WO2022166724A1 - Préparation de solution de fudostéine pour inhalation, son procédé de préparation et son utilisation - Google Patents

Préparation de solution de fudostéine pour inhalation, son procédé de préparation et son utilisation Download PDF

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WO2022166724A1
WO2022166724A1 PCT/CN2022/074104 CN2022074104W WO2022166724A1 WO 2022166724 A1 WO2022166724 A1 WO 2022166724A1 CN 2022074104 W CN2022074104 W CN 2022074104W WO 2022166724 A1 WO2022166724 A1 WO 2022166724A1
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inhalation
fodosteine
solution
preparation
solution formulation
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PCT/CN2022/074104
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English (en)
Chinese (zh)
Inventor
周祎
梁力
顾文斐
周丽娜
孙春艳
罗旭东
吕慧敏
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扬子江药业集团有限公司
扬子江药业集团四川海蓉药业有限公司
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Publication of WO2022166724A1 publication Critical patent/WO2022166724A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
    • A61J1/00—Containers specially adapted for medical or pharmaceutical purposes
    • A61J1/05—Containers specially adapted for medical or pharmaceutical purposes for collecting, storing or administering blood, plasma or medical fluids ; Infusion or perfusion containers
    • A61J1/06—Ampoules or carpules
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/0078—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a nebulizer such as a jet nebulizer, ultrasonic nebulizer, e.g. in the form of aqueous drug solutions or dispersions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/10—Expectorants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/14—Antitussive agents

Definitions

  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the concentration of fodosteine in the inhalation solution formulation is 25-300 mg/ml.
  • the solution preparation for inhalation of fodosteine 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.
  • it 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.
  • the concentration of fodosteine in the inhalation solution formulation is 25-250 mg/ml.
  • the concentration of fodosteine in the inhalation solution formulation is 30-250 mg/ml.
  • 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.
  • the concentration of fodosteine in the inhalation solution formulation is 40-200 mg/ml.
  • the concentration of fadosteine in the solution formulation for inhalation is 50-150 mg/ml.
  • 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.
  • the concentration of fodosteine in the inhalation solution formulation is 50-100 mg/ml.
  • the raw material of the solution formulation for inhalation of fodosteine includes fodosteine or a pharmaceutically acceptable salt or hydrate thereof.
  • the raw material of the solution formulation for fodosteine inhalation further includes water for injection.
  • the solvent formulation of fodosteine for inhalation further comprises one or more pharmaceutical excipients suitable for pulmonary administration or inhalation administration.
  • the pharmaceutical excipients used include osmotic pressure regulators and/or surfactants.
  • the solution formulation for inhalation of fodosteine does not include a pH adjusting agent.
  • the fodosteine inhalation solution formulations of the present disclosure do not contain at least one of the following pH adjusting agents:
  • 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.
  • 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 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.
  • the fodosteine inhalation solution formulations of the present disclosure do not contain at least one of the following complexing or chelating agents:
  • edetate salts such as edetate, disodium edetate, calcium sodium edetate, etc. or a mixture thereof mixed in any proportion.
  • 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.
  • aerosol inhalation administration 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.
  • 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.
  • 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.
  • the single dose of the solution formulation for inhalation of fodosteine is 1-10 ml.
  • the single dose of the solution formulation for inhalation of fodosteine is 2.5-8 ml.
  • the dose range of the fine particles of fodosteine in the solution aerosol for inhalation of fodosteine obtained is ⁇ 15%, preferably ⁇ 30% .
  • the fodosteine inhalation solution formulation delivers a total amount of 100-400 mg.
  • the solution formulation for inhalation of fodosteine has a sustained release time of ⁇ 30 min during the aerosolization process, and directly reaches the lungs.
  • the sustained release time of the solution formulation for inhalation of fodosteine during the nebulization process is 10-30 min.
  • the sustained release time of the fodosteine inhalation solution formulation is ⁇ 20 min during the nebulization process.
  • the delivery rate of the solution formulation for inhalation of fodosteine is 0.07-0.51 mg/s.
  • the delivery rate of the solution formulation for inhalation of fodosteine is 0.1-0.4 mg/s.
  • the fodosteine inhalation solution formulation is contained in a container.
  • the container is an ampoule or a vial.
  • 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.
  • the material of the ampoule or vial is selected from any one of glass, polyethylene plastic, polypropylene plastic, and rubber.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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:
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • plurality means at least two, such as two, three, etc., unless expressly and specifically defined otherwise.
  • 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.
  • 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.
  • the "hydrate of fadosteine” refers to a hemihydrate, monohydrate or polyhydrate of fodosteine.
  • 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.
  • the "complexing agent or chelating agent” is selected from at least one of the following:
  • edetate salts such as edetate, disodium edetate, calcium sodium edetate, etc. or a mixture thereof mixed in any proportion.
  • 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 "pH adjusting agent" is selected from at least one of the following:
  • 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.
  • 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.
  • the osmotic pressure regulator can be, for example, sodium chloride, phosphate, citrate, etc.
  • the surfactant can be, for example, Tween, polyoxyethylene castor oil derivative, poloxamer, lecithin, cyclodextrin Wait.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • Embodiment 1 the preparation of the solution preparation of fodosteine inhalation of the present disclosure
  • Embodiment 2 the preparation of the solution formulation of fodosteine inhalation of the present disclosure
  • Embodiment 3 the preparation of the solution preparation of fodosteine inhalation of the present disclosure
  • Embodiment 4 the preparation of the solution preparation of fodosteine inhalation of the present disclosure
  • Embodiment 5 the preparation of the solution preparation of fodosteine inhalation of the present disclosure
  • Embodiment 6 the preparation of the solution preparation of fodosteine inhalation of the present disclosure
  • Embodiment 7 the preparation of the solution preparation of fodosteine inhalation of the present disclosure
  • Embodiment 8-9 the preparation of the solution formulation of fodosteine inhalation of the present disclosure
  • 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.
  • Example 8 fodosteine 100g 100g Water for Injection to 1000ml to 1000ml nitrogen / Nitrogen filling Package
  • Medium borosilicate glass ampoule Medium borosilicate glass ampoule
  • 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.
  • 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).
  • Phenol red excretion ( ⁇ g/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
  • n is the number of 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.
  • 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.
  • 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.
  • 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.
  • CQAs key quality attributes
  • Tables 11 and 12 show the results of prescription 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.
  • the pH of the solution is 3.0-6.0, and the API concentration is 150 mg/ml.
  • the 15% fodosteine concentration in Table 13 refers to the mass-to-volume ratio of fodosteine in the entire pharmaceutical preparation.
  • the solution preparation for fodosteine inhalation contains 150 mg of fodosteine, and the preparation volume is 1000 ml.
  • Example 8 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.
  • Example 8 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.
  • 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).
  • 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.
  • 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
  • fine particle dose (%) fine particle dose (mg)/total amount delivered
  • 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.
  • 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.
  • the concentration of the solution preparation for inhalation of fodosteine is preferably less than 250 mg/ml.
  • 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.
  • 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.
  • references 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.
  • schematic representations of the above terms are not necessarily directed to the same embodiment or example.
  • the particular features, structures, materials or characteristics described may be combined in any suitable manner in any one or more embodiments or examples.
  • 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.

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Abstract

L'invention concerne une préparation de solution de fudostéine pour inhalation, son procédé de préparation et son utilisation, appartenant au domaine des préparations pharmaceutiques. La concentration de fudostéine dans la préparation de solution pour inhalation est de 25 à 300 mg/ml. La préparation de solution de fudostéine pour inhalation est une solution d'inhalation d'aérosol, qui contient de la fudostéine avec une concentration spécifique. La préparation présente une bonne propriété de formation d'aérosol, et peut être efficacement déposée au niveau du site d'effet du médicament dans les voies respiratoires, de manière à obtenir la concentration de médicament optimale, et surmonter le problème de l'aérosol de la préparation d'inhalation d'aérosol de fudostéine de l'art antérieur ne pouvant pas atteindre l'effet optimal de traitement par inhalation, de telle sorte que l'efficacité médicamenteuse de la préparation est meilleure. En outre, par rapport à l'administration orale, la préparation a une meilleure distribution du médicament dans le système respiratoire à la même dose, un meilleur effet d'élimination des mucosités, ainsi qu'une faible exposition du système et une meilleure sécurité. La préparation de solution de fudostéine pour inhalation présente de meilleures perspectives d'application.
PCT/CN2022/074104 2021-02-04 2022-01-26 Préparation de solution de fudostéine pour inhalation, son procédé de préparation et son utilisation WO2022166724A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030190286A1 (en) * 1997-10-01 2003-10-09 Dugger Harry A. Buccal, polar and non-polar spray or capsule containing drugs for treating allergies or asthma
CN103768011A (zh) * 2012-10-23 2014-05-07 天津药物研究院 福多司坦注射剂及其制备方法
CN108078964A (zh) * 2018-02-05 2018-05-29 迪沙药业集团有限公司 一种福多司坦吸入剂组合物
CN109925300A (zh) * 2017-12-19 2019-06-25 北京盈科瑞创新药物研究有限公司 一种福多司坦雾化吸入用溶液制剂及其制备方法
CN111110662A (zh) * 2018-10-30 2020-05-08 北京盈科瑞创新药物研究有限公司 一种吸入用溶液制剂的制备方法

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030190286A1 (en) * 1997-10-01 2003-10-09 Dugger Harry A. Buccal, polar and non-polar spray or capsule containing drugs for treating allergies or asthma
CN103768011A (zh) * 2012-10-23 2014-05-07 天津药物研究院 福多司坦注射剂及其制备方法
CN109925300A (zh) * 2017-12-19 2019-06-25 北京盈科瑞创新药物研究有限公司 一种福多司坦雾化吸入用溶液制剂及其制备方法
CN108078964A (zh) * 2018-02-05 2018-05-29 迪沙药业集团有限公司 一种福多司坦吸入剂组合物
CN111110662A (zh) * 2018-10-30 2020-05-08 北京盈科瑞创新药物研究有限公司 一种吸入用溶液制剂的制备方法

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