An itraconazole inhalable dry powder and a preparation method and application thereof

Abstract

This invention belongs to the field of pharmaceutical powder formulations, and relates to an itraconazole inhalation dry powder, its preparation method, and its application. The preparation involves preparing itraconazole cocrystals via solvent evaporation, then forming a cocrystal nano-suspension through media milling. The nano-suspension is mixed with an excipient and then spray-dried to prepare the dry powder. The dry powder composition of this invention has spherical particles with an aerodynamic diameter of less than 4 μm. It exhibits an air displacement rate greater than 90%, a fine particle fraction greater than 40%, rapid dispersion after in vitro atomization, and good localization effect in the lungs in vivo.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical powder formulations, and relates to an itraconazole inhalation dry powder, its preparation method, and its application. Background Technology

[0002] Itraconazole, a broad-spectrum and highly effective antifungal drug, is widely used clinically to treat various fungal infections, especially as a first-line treatment for pulmonary aspergillosis, where its efficacy is significant. However, due to its extremely low water solubility, the bioavailability of itraconazole delivered directly is not ideal, which limits its therapeutic effect to some extent. Currently, itraconazole products available on the market are mainly oral and intravenous formulations. Although these two routes of administration are widely used, they both have significant drawbacks. Oral administration requires absorption through the gastrointestinal tract, and due to its poor water solubility, this greatly reduces the absorption efficiency and bioavailability. While intravenous injection ensures rapid entry of the drug into the bloodstream, the drug is distributed throughout the body, often requiring high doses to ensure effective drug concentrations in the lungs. This not only increases the financial burden on patients but may also lead to a series of safety issues, such as liver and kidney damage and drug interactions. Therefore, it is essential to explore new dosage forms and routes of administration to achieve efficient delivery of itraconazole. Summary of the Invention

[0003] The purpose of this invention is to provide an itraconazole inhalation dry powder, its preparation method, and its application.

[0004] To achieve the above objectives, the present invention adopts the following technical solution:

[0005] A method for preparing itraconazole inhalation dry powder involves preparing itraconazole eutectic by solvent evaporation, forming a eutectic nano-suspension by media grinding, and then mixing the nano-suspension with an excipient and preparing dry powder by spray drying.

[0006] The itraconazole cocrystal is obtained by solvent evaporation method, in which itraconazole and cocrystal forming agent are co-dissolved in a mixed solvent and then subjected to rotary evaporation.

[0007] The mixed solvent is chloroform and methanol in a volume ratio of 0.5 to 4:1 or chloroform and tetrahydrofuran in a volume ratio of 0.5 to 4:1; preferably chloroform and tetrahydrofuran in a volume ratio of 0.5 to 4:1.

[0008] The molar ratio of itraconazole to the eutectic agent is 0.5–4:1;

[0009] The total concentration of itraconazole and the eutectic forming agent in the mixed solution is 5% to 20% (v / v); the eutectic forming agent is one or more of oxalic acid, malonic acid, succinic acid, maleic acid, trans-butenedioic acid, and DL-tartaric acid.

[0010] The process of forming a eutectic nano-suspension from itraconazole eutectic through media milling involves dispersing the eutectic in a stabilizer solution to form a preliminary suspension, adding the preliminary suspension and milling beads to a milling jar, and then milling using a ball mill to obtain the itraconazole eutectic nano-suspension. The mass ratio of the stabilizer to the eutectic is (0.5–3):1, and the mass ratio of the milling beads to the eutectic is (40–120):1.

[0011] Furthermore, a stabilizer solution of a specified concentration is prepared, and the eutectic is dispersed in the stabilizer solution, then vortexed for 3 minutes to form a preliminary suspension. The preliminary suspension is added to a grinding jar, followed by grinding beads. The grinding jar is then placed in a ball mill and fixed for grinding. After grinding, the liquid in the grinding jar is aspirated using a syringe, filtered through a 500-mesh sieve to remove the grinding beads, thus obtaining the eutectic nano-suspension.

[0012] The stabilizer is one or more of Tween-80, sodium dodecyl sulfate, poloxamer 407, poloxamer 188, and vitamin E polyethylene glycol succinate.

[0013] The above-mentioned parameters for wet media grinding were examined. The grinding bead particle size ranged from 0.1 mm to 0.5 mm, preferably 0.1 mm. The grinding time ranged from 30 min to 240 min, preferably 120 min.

[0014] The ball mill speed was investigated, ranging from 200 rpm to 600 rpm. Preferably, the ball mill speed was 400 rpm.

[0015] The preparation of dry powder by spray drying after mixing the nano-suspension with the excipient involves centrifuging the nano-suspension, collecting the precipitate and redispersing it, mixing the redispersed eutectic nano-suspension with the excipient and then ultrasonically dispersing it, and finally spray drying the mixture to obtain dry powder; wherein the mass ratio of eutectic to excipient is 1:4 to 1:10.

[0016] Furthermore, the nano-suspension was centrifuged at 10,000 rpm for 8 minutes in a high-speed centrifuge, the supernatant was discarded, and the nano-suspension was redispersed with distilled water to obtain a nano-suspension free of stabilizer. The redispersed nano-suspension was then connected to a spray drying pipeline, and parameters such as spray drying temperature, drying gas flow rate, and pump speed were adjusted. The spray-dried sample was separated by the cyclone separator built into the spray dryer and collected in sample bottles.

[0017] The excipient is one or more of amino acids, sugars and their diffractions.

[0018] The sugar alcohol excipients are: lactose, trehalose, glucose, mannitol, β-cyclodextrin, and sucrose. The amino acid excipients are: glycine, threonine, leucine, and isoleucine. Preferably, mannitol is selected as the sugar alcohol carrier, and leucine is selected as the amino acid excipient.

[0019] The further preferred excipient is mannitol to leucine in a mass ratio of 1 to 10.

[0020] The spray drying conditions are as follows: inlet temperature: 100-130℃, drying gas flow rate: 0.6-0.8 m³ / h. 3 / min, atomization pressure 140-180kPa, liquid pump speed 4.0-8.0mL / min.

[0021] Nanoparticles can further improve drug solubility and dissolution rate. Furthermore, nanoparticles have a higher specific surface area, resulting in stronger mucosal adhesion and improved delivery efficiency. To avoid nanoparticle aggregation caused by spray drying, the particle size of the nanoparticles should be consistent before spray drying and after redispersement.

[0022] Nanoparticles can aggregate due to the gradual evaporation of water from droplets; therefore, sufficient carriers are needed to prevent aggregation. To evaluate the redispersibility of the spray-dried powder particles, it is necessary to control the ratio of drug to carrier (in this invention, the dry powder drug is a eutectic, and the carrier is an excipient). The drug-to-particle ratio of this invention is controlled (see the table below), and the nanoaggregate is defined as the redispersibility index (RDI). Its calculation formula is Eq.1.

[0023]

[0024] In formula Eq.1, R1 is the particle size of the nanoparticles after the dry powder composition is redispersed in water after spray drying, and R0 is the particle size of the nanoparticles in the nano suspension before spray drying.

[0025]

[0026] As can be seen from the table above, when the drug-to-carrier ratio is high, exceeding 1:1, the nanoparticles tend to aggregate during spray drying, resulting in increased particle size after reconstitution, i.e., increased RDI. As the carrier ratio continues to increase, the redispersibility of the nanoaggregates gradually improves. Therefore, a eutectic-to-excipient mass ratio of 1:4 is sufficient. As shown in the table, this ratio consistently exhibits satisfactory redispersibility, with an RDI value below 1.1. Thus, the drug-to-carrier mass ratio should be less than 1:4, and to ensure sufficient drug content, it should be higher than 1:10.

[0027] An itraconazole inhalation dry powder prepared by the method described above has a rough surface and a spherical structure with a particle size of D. 50 2-3 μm itraconazole inhalation dry powder particles.

[0028] An application of the itraconazole inhalation dry powder, specifically its use in the preparation of oral inhalation pulmonary medications.

[0029] The application of the itraconazole inhalation dry powder in the preparation of an oral inhalation antifungal drug for lung use.

[0030] Advantages of this invention:

[0031] In this invention, the dispersed itraconazole nano-cocrystal suspension is spray-dried to prepare low-density, highly fluid aggregate particles. During inhalation, due to shear force, the aggregates can be dispersed into fragments, resulting in superior inhalability and higher deep-lung delivery efficiency. The dry powder form improves the storage stability of itraconazole nanocrystals, reduces storage and transportation costs, and provides better compliance, dose uniformity, and portability when administered as an inhaled powder. Furthermore, the aggregate fragments rapidly disintegrate in lung mucus, releasing the encapsulated nanoparticles, which have a long-lasting release capacity, potentially further improving pulmonary bioavailability. Therefore, the itraconazole nano-cocrystal composition dry powder particles of this invention have significant application potential and advantages as a highly efficient pulmonary delivery agent. Attached Figure Description

[0032] Figure 1 X-ray diffraction pattern of itraconazole cocrystal provided in an embodiment of the present invention.

[0033] Figure 2 Transmission electron microscope image of itraconazole cocrystal nanoparticles provided in an embodiment of the present invention.

[0034] Figure 3 The image shows a scanning electron microscope (SEM) image of the dry powder composition particles provided in an embodiment of the present invention.

[0035] Figure 4A schematic diagram of a two-stage impactor provided in an embodiment of the present invention.

[0036] Figure 5 This is a curve showing the drug concentration in rat plasma at various time points after drug administration in a pharmacokinetic experiment.

[0037] Figure 6 This is a curve showing the drug concentration in rat lung tissue at various time points after drug administration in a pharmacokinetic experiment. Detailed Implementation

[0038] The following examples are used to illustrate the present invention, but are not intended to limit the scope of the invention.

[0039] Where specific techniques or conditions are not specified in the examples, they shall be performed in accordance with the techniques or conditions described in the literature in this field, or in accordance with the product instructions. Reagents or instruments whose manufacturers are not specified are all conventional products that can be purchased through legitimate channels.

[0040] This invention provides an orally inhaled itraconazole dry powder comprising itraconazole, a co-crystal forming agent, and an excipient. A co-crystal formed by itraconazole and a dicarboxylic acid-based co-crystal forming agent is obtained through solvent evaporation; a stable co-crystal nano-suspension is obtained using a media milling method; and the itraconazole dry powder composition is manufactured using a spray drying device. The dry powder composition has spherical particles with an aerodynamic diameter of less than 4 μm. It exhibits an air displacement rate greater than 90%, a fine particle fraction greater than 40%, rapid dispersion after in vitro nebulization, and good localization effect in the lungs.

[0041] Example 1

[0042] Preparation of itraconazole eutectic:

[0043] Chloroform and tetrahydrofuran were mixed in a 2:1 (v / v) ratio to obtain a mixed solvent. 1410 mg of itraconazole and 118 mg of succinic acid were accurately weighed and dissolved in 10 ml of this mixed solvent. The solution was then sonicated in a water bath for 3 min. Subsequently, the mixed solution was evaporated using a rotary evaporator to promote crystallization. After complete evaporation of the solvent, the precipitated crystals were dried in a vacuum environment at 30°C for 12 h to ensure complete removal of the organic solvent, ultimately yielding the eutectic (see [link to original text]). Figure 1 ).

[0044] Depend on Figure 1The X-ray diffraction (XRD) pattern of the itraconazole cocrystal revealed significant new characteristics compared to the physical mixture and individual raw material monomers. Specifically, the green solid line represents the XRD pattern of the physical mixture, the blue solid line represents the XRD pattern of succinic acid, the red solid line represents the XRD pattern of itraconazole, and the black solid line represents the XRD pattern of the itraconazole-succinic acid cocrystal. Compared to the raw material monomers and the physical mixture, the cocrystal sample showed new diffraction peaks at 10.075° and 29.25°. Furthermore, the characteristic peaks of itraconazole at 14.475° and 23.5° completely disappeared in the cocrystal sample, as did the characteristic peaks of succinic acid at 38.125°, 39.3°, 46.25°, and 46.8°. This indicates that a deep structural reorganization occurred between the raw material drug and the ligand drug during the cocrystal formation process, resulting in a new crystal structure rather than a simple physical mixture.

[0045] Example 2

[0046] The preparation process of itraconazole nano-cocrystal suspension is as follows:

[0047] Prepare 20 mL of a 2% (w / v) Tween-80 solution as a stabilizer solution. Disperse 800 mg of the eutectic from Example 1 in the stabilizer solution and vortex for 3 min to form a preliminary suspension. Add the prescribed amount of the preliminary suspension to a 50 mL grinding jar. Weigh 6.4 g of zirconia beads and add them to the grinding jar. Place the grinding jar in a ball mill and fix it in place for grinding. After grinding, use a syringe to aspirate the liquid from the grinding jar, filter it through a 500-mesh sieve to remove the grinding beads, and obtain the eutectic nano-suspension (see [link to product description]). Figure 2 ).

[0048] Depend on Figure 2 The transmission electron microscope (TEM) image of the nanoparticles shows that the nanoparticles are spherical with a diameter of approximately 200 nm.

[0049] Example 3

[0050] Preparation of oral itraconazole dry powder composition microparticles

[0051] Take the itraconazole nano-cocrystal suspension from Example 2, disperse it together with mannitol and leucine in an appropriate amount of water, and sonicate to dissolve the mannitol and leucine to prepare a spray-drying precursor solution.

[0052] The precursor liquid obtained after configuration has the following composition:

[0053] Itraconazole cocrystal: mannitol: leucine = 1:3:1

[0054] The content of itraconazole eutectic particles in the precursor solution is 2% (w / v).

[0055] The spray drying supply pump was connected to the precursor solution. The pump flow rate was 4 mL / min, the inlet temperature was 115℃, the drying gas flow rate was 0.8 m³ / min, and the atomization pressure was 180 kPa. The prepared dry powder was collected through a sample collection bottle (see...). Figure 3 ).

[0056] Depend on Figure 3 Scanning electron microscopy images of the itraconazole dry powder composition show that the particle size is approximately 3 μm. The particles are regularly spherical with slightly wrinkled surfaces.

[0057] The particles obtained in Example 3 were then tested.

[0058] Aerodynamic particle size

[0059] The particle size and distribution of ITZ-DPI were determined using a HELOS & OASIS fully automated wet and dry laser particle size analyzer (Synpatek GmbH, Germany) via the dry method. The test conditions were: R1 lens, dispersion pressure of 3.5 bar, feed rate of 50%, and testing began when the optical concentration reached 1%, with a test duration of 5 seconds. The measured result D[4,3] represents the volume mean diameter (D). v ).

[0060] To evaluate the dynamic behavior of particles in the atomized state, the volume equivalent diameter should be converted to the aerodynamic particle size. The conversion formula is as follows:

[0061]

[0062] Where ρ1 is the effective particle density, and ρ1 is the unit density, i.e., 1 g / cm³. 3 D v ρ is the volume average diameter of the particle, and X is the morphology factor, used to characterize the shape of the particle. When the particle is spherical, its morphology factor is 1. The spray-dried sample particles involved in this study are all close to spherical, so the value of X can be set to 1, and the value of ρ is approximately equal to the tap density ρ of the powder. tap .

[0063] Compression

[0064] Compressibility (CI) is an important indicator for evaluating powder flowability. It reflects the percentage relationship between the volume change of a powder in a free-filled and compressed state and its free-filled volume. Generally, a CI exceeding 25% indicates poor powder flowability, while a CI below 15% indicates good flowability. This study measured the tap density and CI of aspirated dry powder samples using a tap density meter. The specific operating method is as follows:

[0065] A sample of mass m is filled into a 5 mL graduated cylinder, and the initial volume V is recorded. 初 Secure the graduated cylinder containing the sample to the base and tighten it. Adjust the amplitude of the tapped density meter to 3 mm, vibrate 300 times per minute, and set the vibration count to 3000 times (approximately 10 minutes). Start the tapped density meter. When vibration stops, remove the graduated cylinder. If the powder surface is level, the powder volume value can be read directly; if the powder surface is not level after tapping, use the average of the highest and lowest readings of the powder surface after tapping to determine the final powder volume V. 终 Calculate the bulk density (ρ) using the following formula. b Tap density (ρ) tap ) and compression.

[0066] ρ b =m / V 初 #(3-1)

[0067] ρ tap =m / # #(3-2)

[0068] CI=(ρ tap -ρ b ) / ρ tap #(3-3)

[0069] fine particle fraction

[0070] According to the relevant guidelines in the Chinese Pharmacopoeia (2020), the assembled dual-stage impactor ( Figure 4 Fine particle fraction (FPF) was determined.

[0071] Two-stage impactor such as Figure 4 As can be seen, the method for determining the fine particle fraction using conventional experimental container assembly (or conventional impactor) is as follows:

[0072] like Figure 4The apparatus uses methanol as receiving solutions, with 7 mL in primary distribution bottle D and 30 mL in secondary distribution bottle H. The dry powder sample is loaded into a No. 3 HPMC capsule, placed inside the inhaler, and the capsule ends are punctured by pressing the buttons on both sides of the inhaler. The vacuum pump is turned on, and the airflow is adjusted to 60 ± 5 L / min. The inhalation device is then horizontally and tightly connected to inlet A via a suitable rubber connector. After 10 seconds of ventilation, the vacuum pump is turned off. The F connector, as well as the inner and outer walls of the tubing and nozzle of the lower conical flask, are cleaned with blank receiving solution. The washing solution is combined with the receiving solution in secondary distribution bottle H, transferred to a 50 mL volumetric flask, and brought to volume. The concentration is then measured; this is the fine particle dose (FPD). The ratio of FPD to the total amount of sample tested is the fine particle fraction.

[0073] The yield, aerodynamic particle size, compressibility, and fine particle fraction of the collected dry powder were measured, and the results are as follows:

[0074]

[0075] Example 7

[0076] Take the itraconazole nano-cocrystal suspension from Example 2, disperse it together with mannitol and leucine in an appropriate amount of water, and sonicate to dissolve the mannitol and leucine to prepare a spray-drying precursor solution.

[0077] The precursor liquid obtained after configuration has the following composition:

[0078] Itraconazole cocrystal: mannitol: leucine = 1:5:1

[0079] The content of itraconazole eutectic particles in the precursor solution is 2% (w / v).

[0080] Connect the spray drying supply pump to the precursor liquid. The supply pump flow rate is 4 mL / min, the inlet temperature is 115℃, and the drying gas flow rate is 0.8 m³ / min. 3 The atomization rate was 1 / min, and the atomization pressure was 180 kPa. The prepared dry powder was collected through a sample collection bottle.

[0081] The spray drying supply pump was connected to the precursor liquid. The pump flow rate was 4 mL / min, the inlet temperature was 115℃, the drying gas flow rate was 0.8 m³ / min, and the atomization pressure was 180 kPa. The prepared dry powder was collected through a sample collection bottle.

[0082] The yield, aerodynamic particle size, compressibility, and fine particle fraction of the collected dry powder were measured according to the relevant measurement methods in Example 3, and the results are as follows.

[0083]

[0084] Example 8

[0085] Take the itraconazole nano-cocrystal suspension from Example 2, disperse it together with mannitol and leucine in an appropriate amount of water, and sonicate to dissolve the mannitol and leucine to prepare a spray-drying precursor solution.

[0086] The precursor liquid obtained after configuration has the following composition:

[0087] Itraconazole cocrystal: mannitol: leucine = 1:3:1

[0088] The content of itraconazole eutectic particles in the precursor solution is 10% (w / v).

[0089] Connect the spray drying supply pump to the precursor liquid. The supply pump flow rate is 4 mL / min, the inlet temperature is 115℃, and the drying gas flow rate is 0.8 m³ / min. 3 The atomization rate was 1 / min, and the atomization pressure was 180 kPa. The prepared dry powder was collected through a sample collection bottle.

[0090] The yield, aerodynamic particle size, compressibility, and fine particle fraction of the collected dry powder were measured according to the relevant measurement methods in Example 3, and the results are as follows.

[0091]

[0092] Example 9

[0093] Take the itraconazole nano-cocrystal suspension from Example 2, disperse it together with mannitol and leucine in an appropriate amount of water, and sonicate to dissolve the mannitol and leucine to prepare a spray-drying precursor solution.

[0094] The precursor liquid obtained after configuration has the following composition:

[0095] Itraconazole cocrystal: mannitol: leucine = 1:3:1

[0096] The content of itraconazole eutectic particles in the precursor solution is 5% (w / v).

[0097] Connect the spray drying supply pump to the precursor liquid. The supply pump flow rate is 4 mL / min, the inlet temperature is 115℃, and the drying gas flow rate is 0.8 m³ / min. 3 The atomization rate was 1 / min, and the atomization pressure was 180 kPa. The prepared dry powder was collected through a sample collection bottle.

[0098] The yield, aerodynamic particle size, compressibility, and fine particle fraction of the collected dry powder were measured according to the relevant measurement methods in Example 3, and the results are as follows.

[0099]

[0100] Example 10

[0101] Take the itraconazole nano-cocrystal suspension from Example 2, disperse it together with mannitol and leucine in an appropriate amount of water, and sonicate to dissolve the mannitol and leucine to prepare a spray-drying precursor solution.

[0102] The precursor liquid obtained after configuration has the following composition:

[0103] Itraconazole cocrystal: mannitol: leucine = 1:3:1

[0104] The content of itraconazole eutectic particles in the precursor solution is 2% (w / v).

[0105] Connect the spray drying supply pump to the precursor liquid. The supply pump flow rate is 4 mL / min, the inlet temperature is 100℃, and the drying gas flow rate is 0.4 m³ / min. 3 The atomization rate was 1 / min, and the atomization pressure was 140 kPa. The prepared dry powder was collected through a sample collection bottle.

[0106] The yield, aerodynamic particle size, compressibility, and fine particle fraction of the collected dry powder were measured according to the relevant measurement methods in Example 3, and the results are as follows.

[0107]

[0108] Example 11

[0109] Take the itraconazole nano-cocrystal suspension from Example 2, disperse it together with mannitol and leucine in an appropriate amount of water, and sonicate to dissolve the mannitol and leucine to prepare a spray-drying precursor solution.

[0110] The precursor liquid obtained after configuration has the following composition:

[0111] Itraconazole cocrystal: mannitol: leucine = 1:3:1

[0112] The content of itraconazole eutectic particles in the precursor solution is 2% (w / v).

[0113] Connect the spray drying supply pump to the precursor solution. The supply pump flow rate is 6 mL / min.

[0114] Inlet temperature: 130℃, dry gas flow rate: 0.4m³ / h 3 The atomization rate was 1 / min, and the atomization pressure was 180 kPa. The prepared dry powder was collected through a sample collection bottle.

[0115] The yield, aerodynamic particle size, compressibility, and fine particle fraction of the collected dry powder were measured according to the relevant measurement methods in Example 3, and the results are as follows.

[0116]

[0117] The performance of the dry powder inhaler ITZ-DPI obtained in Example 3 above was compared with that of the marketed oral formulation:

[0118] Forty-eight SD rats were randomly divided into two groups of 24 each and labeled. The first group received the ITZ-DPI (Example 3) via inhalation at a dose of 22.5 mg / kg, while the second group received the marketed formulation orally. The administration time was recorded. Rats were euthanized by cervical dislocation at 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, and 12 h after administration. Blood samples were collected by cardiac puncture, and whole lung samples were collected for analysis using HPLC.

[0119] Rats in each group were given both a self-made dry powder inhaler, ITZ-DPI, and an orally administered commercially available formulation. Subsequently, the distribution of the drug in the plasma and lungs was as follows: Figure 4 and Figure 5 As shown in the table below, the pharmacokinetic parameters of ITZ-DPI in rat plasma and lungs are as follows.

[0120]

[0121] according to Figure 4 As shown, 15 minutes after inhalation, the plasma drug concentration rapidly reached 111±7 ng / mL. After 30 minutes, the drug concentration reached a peak of 214±54 ng / mL, indicating rapid initial absorption. However, the drug concentration gradually decreased over time, dropping to 110 ng / mL at 12 hours. In contrast, the peak time for ITZ concentration in rat plasma after oral administration was 2 hours, later than the pulmonary inhalation group. However, the plasma drug concentration C in the oral group... max The concentration was 366±115 ng / mL, higher than that of the inhaled group. Meanwhile, the AUC of the oral group was... 0-12h The value was 2564 ng / mL·h, which was also higher than the 1536 ng / mL·h in the pulmonary administration group. This indicates that, within 12 hours after administration, the total amount of ITZ-DPI entering the bloodstream via pulmonary inhalation is less compared to oral administration.

[0122] Observation diagram Figure 5 There was a significant difference in drug distribution between lung tissue and blood. Fifteen minutes after direct pulmonary administration, the inhalation group reached a peak drug concentration of 39834±3639 ng / g in the lungs, followed by a gradual decrease. Even 12 hours after administration, the drug concentration in the lungs remained at a high level of 3008±358 ng / g. Meanwhile, the AUC of the inhalation group... 0-12hIt also reached a significant level of 92,730 ng / g·h. In contrast, the concentration change trend of the oral drug in the lungs was consistent with that in the plasma, reaching a peak of 662±128 ng / g 2 hours after administration, and then showing a steady and slow decreasing trend in the lungs over the following 2-12 hours.

[0123]

[0124] The table above lists the concentration ratios of the drug in lung tissue to plasma at various time points after administration, thus assessing the formulation's localization effect in the lungs. Specifically, 15 minutes after inhalation, the concentration ratio of ITZ in lung tissue to plasma reached as high as 360.33. This ratio gradually declined as plasma concentration increased, reaching 27.34 at 12 hours. Nevertheless, this ratio was still significantly higher than the maximum value (3.06) in the oral administration group. Therefore, ITZ-DPI delivered via the lungs can effectively target and maintain long-term drug exposure in the lungs, which is highly beneficial for treating localized lung diseases. Simultaneously, its lower distribution in the bloodstream may also reduce adverse reactions caused by systemic drug distribution to some extent.

Claims

1. A process for the preparation of an inhaled dry powder of itraconazole, characterized in that: The itraconazole co-crystal is prepared by solvent evaporation method, the itraconazole co-crystal is further formed into co-crystal nanosuspension by medium grinding method, the co-crystal nanosuspension is mixed with excipient and then spray dried to prepare dry powder, wherein the mass ratio of co-crystal to excipient is 1:4-1:

10. The solvent evaporation method is that itraconazole and co-crystal forming agent are co-dissolved and mixed in a solvent, and itraconazole co-crystal is obtained by rotary evaporation treatment. The mixed solvent is chloroform and methanol with a volume ratio of 0.5-4:1 or chloroform and tetrahydrofuran with a volume ratio of 0.5-4:

1. The molar ratio of itraconazole to co-crystal forming agent is 0.5-4:

1. The co-crystal forming agent is succinic acid.

2. The method of claim 1, wherein the dry powder for inhalation of itraconazole is prepared by: The total volume concentration of itraconazole and co-crystal forming agent in the mixed solution is 5%-20%.

3. The method of claim 1, wherein the dry powder for inhalation of itraconazole is prepared by: The itraconazole co-crystal is further formed into co-crystal nanosuspension by medium grinding method, which is that the co-crystal is dispersed in a stabilizer solution to form a primary suspension, the primary suspension and grinding beads are added into a grinding tank, and the ball mill is used for grinding to obtain itraconazole co-crystal nanosuspension; the mass ratio of stabilizer to co-crystal is (0.5-3):1, and the mass ratio of grinding beads to co-crystal is (40-120):

1.

4. The method of claim 3, wherein the dry powder for inhalation of itraconazole is prepared by: The stabilizer is Tween-80.

5. The method of claim 1, wherein the dry powder for inhalation of itraconazole is prepared by: The nanosuspension is centrifuged, the precipitate is collected and then dispersed, the dispersed co-crystal nanosuspension is mixed with excipient and then ultrasonically dispersed, and the mixed dispersion is spray dried to obtain dry powder.

6. The method of claim 5, wherein the dry powder for inhalation of itraconazole is prepared by: The excipient is one or more of amino acids and saccharides.

7. An inhaled dry powder of itraconazole prepared by the method of claim 1, wherein the powder has a particle size distribution of about 0.5 to about 10 microns. The surface-roughened spherical structures prepared according to the scheme of claim 1 have a particle size D 50 2-3 μm of itraconazole for inhalation in the form of dry powder particles.

8. Use of the dry powder inhalation of itraconazole according to claim 7, characterized in that: The itraconazole inhalable dry powder is used for preparing oral inhalation lung drugs.

9. Use of an inhaled dry powder of itraconazole according to claim 8, characterized in that: The itraconazole inhalable dry powder is used for preparing oral inhalation lung antifungal drugs.

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