WO2023040467A1 - 一种包含妥布霉素吸入溶液的药物组件及其用途 - Google Patents

一种包含妥布霉素吸入溶液的药物组件及其用途 Download PDF

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WO2023040467A1
WO2023040467A1 PCT/CN2022/107735 CN2022107735W WO2023040467A1 WO 2023040467 A1 WO2023040467 A1 WO 2023040467A1 CN 2022107735 W CN2022107735 W CN 2022107735W WO 2023040467 A1 WO2023040467 A1 WO 2023040467A1
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inhalation solution
tobramycin
tobramycin inhalation
atomizer
micropores
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PCT/CN2022/107735
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English (en)
French (fr)
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金方
黄娟
邓炜
杨霞
郦旻
俞雄
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健康元药业集团股份有限公司
广州健康元呼吸药物工程技术有限公司
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Publication of WO2023040467A1 publication Critical patent/WO2023040467A1/zh

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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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/702—Oligosaccharides, i.e. having three to five saccharide radicals attached to each other by glycosidic linkages
    • 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
    • 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
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M11/00—Sprayers or atomisers specially adapted for therapeutic purposes
    • A61M11/001—Particle size control
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M11/00—Sprayers or atomisers specially adapted for therapeutic purposes
    • A61M11/005—Sprayers or atomisers specially adapted for therapeutic purposes using ultrasonics
    • 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

Definitions

  • the invention relates to the technical field of medicine, in particular to a pharmaceutical assembly containing tobramycin inhalation solution and its application.
  • Aminoglycoside antibiotics are named because their molecular structure has an aminocycloalcohol and one or more aminosugar molecules, which are connected by glycosidic bonds to form glycosides. Most of them are polar compounds, which are not easily absorbed by the gastrointestinal tract. Administration by injection. Adverse events such as ototoxicity and nephrotoxicity usually occur clinically due to injection administration.
  • Ototoxicity can be divided into: 1 vestibular dysfunction, more common in streptomycin, kanamycin, gentamicin, tobramycin, the incidence rate after medication is kanamycin > streptomycin > gentamicin Tobramycin > tobramycin; 2 cochlear nerve damage, which is more common in kanamycin, amikacin, sisomicin, gentamicin, etc., and the incidence rate after medication is kanamycin > amikacin Kaxing > sisomicin > gentamicin > tobramycin, the incidence of these "subclinical deafness" reactions is about 10% to 20%.
  • nephrotoxicity is kanamycin and sisalmycin > gentamicin and amikacin > tobramycin > streptomycin. Generally, nephrotoxicity is prone to occur after more than 10 days of systemic medication. toxicity.
  • Tobramycin is an aminoglycoside antibiotic naturally produced by Streptomyces, which mainly causes changes in the permeability of the cell membrane, progressive destruction of the outer membrane of the cell, and eventually cell death by inhibiting protein synthesis. It is bactericidal when it is equal to or slightly greater than its inhibitory concentration. It is the second-generation aminoglycoside antibiotics. Compared with the first-generation aminoglycoside antibiotics, it has the advantages of better curative effect, lower toxicity, and less clinical drug resistance. It has become the most widely used aminoglycoside in the world. One of the glycoside antibiotics.
  • Bronchiectasis (hereinafter referred to as "bronchiectasis”) is a common chronic respiratory disease with a long course of disease, irreversible lesions, and prone to repeated infections, especially extensive bronchiectasis can seriously damage the lung tissue and function of patients, seriously affecting the Quality of life of patients, while causing a heavy socioeconomic burden.
  • Pseudomonas aeruginosa is a common opportunistic pathogen. Studies have shown that patients with bronchiectasis colonized by Pseudomonas aeruginosa have a faster decline in lung function and higher disease severity. At the same time, Pseudomonas aeruginosa has the characteristics of easy colonization, mutation and multi-drug resistance, so it is difficult to eliminate through conventional antibiotic intervention. In particular, the mortality rate of lower respiratory tract infections such as bronchiectasis combined infection caused by multi-drug resistant Pseudomonas aeruginosa is high and difficult to treat.
  • tobramycin inhalation solution has been adopted to overcome the defects of oral or intravenous administration, but these inhalation solutions are generally administered through a jet atomizer, and the atomization device is connected to a compressor through a pipeline, and the compressor uses The compressed air forms a high-speed airflow through the small nozzle, and the negative pressure generated drives the liquid or other fluids to be sprayed onto the barrier together, and splashes around under the high-speed impact to make the liquid droplets become mist particles and spray out from the air outlet pipe.
  • the droplet size distribution is wide, the geometric standard deviation range is large, the volume is large, it is inconvenient to carry, the noise is large, the energy consumption is high, the residual liquid volume is large, and the treatment time is prolonged. , Reduced compliance and other defects.
  • the present invention provides a pharmaceutical assembly containing tobramycin inhalation solution and its application.
  • the drug assembly containing tobramycin inhalation solution of the present invention uses the tobramycin inhalation solution in conjunction with a vibrating sieve nebulizer, so that the particle size distribution of the droplets is concentrated, and the proportion of tiny particle sizes reaching the lungs is greatly increased.
  • the volume of residual liquid medicine is significantly reduced, and the therapeutic effect on bronchiectasis is significantly improved.
  • the present invention provides the use of a pharmaceutical component comprising a tobramycin inhalation solution in the preparation of a pharmaceutical product for the treatment of bronchiectasis,
  • the drug component includes:
  • the central area of the metal mesh of the vibrating screen atomizer has 1400-1800 micropores
  • the droplet size of the tobramycin inhalation solution is: D 10 is 0.5 ⁇ m to 2.5 ⁇ m, D 50 is 2.0 ⁇ m to 4.2 ⁇ m, D 90 is 6.0 ⁇ m to 9.0 ⁇ m; the aerodynamic particle size is less than 5.39 ⁇ m The mass percentage of the particles accounted for the tobramycin inhalation solution is not less than 45%;
  • the fine particle dose (FPD) (aerodynamic particle size less than 5.39 ⁇ m) of the aerosolized particles is not lower than 135 mg. More preferably, the fine particle dose (FPD) (aerodynamic particle size less than 5.39 ⁇ m) of the aerosolized particles is 135 mg-270 mg.
  • the central area of the metal mesh of the vibrating screen atomizer has 1600-1800 micropores.
  • the section of the micropores in the vibrating screen atomizer is distributed in steps, with a taper of 30-50 degrees.
  • the number of micropores with a diameter of 3.8-4.2 ⁇ m accounts for no less than 80% of the total number of micropores.
  • the vibration frequency of the vibrating screen atomizer is 110-160KHz.
  • the atomization rate of the vibrating mesh atomizer is 0.47-0.55ml/min.
  • the current of the vibrating screen atomizer is 1A, ⁇ 2%; the voltage is 5V, ⁇ 2%.
  • the mass percentage of particles with an aerodynamic particle size smaller than 5.39 ⁇ m in the tobramycin inhalation solution is 45%-84%.
  • the droplet size of the tobramycin inhalation preparation is: D 10 is 0.5 ⁇ m to 1.5 ⁇ m, D 50 is 3.0 ⁇ m to 3.5 ⁇ m, and D 90 is 6.0 ⁇ m to 8.5 ⁇ m.
  • the content of tobramycin is 4% to 8% (w/v)
  • the content of sodium chloride is 0.1% to 0.9% (w/v)
  • the pH value is 4.5-7.5.
  • the present invention provides a pharmaceutical assembly comprising a tobramycin inhalation solution, the pharmaceutical assembly comprising:
  • the central area of the metal mesh of the vibrating screen atomizer has 1400-1800 micropores
  • the droplet size of the tobramycin inhalation solution is: D 10 is 0.5 ⁇ m to 2.5 ⁇ m, D 50 is 2.0 ⁇ m to 4.2 ⁇ m, D 90 is 6.0 ⁇ m to 9.0 ⁇ m; the aerodynamic particle size is less than 5.39 ⁇ m The mass percentage of the particles accounted for the tobramycin inhalation solution is not less than 45%;
  • the fine particle dose (FPD) (aerodynamic particle size less than 5.39 ⁇ m) of the aerosolized particles is not lower than 135 mg. More preferably, the fine particle dose (FPD) (aerodynamic particle size less than 5.39 m) of the aerosolized particles is 135 mg-270 mg.
  • the central area of the metal mesh of the vibrating screen atomizer has 1600-1800 micropores.
  • the section of the micropores in the vibrating screen atomizer is distributed in steps, with a taper of 30-50 degrees.
  • the number of micropores with a diameter of 3.8-4.2 ⁇ m accounts for no less than 80% of the total number of micropores.
  • the vibration frequency of the vibrating screen atomizer is 110-160KHz.
  • the atomization rate of the vibrating mesh atomizer is 0.47-0.55ml/min.
  • the current of the vibrating screen atomizer is 1A, ⁇ 2%; the voltage is 5V, ⁇ 2%.
  • the mass percentage of particles with an aerodynamic particle size smaller than 5.39 ⁇ m in the tobramycin inhalation solution is 45%-84%.
  • the droplet size of the tobramycin inhalation solution is: D 10 is 0.5 ⁇ m to 1.5 ⁇ m, D 50 is 3.0 ⁇ m to 3.5 ⁇ m, and D 90 is 6.0 ⁇ m to 8.5 ⁇ m.
  • the content of tobramycin is 4-8% (w/v)
  • the content of sodium chloride is 0.1%-0.9% (w/v)
  • the pH value is 4.5-7.5.
  • the vibrating screen atomizer used in the present invention vibrates up and down through the vibrator, and uses the hole of the nozzle-type net spray head to squeeze out the liquid medicine, and forms the mist droplets by the tiny ultrasonic vibration and the structure of the net spray head.
  • the residual volume of the liquid medicine is small, the atomization time is short, there is no significant temperature rise during the atomization process, the administration volume is small, the atomization efficiency is higher, and it can be carried around.
  • the structure of the vibrating screen atomizer used in the present invention is conventional, for example, refer to the description in CN111569200A.
  • the relative quality of life score (QOL-B-RSS) of the respiratory symptoms of the test group was significantly improved compared with the control group, and there was a statistically significant difference between the two groups (P ⁇ 0.001 ), and the load value of Pseudomonas aeruginosa in the experimental group was significantly lower than that in the control group, and there was a statistically significant difference between the two groups (P ⁇ 0.001).
  • the present invention has at least the following beneficial technical effects:
  • the present invention is aimed at the characteristics of bronchiectasis, has designed tobramycin inhalation solution, and the vibrating screen nebulizer used in conjunction with it, and the quantity, aperture, vibration frequency of the holes in the vibrating sieve nebulizer , current, voltage, and atomization rate were adjusted, and the droplet size and particle size parameters (D 10 ⁇ D 50 ⁇ D 90 ) in the tobramycin inhalation solution were also controlled, not only achieving a good It has the clinical effect of treating bronchiectasis, and at the same time has the advantages of small residual liquid volume, convenient use, portability, and low noise.
  • the drug component of the present invention not only overcomes the defects that only a small amount of drugs can enter the lung tissue after oral or intravenous administration and fails to eliminate Pseudomonas aeruginosa, but also overcomes the wide distribution of droplets of other inhalation products,
  • the geometric standard deviation range is large, the volume is large, it is inconvenient to carry, the noise is high, the energy consumption is high, the residual liquid volume is large, the treatment time is prolonged, and the compliance is reduced.
  • the nebulizer assay method is as follows:
  • the data were measured using a laser particle size analyzer (Sympatec GmbH), whose principle is the light scattering method.
  • a cascade impactor with 7 stages and 1 micropore collector is used to collect the effective inhaled amount of the drug, and then the effective inhaled amount of the collected drug is determined by high performance liquid chromatography.
  • the cascade impactor is connected to the L-shaped throat and placed in an environment of 5°C for 90 minutes, and the effective inhalation test of the drug is carried out within 5 minutes after taking it out, and the atomized particles with a cut-off particle size of 5 ⁇ m or less are collected and used in high-performance liquid phase. Chromatography is measured.
  • the structure of the vibrating mesh atomizer used in the following examples and application examples is as described in CN111569200A, the current is 1A, ⁇ 2%; the voltage is 5V, ⁇ 2%.
  • the prescription of the tobramycin inhalation solution used in the following examples is selected from the following two types:
  • Prescription 1 tobramycin (6w/v%), sodium chloride (0.225w/v%), sulfuric acid (appropriate amount), sodium hydroxide (add appropriate amount if necessary), water for injection. Sulfuric acid (appropriate amount), sodium hydroxide (add appropriate amount if necessary) to adjust the pH value to 4.5-7.5;
  • Prescription 2 Tobramycin (6w/v%), sodium chloride (0.225w/v%), citric acid (0.4w/v%), sulfuric acid (appropriate amount), sodium hydroxide (add appropriate amount if necessary) ,Water for Injection. Sulfuric acid (appropriate amount), sodium hydroxide (add appropriate amount if necessary) to adjust the pH value to 4.5-7.5.
  • Vibrating mesh nebulizers with different numbers of perforations but with the same other parameters were selected to test their influence on the nebulization effect when applied to tobramycin inhalation solution (prescription 1). The results are shown in Table 1.
  • Vibrating mesh nebulizers with different pore diameters but with the same other parameters were selected to test their effect on the nebulization effect of tobramycin inhalation solution (prescription 1). The results are shown in Table 2.
  • Vibrating mesh nebulizers with different vibration frequencies but with the same other parameters were selected to test their effect on the nebulization effect of tobramycin inhalation solution (prescription 2). The results are shown in Table 3.
  • the vibrating screen atomizer selects the atomizer that meets the requirements of the present invention, and the compressed air atomizer selects an imported Nebulizer (Pari TurboBoy N), the two nebulizers nebulize the liquid medicine for the same time, compare the drug delivery effect of the two nebulizers, the results are shown in Table 5.
  • the parameters of the vibrating screen atomizer of the present invention are shown in Table 8.
  • the tobramycin inhalation solution (prescription 1) was used for testing to investigate the influence of different hole tapers on the atomization rate.
  • the test results are shown in Table 9.
  • tobramycin (6w/v%), sodium chloride (0.225w/v%), sulfuric acid (appropriate amount), sodium hydroxide (add appropriate amount if necessary), water for injection, pH value is 6.2.
  • Example 8 0.88 2.06 7.43
  • Example 9 1.04 3.41 7.51
  • Example 10 1.31 4.16 8.18
  • Example 11 1.78 5.40 10.17
  • Delivery rate and total delivery amount check according to the provisions of [Delivery rate and total delivery amount] under the item of inhalation liquid preparations in the Chinese Pharmacopoeia 2020 edition Sibu general rule 0111 inhalation solution.
  • Fine particle fraction fine particle dose/delivered dose, where fine particle dose (FPD) refers to the dose of fine particles with an aerodynamic particle size smaller than 5.39 microns.
  • Test group tobramycin inhalation solution Prescription: tobramycin (6w/v%), sodium chloride (0.225w/v%), sulfuric acid (appropriate amount), sodium hydroxide (add appropriate amount if necessary), water for injection , pH value is 6.0.
  • Control group placebo, normal saline (0.9w/v%)
  • This product is for inhalation use only.
  • the recommended dose is one tablet (300mg), twice a day for 28 days, and there is no need to adjust the dose according to body weight.
  • the drug cycle of this product is 28 days, and there should be an interval of 28 days between the two drug cycles, that is, after the patient continues to use the drug for 28 days, stop the drug for 28 days, and then resume the drug.
  • the interval between two daily doses should be as close to 12 hours as possible, and should not be less than 6 hours. If a dose is missed, it should be refilled as soon as possible at least 6 hours before the next scheduled dose. If it is less than 6 hours before the next planned medication time, there is no need to refill it, and the next time the drug will still be taken according to the original planned time and dose.
  • the project team conducted a multi-center, randomized, double-blind, basic treatment, placebo parallel controlled clinical study to test the effectiveness and safety of tobramycin inhalation solution in the treatment of adult bronchiectasis with pulmonary Pseudomonas aeruginosa infection.
  • a total of 594 subjects with bronchiectasis were screened in this study, and 357 cases were finally enrolled.
  • Subjects who have completed all the examinations during the screening period and are qualified by the investigator's evaluation will undergo visit 2A for sputum culture testing. After the test results met the inclusion criteria, they entered Visit 2B, were randomly assigned to the experimental group or the control group, and entered the treatment period.
  • PA Pseudomonas aeruginosa
  • Test result carry out analysis of covariance for adjusting intention to treat set (MITTS) through taking baseline as covariate, after correcting grouping factor, central factor, randomization control and missing value filling, test group (i.e. technical scheme of the present invention) PA The least squares mean of load decreased by 2.50Log10cfu/g (SE: 0.28), the least squares mean of PA load in the control group decreased by 0.76Log10cfu/g (SE: 0.27), and the difference of least squares mean between the two groups was 1.74Log10cfu/g, The 95% CI was 1.12-2.35 (P ⁇ 0.001), and the center effect was not significant, indicating that the load reduction value of PA in the experimental group was superior to that in the control group.
  • the least square mean value of the QOL-B-RSS score of the test group increased by 8.48 points (SE: 0.97)
  • the least square mean value of the QOL-B-RSS score in the control group increased by 0.56 points (SE: 0.97)
  • the least square mean value difference between the two groups was 7.91 points
  • the 95% CI was 5.72-10.11 (P ⁇ 0.001). Not significant, indicating that the QOL-B-RSS score of the experimental group is superior to that of the control group.
  • the inventor carried out the above experiment for prescription 2, and achieved the same clinical therapeutic effect as prescription 1.

Abstract

一种包含妥布霉素吸入溶液的药物组件及其用途。该药物组件包括：(a)妥布霉素吸入溶液；和(b)与妥布霉素吸入溶液相配合使用的振动筛雾化器；其中，振动筛雾化器的金属网片的中心区域具有1400-1800个微孔；妥布霉素吸入溶液的雾滴粒径是：D 10为0.5μm～2.5μm，D 50为2.0μm～4.2μm，D 90为6.0μm～9.0μm；空气动力学粒径小于5.39μm的粒子占所述妥布霉素吸入溶液的质量百分比不小于45％。该药物组件用于治疗支气管扩张。

Description

一种包含妥布霉素吸入溶液的药物组件及其用途 技术领域
本发明涉及医药技术领域，具体而言，涉及一种包含妥布霉素吸入溶液的药物组件及其用途。
背景技术
氨基糖苷类抗生素因其分子结构都有一个氨基环醇类和一个或多个氨基糖分子，并由配糖键连接成苷而得名，多为极性化合物，胃肠道不易吸收，一般需要注射给药。由于注射给药临床上通常发生耳毒性和肾毒性等不良事件。耳毒性可分为：①前庭功能失调，多见于链霉素、卡那霉素、庆大霉素，妥布霉素，用药后其发生率依次为卡那霉素>链霉素>庆大霉素>妥布霉素；②耳蜗神经损害，多见于卡那霉素、阿米卡星、西索米星、庆大霉素等，用药后其发生率依次为卡那霉素>阿米卡星>西索米星>庆大霉素>妥布霉素，这些“亚临床性耳聋”反应的发生率约为10％～20％。而肾毒性的强弱次序则为卡那霉素和西梭霉素>庆大霉素和丁胺卡那霉素>妥布霉素>链霉素，一般系统性用药10天以上易发生肾毒性。
妥布霉素(Tobramycin,TOB)是一种从链霉菌自然产生的氨基糖苷抗生素，其主要通过抑制蛋白质合成导致细胞膜的渗透性的改变、细胞外被膜的渐进破坏和最终细胞的死亡，在浓度等于或稍大于其抑制浓度时具有杀菌性。它是第二代氨基糖苷类抗生素，相对于第一代氨基糖苷类抗生素而言，其具有疗效更好、毒性更低、临床耐药性更少的优势，成为目前世界临床应用最为广泛的氨基糖甙类抗生素之一。
支气管扩张症(以下简称“支扩”)是一种常见的慢性呼吸道疾病，病程长，病变不可逆转，且容易反复感染，特别是广泛性支气管扩张可严重损害患者肺组织和功能，严重影响了患者的生活质量，同时造成沉重的社会经济负担。
铜绿假单胞菌是一种常见的机会致病菌，有研究表明，铜绿假单胞菌 定植的支扩患者其肺功能下降速度更快，患者的疾病严重程度更高。同时，铜绿假单胞菌具有易定植、易变异和多耐药的特点，因此难以通过常规抗生素干预清除。尤其因多重耐药性铜绿假单胞菌引起的支扩合并感染等下呼吸道感染的病死率高，治疗困难。
对于支扩患者，目前国内的常规临床疗法仍为静脉注射妥布霉素，妥布霉素静脉给药后仅有少量药物能进入肺组织，大多数患者经过规范的口服或者静脉给药后仍未能实现对铜绿假单胞菌的清除。
目前已有采用妥布霉素吸入溶液以克服口服或者静脉给药的缺陷，但是这些吸入溶液一般是通过喷射雾化器进行给药，雾化装置通过管路连接一压缩器，该压缩器利用压缩空气通过细小管口形成高速气流，产生的负压带动液体或其它流体一起喷射到阻挡物上，在高速撞击下向四周飞溅使液滴变成雾状微粒从出气管喷出。利用该雾化器进行给药时，存在雾滴粒径分布较广、几何标准差范围较大、体积较大不便携带、噪音较大、耗能较高、残留药液体积大、治疗时间延长、顺应性降低等缺陷。
因此，开发一种解决上述问题的包含妥布霉素吸入溶液的药物组件成为亟需。
发明内容
为了克服现有技术的不足，本发明提供一种包含妥布霉素吸入溶液的药物组件及其用途。本发明的包含妥布霉素吸入溶液的药物组件通过将妥布霉素吸入溶液和振动筛雾化器配合使用，使得雾滴粒径分布集中，到达肺部的微小粒径比例大幅度提高，残留药液体积明显降低，对支气管扩张症的治疗效果显著提升。
为了实现上述发明目的，本发明采用的技术方案如下：
一方面，本发明提供包含妥布霉素吸入溶液的药物组件在制备用于治疗支气管扩张症的药物产品中的用途，
其中，所述药物组件包括：
(a)妥布霉素吸入溶液；和
(b)与所述妥布霉素吸入溶液相配合使用的振动筛雾化器；
其中，所述振动筛雾化器的金属网片的中心区域具有1400-1800个微孔；
所述妥布霉素吸入溶液的雾滴粒径是：D 10为0.5μm～2.5μm，D 50为2.0μm～4.2μm，D 90为6.0μm～9.0μm；空气动力学粒径小于5.39μm的粒子占所述妥布霉素吸入溶液的质量百分比不小于45％；
优选地，雾化微粒的微细粒子剂量(FPD)(空气动力学粒径小于5.39μm)不低于135mg。更优选地，雾化微粒的微细粒子剂量(FPD)(空气动力学粒径小于5.39μm)为135mg-270mg。
优选地，所述振动筛雾化器的金属网片的中心区域具有1600-1800个微孔。
优选地，所述振动筛雾化器中微孔的断面呈阶梯状分布，锥度为30-50度。
优选地，所述微孔的直径为3.8-4.2μm的微孔数量的占总微孔数量的比例不少于80％。
优选地，所述振动筛雾化器的振动频率为110-160KHz。
优选地，所述振动筛雾化器的雾化速率为0.47-0.55ml/min。
优选地，所述振动筛雾化器的电流为1A，±2％；电压为5V，±2％。
优选地，空气动力学粒径小于5.39μm的粒子占所述妥布霉素吸入溶液的质量百分比为45％～84％。
优选地，所述妥布霉素吸入制剂雾滴粒径是：D 10为0.5μm～1.5μm，D 50为3.0μm～3.5μm，D 90为6.0μm～8.5μm。
优选地，所述妥布霉素吸入溶液中，妥布霉素的含量为4％～8％(w/v)，氯化钠的含量为0.1％～0.9％(w/v)，pH值为4.5-7.5。
另一方面，本发明提供一种包含妥布霉素吸入溶液的药物组件，所述药物组件包括：
(a)妥布霉素吸入溶液；和
(b)与所述妥布霉素吸入溶液相配合使用的振动筛雾化器；
其中，所述振动筛雾化器的金属网片的中心区域具有1400-1800个微孔；
所述妥布霉素吸入溶液的雾滴粒径是：D 10为0.5μm～2.5μm，D 50为2.0μm～4.2μm，D 90为6.0μm～9.0μm；空气动力学粒径小于5.39μm的粒子占所述妥布霉素吸入溶液的质量百分比不小于45％；
优选地，雾化微粒的微细粒子剂量(FPD)(空气动力学粒径小于5.39μm)不低于135mg。更优选地，雾化微粒的微细粒子剂量(FPD)(空气动 力学粒径小于5.39μm)为135mg-270mg。
优选地，所述振动筛雾化器的金属网片的中心区域具有1600-1800个微孔。
优选地，所述振动筛雾化器中微孔的断面呈阶梯状分布，锥度为30-50度。
优选地，所述微孔的直径为3.8-4.2μm的微孔数量的占总微孔数量的比例不少于80％。
优选地，所述振动筛雾化器的振动频率为110-160KHz。
优选地，所述振动筛雾化器的雾化速率为0.47-0.55ml/min。
优选地，所述振动筛雾化器的电流为1A，±2％；电压为5V，±2％。
优选地，空气动力学粒径小于5.39μm的粒子占所述妥布霉素吸入溶液的质量百分比为45％～84％。
优选地，所述妥布霉素吸入溶液雾滴粒径是：D 10为0.5μm～1.5μm，D 50为3.0μm～3.5μm，D 90为6.0μm～8.5μm。
优选地，所述妥布霉素吸入溶液中，妥布霉素的含量为4-8％(w/v)，氯化钠的含量为0.1％～0.9％(w/v)，pH值为4.5-7.5。
本发明使用的振动筛雾化器通过振动子上下振动，利用喷嘴型的网式喷雾头的孔穴将药液挤出，由微小的超声波振动和网式喷雾头构造来形成雾滴。药液的残留体积小，雾化时间短，雾化过程无显著升温，给药体积小，雾化效率更高，同时可随身携带。除非特殊说明，本发明使用的振动筛雾化器结构是常规的，例如可以参考CN111569200A中所述。
本发明的药物组件用于支气管扩张症的临床研究时，试验组较对照组的呼吸道症状的相关生活质量评分(QOL-B-RSS)明显改善，两组间具有统计学显著差异(P<0.001)，且试验组较对照组的铜绿假单胞菌负荷值明显下降，两组间具有统计学显著差异(P<0.001)。
与现有技术相比，本发明至少存在如下有益的技术效果：
(1)本发明针对支气管扩张症的特点，设计了妥布霉素吸入溶液，以及与其相配合使用的振动筛雾化器，并且对振动筛雾化器中的孔的数量、孔径、振动频率、电流、电压、雾化速率进行了调整，对妥布霉素吸入溶液中的雾滴粒径、粒径参数(D 10\D 50\D 90)等也进行了控制，不仅达到了良好的临床治疗支气管扩张的效果，同时具有残留药液体积小、使用方便、便于携 带、噪音小的优势。
(2)本发明的药物组件不仅克服了口服或者静脉给药仅有少量药物能进入肺组织、未能实现对铜绿假单胞菌清除的缺陷，还克服了其他吸入产品雾滴分布较广、几何标准差范围较大、体积较大不便携带、噪音较大、耗能较高、残留药液体积大、治疗时间延长、顺应性降低等缺陷。
具体实施方式
为使本发明的目的、技术方案和优点更加清楚，下面将对本发明的技术方案进行清楚、完整的描述，显然，所描述的实施例仅仅是示例性的，不代表本申请的所有的技术方案。基于本发明的实施例，本领域技术人员在没有做出创造性劳动的前提下所获得的其他技术方案都属于本发明的保护范围。
在以下实施例中，雾化器测定方法如下：
使用激光粒度仪(Sympatec GmbH)测定数据，其原理为光散射法。
用具有7级和1个微孔收集器的级联撞击器收集药物的有效的吸入量，再利用高效液相色谱对收集到的药物的有效的吸入量进行测定。
级联撞击器连接L形喉管将其放置在5℃的环境下90分钟，取出后5min内进行所述药物有效吸入量的测试，收集截止粒径5μm以下的雾化颗粒再利用高效液相色谱进行测定。
如无特殊说明，以下实施例、应用例中使用的振动筛雾化器结构如CN111569200A中所述，电流为1A，±2％；电压为5V，±2％。
如无特殊说明，以下实施例中使用的妥布霉素吸入溶液的处方选自以下两种：
处方1：妥布霉素(6w/v％)、氯化钠(0.225w/v％)、硫酸(适量)、氢氧化钠(必要时加入适量)、注射用水。硫酸(适量)、氢氧化钠(必要时加入适量)以调节pH值为4.5-7.5；
处方2：妥布霉素(6w/v％)、氯化钠(0.225w/v％)、枸橼酸(0.4w/v％)、硫酸(适量)、氢氧化钠(必要时加入适量)、注射用水。硫酸(适量)、氢氧化钠(必要时加入适量)以调节pH值为4.5-7.5。
实施例1
选取不同打孔数量但其他参数均相同的振动筛雾化器，检测其应用于妥 布霉素吸入溶液(处方1)时雾化效果的影响，结果见表1。
表1不同打孔数量对雾化效果的影响
Figure PCTCN2022107735-appb-000001
实施例2
选取不同微孔直径但其他参数均相同的振动筛雾化器，检测其应用于妥布霉素吸入溶液(处方1)雾化效果的影响，结果见表2。
表2不同打孔直径的对雾化效果的影响
Figure PCTCN2022107735-appb-000002
Figure PCTCN2022107735-appb-000003
实施例3
选取不同振动频率但其他参数均相同的振动筛雾化器，检测其应用于妥布霉素吸入溶液(处方2)雾化效果的影响，结果见表3。
表3不同振动频率对雾化效果的影响
Figure PCTCN2022107735-appb-000004
实施例4
选取微孔直径为3.8-4.2μm的微孔数量的占总微孔数量的比例(即孔径占比率)不同但其他参数均相同的振动筛雾化器，检测其应用于妥布霉素吸入溶液(处方2)雾化效果的影响，结果见表4。
表4不同孔径占比率对雾化效果的影响
Figure PCTCN2022107735-appb-000005
Figure PCTCN2022107735-appb-000006
实施例5
比较振动筛雾化器和压缩空气雾化器雾化妥布霉素吸入溶液(处方1)的效果，振动筛雾化器选用符合本发明要求的雾化器，压缩空气雾化器选用某进口雾化器(Pari TurboBoy N)，两款雾化器雾化相同时间内的药液，对比两款雾化器的给药效果，结果见表5。
表5振动筛雾化器与压缩空气雾化器雾化效果比较
Figure PCTCN2022107735-appb-000007
实施例6
选取市场上采购到的不同品牌的振动筛雾化器，检测它们与本发明的振 动筛雾化器应用于妥布霉素吸入溶液(处方1)雾化效果的影响，本发明的振动筛雾化器参数见表6，测试结果见表7。
表6本发明的振动筛雾化器参数
Figure PCTCN2022107735-appb-000008
表7不同振动筛雾化器雾化效果比较
Figure PCTCN2022107735-appb-000009
实施例7
本发明的振动筛雾化器参数见表8，以妥布霉素吸入溶液(处方1)进行测试，考察不同的打孔锥度对雾化速率的影响，测试结果见表9。
表8本发明的振动筛雾化器参数
Figure PCTCN2022107735-appb-000010
表9不同打孔锥度对雾化速率的影响
  序号1 序号2 序号3 序号4 序号5
微孔锥度 20 30 40 50 60
雾化速率/ml/min 0.15 0.47 0.48 0.51 0.46
实施例8-11
处方：妥布霉素(6w/v％)、氯化钠(0.225w/v％)、硫酸(适量)、氢氧化钠(必要时加入适量)、注射用水，pH值为6.2。
工艺：配液罐中加入75kg注射用水，控温不超过60℃，加入原辅料搅拌，使全部溶解，pH约为6.2。补加注射用水至100kg，搅拌10min，灌封于5ml低密度聚乙烯瓶中，即得。通过控制药液的雾滴粒径，测定递送速率、递送总量以及微细粒子剂量。表10显示了实施例8-11的雾滴粒径。
表10实施例8-11的雾滴粒径
  D 10/μm D 50/μm D 90/μm
实施例8 0.88 2.06 7.43
实施例9 1.04 3.41 7.51
实施例10 1.31 4.16 8.18
实施例11 1.78 5.40 10.17
递送速率和递送总量：根据中国药典2020年版四部通则0111吸入溶液中吸入液体制剂项下[递送速率和递送总量]的规定进行检查。
微细粒子剂量：根据中国药典2020年版四部通则0951吸入溶液微细粒子空气动力学特性测定法，采用装置NGI进行测定。测定结果见表11所示。表11实施例8-11的递送速率、递送总量、微细粒子剂量及微细粒子分数
Figure PCTCN2022107735-appb-000011
注：微细粒子分数＝微细粒子剂量/递送剂量，其中微细粒子剂量(FPD)是指空气动力学粒径小于5.39微米的微细粒子的剂量。
应用例1妥布霉素吸入溶液的临床试验
试验药物：
试验组：妥布霉素吸入溶液处方：妥布霉素(6w/v％)、氯化钠(0.225w/v％)、硫酸(适量)、氢氧化钠(必要时加入适量)、注射用水，pH值为6.0。
对照组：安慰剂，生理盐水(0.9w/v％)
用量：
本品仅供吸入使用。推荐剂量为每次一支(300mg)，每日两次，持续28天，无需根据体重调节剂量。
本品用药周期为28天，两个用药周期之间应间隔28天，即患者持续用药28天后，停止用药28天，然后恢复用药。
每日两次用药间隔时间尽可能接近12小时，应不少于6小时。如漏用一次药物，则应在距下次计划用药时间至少6小时前尽快补用。如距下次计划用药时间不足6小时，则无需补用，下次仍按原计划时间及剂量用药。
使用说明：
使用振动筛雾化器(参数如表12所示)，每次雾化时取本品1支，拧开瓶盖后将药液全部挤入雾化器的雾化杯中，开启雾化器，经口吸入至雾化完全(没有起雾产生，约10～15分钟)。
接受多种吸入疗法的患者建议在吸入本品之前吸入其他药物。本品不可稀释，或在雾化器中与其他药物混合使用，不可用于皮下、静脉或鞘内注射。
使用本品前，请仔细阅读患者信息使用说明书，了解如何使用本品的详细信息，并遵循振动筛雾化器的使用和保养说明。吸入本品时，患者应正坐或直立，保持雾化器竖直正握，并通过雾化器的咬嘴/面罩正常呼吸。
表12本发明的振动筛雾化器参数
Figure PCTCN2022107735-appb-000012
Figure PCTCN2022107735-appb-000013
项目组进行多中心、随机、双盲、基础治疗、安慰剂平行对照临床研究，测试妥布霉素吸入溶液治疗伴肺部铜绿假单胞菌感染的成人支气管扩张症有效性和安全性。该研究共筛选594例支气管扩张症受试者，最终入组357例。受试者完成筛选期全部检查且经研究者评估合格的受试者，进行访视2A痰培养检测。检测结果符合纳入标准后进入访视2B，随机分配至试验组或对照组，进入治疗期。在治疗期分别接受妥布霉素吸入溶液(300mg/5ml/次，2次/日)或安慰剂(生理盐水)(5ml/次，2次/日)雾化吸入治疗，受试药物及对照药物均采用用药28天、停药28天的间歇给药方式，循环2次。
研究主要采用两项主要疗效终点指标：1)治疗后第29天痰培养铜绿假单胞菌(PA)的负荷较基线的改变量；2)治疗后第29天QOL-B-RSS评分较基线的改变量。
试验结果：针对调整意向治疗集(MITTS)经过以基线为协变量进行协方差分析，在校正分组因素、中心因素、随机化控制及缺失值填补后，试验组(即本发明的技术方案)PA负荷最小二乘均值下降2.50Log10cfu/g(SE：0.28)，对照组PA负荷最小二乘均值下降0.76Log10cfu/g(SE：0.27)，两组间最小二乘均值差值为1.74Log10cfu/g，95％CI为1.12-2.35(P＜0.001)，中心效应不显著，表明试验组PA的负荷下降值优效于对照组。
针对MITTS经过以基线为协变量进行协方差分析，在校正分组因素、中心因素、随机化控制及缺失值填补后，试验组QOL-B-RSS评分最小二乘均值上升8.48分(SE：0.97)，对照组QOL-B-RSS评分最小二乘均值上升0.56分(SE：0.97)，两组间最小二乘均值差值为7.91分，95％CI为5.72-10.11(P＜0.001)，中心效应不显著，表明了试验组QOL-B-RSS评分优效于对照组。
发明人针对处方2进行了上述实验，达到了和处方1相同的临床治疗效果。

Claims (20)

  1. 包含妥布霉素吸入溶液的药物组件在制备用于治疗支气管扩张症的药物产品中的用途，
    其中，所述药物组件包括：
    (a)妥布霉素吸入溶液；和
    (b)与所述妥布霉素吸入溶液相配合使用的振动筛雾化器；
    其中，所述振动筛雾化器的金属网片的中心区域具有1400-1800个微孔；
    所述妥布霉素吸入溶液的雾滴粒径是：D 10为0.5μm～2.5μm，D 50为2.0μm～4.2μm，D 90为6.0μm～9.0μm；空气动力学粒径小于5.39μm的粒子占所述妥布霉素吸入溶液的质量百分比不小于45％。
  2. 根据权利要求1所述的用途，其特征在于，所述振动筛雾化器的金属网片的中心区域具有1600-1800个微孔。
  3. 根据权利要求1所述的用途，其特征在于，所述振动筛雾化器中微孔的断面呈阶梯状分布，锥度为30-50度。
  4. 根据权利要求1所述的用途，其特征在于，所述微孔的直径为3.8-4.2μm的微孔数量的占总微孔数量的比例不少于80％。
  5. 根据权利要求1所述的用途，其特征在于，所述振动筛雾化器的振动频率为110-160KHz。
  6. 根据权利要求1所述的用途，其特征在于，所述振动筛雾化器的雾化速率为0.47-0.55ml/min。
  7. 根据权利要求1所述的用途，其特征在于，所述振动筛雾化器的电流为1A，±2％；电压为5V，±2％。
  8. 根据权利要求1所述的用途，其特征在于，空气动力学粒径小于5.39μm的粒子占所述妥布霉素吸入溶液的质量百分比为45％～84％。
  9. 根据权利要求1所述的用途，其特征在于，所述妥布霉素吸入溶液雾滴粒径是：D 10为0.5μm～1.5μm，D 50为3.0μm～3.5μm，D 90为6.0μm～8.5μm。
  10. 根据权利要求1所述的用途，其特征在于，所述妥布霉素吸入溶液中，妥布霉素的含量为4％～8％(w/v)，氯化钠的含量为0.1％～0.9％(w/v)，pH值为4.5-7.5。
  11. 一种包含妥布霉素吸入溶液的药物组件，所述药物组件包括：
    (a)妥布霉素吸入溶液；和
    (b)与所述妥布霉素吸入溶液相配合使用的振动筛雾化器；
    其中，所述振动筛雾化器的金属网片的中心区域具有1400-1800个微孔；
    所述妥布霉素吸入溶液的雾滴粒径是：D 10为0.5μm～2.5μm，D 50为2.0μm～4.2μm，D 90为6.0μm～9.0μm；空气动力学粒径小于5.39μm的粒子占所述妥布霉素吸入溶液的质量百分比不小于45％。
  12. 根据权利要求11所述的药物组件，其特征在于，所述振动筛雾化器的金属网片的中心区域具有1600-1800个微孔。
  13. 根据权利要求11所述的药物组件，其特征在于，所述振动筛雾化器中微孔的断面呈阶梯状分布，锥度为30-50度。
  14. 根据权利要求11所述的药物组件，其特征在于，所述微孔的直径为3.8-4.2μm的微孔数量的占总微孔数量的比例不少于80％。
  15. 根据权利要求11所述的药物组件，其特征在于，所述振动筛雾化器的振动频率为110-160KHz。
  16. 根据权利要求11所述的药物组件，其特征在于，所述振动筛雾化器的雾化速率为0.47-0.55ml/min。
  17. 根据权利要求11所述的药物组件，其特征在于，所述振动筛雾化器的电流为1A，±2％；电压为5V，±2％。
  18. 根据权利要求11所述的药物组件，其特征在于，空气动力学粒径小于5.39μm的粒子占所述妥布霉素吸入溶液的质量百分比为45％～84％。
  19. 根据权利要求11所述的药物组件，其特征在于，所述妥布霉素吸入制剂雾滴粒径是：D 10为0.5μm～1.5μm，D 50为3.0μm～3.5μm，D 90为6.0μm～8.5μm。
  20. 根据权利要求11所述的药物组件，其特征在于，所述妥布霉素吸入溶液中，妥布霉素的含量为4-8％(w/v)，氯化钠的含量为0.1％～0.9％(w/v)，pH值为4.5-7.5。
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