How to Use Itraconazole Dry Powder

Abstract

The present disclosure relates to a method of treating a disease or disorder in a subject for which oral itraconazole is contraindicated, comprising administering to the subject's respiratory tract a respirable dry powder comprising itraconazole. The disclosure also relates to a method of administering to a subject in need thereof a combination of itraconazole and a second therapeutic agent, wherein the itraconazole is administered to the subject's respiratory tract as a respirable dry powder, and the second therapeutic agent is a substrate, inducer, and / or inhibitor of an enzyme or receptor that is inhibited by or metabolizes itraconazole.

Description

[Technical Field]

[0001] Related Applications This application claims the benefit of U.S. Provisional Application No. 63 / 402,577, filed August 31, 2022, which is incorporated herein by reference in its entirety. [Background technology]

[0002] Itraconazole is a broad-spectrum triazole antifungal agent that is typically administered orally. It is the active ingredient in the FDA-approved oral antifungal drug SPORANOX®. However, the clinical use of oral itraconazole is limited by concerns regarding its unpredictable and variable pharmacokinetics, poor tolerability, adverse effects, and its high potential for drug-drug interactions (DDIs).

[0003] Itraconazole's potential for DDIs is related to its activity as a potent inhibitor of the isoenzyme cytochrome P450 3A4 (CYP3A4). Itraconazole's effects on the CYP3A4 pathway alter its metabolism and, consequently, the plasma concentrations of other drugs metabolized by this pathway. For this reason, coadministration of itraconazole with many drugs and drug classes is currently contraindicated due to the potential for DDIs. For example, the SPORANOX® package insert lists over 40 contraindicated drugs and another 256 drugs requiring special caution. (See Bergagnini Kolev, et al., The AAPS Journal (2023) 25:62, incorporated herein by reference in its entirety.)

[0004] The potential for DDIs with oral itraconazole significantly limits its use, especially in patient populations that would benefit from itraconazole treatment. For example, itraconazole has shown benefit in treating allergic bronchopulmonary aspergillosis, which has a prevalence of up to 15% in people with cystic fibrosis and an estimated 1.5% in the general asthma population. (See Bergagnani-Kolev, supra.) However, many medications used to treat asthma exacerbations or in the maintenance therapy of cystic fibrosis cannot be used safely with oral itraconazole. (See Bergagnani-Kolev, supra.)

[0005] Thus, there is an unmet need for formulations and methods for treating patients with itraconazole while avoiding drug-drug interactions (DDIs), particularly in patients taking other medications that are substrates for CYP3A4. Summary of the Invention

[0006] The present disclosure relates to respirable dry powders and methods for administering itraconazole to subjects for whom oral itraconazole is contraindicated, and for co-administering itraconazole with a second therapeutic agent for whom oral itraconazole is contraindicated. In particular, the compositions and methods disclosed herein can be used to safely achieve therapeutic concentrations of itraconazole in the lungs of patient populations that are otherwise untreatable with itraconazole, such as subjects already taking CYP3A4 substrates. For example, cystic fibrosis (CF) patients are commonly treated with medications including elexacaftor, ivacaftor, and tezacaftor, which are largely metabolized by CYP3A4, making oral itraconazole unadministerable to these patients. This is problematic because cystic fibrosis patients are highly susceptible to pulmonary infections and could potentially benefit greatly from itraconazole treatment. The methods disclosed herein address this issue because they can be used in conjunction with CYP3A4 substrates. In particular, the compositions and methods disclosed herein may be useful in treating allergic bronchopulmonary aspergillosis (ABPA) in subjects with cystic fibrosis (CF) or asthma, in whom oral itraconazole is contraindicated.

[0007] In some aspects, the disclosure relates to a method of treating a disease or disorder in a subject for which oral itraconazole is contraindicated, comprising administering to the airway of the subject a respirable dry powder comprising itraconazole. 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 by or metabolizes itraconazole.

[0008] In some aspects, the disclosure relates to a method of administering itraconazole in combination with a second therapeutic agent to a subject in need thereof, wherein the itraconazole is administered to the subject's airways as a respirable dry powder, and the second therapeutic agent is a substrate, inducer, and / or inhibitor of an enzyme or receptor that is inhibited by or metabolizes itraconazole.

[0009] The second therapeutic agent can be a substrate, inducer, and / or inhibitor of the isoenzyme cytochrome P450 3A4 (CYP3A4). The second therapeutic agent can be a therapeutic agent that is contraindicated for use with oral itraconazole (e.g., SPORANOX®).

[0010] In some embodiments, the second therapeutic agent is an alpha blocker, a beta blocker, an analgesic, an antiarrhythmic agent, an antibacterial agent, an anticoagulant, an antiplatelet agent, an anticonvulsant, an antidiabetic agent, an anthelmintic agent, an antifungal agent, an antiprotozoal agent, an antimigraine agent, an antitumor agent, an antipsychotic agent, an anxiolytic agent, a hypnotic agent, an antiviral agent, 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 antidepressant or a selective serotonin reuptake inhibitor (SSRI)), a urinary agent, a vasopressin receptor antagonist, a nonsteroidal anti-inflammatory drug (NSAID), or a gastrointestinal agent.

[0011] In some embodiments, 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, isavuconazonium, praziquantel, artemex, cefotaxime ... Ter-lumefantrine, quinine, ergot alkaloids (e.g., dihydroergotamine, ergometrine, ergonovine, methylergometrine, methylergonovine, ergotamine), eletriptan, irinotecan, axitinib, bosutinib, cabazitaxel, cabozantinib, ceritinib, cobimetinib, crizotinib, dabrafenib, dasatinib, docetaxel, ibrutinib, lapatinib, nilotinib, olaparib, pazopanib, regorafenib, sunitinib, trabectedin, trastuzumab-emtansine, vinca alkaloids, bolus Tezomib, brentuximab-vedotin, busulfan, erlotinib, gefitinib, idelalisib, nintedanib, panobinostat, ponatinib, ruxolitinib, sonidegib, vandetanib, imatinib, ixabepilone, alprazolam, aripiprazole, buspirone, diazepam, haloperidol, midazolam, quetiapine, ramelteon, risperidone, suvorexant, zopiclone, lurasidone, pimozide, triazolam, levacetylmethadol (levomethadyl), simeprevir, daclatasvir, indinavir, maraviroc, covi Systat, elvitegravir, ritonavir, saquinavir, tenofovir disoproxil fumarate, nadolol, felodipine, nisoldipine, diltiazem, dihydropyridine, 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, elexacaftor, tezacaftor, SYMDEKO®, ORKAMBI®, KALYDECO®, alitretinoin, cabergoline, cannabinoids, cinacalcet, conivaptan, tolvaptan, Saccharomyces boulardii, meloxicam, ciprofloxacin, erythromycin, clarithromycin, idelalisib, darunavir, fosamprenavir, isoniazid, rifampicin, rifabutin, phenobarbital, phenytoin, efavirenz, nevirapine, drugs that reduce gastric acidity (e.g., acid neutralizers such as aluminum hydroxide, acid secretion inhibitors such as H2 receptor antagonists and proton pump inhibitors), or halofantrine.

[0012] 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, avanafil, ticagrelor, colchicine, fesoterodine, solifenacin, or eliglustat.

[0013] In the methods disclosed herein, a respirable dry powder comprising itraconazole is administered to the subject's airway at a nominal dose of about 1 mg to about 60 mg, about 5 mg to about 40 mg, about 1 mg to about 10 mg, about 10 mg to about 20 mg, about 20 mg to about 30 mg, or about 30 mg to about 40 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.

[0014] The respirable dry powder comprising itraconazole may be administered to the subject's respiratory tract within 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. The itraconazole respirable dry powder may be administered to the subject's respiratory tract 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 on the same day as administration of the second therapeutic agent. The itraconazole respirable dry powder may be administered to the subject's respiratory tract less than about 5 minutes before or after administration of the second therapeutic agent.

[0015] In some embodiments, the respirable dry powder comprises homogeneous respirable dry particles comprising crystalline itraconazole, a stabilizer, a sodium salt, and an excipient. The sodium salt can be sodium sulfate. The stabilizer can be polysorbate 80. The excipient can be leucine.

[0016] The itraconazole can be in the form of crystalline primary particles, the primary particles 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). The 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, the itraconazole has a crystallinity of at least 50%.

[0017] The ratio of itraconazole to stabilizer (wt:wt) in the respirable dry particles can be about 10:1.

[0018] 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, hi some embodiments, the stabilizer (e.g., polysorbate 80) is present in the respirable dry particles in an amount of about 5% by weight.

[0019] In some embodiments, the excipient (e.g., leucine) is present in the respirable dry particles in an amount of about 5% to about 20% by weight, hi some embodiments, the excipient (e.g., leucine) is present in the respirable dry particles in an amount of about 10% by weight.

[0020] In some embodiments, the stabilizer is polysorbate 80. In some embodiments, the excipient is leucine.

[0021] In some embodiments, the respirable dry powder comprises homogenous respirable dry particles comprising about 50 wt% crystalline itraconazole, about 35 wt% sodium sulfate, about 10 wt% leucine, and about 5 wt% polysorbate 80.

[0022] The respirable dry particles may 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 more, or a tap density of 0.2 g / cc to 1.0 g / cc, (iii) a dispersibility ratio at 1 bar / 4 bar (1 / 4 bar) of less than about 1.5, as measured by laser diffraction, and / or (iv) a dispersibility ratio at 0.5 bar / 4 bar (0.5 / 4 bar) of about 1.5 or less, as measured by laser diffraction.

[0023] The respirable dry powder may have (i) a mass median aerodynamic diameter (MMAD) of about 1 micrometer to about 5 micrometers, and / or (ii) a fine particle fraction (FPF) of about 25% or more of the total dose that is less than 5 micrometers.

[0024] In some embodiments, the respirable dry particles, when emitted from a passive dry powder inhaler having a resistance of about 0.036 sqrt (kPa) / liter per minute using a No. 3 capsule containing a total mass of 10 mg (said total mass consisting of the respirable dry particles) at an inhalation flow rate of 30 LPM over a 3 second period, have a capsule emitted powder mass of at least 80%, and the respirable dry particles emitted from the inhaler have a volume median geometric diameter of 5 micrometers or less as measured by laser diffraction.

[0025] In the methods disclosed herein, the respirable dry powder can be delivered to the subject's respiratory tract with a capsule-based passive dry powder inhaler.

[0026] In the methods disclosed herein, the subject may have an infectious disease, allergic bronchopulmonary aspergillosis, a respiratory disease, an acute exacerbation of a respiratory disease, an immunodeficiency disorder, cancer, a cardiovascular disorder, hypertension, hypercholesterolemia, an autoimmune disorder, diabetes, a gastrointestinal disorder, a thrombotic disorder, epilepsy, a psychiatric disorder, migraine, or pain. For example, the subject may have a fungal infection, such as aspergillosis. The subject may have cystic fibrosis, asthma, or pneumonia (e.g., fungal pneumonia). The subject may have HIV or AIDS. The subject may have a form of cancer, such as lung cancer (e.g., non-small cell lung cancer). The subject may have congestive heart failure, arrhythmia, or heart disease. The subject may have bipolar disorder, depression, psychosis, or anxiety. The subject may have acute or chronic pain. The subject may have surgical pain (e.g., pre- or post-operative pain).

[0027] In some aspects, the present disclosure relates to a respirable dry powder disclosed herein for use in a method of treating a disease or disorder 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 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 or metabolizes itraconazole.

[0028] In some aspects, the present disclosure relates to a respirable dry powder of any of the respirable dry powders disclosed herein for use in a method of administering a combination of 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 the second therapeutic agent is a substrate, inducer, and / or inhibitor of an enzyme or receptor that is inhibited by or metabolizes itraconazole.

[0029] In some aspects, the disclosure relates to the use of a respirable dry powder disclosed herein in the manufacture of a medicament for treating a disease or disorder 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 by or metabolizes itraconazole.

[0030] In some aspects, the disclosure relates to the use of a respirable dry powder disclosed herein in the manufacture of a medicament for administering to a subject in need thereof a combination of itraconazole and a second therapeutic agent, wherein the respirable dry powder comprises itraconazole and is administered to the respiratory tract of the subject, and the second therapeutic agent is a substrate, inducer, and / or inhibitor of an enzyme or receptor that is inhibited by or metabolizes itraconazole. [Brief explanation of the drawings]

[0031] [Figure 1] FIG. 1 shows a structural model of first-order absorption from the lungs into the systemic circulation. [Figure 2] (A) and (B) are log-linear plots showing simulated and observed plasma concentration versus time profiles of itraconazole (A) and OH-itraconazole (B) following multiple doses of an exemplary itraconazole dry powder (Formulation I, 35 mg QD for 14 days) in healthy subjects. Shown are simulated data (lines) and observed data (circles, mean of n=6 individuals). The gray lines represent the 5th and 95th percentiles of the simulated population (n=60), and the solid black line is the mean data for that population. [Figure 3](A) and (B) are log-linear plots showing simulated mean plasma concentration versus time profiles of itraconazole (A) and OH-itraconazole (B) following multiple oral doses of an exemplary itraconazole dry powder (Formulation I, 40 mg QD for 14 days) in healthy subjects. Shown are simulated values ​​(lines). The gray lines represent the 5th and 95th percentiles of the simulated population (n=100), and the solid black line is the mean data for that population. [Figure 4] A and B are log-linear plots showing simulated plasma concentration versus time profiles of a single 5 mg dose of midazolam administered in healthy subjects with 35 mg (A) and 40 mg (B) steady-state Formulation I. Shown are simulated plasma concentration versus time profiles of midazolam in the absence of Formulation I (solid line) and on day 14 of a 14-day period when Formulation I was administered (dotted line). The lines represent the average data for the simulated population (n=100). DETAILED DESCRIPTION OF THE INVENTION

[0032] The present disclosure relates to methods of administering itraconazole to the respiratory tract of subjects for whom oral itraconazole is contraindicated, for example, because the subject is being treated with a second therapeutic agent that is not typically combined with oral itraconazole due to the potential for DDIs. Following inhaled delivery of itraconazole, a substantially lower systemic exposure can be achieved relative to conventional oral administration, along with consistently high lung exposure. While not wishing to be bound by theory, it is believed that this limited systemic exposure may be beneficial for use in subjects for whom oral itraconazole is contraindicated, and that inhalation of a respirable dry powder containing itraconazole can safely achieve therapeutic concentrations of itraconazole in the lungs of this patient population, e.g., therapeutic concentrations for treating certain diseases or disorders affecting the respiratory system.

[0033] Thus, in some aspects, the disclosure relates to a method of treating a disease or disorder in a subject for which oral itraconazole is contraindicated, comprising administering to the airway of the subject a respirable 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 or metabolizes itraconazole (e.g., the second therapeutic agent is a substrate, inducer, and / or inhibitor of the isoenzyme cytochrome P450 3A4 (CYP3A4)). In some aspects, the disclosure relates to methods of administering itraconazole in combination with a second therapeutic agent to a subject in need thereof, where the itraconazole is administered as a respirable dry powder to the subject's airways, and the second therapeutic agent is a substrate, inducer, and / or inhibitor of an enzyme or receptor that is inhibited by itraconazole or that metabolizes itraconazole (e.g., the second therapeutic agent is a substrate, inducer, and / or inhibitor of the isoenzyme cytochrome P450 3A4 (CYP3A4)).

[0034] definition As used herein, the term "about" refers to a relative range of ±20% of the stated value, for example, "about 20 mg" would be "20 mg ±4 mg."

[0035] 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, administering may refer to the introduction of a respirable dry powder disclosed herein into the respiratory tract of a subject.

[0036] As used herein, the term "amorphous" refers to the absence of significant crystallinity when analyzed via powder X-ray diffraction (XRD).

[0037] The term "capsule emitted powder mass" or "CEPM," as used herein, refers to the amount of dry powder emitted from a capsule or dose unit container upon actuation of a dry powder inhaler, e.g., during inhalation. CEPM is typically measured gravimetrically by weighing the capsule before and after emission to determine the emitted powder mass. CEPM can be expressed as the emitted powder mass in milligrams or as a percentage of the original powder mass filled in the capsule before emission.

[0038] The term "crystalline particulate form," as used herein, refers to itraconazole (including its pharmaceutically acceptable forms, including salts, crystalline polymorphs, solvates, hydrates, etc.) in the form of particles (i.e., primary particles smaller than the respirable dry particles that make up the dry powders disclosed herein), in which the itraconazole has a crystallinity of at least about 50%. The crystallinity (percent) of itraconazole refers to the proportion of compound that is in a crystalline state relative to the total amount of compound present in the primary particles. If desired, the itraconazole can 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. Crystalline microparticle form of itraconazole may be in the form of particles having a median volume diameter (Dv50) of about 50 nanometers (nm) to about 5,000 nm, preferably a Dv50 of 80 nm to 1750 nm, or preferably a Dv50 of 50 nm to 800 nm.

[0039] The term "dispersibility" is a term of art that describes a characteristic of a dry powder or respirable dry particle that is dispersed into a respirable aerosol. Dispersibility of a dry powder or respirable dry particle is expressed herein, in one embodiment, as the volume median geometric diameter (VMGD) measured at 1 bar dispersion pressure (i.e., regulated pressure) divided by the VMGD measured at 4 bar dispersion pressure (i.e., regulated pressure), or the VMGD at 0.5 bar divided by the VMGD at 4 bar, as measured by laser diffraction, e.g., laser diffraction on a HELOS / RODOS. These quotients are referred to herein as the "1 bar / 4 bar dispersibility ratio" and "0.5 bar / 4 bar dispersibility ratio," respectively, with higher dispersibility correlated with lower quotients. For example, the 1 bar / 4 bar dispersibility ratio refers to the VMGD of a dry powder or respirable dry particle emitted from the orifice of a RODOS dry powder disperser (or equivalent technique) at approximately 1 bar, as measured by a HELOS or other laser diffraction system, divided by the VMGD of the same dry powder or respirable dry particle measured by a HELOS / RODOS at 4 bar. That is, a highly dispersible dry powder or respirable dry particle 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 a low tendency to agglomerate, aggregate, or conglomerate when emitted from an inhaler and inhaled by a subject, and / or, if agglomerate, aggregate, or conglomerate, are easily dispersed or deagglomerated. In another embodiment, dispersibility is assessed by measuring the particle size emitted from the inhaler as a function of flow rate. A decrease in the flow rate through the inhaler reduces the amount of energy in the airflow available to transfer to the powder to disperse it. A highly dispersible powder is one whose size distribution is characterized by a mass median aerodynamic diameter (MMAD) (aerodynamic) or VMGD (geometric) that does not increase substantially over the range of flow rates typical of human inhalation, e.g., about 15 to about 60 liters per minute (LPM), about 20 to about 60 LPM, or about 30 to about 60 LPM. A highly dispersible powder has an emitted powder mass or dose, or capsule emitted powder mass or dose, of about 80% or more even at lower inhalation flow rates. VMGD is sometimes referred to as median volume diameter (VMD), ×50, or Dv50.

[0040] The term "dry particles," as used herein, refers to respirable particles that may contain up to about 15% total water and / or other solvents. Preferably, the dry particles contain up to about 10% total water and / or other solvents by weight of the dry particles, up to about 5% total water and / or other solvents, up to about 1% total water and / or other solvents by weight of the dry particles, or 0.01% to 1% total water and / or other solvents by weight of the dry particles, or can be substantially free of water and / or other solvents.

[0041] The term "dry powder," as used herein, refers to a composition comprising respirable dry particles. The dry powder may contain up to about 15% total water and / or other solvents. Preferably, the dry powder contains up to about 10% total water and / or other solvents by weight of the dry powder, up to about 5% total water and / or other solvents, up to about 1% total water and / or other solvents by weight of the dry powder, or 0.01% to 1% total water and / or other solvents, or can be substantially free of water and / or other solvents. In one aspect, the dry powder is a respirable dry powder.

[0042] The term "effective amount," as used herein, refers to the amount of drug necessary to achieve a desired effect, e.g., a therapeutic effect on a fungal infection or related disorder, e.g., allergic bronchopulmonary aspergillosis (ABPA). The actual effective amount for a particular application may vary depending on the particular dry powder or respirable dry particles, the mode of administration, the age, weight, and general health of the subject, and the severity of the symptom or condition being treated. The appropriate dosage of the dry powder and dry particles, as well as the administration schedule for a particular patient, can be determined by a clinician of ordinary skill based on these and other considerations.

[0043] As used herein, the term "emitted dose" or "ED" refers to the amount of a formulation delivered from a suitable inhalation device after exhalation or dispersion. More specifically, for dry powders, ED is a measure of the percentage of powder drawn from a unit-dose package and expelled from the mouthpiece of the inhalation device. ED is defined as the ratio of the drug or powder delivered by the inhalation device to the nominal dose (i.e., the mass of drug or powder per unit dose placed into a suitable inhalation device before exhalation). ED is an experimentally measured parameter and can be determined using the method of USP Section 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, 13th Revision, pp. 222-225, 2007. This method uses an in vitro device configured to mimic patient administration. ED can also be calculated from results generated by experiments with a Next Generation Impactor (NGI) by combining all drug or powder assayed from the mouthpiece adapter, the NGI induction port, and all stages within the NGI. Results generated through ED testing according to USP 601 and via the NGI typically show good agreement.

[0044] 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 the plasma either at a given time point or over a given range of time points. For example, the lung:plasma ratio may be calculated based on the maximum concentration of itraconazole in the lung or serum (i.e., the "C maxIt may be calculated based on the simultaneous measurement values at any time point. The lung:plasma ratio may be calculated for the total exposure amount (i.e., "area under the curve" i.e., "AUC") over a specific period, for example, a 24-hour period. The lung concentration of itraconazole may be evaluated by measuring the level in sputum, by lung lavage, by biopsy, or by some other method. The lung:plasma ratio may be calculated based on the simultaneous measurement values at any time point in the dosing cycle and may also be calculated based on the simultaneous measurement values before or at steady state.

[0045] The term "nominal dose" as used herein refers to the individual dose of itraconazole. The nominal dose is the total dose of itraconazole in one container, for example, a capsule, blister, or ampoule.

[0046] The terms "FPF(<X)", "FPF(<X micrometers)", and "percentage of particles less than X micrometers" as used herein, when X is, for example, 3.4 micrometers, 4.4 micrometers, 5.0 micrometers, or 5.6 micrometers, refer to the percentage of dry particle samples with an aerodynamic diameter less than X micrometers. For example, FPF(<X) can be determined by dividing the mass of respirable dry particles deposited on stage 2 of a two-stage foldable Andersen cascade impactor (ACI) and the final collection filter by the mass of respirable dry particles weighed into the capsule for delivery to the instrument. This parameter may be defined as "FPF_TD(<X)", where TD means total dose. Similar measurements can be made using an eight-stage ACI. The cut-off values of the eight-stage ACI are different for each at a standard flow rate of 60 L / min, but FPF_TD(<X) can be estimated from the complete dataset of the eight-stage ACI. The results of the eight-stage ACI can also be calculated by the USP method of defining FPF using the dose collected by the ACI instead of the amount put into the capsule. Similarly, a seven-stage next-generation impactor (NGI) can be used.

[0047] The terms "FPD(<X)", "FPD <X micrometers", "FPD(<X micrometers)", and "particle dose less than X micrometers", as used herein, when X is, for example, 3.4 micrometers, 4.4 micrometers, 5.0 micrometers or 5.6 micrometers, refer to the mass of a therapeutic agent delivered by respirable dry particles having an aerodynamic diameter less than X micrometers. FPD <X micrometers can be determined by either directly calculating or estimating the FPD value by summing the mass deposited on the final collection filter using an 8-stage Andersen Cascade Impactor (ACI) or Next Generation Impactor (NGI) at a standard flow rate of 60 L / min. Similarly, a 7-stage Next Generation Impactor (NGI) can be used.

[0048] The term "respirable", as used herein, refers to dry particles or dry powders suitable for delivery by inhalation to the airways (e.g., transpulmonary delivery) in a subject. Respirable dry powders or respirable dry particles have an aerodynamic mass median diameter (MMAD) less than about 10 micrometers, preferably less than or equal to about 5 micrometers.

[0049] As used herein, the term "airways" includes the upper airways (e.g., nasal passages, nasal cavity, pharynx, throat and larynx), the respiratory airways (e.g., trachea, bronchi and bronchioles), and the lungs (e.g., respiratory bronchioles, alveolar ducts, alveolar sacs and alveoli).

[0050] For purposes of describing respirable dry particles, the term "small", as used herein, refers to particles having a geometric median volume diameter (VMGD) of less than or equal to about 10 micrometers, preferably less than or equal to about 5 micrometers or less than 5 micrometers.

[0051] The term "stabilizer," as used herein, refers to a compound that improves the physical stability of itraconazole in crystalline microparticle form (e.g., reduces agglomeration, agglomeration, Ostwald ripening, and / or flocculation of the microparticles) when the itraconazole is suspended in a liquid in which itraconazole is poorly soluble. Suitable stabilizers are surfactants and amphiphiles, such as polysorbates (PS, polyoxyethylated sorbitan fatty acid esters), for example, polysorbate 20 (PS20), polysorbate 40 (PS40), polysorbate 60 (PS60) and polysorbate 80 (PS80), fatty acids, for example, lauric acid, palmitic acid, myristic acid, oleic acid and stearic acid and salts thereof, sorbitan fatty acid esters, for example, Span 20, Span 40, Span 60, Span 80 and Span 85, phospholipids, for example, dipalmitoylphosphatidylcholine (DPPC), 1,2-dipalmitoyl-sn-glycero-3-phospho-L-serine (DPPS), 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DSPC), 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DSPC), 1,2-dipalmitoyl-sn-glycero-3-phospho-L-serine (DPPS), 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DSPC), 1,2-dipalmitoyl-sn-glycero-3-phospho-L-serine ... Examples of stabilizers include palmitoyl-2-oleoylphosphatidylcholine (POPC) and 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), phosphatidylglycerols (PGs) such as diphosphatidylglycerol (DPPG), DSPG, DPPG, and POPG, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE), aliphatic alcohols, benzyl alcohol, polyoxyethylene-9-lauryl ether, glycocholate, surfactin, poloxomers, polyvinylpyrrolidone (PVP), PEG / PPG block copolymers (Pluronics / Poloxamers), polyoxyethylene cholesteryl ether, POE alkyl ethers, tyloxapol, and lecithin. Preferred stabilizers are polysorbates and fatty acids. A particularly preferred stabilizer is polysorbate 80 (PS80).

[0052] The term "homogeneous dry particles," as used herein, refers to particles that are compositionally homogeneous. Homogeneous dry particles disclosed herein have substantially the same composition of itraconazole, stabilizer, and optionally one or more excipients, excluding blends of two or more particles.

[0053] Method of administering itraconazole dry powder The inventors have discovered that administration of the itraconazole-containing dry powder disclosed herein can achieve lung concentrations of itraconazole that are substantially higher than those achievable by oral administration, while maintaining relatively low systemic itraconazole concentrations. While not wishing to be bound by theory, it is believed that by achieving higher lung concentrations of itraconazole using the dry powder disclosed herein, administration thereof can achieve therapeutic concentrations of itraconazole in the respiratory system while minimizing systemic itraconazole concentrations. Minimizing systemic itraconazole concentrations can not only help prevent side effects and toxicity associated with itraconazole, but also minimize inhibition of enzymes or receptors for which itraconazole and OH-itraconazole are inhibitors or substrates, such as CYP3A4. In other words, the respirable dry powders of the present disclosure can be used to minimize systemic itraconazole concentrations and thereby avoid DDIs when treating a subject with a second therapeutic agent for which itraconazole use is contraindicated, for example, because the second therapeutic agent is a substrate, inducer, or inhibitor of the aforementioned enzyme or receptor (e.g., CYP3A4). The respirable dry powders of the present application are particularly useful for co-administration with therapeutic agents that are inhibitors or inducers of CYP3A4 and / or that are metabolized by the same metabolic pathway(s) as itraconazole.

[0054] It is further believed that therapeutic concentrations of itraconazole in the lungs can be achieved using relatively low total doses, e.g., compared to conventional oral administration. For example, studies have demonstrated the systemic and pulmonary pharmacokinetics of oral itraconazole in adults and children, and pharmacokinetic studies of respirable dry powders containing itraconazole have shown that pulmonary exposures that would be considered curative for the treatment of pulmonary aspergillosis can be achieved after a relatively low single inhaled dose of 20 mg of dry powder. (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 which is incorporated herein by reference in its entirety.) Advantageously, the relatively low total dose of itraconazole that needs to be administered to achieve therapeutic effect using the dry powders disclosed herein, compared to the larger doses required for oral administration, can reduce the risk of DDIs, thereby providing the opportunity to combine the itraconazole-containing dry powder with a second therapeutic agent, particularly one that is known to have DDIs and / or for which use of itraconazole is contraindicated, e.g., a substrate, inducer, or inhibitor of CYP3A4.

[0055] Dry powders comprising itraconazole in amorphous form, when inhaled at therapeutic doses, have a shorter lung residence time, resulting in a lower lung to plasma exposure ratio and lower undesirable toxic effects on lung tissue. Without wishing to be bound by any particular theory, it is believed that the dry powders disclosed herein comprising a crystalline form (e.g., nanocrystalline form) of itraconazole have a slower lung dissolution rate relative to the amorphous form, resulting in more continuous exposure over a 24-hour period following administration, minimizing systemic exposure and the potential for DDIs.

[0056] 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) dissolve more rapidly in airway lining fluid than larger crystalline particles, in part due to their greater total surface area. Crystalline itraconazole also dissolves more slowly in airway lining fluid than amorphous itraconazole, in part due to its lower water solubility. Thus, the dry powders described herein can be formulated with crystalline particulate itraconazole to provide a desired crystal size or crystal size range in the dry powder, optionally with appropriate excipients and stabilizers in appropriate ratios with the itraconazole, each of which can be tailored to, for example, affect dissolution rate and provide desired pharmacokinetic properties while avoiding DDI with the second therapeutic agent as well as unacceptable toxicity in the lungs.

[0057] Administration of the dry powder disclosed herein may result in a relatively high lung:systemic concentration ratio of itraconazole. Without wishing to be bound by any particular theory, it is believed that a relatively high lung:systemic concentration ratio not only minimizes off-target effects and / or toxicity associated with itraconazole, but also allows it to be co-administered with a second therapeutic agent for which itraconazole is contraindicated, thereby reducing the risk of DDI. Thus, the methods disclosed herein offer advantages over commercially available itraconazole formulations, which are typically administered orally in large amounts and cannot be co-administered with many other useful therapeutic agents due to the high potential for DDI and associated safety concerns.

[0058] As detailed in the Examples section of this specification, we used PBPK techniques to evaluate the effects of inhaled itraconazole on the metabolism of second therapeutic agents that are substrates, inducers, and / or inhibitors of enzymes or receptors that are inhibited by itraconazole or that metabolize itraconazole, with midazolam serving as a model for the second therapeutic agent. Specifically, existing oral PBPK models for itraconazole and OH-itraconazole were adapted within the Simcyp compound library and robustly validated with clinical DDI data to achieve high confidence in model predictions for respirable dry powders containing itraconazole. Despite pharmacological concentrations of itraconazole in lung tissue, itraconazole exposure is minimal in the intestine and liver. As a result, the predicted effect on midazolam metabolism was minimal, despite overprediction of the active primary metabolite, OH-itraconazole. These results demonstrate that itraconazole can be safely and effectively administered via an inhaled formulation to 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 these second therapeutic agents is clear and should improve the therapeutic potential in vulnerable patients maintained on medications that are contraindicated in the presence of oral itraconazole.

[0059] The methods disclosed herein can include treating a disease or disorder in a subject for which oral itraconazole is contraindicated, the method comprising administering to the subject's respiratory tract a respirable dry powder comprising itraconazole (e.g., crystalline itraconazole). Additionally, the methods disclosed herein can include administering to a subject in need thereof a combination of itraconazole and a second therapeutic agent, wherein the itraconazole is administered to the subject's respiratory tract as a respirable dry powder.

[0060] The second therapeutic agent may be a substrate of an enzyme or receptor (e.g., CYP3A4) that is inhibited by itraconazole or that metabolizes itraconazole. The second therapeutic agent may be an inhibitor of an enzyme or receptor (e.g., CYP3A4) that is inhibited by itraconazole or that metabolizes itraconazole. The second therapeutic agent may be an inducer of an enzyme or receptor (e.g., CYP3A4) that is inhibited by itraconazole or that metabolizes itraconazole.

[0061] The second therapeutic agent may be contraindicated for use with oral itraconazole (e.g., SPORANOX®). For example, the second therapeutic agent may be a substance listed by a regulatory agency as being contraindicated for use with itraconazole, as shown, for example, in the FDA labeling for SPORANOX®.

[0062] There are many different classes of drugs that are contraindicated or otherwise not recommended for combination with oral itraconazole at typical doses. Thus, the respirable dry powders disclosed herein may be combined with many different classes of drugs without significant risk of DDI or other adverse reactions and / or without the need for careful titration or dose restriction to avoid potential DDIs or adverse reactions.

[0063] For example, the methods disclosed herein may comprise co-administering a respirable dry powder of the invention to a subject who is also receiving a second therapeutic agent selected from the group consisting of an alpha blocker, a beta blocker, an analgesic, an antiarrhythmic agent, an antibacterial agent, an anticoagulant, an antiplatelet agent, an anticonvulsant, an antidiabetic agent, an anthelmintic agent, an antifungal agent, an antiprotozoal agent, an antimigraine agent, an antitumor agent, an antipsychotic agent, an anxiolytic agent, a hypnotic agent, an antiviral agent, 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 antidepressant or a selective serotonin reuptake inhibitor (SSRI)), a urinary agent, a vasopressin receptor antagonist, a nonsteroidal anti-inflammatory drug (NSAID), or a gastrointestinal agent.

[0064] The second therapeutic agent may be alfuzosin, silodosin, or tamsulosin. The second therapeutic agent may be methadone, fentanyl, alfentanil, buprenorphine, oxycodone, or sufentanil. The second therapeutic agent may be disopyramide, dofetilide, dronedarone, quinidine, or digoxin. The second therapeutic agent may be bedaquiline, rifabutin, clarithromycin, or trimetrexate. The second therapeutic agent may be ticagrelor, apixaban, rivaroxaban, vorapaxar, cilostazol, dabigatran, warfarin, or carbamazepine. The second therapeutic agent may be repaglinide or saxagliptin. The second therapeutic agent may be isavuconazonium, 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, trastuzumab-emtansine, vinca alkaloid, bortezomib, brentuximab-vedotin, busulfan, erlotinib, gefitinib, idelalisib, nintedanib, panobinostat, ponatinib, ruxolitinib, sonidegib, vandetanib, imatinib, or ixabepilone. The second therapeutic agent may be alprazolam, aripiprazole, buspirone, diazepam, haloperidol, midazolam, quetiapine, ramelteon, risperidone, suvorexant, zopiclone, lurasidone, pimozide, or triazolam. The second therapeutic agent may be levacetylmethadol (levomethadyl), simeprevir, daclatasvir, indinavir, maraviroc, cobicistat, elvitegravir, ritonavir, saquinavir, or tenofovir disoproxil fumarate.The second therapeutic agent may be nadolol. The second therapeutic agent may be felodipine, nisoldipine, diltiazem, dihydropyridine, or verapamil. The second therapeutic agent may be ivabradine, ranolazine, aliskiren, riociguat, sildenafil, tadalafil, bosentan, guanfacine, dienogest, or ulipristal. The second therapeutic agent may be eplerenone. The second therapeutic agent may be cisapride, naloxegol, aprepitant, loperamide, or netupitant. The second therapeutic agent may be everolimus, sirolimus, temsirolimus, budesonide, ciclesonide, cyclosporine, dexamethasone, fluticasone, methylprednisolone, or tacrolimus. The second therapeutic agent may be lomitapide, lovastatin, simvastatin, or atorvastatin. The second therapeutic agent may be salmeterol. The second therapeutic agent may be venlafaxine. The second therapeutic agent may be avanafil, fesoterodine, solifenacin, darifenacin, vardenafil, dutasteride, oxybutynin, or tolterodine. The second therapeutic agent may be colchicine, eliglustat, lumacaftor, ivacaftor, elexacaftor, tezacaftor, SYMDEKO®, ORKAMBI®, KALYDECO®, alitretinoin, or cabergoline. The second therapeutic agent may be a cannabinoid. The second therapeutic agent may be cinacalcet, conivaptan, or tolvaptan. 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 idelalisib. 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, for example, an acid neutralizer such as aluminum hydroxide, an acid secretion inhibitor such as an H2 receptor antagonist or a proton pump inhibitor, or halofantrine.

[0065] In some embodiments, the second therapeutic agent is methadone, disopyramide, dofetilide, dronedarone, quinidine, isavuconazole, ergot alkaloids (e.g., dihydroergotamine, ergometrine (ergonovine), ergotamine, or methylergometrine (methylergonovine)), irinotecan, lurasidone, midazolam, pimozide, triazolam, felodipine, nisoldipine, ivabradine, ranolazine, eplerenone, cisapride, naloxegol, lomitapide, lovastatin, simvastatin, avanafil, ticagrelor, colchicine, fesoterodine, solifenacin, or eliglustat.

[0066] In the methods disclosed herein, the respirable dry powders of the invention may be administered at a nominal dose of about 1 mg to about 60 mg, e.g., about 5 mg to about 40 mg, about 1 mg to about 10 mg, about 10 mg to about 20 mg, about 20 mg to about 30 mg, or about 30 mg to 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.

[0067] Co-administration can refer to administering the respirable dry powder to the subject within about 14 days before or after administering a second therapeutic agent, e.g., 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 administering a second therapeutic agent. In some embodiments, co-administration refers to administering the dry powder to the subject on the same day that the second therapeutic agent is administered to the subject, e.g., administering the respirable dry powder 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 administering the second therapeutic agent. In some embodiments, the itraconazole is administered to the subject less than about 5 minutes before or after administering the second therapeutic agent.

[0068] In the methods disclosed herein, the subject treated with the itraconazole of the present invention may be a subject for whom oral itraconazole is contraindicated, such as because the subject has been administered a second therapeutic agent disclosed herein (e.g., a therapeutic agent for which itraconazole is contraindicated). Nevertheless, due to the favorable pharmacokinetic properties achieved using the respirable dry powders disclosed herein, the subject can be administered the respirable dry powders disclosed herein to safely achieve therapeutic local concentrations of itraconazole in the lungs while avoiding DDIs or adverse events that would be expected when a different itraconazole formulation, such as oral itraconazole, is administered.

[0069] Subjects to be treated with itraconazole of the present invention, which may be subjects for whom oral itraconazole is contraindicated, may have a disease or disorder, which may be the condition that itraconazole is being administered to treat, or may be a condition that is not being treated with itraconazole or a condition that is unrelated to the use of itraconazole. The subject may have an infectious disease (e.g., a fungal infection, e.g., aspergillosis), allergic bronchopulmonary aspergillosis, a respiratory disease (e.g., cystic fibrosis, asthma, pneumonia (e.g., fungal pneumonia)), an acute exacerbation of a respiratory disease, an immunodeficiency disorder (e.g., HIV or AIDS), cancer (e.g., lung cancer, e.g., non-small cell lung cancer), a cardiovascular disorder (e.g., congestive heart failure, arrhythmia, heart disease), hypertension, hypercholesterolemia, an autoimmune disorder, diabetes, a gastrointestinal disorder, a thrombotic disorder, epilepsy, a psychiatric disorder (e.g., bipolar disorder, depression, psychosis, anxiety), migraine, pain (e.g., acute pain, pain caused by surgery, or chronic pain). In some cases, the disease or disorder is a condition treated with itraconazole, such as an infectious disease (e.g., a fungal infection, e.g., 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).

[0070] In some embodiments, the methods disclosed herein are for treating an infectious disease (e.g., a fungal infection, e.g., 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 cancer (e.g., lung cancer, e.g., non-small cell lung cancer) in a subject in need thereof.

[0071] Dry powder for breathing The dry powders disclosed herein can be administered to a subject by inhalation, for example, oral inhalation. To achieve oral inhalation, a dry powder inhaler, for example, a passive dry powder inhaler, can be used. Respirable dry powders comprising itraconazole for use in treating fungal infections are described in WO2018 / 071757, WO2019 / 204583, and WO2019 / 204597, the entire contents of which are incorporated herein by reference.

[0072] Respirable dry powders for use in the methods disclosed herein may comprise homogeneous respirable dry particles comprising 1) itraconazole in crystalline microparticle form, 2) a stabilizer, and, optionally, 3) one or more excipients. Such respirable dry particles can be prepared using any suitable method, for example, by preparing a feedstock in which itraconazole in crystalline microparticle form is suspended in an aqueous solution of excipients, and spray-drying the feedstock.

[0073] The respirable dry particles may contain itraconazole in an amount of about 1% by weight (wt%) to about 95% by weight. The respirable dry particles preferably contain an amount of itraconazole such that a therapeutically effective dose can be administered and maintained without the need to inhale large amounts of dry powder and without the need to inhale the dry powder excessively frequently, e.g., more than three times per day. For example, the respirable dry particles preferably contain itraconazole in an amount of about 30% by weight (wt%) to about 70% by weight, or about 40% by weight to about 60% by weight, e.g., about 45% by weight, about 50% by weight, or about 55% by weight. The amount (by weight) of itraconazole present in the respirable dry particles may also be referred to as the "drug loading."

[0074] The itraconazole may be present in the respirable dry particles in a crystalline particulate form (e.g., nanocrystalline). More specifically, in the form of primary particles having a diameter of about 50 nm to about 5,000 nm (Dv50), the itraconazole preferably has a crystallinity of at least 50%. For example, at any desired loading (sometimes referred to as "drug loading") of itraconazole, the primary particle size can 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 primary particles are about 50 nm to about 2500 nm, about 80 to 1750 nm, about 50 nm to 1000 nm, about 50 nm to 800 nm, about 50 nm to 600 nm, about 50 nm to 500 nm, about 50 nm to 400 nm, about 50 nm to 300 nm, about 50 nm to 200 nm, or about 100 nm to 300 nm. Additionally, for any desired drug loading and primary particle size, the degree of crystallinity of the 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% crystallinity. Preferably, the itraconazole is about 100% crystalline. In some embodiments, the administered dry powder comprises homogenous respirable dry particles comprising itraconazole that are at least 50% crystallinity, e.g., 55% crystallinity, 60% crystallinity, 65% crystallinity, 70% crystallinity, 75% crystallinity, 80% crystallinity, 85% crystallinity, 90% crystallinity, 95% crystallinity, 96% crystallinity, 97% crystallinity, 98% crystallinity, 99% crystallinity, or greater than 99% crystallinity.

[0075] Crystalline microparticle form of itraconazole can be prepared in any desired primary particle size using any suitable method, including stabilizers if desired, for example, by wet milling, jet milling or other suitable method.

[0076] The respirable dry particles also contain a stabilizer. The stabilizer helps maintain the desired size of the crystalline microparticle itraconazole during wet-milling when the feedstock is spray-dried, and also helps wetting and dispersing the itraconazole crystalline microparticle suspension and maintaining the physical stability of the suspension. Preferably, only as little stabilizer as necessary to achieve the above benefits is used. The amount of stabilizer is typically a fixed ratio relative to the amount of itraconazole present in the dry particles, and can range from about 1:1 (itraconazole:stabilizer (wt:wt)) to about 50:1 (wt:wt), with about 10:1 being preferred. For example, the itraconazole:stabilizer (wt:wt) ratio in the dry particles can be about 8:1, about 9:1, about 10:1, about 11:1, or about 12:1.

[0077] The amount of stabilizer present in the dry particles can range from about 1 wt% to about 15 wt%, e.g., from 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% of stabilizer, e.g., 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. A particularly preferred stabilizer for use in the dry powders described herein is polysorbate 80. Unlike conventional dry powders, which use surfactants to prevent crystallization in dry powders, the surfactants in the dry powders disclosed herein are added to stabilize the colloidal suspension of crystalline itraconazole in the antisolvent.

[0078] In some embodiments, the dry powder administered comprises homogenous respirable dry particles comprising itraconazole and polysorbate 80, wherein the ratio of itraconazole to polysorbate 80 (wt:wt) is about 10:1.

[0079] 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 wt% to about 50 wt% of the sodium salt (e.g., sodium sulfate). For example, the respirable dry particles can include about 25 wt% to about 45 wt% of the sodium salt (e.g., sodium sulfate), e.g., about 30 wt%, about 35 wt%, or about 40 wt% of the sodium salt (e.g., sodium sulfate).

[0080] The respirable dry particles also include one or more excipients in any suitable and desired amount. In some embodiments, the one or more excipients are present in an amount of about 5% to about 20% by weight. Many excipients are known in the art and can be included in the dry powders and dry particles described herein. A particularly preferred pharmaceutically acceptable excipient for the dry powders and dry particles described herein includes leucine. For example, the respirable dry particles of the present invention include an excipient (e.g., leucine) in an amount of about 1% to about 20% by weight, such as about 5% to about 20% by weight, e.g., about 10% by weight. In some embodiments, the respirable dry particles include leucine in an amount of about 10% by weight.

[0081] Without wishing to be bound by theory, it is believed that combining itraconazole in a dry powder with leucine and a sodium salt (e.g., sodium sulfate) can provide an optimal dissolution rate for achieving effective therapeutic levels of itraconazole in the lungs without unacceptable toxicity or DDIs when the dry powder is co-administered with a second therapeutic agent. In addition, maintaining a relatively high drug loading of itraconazole (e.g., about 50 wt%) can prevent rapid dissolution of the dry powder in the lungs. For example, the dry powders disclosed herein may dissolve more slowly in the lungs than formulations containing a relatively low amount of itraconazole (e.g., less than 40 wt%) combined with a hydrophilic excipient, such as mannitol.

[0082] Dissolution of dry powders used in the methods disclosed herein may be measured in terms of dissolution half-life. In some embodiments, the dry powders used in the methods disclosed herein have a dissolution half-life of at least about 2 minutes, e.g., about 2 minutes to about 20 minutes, e.g., 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. 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 about 4.13 minutes to about 16.84 minutes.

[0083] In one embodiment, the dry powder of the invention comprises (i) respirable dry particles comprising about 50 wt% itraconazole in crystalline particle form, about 5 wt% stabilizer, about 35 wt% sodium salt, and about 10 wt% leucine. For example, the dry powder may comprise (i) respirable dry particles comprising 50 wt% itraconazole in crystalline particle form, 5 wt% stabilizer (e.g., polysorbate 80), 35 wt% sodium salt (e.g., sodium sulfate), and 10 wt% leucine. The dry powder may consist essentially of (i) respirable dry particles consisting essentially of 50 wt% itraconazole in crystalline particle form, 5 wt% stabilizer (e.g., polysorbate 80), 35 wt% sodium salt (e.g., sodium sulfate), and 10 wt% leucine.

[0084] The dry powders disclosed herein may be free of lactose or other carrier particles.

[0085] The dry powders and / or respirable dry particles are preferably small, mass-dense, and dispersible. Laser diffraction systems, such as the Spraytec system (particle size analyzer, Malvern Instruments) and the HELOS / RODOS system (laser diffraction sensor and dry dispersion unit, Sympatec GmbH), may be used to measure the volume median geometric diameter (VMGD). Respirable dry particles of the present invention have a VMGD of about 10 micrometers or less, about 5 micrometers 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, as measured by laser diffraction using a HELOS / RODOS system at a dispersion pressure setting of 1.0 bar at maximum orifice ring pressure (also referred to as regulated pressure). Preferably, the VMGD is about 5 micrometers or less or about 4 μm or less. In one embodiment, the dry powder and / or respirable dry particles have a minimum VMGD of about 0.5 micrometers or about 1.0 micrometers.

[0086] The dry powder and / or respirable dry particles preferably have a dispersibility ratio at 1 bar / 4 bar and / or a dispersibility ratio at 0.5 bar / 4 bar of less than about 2.0 (e.g., from about 0.9 to about 2), or less than about 1.7 (e.g., from about 0.9 to about 1.7), or less than about 1.5 (e.g., from about 0.9 to about 1.5), or less than about 1.4 (e.g., from about 0.9 to about 1.4), or less than about 1.3 (e.g., from about 0.9 to about 1.3), and preferably at 1 bar / 4 bar and / or 0.5 bar / 4 bar of less than about 1.5 (e.g., from about 1.0 to about 1.5) and / or less than about 1.4 (e.g., from about 1.0 to about 1.4).

[0087] The dry powder and / or respirable dry particles preferably have a tap density of at least about 0.2 g / cm 3 , at least about 0.25 g / cm 3 , a tap density of at least about 0.3 g / cm 3 , at least about 0.35 g / cm 3 , tap density of at least 0.4 g / cm3 For example, the dry powder and / or respirable dry particles may have a tap density of 0.4 g / cm 3 Over (e.g., 0.4 g / cm 3 ~Approx. 1.2g / cm 3 and a tap density of at least about 0.45 g / cm 3 (For example, about 0.45 g / cm 3 ~Approx. 1.2g / cm 3 ), at least about 0.5 g / cm 3 (For example, about 0.5 g / cm 3 ~Approx. 1.2g / cm 3 ), at least about 0.55 g / cm 3 (For example, about 0.55 g / cm 3 ~Approx. 1.2g / cm 3 ), at least about 0.6 g / cm 3 (For example, about 0.6 g / cm 3 ~Approx. 1.2g / cm 3 ) or at least about 0.6 g / cm 3 ~Approx. 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 ~about 0.5g / cm 3 , about 0.05g / cm 3 ~about 0.5g / cm 3 , about 0.1g / cm 3 ~about 0.5g / cm 3 , about 0.1g / cm 3 ~ approx. 0.4g / cm 3 or approximately 0.1 g / cm 3 ~ approx. 0.4g / cm 3 Alternatively, the dry powder and / or respirable dry particles have a tap density of about 0.15 g / cm 3 ~Approx. 1.0g / cm 3 Alternatively, the dry powder and / or respirable dry particles have a tap density of about 0.2 g / cm 3 ~about 0.8g / cm 3 is.

[0088] The dry powder and / or respirable dry particles have a bulk density of at least about 0.1 g / cm 3or 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 ~about 0.6g / cm 3 , about 0.2g / cm 3 ~about 0.7g / cm 3 , about 0.3g / cm 3 ~about 0.8g / cm 3 is.

[0089] The respirable dry particles, and when the dry powder is a respirable dry powder, the dry powder preferably has an MMAD of less than 10 micrometers, and preferably an MMAD of about 5 micrometers or less or about 4 micrometers or less. In one embodiment, the respirable dry powder and / or respirable dry particles preferably have a minimum MMAD of about 0.5 micrometers or about 1.0 micrometer. In one embodiment, the respirable dry powder and / or respirable dry particles preferably have a minimum MMAD of about 2.0 micrometers, about 3.0 micrometers, or about 4.0 micrometers.

[0090] The dry powder and / or respirable dry particles preferably have at least about 35%, preferably at least about 45%, at least about 60%, about 45% to about 80%, or about 60% to about 80% of the total dose having an FPF of less than about 5.6 micrometers (FPF<5.6 μm).

[0091] The dry powder and / or respirable dry particles preferably have at least about 20%, preferably at least about 25%, at least about 30%, at least about 40%, about 25% to about 60%, or about 40% to about 60% of the total dose having an FPF of less than about 3.4 micrometers (FPF<3.4 μm).

[0092] The dry powders and / or respirable dry particles preferably have a total water and / or solvent content of at most about 15% by weight, at most about 10% by weight, at most about 5% by weight, at most about 1% or from about 0.01% to about 1%, or may be substantially free of water or other solvents.

[0093] The dry powder and / or respirable dry particles are preferably administered with low inhalation energy. To correlate the dispersion of powder at different inhalation flow rates, inhalation volumes, and from inhalers with different resistances, the energy required to perform the inhalation strategy can be calculated. The inhalation energy is given by E=R 2 Q 2 V, where E is the inhaled energy in joules and R is kPa 1 / 2 where Q is the inhaler resistance in L / min, Q is the steady state flow rate in L / min, and V is the inspired air volume in L.

[0094] 0.02kPa 1 / 2 / LPM and 0.055kPa 1 / 2 Based on both the FDA guidance document for dry powder inhalers and a study by Tiddens et al. (Journal of Aerosol Med, 19(4), p.456-465, 2006), which found that the average adult inhalation volume across a range of DPIs was 2.2 L, along with peak inspiratory flow rates (PIFR) measured by Clarke et al. (Journal of Aerosol Med, 6(2), p.99-110, 1993) for flow rates Q from two inhaler resistances of 1 / LPM, it is predicted that using an inhalation volume of 2 L, a healthy adult population could achieve inhalation energies ranging from 2.9 Joules at a comfortable inhalation to 22 Joules at a maximal inhalation.

[0095] It is predicted that adult patients with mild COPD will have a maximum inhalation energy of 5.1 to 21 joules, those with moderate COPD will have a maximum inhalation energy of 5.2 to 19 joules, and those with severe COPD will have a maximum inhalation energy of 2.3 to 18 joules. This is also based on using the PIFR measurement in the equation for inhalation energy in relation to flow rate Q. The PIFR achievable in each group is a function of the inhaler resistance during inhalation. Using the study by Broeders et al. (Eur Respir J, 18, p. 780-783, 2001), a resistance of 0.021 kPa was calculated for each group. 1 / 2 / LPM and 0.032kPa 1 / 2 The maximum and minimum achievable PIFR values ​​for the two dry powder inhalers were predicted.

[0096] Similarly, adult asthmatics are predicted to be able to achieve a maximum inhalation energy of 7.4 to 21 joules, based on the same assumptions as the COPD population and the PIFR data from Broeders et al.

[0097] Healthy adults and children, for example, can 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).

[0098] The dry powders and / or respirable dry particles useful in the methods disclosed herein are preferably characterized by high emissions, e.g., CEPM, of at least 75%, at least 80%, at least 85%, at least 90%, or at least 95%, from the passive dry powder inhaler for a subject applying 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 of total inhalation energy to the dry powder inhaler. The dry powder and / or respirable dry particle container may contain about 5 mg, about 7.5 mg, about 10 mg, about 15 mg, about 20 mg, or about 30 mg. In one embodiment, the dry powder and / or respirable dry particles are characterized by a CEPM of 80% or greater and a VMGD of 5 micrometers or less when emitted from a passive dry powder inhaler having a resistance of about 0.036 sqrt (kPa) / liter per minute using a No. 3 capsule containing 10 mg of total mass at an airflow rate of 30 LPM for 3 seconds. In another embodiment, the dry powder and / or respirable dry particles are characterized by a CEPM of 80% or greater and a VMGD of 5 micrometers or less when emitted from a passive dry powder inhaler having a resistance of about 0.036 sqrt (kPa) / liter per minute using a No. 3 capsule containing 10 mg of total mass at an airflow rate of 20 LPM for 3 seconds. In a further aspect, the dry powder and / or respirable dry particles are characterized by a CEPM of 80% or greater and a VMGD of 5 micrometers or less when emitted from a passive dry powder inhaler having a resistance of about 0.036 sqrt (kPa) / liter per minute using a No. 3 capsule containing 10 mg total mass at an airflow rate of 15 LPM for 4 seconds.

[0099] The dry powder can be filled into 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., #000 with a volume capacity of 1.37 mL, #00 with a volume capacity of 950 μL, #0E with a volume capacity of 770 μL, #0 with a volume capacity of 680 μL, #1 with a volume capacity of 480 μL, #2 with a volume capacity of 360 μL, #3 with a volume capacity of 270 μL, and #4 with a volume capacity of 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 blister can be packaged as a single blister or as part of a series of blisters, e.g., 7 blisters, 14 blisters, 28 blisters, or 30 blisters. One or more of the blisters can preferably be at least 30% full, at least 50% full, or at least 70% full.

[0100] An advantage of the dry powders disclosed herein is that they disperse well over a wide range of flow rates and are relatively flow rate independent, making the dry powders and / or respirable dry particles a simple passive DPI available for a wide range of patient populations.

[0101] Dry powders and / or respirable dry particles useful in the methods described herein are preferably characterized by: 1) a VMGD at 1 bar of about 10 micrometers or less, preferably about 5 micrometers or less, as measured using a HELOS / RODOS system; 2) a dispersibility ratio at 1 bar / 4 bar and / or a dispersibility ratio at 0.5 bar / 4 bar of about 1.5 or less, about 1.4 or less, or about 1.3 or less; 3) a MMAD of about 10 micrometers or less, preferably about 5 micrometers or less; 4) at least about 45% or at least about 60% of the total dose having an FPF<5.6 μm; and / or 5) at least about 25% or at least about 40% of the total dose having an FPF<3.4 μm. Desirably, the dry powders and / or respirable dry particles have a tap density of about 0.2 g / cm. 3 More than about 0.3g / cm 3 More than about 0.4g / cm 3 More than 0.4g / cm 3 Super, about 0.45g / cm 3 More than or about 0.5g / cm 3 The above is a further feature.

[0102] Formulation I is an exemplary dry powder that can be used in the methods disclosed herein. The composition and properties of Formulation I are shown in Table 1 below.

[0103] [Table 1]

[0104] Formulation I has a fine particle fraction (FPF) of 57% of the total dose that is less than 5 microns, resulting in a fine particle dose of 2.8 mg less than 5 microns for a total dry powder capsule fill of 10.0 mg.

[0105] Formulation I has a dissolution half-life of 4.35 minutes, as determined by the following protocol: the powder formulation, capsule, and packaging materials were equilibrated at 22.5±2.5°C and 30±5% RH. Formulation I was encapsulated in No. 3 HPMC capsules under the same conditions. The fill weight of the powder preparation was 10 mg. The formulation was aerosolized from capsules in a capsule-based unit-dose DPI device (RS01, Plastiape, Osnago, Italy) using the Plastiape RS01 dry powder inhaler (DPI) at 60 L / min (4 L inhalation volume). The aerosol dose was collected using a UniDose system. Using the UniDose collection system, the entire impactor stage mass (i.e., less than stage 2 of the NGI) was uniformly deposited onto a glass microfiber filter membrane; this mass can be seen as the location of the circle (impacting particle or droplet). The filters were placed in a disk cassette and dissolution tested in 500 ml of PBS (pH 7.4) with 2.0% SDS in a USP Apparatus II POD (paddle-over-disk, USP V) at 37°C. Sink conditions were maintained in the vessel. Samples were taken at predetermined time points and tested for drug content on an Agilent (Santa Clara, CA, USA) 1260 Infinity Series HPLC.

[0106] The dry powders and / or respirable dry particles disclosed herein may be filled into a container, such as a capsule or blister. When the container is a capsule, the capsule may be, for example, a No. 2 or No. 3 capsule, preferably a No. 3 capsule. The capsule material may be, for example, gelatin or HPMC (hydroxypropyl methylcellulose), preferably HPMC.

[0107] The dry powders and / or respirable dry particles described and characterized herein may be contained in a dry powder inhaler (DPI). The DPI may be a capsule-based DPI or a blister-based DPI, preferably a capsule-based DPI. More preferably, the dry powder inhaler is selected from the RS01™ series of dry powder inhalers (Plastiape SpA, Italy). More preferably, the dry powder inhaler is selected from the RS01™ HR or RS01™ UHR2. Most preferably, the dry powder inhaler is an RS01™ HR.

[0108] Methods for preparing dry powders and dry particles Respirable dry particles and dry powders for use in the methods disclosed herein can be prepared using any suitable method, provided that the dry powders are not readily dispersible. Many suitable methods for preparing dry powders and / or respirable dry particles are conventional in the art and include single emulsion solvent evaporation, double emulsion solvent evaporation, spray drying, spray freeze drying, milling (e.g., jet milling), blending, solvent extraction, solvent evaporation, phase separation, simple coacervation, complex coacervation, interfacial polymerization, suitable methods involving the use of supercritical carbon dioxide (CO), ultrasonic crystallization, nanoparticle agglomerate formation, and other suitable methods, including combinations thereof. Respirable dry particles can be prepared using methods known in the art for preparing microspheres or microcapsules. These methods can be used under conditions that result in 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 size and density, can be selected using suitable methods, such as sieving.

[0109] Suitable methods for selecting respirable dry particles with desired properties, such as size and density, include wet sieving, dry sieving, and aerodynamic classifiers (eg, cyclones).

[0110] The respirable dry particles of the present invention are preferably spray-dried. Suitable spray-drying techniques are described, for example, in K. Masters' "Spray Drying Handbook" (John Wiley & Sons, New York (1984)). Generally, during spray drying, heat from a hot gas, such as heated air or heated nitrogen, is used to evaporate solvent from droplets formed by atomizing a continuous liquid feed. When hot air is used, moisture in the air is at least partially removed before its use. When nitrogen is used, the nitrogen gas can be flowed "dry," meaning that no additional water vapor is combined with the gas. If desired, the moisture level of the nitrogen or air can be set to a constant value higher than that of the "dry" nitrogen before the start of the spray-drying operation. If desired, the spray-drying apparatus or other apparatus, such as a jet mill apparatus, used to prepare the dry particles of the present invention can include an in-line geometric particle size measuring device to determine the geometric diameter of the respirable dry particles as they are generated, and / or an in-line aerodynamic particle size measuring device to determine the aerodynamic diameter of the respirable dry particles as they are generated.

[0111] In spray drying, a solution, emulsion, or suspension containing the dry particle components to be produced in a suitable solvent (e.g., aqueous solvent, organic solvent, aqueous-organic mixture, or emulsion) is sprayed into a drying vessel by an atomizing device. For example, a nozzle or rotary atomizer may be used to spray the solution or suspension into the drying vessel. The nozzle may be a two-fluid nozzle, and the nozzle may be in an internal or external mixing configuration. Alternatively, a rotary atomizer with 4 or 24 impellers may be used. Examples of suitable spray dryers that can be equipped with rotary atomizers and / or nozzles include the Mobile Minor Spray Dryer or Model PSD-1 (both manufactured by GEA Niro, Inc., Denmark), the Buchi B-290 Mini Spray Dryer (Buchi Labortechnik AG, Flawil, Switzerland), and the ProCepT Formatrix R&D spray dryer (ProCepT nv, Zelzate, Belgium), among several other spray dryer options. Actual spray drying conditions will vary, in part, depending on the composition of the solution or suspension being spray dried and the material flow rate. Those skilled in the art will be able to determine appropriate conditions based on the composition of the solution, emulsion, or suspension to be spray dried, the desired particle characteristics, and other factors. Typically, the spray dryer inlet temperature is about 90°C to about 300°C. The spray dryer outlet temperature will vary depending on factors such as the feed temperature and the properties of the material being dried. Typically, the outlet temperature is from about 50° C. to about 150° C. If desired, the respirable dry particles produced can be fractionated by volumetric size, e.g., using sieves, separated by aerodynamic size, e.g., using cyclones, and / or further separated according to density using techniques known to those skilled in the art.

[0112] To prepare the respirable dry particles of the present invention, generally, an emulsion or suspension containing the desired components (i.e., raw materials) of the dry powder of the present invention is prepared and spray-dried under appropriate conditions. Preferably, the raw materials have a dissolved or suspended solids concentration of at least about 1 g / L, at least about 2 g / L, at least about 5 g / L, at least about 10 g / L, at least about 15 g / L, at least about 20 g / L, at least about 30 g / L, at least about 40 g / L, at least about 50 g / L, at least about 60 g / L, at least about 70 g / L, at least about 80 g / L, at least about 90 g / L, or at least about 100 g / L. The raw materials can be produced by dissolving, suspending, or emulsifying the appropriate components (e.g., salts, excipients, other active ingredients) in a suitable solvent to prepare a solution, suspension, or emulsion. The solution, emulsion, or suspension can be prepared using any suitable method, such as bulk mixing of dry and / or liquid components or 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 can be dried to form respirable dry particles. Preferably, the atomization step occurs immediately after the components are combined in the static mixer. Alternatively, the atomization step occurs on a bulk-mixed solution.

[0113] The raw material can be prepared using any solvent in which itraconazole in microparticle form has low solubility, such as an organic solvent, an aqueous solvent, or a mixture thereof. 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), perfluorocarbons, dichloromethane, 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, the organic solvents described above). Aqueous solvents include water and buffer solutions. The preferred solvent is water.

[0114] Various methods (e.g., static mixing, bulk mixing) can be used to mix the solute and solvent to prepare the feedstock, and are known in the art. Other suitable methods of mixing may be used if desired. For example, additional ingredients can be included in the feedstock to cause or enhance the mixing. For example, carbon dioxide can act to promote physical mixing of the solute and solvent by causing effervescence.

[0115] The raw material or raw material components can have any desired pH, viscosity, or other properties. If desired, a pH buffer can be added to the solvent or cosolvent, or to the resulting mixture. Generally, the pH of the mixture ranges from about 3 to about 8.

[0116] After the dry powder and / or respirable dry particles are prepared, they can be separated, e.g., by filtration or cyclone centrifugation, to provide a particle sample having a preselected size distribution. For example, more than about 30%, more than about 40%, more than about 50%, more than about 60%, more than about 70%, more than about 80%, or more than about 90% of the respirable dry particles in the sample can have diameters within a predetermined range. The predetermined range within which a particular percentage of the respirable dry particles falls can be, for example, any of the size ranges described herein, e.g., a VMGD of about 0.1 to about 3 micrometers.

[0117] The suspension may be a nanosuspension as well as an intermediate for making a dry powder containing nanocrystalline itraconazole.

[0118] The dry powder can be itraconazole embedded in a matrix material, such as a matrix material comprising sodium sulfate and leucine. Optionally, the dry powder can be spray dried to provide small, densely dispersed particles.

[0119] The dry powder can consist solely of the respirable dry particles described herein, without other carrier or excipient particles (also referred to as a "bulk powder"). If desired, the dry powder can include a blend of the respirable dry particles described herein with other carrier or excipient particles, such as lactose carrier particles that are greater than 10 micrometers, between 20 micrometers and 500 micrometers, and preferably between 25 micrometers and 250 micrometers. In some embodiments, dry powders that include carrier particles (blended powders) are excluded.

[0120] In a preferred embodiment, the dry powder does not include carrier particles. In one aspect, the itraconazole of the present invention is embedded in a matrix including a sodium salt, leucine, and a stabilizer. The dry powder may include respirable dry particles with a uniform content, each particle including the itraconazole. Thus, as used herein, "uniform content" means that all respirable particles include some amount of itraconazole along with the stabilizer, sodium salt, and leucine.

[0121] The dry powder can comprise respirable dry particles, wherein at least 98%, at least 99%, or substantially all (by weight) of the respirable dry particles comprise itraconazole.

[0122] The dry powder is typically produced by first processing crystalline itraconazole and adjusting the particle size using any number of techniques familiar to those skilled in the art (e.g., wet milling, jet milling). For example, crystalline itraconazole may be processed with a stabilizer in an antisolvent to form a suspension. Preferred stabilizers include polysorbates (also known as TWEEN®), such as polysorbate 80 (PS80). The stabilized suspension of crystalline itraconazole is then spray-dried with a sodium salt and leucine. The resulting dry particles contain crystalline itraconazole dispersed throughout the excipient matrix, and each dry particle is homogeneous in composition.

[0123] In certain embodiments, the dry powders of the present invention are made by starting with crystalline itraconazole, and the inhibitor is typically obtained in the microcrystalline size range. The particle size of microcrystalline itraconazole can be reduced to nanocrystalline size using any of a number 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 often preferred because it can achieve a wide range of particle size distributions, including those in the nanometer (<1 μm) size domain. Of particular importance in the submicron size domain is the use of surface-stabilizing components, such as surfactants (e.g., polysorbate 80, also known as TWEEN® 80). Surfactants enable the creation of submicron particles and the formation of physically stable suspensions during milling. Surfactants isolate the many high-energy surfaces created during milling, preventing strong aggregation and precipitation. Therefore, the presence of a surfactant is important for spray-drying homogeneous microparticles. The surfactant ensures the formation of a uniform and stable suspension, ensuring compositional uniformity throughout the particles. The use of a surfactant allows for the formation of microsuspensions or nanosuspensions. The surfactant suspends the nanocrystalline itraconazole particles in a stable colloidal suspension in an antisolvent. The antisolvent for the drug can be water, or a combination of water and another miscible solvent, such as an alcohol or ketone, as a continuous antisolvent phase for the colloidal suspension. The feedstock to be spray-dried can be prepared by dissolving the soluble components in the desired solvent(s) and then dispersing the surfactant-stabilized crystalline itraconazole nanosuspension into the resulting feedstock with mixing, although the process is not limited to this specific order of operations.

[0124] Methods for analyzing the dry powders and / or respirable dry particles of the present invention are found in the Examples section below. [Example]

[0125] 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 water (ASTM Type II) was obtained from a water purification system (Millipore Corp., Billerica, MA) or equivalent.

[0126] PBMK studies were performed in silico. The methods and results of an exemplary respirable dry powder Phase 1 clinical trial used for static equation calculations and model development are summarized in Hava et al. (supra).

[0127] Geometric or volume diameter: Laser diffraction was used to determine the median volume diameter (×50 or Dv50), sometimes referred to as the geometric median volume diameter (VMGD), of the dry powders of the present invention. The apparatus consisted of a HELOS diffractometer and a RODOS dry powder disperser (Sympatec, Inc., Princeton, NJ). The RODOS disperser applies shear force to the particle sample and is controlled by adjusting the pressure of the compressed dry air blown through it (typically set at 1.0 bar at maximum orifice ring pressure). The pressure setting can be changed to vary the amount of energy used to disperse the powder. For example, the dispersion energy can be adjusted by changing the adjusting pressure from 0.2 bar to 4.0 bar. The powder sample is introduced into the RODOS funnel via a microspatula. The dispersed particles travel through a laser beam, and the resulting diffraction light pattern is collected by a series of detectors, typically using an R1 lens. The diffraction ensemble pattern was then converted to a volume-based particle size distribution using the Fraunhofer diffraction model, based on the fact that smaller particles diffract light at larger angles. Using this method, the span of the distribution was also determined according to the formula ((Dv

[90] -Dv

[10] ) / (Dv

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

[0128] Aerodynamic Performance: The aerodynamic characteristics of powders dispersing from the inhalation device were evaluated using a Next Generation Impactor (NGI) (Copley Scientific Limited, Nottingham, UK). For measurements using the NGI, the NGI device was operated under controlled environmental conditions of 18–25°C and 25–35% relative humidity (RH). The device consists of seven stages that separate aerosol particles based on inertial impaction and can operate at various airflow rates. In each stage, the aerosol stream passes through a series of nozzles and impacts a corresponding impaction surface. Particles with sufficiently small inertia are carried forward by the aerosol stream to the next stage, while the remaining particles impact this surface. In each subsequent stage, the aerosol passes through the nozzles at ever-increasing speeds, collecting ever-smaller aerodynamic particles on its plate. After the aerosol leaves the final stage, a microorifice collector collects the smallest remaining particles. Gravimetric 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 powder to a predetermined weight and placed into a handheld, breath-actuated dry powder inhaler (DPI) device: 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 into a cascade impactor operated at a predetermined flow rate relative to 2.0 liters of inhaled air. The cutoff diameter of the stage at that flow rate was calculated. Wetted filters were placed in the device, and the amount of powder impacting the stages was determined by HPLC chemistry to capture these fractions.

[0129] Fine particle dose: The fine particle dose indicates the mass of itraconazole in a given size range and can be used to predict the mass reaching a specific region of the respiratory tract. Fine particle dose can be measured gravimetrically or chemically, either by ACI or NGI. When measured gravimetrically, the dry particles of the present invention are assumed to be homogeneous, and the mass of itraconazole can be determined by multiplying the mass of powder in each stage and each collection filter by the percentage of itraconazole in the formulation. When measured chemically, the powder in each stage or filter is collected, separated, and assayed, for example, by HPLC to determine the itraconazole content. The cumulative mass deposited on each stage at a given flow rate is calculated and the cumulative mass corresponding to particles with a diameter of 5.0 micrometers is interpolated. This cumulative mass of powder contained in one or more capsules and acted upon in the impactor is equivalent to a fine particle dose of less than 5.0 micrometers (FPD<5.0 micrometers).

[0130] Mass Median Aerodynamic Diameter (MMAD): MMAD was determined using information obtained by the Next Generation Impactor (NGI). The cumulative mass below the stage cutoff diameter was calculated for each stage and normalized by the amount of powder recovered. The MMAD for that powder was then formed by linear interpolation of the stage cutoff diameters, bracketing the 50th percentile. An alternative method for measuring MMAD is the Andersen Cascade Impactor (ACI). Like the NGI, MMAD was calculated by the cumulative mass below the stage cutoff diameter, bracketing the 50th percentile, for each stage and normalized by the amount of powder recovered. The MMAD for that powder was then formed by linear interpolation of the stage cutoff diameters, bracketing the 50th percentile.

[0131] Geometric or volumetric diameter of release: The median volume diameter (Dv50) (sometimes referred to as the median volume geometric diameter (VMGD)) of the powders of the present invention after release from a dry powder inhaler was determined using laser diffraction with a Spraytec (Malvern, Inc.) diffraction instrument. The powder was filled into size 3 capsules (V-Caps, Capsugel) and placed in a capsule-based dry powder inhaler (RS01™ Model 7 (high resistance), Plastiape, Italy), or DPI, which was then sealed in a cylinder. The cylinder was connected to a positive pressure air source, and the steady air flow through the system was measured with a mass flow meter and its duration was controlled by a timer-controlled solenoid valve. The outlet of the dry powder inhaler was exposed to room pressure, and the resulting aerosol jet was passed through the laser of a diffraction particle sizer (Spraytec) in its open bench configuration before being captured by a vacuum extractor. The steady air flow rate through the system was initiated using a solenoid valve. A steady airflow rate, typically 60 L / min, was inhaled through the DPI for a predetermined period, typically 2 seconds. Alternatively, airflow rates of 15, 20, or 30 L / min were inhaled through the DPI. The resulting geometric particle size distribution of the aerosol was calculated by software based on scattering pattern measurements from a photodetector, typically with samples taken at 1000 Hz during the inhalation period. The measured Dv50, GSD, and FPF < 5.0 μm were then averaged over the entire inhalation period.

[0132] The emitted dose (ED) refers to the mass of itraconazole released from a suitable inhalation device after exhalation or dispersion. The ED is determined using a method based on USP Section 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, 13th Revision, pp. 222-225, 2007. The capsule contents are dispersed using either an RS01 HR inhaler with a pressure drop of 4 kPa and a typical flow rate of 60 LPM, or a UHR2 RS01 with a pressure drop of 4 kPa and a typical flow rate of 39 LPM. The emitted powder is collected on the filter of a filter holder sampler. The sampler is rinsed with an appropriate solvent, e.g., water, and analyzed using an HPLC method. In gravimetric analysis, a shorter filter holder sampling device is used to reduce the device's volume, and the filter is weighed before and after to determine the mass of powder delivered from the DPI to the filter. The therapeutic agent release amount is then calculated based on the content of the therapeutic agent in the delivered powder. The release amount can be recorded as the mass of therapeutic agent delivered from the DPI or as a percentage of the loading amount.

[0133] Thermogravimetric Analysis: Thermogravimetric analysis (TGA) was performed using either a Q500 model or a Discovery model thermogravimetric analyzer (TA Instruments, New Castle, DE). Samples were placed in either an open aluminum DSC pan or a closed aluminum DSC pan (which was then automatically pierced and opened prior to testing). The tare weight was pre-recorded by the instrument. The following method was used: a temperature ramp from ambient temperature (approximately 35°C) to 200°C at 5.00°C / min. Weight loss was recorded as a function of temperature up to 140°C. TGA allows the content of volatile compounds in the dry powders of the present invention to be calculated. When the process uses water alone or in combination with a volatile solvent, weight loss by TGA is a good estimate of water content.

[0134] Powder X-ray Diffraction: The crystalline nature of the formulations of the present invention was assessed by powder X-ray diffraction (PXRD). 20-30 mg material samples were analyzed on a powder X-ray diffractometer (D8 Discover (Bruker Corporation, Billerica, MA) or equivalent) using a 1.5418 A Cu X-ray tube with a LINXEYE detector, over a scan range of 5-45° 2θ and a step size of 0.02° 2θ, with a data accumulation time of 1.2 seconds per step.

[0135] Itraconazole Content / Purity Using HPLC: A high-performance liquid chromatography (HPLC) method using a reversed-phase C18 column coupled to an ultraviolet (UV) detector has been developed for the analysis of the identity, bulk content, assay, CUPMD, and impurities of itraconazole dry powder. The reversed-phase column was equilibrated at 30°C, and the autosampler was set at 5°C. A gradient elution of the mobile phase, i.e., 20 mM monobasic sodium phosphate (mobile phase A) at pH 2.0 and acetonitrile (mobile phase B), was used, ranging from 59:41 (A:B) to 5:95 (A:B) over a run time of 19.5 minutes. Detection was by UV at 258 nm, with an input volume of 10 μL. The itraconazole content in the powder of the present invention was quantified against a standard curve.

[0136] The identification of known impurities A, B, C, D, E, F, and G (as identified in monograph Ph.Eur.01 / 2011:1335) is confirmed by comparing the retention times of the impurity peaks in the itraconazole dry powder sample with those of the reference standard itraconazole USP impurity mixture spiked with impurity A. Unknown impurities are identified and quantified by their retention times relative to the retention time of the main itraconazole peak, along with the area above the limit of detection (LOD). All impurities are measured by their area percentage relative to the itraconazole peak.

[0137] Particle size reduction: The particle size distribution of the crystalline itraconazole of the present invention can be controlled using a number 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 often preferred because it can achieve a wide range of particle size distributions, including those in the nanometer (less than 1 μm) size domain.

[0138] Particle size reduction using low-energy wet milling: One technique for reducing the particle size of the itraconazole of the present invention was by low-energy wet milling (also known as roller milling or jar milling). A suspension of the itraconazole was prepared in a poor solvent, which could be water or any solvent in which the active agent is poorly soluble. A stabilizer (which can be, but is not limited to, a nonionic surfactant or an amphiphilic polymer) can then be added to the suspension along with grinding media (which can be, but is not limited to, spheres with high abrasion resistance and a size range of 0.03 to 0.70 millimeters in diameter). The suspension is then rotated using a jar mill (US Stoneware, East Palestine, OH, USA), with samples taken periodically to assess particle size (LA-950, HORIBA, Kyoto, Japan). Once the particle size is sufficiently reduced or the minimum particle size is reached, the suspension is sieved to remove the grinding media and the product is recovered.

[0139] Particle size reduction using high-energy wet milling: Another technique for reducing the particle size of the itraconazole of the present invention was by high-energy wet milling using a rotor-stator mill or a media-agitated mill. The itraconazole suspension was prepared in a poor solvent, which could be water or any solvent in which the active agent is poorly soluble. A stabilizer (which can be, but is not limited to, a nonionic surfactant or an amphiphilic polymer) can then be added to the suspension along with grinding media (which can be, but is not limited to, spheres with high abrasion resistance and a size range of 0.03 to 0.70 millimeters in diameter). The suspension is then fed into the mill, which can operate in either batch or recirculation mode. The process consists of the suspension and grinding media being agitated in a milling chamber, which increases the energy input to the system and accelerates the particle size reduction process. The milling chamber and recirculation vessel are jacketed and actively cooled to avoid product overheating. The agitation and recirculation rates of the suspension are controlled during the process. Samples are taken periodically to evaluate particle size (LA-950, HORIBA, Kyoto, Japan). Once the particle size is sufficiently reduced or the minimum particle size is reached, the suspension is discharged from the mill.

[0140] Spray drying: Dry powders were prepared by spray drying in a Buchi B-290 Mini Spray Dryer (Buchi Labortechnik AG, Flawil, Switzerland), and the powder was collected from either a standard cyclone or a high-performance cyclone. The system was operated in open-loop (single-pass) mode with nitrogen as the drying and atomizing gas. When operated with air, the system used a Buchi B-296 dehumidifier to ensure stable temperature and humidity of the air used for spray drying. Additionally, an external LG dehumidifier (model 49007903, LG Electronics, Englewood Cliffs, NJ) was operated continuously when the room relative humidity exceeded 30% RH. When operated with nitrogen, a pressurized nitrogen source was used. Additionally, the system aspirator was adjusted to maintain a system pressure of -2.0 inches of water. A Buchi nozzle with a 1.5 mm cap and a 0.7 liquid tip was used for atomization of the feed liquid. The solid concentration of the liquid raw material was 3%, the inlet temperature of the treatment gas was 127°C to 140°C, the outlet temperature of the treatment gas was 60°C, the flow rate of the drying gas was 17.0 kg / h, the flow rate of the atomizing gas was 30.0 g / min, and the flow rate of the liquid raw material was 6.0 mL / min.

[0141] Stability Assessment: As detailed in the International Conference on Harmonization (ICH) Q1 guidance, the physicochemical stability and aerosol performance of a given formulation were evaluated at 2-8°C, 25°C / 60% RH, and 40°C / 75% RH when material availability permitted. Stability samples were stored in calibrated chambers (Models PH024 and PH074 from Darwin Chambers Company, St. Louis, MO). Bulk powder samples were weighed into amber glass vials, sealed at 30% RH, and induction-sealed in aluminum pouches (Drishield 3000, 3M, St. Paul, MN) with silica desiccant (2.0 g, Multisorb Technologies, Buffalo, NY). Additionally, to assess the stability of the formulation in capsules, target masses of powder were manually weighed into No. 3 HPMC capsules (Capsugel Vcaps, Peapack, NJ) with a tolerance of ±0.2 mg at 30% RH. The filled capsules were then divided into high density polyethylene (HDPE) bottles and sealed in aluminum pouches with silica desiccant by induction sealing.

[0142] Example 1: Preparation and Characterization of Exemplary Dry Powder Formulation I A. Powder preparation Nanocrystalline itraconazole for Formulation I was prepared by combining 30.090 g of itraconazole (Neuland ITI0114005 and ITI0714011) with 87 g of water and 3 g of polysorbate 80. Milling media polystyrene (130 g of 500 μm, Dow Chemical, Midland, MI) was then added to the suspension, and the suspension was milled at 1800 rpm for 1 hour before collection. The final median particle size (Dv(50)) of the milled suspension was 132 nm.

[0143] A feedstock solution was then prepared and used to manufacture the dry powder of the present invention. A drug loading of 50 wt% itraconazole on a dry basis was targeted. The feedstock solution used to spray-dry the particles was made as follows: The required amount of water (1.18 kg) was weighed into an appropriately sized glass container. Sodium sulfate (12.8 g) and leucine (3.7 g) were added to the water and stirred until the solution was visually clear. An itraconazole-containing suspension (containing 18.3 grams of itraconazole and 1.83 grams of polysorbate 80) was then added to the excipient solution and stirred until visually homogenous. The feedstock was then spray-dried. The feedstock was stirred while spray-drying. The weight of the feedstock was approximately 1.22 kg. According to the protocol described above, dry powder Formulation I was prepared from the raw materials by spray drying in a Buchi B-290 Mini Spray Dryer (Buchi Labortechnik AG, Flawil, Switzerland) and the powder was collected in a cyclone.

[0144] The dry powder composition (w / w) of Formulation I on a dry basis is 50% itraconazole, 35% sodium sulfate, 10% leucine and 5% polysorbate 80.

[0145] B. Powder Characterization The bulk particle size characteristics of Formulation I are shown in Table 2 below. The span at 1 bar of 2.10 indicates a relatively narrow size distribution. The 1 bar / 4 bar dispersion ratio of 1.25 indicates that they are relatively independent of dispersion energy, a desirable property that allows for similar particle dispersion across a range of dispersion energies.

[0146] [Table 2]

[0147] Measured and / or calculated geometric particle size and capsule emitted powder mass (CEPM) simulated patient flow rates were measured for Formulation I at 60 liters per minute (LPM) and 30 LPM. 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 unaffected by patient inspiratory flow, resulting in relatively similar therapeutic doses delivered to patients breathing at various flow rates.

[0148] Aerodynamic particle size, fine particle fraction, and fine particle dose were also measured and / or calculated using a Next Generation Impactor (NGI). Formulation I had an MMAD of 4.22 μm and an FPD of 38.3% of the nominal dose that was less than 5 μm. In other words, more than 30% of the nominal dose reached the impactor stage and was therefore predicted to be delivered to the lungs. The MMAD of 4.22 also indicates deposition in the central and conducting airways.

[0149] Thermogravimetric analysis determined the weight loss to be 0.1%.

[0150] The crystallinity of Formulation I was assessed by X-ray diffraction (XRD). The diffraction pattern of itraconazole was observed for the formulation, suggesting that the milling or spray drying process did not affect the solid state of itraconazole.

[0151] Example 2: In silico modeling A physiologically based pharmacokinetic (PBPK) model (Simcyp Simulator, V19), originally developed to simulate the concentration versus time profiles of itraconazole and OH-itraconazole after administration as an oral solution, was modified to simulate administration by oral inhalation. PBPK model parameters accounting for the rate and percentage of absorption from the lung, and the fraction of the inhaled dose swallowed, were optimized by fitting these parameters to observed plasma concentration data collected in a clinical trial in which Formulation I was administered at 35 mg once daily (QD) for 14 days. The area under the curve (AUC) of itraconazole for the simulated population at steady state was 0-24h The geometric mean values ​​(through day 14) for CYP3A4 DDIs were within 0.96-fold of those observed in the Phase 1 clinical trial data for Formulation I and 1.68-fold for OH-itraconazole (see Hava, supra). By applying fundamental static, mechanism-based static, and physiologically based pharmacokinetic (PBPK) models for itraconazole and OH-itraconazole (itraconazole's primary metabolite) to assess the potential risk of itraconazole dry powder as an "interacting drug" for CYP3A4 DDIs, using midazolam as the "interacting" drug and Formulation I as an exemplary itraconazole-based dry powder, the above data were used to identify potential DDIs for orally inhaled itraconazole at doses up to 40 mg.

[0152] Basic Static Models of Reversible Inhibition: The basic static equations and mechanism-based static equations are described in the FDA guidance for in vitro drug-drug interaction testing (FDA DDI Guidance (2020). "Clinical Drug Interaction Studies - Cytochrome P450 Enzyme- and Transporter-Mediated Drug Interactions, Guidance for Industry." USDapartment of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER) (incorporated herein by reference in its entirety).

[0153] C of itraconazole and OH-itraconazole after 14 days of 35 mg formulation I (QD) max The observed values ​​were used to calculate the ratio (R1) of the intrinsic clearance values ​​of the probe substrate in the absence and presence of itraconazole for Formulation I.

[0154] Calculation of the ratio of the intrinsic clearance values ​​of the probe substrate in the absence and presence of inhibitors in the gastrointestinal tract (R1,gut) was used for Formulation I, since itraconazole and OH-itraconazole are inhibitors of CYP3A4. The equation input values ​​are listed in Table 3.

[0155] [Table 3]

[0156] An R1 of 1.02 or greater or an R1,gut of 11 or greater indicates the presence of a clinically significant drug-drug interaction that warrants further investigation.

[0157] Mechanism-based static model of reversible inhibition: The area under the plasma concentration versus time curve (AUCR) of reversible inhibitors was calculated according to FDA guidance for in vitro drug-drug interaction studies. The worst-case scenario was assumed to be that the entire inhaled dose was swallowed and subsequently delivered to the gastrointestinal tract. A weak, moderate, or strong DDI was defined as an AUCR value (weak: ≥1.25-fold <2.00-fold; moderate: ≥2.00-fold <5.00-fold; strong: ≥5.00-fold).

[0158] PBPK Modeling - Study Design and Setup: To achieve the modeling goals, this step in the study consisted of two parts: model optimization and model application. Some of the key factors for each step are listed below. Model optimization and model application were performed using Simcyp (2019, Version 19 Release 2, Certara, Sheffield, UK). Data assembly and plotting were performed using RStudio (Version 4.1.2, R Foundation for Statistical Computing, Vienna, Austria). A virtual Nordic Caucasian population (liver volume and physiological parameters, including blood flow and oxygen abundance) within Simcyp was used for all simulations (Howgate E., et al., Xenobiotica (2006) 36(6):473-497). Except for demographic data, all parameter values ​​for the healthy volunteer (HV) population were the same as those used for the Caucasian population.

[0159] PBPK Modeling—Model Optimization: The Simcyp V19 itraconazole oral solution PBPK model was adapted to simulate the plasma concentration versus time profiles of itraconazole and OH-itraconazole after inhalation administration of 35 mg of Formulation I (QD for 14 days) to include itraconazole absorption through the lungs and gastrointestinal tract. The model assumes first-order absorption from the lungs into the systemic circulation. The structural model is shown in Figure 1. The study 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 of Formulation I QD for 14 days. The study measured itraconazole and OH-itraconazole data, as summarized in Table 4.

[0160] [Table 4]

[0161] To develop the PBPK model, 10 virtual studies were generated with six subjects (33.3% female) aged 21 to 58 years to assess intergroup variability. The virtual study population was selected to match the clinical trial subjects. A range of values ​​was tested for the inhaled dose rate, the fraction of itraconazole absorbed from the lung (Fa,1), and the first-order rate constant for itraconazole absorption from the lung (ka,1). After 35 mg of Formulation I (QD for 14 days), on Study Day 14, these parameters were optimized to best fit the observed plasma concentration versus time profiles and PK parameters of itraconazole and OH-itraconazole after multiple doses of Formulation I. Briefly, on Study Day 14, the inhaled dose rate and Fa,1 were optimized to fit the AUC0-24h of itraconazole. Subsequently, ka,1 was optimized to obtain the C max Multiple doses and C maxIf the simulated values ​​of were within 0.8-1.25 of the observed values, the absorption parameters were further optimized to best predict the concentration versus time profile of OH-itraconazole. The intestinal absorption, distribution, and excretion parameters of itraconazole and OH-itraconazole were unchanged from the validated models for itraconazole and OH-itraconazole, which assumed that itraconazole follows linear kinetics even at low doses. This model assumes that itraconazole is not metabolized to OH-itraconazole in the lungs.

[0162] The primary inhalation parameters were manually optimized by comparing the simulated profiles and data observations for Formulation I. The primary inhalation parameters used to simulate the plasma concentration profiles for Formulation I are shown in Table 5.

[0163] [Table 5]

[0164] PBPK Modeling - Model Application: A representative hypothetical healthy population consisting of 10 hypothetical studies consisting of 10 healthy subjects (50% female) aged 20-50 years was used to predict the CYP3A4 inhibitory potential of Formulation I. The interacting drug (midazolam) was administered as a single 5 mg dose without Formulation I, followed by a daily dose of 35 mg of Formulation I on day 14. The hypothetical DDI study was repeated with the same hypothetical study design and study population, but with Formulation I administered at 40 mg daily for 14 days.

[0165] Calculation of R values ​​for the basic model of reversible inhibition: Using the highest observed concentrations of itraconazole and OH-itraconazole after multiple inhalation doses of Formulation I (35 mg QD) for 14 days, R was calculated for Formulation I. R was calculated to be 1.35. This value exceeded the cutoff value of 1.02 established in the FDA guidance document (see above), thus requiring further investigation of the DDI trend. In addition, R was calculated to be greater than the threshold value of 11, indicating that additional evaluation of the DDI trend was required. Based on these results, a mechanism-based static model was applied to further investigate the CYP3A4 inhibition potential of Formulation I.

[0166] Calculation of AUCR in mechanism-based static equations: The AUCR of midazolam was calculated for Formulation I using the highest observed concentrations of itraconazole and OH-itraconazole after a simulated 14-day multiple inhalation dose (35 mg QD) of Formulation I. To calculate the worst case scenario, it was assumed that all itraconazole absorption occurred through the gastrointestinal tract. The AUCR of midazolam was calculated to be 5.36, further demonstrating the risk of Formulation I as an interacting drug for CYP3A4 DDIs. Based on these results, a PBPK model was developed to further understand the CYP3A4 inhibitory potential of Formulation I.

[0167] PBPK Model Optimization and Application: Simulated plasma concentration data for itraconazole and OH-itraconazole were based on manually optimized values ​​for the inhaled dose rate, (Fa,1), and (ka,1) parameters for Formulation I. Individual mean test concentrations and mean concentration versus time profiles for the entire hypothetical population (n=60) were simulated. The simulated profiles for Formulation I and OH-itraconazole after 14 days of administration of 35 mg / day of Formulation I were comparable to the clinical data, as shown in Figures 2A and 2B. Additionally, the C of itraconazole on day 14 was significantly higher than that of the control group. max The mean geometric predicted values ​​for were within 0.81-fold of the observed values, and the predicted geometric mean values ​​for AUC0-24h were within 0.96-fold of the observed values ​​(Table 6).

[0168] [Table 6]

[0169] C of OH-itraconazole on day 14 max The mean predicted value for AUC0-24h was within 1.47-fold of the observed value, and the mean predicted value for AUC0-24h was 1.68-fold of the observed value (Table 7).

[0170] [Table 7]

[0171] In applying the model, the plasma concentration versus time profile of midazolam after a single oral dose of 5 mg in the absence of Formulation I and on day 14 of a 14-day period in which healthy subjects received Formulation I (35 mg daily or 40 mg daily) was simulated. The simulated mean plasma concentrations of itraconazole and OH-itraconazole after 40 mg daily administration of Formulation I for 14 days are shown in Figures 3A and 3B. The simulated mean plasma concentrations of midazolam after a single oral dose of 5 mg in the absence of Formulation I and on day 14 of a 14-day period in which healthy subjects received Formulation I (35 mg daily or 40 mg daily) are shown in Figures 4A and 4B. The C of midazolam in the presence and absence of Formulation I was max and AUC 0-inf The geometric mean predicted values ​​and corresponding geometric mean ratios are shown in Table 8. When 35 mg daily Formulation I was coadministered with midazolam, the threshold for a weak DDI was not met (AUCR and C max At the higher dose of Formulation I, 40 mg daily, a weak DDI is predicted (AUCR ≥ 1.25 and < 2).

[0172] [Table 8]

[0173] In conclusion, PBPK modeling of Formulation I after multiple inhaled doses predicts minimal effects of Formulation I on CYP3A4 substrates. Based on the criteria in the U.S. Food and Drug Administration (FDA) DDI guidance, no clinically significant CYP3A4 DDIs are predicted after administration of Formulation I QD for 14 days.

Claims

1. 1. A method for treating a disease or disorder in a subject for which oral itraconazole is contraindicated, the method comprising administering to the airways of the subject a respirable dry powder comprising itraconazole.

2. 10. 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. 1. A method of administering itraconazole in combination with a second therapeutic agent to a subject in need thereof, wherein the itraconazole is administered to the subject's airways as a respirable dry powder, and the second therapeutic agent is a substrate, inducer, and / or inhibitor of an enzyme or receptor that is inhibited by itraconazole or that metabolizes itraconazole.

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

5. 5. The method of any one of claims 2 to 4, wherein the second therapeutic agent is contraindicated with oral itraconazole (e.g., SPORANOX®).

6. 6. The method of any one of claims 2 to 5, wherein the second therapeutic agent is an alpha blocker, a beta blocker, an analgesic, an antiarrhythmic agent, an antibacterial agent, an anticoagulant, an antiplatelet agent, an anticonvulsant, an antidiabetic agent, an antihelminthic agent, an antifungal agent, an antiprotozoal agent, an antimigraine agent, an antitumor agent, an antipsychotic agent, an anxiolytic agent, a hypnotic agent, an antiviral agent, 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 antidepressant or a selective serotonin reuptake inhibitor (SSRI)), a urinary agent, a vasopressin receptor antagonist, a nonsteroidal anti-inflammatory drug (NSAID), or a gastrointestinal agent.

7. 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, isavuconazonium, praziquantel, or artemether-lumefantrine; , quinine, ergot alkaloids (e.g., dihydroergotamine, ergometrine, ergonovine, methylergometrine, methylergonovine, ergotamine), eletriptan, irinotecan, axitinib, bosutinib, cabazitaxel, cabozantinib, ceritinib, cobimetinib, crizotinib, dabrafenib, dasatinib, docetaxel, ibrutinib, lapatinib, nilotinib, olaparib, pazopanib, regorafenib, sunitinib, trabectedin, trastuzumab-emtansine, vinca alkaloids, bortezomib, brentuximab Cimab-vedotin, busulfan, erlotinib, gefitinib, idelalisib, nintedanib, panobinostat, ponatinib, ruxolitinib, sonidegib, vandetanib, imatinib, ixabepilone, alprazolam, aripiprazole, buspirone, diazepam, haloperidol, midazolam, quetiapine, ramelteon, risperidone, suvorexant, zopiclone, lurasidone, pimozide, triazolam, levacetylmethadol (levomethadyl), simeprevir, daclatasvir, indinavir, maraviroc, cobicistat, erlotinib, riboflavin ... Vitegravir, ritonavir, saquinavir, tenofovir disoproxil fumarate, nadolol, felodipine, nisoldipine, diltiazem, dihydropyridine, 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, elexacaftor, tezacaftor, SYMDEKO®, ORKAMBI®, KALYDECO®, alitretinoin, cabergoline, cannabinoids, cinacalcet, conivaptan, tolvaptan, Saccharomyces The method according to any one of claims 2 to 6, wherein the active ingredient is IgE, meloxicam, ciprofloxacin, erythromycin, clarithromycin, idelalisib, darunavir, fosamprenavir, isoniazid, rifampicin, rifabutin, phenobarbital, phenytoin, efavirenz, nevirapine, a drug that reduces gastric acidity (e.g., an acid neutralizer such as aluminum hydroxide, an acid secretion inhibitor such as an H2 receptor antagonist and a proton pump inhibitor), or halofantrine.

8. 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, avanafil, ticagrelor, colchicine, fesoterodine, solifenacin, or eliglustat.

9. 10. The method of any one of the preceding claims, wherein the itraconazole is administered to the subject at a nominal dose of about 1 mg to about 60 mg, about 5 mg to about 40 mg, about 1 mg to about 10 mg, about 10 mg to about 20 mg, about 20 mg to about 30 mg, or about 30 mg to 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. 10. The method of any one of claims 2-9, wherein the itraconazole is administered within about 14 days before or after administering the second therapeutic agent to the subject, or 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 administering the second therapeutic agent to the subject.

11. 11. The method of any one of claims 2-10, wherein the itraconazole is administered to 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.

12. 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 the second therapeutic agent is administered.

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

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

15. 15. The method of claim 13 or 14, wherein the itraconazole is in the form of crystalline primary particles 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. 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 method of any one of claims 13 to 16, wherein the itraconazole is at least 50% crystalline.

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

1.

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

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

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

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

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

24. In the respirable dry particles, (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 of 0.2 g / cc to 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 dispersibility ratio at 0.5 bar / 4 bar (0.5 / 4 bar) of about 1.5 or less, as measured by laser diffraction; The method according to any one of claims 13 to 23.

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

26. 26. The method of any one of claims 13 to 25, wherein the respirable dry particles, when emitted from a passive dry powder inhaler having a resistance of about 0.036 sqrt (kPa) / liter per minute under conditions of an inhalation flow rate of 30 LPM over a 3 second period using a No. 3 capsule containing a total mass of 10 mg, have a capsule emitted powder mass of at least 80%, the total mass consisting of the respirable dry particles, and the volume geometric median diameter of the respirable dry particles emitted from the inhaler is 5 micrometers or less as measured by laser diffraction.

27. 27. The method of any one of claims 13 to 26, wherein the respirable dry powder is delivered to the subject's airways by a capsule-based passive dry powder inhaler.

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

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

30. 10. A respirable dry powder for use in a method of treating a disease or disorder 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.

31. 32. The respirable dry powder for use according to 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 that metabolizes itraconazole.

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

33. 1. Use of a respirable dry powder in the manufacture of a medicament for treating a disease or disorder 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.

34. 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 or that metabolizes itraconazole.

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

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