RU2820457C2 - Methods of treating fungal infections - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to therapy, and can be used for treating fungal infections. Method of treating allergic bronchopulmonary aspergillosis (ABPA) involves inhalation into the airways of a patient in need of a dry powder containing: antifungal agent itraconazole in crystalline form in amount of 45 to 85% by weight in the form of subparticles with a volume median geometric diameter (VMGD) of 60 to 1650 nm; stabilizer in amount of 3 to 15% by weight; sodium salt in amount of 3 to 50% by weight; leucine in amount of 1 to 10% by weight. Itraconazole is administered in an amount sufficient to simultaneously achieve a pulmonary concentration of at least 500 ng/g or ng/ml to 8100 ng/g or ng/ml and a plasma concentration of 0.2 ng/ml to 25 ng/ml, pulmonary and plasma concentrations are achieved for at least 24 hours after administration. Itraconazole is administered in a single dose or in an initial dose with the introduction of one subsequent dose or subsequent doses, each of the above doses independently includes a nominal dose of itraconazole from 5 to 35 mg.

EFFECT: use of the invention enables to achieve high and stable exposure of itraconazole in the lungs, higher than the exposure achieved after oral administration, while maintaining a low systemic exposure.

12 cl, 10 tbl, 8 dwg, 4 ex

Description

Related applications

This application claims the benefit of US Patent Application No. 62/659601, filed April 18, 2018, and US Patent Application No. 62/696510, filed July 11, 2018, the entire contents of each of which are incorporated herein by reference.

Prerequisites for creating the invention

Pulmonary fungal infections caused by Aspergillus spp. and other fungi are of increasing concern in patients with reduced respiratory function, such as those with cystic fibrosis (CF). For example, patients may have a chronic pulmonary fungal infection or allergic bronchopulmonary aspergillosis (ABPA), a severe inflammatory condition that is usually treated with a long course of oral steroids. A. fumigatus is the predominant species causing the disease, however other species such as A. niger , A. terrus , A. flavus also infect humans. Pulmonary infections caused by A. fumigatus manifest as a range of diseases depending on the immune status of the host and the underlying lung disease. In immunocompromised hosts, invasive pulmonary aspergillosis (IPA) is a life-threatening disease that occurs in immunocompromised patients as a result of treatment for hematologic cancer, organ transplantation, or other immunosuppressive conditions.

Mortality from IPA in neutropenic patients and hematopoietic stem cell recipients is >50% and >90%, respectively. Because of the significant mortality associated with IPA, antifungal prophylaxis is used to reduce the risk of infection. A. fumigatus also causes chronic infection in patients with chronic lung diseases such as asthma and cystic fibrosis (CF). In asthmatics, fungal colonization and infection can lead to allergic bronchopulmonary aspergillosis (ABPA). ABPA is a complex hypersensitivity reaction that occurs in response to airway colonization by Aspergillus fumigatus, typically in patients with asthma or CF. The immunological response to fungal antigens in the airways leads to the activation of T helper type 2 (Th2) cells and the recruitment of inflammatory cells into the airways, the most significant of which are eosinophils. The expression of interleukin-4 and interleukin-5 (IL-4 and IL-5) plays a central role in these processes. IL-4 stimulates the activation of adhesion molecules involved in eosinophil recruitment and immunoglobulin E (IgE) production by B cells, which in turn leads to mast cell activation. IL-5, produced by both Th2 cells and mast cells, is a key mediator of eosinophil activation. Activation of mast cells and eosinophils leads to the release of mediators that induce bronchoconstriction.

A number of antifungal agents are known, including triazoles (eg, itraconazole), polyenes (eg, amphotericin B) and echinocandins. Antifungals typically have low aqueous solubility and low oral bioavailability, and the preparation of pharmaceutical compositions that can be administered to provide safe and therapeutic levels of antifungals has been challenging. Antifungals are typically administered in oral or intravenous (IV) formulations as a treatment for fungal infections, including pulmonary infection and ABPA. However, such compositions are limited by poor oral bioavailability, adverse side effects and toxicity, and extensive drug-drug interactions. Alternative approaches such as airway delivery by inhalation, which could theoretically reduce systemic side effects, also present challenges. Notably, agents with poor water solubility are well known to cause local pulmonary toxicity (eg, local inflammation, granulomas) if inhaled. The traditional approach to eliminating the local toxicity of poorly soluble agents is to formulate the agent in such a way as to increase its rate of dissolution, for example, using amorphous compositions.

The chemical structure of itraconazole is described in US Pat. No. 4,916,134. Itraconazole is a triazole antifungal agent that provides therapeutic benefits (eg, in the treatment of fungal infections) and is the active ingredient in SPORANOX® (itraconazole; Janssen Pharmaceuticals), which can be administered orally or intravenously. Itraconazole can be synthesized using a variety of methods well known in the art. Although itraconazole is not FDA approved for the treatment of ABPA in patients with asthma, it is considered “standard therapy.” Sporanox, in oral capsule form, has a labeled indication for the treatment of aspergillosis, pulmonary and extrapulmonary, in patients who are intolerant or refractory to amphotericin B therapy. However, oral itraconazole is considered the “standard therapy” for the treatment of ABPA. Although itraconazole is the only antifungal agent with proven efficacy based on randomized controlled trials for the treatment of ABPA, oral doses of itraconazole have variable absorption and interaction with food, and show poor correlation between serum and sputum levels. High plasma concentrations of itraconazole may result in significant drug-drug interactions (DDI) due to inhibition of CYP3A4 in the liver. The poor pharmacokinetic and side effect profile of oral itraconazole limits its therapeutic effectiveness.

There is a need for new methods of administering antifungal agent compositions that can be administered to achieve a significantly higher lung:plasma ratio when administered by oral inhalation compared to oral solution administration for the treatment of fungal infections, thereby reducing systemic effects.

The essence of the invention

The invention relates to methods of treating a patient by administering dry powder compositions comprising homogeneous inhalable dry particles that contain 1) an antifungal agent in the form of crystalline particles, 2) a stabilizer and, optionally, 3) one or more excipients, where the amount of the dry powder composition is sufficient to maintain stable concentration. One advantage of the present invention over the prior art is methods that allow the administration of a dry powder composition that achieves a high pulmonary concentration while maintaining a low plasma concentration, thereby reducing the systemic effects of the antifungal active ingredient. In one particular aspect, the crystalline antifungal agent is not a polyene antifungal agent. In another specific aspect, the invention relates to 1) a triazole antifungal agent in the form of crystalline particles, 2) a stabilizer and, optionally, 3) one or more excipients. In a more specific aspect, the triazole antifungal agent is itraconazole.

In one aspect, the invention relates to a method of treating a fungal infection, comprising administering to the respiratory tract of a patient in need thereof an effective amount of an antifungal agent, wherein said antifungal agent is administered in an amount sufficient to simultaneously achieve a) a lung concentration of the antifungal agent of at least 500 ng/g or ng/ml and b) the plasma concentration of the antifungal agent is not more than 25 ng/ml.

In another aspect, the invention relates to a method of treating aspergillosis, comprising administering to the respiratory tract of a patient in need thereof an effective amount of an antifungal agent, wherein said antifungal agent is administered in an amount sufficient to simultaneously achieve a) a lung concentration of the antifungal agent of at least 500 ng /g or ng/ml and b) the plasma concentration of the antifungal agent is not more than 25 ng/ml.

In another aspect, the invention relates to a method of treating allergic bronchopulmonary aspergillosis (ABPA) comprising administering to the airway of a patient in need thereof an effective amount of an antifungal agent, wherein said antifungal agent is administered in an amount sufficient to simultaneously achieve a) a concentration of the antifungal agent in the lungs at least 500 ng/g or ng/ml and b) the plasma concentration of the antifungal agent is not more than 25 ng/ml.

In yet another aspect, the invention relates to a method of treating or reducing the incidence or severity of an exacerbation of a respiratory disease, comprising administering to the respiratory tract of a patient in need thereof an effective amount of an antifungal agent, wherein said antifungal agent is administered in an amount sufficient to simultaneously achieve a) concentration an antifungal agent in the lungs of at least 500 ng/g or ng/ml; and b) a plasma antifungal agent concentration of no more than 25 ng/ml.

Lung and plasma concentrations may persist for at least approximately 24 hours after administration of a single dose of the antifungal agent.

Lung and plasma concentrations may be steady state concentrations.

The antifungal agent can be administered in the form of a dry powder or in a liquid dosage form.

In another aspect, the invention relates to a method of treating a fungal infection, comprising administering to the respiratory tract of a patient in need thereof an effective amount of an antifungal agent, wherein said antifungal agent is administered in a single dose or an initial dose, followed by one or more subsequent doses, wherein a lung:plasma ratio of at least 100:1 is achieved.

In another aspect, the invention relates to a method of treating aspergillosis, comprising administering to the respiratory tract of a patient in need thereof an effective amount of an antifungal agent, wherein said antifungal agent is administered in a single dose or an initial dose, followed by one or more subsequent doses wherein lung:plasma ratio of at least 100:1.

In another aspect, the invention relates to a method of treating allergic bronchopulmonary aspergillosis (ABPA), comprising administering to the respiratory tract of a patient in need thereof an effective amount of an antifungal agent, wherein said antifungal agent is administered in a single dose or an initial dose, followed by administration of one or more subsequent doses where a lung:plasma ratio of at least 100:1 is achieved.

In another aspect, the invention relates to a method of treating or reducing the incidence or severity of an exacerbation of a respiratory disease, comprising administering to the respiratory tract of a patient in need thereof an effective amount of an antifungal agent, wherein said antifungal agent is administered in a single dose or an initial dose, followed by one or more subsequent doses where a lung:plasma ratio of at least 100:1 is achieved.

The patient may have cystic fibrosis. The patient may have asthma.

In another aspect, the invention relates to a method of treating a fungal infection in an immunocompromised patient, comprising administering to the respiratory tract of a patient in need thereof an effective amount of an antifungal agent, wherein said antifungal agent is administered in an amount sufficient to achieve a) a concentration of the antifungal agent in the lungs at least 500 ng/g or ng/ml and b) the plasma concentration of the antifungal agent is not more than 25 ng/ml.

In another aspect, the invention relates to a method of treating a fungal infection in an immunocompromised patient, comprising administering to the respiratory tract of a patient in need thereof an effective amount of an antifungal agent, wherein said antifungal agent is administered in a single dose or an initial dose, followed by one or more several subsequent doses where a lung:plasma ratio of at least 100:1 is achieved.

The invention also relates to a method of treating a fungal infection, comprising administering to the respiratory tract of a patient in need thereof, first one or more fungicidal doses of a dry powder composition that contains antifungal agents until a steady state is achieved, followed by one or more fungistatic doses to maintain stable condition in a patient in need. The fungistatic dose can be administered less frequently than the fungicidal dose. The fungistatic dose may be less than the fungicidal dose. Each of the dosages may independently comprise a nominal dose of about 2 to about 35 mg of antifungal active ingredient. The interval between doses may be at least about 1 day. The interval between doses may be at least about 2 days. The interval between doses may be at least about 3 days. The number of doses administered per week may be approximately 3 doses.

In one aspect, the invention relates to a method of treating a fungal infection, comprising administering an effective amount of an antifungal agent to the respiratory tract of a patient in need thereof, wherein said antifungal agent is administered to achieve a steady-state concentration of the antifungal agent in the lungs, and then administering the antifungal agent in one or more doses, wherein each dose contains an amount of antifungal agent sufficient to achieve a) a lung concentration of the antifungal agent of at least about 500 ng/g or ng/mL over at least about 24 hours and b) a plasma concentration of the antifungal agent of no more than than about 25 ng/ml for at least about 24 hours.

The invention also relates to a method of treating a fungal infection with itraconazole, comprising administering itraconazole into the respiratory tract of a patient in need thereof, wherein one or more fungicidal doses of itraconazole are administered, followed by one or more fungistatic doses, and wherein the fungicidal and fungistatic doses do not result in concentration itraconazole plasma levels are higher than 25 ng/ml.

In another aspect, the invention relates to a method of treating a fungal infection with itraconazole, comprising i) administering itraconazole into the respiratory tract of a patient in need thereof in an amount sufficient to achieve a fungicidal level of itraconazole in the lungs, ii) determining whether or not the plasma concentration of itraconazole is at level of 25 ng/ml or higher, and iii) if the plasma concentration of itraconazole is 25 ng/ml or higher, reducing the amount of itraconazole administered to the patient to an amount sufficient to achieve a fungistatic level of itraconazole in the lungs; at the same time, the risk of systemic effects of itraconazole is reduced.

In another aspect, the invention relates to a method of treating a fungal infection, comprising administering to the respiratory tract of a patient in need thereof one or more doses of an antifungal agent to achieve a fungicidal level of the antifungal agent in the lungs, followed by administration of one or more doses to maintain a fungistatic level of the antifungal agent in the lungs. The dose of the antifungal agent to achieve a fungicidal level of the antifungal agent in the lungs may be administered less frequently than the dose(s) to maintain a fungistatic level of the antifungal agent in the lungs. The dose to achieve a fungicidal level of the antifungal agent in the lungs may be less than the dose to maintain a fungistatic level of the antifungal agent in the lungs.

In another aspect, the invention relates to a method of treating a fungal infection comprising administering to the respiratory tract of a patient in need thereof one or more loading doses of an antifungal agent to achieve a minimum fungicidal concentration (MFC90) in the lungs for at least about 24 hours, followed by administering one or more maintenance doses to achieve the minimum inhibitory concentration (MIC90) in the lungs for at least about 24 hours. The MFC90 may be at least 2000 ng/g or ng/ml. The MIC90 may be at least 500 ng/g or ng/ml. The maintenance dose can be administered less frequently than the fungicidal dose. The maintenance dose may be less than the loading dose.

Brief description of drawings

Fig. 1A and 1B are graphs showing the simulated kinetics of Composition XIX, Composition XII and Sporanox as plasma exposure (Figure 1A) and pulmonary exposure (Figure 1B) using a model established from animal pharmacokinetic (PK) data and human for Sporanox. In both simulated cases, 5 mg was administered by inhalation once daily (Formulations XIX and XII), whereas a 200 mg dose of Sporanox oral solution was administered twice daily. Itraconazole concentrations were measured over seven days of drug administration.

Fig. 2A and 2B are graphs showing the simulated kinetics of Composition XIX, Composition XII and Sporanox as plasma exposure (Figure 2A) and lung exposure (Figure 2B) using a model established from animal PK data and human data for Sporanox . In both simulations, 20 mg was administered by inhalation once daily (Formulations XII and XIX), while a 200 mg dose of Sporanox oral solution was administered twice daily. Itraconazole concentrations were measured over seven days of drug administration.

Fig. 3 is a graph showing the pharmacokinetic profile in plasma following a single dose of Composition XII over 96 hours in healthy volunteers. Details of the study are presented in Example 4.

Fig. 4 is a graph showing the plasma pharmacokinetic profile of Composition XII over 24 hours after a single dose or after 14 daily doses in healthy volunteers. Details of the study are presented in Example 4.

Fig. 5A and 5B are graphs showing summary systemic pharmacokinetic data following a single inhaled or oral dose in asthmatic patients. Pharmacokinetic profiles of itraconazole in sputum (Figure 5A) and plasma (Figure 5B) following single doses of PUR1900 (π) or oral Sporanox (ρ) administered to asthmatic patients.

Detailed Description of the Invention

The present disclosure relates to methods of treating a patient having a respiratory disease by administering an amount of inhalable dry powder that contains a crystalline antifungal agent sufficient to achieve a steady-state concentration. The present inventors have discovered that administration of a nominal dose of 5 mg or more of an antifungal agent in the form of crystalline particles in a dry powder composition achieves a fungicidal concentration instead of a merely fungistatic concentration. Thus, the present disclosure also relates to a dosage regimen comprising an initial administration of one or more doses comprising fungicidal doses of a dry powder composition that contains antifungals such as itraconazole, which is continued until a steady state is achieved, followed by a fungistatic course (e.g., more low doses or less frequent administration) to maintain steady state.

Dry powders can be administered to a patient by inhalation, such as oral inhalation. For oral inhalation, a dry powder inhaler such as a passive dry powder inhaler can be used. Dry powder compositions can be used to treat or prevent fungal infections in a patient, such as aspergillus infections. Patients who may benefit from administration of dry powders are, for example, those who suffer from cystic fibrosis, asthma and/or who are at high risk of developing fungal infections due to severely reduced immunity. An inhaled antifungal formulation (eg, itraconazole) minimizes many of the negative effects of oral or intravenous (IV) formulations for the treatment of such patients.

Surprisingly, dry powder compositions that contain antifungals such as itraconazole in amorphous form have shorter residence times in the lungs, reduced pulmonary exposure to plasma exposure ratios, and undesirable toxic effects on lung tissue when inhaled at therapeutic doses. Without wishing to be bound by any particular theory, it is believed that crystalline forms (eg, nanocrystalline forms) of the substance have a lower dissolution rate in the lungs, providing longer exposure within 24 hours after administration and minimizing systemic exposure. In addition, the observed local toxicity in the lung tissue following administration of the amorphous agent is not related to the overall effect of the drug on the lung tissue in terms of total dose or duration of exposure. Itraconazole has no known activity in human or animal lung cells, so increased local concentrations do not have local pharmacological activity to account for local toxicity. In contrast, the toxicity of the amorphous form appears to be due to increased solubility secondary to the amorphous nature of itraconazole, which results in drug overload in the interstitial space and consequent recrystallization in the tissue leading to local granulomatous inflammation. Surprisingly, the inventors found that dry powders that contain antifungal agents in the form of crystalline particles are less toxic to lung tissue. This was unexpected because crystalline antifungals have a slower dissolution rate compared to amorphous forms and remain in the lungs longer than the corresponding dose of amorphous antifungal. In addition, antifungals in crystalline form also result in higher pulmonary exposure after a single dose and over 28 days, compared with a corresponding dose of antifungal in amorphous form.

The crystallinity of the antifungal agent, as well as the size of the antifungal crystalline particles, appears to be important for effective therapy and for reducing toxicity in the lungs. Without wishing to be bound by any particular theory, it is believed that smaller crystalline particles of an antifungal agent (e.g., a nanocrystalline or microcrystalline antifungal agent) will dissolve in the mucosal fluid of the respiratory tract more quickly than larger crystalline particles - in part due to the greater total surface area. It is also believed that a crystalline antifungal agent will dissolve more slowly in the mucosal fluid of the respiratory tract than an amorphous antifungal agent. Accordingly, the dry powders described herein can be formulated using antifungal agents in the form of crystalline particles that provide the desired degree of crystallinity and particle size, and can be tailored to achieve the desired pharmacokinetic properties while avoiding unacceptable pulmonary toxicity.

Inhalable dry powders include homogeneous inhalable dry particles that contain 1) an antifungal agent in the form of crystalline particles, 2) a stabilizer and, optionally, 3) one or more excipients. Accordingly, dry powders are characterized by respirable dry particles that contain a stabilizer, optionally one or more excipients, and a subparticle (a particle that is smaller than the respirable dry particle) that includes a crystalline antifungal agent. Such respirable dry particles can be produced using any suitable method, such as preparing a starting material in which the antifungal agent in the form of crystalline particles is suspended in an aqueous solution of excipients, and spray drying the starting material.

Definitions

As used herein, the term “about” refers to the corresponding range plus or minus 5% of the stated value, for example, “about 20 mg” would be “20 mg plus or minus 1 mg.”

As used herein, the terms “administering” or “administrating” inhalable solids refers to introducing inhalable solids into the respiratory tract of a subject.

As used herein, the term “amorphous” indicates a lack of significant crystallinity when analyzed by powder X-ray diffraction (XRD).

As used herein, the term “fungicidal dose” refers to the amount of antifungal agent that is needed to kill a fungus (eg, MFC50, MFC90). The fungicidal dose will vary depending on the specific type of fungal infection, and additional variation will depend on various factors that can be determined by an experienced practitioner.

As used herein, the term “fungistatic dose” refers to the amount of antifungal agent that is necessary to inhibit fungal growth (eg, MIC50, MIC90). The fungistatic dose will vary depending on the specific type of fungal infection, and additional variation will depend on various factors that can be determined by an experienced physician.

The term “capsule release powder mass” or “CEPM” as used herein refers to the amount of dry powder composition released from a capsule or single-dose container upon inhalation. CEPM is measured gravimetrically, usually by weighing the capsule before and after inhalation to determine the extracted mass of the powder composition. CEPM can be expressed either as the extracted mass of powder in milligrams or as a percentage of the initial mass of powder filled into the capsule before inhalation.

The term “in the form of crystalline particles” as used herein refers to an antifungal agent (including pharmaceutically acceptable forms thereof, including salts, hydrates, enantiomers, etc.) that is in the form of a particle (i.e., a subparticle that less than the respirable dry particles that constitute the dry powders disclosed herein) and wherein the antifungal agent is at least about 50% crystalline. The percentage crystallinity of an antifungal agent refers to the percentage of the compound that is in crystalline form relative to the total amount of the compound present in the subparticle. If desired, the antifungal agent may be at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, or about 100% crystalline . The crystalline antifungal agent is in the form of a particle that has a volume median diameter (Dv50) of from about 50 nanometers (nm) to about 5000 nm, preferably from 80 nm to 1750 nm Dv50, or preferably from 50 nm to 800 nm Dv50.

The term “dispersible” is a term known in the art that describes the characteristic of a dry powder or respirable dry particle that is intended to disperse into a respirable aerosol. The dispersibility of a dry powder or respirable dry particle is expressed, in one aspect, as the quotient of the volumetric median geometric diameter (VMGD) measured at a dispersion pressure (i.e., controlled) of 1 bar divided by the VMGD measured at a dispersion pressure (t .e. regulator) 4 bar, or VMGD at 0.5 bar divided by VMGD at 4 bar, as measured by laser diffraction, for example using HELOS/RODOS. These coefficients are specified as “dispersity coefficient 1 bar/4 bar” and “dispersity coefficient 0.5 bar/4 bar”, respectively, and dispersibility correlates with a low coefficient. For example, a dispersion factor of 1 bar/4 bar refers to the VMGD of dry powder or respirable dry particles exiting the orifice of a RODOS dry powder dispenser (or using a similar procedure) at a pressure of approximately 1 bar, measured using a HELOS or other laser diffraction system , divided by the VMGD of the same dry powder or respirable dry particles, measured at 4 bar using HELOS/RODOS. Thus, highly dispersible dry powder or respirable dry particles will have a dispersity factor of 1 bar/4 bar or a dispersity factor of 0.5 bar/4 bar, which is close to 1.0. Highly dispersed powders have a low tendency to agglomerate, aggregate or clump and/or, if agglomerated, aggregated or clumped, readily disperse or deagglomerate when they exit the inhaler and are inhaled by a subject. In another aspect, dispersibility is assessed by measuring the particle size released from the inhaler as a function of flow rate. As the flow rate through the inhaler decreases, the amount of energy in the air stream available to transfer to the powder to disperse it decreases. A well-dispersible powder will have a size distribution, for example, aerodynamically characterized by its mass median aerodynamic diameter (MMAD) or geometrically characterized by its VMGD value, which does not increase significantly over a range of flow rates typical for human inhalation, for example, from about 15 to about 60 liters per minute (L/min), from about 20 to about 60 L/min, or from about 30 L/min to about 60 L/min. A highly dispersible powder will also have a mass or dose of powder released, or a mass or dose released from a capsule, of approximately 80% or greater even at lower inhalation flow rates. VMGD may also be referred to as volumetric median diameter (VMD), x50, or Dv50.

The term “dry particles” as used herein refers to respirable particles, which may contain a total of up to about 15% water and/or other solvent. Preferably, the dry particles contain a total amount of water and/or other solvent of up to about 10%, up to about 5%, up to about 1%, or from 0.01% to 1%, based on the weight of the dry particles, or may be substantially free water and/or other solvent.

The term “dry powder” as used herein refers to compositions that include respirable dry particles. The dry powder may contain a total amount of water and/or other solvent up to approximately 15%. Preferably, the dry powder contains a total amount of water and/or other solvent of up to about 10%, up to about 5%, up to about 1%, or from 0.01% to 1%, based on the weight of the dry particles, or may be substantially free of water and/or other solvent. In one aspect, the dry powder is an inhalable dry powder.

The term “effective amount” as used herein refers to the amount of agent required to achieve the desired effect; such as treating a fungal infection, for example an aspergillus infection, in the respiratory tract of a patient, for example, a patient with cystic fibrosis (CF), a patient with asthma and a patient with compromised immunity; treatment of allergic bronchopulmonary aspergillosis (ABPA); and treating or reducing the incidence or severity of exacerbations of respiratory disease. The actual effective amount for a particular use may vary depending on the particular dry powder or inhalable dry particle, route of administration, age, body weight, general health of the subject and the severity of the symptoms or condition being treated. Suitable amounts of dry powders and dry particles to administer and dosage schedule for a particular patient can be determined by a physician of ordinary skill based on these and other considerations.

As used herein, the term “delivered dose” or “ED” refers to the indication of drug delivery from a suitable inhalation device following an actuation or nebulization event. More specifically, for dry powder compositions, ED is the percentage of powder that is released from the single-dose package and exits the mouthpiece of the inhaler device. ED is defined as the ratio of drug or powder delivered by an inhaler to the nominal dose (ie, the mass of drug or powder per dose unit placed in a suitable inhalation device before actuation). ED is an experimentally measurable parameter and can be determined using the method described in 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, 222-225, 2007. This method uses an in vitro device set up to simulate patient dosing. It can also be calculated from results obtained from Next Generation Impactor (NGI) experiments by summing all the drug or powder analyzed from the mouthpiece adapter, the NGI induction port, and all steps within the NGI. Results obtained by USP 601 ED testing and those obtained by NGI are generally in good agreement.

The term “lung to plasma ratio” or “lung:plasma ratio” refers to the ratio of the concentration of an antifungal agent in the lungs to the concentration of an antifungal agent in the plasma, either at a specific time point or over a specified period of time. For example, the lung:plasma ratio can be calculated from simultaneous measurements at the maximum concentration (ie, “ _Cmax ”) of the antifungal agent in the lungs or serum, or at any point in time. The lung:plasma ratio can also be calculated for total exposure over a period of time (ie, “area under the curve” or “AUC”), such as over a 24-hour period. Concentrations of the antifungal agent in the lungs can be determined by measuring levels in sputum, by pulmonary lavage, by biopsy, or by some other method. The lung:plasma ratio can be calculated from simultaneous measurements at any point in the drug administration cycle and can be calculated from simultaneous measurements before or at steady state.

The term “nominal dose” as used herein refers to an individual dose greater than or equal to 1 mg of antifungal agent. The nominal dose is the total dose of antifungal agent in one capsule, blister or ampoule.

The terms “FPF (<X)”, “FPF (<X microns)” and “fine particle fraction less than X microns” in the context of this application, where X is, for example, 3.4 microns, 4.4 microns, 5, 0 microns or 5.6 microns, refers to the fraction of the dry particle sample that has an aerodynamic diameter less than X microns. For example, FPF (<X) can be determined by dividing the mass of respirable dry particles deposited in stage two and on the final collection filter of a two-stage Andersen cascade impactor (ACI) disrupted by the mass of respirable dry particles weighed into a capsule for delivery to the device. This parameter can also be specified as “FPF_TD(<X)”, where TD means the total dose. Such a measurement can be accomplished using an eight-stage ACI. In the eight-stage ACI, cutoffs differ at a standard flow rate of 60 L/min, but FPF_TD(<X) can be extrapolated from the full eight-stage data set. The eight-stage ACI result can also be calculated by the USP method using the dose collected in the ACI instead of what was in the FPF capsule. Similarly, a seven-stage Next Generation Impactor (NGI) can be used.

The terms “FPD (<X)”, 'FPD <X microns”, FPD(<X microns)” and “fine particle dose less than X microns” as used herein, where X is, for example, 3.4 microns, 4 .4 microns, 5.0 microns, or 5.6 microns, refer to the mass of therapeutic agent delivered by inhaled dry particles that have an aerodynamic diameter less than X microns. FPD <X microns can be determined by using an eight-stage Andersen Cascade Impactor (ACI) or Next Generation Impactor (NGI) at a standard flow rate of 60 L/min and summing the mass deposited on the final collection filter and either directly calculating or extrapolating the FPD value.

The term "respirable" as used herein refers to dry particles or dry powders that are suitable for delivery to the respiratory tract (eg, pulmonary delivery) of a subject by inhalation. The respirable dry powders or dry particles have a mass median aerodynamic diameter (MMAD) of less than about 10 microns, preferably about 5 microns or less.

As used herein, the term “respiratory tract” includes the upper respiratory tract (eg, nasal passages, nasal cavity, throat, pharynx and larynx), respiratory tract (eg, trachea, bronchi and bronchioles) and lungs (eg, respiratory bronchioles, alveolar ducts). , alveolar sacs and alveoli).

As used herein, the term “lower respiratory tract” includes the respiratory tract and lungs.

The term “fine”, as used to describe respirable dry particles, refers to particles that have a volumetric median geometric diameter (VMGD) of about 10 microns or less, preferably about 5 microns or less, or less than 5 microns.

As used herein, the term “stabilizer” refers to a compound that improves the physical stability of antifungal agents in the form of crystalline particles when suspended in a liquid in which the antifungal agent is poorly soluble (eg, reduces aggregation, agglomeration, Ostwald ripening and/or flocculation of particles). Suitable stabilizers are surfactants and amphiphilic materials and include polysorbates (PS; polyoxyethylated sorbitan fatty acid esters) such as PS20, PS40, PS60 and PS80; fatty acids such as lauric acid, palmitic acid, myristic acid, oleic acid and stearic acid; sorbitan fatty acid esters such as Span20, Span40, Span60, Span80 and Span 85; phospholipids such as dipalmitoylphosphatidylcholine (DPPC), 1,2-dipalmitoyl-sn-glycero-3-phospho-L-serine (DPPS), 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DSPC), 1-palmitoyl -2-oleoylphosphatidylcholine (POPC) and 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC); phosphatidylglycerols (PG) such as diphosphatidylglycerol (DPPG), DSPG, DPPG, POPG, etc.; 1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE); fatty alcohols; benzyl alcohol, polyoxyethylene-9-lauryl ether; glycocholate; surfactin; poloxomers; polyvinylpyrrolidone (PVP); PEG/PPG block copolymers (Pluronics/poloxamers); polyoxyethiene chloroesteryl ethers; POE alkyl ethers; tyloxapol; lecithin; and so on. Preferred stabilizers are polysorbates and fatty acids. A particularly preferred stabilizer is PS80. Another preferred stabilizer is oleic acid.

The term “homogeneous dry particles” as used herein refers to particles containing a crystalline drug (eg, nanocrystalline drug) previously formulated into a surfactant-stabilized suspension. Homogeneous dry particles are then prepared by spray drying the surfactant-stabilized suspension with (optional) excipients, yielding dry particles that are compositionally homogeneous or, more specifically, identical in their composition to the surfactant-coated crystalline drug particles and, optionally, one or several excipients.

Therapeutic uses and methods

In one aspect, the invention relates to a method for treating respiratory (eg, pulmonary) diseases such as cystic fibrosis, asthma, especially severe asthma, and severely immunocompromised patients, the method comprising administering dry powders and/or inhalable dry particles to the respiratory tract subject in need thereof, thereby treating respiratory (eg pulmonary) diseases such as cystic fibrosis, asthma, especially severe asthma, and severely immunocompromised patients. This treatment is especially useful in treating aspergillus infections (eg, Aspergillus fumigatus). This treatment is also useful for treating fungal infections that are sensitive to itraconazole. Another aspect of the invention relates to the treatment of allergic bronchopulmonary aspergillosis (ABPA), for example, in patients with pulmonary diseases such as asthma or cystic fibrosis. The invention may also provide the ability to treat a subject with a resistant fungal infection by administering an inhaled antifungal composition.

The amount of dry powder administered to the patient may be sufficient to maintain a steady state of concentration. As used herein, steady state concentration (Css) refers to the concentration of a drug, eg in the lungs or plasma, at the time when a “steady state” is reached and the rates of drug administration and drug elimination are equal. The steady state concentration is the value approached as a limit, which is theoretically reached after the last of an infinite number of equal doses administered at equal intervals. The maximum value under such conditions (Css, max) is defined as Css, max=C0/(1-f), for a drug eliminated by first-order kinetics from a single-compartment system. The ratio Css, max/C0 indicates the degree to which the drug accumulates under the conditions of a certain dose regimen, theoretically indefinitely long; the corresponding ratio 1/(1 - f) is sometimes called the accumulation factor, R. Css is also the limit reached theoretically at the “end” of an infusion of infinite duration at a constant rate.

In some aspects, nominal doses of about 2 mg, about 3 mg, about 4 mg, 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, can be administered. about 50 mg, about 2 mg to about 35 mg, about 5 mg to about 50 mg, about 10 mg to about 50 mg, about 15 mg to about 50 mg. The dose and dosing regimen can be selected to achieve a specific lung:plasma ratio or to achieve specific steady-state lung and plasma concentration states.

The lung:plasma ratio may be at least about 100:1, at least about 200:1, at least about 300:1, at least about 400:1, at least about 500:1, at least about 600:1, at least about 700:1, at least about 800:1, at least about 1000:1, at least about 1300:1, at least about 1600:1, at least about 1900: 1, at least about 2200:1, at least about 2500:1, at least about 2800:1, at least about 3000:1, at least about 3200:1, at least about 3400:1, at least about 3600:1, 3000:1 to 4000:1, 3500:1 to 4000:1, or 3600:1 to 3700:1. Additionally, the lung:plasma ratio may be at least about 2:1, at least 3:1, at least 4:1, at least 5:1, at least 6:1, at least 7: 1, at least 8:1, at least 9:1, at least 10:1, at least 15:1, at least 20:1, at least 25:1, at least 50:1 or at least 75:1. The lung:plasma ratio can be calculated from simultaneous measurements at the maximum concentration (i.e., “ _Cmax ”) of the antifungal agent in the lungs or serum or at any point in time. The lung:plasma ratio can also be calculated for total exposure over a period of time (ie, “area under the curve” or “AUC”), such as over a 24-hour period. The lung:plasma ratio can be calculated from simultaneous measurements at any point in the drug administration cycle and can be calculated from simultaneous measurements before or at steady state.

At steady state, the lung:plasma ratio may be at least about 20:1, at least about 25:1, at least 50:1, at least 75:1, at least about 100:1, at least about 200:1, at least about 300:1, at least about 400:1, at least about 500:1, at least about 600:1, at least about 700:1, at least about 800 :1, at least about 1000:1, at least about 1300:1, at least about 1600:1, at least about 1900:1, at least about 2200:1, at least about 2500:1 , at least about 2800:1, at least about 3000:1, at least about 3200:1, at least about 3400:1, at least about 3600:1, from 3000:1 to 4000:1, from 3500:1 to 4000:1 or from 3600:1 to 3700:1.

The dry powder composition can be administered to achieve a specific plasma concentration. Plasma concentrations may be less than 40 ng/ml, less than 35 ng/ml, less than 30 ng/ml, less than 25 ng/ml, less than 20 ng/ml, less than 15 ng/ml, less than 12 ng/ml, less than 10 ng/ml, less than 8 ng/ml, less than 6 ng/ml, less than 4 ng/ml, less than 2 ng/ml, less than 1.5 ng/ml, less than 1.0 ng/ml, less than 0.5 ng/ml, less than 0.3 ng/ml, or less than 0.2 ng/ml.

The dry powder composition can be administered to achieve a steady state plasma concentration. At steady state, plasma concentrations may be less than 25 ng/ml, less than 20 ng/ml, less than 15 ng/ml, less than 12 ng/ml, less than 10 ng/ml, less than 8 ng/ml, less than 6 ng/ml, less than 4 ng/ml, less than 2 ng/ml, less than 1.5 ng/ml, less than 1.0 ng/ml, less than 0.5 ng/ml, less than 0.3 ng/ml or less than 0.2 ng/ml. In addition, the steady-state plasma concentration is less than 40 ng/ml, less than 35 ng/ml, or less than 30 ng/ml.

The dry powder composition may be administered in one or more doses to achieve pulmonary concentrations of approximately 500 ng/mL, approximately 800 ng/mL, approximately 1200 ng/mL, approximately 1600 ng/mL, approximately 2000 ng/mL, approximately 3000 ng/mL , approximately 4000 ng/ml, approximately 5000 ng/ml, approximately 5000 ng/ml, approximately 6000 ng/ml, approximately 7000 ng/ml, approximately 8000 ng/ml, between 2000 ng/ml to 8000 ng/ml or approximately 2000 ng/ml to 8100 ng/ml. Lung concentration can be measured at the maximum concentration (ie, “ _Cmax ”) of the antifungal agent in lung tissue or at any point in time. Lung concentrations can be measured at any point in the drug administration cycle and can be calculated before or at steady state.

The dry powder composition may be administered in one or more doses to achieve a steady-state pulmonary concentration of approximately 500 ng/mL, approximately 800 ng/mL, approximately 1200 ng/mL, approximately 1600 ng/mL, approximately 2000 ng/mL, approximately 3000 ng/mL ml, approximately 4000 ng/ml, approximately 5000 ng/ml, approximately 5000 ng/ml, approximately 6000 ng/ml, approximately 7000 ng/ml, approximately 8000 ng/ml, 2000 ng/ml to 8000 ng/ml or from approximately 2000 ng/ml to 8100 ng/ml.

The dry powder composition can be administered once daily, twice daily, once every two days, or once every three days for approximately 7 days, 14 days, 21 days, 28 days, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 1 year or for a long time. In some embodiments, the dry powder composition is administered once daily until steady state is achieved, and then less frequently for up to six months. In some embodiments, one or more fungicidal doses are administered daily until steady state is achieved, followed by one or more fungistatic doses (e.g., lower doses, less frequently administered doses) for 1 month, 2 months, 3 months, 4 months, 5 months or 6 months. In some embodiments, one or more doses necessary to achieve a fungicidal concentration of the antifungal agent in the lungs are administered daily until steady state is achieved, followed by one or more doses (e.g., lower doses, less frequently administered doses) necessary to achieve a fungistatic concentration antifungal agent in the lungs for 1 month, 2 months, 3 months, 4 months, 5 months or 6 months.

In another aspect of the invention, a fungicidal dose of dry powders and/or inhalable dry particles can be administered to the respiratory tract of a subject in need thereof, followed by one or more fungistatic doses of dry powders and/or inhalable dry particles, thereby treating respiratory (eg , pulmonary) diseases such as cystic fibrosis, asthma, especially severe asthma, and patients with severely reduced immunity. The fungistatic dose required to achieve the minimum inhibitory concentration (MIC) (eg, MIC50, MIC90) will vary depending on the specific fungus causing the infection, but can range from 0.008-4 µg/ml, 0.008-0.03 µg/ ml, from 0.008-0.06 µg/ml, from 0.03->4 µg/ml, from 0.015-0.5 µg/ml, from 0.004-0.03 µg/ml, from 0.5-1 µg /ml, from 0.5 µg/ml->64 µg/ml, from 0.5-2 µg/ml or from 0.03 mg/l to 32 mg/l. The fungicidal dose required to achieve the minimum fungicidal concentration (MFC) (eg, MFC50, MFC90) will vary depending on the specific fungus causing the infection, but can range from 0.05 mg/L to greater than 16 mg/L. Various methods and assays for determining lung and plasma concentrations are known in the art and can be used to measure lung and plasma concentrations during and after administration of antifungal dry powders. For example, bioassays or high performance HPLC can be used to measure the amount of antifungal active agent in the lungs (eg, using induced sputum production, bronchial lavage, spontaneous sputum production) after a patient has taken the drug for at least about 7 days, at least 14 days, at least 21 days or at least 28 days.

In other aspects, the invention provides a method for treating, reducing the incidence or severity of, or preventing exacerbations caused by a fungal infection in the respiratory tract, such as an aspergillus infection. In another aspect, the invention provides a method for treating, reducing the incidence or severity of, or preventing exacerbations caused by a fungal infection in the respiratory tract, such as an aspergillus infection. In another aspect, the invention provides a method of treating, reducing the incidence or severity of, or preventing exacerbations caused by allergic bronchopulmonary aspergillosis (ABPA), for example, in patients with a pulmonary disease such as asthma or cystic fibrosis. In yet another aspect, the invention provides a method for preventing or treating invasive fungal infections in a population of immunocompromised patients.

In other aspects, the invention provides a method for alleviating symptoms of a respiratory disease and/or chronic pulmonary disease, such as cystic fibrosis, asthma, especially severe asthma, and in severely immunocompromised patients. In another aspect, the invention provides a method for alleviating the symptoms of allergic bronchopulmonary aspergillosis (ABPA) in these patient populations. In yet another aspect, the invention provides a method of reducing inflammation that avoids the use of steroids or reduces the need for steroid treatment.

In other aspects, the invention provides a method for improving lung function in a patient with a respiratory disease and/or chronic pulmonary disease, such as cystic fibrosis, asthma, especially severe asthma, and in patients with severely compromised immunity. In another aspect, the invention provides a method for improving lung function in a patient with allergic bronchopulmonary aspergillosis (ABPA).

Dry powders and/or inhalable dry particles can be administered to the respiratory tract of a subject in need thereof using any suitable method, such as instillation techniques, and/or an inhalation device, such as a dry powder inhaler (DPI) or a metered dose inhaler (MDI). ). Various DPIs are available, such as the inhalers disclosed in US Pat. Nos. 4,995,385 and 4,069,819, Spinhaler ^® (Fisons, Loughborough, UK), Rotahalers ^® , Diskhaler ^® and Diskus ^® (GlaxoSmithKline, Research Triangle Technology Park, North Carolina), FlowCaps ^® (Hovione, Loures, Portugal), Inhalators ^® (Boehringer-Ingelheim, Germany), Aerolizer ^® (Novartis, Switzerland), high-resistance, ultra-high-resistance and low-resistance RS01 (Plastiape, Italy), and others known to specialists in the field.

A complete review of the following dry powder inhaler (DPI) configurations can be found in the following scientific journal articles, incorporated by reference: 1) single-dose capsule-type DPI, 2) multi-dose blister-type DPI, and 3) multi-dose reservoir-type DPI. N. Islam, E. Gladki, “Dry powder inhalers (DPIs)-A review of device reliability and innovation,” International Journal of Pharmaceuticals, 360(2008):1-11. H. Chystyn, “Diskus Review”, International Journal of Clinical Practice, June 2007, 61, 6, 1022-1036. H. Steckel, B. Muller, “In vitro evaluation of dry powder inhalers I: drug deposition of commonly used devices,” International Journal of Pharmaceuticals, 154(1997):19-29. Some representative capsule type DPI devices are RS-01 (Plastiape, Italy), Turbospin ^® (PH&T, Italy), Brezhaler ^® (Novartis, Switzerland), Aerolizer (Novartis, Switzerland), Podhaler ^® (Novartis, Switzerland), HandiHaler ^® (Boehringer Ingelheim, Germany), AIR ^® (Civitas, Maccaachusetts), Dose One ^® (Dose One, Maine) and Eclipse ^® (Rhone Poulenc Rorer). Some representative single-dose DPIs are Conix ^® (3M, Minnesota), Cricket ^® (Mannkind, California), Dreamboat ^® (Mannkind, California), Occoris ^® (Team Consulting, Cambridge, UK), Solis ^® (Sandoz), Trivair ^® ( Trimel Biopharma, Canada), Twincaps ^® (Hovione, Loures, Portugal). Some representative blister type DPI devices are Diskus® ⁽ GlaxoSmithKline (GSK), UK), ^Diskhaler® (GSK), Taper ^Dry® (3M, Minnesota), ^Gemini® (GSK), ^Twincer® (University of Groningen, Netherlands), Aspirair ^® (Vectura, UK), Acu-Breathe ^® (Respirics, Minnesota, USA), Exubra ^® (Novartis, Switzerland), Gyrohaler ^® (Vectura, UK), Omnihaler ^® (Vectura, UK), Microdose ^® (Microdose Therapeutix, USA), Multihaler ^® (Cipla, India) Prohaler ^® (Aptar), Technohaler ^® (Vectura, UK) and Xcelovair ^® (Mylan, Pennsylvania). Some representative reservoir-type DPI devices are Clickhaler ^® (Vectura), Next DPI ^® (Chiesi), Easyhaler ^® (Orion), Novolizer ^® (Meda), Pulmojet ^® (sanofi-aventis), Pulvinal ^® (Chiesi), Skyehaler ^® ( Skyepharma), ^Duohaler® (Vectura), ^Taifun® (Akela), ^Flexhaler® (AstraZeneca, Sweden), ^Turbuhaler® (AstraZeneca, Sweden) and ^Twisthaler® (Merck) and others known to those skilled in the art.

Typically, inhalation devices (eg, DPI) are capable of delivering a maximum amount of dry powder or dry particles in a single inhalation, which is related to the capacity of blisters, capsules (eg, volume 000, 00, 0E, 0, 1, 2, 3 and 4 , with the corresponding volume capacity of 1.37 ml, 950 µl, 770 µl, 680 µl, 480 µl, 360 µl, 270 µl and 200 µl) or other products that contain dry powders and/or inhalable dry particles in the inhaler. Preferably, the blister has a volume of about 360 microliters or less, about 270 microliters or less, or more preferably about 200 microliters or less, about 150 microliters or less, or about 100 microliters or less. Preferably, the capsule is a size 2 capsule or a size 4 capsule. More preferably, the capsule is a size 3 capsule. Accordingly, two or more inhalations may be required to deliver the desired dose or effective amount. Preferably, each dose administered to a subject in need thereof contains an effective amount of inhalable dry particles or dry powder and is administered using no more than about 4 puffs. For example, each dose of dry powder or inhalable dry particles can be administered as one administration or 2, 3 or 4 administrations. Dry powders and/or inhalable dry particles are preferably administered in a single breath-activated step using a passive DPI. When this type of device is used, the subject's inhalation energy disperses inhaled dry particles and also attracts them into the airways.

Dry powders and/or respirable dry particles suitable for use in the methods of the present invention may pass through the upper respiratory tract (i.e., oropharynx and larynx), the lower respiratory tract, which includes the trachea, followed by bifurcations into the bronchi and bronchioles, and through the terminal bronchioles, which in turn divide into respiratory bronchioles leading to the terminal respiratory zone, the alveoli or deep layers of the lungs. In one embodiment of the invention, the majority of the mass of inhaled dry particles is deposited in the deep layers of the lungs. In another embodiment of the invention, delivery is primarily to the central respiratory tract. In another embodiment, delivery is to the upper respiratory tract. In a preferred embodiment, most of the inhaled dry particles are deposited in the conducting airways.

If desired or indicated, the described dry powders and inhalable dry particles can be administered with one or more other therapeutic agents. Other therapeutic agents can be administered by any suitable route, for example, orally, parenterally (eg, intravenous, intraarterial, intramuscular or subcutaneous injection), topically, by inhalation (eg, intrabronchial, intranasal or oral inhalation, intranasal drops), rectally, vaginally and etc. Inhalable dry particles and dry powders can be administered before, substantially simultaneously with, or after the administration of another therapeutic agent. Preferably, the dry powders and/or inhalable dry particles and the other therapeutic agent are administered so as to provide substantial overlap in their pharmacological activity.

The dry powders and inhalable dry particles described herein are intended to be inhaled as such, and the present invention precludes the use of a dry powder composition to form an extemporaneous dispersion. An extemporaneous dispersion is known to those skilled in the art as an extemporaneous formulation, which means immediately before administration of the drug to a patient. In the context of this application, the term “extestoral dispersion” refers to all cases where the solution or suspension is not manufactured directly by the pharmaceutical industry and is not marketed in ready-to-use form, but is prepared at a time after receipt of the dry solid composition, usually at a time immediately before administration to the patient.

Dry powders and dry particles

Dry powder compositions may include respirable dry particles that contain 1) a crystalline antifungal agent, 2) a stabilizer, and 3) one or more excipients. Any desired antifungal agents may be included in the compositions described herein. Many antifungals are well known, for example polyene antifungals such as amphotericin B; triazole antifungals such as itraconazole, ketoconazole, fluconazole, voriconazole and posaconazole; echinocandin antifungals such as caspofungin, micafungin and anidulafungin. Other triazole antifungals include clotrimazole, isavuconazole, and miconazole. A new chemical class of triterpenoid glucan synthase inhibitors is included, such as SCY-078. Also included are orotomide antifungals, such as F901318, which inhibits dihydroorotate dehydrogenase. Other antifungals include the following: acosiborole, amorolfine, amorolfine hydrochloride, arasertaconazole nitrate, bifonazole, butenafine hydrochloride, butoconazole nitrate, carvacrol, chloramine-T, ciclopirox, ciclopirox olamine, croconazole hydrochloride, eberconazole, econazole hydrochloride, econazole, econazole nitrate, fenarimol, fenticonazole nitrate, flucytosine, flutrimazole, formaldehyde, fosravuconazole, griseofulvin, isavuconazonium sulfate, isoconazole nitrate, lanoconazole, liranaftate, luliconazole, miconazole nitrate, naphthitine, natamycincin, nikkomycin Z, novexatin, nystatin, oteseconazole, oxiconazole nitrate, oxton olamine, quilseconazole, rezafungin acetate, SCY-078 citrate, selenium sulfide, sertaconazole nitrate, sulconazole nitrate, taurolidine, tavaborole, terbinafine, terbinafine hydrochloride, terconazole, thiabendazole, thioconazole, tolnaftate, undecylenic acid and zinc pyrithione.

The crystallinity of the antifungal agent, as well as the size of the antifungal subparticles, appears to be important for effective therapy and for reducing toxicity in the lungs. Without wishing to be bound by any particular theory, it is believed that smaller subparticles of an antifungal agent in crystalline form will dissolve in the mucosal fluid of the respiratory tract more quickly than larger particles - in part due to their greater surface area. It is also believed that a crystalline antifungal agent will dissolve more slowly in the mucosal fluid of the respiratory tract than an amorphous antifungal agent. Accordingly, the dry powders described herein can be formulated using antifungal agents in the form of crystalline particles that provide the desired degree of crystallinity and subparticle size, and can be tailored to achieve the desired pharmacokinetic properties while avoiding unacceptable toxicity in the lungs.

The inhaled dry particles contain from about 1% to about 95% antifungal agent by weight (%wt). Preferably, the inhalable dry powder contains such an amount of antifungal agent that a therapeutically effective dose can be administered and maintained without the need for inhalation of large volumes of the dry powder more than three times daily. For example, it is preferred that the respirable dry particles contain about 1%-95%, about 10%-75%, about 15%-75%, about 25%-75%, about 30%-70%, about 40%-60% , from about 50% to about 90%, from about 50% to about 70%, from about 70% to about 90%, from about 60% to about 80%, about 20%, about 50%, about 70% or about 80% antifungal agent by weight (%wt). The inhalable dry particles may contain about 75%, about 80%, about 85%, about 90%, or about 95% antifungal agent by weight (% wt). In specific embodiments, the antifungal agent content of the inhaled dry particles ranges from about 40% to about 90%, from about 55% to about 85%, from about 55% to about 75%, or from about 65% to about 85%, by weight (%wt). The amount of antifungal agent present in inhaled dry particles, by weight, is also reported as the “drug load.”

The antifungal agent is present in the inhaled dry particles in the form of crystalline particles (eg, nanocrystalline). More specifically, in the form of a subparticle that has a Dv50 of from about 50 nm to about 5,000 nm, wherein the antifungal agent is preferably at least 50% crystalline. For example, for loading with any desired drug, the subparticle size may be about 100 nm, about 300 nm, about 1500 nm, about 80 nm to about 300 nm, about 80 nm to about 250 nm, about 80 nm to about 200 nm, from about 100 nm to about 150 nm, from about 1200 nm to about 1500 nm, from about 1500 nm to about 1750 nm, from about 1200 nm to about 1400 nm, or from about 1200 nm to about 1350 nm (Dv50). In specific embodiments, the subparticle has a size between about 50 nm and about 2500 nm, between about 50 nm and 1000 nm, between about 50 nm and 800 nm, between about 50 nm and 600 nm, between about 50 nm and 500 nm, between about 50 nm and 400 nm, between about 50 nm and 300 nm, between about 50 nm and 200 nm, or between about 100 nm and 300 nm. Additionally, for any desired drug loading and subparticle size, the degree of crystallinity of the antifungal agent may 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%. Preferably, the antifungal agent is about 100% crystalline.

The antifungal agent in the form of crystalline particles can be prepared into a subparticle of any desired size using a suitable method, optionally including a stabilizer, such as wet grinding, jet milling or other suitable method.

Inhaled dry particles also include a stabilizer. The stabilizer helps maintain the desired size of the antifungal agent in the form of crystalline particles during wet grinding, spray drying of the starting material and promotes wetting and dispersion. It is preferable to use as much stabilizer as necessary to obtain the desired dry powder. The amount of stabilizer is generally related to the amount of antifungal agent present in the dry particle and can range from about 1:1 (antifungal agent:stabilizer (wt:wt)) to about 50:1 (wt:wt), with In this case, ≥ (greater than or equal to) 10:1 is preferred. For example, the antifungal:stabilizer ratio (wt:wt) in the dry particles may be ≥ (greater than or equal to) 10:1, about 10:1, about 20:1, about 1:1 to about 50:1 , from about 10:1 to about 15:1, or from about 10:1 to about 20:1. In specific embodiments, the ratio is from about 5:1 to about 20:1, from about 7:1 to about 15:1, or from about 9:1 to about 11:1. In addition, the amount of stabilizer that is present in the dry particles may range from about 0.05% to about 45% by weight. (%wt). In specific embodiments, the range is from about 1% to about 15%, from about 4% to about 10%, or from about 5% to about 8% by weight. (%wt). In general, it is preferable that the respirable dry particles contain less than about 10 wt% stabilizer, for example, 9 wt%. or less, 8% wt. or less, 7% wt. or less, 5% wt. or less than or approximately 1% of the mass. Alternatively, the respirable dry particles contain about 5 wt%, about 6 wt%, about 7 wt%, about 7.5 wt%, about 8 wt%. or approximately 10% stabilizer. A particularly preferred stabilizer for use in the dry powders described herein is polysorbate 80. Another preferred stabilizer is oleic acid (or salt forms thereof). Unlike the prior art, which uses a surfactant to prevent the onset of crystallization in the resulting dry powder, the surfactant in the present invention is added to stabilize the colloidal suspension of the crystalline drug in the antisolvent.

The respirable dry particles also include any suitable and desired amount of one or more excipients. The dry particles may have a total excipient content of about 10% by weight. to about 99% by weight, more typically from about 25% by weight. up to approximately 85% of the mass. or from approximately 40% of the mass. up to approximately 55% wt. The dry particles may have a total excipient content of about 1 wt%, about 2 wt%, about 4 wt%, about 6 wt%, about 8 wt%. or less than about 10% of the mass. In specific embodiments, the range is from about 5% to about 50%, from about 15% to about 50%, from about 25% to about 50%, from about 5% to about 40%, from about 5% to about 30% , from about 5% to about 20%, or about 5% to about 15%. In other embodiments, the excipient range is from about 1% to about 9%, from about 2% to about 9%, from about 3% to about 9%, from about 4% to about 9%, from about 5% to about 9%, from about 1% to about 8%, from about 2% to about 8%, from about 3% to about 8%, from about 4% to about 8%, from about 5% to about 8%, from about 1% to about 7%, about 2% to about 7%, about 3% to about 7%, about 4% to about 7%, about 5% to about 7%, about 1% to about 6 %, from about 2% to about 6%, from about 3% to about 6%, or from about 1% to about 5%.

Many excipients are well known in the art and can be included in the dry powders and dry particles described herein. Pharmaceutically acceptable excipients that are particularly preferred for the dry powders and dry particles described herein include monovalent and divalent metal cation salts, carbohydrates, sugar alcohols and amino acids.

Suitable salts of monovalent metal cations include, for example, sodium salts and potassium salts. Suitable sodium salts that may be present in the inhalable dry particles of the invention include, for example, sodium chloride, sodium citrate, sodium sulfate, sodium lactate, sodium acetate, sodium bicarbonate, sodium carbonate, sodium stearate, sodium ascorbate, sodium benzoate, sodium biphosphate , sodium phosphate, sodium bisulfite, sodium borate, sodium gluconate, sodium metasilicate, etc.

Suitable potassium salts include, for example, potassium chloride, potassium bromide, potassium iodide, potassium bicarbonate, potassium nitrite, potassium persulfate, potassium sulfite, potassium bisulfite, potassium phosphate, potassium acetate, potassium citrate, monopotassium glutamate, dipotassium guanylate, potassium gluconate, malate potassium, potassium ascorbate, potassium sorbate, potassium succinate, potassium sodium tartrate and any combination thereof.

Suitable divalent metal cation salts include magnesium salts and calcium salts. Suitable magnesium salts include, for example, magnesium lactate, magnesium fluoride, magnesium chloride, magnesium bromide, magnesium iodide, magnesium phosphate, magnesium sulfate, magnesium sulfite, magnesium carbonate, magnesium oxide, magnesium nitrate, magnesium borate, magnesium acetate, magnesium citrate, gluconate magnesium, magnesium maleate, magnesium succinate, magnesium malate, magnesium taurate, magnesium orotate, magnesium glycinate, magnesium naphthenate, magnesium acetylacetonate, magnesium formate, magnesium hydroxide, magnesium stearate, magnesium hexafluorosilicate, magnesium salicylate, or any combination thereof.

Suitable calcium salts include, for example, calcium chloride, calcium sulfate, calcium lactate, calcium citrate, calcium carbonate, calcium acetate, calcium phosphate, calcium alginate, calcium stearate, calcium sorbate, calcium gluconate and the like.

The preferred sodium salt is sodium sulfate. The preferred sodium salt is sodium chloride. The preferred sodium salt is sodium citrate. A preferred magnesium salt is magnesium lactate.

Carbohydrate excipients useful in this regard include mono- and polysaccharides. Representative monosaccharides include dextrose (anhydrous and monohydrate; also called glucose and glucose monohydrate), galactose, D-mannose, sorbose, and the like. Representative disaccharides include lactose, maltose, sucrose, trehalose, and the like. Representative trisaccharides include raffinose and the like. If desired, other carbohydrate excipients can be used, including dextran, maltodextrin and cyclodextrins such as 2-hydroxypropyl-beta-cyclodextrin. Representative sugar alcohols include mannitol, sorbitol, and the like. The preferred sugar alcohol is mannitol. Preferred carbohydrates are mannitol, lactose, maltodextrin and trehalose.

Suitable amino acid excipients include any naturally occurring amino acids that form a powder using standard pharmaceutical processing techniques, and include non-polar (hydrophobic) amino acids and polar (uncharged, positively charged and negatively charged) amino acids, such amino acids are pharmaceutical grade and generally considered safe (GRAS) as defined by the US Food and Drug Administration. Representative examples of non-polar amino acids include alanine, isoleucine, leucine, methionine, phenylalanine, proline, tryptophan and valine. Representative examples of polar uncharged amino acids include cysteine, glycine, glutamine, serine, threonine and tyrosine. Representative examples of polar, positively charged amino acids include arginine, histidine and lysine. Representative examples of negatively charged amino acids include aspartic acid and glutamic acid. The preferred amino acid is leucine.

In one aspect, the respirable solids include leucine as one or more excipients in an amount of from about 1% to about 9%, from about 2% to about 9%, from about 3% to about 9%, from about 4% to about 9% %, from about 5% to about 9%, from about 1% to about 8%, from about 2% to about 8%, from about 3% to about 8%, from about 4% to about 8%, from about 5 % to about 8%, from about 1% to about 7%, from about 2% to about 7%, from about 3% to about 7%, from about 4% to about 7%, from about 5% to about 7% , from about 1% to about 6%, from about 2% to about 6%, from about 3% to about 6%, from about 1% to about 5%, about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 9%, or about 10%. In another aspect, the respirable dry particles include leucine as one or more excipients in an amount of 10% or more.

The dry particles described herein contain 1) an antifungal agent in the form of crystalline particles, 2) a stabilizer and, optionally, 3) one or more excipients. In some aspects, the dry particles comprise a first excipient that is a salt of a monovalent or divalent metal cation and a second excipient that is an amino acid, a carbohydrate, or a sugar alcohol. For example, the first excipient may be a sodium salt or a magnesium salt, and the second excipient may be an amino acid (such as leucine). In more specific examples, the first excipient may be sodium sulfate, sodium chloride or magnesium lactate, and the second excipient may be leucine. Even more specifically, the first excipient may be sodium sulfate and the second excipient may be leucine. In another example, the first excipient may be a sodium salt or a magnesium salt, and the second excipient may be a sugar alcohol (such as mannitol). In more specific examples, the first excipient may be sodium sulfate, sodium chloride or magnesium lactate, and the second excipient may be mannitol. In another example, the first excipient may be a sodium salt or a magnesium salt, and the second excipient may be a carbohydrate (such as maltodextrin). In other examples, the dry particles include a crystalline antifungal agent, a stabilizer, and one excipient, such as a sodium salt, a magnesium salt, or an amino acid (eg, leucine).

In one aspect, dry powder compositions include respirable dry particles comprising 1) a crystalline antifungal agent, 2) a stabilizer, and 3) one or more excipients, provided that the antifungal agent is not a polyene antifungal agent (eg, amphotericin B).

In one preferred aspect, the dry powder compositions include respirable dry particles comprising 1) a triazole antifungal agent in the form of crystalline particles, 2) a stabilizer, and 3) one or more excipients.

In one aspect, the dry powder compositions include respirable dry particles comprising: (i) about 50% to about 80% triazole antifungal agent in crystalline particulate form, about 4% to about 40% stabilizer, and about 1% to about 9% one or more excipients; (ii) about 45% to about 85% triazole antifungal agent in crystalline particulate form, about 3% to about 15% stabilizer, about 3% to about 50% sodium salt, and about 1% to 9% one or more amino acids; (iii) from about 45% to about 85% triazole antifungal agent in the form of crystalline particles, from about 3% to about 15% stabilizer, from about 3% to about 50% sodium sulfate and from about 1% to 9% leucine; (iv) from about 45% to about 85% triazole antifungal agent in the form of crystalline particles, from about 3% to about 15% stabilizer, from about 3% to about 50% sodium salt, and from about 1% to about 8% one or several amino acids; or (v) about 45% to about 85% triazole antifungal in crystalline particulate form, about 3% to about 15% stabilizer, about 3% to about 50% sodium sulfate, and about 1% to about 8% leucine ; where all percentages are percentages by weight and all compositions add up to 100% on a dry matter basis.

In a particularly preferred aspect, the dry powder compositions comprise respirable dry particles comprising 1) crystalline itraconazole, 2) a stabilizer, and 3) one or more excipients. In this particularly preferred aspect, the dry powder composition does not include lactose. Specific compositions of this particularly preferred embodiment are presented below. In Table 1 below, these examples are more specifically described for itraconazole in crystalline particle form, with specific itraconazole crystalline particle sizes also referred to as itraconazole subparticles.

In one aspect, the dry powder composition includes 50% Itraconazole, 35% sodium sulfate, 10% leucine and 5% polysorbate 80.

In one aspect, the dry powder composition includes 50% Itraconazole, 37% sodium sulfate, 8% leucine and 5% polysorbate 80.

In another aspect, the dry powder composition includes 60% Itraconazole, 26% sodium sulfate, 8% leucine and 6% polysorbate 80.

In another aspect, the dry powder composition includes 70% Itraconazole, 15% sodium, 8% leucine and 7% polysorbate 80.

In another aspect, the dry powder composition includes 75% Itraconazole, 9.5% sodium sulfate, 8% leucine and 7.5% polysorbate 80.

In another aspect, the dry powder composition includes 80% Itraconazole, 4% sodium sulfate, 8% leucine and 8% polysorbate 80.

In another aspect, the dry powder composition includes 80% Itraconazole, 10% sodium sulfate, 2% leucine and 8% polysorbate 80.

In another aspect, the dry powder composition includes 80% Itraconazole, 11% sodium sulfate, 1% leucine and 8% polysorbate 80.

In one aspect, the dry powder composition includes 50% Itraconazole, 35% sodium chloride, 10% leucine and 5% polysorbate 80.

In one aspect, the dry powder composition includes 50% Itraconazole, 37% sodium chloride, 8% leucine and 5% polysorbate 80.

In another aspect, the dry powder composition includes 60% Itraconazole, 26% sodium chloride, 8% leucine and 6% polysorbate 80.

In another aspect, the dry powder composition includes 70% Itraconazole, 15% sodium chloride, 8% leucine and 7% polysorbate 80.

In another aspect, the dry powder composition includes 75% Itraconazole, 9.5% sodium chloride, 8% leucine and 7.5% polysorbate 80.

In another aspect, the dry powder composition includes 80% Itraconazole, 4% sodium chloride, 8% leucine and 8% polysorbate 80.

In another aspect, the dry powder composition includes 80% Itraconazole, 10% sodium chloride, 2% leucine and 8% polysorbate 80.

In another aspect, the dry powder composition includes 80% Itraconazole, 11% sodium chloride, 1% leucine and 8% polysorbate 80.

Dry powders and/or respirable dry particles are preferably fine, dense and dispersible. To measure volumetric median geometric diameter (VMGD), a laser diffraction system can be used, such as the Spraytec system (particle size analyzer, Malvern Instruments) and the HELOS/RODOS system (laser diffraction sensor with solids dosing unit, Sympatec GmbH). Inhalable dry particles have a VMGD, measured by laser diffraction at a dissipation pressure (also called regulator pressure) setting of 1.0 bar at maximum outlet pressure, using the HELOS/RODOS system, of approximately 10 microns or less, approximately 5 microns or less, about 4 µm or less, about 3 µm or less, about 1 µm to about 5 µm, about 1 µm to about 4 µm, about 1.5 µm to about 3.5 µm, about 2 µm to about 5 µm, about 2 µm to about 4 µm or about 2 µm to about 3 µm. Preferably, the VMGD is about 5 microns or less, or about 4 microns or less. In one aspect, the dry powders and/or respirable dry particles have a minimum VMGD of about 0.5 microns or about 1.0 microns.

Dry powders and/or respirable dry particles preferably have a 1 bar/4 bar dispersity ratio and/or a 0.5 bar/4 bar dispersity ratio of less than about 2.0 (e.g., from about 0.9 to less than about 2), about 1.7 or less (e.g., about 0.9 to about 1.7) about 1.5 or less (e.g., about 0.9 to about 1.5), about 1.4 or less (e.g. from about 0.9 to about 1.4) or about 1.3 or less (for example, from about 0.9 to about 1.3) and preferably have 1 bar/4 bar and/or 0.5 bar/4 bar about 1.5 or less (eg, from about 1.0 to about 1.5) and/or about 1.4 or less (eg, from about 1.0 to about 1.4).

The dry powders and/or respirable dry particles preferably have a tapped density of at least about 0.2 g/ ^cm3 , at least about 0.25 g/ ^cm3 , a tapped density of at least about 0.3 g/ ^cm3 , at least about 0.35 g/cm ³ , tapped density at least 0.4 g/cm ³ . For example, dry powders and/or respirable dry particles have a tapped density greater than 0.4 g/cm ³ (e.g., greater than 0.4 g/cm ³ to about 1.2 g/cm ³ ), a tapped density of less than at least about 0.45 g/cm ³ (for example, from about 0.45 g/cm ³ to about 1.2 g/cm ³ ), at least about 0.5 g/cm ³ (for example, from about 0. 5 g/cm ³ to about 1.2 g/cm ³ ), at least about 0.55 g/cm ³ (for example, from about 0.55 g/cm ³ to about 1.2 g/cm ³ ), at least about 0.6 g/cm ³ (for example, from about 0.6 g/cm ³ to about 1.2 g/cm ³ ) or at least from about 0.6 g/cm ³ to about 1, 0 g/cm ³ . Alternatively, the dry powders and/or respirable dry particles preferably have a tapped density of from about 0.01 g/cm ³ to about 0.5 g/cm ³ , from about 0.05 g/cm ³ to about 0.5 g/cm ³ , from about 0.1 g/ ^cm3 to about 0.5 g/ ^cm3 , from about 0.1 g/ ^cm3 to about 0.4 g/ ^cm3 , or from about 0.1 g/ ^cm3 to approximately 0.4 g/cm ³ . Alternatively, the dry powders and/or respirable dry particles have a tapped density of from about 0.15 g/cm ³ to about 1.0 g/cm ³ . Alternatively, the dry powders and/or respirable dry particles have a tapped density of from about 0.2 g/cm ³ to about 0.8 g/cm ³ .

The dry powders and/or respirable dry particles have a bulk density of at least about 0.1 g/cm ³ or at least about 0.8 g/cm ³ . For example, dry powders and/or respirable dry particles have a bulk density of from about 0.1 g/cm ³ to about 0.6 g/cm ³ , from about 0.2 g/cm ³ to about 0.7 g/cm ³ , from about 0.3 g/cm ³ to about 0.8 g/cm ³ .

Respirable dry particles and dry powders, when the dry powders are respirable dry powders, preferably have an MMAD of less than 10 microns, preferably an MMAD of about 5 microns or less, or about 4 microns or less. In one aspect, respirable dry powders and/or respirable dry particles preferably have a minimum MMAD of about 0.5 microns or about 1.0 microns. In one aspect, respirable dry powders and/or respirable dry particles preferably have a minimum MMAD of about 2.0 microns, about 3.0 microns, or about 4.0 microns.

Dry powders and/or respirable dry particles preferably have an FPF of less than about 5.6 microns (FPF<5.6 microns) of the total dose of at least about 35%, preferably at least about 45%, at least about 60% , between about 45% and about 80% or between about 60% and about 80%.

Dry powders and/or respirable dry particles preferably have an FPF of less than about 3.4 microns (FPF<3.4 microns) of the total dose of at least about 20%, preferably at least about 25%, at least about 30% at least about 40%, between about 25% and about 60%, or between about 40% and about 60%.

Dry powders and/or respirable dry particles preferably have a total water and/or solvent content of up to about 15 wt%, up to about 10 wt%, up to about 5 wt%, up to about 1%, or between about 0.01% and about 1%, or may be substantially free of water or other solvent.

Dry powders and/or inhalable dry particles can preferably be administered at low inspiratory energy. To correlate powder dispersion at different inhalation flow rates, volumes, and from inhalers with different resistances, the energy required to perform the inhalation maneuver can be calculated. Inspiratory energy can be calculated using the equation E=R ² Q ² V, where E is the inspiratory energy in Joules, R is the inhaler resistance in kPa ^1/2 /l/min, Q is the steady-state flow rate in l/min and V is the volume inspired air in l.

It is assumed that a healthy adult population will be able to achieve inspiratory energy ranging from 2.9 J for comfortable inhalations to 22 J for maximal inhalations, using peak inspiratory flow rate (PIFR) values measured by Clarke et al. (Journal of Aerosol Med, 6(2), p.99-110, 1993) for flow rate Q from two inhaler resistances of 0.02 and 0.055 kPa ^1/2 /l/min, with an inspiratory volume of 2 l, based on guidelines FDA documents for dry powder inhalers, as well as the work of Tiddens et al. (Journal of Aerosol Med, 19 (4), p.456-465, 2006) who found that adults had an average inspiratory volume of 2.2 L across different DPIs.

Adult patients with mild, moderate, and severe COPD are expected to be able to achieve maximum inspiratory energy of 5.1 to 21 J, 5.2 to 19 J, and 2.3 to 18 J, respectively. This is also based on the use of measured PIFR values for flow rate Q in the equation for inspiratory energy. The PIFR achievable for each group is a function of the resistance of the inhaler through which inhalation is administered. The work of Broeders et al. (Eur Respir J, 18, p.780-783, 2001) was used to predict the maximum and minimum achievable PIFR through two dry powder inhalers with resistances of 0.021 and 0.032 kPa ^1/2 /l/min for each.

Similarly, adult patients with asthma are predicted to be able to achieve peak inspiratory energy of 7.4 to 21 J based on the same assumptions as the COPD population and PIFR data from Broeders et al.

Healthy adults and children, patients with COPD, patients with asthma aged 5 years and older, and patients with CF, for example, are able to provide sufficient inspiratory energy to empty and disperse the dry powder compositions of the invention.

Dry powders and/or inhalable dry particles preferably have a high delivered dose, such as a CEPM of at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, from a dry inhaler powder with a total inhalation energy of approximately 5 J, approximately 3.5 J, approximately 2.4 J, approximately 2 J, approximately 1 J, approximately 0.8 J, approximately 0.5 J, or approximately 0.3 J applied by the subject to a passive dry powder inhaler. The container containing dry powders and/or respirable dry particles may contain about 5 mg, about 7.5 mg, about 10 mg, about 15 mg, about 20 mg, or about 30 mg. In one aspect, dry powders and/or respirable dry particles have a CEPM of 80% or more and a VMGD of 5 microns or less when emitted from a passive dry powder inhaler having a resistance of approximately 0.036 kPa/liters per minute, under the following conditions: air flow rate 30 L/min, cycle for 3 seconds using a size 3 capsule that contains a total mass of 10 mg. In another aspect, dry powders and/or respirable dry particles have a CEPM of 80% or greater and a VMGD of 5 microns or less when emitted from a passive dry powder inhaler having a resistance of approximately 0.036 kPa/liters per minute, under the following conditions: air flow rate 20 l/min, cycle for 3 seconds using a size 3 capsule that contains a total mass of 10 mg. In a further aspect, dry powders and/or respirable dry particles have a CEPM of 80% or more and a VMGD of 5 microns or less when emitted from a passive dry powder inhaler having a resistance of approximately 0.036 kPa/liters per minute, under the following conditions: air flow rate 15 L/min, cycle for 4 seconds using a size 3 capsule that contains a total mass of 10 mg.

The dry powder may fill a single-dose container, or the single-dose container may be at least 2% filled, at least 5% filled, at least 10% filled, at least 20% filled, or at least 30% filled. %, 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 single-dose container may be a capsule ( eg, volume 000, 00, 0E, 0, 1, 2, 3 and 4, with corresponding volume capacities of 1.37 ml, 950 µl, 770 µl, 680 µl, 480 µl, 360 µl, 270 µl and 200 µl). The capsule may be at least about 2% filled, at least about 5% filled, at least about 10% filled, at least about 20% filled, at least about 30% filled, at least about 40% full or at least about 50% full. The single-dose container may be a blister pack. The blister can be packaged as a single blister or as part of a set of blisters, for example 7 blisters, 14 blisters, 28 blisters or 30 blisters. One or more blisters may preferably be at least 30% filled, at least 50% filled or at least 70% filled.

The advantage of powders is that they disperse well at different flow rates and are relatively independent of flow rates. Dry powders and/or respirable dry particles provide the potential for simple passive DPI to be used in a broad patient population.

In particular aspects, the dry powders and/or respirable dry particles comprise an antifungal agent in the form of crystalline particles, also referred to as antifungal subparticles (e.g., an antifungal subparticle ranging in size from about 80 nm to about 1750 nm, such as from about 60 nm to about 175 nm, from about 150 nm to about 400 nm or about 1200 nm to about 1750 nm), a stabilizer, and optionally one or more excipients. The specific dry powders and respirable dry particles have the following compositions shown in Table 1. The dry powders and/or respirable dry particles described herein are preferably characterized by the following: 1) VMGD at 1 bar, measured using the HELOS/RODOS system, approximately 10 micron or less, preferably about 5 microns or less; 2) 1 bar/4 bar dispersion factor and/or 0.5 bar/4 bar dispersion factor of approximately 1.5 or less, approximately 1.4 or less, or approximately 1.3 or less; 3) MMAD of about 10 microns or less, preferably about 5 microns or less; 4) FPF<5.6 μm of the total dose of at least about 45% or at least about 60%; and/or 5) FPF<3.4 μm of the total dose of at least about 25% or at least about 40%. Optionally, the dry powders and/or respirable dry particles are further characterized by a tapped density of about 0.2 g/ ^cm3 or greater, about 0.3 g/ ^cm3 or greater, about 0.4 g/ ^cm3 or greater, greater than 0.4 g/cm ³ , about 0.45 g/cm ³ or more, or about 0.5 g/cm ³ or more.

Table 1 Composition Antifungal agent (wt.%) Excipients (wt.%) Stabilizer
(wt.%) Antifungal subparticle size (left column) and range (right column)
(Dv50nm) A (I) Itraconazole 20% Sodium sulfate 39%
Mannitol 39% PS80 2% 124 60-175 B (II) Itraconazole 50% Sodium sulfate 22.5%
Mannitol 22.5% PS80 5% 124 60-175 C(III) Itraconazole 20% Sodium chloride 62.4%
Leucine 15.6% PS80 2% 124 60-175 D(IV) Itraconazole 50% Sodium chloride 36%
Leucine 9% PS80 5% 124 60-175 E(V) Itraconazole 20% Magnesium lactate 66.3%
Leucine 11.7% PS80 2% 124 60-175 F(VI) Itraconazole 50% Magnesium lactate 38.25%
Leucine 6.75% PS80 5% 124 60-175 G(VII) Itraconazole 50% Sodium sulfate 33.25%
Leucine 14.25% Oleic acid 2.5% 120 60-175 H(VIII) Itraconazole 70% Sodium sulfate 13.25%
Leucine 13.25% Oleic acid 3.5% 120 60-175 I Itraconazole 50% Magnesium lactate 33.25%
Leucine 14.25% Oleic acid 2.5% 120 60-175 J Itraconazole 70% Magnesium lactate 13.25%
Leucine 13.25% Oleic acid 3.5% 120 60-175 K (XI) Itraconazole 50% Sodium sulfate 35%
Leucine 12.5% Oleic acid 2.5% 126 60-175 L (XII) Itraconazole 50% Sodium sulfate 35%
Leucine 10% PS80 5% 132 60-175 M(XIII) Itraconazole 50% Sodium sulfate 35%
Leucine 10% PS80 5% 198 150-250 N (XIV) Itraconazole 50% Sodium sulfate 35%
Leucine 10% PS80 5% 258 200-325 O(XV) Itraconazole 50% Sodium sulfate 35%
Leucine 10% PS80 5% 1600 1200-1650 P(XVI) Itraconazole 50% Sodium sulfate 35%
Leucine 10% PS80 <5% 1510 1200-1650 Q (XVII) Amphotericin B 50% Sodium sulfate 35%
Leucine 10% PS80 5% 120 60-175 R (XVIII) Amphotericin B 50% Sodium chloride 35%
Leucine 10% PS80 5% 120 60-175 S (XIX) Itraconazole 50% Sodium sulfate 35%
Leucine 15% N/A N/A N/A Itraconazole in amorphous form XX Itraconazole 50% Sodium sulfate 35%
Leucine 15% N/A N/A N/A Itraconazole in amorphous form XXI Itraconazole 50% Sodium sulfate 35%,
Leucine 10% PS80 5% 130 60-175 XXII Itraconazole 50% Sodium sulfate 35%,
Leucine 11.57% Oleic acid 3.43% 115 60-175 XXIII Itraconazole 50% Sodium sulfate 35%,
Leucine 13.75% PS80 1.25% 1640 1200-1650 XXIV Itraconazole 50% Sodium sulfate 37%,
Leucine 8% PS80
5% 130 60-175 XXV Itraconazole 60% Sodium sulfate 26%,
Leucine 8% PS80
6% 130 60-175 XXVI Itraconazole 70% Sodium sulfate 15%,
Leucine 8% PS80
7% 130 60-175 XXVII Itraconazole 75% Sodium sulfate 9.5%,
Leucine 8% PS80
7.5% 130 60-175 XXVIII Itraconazole 80% Sodium sulfate 4%,
Leucine 8% PS80
8% 130 60-175 XXIX Itraconazole 80% Sodium sulfate 10%,
Leucine 2% PS80
8% 130 60-175 XXX Itraconazole 80% Sodium sulfate 11%,
Leucine 1% PS80
8% 130 60-175

In a particular aspect, Composition XII has an FPF of less than 5 microns of a total dose of 57%, resulting in a less than 5 microns fines dose of 2.8 mg for a total dry powder capsule fill of 10.0 mg.

Dry powders and/or respirable dry particles described using any of the ranges or specifically disclosed compositions described in the previous subsection can be used to fill a container, such as a capsule or blister. When the container is a capsule, the capsule is, for example, a size 2 capsule or a size 3 capsule, and is preferably a size 3 capsule. The capsule may be of a material such as gelatin or HPMC (hydroxypropyl methylcellulose), and preferably HPMC.

The dry powder and/or respirable dry particles described and characterized above may be contained in a dry powder inhaler (DPI). The DPI may be a capsule type DPI or a blister type DPI, and is preferably a capsule type DPI. More preferably, the dry powder inhaler is selected from the RS01 family of dry powder inhalers (Plastiape S.p.A., Italy). More preferably, the dry powder inhaler is selected from RS01 HR or RS01 UHR2. Most preferably, the dry powder inhaler is RS01 HR.

Examples of compositions that can be used in the methods described herein include, but are not limited to, the following:

Table 1A. Composition Itraconazole
(wt.%) Excipients
(wt.%) Polysorbate 80 (PS 80)
(wt.%) Itraconazole ratio: PS 80 Itraconazole subparticle size range (Dv50 nm) XXXI Itraconazole 20.0% Sodium sulfate 39.2%,
Mannitol 39.2% PS 80 1.66% 12:1 60-175 XXXII Itraconazole 50.0% Sodium sulfate 22.9%,
Mannitol 22.9% PS 80 4.17% 12:1 60-175 XXXIII Itraconazole 50.0% Sodium sulfate 45.8% PS 80 4.17% 12:1 60-175 XXXIV Itraconazole 80.0% Sodium sulfate 6.66%,
Mannitol 6.67% PS 80 6.67% 12:1 60-175 XXXV Itraconazole 80.0% Sodium sulfate 13.3% PS 80 6.67% 12:1 60-175 XXXVI Itraconazole 92.3% N/A PS 80 7.69% 12:1 60-175 XXXVII Itraconazole 20.0% Sodium sulfate 39.5%,
Mannitol 39.5% PS 80 1.00% 20:1 60-175 XXXVIII Itraconazole 50.0% Sodium sulfate 23.8%,
Mannitol 23.8% PS 80 2.50% 20:1 60-175 XXXIX Itraconazole 80.0% Sodium sulfate 8.00%,
Mannitol 8.00% PS 80 4.00% 20:1 60-175 XXXX Itraconazole 20.0% Sodium sulfate 60.9%,
Leucine 17.4% PS 80 1.66% 12:1 60-175 XXXXI Itraconazole 50.0% Sodium sulfate 35.7%,
Leucine 10.2% PS 80 4.16% 12:1 60-175 XXXXII Itraconazole 60.0% Sodium sulfate 27.2%,
Leucine 7.78% PS 80 5.00% 12:1 60-175 XXXXIII Itraconazole 70.0% Sodium sulfate 18.8%,
Leucine 5.37% PS 80 5.83% 12:1 60-175 XXXXIV Itraconazole 80.0% Sodium sulfate 10.4%,
Leucine 2.96% PS 80 6.67% 12:1 60-175 XXXXV Itraconazole 80.0% Sodium sulfate 6.67%,
Leucine 6.66% PS 80 6.67% 12:1 60-175 XXXXVI Itraconazole 80.0% Sodium sulfate 2.96%, Leucine 10.4% PS 80 6.67% 12:1 60-175 XXXXVII Itraconazole 20.0% Sodium sulfate 61.4%, Leucine 17.6% PS 80 1.00% 20:1 60-175 XXXXVIII Itraconazole 50.0% Sodium sulfate 36.9%, Leucine 10.6% PS 80 2.50% 20:1 60-175 XLIX Itraconazole 50.0% Sodium sulfate 47.5% PS 80 2.50% 20:1 60-175 L Itraconazole 60.0% Sodium sulfate 28.8%,
Leucine 8.20% PS 80 3.00% 20:1 60-175 LI Itraconazole 70.0% Sodium sulfate 20.6%,
Leucine 5.89% PS 80 3.50% 20:1 60-175 LII Itraconazole 80.0% Sodium sulfate 12.4%,
Leucine 3.56% PS 80 4.00% 20:1 60-175 LIII Itraconazole 95.2% N/A PS 80 4.76% 20:1 60-175 LIV Itraconazole 20.0% Sodium sulfate 61.7%,
Leucine 17.6% PS 80 0.667% 30:1 60-175 LV Itraconazole 50.0% Sodium sulfate 37.6%,
Leucine 10.7% PS 80 1.67% 30:1 60-175 LVI Itraconazole 60% Sodium sulfate 29.6%,
Leucine 8.44% PS 80 2.00% 30:1 60-175 LVII Itraconazole 70% Sodium sulfate 21.5%,
Leucine 6.15% PS 80 2.33% 30:1 60-175 LVIII Itraconazole 80% Sodium sulfate 13.5%,
Leucine 3.85% PS 80 2.67% 30:1 60-175

Methods for producing dry powders and dry particles

Respirable dry particles and dry powders can be prepared using any suitable method, provided that the dry powder composition is not an extemporaneous dispersion. Many suitable methods for producing dry powders and/or respirable dry particles are common in the art and include single and double emulsion solvent evaporation, spray drying, spray freeze drying, grinding (eg, jet grinding), mixing, solvent extraction, evaporation solvent, phase separation, simple and complex coacervation, interfacial polymerization, suitable methods which include the use of supercritical carbon dioxide (CO ₂ ), sonocrystallization, formation of nanoparticle aggregates and other suitable methods, including combinations thereof. Respirable dry particles can be obtained using methods for producing microspheres or microcapsules known in the art. These methods can be used under conditions that result in the formation of respirable dry particles with desired aerodynamic properties (eg, 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.

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

The inhaled dry particles are preferably spray dried. Suitable spray drying methods are described, for example, in K. Masters, “Spray Drying Handbook”, John Wiley & Sons, New York (1984). Typically, in a spray drying process, the heat of a hot gas, such as heated air or nitrogen, is used to evaporate solvent from droplets produced by atomizing a continuously supplied liquid. When using hot air, the moisture in the air is at least partially removed before it is used. When nitrogen is used, the nitrogen gas is supplied “dry,” meaning that no additional water vapor combines with the gas. If desired, the moisture level of nitrogen or air can be set before spray drying begins at a fixed value higher than that of “dry” nitrogen. If desired, the spray dryer or other devices, such as a jet mill, used to produce dry particles may include an integral geometric particle meter that determines the geometric diameter of the inhaled dry particles during their production and/or an integrated aerodynamic particle meter that determines the aerodynamic diameter inhaled dry particles during their production process.

For spray drying, solutions, emulsions or suspensions that contain dry particle components to be prepared in a suitable solvent (eg, an aqueous solvent, an organic solvent, a water-organic mixture or an emulsion) are distributed into the drying vessel through a spray device. For example, a nozzle or rotary atomizer may be used to distribute the solution or slurry into the drying vessel. The nozzle may be a two-fluid nozzle, which may be in either the internal mixing device or the external mixing device. Alternatively, a rotary sprayer with a 4 or 24 blade wheel can be used. Examples of suitable spray dryers that may be equipped with a rotary atomizer and/or nozzle include the Mobile Minor or Model PSD-1 spray dryer, both manufactured by GEA Niro, Inc. (Denmark), spray dryer B-290 Mini ( Labortechnik AG, Flawil, Switzerland), ProCepT Formatrix R&D spray dryer (ProCepT nv, Zelzate, Belgium), as well as some other spray dryer options. Actual spray drying conditions will vary depending in part on the composition of the spray drying solution or slurry and the flow rate of the material. One of ordinary skill in the art will be able to determine suitable conditions based on the composition of the solution, emulsion or suspension to be spray dried, the desired particle properties and other factors. Typically, the spray dryer inlet temperature is from about 90°C to about 300°C. The spray dryer outlet temperature will vary depending on factors such as the temperature of the feed material and the properties of the materials being dried. Typically the outlet temperature is from about 50°C to about 150°C. If desired, the resulting respirable dry particles may be volumetric size fractionated, such as using a sieve, or aerodynamic size fractionated, such as using a cyclone, and/or further separated by density using methods known to those skilled in the art.

To produce respirable dry particles, typically an emulsion or suspension is prepared that contains the desired dry powder components (ie starting material) and spray dried under suitable conditions. Preferably, the concentration of dissolved or suspended solids in the feed material is 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 starting material can be provided by preparing a simple solution, suspension or emulsion by dissolving, suspending or emulsifying suitable components (eg, salts, excipients, other active ingredients) in a suitable solvent. The solution, emulsion or suspension can be prepared using any suitable methods, such as volumetric mixing of dry and/or liquid components or static mixing of liquid components to form a combination. For example, a hydrophilic component (eg, an aqueous solution) and a hydrophobic component (eg, an organic solution) can be combined using a static mixer to form the combination. The combination can then be nebulized to produce droplets, which are dried to form respirable dry particles. Preferably, the atomization step is carried out immediately after combining the components in a static mixer. Alternatively, the spraying step is carried out using a solution obtained by volumetric mixing.

The starting material can be prepared using any solvent in which the particulate antifungal agent has low solubility, such as an organic solvent, an aqueous solvent, or mixtures thereof. Suitable organic solvents that can be used include, but are not limited to, alcohols such as, for example, ethanol, methanol, propanol, isopropanol, butanols and others. Other organic solvents include, but are not limited to, tetrahydrofuran (THF), perfluorocarbons, dichloromethane, chloroform, ether, ethyl acetate, methyl tert-butyl ether and others. Co-solvents that can be used include an aqueous solvent and an organic solvent, such as, but not limited to, the organic solvents described above. Aqueous solvents include water and buffer solutions. The preferred solvent is water.

Various methods (eg, static mixing, volumetric mixing) can be used to mix solutes and solvents to produce starting material, which are known in the art. If desired, other suitable mixing methods may be used. For example, additional components that cause or facilitate mixing may be included in the starting material. For example, carbon dioxide causes effervescence or foaming and thus can promote physical mixing of the solute and solvents.

The starting material or components of the starting material may have any desired pH level, viscosity or other properties. If desired, a pH buffer may be added to the solvent or cosolvent or to the resulting mixture. Typically the pH of the mixture is in the range of about 3 to about 8.

Dry powder and/or respirable dry particles can be prepared and then separated, for example, by filtration or cyclone centrifugation to obtain a sample of particles with 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 may have diameter in the selected range. The selected range within which a certain percentage of respirable dry particles falls may, for example, be any of the size ranges described herein, for example from about 0.1 to about 3 μm VMGD.

The suspension may be a nanosuspension, like an intermediate for obtaining a dry powder containing a nanocrystalline drug.

The dry powder may be a drug included in a matrix material such as sodium sulfate and leucine. Optionally, the dry powder can be spray dried so that the dry particles are fine, dense and dispersible.

Dry powders may consist only of the respirable dry particles described herein, without other carrier or excipient particles (referred to as “pure powders”). If desired, dry powders may include mixtures of respirable dry particles described herein and other carrier or excipient particles, such as lactose carrier particles, that have a size greater than 10 microns, from 20 microns to 500 microns, preferably from 25 microns up to 250 microns.

In a preferred embodiment, the dry powders do not contain carrier particles. In one aspect, the crystalline drug particles are embedded in a matrix including an excipient and/or stabilizer. The dry powder may include inhalable dry particles of uniform content, where each particle contains a crystalline drug. Thus, as used herein, the term “uniform content” means that each inhaled particle contains an amount of antifungal agent in the form of crystalline particles, a stabilizer and an excipient.

Dry powders may contain respirable dry particles in which at least 98%, at least 99%, or substantially all of the particles (by weight) contain an antifungal agent.

Dry powders may comprise crystalline drug particles dispersed in a matrix including one or more excipients. Excipients may include any number of salts, sugars, lipids, amino acids, surfactants, polymers or other components suitable for pharmaceutical use. Preferred excipients include sodium sulfate and leucine. Dry powders are typically prepared by first treating the crystalline drug to control particle size using any number of procedures known to those skilled in the art (eg, wet grinding, jet grinding). The crystalline drug is treated in an antisolvent with a stabilizer to form a suspension. Preferred stabilizers include polysorbate (Tween) 80 and oleic acid. The stabilized crystalline drug suspension is then spray dried with one or more additional excipients. The resulting dry particles include a crystalline drug dispersed in an excipient matrix, each dry particle having a homogeneous composition.

In a specific embodiment, the dry powder of the present invention is prepared starting from a crystalline drug (eg, itraconazole), which can generally be obtained in the microcrystalline size range. The microcrystalline drug particle size is reduced to nanocrystalline size using any of a number of methods known to those skilled in the art, including, but not limited to, high pressure homogenization, high shear homogenization, jet milling, pin milling, microfluidization or wet grinding (also known as ball milling or bead milling). Wet grinding is often preferred because it can achieve a wide range of particle size distributions, including nanometer (<1 µm) sizes. Particularly important in the submicron range is the use of surface stabilizing components such as surfactants (eg Tween 80). Surfactants enable the production of submicron particles during the grinding process and the formation of physically stable suspensions because they isolate the many high-energy surfaces created during grinding, preventing aggregation and sedimentation. Thus, the presence of a surfactant is important for spray drying of homogeneous microparticles, since the surfactant allows the formation of a uniform and stable suspension, ensuring homogeneity of the composition throughout the particles. The use of a surfactant allows the formation of microsuspensions or nanosuspensions. Using a surfactant, nanocrystalline drug particles (eg ITZ) are suspended in a stable colloidal suspension in an antisolvent. The drug antisolvent can be water or a combination of water and other miscible solvents such as alcohols or ketones as a continuous antisolvent phase for the colloidal suspension. Spray drying starting material can be prepared by dissolving the soluble components in the desired solvent(s) and then dispersing the surfactant-stabilized crystalline drug nanosuspension in the resulting starting material with stirring, although the method is not limited to this particular procedure.

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

Liquid compositions

Liquid compositions for delivery by pressurized metered dose inhaler (pMDI) or liquid inhaler (SMI) can be prepared using any suitable method. For example, for use with pMDI, the starting material may be prepared within a pressurized container in which itraconazole in the form of crystalline particles is suspended in a propellant, such as an HFA propellant or a CFC propellant, optionally stabilized with a stabilizer such as polysorbate 80. The pressurized suspension can then be delivered into the patient's airway by actuating the pMDI. Table 2 contains various embodiments for delivering itraconazole in the form of crystalline particles using pMDI. The concentration of nanoparticle solids can vary from about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, or about 50%. The pMDI dose volume can vary from about 20 μl to about 110 μl. The amount of itraconazole per dose volume may be approximately 15%, 20%, 25%, 30% or 40%. The remainder may be propellant and optionally surfactant. The efficiency of pMDI delivery may be approximately 15%, 20%, 25%, 30% or 40%. Nominal doses of itraconazole in pMDI can range from approximately 0.50 mg to approximately 12 mg. For example, the nominal dose may be about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, or about 12 mg. The calculated dose delivered may range from about 0.1 mg to about 5 mg.

table 2
Pressurized metered dose inhaler (pMDI) Concentration of solid nanoparticles
(%) Dose volume from pMDI
(µl) Amount of drug per dose volume
(%) Efficiency of pMDI delivery
(%) Nominal dose from pMDI
(mg) Delivered dose from pMDI
(mg) 10 25 20 thirty 0.50 0.15 10 25 thirty 20 0.75 0.15 10 25 thirty thirty 0.75 0.23 10 100 20 thirty 2.00 0.60 10 100 thirty 20 3.00 0.60 10 100 thirty thirty 3.00 0.90 25 25 20 thirty 1.25 0.38 25 25 thirty 20 1.88 0.38 25 25 thirty thirty 1.88 0.56 25 100 20 thirty 5.00 1.50 25 100 thirty 20 7.50 1.50 25 100 thirty thirty 7.50 2.25 35 25 20 thirty 1.75 0.53 35 25 thirty 20 2.63 0.53 35 25 thirty thirty 2.63 0.79 35 100 20 thirty 7.00 2.10 35 100 thirty 20 10.50 2.10 35 100 thirty thirty 10.50 3.15 density of water: 1 g/ml Conversion of units of measurement: 1000 mg/g Conversion of units of measurement: 1000 µl/ml

For use with SMI, for example, a starting material may be prepared in which itraconazole in the form of crystalline particles is suspended in a solvent such as water in which itraconazole is poorly soluble and stabilized by a stabilizer such as polysorbate 80. The suspension may be stored in a collapsible pouch within a cartridge, which is loaded inside the device. The volume of suspension measured under pressure flows through a capillary tube into a micropump. Once the SMI is triggered, the dose can be delivered to the patient. Table 3 contains various embodiments for delivering itraconazole in the form of crystalline particles using SMI. The concentration of particulate nanoparticles ranges from about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, or about 50%. The SMI dose volume can vary from about 10 μl to about 25 μl. The composition may include itraconazole in the form of crystalline particles and a surfactant. SMI delivery efficiency may be approximately 65%, 70%, 75%, 80%, or 85%. Nominal doses of itraconazole in pMDI can range from approximately 1.0 mg to approximately 8 mg. For example, the nominal dose may be about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, or about 8 mg. The calculated dose delivered may range from about 0.5 mg to about 5 mg.

Table 3
Liquid inhaler (SMI) Concentration of solid nanoparticles
(%) Dose volume from SMI
(µl) pMDI Delivery Efficiency (%) Nominal dose from pMDI
(mg) Delivered dose from pMDI
(mg) 10 15 75 1.50 1.13 25 15 75 3.75 2.81 35 15 75 5.25 3.94 density of water: 1 g/ml Conversion of units of measurement: 1000 mg/g Conversion of units of measurement: 1000 µl/ml

EXAMPLES

Example 1: Human Simulation: Oral Inhalation and Oral Solution

Some assumptions were made for this human simulation. Systemic pulmonary absorption rates determined using the rat model were used as inputs in human modeling. Lung solubility values from the rat model were used as a starting point for human modeling. Particle size distributions using Alberta Idealized Throat data (MMAD and GSD) were used in conjunction with the ICRP66 model in GastroPlus™ to determine the sedimentable fraction in humans. The actual dose used was approximately 56% deposited in the lungs and approximately 12.6% in the throat; it was assumed that the remaining percentage of the drug remained in the device.

Single dose pharmacokinetic (PK) parameters for Formulation XII were simulated over fourteen days of repeated exposure. A dose-proportional increase in total concentrations in both the lungs and plasma was predicted from 5 mg to 20 mg. A similar half-life was predicted for lung and plasma.

Table 4
Single dose PK parameters Dose
(mg) _Tmax
(h) _Cmax
(ng/ml) DNC _max
(ng/ml/mg) AUC _t
(h × ng/ml) AUC _inf
(h × ng/ml) T _1/2 (h) Plasma exposure parameters for inhaled dose 5 80.7 0.275 0.0551 68.4 87.2 128 10 81.5 0.549 0.0549 136 174 128 20 81.9 1.09 0.0547 272 347 128 Total pulmonary exposure parameters for inhaled dose 5 0.00 2020 403 199000 222000 104 10 0.00 4030 403 398000 444000 104 20 0.00 8070 403 796000 888000 104 AUCinf: area under the concentration-time curve versus time of drug administration (time 0), extrapolated to infinity; AUCt: area under the concentration-time curve from the time of drug administration (time 0) to the specified time (336 hours); Cmax: maximum observed drug concentration; DNCmax: dose-normalized Cmax; t1/2: half-life; Tmax: time to maximum observed concentration

Dose-proportional increases in plasma and lung levels are predicted after multiple doses. After seven days of dosing, the model predicted accumulation in the lungs and greater accumulation in plasma. Based on predictions for humans, some accumulation of undissolved drug in the alveolar interstitial region was expected with subsequent doses. Plasma concentrations following oral solution administration were higher than plasma concentrations at the 5- or 20-mg oral inhalation dose level. However, the total concentration in the lungs was higher after administration by oral inhalation. Thus, the overall lung:plasma ratio was significantly higher for oral inhalation administration compared to oral solution administration.

Table 5
PK Parameters for repeated administration Day 1 Day 7 Dose
(mg) C _max
(ng/ml) AUC _t ^a
(h × ng/ml) _Cmax
(ng/ml) AUC _t
(h × ng/ml) AUC _0-24
(h × ng/ml) AR _Cmax AR AUC _0-24 Plasma exposure parameters 5-mg inhalation dose 0.230 4.11 1.78 409 41.3 7.71 10.1 20 mg inhalation dose 0.902 16.3 7.05 1630 164 7.82 10.1 General exposure parameters in the lungs 5-mg inhalation dose 2010 36900 7190 904000 151000 3.58 4.10 20 mg inhalation dose 8030 148000 28800 3620000 605000 3.58 4.10 ^A AUC _0-t means AUC_0-24For single dose
Abbreviations: AR: accumulation factor; AUC_0-24: area under the plasma concentration-time curve from time 0 to 24 hours; AUC_inf: area under the plasma concentration-time curve versus time of drug administration (time 0), extrapolated to infinity; AUC_t: area under the concentration-time curve from the time of drug administration (time 0) to a specified time (24 hours for a single dose and 360 hours for multiple doses); C_max: maximum observed drug concentration

Table 6 shows simulated human clinical data with Composition XII administered by inhalation (oral inhalation) at 5 or 20 mg doses, or oral Sporanox (oral solution) at 200 mg, after a single dose. Lung:plasma ratio compares lung and plasma AUC data over a 7-day period for each dose. The ratios are substantially higher with the inhaled dose than with the oral dose. And although an oral dose can reach levels in the lungs that can lead to therapeutic levels in the lungs, this may require a higher total dose delivered as well as a higher systemic exposure (it is likely that with 0.2 mg administered by inhalation one can achieve same pulmonary exposure as 200 mg orally administered)

Table 6
Single oral dose versus inhalation (AUC over 7 days) Dosage form Dose (mg) Dosing interval Lung AUC0-168 (ng × h/ml) Plasma
AUC0-168
(ng × h/ml) Lung:plasma ratio Oral inhalation 5 QD 151000 41.4 3650 Oral inhalation 20 QD 605000 164 3690 Oral solution 200 QD 6370 2200 2.90

Table 7 shows exposure over a 24-hour period at 'steady state' on Day 21. Daily administration by inhalation was compared with possible every other day (EOD) administration by inhalation. The EOD route of administration appears to be half the daily dose, so exposure kinetics may be refined based on the mode of administration. Even with EOD administration, pulmonary exposure is significantly higher than that observed after a 200 mg oral dose daily.

Table 7
Steady state after oral versus inhalation administration Dosage form Dosing interval Lung AUC _0-24 (ng × h/ml) Plasma
AUC _0-24 (ng × h/ml) Lung:plasma ratio 20 mg inhalation dose QD 810000 281 2880 20 mg inhalation dose EOD 451000 145 3110 Standard dose of oral solution QD 6590 2280 2.90 Abbreviations: AUC _0-24 : area under the plasma concentration-time curve from time 0 to 24 hours; EOD: every two days; QD: once a day

Fig. 1A and 1B show the kinetics of three antifungal drugs at a dose of 5 mg. On the left (Fig. 1A) the graph shows plasma exposure with the usual clinical regimen of Sporanox administered twice daily compared to once daily administration of Composition XIX or Composition XII. It is clear that inhaled doses resulted in significantly lower systemic exposure, and Composition XII, while resulting in exposure levels similar to Composition XIX, had lower day-to-day variability and significantly lower Cmax.

On the right (Figure 1B) is a representation of pulmonary exposure for the same doses and administration schedules - the dotted line approximates the Aspergillus MIC (~500ng/g or ng/ml). When administered orally, lung levels reach values above the MIC, but only for very short periods of time when administered twice daily, and for most of the exposure period exposure is below the 'effective' level. A very similar pulmonary exposure profile was observed with 5 mg of Composition XIX and Sporanox. However, the exposure profile, even at the lowest dose of 5 mg of Composition XII, resulted in pulmonary exposure higher than the MIC and Sporanox over the entire 24-hour period, even on Day 1 and continuously throughout the 7 days of dosing.

The effectiveness of triazole antifungals is based on AUC/MIC, meaning that exposure above the MIC, both total exposure and time, are critical factors determining effectiveness. It is clear that the Formulation XII drug achieves theoretical exposures much more favorable to efficacy than the Formulation XIX drug or oral Sporanox, all with significantly reduced systemic exposure.

Fig. 2A and FIG. 2B shows the kinetics of three antifungal compositions at a 20 mg dose. The results and interpretation are similar to the 5 mg inhalation doses described above for FIG. 1A and Fig. 1B, except that a higher dose was administered and the corresponding pulmonary and plasma exposures were increased for doses administered by inhalation. Using a higher dose, Composition XIX achieves pulmonary exposure above the MIC over a 24-hour period and higher pulmonary exposure than Sporanox. On the contrary, plasma exposure remains significantly lower compared to Sporanox. The 20 mg dose of Composition XII resulted in higher pulmonary exposure than the 5 mg dose, which remained consistently above the MIC and Sporanox exposure throughout the period.

Example 2. Phase 1/1b: Safety-tolerability study

Safety, tolerability and PK studies in healthy volunteers and asthmatics highlight the benefits of PK in the lungs and plasma compared to oral Sporanox. In Part 1 of the study, single escalating doses (5 mg, 10 mg, 25 mg and 35 mg) of Composition XII were administered to normal healthy volunteers (n=6/cohort). In Part 2 of the study, multiple escalating doses (10 mg, 20 mg) of Formulation XII were administered to healthy volunteers (n=6/cohort), with an optional ^3rd cohort receiving doses up to 35 mg. The safety and tolerability of Composition XII is assessed by administering Composition XII for up to 14 days at doses expected to produce pulmonary exposure that is greater than five times that of oral Sporanox and plasma itraconazole levels that are greater than five times lower than those observed with oral Sporanox.

Part 3 of the study assessed the safety and tolerability of Composition XII or oral Sporanox administered as a single dose to asthmatics (n=16) in a crossover design. Patients taking 200 mg oral Sporanox in the first period will take a 20 mg dose of Composition XII in the second period, while patients taking 20 mg of Composition XII in the first period will take a 200 mg oral dose of Sporanox in the second period. Sputum and plasma levels of itraconazole are measured to assess pulmonary and plasma exposure. This study confirms that pulmonary exposure to Formulation XII results in pulmonary concentrations that are greater than the minimum inhibitory concentration (MIC) level for A. fumigatus and higher than the level achieved with oral Sporanox. Plasma exposure of itraconazole following administration of Composition XII was more than 5X lower than that observed with oral Sporanox.

Example 3: Comparison of Observed Airway Changes in Two Rat and Three Dog Studies with Exposures Following Inhalation of Itraconazole Inhalation Formulations XIX and XII

Studies were carried out using inhaled dry powder formulations of itraconazole, prepared using spray drying, administered to rats and dogs in two testing laboratories. All studies included the same active pharmaceutical ingredient, but the excipients of the formulations in some cases and, in particular, the physicochemical properties of the itraconazole particulates varied. The studies and their results are summarized below.

Rat studies

Study of administration of Composition XIX to rats by inhalation for 28 days followed by a 28-day recovery period

Rats were exposed to air, placebo, or itraconazole formulated as Composition XIX at target doses of 5, 20, or 44 mg/kg/day, with a formulation concentration of 50% itraconazole, for 28 days. Composition XIX-associated changes detected by microscopic examination were present in the lungs and bronchi, larynx and tracheal bifurcation at ≥5 mg/kg/day and in the trachea at ≥20 mg/kg/day. Minimal to mild granulomatous inflammation was present in the lungs and bronchi at itraconazole doses ≥5 mg/kg/day. Granulomatous inflammation was characterized by clusters of macrophages and multinucleated cells in the bronchial mucosa, often forming papillary mucosal folds protruding into the lumen. Macrophages and multinucleated giant cells often contained intracytoplasmic spicules. Alveolar macrophage aggregates were also present in the lungs at levels above baseline in rats administered at ≥20 mg/kg/day. These macrophages were vacuolated, giving the cytoplasm a foamy appearance.

Minimal to mild granulomatous inflammation was present in the larynx and tracheal bifurcation at itraconazole doses ≥5 mg/kg/day. In the lungs, this inflammation was characterized by clusters of macrophages and multinucleated giant cells with intracytoplasmic spicules in the mucosa. Similar minimal granulomatous inflammation was present in the tracheal mucosa of rats when administered at a dose of ≥20 mg/kg/day.

At the end of the 28-day recovery period, bronchiolar granulomatous inflammation was still present in rats treated with 44 mg/kg/day; thus, bronchiolar changes at this dose were not reversed during the recovery period. No granulomatous inflammation was observed in the larynx, tracheal bifurcation, or trachea at the end of the recovery period, suggesting complete recovery of these tissues during the recovery period.

Thus, the main change associated with Composition XIX was granulomatous inflammation characterized by mucosal macrophages and multinucleated giant cells with cytoplasmic spicules. This disorder, which occurred in rats administered a dose of itraconazole ≥5 mg/kg/day, was considered adverse at all doses because it occurred in all airways in which gas exchange occurs, from the larynx to the small bronchioles, and was not reversed in the bronchioles during the recovery period in rats dosed at 44 mg/kg/day (other dose groups were not examined at the end of the recovery period). Aggregates of alveolar macrophages with foamy cytoplasm were also present in the lungs at levels above baseline in rats dosed ≥20 mg/kg/day at sacrifice at the end of the study.

A 28-day study of inhalation administration of Composition XII or Composition XV in rats

Rats were exposed to itraconazole formulated as Composition XII at target doses of 5, 15 or 40 mg/kg/day or Composition XV at doses of 5 or 15 mg/kg/day for 28 days. In both cases, the concentration of itraconazole was 50% based on the total composition. In addition, one group of rats was administered 15 mg/kg of itraconazole as Composition XII every three days. Minimal to moderate foam macrophage accumulations associated with Composition XII and Composition XV were present in the lungs at 15 mg/kg/day, with higher frequency and severity in rats administered Composition XII at 40 mg/kg/day. There may have been minimal accumulation of foamy macrophages in the lungs at 5 mg/kg/day of Composition XII or Composition XV or 15 mg/kg of Composition XII when administered every 3 days, due to the lack of air-exposed or placebo control rats it was not possible to determine whether this was whether this effect is due to the test substance at these doses. Mild subacute inflammation, which was considered to be test substance related and unfavorable, was present in rats dosed at 40 mg/kg/day of Composition XII. It was unclear whether the minimal subacute inflammation that occurred in rats administered 15 mg/kg/day of Composition XII or Composition XV was due to the test substance. There was no clear difference in the incidence or severity of macrophage accumulation or subacute inflammation between male rats administered Composition XII and Composition XV at comparable dose levels. It was suggested that the severity and/or incidence of these disorders in female rats was greater when administered at 15 mg/kg/day of Composition XV compared to Composition XII.

Dog studies

A 7-day study of inhalation administration of Composition XIX in dogs with a 14-day recovery period

Dogs were exposed to itraconazole formulated as Composition XIX at target doses of 5, 10 or 20 mg/kg/day for 7 days. The concentration of itraconazole in the composition was 50% of the total amount of the composition. A 14-day recovery group was included for dogs exposed at 5 mg/kg/day. Composition XIX-associated acute inflammation, minimal to moderate, which was considered adverse, was present in both dogs (one male; one female) at the 20 mg/kg/day dose administered, and minimal acute inflammation was present in the female at the 10 mg/day dose administered. kg/day. Acute inflammation was characterized by the presence of neutrophils, macrophages and a small number of multinucleated giant cells, which appeared to contain spicules in their cytoplasm (observed in microscopic slides after completion of the study). Thus, the acute inflammation showed features of granulomatous inflammation. There were no study substance-related events in dogs at the 5 mg/kg/day dose administered when sacrificed at the end of the study or after reconstitution.

A 28-day study of inhalation administration of Composition XIX in dogs with a 28-day recovery period

Dogs were exposed to air, placebo, or itraconazole formulated at target doses of 5, 10, or 20 mg/kg/day for 28 days. The concentration of itraconazole in the composition was 50% of the total amount of the composition. Composition XIX-associated bronchiolar/peribronchiolar granulomatous inflammation, minimal to moderate, was present in males and females at ≥5 mg/kg/day. The incidence and severity of this event increased with dose in males at ≥5 mg/kg/day and females at 20 mg/kg/day. Granulomatous inflammation was in and around the terminal and respiratory bronchioles and was characterized by aggregates of macrophages and multinucleated giant cells with abundant eosinophilic cytoplasm. Minor granulomatous inflammation that occurred at ≥10 mg/kg/day was considered unfavorable. Granulomatous inflammation completely resolved during the recovery period.

A 14-day study of inhalation administration of Composition XII and Composition XV to dogs

Dogs were exposed to placebo or itraconazole formulated as Composition XII at target doses of 2, 6 or 20 mg/kg/day or Composition XV at target doses of 6 or 20 mg/kg/day, for 14 days. In addition, one group of dogs was administered itraconazole at a target dose of 6 mg/kg as Formulation XII every three days. The concentration of itraconazole in the composition was 50% of the total amount of the composition in all cases. Test substance-related respiratory tract events were present in dogs administered 20 mg/kg/day of Composition XII or Composition XV. Test substance-related mild intra-alveolar mixed-cell inflammation was present in all dogs administered 20 mg/kg/day of Composition XII. Test substance-related mild carinal and tracheal mucosal lymphocytic inflammation was present in 2 of 3 dogs administered 20 mg/kg/day of COMPOSITION XII-02C. In addition, minimal intra-alveolar mixed cell inflammation was present in 1 of 3 dogs administered 20 mg/kg/day of Composition XV. Therefore, the localization of the detected violations was somewhat different between Composition XII and Composition XV. This variability complicates the comparison of Composition XII with Composition XV, although the dose levels at which test substance-related impairment clearly occurred (20 mg/kg/day) were similar for both test substances. Mild mixed cell inflammation was present in 1 of 3 dogs administered 6 mg/kg of Composition XII every three days and in 1 of 3 dogs administered 6 mg/kg/day of Composition XV. Because of the low incidence of this disorder in each of these groups and the absence of disturbances in other areas of the respiratory tract at these doses, the relationship with inhalation of Composition XII or Composition XV was unclear.

Comparison of Composition XIX with Composition XII and Composition XV in a rat study

The changes in the respiratory tract of rats associated with Composition XIX were of a different nature than the changes caused by Composition XII and Composition XV. In addition, the changes associated with Formulation XIX affected more areas (tissues) in the respiratory tract and were likely to be adverse at the lower dose. Recovery was not assessed in rat studies using Composition XII or Composition XV. However, based on experience with other inhalation materials, it is possible that the granulomatous inflammation in the bronchial mucosa that was present after exposure to Composition XIX may have resolved more slowly than the increase in alveolar macrophage levels or subacute inflammation caused by Composition XII or Composition XV.

Granulomas or granulomatous inflammation, consisting of macrophages and multinucleated giant cells, are common responses to substances that do not readily dissolve in cytoplasmic lysosomes, including inhaled foreign bodies. The presence of these cells in the mucosa at several levels in the respiratory tract after inhalation of Composition XIX suggests that the test substance acted and either a) penetrated the epithelium and was phagocytosed by macrophages, or b) dissolved, penetrated the epithelium and recrystallized, in the interstitium, where it phagocytosed by macrophages, or b) dissolves, penetrates the epithelium and recrystallizes in the interstitium, where it is phagocytosed by macrophages. Failure to achieve complete recovery during the reconstitution period is not unexpected for a substance in a poorly soluble form.

Exposure to Composition XII at an administered dose of 40 mg/kg/day resulted in mild subacute inflammation that was considered test substance related and unfavorable. This subacute inflammation occurred in the alveolar parenchyma and was morphologically distinct from the granulomatous mucosal inflammation that occurred with exposure to Composition XIX. It was unclear whether the minimal subacute inflammation that occurred in rats administered 15 mg/kg/day of Composition XII or Composition XV was due to the test substance. When Composition XII was compared with Composition XV, there was no clear difference in the incidence or severity of macrophage accumulation or subacute inflammation between male rats administered these test substances at comparable dose levels. It was suggested that the severity and/or incidence of these disorders in female rats was greater when administered at 15 mg/kg/day of Composition XV compared to Composition XII. Recovery was not tested in trials using Composition XII or Composition XV. However, minimal to moderate subacute inflammation and minimal to moderate macrophage accumulation are considered reversible and are generally expected to recover within a 28-day recovery period.

It is difficult to compare alveolar macrophage accumulation in these rat studies because the Composition XII or Composition XV study did not include air or placebo controls. Different groups of rats under different test conditions may have different baseline rates of minimal alveolar macrophage accumulation. However, data from these studies suggest that minimal to moderate accumulation of alveolar macrophages may have occurred with greater frequency and/or at lower doses in rats administered Composition XII or Composition XV, possibly indicating greater alveolar dispersion of Composition XII or Composition XV in a form that was phagocytosed by macrophages.

Comparison of Composition XIX with Composition XII and Composition XV in Canine Studies

The disorders associated with Composition XIX in the respiratory tract of dogs were of a different nature from the nature of the disorders caused by Composition XII and Composition XV.

Composition XIX-associated acute inflammation, which was considered adverse, was present in a 7-day study in dogs at 10 mg/kg/day. There were no reported effects associated with Formulation XIX at 5 mg/kg/day in the 7-day study. Composition XIX-associated granulomatous inflammation was present in dogs at ≥5 mg/kg/day in the 28-day study, and was mild in severity and considered unfavorable at ≥10 mg/kg/day. In retrospect, the acute inflammation observed in the 7-day study could be described as acute granulomatous inflammation. In summary, the events were similar in the two canine studies using Formulation XIX, but with differences reflecting the duration of the studies. In both studies, events were considered adverse at 10 mg/kg/day. The location of inflammation was predominantly bronchiolar/peribronchiolar, as opposed to inflammation in the alveoli. This localization indicates a conductive orientation of the airway, and thus is somewhat similar to the localization of Composition XIX-related disturbances in rats, although it did not show a mucosal localization and was not as mild as the disturbances in rats. Granulomatous inflammation was similar, but not morphologically identical, in rats and dogs.

Composition XII or Composition XV caused test substance-related events at 20 mg/kg/day in a 14-day study in dogs. Test substance-related mild intra-alveolar mixed-cell inflammation was present in all dogs administered 20 mg/kg/day of Composition XII. Adverse effects were not considered in the 14-day study report, but mild mixed cell inflammation could be considered adverse. Abnormalities at 6 mg/kg/day were not clearly related to the test substance due to the low incidence. Dogs were not exposed to Composition XII or Composition XV at 10 mg/kg/day, so direct comparison with Composition XIX, which was unfavorable at 10 mg/kg/day, was not made. However, it might be more appropriate to compare lung tissue levels in a dose-dependent manner when comparing adverse effects following inhalation, which were significantly higher in animals treated with Composition XII and Composition XV. The granulomatous inflammation associated with Composition XIX completely resolved during the 28-day recovery period. The 14-day study in dogs using Formulation XII and Formulation XV did not include a recovery period. Composition XII- or Composition XV-associated mixed cell inflammation in the dog was morphologically somewhat similar to Composition XII- or Composition XV-associated subacute inflammation in the rat in that it involved the alveoli and was not granulomatous.

Example 4: Phase 1 open-label study to evaluate the safety, tolerability and pharmacokinetics of single and multiple doses of itraconazole administered as a dry powder for inhalation in healthy subjects.

Clinical pharmacokinetics of itraconazole oral solution based on historical data

Itraconazole is metabolized in the liver by the cytochrome P450 3A4 isoenzyme system to the main metabolite hydroxy-itraconazole. Hydroxy-itraconazole is active and has antifungal activity against many clinically important fungi. Itraconazole is highly bound to plasma protein, 99.8% and 99.6%, oral solution and capsules, respectively.

The pharmacokinetics of oral itraconazole have been investigated in both single- and multiple-dose studies in humans. Pharmacokinetics differ between the two formulations presented (solution and capsules), with higher exposure observed with the oral solution. Oral solution and capsules are not recommended to be used interchangeably.

The absolute bioavailability of the oral solution is 55% in healthy volunteers and increases by 30% when taken on an empty stomach. When administered on an empty stomach, _{the 0-24h} steady state AUC is 131±30% of the postprandial exposure, and the oral solution is recommended to be administered on an empty stomach. At steady state, when administered in the fasted state, the mean _Cmax , _tmax and AUC _0-24h of a 200-mg daily dose of itraconazole were 1.963±601 ng/ml, 2.5±0.8 h and 29.271±10.285 ng·h/ml , respectively. The half-life of itraconazole at steady state was 39.7 ± 13 hours.

Pharmacokinetic data from Part 1, SAD in healthy volunteers

Preliminary summary data for systemic pharmacokinetics following a single inhalation dose of Composition XII are presented in Table 8 and concentration-time profiles are shown in FIG. 3. Pharmacokinetic data are important because of their impact on the safety profile of Composition XII compared to oral dosing. The data confirm that inhalation administration of Composition XII results in low systemic exposure. Doses ranged from 5 mg to 35 mg itraconazole. Itraconazole was rapidly absorbed into the systemic circulation, with all subjects having detectable plasma exposure at the earliest time point of 15 minutes. Exposure was generally maintained for the first 18 to 24 hours, indicating prolonged absorption. After 24 hours post-dose, plasma concentrations generally declined in a continuous monoexponential manner at a rate of decline similar to all cohorts (geometric mean K _el range: 0.021-0.032 L/h). Exposure ( _Cmax and AUC) increased monotonically and values were usually less than dose proportional.

Table 8
Pharmacokinetic data after single inhalation doses of Composition XII in healthy volunteers Nominal dose of Itraconazole (mg) AUC _0-24h (h.ng/ml) AUC _0-last (h.ng/ml) AUC _0-inf. (h.ng/ml) C _max (ng/ml) _tmax * (h) 5 15.9 26.1 ^30.2a 0.87 6 10 38.8 93.5 110.4 ^b 2.28 6 25 64.64 179.4 211.3 3.9 3 35 86.76 224.5 182.7 ^s 4.58 18 Data presented are geometric means for each cohort (n=5 for the 5 mg dose; n=6 for the 10, 25 and 35 mg doses). * median values

Pharmacokinetic data from Part 2, MAD in healthy volunteers

Summarized data for systemic pharmacokinetics after a single inhalation dose and 14 days of daily inhalation of Composition XII are presented in Table 9, and concentration-time profiles are shown in FIG. 4. Doses were 10 mg, 20 mg or 35 mg itraconazole. As in Part 1, itraconazole was rapidly absorbed into the systemic circulation, with all subjects having detectable plasma exposure at the earliest sampling time point of 15 minutes. Exposure generally persisted for the first 18 to 24 hours, with a median _Tmax between 7 hours and 18 hours for the study cohorts.

Median plasma concentrations increased with each repeated dose, with concentrations close to steady state by Day 14. Compared with steady-state itraconazole plasma levels reported after administration of the oral solution, exposure after inhalation was 100-400-fold lower based on AUC _0-24h . Between Day 1 and Day 14, itraconazole accumulation was approximately 3-fold for both _Cmax and AUC _0-24h and similar for each dose. As in Part 1, at the end of dosing, plasma concentrations decreased in a continuous monoexponential manner, indicating the absence of any aggregate accumulation in the lungs that could lead to prolonged systemic exposure.

Table 9
Pharmacokinetic data after single and multiple inhalation doses of Composition XII in healthy volunteers Nominal dose of Itraconazole (mg) DAY 1 DAY 14 Accumulation AUC _0-24h (h.ng/ml) C _max (ng/ml) _tmax * (h) AUC _0-24h (h.ng/ml) C _max (ng/ml) t _max * (h) AUC _0-24h C _max 10 24.4 1.29 7 73.2 3.77 5 3.0 2.9 20 53.0 2.64 18 174.4 8.98 4 3.3 3.4 35 102.4 5.23 7 276.5 15.2 0.8 2.7 2.9 Data presented are geometric means for each cohort (n=6 for the 10 mg and 20 mg dose; n=6 for Day 1 and n=5 for Day 14 for the 35 mg dose). * median values

Pharmacokinetic data from Part 3, single doses in adult subjects with stable mild to moderate asthma

Summarized data for systemic pharmacokinetics following a single inhalation or oral dose in asthmatic patients are presented in Table 10, and concentration-time profiles are shown in FIG. 5A and FIG. 5B. Doses were 20 mg itraconazole administered by inhalation as Composition XII or 200 mg itraconazole administered as Sporanox oral solution. At both oral and inhalation doses, itraconazole was rapidly absorbed into the systemic circulation with a median _Tmax of 4.0 hours and 1.5 hours for Composition XII and Sporanox, respectively. Following administration of Composition XII, plasma exposure to itraconazole was generally increased and/or maintained during the first 24 hours, indicating prolonged absorption. In contrast, orally administered itraconazole was rapidly absorbed and eliminated such that exposure peaked immediately after administration and declined rapidly to levels that were 17% of _Cmax 12 hours after administration. Total systemic exposure over 24 hours (AUC _{0-24 hours} ) was approximately 85 times lower after administration of Composition XII compared with exposure after oral administration, and maximum exposure (Cmax) was approximately 250 times lower after administration of Composition XII compared with exposure after oral administration.

Table 10
Pharmacokinetic data following single doses of Composition XII or oral Sporanox in asthmatic patients Nominal dose (mg) AUC _0-24h (h.ng/ml) AUC _0-last (h.ng/ml) AUC _0-inf.
(h.ng/ml) C _max (ng/ml) _tmax * (h) Composition XII 20 41.8 90.5 105.2 2.33 4 Sporanox 200 3618 6118 6649 581 1.5 Data presented are geometric means for each cohort (n=14 for Composition XII and n=15 for Sporanox). * median values

Induced sputum was collected at 2 hours, 6 hours and 24 hours after administration and used to measure itraconazole concentrations using a validated liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS) method with an LLOQ (lower limit of quantitation) of 0 .1 ng/ml. Sputum itraconazole levels were higher with Formulation XII compared to oral Sporanox, with a geometric mean post-inhalation _Cmax of 5381 ng/mL compared with a post-oral _{Cmax of} 116.3 ng/mL (Figure 5A). High pulmonary exposure following administration of Formulation XII was maintained over a 24-hour period, whereas sputum itraconazole concentrations decreased between 2 hours and 6 hours after a single 200 mg oral dose of itraconazole. These data confirm that inhalation administration of Composition XII results in high and sustained pulmonary exposure, higher than exposure achieved by oral administration, while maintaining low systemic exposure. Based on geometric mean lung and plasma _Cmax , Formulation XII resulted in a lung:plasma ratio of approximately 2300:1, and oral administration resulted in a lung:plasma ratio of 1:5.

Claims (17)

1. A method of treating allergic bronchopulmonary aspergillosis (ABPA), comprising administering, by inhalation, into the respiratory tract of a patient in need thereof, a dry powder containing: (i) an antifungal agent, where the antifungal agent is itraconazole in crystalline form and is present in an amount of from 45 to 85% by weight and is in the form of a subparticle with a volumetric median geometric diameter (VMGD) from 60 to 1650 nm; (ii) a stabilizer in an amount of from 3 to 15% by weight; (iii) sodium salt in an amount from 3 to 50% by weight and (iv) leucine in an amount from 1 to 10% by weight, wherein said antifungal agent is administered in an amount sufficient to simultaneously achieve a) a pulmonary antifungal agent concentration of at least 500 ng/g or ng/ml to 8100 ng/g or ng/ml and b) a plasma antifungal agent concentration of 0 .2 ng/ml to 25 ng/ml, with pulmonary and plasma concentrations achieved within at least 24 hours after administration of the antifungal agent and where itraconazole is administered as a single dose or as an initial dose followed by one subsequent dose or subsequent doses doses, each of these doses independently comprising a nominal dose of itraconazole from 5 to 35 mg. 2. The method of claim 1, wherein the patient has a fungal infection, where the method includes administering into the respiratory tract of the patient in need thereof an effective amount of itraconazole, wherein said itraconazole is administered in an amount sufficient to simultaneously achieve a) a concentration of itraconazole in the lungs from 500 ng/g to 8100 ng/mg or ng/ml and b) itraconazole plasma concentrations from 0.2 ng/ml to 25 ng/ml, with lung and plasma concentrations achieved within at least 24 hours after administration itraconazole. 3. The method of claim 1, wherein itraconazole is administered in a single dose or an initial dose followed by one subsequent dose or subsequent doses wherein a lung:plasma ratio of at least 100:1 is achieved. 4. The method of claim 2, wherein itraconazole is administered in a single dose or an initial dose followed by one subsequent dose or subsequent doses wherein a lung:plasma ratio of at least 100:1 is achieved. 5. The method according to claim 1, where the patient has cystic fibrosis, asthma and/or a weakened immune system. 6. The method according to claim 2, where the patient has cystic fibrosis, asthma and/or a weakened immune system. 7. The method of claim 2, comprising administering into the respiratory tract of a patient in need thereof one dose or doses of itraconazole to achieve a fungicidal level of itraconazole in the lungs, followed by administration of one dose or doses to maintain a fungistatic level of itraconazole in the lungs. 8. The method of claim 7, wherein the dose of itraconazole to achieve a fungicidal level of itraconazole in the lungs is administered less frequently than one dose or doses to maintain a fungistatic level of itraconazole in the lungs. 9. The method according to claim 7, wherein the dose to achieve a fungicidal level of itraconazole in the lungs is less than the dose to maintain a fungistatic level of itraconazole in the lungs. 10. The method of claim 1, comprising administering to the respiratory tract of a patient in need thereof one loading dose or loading doses of itraconazole to achieve a minimum fungicidal concentration (MFC90) in the lungs for at least about 24 hours, followed by one maintenance dose. or maintenance doses to achieve the minimum inhibitory concentration (MIC90) in the lungs for at least approximately 24 hours. 11. The method according to claim 10, wherein said MFC90 is at least 2000 ng/g or ng/ml. 12. The method of claim 1, wherein the method comprises administering itraconazole into the respiratory tract of a patient in need thereof, wherein one dose or doses of itraconazole are administered to achieve a fungicidal concentration of itraconazole in the lungs, followed by administration of one dose or doses to achieve a fungistatic concentration of itraconazole in the lungs and where a single dose or doses does not result in plasma itraconazole concentrations that are greater than 25 ng/mL at any time during dosing.

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