WO2019119720A1 - 一种福多司坦雾化吸入用溶液制剂及其制备方法 - Google Patents

一种福多司坦雾化吸入用溶液制剂及其制备方法 Download PDF

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WO2019119720A1
WO2019119720A1 PCT/CN2018/087524 CN2018087524W WO2019119720A1 WO 2019119720 A1 WO2019119720 A1 WO 2019119720A1 CN 2018087524 W CN2018087524 W CN 2018087524W WO 2019119720 A1 WO2019119720 A1 WO 2019119720A1
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fudosteine
injection
preparation
water
complexing agent
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PCT/CN2018/087524
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English (en)
French (fr)
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张保献
胡杰
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北京盈科瑞创新药物研究有限公司
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Priority to JP2020534261A priority Critical patent/JP2021506897A/ja
Priority to EP18892327.0A priority patent/EP3730133A4/en
Publication of WO2019119720A1 publication Critical patent/WO2019119720A1/zh
Priority to US16/904,117 priority patent/US20200316003A1/en

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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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • 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 invention belongs to the field of pharmaceutical preparations, and in particular relates to a solution preparation for fumigsant nebulization and a preparation method thereof.
  • respiratory diseases Due to dense population, high smoking population and environmental pollution, the incidence and mortality of respiratory diseases have remained high in recent years. According to the data of the American Statistical Yearbook, respiratory diseases are classified in all causes of death. The cause of death (excluding tumors) rose from 10th in 1970 to 4th in 1991 (chronic obstructive pulmonary disease) and 8th (pneumonia, flu and upper respiratory tract infection), and respiratory diseases in China The incidence rate is the highest in many age groups. This problem has attracted more and more people's attention. Therefore, the development of drugs for treating respiratory diseases (referred to as respiratory drugs) has become an important research and development field for drug research.
  • respiratory drugs drugs for treating respiratory diseases
  • Cough and sputum are common symptoms of clinical respiratory diseases. Excessive cough, not only increases the pain of patients, affects rest and sleep, increases physical exertion, and even promotes the development of symptoms, resulting in other complications such as pneumonia and chronic Pharyngitis, chronic bronchitis, bronchiectasis, lung abscess and hollow tuberculosis. At this time, in addition to the treatment of respiratory diseases, it is necessary to properly apply antitussive and expectorant drugs to relieve cough. The application of antitussives only relieves symptoms, and it is essential to treat the cause of cough. Most coughs are caused by excessive release of mediators of inflammatory mediators such as bronchitis, asthma, pneumonia, and lung tumors. Therefore, it is necessary to use expectorants for the condition.
  • Fudosteine is a new type of expectorant that belongs to the cysteine derivative. It was first marketed in Japan on December 17, 2001. Its basic pharmacological effects are the inhibition of goblet cell proliferation and the regulation of mucus and dysfunction of mucin in the bronchial secretions.
  • the highly effective and low-toxic peony is expected to be a new generation of similar drugs such as bromhexine, acetylcysteine and carboxymethylcysteine.
  • Fodorstein is a relatively stable compound that, when present alone in the air, is stable even with high humidity and no discoloration occurs. However, when it is used together with a filler which is often used in a solid preparation, such as various sugars, celluloses, and sugar alcohols, discoloration occurs, which not only affects the appearance of the sample, but sometimes causes a decrease in the content.
  • tablets, granules and capsules are marketed in the country, most of which are oral preparations, which have poor fluidity and are easy to absorb moisture, which affects the long-term stability of the preparation, and causes certain damage to the gastrointestinal mucosa during taking.
  • the present invention provides a solution preparation for inhalation of fudosteine which is used for sputum viscous and coughing caused by chronic bronchitis and bronchial asthma. And phlegm block the treatment of tracheal diseases.
  • the solution preparation of fudosteine atomized inhalation of the invention is directly inhaled by the nose and mouth, avoids the first pass effect of the liver and the destruction and degradation of the gastrointestinal tract, and greatly reduces the metabolic process of the drug by the liver and kidney, greatly Reduced organ damage to the patient.
  • the solution formulation of fudosteine nebulized inhalation of the present invention makes up for the gap in the domestic market, and provides a novel safe and effective administration preparation and administration method of fudosteine.
  • the present invention provides a solution preparation for inhalation of fudosteine, which comprises: fudosteine, a salt thereof and/or a hydrate thereof; a metal complexing agent; a pH adjuster and water for injection .
  • the formulation further comprises one or more pharmaceutical excipients suitable for pulmonary administration, the pharmaceutical excipients comprising an antioxidant and a surfactant.
  • the single dose of the preparation comprises: 20 to 120 mg of fudosteine, a salt thereof and/or a hydrate thereof in terms of free formoterol; 0.1 to 5 mg of a metal complexing agent; an appropriate amount of pH adjustment And water for injection.
  • the single dose of the preparation comprises: 50 to 100 mg of fudosteine, a salt thereof and/or a hydrate thereof, 0.5 to 2 mg of a metal complexing agent; and an appropriate amount of pH adjustment And water for injection.
  • the pH adjusting agent is hydrochloric acid or sulfuric acid.
  • the formulation has a pH of from 3 to 9, preferably from 3.5 to 5.5, more preferably from 3.5 to 5.0.
  • the metal complexing agent comprises at least one selected from the group consisting of edetic acid, disodium edetate, and sodium calcium edetate.
  • the formulation is for the treatment of chronic bronchitis, blister thickening caused by bronchial asthma, difficulty in coughing, and obstructive airway disease.
  • the invention also provides a preparation method of the preparation, which comprises the following steps:
  • the drug directly reaches the target organ, avoiding the first-pass effect of the liver and the destruction and degradation of the gastrointestinal tract, and reducing the systemic organs, especially the liver and kidney damage, and the medication is safer.
  • the solution formulation of fudolstat nebulizer for inhalation of the present invention comprises: fudosteine, a salt thereof and/or a hydrate thereof; a metal complexing agent; a pH adjuster; and water for injection.
  • the solution preparation of fudosteine atomized inhalation of the present invention can be used for the treatment of sputum viscous, coughing difficulty, and sputum obstruction of tracheal diseases caused by chronic bronchitis and bronchial asthma.
  • the formulation of the fusidtan aerosol inhalation solution of the present invention is directly inhaled by the nose and mouth, thereby avoiding the first-pass effect of the liver and the destruction and degradation of the gastrointestinal tract, thereby greatly reducing the metabolic process of the drug by the liver and kidney. Greatly reduces organ damage to the patient.
  • the oral dosage form is effective, avoiding the defect that the drug needs to be absorbed by the gastrointestinal tract first, and then exerts a systemic effect with the blood circulation and has a slow onset of action.
  • the solution formulation of fudosteine nebulized inhalation according to the present invention is packaged in a single dose.
  • a single dose refers to the dose of the pharmaceutically active ingredient used in a single inhalation. In the present specification, a single dose means 5 mL.
  • the solution preparation of fudosteine atomized inhalation provided by the invention is a single dose, and the use process is convenient, no dilution and preparation are required, the microbial contamination and waste in the use process can be greatly reduced, and the dose of a single administration is used to avoid the multiple dose.
  • the repeated measurement and repeated dilution caused by the large packaging solution to prepare the microorganisms are easy to breed.
  • the invention provides a new preparation which is lack of medicinal dosage, high quality medicine, stable, safe and simple clinical application and preparation method thereof which is lacking in the prior art.
  • the solution formulation for the inhalation of fudosteine of the present embodiment preferably, it contains 20 to 120 mg of formotetan, a salt thereof and/or a hydrate thereof, more preferably 50 to 50, based on the free form of bupropestan. 100 mg of formotetan, a salt thereof and/or a hydrate thereof.
  • the viscosity of the sputum can be lowered, which is good. It is used for the treatment of chronic bronchitis, bronchial asthma and other sputum viscous, coughing difficulties and obstruction of tracheal diseases.
  • the metal complexing agent contained in the solution preparation for inhalation of fudosteine according to the present invention has a complexing ability and can improve the stability of a solution preparation for fumigsant nebulization.
  • the metal complexing agent examples include edetic acid; edetate such as disodium edetate and sodium edetate. Among these, an edetate is preferred, and disodium edetate is more preferred.
  • edetate such as disodium edetate and sodium edetate.
  • an edetate is preferred, and disodium edetate is more preferred.
  • These metal complexing agents have strong complexing ability to metal ions, and a large number of complexing ions, especially edetate, can avoid the influence of metal ions introduced by the liquid-dispensing process on the quality of the liquid. These metal complexing agents may be used singly or in combination of two or more.
  • the solution preparation for nebulization of fudosteine it is preferably contained in an amount of 0.1 to 5 mg, more preferably 0.5 to 2 mg of a metal complexing agent.
  • a metal complexing agent in the above range, the pharmacological effect of the formulation of the fusidtan aerosol inhalation solution can be promoted, and the stability of the fudosteine can be improved, and even if it is left for a long period of time, the detection indexes are not significantly changed, and it is guaranteed.
  • the product quality is qualified during the validity period.
  • the content of the metal complexing agent is less than 0.1 mg, the stability of fudosteine is deteriorated, and the detection indexes of the long-term placement are significantly changed, and the product quality is lowered. If the content of the metal complexing agent is more than 5 mg, the ingested metal complexing agent such as disodium edetate forms a water-soluble chelate with calcium ions in the human body and is excreted, and excessive intake may cause low Blood calcium or bone calcium loss, so the metal complexing agent in the product, such as disodium edetate content should be reduced as much as possible to ensure effective antioxidant.
  • the solution formulation of the fudosteine atomized inhalation according to the present invention contains a pH adjuster in order to adjust the pH.
  • the pH adjusting agent is not particularly limited as long as it does not impair the effect of the above-described formulation of the solution for inhalation of fudosteine, and examples thereof include hydrochloric acid, sulfuric acid, lactic acid, malic acid, acetic acid, phosphoric acid, and citric acid. These pH adjusters may be used singly or in combination of two or more. Among these, hydrochloric acid or sulfuric acid is more preferable.
  • the content of the pH adjuster can be appropriately determined depending on the content of the other components, so that the pH value of the formulation of the fudosteine atomized inhalation solution becomes a target value.
  • the stability of the fudosteine solution can be increased.
  • the pH of the formulation of the fudosteine atomized inhalation solution of the present invention is preferably from 3 to 9, more preferably from 3.5 to 5.5, still more preferably from 3.5 to 5.0.
  • the solubility of fudosteine can be increased by setting the range of the pH value of the solution preparation for atomization and inhalation of fudosteine to the above range. If the pH is less than 3, there is an adverse effect on the irritation of the human body after inhalation. On the other hand, when the pH exceeds 9, the stability of the solution is deteriorated and the amount of impurities tends to increase, which is not preferable.
  • the solution formulation of the fudosteine nebulized inhalation of the present invention may contain one or more pharmaceutically acceptable excipients suitable for pulmonary administration, as needed.
  • the pharmaceutical excipient is not particularly limited, and examples thereof include an antioxidant, a surfactant, a flavor, a stabilizer, and the like.
  • the pharmaceutical excipients include an antioxidant and a surfactant.
  • the antioxidant may, for example, be preferably sodium metabisulfite, sodium sulfite, sodium hydrogen sulfite, sodium thiosulfate or acetylcysteine.
  • As the surfactant for example, a glycerin fatty acid ester, a sorbitan fatty acid ester, a polyoxyethylene fatty acid ester, a polyethylene glycol fatty acid ester, or a sucrose fatty acid ester can be preferably used.
  • the preparation procedure of the formulation for bupropstatin nebulization in principle, fudosteine, a salt thereof and/or a hydrate thereof; a metal complexing agent; a pH adjuster and an injection Any method of preparing a formulation by mixing with water is suitable for use in the present invention.
  • the preparation method of the solution preparation of the present invention is preferably:
  • Example 1 Preparation of a formulation for bupropstatin nebulization according to the ratio of Formulation 1
  • disodium edetate manufactured by Chengdu Huasheng Pharmaceutical Excipient Manufacturing Co., Ltd.
  • disodium edetate manufactured by Chengdu Huasheng Pharmaceutical Excipient Manufacturing Co., Ltd.
  • the initial filtration was carried out with a 0.45 ⁇ m filter membrane, and the 0.22 ⁇ m filter membrane was subjected to fine filtration, all of which were aseptically filtered, potted in an ampoule, and filled with nitrogen, and the loading amount was 5 mL.
  • the single-dose fustaster spray-inhalation solution preparation obtained in Examples 5 and 8 to 10 (preparation of a solution for bupropestan nebulization according to the formulation of Formulas 5 and 8 to 10) was allowed to stand for one year.
  • the content of fudosteine in the single-dose fostisstat inhalation solution preparation obtained in Examples 5 and 8 to 10 after one year was determined by the following method for measuring the content of fudostatin, and the color of the preparation was visually observed and The change in clarity. The results are shown in Table 1.
  • mice were placed in a special glass bell jar and subjected to a 25% concentrated ammonia quantitative spray using an ultrasonic atomizing sprayer. Immediately after 5 seconds, the mice were removed, and the incubation period from the start of the spray to the occurrence of cough and the number of coughs within 2 minutes were recorded. Remove the person who does not cough 2 minutes after the spray. After 2 days, the qualified mice were randomly divided into a model group, an oral administration group, an injection administration group, and a low-, medium-, and high-dose group for aerosol inhalation administration.
  • the model group was administered with sodium chloride injection by nebulization inhalation, and the preparations used in the low, medium and high dose groups of nebulized inhalation were respectively obtained from Example 1, Example 3 and Example 5, and the doses were 20 in order. 40, 100 mg/kg, the formulation used in the oral administration group and the injection administration group was obtained in Example 5, and the administration dose was 100 mg/kg.
  • the drug was administered once a day for 5 days. One hour after the last administration, 25% concentrated ammonia was quantitatively sprayed, and immediately taken out after 5 s. The incubation period from the start of the spray to the onset of cough and the number of coughs within 2 min were recorded.
  • Table 2 describes the antitussive effect of the model group, the oral administration group of the formulation of fudosteine, the injection group, and the low, medium and high dose groups of nebulized inhalation.
  • mice Sixty mice were randomly divided into a model group, an oral administration group, an injection administration group, and a low-, medium-, and high-dose group for aerosol inhalation according to a random number table. A total of 6 groups, 10 in each group.
  • the model group was inhaled and administered with sodium chloride injection, and the preparations used in the low, medium and high dose groups of nebulized inhalation were prepared from Example 1, Example 3 and Example 5, respectively, and the dose was 12.25.
  • the preparations used in the oral administration group and the injection administration group were prepared at 24.50, 61.25 mg/kg, and the preparation was administered at a dose of 100 mg/kg.
  • Each group was intraperitoneally injected with 0.2 mL of sensitizing solution (OVA 10 ⁇ g + 20 ⁇ g of aluminum hydroxide) on Days 1 and 14 for sensitization. From day 21, the mice were placed at a size of about 0.5 m ⁇ 0.5 m ⁇ 0.5 m. Excitation was carried out in the nebulizer, and 5 mL of 2.5% OVA solution was inhaled by ultrasonic atomizer for 30 min each time, 3 times a week for 6 weeks. The saline group was replaced by intragastric saline, and the other five groups were intragastrically administered, injected, and aerosolized for 10 minutes before each dose of asthma. The amount of 0.1 mL (administerable after appropriate dilution) was administered.
  • the lung tissue was fixed with 40 g/L of paraformaldehyde-phosphate buffer, it was routinely dehydrated and subjected to periodic acid-Schiff (PAS) staining.
  • PAS periodic acid-Schiff
  • Five lung tissue sections were randomly selected from each mouse. Each section was randomly selected from 5 bronchial tubes with a circular cross-section and a diameter of 100 ⁇ m.
  • the bronchial epithelium of each section was measured by image-proplus 6.0 image analysis software.
  • the area of the goblet cells stained in magenta is expressed as a percentage of the total cell area of the bronchial epithelium, and the number of goblet cells is counted. See Table 3 for details of the results of counting the different groups of airway epithelial goblet cells.
  • the dosage of goblet cells was significantly reduced by oral administration or injection of fusidtan.
  • the results were extremely significant (P ⁇ 0.01).
  • low, medium and high doses were administered by nebulization.
  • the dose group was more effective in the experiment of inhibiting goblet cell proliferation than the oral administration group and the injection administration group.

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Abstract

福多司坦雾化吸入用溶液制剂及其制备方法，该福多司坦雾化吸入用溶液制剂包括福多司坦、其盐和/或其水合物；金属络合剂；和注射用水。该福多司坦雾化吸入用溶液制剂的制备方法包含下列步骤：向配液器中加入注射用水，充氮气保护，保持配液罐中氮气为正压，测定残氧小于2 mg/L；称取金属络合剂，搅拌至溶解；加入福多斯坦、其盐和/或其水合物，搅拌至溶解；加入pH调节剂，测定残氧至小于2 mg/L；补加注射用水蛭全量，搅拌至混合均匀；无菌精滤，封装并且充氮气。

Description

一种福多司坦雾化吸入用溶液制剂及其制备方法 技术领域
本发明属于药物制剂领域，具体涉及一种福多司坦雾化吸入用溶液制剂及其制备方法。
背景技术
由于人口密集、吸烟人群较多及环境污染等因素，近年来呼吸***疾病的发病率及病死率均居高不下，据美国统计学年鉴的数据，在所有的死因归类中，与呼吸道相关疾病(不包括肿瘤)的死因排位从1970年的第10位上升到1991年的第4位(慢性阻塞性肺病)及第8位(肺炎、流感及其上呼吸道感染)，而我国呼吸***疾病的发病率在任何年龄组均占多种疾病之首。这一问题日益引起人们的重视，因此治疗呼吸***疾病的药物(简称呼吸药)的开发也成为药物研究的重要研发领域。
咳嗽、咯痰是临床上呼吸***疾病常见的症状，过于频繁的剧咳，不仅增加患者的痛苦，影响休息和睡眠，增加体力消耗，甚至促进病症的发展，产生其他并发症，如肺炎、慢性咽炎、慢性支气管炎、支气管扩张、肺脓肿与空洞型肺结核等。此时除针对呼吸***疾病对症下药治疗外，还需适当应用镇咳祛痰药，以缓解咳嗽。应用镇咳药只是缓解症状，根本的是要针对咳嗽的病因治疗。大多数的咳嗽是由炎症介质如气管炎、哮喘、肺炎和肺肿瘤等病症时过量释放的介质所引起，故还需针对病情使用祛痰药。
福多司坦是一种新型的祛痰药，属于半胱氨酸衍生物。于2001年12月17日首次在日本上市，其基本药理作用是杯状细胞增生抑制和使支气管分泌物中粘蛋白的二巯键断裂对呼吸道的粘液、粘膜正常状态的调节作用，是一种高效低毒的祛痰药，预计将成为溴己新、乙酰半胱氨酸、羧甲基半胱氨酸等同类药的更新换代产品。福多斯坦是一种相对较为稳定的化合物，当其单独存在于空气中时，即使湿度较高也很稳定，而且无变色现象发生。但是，当其与固体制剂中经常使用的填充剂，如各种糖类、纤维素类、糖醇类在一起使用时会发生变色，不仅影响样品的外观，有时还会引起含量的降低。
目前，国内只有片剂、颗粒剂、胶囊剂上市，大多为口服制剂，流动性 差，易吸湿而影响制剂的长期稳定，且在服用中会对胃肠道黏膜造成一定的损伤。
发明内容
技术问题
有鉴于此，本发明要解决的技术问题是，本发明提供了一种福多司坦雾化吸入用溶液制剂，其用于慢性支气管炎、支气管哮喘等引起的痰液粘稠、咳痰困难和痰阻塞气管疾病的治疗。本发明的福多司坦雾化吸入用溶液制剂由口鼻直接吸入，避免了肝脏的首过效应及胃肠道的破坏与降解，并且大大减少了由肝肾对药物的代谢过程，极大降低了对患者的器官损伤。本发明的福多司坦雾化吸入用溶液制剂弥补了目前国内市场上的空白，提供了一种福多司坦新型安全有效的给药制剂及给药方式。
解决方案
本发明提供一种福多司坦雾化吸入用溶液制剂，其特征在于，所述制剂包括：福多司坦、其盐和/或其水合物；金属络合剂；pH调节剂和注射用水。
在优选的实施方案中，所述制剂还包括一种或多种适用于肺部给药的药用辅料，所述药用辅料包括抗氧化剂和表面活性剂。
在优选的实施方案中，所述制剂单剂量包含：以游离福多司坦计20～120mg福多司坦、其盐和/或其水合物；0.1～5mg金属络合剂；适量的pH调节剂；和注射用水。
在优选的实施方案中，所述制剂单剂量包含：以游离福多司坦计50～100mg福多司坦、其盐和/或其水合物；0.5～2mg金属络合剂；适量的pH调节剂；和注射用水。
在优选的实施方案中，所述pH调节剂为盐酸或硫酸。
在优选的实施方案中，所述制剂的pH值为3～9，优选为3.5～5.5，更优选为3.5～5.0。
在优选的实施方案中，所述金属络合剂包含选自由依地酸、依地酸二钠和依地酸钙钠组成的组中的至少一种。
在优选的实施方案中，所述制剂用于慢性支气管炎、支气管哮喘引起的痰液粘稠、咳痰困难和痰阻塞气管疾病的治疗。
本发明还提供一种所述制剂的制备方法，其包括如下步骤：
(1)向配液器中加入50～80％用水总量的注射用水，水温控制在25±10℃，并向注射用水内充氮气保护，持续至配液结束，并保持配液罐中氮气正压，测定残氧小于2mg/L后进行下一步操作；
(2)称取金属络合剂，缓缓加入至上述注射用水中，搅拌至金属络合剂全部溶解；
(3)缓慢加入福多司坦、其盐和/或其水合物，搅拌至其全部溶解；
(4)加入pH调节剂调节pH，同时测定残氧至小于2mg/L进行下一步操作；
(5)补加注射用水至全量，搅拌使其混合均匀；
(6)用0.45μm滤膜进行初滤，0.22μm滤膜进行精滤，均为无菌过滤，灌封于安瓿中，并充氮气，装量为5ml。
有益效果
与现有技术相比，本发明的有益效果是：
(1)与其他剂型相比，药物直接到达靶器官，避免了肝脏的首过效应及胃肠道的破坏与降解，降低了全身器官尤其是肝肾损伤，用药更安全。
(2)本发明的福多司坦雾化吸入用溶液制剂由于是吸入式的，针对呼吸***疾病相比较口服剂型见效快，避免了药物需先经胃肠道吸收，然后再随血液循环发挥全身作用，起效慢的缺陷。
(3)提高了福多司坦的稳定性，长期放置各项检测指标没有明显变化，保证有效期内产品质量合格。
(4)加入的辅料种类少，用药安全性高；生产工艺简单，成本低，可以工业化规模生产。
具体实施方式
以下将详细说明本发明的各种示例性实施例、特征和方面。
另外，为了更好的说明本发明，在下文的具体实施方式中给出了众多的具体细节。本领域技术人员应当理解，没有某些具体细节，本发明同样可以实施。下列实施例仅用于说明本发明，而不应视为限制本发明的范围。凡依照本发明内容进行的任何本领域的等同替换，均属于本发明的保护范围。
本发明的福多司坦雾化吸入用溶液制剂包括：福多司坦、其盐和/或其水 合物；金属络合剂；pH调节剂；和注射用水。
通过使用本发明的福多司坦雾化吸入用溶液制剂，能够用于慢性支气管炎、支气管哮喘等引起的痰液粘稠、咳痰困难和痰阻塞气管疾病的治疗。另外，本发明的福多司坦雾化吸入用溶液制剂由口鼻直接吸入，避免了肝脏的首过效应及胃肠道的破坏与降解，大大减少了由肝肾对药物的代谢过程，极大降低了对患者的器官损伤。并且，针对呼吸***疾病相比较口服剂型见效快，避免了药物需先经胃肠道吸收，然后再随血液循环发挥全身作用，起效慢的缺陷。
本发明所述的福多司坦雾化吸入用溶液制剂采用单剂量药物包装。单剂量是指单次吸入所使用的药用活性成分的剂量。在本说明书中，单剂量表示5mL。
本发明提供的福多司坦雾化吸入用溶液制剂为单剂量，使用过程便捷，无需稀释、配制，可大大降低使用过程中的微生物污染和浪费，采用单次用药的剂量而避免了多剂量大包装溶液所导致的反复量取、反复稀释配制易滋生微生物的弊端。
本发明提供了一种现有技术所缺乏的药用剂量准确、药品质量优质、稳定、临床应用安全、简捷的新制剂及其制备方法。
以下，针对构成本发明所述的福多司坦雾化吸入用溶液制剂的各成分进行说明。
[福多司坦、其盐和/或其水合物]
本实施方案的福多司坦雾化吸入用溶液制剂单剂量中，以游离福多司坦计，优选含有20～120mg福多司坦、其盐和/或其水合物，更优选含有50～100mg福多司坦、其盐和/或其水合物。
本发明所述的福多司坦雾化吸入用溶液制剂单剂量中的福多司坦、其盐和/或其水合物的含量为上述范围内时，能够使痰液的黏稠性降低，良好地用于慢性支气管炎、支气管哮喘等引起的痰液粘稠、咳痰困难和痰阻塞气管疾病的治疗。
[金属络合剂]
本发明所述的福多司坦雾化吸入用溶液制剂中包含的金属络合剂具有络合能力，能够提高福多司坦雾化吸入用溶液制剂的稳定性。
作为金属络合剂的实例，例如可以列举出依地酸；依地酸二钠、依地酸钙钠等依地酸盐等。这些之中，优选依地酸盐，更优选为依地酸二钠。这些金属络合剂对金属离子有较强的络合能力，并且络合的离子种类众多，尤其是依地酸盐，可以避免由配液过程引入的金属离子对药液质量产生影响。这些金属络合剂可以单独使用，或两种以上混合使用。
在福多司坦雾化吸入用溶液制剂单剂量中，优选包含0.1～5mg、更优选包含0.5～2mg金属络合剂。通过以上述范围含有金属络合剂，能够促进福多司坦雾化吸入用溶液制剂的药效发挥，提高福多司坦的稳定性，即使长期放置，各项检测指标也没有明显变化，保证有效期内产品质量合格。
如果金属络合剂的含量小于0.1mg，福多司坦的稳定性变差，长期放置后各项检测指标变化明显，产品质量降低。如果金属络合剂的含量大于5mg，摄入的金属络合剂例如依地酸二钠会与人体中的钙离子形成水溶性螯合物，被排出体外，过多的摄入可能会导致低血钙症或骨钙流失，故产品中金属络合剂例如依地酸二钠含量在保证有效抗氧化的前提下应尽可能降低。
[pH调节剂]
本发明所述的福多司坦雾化吸入用溶液制剂为了调节pH值，包含pH调节剂。
作为pH调节剂，只要不损害上述福多司坦雾化吸入用溶液制剂的效果就没有特别限制，例如可列举出盐酸、硫酸、乳酸、苹果酸、醋酸、磷酸、枸橼酸等。这些pH调节剂可以单独地使用，或也可以组合多种使用。这些之中，更优选盐酸或硫酸。
pH调节剂的含量可根据其它成分的含量适宜决定，以使福多司坦雾化吸入用溶液制剂的pH值变为目标值。通过含有pH调节剂，能够增加福多司坦溶液的稳定性。
本发明所述的福多司坦雾化吸入用溶液制剂的pH值优选为3～9，更优选为3.5～5.5，进一步更优选为3.5～5.0。通过将福多司坦雾化吸入用溶液制剂的pH值的范围设为上述的范围，可以增加福多司坦的溶解性。如果pH值小于3，有吸入后对人体内刺激性过大的不利效果。另一方面，如果pH值超过9，有溶液的稳定性变差，杂质增多的倾向，故不优选。
[药用辅料]
本发明所述的福多司坦雾化吸入用溶液制剂根据需要可以包含一种或多种适用于肺部给药的药用辅料。
对于药用辅料没有特别地限制，其实例包括抗氧化剂、表面活性剂、矫味剂、稳定剂等。优选地，药用辅料包括抗氧化剂和表面活性剂。作为抗氧化剂，例如可优选列举出焦亚硫酸钠、亚硫酸钠、亚硫酸氢钠、硫代硫酸钠、乙酰半胱氨酸等。作为表面活性剂，例如可优选列举出甘油脂肪酸酯、脱水山梨醇脂肪酸酯、聚氧乙烯脂肪酸酯、聚乙二醇脂肪酸酯、蔗糖脂肪酸酯等。
<福多司坦雾化吸入用溶液制剂的制备方法>
在本发明中，对于福多司坦雾化吸入用溶液制剂的制备步骤没有特别限制，原则上将福多司坦、其盐和/或其水合物；金属络合剂；pH调节剂和注射用水混合制备制剂的任何方法均适用于本发明。本发明的溶液制剂的制备方法优选为：
(1)向配液器中加入50～80％用水总量的注射用水，水温控制在25±10℃，并向注射用水内充氮气保护，持续至配液结束，并保持配液器中氮气正压，测定残氧小于2mg/L后进行下一步操作；
(2)称取金属络合剂，缓缓加入至上述注射用水中，搅拌至金属络合剂全部溶解；
(3)缓慢加入福多司坦、其盐和/或其水合物，搅拌至其全部溶解；
(4)加入pH调节剂调节pH，同时测定残氧至小于2mg/L进行下一步操作；
(5)补加注射用水至全量，搅拌使其混合均匀；
(6)用0.45μm滤膜进行初滤，0.22μm滤膜进行精滤，均为无菌过滤，灌封于安瓿中，并充氮气，装量为5ml。
实施例
以下，参照实施例对本发明进行详述，但本发明的保护范围不限于此。
处方1：福多司坦雾化吸入用溶液制剂1000mL
Figure PCTCN2018087524-appb-000001
处方2：福多司坦雾化吸入用溶液制剂1000mL
Figure PCTCN2018087524-appb-000002
处方3：福多司坦雾化吸入用溶液制剂1000mL
Figure PCTCN2018087524-appb-000003
处方4：福多司坦雾化吸入用溶液制剂1000mL
Figure PCTCN2018087524-appb-000004
处方5：福多司坦雾化吸入用溶液制剂1000mL
Figure PCTCN2018087524-appb-000005
处方6：福多司坦雾化吸入用溶液制剂1000mL
Figure PCTCN2018087524-appb-000006
处方7：福多司坦雾化吸入用溶液制剂1000mL
Figure PCTCN2018087524-appb-000007
处方8：福多司坦雾化吸入用溶液制剂1000mL
Figure PCTCN2018087524-appb-000008
处方9：福多司坦雾化吸入用溶液制剂1000mL
Figure PCTCN2018087524-appb-000009
处方10：福多司坦雾化吸入用溶液制剂1000mL
Figure PCTCN2018087524-appb-000010
实施例1：根据处方1的比例，制备福多司坦雾化吸入用溶液制剂
向配液器中加入用水总量70％的注射用水700mL，水温控制在30℃，并向注射用水内充氮气保护，持续至配液结束，并保持配液器中氮气正压，测定残氧为1.6mg/L后进行下一步操作。
然后，称取20mg依地酸二钠(由成都华邑药用辅料制造有限责任公司制造)，缓缓加入至上述注射用水中，搅拌至依地酸二钠全部溶解。
接着，缓慢加入4g福多司坦(由威海迪素制药有限公司制造)，搅拌至其全部溶解。
然后，加入适量盐酸调节pH至3.0，同时测定残氧为1.5mg/L进行下一步操作。
接着，补加注射用水至全量1000mL，搅拌5分钟使其混合均匀。
然后，用0.45μm滤膜进行初滤，0.22μm滤膜进行精滤，均为无菌过滤，灌封于安瓿中，并充氮气，装量为5mL。
实施例2～10
实施例2～10中，除了使用处方2～10代替处方1以外，与实施例1同样地制备福多司坦雾化吸入用溶液制剂。
为了进一步说明本发明的技术效果，提供以下具体实验例。
实验例1
将实施例5、8～10(根据处方5、8～10的配方制备福多司坦雾化吸入用溶液制剂)得到的单剂量福多司坦雾化吸入用溶液制剂放置一年。通过下述福多司坦含量的测定方法测定一年后实施例5、8～10得到的单剂量福多司坦雾化吸入用溶液制剂中福多司坦含量，并且通过目测观察制剂颜色和澄清度的变化。结果示于表1中。
福多司坦含量的测定
(1)使用十八烷基硅烷键合硅胶为填充剂(4.6×150mm，5μm)，以含5mmol/L庚烷磺酸钠溶液的1‰磷酸溶液为流动相，检测波长为210nm，柱温为50℃，流速为1.3mL/min。
(2)精密量取上述试样品适量，用流动相定量稀释制成每lmL中含福多司坦0.5mg的溶液，作为待测试样品溶液；另外精密称取福多司坦对照品适量，加流动相溶解并定量稀释制成每lmL中含福多司坦0.5mg的溶液，作为对照品溶液。精密量取待测试样品溶液与对照品溶液各10μL，分别注入液相色谱仪，记录色谱图。按外标法以峰面积计算，得到福多司坦含量。
表1
Figure PCTCN2018087524-appb-000011
由表1可见，使用盐酸或者硫酸作为pH调节剂，福多司坦雾化吸入用溶液制剂即使放置一年，福多司坦的含量也较高并且稳定性优异，制剂颜色和澄清度变化小。另一方面，使用醋酸和醋酸钠以及使用磷酸和磷酸二氢钠作为pH调节剂，福多司坦雾化吸入用溶液制剂放置一年后，福多司坦的含量下 降，制剂颜色和澄清度变化较大。
实验例2
镇咳实验(浓氨水喷雾法)
实验小鼠置于特制的玻璃钟罩内，使用超声雾化喷雾器进行25％浓氨水定量喷雾，5s后立即取出，记录小鼠从接受喷雾开始到出现咳嗽的潜伏期，以及2min内的咳嗽次数。剔除喷雾后2min不咳嗽者。合格小鼠2d后随机分成模型组、口服给药组、注射剂给药组、雾化吸入给药低、中、高剂量组。
模型组雾化吸入给药氯化钠注射液，雾化吸入给药低、中、高剂量组使用的制剂分别由实施例1、实施例3、实施例5得到，给药剂量依次为20、40、100mg/kg，口服给药组和注射剂给药组使用的制剂由实施例5得到，给药剂量为100mg/kg。每天给药1次，连续给药5d。于末次给药后1h，25％浓氨水定量喷雾，5s后立即取出。记录小鼠从接受喷雾开始到出现咳嗽的潜伏期及2min内的咳嗽次数。具体结果见表2，其中记载了模型组、福多司坦制剂的口服给药组、注射剂给药组及雾化吸入给药低、中、高剂量组的镇咳作用。
表2
Figure PCTCN2018087524-appb-000012
与模型组比较**P<0.01
结果表明，与模型组相比，经口服、注射剂和雾化给药福多司坦制剂均能明显减少动物咳嗽潜伏期，并减少2min内咳嗽次数，差异具有极显著性(P<0.01)。其中雾化吸入给药低、中、高剂量组在延长咳嗽潜伏期和减少2min内咳嗽数上均比口服给药组和注射剂给药组的镇咳效果好。
实验例3
抑制小鼠气道杯状细胞增生实验
3.1哮喘模型的建立
60只小鼠按随机数字表法随机分为模型组、口服给药组、注射剂给药组、雾化吸入给药低、中、高剂量组，共6组，每组10只。模型组雾化吸入给药氯化钠注射液，雾化吸入给药低、中、高剂量组使用的制剂分别由实施例1、实施例3、实施例5制备得到，给药剂量依次为12.25、24.50、61.25mg/kg，口服给药组和注射剂给药组使用的制剂由实施例5制备得到，给药剂量为100mg/kg。
每组均在第1和第14天分别腹腔注射0.2mL致敏液(OVA10μg+氢氧化铝20μg)进行致敏，从第21天起将小鼠置于约0.5m×0.5m×0.5m大小的雾化吸入箱中进行激发，通过超声雾化器雾化吸入2.5％OVA溶液5mL，每次30min，每周3次，连续6周。生理盐水组以灌胃生理盐水代替给药，其他五组每次雾化激发哮喘前10min分别灌胃、注射及雾化给药0.1mL(可适当稀释后给药)的量。
3.2标本收集
末次雾化吸入24h后，以10g/L戊巴比妥钠(40mg/kg)腹腔注射麻醉后，结扎右肺主支气管。1mL注射器注入左主支气管，以20cm H 2O(1cm H 2O＝0.098kPa)压力灌注40g/L的多聚甲醛－磷酸盐缓冲液入左肺，切取左肺并浸泡于40g/L多聚甲醛－磷酸缓冲液中24h。
3.3气道上皮杯状细胞计数
肺组织40g/L多聚甲醛－磷酸缓冲液固定后，常规脱水包埋，进行过碘酸－雪夫(PAS)染色。每只小鼠随机选5张肺组织切片，每张切片以单盲法随机选取横断面较圆、直径100μm的支气管5支进行观察，采用image-proplus6.0图像分析软件测量每张切片支气管上皮中被染成***的杯状细胞的面积，以其占所在支气管上皮总细胞面积的百分比表示，并计算杯状细胞数量。具体见表3，其中示出了不同组别气道上皮杯状细胞的计数结果。
表3
Figure PCTCN2018087524-appb-000013
与模型组比较**P<0.01
与模型组相比，经口服、注射剂雾化给药福多司坦制剂均能明显减少杯状细胞数量，结果具有极显著差异(P＜0.01)；其中雾化吸入给药低、中、高剂量组与口服给药组和注射剂给药组相比，其在抑制杯状细胞增生的实验中效果更好。
以上所述，仅为本发明的具体实施方式，但本发明的保护范围并不局限于此，任何熟悉本技术领域的技术人员在本发明揭露的技术范围内，可轻易想到变化或替换，都应涵盖在本发明的保护范围之内。因此，本发明的保护范围应以所述权利要求的保护范围为准。

Claims (9)

  1. 一种福多司坦雾化吸入用溶液制剂，其特征在于，所述制剂包括：福多司坦、其盐和/或其水合物；金属络合剂；pH调节剂和注射用水。
  2. 根据权利要求1所述的制剂，其特征在于，所述制剂还包括一种或多种适用于肺部给药的药用辅料，所述药用辅料包括抗氧化剂和表面活性剂。
  3. 根据权利要求1或2所述的制剂，其特征在于，所述制剂单剂量包含：以游离福多司坦计20～120mg福多司坦、其盐和/或其水合物；0.1～5mg金属络合剂；适量的pH调节剂；和注射用水。
  4. 根据权利要求1～3任一项所述的制剂，其特征在于，所述制剂单剂量包含：以游离福多司坦计50～100mg福多司坦、其盐和/或其水合物；0.5～2mg金属络合剂；适量的pH调节剂；和注射用水。
  5. 根据权利要求1～4任一项所述的制剂，其特征在于，所述pH调节剂为盐酸或硫酸。
  6. 根据权利要求1～5任一项所述的制剂，其特征在于，所述制剂的pH值为3～9，优选为3.5～5.5，更优选为3.5～5.0。
  7. 根据权利要求1～6任一项所述的制剂，其特征在于，所述金属络合剂包含选自由依地酸、依地酸二钠和依地酸钙钠组成的组中的至少一种。
  8. 根据权利要求1～7任一项所述的制剂，其特征在于，其用于慢性支气管炎、支气管哮喘引起的痰液粘稠、咳痰困难和痰阻塞气管疾病的治疗。
  9. 根据权利要求1～8任一项所述的制剂的制备方法，其特征在于，其包括如下步骤：
    (1)向配液器中加入50～80％用水总量的注射用水，水温控制在25±10℃，并向注射用水内充氮气保护，持续至配液结束，并保持配液罐中氮气正压，测定残氧小于2mg/L后进行下一步操作；
    (2)称取金属络合剂，缓缓加入至上述注射用水中，搅拌至金属络合剂全部溶解；
    (3)缓慢加入福多司坦、其盐和/或其水合物，搅拌至其全部溶解；
    (4)加入pH调节剂调节pH，同时测定残氧至小于2mg/L进行下一步操作；
    (5)补加注射用水至全量，搅拌使其混合均匀；
    (6)用0.45μm滤膜进行初滤，0.22μm滤膜进行精滤，均为无菌过滤，灌 封于安瓿中，并充氮气，装量为5ml。
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