CN-117442587-B - EDTA-free high-stability low-irritation Fudosteine aerosol inhalation preparation and application thereof

Abstract

The invention provides a high-stability low-irritation Fudosteine aerosol inhalation preparation without EDTA (ethylene diamine tetraacetic acid), which consists of Fudosteine, a pH regulator and water, wherein the concentration of Fudosteine in the preparation is 20-140 mg/mL, and the pH is 3.5-4.0, and the pH regulator is organic carboxylic acid. In addition, the invention also provides application of the fodosteine aerosol inhalation preparation in preparation of respiratory tract mucolytic agents. According to the invention, the types of the pH regulator are regulated, so that the Fudosteine aerosol inhalation solution preparation not only effectively reduces adverse reactions caused by auxiliary material components and improves the medication safety, but also ensures that the Fudosteine aerosol inhalation solution preparation has good preparation stability.

Inventors

• HU JIE
• Wei Huanli
• LI CUI
• GONG LI

Assignees

• 北京盈科瑞创新药物研究有限公司
• 上海凯宝药业股份有限公司

Dates

Publication Date

20260512

Application Date

20220718

Claims (6)

1. 1. The EDTA-free high-stability low-irritation fodosteine aerosol inhalation preparation is characterized by comprising fodosteine, a pH regulator and water for injection, wherein the concentration of the fodosteine in the preparation is 20-140 mg/mL, and the pH is 3.5-4.0, and the pH regulator is organic carboxylic acid; the organic carboxylic acid is tartaric acid.
2. 2. The fodosteine aerosol inhalation formulation according to claim 1, wherein the concentration of fodosteine in the formulation is 80mg/mL and the pH of the formulation is 3.7-3.8.
3. 3. The fodosteine aerosol inhalation formulation according to claim 2, characterized in that the pH of the formulation is 3.7.
4. 4. A fodosteine aerosol inhalation formulation according to any one of claims 1 to 3, wherein the site of administration of the formulation comprises one or more of the nose, throat, trachea, oesophagus and main bronchi.
5. 5. Use of a fodosteine aerosol inhalation formulation according to any one of claims 1 to 4 for the preparation of a respiratory mucolytic agent.
6. 6. The use according to claim 5, wherein the formulation is for the expectorant treatment of one or more of bronchial asthma, chronic asthmatic bronchitis, bronchiectasis, tuberculosis, pneumoconiosis, chronic obstructive emphysema, atypical mycobacteriosis, pneumonia, diffuse bronchitis.

Description

EDTA-free high-stability low-irritation Fudosteine aerosol inhalation preparation and application thereof Technical Field The invention relates to the technical field of aerosol inhalation preparations, in particular to a high-stability low-irritation Fudosteine aerosol inhalation preparation without EDTA and application thereof. Background Fudosteine is a novel respiratory tract mucolytic agent, and can effectively inhibit excessive formation of goblet cells secreting sticky sputum in organs, further inhibit generation of high-viscosity fucoidan, reduce viscosity of the sputum and facilitate expectoration. In addition, fudosteine can also improve the secretion of serous trachea, thereby inhibiting tracheitis. Fudosteine related drugs which are currently marketed are all in oral dosage forms (including oral solutions, tablets, capsules, granules), and common adverse effects include rash, nausea, dyspepsia and itching, hypoesthesia, abdominal discomfort and diarrhea, because Fudosteine has a damaging effect on the gastric mucosal barrier. In order to reduce adverse reactions of Fudosteine, the prior art is improved into an aerosol inhalation solution preparation (see Chinese patent publication No. CN 109925300A), so that the medicine can be locally administrated through the lung, and the damage of Fudosteine to the gastric mucosa barrier is effectively avoided. Due to the fudosteine preparation process, trace amounts of metal ions are often present in the solution. The existence of metal ions catalyzes the oxidation reaction to cause the oxidation decomposition of Fudosteine on the one hand, and causes the problems of safety risk, side effect and the like of the medicament on the other hand. In order to solve the problems, EDTA is added into CN109925300A as a metal ion chelating agent (antioxidant), so that the purposes of reducing the metal ion content in the product preparation and improving the stability of the product preparation are achieved. However, EDTA has a certain mucous membrane irritation, and there is a risk of inducing adverse reactions such as cough and asthma when inhaled into an aerosol inhalation solution preparation containing EDTA. Therefore, on the basis of the prior patent, how to solve the problem of reducing the stimulation caused by the metal ion chelating agent while reducing the content of free metal ions is a technical problem to be solved. On the other hand, fudosteine solution formulations are highly pH sensitive, which will give rise to unknown impurities above pH 5.0, leading to yellowing and discoloration of the solution, thus requiring pH adjustment in the preparation of Fudosteine formulations. It is known that the preparation prepared by using inorganic acid as the pH regulator has higher stability, however, when using inorganic acid as the pH regulator of the aerosol inhalant, a small amount of inorganic acid radical ions in the preparation can be in direct contact with lung cells because the medicine directly acts on the lung, and adverse reactions can be caused after long-term use. Disclosure of Invention In order to solve the technical problems, the invention provides a high-stability low-irritation Fudosteine aerosol inhalation preparation and application thereof, which have good preparation stability and low irritation and can effectively improve the safety of patient medication. The invention provides a high-stability low-irritation fodosteine aerosol inhalation preparation, which consists of fodosteine, a pH regulator and water, wherein the concentration of the fodosteine in the preparation is 20-140 mg/mL, and the pH is 3.5-4.0, and the pH regulator is organic carboxylic acid. The organic carboxylic acid has certain metal ion chelating effect, and after the organic carboxylic acid is used as the pH regulator, the preparation has better stability without adding metal ion chelating agents such as EDTA and the like into the preparation. According to the invention, by adjusting the types of the pH regulator, adverse reactions caused by auxiliary ingredients are effectively reduced, the medication safety is improved, and meanwhile, good preparation stability of the Fudosteine atomized inhalation solution preparation is ensured. Preferably, the organic carboxylic acid is a dibasic organic carboxylic acid. The pH range of the dibasic organic carboxylic acid is about 3.5-4.5, and the dibasic organic carboxylic acid is more suitable for being used as a pH regulator of Fudosteine materialized inhalation solution preparation. Preferably, the dibasic organic carboxylic acid is tartaric acid. According to the invention, researches show that Fudosteine is intolerant to most organic carboxylic acids (such as malic acid, citric acid, lactic acid, glacial acetic acid and the like), unknown impurities are easy to generate to cause yellowing and color change of a solution, and the Fudosteine has excellent compatibility with tartaric acid, so that the stability of the prepared prepa