Itraconazole inhalation type dry powder as well as preparation method and application thereof

Abstract

The invention belongs to the field of medicine powder preparations, and relates to itraconazole inhalation type dry powder as well as a preparation method and application thereof. The preparation method comprises the following steps: preparing an itraconazole eutectic through a solvent evaporation method, forming an eutectic nano suspension from the itraconazole eutectic through a medium grinding method, mixing the nano suspension with an excipient, and preparing dry powder through spray drying. The particles of the dry powder composition are spherical, and the aerodynamic diameter is smaller than 4 microns. The emptying rate is greater than 90%, the fraction of fine particles is greater than 40%, and the aerosol can be quickly dispersed after in-vitro atomization and has a good in-vivo lung positioning effect.

Description

Technical Field

[0001] The invention belongs to the field of drug powder preparations and relates to itraconazole inhalation dry powder and a preparation method and application thereof. Background Art

[0002] As a broad-spectrum and highly effective antifungal drug, itraconazole is widely used in the clinic to treat a variety of fungal infections, especially as a first-line treatment for pulmonary aspergillosis, with significant efficacy. However, due to the extremely low water solubility of itraconazole, the bioavailability of direct delivery is not ideal, which to a certain extent limits its therapeutic effect. The itraconazole products currently available on the market are mainly oral and intravenous preparations. Although these two modes of administration are widely used, they both have obvious disadvantages. Oral drugs need to be absorbed through the gastrointestinal tract, which greatly reduces the absorption efficiency and bioavailability of the drug due to the poor water solubility of ITZ. Although intravenous injection can ensure that the drug quickly enters the blood circulation, due to the distribution of the drug throughout the body, in order to ensure that the lungs reach an effective drug concentration, high doses of the drug are often required. This not only increases the economic burden on patients, but may also bring a series of safety issues, such as liver and kidney damage, drug interactions, etc. Therefore, it is very necessary to explore new dosage forms and routes of administration to achieve efficient delivery of itraconazole. Summary of the invention

[0003] The present invention aims to provide an itraconazole inhalation dry powder and a preparation method and application thereof.

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

[0005] A method for preparing itraconazole inhalation dry powder comprises preparing itraconazole cocrystals by a solvent volatilization method, subjecting the itraconazole cocrystals to a medium grinding method to form a cocrystal nanosuspension, mixing the nanosuspension with an excipient, and then spray drying to prepare dry powder.

[0006] The itraconazole co-crystal is prepared by dissolving itraconazole and a co-crystal former in a mixed solvent by a solvent volatilization method, and then performing a rotary evaporation treatment to obtain the itraconazole co-crystal.

[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 cocrystal former is 0.5 to 4:1;

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

[0010] The method of forming a eutectic nanosuspension by medium grinding the itraconazole eutectic is to disperse the eutectic in a stabilizer solution to form a primary suspension, add the primary suspension and grinding beads into a grinding tank, and grind them using a ball mill to obtain the itraconazole eutectic nanosuspension; the mass ratio of the stabilizer to the eutectic is (0.5-3):1, and the mass ratio of the grinding beads to the eutectic is (40-120):1.

[0011] Further, a stabilizer solution of a specified concentration is prepared, the eutectic is dispersed in the stabilizer solution, and vortexed for 3 minutes to form a primary suspension. The primary suspension is added to a grinding jar, and then grinding beads are added, and the grinding jar is placed in a ball mill and fixed for grinding. After grinding, the liquid in the grinding jar is sucked out with a syringe, filtered through a 500-mesh screen, and the grinding beads are removed to obtain a eutectic nanosuspension.

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

[0013] The above-mentioned parameters related to wet medium grinding are investigated, and the grinding bead particle size ranges from 0.1 mm to 0.5 mm, preferably, the grinding bead particle size is 0.1 mm. The grinding time ranges from 30 min to 240 min. Preferably, the grinding time is 120 min.

[0014] The rotation speed of the ball mill is investigated, and the rotation speed range is 200 rpm to 600 rpm. Preferably, the rotation speed of the ball mill is 400 rpm.

[0015] The method of preparing dry powder by spray drying after mixing the nanosuspension with the excipient comprises centrifuging the nanosuspension, collecting the precipitate and redispersing it, mixing the redispersed eutectic nanosuspension with the excipient and then ultrasonically dispersing it, and spray drying the mixed dispersion to obtain dry powder; wherein the mass ratio of the eutectic to the excipient is 1:4 to 1:10.

[0016] Further, the nanosuspension was centrifuged at 10000 rpm for 8 min in a high-speed centrifuge, the supernatant was discarded, and the nanosuspension was dispersed again with distilled water to obtain a nanosuspension without the stabilizer. The redispersed nanosuspension was connected to a spray drying pipeline, and the spray drying temperature, drying gas flow rate, and pump speed and other parameters were adjusted. The spray dried sample was separated by a cyclone separator provided in the spray dryer, and the sample was collected in a sample bottle.

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

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

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

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

[0021] Nano-sizing the cocrystal can further improve the solubility and dissolution rate of the drug. In addition, the nano-sized drug has a higher specific surface area, which makes the drug have stronger mucosal adhesion and improves the delivery efficiency. In order to avoid the aggregation of nanoparticles caused by spray drying, the particle size of the nanoparticles before spray drying and after redispersion should be consistent.

[0022] Nanoparticles will aggregate due to the gradual evaporation of water in the droplets. Therefore, it is necessary to introduce sufficient carriers to prevent aggregation. In order to evaluate the redispersibility of dry powder particles after spray drying, it is necessary to control the ratio of drug and carrier (according to the above-mentioned dry powder drug of the present invention is a co-crystal, and the carrier is an excipient), control the drug-carrier ratio of the particles of the present invention (see the table below), and define the nanoaggregate as the redispersibility index (RDI). The 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 nanosuspension before spray drying.

[0025]

[0026] It can be seen from the above table that when the drug proportion is high, that is, when the ratio of drug to carrier exceeds 1:1, the nanoparticles tend to aggregate during the spray drying process, which is manifested as an increase in particle size after re-dissolution, that is, an increase in RDI; with the continuous increase in the carrier proportion, the redispersibility of the nanoaggregates is gradually improved, and then the mass ratio of co-crystal to excipient is 1:4. It can be seen from the above table that this ratio shows redispersibility that meets the requirements, and the RDI value is lower than 1.1. Therefore, the drug-carrier mass ratio should be less than 1:4, and to ensure the drug content, it should be higher than 1:10.

[0027] An itraconazole inhalation dry powder prepared by the method, wherein the spherical structure obtained by the method has a rough surface and a particle size of D 50 2~3μm itraconazole dry powder particles for inhalation.

[0028] An application of the itraconazole inhalable dry powder, and an application of the itraconazole inhalable dry powder in preparing a medicine for oral inhalation into the lungs.

[0029] The itraconazole inhalable dry powder is used in the preparation of an antifungal drug for oral inhalation into the lungs.

[0030] The advantages of the present invention are:

[0031] In the present invention, the dispersed itraconazole nano-eutectic suspension can be prepared into aggregate microparticles with low density and good fluidity through a spray drying process. During the inhalation process, due to the effect of shear force, the aggregates can be dispersed into fragments, thereby having better inhalability, that is, higher deep lung delivery efficiency; the dry powder form can improve the storage stability of itraconazole nanocrystals, reduce storage and transportation costs, and at the same time, the administration of inhaled powder aerosols has better compliance, delivery dose uniformity and portability. In addition, the aggregate fragments can quickly disintegrate in the lung surface mucus to release the encapsulated nanoparticles, and the released nanoparticles have a long-term release ability, which is expected to further improve its lung bioavailability. Therefore, the itraconazole nano-eutectic composition dry powder microparticles in the present invention have significant application potential and advantages as an efficient lung delivery agent. BRIEF DESCRIPTION OF THE DRAWINGS

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

[0033] Figure 2 This is a transmission electron micrograph of itraconazole cocrystal nanoparticles provided in an embodiment of the present invention.

[0034] Figure 3 This is a scanning electron microscope image of the dry powder composition particles provided in an embodiment of the present invention.

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

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

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

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

[0039] If no specific techniques or conditions are specified in the examples, the techniques or conditions described in the literature in the field or the product instructions are used. If no manufacturer is specified for the reagents or instruments used, they are all conventional products that can be purchased through regular channels.

[0040] The orally inhaled itraconazole dry powder of the present invention comprises itraconazole, a cocrystal former, and an excipient. A cocrystal formed by a combination of itraconazole and a cocrystal former of a dicarboxylic acid substance is obtained by a solvent volatilization method; a stable cocrystal nanosuspension is obtained by a medium grinding method; and an itraconazole dry powder composition is manufactured by a spray drying device. The particles of the dry powder composition are spherical, and the aerodynamic diameter is less than 4 μm. The emptying rate is greater than 90%, the fine particle fraction is greater than 40%, and the composition can be quickly dispersed after atomization in vitro, and has a good lung localization effect in vivo.

[0041] Example 1

[0042] Preparation of Itraconazole Cocrystal:

[0043] Chloroform and tetrahydrofuran were mixed in a ratio of 2:1 (v / v) to obtain a mixed solvent. 1410 mg of itraconazole and 118 mg of succinic acid were accurately weighed and dissolved in 10 ml of the mixed solvent. The mixture was ultrasonicated in a water bath for 3 min. After that, the mixed solution was evaporated using a rotary evaporator to promote the precipitation of crystals. After the solvent was completely evaporated, the precipitated crystals were dried in a vacuum environment at 30°C for 12 h to ensure that the organic solvent was completely removed, and finally a cocrystal was obtained (see Figure 1 ).

[0044] Depend on Figure 1It can be seen from the X-ray diffraction pattern of itraconazole cocrystal that the prepared cocrystal shows significant new features in the XRD spectrum compared with the physical mixture and each raw material monomer. Specifically, the green solid line represents the XRD spectrum of the physical mixture, the blue solid line represents the XRD spectrum of succinic acid, the red solid line represents the XRD spectrum of itraconazole, and the black solid line represents the XRD spectrum of itraconazole-succinic acid cocrystal. Compared with the raw material monomer and the physical mixture, the XRD spectrum of the cocrystal sample has new diffraction peaks at 10.075° and 29.25°, and the characteristic peaks of itraconazole at 14.475° and 23.5° completely disappear in the cocrystal sample, and the characteristic peaks of succinic acid at 38.125°, 39.3°, 46.25° and 46.8° also disappear, indicating that the raw material drug and the ligand drug have undergone deep structural reorganization during the cocrystal formation process, and there is a new crystal structure rather than a simple physical mixture.

[0045] Example 2

[0046] The preparation of itraconazole nano eutectic suspension, the specific preparation process is as follows:

[0047] Prepare 20 mL of 2% (w / v) Tween-80 solution as a stabilizer solution, disperse 800 mg of the eutectic in Example 1 in the stabilizer solution, and vortex for 3 minutes to form a primary suspension. Add the prescribed amount of primary suspension to a 50 mL grinding jar. Weigh 6.4 g of zirconium oxide beads and add them to the grinding jar. Place the grinding jar in a ball mill and fix it for grinding. After grinding, use a syringe to suck out the liquid in the grinding jar, filter through a 500 mesh sieve, remove the grinding beads, and obtain a eutectic nanosuspension (see Figure 2 ).

[0048] Depend on Figure 2 From the transmission electron microscopy image of the nanoparticles, it can be seen that under the transmission electron microscope, the nano drug particles are spherical and have a particle size of about 200nm.

[0049] Example 3

[0050] Preparation of orally inhalable itraconazole dry powder composition microparticles

[0051] The itraconazole nano-eutectic suspension in Example 2 was dispersed together with mannitol and leucine in an appropriate amount of water, and the mannitol and leucine were dissolved by ultrasound to prepare a spray drying precursor solution.

[0052] The precursor liquid composition obtained after configuration is:

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

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

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

[0056] Depend on Figure 3 The scanning electron microscope image of the itraconazole dry powder composition particles shows that the particle size of the dry powder particles is about 3 μm, and the shape is a regular sphere with a slightly wrinkled surface.

[0057] Then the particles obtained in Example 3 were tested:

[0058] Aerodynamic particle size

[0059] The particle size and distribution of ITZ-DPI were measured by dry method using HELOS&OASIS fully automatic dry-wet two-in-one laser particle size analyzer (Synpatek, Germany). The test conditions were R1 lens, dispersion pressure of 3.5 bar, feed rate of 50%, and the test started when the optical concentration reached 1%. The test time was 5 s. The measurement result D[4,3], i.e., volume mean diameter (D v ).

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

[0061]

[0062] Where is the effective particle density, ρ1 is the unit density, i.e. 1g / cm 3 , D v is the volume average diameter of the particles, and X is the morphology factor, which is used to characterize the shape of the particles. When the particles are spherical, their 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 the fluidity of powders. It reflects the percentage relationship between the volume change of powders in free filling and compressed states and their free filling volume. Generally, when CI exceeds 25%, the fluidity of the powder is considered to be poor; when CI is less than 15%, it indicates that its fluidity is good. This study used a tap density tester to measure the tap density and CI of the inhaled dry powder sample. The specific operation method is as follows:

[0065] Fill a 5 mL graduated cylinder with a sample of mass m and read the initial volume V. 初 , fix the measuring cylinder containing the sample on the base and tighten it, adjust the amplitude of the tap density meter to 3mm, vibrate 300 times per minute, set the vibration frequency to 3000 times (about 10 minutes), and start the tap density meter. When the vibration stops, remove the measuring cylinder. If the upper surface of the powder is horizontal, the powder volume value can be read directly; if the upper surface of the powder is not horizontal after vibration, the average of the highest and lowest readings on the upper surface of the powder after vibration is used to confirm the volume of the powder after vibration V 终 The bulk density (Bulkdensity, ρ) is calculated according to the following formula: b ), tap density (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 guidance of the Chinese Pharmacopoeia (2020), the assembled double-stage impactor ( Figure 4 ) was used to measure the fine particle fraction (FPF).

[0071] Double-stage impactor Figure 4 It can be seen that the method for measuring the fine particle fraction using a conventional experimental container assembly (or a conventional impactor) is as follows:

[0072] like Figure 4The device adds 7mL and 30mL of methanol as receiving liquid to the first-level distribution bottle D and the second-level distribution bottle H respectively. The dry powder sample is loaded into a No. 3 HPMC capsule and placed in the inhaler. Press the buttons on both sides of the inhaler to puncture the two ends of the capsule, turn on the vacuum pump to adjust the air flow to 60±5L / min, and connect the inhalation device horizontally and tightly to the inlet A through a suitable rubber interface. Turn off the vacuum pump after ventilation for 10 seconds. Clean the F interface after the above operation and the inner and outer walls of the conduit and the nozzle of the lower conical bottle with a blank receiving liquid, combine the washing liquid with the receiving liquid in the second-level distribution bottle H, transfer it to a 50mL volumetric flask to make up the volume, and determine the content, which is the fine particle dose (FPD). The ratio of FPD to the total amount of samples involved in the test is the fine particle fraction.

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

[0074]

[0075] Example 7

[0076] The itraconazole nano-eutectic suspension in Example 2 was dispersed together with mannitol and leucine in an appropriate amount of water, and the mannitol and leucine were dissolved by ultrasound to prepare a spray drying precursor solution.

[0077] The precursor liquid composition obtained after configuration is:

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

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

[0082] The yield, aerodynamic particle size, compression degree 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] The itraconazole nano-eutectic suspension in Example 2 was dispersed together with mannitol and leucine in an appropriate amount of water, and the mannitol and leucine were dissolved by ultrasound to prepare a spray drying precursor solution.

[0086] The precursor liquid composition obtained after configuration is:

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

[0090] The yield, aerodynamic particle size, compression degree 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] The itraconazole nano-eutectic suspension in Example 2 was dispersed together with mannitol and leucine in an appropriate amount of water, and the mannitol and leucine were dissolved by ultrasound to prepare a spray drying precursor solution.

[0094] The precursor liquid composition obtained after configuration is:

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

[0098] The yield, aerodynamic particle size, compression degree 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] The itraconazole nano-eutectic suspension in Example 2 was dispersed together with mannitol and leucine in an appropriate amount of water, and the mannitol and leucine were dissolved by ultrasound to prepare a spray drying precursor solution.

[0102] The precursor liquid composition obtained after configuration is:

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

[0106] The yield, aerodynamic particle size, compression degree 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] Embodiment 11

[0109] The itraconazole nano-eutectic suspension in Example 2 was dispersed together with mannitol and leucine in an appropriate amount of water, and the mannitol and leucine were dissolved by ultrasound to prepare a spray drying precursor solution.

[0110] The precursor liquid composition obtained after configuration is:

[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 liquid supply pump to the precursor liquid, and the flow rate of the liquid supply pump is 6mL / min.

[0114] Inlet temperature: 130°C, dry gas flow rate 0.4m 3 / min, atomization pressure 180kPa. The prepared dry powder was collected through a sample collection bottle.

[0115] The yield, aerodynamic particle size, compression degree 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 dry powder inhaler ITZ-DPI obtained in Example 3 above was tested for performance against the oral administration formulation on the market:

[0118] 48 SD rats were randomly divided into 2 groups, each with 24 rats, and marked separately. The first group was given ITZ-DPI of Example 3 by inhalation into the lungs at a dose of 22.5 mg / kg, and the second group was given the marketed preparation orally. The administration time was recorded, and the rats were killed by cervical dislocation 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 and analyzed by HPLC.

[0119] Rats in each group inhaled homemade dry powder inhaler ITZ-DPI in their lungs and took the marketed preparation orally After that, the distribution of the drug in plasma and lungs was Figure 4 and Figure 5 The pharmacokinetic parameters of ITZ-DPI in rat plasma and lung are shown in the following two tables.

[0120]

[0121] according to Figure 4 As shown in the figure, 15 minutes after inhalation administration, the drug concentration in plasma quickly reached 111±7 ng / mL. After 30 minutes, the drug concentration reached a peak of 214±54 ng / mL, indicating that the drug was rapidly absorbed in the early stage. However, the drug concentration gradually decreased over time, dropping to 110 ng / mL at 12 hours. In contrast, the peak time of ITZ concentration in the plasma of rats administered orally was 2 hours, which was later than that of the pulmonary inhalation group. However, the plasma drug concentration C max was 366±115ng / mL, which was higher than that of the pulmonary inhalation group. 0-12h The value was 2564 ng / mL·h, which was also higher than the 1536 ng / mL·h in the lung administration group. This indicates that within 12 hours after administration, the total amount of drug entering the blood through the lungs of ITZ-DPI inhaled compared with oral administration is less.

[0122] Observation diagram Figure 5 There is a clear contrast in the distribution of the drug in the lung tissue and blood. 15 minutes after direct administration to the lung, the drug concentration in the inhalation group reached a peak of 39834±3639ng / g in the lung, and then the drug concentration gradually decreased. After 12 hours of administration, the drug concentration in the lung still maintained a high level of 3008±358ng / g. At the same time, the AUC of the inhalation group 0-12hIt also reached a significant 92730ng / g·h. In contrast, the concentration trend of oral drugs in the lungs was consistent with that in plasma, reaching a peak of 662±128ng / g 2 hours after administration, and in the following 2-12 hours, the drug concentration in the lungs showed a steady and slow downward trend.

[0123]

[0124] The above table lists the concentration ratios of the drug in lung tissue and plasma at various time points after administration, in order to evaluate the localization effect of the preparation in the lungs. Specifically, 15 minutes after inhalation administration, the concentration ratio of ITZ in lung tissue and plasma was as high as 360.33. As the plasma concentration gradually increased, this ratio gradually declined, and by 12 hours it had dropped to 27.34. Despite this, the ratio was still significantly higher than the maximum value of the oral administration group (3.06). Accordingly, ITZ-DPI delivered through the lungs can effectively locate and maintain long-term drug exposure in the lungs, which is extremely beneficial for the treatment of local lung diseases. At the same time, its lower distribution in the blood circulation may also reduce adverse reactions caused by systemic distribution of the drug to a certain extent.

Claims

1. A method for preparing itraconazole inhalation dry powder, characterized in that: The itraconazole cocrystal is prepared by a solvent evaporation method, the itraconazole cocrystal is then subjected to a medium grinding method to form a cocrystal nanosuspension, the nanosuspension is mixed with an excipient and then spray-dried to prepare a dry powder.

2. The method for preparing itraconazole inhalation dry powder according to claim 1, characterized in that: The itraconazole co-crystal is prepared by dissolving itraconazole and a co-crystal former in a mixed solvent by a solvent volatilization method, and then performing a rotary evaporation treatment to obtain the itraconazole co-crystal.

3. The method for preparing itraconazole inhalation dry powder according to claim 2, characterized in that: 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; the molar ratio of itraconazole to the eutectic former is 0.5 to 4:1; the total concentration of itraconazole and the eutectic former in the mixed solution is 5% to 20% (v / v); the eutectic former is one or more of oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, and DL-tartaric acid.

4. The method for preparing itraconazole inhalation dry powder according to claim 1, characterized in that: The method of forming a eutectic nanosuspension by medium grinding the itraconazole eutectic is to disperse the eutectic in a stabilizer solution to form a primary suspension, add the primary suspension and grinding beads into a grinding tank, and grind them using a ball mill to obtain the itraconazole eutectic nanosuspension; the mass ratio of the stabilizer to the eutectic is (0.5-3):1, and the mass ratio of the grinding beads to the eutectic is (40-120):

1.

5. The method for preparing itraconazole inhalation dry powder according to claim 4, characterized in that: The stabilizer is one or more of Tween-80, sodium lauryl sulfate, poloxamer 407, poloxamer 188, and vitamin E polyethylene glycol succinate.

6. The method for preparing itraconazole inhalation dry powder according to claim 1, characterized in that: The method of preparing dry powder by spray drying after mixing the nanosuspension with the excipient comprises centrifuging the nanosuspension, collecting the precipitate and redispersing it, mixing the redispersed eutectic nanosuspension with the excipient and then ultrasonically dispersing it, and spray drying the mixed dispersion to obtain dry powder; wherein the mass ratio of the eutectic to the excipient is 1:4 to 1:

10.

7. The method for preparing itraconazole inhalation dry powder according to claim 6, characterized in that: The excipient is one or more of amino acids, sugars and their diffractors.

8. An itraconazole inhalation dry powder prepared by the method of claim 1, characterized in that: The rough spherical structure prepared according to the scheme of claim 1 has a particle size of D 50 2-3 μm itraconazole dry powder particles for inhalation.

9. A use of the itraconazole inhalation dry powder according to claim 8, characterized in that: The itraconazole inhalable dry powder is used in preparing a medicine for oral inhalation into the lungs.

10. The use of itraconazole dry powder for inhalation according to claim 9, characterized in that: The itraconazole inhalable dry powder is used in the preparation of an antifungal drug for oral inhalation into the lungs.

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