WO2023213019A1 - 一种治疗特发性肺纤维化的干粉吸入剂及其制备方法 - Google Patents

一种治疗特发性肺纤维化的干粉吸入剂及其制备方法 Download PDF

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WO2023213019A1
WO2023213019A1 PCT/CN2022/109757 CN2022109757W WO2023213019A1 WO 2023213019 A1 WO2023213019 A1 WO 2023213019A1 CN 2022109757 W CN2022109757 W CN 2022109757W WO 2023213019 A1 WO2023213019 A1 WO 2023213019A1
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nintedanib
micropowder
dry powder
pressure
lactose monohydrate
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English (en)
French (fr)
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叶永浩
韩飞
陈永奇
黄有泉
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珠海瑞思普利医药科技有限公司
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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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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
    • A61K9/0075—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
    • 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
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the invention belongs to the field of pharmaceuticals, and specifically relates to a dry powder inhalant for treating idiopathic pulmonary fibrosis and a preparation method thereof.
  • IPF idiopathic pulmonary fibrosis
  • Nintedanib is a small molecule triple tyrosine kinase inhibitor that simultaneously inhibits vascular endothelial growth factor receptors, thereby inhibiting angiogenesis and fibrosis.
  • the FDA approved nintedanib (trade name Ofev) for the treatment of idiopathic pulmonary fibrosis (IPF) [2] .
  • IPF idiopathic pulmonary fibrosis
  • the European Medicines Agency approved nintedanib combined with docetaxel for the treatment of advanced adenocarcinoma-type non-small cell lung cancer (NSCLC) with local metastasis or local recurrence after first-line chemotherapy. So far, research on nintedanib in the treatment of NSCLC has made a series of new progress.
  • nintedanib has good efficacy as a single agent or in combination in the treatment of NSCLC, and the adverse reactions are mild and tolerable. Its common adverse reactions These include impaired liver function, nausea, vomiting and diarrhea [3] .
  • Nintedanib is currently the mainstream treatment drug for the treatment of IPF and is administered orally through traditional administration routes.
  • gastrointestinal reactions are the most common adverse reactions when using nintedanib, with diarrhea having the highest incidence rate.
  • ALT alanine aminotransferase
  • AST aspartate aminotransferase
  • bilirubin are also common adverse events that may occur during the use of nintedanib [4] .
  • the pulmonary drug delivery system has the advantages of rapid onset, good efficacy, and reduced adverse reactions, and has become a drug delivery method that has attracted much attention.
  • pulmonary inhalation drug delivery systems occupy an extremely important position [5] .
  • Dry powder inhalation preparations are the mainstream drug delivery method for the treatment of respiratory diseases in the world. They have no propellant, low dosage, strong targeting, mild side effects, and are applicable to a wide range of scenarios. However, their research and development difficulty is the highest among all inhalation preparations, so this field has changed.
  • aerosol administration is often considered first, followed by dry powder inhalation preparations last. At present, the aerosol drug delivery of nintedanib has been deployed internationally.
  • the research and development barriers for inhaled preparations mainly focus on three aspects: prescription design, drug particle size and device design, which must ensure uniformity, stability and continuous accuracy in the drug delivery process. specifically:
  • composition of the drug and excipients affects the uniformity and stability of the inhalation preparations. Different composition ratios of drugs and excipients may lead to changes in the formulation of dry powder. Excipients and carriers affect the stability of preparations and the bioavailability of active ingredients, thereby affecting patient compliance.
  • Powders used in dry powder inhalation preparations have very strict particle size requirements. Only particles within a certain particle size range can increase the deposition rate and stabilize the drug absorption. According to the physiological structure of the respiratory tract, in order to effectively distribute the drug at the treatment site, particles that are too large or too small may prevent the drug from being deposited, greatly affecting the efficacy. Changes in the formula have an absolute impact on the particle size of dry powder. Therefore, the development of dry powder formulations requires a lot of research on particle size based on different formulas.
  • dry powder inhalation preparation devices must have excellent portability and operability. These properties require the inhalation device to have absolute reliability in terms of continuity, accuracy and stability of drug delivery. , so inhalation devices are also one of the barriers to the development of dry powder inhalation preparations.
  • the object of the present invention is to overcome at least one shortcoming of the prior art and provide a nintedanib dry powder inhaler and a preparation method thereof.
  • a first aspect of the invention provides:
  • a dry powder inhaler for treating idiopathic pulmonary fibrosis consisting of nintedanib micropowder and lactose monohydrate micropowder.
  • the mass ratio of nintedanib micropowder and lactose monohydrate micropowder is 1: (2-8).
  • the D90 of Danib micropowder is 1 ⁇ 6.5 ⁇ m, and the D90 of lactose monohydrate micropowder is 30 ⁇ 200 ⁇ m.
  • the mass ratio of nintedanib micropowder and lactose monohydrate micropowder is 1: (4-6).
  • the D90 of the nintedanib micropowder is 2 to 4 ⁇ m.
  • the D90 of the lactose monohydrate micropowder is 100-150 ⁇ m.
  • the D90 of the nintedanib micropowder is 2 to 4 ⁇ m, and the D90 of the lactose monohydrate micropowder is 100 to 150 ⁇ m.
  • the mass ratio of nintedanib micropowder and lactose monohydrate micropowder is 1: (4-6), and the D90 of the nintedanib micropowder is 2-4 ⁇ m.
  • the mass ratio of nintedanib micropowder and lactose monohydrate micropowder is 1: (4-6), the D90 of the nintedanib micropowder is 2-4 ⁇ m, and the lactose monohydrate The D90 of micro powder is 100 ⁇ 150 ⁇ m.
  • the nintedanib is nintedanib ethanesulfonate or nintedanib free base.
  • a second aspect of the invention provides:
  • the preparation method of the dry powder inhalant according to the first aspect of the present invention includes the following steps:
  • the crushing pressure is 4 to 8 bar
  • the dispersing pressure is 4 to 8 bar
  • the pressure difference between the crushing pressure and the dispersion pressure does not exceed 0.1 bar.
  • the crushing pressure is 4 to 8 bar
  • the dispersion pressure is 4 to 8 bar
  • the pressure difference between the crushing pressure and the dispersion pressure does not exceed 0.1 bar.
  • the particle size D90 of the nintedanib raw material is 170-220 ⁇ m.
  • the crushing pressure is 6 to 8 bar
  • the dispersion pressure is 6 to 8 bar
  • the pressure difference between the crushing pressure and the dispersion pressure does not exceed 0.1 bar.
  • the nintedanib raw material The particle size D90 of the material is 170 ⁇ 220 ⁇ m.
  • step S1 the fine powder is collected and passed through a 60-mesh screen.
  • the feed speed is 100 to 500 rpm.
  • the feed rate is 100 rpm.
  • the dry powder inhalants of some examples of the present invention realize the inhalation administration of nintedanib, which can significantly improve the bioavailability of nintedanib, reduce toxic and side effects, and improve the clinical therapeutic effect of IPF.
  • the prepared nintedanib dry powder preparation has fewer types of auxiliary materials, is easy to control in quality, has excellent physical performance parameters, is easy to atomize, and has quick effects. It also has reliable quality, high safety, and stability. It has high performance and long storage time.
  • Figure 1 is the aerodynamic particle size distribution of the nintedanib ethanesulfonate inhalation powder aerosols of Examples 12 to 16.
  • Figure 2 shows the effect of the test product on lung function in rats with pulmonary fibrosis.
  • Figure 3 is the effect of the test product on the lung weight index (%) of rats with pulmonary fibrosis.
  • a first aspect of the invention provides:
  • a dry powder inhaler for treating idiopathic pulmonary fibrosis consisting of nintedanib micropowder and lactose monohydrate micropowder.
  • the mass ratio of nintedanib micropowder and lactose monohydrate micropowder is 1: (2-8).
  • the D90 of Danib micropowder is 1 ⁇ 6.5 ⁇ m, and the D90 of lactose monohydrate micropowder is 30 ⁇ 200 ⁇ m.
  • the mass ratio of nintedanib micropowder and lactose monohydrate micropowder is 1: (4-6). More preferably, the mass ratio of nintedanib micropowder and lactose monohydrate micropowder is 1:5.
  • the D90 of the nintedanib micropowder is 2 to 4 ⁇ m.
  • Experimental data shows that the micropowder at this particle size can be better combined with the lactose monohydrate micropowder and has better aerodynamic particle size distribution, which is beneficial to improving bioavailability.
  • the D90 of the lactose monohydrate micropowder is 100-150 ⁇ m.
  • Experimental data shows that lactose monohydrate micropowder with this particle size can better load nintedanib micropowder.
  • the D90 of the nintedanib micropowder is 2 to 4 ⁇ m, and the D90 of the lactose monohydrate micropowder is 100 to 150 ⁇ m. Experimental data shows that this combination has relatively better results.
  • the mass ratio of nintedanib micropowder and lactose monohydrate micropowder is 1: (4-6), and the D90 of the nintedanib micropowder is 2-4 ⁇ m.
  • the mass ratio of nintedanib micropowder and lactose monohydrate micropowder is 1: (4-6), the D90 of the nintedanib micropowder is 2-4 ⁇ m, and the lactose monohydrate The D90 of micro powder is 100 ⁇ 150 ⁇ m.
  • the nintedanib is in the form of commonly used nintedanib such as nintedanib ethanesulfonate or nintedanib free base.
  • a second aspect of the invention provides:
  • the preparation method of the dry powder inhalant according to the first aspect of the present invention includes the following steps:
  • Lactose monohydrate micropowder can be directly used with specified particle size, without further special treatment.
  • the crushing pressure is 4 to 8 bar
  • the dispersing pressure is 4 to 8 bar.
  • the pressure difference between the crushing pressure and the dispersion pressure does not exceed 0.1 bar.
  • the crushing pressure is 4 to 8 bar
  • the dispersion pressure is 4 to 8 bar
  • the pressure difference between the crushing pressure and the dispersion pressure does not exceed 0.1 bar.
  • the particle size D90 of the nintedanib raw material is 170-220 ⁇ m.
  • Experimental data shows that nintedanib raw material with this raw material particle size, under a crushing pressure of about 8 bar, is not only more conducive to obtaining nintedanib micro powder with smaller particle size, but also obtains nintedanib micro powder with smaller particle size. The distribution is narrow, with unexpected effects.
  • the crushing pressure is 6 to 8 bar
  • the dispersion pressure is 6 to 8 bar
  • the pressure difference between the crushing pressure and the dispersion pressure does not exceed 0.1 bar.
  • the nintedanib raw material The particle size D90 of the material is 170 ⁇ 220 ⁇ m.
  • step S1 the fine powder is collected and passed through a 60-mesh screen. This can effectively screen out oversized particles
  • the feed speed is 100 to 500 rpm.
  • the feed rate has no significant effect on the particle size of nintedanib powder.
  • the feed rate is 100 rpm.
  • the present invention prepares nintedanib inhalation powder spray and administers it to the lungs to improve bioavailability, reduce toxic and side effects, and improve the clinical therapeutic effect of IPF.
  • nintedanib ethanesulfonate micropowder and lactose monohydrate micropowder prepared in Examples 1 to 7 were mixed at a mass ratio of 1:5 with a Turbula three-dimensional mixer at a rotation speed of 43 rpm for 40 minutes, and the capsules were manually filled. Capsules 25mg.
  • Table 2 shows that under the same crushing pressure, Examples 10 and 11 have different initial particle sizes of raw materials, and the crushing effects are different.
  • the raw materials with larger initial particle size will have relatively smaller particle sizes after crushing, which has unexpected effects.
  • the particle sizes of lactose used in different examples are shown in Table 3.
  • Example 12 151.48
  • Example 13 148.34
  • Example 14 129.81
  • Example 15 122.01
  • Example 16 100.93
  • This experiment used a total of 40 male SD rats, which were randomly divided into a normal control group (5 rats) and a model group (21 rats) for the first time.
  • the normal control group was given atomized sodium chloride injection (1mL/kg) into the airway, and the animals in the model group were given atomized bleomycin into the airway (4 mg/kg of bleomycin was administered into the airway of the animals on D1 and D4 respectively).
  • 2mg/kg, 1mL/kg to construct a pulmonary fibrosis model.
  • the animals in the D9 model group were again randomly divided into the model control group (sodium chloride injection), the test group (4mg/kg), and the commercially available control group (nintedanib ethanesulfonate soft capsule, 40mg/kg) based on body weight. kg), each group consisted of 7 animals; the normal control group was no longer divided into groups (5 animals). From D10 to D36, the animals in the normal control group, the model control group and the test group were given the corresponding drugs by atomization in the airway, once every 2 days, for a total of 14 times; in the commercial control group, the drugs were administered by gavage once. /day, administered continuously for 27 days. The dosage and route of administration are shown in Table 4.
  • D37 animals were anesthetized for lung function, hydroxyproline and lung weight index testing.
  • the right lung was fixed in 10% neutral buffered formalin solution, embedded in paraffin, sectioned, prepared, and stained with HE to detect inflammatory cells in the lung tissue.
  • the degree of infiltration and Masson staining were used to evaluate the degree of fibrosis in lung tissue.
  • Intra-airway atomization administration The animals in the test group were administered with a micro dry powder atomizer, and the animals in the normal control group and the model control group were administered with a micro liquid atomizer.
  • Dosing frequency and duration This trial is designed to use the commercially available reference substance nintedanib ethanesulfonate soft capsule at a dose of 40 mg/kg, which is approximately 1.5 times the equivalent clinical dose in rats.
  • Group 1 to Group 3 D10, D12, D14, D16, D18, D20, D22, D24, D26, D28, D30, D32, D34, D36, administered once every 2 days, a total of 14 times;
  • Group Part 4 D10 ⁇ D36, 1 time/day, 27 times in total.
  • Blood collection Blood samples were collected from animals before and 5min, 15min, 30min, 1h, 3h, 5h, and 24h after D10 administration.
  • Blood sample processing Immediately after collection, blood samples are transferred to a sampling tube containing separation gel + coagulant, temporarily stored and transported at room temperature, and centrifuged within 2 hours (centrifugation conditions: 3000g, room temperature, 10 min). After centrifugation, transfer the serum to a newly labeled cryovial or centrifuge tube and store it temporarily below -60°C. After the test is completed, relevant tests will be carried out.
  • Use Watson LIMS7.5 system to manage blood samples.
  • the AniRes2005 animal lung function analysis system detects lung compliance (Cdyn), airway resistance (RL), forced vital capacity (FVC) and other indicators.
  • Set the respiratory frequency of the ventilator to 65 times/min, the respiratory ratio to 20:10, the negative pressure controller to 30cmH 2 O, the FVC detection setting to the pressure control mode, the pressure to 30cmH 2 O, the starting mode to automatically detect end-tidal start, click
  • the start button causes the animal to passively inhale and exhale after reaching the set pressure value. After exhalation, click the stop button to complete an FVC test. Each animal is tested for at least 5 FVCs. The system will remove one maximum value and one minimum value, and the final result is the average of the remaining data.
  • the left lung tissue was temporarily stored in crushed ice, and finally stored below -60°C for detection of hydroxyproline content in lung tissue.
  • This experiment uses statistical software SPSS 13.0 and or GraphPad Prism 5 to process the data. All statistical analyzes were two-tailed, and the statistical level was set at P ⁇ 0.05.
  • Hydroxyproline index Compared with the model control group 0.990 ⁇ 0.103, the mean value of hydroxyproline in the lung tissue of animals in the test group was reduced to 0.843 ⁇ 0.135, and the mean value of hydroxyproline in the commercial control group was increased to 1.103 ⁇ 0.131. There were statistical differences between groups (P ⁇ 0.05). There was a statistical difference (P ⁇ 0.05 or P ⁇ 0.01) between the test product group and the commercially available control substance group ( Figure 2).
  • Pathological examination During this test, pulmonary fibrosis model animals were observed under a microscope to show lung and bronchial fibrosis, inflammatory cell infiltration, alveolar hemorrhage, alveolar/bronchiolar dilation, alveolar epithelial/pulmonary pleural hyperplasia, and macrophage accumulation in the alveoli. . Based on the microscopic results of the lungs of animals in each group, compared with the model control group, the degree and incidence of lung lesions in the test group were significantly reduced. It is believed that the test product can improve the pulmonary fibrosis model to a certain extent. degree of disease. In addition, the degree and incidence of lung lesions in the commercially available control group were not significantly reduced compared with the model control group.
  • the pulmonary fibrosis model can be successfully constructed by atomizing bleomycin into the airways of animals D1 and D4.
  • the drug was administered once every 2 days for a total of 14 times, and it had an improvement effect on fibrotic lesions of lung tissue.
  • the effect of the test product is better than that of the commercially available reference substance (nintedanib ethanesulfonate soft capsule).

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Abstract

一种治疗特发性肺纤维化的干粉吸入剂及其制备方法。干粉吸入剂由尼达尼布微粉和一水乳糖微粉组成，尼达尼布微粉和一水乳糖微粉的质量比为1：(2～8)，尼达尼布微粉的D90为1～6.5μm，一水乳糖微粉的D90为30～200μm。

Description

一种治疗特发性肺纤维化的干粉吸入剂及其制备方法 技术领域
本发明属于制药领域，具体涉及一种治疗特发性肺纤维化的干粉吸入剂及其制备方法。
背景技术
特发性肺纤维化(IPF)病因尚未明确，临床常表现为干咳、逐渐加重的呼吸困难，查体可闻及双肺底Velcro杂音，结合影像学表现为普通型间质性肺炎(UIP)并排除如药物、接触环境、结缔组织疾病等已知原因即可以诊断疾病 [1]。
尼达尼布(nintedanib)，是一种小分子三重酪氨酸激酶抑制剂，可同时抑制血管内皮生长因子受体，从而抑制血管生成组织和纤维化。2014年10月15日FDA批准尼达尼布(商品名Ofev)用于治疗特发性肺纤维化(IPF) [2]。欧洲药品管理局批准尼达尼布联合多西他赛用于治疗一线化疗后局部转移或局部复发的晚期腺癌类型非小细胞肺癌(NSCLC)。至今为止，尼达尼布治疗NSCLC的研究已取得了一系列新进展，大量研究证实尼达尼布单药或联合治疗NSCLC均具有较好疗效，且不良反应轻微可耐受，其常见不良反应为肝功能受损、恶心、呕吐和腹泻等 [3]。
尼达尼布是目前治疗IPF主流治疗药物，通过传统的给药途径口服给药。目前，上市产品仅有口服剂型。
研究发现，胃肠道反应是使用尼达尼布治疗最常见的不良反应，其中又以腹泻的发生率最高。肝酶改变，尤其是谷丙转氨酶(ALT)、谷草转氨酶(AST)和胆红素升高，也是使用尼达尼布过程中可能出现的常见不良事件 [4]。
肺部给药系统具有起效快、疗效好、同时减少不良反应等优点，已成为一种倍受关注的给药方式。在全球新型给药系统药物市场中，肺部吸入给药系统占有极为重要的地位 [5]。干粉吸入制剂是国际上治疗呼吸系统疾病的主流给药方式，无抛射剂、剂量少、靶向性强、副作用轻，适用场景广，但其研发难度为所有吸入制剂中最高，因此本领域改变给药途径时，往往先考虑雾化给药，最后才是干粉吸入制剂给药。目前，尼达尼布的雾化药物给药在国际上已有布局。
技术问题
吸入制剂的研发壁垒主要集中在处方设计、药物粒度和装置设计三个方面，须确保药物递送过程中的均一稳定和持续准确。具体地：
1、干粉吸入制剂处方设计方面，药物和辅料的组成影响吸入制剂的均一性和稳定性。药物和辅料的组成比例不同，可导致干粉的处方变化。辅料和载体影响制剂稳定性、活性成分的生物利用度，从而对患者的依从性产生影响。
2、干粉吸入制剂使用粉剂对粒径大小要求十分严格，只有在一定粒径范围内的颗粒才可以提高沉积率，使药物稳定吸收。根据呼吸道生理结构，为使药物有效地分布在治疗部位，粒度过大或过小可能使药物无法沉积，大大影响疗效。而处方的变化对于干粉粒径的影响是绝对的，因此，干粉制剂研发尤其需要基于不同的处方对粒径进行大量研究。
3、不同的干粉制剂原料制作工艺对制剂的影响很大，如粉碎法可引起结构的变化，如喷雾干燥法需考虑水分和其他有机溶剂问题。
4、考虑到患者随时随地的用药需求，干粉吸入制剂装置必须有优良的便携性和可操作性，这些性能要求吸入装置在给药的持续性、准确性和稳定性等方面拥有绝对的可靠性，因此吸入装置也是干粉吸入制剂研发的壁垒之一。
参考文献：
[1]郭友芳，张薇，冯明发，王梦瑶.特发性肺纤维化治疗进展[J].临床肺科杂志，2021，26(10):1591-1594.
[2]赵艳艳，冯建博，彭净，孟路华，张会鲜，吴明丽.尼达尼布上市后不良反应信号挖掘与分析[J].中国医院药学杂志，2019，39(16):1655-1658.
[3]苏建，曾林祥.非小细胞肺癌抗血管生成治疗新药：尼达尼布[J].中国新药与临床杂志，2019，38(11):653-657.
[4]韦鹏，周磊，黎雨，李殷康，杨彩珍，柳广南.尼达尼布在特发性肺纤维化中的应用及不良事件的管理[J].吉林医学，2021，42(07):1759-1762.
[5]万妮，陈斌，李合，叶伟伦，王慧.肺部吸入给药系统的研究进展[J].中国新药杂志，2021，30(15):1386-1395.。
技术解决方案
本发明的目的在于克服现有技术的至少一个不足，提供一种尼达尼布干粉吸入剂及其制备方法。
本发明所采取的技术方案是：
本发明的第一个方面，提供：
一种治疗特发性肺纤维化的干粉吸入剂，由尼达尼布微粉和一水乳糖微粉组成，尼达尼布微粉和一水乳糖微粉的质量比为1：(2～8)，尼达尼布微粉的D90为1～6.5μm，一水乳糖微粉的D90为30～200μm。
在一些干粉吸入剂的实例中，尼达尼布微粉和一水乳糖微粉的质量比为1：(4～6)。
在一些干粉吸入剂的实例中，所述尼达尼布微粉的D90为2～4μm。
在一些干粉吸入剂的实例中，所述一水乳糖微粉的D90为100～150μm。
在一些干粉吸入剂的实例中，所述尼达尼布微粉的D90为2～4μm，所述一水乳糖微粉的D90为100～150μm。
在一些干粉吸入剂的实例中，尼达尼布微粉和一水乳糖微粉的质量比为1：(4～6)，所述尼达尼布微粉的D90为2～4μm。
在一些干粉吸入剂的实例中，尼达尼布微粉和一水乳糖微粉的质量比为1：(4～6)，所述尼达尼布微粉的D90为2～4μm，所述一水乳糖微粉的D90为100～150μm。
在一些干粉吸入剂的实例中，所述尼达尼布为乙磺酸尼达尼布或尼达尼布游离碱。
本发明的第二个方面，提供：
本发明第一个方面所述干粉吸入剂的制备方法，包括如下步骤：
S1)取尼达尼布使用气流粉碎机进行粉碎，粉碎压力2～8bar，分散压力2～8bar，且粉碎压力与分散压力之间的压力差值不超过0.2bar，收集微粉，得到尼达尼布微粉；
S2)取的D90为30～200μm的一水乳糖微粉和所述尼达尼布微粉按比例混合，使用混合机充分混合，包装得到干粉吸入剂。
在一些制备方法的实例中，粉碎压力为4～8bar，分散压力4～8bar。
在一些制备方法的实例中，粉碎压力和分散压力的压力差不超过0.1bar。
在一些制备方法的实例中，粉碎压力为4～8bar，分散压力4～8bar，粉碎压力和分散压力的压力差不超过0.1bar。
在一些制备方法的实例中，所述尼达尼布原料的料粒径D90为170～220μm。
在一些制备方法的实例中，在一些制备方法的实例中，粉碎压力为6～8bar，分散压力6～8bar，粉碎压力和分散压力的压力差不超过0.1bar，所述尼达尼布原料的料粒径D90为170～220μm。
在一些制备方法的实例中，步骤S1)中，收集微粉后过60目筛网。
在一些制备方法的实例中，进料速度为100～500rpm。
在一些制备方法的实例中，进料速度为100rpm。
有益效果
本发明一些实例的干粉吸入剂，实现了尼达尼布的吸入给药，可以显著提高尼达尼布的生物利用度，降低毒副作用，提高IPF临床治疗作用。
本发明一些实例的制备方法，制备得到的尼达尼布干粉制剂辅料种类少，质量易于控制，具有优异的物理性能参数，易于雾化，见效快，其还具有质量可靠、安全性高、稳定性高、贮存时间长的有点。
附图说明
图1是实例12～16的乙磺酸尼达尼布吸入粉雾剂空气动力学粒径分布。
图2是供试品对肺纤维化大鼠肺功能的影响
Figure PCTCN2022109757-appb-000001
图3是供试品对肺纤维化大鼠肺重指数(％)的影响
Figure PCTCN2022109757-appb-000002
本发明的实施方式
本发明的第一个方面，提供：
一种治疗特发性肺纤维化的干粉吸入剂，由尼达尼布微粉和一水乳糖微粉组成，尼达尼布微粉和一水乳糖微粉的质量比为1：(2～8)，尼达尼布微粉的D90为1～6.5μm，一水乳糖微粉的D90为30～200μm。
在一些干粉吸入剂的实例中，尼达尼布微粉和一水乳糖微粉的质量比为1：(4～6)。更优先的，尼达尼布微粉和一水乳糖微粉的质量比为1：5。
在一些干粉吸入剂的实例中，所述尼达尼布微粉的D90为2～4μm。实验数据表明，这一粒径下的微粉可以更好地与一水乳糖微粉结合，具有更好的空气动力学粒径分布，有利于提高生物利用度。
在一些干粉吸入剂的实例中，所述一水乳糖微粉的D90为100～150μm。实验数据表明，这一粒径的一水乳糖微粉可以更好的负载尼达尼布微粉。
在一些干粉吸入剂的实例中，所述尼达尼布微粉的D90为2～4μm，所述一水乳糖微粉的D90为100～150μm。实验数据表明，这一组合下，具有相对更佳的效果。
在一些干粉吸入剂的实例中，尼达尼布微粉和一水乳糖微粉的质量比为1：(4～6)，所述尼达尼布微粉的D90为2～4μm。
在一些干粉吸入剂的实例中，尼达尼布微粉和一水乳糖微粉的质量比为1：(4～6)，所述尼达尼布微粉的D90为2～4μm，所述一水乳糖微粉的D90为100～150μm。
在一些干粉吸入剂的实例中，所述尼达尼布为乙磺酸尼达尼布或尼达尼布游离碱等常用的尼达尼布形式。
本发明的第二个方面，提供：
本发明第一个方面所述干粉吸入剂的制备方法，包括如下步骤：
S1)取尼达尼布使用气流粉碎机进行粉碎，粉碎压力2～8bar，分散压力2～8bar，且粉碎压 力与分散压力之间的压力差值不超过0.2bar，收集微粉，过60目筛网，得到尼达尼布微粉；
S2)取一水乳糖微粉和所述尼达尼布微粉按比例混合，使用混合机充分混合，包装得到干粉吸入剂。
一水乳糖微粉可以直接使用指定粒径的一水乳糖微粉，不需要进一步特别处理。
在一些制备方法的实例中，粉碎压力为4～8bar，分散压力4～8bar。实验数据显示，压力越高，得到的尼达尼布微粉粒径越小，但是粒径分布相对较宽。
在一些制备方法的实例中，粉碎压力和分散压力的压力差不超过0.1bar。
在一些制备方法的实例中，粉碎压力为4～8bar，分散压力4～8bar，粉碎压力和分散压力的压力差不超过0.1bar。
在一些制备方法的实例中，所述尼达尼布原料的料粒径D90为170～220μm。实验数据表明，这一原料粒径的尼达尼布原料，在8bar左右的粉碎压力下，不仅更有利于得到粒径更小的尼达尼布微粉，同时得到的尼达尼布微粉粒径分布较窄，具有意料之外的效果。
在一些制备方法的实例中，在一些制备方法的实例中，粉碎压力为6～8bar，分散压力6～8bar，粉碎压力和分散压力的压力差不超过0.1bar，所述尼达尼布原料的料粒径D90为170～220μm。
在一些制备方法的实例中，步骤S1)中，收集微粉后过60目筛网。这样可以有效筛除过大的颗粒
在一些制备方法的实例中，进料速度为100～500rpm。进料速度对于尼达尼布微粉粒径没有显著影响。
在一些制备方法的实例中，进料速度为100rpm。
本发明通过制备尼达尼布吸入粉雾剂，肺部给药提高生物利用度，降低毒副作用，提高IPF临床治疗作用。
下面结合实施例，进一步说明本发明的技术方案。
不同粉碎工艺参数对微粉粒径的影响
用J-30马西姆气流粉碎机进行粉碎，设定工艺参数，100rpm进料速度，乙磺酸尼达尼布原料粒径D90在174.61～208.35μm。
粉碎结束用新帕泰克粒径检测微粉粒径，设定分散压力3bar，R2检测镜头。工艺参数及检测结果如表1所示。
表1
Figure PCTCN2022109757-appb-000003
分别将实例1～7制得的乙磺酸尼达尼布微粉与一水乳糖微粉按1：5的质量比，用Turbula三维混合机在43rpm转速下，混合40分钟，手工灌装胶囊，每粒25mg。
不同乙磺酸尼达尼布原料粒径对微粉粒径的影响
用J-30马西姆气流粉碎机进行粉碎，设定工艺参数，进料速度100rpm。
粉碎结束用新帕泰克粒径检测微粉粒径，设定分散压力3bar，R2检测镜头。实例8～10使用的乙磺酸尼达尼布原料初始粒径D90在29.61～32.84μm，实施例11使用的乙磺酸尼达尼布原料初始粒径D90在174.61～208.35μm。工艺参数及检测结果如表2所示。
表2
Figure PCTCN2022109757-appb-000004
表1的数据表明，粉碎压力越大，粒径的D90越小，当粉碎压力达到一定值时，粒径不再减少，粉碎压力在6～8bar时，粒径D90约3μm。
表2的数据表明，同样粉碎压力，实例10和11，不同原料的初始粒径，粉碎效果不一样，原料初始粒径较大的，粉碎后粒径相对更小，具有意料之外的效果。
不同乳糖粒径对乙磺酸尼达尼布吸入粉雾剂空气动力学影响
实例12～16采用不同粒径的一水乳糖与乙磺酸尼达尼布微粉(D90＝2.8±0.3μm)按5：1的质量比，用Turbula三维混合机在43rpm转速下，混合40分钟，手工灌装胶囊，每粒25mg。不同实例使用的乳糖粒径如表3所示。
表3
编号 D90/μm
实例12 151.48
实例13 148.34
实例14 129.81
实例15 122.01
实例16 100.93
参照2020年版《中国药典》(四部)通则0951吸入制剂微细粒子空气动力学特性测定法，以新一代药用撞击器(next generation impactor，NGI)为测定装置，确定实例12～16的乙磺酸尼达尼布吸入粉雾剂空气动力学粒径分布。结果如图1所示。从图1中可以看出，不同粒径的一水乳糖与乙磺酸尼达尼布微粉具有不同的结合能力，实例14的结合效果最好，具有意料之外的效果。
下面结合实验，进一步说明本发明的技术方案。
动物实验：
方法：本试验共用40只雄性SD大鼠，首次随机分为正常对照组(5只)、模型组(21只)。D1、D4正常对照组气道内雾化氯化钠注射液(1mL/kg)，模型组动物气道内雾化给予博来霉素(D1、D4动物分别气道内雾化博来霉素4mg/kg、2mg/kg，1mL/kg)构建肺纤维化模型。D9模型组动物根据体重，再次随机分为模型对照组(氯化钠注射液)、供试品组(4mg/kg)、市售对照品组(乙磺酸尼达尼布软胶囊，40mg/kg)，各组均为7只动物；正常对照组不再进行分组(5只)。D10～D36正常对照组、模型对照组及供试品组动物均气道内雾化给予相应药物，每2天给药一次，共给药14次；市售对照品组灌胃给药，1次/天，连续给药27天，给药剂量及途径见表4。D37动物麻醉进行肺功能、羟脯氨酸及肺重指数检测，右肺置于10％中性缓冲福尔马林溶液中固定、石蜡包埋、切片、制片、HE染色进行肺组织炎症细胞浸润程度评价、Masson染色进行肺组织纤维化程度评价。
表4、给药剂量及途径
Figure PCTCN2022109757-appb-000005
注：正常对照组和模型对照组气道内雾化给予氯化钠注射液。
气道内雾化给药：供试品组动物采用微型干粉雾化器给药，正常对照组及模型对照组动物采用微型液体雾化器给药。
给药频率及期限：本试验设计市售对照品乙磺酸尼达尼布软胶囊40mg/kg剂量，约为大鼠等效临床剂量的1.5倍。组别1～组别3：D10、D12、D14、D16、D18、D20、D22、D24、D26、D28、D30、D32、D34、D36，每2天给药一次，共给药14次；组别4：D10～D36，1次/天，共27次。
采血：动物于D10给药前及给药后5min、15min、30min、1h、3h、5h、24h采集血样。
血液样本处理：血样采集后立即转移至含有分离胶+促凝剂的采样管中，室温下暂存和转运，2小时内完成离心(离心条件：3000g、室温、10min)。离心后的血清转移至贴有新标签的冻存管或离心管中，-60℃以下暂存。试验结束后，进行相关检测。使用Watson LIMS7.5系统对血样进行管理。
肺功能检测
AniRes2005动物肺功能分析系统进行肺顺应性(Cdyn)、气道阻力(RL)、用力肺活量(FVC)等指标检测。设置呼吸机呼吸频率65次/min、呼吸比20:10，负压控制器设置30cmH 2O，FVC检测设置压力控制方式，压力设定为30cmH 2O，启动方式选择自动检测呼吸末启动，点击开始按钮动物被动吸气到达设定压力值后转为呼气，呼气结束点击停止按钮，完成一次FVC检测。每只动物至少进行5次FVC检测，系统会去掉一个最大值和一个最小值，最后结果为剩余数据的平均值。
羟脯氨酸检测
D37所有动物全肺组织称量后，取左肺组织暂存于碎冰中，最后于-60℃以下保存，用于肺组织中羟脯氨酸含量检测。
数据采集和统计分析
本试验采用统计学软件SPSS 13.0和或GraphPad Prism 5对数据进行处理。所有统计分析采用双尾分析，统计学水平设在P≤0.05。
实验结果：
羟脯氨酸指标：与模型对照组0.990±0.103比较，供试品组动物的肺组织羟脯氨酸均值分别降低至0.843±0.135，市售对照品组升高至1.103±0.131，供试品组具有统计学差异(P≤0.05)。供试品组与市售对照品组比较，具有统计学差异(P≤0.05或P≤0.01)(图2)。
肺重指数：与模型对照组1.93±0.30比较，供试品组、市售对照品组动物均值分别降低至1.54±0.49、1.40±0.63(图3)。
病理学检测：本试验过程中，肺纤维化模型动物显微镜下观察可见肺及支气管纤维化、炎细胞浸润、肺泡出血、肺泡/细支气管扩张、肺泡上皮/肺胸膜增生和肺泡内巨噬细胞聚集。综合各组动物肺脏的显微镜下结果来看，相比于模型对照组，供试品组肺脏的病变程度和发生率有较明显的降低，认为供试品可在一定程度上改善肺纤维化模型的病变程度。另外，市售对照品组肺脏的病变程度和发生率相比于模型对照组未见明显降低。
结论：
综上所述，在本试验条件下，动物D1、D4气道内雾化给予博来霉素，能够成功构建肺纤维化模型；供试品4mg/kg剂量下，气道内雾化给予肺纤维化模型大鼠，每2天给药1次，共给药14次，对肺组织纤维化病变具有改善作用。供试品效果优于市售对照品(乙磺酸尼达尼布软胶囊)。
以上是对本发明所作的进一步详细说明，不可视为对本发明的具体实施的局限。对于本发明所属技术领域的普通技术人员来说，在不脱离本发明构思的简单推演或替换，都在本发明的保护范围之内。

Claims (11)

  1. 一种治疗特发性肺纤维化的干粉吸入剂，由尼达尼布微粉和一水乳糖微粉组成，其特征在于：尼达尼布微粉和一水乳糖微粉的质量比为1：(2～8)，所述尼达尼布微粉的D90为1～6.5μm，所述一水乳糖微粉的D90为30～200μm。
  2. 根据权利要求1所述的干粉吸入剂，其特征在于：尼达尼布微粉和一水乳糖微粉的质量比为1：(4～6)；和/或
    所述一水乳糖微粉的D90为30～150μm。
  3. 根据权利要求1所述的干粉吸入剂，其特征在于：所述尼达尼布微粉的D90为2～4μm。
  4. 根据权利要求1～3任一项所述的干粉吸入剂，其特征在于：所述一水乳糖微粉的D90为100～150μm。
  5. 根据权利要求1～3任一项所述的干粉吸入剂，其特征在于：所述尼达尼布为乙磺酸尼达尼布或尼达尼布游离碱。
  6. 一种干粉吸入剂的制备方法，其特征在于：所述干粉吸入剂如权利要求1～5任一项所述，包括如下步骤：
    S1)取尼达尼布使用气流粉碎机进行粉碎，粉碎压力2～8bar，分散压力2～8bar，且粉碎压力与分散压力之间的压力差值不超过0.2bar，收集微粉，得到尼达尼布微粉；
    S2)取一水乳糖微粉和所述尼达尼布微粉按比例混合，使用混合机充分混合，包装得到干粉吸入剂。
  7. 根据权利要求6所述的制备方法，其特征在于：粉碎压力为4～8bar，分散压力4～8bar。
  8. 根据权利要求6或7所述的制备方法，其特征在于：粉碎压力和分散压力的压力差不超过0.1bar。
  9. 根据权利要求6或7所述的制备方法，其特征在于：所述尼达尼布原料的料粒径D90为170～210μm。
  10. 根据权利要求6或7所述的制备方法，其特征在于：步骤S1)中，收集微粉后过60目筛网。
  11. 根据权利要求6或7所述的制备方法，其特征在于：进料速度为100～500rpm。
PCT/CN2022/109757 2022-05-05 2022-08-02 一种治疗特发性肺纤维化的干粉吸入剂及其制备方法 WO2023213019A1 (zh)

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