WO2019091082A1 - 一种羧甲司坦雾化吸入用溶液制剂及其制备方法 - Google Patents

一种羧甲司坦雾化吸入用溶液制剂及其制备方法 Download PDF

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WO2019091082A1
WO2019091082A1 PCT/CN2018/087527 CN2018087527W WO2019091082A1 WO 2019091082 A1 WO2019091082 A1 WO 2019091082A1 CN 2018087527 W CN2018087527 W CN 2018087527W WO 2019091082 A1 WO2019091082 A1 WO 2019091082A1
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preparation
water
injection
complexing agent
solution preparation
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French (fr)
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张保献
胡杰
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Beijing Increase Innovation Drug Research Co Ltd
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Beijing Increase Innovation Drug Research Co Ltd
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Priority to EP18876729.7A priority patent/EP3708153A4/en
Publication of WO2019091082A1 publication Critical patent/WO2019091082A1/zh
Priority to US16/868,702 priority patent/US20200261362A1/en
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    • 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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/12—Aerosols; Foams
    • 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
    • A61K9/0012—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
    • 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
    • A61K47/02—Inorganic compounds
    • 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
    • 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
    • A61P11/08—Bronchodilators
    • 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

Definitions

  • the invention belongs to the field of pharmaceutical preparations, and in particular relates to a solution preparation for nebulization of carboxamide 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 coughing, not only increases the suffering of patients, affects rest and sleep, increases physical exertion, and even promotes the development of the disease, causing other complications such as pneumonia. 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.
  • peony drugs are compound chemotherapy drugs with central antitussive drug codeine or dextromethorphan hydrobromide and peopic guaiacol glyceryl ether as active ingredients.
  • the effect of dextromethorphan is similar to or stronger than codeine.
  • the US FDA issued a notice stating that improper use of dextromethorphan may cause death or other negative effects, such as brain damage, loss of consciousness and arrhythmia.
  • Patent Document 1 discloses an oral solution of carboxymethacetin and a preparation method thereof for treating sputum viscous or coughing difficulty caused by diseases such as chronic bronchitis and bronchial asthma.
  • the oral solution comprises 2 to 10% of carboxymethacetin, sodium hydroxide, an antioxidant, a solution stabilizer combination, and a flavoring agent having a pH of 6.0 to 7.5.
  • the above oral solution of carboxymethacetin is prepared by dissolving carboxymethine into a salt with sodium hydroxide solution, then adding an antioxidant, a solution stabilizer combination and a flavoring agent, stirring, constant volume, filtration, canning and Made after sterilization.
  • Patent Document 1 has an adverse effect of a large amount of oral liquid administration, a large amount of liver and kidney metabolism, an easy organ damage, a small amount of drug reaching a target organ, and a slow onset of action.
  • Patent Document 1 CN 104511025A
  • the technical problem to be solved by the present invention is to provide a solution preparation for nebulization of carbamazepine for use in chronic bronchitis, bronchial asthma, etc., sputum viscous, coughing difficulty, and obstruction of the trachea Treatment of the disease.
  • the solution preparation for inhalation of carbostatin of the 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, and greatly reducing Organ damage to the patient.
  • the solution preparation for inhalation of carboxymethacetin 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 carboxymethacetin.
  • the present invention provides a solution preparation for nebulization of carboxamide, which comprises: carboxamide, 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 carboxymethine, a salt thereof and/or a hydrate thereof, of 0.1 to 5 mg of a metal complexing agent; And water for injection.
  • the single dose of the preparation comprises: 50 to 100 mg of carboxymethine, a salt thereof and/or a hydrate thereof, 0.5 to 2 mg of a metal complexing agent, and a suitable amount of pH adjustment. And water for injection.
  • the pH adjusting agent is sodium hydrogencarbonate, sodium hydroxide, disodium hydrogen phosphate, sodium citrate or dipotassium hydrogen phosphate.
  • the formulation has a pH of from 5 to 8.
  • the formulation has a pH of from 6 to 7.
  • the metal complexing agent comprises at least one selected from the group consisting of edetic acid, disodium edetate, and sodium calcium edetate.
  • the solution for inhalation of carboxamide is used for the treatment of chronic bronchitis, sputum viscous bronchial asthma, difficulty in coughing, and obstructive airway disease.
  • the invention also provides a preparation method of the above-mentioned solution preparation for nebulization of carboxamide, 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.
  • auxiliary materials to be added are small, the safety of the medicine is high, the production process is simple, the cost is low, and the production can be industrialized.
  • the solution preparation for nebulization of carbostatin of the present invention comprises: carboxamide, a salt thereof and/or a hydrate thereof; a metal complexing agent; a pH adjuster; and water for injection.
  • the solution preparation for nebulization of carbamazepine 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, bronchial asthma and the like.
  • the solution preparation for inhalation of carbocysteine 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, and 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 preparation for nebulization of carbostatin according to the present invention is packaged in a single dose of a drug.
  • 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 for inhalation of carbostatin provided by the invention is a single dose, and the use process is convenient, no need to be diluted and formulated, the microbial contamination and waste during use can be greatly reduced, and the multi-dose large packaging solution is avoided. Repeatedly measuring and repeatedly diluting the drawbacks of easily breeding microorganisms.
  • the invention provides a new preparation and a preparation method thereof which are lack of the prior art, the medicine dosage is accurate, the medicine quality is high quality and stable, the clinical application is safe and simple.
  • the solution preparation for nebulization of carboplatin in the present embodiment it is preferably contained in an amount of 20 to 120 mg of carboxymethine, a salt thereof and/or a hydrate thereof, and more preferably 50 to 50 parts by weight of carboxymethyl sultan. 100 mg of carboxymethacetin, 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 nebulization of carboxamide of the present invention has a complexing ability and can improve the stability of the preparation.
  • 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.
  • a single dose of the solution preparation for nebulization of carboxamide it is preferred to contain 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, it is possible to promote the pharmacological effect of the solution preparation of the carbostatin atomized inhalation, and to improve the stability of the solution preparation for the inhalation of carboxamide, even if it is left for a long period of time, various detection indexes There has also been no significant change to ensure the quality of the products during the validity period.
  • the content of the metal complexing agent is less than 0.1 mg, the stability of carboxymethacetin 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 preparation for nebulization of carbamazepine 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-mentioned solution for inhalation of carboxamide, and examples thereof include sodium hydrogencarbonate, sodium hydroxide, disodium hydrogen phosphate, sodium citrate, and hydrogen phosphate.
  • These pH adjusters may be used singly or in combination of two or more.
  • sodium hydrogencarbonate, sodium hydroxide, disodium hydrogen phosphate, sodium citrate, and dipotassium hydrogen phosphate are more preferable.
  • the content of the pH adjuster can be appropriately determined depending on the content of the other components, so that the pH of the solution preparation for the inhalation of carboxamide is changed to a target value.
  • the content of the pH adjuster is preferably from 10.8 to 12.4 mg/mL, more preferably from 11.2 to 11.4 mg/mL.
  • the pH of the solution preparation for nebulization of carboxymate according to the present invention is preferably from 5 to 8, more preferably from 6 to 7.
  • the solubility of carboxymethacetin can be increased by setting the range of the pH of the solution preparation for the inhalation of carboxamide to the above range. If the pH is less than 5, there is an unfavorable effect of incomplete dissolution of the carboxymethine raw material in water. On the other hand, when the pH exceeds 8, the color of the solution turns yellow and the amount of impurities tends to increase, which is not preferable.
  • the solution preparation for nebulization of carboplatin according to 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 step of the solution preparation for nebulization of carboxamide is not particularly limited, and in principle, carboxymethacetin, 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 preparation of the present invention is preferably:
  • Prescription 1 Single-dose solution preparation for carboplatin nebulization
  • Prescription 7 Single-dose solution preparation for carboplatin nebulization
  • Prescription 8 Single-dose solution preparation for carboplatin nebulization
  • Prescription 9 Single-dose solution preparation for carboplatin nebulization
  • Prescription 10 Single-dose solution preparation for carboplatin nebulization
  • Prescription 12 Single-dose solution preparation for carboplatin nebulization
  • Prescription 13 Single-dose solution preparation for carboplatin nebulization
  • Prescription 14 Single-dose solution preparation for carboplatin nebulization
  • Example 1 Preparation of a solution of carbamazepine atomized inhalation solution 1000 mL 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.
  • a solution preparation solution for carboplatin nebulization was prepared in the same manner as in Example 1 except that the ratio of the prescriptions 2 to 13 was used instead of the prescription 1.
  • a solution preparation solution for carboplatin nebulization was prepared in the same manner as in Example 1 except that the ratio of the prescription 14 was used instead of the prescription 1.
  • a single-dose solution of carbamazepine nebulized inhalation obtained in Examples 5, 8 and 9 was allowed to stand for one year.
  • the carboxymethylstatin content in the single-dose carbamazepine nebulized solution preparation obtained in Examples 5, 8 and 9 after one year was determined by the following method for measuring the content of carboxymethylstatin, and the color of the preparation was visually observed and Clarity. The results are shown in Table 1.
  • the solution preparation for the nebulization of carbostatin of the present invention has a high content of carboxymethacetin even if it is left for one year, and the stability of carboxymethacetin is excellent, and the color and clarity of the preparation are small.
  • Example 10 to 13 and Comparative Example 1 prepared according to the formulation of Formulations 10 to 14 to prepare a solution preparation for inhalation of carbocystein
  • Example 10 to 13 and Comparative Example 1 were placed in a single dose of a solution for inhalation of carbostatin for one year.
  • the content of carboxymethylstatin in a single-dose solution of carbamazepine nebulized inhalation obtained in Examples 10 to 13 and Comparative Example 1 after one year was measured by the above-described method for measuring the content of carboxymethylstatin, and the color of the preparation was visually observed. And clarity.
  • Table 2 The results are shown in Table 2.
  • the solution preparation for the nebulization of carbostatin of the present invention has a high content of carboxymethacetin even if it is left for one year, and the stability of carboxymethacetin is excellent, and the color and clarity of the preparation are small.
  • Comparative Example 1 which did not contain disodium edetate, the content of carboxymethacetin was significantly lowered after one year of storage, and the color of the preparation was significantly changed, and slight turbidity also occurred.
  • mice Sixty mice (20 ⁇ 2g), half male and half female, were randomly divided into normal control group, oral administration group and nebulized administration group, a total of 3 groups, 20 in each group.
  • the nebulized inhalation administration group was supplied with the solution preparation for nebulization of carboxystatin prepared according to Example 5, and the oral administration group was orally administered with the above-mentioned commercially available carbostatin oral solution, and the normal control group was intraperitoneally injected.
  • the physiological saline was administered continuously for 2 weeks, every day at 10 am and 4 pm, 0.1 mL each time.
  • AST aspartate aminotransferase
  • ALP alkaline phosphatase
  • ALT alanine aminotransferase
  • mice in the oral administration group were significantly increased (P ⁇ 0.01), and the ALP, ALT, and AST activities of the mice in the nebulized administration group were significantly lower (Comparatively).
  • P ⁇ 0.01 the nebulized inhalation administration group had little effect on liver injury, and the medication was safer.

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Abstract

本发明提供一种羧甲司坦雾化吸入用溶液制剂及其制备方法。本发明的羧甲司坦雾化吸入用溶液制剂包括：羧甲司坦、其盐和/或其水合物；金属络合剂；pH调节剂；和注射用水。本发明的羧甲司坦雾化吸入用溶液制剂具有高效、低毒、稳定性好、安全度高的特点，特别是极大地降低了患者用药的肝肾毒性。

Description

一种羧甲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，具体涉及一种羧甲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，近年来呼吸系统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)，而我国呼吸系统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，因此治疗呼吸系统疾病的药物(简称呼吸药)的开发也成为药物研究的重要研发领域。
咳嗽、咯痰是临床上呼吸系统疾病常见的症状，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，甚至还促进病症的发展，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。此时除针对呼吸系统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。
目前常用的祛痰药多是以中枢性镇咳药可待因或氢溴酸右美沙芬与祛痰药愈创木酚甘油醚为有效成份的复方化学药物。右美沙芬作用与可待因相似或较强，2005年6月，美国FDA发布公告指出，右美沙芬不当使用可能造成死亡或者其他负面作用，比如大脑损伤、失去意识和心律不齐等。
近年来，羧甲司坦用于慢性支气管炎、支气管哮喘等疾病引起的痰液粘稠、咳痰困难和痰阻塞气管等疾病的治疗，主要作用于支气管腺体的分泌，使低粘度的唾液粘蛋白分泌增加，高粘度的岩藻粘蛋白产生减少，因而使痰液的粘稠性降低而易于咳出。专利文献1公开了一种羧甲司坦口服溶液及其制备方法，其用于治疗慢性支气管炎、支气管哮喘等疾病引起的痰液粘稠或 咳痰困难。该口服溶液包含2～10％的羧甲司坦、氢氧化钠、抗氧化剂、溶液稳定剂组合和矫味剂，其pH值为6.0～7.5。上述羧甲司坦口服溶液通过将羧甲司坦用氢氧化钠溶液成盐后溶于水中，然后加入抗氧化剂、溶液稳定剂组合和矫味剂，经搅拌、定容、过滤、罐装和灭菌后制得。然而，专利文献1存在口服液服用量大、肝肾代谢较多、容易造成器官损伤、到达靶器官的药量较少、起效较慢等不利效果。
现有技术文献
专利文献
专利文献1：CN 104511025A
发明内容
技术问题
有鉴于此，本发明要解决的技术问题是提供一种羧甲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。本发明的羧甲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。
本发明的羧甲司坦雾化吸入用溶液制剂弥补了目前国内市场上的空白，提供了一种羧甲司坦新型安全有效的给药制剂及给药方式。
解决方案
本发明提供一种羧甲司坦雾化吸入用溶液制剂，其包括：羧甲司坦、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：以游离羧甲司坦计20～120mg羧甲司坦、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：以游离羧甲司坦计50～100mg羧甲司坦、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调节剂为碳酸氢钠、氢氧化钠、磷酸氢二钠、枸橼酸钠或磷酸氢二钾。
在优选的实施方案中，所述制剂的pH值为5～8。
在优选的实施方案中，所述制剂的pH值为6～7。
在优选的实施方案中，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，所述羧甲司坦雾化吸入用溶液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。
本发明还提供一种上述羧甲司坦雾化吸入用溶液制剂的制备方法，其包括以下步骤：
(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)缓慢加入羧甲司坦、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)本发明的羧甲司坦雾化吸入用溶液制剂由于是吸入式的，针对呼吸系统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)提高了羧甲司坦的稳定性，长期放置后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。
<羧甲司坦雾化吸入用溶液制剂>
本发明的羧甲司坦雾化吸入用溶液制剂包括：羧甲司坦、其盐和/或其水合物；金属络合剂；pH调节剂；和注射用水。
通过使用本发明的羧甲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，本发明的羧甲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，针对呼吸系统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。
本发明所述的羧甲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。
本发明提供的羧甲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，并且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、药品质量优质且稳定、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羧甲司坦雾化吸入用溶液制剂的各成分进行说明。
[羧甲司坦、其盐和/或其水合物]
本实施方案的羧甲司坦雾化吸入用溶液制剂单剂量中，以游离羧甲司坦 计，优选含有20～120mg羧甲司坦、其盐和/或其水合物，更优选含有50～100mg羧甲司坦、其盐和/或其水合物。
本发明所述的羧甲司坦雾化吸入用溶液制剂单剂量中的羧甲司坦、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]
本发明所述的羧甲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，可以提高制剂的稳定性。
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，或两种以上组合使用。
在羧甲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，能够促进羧甲司坦雾化吸入用溶液制剂的药效发挥，提高羧甲司坦雾化吸入用溶液制剂的稳定性，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，羧甲司坦的稳定性变差，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]
本发明所述的羧甲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，只要不损害上述羧甲司坦雾化吸入用溶液制剂的效果就没有特别限制，例如可列举出碳酸氢钠、氢氧化钠、磷酸氢二钠、枸橼酸钠、磷酸氢二钾、碳酸钠、磷酸二氢钠、盐酸、硫酸、乳酸、苹果酸、醋酸、磷 酸、枸橼酸等。这些pH调节剂可以单独使用，或两种以上组合使用。这些之中，更优选为碳酸氢钠、氢氧化钠、磷酸氢二钠、枸橼酸钠和磷酸氢二钾。
pH调节剂的含量可根据其它成分的含量适宜决定，以使羧甲司坦雾化吸入用溶液制剂的pH值变为目标值。本发明所述的羧甲司坦雾化吸入用溶液制剂单剂量中，pH调节剂的含量优选为10.8～12.4mg/mL，更优选为11.2～11.4mg/mL。通过以上述范围含有pH调节剂，能够良好地促进羧甲司坦成盐，增加羧甲司坦的溶解性。
本发明所述的羧甲司坦雾化吸入用溶液制剂的pH值优选为5～8，更优选为6～7。通过将羧甲司坦雾化吸入用溶液制剂的pH值的范围设为上述的范围，可以增加羧甲司坦的溶解性。如果pH值小于5，会有羧甲司坦原料在水中溶解不完全的不利效果。另一方面，如果pH值超过8，有溶液颜色变黄、杂质的量增多的倾向，故不优选。
[药用辅料]
本发明所述的羧甲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。
<羧甲司坦雾化吸入用溶液制剂的制备方法>
在本发明中，对于羧甲司坦雾化吸入用溶液制剂的制备步骤没有特别限制，原则上将羧甲司坦、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)缓慢加入羧甲司坦、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：单剂量羧甲司坦雾化吸入用溶液制剂
羧甲司坦                              20mg
依地酸二钠                            0.1mg
氢氧化钠                              适量，pH调至5
处方2：单剂量羧甲司坦雾化吸入用溶液制剂
羧甲司坦                              40mg
依地酸二钠                            0.5mg
氢氧化钠                              适量，pH调至6
处方3：单剂量羧甲司坦雾化吸入用溶液制剂
羧甲司坦                              50mg
依地酸二钠                            2mg
氢氧化钠                              适量，pH调至6
处方4：单剂量羧甲司坦雾化吸入用溶液制剂
羧甲司坦                              80mg
依地酸二钠                            5mg
氢氧化钠                              适量，pH调至7
处方5：单剂量羧甲司坦雾化吸入用溶液制剂
羧甲司坦                              100mg
依地酸二钠                            1.25mg
氢氧化钠                              适量，pH调至8
处方6：单剂量羧甲司坦雾化吸入用溶液制剂
羧甲司坦                              120mg
依地酸二钠                            4mg
氢氧化钠                             适量，pH调至7
处方7：单剂量羧甲司坦雾化吸入用溶液制剂
羧甲司坦                             120mg
依地酸                               3mg
碳酸氢钠                             适量，pH调至7.5
处方8：单剂量羧甲司坦雾化吸入用溶液制剂
羧甲司坦                             100mg
依地酸                               1.25mg
氢氧化钠                             适量，pH调至8
处方9：单剂量羧甲司坦雾化吸入用溶液制剂
羧甲司坦                             100mg
依地酸钠钙                           1.25mg
氢氧化钠                             适量，pH调至8
处方10：单剂量羧甲司坦雾化吸入用溶液制剂
羧甲司坦                             100mg
依地酸二钠                           0.5mg
氢氧化钠                             适量，pH调至8
处方11：单剂量羧甲司坦雾化吸入用溶液制剂
羧甲司坦                             100mg
依地酸二钠                           1mg
氢氧化钠                             适量，pH调至8
处方12：单剂量羧甲司坦雾化吸入用溶液制剂
羧甲司坦                             100mg
依地酸二钠                           2mg
氢氧化钠                             适量，pH调至8
处方13：单剂量羧甲司坦雾化吸入用溶液制剂
羧甲司坦                             100mg
依地酸二钠                           4mg
氢氧化钠                             适量，pH调至8
处方14：单剂量羧甲司坦雾化吸入用溶液制剂
羧甲司坦                              100mg
氢氧化钠                              适量，pH调至8
实施例1：根据处方1的比例，制备羧甲司坦雾化吸入用溶液制剂1000mL
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羧甲司坦(由国药集团汕头金石制药有限公司制造)，搅拌至其全部溶解。
然后，加入适量氢氧化钠调节pH至5，同时测定残氧量为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2～13
除了使用处方2～13的比例代替处方1以外，与实施例1同样地制备羧甲司坦雾化吸入用溶液制剂。
比较例1
除了使用处方14的比例代替处方1以外，与实施例1同样地制备羧甲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和9(根据处方5、8和9的配方制备羧甲司坦雾化吸入用溶液制剂)得到的单剂量羧甲司坦雾化吸入用溶液制剂放置一年。通过下述羧甲司坦含量的测定方法测定一年后实施例5、8和9得到的单剂量羧甲司坦雾化吸入用溶液制剂中羧甲司坦含量，并且通过目测观察制剂颜色和澄清度。结果示于表1中。
羧甲司坦含量的测定
(1)使用十八烷基硅烷键合硅胶为填充剂(4.6×150mm，5μm)，以20mM 的辛烷磺酸钠和20mM磷酸二氢钾溶液(磷酸调节pH至2.5)为流动相，检测波长为210nm，柱温为30℃，流速为1.0mL/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中含羧甲司坦0.25mg的溶液，作为待测试样品溶液；另外精密称取羧甲司坦对照品适量，加流动相溶解并定量稀释制成每lmL中含羧甲司坦0.25mg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20μL，分别注入液相色谱仪，记录色谱图。按外标法以峰面积计算，得到羧甲司坦含量。
表1
  金属络合剂 制剂颜色和澄清度 羧甲司坦含量(％)
实施例5 依地酸二钠 无色，清晰 98.4
实施例8 依地酸 轻微黄色，清晰 93.2
实施例9 依地酸钠钙 轻微黄色，轻微浑浊 97.1
由表1可见，本发明的羧甲司坦雾化吸入用溶液制剂即使放置一年，羧甲司坦的含量也较高，羧甲司坦的稳定性优异，制剂颜色和澄清度变化小。
实验例2
将实施例10～13和比较例1(根据处方10～14的配方制备羧甲司坦雾化吸入用溶液制剂)得到的单剂量羧甲司坦雾化吸入用溶液制剂放置一年。通过上述羧甲司坦含量的测定方法测定一年后实施例10～13和比较例1得到的单剂量羧甲司坦雾化吸入用溶液制剂中羧甲司坦含量，并且通过目测观察制剂颜色和澄清度。结果示于表2中。
表2
Figure PCTCN2018087527-appb-000001
由表2可见，本发明的羧甲司坦雾化吸入用溶液制剂即使放置一年，羧甲司坦的含量也较高，羧甲司坦的稳定性优异，制剂颜色和澄清度变化小。
然而，不含有依地酸二钠的比较例1，放置一年后羧甲司坦的含量明显降低，制剂颜色变化明显，且还出现轻微浑浊现象。
实验例3
本发明的羧甲司坦雾化吸入用溶液制剂(根据实施例5制备)与市售羧甲司坦口服液(商品名：BRONCHOKOD，剂型：口服液，处方组成：羧甲司坦、糖精钠、羟苯甲酯、羟乙基纤维素钠、香精、氢氧化钠和纯化水，由ANATTERMANN & CIE.GMBH制造)在小鼠给药时的肝细胞各监测数据的比较
选小鼠60只(20±2g)，雌雄各半，随机分为正常对照组、口服给药组和雾化吸入给药组，共3组，每组20只。雾化吸入给药组供给根据实施例5制备的羧甲司坦雾化吸入用溶液制剂，口服给药组灌胃等量的上述市售羧甲司坦口服液，正常对照组腹腔注射等量的生理盐水，持续给药2周，每天上午10点、下午4点各1次，每次0.1mL。给药两周后，对各给药组小鼠模型肝细胞上清液中的谷草转氨酶(AST)、碱性磷酸酶(ALP)和谷丙转氨酶(ALT)的数值进行检测，统计分析研究羧甲司坦对致肝损伤的影响，结果示于表3中。
Figure PCTCN2018087527-appb-000002
由表3可见，口服给药组小鼠的ALP、ALT和AST数值显著升高(P<0.01)，雾化吸入给药组小鼠的ALP、ALT、AST活性与之相比明显较低(P<0.01)，雾化吸入给药组对致肝损伤的影响小，用药更安全。
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 (10)

  1. 一种羧甲司坦雾化吸入用溶液制剂，其特征在于，所述制剂包括：羧甲司坦、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：以游离羧甲司坦计20～120mg羧甲司坦、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：以游离羧甲司坦计50～100mg羧甲司坦、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调节剂为碳酸氢钠、氢氧化钠、磷酸氢二钠、枸橼酸钠或磷酸氢二钾。
  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5～8。
  7. 根据权利要求6所述的制剂，其特征在于，所述制剂的pH值为6～7。
  8. 根据权利要求1～7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。
  9. 根据权利要求1～8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。
  10. 根据权利要求1～9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)缓慢加入羧甲司坦、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。
PCT/CN2018/087527 2017-11-08 2018-05-18 一种羧甲司坦雾化吸入用溶液制剂及其制备方法 Ceased WO2019091082A1 (zh)

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