Orally inhalable itraconazole nanocrystal aggregate microparticles and methods of making the same

Abstract

The application discloses an orally inhaled itraconazole nanocrystal composition aggregate microparticle and a preparation method thereof, which comprises itraconazole, a dispersing agent and an excipient, and a stable nanocrystal suspension is obtained through ultrasonic treatment, high-pressure homogenization and magnetic stirring; and an inhalable composition aggregate microparticle is prepared by using a spray freeze-drying technology. The composition aggregate microparticle has a porous and brittle structure, a drug loading capacity greater than 60%, a mass median aerodynamic size less than 4 microns, an emptying rate greater than 90%, a fine particle fraction greater than 60%, and an ultrafine particle fraction greater than 30%, and more than 3.6 mg of itraconazole in 10 mg of the composition aggregate microparticle can enter the deep lung.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical powder formulations and relates to an orally inhalable itraconazole nanocrystal aggregate microparticle, specifically an orally inhalable composite aggregate microparticle with itraconazole as the active pharmaceutical ingredient and its preparation method. Background Technology

[0002] Pulmonary aspergillosis is a lung disease caused by Aspergillus infection, with lesions typically located in the alveoli and prone to metastasis. Itraconazole is a first-line treatment for pulmonary aspergillosis, and oral administration is an important dosage form. However, the pulmonary bioavailability of oral administration is extremely low, requiring large doses to achieve effective therapeutic concentrations in the lungs. This often leads to severe toxic side effects, hindering practical clinical application. Therefore, it is essential to explore new dosage forms and routes of administration to achieve efficient pulmonary delivery of itraconazole. A recent clinical study showed that compared to oral administration of 20 mg itraconazole, inhalation of 20 mg resulted in a 70-fold increase in drug concentration in sputum, while whole blood concentrations were only 1 / 66th of those achieved with oral administration. This study demonstrates the significant potential of inhaled itraconazole formulations (NCT03479411). However, itraconazole has extremely poor water solubility (1-5 ng / mL), and due to the limited volume of mucus on the lung surface, itraconazole is usually difficult to dissolve in lung mucus. This may lead to the phagocytosis of macrophages and the clearance by ciliary beating, which may cause itraconazole on the lung surface to be easily expelled from the lung, which is not conducive to the treatment effect. Summary of the Invention

[0003] This invention provides an itraconazole nanocrystal aggregate microparticle for oral inhalation. The composition comprises itraconazole, a dispersant, and an excipient. A stable precursor solution is obtained through ultrasonic treatment, high-pressure homogenization, and magnetic stirring, followed by spray freeze-drying. The inhaled itraconazole nanocrystal aggregate microparticles have a porous and brittle structure, a drug loading greater than 60%, a median aerodynamic size less than 4 μm, an air displacement rate greater than 90%, a fine particle fraction greater than 60%, and an ultrafine particle fraction greater than 30%. For every 10 mg of this composition aggregate microparticle inhaled, more than 3.6 mg of itraconazole can penetrate deep into the lungs.

[0004] The present invention adopts the following technical solution: A method for preparing orally inhalable itraconazole nanocrystalline aggregates includes the following steps: dispersing an itraconazole composition to obtain a nanocrystalline suspension, followed by spray freeze-drying to obtain orally inhalable itraconazole nanocrystalline aggregates; wherein the itraconazole composition comprises itraconazole, a dispersant, and an excipient, and the resulting product is an inhalable nanocrystalline aggregate containing itraconazole, a dispersant, and an excipient.

[0005] In this invention, the dispersion treatment includes ultrasonic treatment, high-pressure homogenization treatment, and stirring treatment (such as magnetic stirring). That is, the inhalable itraconazole composition aggregate microparticles of this invention are prepared by four unit operations: ultrasonic treatment, high-pressure homogenization treatment, magnetic stirring treatment, and spray freeze-drying treatment of an itraconazole composition consisting of itraconazole, dispersant, excipient, and dispersion medium. It contains more than 60% by mass of itraconazole, has a median aerodynamic size of 1-4 μm, has a porous and brittle structure, has less than 5% water content, has a greater than 90% air release rate, has a greater than 60% fine particle fraction, and has a greater than 30% ultrafine particle fraction. For every 10 mg of this composition aggregate microparticles inhaled, more than 3.6 mg of itraconazole can enter the deep lungs. That is, for every 10 mg of inhalable aggregate microparticles, the absolute amount of drug with an aerodynamic size of less than 5 μm is greater than 3.6 mg, or even greater than 4.6 mg, which can avoid phagocytosis and clearance mechanisms. At the same time, the nanocrystals can gradually dissolve, achieving a longer efficacy.

[0006] In this invention, the dispersant includes vitamin E polyethylene glycol succinate (TPGS), and the excipients include amino acids, sugars and their derivatives; wherein the amino acids include glycine, leucine and isoleucine, and the sugars and their derivatives include lactose, trehalose, sucrose and mannitol; preferably, the excipient is leucine.

[0007] In this invention, the mass ratio of itraconazole to dispersant is (10-30):1, preferably (15-25):1, for example 20:1; the mass ratio of itraconazole / dispersant to excipient is (1-5):1, preferably (1.5-3):1, for example 7:3. Itraconazole / dispersant refers to the total mass of itraconazole and dispersant.

[0008] In this invention, a stable itraconazole composition (itraconazole nanocrystal suspension) is prepared by using water as the dispersion medium through ultrasonic treatment, high-pressure homogenization and magnetic stirring, which can be used for subsequent spray freeze drying. The itraconazole composition has the characteristic of a hydrodynamic median size of less than 700 nm, wherein the solid content is 1 to 4 w / w, preferably 2 w / w.

[0009] In this invention, the itraconazole composition obtained by ultrasonic treatment, high-pressure homogenization and magnetic stirring is spray-frozen dried. Specifically, it is first spray-frozen and then freeze-dried. The freezing temperature used is -30 to -70°C, preferably -50°C.

[0010] Itraconazole nanocrystals can be prepared by assembling itraconazole and surfactants in a liquid phase (usually aqueous phase). However, itraconazole nanocrystals have poor stability in the liquid phase and are prone to irreversible re-aggregation, thus requiring low-temperature storage and cold chain transportation. Furthermore, pulmonary delivery efficiency via nebulized nanocrystal suspensions is low, compliance is poor, and it is highly dependent on patient medication habits; therefore, itraconazole nanocrystal suspensions cannot be used directly.

[0011] In this invention, a dispersed itraconazole nanocrystal suspension is spray-dried to produce porous, brittle, low-density, and highly flowable aggregate microparticles. 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 spray-dried frozen itraconazole nanocrystal composition aggregate microparticles of this invention have significant application potential and advantages as a highly efficient pulmonary delivery agent. Attached Figure Description

[0012] Figure 1 Microscopic image of itraconazole nanocrystal suspension.

[0013] Figure 2 Scanning electron microscope image of the macroscopic morphology of itraconazole nanocrystal aggregates prepared at a freezing temperature of -50℃.

[0014] Figure 3 Scanning electron microscope images of the macroscopic morphology of the itraconazole nanocrystal aggregates for comparison.

[0015] Figure 4 The image shows the macroscopic morphology of itraconazole nanocrystals prepared by spray freeze-drying and spray drying processes using formulation 5 as a precursor liquid, after being dispersed by an inhalation device, in the fifth collection tray of a new generation impactor. Detailed Implementation

[0016] The oral itraconazole nanocrystal aggregates prepared by this invention contain itraconazole at a mass fraction greater than 60%; they have a median aerodynamic size of 1-4 μm, a fine particle fraction (FPF) greater than 60%, and an ultrafine particle fraction (eFPF) greater than 30%, calculated as FPF = FPD / TD and eFPF = eFPD / TD, where FPD is the drug mass contained in particles with an aerodynamic size less than 5 μm in a single capsule, eFPD is the drug mass contained in particles with an aerodynamic size less than 2 μm in a single capsule, and TD is the drug mass contained in all particles in a single capsule; for every 10 mg of the aggregate composition inhaled, more than 3.6 mg of itraconazole has an aerodynamic size less than 5 μm, meaning that the absolute amount of drug that can enter the deep lungs in every 10 mg of inhalable aggregates is greater than 3.6 mg.

[0017] This invention relates to composite aggregates and their preparation methods, using itraconazole as the active pharmaceutical ingredient, TPGS as a dispersant, and amino acids and other substances as excipients, belonging to the field of pharmaceutical powder formulations. The raw materials used in this invention are existing products, and the specific testing and evaluation methods are conventional techniques.

[0018] In this invention, the dispersion process consists of sequential ultrasonic treatment, high-pressure homogenization, and magnetic stirring. The ultrasonic treatment uses a power of 500–1000 W, a frequency of 20–40 kHz, and a duration of 5–30 min. The high-pressure homogenization uses a pressure of 500–700 bar and a duration of 10–30 min. The magnetic stirring process uses a rotation speed of 400–800 rpm. Preferably, the ultrasonic treatment uses a power of 600–800 W, a frequency of 25–30 kHz, and a duration of 5–30 min. The high-pressure homogenization uses a pressure of 500–700 bar and a duration of 15–25 min. The magnetic stirring process uses a rotation speed of 400–600 rpm and is maintained until the spray freeze-drying experiment, specifically for 30–360 min. Example 1

[0019] Preparation of itraconazole nanocrystal suspension Table 1 Formulation of itraconazole nanocrystal suspension

[0020] According to the above formulation design, itraconazole and dispersant TPGS were added to water, first dispersed by ultrasonic treatment, then further dispersed by a high-pressure homogenizer, and then the excipient leucine was added. The mixture was then homogenized using a magnetic stirrer to obtain an itraconazole nanocrystal suspension suitable for spray freeze-drying. The ultrasonic treatment power was 700W, the frequency was 26 kHz, and the time was 20 min; the high-pressure homogenization pressure was 600 bar, and the time was 20 min; the magnetic stirring speed was 500 rpm, and the time was 1 hour.

[0021] Microscopic images of itraconazole nanocrystal suspensions treated with ultrasound, high-pressure homogenization, and magnetic stirring are shown below. Figure 1 As shown, itraconazole nanocrystals exhibit good particle size dispersion, with hydrodynamic median sizes all less than 700 nm. Within a defined range, changing the ratio of itraconazole / TPGS nanocrystals and excipients or the solid content does not significantly affect the hydrodynamic median size, which is measured by laser diffraction. Example 2

[0022] Preparation of oral itraconazole nanocrystal aggregates The itraconazole nanocrystal suspension prepared in Example 1 was used as a precursor solution for spray freeze-drying to prepare itraconazole nanocrystal aggregate dry powder. The precursor solution was loaded into a syringe, the flow rate of the syringe pump was set to 5 mL / min, and the atomized liquid was atomized using an ultrasonic atomizing nozzle. The atomized droplets were then frozen in a refrigerant to obtain ice balls. The freezing temperature was set to -50°C. The collected ice balls were then transferred to a vacuum freeze dryer for freeze-drying. The freeze-drying parameters were as follows: primary drying temperatures of -40°C, -20°C, and -10°C, and secondary drying temperatures of 0°C, 10°C, and 20°C, with a vacuum degree of less than 10 Pa.

[0023] The macroscopic morphology of the obtained itraconazole nanocrystal aggregates is as follows: Figure 2 As shown, when the driving fluid contains only itraconazole TPGS nanocrystals (formula 1), the sample appears as an aggregated nanocrystal. With increasing leucine content, the aggregates tend towards a microparticle "spherical" structure, with the itraconazole TPGS nanocrystals dispersed in a sheet-like matrix composed of excipients (leucine) (formulas 2-4). Increasing the solid content (formulas 5 and 6) further improves the sphericity and integrity of the "spherical" aggregates. For formulations where spherical particles can be observed, the static geometric dimensions measured on a scale are all greater than 60 μm. Figure 2 ).

[0024] Table 2. Dynamic geometric particle size distribution of orally inhalable itraconazole nanocrystal aggregates. 1 1.55 6.33 41.31 2 2.12 8.44 32.50 3 3.76 16.74 45.90 4 6.07 29.31 70.74 5 4.39 21.88 61.96 6 4.73 24.10 81.84 Using laser diffraction, with Breezhaler ® As an inhalation device, the dynamic geometric particle size distribution of the samples measured at an inhalation flow rate of 60 L / min is shown in Table 2. D10, D50, and D90 represent the geometric particle sizes corresponding to a cumulative volume distribution of 10%, 50%, and 90%, respectively. Increasing the leucine content or the solid content in the formulation gradually increases the median geometric particle size of the aggregates in the dispersed state, but all are significantly smaller than the original sample's static size (e.g., ...). Figure 2 (As observed), this is because the airflow from the inhalation device can further shear and disperse the itraconazole nanocrystal aggregates, which is more conducive to improving aerosol performance and achieving higher deep lung delivery efficiency.

[0025] Table 3. Macroscopic delivery performance of orally inhalable itraconazole nanocrystal aggregates to the lungs. 1 -50 74.57 32.92 12.15 4.18 3.14 2 -50 86.79 56.37 17.76 3.34 4.83 3 -50 95.07 69.95 36.17 2.59 4.66 4 -50 94.62 76.53 50.12 1.91 3.64 5 -50 94.21 69.74 36.87 2.50 4.65 6 -50 92.88 58.94 27.51 3.16 3.93 The macroscopic lung delivery performance of itraconazole nanocrystal aggregates is shown in Table 3. All the above performance indicators were obtained by the new generation impactor test (the cascade impactor test is the gold standard for in vitro evaluation of inhaled powders. The new generation impactor is a type of cascade impactor. The test was conducted with reference to Chapter 0951 of the 2020 Chinese Pharmacopoeia, Part IV, "Determination of Aerodynamic Properties of Fine Particles in Inhaled Preparations"). It can be seen that the addition of leucine and the reduction of solid content can significantly improve the macroscopic lung delivery performance of itraconazole nanocrystal aggregates.

[0026] The formulas for calculating the fraction of fine particles (FPF) and the fraction of extremely fine particles (eFPF) are FPF=FPD / TD and eFPF=eFPD / TD, respectively, where FPD is the mass of drug contained in particles with an aerodynamic size of less than 5 μm in a single capsule, and TD is the mass of drug contained in all particles in a single capsule.

[0027] Drug loading = mass of itraconazole powder per unit volume. Taking Formula 1 as an example, in every 100g of solution, there is 0.9524g of itraconazole, 0.0476g of TPGS, and 99g of water. After obtaining the dry powder, the water is removed, leaving 1g of dry powder, which contains 0.9524g of itraconazole and 0.0476g of TPGS. The drug loading is 0.9524g / (0.9524g + 0.0476g) = 95.24%.

[0028] In summary, the composition with TPGS and leucine as excipients, frozen at -50°C, achieves a drug loading of 66.67% under specific formulation and process conditions, with an ultrafine particle fraction of 36.87%. This means that approximately 36.87% of the drug can be delivered to the bronchioles and alveoli in the deep lung region. Simultaneously, approximately 4.65 mg of itraconazole enters the deep lung region with every 10 mg of powder inhaled. The dispersed state of this formulation in the fifth collection tray of the new generation impactor is as follows... Figure 3 As shown, it can be observed that compared to the initial state ( Figure 1 The particles break down significantly, partly due to the impact dispersion effect of inhalation, and partly due to secondary breakage caused by the shearing between particles during flight. Example 3

[0029] Formula 5 in Table 1 was subjected to spray freeze-drying granulation at -30℃ and -70℃ respectively, with the rest being the same. The performance of the final product is shown in Table 4.

[0030] Replacing leucine in Formula 3 of Table 1 with mannitol results in Formula 7, and replacing it with α-lactose monohydrate results in Formula 8. Nanocrystalline aggregates were prepared under the same process conditions, and the properties of the final product are shown in Table 4. Replacing TPGS in Formula 3 of Table 1 with Tween-80 results in Formula 9. Nanocrystalline aggregates were prepared under the same process conditions, and the properties of the final product are shown in Table 4.

[0031] Table 4. Macroscopic delivery performance of orally inhalable itraconazole nanocrystal aggregates to the lungs. 5 -30 92.00 36.81 7.35 5.16 2.45 5 -70 91.21 62.36 25.59 2.88 4.16 7 -50 75.59 35.71 10.30 4.15 2.38 8 -50 89.58 24.84 7.61 4.80 1.66 9 -50 87.92 56.63 17.59 3.37 3.78 Example 4

[0032] Formula 5 (atomized droplets) from Table 1 was spray-dried and granulated at inlet and outlet temperatures of 120°C and 90°C, respectively, with all other parameters remaining the same. The final product performance is shown in Table 5. The dispersed droplets in the fifth collection tray of the new generation impactor are as follows... Figure 4 As shown, the spray-dried itraconazole nanocrystals did not break after dispersion, and the proportion of extremely fine particles was relatively small.

[0033] Table 5. Macroscopic delivery performance of orally inhalable itraconazole nanocrystal aggregates to the lungs. 5 120 / 90 89.65 47.71 14.14 3.63 3.18 Existing technologies utilize Span60 or Span80 as dispersants to prepare itraconazole nanocrystal suspensions via rotary evaporation combined with ultrasonic treatment, and add mannitol as an excipient to prepare itraconazole nanocrystal aggregates via spray drying. The problem is that the optimal sample has only 37.3% fine particles and less than 5% ultrafine particles, resulting in a very low penetration rate into the deep lungs. Furthermore, the combined deposition in the larynx and pre-separator exceeds 20%, meaning this portion of the drug cannot be delivered to the respiratory system and may be absorbed into the digestive tract, causing serious side effects. Existing technologies utilize dispersants to prepare itraconazole nanocrystal suspensions via transient nanoprecipitation, remove organic solvents through ultrafiltration and centrifugation, then resuspend the nanocrystals in an aqueous solution containing dimethyl sulfoxide (DMSO), add MC M20 as an excipient to prepare a precursor solution, and prepare itraconazole nanocrystal aggregates via spray drying. The problems are: first, the preparation process of the itraconazole nanocrystal suspension involves repeated additions and ultrafiltration to remove DMSO, resulting in a cumbersome and costly process with significant limitations for industrial scale-up; second, the transient nanoprecipitation method requires the addition of large amounts of dispersants, and the drying process also involves the addition of large amounts of excipients as protective agents, leading to extremely low drug loading (less than 5%), rendering it impractical. The inventors previously disclosed niclosamide composition microparticles for inhalation, prepared through three unit operations—ultrasonic treatment, high-pressure homogenization, and spray freeze-drying—possesses a fine particle fraction greater than 40%, but an extremely fine particle fraction of less than 10%, resulting in a very low penetration rate into the deep lungs.

Claims

1. A method for preparing orally inhalable itraconazole nanocrystal aggregates, characterized in that, The process includes the following steps: dispersing an itraconazole composition to obtain a nanocrystalline suspension, followed by spray freeze-drying to obtain orally inhalable itraconazole nanocrystalline aggregates; the itraconazole composition consists of itraconazole, a dispersant, and an excipient; the dispersant is vitamin E polyethylene glycol succinate; the excipient is leucine; the mass ratio of itraconazole to dispersant is 20:1; the mass ratio of itraconazole to dispersant to excipient is 7:3; the solid content in the nanocrystalline suspension is 1 w / w% or 2 w / w%; the freezing temperature for spray freeze-drying is set to -50°C, the freeze-drying parameters are: primary drying temperatures of -40°C, -20°C, and -10°C, secondary drying temperatures of 0°C, 10°C, and 20°C, and the vacuum degree is below 10 Pa.

2. The method for preparing orally inhalable itraconazole nanocrystal aggregates according to claim 1, characterized in that, Dispersion treatment includes ultrasonic treatment, high-pressure homogenization treatment, and stirring treatment.

3. The method for preparing orally inhalable itraconazole nanocrystal aggregates according to claim 2, characterized in that, Itraconazole and a dispersant were added to a dispersion medium, and an itraconazole nanocrystal suspension was prepared by ultrasonic treatment and high-pressure homogenization. Then, an excipient was added and the suspension was magnetically stirred to obtain a nanocrystal suspension. Finally, itraconazole nanocrystal aggregates that could be inhaled orally were obtained by spray freeze-drying.

4. The method for preparing orally inhalable itraconazole nanocrystal aggregates according to claim 3, characterized in that, The ultrasonic treatment has a power of 500–1000W, a frequency of 20–40kHz, and a time of 5–30 min; the high-pressure homogenization has a pressure of 500–700 bar and a time of 10–30 min; the magnetic stirring treatment has a rotation speed of 400–800 rpm.

5. Orally inhalable itraconazole nanocrystal aggregates prepared by the method for preparing orally inhalable itraconazole nanocrystal aggregates according to claim 1.

6. The use of the orally inhalable itraconazole nanocrystal aggregates of claim 5 in the preparation of orally inhaled pulmonary medicaments.

7. The use of the orally inhalable itraconazole nanocrystal aggregates of claim 5 in the preparation of orally inhaled drugs.

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