An inhaled acetylcysteine solution and its preparation method
By adding disodium ethylenediaminetetraacetate and modified polyvinylpyrrolidone to the inhaled acetylcysteine solution, the pH value is controlled, solving the stability problem of the acetylcysteine solution, achieving higher chemical stability and antioxidant properties, and ensuring the safety and efficacy of the drug.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- HAINAN HUALON PHARM
- Filing Date
- 2024-12-31
- Publication Date
- 2026-06-30
AI Technical Summary
Existing inhaled acetylcysteine solutions have poor stability and are prone to oxidation, leading to reduced efficacy.
A solution composed of acetylcysteine, disodium ethylenediaminetetraacetate, modified polyvinylpyrrolidone, and a pH adjuster was used. By controlling the pH value to 6.5-6.9 and using modified polyvinylpyrrolidone as a stabilizer, oxidation reactions were prevented and the chemical stability of the solution was improved.
This improved the stability of inhaled acetylcysteine solution, reduced oxidation reactions, and ensured the safety and efficacy of the drug.
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Abstract
Description
Technical Field
[0001] This invention belongs to the field of pharmaceutical technology, and in particular relates to an inhaled acetylcysteine solution and its preparation method. Background Technology
[0002] Inhaled acetylcysteine solution is an expectorant specifically designed for nebulization. Its main component is acetylcysteine, a derivative of cysteine. Acetylcysteine is the expectorant with the most comprehensive mechanism of action in clinical practice. It belongs to the mucolytic drug category and mainly works by breaking the disulfide bonds of acidic glycoprotein polypeptides in mucus and cleaving DNA in purulent sputum through the sulfhydryl groups in the molecule. It can exert a strong mucolytic effect on both white sputum and mucopurulent sputum, thereby reducing the viscosity of sputum and making it easier to cough up.
[0003] Acetylcysteine is available in China in various dosage forms, including granules, tablets, injections, eye drops, and inhalation solutions. Compared to oral and injection formulations, inhaled acetylcysteine solutions can reach the upper respiratory tract and lungs more directly, offering advantages such as rapid onset of action and fewer systemic adverse reactions, making them particularly suitable for pediatric patients.
[0004] Currently, although inhaled acetylcysteine solution is widely used, the acetylcysteine molecule contains disulfide bonds, which are easily oxidized, resulting in poor stability and reduced efficacy. Summary of the Invention
[0005] This invention provides an inhaled acetylcysteine solution and its preparation method, thereby solving the technical problem of poor stability of current inhaled acetylcysteine solutions.
[0006] In view of this, the present invention provides an inhaled acetylcysteine solution, which is prepared from acetylcysteine, disodium ethylenediaminetetraacetate, a stabilizer, a pH adjuster, and water for injection. The amount of acetylcysteine added is 10g / 100mL, and the amount of disodium ethylenediaminetetraacetate added is...
[0007] The stabilizer is modified polyvinylpyrrolidone, and the amount of modified polyvinylpyrrolidone added is 15-45 mg / 100 mL. The amount of pH adjuster added is to control the pH value of the acetylcysteine solution to 6.5-6.9, and the balance is water for injection.
[0008] Optionally, the modified polyvinylpyrrolidone is prepared by modifying polyvinylpyrrolidone with hydroxytyrosol.
[0009] Optionally, the stabilizer is prepared using the following method:
[0010] Polyvinylpyrrolidone was placed in water, ultrasonically dispersed, and mixed evenly to obtain mixture A;
[0011] Hydroxytyrosol was added to water and mixed thoroughly to obtain mixture B;
[0012] Add mixture A to mixture B, add catalyst, mix well, heat to increase temperature, react, filter after reaction, collect filtrate, concentrate to precipitate crystals, dry to obtain stabilizer.
[0013] Furthermore, the stabilizer is prepared using the following method:
[0014] Polyvinylpyrrolidone was placed in water, ultrasonically dispersed, and mixed evenly to obtain mixture A;
[0015] Hydroxytyrosol was added to water and mixed thoroughly to obtain mixture B;
[0016] Add mixture A to mixture B, add catalyst, mix well, heat to 30-50℃, react for 20-40 minutes. After the reaction is complete, filter to remove catalyst, collect liquid, concentrate and crystallize, filter, and dry to obtain stabilizer.
[0017] The amount of water added per 1g of polyvinylpyrrolidone is 20-30mL, the amount of water added per 1g of hydroxytyrosol is 15-25mL, the weight ratio of polyvinylpyrrolidone to catalyst is 1:(0.1-0.3), and the catalyst is zinc oxide.
[0018] Optionally, the weight ratio of polyvinylpyrrolidone and hydroxytyrosol is 1:(0.6-0.9).
[0019] Optionally, the polyvinylpyrrolidone is further pretreated by the following method before use: polyvinylpyrrolidone is placed in water, mixed evenly, filtered through an ion exchange resin, the filtrate is collected, concentrated and crystallized to obtain pretreated polyvinylpyrrolidone.
[0020] Furthermore, the polyvinylpyrrolidone is pretreated by the following method before use: polyvinylpyrrolidone is placed in water, mixed evenly, filtered through ion exchange resin, the filtrate is collected, concentrated and crystallized to obtain pretreated polyvinylpyrrolidone.
[0021] The amount of water added to each 1g of polyvinylpyrrolidone is 20-30mL, and the ion exchange resin is a macroporous adsorption resin.
[0022] Optionally, the pH adjuster is any one of sodium hydroxide, sodium carbonate, and potassium hydroxide.
[0023] A method for preparing an inhaled acetylcysteine solution includes the following steps:
[0024] S1: Add disodium ethylenediaminetetraacetate and the stabilizer to a portion of water for injection and mix thoroughly.
[0025] Heating to a higher temperature yields the first mixture;
[0026] S2: Add acetylcysteine to the first mixture, mix well, adjust the pH to 6.5-6.9 with a pH adjuster, then add the remaining water for injection, mix well, and obtain the second mixture;
[0027] S3: The second mixture is filtered through a polyethersulfone filter, then filled and sterilized to obtain a cysteine solution for inhalation.
[0028] Further, S1: Disodium ethylenediaminetetraacetate and the stabilizer are placed in a portion of water for injection, mixed evenly, and heated to 20-40℃ to obtain the first mixture;
[0029] S2: Add acetylcysteine to the first mixture, mix well, adjust the pH to 6.5-6.9 with a pH adjuster, then add the remaining water for injection to make up to 100 mL, mix well, and obtain the second mixture;
[0030] S3: The second mixture is filtered through a polyethersulfone filter, then filled and sterilized to obtain a cysteine solution for inhalation.
[0031] Optionally, nitrogen purging protection is provided throughout steps S1, S2, and S3.
[0032] As can be seen from the above technical solutions, the embodiments of the present invention have the following advantages:
[0033] 1. This application uses acetylcysteine, disodium ethylenediaminetetraacetate (EDTA), a stabilizer, a pH adjuster, and water for injection as raw materials for an inhaled acetylcysteine solution. Acetylcysteine is the main component. Disodium EDTA stabilizes the active ingredient of acetylcysteine, preventing unnecessary chemical reactions and acting as a chelating agent to protect acetylcysteine from interference by metal ions. The pH adjuster is used to adjust the pH value of the solution, and water for injection is used as a solvent. The stabilizer is modified polyvinylpyrrolidone, which is non-toxic and will not irritate or toxicize the patient's respiratory tract, thus ensuring the safety of the inhaled acetylcysteine solution. It also has good chemical stability and antioxidant properties, is not prone to chemical reactions with other components, and further improves the stability of the inhaled acetylcysteine solution.
[0034] 2. This application uses hydroxytyrosol to modify polyvinylpyrrolidone. Hydroxytyrosol is an antioxidant compound that can scavenge free radicals and prevent oxidation reactions. It can also introduce functional groups such as hydroxyl groups onto polyvinylpyrrolidone, thereby further improving the antioxidant properties of polyvinylpyrrolidone, thereby improving the antioxidant properties of inhaled acetylcysteine, reducing dissolved oxygen content, and thus improving the stability of inhaled acetylcysteine solution. Detailed Implementation
[0035] To enable those skilled in the art to better understand the present invention, the technical solutions in the embodiments of the present invention are clearly and completely described below. Obviously, the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention. Unless otherwise specified, all raw materials, reagents, instruments, and equipment used in the present invention can be purchased on the market or prepared by existing methods.
[0036] The pH adjuster is sodium hydroxide; the polyvinylpyrrolidone is K30.
[0037] Preparation Example
[0038] Preparation Example 1
[0039] A stabilizer prepared by the following method:
[0040] 2 kg of polyvinylpyrrolidone was placed in 50 L of water, ultrasonically dispersed, and mixed evenly to obtain mixture A;
[0041] 1.2 kg of hydroxytyrosol was placed in water and mixed evenly to obtain mixture B; wherein, the amount of water added to each 1 g of hydroxytyrosol was 20 mL.
[0042] Add mixture A to mixture B, add 0.4 kg of zinc oxide, mix well, heat to 40°C, react for 30 min, after the reaction is complete, first centrifuge to remove the catalyst, collect the filtrate, then concentrate and crystallize, filter, dry to obtain the stabilizer.
[0043] Preparation Example 2
[0044] A stabilizer, which differs from Preparation Example 1 in that the amount of hydroxytyrosol added is different; in Preparation Example 2, the amount of hydroxytyrosol added is 1.5 kg.
[0045] Preparation Example 3
[0046] A stabilizer, which differs from Preparation Example 1 in that the amount of hydroxytyrosol added is different; in Preparation Example 3, the amount of hydroxytyrosol added is 1.8 kg.
[0047] Preparation Example 4
[0048] A stabilizer, which differs from Preparation Example 1 in that the amount of hydroxytyrosol added is different; in Preparation Example 4, the amount of hydroxytyrosol added is 0.1 kg.
[0049] Preparation Example 5
[0050] A stabilizer, which differs from Preparation Example 1 in that the amount of hydroxytyrosol added is different; in Preparation Example 5, the amount of hydroxytyrosol added is 5 kg.
[0051] Example
[0052] Example 1
[0053] An inhaled acetylcysteine solution, the proportions of which are shown in Table 1.
[0054] A method for preparing an inhaled acetylcysteine solution includes the following steps:
[0055] S1: Under nitrogen protection throughout the process, disodium ethylenediaminetetraacetate and the stabilizer prepared in Preparation Example 1 were placed into a portion of water for injection, mixed evenly, and heated to 30°C to obtain the first mixture.
[0056] S2: Under nitrogen protection throughout the process, add acetylcysteine to the first mixture, mix well, adjust the pH value to 6.5 with pH adjuster, then add the remaining water for injection to make up to 100mL, mix well, and obtain the second mixture;
[0057] S3: Under full nitrogen protection, the second mixture is filtered through a polyethersulfone filter, then filled and sterilized to obtain an inhalation cysteine solution.
[0058] Examples 2-5
[0059] An inhaled acetylcysteine solution differs from Example 1 in that the raw material ratios are different. The raw material ratios for Examples 2-5 are shown in Table 1.
[0060] Table 1 Weight of each raw material
[0061] raw material Example 1 Example 2 Example 3 Example 4 Example 5 Acetylcysteine (g / 100mL) 10 10 10 10 10 Disodium EDTA (mg / 100mL) 100 100 100 120 150 Stabilizer (mg / 100mL) 15 30 45 30 30 Water for Injection margin margin margin margin margin
[0062] Example 6
[0063] An inhaled acetylcysteine solution, which differs from Example 4 in that the pH value in Example 6 is adjusted to 6.7 using a pH adjuster.
[0064] Example 7
[0065] An inhaled acetylcysteine solution, which differs from Example 4 in that the pH value in Example 7 was adjusted to 6.9 using a pH adjuster.
[0066] Examples 8-11
[0067] An inhaled acetylcysteine solution differs from Example 6 in that the stabilizer is from a different source; the stabilizers in Examples 8-11 were prepared using Preparation Examples 2-5, respectively.
[0068] Example 12
[0069] An inhaled acetylcysteine solution differs from Example 8 in that the polyvinylpyrrolidone is pretreated by the following method before use: polyvinylpyrrolidone is placed in water, mixed evenly, filtered through macroporous adsorption resin, the filtrate is collected, concentrated and crystallized to obtain pretreated polyvinylpyrrolidone; wherein, the amount of water added to each 1g of polyvinylpyrrolidone is 25mL.
[0070] Comparative Example
[0071] Comparative Example 1
[0072] An inhaled acetylcysteine solution, which differs from Example 1 in that no stabilizer is added.
[0073] Comparative Example 2
[0074] An inhaled acetylcysteine solution, which differs from Example 1 in that the stabilizer is replaced in equal amounts with polyvinylpyrrolidone.
[0075] Performance testing
[0076] The following performance tests were performed on the inhaled acetylcysteine solutions from Examples 1-12 and Comparative Examples 1-2:
[0077] Residual oxygen content: The residual oxygen content of the inhaled acetylcysteine solution was determined, and the results are shown in Table 2.
[0078] Dissolved oxygen content: The dissolved oxygen content of the inhaled acetylcysteine solution was measured, and the results are shown in Table 2.
[0079] Stability: The acetylcysteine solution for inhalation was placed under accelerated conditions of 40℃ and RH 75% for 12 months, and the contents of three impurities, L-cysteine, N,N-diacetyl-L-cysteine and N,S-diacetyl-L-cysteine, were tested. The test results are shown in Table 3.
[0080] Table 2 Detection Results
[0081]
[0082]
[0083] Table 3 Detection Results
[0084]
[0085] As can be seen from Tables 2 and 3, the acetylcysteine solution for inhalation of this application effectively reduces residual oxygen and dissolved oxygen through the synergistic effect between the raw materials, and also improves stability.
[0086] Combining Example 1 and Comparative Examples 1-2, it can be seen that the residual oxygen content (0.35%), dissolved oxygen content (1900 ppb), and impurity content in Example 1 are all better than those in Comparative Examples 1-2. This indicates that using hydroxytyrosol to modify polyvinylpyrrolidone (PVP) is more suitable as a stabilizer. Introducing functional groups such as hydroxyl groups onto PPV can further improve the antioxidant properties of PPV, thereby improving the antioxidant properties of inhaled acetylcysteine, reducing dissolved oxygen content, and improving the stability of the inhaled acetylcysteine solution.
[0087] As can be seen from Examples 1-3, the residual oxygen content (0.33%), dissolved oxygen content (1700 ppb), and impurity content in Example 2 are all superior to those in other examples. This indicates that the amount of stabilizer added in Example 2 is more appropriate. If the amount of stabilizer added is too small, it will not play a better role and will not be able to improve the stability of the inhaled acetylcysteine solution. If the amount of stabilizer added is too large, it will easily disrupt the equilibrium of the solution, leading to a decrease in the stability of the solution and also easily introducing more impurities, which will damage the stability of the solution.
[0088] As can be seen from Examples 2 and 4-7, the residual oxygen and dissolved oxygen in Example 4 are better than those in other examples, indicating that the amount of disodium ethylenediaminetetraacetate added in Example 4 is more suitable, and the pH value in Example 6 is more suitable, which can better improve the stability of the acetylcysteine solution for inhalation.
[0089] As can be seen from Examples 6 and 8-11, the residual oxygen content, dissolved oxygen content, and impurity content in Example 8 are all better than those in other examples, which indicates that the stabilizer prepared by Preparation Example 2 is more suitable. Furthermore, the amount of hydroxytyrosol added in the stabilizer of Preparation Example 2 is more appropriate. If the amount of hydroxytyrosol added is too small, it will not play a better modifying role, while if the amount of hydroxytyrosol added is too large, it will reduce the effect of the stabilizer and affect its function, thereby affecting the stability of the inhaled acetylcysteine solution.
[0090] As can be seen from Examples 8 and 12, the residual oxygen content, dissolved oxygen content, and impurity content in Example 12 are all better than those in Example 8, which indicates that pretreatment of polyvinylpyrrolidone before use is more appropriate, enabling it to exert a better effect and improve the stability of the acetylcysteine solution for inhalation.
[0091] The above-described embodiments are only used to illustrate the technical solutions of the present invention, and are not intended to limit it. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some of the technical features. Such modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the spirit and scope of the technical solutions of the embodiments of the present invention.
Claims
1. An acetylcysteine solution for inhalation, characterized in that: It is prepared from acetylcysteine, disodium ethylenediaminetetraacetate, stabilizer, pH adjuster, and water for injection. The amount of acetylcysteine added is 10g / 100mL, the amount of disodium ethylenediaminetetraacetate added is 100-150mg / 100mL, the stabilizer is modified polyvinylpyrrolidone, and the amount of modified polyvinylpyrrolidone added is 15-45mg / 100mL. The amount of pH adjuster added is to control the pH value of the acetylcysteine solution to 6.5-6.9, and the balance is water for injection.
2. The acetylcysteine solution for inhalation according to claim 1, characterized in that: The modified polyvinylpyrrolidone was prepared by modifying polyvinylpyrrolidone with hydroxytyrosol.
3. The acetylcysteine solution for inhalation according to claim 2, characterized in that: The stabilizer is prepared using the following method: Polyvinylpyrrolidone was placed in water, ultrasonically dispersed, and mixed evenly to obtain mixture A; Hydroxytyrosol was added to water and mixed thoroughly to obtain mixture B; Add mixture A to mixture B, add catalyst, mix well, heat to increase temperature, react, filter after reaction, collect filtrate, concentrate to precipitate crystals, dry to obtain stabilizer.
4. The acetylcysteine solution for inhalation according to claim 2, characterized in that: The weight ratio of polyvinylpyrrolidone and hydroxytyrosol is 1:(0.6-0.9).
5. The acetylcysteine solution for inhalation according to claim 2, characterized in that: Before use, the polyvinylpyrrolidone is pretreated by the following method: polyvinylpyrrolidone is placed in water, mixed evenly, filtered through an ion exchange resin, the filtrate is collected, concentrated and crystallized to obtain pretreated polyvinylpyrrolidone.
6. The acetylcysteine solution for inhalation according to claim 1, characterized in that: The pH adjuster is any one of sodium hydroxide, sodium carbonate, and potassium hydroxide.
7. A method for preparing an inhaled acetylcysteine solution as described in claims 1-6, characterized in that: Includes the following steps: S1: Disodium ethylenediaminetetraacetate and stabilizer are placed in a portion of water for injection, mixed evenly, and heated to obtain the first mixture; S2: Add acetylcysteine to the first mixture, mix well, adjust the pH to 6.5-6.9 with a pH adjuster, then add the remaining water for injection, mix well, and obtain the second mixture; S3: The second mixture is filtered through a polyethersulfone filter, then filled and sterilized to obtain a cysteine solution for inhalation.
8. The method for preparing an inhaled acetylcysteine solution according to claim 7, characterized in that: Nitrogen purging protection is applied throughout steps S1, S2, and S3.