A method for preparing a pharmaceutical composition for inhalation and products thereof

Abstract

The present application belongs to the technical field of pharmaceutical preparations, and relates to a preparation method of a medicine composition for inhalation and a product thereof. Specifically, the preparation method of the present application comprises a solid mixing step for mixing remdesivir or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. Preferably, the preparation method of the present application further comprises an airflow pulverization step, an aging step, a transportation and / or storage step and the like. The medicine composition for inhalation prepared by the preparation method of the present application has the characteristics of good particle stability, good powder flowability and no agglomeration, has significant advantages compared with existing remdesivir preparations, and is suitable for use in clinical practice. Moreover, the preparation method of the present application avoids the solvent residue problem existing in the thin film freeze-drying method, and does not require harsh conditions of ultralow temperature in the process.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical formulation technology, and relates to a method for preparing an inhaled pharmaceutical composition and its product, particularly to a method for preparing an inhaled pharmaceutical composition containing remdesivir as the active pharmaceutical ingredient for infections such as Marburg virus, Ebola virus, Nipah virus, respiratory syncytial virus, hepatitis C virus, human immunodeficiency virus, and 2019 novel coronavirus. Background Technology

[0002] Remdesivir is a nucleoside analogue with a broad-spectrum antiviral mechanism of action. It has been reported to be effective against infections caused by Marburg virus (MV), Ebola virus (EV), Nipah virus (NV), respiratory syncytial virus (RSV), hepatitis C virus (HCV), human immunodeficiency virus (HIV), and SARS-CoV-2. However, intravenous administration typically causes adverse reactions (such as allergic reactions) and other side effects; additionally, injection can cause local pain and lead to patient rejection.

[0003] In recent years, pulmonary inhalation has provided a non-invasive drug delivery method, delivering medication directly to the lungs through the respiratory tract. This allows for effective targeted drug delivery and rapid administration. Compared to intravenous injection, inhaled formulations cause less mechanical damage, are easier to administer, and have better patient compliance. Compared to oral formulations, inhaled formulations have higher bioavailability, act directly on the lungs, and avoid the first-pass effect of the liver. Furthermore, the dosage required for inhalation is generally less than that for oral or injectable administration. Therefore, inhalation can be used alone or in combination with oral or injectable administration to increase local drug concentration in the lungs and reduce side effects.

[0004] Inhaled drug delivery typically requires a combination of medical devices, such as nebulizers, metered-dose inhalers (pMDIs), dry powder inhalers (DPIs), and soft mist inhalers (SMIs). Nebulizers can deliver high doses of medication but are inconvenient and the treatment process is lengthy. PPIs are portable and widely used, but require a propellant and hand-mouth coordination. Dry powder inhalers offer high drug stability and do not require a cold chain, but lung deposition rates are often low. Soft mist inhalers offer high lung deposition rates but are also more expensive.

[0005] Generally, inhaled administration of drugs (such as remdesivir) can be divided into nebulized inhalation and dry powder inhalation. For severely ill patients, whose spontaneous breathing pressure is insufficient, nebulized inhalation is more suitable. However, for mild to moderate patients, dry powder inhalation is more portable, has better compliance, does not require a cold chain, and is less expensive. Therefore, by preparing the drug into a dry powder form, mixing it with a carrier and / or excipients, and administering it through a specific delivery device, effective pulmonary delivery can be achieved.

[0006] A research team at the University of Texas at Austin (UT-Austin) has developed a dry powder inhaler for remdesivir (see Sahakijpijarn S., Development of Remdesivir as a Dry Powder for Inhalation by Thin Film Freezing[J], Pharmaceutics, 2020, 12: 1002). However, the team used thin film freeze-drying (TFF) technology to prepare the dry powder inhaler for remdesivir, resulting in poor product stability and poor particle morphology uniformity. The project is still in the experimental stage and is unlikely to meet clinical needs.

[0007] Furthermore, the film-film freeze-drying technology inevitably uses polar organic solvents to dissolve remdesivir, as exemplified by the research team at the University of Texas at Austin who used acetonitrile / aqueous solution or dioxane to dissolve it. In pharmaceutical formulations, solvents such as acetonitrile and dioxane are generally avoided due to their potential hepatotoxicity, nephrotoxicity, and neurotoxicity; therefore, pharmacopoeias impose very stringent requirements on solvent residues. The 2020 edition of the pharmacopoeia defines both acetonitrile and dioxane as Class I solvents, with a solvent residue limit of 0.041% for acetonitrile and 0.038% for dioxane (see the Pharmacopoeia of the People's Republic of China (2020 edition), Part IV, page 0861). Additionally, film-film freeze-drying technology requires stringent freeze-drying conditions of -100°C, which is highly disadvantageous for pharmaceutical manufacturers, making the process difficult to achieve and increasing production costs. These technical limitations render remdesivir freeze-dried powder prepared using film-film freeze-drying technology unsuitable for use as a remdesivir inhalation formulation by pharmaceutical manufacturers. In addition, the University of Texas at Austin only studied the stability of remdesivir in the formulation when it studied the stability of the formulation, and did not study the overall stability of the remdesivir dry powder formulation, which is very important for drug formulations.

[0008] Therefore, how to prepare a remdesivir dry powder inhaler with good stability is an urgent problem to be solved. In addition, how to develop a remdesivir dry powder inhaler with no toxic organic solvent residue and convenient for human administration is also a technical problem that urgently needs to be solved in this field. Summary of the Invention

[0009] The problem the invention aims to solve

[0010] Given that systemic metabolic concentrations of remdesivir are not positively correlated with efficacy when used to treat COVID-19 infection via intravenous administration, and that local drug concentrations in the lungs are too low, there is a need to develop a new method to prepare safe and stable drug compositions suitable for inhalation.

[0011] Solution for solving the problem

[0012] On one hand, the present invention provides a method for preparing an inhaled pharmaceutical composition, which includes a solid mixing step.

[0013] Furthermore, in the above method, the solid-mixing step involves mixing the active pharmaceutical ingredient and a pharmaceutically acceptable carrier, preferably mixing 1 wt%-70 wt% of the active pharmaceutical ingredient and 30 wt%-99 wt% of the pharmaceutically acceptable carrier, more preferably mixing 1 wt%-50 wt% of the active pharmaceutical ingredient and 50 wt%-99 wt% of the pharmaceutically acceptable carrier, or even more preferably mixing 20 wt%-70 wt% of the active pharmaceutical ingredient and 30 wt%-80 wt% of the pharmaceutically acceptable carrier.

[0014] Furthermore, in the above method, the active pharmaceutical ingredient is a compound as shown in formula (I) or a pharmaceutically acceptable salt thereof.

[0015]

[0016] Preferably, the particle size distribution characteristics of the active pharmaceutical ingredient are as follows: D 50 Below 161 μm, and D 90 Below 361 μm, D is preferred. 50 Below 5μm, and D 90 Below 10 μm, D is preferred. 10 Below 0.5μm.

[0017] Furthermore, the particle size of the active pharmaceutical ingredient was determined using particle size analysis-laser diffraction.

[0018] Furthermore, in the above method, the pharmaceutically acceptable carrier is selected from one or more of sugars and sugar alcohols, amino acids, lipids, inorganic salts, and polymers, wherein: the sugars and sugar alcohols are selected from one or more of lactose, mannitol, maltose, sucrose, trehalose, glucose, and their hydrates; the amino acids are selected from one or more of phenylalanine, leucine, and glycine; the lipids are selected from one or more of stearic acid, magnesium stearate, calcium stearate, sucrose fatty acid esters, sodium stearate fumarate, and lecithin; the inorganic salts are selected from one or more of sodium phosphate, sodium chloride, calcium phosphate, and dicalcium phosphate; and the polymers are selected from one or two of polylactose and lactic acid-glycolic acid copolymers.

[0019] Preferably, the pharmaceutically acceptable carrier is a sugar and sugar alcohol, lipid, or a combination thereof.

[0020] More preferably, the sugar and sugar alcohol are lactose monohydrate; and the lipid is magnesium stearate.

[0021] More preferably, the pharmaceutically acceptable carrier is a sugar or sugar alcohol, preferably lactose monohydrate. Alternatively, more preferably, the pharmaceutically acceptable carrier is a combination of sugars and sugar alcohols and lipids, preferably a combination of lactose monohydrate and magnesium stearate.

[0022] Furthermore, the lactose monohydrate is a combination of a first lactose monohydrate and a second lactose monohydrate, wherein: the particle size distribution characteristics of the first lactose monohydrate meet condition 1: D 10 Between 10-50 μm, D 50 Between 40-70 μm, and D 90 The particle size distribution of the second lactose monohydrate is between 60 and 120 μm; and the particle size distribution characteristics of the second lactose monohydrate meet condition 2: D 10 Below 5μm, D 50 Below 30μm, and D 90 Below 70μm.

[0023] Preferably, the lactose monohydrate is a combination of a first lactose monohydrate with particle size distribution characteristics meeting condition 1 and a second lactose monohydrate with particle size distribution characteristics meeting condition 2, wherein: the particle size distribution characteristics of the first lactose monohydrate also meet condition 3: D 10 Between 19 and 43 μm, D 50 Between 53-66 μm, and D 90 Between 75 and 106 μm.

[0024] Alternatively, preferably, the lactose monohydrate is a combination of a first lactose monohydrate with particle size distribution characteristics meeting condition 1 and a second lactose monohydrate with particle size distribution characteristics meeting condition 2, wherein: the particle size distribution characteristics of the second lactose monohydrate also meet condition 4: D 10 Between 1.4 and 3.3 μm, D 50 Between 10.9 and 24.9 μm, and D 90 Between 32.6 and 60.4 μm.

[0025] More preferably, the lactose monohydrate is a combination of a first lactose monohydrate whose particle size distribution characteristics meet condition 3 and a second lactose monohydrate whose particle size distribution characteristics meet condition 4.

[0026] Furthermore, the particle size of the first lactose monohydrate is controlled by sieving, and the particle size of the second lactose monohydrate is controlled by pulverization.

[0027] Furthermore, the particle size of the lactose monohydrate was determined using particle size analysis-laser diffraction.

[0028] Furthermore, the weight ratio of the second lactose monohydrate to the first lactose monohydrate is 50:50 to 100:0, preferably 40:40 to 60:20 or 60:20 to 80:0, and more preferably 70:10 to 75:5.

[0029] Alternatively, further, the lactose monohydrate is a combination of a second lactose monohydrate and a third lactose monohydrate, wherein: the particle size distribution characteristics of the second lactose monohydrate meet condition 2: D 10 Below 5μm, D 50 Below 30μm, and D 90 Below 70 μm; and the particle size distribution characteristics of the third lactose monohydrate meet condition 5: D 50 Below 5μm, and D 90 Below 10μm.

[0030] Preferably, the lactose monohydrate is a combination of a second lactose monohydrate with particle size distribution characteristics meeting condition 2 and a third lactose monohydrate with particle size distribution characteristics meeting condition 5, wherein: the particle size distribution characteristics of the second lactose monohydrate also meet condition 4: D 10 Between 1.4 and 3.3 μm, D 50 Between 10.9 and 24.9 μm, and D 90 Between 32.6 and 60.4 μm.

[0031] Furthermore, the particle size of the second lactose monohydrate and the third lactose monohydrate is controlled by pulverization.

[0032] Furthermore, the particle size of the lactose monohydrate was determined using particle size analysis-laser diffraction.

[0033] Furthermore, the weight ratio of the second lactose monohydrate to the third lactose monohydrate is 50:50 to 100:0, preferably 40:40 to 60:20 or 60:20 to 80:0, and more preferably 70:10 to 75:5.

[0034] Furthermore, the particle size distribution characteristics of the magnesium stearate are as follows: D 10 Between 1-3 μm, D 50 Between 5-25 μm, and D 90 Between 50-100μm.

[0035] Furthermore, the particle size of the magnesium stearate was determined using particle size analysis-laser diffraction.

[0036] Furthermore, the pharmaceutically acceptable carrier is a combination of lactose monohydrate and magnesium stearate, wherein the weight ratio of magnesium stearate to lactose monohydrate is 0.05:100 to 5:100, preferably 0.05:100 to 1:100, and more preferably 1:100.

[0037] Preferably, the above method further includes an air jet milling step.

[0038] Furthermore, the air jet milling step pulverizes the mixture of the active pharmaceutical ingredient and a pharmaceutically acceptable carrier to obtain co-air powder.

[0039] Preferably, when the pharmaceutically acceptable carrier is a combination of sugars, sugar alcohols, and lipids, the air jet milling step pulverizes the mixture of the active pharmaceutical ingredient and lipids (i.e., a partially pharmaceutically acceptable carrier) to obtain co-air powder.

[0040] Preferably, the shearing airflow in the airflow pulverization step uses nitrogen or air with a relative humidity of less than 20%.

[0041] Preferably, the central ring pressure of the airflow pulverization step is 0.5-12 bar, more preferably 0.5-6 bar; the venturi pressure is 1-14 bar, more preferably 1-6.5 bar.

[0042] Preferably, the feed rate of the air jet milling step is 0.1-3 g / min.

[0043] Preferably, the above method further includes an aging step.

[0044] Furthermore, the aging step ages the co-gas powder obtained from the airflow pulverization step.

[0045] Preferably, the aging step is carried out under conditions of ventilation, temperature of 5-88°C, and relative humidity of 10%-95%.

[0046] More preferably, the ventilation uses air.

[0047] More preferably, the temperature is 10-50°C, more preferably 24-50°C.

[0048] More preferably, the relative humidity is 30-90%, more preferably 45-90%, more preferably 50-88%, and even more preferably 60-87%.

[0049] More preferably, the aging step takes 10-180 minutes, more preferably 30-60 minutes.

[0050] Furthermore, the equipment used in the solid mixing step includes a low-shear mixer or a high-shear mixer.

[0051] Preferably, the low-shear mixer is Mixer.

[0052] Preferably, the high-shear mixer is mixer or Mixer.

[0053] Furthermore, the above method further includes transportation and / or preservation steps.

[0054] Preferably, the transportation and / or storage steps are carried out at a temperature of -20 to 25°C and a relative humidity of 45% to 75%.

[0055] On the other hand, the present invention provides an inhaled pharmaceutical composition prepared by the above method.

[0056] The effects of the invention

[0057] The inhaled drug composition (Remdesivir dry powder inhaler) prepared by the method of this invention has the characteristics of good particle stability, good powder flowability, and no clumping, which has significant advantages over UT-Austin's Remdesivir formulation and is suitable for clinical use. Furthermore, the preparation method of this invention avoids the solvent residue problem of the film freeze-drying method and does not require harsh ultra-low temperature conditions.

[0058] In addition, the inventors of this invention were surprised to discover during the research and development process that magnesium stearate is essential for maintaining the good stability of remdesivir dry powder inhaler. The stability of remdesivir formulations without magnesium stearate or with other lipids as substitutes for magnesium stearate is significantly inferior to that of remdesivir formulations using a mixed carrier of lactose monohydrate and magnesium stearate. Attached Figure Description

[0059] Figure 1 SEM (x2k) of Remdesivir / magnesium stearate micropowder in Example 1 at a 20 μm scale.

[0060] Figure 2 SEM (x5k) of Remdesivir / magnesium stearate micropowder in Example 1 at a 10μm scale.

[0061] Figure 3 SEM (x25k) showing the remdesivir / magnesium stearate micropowder of Example 1 at a 2μm scale.

[0062] Figure 4 SEM (x100) showing the inhalation pharmaceutical composition of Example 1 at a scale of 500 μm;

[0063] Figure 5 SEM (x1k) showing the inhalation pharmaceutical composition of Example 1 at a 50 μm scale;

[0064] Figure 6 SEM (x4k) showing the inhalation pharmaceutical composition of Example 1 at a 10μm scale;

[0065] Figure 7 SEM (x2k) of Remdesivir / magnesium stearate micropowder in Example 2 at a 20 μm scale.

[0066] Figure 8 SEM (x5k) of Remdesivir / magnesium stearate micropowder in Example 2 at a 10μm scale.

[0067] Figure 9 SEM (x25k) of Remdesivir / magnesium stearate microparticles in Example 2 at a 2μm scale. Detailed Implementation

[0068] First, the present invention provides a method for preparing a pharmaceutical composition suitable for inhalation administration. The preparation method of the present invention may include a solid-mixing step for mixing the active pharmaceutical ingredient with a pharmaceutically acceptable carrier.

[0069] Unless otherwise stated, the "pharmaceutical active ingredient" in this invention may be remdesivir or a pharmaceutically acceptable salt thereof.

[0070] Unless otherwise stated, the term "remdesivir" as used in this invention refers to the compound shown in formula (I), whose English name is Remdesivir, chemical name is (S)-2-ethylbutyl-2-((S)-(((2R,3S,4R,5R)-5-(4-aminopyrrolo[1,2-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphorylamino)propionate, CAS registry number is 1809249-37-3, and chemical formula is C 27 H 35 N6O8P has a molecular weight of 602.58.

[0071]

[0072] Unless otherwise stated, examples of the term "pharmaceutically acceptable salt" as used in this invention include: hydrohalides (or halides), such as hydrofluoric acid salts (or fluorides), hydrochlorides (or chlorides), hydrobromide salts (or bromides), and hydroiodide salts (or iodides); oxygen-containing inorganic salts, such as nitrates, perchlorates, sulfates, and phosphates; alkyl sulfonates, such as methanesulfonates, ethanesulfonates, and trifluoromethanesulfonates; aryl sulfonates, such as benzenesulfonates and p-toluenesulfonates; organic salts, such as acetates, trifluoroacetates, citrates, and alcoholic beverages. Chloride, oxalate, and maleate salts; amino acid salts, such as glycine, lysine, arginine, ornithine, glutamate, and aspartate; alkali metal salts, such as lithium, sodium, and potassium salts; alkaline earth metal salts, such as calcium and magnesium salts; other metal salts, such as aluminum, iron, zinc, copper, nickel, and cobalt salts; organic amine salts or organic ammonium salts, such as ammonium salts, tert-octylamine salts, dibenzylamine salts, morpholine salts, glucosamine salts, ethylenediamine salts, guanidine salts, diethylamine salts, triethylamine salts, dicyclohexylamine salts, procaine salts, ethanolamine salts, diethanolamine salts, piperazine salts, and tetramethylammonium salts. Preferably, in this invention, pharmaceutically acceptable salts are alkali metal salts, such as lithium, sodium, or potassium salts; organic acid salts, such as acetates or trifluoroacetates; or inorganic acid salts, such as hydrochlorides or sulfates.

[0073] In one embodiment of the present invention, the content of the active pharmaceutical ingredient in the pharmaceutical composition may be 1wt%-70wt% by weight percentage (wt%). For example, the content of the active pharmaceutical ingredient can be 1 wt%, 2 wt%, 3 wt%, 4 wt%, 5 wt%, 6 wt%, 7 wt%, 8 wt%, 9 wt%, 10 wt%, 11 wt%, 12 wt%, 13 wt%, 14 wt%, 15 wt%, 16 wt%, 17 wt%, 18 wt%, 19 wt%, 20 wt%, 21 wt%, 22 wt%, 23 wt%, 24 wt%, 25 wt%, 26 wt%, 27 wt%, 28 wt%, 29 wt%, 30 wt%, 31 wt%, 32 wt%, 33 wt%, 34 wt%, 35 wt%, 36 wt%, 37 wt%, 38 wt%, 39 wt%, 40 wt%, 45 wt%, 50 wt%, 55 wt%, 60 wt%, 65 wt%, or 70 wt%.

[0074] In a preferred embodiment of the present invention, the content of the active pharmaceutical ingredient in the pharmaceutical composition can be 1wt%-50wt%. For example, the content of the active pharmaceutical ingredient can be 1wt%, 5wt%, 10wt%, 15wt%, 20wt%, 30wt%, 40wt%, or 50wt%.

[0075] In another preferred embodiment of the invention, the content of the active pharmaceutical ingredient in the pharmaceutical composition can be 20wt%-70wt%. For example, the content of the active pharmaceutical ingredient can be 20wt%, 30wt%, 40wt%, 50wt%, 60wt%, or 70wt%.

[0076] The active pharmaceutical ingredient in this pharmaceutical composition may have a specific particle size.

[0077] Unless otherwise stated, the term "D" as used in this invention... 10 “D” 50 "and "D 90 "These represent the particle sizes at 10%, 50%, and 90% of the cumulative particle size distribution curve, respectively."

[0078] In one embodiment of the present invention, the particle size distribution characteristics of the active pharmaceutical ingredient can be as follows: D 50 Below 161 μm, and D 90 Below 361μm.

[0079] In a preferred embodiment of the present invention, the particle size distribution characteristics of the active pharmaceutical ingredient can be as follows: D 50 Below 5μm, and D 90 Below 10μm.

[0080] In a more preferred embodiment of the present invention, the particle size distribution characteristics of the active pharmaceutical ingredient may further be as follows: D 10 Below 0.5μm.

[0081] In addition, the above particle size can be determined using particle size analysis-laser diffraction.

[0082] In one embodiment of the present invention, the content of the carrier in the pharmaceutical composition may be 30wt%-99wt%. For example, the carrier content can be 99wt%, 98wt%, 97wt%, 96wt%, 95wt%, 94wt%, 93wt%, 92wt%, 91wt%, 90wt%, 89wt%, 88wt%, 87wt%, 86wt%, 85wt%, 84wt%, 83wt%, 82wt%, 81wt%, 80wt%, 79wt%, 78wt%, 77wt%, 76wt%, 75wt%, 74wt%, 73wt%, 72wt%, 71wt%, 70wt%, 69wt%, 68wt%, 67wt%, 66wt%, 65wt%, 64wt%, 63wt%, 62wt%, 61wt%, 60wt%, 55wt%, 50wt%, 45wt%, 40wt%, 35wt%, or 30wt%.

[0083] In one embodiment of the present invention, the content of the carrier in the pharmaceutical composition can be 50wt%-99wt%. For example, the content of the carrier can be 99wt%, 95wt%, 90wt%, 85wt%, 80wt%, 70wt%, 60wt%, or 50wt%.

[0084] In another preferred embodiment of the invention, the carrier content in the pharmaceutical composition can be 30wt%-80wt%. For example, the carrier content can be 80wt%, 70wt%, 60wt%, 50wt%, 40wt%, or 30wt%.

[0085] In one embodiment of the invention, the carrier in the pharmaceutical composition may be selected from a variety of options, such as one or more selected from sugars and sugar alcohols, amino acids, lipids, inorganic salts and polymers.

[0086] When the carrier is a sugar or sugar alcohol, the sugar or sugar alcohol can be a sugar, a sugar alcohol, or a combination of sugar and sugar alcohol, for example, selected from one or more of lactose, mannitol, maltose, sucrose, trehalose, glucose and their hydrates.

[0087] When the carrier is an amino acid, the amino acid can be an L-amino acid, a D-amino acid, or a combination of L-amino acids and D-amino acids, for example, one or more selected from phenylalanine (especially L-type), leucine (especially L-type), and glycine (especially L-type).

[0088] When the carrier is a lipid, the lipid can be a fatty acid, a fatty acid salt (e.g., an alkali metal salt or an alkaline earth metal salt), a fatty acid ester (e.g., a glyceride or a glycol ester), or any combination of the above components, such as one or more selected from stearic acid, magnesium stearate, calcium stearate, sucrose fatty acid ester, sodium stearate fumarate, and lecithin.

[0089] When the carrier is an inorganic salt, the inorganic salt can be an inorganic oxyacid salt (e.g., hydrochloride), an inorganic oxyacid salt (e.g., phosphate or acid phosphate), or a combination of inorganic oxyacid salts and inorganic oxyacid salts, such as one or more selected from sodium phosphate, sodium chloride, calcium phosphate, and calcium hydrogen phosphate.

[0090] When the carrier is a polymer, the polymer can be a homopolymer obtained from the same monomer, a copolymer obtained from different monomers, or a combination of homopolymer and copolymer, such as one or both selected from polylactose and lactic acid-glycolic acid copolymer.

[0091] In a preferred embodiment of the present invention, the carrier in the pharmaceutical composition may be sugars and sugar alcohols, lipids, or combinations thereof.

[0092] When the carrier is a sugar or sugar alcohol, the sugar or sugar alcohol can be lactose hydrate, such as lactose monohydrate (or lactose monohydrate).

[0093] When the carrier is a lipid, the lipid can be magnesium stearate.

[0094] In a more preferred embodiment of the present invention, the carrier in the pharmaceutical composition may be a sugar or sugar alcohol, preferably lactose monohydrate.

[0095] In another preferred embodiment of the invention, the carrier in the pharmaceutical composition may be a combination of sugars, sugar alcohols and lipids, preferably a combination of lactose monohydrate and magnesium stearate.

[0096] When the carrier in the pharmaceutical composition contains lactose monohydrate, the lactose monohydrate may consist of two parts, namely a first lactose monohydrate and a second lactose monohydrate.

[0097] In one embodiment of the present invention, the particle size distribution characteristics of the first lactose monohydrate in the lactose monohydrate can meet condition 1: D 10Between 10-50 μm, D 50 Between 40-70 μm, and D 90 The particle size distribution of the second lactose monohydrate is between 60 and 120 μm; and the particle size distribution characteristics of the second lactose monohydrate meet condition 2: D 10 Below 5μm, D 50 Below 30μm, and D 90 Below 70μm.

[0098] In a preferred embodiment of the present invention, the lactose monohydrate may be composed of a first lactose monohydrate that meets condition 1 and a second lactose monohydrate that meets condition 2, wherein: the particle size distribution characteristics of the first lactose monohydrate may also meet condition 3: D 10 Between 19 and 43 μm, D 50 Between 53-66 μm, and D 90 Between 75 and 106 μm.

[0099] In another preferred embodiment of the present invention, the lactose monohydrate may be composed of a first lactose monohydrate that meets condition 1 and a second lactose monohydrate that meets condition 2, wherein the particle size distribution characteristics of the second lactose monohydrate may also meet condition 4: D 10 Between 1.4 and 3.3 μm, D 50 Between 10.9 and 24.9 μm, and D 90 Between 32.6 and 60.4 μm.

[0100] In a more preferred embodiment of the invention, the lactose monohydrate may be composed of a first lactose monohydrate that meets condition 3 and a second lactose monohydrate that meets condition 4.

[0101] Furthermore, the particle size of the first lactose monohydrate can be controlled by sieving, and the particle size of the second lactose monohydrate can be controlled by pulverization. Moreover, the particle size of both can be determined using particle size analysis-laser diffraction.

[0102] When the carrier in the pharmaceutical composition contains lactose monohydrate, the first lactose monohydrate and the second lactose monohydrate in the lactose monohydrate can have a specific ratio.

[0103] In one embodiment of the invention, the weight ratio of the second lactose monohydrate to the first lactose monohydrate, based on 100 parts by weight, can be from 50:50 to 100:0. For example, the weight ratio can be 50:50, 55:45, 60:40, 65:35, 70:30, 71:29, 72:28, 73:27, 74:26, 75:25, 76:24, 77:23, 78:22, 79:21, 80:20, 85:15, 90:10, 95:5, or 100:0.

[0104] In a preferred embodiment of the invention, the weight ratio of the second lactose monohydrate to the first lactose monohydrate, based on 80 parts by weight, can be from 40:40 to 60:20. For example, the weight ratio can be 40:40, 45:35, 50:30, 55:25, or 60:20.

[0105] In another preferred embodiment of the invention, the weight ratio of the second lactose monohydrate to the first lactose monohydrate, based on 80 parts by weight, can be from 60:20 to 80:0. For example, the weight ratio can be 60:20, 65:15, 70:10, 75:5, or 80:20.

[0106] In a more preferred embodiment of the invention, the weight ratio of the second lactose monohydrate to the first lactose monohydrate, based on 80 parts by weight, can be from 70:10 to 75:5. For example, the weight ratio can be 70:10 or 75:5.

[0107] When the carrier in the pharmaceutical composition contains lactose monohydrate, the lactose monohydrate may also consist of a second lactose monohydrate and a third lactose monohydrate.

[0108] In one embodiment of the present invention, the particle size distribution characteristics of the second lactose monohydrate in the lactose monohydrate can meet condition 2: D 10 Below 5μm, D 50 Below 30μm, and D 90 Below 70 μm; and the particle size distribution characteristics of the third lactose monohydrate can meet condition 5: D 50 Below 5μm, and D 90 Below 10μm.

[0109] In a preferred embodiment of the present invention, the lactose monohydrate may be composed of a second lactose monohydrate that meets condition 2 and a third lactose monohydrate that meets condition 5, wherein: the particle size distribution characteristics of the second lactose monohydrate may also meet condition 4: D 10 Between 1.4 and 3.3 μm, D 50 Between 10.9 and 24.9 μm, and D90 Between 32.6 and 60.4 μm.

[0110] Furthermore, the particle sizes of the second and third lactose monohydrates can be controlled by pulverization. And their particle sizes can be determined using particle size analysis-laser diffraction.

[0111] When the carrier in the pharmaceutical composition contains lactose monohydrate, the second lactose monohydrate and the third lactose monohydrate in the lactose monohydrate can have a specific ratio.

[0112] In one embodiment of the invention, the weight ratio of the second lactose monohydrate to the third lactose monohydrate is 50:50 to 100:0 per 100 parts by weight. For example, the weight ratio can be 50:50, 55:45, 60:40, 65:35, 70:30, 71:29, 72:28, 73:27, 74:26, 75:25, 76:24, 77:23, 78:22, 79:21, 80:20, 85:15, 90:10, 95:5, or 100:0.

[0113] In a preferred embodiment of the invention, the weight ratio of the second lactose monohydrate to the third lactose monohydrate, based on 80 parts by weight, can be from 40:40 to 60:20. For example, the weight ratio can be 40:40, 45:35, 50:30, 55:25, or 60:20.

[0114] In another preferred embodiment of the invention, the weight ratio of the second lactose monohydrate to the third lactose monohydrate, based on 80 parts by weight, can be from 60:20 to 80:0. For example, the weight ratio can be 60:20, 65:15, 70:10, 75:5, or 80:20.

[0115] In a more preferred embodiment of the present invention, the weight ratio of the second lactose monohydrate to the third lactose monohydrate may be 70:10, based on 80 parts by weight.

[0116] When the carrier in the pharmaceutical composition contains magnesium stearate, the magnesium stearate may have a specific particle size.

[0117] In one embodiment of the present invention, the particle size distribution characteristics of the magnesium stearate can be as follows: D 10 Between 1-3 μm, D 50 Between 5-25 μm, and D 90 Between 50-100μm.

[0118] In addition, the above particle size can be determined using particle size analysis-laser diffraction.

[0119] When the carrier in the pharmaceutical composition is a combination of lactose monohydrate and magnesium stearate, the magnesium stearate and the lactose monohydrate can have a specific ratio.

[0120] In one embodiment of the invention, the weight ratio of the magnesium stearate to the lactose monohydrate can be from 0.05:100 to 5:100. For example, the weight ratio can be 0.05:100, 0.1:100, 0.2:100, 0.5:100, 1:100, 1.5:100, 2:100, 2.5:100, 3:100, 3.5:100, 4:100, 4.5:100, or 5:100.

[0121] In a preferred embodiment of the invention, the weight ratio of the magnesium stearate to the lactose monohydrate can be from 0.05:100 to 1:100. For example, the weight ratio can be 0.05:100, 0.1:100, 0.2:100, 0.5:100 or 1:100.

[0122] In a more preferred embodiment of the present invention, the weight ratio of the magnesium stearate to the lactose monohydrate may be 1:100.

[0123] In the preparation method of the present invention, the equipment used in the solid mixing step can be either a low-shear mixer or a high-shear mixer.

[0124] In one embodiment of the invention, the low-shear mixer can be Mixer.

[0125] In another embodiment of the invention, the high-shear mixer can be Mixer.

[0126] In yet another embodiment of the invention, the high-shear mixer can be Mixer.

[0127] In some cases, the preparation method of the present invention may further include an air jet milling step for pulverizing a mixture of the active pharmaceutical ingredient and a pharmaceutically acceptable carrier (e.g., a flow aid) to obtain co-air powder (or drug-containing micro powder).

[0128] For example, when the pharmaceutically acceptable carrier is a combination of sugars and sugar alcohols (e.g., lactose monohydrate) and lipids (e.g., magnesium stearate), the air-jet milling step can pulverize the mixture of the active pharmaceutical ingredient (e.g., remdesivir) and the lipid portion (e.g., magnesium stearate) to obtain a co-powder. Specifically, the air-jet milling step may include: air-jet milling a mixture of the active pharmaceutical ingredient (e.g., remdesivir) and the lipid portion (e.g., magnesium stearate) of the carrier to obtain a co-powder. Subsequently, the co-powder is mixed with the sugar and sugar alcohol portion (e.g., lactose monohydrate) of the carrier to finally obtain an inhalation pharmaceutical composition.

[0129] In one embodiment of the invention, the shear gas flow of the airflow pulverization step can be nitrogen or air with a relative humidity of less than 20%.

[0130] In one embodiment of the invention, the central ring pressure of the airflow pulverization step can be 0.5-12 bar. For example, the central ring pressure can be 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 6.0, 7.0, 8.0, 9.0, 10.0, 11.0, or 12.0 bar.

[0131] In a preferred embodiment of the invention, the central ring pressure of the airflow pulverization step can be 0.5-6 bar. For example, the central ring pressure can be 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0 or 6.0 bar.

[0132] In one embodiment of the invention, the Venturi pressure of the airflow pulverization step can be 1-14 bar. For example, the Venturi pressure can be 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, or 14 bar.

[0133] In a preferred embodiment of the invention, the Venturi pressure of the airflow pulverization step can be 1-6.5 bar. For example, the Venturi pressure can be 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, or 6.5 bar.

[0134] In one embodiment of the present invention, the feed rate of the air jet milling step can be 0.1-3 g / min. For example, the feed rate can be 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 2.0, 2.5 or 3.0 g / min.

[0135] In some cases, the preparation method of the present invention may further include an aging step for aging the co-gas powder obtained from the gas jet pulverization step.

[0136] For example, when the pharmaceutically acceptable carrier is a combination of sugars and sugar alcohols (e.g., lactose monohydrate) and lipids (e.g., magnesium stearate), the aging step can be carried out under ventilated conditions at a temperature of 5-88°C and a relative humidity of 10%-95%, exposing the co-aerated powder of the mixture of the active pharmaceutical ingredient (e.g., remdesivir) and lipids (e.g., magnesium stearate) to these conditions. Subsequently, the aged co-aerated powder is mixed with the sugar and sugar alcohol fraction (e.g., lactose monohydrate) to obtain the final inhalation pharmaceutical composition.

[0137] In a preferred embodiment of the invention, the ventilating atmosphere for the aging step can be air.

[0138] In a preferred embodiment of the present invention, the ambient temperature for the aging step can be 10-50°C. For example, the ambient temperature can be 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 35, 40, 45 or 50°C.

[0139] In a more preferred embodiment of the present invention, the ambient temperature for the aging step can be 24-50°C. For example, the ambient temperature can be 24, 25, 26, 27, 28, 29, 30, 35, 40, 45 or 50°C.

[0140] In a preferred embodiment of the present invention, the relative humidity of the environment during the aging step can be 30%-90%. For example, the relative humidity can be 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, or 90%.

[0141] In a more preferred embodiment of the present invention, the relative humidity of the environment during the aging step can be 45%-90%. For example, the relative humidity can be 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, or 90%.

[0142] In one or even more preferred embodiment of the present invention, the relative humidity of the environment during the aging step can be 50%-88%. For example, the relative humidity can be 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 86%, 87%, or 88%.

[0143] In a further preferred embodiment of the invention, the relative humidity of the environment during the aging step can be 60%-87%. For example, the relative humidity can be 60%, 65%, 70%, 75%, 80%, 85%, 86%, or 87%.

[0144] In a preferred embodiment of the invention, the aging step can last for 10-180 minutes. For example, the time can be 10, 20, 30, 40, 50, 60, 80, 100, 120, 140, 160 or 180 minutes.

[0145] In a more preferred embodiment of the invention, the aging step may take 30-60 minutes. For example, the time may be 30, 40, 50 or 60 minutes.

[0146] In some cases, the preparation method of the present invention may further include transportation and / or storage steps to maintain the stability of the properties of the pharmaceutical composition under specific conditions.

[0147] In one embodiment of the invention, the transportation and / or storage steps can be carried out at a temperature of -20 to 25°C and a relative humidity of 45% to 75%.

[0148] Furthermore, the present invention provides a pharmaceutical composition suitable for inhalation administration prepared by the above method. This pharmaceutical composition can be used to prevent and / or treat diseases caused by viral infections, wherein the infecting virus can be a Filoviridae virus, a Paramyxoviridae virus, a Flaviviridae virus, a Retroviridae virus, or a Coronaviridae virus, preferably one or more of Marburg virus, Ebola virus, Nipah virus, respiratory syncytial virus, hepatitis C virus, human immunodeficiency virus, and novel coronavirus, more preferably the novel coronavirus.

[0149] The present invention will be further described below with reference to the accompanying drawings and specific embodiments, but these drawings and embodiments should not be regarded as limiting the scope of protection of the present invention.

[0150] Experimental materials

[0151] Table 1 lists the lactose monohydrate and magnesium stearate used in the following examples. The particle size of the materials was determined using particle size analysis-laser diffraction. The three commercially available lactose monohydrates are referred to as lactose 1, lactose 2, and lactose 3, respectively.

[0152] Table 1. Particle size distribution of lactose monohydrate and magnesium stearate used as carriers

[0153]

[0154] Examples 1-16: Preparation of Remdesivir dry powder inhaler.

[0155] First, weigh each material according to the prescription amounts in Table 3; second, add magnesium stearate, calcium stearate, or stearic acid to remdesivir and mix, then perform air jet milling (e.g., shear gas flow is nitrogen or air with RH% less than 20%, central ring pressure is 0.5-12 bar, e.g., 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 6.0, 7.0, 8.0, 9.0, 10.0, or 12.0 bar), venturi pressure is 1-14 bar, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 12.5, 13, 13.5, or 14 bar), feed rate is 0.1- After applying a flow rate of 3 g / min (e.g., 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.3, 1.5, 2.0, 2.5, or 3.0 g / min), drug-containing micropowders of different particle sizes were obtained. (The components such as magnesium stearate, used as gliding agents, have almost no effect on the particle size measurement results of remdesivir; therefore, the particle size measurement results of the drug-containing micropowders can still reflect the particle size of the active ingredient remdesivir to a certain extent.) (Preferably, the micropowders are then subjected to an aging treatment, for example, exposed to an environment with a temperature of 5-88°C and a RH% of 10%-95% for at least 60 minutes). The SEM images of the drug-containing micropowders in Examples 1 and 2 are shown below. Figure 1-3 As shown in Figures 7-9; finally, the pre-sieved lactose and the drug-containing micropowder were physically mixed in a solid mixing device (e.g., a Turbula mixer (Willy A. Bachofen AG)) to obtain the inhalation drug compositions of Examples 1 to 16. The SEM image of the inhalation drug composition of Example 1 is shown in Figure 7-9. Figure 4-6 As shown. The above preparation process was carried out in an environment with a temperature of 19-27℃ and a RH% of 30%-65%.

[0156] Table 2 lists the D values ​​of the drug-containing micropowders from each embodiment, determined by particle size analysis-laser diffraction. 10 D 50 and D 90Particle size; Table 3 lists the formulation composition of the pharmaceutical compositions of each embodiment.

[0157] Table 2. Particle size distribution of the active ingredients in Examples 1, 2, and 9 to 16

[0158]

[0159] Table 3. Formulation composition of the pharmaceutical compositions in Examples 1 to 16

[0160]

[0161] *1 indicates the content of the active ingredient in the pharmaceutical composition (wt%, converted to anhydrous form); taking Example 1 as an example, the content of the active ingredient in the pharmaceutical composition is 20wt%, and correspondingly, the content of the carrier composed of lactose 1, lactose 2 and magnesium stearate is 80wt%.

[0162] *2 indicates the relative amount of carrier in parts by weight; taking Example 1 as an example, the weight parts of lactose 1, lactose 2 and magnesium stearate as carriers are 70 parts, 10 parts and 0.8 parts, respectively, and the content of carrier in the pharmaceutical composition is 80 wt%.

[0163] Examples 17-20: Preparation of Remdesivir dry powder inhaler.

[0164] First, weigh each material according to the prescription amount in Table 5; second, referring to the process conditions in Examples 1-16, add magnesium stearate to remdesivir and mix, then air-jet pulverize to obtain drug-containing micro powders of different particle sizes; finally, place the pre-sieved lactose and drug-containing micro powders in a solid mixing device for physical mixing to obtain the inhalation drug compositions of Examples 17 to 20.

[0165] Table 4 lists the D values ​​of the drug-containing micropowders from each embodiment, determined by particle size analysis-laser diffraction. 10 D 50 and D 90 Particle size; Table 5 lists the formulation composition of the pharmaceutical compositions of each embodiment.

[0166] Table 4. Particle size distribution of the active ingredients in Examples 17 to 20

[0167]

[0168] Table 5. Formulation composition of the pharmaceutical compositions in Examples 17 to 20

[0169]

[0170] Examples 21-22: Preparation of Remdesivir dry powder inhaler.

[0171] First, weigh each material according to the prescription amount in Table 7; second, referring to the process conditions in Examples 1-16, add magnesium stearate to remdesivir and mix, then air-jet pulverize to obtain drug-containing micro powders of different particle sizes; finally, place the pre-sieved lactose and drug-containing micro powders in a solid mixing device for physical mixing to obtain the inhalation drug compositions of Examples 21 to 22.

[0172] Table 6 lists the D values ​​of the drug-containing micropowders from each embodiment, determined by particle size analysis-laser diffraction. 10 D 50 and D 90 Particle size; Table 7 lists the formulation composition of the pharmaceutical compositions of each embodiment.

[0173] Table 6. Particle size distribution of the active ingredients in Examples 21 to 22

[0174]

[0175] Table 7. Formulation composition of the pharmaceutical compositions in Examples 21 to 22

[0176]

[0177] Examples 23-26: Preparation of Remdesivir dry powder inhaler.

[0178] First, weigh each material according to the prescription amount in Table 9; second, refer to the process conditions in Examples 1-16, air-jet pulverize remdesivir (Examples 23 and 24), or add magnesium stearate to remdesivir and mix before air-jet pulverizing (Examples 25 and 26) to obtain drug-containing micro powders of different particle sizes; finally, place the pre-sieved lactose and drug-containing micro powders in a solid mixing device for physical mixing to obtain the inhalation drug compositions of Examples 23 to 26.

[0179] Table 8 lists the D values ​​of the drug-containing micropowders from each embodiment, determined by particle size analysis-laser diffraction. 10 D 50 and D 90 Particle size; Table 9 lists the formulation composition of the pharmaceutical compositions of each embodiment.

[0180] Table 8. Particle size distribution of the active ingredients in Examples 23 to 26

[0181]

[0182] Table 9. Formulation composition of the pharmaceutical compositions in Examples 23 to 26

[0183]

[0184] Examples 27-28: Preparation of Remdesivir dry powder inhaler.

[0185] First, weigh each material according to the prescription amount in Table 11; second, referring to the process conditions in Examples 1-16, pulverize Remdesivir by air jet to obtain drug-containing micro powders of different particle sizes; finally, place the pre-sieved lactose and drug-containing micro powders in a solid mixing device for physical mixing to obtain the inhalation drug compositions of Examples 27 to 28.

[0186] Table 10 lists the particle size distribution (D) of the drug-containing micropowders in each embodiment, determined by particle size analysis-laser diffraction. 10 D 50 and D 90 Particle size; Table 11 lists the formulation composition of the pharmaceutical compositions of each embodiment.

[0187] Table 10. Particle size distribution of the active ingredients in Examples 27 to 28

[0188]

[0189] Table 11. Formulation composition of the pharmaceutical compositions of Examples 27 to 28

[0190]

[0191] Examples 29-40: Preparation of Remdesivir dry powder inhaler.

[0192] First, the materials were weighed according to the prescribed amounts in Table 13. Second, magnesium stearate was added to remdesivir and mixed, then air-jet milled to obtain drug-containing microparticles of different particle sizes. Finally, the pre-sieved lactose and drug-containing microparticles were physically mixed in a solid mixing device (e.g., a Turbula mixer (Willy A. Bachofen AG)) to obtain the inhalation drug compositions of Examples 29 to 40. The above preparation process was carried out in an environment with a temperature of 19-27°C and a RH% of 30%-65%.

[0193] Table 12 lists the D values ​​of the drug-containing micropowders from each embodiment, determined by particle size analysis-laser diffraction. 10 D 50 and D 90 Particle size; Table 13 lists the formulation composition of the pharmaceutical compositions of each embodiment.

[0194] Table 12. Particle size distribution of the active ingredients in Examples 29 to 40

[0195]

[0196] Table 13. Formulation composition of the pharmaceutical compositions in Examples 29 to 40

[0197]

[0198] Example of effectiveness: Examining the fine particle percentage (FPF) and fine particle dose (FPD) of remdesivir dry powder inhaler.

[0199] When evaluating the ability of an inhaled formulation to reach the respiratory system through in vitro studies (examining the relationship between major drug particle size and FPF), a multistage impactor sampler is typically used to determine the amount of fine particles (e.g., see USP 31). <601> Aerosol / physical testing, and European Pharmacopoeia inhaled preparations: aerodynamic evaluation of fine particles).

[0200] This method uses a device for classifying drug particles, wherein drug particles are introduced from the inhaler by being drawn into a multi-stage impactor sampler using a pump. The introduced drug particles, depending on their size, reach any of the 12 sections of the multi-stage impactor sampler (cannula, pre-separator, inhaler, stages 0-7, and filter). Larger particles (such as diluent particles, drug particles not released from the diluent, and aggregates) are collected at the cannula, pre-separator, and inhaler. Drug particles released from the diluent reach any of stages 0-7 in the filter, while smaller particles reach stages with higher numbers. Drug particles that have passed through stage 7 are collected at the filter.

[0201] It is known that in clinical use, the amount of drug reaching a specific part of the respiratory system, or the proportion of that amount to the labeled amount, is related to the drug's ability to reach the respiratory system (e.g., see USP 31). <601> (Aerosol / Physical Testing). The former is called fine particle dose (hereinafter referred to as FPD), and the latter is called fine particle percentage (hereinafter referred to as FPF). Regarding the labeled amount in the pharmaceutical composition of the present invention, FPD is defined as the amount of drug reaching the filter from stage 3, and FPF is defined as the proportion of FPD in the labeled amount. These parameters are used to evaluate the ability to reach the respiratory system.

[0202] Table 14 lists the FPF results of the pharmaceutical compositions of the present invention. Table 15 lists the FPD results of the pharmaceutical compositions of the present invention.

[0203] Table 14. FPF of the pharmaceutical compositions in Examples 1, 2 and 9 to 40

[0204]

[0205] Table 15. FPD of the pharmaceutical compositions in Examples 1, 2 and 9 to 40

[0206]

[0207] During the research process, the present invention surprisingly discovered that when lactose 1, lactose 2 (or lactose 3) and magnesium stearate were selected as carriers, the prepared remdesivir inhaler had a high FPF value. However, using stearic acid and / or calcium stearate instead of magnesium stearate or omitting lipids would result in an FPF value that was either too low (too low would prevent the inhaler from settling sufficiently in the user's airway) or too high (too high would cause the inhaler already inhaled into the user's airway to be expelled with respiration). This indicates that the combination of lactose 1, lactose 2 (or lactose 3) and magnesium stearate as carriers achieved unexpected technical effects.

[0208] Samples from Examples 39 and 40, which showed relatively ideal FPF and FPD results, were selected as preferred pharmaceutical compositions and placed under accelerated stability test conditions (75% RH ± 5%, 40°C) for one month. Their respective FPF and FPD were then measured, and the results are shown in Tables 16 and 17.

[0209] Table 16. FPF of the pharmaceutical compositions of Examples 39 and 40 after stability testing

[0210] 39 58.55 40 59.40

[0211] Table 17. FPD of the pharmaceutical compositions of Examples 39 and 40 after stability testing

[0212] 39 8.97 40 8.85

[0213] When lactose 1, lactose 2, and magnesium stearate were selected as carriers, the prepared 70wt% remdesivir inhaler had a high FPF value, and the FPF value decreased slightly after one month of storage under accelerated test conditions (75%RH±5%, 40℃), indicating that the formulation had good stability.

Claims

1. A method for preparing an inhaled pharmaceutical composition, comprising a solid mixing step; The solid-mixing step involves mixing the active pharmaceutical ingredient with a pharmaceutically acceptable carrier. The inhaled pharmaceutical composition comprises 20wt%-70wt% of the active pharmaceutical ingredient and 30wt%-80wt% of the pharmaceutically acceptable carrier; The active pharmaceutical ingredient is a compound of formula (I) or a pharmaceutically acceptable salt thereof. ； The particle size distribution characteristics of the active pharmaceutical ingredient are as follows: D 10 Below 0.5μm, D 50 Below 5μm, and D 90 Below 10μm; The pharmaceutically acceptable carriers are sugars and combinations of sugar alcohols and lipids; The sugar and sugar alcohols mentioned are lactose monohydrate; The lipid is magnesium stearate; The lactose monohydrate is a combination of the first lactose monohydrate and the second lactose monohydrate, wherein: The particle size distribution characteristics of the first lactose monohydrate meet condition 3: D 10 Between 19 and 43 μm, D 50 Between 53-66 μm, and D 90 The particle size distribution of the second lactose monohydrate is between 75 and 106 μm; and the particle size distribution characteristics of the second lactose monohydrate meet condition 4: D 10 Between 1.4 and 3.3 μm, D 50 Between 10.9 and 24.9 μm, and D 90 Between 32.6 and 60.4 μm; the weight ratio of the second lactose monohydrate to the first lactose monohydrate is 70:10 to 75:5; The particle size distribution characteristics of the magnesium stearate are as follows: D 10 Between 1-3 μm, D 50 Between 5-25 μm, and D 90 Between 50-100 μm; The weight ratio of the magnesium stearate to the lactose monohydrate is from 0.05:100 to 1:100; It further includes an airflow pulverization step; The air jet milling step pulverizes the mixture of the active pharmaceutical ingredient and the lipids to obtain a co-powder, and then mixes the co-powder with the sugar and sugar alcohols to finally obtain an inhalation drug composition; The shearing airflow in the airflow pulverization step uses nitrogen or air with a relative humidity of less than 20%. The central ring pressure of the airflow pulverization step is 0.5-12 bar; the Venturi pressure is 1-14 bar. The feed rate for the air jet milling step is 0.1-3 g / min.

2. The preparation method according to claim 1, characterized in that, The pressure of the central ring is 0.5-6 bar.

3. The preparation method according to claim 1, characterized in that, The Venturi pressure is 1-6.5 bar.

4. The preparation method according to claim 1, characterized in that, It further includes an aging process; The aging step is used to age the co-gas powder obtained from the airflow pulverization step.

5. The preparation method according to claim 4, characterized in that, The aging process is carried out under conditions of ventilation, temperature of 5-88℃, and relative humidity of 10%-95%.

6. The preparation method according to claim 5, characterized in that, The temperature is 10-50℃.

7. The preparation method according to claim 5, characterized in that, The temperature is 24-50℃.

8. The preparation method according to claim 5, characterized in that, The relative humidity is 30-90%.

9. The preparation method according to claim 5, characterized in that, The relative humidity is 45-90%.

10. The preparation method according to claim 5, characterized in that, The relative humidity is 50-88%.

11. The preparation method according to claim 5, characterized in that, The relative humidity is 60-87%.

12. The preparation method according to claim 5, characterized in that, The aging process takes 10-180 minutes.

13. The preparation method according to claim 5, characterized in that, The aging process takes 30-60 minutes.

14. The preparation method according to claim 5, characterized in that, The ventilation uses air.

15. The preparation method according to claim 1, characterized in that, It further includes transportation and / or storage steps; The transportation and / or storage steps are carried out at a temperature of -20 to 25°C and a relative humidity of 45% to 75%.

16. An inhaled pharmaceutical composition prepared by any one of claims 1 to 15.

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