Methods of using itraconazole dry powder

Abstract

The present disclosure relates to a method of treating a disease or condition in a subject forbidding oral administration of itraconazole, comprising administering to the respiratory tract of the subject an inhalable dry powder comprising itraconazole. The present disclosure also relates to methods of co-administering itraconazole to a subject in need thereof with a second therapeutic agent wherein the itraconazole is administered to the respiratory tract of the subject in the form of an inhalable dry powder, and wherein the second therapeutic agent is a substrate, inducer and / or inhibitor of an enzyme or receptor that is inhibited by itraconazole or metabolizes itraconazole.

Description

[0001] Related Applications

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 402,577, filed on August 31, 2022, which is incorporated herein by reference in its entirety. Background Art

[0003] Itraconazole is a triazole antifungal drug with broad-spectrum activity that is usually administered orally. Itraconazole is an FDA-approved oral antifungal drug. However, the clinical use of oral itraconazole is limited by unpredictable and variable pharmacokinetics, poor tolerability, adverse effects, and problems associated with its high drug-drug interaction (DDI) potential.

[0004] The DDI potential of itraconazole is related to its activity as a potent inhibitor of the cytochrome P450 3A4 (CYP3A4) isozyme. The effects of itraconazole on the CPY3A4 pathway alter metabolism and, therefore, plasma concentrations of other drugs metabolized by this pathway. Therefore, a long list of drugs and drug classes are currently contraindicated for co-administration with itraconazole due to potential DDIs. For example, The package insert of lists more than 40 contraindicated drugs and an additional 256 drugs that require special attention. (See Bergagnini-Kolev et al. The AAPS Journal (2023) 25:62; which is incorporated herein by reference in its entirety).

[0005] The potential DDI of oral itraconazole greatly limits its use, especially in those patients who can benefit from itraconazole treatment. For example, itraconazole has shown benefit in treating allergic bronchopulmonary aspergillosis, which has a prevalence of up to 15% in patients with cystic fibrosis and an estimated prevalence of 1.5% in the general population with asthma. (See Bergagnani-Kolev, supra). However, many drugs used to treat asthma exacerbations or for maintenance therapy of cystic fibrosis cannot be safely used in combination with oral itraconazole (see Bergagnani-Kolev, supra).

[0006] Therefore, there is an unmet need for formulations and methods for treating patients with itraconazole and avoiding drug-drug interactions (DDIs), particularly in patients taking other drugs that are substrates for CYP3A4. Summary of the invention

[0007] The present disclosure relates to a respirable dry powder and a method for administering itraconazole to a subject for whom oral itraconazole is contraindicated, as well as a method for co-administering itraconazole and a second therapeutic agent for which oral itraconazole is contraindicated. Specifically, the compositions and methods disclosed herein can be used to safely achieve therapeutic concentrations of itraconazole in the lungs of a patient population that could not otherwise be treated with itraconazole, such as a subject who has taken a CYP3A4 substrate. For example, cystic fibrosis (CF) patients are typically treated with drugs including elexacaftor, ivacaftor, and tezacaftor, which are extensively metabolized by CYP3A4, and therefore these patients cannot take itraconazole orally. This is problematic because cystic fibrosis patients are extremely susceptible to lung infections and can benefit greatly from itraconazole treatment. The methods disclosed herein address this problem because they can be used with CYP3A4 substrates. In particular, the compositions and methods disclosed herein can be used to treat allergic bronchopulmonary aspergillosis (ABPA) in subjects with cystic fibrosis (CF) or asthma for whom oral itraconazole is contraindicated.

[0008] In some aspects, the present disclosure relates to a method of treating a disease or condition in a subject for which oral itraconazole is contraindicated, comprising administering to the respiratory tract of the subject an inhalable dry powder comprising itraconazole. The subject may be treated with a second therapeutic agent that is a substrate, inducer and / or inhibitor of an enzyme or receptor that is inhibited by itraconazole or metabolizes itraconazole.

[0009] In some aspects, the present disclosure relates to a method of co-administering itraconazole with a second therapeutic agent to a subject in need thereof, wherein the itraconazole is administered to the respiratory tract of the subject in the form of an inhalable dry powder, and wherein the second therapeutic agent is a substrate, inducer and / or inhibitor of an enzyme or receptor that is inhibited by itraconazole or metabolizes itraconazole.

[0010] The second therapeutic agent may be a substrate, inducer and / or inhibitor of the cytochrome P450 3A4 (CYP3A4) isozyme. The second therapeutic agent may be a drug that is contraindicated with oral itraconazole (e.g. ).

[0011] In some embodiments, the second therapeutic agent is an alpha blocker, a beta blocker, an analgesic, an antiarrhythmic, an antibacterial, an anticoagulant, an antiplatelet, an anticonvulsant, an antidiabetic, an anthelmintic, an antifungal, an antiprotozoal, an antimigraine, an antineoplastic, an antipsychotic, an anxiolytic, a hypnotic, an antiviral, a calcium channel blocker, a cardiovascular agent, a contraceptive, a diuretic, an anticonvulsant, an immunosuppressant, a lipid-lowering agent, a respiratory agent (e.g., an asthma treatment), an antidepressant (e.g., a tricyclic or a selective serotonin reuptake inhibitor (SSRI)), a urological agent, a vasopressin receptor antagonist, a nonsteroidal anti-inflammatory drug (NSAID), or a gastrointestinal agent.

[0012] In some embodiments, the second therapeutic agent is alfuzosin, silodosin, tamsulosin, methadone, fentanyl, alfentanil, buprenorphine, oxycodone, sufentanil, disopyramide, dofetilide, dronedarone, quinidine, digoxin, bedaquiline bedaquiline, rifabutin, clarithromycin, trimetrexate, ticagrelor, apixaban, rivaroxaban, vorapaxar, cilostazol, dabigatran, warfarin, carbamazepine, repaglinide, saxagliptin, isavuconazonium, praziquantel, artemether-lumefantrine, quinine, ergot alkaloids (e.g., dihydroergotamine, ergometrine, ergonovine, methylergometrine, methylergonovine, ergotamine), eletriptan, irinotecan, axitinib, bosutinib, cabazitaxel, cabozantinib (cabozantinib), ceritinib, cobimetiniba, crizotinib, dabrafenib, dasatinib, docetaxel, ibrutinib, lapatinib, nilotinib, olapariba, pazopanib, regorafenib, sunitinib, trabectedin,trastuzumab-emtansine, vinca alkaloids, bortezomib, brentuximab-vedotin, busulfan, erlotinib, gefitinib, idelalisib, nintedanib, panobinostat, ponatinib, ruxolitinib, sonidegib, vandetanib, imatinib, ixabepilone, alprazolam, aripiprazole, buspirone, diazepam pam), haloperidol, midazolam, quetiapine, ramelteon, risperidone, suvorexant, zopiclone, lurasidone, pimozide, triazolam, levacetylmethadol / levomethadyl, simeprevir, daclatasvir, indinavir, maraviroc, cobicistat, elvitegravir, ritonavir, saquinavir, tenofovir disoproxil fumarate, disoproxil fumarate), nadolol, felodipine, nisoldipine, diltiazem, dihydropyridines, verapamil, ivabradine, ranolazine, aliskiren, riociguat, sildenafil, tadalafil, bosentan, guanfacine, dienogest, ulipristal,eplerenone, cisapride, naloxegol, aprepitant, loperamide, netupitant, everolimus, sirolimus, temsirolimus, budesonide, ciclesonide, cyclosporine, dexamethasone, fluticasone, methylprednisolone, tacrolimus, lomitapide, lovastatin, simvastatin, atorvastatin, salmeterol, venlafaxine, avanafil, fesoterodine, solifenacin, darifenacin, vardenafil, dutasteride, oxybutynin, tolterodine, colchicine, eliglustat, lumacaftor, ivacaftor, electrostat, tizancator, alitretinoin, cabergoline, cannabinoids, cinacalcet, conivaptan, volvaptan, Saccharomyces boulardii, meloxicam, ciprofloxacin, erythromycin, clarithromycin, idelalisib, darunavir, fosamprenavir, isoniazid, rifampicin, rifabutin, phenobarbital, phenytoin, efavirenz, nevirapine, or drugs that reduce gastric acidity (e.g., acid neutralizing drugs such as aluminum hydroxide, acid secretion inhibitors such as H2-receptor antagonists, and proton pump inhibitors) or halofantrine.

[0013] In some embodiments, the second therapeutic agent is methadone, disopyramide, dofetilide, dronedarone, quinidine, isavuconazole, ergot alkaloids (e.g., dihydroergotamine, ergometrine / ergonovine, ergotamine, methylergometrine / methylergonovine), irinotecan, lurasidone, midazolam, pimozide, triazolam, felodipine, nisoldipine, ivabradine, ranolazine, eplerenone, cisapride, naloxegol, lomitapide, lovastatin, simvastatin, avadil, ticagrelor, colchicine, fesoterodine, solifenacin, or ilukastat.

[0014] In the methods disclosed herein, an inhalable dry powder comprising itraconazole is administered to the respiratory tract of a subject at a nominal dose of between 1 mg and about 60 mg, between about 5 mg and about 40 mg, between about 1 mg and about 10 mg, between about 10 mg and about 20 mg, between about 20 mg and about 30 mg, or between about 30 mg and about 40 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, or about 40 mg.

[0015] The inhalable dry powder comprising itraconazole can be administered to the respiratory tract of the subject no more than about 14 days before or after the administration of the second therapeutic agent, less than about 14 days before or after the administration of the second therapeutic agent, less than about 12 days, less than about 10 days, less than about 8 days, less than about 7 days, less than about 6 days, less than about 5 days, less than about 4 days, less than about 3 days, less than about 2 days, or less than about 1 day. The inhalable dry powder comprising itraconazole can be administered to the respiratory tract of the subject on the same day as the administration of the second therapeutic agent, less than about 20 hours, less than about 18 hours, less than about 16 hours, less than about 14 hours, less than about 12 hours, less than about 11 hours, less than about 10 hours, less than about 9 hours, less than about 8 hours, less than about 7 hours, less than about 6 hours, less than about 5 hours, less than about 4 hours, less than about 3 hours, less than about 2 hours, less than about 1 hour, less than about 45 minutes, less than about 30 minutes, less than about 20 minutes, less than about 10 minutes, or less than about 5 minutes before or after the administration of the second therapeutic agent. The inhalable dry powder comprising itraconazole can be administered to the respiratory tract of the subject less than about 5 minutes before or after administration of the second therapeutic agent.

[0016] In some embodiments, the respirable dry powder comprises homogeneous respirable dry particles, wherein the homogeneous respirable dry particles comprise crystalline itraconazole, a stabilizer, a sodium salt, and an excipient. The sodium salt may be sodium sulfate. The stabilizer may be polysorbate 80. The excipient may be leucine.

[0017] Itraconazole may be in the form of crystalline subparticles, wherein the size of the subparticles is about 50 nm to about 5,000 nm (Dv50), about 50 nm to about 800 nm (Dv50), about 50 nm to about 300 nm (Dv50), about 50 nm to about 200 nm (Dv50), or about 100 nm to about 300 nm (Dv50). Itraconazole may be present in the respirable dry particles in an amount of about 30% to about 70% by weight, about 40% to about 60% by weight, about 45% by weight, about 50% by weight, or about 55% by weight. In some embodiments, at least 50% of itraconazole is crystalline.

[0018] The ratio (wt:wt) of itraconazole to stabilizer in the respirable dry particles may be about 10:1.

[0019] In some embodiments, the stabilizer (e.g., polysorbate 80) is present in the respirable dry particles in an amount of about 3% to about 7% by weight. In some embodiments, the stabilizer (e.g., polysorbate 80) is present in the respirable dry particles in an amount of about 5% by weight.

[0020] In some embodiments, the excipient (e.g., leucine) is present in the respirable dry particles in an amount of about 5% by weight to about 20% by weight. In some embodiments, the excipient (e.g., leucine) is present in the respirable dry particles in an amount of about 10% by weight.

[0021] In some embodiments, the stabilizer is polysorbate 80. In some embodiments, the excipient is leucine.

[0022] In some embodiments, the respirable dry powder comprises homogeneous respirable dry particles comprising about 50 weight % crystalline itraconazole, about 35 weight % sodium sulfate, about 10 weight % leucine, and about 5 weight % polysorbate 80.

[0023] The respirable dry particles may have: (i) a volume median geometric diameter (VMGD) of about 10 microns or less or about 5 microns or less; (ii) a tap density of about 0.2 g / cc or greater or a tap density between 0.2 g / cc and 1.0 g / cc; (iii) a 1 bar / 4 bar dispersibility ratio (1 / 4 bar) of less than about 1.5 as measured by laser diffraction; and / or (iv) a 0.5 bar / 4 bar dispersibility ratio (0.5 / 4 bar) of about 1.5 or less as measured by laser diffraction.

[0024] The respirable dry powder can have: (i) a mass median aerodynamic diameter (MMAD) between about 1 micron and about 5 microns; and / or (ii) a fine particle fraction (FPF) of about 25% or more of the total dose that is less than 5 microns.

[0025] In some embodiments, the respirable dry particles have at least 80% of the capsule ejected powder mass when ejected from a passive dry powder inhaler having a resistance of about 0.036 sqrt (kPa) / liter / minute under the following conditions; using a Size 3 capsule containing 10 mg of total mass, at an inhalation flow rate of 30 LPM for a period of 3 seconds, wherein the total mass consists of respirable dry particles, and wherein the volume median geometric diameter of the respirable dry particles discharged from the inhaler as measured by laser diffraction is 5 microns or less.

[0026] In the methods disclosed herein, a capsule-based passive dry powder inhaler can be used to deliver the inhalable dry powder to the respiratory tract of a subject.

[0027] In the methods disclosed herein, the subject may suffer from infection, allergic bronchopulmonary aspergillosis, respiratory disease, acute exacerbation of respiratory disease, immunodeficiency disorder, cancer, cardiovascular disease, hypertension, hypercholesterolemia, autoimmune disorders, diabetes, gastrointestinal disorders, thrombotic disorders, epilepsy, psychiatric disorders, migraine or pain. For example, the subject may suffer from fungal infection, such as aspergillosis. The subject may suffer from cystic fibrosis, asthma or pneumonia (e.g., fungal pneumonia). The subject may suffer from HIV or AIDS). The subject may suffer from a form of cancer, such as lung cancer (e.g., non-small cell lung cancer). The subject may suffer from congestive heart failure, cardiac rhythm disorders or heart disease. The subject may suffer from bipolar disorder, depression, psychosis or anxiety. The subject may suffer from acute pain or chronic pain. The subject may suffer from surgical pain (e.g., perioperative pain or postoperative pain).

[0028] In some aspects, the present disclosure relates to a respirable dry powder disclosed herein for use in a method of treating a disease or condition in a subject for which oral itraconazole is contraindicated, wherein the respirable dry powder comprises itraconazole and is administered to the respiratory tract of the subject. For example, the subject can be treated with a second therapeutic agent that is a substrate, inducer and / or inhibitor of an enzyme or receptor that is inhibited or metabolized by itraconazole.

[0029] In some aspects, the present disclosure relates to a respirable dry powder disclosed herein for use in a method of co-administering itraconazole and a second therapeutic agent to a subject in need thereof, wherein the respirable dry powder comprises itraconazole and is administered to the respiratory tract of the subject, and wherein the second therapeutic agent is a substrate, inducer and / or inhibitor of an enzyme or receptor that is inhibited by itraconazole or metabolizes itraconazole.

[0030] In some aspects, the present disclosure relates to the use of the respirable dry powder disclosed herein in the preparation of a medicament for treating a disease or condition in a subject for which oral itraconazole is contraindicated, wherein the respirable dry powder comprises itraconazole and is administered to the respiratory tract of the subject. The subject may be treated with a second therapeutic agent that is a substrate, inducer and / or inhibitor of an enzyme or receptor that is inhibited or metabolized by itraconazole.

[0031] In some aspects, the present disclosure relates to the use of the respirable dry powder disclosed herein in the preparation of a medicament for co-administering itraconazole and a second therapeutic agent to a subject in need thereof, wherein the respirable dry powder comprises itraconazole and is administered to the respiratory tract of the subject, and wherein the second therapeutic agent is a substrate, inducer and / or inhibitor of an enzyme or receptor that is inhibited by itraconazole or metabolizes itraconazole. BRIEF DESCRIPTION OF THE DRAWINGS

[0032] Figure 1 is a diagram depicting a structural model of primary absorption from the lungs to the systemic circulation.

[0033] Figure 2A and 2B is a log-linear graph depicting the changes in itraconazole ( Figure 2A ) and OH-itraconazole ( Figure 2B ) simulated and observed plasma-concentration time curves. Simulated data (lines) and observed data (circles; mean values ​​of n=6 individuals) are depicted. The gray line represents the 5th and 95th percentiles, and the black solid line represents the mean data of the simulated population (n=60).

[0034] Figure 3A and 3B is a log-linear graph depicting the changes in itraconazole ( Figure 3A ) and OH-itraconazole ( Figure 3B ) simulated mean plasma-concentration time curves of . The simulated data (lines) are depicted. The grey lines represent the 5th and 95th percentiles, and the black solid line represents the mean data of the simulated population (n=100).

[0035] Figure 4A and 4B is a log-linear graph depicting the effect of 35 mg ( Figure 4A ) and 40mg( Figure 4B) of a single 5 mg dose of midazolam co-administered with steady-state Formulation I. The simulated midazolam plasma concentration-time profiles in the absence of Formulation I (solid line) and on day 14 of 14 days of Formulation I administration (dashed line) are depicted. The lines represent the average data of the simulated population (n=100). DETAILED DESCRIPTION

[0036] The present disclosure relates to a method for applying itraconazole to the respiratory tract of a subject who is contraindicated to oral itraconazole, for example, because the subject is being treated with a second therapeutic agent, which is usually not used in combination with oral itraconazole due to potential DDI. Relative to conventional oral administration, itraconazole can achieve higher and sustained lung exposure after inhalation delivery, while significantly reducing systemic exposure. Without wishing to be bound by theory, it is believed that this limited systemic exposure may be beneficial for subjects who are contraindicated to oral itraconazole, and using an inhalable dry powder containing itraconazole, it is possible to safely achieve therapeutic concentrations of itraconazole in the lungs of this patient population, such as for the treatment of certain diseases or conditions that affect the respiratory system.

[0037] Therefore, in some aspects, the present disclosure relates to a method for treating a disease or condition of a subject for which oral itraconazole is contraindicated, comprising administering a respirable dry powder comprising itraconazole to the respiratory tract of the subject. The subject can be treated with a second therapeutic agent, which is a substrate, inducer and / or inhibitor of an enzyme or receptor that is inhibited or metabolized by itraconazole (e.g., wherein the second therapeutic agent is a substrate, inducer and / or inhibitor of a cytochrome P450 3A4 (CYP3A4) isozyme). In some aspects, the present disclosure relates to a method for co-administering itraconazole and a second therapeutic agent to a subject in need, wherein itraconazole is administered to the respiratory tract of the subject in the form of a respirable dry powder, and wherein the second therapeutic agent is a substrate, inducer and / or inhibitor of an enzyme or receptor that is inhibited or metabolized by itraconazole (e.g., wherein the second therapeutic agent is a substrate, inducer and / or inhibitor of a cytochrome P450 3A4 (CYP3A4) isozyme).

[0038] definition

[0039] As used herein, the term "about" refers to a relative range of + / - 20% of a specified value, for example, "about 20 mg" would be "20 mg + / - 4 mg".

[0040] As used herein, the term "administration" or "administering" refers to the introduction of a therapeutic agent or a composition comprising a therapeutic agent into a subject. For example, administration may refer to the introduction of a respirable dry powder disclosed herein into the respiratory tract of a subject.

[0041] As used herein, the term "amorphous" indicates a lack of significant crystallinity when analyzed via powder X-ray diffraction (XRD).

[0042] As used herein, the term "capsule ejected powder mass" or "CEPM" refers to the amount of dry powder ejected from a capsule or dosage unit container during actuation of a dry powder inhaler, such as during an inhalation maneuver. CEPM is measured gravimetrically, typically by weighing the capsule before and after the firing event to determine the mass of powder removed. CEPM can be expressed as the mass of powder removed (in milligrams), or as a percentage of the initial fill powder mass in the capsule before the firing event.

[0043] As used herein, the term "crystalline microparticle form" refers to itraconazole (including pharmaceutically acceptable forms thereof, including salts, polymorphs, solvates, hydrates, etc.) in particle form (i.e., smaller than the subparticles constituting the respirable dry particles of the dry powder disclosed herein), wherein itraconazole is at least about 50% crystalline. The percentage crystallinity of itraconazole refers to the percentage of the compound in crystalline form relative to the total amount of the compound present in the subparticles. If desired, itraconazole may be at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, or about 100% crystalline. Itraconazole in the form of crystalline microparticles may be in the form of particles having a volume median diameter (Dv50) of about 50 nanometers (nm) to about 5,000 nm, preferably 80 nm to 1750 nm Dv50, or preferably 50 nm to 800 nm Dv50.

[0044] The term "dispersible" is a professional term describing the characteristics of dry powder or inhalable dry particles to be dispersed into an inhalable aerosol. On the one hand, the dispersibility of dry powder or inhalable dry particles is expressed herein as the quotient of the volume median geometric diameter (VMGD) measured at a dispersion (i.e., a modifier) ​​pressure of 1 bar divided by the VMGD measured at a dispersion (i.e., a modifier) ​​pressure of 4 bars, or the quotient of the VMGD at 0.5 bar divided by the VMGD at 4 bars, which is measured by laser diffraction such as HELOS / RODOS. These quotients are referred to herein as "1 bar / 4 bar dispersibility ratio" and "0.5 bar / 4 bar dispersibility ratio", respectively, and dispersibility is associated with low quotients. For example, 1 bar / 4 bar dispersibility ratio refers to the VMGD (measured by HELOS or other laser diffraction system) of the dry powder or respirable dry particles ejected from the orifice of the RODOS dry powder disperser (or equivalent technology) at about 1 bar divided by the VMGD of the same dry powder or respirable dry particles measured by HELOS / RODOS at 4 bar. Therefore, highly dispersible dry powders or respirable dry particles will have a 1 bar / 4 bar dispersibility ratio or a 0.5 bar / 4 bar dispersibility ratio close to 1.0. Highly dispersible powders have lower agglomeration, aggregation or caking tendency, and / or if agglomeration, aggregation or caking, then when they are ejected from the inhaler and inhaled by the subject, it is easy to disperse or deagglomerate. On the other hand, dispersibility is evaluated by measuring the function of the particle size ejected from the inhaler as a function of flow rate. As the flow rate through the inhaler decreases, the amount of energy that can be used to be transferred to the powder to disperse the powder in the airflow decreases. A highly dispersible powder will have a size distribution, such as aerodynamically characterized by its mass median aerodynamic diameter (MMAD), or geometrically characterized by a VMGD that does not substantially increase over a typical flow rate range for human inhalation, such as about 15 to about 60 liters / minute (LPM), about 20 to about 60 LPM, or about 30 LPM to about 60 LPM. Even at lower inhalation flow rates, a highly dispersible powder will have an ejected powder mass or dose of about 80% or more, or a capsule ejected powder mass or dose. VMGD may also be referred to as volume median diameter (VMD), x50, or Dv50.

[0045] As used herein, the term "dry particles" refers to respirable particles that may contain up to about 15% water and / or another solvent in a total amount. Preferably, the dry particles contain up to about 10% water and / or another solvent in a total amount, up to about 5% water, up to about 1% water, or between 0.01% and 1% water and / or another solvent in a total amount, or may be substantially free of water and / or other solvents, based on the weight of the dry particles.

[0046] As used herein, the term "dry powder" refers to a composition comprising respirable dry particles. The dry powder may contain water and / or another solvent in a total amount of up to about 15%. Preferably, the dry powder contains water and / or another solvent in a total amount of up to about 10%, a total amount of up to about 5%, a total amount of up to about 1%, or a total amount of between 0.01% and 1%, by weight of the dry powder, or may be substantially free of water and / or other solvents. In one aspect, the dry powder is a respirable dry powder.

[0047] As used herein, the term "effective amount" refers to the amount of a medicament required to achieve the desired effect; such as treatment of fungal infections or related conditions, such as allergic bronchopulmonary aspergillosis (ABPA). The actual effective amount for a particular use may vary depending on the particular dry powder or respirable dry particles, the mode of administration, and the age, weight, general health of the subject, and the severity of the symptoms or conditions being treated. The appropriate amount of dry powder and dry particles to be administered and the dosage schedule for a particular patient can be determined by a clinician of ordinary skill based on these and other considerations.

[0048] As used herein, the term "ejected dose" or "ED" refers to an indication of a drug formulation delivered from a suitable inhaler device after an emission or dispersion event. More specifically, for dry powder, ED is a measure of the percentage of powder that is drawn from a unit dose package and leaves the mouthpiece of an inhaler device. ED is defined as the ratio of the drug or powder delivered by the inhaler device to the nominal dose (i.e., the mass of the drug or powder per unit dose placed in a suitable inhaler device before emission). ED is an experimentally measured parameter and can be determined using USP Part 601 Aerosols, Metered-Dose Inhalers and Dry Powder Inhalers, Delivered-Dose Uniformity, Sampling the Delivered Dose from Dry Powder Inhalers, United States Pharmacopeia convention, Rockville, MD, the 13th revised edition, 222-225, 2007. The method utilizes an in vitro device that is configured to simulate patient administration. The ED can also be calculated from results generated by a Next Generation Impactor (NGI) experiment by summing all drug or powder measured from the interface adapter, the NGI inlet orifice, and all stages within the NGI. Results generated by ED testing according to USP 601 and those generated by NGI are generally very consistent.

[0049] The term "lung-to-plasma ratio" or "lung:plasma ratio" refers to the ratio of the concentration of itraconazole in the lung to the concentration of itraconazole in plasma at a specific point in time or over a specific time period. For example, the lung:plasma ratio can be calculated based on the maximum concentration of itraconazole in the lung or serum (i.e., "C max ") or simultaneous measurements at any point in time. The lung:plasma ratio of the total exposure (i.e., "area under the curve" or "AUC") over a period of time such as a 24-hour period can also be calculated. The pulmonary concentration of itraconazole can be evaluated by measuring the concentration in sputum, by lung lavage, by biopsy, or by some other method. The lung:plasma ratio can be calculated based on simultaneous measurements at any point during the dosing cycle and can be calculated based on simultaneous measurements before or at steady state.

[0050] As used herein, the term "nominal dose" refers to a single dose of itraconazole. The nominal dose is the total dose of itraconazole within a container such as a capsule, blister, or ampoule.

[0051] As used herein, the terms "FPF(<X)", "FPF(<X microns)", and "fine particle fraction less than X microns", where X is equal to, for example, 3.4 microns, 4.4 microns, 5.0 microns, or 5.6 microns, refer to the portion of a dry particle sample with an aerodynamic diameter less than X microns. For example, FPF(<X) can be determined by dividing the mass of respirable dry particles deposited on the second stage and final collection filter of a two-stage, folded Andersen Cascade Impactor (ACI) by the mass of respirable dry particles weighed into the capsule for delivery to the instrument. This parameter can also be designated "FPF_TD(<X)", where TD means total dose. Similar measurements can be made using an eight-stage ACI. The eight-stage ACI cut-off values are different at a standard flow rate of 60 L / min, but FPF_TD(<X) can be derived from the eight-stage complete data set. The eight-stage ACI results can also be calculated by the USP method, which uses the dose collected in the ACI rather than the dose in the capsule to determine FPF. Similarly, a seven-stage Next Generation Impactor (NGI) can be used.

[0052] As used herein, the terms "FPD(<X)", "FPD <X microns", "FPD(<X microns)", and "fine particle dose less than X microns", where X is equal to, for example, 3.4 microns, 4.4 microns, 5.0 microns, or 5.6 microns, refer to the mass of therapeutic agent delivered by respirable dry particles with an aerodynamic diameter less than X microns. FPD <X microns can be determined by using an eight-stage Andersen Cascade Impactor (ACI) or Next Generation Impactor (NGI) at a standard flow rate of 60 L / min, summing the mass deposited on the final collection filter, and directly calculating or extrapolating the FPD value. Similarly, a seven-stage Next Generation Impactor (NGI) can be used.

[0053] As used herein, the term "inhalable" refers to dry particles or dry powders suitable for delivery to the respiratory tract (e.g., pulmonary delivery) of a subject by inhalation. Inhalable dry powders or dry particles have a mass median aerodynamic diameter (MMAD) of less than about 10 microns, preferably about 5 microns or less.

[0054] As used herein, the term "respiratory tract" includes the upper respiratory tract (e.g., nasal passages, nasal cavity, pharynx, pharynx, and larynx), respiratory airways (e.g., trachea, bronchi, and bronchioles), and lungs (e.g., respiratory bronchioles, alveolar ducts, alveolar sacs, and alveoli).

[0055] The term "small" as used herein to describe respirable dry particles refers to particles having a volume median geometric diameter (VMGD) of about 10 microns or less, preferably about 5 microns or less, or less than 5 microns.

[0056] As used herein, the term "stabilizer" refers to a compound that improves the physical stability of itraconazole in the form of crystalline microparticles (e.g., reduces aggregation, agglomeration, Ostwald ripening and / or flocculation of the microparticles) when suspended in a liquid in which itraconazole is poorly soluble. Suitable stabilizers are surfactants and amphiphilic materials, and include polysorbates (PS; polyoxyethylene sorbitan fatty acid esters), such as polysorbate 20 (PS20), polysorbate 40 (PS40), polysorbate 60 (PS60) and polysorbate 80 (PS80); fatty acids, such as lauric acid, palmitic acid, myristic acid, oleic acid and stearic acid, and salts thereof; sorbitan fatty acid esters, such as Span20, Span40, Span60, Span80 and Span 85; phospholipids such as dipalmitoylphosphatidylcholine (DPPC), 1,2-dipalmitoyl-sn-glycero-3-phospho-L-serine (DPPS), 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DSPC), 1-palmitoyl-2-oleoylphosphatidylcholine (POPC) and 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC); phosphatidylglycerols (PG), such as diphosphatidylglycerol (DPPS); PG), DSPG, DPPG, POPG, etc.; 1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE); fatty alcohol; benzyl alcohol, polyoxyethylene-9-lauryl ether; glycocholate; surfactin; poloxamer; polyvinyl pyrrolidone (PVP); PEG / PPG block copolymer (Pluronic / Poloxamer); polyoxyethylene chloroester ether; POE alkyl ether; tyloxapol; lecithin; etc. Preferred stabilizers are polysorbates and fatty acids. A particularly preferred stabilizer is polysorbate 80 (PS80).

[0057] As used herein, the term "homogeneous dry granules" refers to granules that are uniform in composition. The uniform dry granules disclosed herein are substantially identical in composition of itraconazole, stabilizer, and optionally one or more excipients, and do not include a mixture of two or more granules.

[0058] Methods of administering itraconazole dry powder

[0059] The inventors have found that the use of dry powders comprising itraconazole disclosed herein can achieve a pulmonary concentration of itraconazole substantially higher than that achievable by oral administration, while maintaining a relatively low systemic concentration of itraconazole. Without wishing to be bound by theory, it is believed that by using dry powders disclosed herein to achieve higher pulmonary concentrations of itraconazole, administration can achieve a therapeutic concentration of itraconazole in the respiratory system while minimizing the systemic concentration of itraconazole. Minimizing the systemic concentration of itraconazole can not only help prevent the side effects and toxicity associated with itraconazole, but also minimize the inhibition of enzymes or receptors (such as CYP3A4) for which itraconazole and OH-itraconazole are inhibitors or substrates. In other words, by minimizing the systemic concentration of itraconazole, when treating a subject with a second therapeutic agent (e.g., because it is a substrate, inducer or inhibitor of the same enzyme or receptor (e.g., CYP3A4)) that is contraindicated with the use of itraconazole, the inhalable dry powder of the present disclosure can be used to avoid DDI. The inhalable dry powder of the present application is particularly useful for co-administration with therapeutic agents that are inhibitors or inducers of CYP3A4 and / or are metabolized through the same metabolic pathway as itraconazole.

[0060] It is further believed that, for example, relative to conventional oral administration, even a relatively low total dose can achieve a therapeutic concentration of itraconazole in the lung. For example, studies have documented the systemic and pulmonary pharmacokinetics of oral itraconazole in adults and children, and pharmacokinetic studies examining inhalable dry powders containing itraconazole have shown that after a relatively low single inhalation dose of 20 mg dry powder, lung exposure considered to be a therapeutic agent for the treatment of pulmonary aspergillosis can be achieved. (See Conte, JE et al. Antimicrob. Agents Chemother. (2004) 48: 3823–3827; See also Hava, DL et al., Brit. J. Clin. Pharmacol. (2020) 86 (4): 723–733; Each of the documents is incorporated herein by reference in its entirety). Advantageously, the relatively low total dose of itraconazole required to achieve a therapeutic effect using the dry powders disclosed herein, compared to the large doses required for oral administration, can reduce the risk of DDI, which provides an opportunity to combine the dry powders comprising itraconazole with a second therapeutic agent, particularly a therapeutic agent known to have a DDI and / or a therapeutic agent for which the use of itraconazole is contraindicated, such as a substrate, inducer or inhibitor of CYP3A4.

[0061] When inhaled at a therapeutic dose, a dry powder comprising itraconazole in an amorphous form has a shorter lung retention time, a reduced lung to plasma exposure ratio, and undesirable toxic effects on lung tissue. Without wishing to be bound by any particular theory, it is believed that the dry powder comprising itraconazole in a crystalline form (e.g., nanocrystalline form) disclosed herein has a slower dissolution rate in the lung relative to the amorphous form, providing more sustained exposure within a 24-hour period after administration, and minimizing systemic exposure and DDI potential.

[0062] Furthermore, without wishing to be bound by any particular theory, it is believed that smaller crystalline particles of itraconazole (e.g., nanocrystalline or microcrystalline itraconazole) will dissolve faster in the airway lining fluid than larger crystalline particles, in part due to the greater total surface area. It is also believed that crystalline itraconazole will dissolve more slowly in the airway lining fluid than amorphous itraconazole, in part due to lower water solubility. Thus, the dry powders described herein can be formulated using itraconazole in the form of crystalline microparticles of the desired crystal size or crystal size range in the dry powder, and optionally wherein suitable excipients and stabilizers are in a suitable ratio with itraconazole, wherein each excipient and stabilizer can be adjusted to affect, for example, dissolution rate, and achieve desired pharmacokinetic properties while avoiding unacceptable toxicity in the lungs, and further avoiding DDI with a second therapeutic agent.

[0063] The use of dry powder disclosed herein can achieve a relatively high lung concentration of itraconazole: systemic concentration ratio. Without wishing to be bound by any particular theory, it is believed that a relatively high lung concentration: systemic concentration ratio can not only minimize off-target effects and / or toxicity associated with itraconazole, but also allow for co-administration with a second therapeutic agent that is contraindicated with the use of itraconazole, and reduce the risk of DDI. Therefore, the method disclosed herein provides advantages over commercially available itraconazole preparations, which are usually administered orally in large quantities and cannot be co-administered with many other useful therapeutic agents due to the high possibility of DDI and related safety issues.

[0064] As detailed in the Examples section of this article, PBPK techniques were used to evaluate the effect of inhaled itraconazole on the metabolism of a second therapeutic agent that is a substrate, inducer, and / or inhibitor of an enzyme or receptor that is inhibited by itraconazole or metabolizes itraconazole, using midazolam as a model second therapeutic agent. Specifically, an existing oral PBPK model for itraconazole and OH-itraconazole was adapted from the Simcyp compound library, which has been robustly validated using clinical DDI data and has high confidence in model predictions for inhalable dry powders containing itraconazole. Despite high drug concentrations of itraconazole in lung tissue, itraconazole exposure in the gut and liver is minimal. Therefore, although the prediction for the major active metabolite OH-itraconazole is overestimated, the predicted impact on midazolam metabolism is minimal. These results indicate that itraconazole can be safely and effectively administered via an inhaled formulation, even in patients taking a second therapeutic agent that is a substrate, inducer, and / or inhibitor of an enzyme or receptor (e.g., CYP3A4) that is inhibited by itraconazole or that metabolizes itraconazole. The clinical significance of being able to safely administer itraconazole with one of those second therapeutic agents is clear and should increase the likelihood of maintaining treatment in vulnerable patients taking medications that are contraindicated in the presence of oral itraconazole.

[0065] The methods disclosed herein may include treating a disease or condition in a subject for which oral itraconazole is contraindicated, comprising administering to the subject's respiratory tract an inhalable dry powder comprising itraconazole (e.g., crystalline itraconazole). In addition, the methods disclosed herein may include administering itraconazole together with a second therapeutic agent to a subject in need thereof, wherein itraconazole is administered to the subject's respiratory tract in the form of an inhalable dry powder.

[0066] The second therapeutic agent may be a substrate of an enzyme or receptor (e.g., CYP3A4) that is inhibited by itraconazole or metabolizes itraconazole. The second therapeutic agent may be an inhibitor of an enzyme or receptor (e.g., CYP3A4) that is inhibited by itraconazole or metabolizes itraconazole. The second therapeutic agent may be an inducer of an enzyme or receptor (e.g., CYP3A4) that is inhibited by itraconazole or metabolizes itraconazole.

[0067] The second therapeutic agent may be combined with oral itraconazole (eg ) is contraindicated. For example, the second therapeutic agent can be a substance that is listed by a regulatory agency as contraindicated for use with itraconazole, for example, as described in the label.

[0068] There are many different classes of drugs that are contraindicated or not originally recommended for use in combination with normal doses of oral itraconazole. Therefore, the inhalable dry powder disclosed herein can be combined with many different classes of drugs without significant risk of DDI or other adverse reactions, and / or without the need to carefully adjust or limit the dose to avoid potential DDI or adverse reactions.

[0069] For example, the methods disclosed herein may comprise administering the respirable dry powder to a subject in combination with a second therapeutic agent or administering the respirable dry powder to a subject who is also administered a second therapeutic agent, wherein the second therapeutic agent is selected from the group consisting of an alpha blocker, a beta blocker, an analgesic, an antiarrhythmic, an antibacterial, an anticoagulant, an antiplatelet, an anticonvulsant, an antidiabetic, an anthelmintic, an antifungal, an antiprotozoal, an antimigraine, an antineoplastic, an antipsychotic, an anxiolytic, a hypnotic, an antiviral, a calcium channel blocker, a cardiovascular drug, a contraceptive, a diuretic, an anticonvulsant, an immunosuppressant, a lipid-lowering drug, a respiratory drug (e.g., an asthma treatment drug), an antidepressant (e.g., a tricyclic or a selective serotonin reuptake inhibitor (SSRI)), a urological drug, a vasopressin receptor antagonist, a nonsteroidal anti-inflammatory drug (NSAID), or a gastrointestinal drug.

[0070] The second therapeutic agent can be alfuzosin, silodosin or tamsulosin. The second therapeutic agent can be methadone, fentanyl, alfentanil, buprenorphine, oxycodone or sufentanil. The second therapeutic agent can be disopyramide, dofetilide, dronedarone, quinidine or digoxin. The second therapeutic agent can be bedaquiline, rifabutin, clarithromycin or trimetrexate. The second therapeutic agent can be ticagrelor, apixaban, rivaroxaban, vorapaxar, cilostazol, dabigatran, warfarin or carbamazepine. The second therapeutic agent can be repaglinide or saxagliptin. The second therapeutic agent can be isavuconazolium, praziquantel, artemether-lumefantrine or quinine. The second therapeutic agent may be an ergot alkaloid, such as dihydroergotamine, ergometrine, ergonovine, methylergometrine, methylergonovine, ergotamine. The second therapeutic agent may be eletriptan. The second therapeutic agent can be irinotecan, axitinib, bosutinib, cabazitaxel, cabozantinib, ceritinib, cobimetinib, crizotinib, dabrafenib, dasatinib, docetaxel, ibrutinib, lapatinib, nilotinib, olaparib, pazopanib, regorafenib, sunitinib, trabectedin, emtansine, vinca alkaloids, bortezomib, brentuximab, busulfan, erlotinib, gefitinib, idelalisib, nintedanib, panobinostat, ponatinib, ruxolitinib, sonidegi, vandetanib, imatinib, or ixabepilone. The second therapeutic agent can be alprazolam, aripiprazole, buspirone, diazepam, haloperidol, midazolam, quetiapine, ramelteon, risperidone, suovorexin, zopiclone, lurasidone, pimozide or triazolam. The second therapeutic agent can be levacetylmethadol, simeprevir, daclatasvir, indinavir, maraviroc, cobicistat, elvitegravir, ritonavir, saquinavir or tenofovir disoproxil fumarate. The second therapeutic agent can be nadolol. The second therapeutic agent can be felodipine, nisoldipine, diltiazem, dihydropyridines or verapamil. The second therapeutic agent can be ivabradine, ranolazine, aliskiren, riociguat, sildenafil, tadalafil, bosentan, guanfacine, dienogest or ulipristal. The second therapeutic agent can be eplerenone. The second therapeutic agent can be cisapride, naloxegol, aprepitant, loperamide or netupitant. The second therapeutic agent can be everolimus, sirolimus, temsirolimus, budesonide, ciclesonide, cyclosporine, dexamethasone, fluticasone, methylprednisolone or tacrolimus. The second therapeutic agent can be lomitapide, lovastatin, simvastatin or atorvastatin. The second therapeutic agent can be salmeterol. The second therapeutic agent can be venlafaxine. The second therapeutic agent can be afadil, fesoterodine, solifenacin, darifenacin, vardenafil, dutasteride, oxybutynin or tolterodine.The second therapeutic agent can be colchicine, ilukastat, lumacator, avacato, elecator, tizacator,. or cabergoline. The second therapeutic agent may be a cannabinoid. The second therapeutic agent may be cinacalcet, conivaptan or vilvaptan. The second therapeutic agent may be a Saccharomyces boulardii composition. The second therapeutic agent may be meloxicam. The second therapeutic agent may be ciprofloxacin, erythromycin or clarithromycin. The second therapeutic agent may be idelalis. The second therapeutic agent may be darunavir or fosamprenavir. The second therapeutic agent may be isoniazid, rifampicin or rifabutin. The second therapeutic agent may be phenobarbital, phenytoin, efavirenz or nevirapine. The second therapeutic agent may be a drug that reduces gastric acidity, such as an acid neutralizing drug (e.g., aluminum hydroxide), an acid secretion inhibitor (e.g., an H2 receptor antagonist) or a proton pump inhibitor. The second therapeutic agent may be halofantrine.

[0071] In some embodiments, the second therapeutic agent is methadone, disopyramide, dofetilide, dronedarone, quinidine, isavuconazole, ergot alkaloids (such as dihydroergotamine, ergonovine, ergotamine, or methylergonovine), irinotecan, lurasidone, midazolam, pimozide, triazolam, felodipine, nisoldipine, ivabradine, ranolazine, eplerenone, cisapride, naloxegol, lomitapide, lovastatin, simvastatin, avadil, ticagrelor, colchicine, fesoterodine, solifenacin, or ilurustat.

[0072] In the methods disclosed herein, the respirable dry powder can be administered in a nominal dose of between 1 mg and about 60 mg, for example, between about 5 mg and about 40 mg, between about 1 mg and about 10 mg, between about 10 mg and about 20 mg, between about 20 mg and about 30 mg, or between about 30 mg and about 40 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, or about 40 mg.

[0073] Co-administration can mean administering the respirable dry powder to the subject no more than about 14 days before or after administration of the second therapeutic agent, for example, less than about 14 days, less than about 12 days, less than about 10 days, less than about 8 days, less than about 7 days, less than about 6 days, less than about 5 days, less than about 4 days, less than about 3 days, less than about 2 days, or less than about 1 day before or after administration of the second therapeutic agent. In some embodiments, co-administration refers to administering a dry powder to a subject, such as administering a respirable dry powder, on the same day as administration of the second therapeutic agent, less than about 20 hours, less than about 18 hours, less than about 16 hours, less than about 14 hours, less than about 12 hours, less than about 11 hours, less than about 10 hours, less than about 9 hours, less than about 8 hours, less than about 7 hours, less than about 6 hours, less than about 5 hours, less than about 4 hours, less than about 3 hours, less than about 2 hours, less than about 1 hour, less than about 45 minutes, less than about 30 minutes, less than about 20 minutes, less than about 10 minutes, or less than about 5 minutes before or after administration of the second therapeutic agent. In some embodiments, itraconazole is administered to a subject less than about 5 minutes before or after administration of the second therapeutic agent.

[0074] In the method disclosed herein, the subject to be treated with itraconazole may be a subject for whom oral itraconazole is contraindicated. This may be due to the subject having applied a second therapeutic agent disclosed herein (e.g., a therapeutic agent contraindicated with the use of itraconazole). Due to the use of the inhalable dry powder disclosed herein to achieve favorable pharmacokinetic properties, the subject can still apply the inhalable dry powder disclosed herein in a safe manner to achieve local therapeutic concentrations of itraconazole in the lungs, and to avoid the expected DDI or adverse events when applying different formulations of itraconazole (e.g., oral itraconazole).

[0075] Subjects to be treated with itraconazole, may be subjects for whom oral itraconazole is contraindicated, may suffer from a disease or condition. The specific disease or condition may be a condition for which itraconazole is being administered, or may be a condition for which itraconazole is not being treated, or may be a condition unrelated to the use of itraconazole. Subjects may suffer from infections (e.g., fungal infections, such as aspergillosis), allergic bronchopulmonary aspergillosis, respiratory diseases (e.g., cystic fibrosis, asthma, pneumonia (e.g., fungal pneumonia)), acute exacerbations of respiratory diseases, immunodeficiency disorders (e.g., HIV or AIDS), cancer (e.g., lung cancer, such as non-small cell lung cancer), cardiovascular disorders (e.g., congestive heart failure, cardiac rhythm disorders, heart disease), hypertension, hypercholesterolemia, autoimmune disorders, diabetes, gastrointestinal disorders, thrombotic disorders, epilepsy, psychiatric disorders (e.g., bipolar disorder, depression, psychosis or anxiety), migraine, pain (e.g., acute pain, pain caused by surgery or chronic pain). In some instances, the disease or condition is a condition treated with itraconazole, such as an infection (e.g., a fungal infection such as aspergillosis), allergic bronchopulmonary aspergillosis, a respiratory disease (e.g., cystic fibrosis, asthma, pneumonia (e.g., fungal pneumonia)), an acute exacerbation of a respiratory disease, or a cancer (e.g., lung cancer, e.g., non-small cell lung cancer).

[0076] In some embodiments, the methods disclosed herein are used to treat an infection (e.g., a fungal infection, such as aspergillosis), allergic bronchopulmonary aspergillosis, a respiratory disease (e.g., cystic fibrosis, asthma, pneumonia (e.g., fungal pneumonia)), an acute exacerbation of a respiratory disease, or a cancer (e.g., lung cancer, such as non-small cell lung cancer) in a subject in need thereof.

[0077] Inhalable dry powder

[0078] The dry powder disclosed herein can be administered to a subject by inhalation (e.g., oral inhalation). In order to achieve oral inhalation, a dry powder inhaler, such as a passive dry powder inhaler, can be used. Inhalable dry powders comprising itraconazole for treating fungal infections are described in WO 2018 / 071757, WO 2019 / 204583, and WO2019 / 204597, the entire contents of which are incorporated herein by reference in their entirety.

[0079] The respirable dry powder used in the methods disclosed herein may include homogeneous respirable dry particles comprising 1) itraconazole in the form of crystalline microparticles, 2) a stabilizer, and optionally 3) one or more excipients. Such respirable dry particles may be prepared by any suitable method, such as by preparing a raw material in which itraconazole in the form of crystalline microparticles is suspended in an aqueous solution of an excipient and then spray drying the raw material.

[0080] The respirable dry particles may contain about 1% to about 95% by weight (wt%) of itraconazole. Preferably, the respirable dry particles contain a certain amount of itraconazole so that a therapeutically effective dose can be administered and maintained without the need to inhale a large amount of dry powder or to inhale the dry powder too frequently, for example, more than three times a day. For example, preferably, the respirable dry particles contain about 30% to about 70% by weight or about 40% to about 60% by weight, for example, about 45%, about 50% by weight or about 55% by weight (wt%) of itraconazole. The weight content of itraconazole present in the respirable dry particles can also be referred to as "drug loading".

[0081] Itraconazole may be present in the respirable dry particles in the form of crystalline microparticles (e.g., nanocrystals). More specifically, in the form of subparticles of about 50 nm to about 5,000 nm (Dv50), preferably, wherein the itraconazole is at least 50% crystalline. For example, for any desired itraconazole loading (sometimes referred to as "drug loading"), the subparticle size may be about 100 nm, about 300 nm, about 1500 nm, about 80 nm to about 300 nm, about 80 nm to about 250 nm, about 80 nm to about 200 nm, about 100 nm to about 150 nm, about 1200 nm to about 1500 nm, about 1500 nm to about 1750 nm, about 1200 nm to about 1400 nm, or about 1200 nm to about 1350 nm (Dv50). In certain embodiments, the subparticles are between about 50 nm and about 2500 nm, between about 80 nm and 1750 nm, between about 50 nm and 1000 nm, between about 50 nm and 800 nm, between about 50 nm and 600 nm, between about 50 nm and 500 nm, between about 50 nm and 400 nm, between about 50 nm and 300 nm, between about 50 nm and 200 nm, or between about 100 nm and 300 nm. In addition, for any desired drug loading and subparticle size, the crystallinity of itraconazole can be at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, or about 100% crystalline. Preferably, itraconazole is about 100% crystalline. In some embodiments, the dry powder administered comprises homogeneous respirable dry particles comprising at least 50% crystalline, e.g., 55% crystalline, 60% crystalline, 65% crystalline, 70% crystalline, 75% crystalline, 80% crystalline, 85% crystalline, 90% crystalline, 95% crystalline, 96% crystalline, 97% crystalline, 98% crystalline, 99% crystalline, or more than 99% crystalline itraconazole.

[0082] Itraconazole in the form of crystalline microparticles may be prepared to any desired subparticle size by suitable methods, including stabilizers if necessary, such as by wet milling, jet milling or other suitable methods.

[0083] The respirable dry particles also include a stabilizer. The stabilizer helps to maintain the desired size of itraconazole in the form of crystalline microparticles in the spray-dried raw material during wet milling, and helps to wet and disperse the itraconazole crystalline microparticle suspension and maintain its physical stability. It is preferred to use a small amount of stabilizer required to achieve the above benefits. The amount of stabilizer is usually in a fixed ratio with the amount of itraconazole present in the dry particles, and the range can be from about 1: 1 (itraconazole: stabilizer (wt: wt)) to about 50: 1 (wt: wt), and about 10: 1 is preferred. For example, the ratio of itraconazole in the dry particles: stabilizer (wt: wt) can be about 8: 1, about 9: 1, about 10: 1, about 11: 1 or about 12: 1.

[0084] The amount of stabilizer present in the dry particles can be in the range of about 1 wt % to about 15 wt %, such as about 3 wt % to about 7 wt % or about 5 wt %. It is generally preferred that the respirable dry particles contain less than about 10 wt %, such as 9 wt % or less, 8 wt % or less, 7 wt % or less, 5 wt % or less, 4 wt % or less, 3 wt % or less, 2 wt % or less or 1 wt % or less of stabilizer. A particularly preferred stabilizer for the dry powder described herein is polysorbate 80. In contrast to conventional dry powders that use surfactants to prevent the dry powder from starting to crystallize, surfactants are added to the dry powders disclosed in the present invention to stabilize the colloidal suspension of crystalline itraconazole in the antisolvent.

[0085] In some embodiments, the dry powder administered comprises homogenous respirable dry particles comprising itraconazole and polysorbate 80, wherein the ratio of itraconazole:polysorbate 80 (wt:wt) is about 10:1.

[0086] The respirable dry particles also include a sodium salt (e.g., sodium sulfate or sodium chloride). For example, the dry particles may include sodium sulfate. In a preferred embodiment, the respirable dry particles include about 15% to about 50% by weight of a sodium salt (e.g., sodium sulfate). For example, the respirable dry particles may include about 25% to about 45% by weight of a sodium salt, such as about 30%, 35% or 40% by weight of a sodium salt (e.g., sodium sulfate).

[0087] The inhalable dry particles also include any suitable and desired amount of one or more excipients. In some embodiments, one or more excipients are present in an amount of about 5% by weight to about 20% by weight. Many excipients are well known in the art and may be included in dry powders and dry particles as described herein. Pharmaceutically acceptable excipients particularly preferably used for dry powders and dry particles as described herein include leucine. For example, the inhalable dry particles include an excipient (e.g., leucine) in an amount of about 1% by weight to about 20% by weight, for example, between about 5% by weight to about 20% by weight, for example, about 10% by weight. In some embodiments, the inhalable dry particles include the leucine in an amount of about 10% by weight.

[0088] Without wishing to be bound by theory, it is believed that combining itraconazole in dry powder form with leucine and a sodium salt (e.g., sodium sulfate) can provide an optimal dissolution rate, thereby obtaining effective therapeutic levels of itraconazole in the lungs without unacceptable toxicity or DDI when the dry powder is co-administered with a second therapeutic agent. In addition, maintaining a relatively high itraconazole drug load (e.g., about 50% by weight) can prevent the dry powder from dissolving rapidly in the lungs. For example, the dry powder disclosed herein dissolves more slowly in the lungs than a formulation combining a relatively low amount of itraconazole (e.g., less than 40% by weight) with a hydrophilic excipient such as mannitol.

[0089] The dissolution of the dry powder used in the method disclosed herein can be measured according to the dissolution half-life. In some embodiments, the dry powder used in the method disclosed herein has at least about 2 minutes, such as between about 2 minutes to about 20 minutes, such as about 2 minutes, about 3 minutes, about 4 minutes, about 5 minutes, about 6 minutes, about 7 minutes, about 8 minutes, about 9 minutes or about 10 minutes of dissolution half-life. In some embodiments, the dissolution half-life is about 4.1 minutes, about 4.2 minutes, about 4.3 minutes or about 4.4 minutes. In some embodiments, the dissolution half-life is between about 4.13 minutes to about 16.84 minutes.

[0090] In one aspect, the dry powder comprises respirable dry particles comprising: (i) about 50% by weight of itraconazole in the form of crystalline microparticles, about 5% by weight of a stabilizer, about 35% by weight of a sodium salt, and about 10% by weight of leucine. For example, the dry powder may comprise respirable dry particles comprising: (i) 50% by weight of itraconazole in the form of crystalline microparticles, 5% by weight of a stabilizer (e.g., polysorbate 80), 35% by weight of a sodium salt (e.g., sodium sulfate), and 10% by weight of leucine. The dry powder may consist essentially of respirable dry particles, which consist essentially of: (i) 50% by weight of itraconazole in the form of crystalline microparticles, 5% by weight of a stabilizer (e.g., polysorbate 80), 35% by weight of a sodium salt (e.g., sodium sulfate), and 10% by weight of leucine.

[0091] The dry powders disclosed herein may be free of lactose or other carrier particles.

[0092] Dry powders and / or respirable dry particles are preferably small, dense and dispersible. In order to measure the volume median geometric diameter (VMGD), a laser diffraction system can be used, such as a Spraytec system (particle size analysis instrument, Malvern Instruments) and a HELOS / RODOS system (laser diffraction sensor with a dry distribution unit, Sympatec GmbH). The respirable dry particles have the following VMGD, as measured by laser diffraction at a maximum aperture ring pressure using a HELOS / RODOS system at a dispersion pressure setting of 1.0 bar (also referred to as a regulator pressure): about 10 microns or less, about 5 microns or less, about 4 μm or less, about 3 μm or less, about 1 μm to about 5 μm, about 1 μm to about 4 μm, about 1.5 μm to about 3.5 μm, about 2 μm to about 5 μm, about 2 μm to about 4 μm, or about 2 μm to about 3 μm. Preferably, the VMGD is about 5 microns or less or about 4 μm or less. In one aspect, the dry powder and / or respirable dry particles have a minimum VMGD of about 0.5 microns or about 1.0 microns.

[0093] The dry powder and / or respirable dry particles preferably have a 1 bar / 4 bar dispersibility ratio and / or a 0.5 bar / 4 bar dispersibility ratio of less than about 2.0 (e.g., about 0.9 to less than about 2), about 1.7 or less (e.g., about 0.9 to about 1.7), about 1.5 or less (e.g., about 0.9 to about 1.5), about 1.4 or less (e.g., about 0.9 to about 1.4), or about 1.3 or less (e.g., about 0.9 to about 1.3), and preferably have a 1 bar / 4 bar dispersibility ratio and / or a 0.5 bar / 4 bar dispersibility ratio of about 1.5 or less (e.g., about 1.0 to about 1.5) and / or about 1.4 or less (e.g., about 1.0 to about 1.4).

[0094] The dry powder and / or respirable dry particles preferably have a particle size of at least about 0.2 g / cm 3 The tap density is at least about 0.25 g / cm 3 The tap density is at least about 0.3 g / cm 3 The tap density is at least about 0.35 g / cm 3 The tap density is at least about 0.4 g / cm 3 For example, the dry powder and / or the respirable dry particles have a tap density greater than 0.4 g / cm 3 (For example, greater than 0.4 g / cm 3 To about 1.2g / cm 3 ) of a tap density of at least about 0.45 g / cm 3 (For example, about 0.45 g / cm3 To about 1.2g / cm 3 ), at least about 0.5 g / cm 3 (For example, about 0.5 g / cm 3 To about 1.2g / cm 3 ), at least about 0.55 g / cm 3 (For example, about 0.55 g / cm 3 To about 1.2g / cm 3 ), at least about 0.6 g / cm 3 (For example, about 0.6 g / cm 3 To about 1.2g / cm 3 ) or at least about 0.6 g / cm 3 To about 1.0g / cm 3 Alternatively, the dry powder and / or respirable dry particles preferably have a tap density of about 0.01 g / cm 3 To about 0.5g / cm 3 , about 0.05g / cm 3 To about 0.5g / cm 3 , about 0.1g / cm 3 To about 0.5g / cm 3 , about 0.1g / cm 3 To about 0.4g / cm 3 or about 0.1g / cm 3 To about 0.4g / cm 3 Alternatively, the dry powder and / or respirable dry particles have a tap density of about 0.15 g / cm 3 To about 1.0g / cm 3 Alternatively, the dry powder and / or respirable dry particles have a tap density of about 0.2 g / cm 3 To about 0.8g / cm 3 The tap density.

[0095] The dry powder and / or respirable dry particles have a particle size of at least about 0.1 g / cm 3 or at least about 0.8 g / cm 3 For example, the dry powder and / or respirable dry particles have a bulk density of about 0.1 g / cm 3 To about 0.6g / cm 3 , about 0.2g / cm 3 To about 0.7g / cm 3 , about 0.3g / cm 3 To about 0.8g / cm 3 The bulk density.

[0096] When the dry powder is a respirable dry powder, the respirable dry particles and dry powder preferably have an MMAD of less than 10 microns, preferably an MMAD of about 5 microns or less or about 4 microns or less. In one aspect, the respirable dry powder and / or the respirable dry particles preferably have a minimum MMAD of about 0.5 microns or about 1.0 microns. In one aspect, the respirable dry powder and / or the respirable dry particles preferably have a minimum MMAD of about 2.0 microns, about 3.0 microns or about 4.0 microns.

[0097] The dry powder and / or respirable dry particles preferably have an FPF of less than about 5.6 microns (FPF<5.6 μm), which accounts for at least about 35% of the total dose, preferably at least about 45%, at least about 60%, between about 45% and about 80%, or between about 60% and about 80%.

[0098] The dry powder and / or respirable dry particles preferably have an FPF of less than about 3.4 microns (FPF<3.4 μm), which accounts for at least about 20% of the total dose, preferably at least about 25%, at least about 30%, at least about 40%, between about 25% and about 60%, or between about 40% and about 60%.

[0099] The dry powder and / or respirable dry particles preferably have a total water and / or solvent content of up to about 15% by weight, up to about 10% by weight, up to about 5% by weight, up to about 1%, or between about 0.01% and about 1%, or may be substantially free of water or other solvents.

[0100] Dry powders and / or inhalable dry particles can preferably be administered with low inhalation energy. In order to correlate different inhalation flow rates, volumes, and dispersions of powders from inhalers of different resistances, the energy required to perform the inhalation action can be calculated. The inhalation energy can be calculated by the following equation: E = R 2 Q 2 V, where E is the inhalation energy in joules and R is the inhaler resistance in kPa 1 / 2 / LPM, Q is the steady flow rate in L / min, V is the volume of inhaled air in L.

[0101] Healthy adult populations were predicted to be able to achieve inhalation energies ranging from 2.9 joules (comfortable inhalation) to 22 joules (maximum inhalation) using the peak inspiratory flow rate (PIFR) values ​​measured by Clarke et al. (Journal of Aerosol Med, 6(2), pp. 99-110, 1993), which were based on FDA dry powder inhaler guidance documents and the work of Tiddens et al. (Journal of Aerosol Med, 19(4), pp. 456-465, 2006) (who found that the average volume inhaled by adults through various DPIs was 2.2 L), with respect to flow rate Q, from two inhaler resistances (0.02 and 0.055 kPa, respectively). 1 / 2 / LPM), measured at an inhaled volume of 2L.

[0102] It is predicted that mild, moderate and severe adult COPD patients can achieve maximum inhalation energy of 5.1 to 21 joules, 5.2 to 19 joules and 2.3 to 18 joules respectively. This is also based on the measured PIFR value for flow rate Q in the inhalation energy equation. Each group of achievable PIFR is a function of the inhaler resistance through which inhalation is passed. Use the work of Broeders et al. (Eur Respir J, 18, p.780-783, 2001) to predict that two resistances are respectively 0.021 and 0.032 kPa 1 / 2 Maximum and minimum PIFR achievable with a dry powder inhaler of 100 / 100 LPM.

[0103] Similarly, based on the same assumptions as for the COPD population and PIFR data from Broeders et al., it was predicted that adult asthmatics would be able to achieve a maximum inhaled energy of 7.4 to 21 J.

[0104] For example, healthy adults and children are able to provide sufficient inhalation energy to disperse the dry powders of the present disclosure, for example, from a suitable inhalation device (eg, a dry powder inhaler).

[0105] The dry powder and / or respirable dry particles that can be used in the methods disclosed herein are preferably characterized by a high ejected dose, such as at least 75%, at least 80%, at least 85%, at least 90%, at least 95% CEPM from a passive dry powder inhaler subjected to a total inhalation energy of about 5 joules, about 3.5 joules, about 2.4 joules, about 2 joules, about 1 joule, about 0.8 joules, about 0.5 joules, or about 0.3 joules applied to the dry powder inhaler. The container containing the dry powder and / or respirable dry particles can contain about 5 mg, about 7.5 mg, about 10 mg, about 15 mg, about 20 mg, or about 30 mg. In one aspect, the dry powder and / or respirable dry particles are characterized in that the CEPM is 80% or greater and the VMGD is 5 microns or less when ejected from a passive dry powder inhaler having a resistance of about 0.036 sqrt (kPa) / liter / minute under the following conditions: air flow rate of 30 LPM, using a size 3 capsule containing 10 mg total mass for 3 seconds. In another aspect, the dry powder and / or respirable dry particles are characterized in that the CEPM is 80% or greater and the VMGD is 5 microns or less when ejected from a passive dry powder inhaler having a resistance of about 0.036 sqrt (kPa) / liter / minute under the following conditions: air flow rate of 20 LPM, using a size 3 capsule containing 10 mg total mass for 3 seconds. In another aspect, the dry powder and / or respirable dry particles are characterized by a CEPM of 80% or greater and a VMGD of 5 microns or less when ejected from a passive dry powder inhaler having a resistance of about 0.036 sqrt (kPa) / liter / minute under the following conditions: air flow rate of 15 LPM, running for 4 seconds using a size 3 capsule with a total mass of 10 mg.

[0106] The dry powder can fill a unit dose container, or the unit dose container can be at least 2% full, at least 5% full, at least 10% full, at least 20% full, at least 30% full, at least 40% full, at least 50% full, at least 60% full, at least 70% full, at least 80% full, or at least 90% full. The unit dose container can be a capsule (e.g., No. 000, 00, 0E, 0, 1, 2, 3, and 4, each of which has a volume capacity of 1.37 mL, 950 μL, 770 μL, 680 μL, 480 μL, 360 μL, 270 μL, and 200 μL). The capsule can be at least about 2% full, at least about 5% full, at least about 10% full, at least about 20% full, at least about 30% full, at least about 40% full, or at least about 50% full. The unit dose container can be a blister. The blisters may be packaged as a single blister or as part of a group of blisters (e.g., 7 blisters, 14 blisters, 28 blisters, or 30 blisters). One or more blisters may preferably be at least 30% full, at least 50% full, or at least 70% full.

[0107] An advantage of the dry powders disclosed herein is that they disperse well over a wide range of flow rates and are relatively independent of flow rate.Dry powders and / or respirable dry particles allow for the use of simple, passive DPIs for a wide range of patient populations.

[0108] The dry powders and / or respirable dry particles that can be used in the methods described herein are preferably characterized by: 1) a VMGD of about 10 microns or less, preferably about 5 microns or less at 1 bar, as measured using a HELOS / RODOS system; 2) a 1 bar / 4 bar dispersibility ratio and / or a 0.5 bar / 4 bar dispersibility ratio of about 1.5 or less, about 1.4 or less, or about 1.3 or less; 3) an MMAD of about 10 microns or less, preferably about 5 microns or less; 4) at least about 45% or at least about 60% of the total dose has an FPF < 5.6 μm; and / or 5) at least about 25% or at least about 40% of the total dose has an FPF < 3.4 μm. If desired, the dry powders and / or respirable dry particles are further characterized by about 0.2 g / cm 3 or larger, about 0.3g / cm 3 or larger, about 0.4g / cm 3 Or larger, greater than 0.4g / cm 3 , about 0.45g / cm 3 or greater or about 0.5g / cm 3 or greater tap density.

[0109] Formulation I is an exemplary dry powder that can be used in the methods disclosed herein. The composition and properties of Formulation I are provided in Table 1 below.

[0110] Table 1. Composition and properties of Formulation I

[0111]

[0112] Formulation I had a fine particle fraction (FPF) of 57% of the total dose less than 5 microns, which resulted in a fine particle dose of 2.8 mg less than 5 microns for a total dry powder capsule fill of 10.0 mg.

[0113] Formulation I has a dissolution half-life of 4.35 minutes, as determined by the following protocol: the powder formulation, capsules, and packaging materials are equilibrated at 22.5±2.5°C and 30±5% RH. Formulation I was encapsulated into No. 3 HPMC capsules under the same conditions. The fill weight of the powder formulation was 10 mg. The formulation was aerosolized from capsules in a unit dose, capsule-based DPI device (RS01, Plastiape, Osnago, Italy) using a Plastiape RS01 dry powder inhaler (DPI) at 60 L / min (4 L inhalation volume). Aerosol doses were collected in a UniDose system. The entire impactor level mass (i.e., below level 2 of NGI) was uniformly deposited onto a glass microfiber filter using a UniDose collection system, which can be viewed as the location where the circles (representing particles or droplets) were deposited. The filter was placed in a disk box and the dissolution study was performed in a USP Apparatus II POD (Paddle OverDisk, USP V) at 37°C using 500 ml PBS pH 7.4 + 2.0% SDS. The sink state was maintained in the container. Samples were obtained at designated time points and tested for drug content on an Agilent (Santa Clara, CA, USA) 1260 Infinity series HPLC.

[0114] The dry powder and / or inhalable dry particles disclosed herein can be filled into a container, such as a capsule or a blister. When the container is a capsule, the capsule is, for example, a No. 2 or No. 3 capsule, and preferably a No. 3 capsule. The capsule material can be, for example, gelatin or HPMC (hydroxypropyl methylcellulose), and is preferably HPMC.

[0115] The dry powder and / or respirable dry particles described and characterized herein are contained in a dry powder inhaler (DPI). The DPI can be a capsule-based DPI or a blister-based DPI, and is preferably a capsule-based DPI. More preferably, the dry powder inhaler is selected from RS01 TM Series dry powder inhaler (Plastiape SpA, Italy). More preferably, the dry powder inhaler is selected from RS01 TM HR or RS01 TM UHR2. Most preferably, the dry powder inhaler is RS01 TM HR.

[0116] Method for preparing dry powders and dry granules

[0117] The respirable dry particles and dry powders used in the methods disclosed herein can be prepared using any suitable method, provided that the dry powder is not a temporary dispersion. Many suitable methods for preparing dry powders and / or respirable dry particles are conventional in the art and include single emulsion solvent evaporation and double emulsion solvent evaporation, spray drying, spray freeze drying, milling (e.g., jet milling), blending, solvent extraction, solvent evaporation, phase separation, simple and complex coacervation, interfacial polymerization, involving the use of supercritical carbon dioxide (CO 2 ), sonication, nanoparticle aggregate formation, and other suitable methods, including combinations thereof. The respirable dry particles can be prepared using methods known in the art for preparing microspheres or microcapsules. These methods can be used under conditions where the result is the formation of respirable dry particles with desired aerodynamic properties (e.g., aerodynamic diameter and geometric diameter). If desired, respirable dry particles with desired properties (such as particle size and density) can be selected using suitable methods (such as sieving).

[0118] Suitable methods for selecting respirable dry particles having desired properties, such as particle size and density, include wet sieving, dry sieving, and aerodynamic classifiers, such as cyclones.

[0119] Respirable dry particles are preferably spray-dried. Suitable spray-drying techniques are described, for example, by K.Masters in "Spray Drying Handbook", John Wiley & Sons, New York (1984). Generally speaking, during spray drying, heat from hot gases (such as heated air or nitrogen) is used to evaporate solvent from droplets (formed by atomizing continuous liquid feed). When hot air is used, the moisture in the air is at least partially removed before use. When nitrogen is used, nitrogen can be "dry" operated, which means that there is no additional water vapor combined with the gas. If necessary, the humidity of nitrogen or air can be set to a fixed value higher than "dry" nitrogen before the spray-drying operation starts. If necessary, spray drying or other instruments for preparing dry particles, such as jet milling instruments, can include an inline geometric particle size analyzer (determining the geometric diameter when the respirable dry particles are produced) and / or an inline aerodynamic particle size analyzer (determining the aerodynamic diameter when the respirable dry particles are produced).

[0120] For spray drying, a solution, emulsion or suspension of components containing dry particles is distributed into a drying container by an atomizing device, and the dry particles will be produced in a suitable solvent (e.g., an aqueous solvent, an organic solvent, an aqueous solvent-organic solvent mixture or an emulsion). For example, a nozzle or a rotary atomizer can be used to distribute the solution or suspension into the drying container. The nozzle can be a two-fluid nozzle, which can be in an internal mixing arrangement or an external mixing arrangement. Alternatively, a rotary atomizer with 4 or 24 blade wheels can be used. Examples of suitable spray dryers that can be equipped with a rotary atomizer and / or a nozzle include a mobile mini-spray dryer or a PSD-1 type (both of which are manufactured by GEA Niro, Inc. (Denmark)), a Büchi B-290 micro-spray dryer ( The spray dryer is a spray dryer that can be used to dry liquids or liquids. The spray dryer can be used to dry liquids or liquids in a variety of ways ...

[0121] In order to prepare inhalable dry particles, usually, an emulsion or suspension containing the desired components of dry powder (i.e. raw material) is prepared, and spray dried under suitable conditions. Preferably, the solid concentration of the dissolution or suspension in the raw material is at least about 1g / L, at least about 2g / L, at least about 5g / L, at least about 10g / L, at least about 15g / L, at least about 20g / L, at least about 30g / L, at least about 40g / L, at least about 50g / L, at least about 60g / L, at least about 70g / L, at least about 80g / L, at least about 90g / L or at least about 100g / L. Raw material can be provided by dissolving, suspending or emulsifying suitable components (e.g., salt, excipient, other active ingredients) in a suitable solvent to prepare a single solution, suspension or emulsion. Solution, emulsion or suspension can be prepared using any suitable method, such as the bulk mixing of dry and / or liquid components or the static mixing of liquid components to form a combination. For example, a hydrophilic component (e.g., an aqueous solution) and a hydrophobic component (e.g., an organic solution) can be combined using a static mixer to form a combination. The combination can then be atomized to produce droplets, which are dried to form inhalable dry particles. Preferably, the atomization step is performed immediately after the components are combined in a static mixer. Alternatively, the bulk mixed solution is subjected to an atomization step.

[0122] Itraconazole in particulate form can be used in any solvent in which it has low solubility, such as an organic solvent, an aqueous solvent or a mixture thereof to prepare the raw material. Suitable organic solvents that can be used include, but are not limited to, alcohols, such as ethanol, methanol, propanol, isopropanol, butanol, etc. Other organic solvents include, but are not limited to, tetrahydrofuran (THF), perfluorocarbon, methylene chloride, chloroform, ether, ethyl acetate, methyl tert-butyl ether, etc. Co-solvents that can be used include aqueous solvents and organic solvents, such as, but not limited to, organic solvents as described above. Aqueous solvents include water and buffer solutions. The preferred solvent is water.

[0123] Various methods (e.g., static mixing, bulk mixing) can be used to mix solute and solvent to prepare raw materials, which is known in the art. If necessary, other suitable mixing methods can be used. For example, additional components that cause or promote mixing can be included in the raw material. For example, carbon dioxide bubbles or effervescence, therefore can be used to promote the physical mixing of solute and solvent.

[0124] Raw material or raw material component can have any desired pH, viscosity or other properties. If necessary, pH buffer can be added in solvent or cosolvent or in the formed mixture. Usually, the pH of mixture is in the range of about 3 to about 8.

[0125] Dry powders and / or respirable dry particles can be manufactured and then separated, for example, by filtration or centrifugation with a cyclone separator to provide a particle sample having a preselected size distribution. For example, greater than about 30%, greater than about 40%, greater than about 50%, greater than about 60%, greater than about 70%, greater than about 80%, or greater than about 90% of the respirable dry particles in the sample have a diameter that can be within a selected range. The selected range into which a particular percentage of the respirable dry particles falls can be, for example, any size range described herein, such as between about 0.1 and about 3 microns VMGD.

[0126] The suspension may be a nanosuspension, similar to the intermediate used to prepare the dry powder comprising nanocrystalline itraconazole.

[0127] The dry powder may be itraconazole embedded in a matrix material, such as a matrix material comprising sodium sulfate and leucine. Optionally, the dry powder may be spray dried so that the dry particles are small, dense and dispersible.

[0128] The dry powder may consist solely of the respirable dry particles described herein without other carrier or excipient particles (referred to as "pure powder"). If desired, the dry powder may contain the respirable dry particles described herein and other carrier or excipient particles, such as a blend of lactose carrier particles greater than 10 microns, 20 microns to 500 microns, and preferably between 25 microns and 250 microns. In some embodiments, a dry powder containing carrier particles (blended powder) is not included.

[0129] In a preferred embodiment, the dry powder does not contain carrier particles. In one aspect, itraconazole is embedded in a matrix comprising sodium salt, leucine and a stabilizer. The dry powder may contain a uniform content of inhalable dry particles, wherein each particle contains itraconazole. Therefore, as used herein, "uniform content" means that each inhalable particle contains a certain amount of itraconazole, as well as a stabilizer, sodium salt and leucine.

[0130] The dry powder may comprise respirable dry particles wherein at least 98%, at least 99%, or substantially all of the particles (by weight) comprise itraconazole.

[0131] Dry powders are generally prepared by first processing itraconazole in crystalline form to adjust the particle size using a number of techniques well known to those skilled in the art (e.g., wet milling, jet milling). For example, crystalline itraconazole may be processed in an antisolvent containing a stabilizer to form a suspension. Preferred stabilizers include polysorbates (also known as ), such as polysorbate 80 (PS80). The stable suspension of crystalline itraconazole is then spray dried with sodium salt and leucine. The resulting dry particles contain crystalline itraconazole dispersed throughout the excipient matrix, and each dry particle has a uniform composition.

[0132] In a particular embodiment, the dry powder of the present invention is prepared by starting with crystalline itraconazole, which is generally obtained in the micron crystalline size range. The particle size of micron crystalline itraconazole is reduced to nanocrystalline size using any of a variety of techniques familiar to those skilled in the art, including but not limited to high pressure homogenization, high shear homogenization, jet milling, pin milling, microfluidization or wet milling (also known as ball milling, pearl milling or bead milling). Wet milling is generally preferred because it can achieve a wide particle size distribution, including a particle size distribution in the nanometer (<1 μm) particle size range. It becomes particularly important in the submicron size range to use a surface stabilizing component, such as a surfactant (e.g., polysorbate 80, also known as 80). Surfactants are able to produce submicron particles during milling and form physically stable suspensions because they isolate many high energy surfaces generated during milling, thereby preventing aggregation and precipitation. Therefore, the presence of surfactants is important for spray drying uniform microparticles because surfactants allow the formation of uniform and stable suspensions, ensuring compositional uniformity throughout the particles. The use of surfactants allows the formation of micron or nano suspensions. In the case of using surfactants, nanocrystalline itraconazole particles are suspended in a stable colloidal suspension in an antisolvent. The antisolvent for the drug can utilize water or a combination of water and other miscible solvents such as alcohols or ketones as the continuous antisolvent phase of the colloidal suspension. The spray drying feed can be prepared by dissolving the soluble components in the desired solvent and then dispersing the surfactant-stabilized crystalline itraconazole nanosuspension in the resulting feed while mixing, although the method is not limited to this specific sequence of operations.

[0133] Methods for analyzing dry powders and / or respirable dry particles can be found in the Examples section below.

[0134] example

[0135] The materials used in the following examples and their sources are listed below. Sodium sulfate, polysorbate 80, and L-leucine were obtained from Sigma-Aldrich Co. (St. Louis, MO), Spectrum Chemicals (Gardena, CA), Applichem (Maryland Heights, MO), Alfa Aesar (Tewksbury, MA), Thermo Fisher (Waltham, MA), Croda Chemicals (East Yorkshire, United Kingdom), or Merck (Darmstadt, Germany). Itraconazole was obtained from Neuland (Princeton, NJ). Ultrapure (Type II ASTM) water was from a water purification system (Millipore Corp., Billerica, MA) or equivalent.

[0136] In silico PBMK studies. Hava et al. (supra) outline the methods and results of a Phase 1 clinical study using an exemplary respirable dry powder for static equation calculations and model development.

[0137] Geometric diameter or volume diameter: The volume median diameter (x50 or Dv50) of the dry powder is determined using a laser diffraction technique, which may also be referred to as the volume median geometric diameter (VMGD). The device consists of a HELOS diffractometer and a RODOS dry powder disperser (Sympatec, Inc., Princeton, NJ). The RODOS disperser applies a shear force to the particle sample, which is controlled by the regulator pressure (usually set to 1.0 bar, maximum orifice ring pressure) of the incoming compressed dry air. The pressure setting can be changed to change the amount of energy used to disperse the powder. For example, the dispersion energy can be adjusted by changing the regulator pressure from 0.2 bar to 4.0 bar. The powder sample is dispensed from a micro spatula into a RODOS funnel. The dispersed particles travel through a laser beam, and the diffracted light pattern generated (usually using an R1 lens) is collected by a series of detectors. The ensemble diffraction pattern is then converted to a volume-based particle size distribution using the Fraunhofer diffraction model, which is based on the fact that smaller particles diffract light at larger angles. Using this method, the span of the distribution is also determined according to the formula ((Dv

[90] -Dv[10)) / (Dv

[50] ). The span value gives a relative indication of the polydispersity of the particle size distribution.

[0138] Aerodynamic performance: The aerodynamic properties of powders dispersed from the inhaler device were evaluated using the Next Generation Impactor (Copley Scientific Limited, Nottingham, UK) (NGI). For measurements using the NGI, the NGI instrument was run at controlled ambient conditions of 18 to 25°C and relative humidity (RH) between 25% and 35%. The instrument consists of seven stages, separates aerosol particles based on inertial impaction, and can be run at various air flow rates. At each stage, the aerosol stream passes through a set of nozzles and impacts the corresponding impact surface. Particles with sufficiently small inertia will continue to enter the next stage with the aerosol stream, while the remaining particles will impact the surface. At each successive stage, the aerosol passes through the nozzle at a higher speed, and the aerodynamically smaller particles are collected on the plate. After the aerosol passes through the last stage, the micro-orifice collector collects the remaining smallest particles. Gravimetric analysis and / or chemical analysis can then be performed to determine the particle size distribution. Capsules (HPMC, No. 3; Capsugel Vcaps, Peapack, NJ) were filled with a specific weight of powder and placed in a handheld breath-activated dry powder inhaler (DPI) device, either high resistance RS01 DPI or ultra high resistance RS01 DPI (both manufactured by Plastiape, Osnago, Italy). The capsules were punctured and the powder was drawn through a cascade impactor that operated 2.0 liters of inhaled air at a specified flow rate. At the specified flow rate, the cutoff diameters of each stage were calculated. Fractions were collected by placing a wetted filter in the device and determining the amount of powder that impacted the filter (by chemical measurement on HPLC).

[0139] Fine Particle Dose: Fine particle dose indicates the mass of itraconazole in a specific size range and can be used to predict the mass that will reach a certain area of ​​the respiratory tract. Fine particle dose can be measured gravimetrically or chemically by ACI or NGI. If measured gravimetrically, the mass of powder on each stage and collection filter can be multiplied by the fraction of itraconazole in the formulation to determine the mass of itraconazole, since the dry particles are assumed to be uniform. If measured chemically, the powder from each stage or filter is collected, separated, and analyzed, for example, on HPLC, to determine the content of itraconazole. The accumulated mass deposited on each stage at a specified flow rate is calculated, and the accumulated mass corresponding to particles of 5.0 micron diameter is interpolated. The accumulated mass of a single dose of powder contained in one or more capsules and actuated to the impactor is equal to the fine particle dose less than 5.0 microns (FPD<5.0 microns).

[0140] Mass Median Aerodynamic Diameter (MMAD): MMAD is determined using information obtained by the Next Generation Impactor (NGI). The accumulated mass at the stage cutoff diameter for each stage is calculated and normalized by the recovered powder dose. The MMAD of the powder is then calculated by linear interpolation of the stage cutoff diameters including the 50th percentile. An alternative method to measure MMAD is to use the Anderson Cascade Collider (ACI). As with the NGI, MMAD is calculated by calculating the accumulated mass at the stage cutoff diameter for each stage and normalizing the accumulated mass by the recovered powder dose. The MMAD of the powder is then calculated by linear interpolation of the stage cutoff diameters including the 50th percentile.

[0141] Geometric or volumetric diameter of the spray: After the powder is sprayed from the dry powder inhaler, the volume median diameter (Dv50) of the powder (also known as the volume median geometric diameter (VMGD)) is measured by a Spraytec diffractometer (Malvern, Inc.) using a laser diffraction technique. The powder is filled into a No. 3 capsule (V-Caps, Capsugel) and placed in a capsule-based dry powder inhaler (RS01TM Model 7 High resistance, Plastiape, Italy) or DPI, and the DPI is sealed in a cylinder. The cylinder is connected to a positive pressure air source to allow a steady flow of air to pass through the system, which is measured by a mass flow meter and the duration is controlled by a solenoid valve controlled by a timer. The outlet of the dry powder inhaler is exposed to room pressure, and the resulting aerosol jet is passed through the laser of a diffraction particle size analyzer (Spraytec) in an open configuration, and then the aerosol jet is captured by a vacuum extractor. A solenoid valve is used to start a steady air flow rate through the system. The steady air flow rate drawn through the DPI is typically 60L / min for a set period of time, typically 2 seconds. Alternatively, the air flow rate drawn through the DPI is sometimes run at 15L / min, 20L / min, or 30L / min. The geometric size distribution of the resulting aerosol is calculated by software based on the scattering pattern measured on the photodetector, and samples are typically collected at 1000Hz during inhalation. The Dv50, GSD, FPF<5.0μm measured during inhalation are then averaged.

[0142] Ejected dose (ED) refers to the mass of itraconazole that leaves a suitable inhaler device after an emission or dispersion event. ED is determined using the method based on USP Part 601 Aerosols, Metered-Dose Inhalers and Dry Powder Inhalers, Delivered-Dose Uniformity, Sampling the Delivered Dose from Dry Powder Inhalers, United States Pharmacopeia convention, Rockville, MD, the 13th revised edition, 222-225, 2007. Use RS01 HR inhaler (pressure drop is 4kPa, and typical flow rate is 60LPM) or UHR2 RS01 (pressure drop is 4kPa, and typical flow rate is 39LPM) to disperse the contents of the capsule. The sprayed powder is collected on the filter in the filter holder sampling device. Rinse the sampling device with a suitable solvent (such as water) and analyze using the HPLC method. For gravimetric analysis, a shorter length filter holder sampling device is used to reduce deposition in the device, and the filter is weighed before and after to determine the mass of powder delivered from the DPI to the filter. The emitted dose of therapeutic agent is then calculated based on the content of therapeutic agent in the delivered powder. The emitted dose can be reported as the mass of therapeutic agent delivered from the DPI or as a percentage of the dose filled.

[0143] Thermogravimetric analysis: Thermogravimetric analysis (TGA) was performed using a Q500 or Discovery thermogravimetric analyzer (TA Instruments, New Castle, DE). The sample was placed in an open aluminum DSC pan or a sealed aluminum DSC pan, which was then automatically flushed before testing. The dead weight was pre-recorded by the instrument. The following method was used: a jump from ambient temperature (about 35°C) to 200°C at 5.00°C / min. The weight loss was reported as a function of temperature, up to 140°C. TGA can calculate the content of volatile compounds in dry powders. When a process using only water or a combination of water and volatile solvents is used, the weight loss measured by TGA can be a good estimate of the water content.

[0144] X-ray powder diffraction: The crystalline characteristics of the formulations were evaluated by powder X-ray diffraction (PXRD). 20-30 mg samples of the material were analyzed in a powder X-ray diffractometer (D8 Discover with LINXEYE detector; Bruker Corporation, Billerica, MA or equivalent) using a 1.5418A Cu X-ray tube with a data accumulation time of 1.2 seconds per step, a scan range of 5 to 45° 2θ, and a step size of 0.02° 2θ.

[0145] Itraconazole content / purity using HPLC: For the identification, bulk content, determination, CUPMD and impurity analysis of itraconazole dry powder, a high performance liquid chromatography (HPLC) method has been developed using a reverse phase C18 column coupled to an ultraviolet (UV) detector. The reverse phase column was equilibrated to 30°C and the autosampler was set to 5°C. The mobile phases, 20 mM sodium dihydrogen phosphate at pH 2.0 (mobile phase A) and acetonitrile (mobile phase B) were used for gradient elution in a ratio of 59:41 (A:B) to 5:95 (A:B) with a total run time of 19.5 minutes. Detection was performed by UV at 258 nm with an injection volume of 10 μL. The itraconazole content in the powder was quantified relative to a standard curve.

[0146] The identification of known impurities A, B, C, D, E, F and G (as indicated in the monograph Ph.Eur.01 / 2011:1335) was confirmed by comparing the retention time of the impurity peaks in the itraconazole dry powder sample with the retention time of the itraconazole USP impurity mixture reference standard spiked with impurity A. Unknown impurities were identified and quantified by the relative retention time of the itraconazole main peak and the area above the limit of detection (LOD). All impurities were measured by the area percentage of the itraconazole peak.

[0147] Particle size reduction: The particle size distribution of crystalline itraconazole can be adjusted using a variety of techniques familiar to those skilled in the art, including but not limited to high pressure homogenization, high shear homogenization, jet milling, pin milling, microfluidization or wet milling (also known as ball milling, pearl milling or bead milling). Wet milling is generally preferred because it can achieve a wide particle size distribution, including particle size distributions in the nanometer (<1 μm) particle size range.

[0148] The particle size reduction produced by low-energy wet grinding. A technique for reducing the particle size of itraconazole is carried out by low-energy wet grinding (also referred to as roller mill or pot mill). The suspension of itraconazole is prepared in an antisolvent, and the antisolvent can be any solvent in which water or an active agent is obviously insoluble. Then a stabilizer is added to the suspension together with a grinding medium, and the stabilizer can be, but is not limited to, a nonionic surfactant or an amphiphilic polymer, and the grinding medium can be, but is not limited to, a spherical object with high wear resistance and a particle size range of 0.03 to 0.70 mm diameter. Then a pot mill (US Stoneware, East Palestine, OH USA) is used to rotate the container containing the suspension, and regular sampling is performed to assess the particle size (LA-950, HORIBA, Kyoto, Japan). When the particle size is significantly reduced, or when the particle size minimum is reached, the suspension is filtered through a sieve to remove the grinding medium, and the product is recovered.

[0149] Using high energy wet grinding to reduce particle size: Another technique for reducing the particle size of itraconazole is high energy wet grinding using a rotor-stator or stirred media mill. A suspension of itraconazole is prepared in an antisolvent, which can be water or any solvent in which the active agent is significantly insoluble. A stabilizer is then added to the suspension along with a grinding medium, the stabilizer can be, but is not limited to, a nonionic surfactant or an amphiphilic polymer, and the grinding medium can be, but is not limited to, a spherical object with high wear resistance and a particle size range of 0.03 to 0.70 mm diameter. The suspension is then loaded into a mill, which can be operated in an intermittent or recirculation mode. The process consists of suspending and stirring the grinding media in a milling chamber, which increases the energy input of the system and accelerates the particle size reduction process. The milling chamber and the recirculation container are jacketed and actively cooled to avoid an increase in product temperature. The stirring rate and recirculation rate of the suspension are controlled during this process. Sampling is performed regularly to assess particle size (LA-950, HORIBA, Kyoto, Japan). When the particle size has been significantly reduced, or when a particle size minimum has been reached, the suspension is discharged from the mill.

[0150] Spray drying: The powder was dried in a Büchi B-290 mini spray dryer ( The system was prepared by spray drying performed on a 100 μm cyclone (Labortechnik AG, Flawil, Switzerland), and the powder was collected from a standard or high-efficiency cyclone separator. The system was operated in an open loop (single pass) mode using nitrogen as the drying and atomizing gas. When air was used, the system used a Büchi B-296 dehumidifier to ensure that the temperature and humidity of the air used for spray drying were stable. In addition, an external LG dehumidifier (model 49007903, LG Electronics, Englewood Cliffs, NJ) was continuously operated when the room relative humidity exceeded 30% RH. When nitrogen was used, a pressurized nitrogen source was used. In addition, the aspirator of the system was adjusted to maintain the system pressure at -2.0" water column. Atomization of the liquid feed utilized a Büchi nozzle with a 1.5 mm cap and a 0.7 liquid tip. The liquid feed solids concentration was 3%, the process gas inlet temperature was 127°C to 140°C, the process gas outlet temperature was 60°C, the drying gas flow rate was 17.0 kg / hr, the atomizing gas flow rate was 30.0 g / min, and the liquid feed flow rate was 6.0 mL / min.

[0151] Stability Assessment: The physicochemical stability and aerosol performance of the selected formulations were evaluated at 2-8°C, 25°C / 60% RH conditions, and if the amount of material allowed, at 40°C / 75% RH conditions, as described in the International Conference on Harmonisation (ICH) Q1 guidelines. Stability samples were stored in a calibration chamber (Darwin Chambers Company Models PH024 and PH074, St. Louis. MO). The bulk powder samples were weighed into amber glass vials, sealed at 30% RH, and induction sealed in aluminum bags (Drishield 3000, 3M, St. Paul, MN) with a silica desiccant (2.0 g, Multisorb Technologies, Buffalo, NY). In addition, to evaluate the stability of the formulation in the capsule, the target mass of powder was manually weighed into a No. 3 HPMC capsule (Capsugel Vcaps, Peapack, NJ) with a tolerance of + / -0.2 mg at 30% RH. The filled capsules were then aliquoted into high density polyethylene (HDPE) bottles and induction sealed in aluminum bags with silica desiccant.

[0152] Example 1: Preparation and Characterization of Exemplary Dry Powder Formulation I

[0153] A. Powder preparation.

[0154] Nanocrystalline itraconazole of Formulation I was prepared by compounding 30.090 g of itraconazole (Neuland ITI0114005 and ITI0714011) in 87 g of water and 3 g of polysorbate 80. Polystyrene grinding media (130 g of 500 μm; Dow Chemical, Midland MI) was then added to the suspension and the suspension was milled at 1800 rpm for one hour before collection. The final median particle size (Dv(50)) of the milled suspension was 132 nm.

[0155] Then prepare the stock solution and use it to make dry powder. Based on dry weight, the target drug loading is 50% by weight itraconazole. The stock solution for spray-dried particles is prepared as described below. The required amount of water (1.18kg) is weighed into a glass container of suitable size. Sodium sulfate (12.8g) and leucine (3.7g) are added to the water, and the solution is stirred until visually clear. Then the suspension containing itraconazole (containing 18.3 grams of itraconazole and 1.83 grams of polysorbate 80) is added to the excipient solution and stirred until visually uniform. Then the raw material is spray-dried. Stir the raw material while spraying and drying. The raw material mass is about 1.22kg. Dry powder formulation I follows the above scheme by the raw material through the Büchi B-290 small spray dryer ( Prepared by spray drying on a 100% ethanol stream (Labortechnik AG, Flawil, Switzerland).

[0156] Formulation I had the following dry powder composition (w / w) based on dry weight: 50% itraconazole, 35% sodium sulfate, 10% leucine, and 5% polysorbate 80.

[0157] B. Powder Characterization.

[0158] The bulk particle size characteristics of Formulation 1 are provided in Table 2 below. A span of less than 2.10 at 1 bar indicates a relatively narrow size distribution. A 1 bar / 4 bar dispersibility ratio of less than 1.25 indicates that the powder is relatively independent of dispersion energy, which is a desirable feature that allows similar particle dispersion to be achieved within a range of dispersion energies.

[0159] Table 2: Bulk Particle Size Characteristics of Formulation I

[0160]

[0161] The measured and / or calculated geometric particle size and capsule expelled powder mass (CEPM) of Formulation I at simulated patient flow rates of 60 liters per minute (LPM) and 30 LPM were also measured. At 30 LPM, Formulation I had a CEPM of 99.3% and a Dv50 of 4.35 μm. At 60 LPM, Formulation I had a CEPM of 99.8% and a Dv50 of 3.97 μm. The small changes in CEPM and geometric size from 60 LPM to 30 LPM indicate that the dry powder is relatively independent of the patient's inspiratory flow rate, indicating that patients breathing at different flow rates will receive relatively similar therapeutic doses.

[0162] Aerodynamic particle size, fine particle fraction and fine particle dose were also measured and / or calculated using the Next Generation Impactor (NGI). Formulation I had an MMAD of 4.22 μm and a FPD < 5 μm of 38.3% of the nominal dose. In other words, more than 30% of the nominal dose reached the impactor stage and was therefore expected to be delivered to the lungs. The MMAD of 4.22 also indicated deposition in the central and conducting airways.

[0163] Thermogravimetric analysis determined the weight loss to be 0.1%.

[0164] The crystallinity of Formulation I was evaluated by X-ray diffraction (XRD). A diffraction pattern of itraconazole was observed in the formulation, indicating that the solid state of itraconazole was not affected by the milling or spray drying process.

[0165] Example 2: Computer simulation

[0166] The physiologically based pharmacokinetic (PBPK) model was originally developed to simulate the concentration-time profiles of itraconazole and OH-itraconazole after administration of oral itraconazole as an oral solution (Simcyp Simulator, V19), and the model has been modified to simulate administration by oral inhalation. The PBPK model parameters describing the fraction and absorption rate absorbed from the lungs and the fraction of inhaled dose swallowed were optimized by fitting these parameters to the observed plasma concentration data collected in clinical studies, in which 35 mg of Formulation I was administered once a day (QD) for 14 days. Simulated population geometric mean itraconazole and OH-itraconazole area under the curve (AUC) at steady state (to day 14) 0-24hThe values ​​are within 0.96-fold and 1.68-fold of the observed data in the Phase 1 clinical trial using Formulation I, respectively. See Hava, supra). By applying a basic static model, a mechanistic static model, and a physiologically based pharmacokinetic (PBPK) model for itraconazole and its major metabolite OH-itraconazole, the data can be used to determine the DDI potential of itraconazole at a maximum dose of 40 mg orally inhaled to evaluate the potential risk of itraconazole dry powder as a CYP3A4 DDI "perpetrator", using midazolam as the "victim" drug and using Formulation I as an exemplary itraconazole-based dry powder.

[0167] Basic static model of reversible inhibition: The basic static equation and the mechanistic static equation have been described in the FDA In Vitro Drug Interaction Study Guidance (FDA DDI Guidance (2020). "Clinical Drug Interaction Studies—Cytochrome P450 Enzyme-and Transporter-Mediated Drug Interactions, Guidance for Industry." USDepartment of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER); incorporated herein by reference in its entirety).

[0168] For Formulation I, after 14 days of 35 mg formulation IQD, the observed C values ​​for itraconazole and OH-itraconazole were max , the ratio of the intrinsic clearance values ​​of the probe substrate in the absence and presence of itraconazole (R1) was calculated.

[0169] Since itraconazole and OH-itraconazole are inhibitors of CYP3A4, calculation of the ratio of intrinsic clearance values ​​of the probe substrate in the presence and absence of the inhibitor (R1, intestine) in the intestine was used for Formulation I. The equation input values ​​are listed in Table 3.

[0170] Table 3. Parameters used to calculate R values ​​for the reversible inhibition static equation.

[0171]

[0172]

[0173] R1 ≥ 1.02 or R1, entero ≥ 11 indicates the possibility of clinically significant drug-drug interactions and the need for further investigation.

[0174] Mechanistic static model of reversible inhibition: The area under the plasma concentration-time curve (AUCR) of the reversible inhibitor was calculated according to the FDA guidance for in vitro drug interaction studies. As a worst-case scenario, it was assumed that all inhaled doses were swallowed and subsequently delivered to the intestine. Weak, moderate, or strong DDIs were defined as the calculated AUCR (weak: ≥1.25-fold, but <2.00-fold; moderate: ≥2.00-fold, but <5.00-fold; strong: ≥5.00-fold).

[0175] PBPK modeling-study design and setting: In order to achieve the modeling goals, the steps in the study consist of two parts, namely model optimization and application. Some key factors associated with each step are as follows. Simcyp (2019, Version 19 Release 2, Certara, Sheffield, UK) was used for model optimization and application. Data combination and drawing were performed using RStudio (Version 4.1.2; R Foundation for Statistical Computing, Vienna, Austria). The virtual Nordic Caucasian population in Simcyp (physiological parameters, including liver volume and blood flow, enzyme abundance) was used for all simulations (Howgate E. et al., Xenobiotica (2006) 36 (6): 473–497). Except for demographic data, all parameter values ​​of the healthy volunteer (HV) population were the same as those used for the Caucasian population.

[0176] PBPK Modeling – Model Optimization: To simulate the plasma concentration-time profiles of itraconazole and OH-itraconazole following inhaled administration of 35 mg Formulation I (QD for 14 days), the Simcyp V19 itraconazole oral solution PBPK model was adjusted to include the absorption of itraconazole through the lungs as well as the intestine. The model assumes first-order absorption from the lungs to the systemic circulation. The structural model is shown in Figure 1 The experimental design used to optimize the primary inhalation parameters was based on the study described in Hava et al. (supra), in which subjects received 35 mg QD of Formulation I for 14 days. The study measured data for itraconazole and OH-itraconazole as summarized in Table 4.

[0177] Table 4. Primary inhalation parameters of itraconazole and OH-itraconazole using Formulation I.

[0178]

[0179] To develop the PBPK model, ten virtual trials were conducted with six subjects aged 21 to 58 years (33.3% female) to assess intergroup variability. The population of the virtual trials was selected to match the clinical study subjects. A range of values ​​for the ratio of inhaled dose, the fraction of itraconazole absorbed from the lungs (Fa,1), and the first-order rate constant for the absorption of itraconazole from the lungs (ka,1) were tested. These parameters were optimized to best fit the observed plasma concentration-time profiles and pharmacokinetic parameters of itraconazole and OH-itraconazole after multiple-dose administration of Formulation I at 35 mg (QD for 14 days) on Study Day 14. Briefly, the ratio of inhaled dose and Fa,1 were optimized to match itraconazole AUC0–24h on Study Day 14. Then, ka,1 was optimized to capture the C max Once the simulated multiple doses and C max Within the range of 0.8 to 1.25 of the observed values, the absorption parameters were further optimized to best predict the concentration-time profile of OH-itraconazole. The intestinal absorption, distribution, and elimination parameters of itraconazole and hydroxyitraconazole were unchanged from the validated model for itraconazole and OH-itraconazole, assuming that itraconazole follows linear kinetics even at low doses. The model assumes that itraconazole is not metabolized to OH-itraconazole in the lung.

[0180] The primary inhalation parameters were manually optimized by comparing the simulated curves for Formulation I with the observed data. The primary inhalation parameters used to simulate the plasma concentration curves for Formulation I are shown in Table 5.

[0181] Table 5. Final input optimized absorption parameters for Formulation I.

[0182] parameter Formulation I References Ratio of inhaled dose (%) 99.9 Manual Optimization <![CDATA[F a,1 ]]> 0.265 Manual Optimization <![CDATA[K a,1 (1 / hr)]]> 0.028 Manual Optimization

[0183] PBPK Modeling – Model Application: A representative virtual healthy population consisting of ten virtual trials of ten healthy subjects aged 20 to 50 years (50% female) was used to predict the CYP3A4 inhibition potential of Formulation I. The victim drug (midazolam) was administered as a single dose of 5 mg without Formulation I and then again on day 14 with daily administration of Formulation I 35 mg. The virtual DDI trial was repeated with the same virtual trial design and study population, with daily administration of 40 mg Formulation I for 14 days.

[0184] Calculation of R value for basic model of reversible inhibition: After multiple inhaled doses of Formulation I (35 mg QD) for 14 days, the observed maximum concentrations of itraconazole and OH-itraconazole were used to calculate the R1 of Formulation I. R1 was calculated to be 1.35. Because this value exceeds the critical value of 1.02 specified in the FDA guidance document (supra), further study of DDI liability is required. In addition, R1, intestinal was calculated to be greater than the threshold of 11, indicating that additional assessment of DDI liability is required. Based on these results, a mechanistic static model was applied to further study the CYP3A4 inhibition potential of Formulation I.

[0185] AUCR was calculated for the mechanical static equation: The observed maximum concentrations of itraconazole and OH-itraconazole were used to calculate the midazolam AUCR for Formulation I after multiple simulated inhaled doses of Formulation I (35 mg QD) for 14 days. To calculate the worst case, it was assumed that all of itraconazole was absorbed through the intestine. The AUCR for midazolam was calculated to be 5.36, further indicating the risk of Formulation I as a CYP3A4 DDI perpetrator. Based on these results, a PBPK model was developed to further understand the CYP3A4 inhibition potential of Formulation I.

[0186] PBPK model optimization and application: The simulated itraconazole and OH-itraconazole plasma concentration data were based on the manually optimized inhaled dose ratio, (Fa,1) and (ka,1) parameters of Formulation I. The mean test concentrations of individuals and the mean concentration-time curves of the total virtual population (n = 60) were simulated. Figure 2A and 2B As shown, after 14 days of dosing with 35 mg / day of Formulation I, the simulated curves for Formulation I and OH-itraconazole were comparable to the clinical data. In addition, the predicted geometric mean C of itraconazole on Day 14 was max and AUC0–24h values ​​were within 0.81- and 0.96-fold of the observed values, respectively (Table 6).

[0187] Table 6. Predicted and observed itraconazole C after multiple inhalations of 35 mg doses of Formulation I (QD 14 days) max and AUC 0–24h .

[0188]

[0189] Predicted mean C of OH-itraconazole on day 14 max and AUC0–24h values ​​were within 1.47- and 1.68-fold of the observed values, respectively (Table 7).

[0190] Table 7. Predicted and observed OH-itraconazole C after multiple inhalations of 35 mg doses of Formulation I (QD 14 days) max and AUC0–24h .

[0191]

[0192] For model application, the plasma concentration-time profiles of midazolam were simulated in healthy subjects after a single oral dose of 5 mg in the absence of Formulation I and on day 14 after 14 days of administration of Formulation I (35 mg daily or 40 mg daily). The mean simulated plasma concentrations of itraconazole and OH-itraconazole after 14 days of daily administration of 40 mg Formulation I are presented in Figure 3A and 3B The mean simulated plasma midazolam concentrations of healthy subjects after a single oral 5 mg dose in the absence of Formulation I and on Day 14 of 14 days of administration of Formulation I (35 mg daily or 40 mg daily) are shown in Figure 4A and 4B Predicted geometric mean C of midazolam in the presence and absence of Formulation I max and AUC 0-inf The values ​​and the corresponding geometric mean ratios are shown in Table 8. When midazolam was co-administered with 35 mg daily of Formulation I, the threshold for weak DDI (AUCR and C max At the higher dose of 40 mg daily of Formulation I, a weak DDI was predicted (AUCR ≥ 1.25 but < 2).

[0193] Table 8. Predicted geometric mean C of midazolam in the absence and presence of Formulation I (35 mg or 40 mg QD for 14 days) in healthy subjects max and AUC 0-inf values ​​and the corresponding geometric mean ratios.

[0194]

[0195] In summary, the PBPK model of Formulation I predicted minimal effects on CYP3A4 substrates after multiple inhaled doses. Based on the criteria of the US Food and Drug Administration (FDA) DDI guidance, no clinically significant CYP3A4 DDI was predicted after administration of Formulation I QD for 14 days.

Claims

1. A method of treating a disease or condition in a subject for which oral itraconazole is contraindicated, comprising administering to the respiratory tract of the subject an inhalable dry powder comprising itraconazole.

2. The method of claim 1, wherein the subject is treated with a second therapeutic agent that is a substrate, inducer and / or inhibitor of an enzyme or receptor that is inhibited by or metabolizes itraconazole.

3. A method of co-administering itraconazole and a second therapeutic agent to a subject in need thereof, wherein the itraconazole is administered to the respiratory tract of the subject in the form of an inhalable dry powder, and wherein the second therapeutic agent is a substrate, inducer and / or inhibitor of an enzyme or receptor that is inhibited by itraconazole or metabolizes itraconazole.

4. The method of claim 2 or 3, wherein the second therapeutic agent is a substrate, inducer and / or inhibitor of the cytochrome P450 3A4 (CYP3A4) isozyme.

5. The method of any one of claims 2-4, wherein the second therapeutic agent is administered with oral itraconazole (e.g. )There are taboos.

6. The method of any one of claims 2-5, wherein the second therapeutic agent is an alpha blocker, a beta blocker, an analgesic, an antiarrhythmic, an antibacterial, an anticoagulant, an antiplatelet, an anticonvulsant, an antidiabetic, an anthelmintic, an antifungal, an antiprotozoal, an antimigraine, an antineoplastic, an antipsychotic, an anxiolytic, a hypnotic, an antiviral, a calcium channel blocker, a cardiovascular drug, a contraceptive, a diuretic, an anticonvulsant, an immunosuppressant, a lipid-lowering drug, a respiratory drug (e.g., an asthma treatment), an antidepressant (e.g., a tricyclic or a selective serotonin reuptake inhibitor (SSRI)), a urological drug, a vasopressin receptor antagonist, a nonsteroidal anti-inflammatory drug (NSAID), or a gastrointestinal drug.

7. The method of any one of claims 2-6, wherein the second therapeutic agent is alfuzosin, silodosin, tamsulosin, methadone, fentanyl, alfentanil, buprenorphine, oxycodone, sufentanil, disopyramide, dofetilide, dronedarone, quinidine, digoxin, bedaquiline, rifabutin, clarithromycin, trimetrexate, ticagrelor, apixaban, rivaroxaban, vorapaxar, cilostazol, dabigatran, warfarin, carbamazepine, repaglinide, saxagliptin, isavuconazolium, praziquantel, artemether-lumefantrine, quinine, ergot alkaloids (e.g., dihydroergotamine, Ergonovine, ergometrine, methylergonovine, methylergometrine, ergotamine), eletriptan, irinotecan, axitinib, bosutinib, cabazitaxel, cabozantinib, ceritinib, cobimetinib, crizotinib, dabrafenib, dasatinib, docetaxel, ibrutinib, lapatinib, nilotinib, olaparib, pazopanib, regorafenib, sunitinib, trabectedin, emtansine, vinca alkaloids, bortezomib, brentuximab, busulfan, erlotinib, gefitinib, idelalisib, nintedanib, panobinostat, ponatinib, ruxolitinib, sonidegi, Vandetanib, imatinib, ixabepilone, alprazolam, aripiprazole, buspirone, diazepam, haloperidol, midazolam, quetiapine, ramelteon, risperidone, suovorexin, zopiclone, lurasidone, pimozide, triazolam, levomethadol acetate, simeprevir, daclatasvir, indinavir, maraviroc, cobicistat, elvitegravir, ritonavir, saquinavir, tenofovir disoproxil fumarate, nadolol, felodipine, nisoldipine, diltiazem, dihydropyridines, verapamil, ivabradine, ranolazine, aliskiren, riociguat, sildenafil, tadalafil, bosen Tan, guanfacine, dienogest, ulipristal, eplerenone, cisapride, naloxone, aprepitant, loperamide, netupitant, everolimus, sirolimus, temsirolimus, budesonide, ciclesonide, cyclosporine, dexamethasone, fluticasone, methylprednisolone, tacrolimus, lomitapide, lovastatin, simvastatin, atorvastatin, salmeterol, venlafaxine, avadil, fesoterodine, solifenacin, darifenacin, vardenafil, dutasteride, oxybutynin, tolterodine, colchicine, ilukastat, lumacato, avacato, electrocato, tizancato, Alitretinoin, cabergoline, cannabinoids, cinacalcet, conivaptan, vilvaptan, Saccharomyces boulardii, meloxicam, ciprofloxacin, erythromycin, clarithromycin, idelalisib, darunavir, fosamprenavir, isoniazid, rifampin, rifabutin, phenobarbital, phenytoin, efavirenz, nevirapine, or drugs that reduce gastric acidity (e.g., acid neutralizing drugs such as aluminum hydroxide, acid secretion inhibitors such as H2-receptor antagonists, and proton pump inhibitors) or halofantrine.

8. The method of any one of claims 2-7, wherein the second therapeutic agent is methadone, disopyramide, dofetilide, dronedarone, quinidine, isavuconazole, ergot alkaloids (e.g., dihydroergotamine, ergonovine (ergotoxin), ergotamine, methylergonovine (methylergotoxin)), irinotecan, lurasidone, midazolam, pimozide, triazolam, felodipine, nisoldipine, ivabradine, ranolazine, eplerenone, cisapride, naloxegol, lomitapide, lovastatin, simvastatin, avadil, ticagrelor, colchicine, fesoterodine, solifenacin, or ilutorstat.

9. The method of any of the preceding claims, wherein the itraconazole is administered to the subject at a nominal dose of between 1 mg and about 60 mg, between about 5 mg and about 40 mg, between about 1 mg and about 10 mg, between about 10 mg and about 20 mg, between about 20 mg and about 30 mg, or between about 30 mg and about 40 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, or about 40 mg.

10. The method of any one of claims 2-9, wherein the itraconazole is administered to the subject no more than about 14 days before or after administration of the second therapeutic agent, less than about 14 days, less than about 12 days, less than about 10 days, less than about 8 days, less than about 7 days, less than about 6 days, less than about 5 days, less than about 4 days, less than about 3 days, less than about 2 days, or less than about 1 day before or after administration of the second therapeutic agent.

11. The method of any one of claims 2-10, wherein the itraconazole is administered to the subject on the same day, less than about 20 hours, less than about 18 hours, less than about 16 hours, less than about 14 hours, less than about 12 hours, less than about 11 hours, less than about 10 hours, less than about 9 hours, less than about 8 hours, less than about 7 hours, less than about 6 hours, less than about 5 hours, less than about 4 hours, less than about 3 hours, less than about 2 hours, less than about 1 hour, less than about 45 minutes, less than about 30 minutes, less than about 20 minutes, less than about 10 minutes, or less than about 5 minutes before or after administration of the second therapeutic agent.

12. The method of any one of claims 2-11, wherein the itraconazole is administered to the subject less than about 5 minutes before or after administration of the second therapeutic agent.

13. The method of any one of the preceding claims, wherein the respirable dry powder comprises homogeneous respirable dry particles comprising crystalline itraconazole, a stabilizer, a sodium salt, and an excipient.

14. The method of claim 13, wherein the sodium salt is sodium sulfate.

15. The method of claim 13 or 14, wherein the itraconazole is crystalline subparticles having a size of about 50 nm to about 5,000 nm (Dv50), about 50 nm to about 800 nm (Dv50), about 50 nm to about 300 nm (Dv50), about 50 nm to about 200 nm (Dv50), or about 100 nm to about 300 nm (Dv50).

16. The method of any one of claims 13-15, wherein the itraconazole is present in the respirable dry particles in an amount of about 30% to about 70% by weight, about 40% to about 60% by weight, about 45% by weight, about 50% by weight, or about 55% by weight.

17. The process of any one of claims 13-16, wherein the itraconazole is at least 50% crystalline.

18. The method of any one of claims 13-17, wherein the ratio of itraconazole:stabilizer (wt:wt) in the respirable dry particles is about 10:

1.

19. The method of any one of claims 13-18, wherein the stabilizer is present in the respirable dry particles in an amount of about 3 wt % to about 7 wt % or about 5 wt %.

20. The method of any one of claims 13-19, wherein the excipient is present in the respirable dry particles in an amount of about 5 wt % to about 20 wt % or about 10 wt %.

21. The method of any one of claims 13-20, wherein the stabilizer is polysorbate 80.

22. The method of any one of claims 13-21, wherein the excipient is leucine.

23. The method of any of the preceding claims, wherein the respirable dry powder comprises homogeneous respirable dry particles comprising about 50% by weight crystalline itraconazole, about 35% by weight sodium sulfate, about 10% by weight leucine, and about 5% by weight polysorbate 80.

24. The method of any one of claims 13-23, wherein the respirable dry particles have: (i) a volume median geometric diameter (VMGD) of about 10 micrometers or less or about 5 micrometers or less; (ii) a tap density of about 0.2 g / cc or greater or a tap density between 0.2 g / cc and 1.0 g / cc; (iii) a 1 bar / 4 bar dispersity ratio (1 / 4 bar) of less than about 1.5 as measured by laser diffraction; and / or (iv) a 0.5 bar / 4 bar dispersity ratio (0.5 / 4 bar) of about 1.5 or less as measured by laser diffraction.

25. The method of any one of claims 13-24, wherein the inhalable dry powder has: (i) a mass median aerodynamic diameter (MMAD) between about 1 micrometer and about 5 micrometers; and / or (ii) a fine particle fraction (FPF) of about 25% or more of the total dose, less than 5 microns.

26. The method of any one of claims 13-25, wherein the respirable dry particles have at least 80% of the capsule ejected powder mass when ejected from a passive dry powder inhaler having a resistance of about 0.036 sqrt (kPa) / liter / minute under the following conditions: using a size 3 capsule containing 10 mg of total mass, at an inhalation flow rate of 30 LPM for 3 seconds, the total mass consisting of the respirable dry particles, and wherein the volume median geometric diameter of the respirable dry particles ejected from the inhaler as measured by laser diffraction is 5 microns or less.

27. The method of any one of claims 13-26, wherein the inhalable dry powder is delivered to the respiratory tract of the subject using a capsule-based passive dry powder inhaler.

28. The method of any of the preceding claims, wherein the subject suffers from an infection, allergic bronchopulmonary aspergillosis, a respiratory disease, an acute exacerbation of a respiratory disease, an immunodeficiency disorder, cancer, cardiovascular disease, hypertension, hypercholesterolemia, an autoimmune disorder, diabetes, a gastrointestinal disorder, a thrombotic disorder, epilepsy, a psychiatric disorder, migraine, or pain.

29. The method of any one of claims 1, 2, or 4-28, wherein the disease or condition is an infection, allergic bronchopulmonary aspergillosis, a respiratory disease, an acute exacerbation of a respiratory disease, or cancer.

30. A respirable dry powder for use in a method of treating a disease or condition in a subject for which oral itraconazole is contraindicated, wherein the respirable dry powder comprises the itraconazole and is administered to the respiratory tract of the subject.

31. The respirable dry powder for use of claim 31, wherein the subject is treated with a second therapeutic agent that is a substrate, inducer, and / or inhibitor of an enzyme or receptor that is inhibited by or metabolizes itraconazole.

32. A respirable dry powder for use in a method of co-administering itraconazole and a second therapeutic agent to a subject in need thereof, wherein the respirable dry powder comprises the itraconazole and is administered to the respiratory tract of the subject, and wherein the second therapeutic agent is a substrate, inducer and / or inhibitor of an enzyme or receptor that is inhibited by or metabolizes itraconazole.

33. Use of an inhalable dry powder in the preparation of a medicament for treating a disease or condition in a subject for which oral itraconazole is contraindicated, wherein the inhalable dry powder comprises the itraconazole and is administered to the respiratory tract of the subject.

34. The use of claim 33, wherein the subject is treated with a second therapeutic agent that is a substrate, inducer and / or inhibitor of an enzyme or receptor that is inhibited by itraconazole or metabolizes itraconazole.

35. Use of an inhalable dry powder in the preparation of a medicament for co-administering itraconazole and a second therapeutic agent to a subject in need thereof, wherein the inhalable dry powder comprises the itraconazole and is administered to the respiratory tract of the subject, and wherein the second therapeutic agent is a substrate, inducer and / or inhibitor of an enzyme or receptor that is inhibited by itraconazole or metabolizes itraconazole.

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