Nintedanib dry powder inhalant as well as preparation method and application thereof

Abstract

The invention relates to a nintedanib dry powder inhalant as well as a preparation method and application thereof. The dry powder inhalant comprises nintedanib and magnesium stearate. According to the nintedanib dry powder inhalant, by controlling the adding proportion of magnesium stearate and the particle size distribution of co-micro powder, the dosage of fine particles can be remarkably increased, the nintedanib dry powder inhalant still has the high dosage of fine particles under the high drug loading capacity, the drug bioavailability is high, and the safety risk of a patient in the medication period can be reduced. Meanwhile, the preparation method of the nintedanib dry powder inhalant is simple and controllable, and the final product is safe, reliable and high in stability.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical technology, and particularly to a nintedanib dry powder inhaler and its preparation method and application. Background Art

[0002] Idiopathic pulmonary fibrosis (IPF) is a large class of lung diseases characterized by fibroblast proliferation, massive extracellular matrix aggregation, accompanied by inflammatory damage and tissue structure destruction. After diagnosis, the average survival period of patients with idiopathic pulmonary fibrosis is only 2-3 years.

[0003] Currently, the only drugs for the treatment of idiopathic pulmonary fibrosis (IPF) are pirfenidone and nintedanib, and the marketed dosage forms are all oral preparations. Among them, nintedanib is a small molecule tyrosine kinase inhibitor developed by Boehringer Ingelheim International GmbH, which can simultaneously inhibit vascular endothelial growth factor receptors, thereby inhibiting angiogenesis tissue and fibrosis. It was approved for marketing in the United States by the FDA in October 2014, and the trade name is It was approved for marketing in China in September 2017, and the trade name is The dosage form is an oral soft capsule, and the recommended dosage is 150 mg / time, twice a day. The drug dosage is relatively high, but due to the transport effect and significant first-pass metabolism effects, the absorption and bioavailability are significantly reduced, and the absolute bioavailability is only 4.69%. In addition, oral administration has very common adverse reactions such as diarrhea, nausea, abdominal pain, and elevated liver enzymes.

[0004] Inhalation preparations, as drug dosage forms for the treatment of respiratory diseases (such as chronic obstructive pulmonary disease (COPD), bronchitis, asthma, etc.), have been clinically used for many years. Compared with oral administration, due to the significant reduction of the first-pass metabolism effect, only a relatively small drug dose is required to achieve effective treatment, thereby reducing the systemic exposure of the drug and minimizing side effects. Moreover, inhalation administration uses the lungs as the target organ for drug delivery, with rapid onset, which can significantly increase the drug concentration at the treatment site, reduce the dosage of the drug, and significantly reduce the gastrointestinal irritation and systemic toxic and side effects caused by oral administration, greatly improving the safety of patients during the medication cycle.

[0005] Compared with other types of inhalation preparations, dry powder inhalers (DPI) do not contain propellants, have strong targeting, excellent stability, mild side effects, wide application scenarios, are convenient to use and portable, have a high drug loading capacity, can achieve large-dose drug delivery, and have a high drug lung deposition rate, and are increasingly becoming the mainstream drug delivery method for the treatment of respiratory diseases.

[0006] The prior art only discloses the preparation of a nintedanib dry powder inhaler (CN114869866A). The prepared nintedanib dry powder inhaler has a low fine particle dose, that is, at the same dose, the proportion of the drug that can be delivered to the lesion site to exert a therapeutic effect is low. To achieve the same therapeutic effect as the prototype drug, more drugs may need to be inhaled, thereby increasing the safety risk of the patient's inhaled medication. Moreover, it is difficult to achieve high-dose administration in the prior art: the proportion of the active pharmaceutical ingredient in the formulation is low, and the proportion of lactose is high. Limited by the capsule size and the fine particle dose, if a higher administration dose is to be achieved, multiple inhalations may be required, thereby resulting in poor patient medication compliance. Therefore, there is an urgent need in the art for a nintedanib dry powder inhaler with a higher fine particle dose and capable of achieving high-dose administration, so as to improve the drug bioavailability and patient medication compliance. Summary of the Invention

[0007] Problems to be Solved by the Invention

[0008] In order to solve the above technical problems existing in the prior art, the object of the present invention is to provide a nintedanib dry powder inhaler and its preparation method, which can improve the drug bioavailability, reduce the safety risk during the patient's medication cycle, and improve the patient's medication compliance.

[0009] Solutions for Solving the Problems

[0010] The present invention provides a nintedanib co-micropowder, which comprises nintedanib and magnesium stearate, wherein the mass ratio of nintedanib to magnesium stearate is 1:1 - 400:1.

[0011] Preferably, the mass ratio of nintedanib to magnesium stearate is 10:1 - 300:1; more preferably, the mass ratio of nintedanib to magnesium stearate is 20:1 - 200:1.

[0012] Preferably, the D90 of the co-micropowder is 2 - 6.5 μm, more preferably, the D90 of the co-micropowder is 2.5 - 5.5 μm.

[0013] Preferably, the nintedanib is nintedanib free base, nintedanib ethanesulfonate or other pharmaceutically acceptable salts; more preferably, the nintedanib is one or more of nintedanib free base, nintedanib ethanesulfonate, nintedanib hydrobromide, nintedanib diethanesulfonate, nintedanib ethanesulfonate monohydrate; further preferably, the nintedanib is nintedanib ethanesulfonate.

[0014] The present invention also provides a nintedanib dry powder inhaler, which comprises the nintedanib co-micropowder and other pharmaceutically acceptable carriers.

[0015] Preferably, the other pharmaceutically acceptable carriers are selected from one or more of lactose, mannitol, erythritol, xylitol, gum arabic, amino acids, phospholipids and dextran; more preferably, the other pharmaceutically acceptable carriers are lactose and / or mannitol; further preferably, the other pharmaceutically acceptable carrier is lactose.

[0016] Preferably, the dry powder inhaler is composed of the following components by weight percentage: 5% to 100% of nintedanib co - micronized substance and 0% to 95% of other pharmaceutically acceptable carriers;

[0017] More preferably, the dry powder inhaler is composed of the following components by weight percentage: 15% to 100% of nintedanib co - micronized substance and 0% to 85% of other pharmaceutically acceptable carriers;

[0018] Further preferably, the dry powder inhaler is composed of the following components by weight percentage: 25% to 100% of nintedanib co - micronized substance and 0% to 75% of other pharmaceutically acceptable carriers.

[0019] Preferably, the D90 of the other pharmaceutically acceptable carriers is 65 - 170 μm; more preferably, the D90 of the other pharmaceutically acceptable carriers is 75 - 160 μm.

[0020] Preferably, the dry powder inhaler is a capsule - type dry powder inhaler.

[0021] The present invention also provides a preparation method of the co - micronized substance or the dry powder inhaler as described above, and the method comprises the following steps:

[0022] (1) Mix nintedanib and magnesium stearate;

[0023] (2) Grind the mixture prepared in step (1) to obtain the co - micronized substance;

[0024] Preferably, the preparation method of the dry powder inhaler further comprises the following steps:

[0025] (3) Mix the co - micronized substance with other pharmaceutically acceptable carriers;

[0026] (4) Capsule filling.

[0027] Preferably, the grinding in step (2) is carried out by air - flow grinding, the grinding pressure is 2.0 - 6.0 bar, the inlet air pressure is 2.5 - 7.5 bar, and more preferably, the inlet air pressure is at least 0.5 bar higher than the grinding pressure;

[0028] Preferably, the mixing in step (3) is two-dimensional mixing, three-dimensional mixing or high-energy mixing. More preferably, the mixing in step (3) is three-dimensional mixing or high-energy mixing. Further preferably, the mixing in step (3) is high-energy mixing;

[0029] Preferably, the capsule is a gelatin or HPMC capsule. More preferably, the capsule is an HPMC material 3# inhalation capsule.

[0030] The present invention also provides an application of the co-micropowder or the dry powder inhaler in the preparation of a drug for treating fibrotic diseases; preferably, the fibrotic disease is idiopathic pulmonary fibrosis.

[0031] Effects of the Invention

[0032] The nintedanib dry powder inhaler provided by the present invention can significantly increase the fine particle dose, and still has a high fine particle dose under a high drug loading amount. The drug has high bioavailability, can reduce the safety risk during the medication cycle of patients, and improve the medication compliance of patients. At the same time, the preparation method of the nintedanib dry powder inhaler of the present invention is simple and controllable, and the final product is safe, reliable and has high stability. Description of the Drawings

[0033] Figure 1 Shows the aerodynamic particle size distribution of the nintedanib dry powder inhaler. Detailed Embodiments

[0034] To make the technical solutions and beneficial effects of the present invention more obvious and understandable, the following will be described in detail by listing specific embodiments. Among them, the drawings are not necessarily drawn to scale, and local features can be enlarged or reduced to more clearly show the details of the local features; unless otherwise defined, the technical and scientific terms used herein have the same meanings as those in the technical and scientific fields to which this application belongs.

[0035] Unless otherwise specified, the experimental methods without specific conditions in the following embodiments are usually carried out under conventional conditions or according to the conditions recommended by the manufacturer. Unless otherwise specified, all percentages, ratios, proportions, or parts are by weight. Unless otherwise specified, the various materials and reagents used in the present invention can be obtained by conventional methods in the art or through commercial channels.

[0036] As used herein, the term "pharmaceutically acceptable" means that the components of the pharmaceutical composition must be compatible with each other and do not have a harmful effect on its recipient.

[0037] As used herein, the term "pharmaceutically acceptable salt" refers to salts that are safe, non-toxic, and neither biologically nor otherwise undesirable, and includes salts that are pharmaceutically acceptable for veterinary use as well as for human pharmaceutical use and have the desired pharmacological activity. Such salts include, but are not limited to, acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and / or phosphoric acid; or acid addition salts formed with organic acids such as acetic acid, trifluoroacetic acid, propionic acid, hexanoic acid, heptanoic acid, cyclopentanepropionic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, o-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, trifluoromethanesulfonic acid, 1,2-ethanedisulfonic acid, benzenesulfonic acid, p-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]oct-2-ene-1-carboxylic acid, glucuronic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, dodecylsulfuric acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, citric acid, lysine, arginine, aspartic acid, 2-hydroxypropionic acid, oxalic acid, and / or mucic acid, etc.

[0038] As used herein, the term "pharmaceutically acceptable carrier" refers to a diluent, adjuvant, excipient, or vehicle administered together with a therapeutic agent and is suitable, within the scope of reasonable medical judgment, for contact with the tissues of humans and / or other animals without undue toxicity, irritation, allergic response, or other problems or complications commensurate with the reasonable benefit / risk.

[0039] As used herein, the terms "dry powder inhaler", "powder aerosol", "Dry Power Inhalation", or "DPI", which are used interchangeably, refer to a preparation in which micronized drug and / or carrier is in the form of a single-dose or multi-dose reservoir and is inhaled by the patient, either actively or passively, through a special dry powder inhalation device into the respiratory tract and even the lungs.

[0040] As used herein, the term "micropowder" refers to particles having a size in the micron range, for example, particles having a size of 0.1 μm to 200 μm. Micronized particles can be obtained by techniques based on friction (such as milling or grinding under wet or dry conditions). However, micronized particles can also be produced by any other suitable method, such as precipitation, rapid expansion of supercritical solutions, spray drying, classification or differentiation of naturally occurring sand or mud, filtration of water, sol-gel methods, spray reaction synthesis, flame synthesis, or liquid foaming synthesis.

[0041] As used herein, the term "treatment" refers to a method of alleviating or reducing a disease and / or its accompanying symptoms, including prevention, blocking, inhibition, alleviation, protection, regulation, reversal of the effects of adverse effects of a disease condition, for example, and reduction of its occurrence.

[0042] As used herein, the terms "administering" or "administration" include the routes by which a compound is introduced into a subject to effect its intended function. Examples of administration routes that can be used include injection (subcutaneous, intravenous, parenteral, intraperitoneal, intrathecal), topical, oral, inhalation, rectal, and transdermal.

[0043] The present invention provides a nintedanib co - microparticle, which comprises nintedanib and magnesium stearate, wherein the mass ratio of nintedanib to magnesium stearate is 1:1 - 400:1.

[0044] In certain embodiments, the mass ratio of nintedanib to magnesium stearate is 1:1, or 2:1, or 3:1, or 4:1, or 5:1, or 6:1, or 7:1, or 8:1, or 9:1, or 10:1, or 11:1, or 12:1, or 13:1, or 14:1, or 15:1, or 16:1, or 17:1, or 18:1, or 19:1, or 20:1, or 21:1, or 22:1, or 23:1, or 24:1, or 25:1, or 26:1, or 27:1, or 28:1, or 29:1, or 30:1, or 35:1, or 40:1, or 45:1, or 50:1, or 55:1, or 60:1, or 65:1, or 70:1, or 75:1, or 80:1, or 85:1, or 90:1, or 95:1, or 100:1, or 105:1, or 110:1, or 115:1, or 120:1, or 125:1, or 130:1, or 135:1, or 140:1, or 145:1, or 150:1, or 155:1, or 160:1, or 165:1, or 170:1, or 175:1, or 180:1, or 185:1, or 190:1, or 195:1, or 196:1, or 197:1, or 198:1, or 199:1, or 200:1, or 201:1, or 202:1, or 203:1, or 204:1, or 205:1, or 210:1, or 215:1, or 220:1, or 225:1, or 230:1, or 235:1, or 240:1, or 245:1, or 250:1, or 255:1, or 260:1, or 265:1, or 270:1, or 275:1, or 280:1, or 285:1, or 290:1, or 295:1, or 300:1, or 310:1, or 320:1, or 330:1, or 340:1, or 350:1, or 360:1, or 370:1, or 380:1, or 390:1, or 400:1.

[0045] In certain embodiments, the mass ratio of nintedanib to magnesium stearate is 10:1 - 300:1.

[0046] In certain embodiments, the mass ratio of the nintedanib to the magnesium stearate is 20:1 - 200:1.

[0047] In certain embodiments, the co - micronized product consists of the nintedanib and the magnesium stearate.

[0048] In certain embodiments, the D90 of the co - micronized product is 2 - 6.5 μm.

[0049] In certain embodiments, the D90 of the co - micronized product is 2.5 - 5.5 μm.

[0050] In certain embodiments, the D90 of the co - micronized product is 3.26 - 5.20 μm.

[0051] In certain embodiments, the D50 of the co - micronized product is 1 - 4 μm.

[0052] In certain embodiments, the D50 of the co - micronized product is 1.5 - 3.0 μm.

[0053] In certain embodiments, the D50 of the co - micronized product is 1.85 - 2.41 μm.

[0054] In certain embodiments, the D90 of the co - micronized product is 3.54 μm and the D50 is 1.97 μm.

[0055] In certain embodiments, the D90 of the co - micronized product is 3.65 μm and the D50 is 2.02 μm.

[0056] In certain embodiments, the D90 of the co - micronized product is 3.26 μm and the D50 is 1.85 μm.

[0057] In certain embodiments, the D90 of the co - micronized product is 3.96 μm and the D50 is 2.16 μm.

[0058] In certain embodiments, the D90 of the co - micronized product is 5.20 μm and the D50 is 2.41 μm.

[0059] In certain embodiments, the D90 of the nintedanib before co - micronization is ≤100 μm.

[0060] In certain embodiments, the D90 of the nintedanib before co - micronization is ≤50 μm.

[0061] In certain embodiments, the D90 of the nintedanib before co - micronization is 32 μm.

[0062] In certain embodiments, the D90 of the magnesium stearate before co - micronization is ≤40 μm.

[0063] In certain embodiments, D90 of the magnesium stearate before co - micronization ≤ 30 μm.

[0064] In certain embodiments, D90 of the magnesium stearate before co - micronization = 24.3 μm.

[0065] In certain embodiments, the nintedanib is nintedanib free base, nintedanib etesilate or other pharmaceutically acceptable salts.

[0066] In certain embodiments, the nintedanib is one or more of nintedanib free base, nintedanib etesilate, nintedanib hydrobromide, nintedanib di - etesilate, nintedanib etesilate monohydrate.

[0067] In certain embodiments, the nintedanib is nintedanib etesilate.

[0068] The present invention also provides a dry powder inhaler of nintedanib, and the dry powder inhaler comprises the nintedanib co - micronized product. In certain embodiments, the dry powder inhaler comprises the nintedanib co - micronized product and other pharmaceutically acceptable carriers.

[0069] In certain embodiments, the dry powder inhaler is composed of the nintedanib co - micronized product and other pharmaceutically acceptable carriers.

[0070] In certain embodiments, the other pharmaceutically acceptable carriers are selected from one or more of lactose, mannitol, erythritol, xylitol, arabic gum, amino acids, phospholipids and dextran.

[0071] In certain embodiments, the other pharmaceutically acceptable carriers are lactose and / or mannitol.

[0072] In certain embodiments, the other pharmaceutically acceptable carrier is lactose.

[0073] In certain embodiments, the dry powder inhaler is composed of the following components by weight percentage: 5% - 100% nintedanib co - micronized product and 0% - 95% other pharmaceutically acceptable carriers.

[0074] In certain embodiments, the dry powder inhaler is composed of the following components by weight percentage: 15% - 100% nintedanib co - micronized product and 0% - 85% other pharmaceutically acceptable carriers.

[0075] In certain embodiments, the dry powder inhaler is composed of the following components by weight percentage: 25% - 100% nintedanib co - micronized product and 0% - 75% other pharmaceutically acceptable carriers.

[0076] In certain embodiments, the dry powder inhalant consists of the following components by weight percentage: 100% of the co - micronized nintedanib.

[0077] In certain embodiments, the dry powder inhalant consists of the following components by weight percentage: 66.78% of the co - micronized nintedanib and 33.22% of lactose.

[0078] In certain embodiments, the dry powder inhalant consists of the following components by weight percentage: 67.8% of the co - micronized nintedanib and 32.2% of lactose.

[0079] In certain embodiments, the dry powder inhalant consists of the following components by weight percentage: 26.32% of the co - micronized nintedanib and 73.68% of lactose.

[0080] In certain embodiments, the D90 of the pharmaceutically acceptable carrier is 65 - 170 μm.

[0081] In certain embodiments, the D90 of the pharmaceutically acceptable carrier is 75 - 160 μm.

[0082] In certain embodiments, the D10 of the pharmaceutically acceptable carrier is 5 - 50 μm.

[0083] In certain embodiments, the D10 of the pharmaceutically acceptable carrier is 10 - 40 μm.

[0084] In certain embodiments, the dry powder inhalant is a capsule - type dry powder inhalant.

[0085] The present invention also provides a preparation method of the co - micronized product and the dry powder inhalant, and the method comprises the following steps:

[0086] (1) Mix nintedanib and magnesium stearate;

[0087] (2) Grind the mixture prepared in step (1) to obtain the co - micronized product.

[0088] In certain embodiments, the preparation method of the dry powder inhalant further comprises the following steps:

[0089] (3) Mix the co - micronized product with other pharmaceutically acceptable carriers;

[0090] (4) Capsule filling.

[0091] In certain embodiments, the mixing in step (1) is three - dimensional mixing.

[0092] In certain embodiments, the mixing in step (1) is carried out in a three - dimensional mixer at a rotation speed of 50 rpm for 60 min.

[0093] In certain embodiments, the comminution described in step (2) is carried out by air jet milling, with a grinding pressure of 2.0 - 6.0 bar and an inlet pressure of 2.5 - 7.5 bar.

[0094] In certain embodiments, the inlet pressure is at least 0.5 bar higher than the grinding pressure.

[0095] In certain embodiments, the feeding speed of the comminution described in step (2) is 5 - 50 rpm.

[0096] In certain embodiments, step (2) further includes sieving the co - micronized material.

[0097] In certain embodiments, the sieving is through a 60 - mesh sieve.

[0098] In certain embodiments, the mixing described in step (3) is two - dimensional mixing, three - dimensional mixing, or high - energy mixing.

[0099] In certain embodiments, the mixing described in step (3) is three - dimensional mixing or high - energy mixing.

[0100] In certain embodiments, the mixing described in step (3) is three - dimensional mixing.

[0101] In certain embodiments, the mixing described in step (3) is carried out using a three - dimensional mixer at a rotation speed of 50 rpm for 120 min.

[0102] In certain embodiments, the mixing described in step (3) is high - energy mixing.

[0103] In certain embodiments, the mixing described in step (3) is carried out using a high - energy mixer at a rotation speed of 500 rpm for 20 min.

[0104] In certain embodiments, the capsule described in step (4) is a gelatin or HPMC capsule.

[0105] In certain embodiments, the capsule described in step (4) is an HPMC capsule.

[0106] In certain embodiments, the capsule described in step (4) is an HPMC - based 3# inhalation capsule.

[0107] In certain embodiments, the specification of the capsule described in step (4) is 10 - 50 mg.

[0108] In certain embodiments, the specification of the capsule described in step (4) is 10 mg, or 20 mg, or 30 mg, or 40 mg, or 50 mg.

[0109] In certain embodiments, the specification of the capsule described in step (4) is 20 mg.

[0110] The present invention also provides an application of the co - micronized substance or the dry powder inhalant in the preparation of a medicament for treating fibrotic diseases.

[0111] In certain embodiments, the fibrotic disease is idiopathic pulmonary fibrosis.

[0112] Magnesium stearate, lactose, and nintedanib ethanesulfonate used in the present invention are all commercially available;

[0113] Among them, the particle size of magnesium stearate: D90 = 24.3 μm; the particle size of nintedanib ethanesulfonate: D90 = 32 μm; the particle size of lactose: D90 = 91 μm.

[0114] Example 1: Preparation of a dry powder inhalant from micronized nintedanib raw material

[0115] The nintedanib dry powder inhalant of this example is prepared by the following method:

[0116] 1. Preparation of micronized nintedanib raw material: MC Using a Model 30 spiral air - flow pulverizer, controlling the grinding pressure at 2.0 - 6.0 bar, the inlet pressure at 2.5 - 7.5 bar, and the feeding speed at 5 - 50 rpm, where the inlet pressure is at least 0.5 bar higher than the grinding pressure, for micronization. The micronized product is sieved through a 60 - mesh sieve to obtain micronized nintedanib. The particle size is detected using a MAZ3000 laser particle size analyzer, and the results are shown in Table 1;

[0117] 2. Mixing: The micronized nintedanib and lactose are mixed in a mass ratio of 1:3 using a Turbula three - dimensional mixer at a rotation speed of 50 rpm for 120 min;

[0118] 3. Capsule filling: Filling 3# inhalation capsules made of HPMC material according to the 20 - mg specification.

[0119] Table 1 Ratio and particle size of micronized nintedanib raw material dry powder inhalant

[0120]

[0121] Examples 2 - 6: Preparation of dry powder inhalant from co - micronized substance (three - dimensional mixing)

[0122] The formulations of the nintedanib dry powder inhalants in Examples 2 - 6 are shown in Table 2, and the specific preparation method is as follows:

[0123] 1. Mixing of magnesium stearate and nintedanib: Weigh nintedanib ethanesulfonate and magnesium stearate and add them to the mixing tank of a Turbula three - dimensional mixer at a rotation speed of 50 rpm for 60 min to obtain a mixture;

[0124] 2. Preparation of co - micronized product: Use MC to process the mixture prepared in step 1 with a Model 30 spiral air - jet mill for micronization, controlling the grinding pressure at 2.0 - 6.0 bar, the inlet air pressure at 2.5 - 7.5 bar, and the feeding speed at 5 - 50 rpm. The inlet air pressure is at least 0.5 bar higher than the grinding pressure. The micronized product is sieved through a 60 - mesh sieve to obtain the co - micronized product. Use a MAZ3000 laser particle size analyzer to detect the particle size, and the results are shown in Table 2;

[0125] 3. Mixing: Use a Turbula three - dimensional mixer. Weigh lactose and the co - micronized product prepared in step 2 and add them to the mixing tank, with a rotation speed of 50 rpm and mix for 120 min (in the prescriptions of Example 2 and Example 4, there is no lactose, so this mixing step is not carried out).

[0126] 4. Capsule filling: Use 3# inhalation capsules made of HPMC material and fill the capsules according to the 20 - mg specification.

[0127] Table 2 Ratio and particle size of the co - micronized product dry powder inhaler by three - dimensional mixing

[0128]

[0129] Example 7: Preparation of dry powder inhaler from co - micronized product (high - energy mixing)

[0130] The formulation of the nintedanib dry powder inhaler in this example is shown in Table 3; the specific preparation method is as follows:

[0131] 1. Mix magnesium stearate and nintedanib: Weigh nintedanib ethanesulfonate and magnesium stearate and add them to the mixing tank of a Turbula three - dimensional mixer, with a rotation speed of 50 rpm and mix for 60 min.

[0132] 2. Preparation of co - micronized product: Use MC with a Model 30 spiral air - jet mill, control the grinding pressure at 2.0 - 6.0 bar, the inlet air pressure at 2.5 - 7.5 bar, and the feeding speed at 5 - 50 rpm. The inlet air pressure is at least 0.5 bar higher than the grinding pressure for micronization. The micronized product is sieved through a 60 - mesh sieve to obtain the co - micronized product. Use a MAZ3000 laser particle size analyzer to detect the particle size, and the results are shown in Table 3.

[0133] 3. Mixing: Use a PcM - TRV3 type high - energy mixer. Weigh lactose and the co - micronized product and add them to the mixing pot, with the stirring paddle rotation speed at 500 rpm and mix for 20 min.

[0134] 4. Capsule filling: Use 3# inhalation capsules made of HPMC material and fill the capsules according to the 20 - mg specification.

[0135] Table 3 Ratio and particle size of the co - micronized product dry powder inhaler by high - energy mixing

[0136]

[0137] Example 8: Preparation of Dry Powder Inhaler by High-Energy Mixing

[0138] The formulation of the nintedanib dry powder inhaler in this example is shown in Table 4; the specific preparation method is as follows:

[0139] 1. Preparation of nintedanib micropowder: Nintedanib ethanesulfonate was pulverized to obtain nintedanib ethanesulfonate micropowder;

[0140] 2. Mixing of magnesium stearate and nintedanib micropowder: Weigh nintedanib ethanesulfonate micropowder and magnesium stearate and add them to the mixing tank of a Turbula three-dimensional mixer at a rotation speed of 50 rpm and mix for 60 min.

[0141] 3. Adding carrier for mixing: Using a PcM-TRV3 type high-energy mixer, weigh lactose, micronized nintedanib ethanesulfonate and the magnesium stearate blend and add them to the mixing pot, with the stirring paddle rotating at 500 rpm and mix for 20 min.

[0142] 4. Capsule filling: 3# inhalation capsules made of HPMC were filled according to the 20 mg specification.

[0143] Table 4 Ratio of Dry Powder Inhaler of High-Energy Mixed Coprecipitate

[0144] Proportion of nintedanib ethanesulfonate (%) 25.00 Proportion of magnesium stearate (%) 1.32 Proportion of lactose (%) 73.68

[0145] Example 9: Preparation of Dry Powder Inhaler by High-Energy Mixing

[0146] 1. Preparation of nintedanib micropowder: Nintedanib ethanesulfonate was pulverized to obtain nintedanib ethanesulfonate micropowder;

[0147] 2. Mixing of magnesium stearate and carrier: Weigh lactose and magnesium stearate and add them to the mixing pot of a Turbula PcM-TRV3 type high-energy mixer at a rotation speed of 500 rpm and mix for 10 min.

[0148] 3. Adding nintedanib micropowder for mixing: Weigh nintedanib ethanesulfonate micropowder and add it to the mixing pot, with the stirring paddle rotating at 500 rpm and mix for 20 min.

[0149] 4. Capsule filling: 3# inhalation capsules made of HPMC were filled according to the 20 mg specification.

[0150] Table 5 Ratio of Dry Powder Inhaler of High-Energy Mixed Coprecipitate

[0151] Proportion of nintedanib ethanesulfonate (%) 25.00 Proportion of magnesium stearate (%) 1.32 Proportion of lactose (%) 73.68

[0152] Example 10: Aerodynamic Particle Size Distribution and Fine Particle Dose

[0153] Referring to the General Principles 0951 "Determination Method for Aerodynamic Characteristics of Fine Particles in Inhalation Preparations" in the Chinese Pharmacopoeia (2020 Edition), the device 3 (next generation impactor, NGI) was used to measure the aerodynamic particle size distribution of the nintedanib dry powder inhaler in Examples 1 to 9 (the results are as Figure 1 shown in Table 6), and the fine particle dose was calculated (the results are shown in Table 6).

[0154] Table 6 Aerodynamic Particle Size Distribution of Nintedanib Dry Powder Inhaler

[0155]

[0156]

[0157] *FPF (fine particle fraction): Fine particle dose, which refers to the percentage of the cumulative deposition content with an aerodynamic particle size less than 5 μm to the total output content, reflecting the effective deposition rate of the drug in the lungs.

[0158] Comparative analysis of the data in Table 6 shows that:

[0159] (1) Comparing Example 1 and Example 6: With the addition of magnesium stearate in the formulation, the fine particle dose increased significantly, with an increase of up to 137%; comparing Example 3 and Example 5: With the increase in the amount of magnesium stearate added in the formulation, the fine particle dose increased accordingly.

[0160] Thus, it can be seen that the dry powder inhaler of the present invention can significantly increase the fine particle dose (i.e., the proportion of the drug that can be delivered to the lesion site to exert the therapeutic effect) by controlling the addition ratio of magnesium stearate, improve the drug bioavailability, and thus improve the safety during the patient's medication cycle.

[0161] (2) Comparing Examples 2 to 6: When the carrier lactose ratio is 0 - 73.68%, that is, at different high and low drug loadings, the nintedanib dry powder inhaler in the present invention still has a very significant fine particle dose.

[0162] Thus, it can be seen that the dry powder inhaler of the present invention can significantly reduce the dependence on the carrier, and has significant advantages in fine particle dose delivery and stability at different high and low drug loadings, and can flexibly adjust the clinical dosage.

[0163] (3) Comparing Example 6 and Example 7: Both three-dimensional mixing and high-energy mixing can achieve a relatively high fine particle dose. Compared with three-dimensional mixing, high-energy mixing has a higher fine particle dose, and high-energy mixing is preferred.

[0164] (4) Comparison between Example 1 and Examples 6 - 9: The way of adding magnesium stearate is one of the key factors affecting delivery. Among them, the way of adding magnesium stearate and the API co - micronized powder is far better than the way of adding magnesium stearate in Examples 8 and 9.

[0165] Example 11: Animal experiment

[0166] Test method: Male Sprague - Dawley rats were randomly divided into two groups, namely the intragastric administration group (12 rats) and the inhalation administration group (12 rats). Among them, the intragastric administration group was given a dose of 30 mg / kg according to the administration method in the FDA - published literature "Pharmacological Reviews" (reference drug: nintedanib ethanesulfonate soft capsules, trade name ). The inhalation administration group inhaled Example 2 through a small - animal nose - mouth inhalation exposure system, with a dose of 30 mg / kg (delivered dose, deposited dose was 3 mg / kg). After the animals were administered, blood samples and whole lungs were collected at 0.25 h, 2 h, 6 h, and 12 h respectively, and the drug concentrations in the blood samples and whole lungs were analyzed.

[0167] Table 7 Administration dose and route

[0168]

[0169] Table 8 Exposure amount in animals

[0170] Route of administration Dose administered (mg / kg) <![CDATA[T max > <![CDATA[C max / (ng / ml)]]> <![CDATA[AUC 0-t / (h*ng / ml)]]> Gavage 30 2h 106 380 Nasal and oral inhalation 30 5 min 2 17

[0171] Table 9 Exposure amount in animal lung tissue

[0172] Route of administration Dose administered (mg / kg) <![CDATA[T max > <![CDATA[C max / (ng / g)]]> <![CDATA[AUC 0-t / (h*ng / g)]]> Gavage 30 2h 4000 33000 Nasal and oral inhalation 30 5 min 6000 41000

[0173] By comparing and analyzing the data in Tables 7 - 9, it can be seen that compared with oral administration, inhalation administration has a rapid onset. The exposure amount in the body of inhalation administration is much lower than that of oral administration, but the concentration in the targeted tissue is much higher than that of oral administration, showing significant clinical advantages.

[0174] It should be understood that the above examples are all exemplary and do not cover all possible implementation manners included in the claims. Without departing from the scope of the present disclosure, various deformations and changes can be made based on the above examples. Similarly, any combination of the technical features of the above examples can be made to form additional embodiments of the present invention that may not be clearly described. Therefore, the above examples only represent several implementation manners of the present invention and do not limit the protection scope of the present invention patent.

Claims

1. A nintedanib co - micronized substance, characterized in that, The co - micronized product comprises nintedanib and magnesium stearate, wherein the mass ratio of nintedanib to magnesium stearate is 1:1 - 400:

1.

2. The co - fine powder according to claim 1, wherein, The mass ratio of nintedanib to magnesium stearate is 10:1 - 300:1; preferably, the mass ratio of nintedanib to magnesium stearate is 20:1 - 200:

1.

3. The co-fine powder according to claim 1, wherein The D90 of the co - micronized product is 2 - 6.5 μm, preferably, the D90 of the co - micronized product is 2.5 - 5.5 μm.

4. The co-fine powder according to any one of claims 1-3, characterized in that, The nintedanib is nintedanib free base, nintedanib ethanesulfonate or other pharmaceutically acceptable salts; preferably, the nintedanib is one or more of nintedanib free base, nintedanib ethanesulfonate, nintedanib hydrobromide, nintedanib diethanesulfonate, nintedanib ethanesulfonate monohydrate; more preferably, the nintedanib is nintedanib ethanesulfonate.

5. A nintedanib dry powder inhaler, characterized in that, The dry powder inhaler comprises the nintedanib co - micronized product according to any one of claims 1 - 4 and other pharmaceutically acceptable carriers; Preferably, the other pharmaceutically acceptable carriers are selected from one or more of lactose, mannitol, erythritol, xylitol, arabic gum, amino acids, phospholipids and dextran; more preferably, the other pharmaceutically acceptable carriers are lactose and / or mannitol; further preferably, the other pharmaceutically acceptable carrier is lactose.

6. The dry powder inhaler according to claim 5, wherein, The dry powder inhaler is composed of the following components by weight percentage: 5% - 100% nintedanib co - micronized product and 0% - 95% other pharmaceutically acceptable carriers; Preferably, the dry powder inhaler is composed of the following components by weight percentage: 15% - 100% nintedanib co - micronized product and 0% - 85% other pharmaceutically acceptable carriers; More preferably, the dry powder inhaler is composed of the following components by weight percentage: 25% - 100% nintedanib co - micronized product and 0% - 75% other pharmaceutically acceptable carriers.

7. The dry powder inhaler according to any one of claims 5-6, characterized in that, The D90 of the other pharmaceutically acceptable carriers is 65 - 170 μm; more preferably, the D90 of the other pharmaceutically acceptable carriers is 75 - 160 μm.

8. The dry powder inhaler according to any one of claims 5-7, characterized in that, The dry powder inhaler is a capsule - type dry powder inhaler.

9. A method for preparing the co-micropowder according to any one of claims 1-4 or the dry powder inhaler according to any one of claims 5-8, characterized in that, The method comprises the following steps: (1) Mix nintedanib and magnesium stearate; (2) Grind the mixture prepared in step (1) to obtain the co - micronized product; Preferably, the preparation method of the dry powder inhaler further comprises the following steps: (3) Mix the co - micronized product with other pharmaceutically acceptable carriers; (4) Capsule filling; Preferably, the grinding in step (2) is carried out by air - jet milling, the grinding pressure is 2.0 - 6.0 bar and the inlet pressure is 2.5 - 7.5 bar, more preferably, the inlet pressure is at least 0.5 bar higher than the grinding pressure; Preferably, the mixing in step (3) is two - dimensional mixing, three - dimensional mixing or high - energy mixing, more preferably, the mixing in step (3) is three - dimensional mixing or high - energy mixing, further preferably, the mixing in step (3) is high - energy mixing; Preferably, the capsule in step (4) is a gelatin or HPMC capsule, more preferably, the capsule is a 3# inhalation capsule made of HPMC material.

10. Use of the co-micropowder according to any one of claims 1-4, or the dry powder inhaler according to any one of claims 5-8, in the preparation of a medicament for treating fibrotic diseases; preferably, the fibrotic disease is idiopathic pulmonary fibrosis.

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