WO2022166724A1 - Fudosteine solution preparation for inhalation, preparation method therefor and use thereof - Google Patents

Abstract

A fudosteine solution preparation for inhalation, a preparation method therefor and the use thereof, which belong to the field of pharmaceutical preparations. The concentration of fudosteine in the solution preparation for inhalation is 25-300 mg/mL. The fudosteine solution preparation for inhalation is an aerosol inhalation solution, which contains fudosteine with a specific concentration. The preparation has a good aerosol forming property, and can be effectively deposited at the drug effect site of the respiratory tract, so as to achieve the optimal drug concentration, and overcome the problem of the aerosol of the fudosteine aerosol inhalation preparation in the prior art not being able to achieve the optimal inhalation treatment effect, such that the drug efficacy of the preparation is better. In addition, compared with oral administration, the preparation has a higher drug distribution in the respiratory system at the same dose, a better phlegm-removing effect, and a low system exposure and better safety. The fudosteine solution preparation for inhalation has a better application prospect.

Description

A kind of solution preparation of fodosteine for inhalation and preparation method and use thereof

priority information

This application claims the priority and rights and interests of the patent application No. 202110156464.1 filed with the State Intellectual Property Office of China on February 4, 2021, which is hereby incorporated by reference in its entirety.

technical field

The present disclosure relates to the field of pharmaceutical preparations, in particular to a solution preparation for inhalation of fodosteine and a preparation method and application thereof.

Background technique

Respiratory system disease is one of the diseases people are familiar with. Respiratory system disease accounts for about 1/4 of medical patients, which brings mental and physical pain to patients. In my country's population statistics, respiratory system disease is the second cause of death. , but there are not many clinically available drugs, and the onset of action is slow.

Sputum is a common symptom of respiratory diseases, and the increase of sputum can stimulate the mucous membrane of the respiratory tract and cause cough. When the sputum blocks the bronchioles, it can not only cause asthma, but also cause secondary infection, further damage the respiratory tract, aggravate cough, expectoration and asthma, and in severe cases can suppress breathing or suffocate to death. Excessive secretion of mucus can cause dysfunction of mucociliary clearance and damage to local defense function, resulting in uncontrollable infection and aggravation of airway obstruction, which directly affects the progression of the disease and the subjective feelings of patients. Therefore, the use of expectorants to promote the rapid efflux of airway secretions is a An important adjunct to the treatment of airway inflammation.

Expectorants can make sputum thinner and less viscous and easier to expectorate, or can accelerate the mucociliary movement of the respiratory tract and improve the function of sputum transport. Expectorants can promote the excretion of phlegm in the lumen of the respiratory tract, reduce the irritation to the respiratory mucosa, indirectly play the role of antitussive and asthma, and also help to control secondary infections.

Fodosteine, chemically named (-)-(R)-2-amino-3-(3-hydroxypropylthio)propionic acid, is a new type of expectorant, developed by Japan's Mitsubishi Pharmaceutical Co., Ltd. and S.S Pharmaceutical Co., Ltd. has developed a class of cysteine derivatives with expectorant effects with a steine basic skeleton. It has multiple pharmacological effects on chronic respiratory diseases: inhibits the proliferation of respiratory epithelial cells, normalizes the ratio of trehalose/sialic acid in sputum, restores the state of cilia transporting airway secretions, and has anti-inflammatory effects; has strong medicinal effects , small side effects, wide indications, large market potential and other advantages; suitable for bronchial asthma, chronic bronchitis, bronchiectasis, tuberculosis, pneumoconiosis, emphysema, atypical mycobacterial infection, diffuse bronchiolitis and other chronic diseases Expectorant for respiratory diseases.

The oral preparation of currently listed fodosteine contains tablet, capsule, granule, although oral solid preparation is convenient to take, but the dosage is large, the onset is slow, the whole body plays a role, and the side effect is large. Inhalation is a new dosage form of medicine, which can directly act on the patient site, increase the concentration of administration in the respiratory tract or lung, and has a fast onset of action. It improves the bioavailability of drugs, reduces the distribution of drugs in other tissues, and reduces side effects.

Patent CN108078964A discloses a kind of dry powder inhalation of fodosteine, the dosage of this inhalant is obviously lower than that of oral solid preparation, and the therapeutic effect is high and the onset is fast; Certain skills, inconvenient patient administration, uneven inhalation dose for multiple administrations, and expensive production of special equipment. Patent CN109925300A discloses a solution formulation of fodosteine for atomization inhalation and a preparation method thereof. Compared with oral formulations, the solution formulation of fodosteine for atomization inhalation has high efficiency, low toxicity, good stability and high safety. However, the aerosol generation characteristics of the inhalant are not clear, and the aerosol drug concentration and particle size distribution have not been studied, and the single dose of its preparation cannot achieve the best inhalation therapeutic effect. The pH adjuster and the like make the prescription too complicated, the drug load of the preparation is low, and the safety hazard is relatively high.

It can be seen that the solid particles inhaled by the dry powder of fodosteine inhalation preparations in the prior art are irritating to the respiratory tract, have certain skill in use, are inconvenient for patients to administer, and the inhaled dose of multiple administrations is uneven, and the production cost of special equipment. It is expensive, and the therapeutic effect of the aerosol inhalation preparation needs to be improved. Therefore, a new fodosteine inhalation preparation is urgently needed.

SUMMARY OF THE INVENTION

The purpose of the present disclosure is to provide a solution formulation of fodosteine for inhalation and its preparation method and use. The solution preparation for inhalation contains fodosteine at a specific concentration, has excellent aerosol generation properties, can be effectively deposited on the drug effect site of the respiratory tract, and achieves an excellent drug concentration.

A first aspect of the present disclosure provides a solution formulation of fodosteine for inhalation. According to an embodiment of the present disclosure, the concentration of fodosteine in the inhalation solution formulation is 25-300 mg/ml.

The solution preparation for inhalation of fodosteine provided by the present disclosure contains fodosteine at a specific concentration, has excellent aerosol generation properties, can be effectively deposited in the drug effect site of the respiratory tract, achieves an excellent drug concentration, and overcomes the problems of the prior art Fodor The problem that the aerosol of the Stan nebulized inhalation preparation does not achieve the best inhalation therapeutic effect makes it more effective. At the same time, compared with oral administration, at the same dose, it has higher drug distribution in the respiratory system, better expectorant efficacy, and lower systemic exposure, with better safety. Has a good application prospect.

According to an embodiment of the present disclosure, the concentration of fodosteine in the inhalation solution formulation is 25-250 mg/ml.

According to an embodiment of the present disclosure, the concentration of fodosteine in the inhalation solution formulation is 30-250 mg/ml. When the concentration of fodosteine in the solution preparation for inhalation is 30-250 mg/ml, the aerosol generation characteristics can be further improved to achieve a more effective drug concentration.

According to an embodiment of the present disclosure, the concentration of fodosteine in the inhalation solution formulation is 40-200 mg/ml.

According to an embodiment of the present disclosure, the concentration of fadosteine in the solution formulation for inhalation is 50-150 mg/ml.

According to the embodiments of the present disclosure, the inventors found that in the low temperature cycle, as the concentration of fodosteine increases, the color of the solution formulation for inhalation of fadosteine becomes darker, so it is preferred that fodosteine in the solution formulation for inhalation The concentration of 50-150mg/ml. Solution formulations of fodosteine for inhalation in this range are colorless or slightly yellowish.

According to an embodiment of the present disclosure, the concentration of fodosteine in the inhalation solution formulation is 50-100 mg/ml.

According to an embodiment of the present disclosure, the raw material of the solution formulation for inhalation of fodosteine includes fodosteine or a pharmaceutically acceptable salt or hydrate thereof.

According to an embodiment of the present disclosure, the raw material of the solution formulation for fodosteine inhalation further includes water for injection.

According to an embodiment of the present disclosure, the solvent formulation of fodosteine for inhalation further comprises one or more pharmaceutical excipients suitable for pulmonary administration or inhalation administration.

According to embodiments of the present disclosure, the pharmaceutical excipients used include osmotic pressure regulators and/or surfactants.

According to an embodiment of the present disclosure, the solution formulation for inhalation of fodosteine does not include a pH adjusting agent. For example, the fodosteine inhalation solution formulations of the present disclosure do not contain at least one of the following pH adjusting agents:

Sodium hydroxide, sodium bicarbonate, sodium carbonate, sodium citrate, citric acid, sodium citrate, benzoic acid, ascorbic acid, hydrochloric acid, succinic acid, acetic acid, sulfuric acid, phosphoric acid, tartaric acid, maleic acid, malic acid, ethyl acetate Diamine, ethanolamine phosphate buffer, borate buffer, borate buffer and combinations. In addition, the types of pH adjusters not contained in the solution formulation for fodosteine inhalation of the present disclosure are not limited to this, and may be other types.

According to embodiments of the present disclosure, no complexing or chelating agents are included in the fodosteine inhalation solution formulation.

Some existing solution preparations for inhalation of fodosteine contain complexing agents or chelating agents, and these reagents have brought potential safety hazards to the medicine. The inventors found that when the solution preparations for inhalation contained a specific concentration of It can maintain the stability of the solution preparation for inhalation of fodosteine without adding a complexing agent or a chelating agent, and eliminates the potential safety hazard of the drug. The 250 mg/ml fodosteine has a high atomization speed, overcomes the problem that the aerosol of the fodosteine nebulized inhalation preparation in the prior art does not achieve the best inhalation therapeutic effect, and makes its efficacy more excellent.

For example, the fodosteine inhalation solution formulations of the present disclosure do not contain at least one of the following complexing or chelating agents:

One of edetate salts such as edetate, disodium edetate, calcium sodium edetate, etc. or a mixture thereof mixed in any proportion. In addition, the types of complexing agents or chelating agents not contained in the solution formulation for inhalation of fodosteine of the present disclosure are not limited to this, and may be other types.

The administration route of the solution preparation for inhalation of fodosteine provided by the present disclosure is aerosol inhalation administration, which is to disperse the drug or water through the device into mist or particles suspended in the gas, and deposit in the respiratory tract and ( Or) lung, so as to achieve the role of local treatment of respiratory tract. Generally, in the prescription of aerosol inhalation preparations, pH adjusters or complexing agents are often used to adjust the stability or solubility of the product. The solution formulation contains a specific concentration of fodosteine, and at this concentration, there is no need to add pH adjusters and/or complexing agents, chelating agents, and still maintain very good stability and solubility.

According to an embodiment of the present disclosure, the solution formulation of fadosteine for inhalation consists of fadosteine or a pharmaceutically acceptable salt or hydrate thereof and water for injection.

The solution preparation for inhalation of fodosteine, which is composed of fodosteine or a pharmaceutically acceptable salt or hydrate thereof and water for injection, is simple in composition and good in safety. At the same time, it can maintain good stability (especially long-term stability) and a suitable atomization speed. The aerosol generation properties are excellent, and it can effectively deposit in the drug effect site of the respiratory tract to achieve an excellent drug concentration and overcome the disadvantages of the prior art. The problem that aerosols of dosteine nebulized inhalation formulations do not achieve optimal inhalation therapeutic effects.

According to an embodiment of the present disclosure, the single dose of the solution formulation for inhalation of fodosteine is 1-10 ml.

According to an embodiment of the present disclosure, the single dose of the solution formulation for inhalation of fodosteine is 2.5-8 ml.

According to an embodiment of the present disclosure, after the solution preparation for inhalation of fodosteine is atomized, the dose range of the fine particles of fodosteine in the solution aerosol for inhalation of fodosteine obtained is ≥15%, preferably ≥30% .

According to an embodiment of the present disclosure, the fodosteine inhalation solution formulation delivers a total amount of 100-400 mg.

According to an embodiment of the present disclosure, the solution formulation for inhalation of fodosteine has a sustained release time of ≤30 min during the aerosolization process, and directly reaches the lungs. For example, the sustained release time of the solution formulation for inhalation of fodosteine during the nebulization process is 10-30 min.

According to an embodiment of the present disclosure, the sustained release time of the fodosteine inhalation solution formulation is ≤20 min during the nebulization process.

According to an embodiment of the present disclosure, the delivery rate of the solution formulation for inhalation of fodosteine is 0.07-0.51 mg/s.

According to an embodiment of the present disclosure, the delivery rate of the solution formulation for inhalation of fodosteine is 0.1-0.4 mg/s.

According to an embodiment of the present disclosure, the fodosteine inhalation solution formulation is contained in a container.

According to an embodiment of the present disclosure, the container is an ampoule or a vial.

According to an embodiment of the present disclosure, the vessel is protected by nitrogen.

The ampoules are protected by nitrogen filling. Nitrogen-filled protection can improve the stability of fodosteine solution formulation for inhalation under high temperature and high light.

According to an embodiment of the present disclosure, the material of the ampoule or vial is selected from any one of glass, polyethylene plastic, polypropylene plastic, and rubber. For example, the ampoule may be a medium borosilicate glass ampoule.

A second aspect of the present disclosure provides a method for preparing the solution formulation of fodosteine for inhalation described in the first aspect. According to an embodiment of the present disclosure, the method includes: adding fodosteine to water for injection, and stirring until it is completely dissolved.

A third aspect of the present disclosure provides the use of the solution formulation of fodosteine for inhalation described in the first aspect in the preparation of a medicament for treating pulmonary diseases or respiratory diseases.

According to an embodiment of the present disclosure, the drug for treating lung disease or respiratory disease includes expectorant and/or cough suppressant.

The fourth aspect of the present disclosure provides the solution preparation for inhalation of fodosteine described in the first aspect or the solution preparation for inhalation of fodosteine prepared by the method of the second aspect in preventing and/or treating pulmonary diseases or respiratory diseases. use.

According to an embodiment of the present disclosure, the lung disease or respiratory disease comprises selected from the group consisting of bronchial asthma, chronic bronchitis, bronchiectasis, tuberculosis, pneumoconiosis, emphysema, atypical mycobacterial infection, diffuse bronchiolitis at least one of the. The types of lung diseases or respiratory diseases described in the present disclosure are not limited thereto, and may also be other lung diseases or respiratory diseases known in the art.

A fifth aspect of the present disclosure provides a method of preventing and/or treating pulmonary disease or respiratory disease. According to an embodiment of the present disclosure, the method includes:

Administering the solution formulation of fadosteine for inhalation described in the first aspect or the solution formulation of fodosteine for inhalation prepared by the method described in the second aspect to a subject having or suspected of having a pulmonary disease or respiratory disease .

According to an embodiment of the present disclosure, the lung disease or respiratory disease comprises selected from the group consisting of bronchial asthma, chronic bronchitis, bronchiectasis, tuberculosis, pneumoconiosis, emphysema, atypical mycobacterial infection, diffuse bronchiolitis at least one of the. The types of lung diseases or respiratory diseases described in the present disclosure are not limited thereto, and may also be other lung diseases or respiratory diseases known in the art.

Beneficial effects:

The fodosteine inhalation solution formulation of the present disclosure is a nebulized inhalation solution that contains a specific concentration of fodosteine, and the fodosteine inhalation solvent aerosol is derived from the combination of the delivery rate and the total amount of delivery and fine particle aerodynamics It has excellent generation properties, can be effectively deposited in the drug effect site of the respiratory tract, and achieves an excellent drug concentration, overcomes the problem that the aerosol of the fudosteine nebulized inhalation preparation in the prior art does not achieve the best inhalation therapeutic effect, and makes its drug efficacy better. At the same time, compared with oral administration, at the same dose, it has higher drug distribution in the respiratory system, better expectorant efficacy, and lower systemic exposure, with better safety. Has a good application.

The solution formulation of fodosteine for inhalation of the present disclosure does not contain a complexing agent and/or a pH adjusting agent and still has good long-term stability, especially for more than 1 year.

The solution preparation for aerosol inhalation provided by the present disclosure is single-dose, which is convenient in use and preparation; microbial contamination and waste during use can be greatly reduced, and a single dose of medication is used to avoid repeated doses caused by large-packed solutions. The disadvantages of measuring and repeatedly diluting to prepare microorganisms are easy to breed. The present disclosure provides a new preparation with accurate medicinal dosage, high quality and stable medicinal quality, safe and simple clinical application, and a preparation method thereof, which are lacking in the prior art.

The above-mentioned content of the present disclosure will be further described in detail below through the specific implementation in the form of examples. It should not be understood, however, that the scope of the above-described subject matter of the present disclosure is limited to the following examples. All technologies implemented based on the above contents of the present disclosure belong to the scope of the present disclosure.

Detailed description of the invention

Embodiments of the present disclosure are described in detail below. The embodiments described below are exemplary only for explaining the present disclosure, and should not be construed as limiting the present disclosure. If no specific technique or condition is indicated in the examples, the technique or condition described in the literature in the field or the product specification is used. The reagents or instruments used without the manufacturer's indication are conventional products that can be obtained from the market.

In addition, the terms "first" and "second" are only used for descriptive purposes, and should not be construed as indicating or implying relative importance or implying the number of indicated technical features. Thus, a feature delimited with "first", "second" may expressly or implicitly include at least one of that feature. In the description of the present disclosure, "plurality" means at least two, such as two, three, etc., unless expressly and specifically defined otherwise.

the term

According to an embodiment of the present disclosure, the preferred route of administration of the "fodosteine solution for inhalation" is aerosol inhalation administration, which is to disperse fodosteine and other raw materials into a mist suspended in a gas through a device Granules or microparticles are deposited in the respiratory tract and/or lungs by inhalation, so as to achieve the effect of local treatment of the respiratory tract.

According to one embodiment of the present disclosure, the "pharmaceutically acceptable salt" refers to a salt of fodosteine with an inorganic or organic acid, wherein the inorganic or organic acid is selected from hydrochloric acid, hydrobromic acid, sulfuric acid, Phosphoric acid, methanesulfonic acid, benzenemethanesulfonic acid, oxalic acid, tartaric acid, maleic acid, citric acid or ascorbic acid.

According to one embodiment of the present disclosure, the "hydrate of fadosteine" refers to a hemihydrate, monohydrate or polyhydrate of fodosteine.

According to a preferred embodiment of the present disclosure, the raw materials of the solution formulation for fadosteine inhalation include fadosteine and water for injection, and do not include complexing agents or chelating agents and pH adjusting agents.

According to an embodiment of the present disclosure, wherein the "complexing agent or chelating agent" is selected from at least one of the following:

One of edetate salts such as edetate, disodium edetate, calcium sodium edetate, etc. or a mixture thereof mixed in any proportion. In addition, the types of complexing agents or chelating agents not contained in the solution formulation for inhalation of fodosteine of the present disclosure are not limited to this, and may be other types.

According to an embodiment of the present disclosure, wherein the "pH adjusting agent" is selected from at least one of the following:

Sodium hydroxide, sodium bicarbonate, sodium carbonate, sodium citrate, citric acid, sodium citrate, benzoic acid, ascorbic acid, hydrochloric acid, succinic acid, acetic acid, sulfuric acid, phosphoric acid, tartaric acid, maleic acid, malic acid, ethyl acetate Diamine, ethanolamine phosphate buffer, borate buffer, borate buffer and combinations. In addition, the types of pH adjusters not contained in the solution formulation for inhalation of fodosteine of the present disclosure are not limited to this, and may be other types.

According to an embodiment of the present disclosure, the "pharmaceutical excipients suitable for pulmonary administration or inhalation administration" in the present disclosure may be, for example, osmotic pressure regulators, surfactants, etc., or may be other known in the art Any kind of pharmaceutical excipient for pulmonary or inhalation administration. Among them, the osmotic pressure regulator can be, for example, sodium chloride, phosphate, citrate, etc., and the surfactant can be, for example, Tween, polyoxyethylene castor oil derivative, poloxamer, lecithin, cyclodextrin Wait.

According to an embodiment of the present disclosure, the "single dose" refers to a pharmaceutical preparation obtained after a single dose of a solution preparation for inhalation of fodosteine to be taken by a patient is sealed by means of a packaging container. The packaging container can be an ampoule or other sealed container, preferably a nitrogen-filled ampoule made of glass, polyethylene plastic, polypropylene plastic and other materials. According to an embodiment of the present disclosure, the single dose of the solution preparation for inhalation of fodosteine in the present disclosure is 1-10 ml, and the preparation may also be diluted for dilution during actual use. According to an embodiment of the present disclosure, the total delivery amount of the solution formulation for inhalation of fodosteine in the present disclosure is 100-400 mg, and the solution formulation for inhalation of fodosteine is continuously released in the body for ≤30 min, and directly reaches the lungs, thereby being used for It is used as an expectorant for bronchial asthma, chronic bronchitis, bronchiectasis, tuberculosis, pneumoconiosis, emphysema, atypical mycobacterial infection, diffuse bronchiolitis and other chronic respiratory diseases.

According to one embodiment of the present disclosure, "fine particle dose" refers to the total mass of active material that is emitted from the device with actuation in an aerodynamic particle size that is less than a specified limit.

According to one embodiment of the present disclosure, "total delivered" refers to the total amount of actives collected by all filter papers and filter paper devices when a breathing simulator is used to simulate human moist breathing.

Example

Embodiment 1, the preparation of the solution preparation of fodosteine inhalation of the present disclosure

Add fodosteine to a certain amount of water for injection, stir until it is completely dissolved, and then make up to volume with water for injection. The dosage of each ingredient is shown in Table 1 below. The fodosteine concentration in the obtained solution preparation for fadosteine inhalation was 30 mg/ml.

Table 1

Element	effect	Dosage
fodosteine	active substance	30g
Water for Injection	solvent	to 1000ml

Embodiment 2, the preparation of the solution formulation of fodosteine inhalation of the present disclosure

Add fodosteine to a certain amount of water for injection, stir until it is completely dissolved, and then make up the volume with water for injection. The dosage of each ingredient is shown in Table 2 below. The concentration of fadosteine in the obtained solution preparation for inhalation of fadosteine was 250 mg/ml.

Table 2

Element	effect	Dosage
fodosteine	active substance	250g
Water for Injection	solvent	to 1000ml

Embodiment 3, the preparation of the solution preparation of fodosteine inhalation of the present disclosure

Add fodosteine to a certain amount of water for injection, stir until it is completely dissolved, and then use water for injection to make up the volume. The dosage of each ingredient is shown in Table 3 below. The fadosteine concentration in the obtained solution preparation for fadosteine inhalation was 40 mg/ml.

table 3

Element	effect	Dosage
fodosteine	active substance	40g
Water for Injection	solvent	to 1000ml

Embodiment 4, the preparation of the solution preparation of fodosteine inhalation of the present disclosure

Add fodosteine to a certain amount of water for injection, stir until it is completely dissolved, and then use water for injection to make up the volume. The dosage of each ingredient is shown in Table 4 below. The concentration of fadosteine in the obtained solution preparation for fadosteine inhalation was 200 mg/ml.

Table 4

Element	effect	Dosage
fodosteine	active substance	200g
Water for Injection	solvent	to 1000ml

Embodiment 5, the preparation of the solution preparation of fodosteine inhalation of the present disclosure

Add fodosteine to a certain amount of water for injection, stir until it is completely dissolved, and then make up the volume with water for injection. The dosage of each ingredient is shown in Table 5 below. The fadosteine concentration in the obtained solution preparation for fadosteine inhalation was 50 mg/ml.

table 5

Element	effect	Dosage
fodosteine	active substance	50g
Water for Injection	solvent	to 1000ml

Embodiment 6, the preparation of the solution preparation of fodosteine inhalation of the present disclosure

Add fodosteine to a certain amount of water for injection, stir until it is completely dissolved, and then use water for injection to make up the volume. The dosage of each ingredient is shown in Table 6 below. The fodosteine concentration in the obtained solution preparation for fadosteine inhalation was 100 mg/ml.

Table 6

Element	effect	Dosage
fodosteine	active substance	100g

Water for Injection

solvent

to 1000ml

Embodiment 7, the preparation of the solution preparation of fodosteine inhalation of the present disclosure

Add fodosteine to a certain amount of water for injection, stir until it is completely dissolved, and then make up the volume with water for injection. The dosage of each ingredient is shown in Table 7 below. The concentration of fadosteine in the obtained solution preparation for inhalation of fadosteine was 150 mg/ml.

Table 7

Element	effect	Dosage
fodosteine	active substance	150g
Water for Injection	solvent	to 1000ml

Embodiment 8-9, the preparation of the solution formulation of fodosteine inhalation of the present disclosure

Add 100 g of fodosteine to a certain amount of water for injection, stir until it is completely dissolved, and then make up to 1000 ml with water for injection, and set aside for use; Example 8 Filling the prepared solution into a medium borosilicate glass ampoule, Example 9 The prepared solution is filled into borosilicate glass ampoules after the air has been replaced with pure nitrogen. The dosage of each ingredient is shown in Table 8 below. The fodosteine concentration in the obtained solution preparation for fadosteine inhalation was 100 mg/ml.

Table 8

Element	Example 8	Example 9
fodosteine	100g	100g
Water for Injection	to 1000ml	to 1000ml
nitrogen	/	Nitrogen filling
Package	Medium borosilicate glass ampoule	Medium borosilicate glass ampoule

Example 10. Pharmacokinetics and tissue distribution experiments of inhaled or oral fodosteine in rats

24 male SD rats, weighing 180-200 g, were used in the experiment. Randomly divided into groups according to body weight, divided into fodosteine oral administration group and fodosteine nebulization inhalation administration group, 12 in each group. The doses of both groups were 30 mg/kg. Blood collection time points in each group: before administration, 15min, 30min, 50min, 2h, 4h, 8h, and 24h after administration, there were 3 animals at each time point, blood samples were centrifuged to separate plasma by heparin sodium anticoagulation; Tissue collection time points: 15min, 50min, 4h, 24h after administration, 3 animals at each time point. The samples were processed and detected using LC-MS analytical methods with the target analyte being fodosteine. The experimental results are shown in Table 9:

Table 9

The results showed that compared with oral administration, the drug concentration and exposure in lung tissue and trachea were increased by aerosol inhalation at the same dose. The drug concentration and exposure in lung tissue increased to 1.80 and 1.92 times, respectively, and in trachea to 6.38 and 6.93 times, respectively. The plasma exposure decreased, and the drug concentration and exposure decreased to 0.66 and 0.90 times, respectively.

Example 11. Experiment on promoting the excretion of phenol red in mice

60 experimental mice were randomly divided into 6 groups according to body weight, 10 mice in each group, respectively: control group, oral administration group of 60 mg/kg of fodosteine, 60 mg/kg, 40 mg/kg, 20 mg/kg of fodosteine , 10mg/kg aerosol inhalation administration group. The control group was inhaled with normal saline, and the administration group was administered orally or inhaled with corresponding doses of fodosteine (the fodosteine solution obtained in Example 6). 30min after administration, 1% phenol red physiological saline solution was injected intraperitoneally, 30min later, the mice were euthanized by excessive inhalation of _CO2 , after the blood in the mice was coagulated, the neck skin was incised, the trachea was separated, and a 0.8ml 5% _NaHCO3 syringe was placed Insert into the trachea and slowly inject it, and then slowly suck it out. Repeat this 3 times. The combined lavage solution of the 3 times is placed for a certain period of time to allow impurities to precipitate, and a transparent red supernatant is obtained. Calculate the amount of phenol red. The experimental results are shown in Table 10:

Table 10. Effects of different routes of administration of fodosteine on the excretion of phenol red in mice

group	n	Phenol red excretion (μg/mL)
control group	10	1.38±0.46
Fodosteine 60mg/kg, P.O	10	1.96±0.49
Fodosteine 60mg/kg, inhaled	9	3.33±1.74 ## **
Fodosteine 40mg/kg, inhaled	10	2.86±0.57**
Fodosteine 20mg/kg, inhaled	10	2.25±0.72
Fodosteine 10mg/kg, inhaled	9	1.38±0.45

^** P<0.01 vs. control

^## P<0.01vs.60mg/kg PO

n is the number of mice

In the excretion test of phenol red in mice, inhalation administration of 20-60 mg/kg of fodosteine can increase the excretion of phenol red in mice, and the level of increase increases with the increase of the inhaled dose. Among them, inhalation administration of 60 mg/kg and 40 mg/kg fodosteine can significantly increase the excretion of phenol red in mice. It is indicated that the aerosol inhalation of fodosteine can dilute the sputum by promoting the secretion of airway serous fluid, and play an expectorant effect, and the effect is dose-dependent. Compared with oral administration (P.O) of 60 mg/kg, inhalation administration of 20-60 mg/kg of fodosteine was more effective, and the expectorant effect of inhalation administration of fodosteine was significantly better than oral administration at the same dose.

Experimental example 12. Toxicity test of repeated administration of fodosteine aerosol inhalation

SD rats were given normal saline or fodosteine by inhalation once a day for 4 consecutive weeks (using the fodosteine solution of Example 2, fully exposed to the maximum feasible dose, respectively: 39.34 mg/kg, 236.03 mg/kg ). During the experiment, each dose group survived normally until the end of the experiment, and there was no abnormality in animal body weight, food consumption, and detailed clinical conditions, and clinical pathological indicators (including hematology, serum biochemistry, coagulation and urinalysis) were not found to be related to the test. There were no toxicological changes related to the test product, and no abnormality related to the test product was found in the animal's gross anatomy, organ weight and pathological examination. In toxicokinetic experiments, the exposure of fodosteine inhalation solution formulations increased with increasing dose. Under the experimental conditions, the no-damaging dose level (NOAEL) of the solution formulation for inhalation of fodosteine in SD rats was 236.03 mg/kg. It indicated that the inhalation administration of fodosteine solution was safe.

Conclusion: The fodosteine solution prepared by the present disclosure is used for aerosol inhalation administration. Compared with oral administration, the exposure of the respiratory system can be increased. The exposure of the same dose in the trachea is increased by nearly 6 times, and the exposure in the lung tissue is increased by nearly 1. times. The pharmacodynamic mechanism of fodosteine is comprehensive, and in the efficacy experiment of increasing phenol red excretion, compared with oral administration, inhalation of one-quarter to equal doses can achieve equivalent or better effects, when the inhaled dose is oral. The drug does not work well at one-sixth the dose. The toxicity test showed that the aerosol inhalation of fodosteine was safe. The clinical dosage of fodosteine oral preparation is 400 mg each time for adults, 3 times a day. Based on the fodosteine solutions prepared in Examples 1-6, combined with the research results of Experimental Examples 10-12, it is speculated that 100-400 mg of fodosteine per atomization inhalation can achieve equivalent or better than oral administration. Effective and safe. On this basis, further pharmaceutical research is carried out, combined with the requirements of clinical aerosol inhalation medication specifications, to explore the optimal fudosteine aerosol inhalation preparation, in order to achieve the best comprehensive benefits in clinical use.

Experimental example 13. Risk assessment of prescription variables

The active ingredient of this product (fodosteine is weakly acidic at a concentration of 50 mg/ml and the pH is 5.5), solvent (purified water), and the influence of pH adjusters (citric acid and sodium citrate) on the stability of formulation development.

Methods: The key quality attributes (CQAs) such as character, pH value, color, related substances and content were mainly investigated, and the prescriptions were screened and optimized. Tables 11 and 12 show the results of prescription risk assessment.

Table 11 Prescribing Risk Assessment

Table 12 Basis for Prescribing Risk Assessment

Embodiment 14, pH value screening

This product initially selects sodium citrate and citric acid as pH adjusters. The pH value of the solution may affect the product stability. Use citric acid and 0.1mol/L citric acid solution and 0.1mol/L sodium citrate solution The pH of the solution is 3.0-6.0, and the API concentration is 150 mg/ml. By detecting the properties, pH value, color, related substances, and content of the sample, investigating its influence on the formulation, stability, etc., and screening the pH value control range of this product solution, the results are shown in Tables 13 and 14.

Table 13 Screening of the dosage of sodium citrate and anhydrous citric acid

The 15% fodosteine concentration in Table 13 refers to the mass-to-volume ratio of fodosteine in the entire pharmaceutical preparation. For example, the solution preparation for fodosteine inhalation contains 150 mg of fodosteine, and the preparation volume is 1000 ml.

Table 14 Investigation of pH stability of different solutions

From the results of pH screening, it can be seen that there is no difference in the stability of the samples under low temperature cycle, high temperature and light conditions when the pH adjuster is added to adjust the pH value to 3.0-6.0 and the sample is directly prepared with pure water.

Experimental Example 15. Stability test of solution formulation for inhalation of fodosteine of the present disclosure

The stability of the solution preparation for inhalation with a concentration of 100 mg/ml of fodosteine in Example 8 of the present disclosure was tested for 1 month, 2 months, 3 months, and 6 months, respectively. The results are shown in Tables 15 and 16. , among which Tables 15 and 16 are the results under different temperatures and humidity, and Table 15 only shows the results of placing for 3 months and 6 months.

Table 15 Data of long-term test (30℃±2℃, 65%RH±5%RH) of fodosteine solution for inhalation

Table 16 Accelerated test (40°C±2°C, 75%RH±5%RH) data of fodosteine solution (5ml:500mg) for inhalation

Conclusion: The stability of the solution preparation for inhalation of fodosteine provided in Example 8 in the high temperature and high humidity environment was accelerated. There was no significant change in each index except for the related substances, and the related substances increased slightly, which can be passed through. Nitrogen to improve. According to ICH Q1 stability guidelines, this product is expected to achieve long-term stability for at least 12 months.

Table 17 below shows the stability of the solution formulations of fadosteine for inhalation in Examples 8 and 9 under nitrogen-free and nitrogen-filled conditions.

Table 17 Investigation on the stability of nitrogen protection samples

Conclusion: From the results in Table 17, it can be seen that there is no significant change in related substances at high temperature for 30 days after nitrogen charging, so nitrogen charging can improve the stability of this product.

Experimental Example 16. The aerosol generation experiment of the solution formulation for inhalation of fodosteine of the present disclosure

The solutions for inhalation of fodosteine with different concentrations and volumes prepared in the prescription were investigated to investigate the delivery rate, total delivery amount, and fine particle dose.

Determination of delivery rate and total delivery: determined according to the delivery rate and total delivery method of liquid preparations for nebulizer (Chinese Pharmacopoeia 2020 Edition Four General Chapters 0111).

Use a compressed air-driven atomizer (Bairui), take 1 bottle of this product, and transfer all the contents to the atomizer. Set up the device according to the requirements of the Chinese Pharmacopoeia, and select the "adult mode" for the breathing mode. Start the nebulizer at the beginning of the breathing cycle and turn off the nebulizer at the end of the breathing cycle. The amount of drug collected on the filter paper was determined according to high performance liquid chromatography (General Chapter 0512 of the Fourth Volume of the Chinese Pharmacopoeia, 2020 edition). The amount of drug collected per unit time is the average delivery rate, and the total amount of drug collected is the total amount delivered.

Dosimetry of fine particles: refer to (Chinese Pharmacopoeia 2020 Edition Four General Principles 0951) Determination of Aerodynamic Characteristics of Fine Particles of Inhaled Preparations, select Device 3 (Next Generation Impactor, NGI), and test method 3 under the method of inhalation liquid preparations.

Use a compressed air-driven atomizer (Bairui), take 1 bottle of this product, and transfer all the contents to the atomizer. Connect the nozzle to the L-connector via the adapter. Turn on the compressor and set the atomization time to 2min. Turn off the compressor, remove the nebulizer from the L-connector, and turn off the vacuum pump. Remove the impactor, wash the levels S4, S5, S6, S7 and additional filter paper (MOC) with eluent, and measure the amount of drugs collected from S4 to MOC according to high performance liquid chromatography (Chinese Pharmacopoeia 2020 Edition Four General Rules 0512), namely Get the fine particle dose (mg).

Results: as shown in Tables 18 and 19.

Table 18 Summary of delivery rate and total delivery test results

Note: In this experiment, the PIRI boy compression spray atomizer was used for detection, and the maximum volume of the atomization cup was 10ml.

Table 19 Summary of fine particle dose detection

concentration	Fine particle dosage (%)
10mg/ml	56.0
25mg/ml	53.5
37.5mg/ml	53.2
50mg/ml	59.7
100mg/ml	58.0
125mg/ml	51.8
150mg/ml	52.1
200mg/ml	53.0

Note: fine particle dose (%) = fine particle dose (mg)/total amount delivered

CONCLUSIONS: Delivery rate, total volume delivered, and fine particle dose may affect the amount of drug inhaled by a patient, which will affect product safety and efficacy.

It can be seen from the above results that the concentration of this product is 25mg/ml ~ 250mg/ml, which can satisfy the total delivery amount of 100 ~ 400mg, and can achieve the corresponding efficacy. However, the higher the concentration, the crystals will be precipitated from the atomizing cup. Excessive crystal precipitation can lead to a lower effective utilization rate of this product. Therefore, the concentration of the solution preparation for inhalation of fodosteine is preferably less than 250 mg/ml.

According to fudosteine inhalation solution for clinical nebulization inhalation drug treatment, the nebulization time should not exceed 30min. It can be seen from the above results that the concentration of the solution preparation for inhalation of fodosteine should be ≥30 mg/ml.

From Table 19, it can be seen from the dosage of fine particles that the active ingredient concentration of the formulation of the solution formulation for inhalation of fodosteine of the present disclosure is in the range of 25 mg to 200 mg/ml. It is more convenient for clinical use and the compliance of patients is preferably within 25 minutes to achieve better clinical application effect, preferably 50-200 mg/ml.

Embodiment 17, the use method of the solution preparation of fodosteine inhalation of the present disclosure

The method for using the solution preparation of fodosteine for inhalation of the present disclosure: the solution preparation for inhalation of fodosteine prepared in any one of Examples 1 to 9 is used directly (it can be appropriately diluted), and the use volume is 1-10 ml.

In the description of this specification, reference to the terms "one embodiment," "some embodiments," "example," "specific example," or "some examples", etc., means a specific feature described in connection with the embodiment or example, A structure, material, or feature is included in at least one embodiment or example of the present disclosure. In this specification, schematic representations of the above terms are not necessarily directed to the same embodiment or example. Furthermore, the particular features, structures, materials or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, those skilled in the art may combine and combine the different embodiments or examples described in this specification, as well as the features of the different embodiments or examples, without conflicting each other.

Although the embodiments of the present disclosure have been shown and described above, it should be understood that the above-described embodiments are exemplary and should not be construed as limitations of the present disclosure, and those of ordinary skill in the art may interpret the above-described embodiments within the scope of the present disclosure. Embodiments are subject to variations, modifications, substitutions and variations.

Claims (21)

1. A solution preparation of fadosteine for inhalation, wherein the concentration of fadosteine in the solution preparation for inhalation is 25-300 mg/ml, preferably 25-250 mg/ml.
2. A solution preparation for inhalation of fadosteine, wherein the concentration of fadosteine in the solution preparation for inhalation is 30-250 mg/ml.
3. The solution formulation for inhalation of fadosteine according to claim 2, wherein the concentration of fadosteine in the solution formulation for inhalation is 40-200 mg/ml, preferably 50-150 mg/ml, more preferably 50-200 mg/ml 100mg/ml.
4. The solution formulation for inhalation of fodosteine according to any one of claims 1 to 3, wherein the raw material of the solution formulation for inhalation of fodosteine comprises fodosteine or a pharmaceutically acceptable salt thereof or its hydrate.
5. The solution preparation for inhalation of fodosteine according to any one of claims 1 to 4, wherein the raw material of the solution preparation for inhalation of fodosteine further comprises water for injection.
6. The solution formulation for inhalation of fodosteine according to any one of claims 1 to 5, wherein the solvent formulation for inhalation of fodosteine further comprises one or more suitable for pulmonary administration or inhalation Pharmaceutical excipients for administration;

   Optionally, the pharmaceutical excipients include osmotic pressure regulators and/or surfactants.
7. The solution formulation for inhalation of fodosteine according to any one of claims 1 to 6, wherein the solution formulation for inhalation of fodosteine does not include a pH adjuster.
8. The solution formulation for inhalation of fodosteine according to any one of claims 1 to 7, wherein the solution formulation for inhalation of fadosteine does not include a complexing agent or a chelating agent.
9. The solution formulation for fodosteine for inhalation according to any one of claims 1 to 8, wherein the solution formulation for fodosteine inhalation is composed of fodosteine or a pharmaceutically acceptable salt thereof or a hydrate thereof composition with water for injection.
10. The solution preparation for inhalation of fodosteine according to any one of claims 1 to 9, wherein a single dose of the solution preparation for inhalation of fodosteine is 1-10 ml, preferably 2.5-8 ml.
11. The solution formulation for inhalation of fodosteine according to any one of claims 1 to 10, wherein the solution formulation for inhalation of fodosteine is atomized to obtain a solution aerosol for inhalation of fodosteine The dose range of Fadosteine fine particles is ≥ 15%, preferably ≥ 30%.
12. The solution formulation for inhalation of fodosteine according to any one of claims 1 to 11, wherein the solution formulation for inhalation of fodosteine delivers a total amount of 100-400 mg.
13. The solution formulation for inhalation of fodosteine according to any one of claims 1 to 12, wherein the solution formulation for inhalation of fodosteine has a sustained release time of ≤30 min during the atomization process, and directly reaches the lungs; Preferably ≤ 20min.
14. The solution formulation for inhalation of fodosteine according to any one of claims 1 to 13, wherein the delivery rate of the solution formulation for inhalation of fodosteine is 0.07-0.51 mg/s, preferably 0.1-0.4 mg /s.
15. The solution formulation for inhalation of fodosteine according to any one of claims 1 to 14, wherein the solution formulation for inhalation of fodosteine is contained in a container;

    Optionally, the container is an ampoule or vial;

    Optionally, there is nitrogen protection in the container;

    Optionally, the material of the ampoule or vial is selected from any one of glass, polyethylene plastic, polypropylene plastic, and rubber.
16. A method for preparing the solution formulation of fodosteine for inhalation according to any one of claims 1 to 15, comprising: adding fodosteine to water for injection, and mixing until it is completely dissolved.
17. Use of the solution preparation for inhalation of fodosteine according to any one of claims 1 to 15 in the preparation of a medicament for the treatment of pulmonary diseases or respiratory diseases;

    Optionally, the drug for treating pulmonary or respiratory diseases includes expectorant and/or antitussive drugs.
18. The solution preparation for inhalation of fodosteine according to any one of claims 1 to 15 or the solution preparation for inhalation of fodosteine prepared by the method according to claim 16 is used in the prevention and/or treatment of pulmonary diseases or respiratory diseases. use in.
19. The use according to claim 18, wherein the pulmonary disease or respiratory tract disease is selected from the group consisting of bronchial asthma, chronic bronchitis, bronchiectasis, pulmonary tuberculosis, pneumoconiosis, emphysema, atypical mycobacterial infection, diffuse at least one of bronchiolitis.
20. A method of preventing and/or treating pulmonary disease or respiratory disease, wherein the method comprises:

    Administering the solution formulation of fodosteine for inhalation according to any one of claims 1 to 15 or the fadosteine prepared by the method of claim 16 to a subject suffering from or suspected of suffering from pulmonary disease or respiratory disease Stan is a solution for inhalation.
21. The method of claim 20, wherein the lung disease or respiratory disease comprises a disease selected from the group consisting of bronchial asthma, chronic bronchitis, bronchiectasis, pulmonary tuberculosis, pneumoconiosis, emphysema, atypical mycobacterial infection, diffuse at least one of bronchiolitis.