Inhalation solution for bronchial constriction maintenance treatment of chronic obstructive pulmonary disease patient and preparation method of inhalation solution

Abstract

The invention provides an inhalation solution for bronchial constriction maintenance treatment of a chronic obstructive pulmonary disease patient and a preparation method of the inhalation solution, and relates to the technical field of pharmaceutical preparations. The preparation method comprises the following steps: adding 50-95% of water for injection into a liquid preparation tank, cooling the water for injection to 50 DEG C, starting stirring, synchronously and sequentially adding sodium chloride, citric acid and sodium citrate according to the prescription dosage, stirring to dissolve the sodium chloride, the citric acid and the sodium citrate, continuously cooling to 40 DEG C, adding formoterol fumarate according to the prescription dosage, stirring to dissolve for 60 minutes, fixing the volume, and stirring again for 10 minutes for later use. According to the preparation method of the formoterol fumarate inhalation solution provided by the invention, process parameters are accurately controlled, so that the sterility guarantee level of the formoterol fumarate inhalation solution can be improved, the increase of the impurity content can be effectively controlled, and good stability of the formoterol fumarate inhalation solution is ensured.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparation technology, specifically relating to an inhalation solution for maintaining bronchoconstriction in patients with chronic obstructive pulmonary disease and its preparation method. Background Technology

[0002] Formoterol fumarate is a long-acting β2-adrenergic receptor agonist primarily used for the maintenance therapy of bronchoconstriction in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and emphysema, but not for the treatment of acute exacerbations of COPD or asthma.

[0003] Formoterol fumarate inhalation solution was developed by MYLAN SPECIALTY LP and was first approved for marketing in the United States on May 11, 2007, under the brand name PERFOROMIS. It is an inhalation solution with a strength of 0.02 mg / 2 ml.

[0004] Approximately 210 million people worldwide suffer from emphysema, one of the most threatening diseases to humanity. It is projected to become the third leading cause of death from COPD by 2020, causing 3 million deaths annually, accounting for 6% of global deaths. Statistics show that China currently has 90 million people with COPD, meaning that one in every 14-15 people suffers from this disease, making it a major contributor to the healthcare burden on individuals and the nation. Most cases are caused by smoking and the accumulation of other environmental risk factors.

[0005] Formoterol fumarate inhalation solution is suitable for maintenance treatment of bronchoconstriction in patients with chronic obstructive pulmonary disease. Currently, research on this inhalation formulation is limited. From the perspective of clinical and market demand, there is an urgent need to develop such an inhalation formulation to alleviate the medical burden on individuals and the country. Summary of the Invention

[0006] This invention addresses the problems existing in the prior art by providing an inhaled solution for bronchoconstriction maintenance therapy in patients with chronic obstructive pulmonary disease and its preparation method. The preparation process of this invention, by controlling the dissolution temperature of excipients, stirring speed, filter membrane material, and sterilization method, produces a formulation with low impurity content, good stability, and high safety.

[0007] To achieve the above objectives, the technical solution adopted by the present invention is as follows:

[0008] On one hand, the present invention provides a method for preparing an inhaled solution for bronchoconstriction maintenance therapy in patients with chronic obstructive pulmonary disease, comprising the following steps: adding 50%-95% water for injection to a mixing tank, cooling the water for injection to 50°C and starting stirring, simultaneously adding the prescribed amounts of sodium chloride, citric acid, and sodium citrate, stirring to dissolve, continuing to cool to 40°C, adding the prescribed amount of formoterol fumarate, stirring to dissolve for 60 minutes, making up the volume, stirring again for 10 minutes, and then setting aside.

[0009] Furthermore, in the preparation step, stirring is started, and the stirring speed is 40Hz.

[0010] Furthermore, in the preparation step, sodium chloride, citric acid, and sodium citrate are added in sequence and stirred until dissolved.

[0011] Furthermore, in the preparation step, after the sodium chloride, citric acid, and sodium citrate are completely dissolved, the temperature in the mixing tank is further reduced to 40°C, the prescribed amount of formoterol fumarate is added, and the mixture is stirred at 40Hz for 60 minutes to dissolve. The volume is then adjusted, and the mixture is stirred at 40Hz again for 10 minutes for later use.

[0012] This invention strictly controls the dissolution temperature of raw and auxiliary materials during the preparation process, which can prevent the degradation of raw and auxiliary materials and the generation of impurities, and further control the generation of impurity content.

[0013] Furthermore, a sterilization step is set after the preparation step: sterilization is carried out by sterilization filtration, and the filter is filtered through two 5-inch sterilization filters to the receiving tank of the filling machine. The filter membrane material is polyethersulfone.

[0014] Furthermore, after the sterilization step, a filling step is set: turn on the blow-fill-seal machine, the equipment heating module heats up, before filling, confirm that the extruder temperature reaches 150-220℃, the extruder speed is 50-100 rpm, the cooling water pressure is not less than 5 bar, the cooling water temperature does not exceed 10℃, the compressed air pressure is not less than 10 bar, the ASR blower is operating normally, after manually venting the pipeline, turn on the filling machine, control the filling volume to 2.1-2.2 ml, discard the waste material, and start normal filling.

[0015] On the other hand, the present invention provides an inhalation solution prepared by the above preparation method for bronchoconstriction maintenance therapy in patients with chronic obstructive pulmonary disease.

[0016] Preferably, the concentration of formoterol fumarate in the inhalation solution is 2 ml: 20 μg.

[0017] Preferably, the inhalation solution comprises, by weight, the following components: 1-3 parts formoterol fumarate, 13-40 parts citric acid, 41-125 parts sodium citrate, 79-240 parts sodium chloride, and the remainder being water for injection.

[0018] More preferably, the injection solution comprises, by weight, the following components: 2 parts formoterol fumarate, 27 parts citric acid, 80 parts sodium citrate, 157 parts sodium chloride, and the remainder being water for injection.

[0019] The method for preparing formoterol fumarate inhalation solution provided by this invention has the following beneficial effects:

[0020] 1. The method for preparing formoterol fumarate inhalation solution provided by the present invention further avoids the degradation of raw materials and excipients due to excessively high temperature during the production process, thereby producing an injection solution with low impurity content and stable drug solution by controlling the dissolution temperature of raw materials and excipients in the preparation step.

[0021] 2. The method for preparing formoterol fumarate inhalation solution provided by the present invention avoids splashing of raw and auxiliary materials due to excessively fast stirring speed by controlling the stirring speed in the preparation step, and also avoids product degradation due to prolonged preparation time caused by excessively slow stirring speed. Reasonable stirring speed can also make the product composition uniform and have better stability.

[0022] 3. The preparation method of formoterol fumarate inhalation solution provided by the present invention avoids degradation of formoterol fumarate caused by excessively high temperature by selecting a suitable sterilization method, thus ensuring the qualification of related substances in the drug solution. Detailed Implementation

[0023] The following non-limiting embodiments are intended to provide a more comprehensive understanding of the invention by those skilled in the art, but do not limit the invention in any way. The following description is merely an exemplary illustration of the scope of protection claimed by the invention. Those skilled in the art can make various changes and modifications to the invention based on the disclosed content, and these should also fall within the scope of protection claimed by the invention. When numerical ranges are given in the embodiments, it should be understood that, unless otherwise stated in the invention, the two endpoints of each numerical range and any value between the two endpoints may be selected. Unless otherwise defined, all technical and scientific terms used in this invention have the same meaning as commonly understood by those skilled in the art to which this invention pertains.

[0024] The present invention will be further described below by way of specific embodiments. Unless otherwise specified, all chemical reagents used in the embodiments of the present invention are obtained through conventional commercial means.

[0025] Example 1

[0026] An inhalation solution for maintaining bronchoconstriction in patients with chronic obstructive pulmonary disease, with a specification of 2ml:20μg:2 parts.

[0027] Formoterol fumarate, 27 parts citric acid, 80 parts sodium citrate, 157 parts sodium chloride, and water for injection to make up the remainder to the required volume. The preparation method of the inhalation solution includes the following steps:

[0028] ① Preparation: Add 50%-95% water for injection to the mixing tank, cool the water for injection to 50°C and start stirring. Simultaneously add the prescribed amounts of sodium chloride, citric acid, and sodium citrate, stirring until dissolved. Continue cooling to 40°C, then add the prescribed amount of formoterol fumarate, stirring to dissolve for 60 minutes. Make up to volume, stir again for 10 minutes, and set aside.

[0029] ② Sterilization: The prepared solution is sterilized by sterilization filtration, and then filtered through two 5-inch sterilization filters into the receiving tank of the filling machine. The filter membrane material is polyethersulfone.

[0030] ③ Filling and sealing: Turn on the blow-fill-seal integrated machine, and the equipment heating module will heat up. Before filling, confirm that the extruder temperature reaches 150-220℃, the extruder speed is 50-100 rpm, the cooling water pressure is not lower than 5 bar, the cooling water temperature does not exceed 10℃, the compressed air pressure is not lower than 10 bar, the ASR blower is running normally, and after manually venting the pipeline, turn on the filling machine, control the filling volume to 2.1-2.2 ml, discard the waste material, and start normal filling.

[0031] Three batches of formoterol fumarate inhalation solution were prepared according to the method in Example 1 of this invention, and their packaging was simulated for market use.

[0032] Accelerated Conditioning Test

[0033] The samples were placed under accelerated testing conditions of 25℃±2℃ and 60%RH±5%RH for 6 months, with measurements taken at the end of 0, 1, 2, 3, and 6 months.

[0034] The sampling and investigation results are shown in Table 1 below.

[0035] Table 1

[0036]

[0037] Comparative Example 2: Water for Injection Temperature Adjustment

[0038] The inhalation solution was prepared according to the preparation method and procedure described in Example 1. Compared to the preparation method of the inhalation solution in Example 2, the dissolution temperature of the excipients was changed. The specific differences are as follows:

[0039] Comparative Example 2.1: 50%-95% water for injection was added to the preparation vessel. The water for injection was cooled to 75°C, and stirring was started. Simultaneously, the prescribed amounts of sodium chloride, citric acid, and sodium citrate were added sequentially, and stirred until dissolved. The temperature was further lowered to 40°C, and the prescribed amount of formoterol fumarate was added. The mixture was stirred and dissolved for 60 minutes, then brought to a final volume. After stirring for another 10 minutes, it was ready for use. The remaining steps and parameters were the same as in Example 1.

[0040] Comparative Example 2.2: Add 50%-95% water for injection to the mixing tank, cool the water for injection to 60°C, and start stirring. Simultaneously add the prescribed amounts of sodium chloride, citric acid, and sodium citrate, stirring until dissolved. Continue cooling to 40°C, then add the prescribed amount of formoterol fumarate, stirring to dissolve for 60 minutes. Make up to volume, and stir again for 10 minutes. Set aside. The remaining steps and parameters are the same as in Example 1.

[0041] Related substances and pH values ​​were tested for the formulations of Comparative Example 2.1 and Comparative Example 2.2, respectively. The test results are shown in Table 2.

[0042] Table 2

[0043]

[0044] The results above show that when the excipients are dissolved at 75℃ and 60℃, the impurity content increases, affecting the quality and stability of the product.

[0045] Finally, it should be noted that the above content is only used to illustrate the technical solution of the present invention, and is not intended to limit the scope of protection of the present invention. Simple modifications or equivalent substitutions made by those skilled in the art to the technical solution of the present invention do not depart from the essence and scope of the technical solution of the present invention.

Claims

1. An inhalation solution for maintaining bronchoconstriction in patients with chronic obstructive pulmonary disease and its preparation method, characterized in that, Composed of formoterol fumarate, sodium chloride, citric acid, sodium citrate, and water for injection, the solution comprises, by weight: 1-3 parts formoterol fumarate, 13-40 parts citric acid, 41-125 parts sodium citrate, 79-240 parts sodium chloride, with water for injection as the balance. The preparation steps include: adding 50%-95% water for injection to a mixing tank; cooling the water for injection to 50°C and starting stirring; simultaneously adding the prescribed amounts of sodium chloride, citric acid, and sodium citrate, stirring until dissolved; continuing to cool to 40°C; adding the prescribed amount of formoterol fumarate; stirring to dissolve for 60 minutes; bringing the volume to a final volume; stirring again for 10 minutes; and then sterilizing the prepared solution using a sterile filtration method, filtering through two 5-inch sterile filters to the receiving tank of the filling machine. The filter membrane material is polyethersulfone. The blow-fill-seal machine is turned on, and the equipment heating module heats up. Before filling, confirm that the extruder temperature reaches 150-220℃, the extruder speed is 50-100 rpm, the cooling water pressure is not less than 5 bar, the cooling water temperature does not exceed 10℃, the compressed air pressure is not less than 10 bar, the ASR blower is running normally, and after manually venting the pipeline, the filling machine is turned on. The filling volume is controlled at 2.1-2.2 ml. After discarding the waste material, normal filling begins to obtain the inhaled solution.

2. The formoterol fumarate inhalation solution prepared by the method according to claim 1.

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