Procaterol hydrochloride solution for inhalation and preparation method thereof

Abstract

The invention is suitable for the technical field of pharmaceutical preparations, and provides a procaterol hydrochloride solution for inhalation and a preparation method thereof, per 100 mL of water for injection contains 0.01 g of procaterol hydrochloride, 0.15-0.25 g of citric acid, 0.1-0.15 g of vitamin C, and 520-560 [mu] L of a 5-10% sodium hydroxide solution. The procaterol hydrochloride, the citric acid and the vitamin C are compounded in proportion, meanwhile, the pH value of the system is regulated and controlled through the 5-10% sodium hydroxide solution, the quality stability of the procaterol hydrochloride solution for inhalation can be improved, and meanwhile the preparation method is simple and feasible in process, controllable in impurity amount and capable of achieving batch production.

Description

Technical Field

[0001] The present application belongs to the technical field of pharmaceutical preparations, and in particular relates to a Procaterol hydrochloride solution for inhalation and a preparation method thereof. Background Art

[0002] Procaterol hydrochloride is a β2 receptor agonist, which has a high selectivity for the β2 adrenergic receptors of bronchial smooth muscle, thereby relaxing the bronchial smooth muscle. It also has certain anti-allergic effects and promotes the movement of respiratory cilia. It is widely used in the treatment of bronchial asthma, asthmatic bronchitis, chronic obstructive pulmonary disease (COPD) and other diseases in clinical practice. The dosage forms include tablets, capsules, granules, oral liquid, and inhalation powder.

[0003] Among them, inhalation is the most common way of administering β2 receptor agonists. After inhalation, the drug can quickly reach the trachea to dilate the bronchi, and usually takes effect within a few minutes after inhalation. However, since Procaterol hydrochloride is easily oxidized in the presence of moisture and air, the preparation of liquid preparations has problems such as high impurity content, easy oxidation, and short shelf life. Summary of the invention

[0004] The purpose of the embodiments of the present application is to provide a Procaterol hydrochloride solution for inhalation, which aims to solve the problems of high impurity content, easy oxidation, short shelf life, etc. of the existing Procaterol hydrochloride liquid preparation.

[0005] The embodiment of the present application is implemented as follows: a Procaterol hydrochloride solution for inhalation contains 0.01g of Procaterol hydrochloride, 0.15-0.25g of citric acid, 0.1-0.15g of vitamin C, and 520-560μL of 5-10% sodium hydroxide solution per 100mL of water for injection.

[0006] Another object of the embodiment of the present application is a method for preparing the Procaterol hydrochloride solution for inhalation according to claim 1, comprising:

[0007] Add a portion of the injection water into the preparation tank, control the water temperature at 20±5℃, and simultaneously fill in inert protective gas until the dissolved oxygen content is less than 4000ppb;

[0008] dissolving Procaterol hydrochloride in citric acid solution to obtain a first mixed solution;

[0009] Adding vitamin C to the first mixed solution and stirring to dissolve the mixture to obtain a second mixed solution;

[0010] The second mixed liquid is added into the preparation tank and uniformly mixed with the water for injection, and then a sodium hydroxide solution with a mass fraction of 5-10% is added to adjust the pH value to 3.0-4.0;

[0011] Add water for injection to the full amount and stir evenly, filter and fill to obtain the Procaterol hydrochloride solution for inhalation.

[0012] Preferably, the mass fraction of the sodium hydroxide solution is 8.5%.

[0013] Preferably, the mass ratio of Procaterol hydrochloride to citric acid is 1:(15-25).

[0014] Preferably, the mass ratio of Procaterol hydrochloride to vitamin C is 1:(10-15).

[0015] The embodiment of the present application is beneficial to increasing the quality stability of the Procaterol hydrochloride solution for inhalation by compounding Procaterol hydrochloride, citric acid and vitamin C in proportion and using 5-10% sodium hydroxide solution to control the pH value of the system. At the same time, the preparation method is simple and feasible, the impurity content is controllable, and batch production is possible. DETAILED DESCRIPTION

[0016] In order to make the purpose, technical solution and advantages of the present application more clear, the present application is further described in detail below in conjunction with the embodiments. It should be understood that the specific embodiments described here are only used to explain the present application and are not used to limit the present application.

[0017] In order to solve the problems of high impurity content, easy oxidation, short shelf life, etc. in the existing liquid preparations of Procaterol hydrochloride, the embodiment of the present application proposes a Procaterol hydrochloride solution for inhalation. Procaterol hydrochloride, citric acid and vitamin C are compounded in proportion, and the pH value of the system is regulated by 5-10% sodium hydroxide solution, which is beneficial to increasing the quality stability of the Procaterol hydrochloride solution for inhalation. At the same time, the preparation method is simple and feasible, the impurity content is controllable, and batch production is possible.

[0018] Specifically, the embodiment of the present application provides a Procaterol hydrochloride solution for inhalation, which contains 0.1g of Procaterol hydrochloride, 1.5-2.5g of citric acid, 1-1.5g of vitamin C, and 5200-5600μL of 5-10% sodium hydroxide solution per 1000mL of water for injection.

[0019] Optionally, the specification of the Procaterol hydrochloride solution for inhalation is 0.5 mL or 100 mL, containing 0.05 mg or 0.01 g of Procaterol hydrochloride, respectively.

[0020] In the embodiment of the present application, the method for preparing the above-mentioned Procaterol hydrochloride solution for inhalation comprises the following steps:

[0021] Add a portion of the injection water into the preparation tank, control the water temperature at 20±5℃, and simultaneously fill in inert protective gas until the dissolved oxygen content is less than 4000ppb;

[0022] dissolving Procaterol hydrochloride in citric acid solution to obtain a first mixed solution;

[0023] Adding vitamin C to the first mixed solution and stirring to dissolve the mixture to obtain a second mixed solution;

[0024] The second mixed liquid is added into the preparation tank and uniformly mixed with the water for injection, and then a sodium hydroxide solution with a mass fraction of 5-10% is added to adjust the pH value to 3.0-4.0;

[0025] Add water for injection to the full amount and stir evenly, filter and fill to obtain the Procaterol hydrochloride solution for inhalation.

[0026] Among them, 1g of Procaterol hydrochloride raw material dissolves in about 20mL of water at 20°C. This application considers that the concentration of the preparation (0.01%) is much smaller than the solubility of the raw material in water (5%); impurity I is an isomer impurity, which is conducive to the formation of this impurity at a higher temperature, and the product has no solubility risk under laboratory room temperature conditions. Therefore, the preparation temperature of this product is controlled to be consistent with the long-term storage temperature of the product, that is, the preparation temperature is below 25°C.

[0027] Among them, the inert gas is preferably nitrogen. The present application takes into account that the impurity II of this product is an oxidizing impurity. Therefore, the influence of nitrogen filling during the preparation process of this product and nitrogen filling in the outer packaging aluminum foil composite bag on the quality of the self-made product is investigated, and the influencing factor 60℃-10 days is investigated. The results show that there is no significant difference in the relevant substances between the samples filled with nitrogen and those not filled with nitrogen under the conditions of 60℃-10 days; the test results of the samples at 60℃-10 days show that the generation of impurity II can be effectively suppressed under the conditions of nitrogen filling in the outer packaging. Therefore, the present application embodiment fills the liquid preparation process with nitrogen and performs nitrogen filling protection during the outer packaging process.

[0028] In the examples of the present application, the mass ratio of Procaterol hydrochloride to citric acid is 1:(15-25), preferably 1:20.

[0029] In the examples of the present application, the mass ratio of Procaterol hydrochloride to vitamin C is 1:(10-15), preferably 1:13.

[0030] Among them, the compounding of Procaterol hydrochloride with citric acid and vitamin C in proportion is beneficial to increase the stability of the Procaterol hydrochloride solution for inhalation. In order to reduce the generation of impurity II as much as possible, the preparation sequence is investigated and determined as follows: 80% ultrapure water → citric acid, Procaterol hydrochloride (Procaterol hydrochloride is pre-dissolved in citric acid solution, and the citric acid solution is obtained by pre-dissolving citric acid in an appropriate amount of water for injection) → vitamin C → 5-10% sodium hydroxide.

[0031] Secondly, regarding the filter membrane material used for sterilization filtration, this application used polyethersulfone (PES) material filter membrane and polyvinylidene fluoride (PVDF) material filter membrane for cyclic filtration for 1h and 2h; at the same time, PES and PVDF material needle filters were used, and the filtrate was collected after discarding 5mL and 10mL respectively, and the adsorption of filter membranes of different materials was compared. The results were: there was basically no difference in the relevant substances after the drug solution was filtered through PES and PVDF materials, and different filter membrane materials had basically no adsorption on this product; therefore, the filter membrane material of this application was selected as PVDF material.

[0032] In addition, the amount and mass fraction of sodium hydroxide are also key factors affecting the amount of impurity II produced. The present application investigates the amount of sodium hydroxide with 10% sodium hydroxide and compares the results of different amounts of sodium hydroxide. As the amount of sodium hydroxide increases, impurity II tends to increase. This may be due to the high concentration of 10% sodium hydroxide solution during the sodium hydroxide addition process, resulting in local over-alkali leading to the growth of impurity II. Therefore, it is preferred that the mass fraction of sodium hydroxide is controlled to be less than 10%, more preferably 8.5%.

[0033] The following are specific examples of the embodiments of the present application, which are not intended to limit the scope of the present application. In addition, it should be noted that the numerical values ​​given in the following examples are as accurate as possible.

[0034] Investigation of different prescription amounts of Example 1-Example 7

[0035] Prepare the Procaterol hydrochloride solution for inhalation according to the prescription amount in Table 1 below;

[0036] Add 70mL of water for injection to preparation tank 1 and preparation tank 2 respectively (turn on the heat exchanger), control the water temperature at 20°C, and detect the dissolved oxygen content after nitrogen filling for 30 minutes. The dissolved oxygen content is less than 4000ppb; proceed to the next step if qualified; if unqualified, continue to fill with nitrogen until qualified; take water for injection from preparation tank 2 to dissolve sodium hydroxide so that the mass fraction of the obtained sodium hydroxide solution is 8.5%; then take an appropriate amount of water for injection from preparation tank 2 to dissolve citric acid to obtain citric acid solution; dissolve Procaterol hydrochloride in the citric acid solution to obtain a first mixed solution; add vitamin C to the first mixed solution and stir to dissolve to obtain a second mixed solution; add the second mixed solution to the preparation tank and mix it evenly with the water for injection, then add 8.5% sodium hydroxide solution to adjust the pH value to 3.0-4.0, and rinse the container containing the sodium hydroxide solution and the second mixed solution with water for injection 3 times, and transfer the rinse solution to the preparation tank; Add water for injection to 100mL and stir evenly, stirring (stirring frequency 30Hz) for no less than 10 minutes; take samples to test the uniformity of the prepared liquid and the intermediate product test; after the intermediate product test is qualified, the liquid storage tank is filled with nitrogen and oxygen is discharged before transfer (first vacuum to 0.6Bar, then nitrogen is filled to 1.2Bar, vacuum is repeated 3 times, nitrogen is filled 3 times, and the last nitrogen filling pressure is (1.5-2.0Bar). The liquid is transferred to a 500L liquid storage tank through pre-filtration (0.45μm, polyvinylidene fluoride material, manufacturer Hangzhou Kebet Filter Equipment Co., Ltd.) and sterilization filtration (0.22μm, polyvinylidene fluoride material, manufacturer Hangzhou Kebet Filter Equipment Co., Ltd.). The liquid is terminally filtered (0.22μm, polyvinylidene fluoride material, manufacturer Hangzhou Kebet Filter Equipment Co., Ltd.), and stably transported to the buffer tank of the blow-fill-seal (BFS) production line, and the blow-fill-seal operation is performed to obtain the Procaterol hydrochloride solution for inhalation.

[0037] Table 1

[0038]

[0039] The Procaterol hydrochloride solutions for inhalation prepared in Examples 1-7 were placed at 60° C. for 10 days and 30 days, respectively, and samples were taken for testing. The results were compared with those on day 0 to examine the stability of the samples. The results are shown in Table 2.

[0040] Table 2

[0041]

[0042] In summary, it can be seen from Table 2 that the embodiment of the present application is beneficial to increasing the quality stability of the Procaterol hydrochloride solution for inhalation by compounding Procaterol hydrochloride, citric acid and vitamin C in proportion and regulating the pH value of the system with 8.5% sodium hydroxide solution.

[0043] Embodiment 8: the investigation of sodium hydroxide dosage

[0044] Add 70mL of water for injection to preparation tank 1 and preparation tank 2 respectively (turn on the heat exchanger), control the water temperature at 20°C, and detect the dissolved oxygen content after nitrogen filling for 30 minutes. The dissolved oxygen content is less than 4000ppb; proceed to the next step if qualified; if unqualified, continue to fill with nitrogen until qualified; take water for injection from preparation tank 2 to dissolve sodium hydroxide so that the mass fraction of the obtained sodium hydroxide solution is 10%; then take an appropriate amount of water for injection from preparation tank 2 to dissolve 0.20g of citric acid to obtain a citric acid solution; dissolve 0.01g of Procaterol hydrochloride in the citric acid solution to obtain a first mixed solution; add 0.13g of vitamin C to the first mixed solution and stir to dissolve to obtain a second mixed solution; add the second mixed solution to the preparation tank and mix it evenly with the water for injection, add different amounts of sodium hydroxide solution with a mass fraction of 10%, and rinse the container containing the sodium hydroxide solution and the second mixed solution with water for injection 3 times, and transfer the rinse solution to the preparation tank In the middle; add water for injection to 100mL and stir evenly, stirring (stirring frequency 30Hz) for no less than 10 minutes; take samples to test the uniformity of the prepared liquid and the intermediate product test; after the intermediate product test is qualified, the liquid storage tank is filled with nitrogen and oxygen is discharged before transfer (first vacuum to 0.6Bar, then nitrogen is filled to 1.2Bar, vacuum is repeated 3 times, nitrogen is filled 3 times, and the last nitrogen filling pressure is (1.5-2.0Bar). The liquid is transferred to a 500L liquid storage tank through pre-filtration (0.45μm, polyvinylidene fluoride material, manufacturer is Hangzhou Kebet Filter Equipment Co., Ltd.) and sterilization filtration (0.22μm, polyvinylidene fluoride material, manufacturer is Hangzhou Kebet Filter Equipment Co., Ltd.). The liquid is terminally filtered (0.22μm, polyvinylidene fluoride material, manufacturer is Hangzhou Kebet Filter Equipment Co., Ltd.), and stably transported to the buffer tank of the blow-fill-seal (BFS) production line, and the blow-fill-seal operation is performed to obtain the Procaterol hydrochloride solution for inhalation.

[0045] This example investigates the quality of products with different sodium hydroxide addition amounts, and at the same time places the influencing factors for 24 hours for investigation to determine the stability of products with different pH values. The specific investigation results are shown in Tables 3-5 below.

[0046] Table 3: Sodium hydroxide dosage investigation

[0047]

[0048] Table 4: Sodium hydroxide dosage 0 day test results

[0049]

[0050] Table 5: 24-hour test results of sodium hydroxide dosage

[0051]

[0052]

[0053] In summary, it can be seen from Tables 3-5 that, by comparing the results of relevant substance and content detection at 0 hours and 24 hours under different pH conditions, there is no significant change in the samples after being placed for 24 hours under different pH conditions; by comparing the results of different sodium hydroxide dosages, as the amount of sodium hydroxide increases, impurity II has an increasing trend, which may be due to the high concentration of 10% sodium hydroxide solution during the addition of sodium hydroxide, resulting in local over-alkalinity and leading to the growth of impurity II. At the same time, when the pH value of the sample is 3.5, its osmotic pressure molar concentration is 23mOsmol / kg, which is consistent with the osmotic pressure molar concentration of the reference preparation 2A86DA of 23mOsmol / kg. Therefore, it is determined that the pH value of this application is controlled to be about 3.5. In order to control the growth of impurity II, the mass fraction of sodium hydroxide is controlled to 8-9%, and the dosage is 54mg / 100mL.

[0054] Example 9: Carry out a large-scale test according to the prescription ratio of Example 3

[0055] Add about 80kg of water for injection to a 100L preparation tank, start stirring at a frequency of 30Hz, and control the water temperature at 0-30℃. Turn on nitrogen filling. Add about 40kg of water for injection to a 500L preparation tank, control the water temperature at 0-25℃, and set aside; stir and dissolve the weighed sodium hydroxide in a beaker with about 2L-3L water for injection (water from the 500L preparation tank); stir and dissolve the weighed citric acid in a beaker with about 2L water for injection (water from the 500L preparation tank); after the citric acid is completely dissolved, add the weighed Procaterol hydrochloride to the citric acid solution, stir and dissolve, then add the weighed vitamin C and stir and dissolve; when the water temperature in the preparation tank drops to 0-25℃ and the Procaterol hydrochloride is completely dissolved, transfer it to the preparation tank and take 1500mL of left Rinse the beaker with water for injection three times on the right. After the rinsing liquid is transferred to the preparation tank, the stirring time is not less than 5 minutes. After the stirring time is over, add sodium hydroxide solution to the preparation tank, take about 1500mL of water for injection to rinse the beaker three times. After the rinsing liquid is transferred to the preparation tank, the stirring time is not less than 10 minutes. Stop stirring, turn off nitrogen filling, and adjust the weight of the fixed volume of the drug solution to 100.15kg±0.3kg; start stirring (stirring frequency 30Hz) and start nitrogen filling. When the dissolved oxygen content of the drug solution is <4000ppb, stir for 10, 15, and 20min respectively, and take samples to test the uniformity of the preparation solution and the intermediate detection.

[0056] Table 6 Magnification of the uniformity of the batch preparation test results

[0057]

[0058] The data in the table above show that there is no significant difference in properties, pH value, osmotic pressure molar concentration and content among samples with different stirring times, and all meet the quality standard requirements of the intermediate of this product. This shows that the content uniformity of stirring for 10min to 20min meets the requirements. In order to ensure the uniformity of subsequent large-scale production, the stirring time is selected as 15min, and the uniformity of the liquid preparation is confirmed through the subsequent three batches of verification batch production.

[0059] Table 7 Amplification of the test results of the time limit for the preparation of the liquid

[0060]

[0061]

[0062] The above data show that within the preparation time limit of 8 hours, there is no significant difference in the test data of samples from different sampling points compared with the intermediates, and all meet the quality standard requirements of the intermediates of this product.

[0063] The microbial load data showed that the microbial limits of the preparation time of 4h and 8h were both less than 10cfu / 100mL, and the microbial limits met the sterilization filtration limit requirements. Therefore, the preparation time limit of this product was determined to be 8h.

[0064] Sterilization filtration process: The prepared liquid is filtered with nitrogen through two filters of 0.45μm and 0.22μm into the liquid storage tank. The properties, pH value, content, related substances and microbial limits of the samples before and after filtration are tested and compared with the drug solution before filtration to investigate the preliminary compatibility of the filtration system. The results are summarized as follows:

[0065] Table 8: Comparison and summary of the test results of the drug solution before and after the large-scale filtration

[0066]

[0067]

[0068] The data in the table above show that when the drug solution is stored for 40 hours after sterilization and filtration, its various test data (properties, content, pH, related substances) are not significantly different from those of the intermediate product. The related substances have increased slightly, but are far below the limit requirements; the drug solution before and after filtration meets the quality standard requirements of the intermediate product of this product. The preliminary compatibility of the filtration system meets the requirements. This product is a sterile product without terminal sterilization. The filtration system is a key factor and verification of the filtration system is required. The microbial limit is less than 10cfu / 100mL, and the microbial limit of the sterilization filtration retention time of 40h meets the regulations.

[0069] The discarded liquid medicine before filling and the samples before, during and after the filling process were tested to ensure the uniformity and stability of the content of the filled product. The results are summarized as follows:

[0070] Table 9 Investigation results of filling and discarding liquid medicine

[0071]

[0072] The data results in the table above show that when the discard volume is 3L, the difference between its content and the intermediate content and the discarded 6L content is less than 2%. The discard volume is selected for filling. The discard volume is verified and confirmed during process validation.

[0073] Table 10: Results of the investigation on uniformity and filling time limit of the batch filling process

[0074]

[0075]

[0076] The data in the table above show that there is no significant difference in properties, pH value and content between samples at different filling time periods. It can be seen that foreign matter, filling volume and sterility are in compliance with regulations. The related substances have increased slightly, and the main increased impurities are known impurities I and II, which are far below the limit requirements. Based on the above results, the filling time limit can be up to 40 hours.

[0077] The above-mentioned embodiments only express several implementation methods of the present application, and the descriptions thereof are relatively specific and detailed, but they cannot be understood as limiting the scope of the present application. It should be pointed out that, for a person of ordinary skill in the art, several variations and improvements can be made without departing from the concept of the present application, and these all belong to the protection scope of the present application. Therefore, the protection scope of the present application shall be subject to the attached claims.

[0078] 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 Procaterol hydrochloride solution for inhalation, characterized in that: Every 100 mL of water for injection contains 0.01 g of Procaterol hydrochloride, 0.15-0.25 g of citric acid, 0.1-0.15 g of vitamin C, and 520-560 μL of 5-10% sodium hydroxide solution.

2. The Procaterol hydrochloride solution for inhalation according to claim 1, characterized in that The mass fraction of the sodium hydroxide solution is 8.5%.

3. The Procaterol hydrochloride solution for inhalation according to claim 1, characterized in that The specification of the Procaterol hydrochloride solution for inhalation is 0.5 mL or 100 mL, containing 0.05 mg and 0.01 g of Procaterol hydrochloride respectively.

4. A method for preparing the Procaterol hydrochloride solution for inhalation according to claim 1, characterized in that: include: Add a portion of the injection water into the preparation tank, control the water temperature at 20±5℃, and simultaneously fill in inert protective gas until the dissolved oxygen content is less than 4000ppb; dissolving Procaterol hydrochloride in citric acid solution to obtain a first mixed solution; Adding vitamin C to the first mixed solution and stirring to dissolve the mixture to obtain a second mixed solution; The second mixed liquid is added into the preparation tank and uniformly mixed with the water for injection, and then a sodium hydroxide solution with a mass fraction of 5-10% is added to adjust the pH value to 3.0-4.0; Add water for injection to the full amount and stir evenly, filter and fill to obtain the Procaterol hydrochloride solution for inhalation.

5. The method for preparing the Procaterol hydrochloride solution for inhalation according to claim 4, characterized in that: The mass ratio of Procaterol hydrochloride to citric acid is 1:(15-25).

6. The method for preparing the Procaterol hydrochloride solution for inhalation according to claim 5, characterized in that: The mass ratio of Procaterol hydrochloride to citric acid is 1:

20.

7. The method for preparing the Procaterol hydrochloride solution for inhalation according to claim 4, characterized in that: The mass ratio of Procaterol hydrochloride to vitamin C is 1:(10-15).

8. The method for preparing the Procaterol hydrochloride solution for inhalation according to claim 7, characterized in that: The mass ratio of Procaterol hydrochloride to vitamin C is 1:

13.

9. The method for preparing the Procaterol hydrochloride solution for inhalation according to claim 4, characterized in that: The inert gas is nitrogen.

10. The method for preparing the Procaterol hydrochloride solution for inhalation according to claim 4, characterized in that: The mass fraction of the sodium hydroxide solution is 8.5%.

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