active ingredients and activity of the drug within a certain period of time, and reduce the side effects caused by drug degradation or deterioration. The injection undergoes strict sterilization during the production process to ensure sterility and reduce the risk of infection caused by microbial contamination. In addition, edaravone dexamethasone injection can be directly administered by intravenous drip, the dosage is more accurate, easy to control, avoids the first-pass effect and gastrointestinal irritation that may be caused by oral drugs, and improves the bioavailability and efficacy of the drug.

[0046] In some possible implementations, edaravone and dextroborneol injection is diluted with normal saline when used, avoiding possible incompatibility and adverse reactions caused by mixing with other drugs. The use of a dedicated diluent can ensure that the concentration of the drug is stable during the infusion process, thereby ensuring the therapeutic effect.

[0047] In some possible implementations, water for injection refers to water that complies with the provisions of the Chinese Pharmacopoeia Water for Injection. It is water obtained by distilling distilled water or deionized water, also known as double distilled water. Water for injection is obtained by distilling purified water. In this process, water is heated to boiling, and the water vapor is condensed and collected to obtain purer water. Since most impurities and microorganisms can be removed during the distillation process, water for injection has high purity and sterility. Water for injection must meet strict quality requirements, including compliance with bacterial endotoxin test requirements. During production, storage and packaging, a series of measures need to be taken to prevent the production of bacterial endotoxins. In addition, the pH value, conductivity, heavy metal content, etc. of water for injection also need to be controlled within a certain range to ensure its safety and effectiveness. Water for injection has a wide range of applications in the medical field. It is often used as a solvent or diluent for the preparation of injections, eye drops, etc., as well as water for fine washing of containers. In addition, water for injection can also be used as a water source for the preparation of sterile water for injection, as well as as a flushing agent for various endoscopes.

[0048] In some possible implementations, the dissolved oxygen residual of the edaravone-dexborneol solution is below 2.0 ppm (mg / L), the headspace oxygen residual is below 2.0%, the impurity content is low, the pH value is stable, the product has high quality and stability, and can be stored for a long time.

[0049] In the above step S10:

[0050] In some possible implementations, the step of dissolving edaravone in a heated organic solvent includes: adding an organic solvent to a liquid preparation tank, filling with nitrogen and heating to 55°C to 65°C, and then adding edaravone and stirring until dissolved. Under this heating condition, the dissolution efficiency of edaravone can be effectively improved, and nitrogen filling and deoxygenation avoid the risk of impurities in edaravone under high temperature conditions. Exemplarily, the heating temperature can be 55°C, 56°C, 57°C, 58°C, 59°C, 60°C, 61°C, 62°C, 63°C, 64°C, 65°C, etc., typical but non-restrictive arbitrary point values ​​or interval values ​​between any two point values.

[0051] In some possible implementations, the organic solvent includes at least one of propylene glycol, polyethylene glycol, and ethanol. These organic solvents have good dissolution efficiency for edaravone and dextroborneol. In some specific embodiments, the organic solvent includes propylene glycol.

[0052] In some possible implementations, edaravone is dissolved in a heated organic solvent, and after cooling to typical but non-limiting arbitrary point values ​​or interval values ​​between any two points such as 30°C, 29°C, 28°C, 27°C, 26°C, 25°C, 24°C, 23°C, 22°C, 21°C, 20°C, 19°C, 18°C, 17°C, 16°C, 15°C, etc., dextroborneol is added for dissolution to obtain a mixed solution.

[0053] In some possible implementations, at least one organic solvent selected from propylene glycol, polyethylene glycol, and ethanol is added to a liquid preparation tank, filled with nitrogen and heated to 60° C., edaravone is added and stirred until dissolved, cooled to below 25° C. (0° C. to 25° C.), and dextroborneol is added and stirred until dissolved to obtain a mixed solution. In this case, the dissolution efficiency of edaravone and dextroborneol can be better improved, and the generation of impurity byproducts can be reduced.

[0054] In the above step S20:

[0055] In some possible implementations, the water added to the mixed solution is water for injection with a temperature below 30° C. and nitrogen gas filled for more than 30 minutes. By filling with nitrogen to reduce the dissolved oxygen content in the water for injection and controlling the temperature below 30° C., it is beneficial to maintain the preparation stability of the edaravone-dexamethasone solution.

[0056] In some possible implementations, the antioxidant includes at least one of sodium metabisulfite, sodium bisulfite, sodium thiosulfate, and cysteine; these antioxidants in edaravone and dexamethasone injection can exert multiple therapeutic effects through antioxidant effects, which is of great significance for patients with acute ischemic stroke and neurodegenerative diseases.

[0057] In some possible implementations, the pH adjusting agent used to adjust the pH value includes at least one of hydrochloric acid, phosphoric acid, sodium hydroxide, and potassium hydroxide. These pH adjusting agents can effectively adjust the pH value of the edaravone and dextroborneol solution, and have little effect on the stability of edaravone and dextroborneol.

[0058] In some possible implementations, after adjusting the pH value, the process also includes volume fixing, filtration, filling and sterilization.

[0059] In some possible implementations, the volume adjustment process includes the steps of adding water for injection to adjust the volume, filling with nitrogen and stirring.

[0060] In some possible implementations, the filtration process uses a filter element with a pore size of no greater than 0.22 μm to perform at least two filtrations, and the impurities and incompletely dissolved raw material components are fully removed by the filtration process.

[0061] In some possible implementations, the filling process includes the steps of: filling the prepared solution with nitrogen to control the residual oxygen content in the headspace to be less than 2.0%, thereby improving the storage stability of the edaravone-dexamethasone solution.

[0062] In some possible implementations, the temperature condition of the sterilization treatment is 100°C to 130°C, and the duration is 12 minutes to 15 minutes. Sterilization can kill bacteria, fungi and other microorganisms in the injection to ensure the sterility of the injection. Sterilization destroys the growth environment of microorganisms in the injection, thereby extending the shelf life of the injection. Under sterile conditions, the active ingredients in the injection can remain stable and are not prone to degradation or deterioration, thereby ensuring that the drug can exert normal therapeutic effects within the validity period. Sterilization is not only a microbial control of the injection, but also an important link in improving the quality of the drug. During the sterilization process, the injection can be further purified and treated to remove impurities and potential harmful substances, thereby improving the purity and quality of the drug.

[0063] In some embodiments, the preparation of edaravone and dextroborneol injection comprises the steps of:

[0064] (1) Add 95% of the prescribed amount of water for injection into the liquid preparation tank 1, cool it to no higher than 30° C., preferably 0 to 25° C., and fill it with nitrogen for 30 minutes for standby use;

[0065] (2) Add the prescribed amount of propylene glycol to the liquid preparation tank 2, fill it with nitrogen and heat it to 55° C. to 65° C., preferably 60° C.;

[0066] (3) Add edaravone to the liquid preparation tank 2, stir until dissolved, and cool to no higher than 30° C., preferably 0 to 25° C.;

[0067] (4) adding dextroborneol to the liquid preparation tank 2 and stirring until dissolved;

[0068] (5) Add the water for injection in the preparation tank 1, stir evenly, and then add sodium metabisulfite;

[0069] (6) Adjusting the pH of the solution to 4.0-4.5 with sodium hydroxide solution or phosphoric acid;

[0070] (7) Add water for injection to make it dissolve, stir for more than 30 minutes, and fill with nitrogen for 30 minutes to make the dissolved oxygen residue in the solution 1.5 ppm (mg / L);

[0071] (8) The drug solution is finely filtered through two 0.22 μm microporous filters in sequence;

[0072] (9) Nitrogen filling, controlling the headspace oxygen residual to be below 2.0%, preferably below 2.0%;

[0073] (10) Terminal sterilization is adopted, the sterilization temperature is 121°C, and the sterilization time is 12 min to 15 min, preferably 12 min.

[0074] The dissolved oxygen residue in the sterilized edaravone and dextroborneol injection is less than 2.0 ppm (mg / L), and the headspace oxygen residue is less than 2.0%.

[0075] In the second aspect, an embodiment of the present application provides an edaravone-dextroborneol solution prepared by the above method, comprising edaravone, dextroborneol, an organic solvent, an antioxidant, a pH adjuster and water, wherein the pH value of the edaravone-dextroborneol solution is 4 to 4.5.

[0076] The edaravone and dextroborneol solution of the present application embodiment is prepared by the above method, comprising edaravone, dextroborneol, an organic solvent, an antioxidant, a pH regulator and water, and the pH value of the edaravone and dextroborneol solution is 4 to 4.5. The solubility of edaravone and dextroborneol in water is improved, the problem that edaravone is easily oxidized and dextroborneol is easily volatilized at room temperature is solved, the impurity content is low, the pH value is stable, the product has high quality and stability, and can be stored for a long time.

[0077] In some possible implementations, the edaravone-dexamethasone solution is an edaravone-dexamethasone injection, wherein the water is water for injection, the concentration of edaravone is 0.10% to 0.3%, the concentration of dexamethasone is 0.025% to 0.1%, the concentration of the organic solvent is 4% to 12%, and the concentration of the antioxidant is 0.05% to 0.2%. In this case, the edaravone-dexamethasone injection has better stability and quality.

[0078] In some possible implementations, the edaravone and dextroborneol injection is stored in nitrogen-filled bottles, and the dissolved oxygen residual of the edaravone and dextroborneol injection is below 2.0 ppm (mg / L), the headspace oxygen residual is below 2.0%, the impurity content is low, the pH value is stable, the product has high quality and stability, and can be stored for a long time.

[0079] In some possible implementations, the organic solvent includes at least one of propylene glycol, polyethylene glycol, and ethanol.

[0080] In some possible implementations, the pH adjuster includes at least one of hydrochloric acid, phosphoric acid, sodium hydroxide, and potassium hydroxide.

[0081] In some possible implementations, the antioxidant includes at least one of sodium metabisulfite, sodium bisulfite, sodium thiosulfate, and cysteine.

[0082] In some possible implementations, the edaravone and dexamethasone injection includes 1.0 g to 3.0 g of edaravone, 0.25 g to 1.0 g of dexamethasone, 40 g to 120 g of propylene glycol, and 0.5 g to 2.0 g of sodium metabisulfite. The pH is adjusted to 4.0 to 4.5, and the remainder is purified water / water for injection to make up to 1000 mL.

[0083] The technical effects of the above embodiments of the present application have been discussed in the previous text and will not be repeated here.

[0084] In a third aspect, an embodiment of the present application provides an application of an edaravone-dextrocarbamide solution, wherein the edaravone-dextrocarbamide solution prepared by the above method or the above-mentioned edaravone-dextrocarbamide solution is applied to at least one drug for scavenging free radicals, anti-inflammation, and protecting the blood-brain barrier.

[0085] The edaravone and dextroborneol solution of the embodiment of the present application has powerful antioxidant, anti-inflammatory, microcirculation improvement, mitochondrial function protection and nerve repair promotion effects. Therefore, the edaravone and dextroborneol solution can be applied to at least one of the drugs for scavenging free radicals, anti-inflammatory, and protecting the blood-brain barrier to improve related symptoms.

[0086] In some embodiments, edaravone and dextroborneol injection is mainly used to treat acute ischemic stroke, which can significantly improve related neurological symptoms and increase the patient's chance of recovery.

[0087] In order to enable the above implementation details and operations of the present application to be clearly understood by those skilled in the art, as well as to demonstrate the significant improvement in the performance of the edaravone dextromethorphan solution and the preparation method thereof in the embodiments of the present application, the above technical scheme is illustrated by means of multiple embodiments below.

[0088] Example 1

[0089] An edaravone and dextroborneol injection, the ingredients and dosage of which are shown in Table 1 below:

[0090] The preparation process comprises the following steps:

[0091] (1) Add 95% of the prescribed amount of water for injection into the liquid preparation tank 1, cool it to no higher than 30°C, and fill it with nitrogen for 30 minutes;

[0092] (2) Add the prescribed amount of propylene glycol to the liquid preparation tank 2, fill it with nitrogen and heat it to 60° C.

[0093] (3) Add edaravone to the liquid preparation tank 2, stir until dissolved, and cool to 30° C.;

[0094] (4) adding dextroborneol to the liquid preparation tank 2 and stirring until dissolved;

[0095] (5) Add the water for injection in the preparation tank 1, stir evenly, and then add sodium metabisulfite;

[0096] (6) Adjusting the pH of the solution to 4.0-4.5 with sodium hydroxide solution or phosphoric acid;

[0097] (7) Add water for injection to dissolve, stir and fill with nitrogen for 30 minutes;

[0098] (8) The drug solution is finely filtered through two 0.22 μm microporous filter elements in sequence;

[0099] (9) Nitrogen filling, control the headspace oxygen residual content below 2.0%;

[0100] (10) Terminal sterilization is adopted, the sterilization temperature is 121°C, and the sterilization time is 12 min to 15 min, preferably 12 min.

[0101] The obtained edaravone and dextroborneol injection had a dissolved oxygen residue of less than 2.0 ppm (mg / L) and a headspace oxygen residue of less than 2.0%.

[0102] Example 2-Example 4

[0103] According to the process of Example 1, different organic solvent materials, such as propylene glycol, polyethylene glycol or ethanol, and different antioxidant materials, such as sodium pyrosulfite or sodium bisulfite, are provided. The material components and amounts in each example are specifically shown in Table 1 below:

[0104] Table 1

[0105]

[0106] The edaravone and dextroborneol injections prepared in Examples 1 to 4 were placed at 50°C for stability comparison, and samples were taken at 0 days and 30 days to detect the impurity concentration. The test results are shown in Table 2 below:

[0107] Table 2

[0108]

[0109] From the above test results, it can be seen that the edaravone and dextroborneol injection prepared in the examples of the present application was placed at 50°C for 30 days, and the impurities of the samples prepared with different organic solvents and antioxidants were not obvious, among which the impurities of propylene glycol (Example 1) were lower than those of the other two solvents; the impurities of sodium metabisulfite (Example 1) were lower than those of sodium bisulfite as an antioxidant.

[0110] Example 5-Example 11

[0111] According to the process of Example 1, edaravone and dexamethasone injections with pH values ​​of 3.0, 3.5, 4.0, 4.5, 5.0, 5.5 and 6.0 were prepared respectively. The specific substances and amounts of each component are shown in Table 3 below:

[0112] Table 3

[0113]

[0114]

[0115] The edaravone and dextroborneol injections prepared in Examples 5 to 11 were placed at 40°C for stability comparison, and samples were taken at 0 days and 30 days to detect the impurity concentration. The test results are shown in Table 4 below:

[0116] Table 4

[0117]

[0118] From the above test results, it can be seen that the lower the pH value, the less impurity content and the better the stability. The increase in impurities in samples with a pH value greater than 4.5 is significantly higher than that with a pH value less than 4.5. However, when the pH value is too low, it is not conducive to control and will also affect the stability of the product. Therefore, the pH value of the edaravone dextroborneol solution is maintained in the range of 4 to 4.5, the pH fluctuation is small, the pH value is easy to control, the product has good stability, and is conducive to long-term storage.

[0119] Example 12-Example 14

[0120] Propylene glycol at different temperatures was used to dissolve Edaravone, and the dissolution time of Edaravone under the preparation conditions of propylene glycol at different temperatures was detected, and the influence on the impurity content in Edaravone was tested. The test results are shown in Table 5 below:

[0121] Table 5

[0122]

[0123]

[0124] From the test results in Table 5 above, it can be seen that propylene glycol at different temperatures has a certain effect on the dissolution rate of edaravone. The higher the temperature, the faster the dissolution rate. Temperature can increase the dissolution rate of edaravone. However, the dissolution rate is slow at low temperatures, which is not conducive to the process. When the temperature is about 60°C, edaravone has both a higher dissolution rate and a lower impurity content.

[0125] Example 15-Example 16

[0126] According to the prescription of Example 1, propylene glycol at different temperatures was used to dissolve borneol, and the dissolution time of borneol under the preparation conditions of propylene glycol at different temperatures and the influence on the borneol content were detected. The test results are shown in Table 6 below:

[0127] Table 6

[0128]

[0129] As can be seen from the test results in Table 6 above, different propylene glycol temperatures have a certain effect on the dissolution rate of right-borneol, and increasing the temperature is conducive to increasing the dissolution rate of right-borneol. However, the increase in temperature will have a significant effect on the right-borneol content dissolved in the solution. The higher the temperature, the easier it is for right-borneol to volatilize. It can be seen that when the temperature is 40°C, the content of right-borneol in the solution is significantly lower than the content at 30°C, indicating that the volatilization rate of right-borneol increases accordingly after the temperature increases. And the longer the time, the more obvious the reduction in the content of right-borneol in the solution at a temperature of 40°C, while the trend of the reduction in the content of right-borneol in the solution at a temperature of 30°C is significantly lower, indicating that 30°C is more conducive to avoiding the volatilization of right-borneol.

[0130] Comparative Example 1

[0131] This comparative example provides a commercially available edaravone and dexamethasone concentrated solution (Xiansheng, batch number: 181-240302).

[0132] In order to verify the progress of the embodiments of the present application, the following performance tests were performed on the above embodiments and comparative examples respectively:

[0133] The edaravone and dextroborneol injection provided in the above embodiment and comparative example 1 were placed at 50° C. for stability comparison and inspection, and samples were taken at 0 days, 10 days, and 30 days, respectively. The results are shown in Table 7 below:

[0134] Table 7

[0135]

[0136] It can be seen from the above test results that the impurities of the edaravone and dexamethasone injection provided in the examples of the present application are lower than those of the commercially available edaravone and dexamethasone concentrated solution in comparative example 1 (Xiansheng, batch number: 181-240302).

[0137] Comparative Example 2

[0138] In the comparative example where all raw material components are mixed with water at the same time, the materials are mixed in the order of purified water-edaravone-dexamethasone-sodium sulfite-pH adjustment-constant volume, that is, the materials are not mixed in the specific order and conditions of "propylene glycol-edaravone-dexamethasone-purified water-sodium sulfite-pH adjustment-constant volume" of the present application. In this comparative example, the components in the concentrated solution of edaravone and dexamethasone cannot be completely dissolved and cannot be directly used.

[0139] The above description is only a preferred embodiment of the present application and is not intended to limit the present application. Any modifications, equivalent substitutions and improvements made within the spirit and principles of the present application should be included in the protection scope of the present application.

Claims

1. A preparation process of edaravone dextroborneol solution, characterized in that: The following steps are involved: Under an inert atmosphere, dissolving edaravone in a heated organic solvent, cooling the mixture to no higher than 30° C., and adding dextroborneol to dissolve the mixture to obtain a mixed solution; Under an inert atmosphere, water and an antioxidant are added to the mixed solution for mixing, and the pH value of the solution is adjusted to 4-4.5 to obtain an edaravone-dexamethasone solution.

2. The preparation process of the edaravone-dexamethasone solution according to claim 1, characterized in that: In the preparation of the edaravone-dexborneol solution, the concentration of the edaravone is 0.10% to 0.3%, the concentration of the dexborneol is 0.025% to 0.1%, the concentration of the organic solvent is 4% to 12%, and the concentration of the antioxidant is 0.05% to 0.2%.

3. The preparation process of the edaravone dextroborneol solution according to claim 1 or 2, characterized in that: The water is water for injection, and the prepared edaravone and dextroborneol solution is edaravone and dextroborneol injection; And / or, the dissolved oxygen residual of the edaravone-dexamethasone solution is less than 2.0 ppm, and the headspace oxygen residual is less than 2.0%.

4. The preparation process of the edaravone-dexamethasone solution according to claim 3, characterized in that: The step of dissolving edaravone in a heated organic solvent comprises: adding the organic solvent into a liquid preparation tank, filling it with nitrogen and heating it to 55° C. to 65° C., and then adding the edaravone and stirring until it is dissolved; And / or, the water added to the mixed solution is water for injection with a temperature below 30° C. and filled with nitrogen for more than 30 minutes.

5. The preparation process of the edaravone-dexamethasone solution according to claim 4, characterized in that: The organic solvent includes at least one of propylene glycol, polyethylene glycol, and ethanol; And / or, the antioxidant includes at least one of sodium pyrosulfite, sodium bisulfite, sodium thiosulfate, and cysteine; And / or, the pH adjuster used to adjust the pH value includes at least one of hydrochloric acid, phosphoric acid, sodium hydroxide and potassium hydroxide.

6. The process for preparing the edaravone-dexamethasone solution according to any one of claims 1, 2, 4 or 5, characterized in that: After adjusting the pH value, the process also includes volume fixing, filtering, filling and sterilization.

7. The process for preparing the edaravone-dexamethasone solution according to claim 6, wherein: The volume fixing treatment comprises the steps of: adding water for injection to fix the volume, filling with nitrogen and stirring; And / or, the filtration treatment is performed at least twice using a filter element with a pore size not higher than 0.22 μm; And / or, the filling process comprises the steps of: filling the prepared solution with nitrogen to control the residual oxygen content in the headspace to be less than 2.0%; And / or, the temperature condition of the sterilization treatment is 100° C. to 130° C., and the duration is 12 min to 15 min.

8. An edaravone-dexamethasone solution prepared by the method according to any one of claims 1 to 7, characterized in that: The invention comprises edaravone, dextroborneol, an organic solvent, an antioxidant, a pH regulator and water. The pH value of the edaravone and dextroborneol solution is 4-4.

5.

9. The edaravone-dexamethasone solution according to claim 8, wherein The edaravone and dextroborneol solution is an edaravone and dextroborneol injection, wherein the water is water for injection, the concentration of the edaravone is 0.10% to 0.3%, the concentration of the dextroborneol is 0.025% to 0.1%, the concentration of the organic solvent is 4% to 12%, and the concentration of the antioxidant is 0.05% to 0.2%.

10. An application of edaravone and dextroborneol solution, characterized in that: The edaravone dextroborneol solution prepared by the method according to any one of claims 1 to 7 or the edaravone dextroborneol solution according to any one of claims 8 to 9 is applied to at least one drug for scavenging free radicals, anti-inflammation, and protecting the blood-brain barrier.

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