A high-stability low-irritation fudosteine aerosol inhalation preparation without EDTA and use thereof

Abstract

The present application provides a high-stability low-irritation fudosteine aerosol inhalation preparation without EDTA, which is composed of fudosteine, a pH regulator and water, the concentration of fudosteine in the preparation is 20-140 mg / mL, the pH is 3.5-4.0, and the pH regulator is an organic carboxylic acid. In addition, the present application also provides the use of the above-mentioned fudosteine aerosol inhalation preparation in the preparation of respiratory tract mucus dissolving agents. By adjusting the type of pH regulator, the fudosteine aerosol inhalation solution preparation not only effectively reduces the adverse reactions caused by the auxiliary material components, improves the drug safety, but also ensures that the fudosteine aerosol inhalation solution preparation has good preparation stability.

Description

Technical Field

[0001] This invention relates to the field of nebulized inhalation formulation technology, and in particular to a highly stable and low-irritant fudostein nebulized inhalation formulation that does not contain EDTA and its application. Background Technology

[0002] Fudosteine ​​is a novel respiratory mucolytic that effectively inhibits the excessive formation of goblet cells that secrete viscous mucus in the respiratory tract, thereby inhibiting the production of highly viscous fucoidin, reducing the viscosity of sputum, and making it easier to cough up. In addition, fudosteine ​​can enhance the secretory function of serous trachea, thus inhibiting tracheal inflammation.

[0003] Currently marketed fodosteine-related drugs are all oral dosage forms (including oral solutions, tablets, capsules, and granules). Common adverse reactions include rash, nausea, indigestion and itching, decreased sensation, abdominal discomfort, and diarrhea, because fodosteine ​​damages the gastric mucosal barrier. To reduce the adverse reactions of fodosteine, existing technology has improved it into a nebulized inhalation solution formulation (see Chinese Patent Publication No. CN109925300A), allowing the drug to be administered locally through the lungs, effectively avoiding damage to the gastric mucosal barrier. Due to the manufacturing process of fodosteine, trace amounts of metal ions are often present in its solution. The presence of metal ions catalyzes oxidation reactions, leading to the oxidative decomposition of fodosteine, and also poses safety risks and side effects. To address these issues, CN109925300A adds EDTA as a metal ion chelating agent (antioxidant), thereby reducing the metal ion content in the product formulation and improving its stability. However, EDTA has a certain degree of mucosal irritation, and there is a risk of inducing adverse reactions such as coughing and asthma when inhaling nebulized inhalation solutions containing EDTA. Therefore, based on prior patents, how to reduce the content of free metal ions while simultaneously reducing the irritation caused by metal ion chelating agents has become an urgent technical problem to be solved.

[0004] On the other hand, fodosteine ​​solution formulations are highly sensitive to pH; at pH levels above 5.0, unknown impurities will be generated, causing the solution to turn yellow. Therefore, pH adjustment is necessary during the preparation of fodosteine ​​formulations. It is known that formulations prepared using inorganic acids as pH adjusters have high stability. However, when using inorganic acids as pH adjusters in nebulized inhalers, because the drug acts directly on the lungs, small amounts of inorganic acid ions in the formulation may come into direct contact with lung cells, potentially leading to adverse reactions with long-term use. Summary of the Invention

[0005] To address the aforementioned technical problems, this invention provides a highly stable and low-irritant fodosteine ​​nebulized inhalation formulation and its application, which combines good formulation stability and low irritation, effectively improving patient safety.

[0006] The first objective of this invention is to provide a highly stable and low-irritant fodosteine ​​nebulized inhalation formulation, the formulation comprising fodosteine, a pH adjuster and water, wherein the concentration of fodosteine ​​in the formulation is 20-140 mg / mL and the pH is 3.5-4.0, wherein the pH adjuster is an organic carboxylic acid.

[0007] Organic carboxylic acids possess a certain metal ion chelating effect. Using organic carboxylic acids as pH adjusters eliminates the need to add metal ion chelating agents such as EDTA to the formulation, achieving good stability. This invention, by adjusting the type of pH adjuster, not only effectively reduces adverse reactions caused by excipients and improves medication safety, but also ensures good formulation stability of the fudostein nebulized inhalation solution.

[0008] Preferably, the organic carboxylic acid is a dicarboxylic acid.

[0009] Dicarboxylic acids have a pH range of approximately 3.5-4.5, making them more suitable as pH adjusters for fodostatin physicochemical inhalation solution formulations.

[0010] Preferably, the dicarboxylic acid is tartaric acid.

[0011] This invention has found that fodosteine ​​is incompatible with most organic carboxylic acids (such as malic acid, citric acid, lactic acid, glacial acetic acid, etc.) and easily produces unknown impurities that cause the solution to turn yellow and discolor. It only has excellent compatibility with tartaric acid. The stability of the preparation obtained is similar to that of the preparation obtained using hydrochloric acid, with no significant difference.

[0012] Preferably, the pH of the fodosteine ​​nebulized inhalation formulation is 3.7 to 3.8.

[0013] More preferably, the pH of the fodosteine ​​nebulized inhalation formulation is 3.7.

[0014] Preferably, the concentration of fodosteine ​​in the formulation is 80 mg / mL.

[0015] Preferably, the administration site of the formulation includes one or more of the following: nose, pharynx, trachea, esophagus, and main bronchus.

[0016] A second objective of this invention is to provide the application of the above-mentioned fudostein nebulized inhalation formulation in the preparation of respiratory mucolytics.

[0017] Preferably, the above-mentioned fudostein nebulized inhalation formulation of the present invention is used for expectorant treatment of one or more of the following: bronchial asthma, chronic wheezing bronchitis, bronchiectasis, pulmonary tuberculosis, pneumoconiosis, chronic obstructive emphysema, atypical mycobacterial disease, pneumonia, and diffuse bronchitis.

[0018] The present invention has the following beneficial effects:

[0019] (1) The fudostein nebulized inhalation preparation disclosed in this invention is composed of fudostein, organic carboxylic acid and water. Compared with the prior art, this invention successfully reduces the irritation of the fudostein nebulized inhalation preparation to the human body and achieves the effect of reducing adverse reactions caused by excipients and improving medication safety.

[0020] (2) In this invention, tartaric acid is specifically selected as a pH adjuster, which can not only reduce adverse reactions caused by excipients and improve the safety of medication, but also improve the stability of solution preparations.

[0021] (3) The fudostem nebulized inhalation formulation of the present invention has the best stability at a pH of 3.7. Attached Figure Description

[0022] Figure 1 The colors of samples from Example 1 at different pH values ​​after being placed at 60°C for 10 days;

[0023] Figure 2 This is a schematic diagram comparing related substances in the screening test of influencing factors for pH adjusters (citric acid, buffer pair). The chromatographic peaks from top to bottom are: buffer pair -0 days, citric acid -0 days, buffer pair -60℃ 10 days, citric acid 60℃ 10 days, buffer pair -60℃ 30 days, citric acid -60℃ 30 days, buffer pair empty -60℃ 15 days, and citric acid empty -60℃ 15 days.

[0024] Figure 3 A comparative diagram of relevant substances in the screening experiment for pH adjusters (malic acid, glacial acetic acid, lactic acid) to identify influencing factors.

[0025] Figure 4 This is the HPLC chromatogram of a sample prepared using hydrochloric acid as a pH adjuster.

[0026] Figure 5 This is an HPLC chromatogram of a sample prepared using tartaric acid as a pH adjuster.

[0027] Figure 6 This is the HPLC chromatogram of the sample prepared using citric acid as a pH adjuster;

[0028] Figure 7 This is an HPLC chromatogram of a sample prepared using citric acid / sodium citrate as a pH adjuster. Detailed Implementation

[0029] To further illustrate the present invention, the following detailed description of the folic acid nebulized inhalation formulation and its application, in conjunction with embodiments, is provided.

[0030] Example 1: pH Screening Experiment

[0031] Take 0.8 g of fodosteine ​​and 10 mL of water for injection. Adjust the pH to 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 6.0, and 7.0 with hydrochloric acid or sodium hydroxide. Determine the impurities. The results are shown in Table 1 and... Figure 1 As shown.

[0032] Table 1 Results of samples at different pH levels

[0033]

[0034] From Table 1 and Figure 1 It can be seen that the fodosteine ​​solution is almost colorless when the pH is 2.5-4.0, proving that the impurity content is low and the raw material has high stability under these pH conditions. The stability is best when the pH is 3.5-4.0.

[0035] Example 2: Screening Experiment of Organic pH Adjusters

[0036] Take 0.8 g of fodosteine ​​and 10 mL of water for injection, add hydrochloric acid (control) and organic carboxylic acid pH adjusters (tartaric acid, citric acid, citric acid / sodium citrate buffer pair, lactic acid, glacial acetic acid, and malic acid in that order), adjust the pH to 3.7, and obtain fodosteine ​​nebulized inhalation formulations with different pH adjusters. The impurities were determined, and the results are shown in Table 2. Figures 2 to 7 As shown.

[0037] Table 2. Results of Experiments on Factors Affecting the Screening of pH Adjusters

[0038]

[0039]

[0040] from Figure 2 and Figure 3 It can be seen that when citric acid, citric acid and sodium citrate buffer, malic acid, lactic acid and glacial acetic acid are used as pH adjusters, and the system has large impurities when the related substances are checked on day 0, it indicates that the above acids have poor compatibility with fodosteine ​​and react with the amino groups in the fodosteine ​​structure to generate impurities. Accelerated tests show that impurities are still being generated.

[0041] The inventors were surprised to find that when tartaric acid was used as a pH adjuster, the impurity content in the system was extremely low, with no significant difference compared to when hydrochloric acid was used as a pH adjuster. This indicates that tartaric acid and fodosteine ​​have excellent compatibility. Using tartaric acid as a pH adjuster can ensure the stability and uniformity of fodosteine ​​nebulized inhalation formulation while adjusting the system to the stable pH range of fodosteine.

[0042] Example 3 Antioxidant Study

[0043] Sample 1 was prepared from the following formulation: fodosteine ​​(80 mg / mL), tartaric acid (appropriate amount), sodium hydroxide (appropriate amount added if necessary), and water for injection. The pH was adjusted to 3.7 using tartaric acid and sodium hydroxide.

[0044] Sample 2 was prepared from the following formulation: fudostein (80 mg / mL), EDTA (0.5 mg / mL), hydrochloric acid (appropriate amount), sodium hydroxide (appropriate amount added if necessary), and water for injection. The pH was adjusted to 3.7 using hydrochloric acid and sodium hydroxide.

[0045] The impurities and formulation stability of Sample 1 and Sample 2 were determined respectively, and the results are shown in Tables 3 and 4.

[0046] Table 3 Stability of Sample 1

[0047]

[0048]

[0049] Table 4 Stability of Sample 2

[0050]

[0051] As can be seen from Tables 3 and 4, the stability of Sample 1 and Sample 2 is almost identical. This indicates that tartaric acid has the function of chelating metal ions. Using tartaric acid can avoid the use of irritating EDTA and reduce the amount of irritating inorganic acids, thereby reducing the adverse reactions caused by excipients.

[0052] The above description of the embodiments is only for the purpose of helping to understand the method and core ideas of the present invention. It should be noted that those skilled in the art can make several improvements and modifications to the present invention without departing from the principles of the present invention, and these improvements and modifications also fall within the protection scope of the claims of the present invention.

Claims

1. A highly stable and low-irritant fudostatin nebulized inhalation formulation without EDTA, characterized in that: The formulation comprises fodosteine, a pH adjuster, and water for injection. The concentration of fodosteine ​​in the formulation is 20-140 mg / mL, and the pH is 3.5-4.

0. The pH adjuster is an organic carboxylic acid. The organic carboxylic acid is tartaric acid.

2. The fodostatin nebulized inhalation formulation according to claim 1, characterized in that, The formulation has a fodosteine ​​concentration of 80 mg / mL and a pH of 3.7-3.

8.

3. The fodostatin nebulized inhalation formulation according to claim 2, characterized in that, The pH of the formulation is 3.

7.

4. The fodostatin nebulized inhalation formulation according to any one of claims 1-3, characterized in that, The administration sites of the formulation include one or more of the following: nose, pharynx, trachea, esophagus, and main bronchus.

5. The use of the fodosteine ​​nebulized inhalation formulation according to any one of claims 1-4 in the preparation of a respiratory mucolytic.

6. The application according to claim 5, characterized in that, The preparation is used for expectorant treatment of one or more of the following: bronchial asthma, chronic wheezing bronchitis, bronchiectasis, pulmonary tuberculosis, pneumoconiosis, chronic obstructive emphysema, atypical mycobacterial disease, pneumonia, and diffuse bronchitis.

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