Terbutaline sulfate aerosol inhalation solution and preparation method thereof

Abstract

The invention provides a terbutaline sulfate aerosol inhalation solution and a preparation method, and relates to the technical field of terbutaline sulfate aerosol inhalation solutions, the inhalation solution comprises the following materials by weight: 5-10 parts of terbutaline sulfate, 9-12 parts of sodium chloride, 0.1-0.4 part of edetate disodium, 10-100 parts of hydrochloric acid, and 1000-1800 parts of water for injection; the preparation method comprises the four steps of material preparation, treatment before solution preparation, solution preparation and solution adjustment and treatment. On the basis of a traditional preparation process, an ultrasonic dispersion technology and a sectional feeding mode are introduced, sodium chloride, edetate disodium and terbutaline sulfate are sequentially added and mixed, medicine loss and deterioration are reduced, then a heating and nitrogen filling matching mode is adopted, air in a solution is better removed, and the medicine quality is improved. And finally, alternately sterilizing and filtering to remove impurities in the solution so as to guarantee the stability of the product.

Description

Technical Field

[0001] The invention relates to the technical field of terbutaline sulfate atomized inhalation solution, in particular to a terbutaline sulfate atomized inhalation solution and a preparation method thereof. Background Art

[0002] With the decline of global air quality and the impact of environmental pollution, the incidence of respiratory diseases has also shown an increasing trend year by year, among which the incidence and mortality of asthma are also increasing. Terbutaline sulfate is a fast-acting short-acting β-adrenergic receptor agonist that can selectively stimulate β2 receptors, relax bronchial smooth muscles, inhibit the release of endogenous spasmogens, and inhibit edema caused by increased clearance of endogenous transmitters and mucociliary cells. It is mainly used clinically to treat bronchial asthma, asthmatic bronchitis, emphysema, and bronchospasm in chronic obstructive pulmonary disease.

[0003] Then, the terbutaline sulfate nebulized inhalation solution is used in conjunction with a nebulizer in clinical practice, which is convenient for patients to use. In the prior art, in the preparation process of the terbutaline sulfate nebulized inhalation solution, the raw materials of the terbutaline sulfate nebulized inhalation solution are usually directly stirred and mixed, and then filtered and sterilized after mixing. In the overall preparation process, although the process is simple, it is not easy to control the stability of the finished product, resulting in the preparation efficiency being affected. Therefore, the present invention proposes a terbutaline sulfate nebulized inhalation solution and a preparation method to solve the problems existing in the prior art. Summary of the invention

[0004] In view of the above problems, the purpose of the present invention is to provide a terbutaline sulfate nebulized inhalation solution and a preparation method thereof, which has the advantages of good product stability and high preparation efficiency and can solve the problems existing in the prior art.

[0005] To achieve the purpose of the present invention, the present invention is implemented by the following technical scheme: a terbutaline sulfate atomization inhalation solution, comprising the following materials in parts by weight: 5 to 10 parts of terbutaline sulfate, 9 to 12 parts of sodium chloride, 0.1 to 0.4 parts of disodium edetate, 10 to 100 parts of hydrochloric acid and 1000 to 1800 parts of water for injection.

[0006] A method for preparing a terbutaline sulfate atomized inhalation solution comprises the following steps:

[0007] Step 1: Preparation of materials

[0008] According to the formula of terbutaline sulfate nebulized inhalation solution, corresponding materials are prepared, wherein the formula includes terbutaline sulfate, sodium chloride, disodium edetate, hydrochloric acid and water for injection, and then pre-treated;

[0009] Step 2: Treatment before solution preparation

[0010] Add water for injection into the ultrasonic reactor, start heating, heat to 55-70°C, maintain for 5-8 minutes, cool to room temperature, introduce nitrogen to remove oxygen;

[0011] Step 3: Preparation of solution

[0012] Sequentially add the sodium chloride, disodium edetate and terbutaline sulfate reserved in step 1 into the reactor in step 2, and start the ultrasonic stirring function to obtain the prepared solution after stirring;

[0013] Step 4: Solution Adjustment and Treatment

[0014] Hydrochloric acid is added to the solution using a pipette to adjust the pH value of the solution to a preset appropriate range, and then the solution is sterilized and filtered to obtain a finished product.

[0015] A further improvement is that in the step 1, terbutaline sulfate, sodium chloride and disodium edetate are placed in a vacuum drying oven respectively for drying and then kept for later use.

[0016] A further improvement is that in the step 1, the purity of terbutaline sulfate is greater than 98.0%, the purity of sodium chloride is greater than 99.5%, and the purity of edetate disodium is greater than 99.0%.

[0017] A further improvement is that in step 2, the specific method of removing oxygen is: nitrogen is slowly introduced into the ultrasonic reactor at a rate of 300 to 500 mL / min, and the ultrasonic stirring function of the ultrasonic reactor is turned on.

[0018] A further improvement is that in the step 3, after sodium chloride is added to the reactor, ultrasonic stirring is first performed for 8 to 12 minutes, then disodium edetate is added, stirring is continued, and finally terbutaline sulfate is added for the same stirring time as that of sodium chloride.

[0019] A further improvement is that in step 4, the specific method of adjusting the pH value is: using a pipette to add hydrochloric acid dropwise to the solution, and at the same time starting the ultrasonic stirring function, when the pH value of the solution approaches the target value, slowing down the rate of acid addition until the pH value reaches a predetermined appropriate range, and then stopping the acid addition.

[0020] A further improvement is that after stopping the addition of acid, wait for 5 to 8 minutes, then measure the pH value of the solution and compare it with the preset appropriate range. When it is lower than the preset appropriate range, continue to add hydrochloric acid for adjustment.

[0021] A further improvement is that in step 4, the suitable range is 3.4 to 3.7.

[0022] The beneficial effects of the present invention are as follows: the terbutaline sulfate atomized inhalation solution and the preparation method provided by the present invention introduce ultrasonic dispersion technology and a segmented feeding method on the basis of a traditional preparation process, and sequentially add and mix sodium chloride, disodium edetate and terbutaline sulfate to reduce drug loss and deterioration; secondly, heating and nitrogen filling are combined to better remove air in the solution; finally, sterilization and filtration are performed alternately to remove impurities in the solution, thereby ensuring the stability of the product and further improving the preparation efficiency of the terbutaline sulfate atomized inhalation solution. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figure 1 It is a schematic diagram of the steps of the present invention. DETAILED DESCRIPTION

[0024] In order to deepen the understanding of the present invention, the present invention will be further described in detail below in conjunction with examples. The examples are only used to explain the present invention and do not constitute a limitation on the protection scope of the present invention.

[0025] In the following examples, all materials are purchased from the market, the purity of terbutaline sulfate is greater than 98.0%, the purity of sodium chloride is greater than 99.5%, the purity of edetate disodium is greater than 99.0%, and hydrochloric acid is pharmaceutical hydrochloric acid.

[0026] Unless otherwise specified, room temperature refers to 25±2℃.

[0027] Embodiment 1

[0028] according to Figure 1 As shown, this embodiment proposes a terbutaline sulfate atomized inhalation solution and a preparation method thereof, comprising the following materials in parts by weight: 5 parts of terbutaline sulfate, 9 parts of sodium chloride, 0.1 parts of edetate disodium, 10 parts of hydrochloric acid and 1000 parts of water for injection.

[0029] A method for preparing a terbutaline sulfate atomized inhalation solution comprises the following steps:

[0030] Step 1: Preparation of materials

[0031] According to the formula of the above-mentioned terbutaline sulfate nebulized inhalation solution, the materials corresponding to the formula are accurately weighed and pretreated, and the pretreatment method is to put terbutaline sulfate, sodium chloride and disodium edetate into a vacuum drying oven respectively, and adopt a low-temperature drying method, wherein the temperature is 45° C. and the drying time is 10 minutes, in order to remove possible moisture and avoid affecting the quality of subsequent finished products. Accordingly, after drying, they are respectively placed in sealed containers for standby;

[0032] Step 2: Treatment before solution preparation

[0033] In the process of solution preparation, the water for injection is first treated, and the water for injection is added to an ultrasonic reactor, which has the functions of sealing, heating, and ultrasonic stirring. First, heating is started, heated to 70°C, maintained for 5 minutes, and then cooled to room temperature. The reactor is connected to an external nitrogen supply device, and nitrogen is introduced, that is, nitrogen is input into one end of the reactor, and the other end is used to discharge the original air (including oxygen). Specifically, nitrogen is slowly introduced into the reactor at a speed of 300 mL / min, and the overall continuous process is 20 minutes, and the ultrasonic stirring function of the reactor is turned on. The purpose of stirring is to make the water for injection in the reactor in a fluctuating state, so as to increase the contact area between nitrogen and water and promote the discharge of air in the water. In this embodiment, the pressure of nitrogen should be slightly higher than atmospheric pressure to ensure that nitrogen can fully replace the air in the water;

[0034] Step 3: Preparation of solution

[0035] Sequentially add the sodium chloride, disodium edetate and terbutaline sulfate reserved in step one into the reactor in step two, and turn on the ultrasonic stirring function. Specifically, after sodium chloride is first added to the reactor, ultrasonic stirring is first performed for 8 minutes. Sodium chloride, as a stabilizer and osmotic pressure regulator, needs to be evenly distributed in the solution. Then disodium edetate is added. As a chelating agent, it can bind to metal ions to prevent them from interfering with the stability of the drug. At the same time, disodium edetate is added on the basis that sodium chloride has been dissolved, which can avoid the interaction between the two substances and ensure that their respective functions are not affected. Then continue to stir for 8 minutes, then add terbutaline sulfate, and stir for 8 minutes. In this embodiment, terbutaline sulfate is added when sodium chloride and disodium edetate are dissolved and evenly distributed, which can minimize the loss and deterioration of the drug. After stirring is completed, a prepared solution is obtained.

[0036] Step 4: Solution Adjustment and Treatment

[0037] Use a pipette to add hydrochloric acid to the solution to adjust the pH value of the solution to a preset suitable range, which is 3.4 to 3.7. In this embodiment, the hydrochloric acid is not directly added to the solution in its entirety, and in this embodiment, it is not necessary to add it in its entirety to the solution. Instead, the hydrochloric acid is added dropwise to the solution using a pipette, and the ultrasonic stirring function is started at the same time. When the pH value of the solution approaches the target value, the rate of acid addition is slowed down until the pH value reaches a predetermined suitable range, and then the acid addition is stopped. In this embodiment, accordingly, after the acid addition is stopped, it is stabilized for 5 minutes to provide a stabilization period, and then the pH value of the solution is measured and compared with the preset The suitable range is compared. When it is lower than the preset suitable range, hydrochloric acid is continued to be added for adjustment. After the pH value is completed, sterilization and filtration are carried out. The specific method is: the solution is filtered once through a sterile filter membrane (0.45μm) to obtain a filtered solution, and then the filtered solution is sterilized at high temperature, and then filtered twice through a sterile filter membrane (0.20μm), and then microwave sterilization is performed. The method of primary filtration is to filter out some impurities first to make the solution purer, and then sterilize it, and then filter on both sides for further purification, and then sterilize it again to obtain the finished product.

[0038] Embodiment 2

[0039] according to Figure 1 As shown, this embodiment proposes a terbutaline sulfate aerosol inhalation solution, comprising the following materials in parts by weight: 10 parts of terbutaline sulfate, 12 parts of sodium chloride, 0.4 parts of edetate disodium, 100 parts of hydrochloric acid and 1800 parts of water for injection.

[0040] A terbutaline sulfate atomized inhalation solution and preparation method, step 1, material preparation

[0041] According to the formula of the above-mentioned terbutaline sulfate nebulized inhalation solution, the materials corresponding to the formula are accurately weighed and pretreated, and the pretreatment method is to put terbutaline sulfate, sodium chloride and disodium edetate into a vacuum drying oven respectively, and adopt a low-temperature drying method, wherein the temperature is 45° C. and the drying time is 10 minutes, in order to remove possible moisture and avoid affecting the quality of subsequent finished products. Accordingly, after drying, they are respectively placed in sealed containers for standby;

[0042] Step 2: Treatment before solution preparation

[0043] In the process of solution preparation, the water for injection is first treated, and the water for injection is added to an ultrasonic reactor, which has the functions of sealing, heating, and ultrasonic stirring. First, heating is started, heated to 55°C, maintained for 8 minutes, and then cooled to room temperature. The reactor is connected to an external nitrogen supply device, and nitrogen is introduced, that is, nitrogen is input at one end of the reactor, and the other end is used to discharge the original air (including oxygen). Specifically, nitrogen is slowly introduced into the reactor at a speed of 300mL / min, and the overall continuous process is 20min, and the ultrasonic stirring function of the reactor is turned on. The purpose of stirring is to make the water for injection in the reactor in a fluctuating state, so as to increase the contact area between nitrogen and water and promote the discharge of air in the water. In this embodiment, the pressure of nitrogen should be slightly higher than atmospheric pressure to ensure that nitrogen can fully replace the air in the water;

[0044] Step 3: Preparation of solution

[0045] Sequentially add the sodium chloride, disodium edetate and terbutaline sulfate reserved in step one into the reactor in step two, and turn on the ultrasonic stirring function. Specifically, after sodium chloride is first added to the reactor, ultrasonic stirring is first performed for 12 minutes. Sodium chloride, as a stabilizer and osmotic pressure regulator, needs to be evenly distributed in the solution. Then disodium edetate is added. As a chelating agent, it can bind to metal ions to prevent them from interfering with the stability of the drug. At the same time, disodium edetate is added on the basis that sodium chloride has been dissolved, which can avoid the interaction between the two substances and ensure that their respective functions are not affected. Then continue stirring for 12 minutes, then add terbutaline sulfate, and stir for 12 minutes. In this embodiment, terbutaline sulfate is added when sodium chloride and disodium edetate are dissolved and evenly distributed, which can minimize the loss and deterioration of the drug. After stirring is completed, a prepared solution is obtained.

[0046] Step 4: Solution Adjustment and Treatment

[0047] Hydrochloric acid is added to the solution using a pipette to adjust the pH value of the solution to a preset suitable range, which is 3.4 to 3.7. In this embodiment, the hydrochloric acid is not directly added to the solution in its entirety, and in this embodiment, it is not necessary to add it in its entirety to the solution. Instead, the hydrochloric acid is added dropwise to the solution using a pipette, and the ultrasonic stirring function is started at the same time. When the pH value of the solution approaches the target value, the rate of acid addition is slowed down until the pH value reaches a predetermined suitable range, and then the acid addition is stopped. In this embodiment, accordingly, after the acid addition is stopped, wait for 8 minutes to provide a stable period, and then measure the pH value of the solution (a pH electrode is provided at the bottom of the ultrasonic reactor, and the electrode is in contact with the external The pH value is adjusted by adding hydrochloric acid to adjust the pH value. After the pH value is adjusted, sterilization and filtration are performed. The specific method is as follows: the solution is filtered once through a sterile filter membrane (0.45 μm) to obtain a filtered solution, and then the filtered solution is sterilized at high temperature, and then filtered twice through a sterile filter membrane (0.20 μm), and then microwave sterilization is performed. The method of primary filtration is to filter out some impurities first to make the solution purer, and then sterilize, and then filter on both sides for further purification, and then sterilize again to obtain the finished product.

[0048] The above shows and describes the basic principles, main features and advantages of the present invention. It should be understood by those skilled in the art that the present invention is not limited by the above embodiments. The above embodiments and descriptions are only for explaining the principles of the present invention. Without departing from the framework and scope of application of the present invention, the present invention may have various changes and improvements, which fall within the scope of the present invention to be protected. The scope of protection of the present invention is defined by the attached claims and their equivalents.

Claims

1. A terbutaline sulfate atomized inhalation solution, characterized in that: The invention comprises the following materials in parts by weight: 5-10 parts of terbutaline sulfate, 9-12 parts of sodium chloride, 0.1-0.4 parts of disodium edetate, 10-100 parts of hydrochloric acid and 1000-1800 parts of water for injection.

2. A method for preparing a terbutaline sulfate atomized inhalation solution according to claim 1, characterized in that: The following steps are involved: Step 1: Preparation of materials According to the formula of terbutaline sulfate nebulized inhalation solution, corresponding materials are prepared, wherein the formula includes terbutaline sulfate, sodium chloride, disodium edetate, hydrochloric acid and water for injection, and then pre-treated; Step 2: Treatment before solution preparation Add water for injection into the ultrasonic reactor, start heating, heat to 55-70°C, maintain for 5-8 minutes, cool to room temperature, introduce nitrogen to remove oxygen; Step 3: Preparation of solution Sequentially add the sodium chloride, disodium edetate and terbutaline sulfate reserved in step 1 into the reactor in step 2, and start the ultrasonic stirring function to obtain the prepared solution after stirring; Step 4: Solution Adjustment and Treatment Hydrochloric acid is added to the solution using a pipette to adjust the pH value of the solution to a preset appropriate range, and then the solution is sterilized and filtered to obtain a finished product.

3. The method for preparing a terbutaline sulfate atomized inhalation solution according to claim 2, wherein: In the step 1, terbutaline sulfate, sodium chloride and disodium edetate are placed in a vacuum drying oven respectively for drying and then used for later use.

4. The method for preparing a terbutaline sulfate atomized inhalation solution according to claim 2, wherein: In the step 1, the purity of terbutaline sulfate is greater than 98.0%, the purity of sodium chloride is greater than 99.5%, and the purity of edetate disodium is greater than 99.0%.

5. The method for preparing a terbutaline sulfate atomized inhalation solution according to claim 2, wherein: In the step 2, the specific method of removing oxygen is: nitrogen is slowly introduced into the ultrasonic reactor at a rate of 300 to 500 mL / min, and the ultrasonic stirring function of the ultrasonic reactor is turned on.

6. The method for preparing a terbutaline sulfate atomized inhalation solution according to claim 2, wherein: In the step 3, after sodium chloride is added to the reactor, ultrasonic stirring is first performed for 8 to 12 minutes, then disodium edetate is added, stirring is continued, and finally terbutaline sulfate is added for the same stirring time as that of sodium chloride.

7. The method for preparing a terbutaline sulfate atomized inhalation solution according to claim 2, characterized in that: In step 4, the specific method of adjusting the pH value is: using a pipette to add hydrochloric acid dropwise to the solution, while starting the ultrasonic stirring function, when the pH value of the solution approaches the target value, slowing down the rate of acid addition until the pH value reaches a predetermined appropriate range, and then stopping acid addition.

8. The method for preparing a terbutaline sulfate atomized inhalation solution according to claim 7, characterized in that: After stopping the addition of acid, wait for 5 to 8 minutes, then measure the pH value of the solution and compare it with the preset appropriate range. When it is lower than the preset appropriate range, continue to add hydrochloric acid for adjustment.

9. The method for preparing a terbutaline sulfate atomized inhalation solution according to claim 2, characterized in that: In the step 4, the suitable range is 3.4 to 3.7.

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