Voriconazole inhalation powder inhalation and preparation method thereof

Abstract

The invention provides a voriconazole inhalation dry powder inhalation. The voriconazole inhalation dry powder inhalation comprises the following components in parts by weight: 60-80 parts of voriconazole; 20.3-30 parts by weight of a phospholipid emulsifier; 1.4 to 2.5 parts by weight of a divalent cation chloride; 0-11 parts by weight of a crystal inhibitor; and no flow aid is contained. Compared with the prior art, by selecting the specific emulsifier and adopting the divalent cation chloride as the emulsion stabilizer, honeycomb structures and wrinkles are generated on the surfaces of the drug particles, so that the specific surface area is increased, the aerodynamic performance of the particles is better, the particles are easier to deliver to the lung, and the purpose of increasing the effective delivery dosage is achieved; and sugar glidants such as lactose do not need to be added, so that the possibility of layering of active ingredients and inactive ingredients in a pharmaceutical preparation process is avoided, and the stability of a preparation process can be effectively improved.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of pharmaceutical preparations, and particularly relates to a voriconazole inhalation powder aerosol and a preparation method thereof. BACKGROUND

[0002] Voriconazole, chemical name: (2R, 3S)-2-(2, 4-difluorophenyl)-3-(5-fluoro-4-pyrimidinyl)-1-(1H-1, 2, 4-triazol-1-yl)-2-butanol, has the following structural formula:

[0003]

[0004] Voriconazole is a broad-spectrum triazole antifungal drug, mainly used for the treatment of patients with progressive and possibly life-threatening fungal infections. It is also used to prevent invasive fungal infections in high-risk patients receiving allogeneic hematopoietic stem cell transplantation (HSCT).

[0005] At present, the main administration route of voriconazole is injection or oral administration. Since the drug concentration at the infection site is much lower than that in the liver, kidney and brain, the effect of injection or oral administration of triazole antifungal drugs on airway infection is not good, and there are obvious hepatotoxicity and drug interactions (most fungal infection patients are accompanied by diseases such as low immune function).

[0006] Inhalation preparation refers to a preparation that delivers drugs in the form of mist to the respiratory tract and / or lungs through a specific device to exert local or systemic effects. Compared with ordinary oral preparations, the drugs of inhalation preparations can directly reach the absorption or action site, absorption or action is fast, liver first-pass effect can be avoided, and drug dosage can be reduced. Compared with injection preparations, patient compliance can be improved, and some adverse reactions can be reduced or avoided.

[0007] Voriconazole is developed as an oral inhalation administration preparation, which directly acts on the bronchus, trachea and lung, and improves the clinical effect of patients with pulmonary fungal infection. However, there is no voriconazole inhalation drug preparation on the market worldwide.

[0008] The literature reports on voriconazole inhalation preparations are as follows:

[0009] 1. Nebulized inhalation: Chinese patent CN114632075A discloses a nebulized inhalation of voriconazole, which is prepared by preparing a clathrate of a weak organic acid solution of voriconazole, polyoxyethylene hydrogenated castor oil, pentaerythritol monostearate and a cyclodextrin aqueous solution, and then using a freeze-drying process to prepare a voriconazole nebulized inhalation. In use, the voriconazole inhalation is reconstituted with water for injection and then inhaled by the patient after being atomized by a nebulizer. The administration of the voriconazole inhalation requires the use of medical devices and equipment such as a nebulizer, which is not convenient for clinical use.

[0010] 2. Dry powder inhalation (DPI) refers to a formulation in which a micronized drug and / or carrier is delivered in single- or multi-dose reservoir form to the respiratory tract or lungs via a specialized dry powder inhaler.

[0011] 1) Chinese Patent CN116440084A discloses an inhalable powder formulation of voriconazole, with excipients including amino acids and mannitol. The preparation process is freeze-drying. The maximum effective delivery dose to the lungs of the inhaled powder prepared using this formulation is only 47.5% (effective site deposition rate in paragraph 220 of the specification);

[0012] 2) Chinese Patent Publication No. CN116509825A discloses an inhalable powder formulation capsule of voriconazole. This powder inhaler uses phospholipids as a crystallization inhibitor, sodium chloride, potassium chloride, calcium chloride, magnesium chloride, and barium chloride as stabilizers, and sugar or sugar alcohol as a flow aid. The preparation method involves freeze-drying and pulverizing voriconazole, phospholipids, and stabilizers into a powder, and then adding two types of lactose to prepare the inhalation powder. This type of inhalation powder inhaler has a low effective site deposition rate (47.07%, FPF of Example 10 in 202310356529.6).

[0013] However, lyophilized powder has poor flowability, small particle size, and is prone to agglomeration after freeze-drying. The relatively smooth surface of the drug particles also results in poor aerodynamic properties, which is detrimental to delivery to the lungs. A 30% flow aid is needed to improve the flowability and delivery performance of the powder. Furthermore, there is a possibility of stratification between the active and inactive ingredients during capsule filling.

[0014] Meanwhile, the research process revealed that voriconazole has unique physical properties, such as high actual density, strong viscosity, and difficulty in dispersing particles. Moreover, voriconazole is a poorly soluble drug, which makes it prone to polymerization and fusion in water. This leads to the growth of drug crystals during the process, resulting in an increase in the particle size of the dry powder obtained by spray drying, which in turn directly affects the effective delivery dose of the dry powder when administered by inhalation.

[0015] For inhaled formulations, a higher effective delivery dose to the lungs results in less powder being inhaled to achieve the same therapeutic effect, leading to greater patient safety and better adherence. Through extensive experimental research, the inventors developed a voriconazole inhalation powder formulation that can improve the effective delivery dose to the lungs, ultimately leading to this invention. Summary of the Invention

[0016] In view of this, the technical problem to be solved by the present invention is to provide a voriconazole inhalation powder and its preparation method, wherein the powder has a high dose of fine particles, and the aerodynamic particle size distribution indicators such as mass median diameter (MMAD) and geometric standard deviation (GSD) meet the requirements of inhalation formulations, and the process has good reproducibility.

[0017] This invention provides a voriconazole inhalation powder, comprising: 60-80 parts by weight of voriconazole, 20.3-30 parts by weight of phospholipid emulsifier, 1.4-2.5 parts by weight of divalent cationic chloride, and 0-11 parts by weight of crystal inhibitor, without a flow aid.

[0018] Preferably, the phospholipid emulsifier is selected from distearylphosphatidylcholine and / or dipalmitoylphosphatidylcholine;

[0019] And / or, the divalent cationic chloride is selected from one or more of magnesium chloride, calcium chloride, zinc chloride and copper chloride.

[0020] And / or, the crystallization inhibitor is selected from one or more of polyethylene glycol, carrageenan, magnesium stearate, glycerin, sorbitol ester, hydroxypropyl cellulose and hydroxypropyl methylcellulose.

[0021] Preferably, the voriconazole inhalation powder is obtained by spray drying of an oil-in-water voriconazole suspension.

[0022] Preferably, the mass of the aqueous phase in the oil-in-water voriconazole suspension is 20 to 45 times the total weight of all solids;

[0023] The mass of the oil phase in the oil-in-water voriconazole suspension is 3 to 14 times the mass of voriconazole.

[0024] Preferably, the oil phase is selected from tert-butanol or perfluorooctane;

[0025] And / or, the aqueous phase is deionized water and / or any type of water that meets the quality requirements of inhalation formulations.

[0026] Preferably, the particle size D90 of the oil-in-water voriconazole suspension is less than or equal to 8.5 μm;

[0027] The particle size D50 of the oil-in-water voriconazole suspension is less than or equal to 4.5 μm;

[0028] The particle size D10 of the oil-in-water voriconazole suspension is less than or equal to 2 μm.

[0029] Preferably, the particle size D90 of the voriconazole inhalation powder is less than or equal to 7 μm;

[0030] The particle size D50 of the voriconazole inhalation powder is less than or equal to 4 μm;

[0031] The particle size D10 of the voriconazole inhalation powder is less than or equal to 1.5 μm.

[0032] Preferably, the tapped density of the voriconazole inhalation powder is less than or equal to 0.4 g / mL; and the BET specific surface area of ​​the voriconazole inhalation powder is greater than or equal to 50 m². 2 / g.

[0033] The present invention also provides a method for preparing the above-mentioned voriconazole inhalation powder, comprising the following steps:

[0034] S1A) A divalent cationic chloride, a phospholipid emulsifier and an aqueous phase are mixed and subjected to a first high-speed shearing to obtain a first mixture;

[0035] S2A) The mixture, the crystal inhibitor and voriconazole are mixed and subjected to a second high-speed shearing to obtain a second mixture;

[0036] S3A) The second mixture is mixed with the oil phase, subjected to a third high-speed shearing, and then homogenized under high pressure to obtain an oil-in-water voriconazole suspension;

[0037] S4A) The oil-in-water voriconazole suspension is spray-dried to obtain voriconazole inhalation powder;

[0038] Or it may include the following steps:

[0039] S1B) A divalent cationic chloride, a phospholipid emulsifier and an aqueous phase are mixed and subjected to a first high-speed shearing to obtain a first mixture;

[0040] S2B) The mixture, the crystal inhibitor and the oil phase are mixed and subjected to a second high-speed shearing to obtain a second mixture;

[0041] S3B) The second mixture is mixed with voriconazole, subjected to a third high-speed shearing, and then homogenized under high pressure to obtain an oil-in-water voriconazole suspension.

[0042] S4B) The oil-in-water voriconazole suspension is spray-dried to obtain voriconazole inhalation powder.

[0043] Preferably, the rotational speed of the first high-speed shearing in step S1A) and step S1B) is independently 8000-26000 rpm; the time of the first high-speed shearing in step S1A) and step S1B) is independently 5-15 min.

[0044] The rotational speed of the second high-speed shearing in steps S2A) and S2B) is independently 8000-26000 rpm; the time of the second high-speed shearing in steps S2A) and S2B) is independently 3-8 min.

[0045] The rotational speed of the third high-speed shear in steps S3A) and S3B) is independently 8000-26000 rpm; the time of the first high-speed shear in steps S3A) and S3B) is independently 5-15 min.

[0046] The pressure of high-pressure homogenization in steps S3A) and S3B) is independently 1000-2000 bar; the number of times high-pressure homogenization is performed in steps S3A) and S3B) is independently 3-30 times.

[0047] In steps S4A) and S4B), the inlet temperature for spray drying is independently 105℃~145℃; the spray gas flow rate is independently 1500~1800L / h; and the drying gas flow rate is independently 20~35m³ / h. 3 / h; the liquid inlet rate for each spray dryer is 5 to 20 mL / min; the outlet temperature for each spray dryer is 40℃ to 70℃.

[0048] This invention provides a voriconazole inhalation powder, comprising: 60-80 parts by weight of voriconazole; 20.3-30 parts by weight of a phospholipid emulsifier; 1.4-2.5 parts by weight of a divalent cationic chloride; 0-11 parts by weight of a crystallizer; and no flow aid. Compared with the prior art, this invention, by selecting specific emulsifiers and using divalent cationic chloride as an emulsion stabilizer, creates a honeycomb structure and wrinkles on the surface of the drug particles, thereby increasing the specific surface area, improving the aerodynamic properties of the particles, and making them easier to deliver to the lungs, thus increasing the effective delivery dose. Furthermore, it eliminates the need for sugar-based flow aids such as lactose, avoiding the possibility of stratification between active and inactive ingredients during drug formulation, and effectively improving the stability of the formulation process. Attached Figure Description

[0049] Figure 1 The image shows a scanning electron microscope (SEM) image of voriconazole inhalation powder from Comparative Example 1.

[0050] Figure 2 The image shows a scanning electron microscope (SEM) image of voriconazole inhalation powder for Comparative Example 2.

[0051] Figure 3 Here is a scanning electron microscope image of the voriconazole inhalation powder of Example 7 (S7-2);

[0052] Figure 4 The NGI results are for the voriconazole inhalation powder of Comparative Example 1.

[0053] Figure 5The NGI results are for the voriconazole inhalation powder of Comparative Example 2.

[0054] Figure 6 The results of NGI determination for voriconazole inhalation powder in Example 1 (S1-2);

[0055] Figure 7 The results of NGI determination for voriconazole inhalation powder in Example 2 are shown.

[0056] Figure 8 The results of NGI determination for voriconazole inhalation powder in Example 3 are shown.

[0057] Figure 9 The results of NGI determination for voriconazole inhalation powder in Example 5 (S5-3);

[0058] Figure 10 The results of NGI determination for voriconazole inhalation powder in Example 6;

[0059] Figure 11 The results are the NGI determination results for the voriconazole inhalation powder of Example 7 (S7-2). Detailed Implementation

[0060] The technical solutions of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative effort are within the scope of protection of the present invention.

[0061] This invention provides a voriconazole inhalation powder, comprising: 60-80 parts by weight of voriconazole, 20.3-30 parts by weight of phospholipid emulsifier, 1.4-2.5 parts by weight of divalent cationic chloride, and 0-11 parts by weight of crystal inhibitor, without a flow aid.

[0062] According to the present invention, the content of voriconazole in the voriconazole inhalation powder is preferably 64-80 parts by weight, more preferably 66-76 parts by weight, and even more preferably 67-76 parts by weight; in some embodiments provided by the present invention, the content of voriconazole in the voriconazole inhalation powder is specifically 76.05 parts by weight, 75.76 parts by weight, 75.19 parts by weight, 74.62 parts by weight, 72.73 parts by weight, 66.67 parts by weight, 68.97 parts by weight, 75.62 parts by weight, 75.56 parts by weight, 75.50 parts by weight, 75.45 parts by weight, 75.38 parts by weight, 74.08 parts by weight, 71.43 parts by weight, 68.03 parts by weight, or 66.66 parts by weight; the particle size D90 of the voriconazole is preferably less than 30 μm, more preferably less than 25 μm.

[0063] According to the present invention, the content of the phospholipid emulsifier in the voriconazole inhalation powder is preferably 20.3-28 parts by weight, more preferably 20.3-26 parts by weight, and even more preferably 20.3-23 parts by weight; the phospholipid emulsifier is preferably a phosphatidylcholine emulsifier, more preferably distearylphosphatidylcholine (DSPC) and / or dipalmitoylphosphatidylcholine (DPPC), and even more preferably distearylphosphatidylcholine (DSPC); in some embodiments provided by the present invention In the example, the content of the phospholipid emulsifier in the voriconazole inhalation powder is specifically 22.81 parts by weight, 22.73 parts by weight, 22.55 parts by weight, 22.39 parts by weight, 25.0 parts by weight, 25.86 parts by weight, 22.68 parts by weight, 22.67 parts by weight, 22.65 parts by weight, 22.63 parts by weight, 22.62 parts by weight, 22.22 parts by weight, 21.43 parts by weight, 20.69 parts by weight, or 20.41 parts by weight.

[0064] According to the present invention, the content of the divalent cationic chloride in the voriconazole inhalation powder is preferably 1.5 to 2.5 parts by weight, more preferably 1.5 to 2.3 parts by weight, even more preferably 1.5 to 2.2 parts by weight, even more preferably 1.5 to 2.0 parts by weight, and most preferably 1.5 to 1.9 parts by weight. In some embodiments provided by the present invention, the content of the divalent cationic chloride in the voriconazole inhalation powder is specifically 1.51 parts by weight, 2.26 parts by weight, 1.82 parts by weight, 1.66 parts by weight, 1.72 parts by weight, 1.85 parts by weight, 1.78 parts by weight, 1.69 parts by weight, 1.67 parts by weight, or 1.81 parts by weight. The divalent cationic chloride is preferably one or more of magnesium chloride (MgCl2), calcium chloride (CaCl2), zinc chloride (ZnCl2), and copper chloride (CuCl2), more preferably magnesium chloride (MgCl2) and / or calcium chloride (CaCl2).

[0065] According to the present invention, the mass ratio of the phospholipid emulsifier to the divalent cationic chloride is (9-15):1, more preferably (10-15):1.

[0066] According to the present invention, the content of the anti-crystallization agent in the voriconazole inhalation powder is preferably 0-10 parts by weight; the anti-crystallization agent is preferably one or more of polyethylene glycol, carrageenan, magnesium stearate, glycerin, sorbitol ester, hydroxypropyl cellulose, and hydroxypropyl methylcellulose, more preferably one or more of polyethylene glycol 1000, carrageenan, magnesium stearate, glycerin, sorbitol ester, hydroxypropyl cellulose, and hydroxypropyl methylcellulose, and even more preferably magnesium stearate and / or hydroxypropyl methylcellulose; more specifically, when the anti-crystallization agent is magnesium stearate, the content of the anti-crystallization agent in the voriconazole inhalation powder is preferably 0.19-0.49 parts by weight; in some embodiments provided by the present invention When the crystal inhibitor is magnesium stearate, the content of the crystal inhibitor in the voriconazole inhalation powder is specifically 0.19 parts by weight, 0.26 parts by weight, 0.34 parts by weight, 0.41 parts by weight, or 0.49 parts by weight; when the crystal inhibitor is hydroxypropyl methylcellulose, the content of the crystal inhibitor in the voriconazole inhalation powder is preferably 1.8 to 10 parts by weight; in some embodiments provided by the present invention, when the crystal inhibitor is hydroxypropyl methylcellulose, the content of the crystal inhibitor in the voriconazole inhalation powder is specifically 3.45 parts by weight, 1.85 parts by weight, 3.64 parts by weight, 5.36 parts by weight, 8.62 parts by weight, or 9.86 parts by weight. In this invention, the anti-crystallization agent can be called a thickener, surfactant, suspending agent or solution stabilizer. The purpose of adding the anti-crystallization agent is to obtain a suitable particle size (particle size distribution D90 < 8 μm) of API suspended in the emulsion with fewer high-pressure homogenizations. Without the anti-crystallization agent, it is necessary to increase the number of homogenizations to obtain the desired suitable particle size of API in the suspension.

[0067] According to the present invention, the voriconazole inhalation powder provided by the present invention does not contain a flow aid, especially not a sugar-based flow aid.

[0068] In one specific embodiment of the present invention, the voriconazole inhalation powder comprises 66-76 parts by weight of voriconazole, 20.3-26 parts by weight of phospholipid emulsifier, 1.5-2.3 parts by weight of divalent cationic chloride, and 0-10 parts by weight of crystal inhibitor.

[0069] In another specific embodiment of the present invention, the voriconazole inhalation powder includes 67-76 parts by weight of voriconazole, 20.3-23 parts by weight of phospholipid emulsifier, 1.5-1.9 parts by weight of divalent cationic chloride, and 0-10 parts by weight of crystal inhibitor.

[0070] In one specific embodiment of the present invention, the voriconazole inhalation powder is obtained by spray drying an oil-in-water voriconazole suspension; the mass of the aqueous phase in the oil-in-water voriconazole suspension is preferably 20 to 45 times the total weight of all solids; the aqueous phase is preferably deionized water and / or any type of water that meets the quality requirements of inhalation preparations; the mass of the oil phase in the oil-in-water voriconazole suspension is preferably 3 to 14 times the mass of voriconazole; the oil phase is preferably tert-butanol or perfluorobromooctane; the inlet temperature of the spray drying is preferably 105°C to 145°C. More preferably, the temperature is 110℃~140℃, even more preferably, 115℃~135℃, even more preferably, 115℃~130℃, even more preferably, 115℃~125℃, and most preferably, 120℃; the spray gas flow rate for spray drying is preferably 1500~1800L / h, more preferably 1550~1800L / h, even more preferably 1600~1800L / h, even more preferably 1650~1800L / h, even more preferably 1700~1800L / h, and most preferably 1750L / h; the drying gas flow rate for spray drying is preferably 20~35m³ / h. 3 / h, more preferably 25-35m 3 / h, preferably 28-32m 3 / h, the optimal value is 30m 3 / h; the preferred liquid inlet rate for spray drying is 5-20 mL / min, more preferably 10-20 mL / min, even more preferably 12-18 mL / min, and most preferably 15 mL / min; the preferred outlet temperature for spray drying is 40℃-70℃, more preferably 45℃-70℃, even more preferably 50℃-70℃, even more preferably 55℃-70℃, and most preferably 60℃-65℃.

[0071] In one specific embodiment of the present invention, the particle size D90 of the oil-in-water voriconazole suspension is preferably less than or equal to 8.5 μm, more preferably less than or equal to 8.3 μm, even more preferably less than or equal to 8.0 μm, even more preferably less than or equal to 7.8 μm, and most preferably 4.4–3.6 μm. In some embodiments of the present invention, the particle size D90 of the oil-in-water voriconazole suspension is specifically 5.6 μm, 6.3 μm, 6.1 μm, 8.3 μm, 5.2 μm, 5.0 μm, 4.9 μm, 4.7 μm, 5.4 μm, 4.8 μm, 4.6 μm, 4.4 μm, 4.3 μm, or 7.8 μm.

[0072] In one specific embodiment of the present invention, the particle size D50 of the oil-in-water voriconazole suspension is preferably less than or equal to 4.5 μm, more preferably less than or equal to 4.4 μm, even more preferably less than or equal to 4.0 μm, even more preferably 2.0–3.7 μm, and most preferably 2.5–3.7 μm. In some embodiments of the present invention, the particle size D50 of the oil-in-water voriconazole suspension is specifically 2.9 μm, 3.7 μm, 3.6 μm, 4.4 μm, 2.7 μm, 2.6 μm, 3.1 μm, 3.2 μm, 2.5 μm, or 4.5 μm.

[0073] In one specific embodiment of the present invention, the particle size D10 of the oil-in-water voriconazole suspension is preferably less than or equal to 2 μm, more preferably less than or equal to 1.5 μm, even more preferably less than or equal to 1.3 μm, and most preferably 0.5 to 1.3 μm; in some embodiments of the present invention, the particle size D10 of the oil-in-water voriconazole suspension is specifically 0.5 μm, 1.0 μm, 0.8 μm, 1.1 μm, 1.2 μm, 0.9 μm, 0.7 μm, 0.6 μm or 1.3 μm.

[0074] In one specific embodiment of the present invention, the particle size D90 of the voriconazole inhalation powder is preferably less than or equal to 7 μm, more preferably less than or equal to 6.6 μm, and even more preferably 4.6 to 6.6 μm; in some embodiments of the present invention, the particle size D90 of the voriconazole inhalation powder is specifically 5.8 μm, 5.9 μm, 6.6 μm, 6.5 μm, 5.4 μm, 5.2 μm, 5.0 μm, 4.8 μm, 5.5 μm, 5.1 μm, 4.6 μm, or 4.9 μm.

[0075] In one specific embodiment of the present invention, the particle size D50 of the voriconazole inhalation powder is less than or equal to 4 μm, more preferably 2.6–3.8 μm; in some embodiments of the present invention, the particle size D50 of the voriconazole inhalation powder is specifically 3.1 μm, 3.7 μm, 3.8 μm, 3.2 μm, 2.9 μm, 2.7 μm, 3.3 μm, 3.0 μm, 2.8 μm, or 2.6 μm.

[0076] In one specific embodiment of the present invention, the particle size D10 of the voriconazole inhalation powder is preferably less than or equal to 1.5 μm, more preferably 0.7 to 1.4 μm; in some embodiments of the present invention, the particle size D10 of the voriconazole inhalation powder is specifically 1.1 μm, 1.0 μm, 0.9 μm, 1.2 μm, 0.8 μm or 0.7 μm.

[0077] In one specific embodiment of the present invention, the tapped density of the voriconazole inhalation powder is preferably less than or equal to 0.4 g / mL, more preferably less than or equal to 0.37 g / mL, and even more preferably 0.24 to 0.37 g / mL; in some embodiments of the present invention, the tapped density of the voriconazole inhalation powder is specifically 0.35 g / mL, 0.30 g / mL, 0.37 g / mL, 0.31 g / mL, 0.25 g / mL, 0.24 g / mL, or 0.26 g / mL.

[0078] In one specific embodiment of the present invention, the BET specific surface area of ​​the voriconazole inhalation powder is preferably greater than or equal to 50 m². 2 / g, more preferably 50-100m 2 / g, preferably 50-90m 2 / g, preferably 50-85m 2 / g, the optimal value is 51.2~81.3m 2 / g; In some embodiments provided by the present invention, the BET specific surface area of ​​the voriconazole inhalation powder is specifically 63.4m². 2 / g、68.6m 2 / g, 51.2m 2 / g, 71.4m 2 / g, 75.6m 2 / g, 81.3m 2 / g, 76.3m 2 / g or 79.6m 2 / g.

[0079] This invention also provides a method for preparing the above-mentioned voriconazole inhalation powder, comprising the following steps: S1A) mixing a divalent cationic chloride, a phospholipid emulsifier, and an aqueous phase, and subjecting the mixture to a first high-speed shearing to obtain a first mixture; S2A) mixing the mixture, a crystal inhibitor, and voriconazole, and subjecting the mixture to a second high-speed shearing to obtain a second mixture; S3A) mixing the second mixture with an oil phase, subjecting the mixture to a third high-speed shearing, and then homogenizing under high pressure to obtain an oil-in-water voriconazole suspension; S4A) spray-drying the oil-in-water voriconazole suspension to obtain the voriconazole inhalation powder.

[0080] In this invention, there are no special restrictions on the source of any raw materials; commercially available materials are acceptable. The divalent cationic chloride, phospholipid emulsifier, aqueous phase, crystal inhibitor, voriconazole, and oil phase are all as described above and will not be repeated here.

[0081] A first mixture is obtained by mixing a divalent cationic chloride, a phospholipid emulsifier, and an aqueous phase and performing a first high-speed shearing. The mixing temperature is preferably 55℃~75℃, more preferably 60℃~70℃, and even more preferably 65℃. In this invention, it is preferable to first mix the divalent cationic chloride and the aqueous phase under heating conditions, then add the phospholipid emulsifier and mix, and then perform a first high-speed shearing. The rotation speed of the first high-speed shearing is preferably 8000~26000 rpm, more preferably 8000~25000 rpm, even more preferably 8000~22000 rpm, even more preferably 8000~20000 rpm, even more preferably 8000~18000 rpm, even more preferably 8000~16000 rpm, and most preferably 10000~12000 rpm. The time of the first high-speed shearing is preferably 5~15 min, more preferably 8~12 min, and even more preferably 10 min. During the first high-speed shearing, the solution temperature is preferably maintained at 55℃~75℃.

[0082] The mixture, the crystal inhibitor, and voriconazole are mixed and subjected to a second high-speed shearing to obtain a second mixture. The rotation speed of the second high-speed shearing is preferably 8000–26000 rpm, more preferably 8000–25000 rpm, even more preferably 8000–22000 rpm, even more preferably 8000–20000 rpm, even more preferably 8000–18000 rpm, even more preferably 8000–16000 rpm, and most preferably 10000–12000 rpm. The time of the second high-speed shearing is preferably 3–8 min, more preferably 4–6 min, and even more preferably 5 min. During the second high-speed shearing, the temperature of the solution is preferably maintained at 55°C–75°C.

[0083] The second mixture is mixed with the oil phase, subjected to a third high-speed shearing, and then homogenized under high pressure to obtain an oil-in-water voriconazole suspension. The rotational speed of the third high-speed shearing is preferably 8000–26000 rpm, more preferably 8000–25000 rpm, even more preferably 8000–22000 rpm, even more preferably 8000–20000 rpm, even more preferably 8000–18000 rpm, even more preferably 8000–16000 rpm, and most preferably 10000–12000 rpm. The duration of the third high-speed shearing is preferably 5–15 min, more preferably 8–12 min, and even more preferably 10 min. During the third high-speed shearing process, the solution temperature is preferably maintained at 55°C. The temperature is ℃~75℃; the pressure of the high-pressure homogenization is preferably 1000~2000 bar, more preferably 1200~1800 bar, even more preferably 1400~1600 bar, and most preferably 1500 bar; the number of high-pressure homogenizations is preferably 3~30 times; in this invention, the number of high-pressure homogenizations is selected according to the composition of the formula. When the content of the anti-crystallizing agent is 0, the number of high-pressure homogenizations is preferably 20~30 times, more preferably 22~28 times, even more preferably 24~26 times, and most preferably 25 times; when the content of the anti-crystallizing agent is not 0, the number of high-pressure homogenizations is preferably 3~20 times, more preferably 3~15 times, even more preferably 3~10 times, even more preferably 3~8 times, and most preferably 4~6 times.

[0084] The oil-in-water voriconazole suspension is spray-dried to obtain voriconazole inhalation powder. The inlet temperature of the spray drying is preferably 105℃~145℃, more preferably 110℃~140℃, even more preferably 115℃~135℃, even more preferably 115℃~130℃, even more preferably 115℃~125℃, and most preferably 120℃. The spray gas flow rate is preferably 1500~1800 L / h, more preferably 1550~1800 L / h, even more preferably 1600~1800 L / h, even more preferably 1650~1800 L / h, even more preferably 1700~1800 L / h, and most preferably 1750 L / h. The drying gas flow rate is preferably 20~35 m³ / h. 3 / h, more preferably 25-35m 3 / h, preferably 28-32m 3 / h, the optimal value is 30m 3The preferred inlet rate for spray drying is 5–20 mL / min, more preferably 10–20 mL / min, even more preferably 12–18 mL / min, and most preferably 15 mL / min. The preferred outlet temperature for spray drying is 40℃–70℃, more preferably 45℃–70℃, even more preferably 50℃–70℃, even more preferably 55℃–70℃, and most preferably 60℃–65℃. Specifically, the purpose of using the above-mentioned emulsion followed by spray drying is to coat the surface of voriconazole with a layer of phospholipids. Through spray drying, after the oil phase evaporates, a honeycomb structure and wrinkles are formed on the surface of the drug particles, thereby increasing the specific surface area, improving the aerodynamic properties of the particles, and making them easier to deliver to the lungs, thus increasing the effective delivery dose.

[0085] This invention also provides another method for preparing the above-mentioned voriconazole inhalation powder, comprising the following steps: S1B) mixing a divalent cationic chloride, a phospholipid emulsifier, and an aqueous phase, and performing a first high-speed shearing to obtain a first mixture; S2B) mixing the mixture, a crystal inhibitor, and an oil phase, and performing a second high-speed shearing to obtain a second mixture; S3B) mixing the second mixture with voriconazole, performing a third high-speed shearing, and then homogenizing under high pressure to obtain an oil-in-water voriconazole suspension; S4B) spray-drying the oil-in-water voriconazole suspension to obtain the voriconazole inhalation powder.

[0086] In this invention, there are no special restrictions on the source of any raw materials; commercially available materials are acceptable. The divalent cationic chloride, phospholipid emulsifier, aqueous phase, crystal inhibitor, voriconazole, and oil phase are all as described above and will not be repeated here.

[0087] A first mixture is obtained by mixing a divalent cationic chloride, a phospholipid emulsifier, and an aqueous phase and performing a first high-speed shearing. The mixing temperature is preferably 55℃~75℃, more preferably 60℃~70℃, and even more preferably 65℃. In this invention, it is preferable to first mix the divalent cationic chloride and the aqueous phase under heating conditions, then add the phospholipid emulsifier and mix, and then perform a first high-speed shearing. The rotation speed of the first high-speed shearing is preferably 8000~26000 rpm, more preferably 8000~25000 rpm, even more preferably 8000~22000 rpm, even more preferably 8000~20000 rpm, even more preferably 8000~18000 rpm, even more preferably 8000~16000 rpm, and most preferably 10000~12000 rpm. The time of the first high-speed shearing is preferably 5~15 min, more preferably 8~12 min, and even more preferably 10 min. During the first high-speed shearing, the solution temperature is preferably maintained at 55℃~75℃.

[0088] The mixture, the crystal inhibitor, and the oil phase are mixed and subjected to a second high-speed shearing to obtain a second mixture. The rotational speed of the second high-speed shearing is preferably 8000–26000 rpm, more preferably 8000–25000 rpm, even more preferably 8000–22000 rpm, even more preferably 8000–20000 rpm, even more preferably 8000–18000 rpm, even more preferably 8000–16000 rpm, and most preferably 10000–12000 rpm. The duration of the second high-speed shearing is preferably 3–8 min, more preferably 4–6 min, and even more preferably 5 min. During the second high-speed shearing process, the solution temperature is preferably maintained at 55°C–75°C.

[0089] The second mixture is mixed with voriconazole, subjected to a third high-speed shearing, and then homogenized under high pressure to obtain an oil-in-water voriconazole suspension. The rotation speed of the third high-speed shearing is preferably 8000–26000 rpm, more preferably 8000–25000 rpm, even more preferably 8000–22000 rpm, even more preferably 8000–20000 rpm, even more preferably 8000–18000 rpm, even more preferably 8000–16000 rpm, and most preferably 10000–12000 rpm. The duration of the third high-speed shearing is preferably 5–15 min, more preferably 8–12 min, and even more preferably 10 min. During the third high-speed shearing process, the solution temperature is preferably maintained at 5°C. The temperature is 5℃~75℃; the pressure of the high-pressure homogenization is preferably 1000~2000 bar, more preferably 1200~1800 bar, even more preferably 1400~1600 bar, and most preferably 1500 bar; the number of high-pressure homogenizations is preferably 3~30 times; in this invention, the number of high-pressure homogenizations is selected according to the composition of the formula. When the content of the anti-crystallizer is 0, the number of high-pressure homogenizations is preferably 20~30 times, more preferably 22~28 times, even more preferably 24~26 times, and most preferably 25 times; when the content of the anti-crystallizer is not 0, the number of high-pressure homogenizations is preferably 3~20 times, more preferably 3~15 times, even more preferably 3~10 times, even more preferably 3~8 times, and most preferably 4~6 times.

[0090] The oil-in-water voriconazole suspension is spray-dried to obtain voriconazole inhalation powder. The inlet temperature of the spray drying is preferably 105℃~145℃, more preferably 110℃~140℃, even more preferably 115℃~135℃, even more preferably 115℃~130℃, even more preferably 115℃~125℃, and most preferably 120℃. The spray gas flow rate is preferably 1500~1800 L / h, more preferably 1550~1800 L / h, even more preferably 1600~1800 L / h, even more preferably 1650~1800 L / h, even more preferably 1700~1800 L / h, and most preferably 1750 L / h. The drying gas flow rate is preferably 20~35 m³ / h. 3 / h, more preferably 25-35m 3 / h, preferably 28-32m 3 / h, the optimal value is 30m 3 The preferred inlet rate for spray drying is 5–20 mL / min, more preferably 10–20 mL / min, even more preferably 12–18 mL / min, and most preferably 15 mL / min. The preferred outlet temperature for spray drying is 40℃–70℃, more preferably 45℃–70℃, even more preferably 50℃–70℃, even more preferably 55℃–70℃, and most preferably 60℃–65℃. Specifically, the purpose of using the above-mentioned emulsion followed by spray drying is to coat the surface of voriconazole with a layer of phospholipids. Through spray drying, after the oil phase evaporates, a honeycomb structure and wrinkles are formed on the surface of the drug particles, thereby increasing the specific surface area, improving the aerodynamic properties of the particles, and making them easier to deliver to the lungs, thus increasing the effective delivery dose.

[0091] The present invention also provides a pharmaceutical formulation comprising the above-mentioned voriconazole inhalation powder; preferably, it further comprises a capsule shell; wherein the capsule shell contains the voriconazole inhalation powder.

[0092] More specifically, the capsule shell is preferably a hydroxypropyl methylcellulose hollow capsule for inhalation preparations.

[0093] The voriconazole inhalation powder provided by this invention has the following advantages:

[0094] 1. Voriconazole is prone to aggregation and fusion in aqueous solution, which leads to particle agglomeration and growth during the powder preparation process. This is reflected in the larger particle size of the suspension and the larger particle size of the final inhaled powder. Therefore, it is necessary to increase the number of high-pressure homogenization cycles to reduce the absolute size of the suspension particles, or to select a suitable anti-crystallization agent to slow down the increase in particle size caused by particle aggregation in the suspension.

[0095] To inhibit the crystallization of voriconazole, we need to address two aspects: reducing the adsorption energy on the surface of voriconazole particles and slowing down the Brownian motion rate of voriconazole in solution.

[0096] To avoid being excluded from pharmaceutical use, this invention searched the FDA's IID database, identifying approximately 70 excipients used in approved inhalation formulations. Based on the aforementioned mechanisms of action that inhibit the aggregation or fusion of active ingredients in solution, the excipients were screened. Voriconazole was mixed with these excipients separately, and it was found that some failed to inhibit crystal formation, while others had only a weak effect. Ultimately, seven excipients were selected (polyethylene glycol 1000, carrageenan, magnesium stearate, glycerin, sorbitol 80, hydroxypropyl cellulose, or hydroxypropyl methylcellulose), and further experiments were conducted.

[0097] When investigating the particle size of voriconazole-in-water suspensions, with glycerol and sorbitol 80 as the crystal inhibitors, the intermediate particle sizes (D90) of the voriconazole-in-water suspensions were 8.3 μm and 7.6 μm, respectively, and the D50 were 4.4 μm and 4.5 μm, respectively. During stability testing, glycerol or sorbitol 80 showed stratification after 2 hours and 4 hours, respectively, indicating poor emulsion stability. Therefore, glycerol and sorbitol 80 cannot be used as crystal inhibitors for voriconazole.

[0098] Therefore, polyethylene glycol 1000, carrageenan, magnesium stearate, hydroxypropyl cellulose, or hydroxypropyl methylcellulose were ultimately selected as crystal inhibitors. The particle size D90 of the oil-in-water voriconazole suspension was 4.4–6.3 μm, and the D50 was 2.5–3.7 μm.

[0099] 2. In this invention, phosphatidylcholine-based substances are used as emulsifiers and divalent cationic chlorides are used as emulsion stabilizers. With or without the addition of crystal inhibitors, an oil-in-water voriconazole suspension is prepared by emulsion preparation method, and then spray-dried to obtain the contents of voriconazole inhalation powder that can be directly encapsulated.

[0100] The voriconazole inhalation powder provided by the above excipients and preparation process has a higher effective delivery dose to the lungs, with an effective delivery dose exceeding 53.8-68.4% (effective lung deposition rate), MMAD < 4 μm, and GSD < 2.

[0101] 3. The emulsification and spray drying preparation process of the present invention combines voriconazole with other raw materials into a whole through the formulation process. It can be used to directly fill capsules to make inhalation powder without mixing with other gliding agents such as lactose before filling capsules. This avoids the possibility of stratification between active and inactive ingredients during capsule filling and can effectively improve the stability of the formulation process.

[0102] To further illustrate the present invention, the following describes in detail, with reference to embodiments, a voriconazole inhalation powder and its preparation method.

[0103] All reagents used in the following examples are commercially available.

[0104] In the following examples and comparative examples, the formulation composition, material ratios, and test results of inhaled powder inhalers are described based on 20mg voriconazole.

[0105] It should be noted that emulsifying stabilizers may or may not contain water of crystallization.

[0106] All the raw materials listed below are commercially available products. Hydroxypropyl methylcellulose is selected from Ashland's F-series substituted type 2906 or E-series substituted type 2910 hydroxypropyl methylcellulose (labeled viscosity ≤50mPa.s), magnesium stearate is selected from Peter Greven's inhalation grade magnesium stearate (model MF-2-V), and hydroxypropyl cellulose is selected from Nippon Soda Co., Ltd.'s inhalation grade highly substituted hydroxypropyl cellulose (model SSL).

[0107] 1. Description of some instruments:

[0108] 1) Volumetric particle size analysis was performed using a NewPatek laser particle size analyzer.

[0109] 2) Morphological analysis was performed using a German Zeiss scanning electron microscope.

[0110] 3) Aerodynamic particle size distribution (APSD) was measured using a new generation pharmaceutical disc impactor (NGI) purchased from Beijing Huironghe Technology Co., Ltd.

[0111] 4) Spray dryer, model S300, purchased from BUCHI, Switzerland.

[0112] 5) The machine used for high-pressure homogenization can be a high-pressure homogenizer or a micro-jet homogenizer. This invention uses a high-pressure homogenizer, model AH-NANO, purchased from Antos Nanotechnology Co., Ltd.

[0113] 6) High-speed shearing machine, model HR-25D, purchased from Shanghai Huxi Industrial Co., Ltd.

[0114] 2. The unit of weight can be mg, g, or kg.

[0115] It should be noted that this embodiment is merely an example of spray drying operation. When the spray drying inlet flow rate is outside the range of this invention, any person skilled in pharmaceutical technology can easily prepare a voriconazole inhalation powder that meets the requirements based on the formulation described in this invention by adjusting other spray drying parameters (such as inlet temperature, spray gas flow rate, and drying gas flow rate). The above spray drying process parameters are only used to illustrate the range of process parameters in this embodiment and are not intended to limit the range of spray drying process parameters.

[0116] Example 1: Voriconazole inhalation powder

[0117] 1. Raw material composition: Voriconazole (particle size distribution D90 < 30 μm), distearate phosphatidylcholine (DSPC), anhydrous calcium chloride (CaCl2), deionized water, perfluorooctane (PFOB), see Table 1. (Weight units are mg, g, or kg)

[0118] Table 1: Composition and weight percentage of voriconazole inhalation powder formulation

[0119]

[0120] 2. Preparation method:

[0121] 1) Weigh each ingredient according to the proportions of prescription S1-1 to S1-4 and set aside;

[0122] 2) Dissolve anhydrous calcium chloride in deionized water, heat to 65°C, then add DSPC and shear at high speed for 10 minutes (shearing speed 10000 rpm) to disperse it evenly, maintaining the solution temperature at 55-75°C during the process;

[0123] 3) Add voriconazole to the mixture in step 2) and shear it at high speed for 5 minutes (shearing speed 10000 rpm) to disperse it evenly;

[0124] 4) Add PFOB dropwise to the mixture in step 3) and shear at high speed for 10 minutes (shearing speed 10000 rpm) to disperse it evenly.

[0125] 5) Homogenize the above suspension 25 times under a pressure of 1500 bar to prepare an oil-in-water voriconazole suspension.

[0126] 6) Spray dry the suspension at an inlet temperature of 120℃, a spray gas flow rate of 1650 L / h, and a drying gas flow rate of 25 m³ / h. 3 The influent flow rate is 15 mL / min, and the outlet temperature is maintained at 50–60°C during the process. The capsules are then filled to obtain the inhalation powder / inhalation capsule formulation.

[0127] Experimental Example 1: Investigation of the Hygroscopicity of Powder

[0128] The main function of calcium chloride in formulation is to release calcium ions during emulsion preparation and bind with DSPC. After spray drying, this reduces the hygroscopicity of DSPC, thereby making the resulting inhalation formulation more stable during storage. Therefore, the amount of calcium chloride used directly affects the hygroscopicity of the spray-dried powder.

[0129] 1. Samples: Prescription S1-1 to S1-4 samples.

[0130] 2. Detection method:

[0131] The samples were exposed to an environment of 25°C and 65% relative humidity for 24 hours and weighed for comparison.

[0132] 3. Test Results: It was found that when the proportion of calcium chloride in the formulation was between 1.5% and 2.5% (formulations S1-2 and S1-3), the sample weight gain due to moisture absorption was less than 5%; when the proportion of calcium chloride was less than 1.5% (formulation S1-1) or greater than 2.5% (formulation S1-4), the sample weight gain due to moisture absorption was greater than 5%. Therefore, the preferred proportion of calcium chloride in the formulation is 1.5% to 2.5%, and the weight ratio of DSPC to calcium chloride is 9 to 15:1.

[0133] Note: Subsequent embodiments and comparative examples of this invention are based on prescriptions S1-2, with adjustments made to the amount of calcium chloride and explanations of its effects.

[0134] Example 2: Voriconazole inhalation powder

[0135] 1. Raw material composition: Voriconazole (particle size distribution D90 < 30 μm), distearate phosphatidylcholine (DSPC), anhydrous calcium chloride (CaCl2), polyethylene glycol 1000, deionized water, perfluorooctane (PFOB), see Table 2. (Weight units are mg, g, or kg)

[0136] Table 2: Composition and weight percentage of voriconazole inhalation powder formulation

[0137]

[0138] 2. Preparation method:

[0139] 1) Weigh each ingredient according to the proportions and set aside;

[0140] 2) Dissolve anhydrous calcium chloride in deionized water, heat to 65°C, then add DSPC and shear at high speed for 10 minutes (shearing speed 10000 rpm) to disperse it evenly, maintaining the solution temperature at 55-75°C during the process;

[0141] 3) Add the crystal inhibitor and voriconazole to the mixture in step 2) and shear at high speed for 5 minutes (shearing speed 10000 rpm) to disperse it evenly.

[0142] 4) Add PFOB dropwise to the mixture in step 3) and shear at high speed for 10 minutes (shearing speed 10000 rpm) to disperse it evenly;

[0143] 5) The above suspension was homogenized four times under a pressure of 1500 bar to prepare an oil-in-water voriconazole suspension.

[0144] 6) Spray dry the suspension at an inlet temperature of 120℃, a spray gas flow rate of 1750 L / h, and a drying gas flow rate of 30 m³ / h. 3 The liquid inlet rate is 15 mL / min, and the outlet temperature is 60-65℃ during the process. After filling the capsule, the inhalation powder capsule is obtained.

[0145] Example 3: Voriconazole inhalation powder

[0146] 1. Raw material composition: Voriconazole (particle size distribution D90 < 30 μm), distearate phosphatidylcholine (DSPC), anhydrous calcium chloride (CaCl2), carrageenan, deionized water, perfluorooctane (PFOB), see Table 3. (Weight units are mg, g, or kg)

[0147] Table 3: Formulation composition and weight percentage of voriconazole inhalation powder

[0148]

[0149] 2. Preparation method: Same as in Example 2.

[0150] Example 4: Voriconazole inhalation powder

[0151] 1. Raw material composition: Voriconazole (particle size distribution D90 < 30 μm), distearate phosphatidylcholine (DSPC), anhydrous calcium chloride (CaCl2), glycerol, deionized water, perfluorooctane (PFOB), see Table 4. (Weight units are mg, g, or kg)

[0152] Table 4: Formulation composition and weight percentage of voriconazole inhalation powder

[0153]

[0154] 2. Preparation method: Same as in Example 2.

[0155] Example 5: Voriconazole inhalation powder

[0156] The FDA Inactive Ingredient Database discloses a safe single-dose dose of magnesium stearate for inhalation formulations of 0.13 mg. Therefore, the appropriate dosage of magnesium stearate for the inhalation powder of the present invention is discussed in each formulation of Example 5 within the above-mentioned safe value range.

[0157] 1. Raw material composition: Voriconazole (particle size distribution D90 < 30 μm), distearate phosphatidylcholine (DSPC), anhydrous calcium chloride (CaCl2), magnesium stearate, deionized water, perfluorooctane (PFOB). Detailed dosages of each component are shown in Tables 5-1 and 5-2. (Units: mg, g, or kg)

[0158] Table 5-1: Formulation composition and weight percentage of voriconazole inhalation powder

[0159]

[0160]

[0161] Table 5-2: Formulation composition and weight percentage of voriconazole inhalation powder

[0162]

[0163] 2. Preparation method: Same as in Example 2.

[0164] Example 6: Voriconazole inhalation powder

[0165] 1. Raw material composition: Voriconazole (particle size distribution D90 < 30 μm), distearate phosphatidylcholine (DSPC), anhydrous calcium chloride (CaCl2), hydroxypropyl cellulose, deionized water, perfluorooctane (PFOB), see Table 6. (Weight units are mg, g or kg) Table 6: Formulation composition and weight percentage of voriconazole inhalation powder

[0166]

[0167] 2. Preparation method: Same as in Example 2.

[0168] Example 7: Voriconazole inhalation powder

[0169] 1. Raw material composition: Voriconazole (particle size distribution D90 < 30 μm), distearate phosphatidylcholine (DSPC), anhydrous calcium chloride (CaCl2), hydroxypropyl methylcellulose, deionized water, perfluorooctane (PFOB), see Tables 7-1 and 7-2. (Weight units are mg, g, or kg)

[0170] Table 7-1: Formulation composition and weight percentage of voriconazole inhalation powder

[0171]

[0172] Table 7-2: Weight percentage of each component in the formulation of voriconazole inhalation powder

[0173]

[0174]

[0175] 2. Preparation method: Same as in Example 2.

[0176] 3. Phenomena during the preparation process:

[0177] During the spray drying process, it was found that the yield of the spray-dried powder decreased with increasing hydroxypropyl methylcellulose (HMC) content in the formulation. When the inhibitor content reached approximately 10% (Formula S7-5), the filter bag pressure differential of the spray drying equipment increased to -83 mbar. Furthermore, when the inhibitor content exceeded 11% (Formula S7-6), the filter bag pressure differential reached -92 mbar, exceeding the control range (which should be less than -90 mbar). At this point, the spray drying efficiency was uncontrolled, and the batch-to-batch quality variation of the spray-dried powder increased. Therefore, when using HMC as an inhibitor in the formulation, its content should not exceed 10%.

[0178] Example 8: Voriconazole inhalation powder

[0179] 1. Raw material composition: Voriconazole (particle size distribution D90 < 30 μm), distearate phosphatidylcholine (DSPC), anhydrous calcium chloride (CaCl2), sorbitol 80, deionized water, perfluorooctane (PFOB), see Table 8. (Weight units are mg, g or kg) Table 8: Formulation composition and weight percentage of voriconazole inhalation powder

[0180]

[0181] 2. Preparation method: Same as in Example 2.

[0182] Example 9: Voriconazole inhalation powder

[0183] The difference between this formulation and the one in Example 7 (S7-2) is that the emulsifying stabilizer in this formulation is anhydrous magnesium chloride (MgCl2).

[0184] 1. Raw material composition: Voriconazole (particle size distribution D90 < 30 μm), distearate phosphatidylcholine (DSPC), anhydrous magnesium chloride (MgCl2), hydroxypropyl methylcellulose, deionized water, perfluorooctane (PFOB), see Table 9. (Weight units are mg, g, or kg)

[0185] Table 9: Formulation composition and weight percentage of voriconazole inhalation powder in Example 9

[0186]

[0187] 2. Preparation method: Same as in Example 2.

[0188] Example 10: Voriconazole Inhalation Powder

[0189] The difference from Example 7 is that the order in which voriconazole and PFOB are added in the process of preparing voriconazole suspension is adjusted.

[0190] 1. Raw material composition: Same as prescription S7-2 in Example 7.

[0191] 2. Preparation method:

[0192] 1) Weigh each ingredient according to the proportions and set aside;

[0193] 2) Dissolve anhydrous calcium chloride in deionized water, heat to 65°C, then add DSPC and shear at high speed for 10 minutes (shearing speed 10000 rpm) to disperse it evenly, maintaining the solution temperature at 55-75°C during the process;

[0194] 3) Add hydroxypropyl methylcellulose and PFOB to the mixture in step 2) and shear at high speed for 5 minutes (shear speed 10000 rpm) to disperse it evenly;

[0195] 4) Add voriconazole to the mixture in step 3) and shear at high speed for 10 min (shearing speed 10000 rpm) to disperse it evenly.

[0196] 5) The above suspension was homogenized four times under a pressure of 1500 bar to prepare an oil-in-water voriconazole suspension.

[0197] 6) The suspension is spray-dried at an inlet temperature of 120℃, a spray gas flow rate of 1750 L / h, and a drying gas flow rate of 30 m³ / h. 3 The liquid inlet rate is 15 mL / min, and the outlet temperature is 60-65℃ during the process. After filling the capsule, the inhalation powder capsule is obtained.

[0198] Comparative Example 1:

[0199] The difference from Example 7 is that the emulsifier in the formulation is dipalmitoylphosphatidylcholine (DPPC).

[0200] 1. Raw material composition: Voriconazole (particle size distribution D90 < 30 μm), dipalmitoylphosphatidylcholine (DPPC), anhydrous calcium chloride (CaCl2), hydroxypropyl methylcellulose, deionized water, perfluorooctane (PFOB), see Table 10. (Weight units are mg, g, or kg)

[0201] Table 10: Formulation composition and weight percentage of Comparative Example 1

[0202]

[0203] 2. Preparation method: Same as in Example 2.

[0204] Comparative Example 2: Voriconazole Inhalation Powder

[0205] The difference between this formulation and the formulation S7-2 in Example 7 is that tert-butanol is used instead of the solvent PFOB in this formulation, to illustrate the effect of solvent adjustment on the formulation.

[0206] 1. Raw material composition: Composed of voriconazole (particle size distribution D90 < 30 μm), distearate phosphatidylcholine (DSPC), anhydrous calcium chloride (CaCl2), hydroxypropyl methylcellulose, deionized water, and tert-butanol, as shown in Table 11. (Weight units are mg, g, or kg)

[0207] Table 11: Formulation composition and weight percentage of Comparative Example 2

[0208]

[0209] 2. Preparation method:

[0210] 1) Weigh each ingredient according to the proportions and set aside;

[0211] 2) Dissolve anhydrous calcium chloride in deionized water, heat to 65°C, then add DSPC and shear at high speed for 10 minutes (shearing speed 10000 rpm) to disperse it evenly, maintaining the solution temperature at 55-75°C during the process;

[0212] 3) Add hydroxypropyl methylcellulose and voriconazole to the mixture in step 2) and shear at high speed for 5 minutes (shearing speed 10000 rpm) to disperse them evenly.

[0213] 4) Add tert-butanol dropwise to the mixture in step 3), and shear at high speed for 10 minutes (shear speed 10000 rpm) to disperse it evenly;

[0214] 5) The above suspension was homogenized four times under a pressure of 1500 bar to prepare an oil-in-water voriconazole suspension.

[0215] 6) The suspension is spray-dried at an inlet temperature of 105℃, a spray gas flow rate of 1700 L / h, and a drying gas flow rate of 25 m³ / h. 3 The liquid inlet rate is 15 mL / min, and the outlet temperature is 57-65℃ during the process. After filling the capsule, the inhalation powder capsule is obtained.

[0216] Experiment Example 2: Screening the number of homogenization cycles for formulations without crystal inhibitors

[0217] 1. Samples: The initial particle size of voriconazole in formulation S1-2 of Example 1 was adjusted. Water-in-oil suspensions were prepared using voriconazole raw materials with initial particle sizes of 25 μm, 15 μm, 10 μm, and 7 μm, respectively. The target value was the particle size (D90) of 4.8 μm of the suspension in Example 7 (S7-2). The number of high-pressure homogenization cycles required for different initial particle sizes of voriconazole and the aerodynamic performance of the inhaled powder prepared were investigated.

[0218] 2. Evaluation Indicators

[0219] 2.1 Homogenization times

[0220] During the suspension preparation process, the number of high-pressure homogenization cycles required to homogenize to the target particle size of the suspension is recorded in real time.

[0221] 2.2 Particle size detection of suspension

[0222] Laser diffraction (wet method): Take about 3 mL of sample into the injector, select water as the dispersed phase, set the refractive index to 1.489, stir at 2500 rpm, and measure for 10 s. Each batch of samples is measured in parallel 3 times, and the average particle size distribution is taken.

[0223] 3. Experimental Results

[0224] The number of high-pressure homogenization cycles and the particle size detection results of voriconazole with different initial particle sizes are shown in Table 12.

[0225] Table 12: Screening Results of Homogenization Times for Formulations Without Desiccant

[0226]

[0227] The results showed that the larger the initial particle size of voriconazole, the more high-pressure homogenization cycles were required to obtain the target particle size of the suspension. When the initial particle size of voriconazole was greater than 10 μm, the suspension particle size decreased by about 1 μm with each homogenization cycle until the suspension particle size decreased to about 10 μm. Afterward, the degree of particle size reduction decreased with increasing homogenization cycles. Conversely, the smaller the initial particle size of voriconazole, the fewer homogenization cycles were required to obtain the target suspension particle size.

[0228] The results show that, in the absence of a crystal inhibitor in the formulation, the same suspension particle size as that of a formulation containing a crystal inhibitor can be achieved by increasing the number of high-pressure homogenization cycles.

[0229] Experiment Example 3: Screening the Amount of Oil Phase

[0230] 1. Samples: When adjusting the oil phase in the formulation S7-2 of Example 7, the oil phase was adjusted to 2 times, 3 times, 14 times, and 15 times the amount of voriconazole in 4 samples and the formulation S7-2 of Example 7.

[0231] 2. Detection indicators

[0232] 2.1 Study on the suspension stability of the suspension

[0233] Take about 8 mL of each of the voriconazole suspension or solution prepared for the sample, place them in a vial, seal and cap the vial, shake thoroughly, and place it in a 40℃ oven. Observe and record the layering every 1 hour.

[0234] 2.2 Particle size distribution: Using a NewPatek laser particle size analyzer, the particle size distribution (dry method) determination program was followed, the dispersion pressure was set to 3 bar, and each batch of samples was measured in parallel 3 times. The average particle size distribution was then taken.

[0235] 2.3 Tap density: According to the Chinese Pharmacopoeia 2020 edition, Part IV, 0993, the tap density of each sample was determined by the first tap density method.

[0236] 2.4 Specific Surface Area (BET): Based on the specific surface area determination method in Section IV, 0991 of the 2020 edition of the Chinese Pharmacopoeia, approximately 0.1 g of sample was taken. A Micron ASAP 2020 specific surface area analyzer (USA) was used, with the analytical cell temperature set to -195℃ and the low-pressure dose at 5.0 cm³. 3 / g, adsorption medium is N2, equilibrium time is 30s, automatic degassing, and specific surface area of ​​each sample is measured.

[0237] 3. Experimental Results:

[0238] 3.1 Suspension stability: See Table 13-1.

[0239] Table 13-1: Screening Results of Suspension Stability Study Based on Oil Phase Content

[0240]

[0241] The results showed that when the oil phase was twice the amount of voriconazole, the resulting suspension separated into layers within 1 hour, and its suspension stability decreased. When the amount of oil phase was increased to three times the amount of voriconazole, the resulting suspension did not separate into layers within 4 hours.

[0242] The results show that the amount of PFOB also has a certain impact on the suspension stability of the suspension. When the amount of PFOB is less than 3 times that of voriconazole, the suspension stability of the suspension is poor.

[0243] 3.2 Tap density and test results of voriconazole spray-dried powder: See Table 13-2.

[0244] Table 13-2: Results of particle size, tap density, and specific surface area tests for voriconazole inhalation powder

[0245]

[0246] Table 13-2 Results Analysis:

[0247] 1) Particle size data: When adjusting the amount of PFOB (3 to 14 times the total amount of active ingredients) in the formulation within a suitable ratio range, it will not have a significant impact on the particle size of the spray-dried powder.

[0248] 2) Tap density: When the amount of oil phase reaches 15 times the amount of voriconazole, the tap density of the spray-dried powder is too low (below 0.2 g / mL), resulting in poor powder flowability and high static electricity, which is not conducive to capsule filling. However, when the amount of oil phase is 14 times the amount of voriconazole, the flowability of the spray-dried powder is acceptable, and the tap density is 0.21 g / mL, which basically meets the requirements for capsule filling. The amount of PFOB in the formulation is negatively correlated with the tap density of the prepared inhalation powder. However, when the amount of PFOB is 3 to 14 times the amount of voriconazole, the flowability of the spray-dried powder meets the requirements for capsule filling, and the tap density is 0.2 to 0.4 g / mL (meeting the requirements for powder aerosols).

[0249] 3) Specific surface area: The amount of PFOB in the formulation is positively correlated with the specific surface area of ​​the prepared inhaled powder. However, when the amount of PFOB reaches 15 times that of voriconazole, the honeycomb structure of the spray-dried powder increases, and the specific surface area increases to 93.4 m². 2 / g, at this point, the powder has a large static electricity and poor flowability, which is not conducive to capsule filling. Therefore, the amount of PFOB in the formula should not exceed 15 times the amount of voriconazole.

[0250] Therefore, in this invention, the amount of PFOB in the oil phase should not be more than 14 times the amount of voriconazole and not less than 3 times the amount of voriconazole.

[0251] Experiment Example 4: Screening the Amount of Aqueous Phase

[0252] 1. Samples: When adjusting the aqueous phase in the formulation S7-2 of Example 7, two samples were prepared by adjusting the aqueous phase to 20 times and 45 times the total amount of solids, respectively, as well as the formulation S7-2 of Example 7.

[0253] 2. The detection indicators are particle size distribution, tap density and specific surface area, and the specific methods are the same as in Experiment Example 2.

[0254] 3. Test results: See Table 14.

[0255] Table 14: Results of particle size distribution analysis of voriconazole inhalation powder

[0256]

[0257]

[0258] Results analysis:

[0259] 1) Particle size: When the amount of water in the formula is 20 to 45 times the total amount of solids, it will not have a significant effect on the particle size of the spray-dried powder.

[0260] 2) Tap density: When the amount of water in the formulation increases, the tap density of the spray-dried powder tends to increase. However, the flowability of the spray-dried powder was still good during the process, indicating that the change in the amount of water in the above range will cause changes in the tap density of the powder, but overall it can still meet the requirements of the formulation process.

[0261] Experiment Example 5: Suspension Detection

[0262] The voriconazole suspension was evaluated, and the evaluation indicators included particle size (D90 < 8 μm) and suspension stability (stable suspension time of not less than 4 hours under heat preservation).

[0263] 1. Samples: Voriconazole suspensions prepared in Comparative Examples 1, Examples 1-8 and Example 10 of this invention (samples taken before spray drying).

[0264] 2. Detection method:

[0265] 2.1 Laser diffraction method (wet method): Take about 3 mL of sample into the injector, select water as the dispersed phase, set the refractive index to 1.489, stir at 2500 rpm, and measure for 10 s. Each batch of samples is measured in parallel 3 times, and the average particle size distribution is taken.

[0266] 2.2 Study on the suspension stability of the suspension

[0267] Take about 8 mL of each sample, place them in a vial, seal and cap, shake thoroughly, and place in a 40℃ oven. Observe and record the layering every 1 hour.

[0268] 3. Test Results:

[0269] 3.1 Particle size detection results of suspension by laser diffraction: see Table 15.

[0270] Table 15: Results of particle size distribution analysis of voriconazole suspension

[0271]

[0272] Table 15 shows that the suspension particle size D90 of Comparative Example 1 is < 8 μm; under the same number of high-pressure homogenization cycles (Examples 1-8 or Example 10), the suspension particle sizes D90 of Examples 4 and 8 are 8.3 μm and 7.8 μm, respectively, and D50 is 4.4 μm and 4.5 μm, respectively. The particle sizes of the other examples are: D90 is 4.4-6.3 μm, and D50 is 2.5-3.7 μm; the suspension prepared without the use of a crystal inhibitor (Example 1) also meets the requirements.

[0273] Results presentation:

[0274] The particle size requirement for inhaled powder is D90 < 8 μm for active ingredients. The particle size of the suspension in Comparative Example 1 is D90 < 8 μm, indicating that under the same process parameters, changing the type of phosphatidylcholine in the formulation will not affect the particle size of the suspension.

[0275] Under the same number of high-pressure homogenization cycles (Examples 1-8, Example 10), the suspension particle size D90 of Example 4 is >8 μm, indicating that glycerol is not a preferred crystal inhibitor.

[0276] The suspension prepared without the use of a crystal inhibitor (Example 1) also met the particle size requirements. This was mainly because the suspension was homogenized under high pressure 25 times, significantly more times than in the example using the crystal inhibitor (4 times). This indicates that using a crystal inhibitor in the formulation can significantly reduce the number of homogenization times during suspension preparation, thereby reducing the possibility of introducing metal particles during homogenization, which is beneficial for improving formulation safety.

[0277] The suspension particle size data of Examples 5 (Formulas 5-1 to 5-4) and Examples 7 (Formulas 7-1 to 7-5) show that when the amount of crystal inhibitor in the formulation increases, the particle size D90 of the prepared suspension decreases.

[0278] 3.2 Results of the suspension stability test: see Table 16.

[0279] Table 16: Results of suspension stability study of voriconazole suspension

[0280]

[0281] Table 16 shows that: Examples 4 and 8 showed stratification after 2 hours and 4 hours, respectively, while Comparative Example 1 and other examples besides Examples 4 and 8 could be stably suspended within 4 hours under a heat preservation condition of 40°C.

[0282] Results analysis:

[0283] The suspension should remain stable for at least 4 hours under heat preservation conditions.

[0284] The suspension in Comparative Example 1 remained stable for 4 hours, indicating that changing the type of phosphatidylcholine in the formulation does not affect the suspension stability under the same process parameters.

[0285] The particle size distribution and stability data in Tables 14 and 15 show that when voriconazole cannot be dissolved in the selected solvent, the addition of a suitable anti-crystallization agent to the formulation can greatly reduce the number of high-pressure homogenization cycles of the suspension and shorten the process time for preparing the suspension when using a spray drying process for the preparation of the inhalation powder. In Examples 4 and 8, stratification occurred within 4 hours, proving that glycerol or sorbitol 80 is not a preferred anti-crystallization agent of this invention.

[0286] Data from Examples 2, 3, 5, 6, and 7 show that polyethylene glycol 1000, carrageenan, magnesium stearate, hydroxypropyl cellulose, and hydroxypropyl methylcellulose have superior crystallization inhibition effects. They can all maintain the voriconazole suspension in a stable suspension state within the time required by the process, ensuring the uniformity of the content of the spray-dried material and meeting the requirements of formulation production.

[0287] Data from Examples 7 (Formulas S7-1 to S7-5) and Example 10 show that, when the formulation remains unchanged, changing the order of material addition in the preparation of voriconazole suspension does not cause changes in the key properties of the suspension.

[0288] In summary, the voriconazole inhalation powder provided by this invention has a suspension particle size that meets the requirements for inhalation powder and exhibits good stability.

[0289] Experimental Example 6: Detection of Powder Properties for Inhalation Use

[0290] The powder characteristics of voriconazole inhalation powders obtained from different formulations or preparation processes were evaluated. The evaluation indicators included particle size distribution, density, and specific surface area.

[0291] 1. Samples: Voriconazole inhalation powder provided in Comparative Examples 1, 2, 1-3, 5-7, and 9-10.

[0292] 2. The detection indicators are particle size distribution, tap density and specific surface area, and the specific methods are the same as in Experiment Example 2.

[0293] 3. Test Results

[0294] 3.1 Results of particle size distribution determination of voriconazole inhalation powder: see Table 17.

[0295] Table 17: Results of particle size distribution analysis of voriconazole inhalation powder

[0296]

[0297] Table 17 shows that the particle size of Comparative Example 1 is 45.9 μm, D50 is 19.3 μm, and D10 is 2.2 μm; the particle sizes of other comparative examples and embodiments are: D90 is 4.6–6.6 μm, D50 is 2.6–3.8 μm, and D10 is 0.7–1.4 μm.

[0298] Results analysis:

[0299] The particle size data of Comparative Example 1 and Example 7 show that the particle size of the inhaled powder significantly increased after replacing DSPC with DPPC in the formulation. Analysis revealed that DPPC has a lower phase transition temperature (approximately 41°C), and partially melted DPPC causes the powder particles to adhere to each other, leading to a larger particle size. To ensure that the solvent in the formulation (especially organic solvents such as PFOB) is removed to an acceptable range (below 0.5%), the spray drying outlet temperature often needs to be higher than the DPPC phase transition temperature (the spray drying outlet temperature suitable for the formulation of this invention is 50–65°C). Therefore, the emulsifier of this invention is preferably distearylphosphatidylcholine (DSPC), which has a higher phase transition temperature (approximately 55°C).

[0300] The particle size data of the samples in Example 7 (Formulas S7-1 to S7-5) and Example 10 show that adjusting the order of material addition during the preparation of the suspension does not significantly affect the particle size of the inhaled powder.

[0301] 3.2 Results of tap density and specific surface area determination of voriconazole spray-dried powder: see Table 18.

[0302] Table 18: Results of tapped density test of voriconazole inhalation powder

[0303]

[0304]

[0305] Results analysis:

[0306] 1) Tap density: The tap density of the inhaled powder is related to the type of oil phase in the formulation (tert-butanol in Comparative Example 2, and PFOB in the other comparative examples and examples).

[0307] For the formulation of this invention, using an appropriate amount of PFOB as the oil phase is obviously better, as it can give the inhaled powder a smaller tap density, making the powder more fluffy. For inhaled powders with a smaller dosage, the unit mass has a larger volume, which is beneficial to improving the stability of the subsequent capsule filling process.

[0308] Density data from Examples 7 and 9 show that, regardless of whether the emulsifying stabilizer used in the formulation is calcium chloride (Example 7) or magnesium chloride (Example 10), there is no significant difference in the density of the spray-dried powder.

[0309] Density data from Examples 7 and 10 show that changing the order of material addition during the preparation of voriconazole suspension has no effect on the density of the resulting inhaled powder.

[0310] 2) Specific surface area: The specific surface area of ​​the inhaled powder is related to the type of oil phase in the formulation (tert-butanol in Comparative Example 2, and PFOB in the other examples). For the formulation of the present invention, it is obviously better to use an appropriate amount of PFOB as the oil phase, which can make the inhaled powder have a higher specific surface area, thereby giving the particles better aerodynamic properties and helping to improve the effective delivery rate of the powder to the lungs.

[0311] The results in Tables 17 and 18 show that the voriconazole inhalation powder prepared using the formulation of the present invention has the characteristics necessary for inhalation powders, such as smaller particle size, suitable tap density, and higher specific surface area. These excellent properties can effectively support the development of voriconazole into an inhalation powder with higher delivery efficiency.

[0312] Experimental Example 7: Microscopic Morphology Examination and Results of Voriconazole Inhalation Powder

[0313] The powder morphology of the samples provided in Comparative Example 1, Comparative Example 2 and Example 7 (Formula S7-2) of this invention was examined.

[0314] 1. Samples: Comparative Example 1, Comparative Example 2 and Example 7 (Formula S7-2).

[0315] 2. Detection method: Using a German Zeiss scanning electron microscope, an appropriate amount of sample was placed on the sample platform, sputtered with gold, and scanned at a voltage of 3KV under a field of view of 4-5mm to observe the morphological characteristics of the sample at different magnifications.

[0316] 3. Results Description and Analysis:

[0317] The sample in Comparative Example 1 appeared as multi-agglomerated spherical particles (see details). Figure 1 This indicates that under the same process conditions, using DPPC as an emulsifier in the formulation will lead to particle adhesion and affect the delivery effect of the formulation. DPPC is not a preferred emulsifier in this invention.

[0318] The sample in Comparative Example 2 appears as cuboid particles with a small amount of honeycomb structure on the surface (see details). Figure 2 This indicates that, under the same process conditions, using tert-butanol as a solvent in the formulation will lead to a reduction in the honeycomb structure on the surface of the inhaled powder, affecting the delivery effect of the formulation. Therefore, tert-butanol is not a preferred solvent (oil phase) in this invention.

[0319] The sample in Example 7 exhibited irregular, honeycomb-like particles with multiple folds (see details). Figure 3 These particles have a larger specific surface area and better aerodynamic structure, which is more conducive to the delivery of drug powder to the lungs under the action of airflow. Generally speaking, with the same particle size, the more wrinkles and honeycomb structures on the particle surface, the larger the specific surface area of ​​the particle, the lighter the particle weight, and the better the aerodynamic performance at the same airflow velocity.

[0320] The results show that the voriconazole powder prepared by the formulation process of the present invention meets the general requirements for the development of inhaled powder inhalers.

[0321] Experimental Example 8: Determination of Key Quality Attributes of Voriconazole Inhalation Powder

[0322] Based on the powder characteristics and morphology measurement results of the comparative examples and embodiments, in order to further illustrate the superiority of the formulation and process of the present invention for the preparation of voriconazole inhalation powder, key quality attributes of some samples of the comparative examples and embodiments were evaluated. The evaluation indicators included: moisture, related substances, fine particle dose (FPD), fine particle percentage (FPF), aerodynamic mass diameter (MMAD), geometric standard deviation (GSD), residual solvent, etc.

[0323] 1. Samples: Voriconazole inhalation powder provided in Comparative Example 1, Comparative Example 2, Examples 1-3, Examples 5-7, and Example 10.

[0324] 2. Detection Method

[0325] 2.1 Moisture content determination: Using the Fischer method, take approximately 100 mg of this product, weigh it accurately, and determine the moisture content according to the method for moisture determination (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0832, Method I).

[0326] 2.2 Detection of related substances:

[0327] Determined by high performance liquid chromatography (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0512).

[0328] 1) Reference Standard

[0329] Main component reference standard: voriconazole, purity 99.8%.

[0330] Impurity reference standards: Impurity A, content 99.2%; Impurity B, content 98.6%; Impurity C, content 97.2%.

[0331] 2) Preparation of sample solvent: 0.02 mol / L ammonium acetate buffer (pH adjusted to 4.0±0.3 with acetic acid)-methanol-acetonitrile (55:15:30) was selected as the solvent, which was also used as the blank solution.

[0332] 3) Preparation of test solution: Take an appropriate amount of the fine powder of this product, add the mobile phase to dissolve and dilute to prepare a solution containing about 1 mg of voriconazole per 1 mL.

[0333] 4) Preparation of system suitability solution: Take voriconazole and reference standards of impurities A, B, and C, dissolve and dilute them in the mobile phase to prepare a mixed solution containing approximately 0.5 mg of voriconazole and 0.5 μg each of impurities A, B, and C per 1 mL.

[0334] 5) Chromatographic conditions: An octadecylsilane-bonded silica column (C18, 4.6 mm × 250 mm, 5 μm or equivalent column) was used, with isocratic elution, a flow rate of 1.0 mL per minute, a detection wavelength of 256 nm, a column temperature of 35 °C, and an injection volume of 10 μL.

[0335] 2.3 Aerodynamic characteristics testing:

[0336] According to the method for determining the aerodynamic properties of fine particles in inhaled preparations (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0951), a new generation of disc-type multi-stage impactor (NGI) was used, and the air flow rate was 60 L / min.

[0337] 2.4 Solvent Residue Detection:

[0338] Determined by gas chromatography (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0521).

[0339] 1) Reference Standard

[0340] Main component reference standards: perfluorooctane, purity 99.5%; ethanol, purity 99.9%.

[0341] 2) Preparation of reference solutions 1 and 2:

[0342] Reference Standard 1: Weigh an appropriate amount of perfluorobromooctane and dilute it with methyl tert-butyl ether to prepare a solution containing approximately 0.025 mg of perfluorobromooctane per mL.

[0343] Reference standard 2: Weigh an appropriate amount of ethanol and dilute it with methyl tert-butyl ether to prepare a solution containing 0.025 mg of ethanol per 1 mL.

[0344] 3) Preparation of test solution: Weigh an appropriate amount of test sample, dilute with methyl tert-butyl ether to prepare a solution containing approximately 5 mg of test sample per 1 mL, filter and take the sample.

[0345] 4) Chromatographic conditions: An Agilent DB-1 (60m × 0.250mm, 1μm) column was used with an FID detector. The flow rate was set to 3 mL / min, the injection port temperature to 220℃, the detector temperature to 200℃, and the injection volume to 1 μL. Splitless direct injection was used. Temperature program: Initial temperature 35℃, hold for 7 min, then increase to 185℃ at a rate of 20℃ / min, hold for 4.5 min.

[0346] 3. Test Results:

[0347] 3.1 The NGI (Aerodynamic Performance Detection) measurement results of Comparative Examples 1 and 2, Examples 1-3, and Examples 5-7 are shown in [reference needed]. Figures 4-11 .

[0348] 3.2 Results of key quality attributes of voriconazole inhalation powder: see Tables 19 and 20.

[0349] Table 19: Results of Key Quality Attributes Determination for Voriconazole Inhalation Powder (Comparative Example)

[0350]

[0351]

[0352] Table 20: Results of Key Quality Attributes Determination for Voriconazole Inhalation Powder (Example)

[0353]

[0354] The results in Tables 19 and 20 show that the fine particle dose and fine particle percentage (effective lung delivery rate) of Comparative Examples 1 and 2 were low, with MMAD > 4 μm; the fine particle dose (FPD) and fine particle percentage (FPF) of Examples 1-3 and Examples 5-7 were 9.2-13.2 mg and 53.8-68.4%, respectively, with MMAD < 4 μm.

[0355] Results analysis:

[0356] For voriconazole inhalation powder, the percentage of fine particles (FPF) is positively correlated with the effective dose delivered to the lungs, and a median diameter at mass (MMAD) of 1–4 μm is generally required for effective delivery of inhalation powder to the lungs. While the aerodynamic properties of the formulation meet the requirements, the levels of moisture, content, and related substances often affect the stability and safety of the formulation.

[0357] The MMAD of Comparative Example 1 is greater than 5μm, which does not meet the general requirements for particle diameter in inhaled powders, indicating that DPPC, as an emulsifier used in this product with spray drying process, is not as effective as DSPC.

[0358] The effective lung delivery of Comparative Example 2 was lower than that of Examples 1-3 and Examples 5-7. This was due to its relatively small powder specific surface area, fewer honeycomb structures on the particle surface, and relatively poor aerodynamic performance, which further illustrates that PFOB is the preferred solvent of the present invention.

[0359] The data results show that the key quality attributes of the voriconazole inhalation powder produced by the formulation and process of this invention meet the requirements of inhaled formulations and show superiority in effective drug delivery. This indicates that the formulation and preparation process of this invention have good reproducibility and can effectively support the development of high-quality voriconazole inhalation powder.

[0360] In summary, the formulation process provided by this invention solves the problem of easy fusion or polymerization of active ingredients in the process of preparing voriconazole into an inhalation formulation. The prepared voriconazole inhalation powder has excellent aerodynamic properties and effective lung deposition rate, achieving the expected pharmaceutical effects.

[0361] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A voriconazole inhalation powder, characterized in that, include: The formula contains 60-80 parts by weight of voriconazole, 20.3-30 parts by weight of phospholipid emulsifier, 1.4-2.5 parts by weight of divalent cationic chloride, and 0-11 parts by weight of crystal inhibitor, without flow aid.

2. The voriconazole inhalation powder according to claim 1, characterized in that, The phospholipid emulsifier is selected from distearylphosphatidylcholine and / or dipalmitoylphosphatidylcholine; And / or, the divalent cationic chloride is selected from one or more of magnesium chloride, calcium chloride, zinc chloride and copper chloride; And / or, the crystallization inhibitor is selected from one or more of polyethylene glycol, carrageenan, magnesium stearate, glycerin, sorbitol ester, hydroxypropyl cellulose and hydroxypropyl methylcellulose.

3. The voriconazole inhalation powder according to claim 1, characterized in that, The voriconazole inhalation powder is obtained by spray drying of an oil-in-water voriconazole suspension.

4. The voriconazole inhalation powder according to claim 1, characterized in that, The mass of the aqueous phase in the oil-in-water voriconazole suspension is 20 to 45 times the total weight of all solids. The mass of the oil phase in the oil-in-water voriconazole suspension is 3 to 14 times the mass of voriconazole.

5. The voriconazole inhalation powder according to claim 4, characterized in that, The oil phase is selected from tert-butanol or perfluorooctane; And / or, the aqueous phase is deionized water and / or any type of water that meets the quality requirements of inhalation formulations.

6. The voriconazole inhalation powder according to claim 1, characterized in that, The particle size D90 of the oil-in-water voriconazole suspension is less than or equal to 8.5 μm; The particle size D50 of the oil-in-water voriconazole suspension is less than or equal to 4.5 μm; The particle size D10 of the oil-in-water voriconazole suspension is less than or equal to 2 μm.

7. The voriconazole inhalation powder according to claim 1, characterized in that, The particle size D90 of the voriconazole inhalation powder is less than or equal to 7 μm; The particle size D50 of the voriconazole inhalation powder is less than or equal to 4 μm; The particle size D10 of the voriconazole inhalation powder is less than or equal to 1.5 μm.

8. The voriconazole inhalation powder according to claim 1, characterized in that, The tapped density of the voriconazole inhalation powder is less than or equal to 0.4 g / mL; the BET specific surface area of ​​the voriconazole inhalation powder is greater than or equal to 50 m². 2 / g.

9. A method for preparing the voriconazole inhalation powder according to any one of claims 1 to 8, characterized in that, Includes the following steps: S1A) A divalent cationic chloride, a phospholipid emulsifier and an aqueous phase are mixed and subjected to a first high-speed shearing to obtain a first mixture; S2A) The mixture, the crystal inhibitor and voriconazole are mixed and subjected to a second high-speed shearing to obtain a second mixture; S3A) The second mixture is mixed with the oil phase, subjected to a third high-speed shearing, and then homogenized under high pressure to obtain an oil-in-water voriconazole suspension; S4A) The oil-in-water voriconazole suspension is spray-dried to obtain voriconazole inhalation powder; Or it may include the following steps: S1B) A divalent cationic chloride, a phospholipid emulsifier and an aqueous phase are mixed and subjected to a first high-speed shearing to obtain a first mixture; S2B) The mixture, the crystal inhibitor and the oil phase are mixed and subjected to a second high-speed shearing to obtain a second mixture; S3B) The second mixture is mixed with voriconazole, subjected to a third high-speed shearing, and then homogenized under high pressure to obtain an oil-in-water voriconazole suspension. S4B) The oil-in-water voriconazole suspension is spray-dried to obtain voriconazole inhalation powder.

10. The preparation method according to claim 9, characterized in that, The rotational speed of the first high-speed shearing in steps S1A) and S1B) is independently 8000-26000 rpm; the time of the first high-speed shearing in steps S1A) and S1B) is independently 5-15 min. The rotational speed of the second high-speed shearing in steps S2A) and S2B) is independently 8000-26000 rpm; the time of the second high-speed shearing in steps S2A) and S2B) is independently 3-8 min. The rotational speed of the third high-speed shear in steps S3A) and S3B) is independently 8000-26000 rpm; the time of the first high-speed shear in steps S3A) and S3B) is independently 5-15 min. The pressure of high-pressure homogenization in steps S3A) and S3B) is independently 1000-2000 bar; the number of times high-pressure homogenization is performed in steps S3A) and S3B) is independently 3-30 times. In steps S4A) and S4B), the inlet temperature for spray drying is independently 105℃~145℃; the spray gas flow rate is independently 1500~1800L / h; and the drying gas flow rate is independently 20~35m³ / h. 3 / h; the liquid inlet rate for each spray dryer is 5 to 20 mL / min; the outlet temperature for each spray dryer is 40℃ to 70℃.

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