Dobutamine hydrochloride medicine composition as well as preparation method and application thereof

Abstract

The invention discloses a dobutamine hydrochloride medicine composition as well as a preparation method and application thereof. The dobutamine hydrochloride pharmaceutical composition comprises dobutamine hydrochloride, an osmotic pressure regulator, a pH regulator and a solvent, and does not comprise a complexing agent or an antioxidant. The dobutamine hydrochloride pharmaceutical composition does not contain an antioxidant and a complexing agent, and has better safety on the basis of meeting good stability.

Description

Technical Field

[0001] The invention relates to a dobutamine hydrochloride pharmaceutical composition and a preparation method and application thereof. Background Art

[0002] Dobutamine is a sympathomimetic amine cardiotonic drug with a positive inotropic effect. Its main mechanism is to excite the heart's β-adrenergic receptors, activate adenylcyclase (AC), convert adenosine triphosphate (ATP) into cyclic adenosine monophosphate (cAMP), promote calcium entry into myocardial cells, selectively increase myocardial contractility, increase cardiac output, reduce pulmonary capillary wedge pressure, and improve cardiac function.

[0003] The structural formula of dobutamine hydrochloride is shown in Formula I. Dobutamine hydrochloride is a white or off-white crystalline powder; it is almost odorless; its color gradually darkens when exposed to air and light; it is slightly soluble in water or anhydrous ethanol, and is almost insoluble in chloroform.

[0004]

[0005] Formula I

[0006] Dobutamine is more effective than dopamine in treating heart failure, especially chronic heart failure. Its positive inotropic effect is much stronger than digitalis. Short-term use of dobutamine and sodium nitroprusside for a few days in treating various refractory or intractable heart failure can often achieve significant results.

[0007] At present, the commercially available dosage forms of dobutamine hydrochloride are all injections, including injection solutions and lyophilized preparations for injection. Injections have the characteristics of rapid efficacy and reliable effects.

[0008] Dobutamine hydrochloride is white or off-white shiny crystals or crystalline powders, slightly soluble in water, and gradually darkens in color when exposed to air and light. Antioxidants are added to existing dobutamine hydrochloride injection products at home and abroad to increase the stability of dobutamine hydrochloride in the injection.

[0009] At present, in order to improve the stability of dobutamine hydrochloride injection, complexing agents are used in the art. For example, Chinese patent document (CN118340724 A) discloses a prescription and preparation method of dobutamine hydrochloride injection, and the patent uses complexing agents to improve the stability of dobutamine hydrochloride. Another option is to use antioxidants. For example, Chinese patent document (CN114617844A) and Chinese patent document (CN102085180B) respectively disclose the use of sodium bisulfite or cysteine ​​hydrochloride to improve the stability of dobutamine hydrochloride.

[0010] Antioxidants can remove various free radicals, and their typical medical application is the production of injections and eye drops. Anhydrous sodium sulfate and commonly used sodium sulfite and sodium phosphate are safe when the safe addition strength is 0.1% to 0.2%, but it also varies due to individual differences, and there are certain safety risks in clinical use.

[0011] The concentrations of dobutamine hydrochloride injection currently marketed and sold are 10 mg / mL and 20 mg / mL. The preparation is diluted to about 1-3 mg / mL with various injections of 5% glucose injection, 5% saline, fructose, 5% xylitol, 5% sorbitol, 20% mannitol or lactated sodium Ringer's before administration. Since the injection form of dobutamine hydrochloride is often used in emergency situations (such as acute circulatory failure), it is important to provide a pre-filled, ready-to-use injection at the required dosage concentration. Summary of the invention

[0012] The technical problem to be solved by the present invention is to overcome the safety problem of dobutamine hydrochloride injection in the prior art caused by the antioxidant and chelating agent improving the stability, and provide a dobutamine hydrochloride pharmaceutical composition and a preparation method thereof. The dobutamine hydrochloride pharmaceutical composition of the present invention does not include an antioxidant and a chelating agent, and has better safety on the basis of satisfying good stability.

[0013] The present invention mainly adopts the following technical solutions to solve the above technical problems.

[0014] The invention provides a dobutamine hydrochloride pharmaceutical composition, which comprises dobutamine hydrochloride, an osmotic pressure regulator, a pH regulator and a solvent, but does not comprise a complexing agent or an antioxidant.

[0015] In the present invention, preferably, in the dobutamine hydrochloride pharmaceutical composition, the concentration of dobutamine hydrochloride is 5-25 mg / mL, preferably 10-20 mg / mL, more preferably 15-20 mg / mL, for example 12 mg / mL, 16 mg / mL, 16.67 mg / mL, 20 mg / mL or 25 mg / mL.

[0016] In the present invention, preferably, the osmotic pressure regulator is selected from one or more of mannitol, sodium chloride and potassium chloride; for example, mannitol.

[0017] In the present invention, preferably, in the dobutamine hydrochloride pharmaceutical composition, the concentration of the osmotic pressure regulator is 1-25 mg / mL, preferably 1-20 mg / mL, more preferably 5-20 mg / mL, for example 3.33 mg / mL, 4 mg / mL, 13.33 mg / mL or 20 mg / mL.

[0018] In the present invention, preferably, the pH adjuster is selected from one or more of hydrochloric acid, tartaric acid, acetic acid and citric acid; for example, hydrochloric acid.

[0019] In the present invention, preferably, the pH of the dobutamine hydrochloride pharmaceutical composition is 2.0-7.0, preferably 2.0-4.0, more preferably 2.5-3.5, such as 2.0-3.0, 3.0-4.0 or 2.5-3.5.

[0020] In the present invention, preferably, the solvent is selected from water, such as water for injection.

[0021] In the present invention, preferably, the dobutamine hydrochloride pharmaceutical composition is composed of dobutamine hydrochloride, an osmotic pressure regulator, a pH regulator and a solvent; more preferably, the dobutamine hydrochloride pharmaceutical composition satisfies the following conditions in parts by mass:

[0022] 0.6-1.5 parts of dobutamine hydrochloride,

[0023] Osmotic pressure regulator 0.2-1.0 parts,

[0024] 50-60 parts of solvent,

[0025] The pH of the dobutamine hydrochloride pharmaceutical composition is 2.0-4.0.

[0026] In a specific embodiment of the present invention, the dobutamine hydrochloride pharmaceutical composition is selected from one of the following schemes by weight:

[0027] Solution 1:

[0028] 1.5 parts of dobutamine hydrochloride,

[0029] Mannitol 0.8 parts,

[0030] 60 parts of water for injection,

[0031] The pH of the dobutamine hydrochloride pharmaceutical composition is 2.0-3.0;

[0032] Option 2:

[0033] 1 part of dobutamine hydrochloride,

[0034] 0.2 parts of sodium chloride,

[0035] 60 parts of water for injection,

[0036] The pH of the dobutamine hydrochloride pharmaceutical composition is 3.0-4.0;

[0037] Option 3:

[0038] 0.8 parts of dobutamine hydrochloride,

[0039] 0.2 parts of potassium chloride,

[0040] 50 parts of water for injection,

[0041] The pH of the dobutamine hydrochloride pharmaceutical composition is 2.5-3.5;

[0042] Option 4:

[0043] 0.6 parts of dobutamine hydrochloride,

[0044] 1 part of mannitol,

[0045] 50 parts of water for injection,

[0046] The pH of the dobutamine hydrochloride pharmaceutical composition is 2.5-3.5.

[0047] In the present invention, preferably, the dobutamine hydrochloride pharmaceutical composition is filled in a prefilled syringe;

[0048] More preferably, the material of the syringe is selected from one or more of borosilicate glass, cycloolefin polymer and cyclic polyolefin; preferably, the borosilicate glass is medium borosilicate glass and / or high borosilicate glass; for example, medium borosilicate glass;

[0049] More preferably, the specification of the prefilled syringe is 0.5-50 mL, preferably 1-20 ml, more preferably 2-10 ml, such as 2 mL, 5 mL or 10 mL.

[0050] The present invention also provides a method for preparing the dobutamine hydrochloride pharmaceutical composition as described above, characterized in that it comprises the following steps:

[0051] Mixing: Mix the raw materials evenly to obtain liquid medicine;

[0052] Sterilization: sterilize the liquid medicine;

[0053] Filling: Fill the liquid medicine into the pre-filled syringe.

[0054] In the present invention, preferably, before the mixing step, a step of evacuating the container of the mixed raw materials is also included. More preferably, the container is a liquid preparation tank.

[0055] More preferably, the step of filling with nitrogen is further included after the vacuuming.

[0056] Further preferably, the step of filling with nitrogen is to fill the solvent with nitrogen below the liquid surface.

[0057] More preferably, the nitrogen filling step further includes a stirring step.

[0058] More preferably, the vacuum degree of the container of the mixed raw materials after the vacuuming is 0-25 kPa, for example, 0-20 kPa, preferably 0-15 kPa, and more preferably 0-10 kPa.

[0059] More preferably, the dissolved oxygen content of the container of the mixed raw materials after the vacuuming is 0-50 ppm, more preferably 0-30 ppm, and more preferably 0-10 ppm.

[0060] In the present invention, preferably, before the mixing step, a step of heating the solvent is also included.

[0061] More preferably, after the heating, the temperature of the solvent is 30-60°C, preferably 40-60°C, for example 30-40°C, 40-50°C or 50-60°C.

[0062] In the present invention, preferably, in the mixing step, the dobutamine hydrochloride, the osmotic pressure regulator and the solvent are first mixed, and then the pH regulator is added and mixed.

[0063] More preferably, after adding the pH adjuster, the method further comprises adding the solvent to adjust the volume.

[0064] Further preferably, after the step of fixing the volume, a cooling and stirring step is also included; the temperature after cooling is preferably 20-40°C, for example 20-25°C, 20-30°C or 30-40°C; the stirring time is preferably 10-30min, for example 10-15min, 10-20min, 15-20min or 20-30min.

[0065] In the present invention, preferably, in the sterilization step, the sterilization is achieved by filtration.

[0066] More preferably, the filtration uses a filter element and / or a filter membrane.

[0067] Further preferably, the pore size of the filter element is 0.2 μm.

[0068] Further preferably, the material of the filter element is polyethersulfone.

[0069] In the present invention, preferably, in the potting step, the potting is performed by vacuum plugging.

[0070] More preferably, when the vacuum plugging method is used for filling, the residual gas between the rubber plug and the liquid surface is ≤0.1 mL.

[0071] In the present invention, preferably, after the potting step, a sterilization and / or light inspection step is also included.

[0072] More preferably, the sterilization operation after the encapsulation step is sterilization at 121° C. for 15 minutes.

[0073] The present invention also provides the use of the dobutamine hydrochloride pharmaceutical composition as described above in preparing an infusion drug. Preferably, the infusion is 5% glucose injection, physiological saline, 20% mannitol or sodium lactate Ringer's. More preferably, the dobutamine hydrochloride pharmaceutical composition is directly used after being combined with the infusion.

[0074] On the basis of being in accordance with the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

[0075] The reagents and raw materials used in the present invention are commercially available.

[0076] The positive and progressive effects of the present invention are:

[0077] The dobutamine hydrochloride pharmaceutical composition of the present invention does not include antioxidants and complexing agents, and on the basis of satisfying good stability, improves the safety of clinical use and can avoid various toxic reactions and allergic reactions caused by antioxidants.

[0078] In addition, after the dobutamine hydrochloride drug composition of the present invention is sealed in the prefilled syringe, "drug storage" and "injection function" are integrated, and it is a practical and novel dosage form with high technical content. Compared with the traditional vial or ampoule packaging, the prefilled syringe is not only easier to use, but also more accurate in dosage. The prefilled syringe has obvious advantages in protecting the safety of patients and medical staff, such as one-time use, avoiding repeated suction after using the diluent, and reducing the chance of secondary contamination. DETAILED DESCRIPTION

[0079] The present invention is further described below by way of examples, but the present invention is not limited to the scope of the examples. The experimental methods in the following examples without specifying specific conditions are carried out according to conventional methods and conditions, or selected according to the product specifications.

[0080] The information of the main raw materials used in the examples and comparative examples of the present invention is shown in Table 1:

[0081] Table 1

[0082]

[0083] Example 1

[0084] This embodiment provides a dobutamine hydrochloride pharmaceutical composition, and the preparation method thereof comprises the following steps:

[0085] (1) Take 40L-45L of water for injection and add it to the liquid preparation tank. Evacuate the liquid preparation tank to 0-10kPa, fill it with nitrogen, stir, and control the dissolved oxygen content to 0-50ppm;

[0086] (2) Control the temperature to 40-50°C; add 0.8 kg of mannitol and 1.5 kg of dobutamine hydrochloride to the liquid preparation tank of step (1) in sequence;

[0087] (3) After stirring and dissolving completely, adjust the pH value to 2.0-3.0 with 1 mol / L acetic acid to obtain a mixed solution;

[0088] (4) Then dilute the mixed solution of step (3) to 60 L with water for injection, cool to 20-30°C, and stir for 15-20 minutes to obtain a drug solution;

[0089] (5) Filter the drug solution of step (4) in sequence through two 0.2 μm polyethersulfone filter cartridges, vacuum fill it into a 2 mL cyclic polyolefin prefilled syringe, and add a stopper; wherein, during vacuum filling, the gas residue between the stopper and the liquid surface is ≤ 0.1 mL;

[0090] (6) Sterilize at 121℃ for 15 minutes. The product can be used after passing the light inspection.

[0091] Example 2

[0092] This embodiment provides a dobutamine hydrochloride pharmaceutical composition, and the preparation method thereof comprises the following steps:

[0093] (1) Take 30L-35L of water for injection and add it to the liquid preparation tank. Evacuate the liquid preparation tank to 0-20kPa, fill it with nitrogen, stir, and control the dissolved oxygen content to 0-30ppm;

[0094] (2) Control the temperature to 50-60°C; add 0.2 kg of sodium chloride and 1.0 kg of dobutamine hydrochloride to the liquid preparation tank of step (1) in sequence;

[0095] (3) After stirring and dissolving completely, adjust the pH value to 3.0-4.0 with 1 mol / L hydrochloric acid to obtain a mixed solution;

[0096] (4) Then dilute the mixed solution of step (3) to 60 L with water for injection, cool to 30-40°C, and stir for 10-15 minutes to obtain a drug solution;

[0097] (5) Filter the drug solution of step (4) in sequence through two 0.2 μm polyethersulfone filter cartridges, vacuum fill it into a 5 mL borosilicate glass pre-filled syringe, and add a stopper. During vacuum filling, the gas residue between the stopper and the liquid surface should be ≤ 0.1 mL;

[0098] (6) Sterilize at 121℃ for 15 minutes. The product can be used after passing the light inspection.

[0099] Example 3

[0100] This embodiment provides a dobutamine hydrochloride pharmaceutical composition, and the preparation method thereof comprises the following steps:

[0101] (1) Take 30L-35L of water for injection and add it to the liquid preparation tank. Evacuate the liquid preparation tank to 0-25kPa, fill it with nitrogen, stir, and control the dissolved oxygen content to 0-30ppm;

[0102] (2) Control the temperature to 30-40°C; add 0.2 kg of potassium chloride and 0.8 kg of dobutamine hydrochloride to the liquid preparation tank in step (1);

[0103] (3) After stirring and dissolving completely, adjust the pH value to 2.5-3.5 with 1 mol / L hydrochloric acid to obtain a mixed solution;

[0104] (4) Then dilute the mixed solution of step (3) to 50 L with water for injection, cool to 20-30°C, and stir for 20-30 minutes to obtain a drug solution;

[0105] (5) Filter the drug solution of step (4) in sequence through two 0.2 μm polyethersulfone filter cartridges, vacuum fill it into a 5 mL cycloolefin polymer prefilled syringe, and add a stopper; wherein, during vacuum filling, the gas residue between the stopper and the liquid surface is ≤ 0.1 mL;

[0106] (6) Sterilize at 121℃ for 15 minutes. The product can be used after passing the light inspection.

[0107] Example 4

[0108] This embodiment provides a dobutamine hydrochloride pharmaceutical composition, and the preparation method thereof comprises the following steps:

[0109] (1) Take 30L-40L of water for injection and add it to the liquid preparation tank. Evacuate the liquid preparation tank to 0-10kPa, fill it with nitrogen, stir, and control the dissolved oxygen content to 0-50ppm;

[0110] (2) Control the temperature to 40-50°C; add 1.0 kg of mannitol and 0.6 kg of dobutamine hydrochloride to the liquid preparation tank of step (1);

[0111] (3) After stirring and dissolving completely, adjust the pH value to 2.5-3.5 with 1 mol / L hydrochloric acid to obtain a mixed solution;

[0112] (4) Then dilute the mixed solution of step (3) to 50 L with water for injection, cool to 20-30°C, and stir for 15-20 minutes to obtain a drug solution;

[0113] (5) Filter the drug solution of step (4) in sequence through two 0.2 μm polyethersulfone filter cartridges, vacuum fill it into a 10 mL borosilicate glass pre-filled syringe, and add a stopper; wherein, during vacuum filling, the gas residue between the stopper and the liquid surface is ≤ 0.1 mL;

[0114] (6) Sterilize at 121℃ for 15 minutes. The product can be used after passing the light inspection.

[0115] Comparative Example 1

[0116] This comparative example provides a dobutamine hydrochloride pharmaceutical composition, and its preparation method comprises the following steps:

[0117] (1) Take 40L-45L of water for injection and add it to the liquid preparation tank. Fill the water for injection in the liquid preparation tank with nitrogen and stir.

[0118] (2) Control the temperature to 40-50°C; add 13.5 kg of dobutamine hydrochloride and 1.2 kg of mannitol to the liquid preparation tank of step (1);

[0119] (3) After stirring and dissolving completely, cool the solution to 20-30°C, add 29g of sodium bisulfite and stir to dissolve completely, and adjust the pH value to 2.5-3.5 with 1mol / L hydrochloric acid to obtain a mixed solution;

[0120] (4) Then dilute the mixed solution of step (3) to 60 L with water for injection and stir evenly to obtain a drug solution;

[0121] (5) Using two 0.2 μm polyethersulfone filter cartridges, filter the drug solution from step (4) in sequence, fill it into a glass ampoule, introduce an appropriate amount of nitrogen before and after filling, and seal it by melting;

[0122] (6) Sterilize at 121℃ for 15 minutes. The product can be used after passing the light inspection.

[0123] Effect Example 1

[0124] The products obtained in Examples 1-4 and Comparative Example 1 were subjected to high temperature and light tests at 60°C and 5000Lx. The pH, content, and related substances of dobutamine hydrochloride in the injection were measured on the 10th and 30th days, respectively. The content of dobutamine hydrochloride was determined by high performance liquid chromatography.

[0125] In the high performance liquid chromatography method, the chromatographic column is Kromasil 100-5-C18; 250*4.6mm, 5μm or a chromatographic column with equivalent performance; the mobile phase A is an aqueous solution of sodium octane sulfonate, wherein the preparation method of the aqueous solution of sodium octane sulfonate is: take 2.6g of sodium octane sulfonate, add 1000mL of water to dissolve, add 3ml of triethylamine, and adjust the pH value to 2.5 with phosphoric acid; the mobile phase B is acetonitrile-methanol (volume ratio is 18:82); the elution method is gradient elution, and the specific elution procedure is shown in Table 2 below:

[0126] Table 2

[0127]

[0128] The pH, content, related substances and content of dobutamine hydrochloride of the products obtained in Examples 1-4 and Comparative Example 1 are shown in Table 3. Wherein: impurities A, B and C are degradation products of dobutamine hydrochloride, respectively, and total impurities are the total amount of other impurities except impurities A, B and C. The content is calculated according to the peak area normalization method.

[0129] Table 3 High temperature and light test results

[0130]

[0131]

[0132]

[0133] Note: ND means not detected.

[0134] As shown in Table 3, under the conditions of high temperature of 60°C and light of 5000 lx, there is no significant change in each test item at 30 days compared with 0 days and 10 days for each embodiment and comparative example sample.

[0135] Effect Example 2

[0136] The products obtained in Examples 1-4 and Comparative Example 1 were subjected to a compatibility stability test. Compatible solutions were prepared with 5% glucose injection and sodium lactate Ringer's injection, respectively. The solutions were placed at room temperature for 24 hours, and key test items were tested at 5 hours and 24 hours, respectively. The results are shown in Table 4.

[0137] Table 4 Stability test results

[0138]

[0139]

[0140] As shown in Table 4, under room temperature, the test items of the solutions of Examples 1-4 and the comparative example were not significantly changed after being placed for 24 hours, and the change trends were consistent. This shows that the product prepared by the present invention still maintains good stability of dobutamine hydrochloride compared with the prior art, and the product quality is equivalent to that of the prior art product.

[0141] In addition, the present application does not add antioxidants and chelating agents, thereby improving the prescription composition and enhancing the safety of dobutamine hydrochloride injection.

Claims

1. A dobutamine hydrochloride pharmaceutical composition, characterized in that: include: dobutamine hydrochloride, an osmotic pressure regulator, a pH regulator and a solvent, and does not include a chelating agent or an antioxidant.

2. The dobutamine hydrochloride pharmaceutical composition according to claim 1, characterized in that It meets one or more of the following conditions: (1) In the dobutamine hydrochloride pharmaceutical composition, the concentration of dobutamine hydrochloride is 5-25 mg / mL, preferably 10-20 mg / mL, more preferably 15-20 mg / mL, for example 12 mg / mL, 16 mg / mL, 16.67 mg / mL, 20 mg / mL or 25 mg / mL; (2) The osmotic pressure regulator is selected from one or more of mannitol, sodium chloride and potassium chloride; for example, mannitol; (3) In the dobutamine hydrochloride pharmaceutical composition, the concentration of the osmotic pressure regulator is 1-25 mg / mL, preferably 1-20 mg / mL, more preferably 5-20 mg / mL, for example 3.33 mg / mL, 4 mg / mL, 13.33 mg / mL or 20 mg / mL; (4) The pH adjuster is selected from one or more of hydrochloric acid, tartaric acid, acetic acid and citric acid; for example, hydrochloric acid; (5) The pH of the dobutamine hydrochloride pharmaceutical composition is 2.0-7.0, preferably 2.0-4.0, more preferably 2.5-3.5, such as 2.0-3.0, 3.0-4.0 or 2.5-3.5; (6) The solvent is selected from water, such as water for injection.

3. The dobutamine hydrochloride pharmaceutical composition according to claim 1, characterized in that The dobutamine hydrochloride pharmaceutical composition consists of dobutamine hydrochloride, an osmotic pressure regulator, a pH regulator and a solvent; Preferably, the dobutamine hydrochloride pharmaceutical composition satisfies the following conditions in parts by mass: 0.6-1.5 parts of dobutamine hydrochloride, Osmotic pressure regulator 0.2-1.0 parts, 50-60 parts of solvent, The pH of the dobutamine hydrochloride pharmaceutical composition is 2.0-4.0; More preferably, the dobutamine hydrochloride pharmaceutical composition is selected from one of the following schemes by weight: Solution 1: 1.5 parts of dobutamine hydrochloride, Mannitol 0.8 parts, 60 parts of water for injection, The pH of the dobutamine hydrochloride pharmaceutical composition is 2.0-3.0; Option 2: 1 part of dobutamine hydrochloride, 0.2 parts of sodium chloride, 60 parts of water for injection, The pH of the dobutamine hydrochloride pharmaceutical composition is 3.0-4.0; Option 3: 0.8 parts of dobutamine hydrochloride, 0.2 parts of potassium chloride, 50 parts of water for injection, The pH of the dobutamine hydrochloride pharmaceutical composition is 2.5-3.5; Option 4: 0.6 parts of dobutamine hydrochloride, 1 part of mannitol, 50 parts of water for injection, The pH of the dobutamine hydrochloride pharmaceutical composition is 2.5-3.

5.

4. The dobutamine hydrochloride pharmaceutical composition according to claim 1, characterized in that: The dobutamine hydrochloride pharmaceutical composition is filled in a prefilled syringe; Preferably, the material of the syringe is selected from one or more of borosilicate glass, cycloolefin polymer and cyclic polyolefin; preferably, the borosilicate glass is medium borosilicate glass and / or high borosilicate glass; for example, medium borosilicate glass; Preferably, the specification of the prefilled syringe is 0.5-50 mL, preferably 1-20 ml, more preferably 2-10 ml, such as 2 mL, 5 mL or 10 mL.

5. A method for preparing the dobutamine hydrochloride pharmaceutical composition according to any one of claims 1 to 4, characterized in that: The following steps are involved: Mixing: Mix the raw materials evenly to obtain liquid medicine; Sterilization: sterilize the liquid medicine; Filling: Fill the liquid medicine into the pre-filled syringe.

6. The method for preparing the dobutamine hydrochloride pharmaceutical composition according to claim 5, characterized in that: It meets one or more of the following conditions: (1) Before the mixing step, the method further comprises the step of evacuating the container of the mixed raw materials. Preferably, the container is a liquid preparation tank; (2) Before the mixing step, the method further comprises the step of heating the solvent; (3) In the mixing step, the dobutamine hydrochloride, the osmotic pressure regulator and the solvent are first mixed, and then the pH regulator is added and mixed; (4) In the sterilization step, the sterilization is achieved by filtration; (5) In the encapsulation step, encapsulation is performed by vacuum plugging; (6) After the encapsulation step, the method further includes sterilization and / or light inspection steps.

7. The method for preparing the dobutamine hydrochloride pharmaceutical composition according to claim 6, characterized in that: It meets one or more of the following conditions: (1) After the vacuuming, the step of filling with nitrogen is also included; (2) The vacuum degree of the container of the mixed raw materials after the vacuum pumping is 0-25 kPa, for example, 0-20 kPa, preferably 0-15 kPa, and more preferably 0-10 kPa; (3) The dissolved oxygen content of the mixed raw material container after the vacuum is 0-50 ppm, preferably 0-30 ppm, and more preferably 0-10 ppm; (5) After the heating, the temperature of the solvent is 30-60°C, preferably 40-60°C, for example 30-40°C, 40-50°C or 50-60°C; (6) After adding the pH adjuster, the step of further adding the solvent to fix the volume is included; (7) The filtration adopts a filter element and / or a filter membrane; (8) When the vacuum plugging method is used for filling, the gas residue between the rubber plug and the liquid surface is ≤ 0.1 mL; (9) The sterilization operation after the filling step is sterilization at 121°C for 15 minutes.

8. The method for preparing the dobutamine hydrochloride pharmaceutical composition according to claim 7, characterized in that: It meets one or more of the following conditions: (1) The nitrogen filling step is to fill the solvent with nitrogen below the liquid surface; (2) the step of filling with nitrogen also includes a stirring step; (3) After the step of fixing the volume, the step of cooling and stirring is also included; (4) The pore size of the filter element is 0.2 μm; (5) The material of the filter element is polyethersulfone.

9. The method for preparing the dobutamine hydrochloride pharmaceutical composition according to claim 8, characterized in that: It satisfies (1) and / or (2) of the following conditions: (1) In the cooling step after the volume is fixed, the temperature after the cooling is 20-40°C, such as 20-25°C, 20-30°C or 30-40°C; (2) In the stirring step after the volume is fixed, the stirring time is 10-30 min, for example, 10-15 min, 10-20 min, 15-20 min or 20-30 min.

10. Use of the dobutamine hydrochloride pharmaceutical composition according to any one of claims 1 to 4 in the preparation of an infusion drug, preferably, the infusion is 5% glucose injection, physiological saline, 20% mannitol or sodium lactate Ringer's, more preferably, the dobutamine hydrochloride pharmaceutical composition is directly used after being combined with the infusion.

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