CN-122005528-A - Fudosteine pharmaceutical composition, preparation method and application thereof

CN122005528ACN 122005528 ACN122005528 ACN 122005528ACN-122005528-A

Abstract

The invention discloses a Fudosteine pharmaceutical composition, a preparation method and application thereof. The invention provides a Fudosteine pharmaceutical composition which comprises a pharmaceutical active ingredient, a pH regulator and water, wherein the concentration of Fudosteine in the composition is 20 mg/ml-200 mg/ml, the pH value is 3.0-6.0, and the pharmaceutical active ingredient is one or more of Fudosteine, pharmaceutically acceptable salts and hydrates thereof. The Fudosteine composition disclosed by the invention has the advantages of good stability, smaller irritation, small effective dose, high curative effect, good patient medication compliance, strong production controllability, no antioxidant and/or surfactant, lower occurrence rate of adverse reaction, better safety and good market prospect.

Inventors

YING SHUHUAN
FU JUN
CHEN BANGYIN
GUO ZHEN
WANG JULONG
QIAN RUI
WANG TINGTING

Assignees

上海云晟研新生物科技股份有限公司

Dates

Publication Date: 20260512
Application Date: 20251111
Priority Date: 20241111

Claims (10)

1. A Fudosteine pharmaceutical composition is characterized by comprising a pharmaceutical active ingredient, a pH regulator and water, wherein the concentration of Fudosteine in the composition is 20 mg/ml-200 mg/ml, the pH value is 3.0-6.0, and the pharmaceutical active ingredient is one or more of Fudosteine, pharmaceutically acceptable salts and hydrates thereof.
2. The pharmaceutical composition of claim 1, wherein the pH adjustor is an inorganic base, an inorganic acid, a buffer system formed by an inorganic acid and an inorganic acid salt, or a buffer system formed by an organic acid or an organic acid and an organic acid salt; preferably, the inorganic acid is selected from one or more of hydrochloric acid, sulfuric acid and phosphoric acid; preferably, the inorganic acid salt is selected from one or more of sodium carbonate, sodium bicarbonate, disodium hydrogen phosphate and sodium dihydrogen phosphate; Preferably, the organic acid is selected from one or more of tartaric acid, lactic acid, citric acid, glacial acetic acid and malic acid; preferably, the organic acid salt is selected from sodium citrate; Preferably, the inorganic base is selected from one or more of sodium hydroxide, potassium hydroxide, sodium bicarbonate and triethylamine; further preferably, the pH adjuster is one or more of hydrochloric acid, sulfuric acid, tartaric acid and sodium hydroxide.
3. The pharmaceutical composition of claim 1, wherein the pH is 3.0 to 3.4, 3.4 to 4.0, or 4.1 to 6.0, such as 3.0, 3.4, 3.5, 3.7, 3.8, 4.0, 4.1, 4.5, 5.0, 5.5, or 6.0; Preferably, when the pH adjuster is selected from inorganic acid or a buffer system formed by inorganic acid and inorganic acid salt (for example, the pH adjuster is hydrochloric acid), the pH value of the Fudosteine pharmaceutical composition is 3.0-5.0; Preferably, when the pH adjuster is selected from inorganic bases (e.g., the pH adjuster is sodium hydroxide), the pH of the fudosteine pharmaceutical composition is greater than 5.0 and no more than 6.0.
4. The pharmaceutical composition of claim 1, wherein the concentration of the pharmaceutically active ingredient is 50mg/ml to 150mg/ml, such as 50mg/ml, 80mg/ml, 100mg/ml or 150mg/ml, and the concentration is the ratio of the mass of the pharmaceutically active ingredient to the volume of the Fudosteine pharmaceutical composition.
5. The pharmaceutical composition of claim 1, wherein the fudosteine pharmaceutical composition does not include one or more of an antioxidant, a surfactant, and a metal chelator; for example, the surfactant is selected from tween, span, stearic acid, sodium dodecyl benzene sulfonate or lecithin; for example, the antioxidant is selected from tertiary butyl hydroquinone, vitamin C or vitamin E; For example, the metal ion chelating agent is ethylenediamine tetraacetic acid.
6. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition comprises Fudosteine, a pH regulator and water, wherein the concentration of the Fudosteine is 20 mg/ml-200 mg/ml, and the pH regulator is selected from inorganic acid or a buffer system formed by inorganic acid and inorganic acid salt (for example, the pH regulator is hydrochloric acid); the pH value of the Fudosteine pharmaceutical composition is 3.0-5.0; the fudosteine pharmaceutical composition does not comprise an antioxidant, a surfactant and a metal chelator; or the Fudosteine pharmaceutical composition comprises Fudosteine, a pH regulator and water, wherein the concentration of the Fudosteine is 20 mg/ml-200 mg/ml, and the pH regulator is selected from inorganic alkali (for example, the pH regulator is sodium hydroxide); The pH value of the Fudosteine medicine composition is more than 5.0 and not more than 6.0; the fudosteine pharmaceutical composition does not comprise an antioxidant, a surfactant and a metal chelator; for example, the fudosteine pharmaceutical composition is any one of the following prescriptions: prescription 1 is Fudosteine 100mg/ml, hydrochloric acid and water for injection, and the pH value is adjusted to 3.7-3.8; Prescription 2, 150mg/ml Fudosteine, hydrochloric acid and water for injection, and adjusting the pH value to 3.7-3.8; Prescription 3 is Fudosteine 200mg/ml, hydrochloric acid and water for injection, and the pH value is adjusted to 3.7-3.8; prescription 4, fudosteine 80mg/ml, hydrochloric acid and water for injection, and adjusting the pH value to 3.7-3.8; prescription 5 is Fudosteine 80mg/ml, hydrochloric acid and water for injection, and the pH value is adjusted to 3.7-3.8; prescription 6 Fudosteine 80mg/ml, hydrochloric acid and water for injection, and adjusting the pH value to 3.0; Prescription 7, fudosteine 80mg/ml, hydrochloric acid and water for injection, and adjusting the pH value to 3.5; Prescription 8 Fudosteine 80mg/ml, hydrochloric acid and water for injection, and adjusting the pH value to 4.0; prescription 9 Fudosteine 80mg/ml, hydrochloric acid and water for injection, and adjusting the pH value to 4.5; Prescription 10, fudosteine 80mg/ml, hydrochloric acid and water for injection, and adjusting the pH value to 5.0; Prescription 11, fudosteine 80mg/ml, sodium hydroxide and water for injection, and adjusting the pH value to 5.5; prescription 12 Fudosteine 80mg/ml, sodium hydroxide and water for injection, and the pH value is adjusted to 6.0.
7. A pharmaceutical formulation comprising the fudosteine pharmaceutical composition of any one of claims 1-6; preferably, the pharmaceutical formulation is an aerosol inhalation formulation; Preferably, the pharmaceutical formulation is a single dose of 1.0ml to 10.0ml, preferably 1.0ml to 5.0ml, more preferably 1.0ml to 2.5ml.
8. The use of a fudosteine pharmaceutical composition according to any one of claims 1-6 for the preparation of a medicament for the treatment and/or prophylaxis of bronchial asthma, chronic asthmatic bronchitis, bronchiectasis, tuberculosis, pneumoconiosis, chronic obstructive emphysema, atypical mycobacteriosis, pneumonia, diffuse bronchitis; Preferably, the fudosteine pharmaceutical composition is administered at the site of one or more of the nose, throat, trachea, esophagus and main bronchi.
9. The preparation process of the Fudosteine pharmaceutical composition according to any one of claims 1-6, which comprises the following steps of mixing the components in the pharmaceutical composition; preferably, the preparation method further comprises the steps of carrying out sterilization and filtration treatment on the mixed components, wherein the sterilization and filtration is preferably carried out by adopting a polyethersulfone filter membrane; Preferably, the preparation method further comprises the step of further packaging the pharmaceutical composition in a container, wherein the container is an ampoule or a penicillin bottle, the ampoule or the penicillin bottle is made of any one of glass, polypropylene plastic, polyethylene plastic and polyester, and is preferably a glass ampoule or a low-density polyethylene ampoule, and the container is protected by nitrogen; further preferably, the pharmaceutical composition is preferably packaged in a container, then is protected by nitrogen and is encapsulated, and preferably the dissolved oxygen after encapsulation is less than or equal to 1.0mg/L.
10. An aerosolization assembly comprising an aerosolization inhalation device and the fudosteine pharmaceutical composition of any one of claims 1-6; The aerosol inhalation device is selected from a compression type aerosol inhalation device or a screen type aerosol inhalation device; for example, the atomization parameters include a flow rate of 5-30L/min, an atomization time of 30-120s, a pre-cooling time of 60-180min, and/or a pre-cooling temperature of 2-8deg.C; For example, the result of the aerodynamic particle size distribution of the fodosteine pharmaceutical composition is that the proportion of fine particles (FPF%) is not less than 40% or 40% -70%, the amount of Fine Particles (FPD) is not less than 10mg or 10 mg-25 mg, and/or the mass median aerodynamic particle size distribution (MMAD) is not more than 10 μm or 1 μm-10 μm, 3 μm-6 μm; For example, the delivery rate is not lower than 5mg/min or 5mg/min to 12mg/min, the total delivery amount is not lower than 20mg or 20 to 110mg, 20 to 70mg, and the residual amount is not higher than 150mg or 90 to 150mg.

Description

Fudosteine pharmaceutical composition, preparation method and application thereof The application claims priority rights of prior application entitled "Fudosteine pharmaceutical composition, preparation method and application" filed by 11 months of 2024 to China State intellectual property agency on 11 days, patent application number 2024115967995. The entire contents of said prior application are incorporated by reference into the present application. Technical Field The invention relates to a Fudosteine pharmaceutical composition, a preparation method 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 (Fudosteine), the chemical name of which is (-) - (R) -2-amino-3- (3-hydroxypropyl thio) propionic acid, controllable phlegm, phlegm resolving, thin phlegm resolving, phlegm expelling, anti-inflammatory and antioxidant, and six effects are combined into a whole, is a novel powerful phlegm eliminating drug, is marketed in Japan for the first time in 2001, and is a cysteine derivative which has a basic skeleton of setan (steine) and is developed by Mitsubishi pharmaceutical Co Ltd and S.S. pharmaceutical Co. The Chinese medicinal composition has multiple pharmacological effects on chronic respiratory diseases, has the advantages of inhibiting the proliferation of airway epithelial cells, normalizing the ratio of trehalose to sialic acid in phlegm, recovering the state of ciliated transported airway secretion, resisting inflammation, along with strong medicinal effect, small side effect, wide application range, large market potential and the like, and is suitable for eliminating phlegm of the chronic respiratory diseases such as bronchial asthma, chronic bronchitis, bronchiectasis, phthisis, pneumoconiosis, emphysema, atypical mycobacterium infection, diffuse bronchiolitis and the like. 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 medicine 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. Chinese patent document CN117442587A, CN115068450B discloses a fodosteine aerosol inhalation solution composition, which does not contain metal ion chelating agent, but has a narrower pH range, is more strict in production controllability, and is easy to choke and cough in the inhalation process. Therefore, the search for a solution to reduce the content of free metal ions while reducing the irritation and production operability caused by metal ion chelating agents is a technical problem to be solved. Disclosure of Invention The invention solves the technical problems of high content of free metal ions, large side effect, poor feasibility of production operation and the like in a Fudosteine aerosol inhalation solution composition in the prior art, and provides a Fudosteine pharmaceutical composition, a preparation method and application thereof. The Fudosteine composition disclosed by the invention has the advantages of good stability, smaller irritation, small effective dose, high curative effect, good patient medication compliance, strong production controllability, no antioxidant and/or surfactant, lower occurrence rate of adverse reaction, better safety and good market prospect. The invention provides a Fudosteine pharmaceutical composition which comprises a pharmaceutical active ingredient, a pH regulator and water, wh