Nintedanib esylate inhalation powder and preparation method therefor

Abstract

Disclosed is a nintedanib esylate inhalation powder composed of micronized nintedanib esylate and lactose monohydrate. Further disclosed are a preparation method for the nintedanib esylate inhalation powder and use thereof in the preparation of a drug for treating pulmonary diseases such as pulmonary diseases with fibrosis or lung cancer.

Description

A Nintedanib Ethylene Sulfate Inhalation Powder and its Preparation Method

[0001] Citation of relevant applications

[0002] This disclosure claims priority to patent application No. 202411657839.2 entitled “A Nintedanib Ethylene Sulfate Inhalation Powder and Preparation Method thereof”, filed on November 20, 2024 with the State Intellectual Property Office of the People’s Republic of China, which is incorporated herein by reference in its entirety. Technical Field

[0003] This disclosure pertains to the pharmaceutical field, specifically relating to an inhalation powder formulation of nintedanib ethanesulfonate, its preparation method, and its uses. Background Technology

[0004] Idiopathic pulmonary fibrosis (IPF) is a lung disease of unknown cause, characterized by progressive, nonspecific alveolar inflammation accompanied by interstitial fibrosis. It has a poor prognosis, with a median survival of only 3-5 years for diagnosed patients. IPF is characterized by uncontrolled proliferation and differentiation of pulmonary fibroblasts / myofibroblasts and excessive collagen deposition in lung tissue. Multiple growth factors and peptide mediators, including vascular endothelial growth factor (VEGF), basic fibroblast growth factor 2 (bFGF-2), platelet-derived growth factor (PDGF), and transforming growth factor-β (TGF-β), play a crucial role in the fibrotic pathology, causing excessive extracellular matrix deposition, lung parenchymal scarring and structural remodeling, leading to decreased lung compliance and progressive loss of lung gas exchange function. Clinically, IPF manifests as progressive, irreversible dyspnea, severely impacting patients' quality of life; almost all IPF patients eventually die from respiratory failure. Lung transplantation is an effective and complete treatment for IPF, but the survival rate after transplantation is only about 5 years for approximately 50% of patients.

[0005] Nintedanib is a multiplex tyrosine kinase receptor inhibitor (TKI) developed by Boehringer Ingelheim. The US FDA and the EU EMA approved it for the treatment of idiopathic pulmonary fibrosis (IPF) in October 2014 and January 2015, respectively, making it the second drug globally specifically for IPF treatment. On September 20, 2017, nintedanib ethsylate received approval from the China National Medical Products Administration (NMPA) under the brand name [Brand Name Missing]. (H20170354; H20170355) is an oral capsule formulation. Currently, this drug is approved for the treatment of idiopathic pulmonary fibrosis (IPF), systemic sclerosis-associated interstitial lung disease (SSc ILD), and chronic fibrotic interstitial lung disease (ILD) with a progressive phenotype. In addition, nintedanib is also approved in the United States for use in combination with docetaxel for the treatment of locally advanced, metastatic, or locally recurrent adenocarcinoma-related non-small cell lung cancer (NSCLC) following first-line chemotherapy.

[0006] However, the oral bioavailability of nintedanib is only 4.69%. Boehringer Ingelheim's clinical studies have demonstrated that only high doses are beneficial for the progression of pulmonary fibrosis. The increased side effects associated with higher doses, including diarrhea, nausea or vomiting, elevated liver enzymes, liver damage, and renal insufficiency, prevent further dose increases. In a 6-month study investigating adherence to pirfenidone and nintedanib in 2331 IPF patients, 23.8% of pirfenidone patients and 33.5% of nintedanib patients discontinued their medication.

[0007] Inhalation is a method of drug delivery that uses a delivery device and the patient's breathing to deliver medication to the respiratory tract or lungs for the prevention, treatment, or diagnosis of local and systemic diseases. It has become the preferred route of administration for the treatment of asthma and chronic obstructive pulmonary disease (COPD). Because the oral bioavailability of nintedanib is only 4.69%, with a significant first-pass effect, and since IPF is a local lung disease, inhaled formulations can increase local drug concentration, reducing the amount of drug entering the bloodstream and significantly reducing gastrointestinal adverse reactions and liver and kidney damage. Inhaled formulations do not have a first-pass effect, allowing for equivalent efficacy at lower doses, thus enabling long-term administration.

[0008] Inhaled formulations include inhaled solutions (nebuliser), inhaled aerosols (pMID), and inhaled powders (DPI). Preliminary pharmacodynamic studies indicate that nintedanib requires a relatively high dosage (approximately 60 mg / day), inhaled solutions require a long nebulization time, and have poor compliance. Inhaled aerosols can only deliver 100-200 μg of the active ingredient per dose; therefore, inhaled powders are the preferred formulation for high-dose APIs. Summary of the Invention

[0009] CN114869866A discloses a nintedanib inhalation powder and its preparation method, wherein the formulation consists of micronized nintedanib issylate and lactose monohydrate in a mass ratio of 1:(4-6). However, in this patent, nintedanib requires a relatively high dose (4 mg / kg in rats) to be effective. Furthermore, the inventors of this disclosure, referring to this patent, used a three-dimensional mixing process to mix micronized nintedanib issylate and lactose monohydrate, and tested the aerodynamic particle size distribution of the obtained sample. They found that the fine particle deposition (FPF) was low and the formulation stability was poor; the fine particle dose (FPD) decreased significantly with increasing storage time. Therefore, developing a stable nintedanib powder is extremely important for the treatment of pulmonary fibrosis.

[0010] To address the aforementioned technical deficiencies, this disclosure provides a stable nintedanib isosulfate inhalation powder that exhibits no significant change in fine particle dose (FPD) during storage; furthermore, the powder has high delivery efficiency, allowing for good therapeutic effects with low-dose administration.

[0011] In a first aspect, this disclosure provides a nintedanib ethanesulfonate inhalation powder, composed of micronized nintedanib ethanesulfonate and lactose monohydrate, wherein:

[0012] The mass ratio of micronized nintedanib ethoxylate to lactose monohydrate is 1:(3-20), preferably 1:(3-10), 1:(4-10), 1:(4-7), 1:(4-6), 1:(4.5-6), or 1:(4-5;

[0013] The D90 of micronized nintedanib ethoxylate is 2-5 μm, preferably 2-4.5 μm, 2.5-4.5 μm, 2-4 μm, 2.5-4 μm, or 2-3 μm; for example, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5 μm, or any range between any two of the aforementioned values.

[0014] The D90 of lactose monohydrate is 120-200 μm, preferably 124-194 μm, more preferably 130-160 μm or 130-150 μm. For example, 120, 130, 140, 150, 160, 170, 180, 190, 200 μm or any range between two of the aforementioned values.

[0015] In some embodiments, the D50 of the micronized nintedanib ethoxylate is 0.7-3.0 μm, preferably 1.0-2.5 μm, more preferably 1.1-2.1 μm, 1.2-2 μm, 1.2-1.9 μm, 1.3-1.8 μm, 1.0-2.0 μm, or 1.0-1.5 μm, for example, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5 μm, or any range between any two of the aforementioned values.

[0016] In some embodiments, the D50 of lactose monohydrate is 30-70 μm, preferably 35-65 μm, 37-61 μm, or 35-60 μm, more preferably 40-60 μm or 40-50 μm. For example, 30, 35, 37, 40, 45, 50, 55, 60, 61, 65, 70 μm or any range between two of the aforementioned values.

[0017] In some implementations, the amount of lactose monohydrate is 100 ml.

[0018] In some embodiments, after long-term storage, the fine particle dose (FPD) of the nintedanib isethionate inhalation powder decreases by ≤20% relative to day 0, preferably ≤18%, ≤15%, ≤10%, ≤8%, ≤7%, or ≤6%. In some embodiments, long-term storage refers to storage for 3 or 6 months at a temperature of 25°C ± 2°C and a humidity of 60%RH ± 5%RH. In some embodiments, after storage for 3 months at a temperature of 25°C ± 2°C and a humidity of 60%RH ± 5%RH, the FPD decreases by ≤10% relative to day 0, preferably ≤8%, ≤7%, or ≤6%. In some embodiments, after storage for 6 months at a temperature of 25°C ± 2°C and a humidity of 60%RH ± 5%RH, the FPD decreases by ≤20% relative to day 0, preferably ≤18% or ≤15%.

[0019] In some embodiments, the fine particle fraction (FPF) of the nintedanib ethoxylate inhalation powder is 10% or more, preferably 15% or more, 20% or more, 25% or more, 30% or more, 35% or more, 40% or more, 45% or more, 48% or more, 50% or more, 52% or more, or 55% or more.

[0020] In some embodiments, the mass median aerodynamic diameter (MMAD) of the nintedanib ethanesulfonate inhalation powder is 1.5 μm-3 μm, preferably 1.5 μm-2.8 μm or 1.5 μm-2.5 μm.

[0021] In some embodiments, the geometric standard deviation (GSD) of the nintedanib ethanesulfonate inhalation powder is less than 2, preferably less than 1.8.

[0022] In some embodiments, the RSD value of the blend uniformity (BU) of the nintedanib isethionate inhalation powder is less than 4%, preferably less than 3.5%, less than 3%, less than 2.5%, less than 2%, less than 1.5%, or less than 1%.

[0023] Secondly, this disclosure provides a method for preparing the above-mentioned nintedanib ethanesulfonate inhalation powder, comprising the following steps:

[0024] (1) Pulverize nintedanib ethanesulfonate raw material to obtain micronized nintedanib ethanesulfonate;

[0025] (2) Weigh out the micronized nintedanib ethsulfate and lactose monohydrate according to the prescription amount, and pass them through a 60-mesh sieve and a 40-mesh sieve respectively.

[0026] (3) Mix micronized nidanib ethoxylate with lactose monohydrate.

[0027] Optionally includes step (4) of filling capsules.

[0028] In some embodiments, step (1) involves pulverizing the nintedanib ethanesulfonate raw material using an air jet mill. In some embodiments, the pulverizing pressure in step (1) is 4-10.5 bar, the feed pressure is 4.5-11 bar, and the feed pressure is 0.3-1 bar higher than the pulverizing pressure; the feed speed is 2-10 rpm or 2-7 rpm. Preferably, the pulverizing pressure is 4-10 bar, the feed pressure is 4.5-10.5 bar, and the feed pressure is 0.5 bar higher than the pulverizing pressure; the feed speed is 2-8 rpm or 2-5 rpm.

[0029] In some embodiments, the mixing in step (3) includes premixing and total mixing. In some embodiments, the premixing uses a two-dimensional mixing process, and / or the total mixing uses a high-energy mixing process. In some preferred embodiments, the premixing uses a two-dimensional mixer, and / or the total mixing uses a high-speed mixer.

[0030] In some embodiments, the mixer used for premixing operates at a speed of 5-25 rpm, preferably 15-25 rpm; the premixing time is 5-20 min, preferably 10-15 min. The mixer used for final mixing operates at a speed of 500-1500 rpm, preferably 500-1300 rpm, 500-1200 rpm, 600-1200 rpm, or 500-900 rpm; the final mixing time is 5-20 min, preferably 7-15 min, 8-13 min, or 8-12 min.

[0031] In some embodiments, the premixing uses a two-dimensional mixer with a rotation speed of 5-25 rpm, preferably 15-25 rpm; the premixing time is 5-20 min, preferably 10-15 min. The final mixing uses a high-speed mixer with a rotation speed of 500-1500 rpm, preferably 500-1300 rpm, 500-1200 rpm, 600-1200 rpm, or 500-900 rpm; the final mixing time is 5-20 min, preferably 7-15 min, 8-13 min, or 8-12 min.

[0032] Thirdly, this disclosure provides the use of the above-mentioned nintedanib ethoxylate inhalation powder in the preparation of a medicament for the treatment of lung diseases with fibrosis.

[0033] Fourthly, this disclosure provides a method for treating lung diseases with fibrosis, comprising administering the nintedanib ethsulfate inhalation powder of this disclosure to a patient or subject requiring treatment.

[0034] Fifthly, this disclosure provides the aforementioned nintedanib ethsulfate inhalation powder for the treatment of lung diseases with fibrosis.

[0035] In some embodiments, the lung disease with fibrosis is selected from:

[0036] (1) Chronic obstructive pulmonary disease (COPD), chronic bronchitis and emphysema, preferably fibrosis and remodeling of lung tissue in chronic obstructive pulmonary disease (COPD), chronic bronchitis and emphysema.

[0037] (2) Pulmonary fibrosis and lung diseases with fibrotic components, including but not limited to idiopathic pulmonary fibrosis (IPF), interstitial lung disease, giant cell interstitial pneumonia (GIP), sarcoidosis, cystic fibrosis, acute respiratory distress syndrome (ARDS), granulomatous disease, silicosis, drug-induced pulmonary fibrosis (e.g., pulmonary fibrosis caused by drugs such as bleomycin, carmustine, cyclophosphamide, amiodarone, procainamide, penicillamine, gold or nitrofurantoin), asbestosis, and systemic scleroderma;

[0038] (3) Asthma, preferably fibrosis and remodeling in asthma.

[0039] In some embodiments, the fibrotic lung disease is selected from the group consisting of idiopathic pulmonary fibrosis (IPF) and interstitial lung disease. In some embodiments, the interstitial lung disease is selected from the group consisting of systemic sclerosis-associated interstitial lung disease (SSc-ILD) and chronic fibrotic interstitial lung disease (ILD) with a progressive phenotype.

[0040] Sixthly, this disclosure provides the use of the above-mentioned nintedanib ethsulfate inhalation powder in the preparation of a medicament for the treatment of lung cancer.

[0041] In a seventh aspect, this disclosure provides a method for treating lung cancer, comprising administering the nintedanib ethsulfate inhalation powder of this disclosure to a patient or subject requiring treatment.

[0042] Eighthly, this disclosure provides the above-mentioned nintedanib ethsulfate inhalation powder for the treatment of lung cancer.

[0043] In some embodiments, the lung cancer is non-small cell lung cancer (NSCLC), and preferably, the lung cancer is lung adenocarcinoma.

[0044] For the sake of brevity, the term "about" is not used for some quantitative data herein. It should be understood that, whether the term "about" is explicitly used or not, every numerical value given herein includes not only the actual given value (the given value), but also an approximation of the given value based on reasonable deduction by one of ordinary skill in the art, including equivalents and approximations of the given value due to experimental and / or measurement conditions. These approximations are preferably ±20%, ±15%, ±10%, ±8%, ±6%, ±5%, ±4%, ±3%, 2%, or ±1% of the given value. In some embodiments, the approximations are obtained by rounding.

[0045] Terminology Definition

[0046] D10 refers to the particle size value corresponding to a cumulative distribution percentage of 10%, reflecting the distribution of small particles in the powder and is often used to indicate the fineness of the powder.

[0047] D50 refers to the particle size value corresponding to a cumulative distribution percentage of 50%, also known as the median particle size or median particle size. It represents the average particle size of the powder and is a commonly used indicator in powder engineering.

[0048] D90 refers to the particle size value corresponding to a cumulative distribution percentage of 90%, reflecting the distribution of larger particles in the powder, and is often used to indicate the coarse end particle size of the powder.

[0049] Span value (SPAN) is a commonly used way to characterize the width of particle size distribution. It is defined as follows: Span value (SPAN) = (D90 – D10) / D50. The larger the SPAN value, the wider the particle size distribution.

[0050] Aerodynamic particle size distribution (APSD) is the most critical quality attribute for oral inhalation formulations and nasal sprays, and is commonly determined using the impactor method. Aerosol particles are trapped in different stages according to their different sizes, achieving particle size classification.

[0051] Fine particle dose (FPD) is an important parameter of APSD, referring to the total mass of drug fine particles with an aerodynamic diameter of less than 5.0 μm emitted from the device by the actuation device. A higher FPD value indicates that more drug mass of the formulation can reach the lungs.

[0052] Fine particle fraction (FPF) is the fraction or percentage of drug mass contained in an aerosol with an aerodynamic particle size of less than 5.0 μm. A higher FPF value indicates that a greater proportion of the drug from the formulation reaches the lungs.

[0053] The mass median aerodynamic diameter (MMAD) is the particle size at which the accumulated particle mass across all levels in the APSD reaches or is closest to 50% of the total particle mass. It reflects the central tendency and median diameter of the APSD curve. A larger MMAD value indicates a larger drug particle size.

[0054] The geometric standard deviation (GSD) is the ensemble standard deviation of the APSD curve for particles that follow a unimodal log-normal distribution. It represents the dispersion of the APSD curve. A larger GSD value indicates a wider particle size distribution.

[0055] The delivered dose (DD) refers to the dose of an inhaled formulation released from the device during use, which is the total mass of particles from A to MOC in the aerodynamic particle size distribution.

[0056] Blend uniformity (BU) refers to the degree to which the particles of each component are evenly distributed in any volume when various materials are mixed together under the action of external force.

[0057] The full name of a two-dimensional mixer is a two-dimensional motion mixer, which is a device that mixes materials by rotating a drum in two directions simultaneously.

[0058] A three-dimensional mixer is a device that achieves efficient and uniform mixing of materials through the multi-directional movement of a mixing drum in three-dimensional space.

[0059] A high-speed mixer is a device that uses high-speed rotating agitator blades or paddles to violently stir, shear, and mix materials in a closed container.

[0060] Two-dimensional mixing technology refers to a mixing method that involves simultaneous movement in two directions, which can achieve uniform dispersion and optimized combination of drugs and carriers.

[0061] High-energy mixing technology refers to the use of high-energy methods such as high-speed stirring, shearing or airflow to tightly bind micronized drug particles with a carrier (such as lactose) to form a stable "drug-carrier" complex.

[0062] Three-dimensional mixing refers to the process of using specific mixing equipment and processes to enable drug particles and carrier particles to undergo sufficient convection, diffusion and shear mixing in three-dimensional space to achieve uniform dispersion. Attached Figure Description

[0063] Figure 1 shows the aerodynamic particle size distribution of nidanib ethanesulfonate inhalation powder using different mixing methods.

[0064] Figure 2 shows the aerodynamic particle size distribution of nintedanib ethanesulfonate inhalation powder using lactose carriers of different particle sizes.

[0065] Figure 3 shows the histopathological examination results of a typical case in the pharmacodynamic study of nintedanib ethanesulfonate inhalation powder, in which:

[0066] (1) A in Figure 3: Model control group. Moderate inflammatory cell infiltration with mild macrophage aggregation was observed in the right middle lobe of the lung, around the alveoli / bronchus / vascular area. Histopathological grade was 5. HE staining, 100×.

[0067] (2) B in Figure 3: test sample group-4, no obvious abnormalities were found in the accessory lobe of the lung, histopathological grade was 1, HE staining, 200×.

[0068] (3) C in Figure 3: model control group, grade 6 fibrosis of the pulmonary septum can be seen in the right lower lobe of the lung, Masson staining, 200×.

[0069] (4) D in Figure 3: test sample group-1, grade 2 fibrosis of the septum is visible in the accessory lobe of the lung, Masson staining, 200×.

[0070] Figure 4 shows the aerodynamic particle size distribution of samples 6-1 and 6-2. Detailed Implementation

[0071] The present disclosure is further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the disclosure. Unless specific conditions for experimental methods are specified in the following embodiments, they are generally performed under conventional conditions or as recommended by the manufacturer.

[0072] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as are familiar to those skilled in the art. Furthermore, any methods and materials similar to or equivalent to those described herein may be applied to the methods of this disclosure. The preferred embodiments and materials described herein are merely examples.

[0073] I. Materials

[0074] Nintedanib ethanesulfonate raw material, supplied by CSPC Ouyi Pharmaceutical Co., Ltd. D 50 It is 11μm, D 90 It is 38μm.

[0075] Lactose monohydrate, commercially available. Specific models and particle size distribution are as follows:

[0076] II. Detection Methods

[0077] 1. Aerodynamic particle size distribution

[0078] Referring to the General Chapter 0951 of the 2020 edition of the Chinese Pharmacopoeia (Volume IV), the aerodynamic particle size distribution of nintedanib ethanesulfonate inhalation powder (capsules) was determined using a next-generation pharmaceutical impactor (NGI, Copley Scientific Ltd., UK) as the measuring device.

[0079] 2. Micronized Particle Size Distribution

[0080] The particle size of the micro powder was measured using a new Partek laser particle size analyzer (HELOS-RODOS), with a dispersion pressure of 3 bar and an R2 detection lens.

[0081] 3. Content of nidanib and related substances

[0082] The determination was performed using high performance liquid chromatography (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0512).

[0083] Example 1: Formulation and preparation method of nintedanib ethanesulfonate inhalation powder.

[0084] Table 1. Formulation of Nintedanib Ethylened Inhalation Powder

[0085] Note: All formulation specifications described in this disclosure are expressed as nintedanib amount / total capsule contents. 1.204 mg nintedanib ethanesulfonate is equivalent to 1 mg nintedanib. Drug-carrier ratio = nintedanib ethanesulfonate : lactose monohydrate.

[0086] Preparation process:

[0087] (1) The raw material of nintedanib ethanesulfonate was pulverized using an ultra-micro powder air jet mill (Micron JETMILL Pilot, Norze Fluid Technology (Shanghai) Co., Ltd.) to obtain micronized nintedanib ethanesulfonate;

[0088] (2) Weigh out the micronized nintedanib ethsulfate and lactose monohydrate according to the prescription amount, and pass them through a 60-mesh sieve and a 40-mesh sieve respectively.

[0089] (3) Add the micronized nintedanib ethoxylate and lactose monohydrate to a mobile micro mixer (two-dimensional mixer, WHJ-50, Huaxing Pharmaceutical Equipment Co., Ltd.) for premixing at a speed of 5-25 rpm for 5-20 min. After passing through a 40-mesh sieve, use a high-speed mixer (DPI Mixer10, Noze Fluid Technology (Shanghai) Co., Ltd.) for total mixing at a speed of 500-1500 rpm for 5-20 min.

[0090] (4) Fill capsules with 25mg each using a manual powder filling machine (LM-14, M&O PERRY INDUSTRIES.INC.).

[0091] Screening Example 1: Effect of grinding process on particle size of micronized nintedanib ethanesulfonate

[0092] Referring to Formulation 1-1 and its preparation method in Example 1, using the same batch of nintedanib ethsulfate raw material, the effects of different pulverizing pressures, feeding pressures, and feeding speeds in step (1) on the particle size of micronized nintedanib ethsulfate were investigated. The process parameters and test results are shown in Table 2.

[0093] Table 2. Effect of grinding process on particle size of micronized nintedanib ethanesulfonate (average value, n=3) Note: Span value (SPAN) = (D 90 –D 10 ) / D 50

[0094] The results showed that, with the following air jet mill parameters set: milling pressure 4-10 bar, feed pressure 4.5-10.5 bar, pressure difference between milling pressure and feed pressure approximately 0.5 bar, and feed speed within the range of 2-5 rpm or 2-8 rpm, the D90 of micronized nintedanib ethanesulfonate was 2-4 μm. 50The particle size is 1.2-1.9 μm, and the particle size span (SPAN) is 1.5-1.8, indicating a relatively uniform particle size distribution that meets the requirements of formulation.

[0095] Screening Example 2: Impact of Hybrid Methods on Product Delivery Performance

[0096] Referring to Formulation 1-1 of Example 1 and its preparation method, the effects of high-energy mixing and three-dimensional mixing processes on product delivery performance were compared. Sample specifications were 1 mg / 25 mg, and the particle size D of the micronized nintedanib ethoxylate was... 50 =1.77μm, using ML001 lactose as a carrier, it was first premixed (25rpm / 15min) using a mobile micro mixer (two-dimensional mixer, WHJ-50, Huaxing Pharmaceutical Equipment Co., Ltd.), and then high-energy mixed using a high-speed mixer (DPI Mixer10, Nozer Fluid Technology (Shanghai) Co., Ltd.) or a three-dimensional swing mixer (three-dimensional mixer, T2F (Swiss WAB) is used for three-dimensional mixing and filling into capsules.

[0097] Table 3. Sample formulation process information and delivery performance for different mixing methods (average, n=3)

[0098] The results in Table 3 and Figure 1 show that, comparing samples 3-2 and 3-3, with the same API (micronized nintedanib ethoxylate) and lactose particle size, the high-energy mixing process produces samples with smaller median mass aerodynamic diameter (MMAD) and geometric standard deviation (GSD) compared to the three-dimensional mixing process. These samples also exhibit higher fine particle dose (FPD) and fine particle fraction (FPF), suggesting that samples prepared using the high-energy mixing process have smaller particle sizes and narrower particle size distributions, resulting in a greater mass and proportion of drug reaching the lungs and thus a better therapeutic effect. Therefore, the high-energy mixing process is preferred.

[0099] As can be seen from the detection results of samples 3-1 and 3-2 (see Figure 1), although the MMAD value decreased slightly with the extension of mixing time, the amount of P-level deposition increased and the fine particle dose (FPD) decreased significantly.

[0100] Screening Example 3: Effect of different particle size carrier lactose on product performance

[0101] Referring to Formulation 1-1 and its preparation method in Example 1, the effect of different particle sizes of the carrier lactose on product performance was investigated. The sample specification was 1 mg / 25 mg, and the particle size D50 of the micronized nintedanib ethoxylate was 1.77 μm. It was first premixed using a mobile micro-mixer (two-dimensional mixer, WHJ-50, Huaxing Pharmaceutical Equipment Co., Ltd.) (25 rpm / 15 min), and then fully mixed using a high-speed mixer (DPI Mixer 10, Nozer Fluid Technology (Shanghai) Co., Ltd.) (900 rpm / 10 min), and then filled into capsules.

[0102] Table 4-1 Formulation information and particle size distribution of carriers with different particle sizes (average value, n=3) Note: Mixed powder refers to the powder formed by mixing micronized nintedanib ethanesulfonate with the carrier lactose.

[0103] Table 4-2 Aerodynamic particle size distribution of different samples (average, n=3)

[0104] The results showed that when using lactose carriers of different particle sizes, there were no significant differences in delivery dose (DD), median mass aerodynamic diameter (MMAD), and geometric standard deviation (GSD). However, the ML001 lactose carrier exhibited a higher fine particle dose (FPD) and a higher fine particle fraction (FPF). Therefore, ML001 lactose was preferred as the carrier.

[0105] Screening Example 4: The Influence of API Particle Size and Mixing Process Parameters on Product Performance

[0106] Referring to formulations 1-1, 1-2, and 1-4 of Example 1 and the preparation method, samples with specifications of 1 mg / 25 mg, 2 mg / 25 mg, and 3.5 mg / 25 mg were prepared respectively. Using ML001 as a carrier, the samples were first premixed (25 rpm / 15 min) using a mobile micro mixer (two-dimensional mixer, WHJ-50, Huaxing Pharmaceutical Equipment Co., Ltd.), and then fully mixed using a high-speed mixer (DPI Mixer10, Nozer Fluid Technology (Shanghai) Co., Ltd.) and a high-energy mixing process (specific mixing parameters are shown in Table 5-1).

[0107] The effects of API (micronized nintedanib ethanesulfonate) particle size and mixing process parameters on product performance were investigated.

[0108] Table 5-1 Effects of API Particle Size and Mixing Process Parameters on Product Performance (Test Process Parameters)

[0109] Table 5-2 Experimental results on the influence of API particle size and mixing process parameters on product performance (n=3)

[0110] The results above show that, under the experimental conditions, the RSD of the mixing uniformity (BU) decreases with increasing mixing speed and mixing time. For the 1mg / 25mg and 2mg / 25mg specifications, the FPD shows a decreasing trend with increasing total mixing speed and mixing time; however, this trend is not significant for the 3.5mg / 25mg specification.

[0111] Based on the above research, the preferred particle size (API D) of the micronized nintedanib ethoxylate prepared by the method described in this disclosure is... 50 The total mixing speed is within the range of 1.3-2.0μm, the total mixing speed is within the range of 600-1200rpm, and the total mixing time is 8-12min.

[0112] Samples of 3.5mg / 25mg specifications were selected, and the total mixing was carried out using a high-energy mixing process with specific parameters of 1200rpm*10min (F3-1), 900rpm*10min (F3-2), and 600rpm*10min (F3-3). The samples were placed at a temperature of 25℃±2℃ and a humidity of 60%RH±5%RH for 6 months, and the product performance was tested.

[0113] Table 5-3 Aerodynamic particle size distribution of samples with different mixing process parameters

[0114] As can be seen from Table 5-3, the delivery performance of samples with different mixing process parameters on day 0 is not significantly different.

[0115] The nitedanib ethanesulfonic acid powder aerosol (sample F3-1) prepared by the high-energy mixing process at 1200 rpm for 10 min showed a decrease in FPD of approximately 15% compared to that after 6 months of storage at day 0.

[0116] The high-energy mixing process was performed at 900 rpm for 10 min per batch (F3-2 sample), resulting in a 10% reduction in FPD compared to samples placed for 6 months after 0 days.

[0117] The high-energy mixing process was performed at 600 rpm for 10 min per batch (F3-3 sample), resulting in an approximately 8% reduction in FPD compared to samples placed for 6 months after 0 days.

[0118] It can be seen that the aerodynamic particle size distribution of the three samples prepared by the above process still meets the requirements after being placed at a temperature of 25℃±2℃ and a humidity of 60%RH±5%RH for 6 months; and the high-energy mixing process of 600-900rpm*10min shows that the stability of FPD and FPF is better than that of the mixing process of 1200rpm*10min.

[0119] Screening Example 5: The Effect of Different Formulation Strengths on Product Performance

[0120] Referring to the formulation and preparation method in Example 1, the effects of different formulation specifications on product performance were investigated. Using ML001 as a carrier, the product was first premixed (25 rpm / 15 min) using a mobile micro mixer (two-dimensional mixer, WHJ-50, Huaxing Pharmaceutical Equipment Co., Ltd.), and then fully mixed using a high-speed mixer (DPI Mixer10, Nozer Fluid Technology (Shanghai) Co., Ltd.) employing a high-energy mixing process (specific mixing parameters are shown in Table 6-1), and then filled into capsules.

[0121] Table 6-1 Formulation and process information for samples of different formulation specifications

[0122] Table 6-2 Mixing uniformity and aerodynamic particle size distribution of samples with different formulation specifications Note: The sample was placed under the following conditions: temperature 25℃±2℃; humidity 60%RH±5%RH.

[0123] As shown in Table 6-2:

[0124] (1) Mixing uniformity

[0125] The 1mg / 25mg, 2mg / 25mg, 3mg / 25mg, 3.5mg / 25mg and 4mg / 25mg formulations showed good mixing homogeneity with an RSD of less than 4%; the 5mg / 25mg formulation showed poor mixing homogeneity with an RSD greater than 5%.

[0126] (2) Delivery performance

[0127] The FPD value of 1mg / 25mg nintedanib isosulfate inhalation powder decreased slightly with prolonged storage time. The FPD decreased by about 6% after 3 months of storage compared to 0 days, and by about 11% after 6 months of storage compared to 0 days.

[0128] The FPD value of 2mg / 25mg nintedanib isosulfate inhalation powder decreased slightly with prolonged storage time. The FPD decreased by about 4.2% after 3 months of storage compared to 0 days, and by about 13% after 6 months of storage compared to 0 days.

[0129] The FPD value of 3mg / 25mg nintedanib isosulfate inhalation powder decreased slightly with prolonged storage time. The FPD decreased by about 3.4% after 3 months of storage compared to 0 days, and by about 11% after 6 months of storage compared to 0 days.

[0130] The 3.5mg / 25mg nintedanib isosulfate inhalation powder reduced FPD by approximately 3.1% after 3 months of storage compared to day 0, and by approximately 10% after 6 months of storage compared to day 0.

[0131] The 4mg / 25mg nintedanib isosulfate inhalation powder reduced FPD by approximately 6% after 3 months of storage compared to day 0, and by approximately 13% after 6 months of storage compared to day 0.

[0132] The 5mg / 25mg nintedanib isosulfate inhalation powder showed a significant decrease in FPD (approximately 11.3%) after 14 days of storage, compared to a decrease of approximately 16.8% after 3 months of storage from day 0 and approximately 19% after 6 months of storage from day 0.

[0133] This demonstrates that formulation strength affects the delivery efficacy of nintedanib issylate inhalation powder. Formulations with 1 mg / 25 mg, 2 mg / 25 mg, 3 mg / 25 mg, 3.5 mg / 25 mg, and 4 mg / 25 mg exhibit excellent long-term stability, with only a slight decrease in FPD values ​​over extended storage time. In contrast, the 5 mg / 25 mg formulation shows poor mixing uniformity and inadequate long-term stability, with a significant decrease in FPD values ​​over extended storage time.

[0134] (3) Nydanib content and related substance content

[0135] The long-term stability of samples of different specifications was investigated. After being stored for 3 months (temperature 25℃±2℃, relative humidity 60%±5%), the content of nintedanib and related substances was detected by high performance liquid chromatography. The results showed that the content of active ingredients and related substances in nintedanib issylate inhalation powder did not change significantly, and the chemical stability of each specification of formulation met the requirements.

[0136] Table 6-3. Results of related substances detection in samples of different formulation specifications

[0137] Experimental Example 1: Pharmacodynamic Study of Nintedanib Ethylenediol Inhalation Powder

[0138] 1. Experimental Materials

[0139] Test sample: Sample 5-2 from Screening Example 5 (2mg / 25mg specification).

[0140] 2. Experimental Methods

[0141] On day 1 (D1), 70 male SD rats (5-7 weeks old, Zhejiang Vital River Laboratory Animal Technology Co., Ltd.) were administered bleomycin (2 mg / kg, 1 mL / kg) via nebulization, twice daily (morning and afternoon). On day 7 (D7), 40 rats were randomly selected based on body weight and randomly divided into four groups: model control group, test drug group 1 (0.23 mg / kg), test drug group 2 (0.49 mg / kg), test drug group 3 (1.0 mg / kg), and test drug group 4 (0.73 mg / kg), with 8 rats in each group. The average body weight of the animals in each group was similar, with no significant difference (P>0.05). Eight normal male SD rats were used as the normal control group and administered physiological saline (1 mL / kg) via nebulization on day 1 (D1).

[0142] Begin administration on day 8 (D8) and continue for 14 consecutive days:

[0143] The normal control group and the model control group were given clean air via nebulization, 60 min / time, once a day, for a total of 14 times;

[0144] The test sample group was administered the medication via nebulized inhalation:

[0145] (1) Test sample group 1, 5 min / time, once a day, for a total of 14 times;

[0146] (2) Test sample group 2, 10 min / time, once a day, for a total of 14 times;

[0147] (3) Test sample group 3: 10 min / time, 2 times / day, with an interval of at least 3 hours between the two inhalation administrations, for a total of 28 times;

[0148] (4) Test sample group 4: 15 min / time, once a day, for a total of 14 times.

[0149] All animals were euthanized on day 22 (D22) for systematic dissection. Lungs were harvested and weighed, and the lung index was calculated (lung index = lung weight ÷ body weight × 100%). Gross observation of the lungs, trachea, and bronchi was performed. Right lung tissue and bronchial tissue were fixed in 10% neutral buffered formalin and routinely embedded in paraffin, sectioned, and stained with hematoxylin and eosin (HE) and Masson's stain. Histopathological examination was conducted by the head of the pathology team using an optical microscope. HE staining was used to grade lung tissue inflammation using a 5-point scale: no lesion (-); + (mild lesion); mild lesion (++); moderate lesion (+++); significant lesion (++++); severe lesion (+++++). For Masson's staining, a modified Ashcroft scoring system was used to evaluate the degree of pulmonary fibrosis, graded from 0 to 8, with higher grades indicating more severe fibrosis.

[0150] Table 7-1 Animal grouping and administration regimen

[0151] 3. Experimental Results

[0152] Table 7-2 Efficacy results of nintedanib ethsulfate inhalation powder in the treatment of pulmonary fibrosis Note: (1) Compared with the model control group, *P<0.05; **P<0.01;

[0153] In this experiment, bleomycin was nebulized into the airway to induce pulmonary fibrosis. Mild to moderate inflammatory cell infiltration was observed in the alveoli, bronchi, and perivascular areas of the lungs in the model group rats. The pulmonary septa showed grade 4-7 fibrosis, accompanied by varying degrees of alveolar macrophage aggregation, multifocal edema, and multifocal alveolar cavity dilation, indicating that the pulmonary fibrosis model was successfully established.

[0154] The nintedanib ethsulfate inhalation powder disclosed herein, when inhaled for 5 minutes daily at a pulmonary deposition dose of 0.23 mg / kg, significantly improves pulmonary inflammation and fibrosis, and improves the lung coefficient (see test sample group-1). This suggests that the nintedanib ethsulfate inhalation powder disclosed herein can exert a good therapeutic effect at a pulmonary deposition dose of 0.23 mg / kg.

[0155] In conclusion, for the treatment of nintedanib in pulmonary fibrosis, the formulation of nintedanib ethsulfate inhalation powder can directly deliver the drug to the lesion site, improve efficacy, and reduce adverse reactions. Compared with the currently marketed oral formulations, it has significant clinical advantages.

[0156] Comparative Study of Self-Developed Process Samples and Samples Prepared by Process CN114869866B

[0157] Patent CN114869866B provides a nintedanib ethanesulfonic acid inhalation powder. Sample 6-1 was prepared according to the mixing process described in the patent, and its performance was compared with that of sample 6-2 prepared by the mixing process of this project.

[0158] The particle sizes of the micronized nintedanib ethanesulfonate are shown in Table 8-1, using ML001 as the carrier. Sample 6-1 was prepared using a three-dimensional rocking mixer (three-dimensional mixer, T2F (WAB, Switzerland) was mixed using a three-dimensional mixing process. Sample 6-2 was first premixed using a mobile micro mixer (two-dimensional mixer, WHJ-50, Huaxing Pharmaceutical Equipment Co., Ltd.) using a two-dimensional mixing process, and then fully mixed using a high-speed mixer (DPI Mixer10, Nozer Fluid Technology (Shanghai) Co., Ltd.) using a high-energy mixing process (specific mixing parameters are shown in Table 8-1).

[0159] Table 8-1 Sample Process Information (Average Values, n=3)

[0160] Table 8-2 Aerodynamic particle size distribution of the samples (average, n=3)

[0161] As can be seen from Table 8-2 and Figure 4:

[0162] (1) Mixing uniformity

[0163] Samples 6-1 and 6-2 showed good mixing uniformity, and sample 6-2 had a smaller RSD of mixing uniformity, indicating better mixing uniformity.

[0164] (2) Fine Particle Count (FPF)

[0165] The FPF value of sample 6-1 (47.32%) was significantly lower than that of sample 6-2 (57.59%), indicating that the self-developed process sample had higher delivery efficiency.

[0166] (3) Fine particle dose (FPD)

[0167] The FPD value of sample 6-1 (1448.64) was significantly lower than that of sample 6-2 (1884.56) using the self-developed process, indicating that the self-developed process sample could reach a greater quantity of drug in the lungs.

Claims

1. A nintedanib ethanesulfonate inhalation powder, comprising micronized nintedanib ethanesulfonate and lactose monohydrate, wherein: The mass ratio of micronized nintedanib ethoxylate to lactose monohydrate is 1:(3-20), preferably 1:(3-10), 1:(4-10), 1:(4-7), 1:(4-6), 1:(4.5-6), or 1:(4-5; The D90 of micronized nintedanib ethoxylate is 2-5 μm, preferably 2-4.5 μm, 2.5-4.5 μm, 2-4 μm, 2.5-4 μm, or 2-3 μm, for example 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5 μm, or any range between any two of the aforementioned values; The D90 of lactose monohydrate is 120-200 μm, preferably 124-194 μm, more preferably 130-160 μm or 130-150 μm, for example 120, 130, 140, 150, 160, 170, 180, 190, 200 μm or any range between two of the aforementioned values.

2. The nintedanib isosulfate inhalation powder as described in claim 1, wherein the D50 of the micronized nintedanib is 0.7-3.0 μm, preferably 1.0-2.5 μm, more preferably 1.1-2.1 μm, 1.2-2 μm, 1.2-1.9 μm, 1.3-1.8 μm, 1.0-2.0 μm, or 1.0-1.5 μm, for example, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5 μm or any range between any two of the aforementioned values.

3. The nintedanib ethanesulfonate inhalation powder as described in claim 1, wherein the D50 of the lactose monohydrate is 30-70 μm, preferably 35-65 μm, 37-61 μm, or 35-60 μm, more preferably 40-60 μm or 40-50 μm; for example, 30, 35, 37, 40, 45, 50, 55, 60, 61, 65, 70 μm or any range between any two of the aforementioned values.

4. The nintedanib isosulfate inhalation powder as described in claim 1, wherein after long-term storage, the fine particle dose (FPD) of the nintedanib isosulfate inhalation powder decreases by ≤20% relative to day 0, preferably ≤18%, ≤15%, ≤10%, ≤8%, ≤7%, or ≤6%. Preferably, the long-term storage refers to placing the product at a temperature of 25℃±2℃ and a humidity of 60%RH±5%RH for 3 months or 6 months. Preferably, the nintedanib ethanesulfonate inhalation powder, after being stored at 25°C ± 2°C and 60% RH ± 5% RH for 3 months, exhibits a decrease in FPD relative to day 0 of ≤10%, preferably ≤8%, ≤7%, or ≤6%; and / or The nintedanib ethanesulfonate inhalation powder, when stored at 25℃±2℃ and 60%RH±5%RH for 6 months, showed a decrease in FPD relative to day 0 of ≤20%, preferably ≤18% or ≤15%.

5. The nintedanib isosulfate inhalation powder as described in claim 1, wherein the fine particle fraction (FPF) of the nintedanib isosulfate inhalation powder is 10% or more, preferably 15% or more, 20% or more, 25% or more, 30% or more, 35% or more, 40% or more, 45% or more, 48% or more, 50% or more, 52% or more, or 55% or more.

6. The nintedanib isosulfonate inhalation powder as described in claim 1, wherein the mass median aerodynamic diameter (MMAD) of the nintedanib isosulfonate inhalation powder is 1.5 μm-3 μm, preferably 1.5 μm-2.8 μm or 1.5 μm-2.5 μm.

7. The nintedanib ethanesulfonate inhalation powder as described in claim 1, wherein the geometric standard deviation (GSD) of the nintedanib ethanesulfonate inhalation powder is less than 2, preferably less than 1.

8.

8. The nintedanib isosulfate inhalation powder as described in claim 1, wherein the RSD value of the blend uniformity (BU) of the nintedanib isosulfate inhalation powder is less than 4%, preferably less than 3.5%, less than 3%, less than 2.5%, less than 2%, less than 1.5%, or less than 1%.

9. A method for preparing nintedanib ethanesulfonate inhalation powder as described in any one of claims 1-8, comprising the following steps: (1) Pulverize nintedanib ethanesulfonate raw material to obtain micronized nintedanib ethanesulfonate; (2) Weigh out the micronized nintedanib ethsulfate and lactose monohydrate according to the prescription amount, and pass them through a 60-mesh sieve and a 40-mesh sieve respectively. (3) Mix micronized nintedanib ethanesulfonate with lactose monohydrate; Optionally includes step (4) of filling capsules; in, The mixing in step (3) includes premixing and total mixing; preferably, the premixing uses a two-dimensional mixing process and / or the total mixing uses a high-energy mixing process, more preferably, the premixing uses a two-dimensional mixer and / or the total mixing uses a high-speed mixer; Preferably, the mixing speed of the mixer used for total mixing is 500-1500 rpm, preferably 500-1300 rpm, 500-1200 rpm, 600-1200 rpm, or 500-900 rpm, and the total mixing time is 5-20 min, preferably 7-15 min, 8-13 min, or 8-12 min; preferably, the total mixing uses a high-speed mixer with a speed of 500-1500 rpm, preferably 500-1300 rpm, 500-1200 rpm, 600-1200 rpm, or 500-900 rpm, and the total mixing time is 5-20 min, preferably 7-15 min, 8-13 min, or 8-12 min.

10. The preparation method according to claim 9, wherein step (1) uses an air jet mill to pulverize nintedanib ethanesulfonate raw material; the pulverizing pressure in step (1) is 4-10.5 bar, the feed pressure is 4.5-11 bar, and the feed pressure is 0.3-1 bar greater than the pulverizing pressure, and the feed speed is 2-10 rpm or 2-7 rpm; preferably, the pulverizing pressure is 4-10 bar, the feed pressure is 4.5-10.5 bar, and the feed pressure is 0.5 bar greater than the pulverizing pressure, and the feed speed is 2-8 rpm or 2-5 rpm.

11. The preparation method according to claim 9, wherein the speed of the mixer used for premixing in step (3) is 5-25 rpm, preferably 15-25 rpm, and the premixing time is 5-20 min, preferably 10-15 min; preferably, the premixing uses a two-dimensional mixer with a speed of 5-25 rpm, preferably 15-25 rpm, and a premixing time of 5-20 min, preferably 10-15 min.

12. Use of nintedanib ethanesulfonate inhalation powder as described in any one of claims 1-8 in the preparation of a medicament for the treatment of lung diseases with fibrosis or lung cancer.

13. A method of treating lung disease or lung cancer with fibrosis, comprising administering nintedanib ethsulfate inhalation powder as described in any one of claims 1-8 to a patient or subject requiring treatment.

14. The use as described in claim 12 or the treatment method as described in claim 13, wherein the fibrotic lung disease is selected from: (1) Chronic obstructive pulmonary disease (COPD), chronic bronchitis and emphysema, preferably fibrosis and remodeling of lung tissue in chronic obstructive pulmonary disease (COPD), chronic bronchitis and emphysema. (2) Pulmonary fibrosis and lung diseases with fibrotic components, including but not limited to idiopathic pulmonary fibrosis (IPF), interstitial lung disease, giant cell interstitial pneumonia (GIP), sarcoidosis, cystic fibrosis, acute respiratory distress syndrome (ARDS), granulomatous disease, silicosis, drug-induced pulmonary fibrosis (e.g., pulmonary fibrosis caused by drugs such as bleomycin, carmustine, cyclophosphamide, amiodarone, procainamide, penicillamine, gold or nitrofurantoin), asbestosis, and systemic scleroderma; (3) Asthma, with preference given to fibrosis and remodeling in asthma; And / or, the lung cancer is non-small cell lung cancer (NSCLC); preferably, the lung cancer is lung adenocarcinoma.

15. The use as described in claim 12 or the treatment method as described in claim 13, wherein the fibrotic lung disease is selected from the group consisting of idiopathic pulmonary fibrosis (IPF) and interstitial lung disease; preferably, the interstitial lung disease is selected from the group consisting of systemic sclerosis-associated interstitial lung disease (SSc-ILD) and chronic fibrotic interstitial lung disease (ILD) with a progressive phenotype.

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