Pharmaceutical composition for treating respiratory diseases and method for preparing the same

Abstract

The application discloses a kind of pharmaceutical compositions for treating respiratory diseases, which is made of the following raw and auxiliary materials: acetylcysteine as expectorant component, budesonide as glucocorticoid component, pH regulator, dispersion medium, dispersant, stabilizer and protective gas; the pH value of the pharmaceutical composition is 6.2-7.2.The combination of glucocorticoid and expectorant drug in the application has good stability, is safe to use, and thus better meets the clinical drug demand.

Description

Technical Field

[0001] This invention belongs to the field of respiratory disease drug technology, specifically relating to a pharmaceutical composition for treating respiratory diseases and its preparation method. Background Technology

[0002] Chronic respiratory diseases are second only to cardiovascular and cerebrovascular diseases and tumors. Asthma and chronic obstructive pulmonary disease are the most common chronic respiratory diseases, with a huge patient base and a severe situation for diagnosis and treatment.

[0003] Asthma is a chronic inflammatory disease of the airways caused by a combination of genetic and environmental factors. Also known as bronchial asthma, it is a chronic airway inflammation involving multiple cells and cellular components. This inflammation is often accompanied by increased airway reactivity, leading to recurrent episodes of wheezing, shortness of breath, chest tightness, and coughing, which mostly occur at night and in the early morning, and are often accompanied by widespread and variable airflow obstruction.

[0004] Chronic obstructive pulmonary disease (COPD) is a disease characterized by airflow obstruction, with severe COPD affecting over 30% of all patients. COPD is a preventable and treatable disease characterized by incompletely reversible airway obstruction, with persistent respiratory symptoms and airflow limitation. COPD is a multifactorial disease; exposure to risk factors such as smoking and air pollution, as well as host factors such as genetic abnormalities and lung developmental abnormalities, can all lead to COPD in individuals. In 2019, the prevalence of COPD among residents aged 20 and above was 8.6%, with a prevalence reaching 13.7% among those aged 40 and above. The number of male patients was 2.2 times that of female patients, and the total number of COPD patients reached 99.9 million (68.4 million males and 31.5 million females).

[0005] In Europe and the United States, medications for asthma and COPD are administered via intravenous injection, inhalation, and oral administration, with the vast majority being inhaled formulations. Inhaled formulations are a special dosage form that delivers medication directly to the lungs, allowing for rapid and direct absorption and efficacy through local administration, reducing the dosage and improving therapeutic effect. Compared to intravenous injection, inhaled formulations cause less mechanical damage, are easier to administer, and have better patient compliance; compared to oral formulations, inhaled formulations have higher bioavailability and act directly on the lungs. Considering both onset time and efficacy, inhaled formulations have consistently been the mainstream treatment for respiratory diseases in the European and American markets. Currently, inhaled corticosteroids are the primary medications for treating asthma and COPD. Glucocorticoids can inhibit the release of inflammatory mediators and suppress cytokine-mediated immune responses, playing a role in the treatment of asthma and COPD. However, clinical experience has shown that excessive thick mucus secretions in the airways can affect the efficacy of corticosteroids, a problem that requires attention and resolution.

[0006] Budesonide is a glucocorticoid with strong anti-inflammatory effects. It can inhibit the production of inflammatory and sensitizing mediators and cytokines, constrict dilated mucosal blood vessels, and increase the sensitivity of bronchial smooth muscle and inflammatory cells to β2 agonists. It can produce good therapeutic effects on both exogenous and endogenous asthma. Budesonide can also relieve or to some extent reverse airway mucosal edema and airway inflammatory remodeling lesions such as thickening of the basement membrane due to collagen deposition in the subepithelial region in patients with chronic asthma. The airway anti-inflammatory potency of this drug is 600 times that of hydrocortisone and 500 times that of dexamethasone. However, because this drug has a high first-pass metabolism effect in the liver (approximately 85-90% is degraded by the liver) and its metabolites have low bioactivity, the amount of drug entering the systemic circulation is significantly reduced, making it unsuitable for oral administration. In contrast, this drug is more suitable as an inhaled formulation, acting directly on the body through the respiratory system, improving drug utilization, while having significantly fewer systemic side effects than oral corticosteroids. Inhaled budesonide can act locally on the respiratory tract, reducing the airway's response to direct and indirect stimuli, resulting in a very high local drug concentration in the respiratory tract. It is suitable for patients with bronchial asthma, COPD, and other inflammatory airway diseases, or chronic bronchitis.

[0007] Acetylcysteine ​​has been widely used clinically as an expectorant since the 1960s and is the expectorant with the most comprehensive mechanism of action in clinical practice. Because acetylcysteine ​​contains a sulfhydryl group (-SH), it can break the disulfide bonds (-SS-) in the polypeptide chain, reduce the viscosity of sputum, make sputum easier to expel, and enhance sputum clearance by stimulating the movement of airway epithelial cilia.

[0008] Clinical experience has shown that nebulized budesonide is not suitable when there is excessive thick mucus in the airways, as this can affect budesonide deposition. In such cases, the use of acetylcysteine ​​can resolve the issue of thick mucus affecting the efficacy of budesonide.

[0009] Acetylcysteine ​​has strong reducing properties and is easily oxidized and degraded in solution. Furthermore, the oxidative degradation of acetylcysteine ​​is easily affected by metal ions such as iron and copper. To improve the stability of acetylcysteine ​​in solution, existing technologies employ nitrogen purging to reduce the residual oxygen content in the drug solution, while simultaneously adding stabilizers to the formulation to enhance the stability of the drug composition. Summary of the Invention

[0010] Budesonide is a potent anti-inflammatory drug that is effective in treating both exogenous and endogenous asthma. Acetylcysteine ​​is widely used clinically as an expectorant. To meet the requirements of convenient clinical use, objective efficacy, and patient compliance, this invention provides a pharmaceutical composition for treating respiratory diseases and its preparation method. This invention focuses on the formulation process of the pharmaceutical composition.

[0011] A first aspect of the present invention discloses a pharmaceutical composition for treating respiratory diseases, made from the following raw and excipient materials:

[0012] The expectorant component is acetylcysteine, the glucocorticoid component is desonide, the pH adjuster, the dispersion medium, the dispersant, the stabilizer, and the protective gas;

[0013] The pH value of the pharmaceutical composition is 6.2-7.2.

[0014] In some embodiments of the present invention, the weight ratio of the expectorant component acetylcysteine ​​to the glucocorticoid component desonide is 300:(0.5-1.0).

[0015] In some embodiments of the present invention, the particle size D90 of the glucocorticoid budesonide is not greater than 5 μm.

[0016] In some embodiments of the present invention, the pharmaceutical composition is a compound solution preparation.

[0017] In some embodiments of the present invention, the pH adjuster is selected from one or more of sulfuric acid, hydrochloric acid, citric acid, phosphoric acid, tartaric acid, lactic acid, sodium hydroxide, sodium bicarbonate, and disodium hydrogen phosphate.

[0018] In some embodiments of the present invention, the dispersion medium is water for injection.

[0019] In some embodiments of the present invention, the dispersant is one or more of sorbitol and propylene glycol, preferably sorbitol.

[0020] In some embodiments of the present invention, the stabilizer is selected from one or more of calcium sodium edetate and disodium edetate.

[0021] In some embodiments of the present invention, the protective gas is nitrogen.

[0022] In some embodiments of the present invention, the concentration of the stabilizer is 0.10%-0.48% by w / v.

[0023] In some embodiments of the present invention, the concentration of the dispersant is not greater than 50% by w / v;

[0024] A second aspect of the present invention discloses a method for preparing the pharmaceutical composition described in the first aspect, comprising the following steps:

[0025] S1. First, pour the required water for injection into the mixing tank, fill it with protective gas, and then add the dispersant and stabilizer in sequence to obtain mixture A.

[0026] S2, adjust the pH value of the mixture A with a pH adjuster to obtain mixture B;

[0027] S3, add acetylcysteine ​​to mixture B to obtain solution C;

[0028] S4, add budesonide to solution C, stir, and sterilize;

[0029] S5, filling, while simultaneously filling with protective gas.

[0030] In some embodiments of the present invention, in step S1, after the protective gas is filled for 20-30 minutes, the dispersant and stabilizer are added sequentially.

[0031] In some embodiments of the present invention, protective gas is continuously injected throughout the entire process from the start of the self-preparation process to the end of the filling process.

[0032] In some embodiments of the present invention, in step S2, the pH value is adjusted to 6.2-7.2.

[0033] In some embodiments of the present invention, the temperature is controlled below 40°C during the solution preparation process, preferably 20-30°C.

[0034] In some embodiments of the present invention, the sterilization is a terminal sterilization process.

[0035] The beneficial effects of this invention are:

[0036] The glucocorticoid and expectorant combination of the present invention has good stability and is safe to use, thus better meeting the needs of clinical medication.

[0037] The key process steps of the compound inhalation solution formulation described in this invention are solution preparation, aseptic assurance, and nitrogen purging. During solution preparation, changes in the dissolution temperature of the active pharmaceutical ingredient (API) may affect the stability of the product; therefore, the solution preparation temperature must be appropriately controlled. Because acetylcysteine ​​in this invention is easily oxidized, nitrogen gas must be introduced into the drug composition during solution preparation and filling. Therefore, the drug composition is a sterile formulation, and its aseptic assurance process requires close attention. According to the "Guidelines for Sterilization / Aseptic Process Validation" issued by the National Medical Products Administration, terminal sterilization should be the preferred method for sterile drugs. Therefore, terminal sterilization is the preferred method for ensuring the aseptic quality of this drug composition. Detailed Implementation

[0038] The following specific examples illustrate the implementation of the present invention. Those skilled in the art can easily understand other advantages and effects of the present invention from the content disclosed in this specification. The present invention can also be implemented or applied through other different specific embodiments, and various details in this specification can also be modified or changed based on different viewpoints and applications without departing from the spirit of the present invention.

[0039] Unless otherwise specified, the examples and comparative examples are parallel experiments with the same components, component content, preparation steps, and preparation parameters.

[0040] In the following examples, the long-term stability test conditions are: temperature below 30°C and relative humidity 60% ± 10%. Terminal sterilization refers to moist heat sterilization; unless otherwise stated, over-sterilization refers to sterilization at 121°C for 10 minutes. All data in this example were analyzed using HPLC.

[0041] Example 1A

[0042] Budneid 1.0 Acetylcysteine 300 Sodium edetate 0.003 Sorbitol 0.75 Hydrochloric acid / sodium hydroxide Adjust the pH to 6.7. Water for Injection Adjust the volume to 3L.

[0043] Pour the prescribed amount of water for injection into the mixing tank at a temperature of 55±5℃, and purge with nitrogen for 20-30 minutes. After nitrogen purging, add the prescribed amounts of disodium edetate and sorbitol to the mixing tank sequentially, stirring until all excipients are dissolved. When the solution temperature drops to 30±5℃, adjust the pH to 6.7 using hydrochloric acid / sodium hydroxide. Add the prescribed amount of acetylcysteine ​​and stir until dissolved. Add the prescribed amount of budesonide and stir until homogeneous. Nitrogen purging continues throughout the mixing and filling process. Terminal sterilization is used to ensure aseptic treatment of the product during the preparation process.

[0044] Example 2A

[0045] Budneid 0.5 Acetylcysteine 300 Sodium edetate 0.003 Sorbitol 0.75 Hydrochloric acid / sodium hydroxide Adjust the pH to 6.5. Water for Injection Adjust the volume to 3L.

[0046] Pour the prescribed amount of water for injection into the mixing tank at a temperature of 55±5℃, and purge with nitrogen for 20-30 minutes. After nitrogen purging, add the prescribed amounts of disodium edetate and sorbitol to the mixing tank sequentially, stirring until all excipients are dissolved. When the solution temperature drops to 30±5℃, adjust the pH to 6.5 using hydrochloric acid / sodium hydroxide. Add the prescribed amount of acetylcysteine ​​and stir until dissolved. Add the prescribed amount of budesonide and stir until homogeneous. Nitrogen purging continues throughout the mixing and filling process. Terminal sterilization is used to ensure aseptic treatment of the product during the preparation process.

[0047] Example 3A

[0048] Budneid 1.0 Acetylcysteine 300 Sodium edetate 0.0029 Sorbitol 0.75 Hydrochloric acid / sodium hydroxide Adjust the pH to 6.2. Water for Injection Adjust the volume to 3L.

[0049] Pour the prescribed amount of water for injection into the mixing tank at a temperature of 55±5℃, and purge with nitrogen for 20-30 minutes. After nitrogen purging, add the prescribed amounts of disodium edetate and sorbitol to the mixing tank sequentially, stirring until all excipients are dissolved. When the solution temperature drops to 30±5℃, adjust the pH to 6.2 using hydrochloric acid / sodium hydroxide. Add the prescribed amount of acetylcysteine ​​and stir until dissolved. Add the prescribed amount of budesonide and stir until homogeneous. Nitrogen purging continues throughout the mixing and filling process. Terminal sterilization is used to aseptically process the product during preparation.

[0050] Example 4A

[0051]

[0052]

[0053] Pour the prescribed amount of water for injection into the mixing tank at a temperature of 55±5℃, and purge with nitrogen for 20-30 minutes. After nitrogen purging, add the prescribed amounts of disodium edetate and sorbitol to the mixing tank sequentially, stirring until all excipients are dissolved. When the solution temperature drops to 30±5℃, adjust the pH to 6.2 using hydrochloric acid / sodium hydroxide. Add the prescribed amount of acetylcysteine ​​and stir until dissolved. Add the prescribed amount of budesonide and stir until homogeneous. Nitrogen purging continues throughout the mixing and filling process. Terminal sterilization is used to aseptically process the product during preparation.

[0054] Comparative Example 1A

[0055] Budneid 1.0 Acetylcysteine 300 Sodium edetate 0.0027 Sorbitol 0.72 Hydrochloric acid / sodium hydroxide Adjust the pH to 6.4. Water for Injection Adjust the volume to 3L.

[0056] Pour the prescribed amount of water for injection into the mixing tank at a temperature of 55±5℃. Add the prescribed amounts of sodium calcium edetate and sorbitol sequentially to the mixing tank, stirring until all excipients are dissolved. When the solution temperature drops to 30±5℃, adjust the pH to 6.4 using hydrochloric acid / sodium hydroxide. Add the prescribed amount of acetylcysteine ​​and stir until dissolved. Add the prescribed amount of budesonide and stir until homogeneous. Terminal sterilization is used to ensure aseptic processing of the product during the preparation process.

[0057] Comparative Example 2A

[0058] Budneid 1.0 Acetylcysteine 300 Sodium edetate 0.0027 Propylene glycol 1.53 Hydrochloric acid / sodium hydroxide Adjust the pH to 6.3. Water for Injection Adjust the volume to 3L.

[0059] Pour the prescribed amount of water for injection into the mixing tank at a temperature of 55±5℃. Purge with nitrogen for 20-30 minutes. After nitrogen purging, add the prescribed amounts of disodium edetate and propylene glycol to the mixing tank sequentially, stirring until all excipients are dissolved. When the solution temperature drops to 30±5℃, adjust the pH to 6.3 using hydrochloric acid / sodium hydroxide. Add the prescribed amount of acetylcysteine ​​and stir until dissolved. Add the prescribed amount of budesonide and stir until homogeneous. Nitrogen purging continues throughout the mixing and filling process. Terminal sterilization is used to ensure aseptic treatment of the product during the preparation process.

[0060] Comparative Example 3A

[0061] Budneid 1.0 Acetylcysteine 300 Sodium calcium edetate 0.0033 Sorbitol 0.73 Hydrochloric acid / sodium hydroxide Adjust the pH to 6.7. Water for Injection Adjust the volume to 3L.

[0062] Pour the prescribed amount of water for injection into the mixing tank at a temperature of 55±5℃, and purge with nitrogen for 20-30 minutes. After nitrogen purging, add the prescribed amounts of sodium calcium edetate and sorbitol to the mixing tank sequentially, stirring until all excipients are dissolved. When the solution temperature drops to 30±5℃, adjust the pH to 6.7 using hydrochloric acid / sodium hydroxide. Add the prescribed amount of acetylcysteine ​​and stir until dissolved. Add the prescribed amount of budesonide and stir until homogeneous. Nitrogen purging continues throughout this mixing and filling process. Terminal sterilization is used to aseptically process the product during preparation.

[0063] Example 5A

[0064] The pharmaceutical compositions prepared in Examples 1A, 2A, 3A, and Comparative Examples 1A, 2A, and 3A were placed under long-term stability test conditions for 12 months, and the results are as follows.

[0065] Table 1 Stability Test

[0066]

[0067] According to the data in Table 1, the pharmaceutical compositions prepared in Examples 1A-4A showed no significant changes in pH and related substances after being placed under long-term stability test conditions for 12 months, indicating that the pharmaceutical compositions have strong stability and controllable quality.

[0068] Studies have shown that, under the same preparation process conditions, nitrogen gas has a significant impact on the stability of this pharmaceutical composition. For example, in Comparative Example 1A, where nitrogen purging was not performed during the preparation of this pharmaceutical composition, after being stored under long-term conditions for one month, a significant increase in related substances was observed, with a large increase in the amount. The nitrogen gas and nitrogen purging process used in this invention have a protective effect on the related substances of this pharmaceutical composition.

[0069] Studies have shown that, under the same preparation process conditions, sorbitol is more suitable as a dispersant. For example, in Comparative Example 2A, when propylene glycol was chosen as the dispersant, the amount of this excipient used was significantly higher than when sorbitol was used. Considering the product characteristics, sorbitol, which requires a smaller dosage yet achieves the desired effect, is a more suitable dispersant.

[0070] Studies have shown that, under the same preparation process conditions, products using sodium calcium edetate as a stabilizer, such as Comparative Example 3A, exhibit comparable product stability during the stabilization period to those using disodium edetate as a stabilizer.

[0071] Example 6A

[0072] The effect of different dosages of disodium edetate on product stability was investigated according to the formulation and process of Example 1A, and the results are shown in Table 2.

[0073] Table 2. Effect of disodium edetate dosage on product stability

[0074]

[0075]

[0076] According to the data in Table 2, when the dosage of disodium edetate is 0.1 w / v%-0.48 w / v%, after the drug composition is stored under long-term experimental conditions for 12 months, the related substances test results are similar to those of the product at day 0, indicating that the physicochemical state of the drug composition is relatively stable.

[0077] Example 7A

[0078] According to the formulation process of Example 1A, the prescribed amount of water for injection is poured into the preparation tank at a temperature of 55±5℃, and nitrogen gas is purged for 20-30 minutes. After nitrogen purging, the prescribed amounts of disodium edetate and sorbitol are added to the preparation tank in sequence, and stirred until all excipients are dissolved. When the solution temperature drops to the unused temperature (50℃, 40℃, and 30℃ respectively), the pH is adjusted to 6.7 using hydrochloric acid / sodium hydroxide. The prescribed amount of acetylcysteine ​​is added and stirred to dissolve, and the prescribed amount of budesonide is added and stirred evenly. Nitrogen gas is continuously purged during this preparation and filling process.

[0079] Table 3. Effects of dissolution of active pharmaceutical ingredient in solution at different temperatures on product stability.

[0080]

[0081] According to the data in Table 3, the temperature of the solution has a significant impact on the stability of the active pharmaceutical ingredient (API). When the temperature of the solution in which the API is dissolved is controlled between 20-40℃, there is no growth of related substances in the drug composition, and the sample is stable.

[0082] Example 8A

[0083] Following the formulation process of Example 1A, the prescribed amount of water for injection was poured into the preparation tank at a temperature of 55±5℃, and nitrogen gas was purged for 20-30 minutes. After nitrogen purging, the prescribed amounts of disodium edetate and sorbitol were added to the preparation tank sequentially, and stirred until all excipients were dissolved. When the solution temperature dropped to 30±5℃, the pH was adjusted to 6.7 using hydrochloric acid / sodium hydroxide. The prescribed amount of acetylcysteine ​​was added and stirred until dissolved. The prescribed amount of budesonide was then added and stirred until homogeneous. Nitrogen gas was continuously purged during this preparation and filling process. After sterilizing the drug composition using aseptic filtration and terminal sterilization methods, the drug solution was stored under long-term conditions for 12 months.

[0084] Table 4. The impact of different sterilization processes on product quality

[0085]

[0086] According to the data in Table 4, both the terminal mold sterilization process and the aseptic filtration process meet the production requirements of this pharmaceutical composition. Based on the "Guidelines for Sterilization / Aseptic Process Validation," terminal sterilization should be the preferred method for sterile pharmaceutical products; therefore, the terminal mold sterilization process is selected in this invention as the aseptic assurance method for this pharmaceutical composition.

[0087] The preferred embodiments and examples of the present invention have been described in detail above. However, the present invention is not limited to the above embodiments and examples. Within the scope of knowledge possessed by those skilled in the art, various changes can be made without departing from the concept of the present invention.

Claims

1. A pharmaceutical composition for treating respiratory diseases, characterized in that, Made from the following raw and auxiliary materials: Acetylcysteine, budesonide, pH adjuster, dispersion medium, dispersant, stabilizer and protective gas; The weight ratio of acetylcysteine ​​to budesonide is 300:(0.5-1.0). The pharmaceutical composition is a compound solution preparation; the dispersion medium is water for injection; the dispersant is sorbitol; the stabilizer is selected from one or more of calcium sodium edetate and disodium edetate; the protective gas is nitrogen. The concentration of the stabilizer, on a w / v basis, is 0.10%-0.48%; The pH value of the pharmaceutical composition is 6.2-7.2; The temperature during the preparation of the pharmaceutical composition is 20-40℃.

2. The pharmaceutical composition according to claim 1, characterized in that, The particle size D90 of the budesonide is no greater than 5 μm.

3. The pharmaceutical composition according to claim 1, characterized in that, The pH adjuster is selected from one or more of sulfuric acid, hydrochloric acid, citric acid, phosphoric acid, tartaric acid, lactic acid, sodium hydroxide, sodium bicarbonate, and disodium hydrogen phosphate.

4. The pharmaceutical composition according to claim 1, characterized in that, The concentration of the dispersant is no more than 50% on a w / v basis.

5. The method for preparing the pharmaceutical composition according to any one of claims 1-4, characterized in that, Includes the following steps: S1. First, pour the required water for injection into the mixing tank, fill it with protective gas, and then add the dispersant and stabilizer in sequence to obtain mixture A. S2, adjust the pH value of the mixture A with a pH adjuster to obtain mixture B; S3, add acetylcysteine ​​to mixture B to obtain solution C; S4, add budesonide to solution C, stir, and sterilize; S5, filling, while simultaneously filling with protective gas.

6. The method for preparing the pharmaceutical composition according to claim 5, characterized in that, In S1, after filling with protective gas for 20-30 minutes, dispersant and stabilizer are added sequentially.

7. The method for preparing the pharmaceutical composition according to claim 5 or 6, characterized in that, From the start of the liquid preparation process to the end of the filling process, protective gas is continuously injected throughout the entire process.

8. The method for preparing the pharmaceutical composition according to claim 5, characterized in that, In S2, adjust the pH value to 6.2-7.

2.

9. The method for preparing the pharmaceutical composition according to claim 5, characterized in that, During the solution preparation process, the temperature is 20-30℃.

10. The method for preparing the pharmaceutical composition according to claim 5, characterized in that, The sterilization process is terminal sterilization.

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