Compositions Comprising Voriconazole Inhalation Powder and Methods of Making and Using Same

Abstract

The present invention generally encompasses compositions and methods comprising inhalable voriconazole or a pharma- ceutically acceptable salt thereof produced in an amorphous form using thin film freezing. In various embodiments, the present invention includes dry powder voriconazole formulations that can be inhaled, for example, using a dry powder inhaler, and are well tolerated as a daily regimen for treating or preventing fungal infections. The compositions and methods of the present invention avoid or reduce systemic circulation of voriconazole, thus overcoming adverse events associated with circulating voriconazole.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of and priority to U.S. Provisional Patent Application No. 63 / 291,055, filed December 17, 2021, which is incorporated herein by reference in its entirety.

[0002] The present invention generally encompasses compositions and methods comprising inhalable voriconazole or a pharma- ceutically acceptable salt thereof produced in nanocrystalline form using thin film freezing. In various embodiments, the present invention includes dry powder voriconazole formulations that can be inhaled, for example, using a dry powder inhaler, and are well tolerated as a daily regimen for treating or preventing fungal infections. The compositions and methods of the present invention avoid or reduce systemic circulation of voriconazole, thus overcoming adverse events associated with systemic circulating voriconazole. [Background technology]

[0003] Aspergillus is a fungus commonly found in soil, food, plant debris, and indoor environments. Spores are easily aerosolized and inhaled. In the airway mucosa, spores grow into hyphae that can invade the mucosa and cause invasive pulmonary aspergillosis (IPA). Both innate immune responses and inflammatory cells typically limit fungal growth and prevent disease in most individuals. However, for immune-compromised or otherwise susceptible individuals, inhalation of spores can trigger a disease cascade that can lead to invasive pulmonary aspergillosis (IPA) and invasive aspergillosis (IA), which can be severe and often fatal infections. The main risk factor for IPA is immunodeficiency resulting from multiple factors, such as neutropenia, hematopoietic stem cell transplantation (HSCT), solid organ transplantation, long-term therapy with high-dose corticosteroids, hematological malignancies, cytotoxic therapy, advanced acquired immune deficiency syndrome (AIDS), chronic granulomatous disease, and patients with liver failure. Furthermore, there is an increasing number of documented reports of IPA in immune-compromised patients without classical risk factors, including patients with severe chronic obstructive pulmonary disorder (COPD) and critically ill patients. In addition, patients with COPD may have increased susceptibility to IPA, which may lead to increased morbidity. The increased risk is due to many factors. More recently, IPA has been associated with severe influenza and SARS-CoV-2 infections.

[0004] Invasive pulmonary aspergillosis has also become an infectious disease of concern in intensive care unit (ICU) patients without classical risk factors (neutropenia, leukemia, HSCT). A retrospective study of one medical ICU found an incidence of IA of 5.8%, with most cases having pulmonary involvement. Seventy percent (70%) of cases were found in patients without leukemia or cancer, and the mortality rate was greater than 90%.

[0005] Voriconazole is a potent broad-spectrum triazole antifungal agent whose primary mechanism of action is the inhibition of fungal cytochrome P450-dependent 14-α-sterol demethylase CYP51 by binding to its heme group, an enzyme essential for ergosterol biosynthesis. Current treatment guidelines for aspergillosis recommend oral and / or IV voriconazole (VFEND®) as first-line therapy for IA. Voriconazole is increasingly used in patients after bone marrow or solid organ transplants as prophylaxis against IPA, although only posaconazole is licensed for this indication. In the hospital setting, patients are typically treated initially with IV voriconazole if they are unable to take medication orally. This treatment is switched to oral voriconazole (e.g., 200 mg taken twice daily) as soon as the patient is stable and tolerates oral medication.

[0006] However, with oral voriconazole, there is considerable variability in systemic exposure due to voriconazole drug metabolism by CYP2C9, CYP2C19, and CYP3A4, as well as reduced absorption due to food (e.g., VFEND label). In addition to variability in metabolic clearance, there are clinical drug-drug interactions (DDIs) due to voriconazole's ability to inhibit CYP2B6, CYP2C9, CYP2C19, and CYP3A (e.g., VFEND label). Thus, the challenge for clinicians is to prescribe a delivery dose that is neither too small nor too large to achieve the desired antifungal activity while minimizing potentially serious systemic side effects, especially in patients on immunosuppressive therapy that is metabolized by CYP3A, such as tacrolimus, leading to highly variable and unpredictable increases in tacrolimus systemic exposure.

[0007] In addition to the challenges of voriconazole metabolism and DDI for patients receiving oral or IV therapy, the amount of voriconazole that reaches the lungs, the organ where Aspergillus infections are localized before spreading to distant organs, is a small fraction of the total voriconazole administered to patients. Notably, the voriconazole concentration that must be achieved in the lungs for efficacy has not been determined. However, it has been reported that airway epithelial lining fluid (ELF) concentrations 12 hours after the last dose of a 3-day twice-daily (BID) dosing regimen with 200 mg oral voriconazole averaged 8,827 ng / mL (range 4,369-35,172 ng / mL), while the corresponding plasma levels were 1,224 ng / mL (range 535-2,341 ng / mL). Estimates of ELF volume range from 10-50 mL in the average human lung.

[0008] Considering the potential for increasing the local concentration of voriconazole while reducing drug-drug interactions and toxicity, the inventors developed voriconazole as a dry powder inhalation product to improve delivery of voriconazole for potential treatment and / or prevention in patients, e.g., patients with IPA or at high risk for IPA. The inventors have surprisingly discovered that voriconazole as a dry powder inhalation product improves the reliability and consistency of voriconazole dosing and enhances drug delivery to the target organ (i.e., lung) in IPA while reducing systemic exposure that can lead to dose-limiting side effects. The inventors have further discovered that inhalation of voriconazole directly avoids the variability associated with gastrointestinal absorption and metabolism in patients for diverse concomitant medications, translating into a more reliable and versatile dosing paradigm for treatment or prevention. Summary of the Invention

[0009] In various embodiments, the invention encompasses compositions or methods for treating or preventing a fungal infection in a subject in need thereof, the methods comprising administering by inhalation to the subject voriconazole, or a pharma- ceutically acceptable salt thereof, in an amount of about 10 mg to about 80 mg, wherein administration by inhalation achieves a maximum circulating plasma concentration of voriconazole of less than 1,000 ng / mL.

[0010] In certain embodiments, the amount of voriconazole or a pharma- ceutically acceptable salt thereof is about 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, 60, 62, 64, 66, 68, 70, 72, 74, 76, 78 or about 80 mg.

[0011] In various embodiments, the amount of voriconazole or a salt thereof administered to a subject is about 5 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, or about 200 mg. In certain embodiments, the amount of voriconazole is administered in multiple single doses, e.g., eight doses of 10 mg capsules, using a dry powder inhaler.

[0012] In certain embodiments, the administration of voriconazole or a salt thereof comprises an amount of about 10 mg to about 120 mg, preferably about 40 mg to about 80 mg, and most preferably about 40 mg or about 80 mg. The administration of voriconazole or a salt thereof is about once a day, twice a day, three times a day, four times a day, five times a day, six times a day, seven times a day, eight times a day, nine times a day, or ten times a day.

[0013] In various embodiments, the maximum circulating plasma concentration of voriconazole is less than about 1000 ng / mL, 900 ng / mL, 800 ng / mL, 700 ng / mL, 600 ng / mL, 500 ng / mL, 400 ng / mL, 300 ng / mL, 200 ng / mL, or less than 100 ng / mL.

[0014] In certain embodiments, the maximum circulating plasma concentration of voriconazole is less than 500 ng / mL.In certain embodiments, the maximum circulating plasma concentration of voriconazole is less than 300 ng / mL.

[0015] In certain embodiments, the fungal infection is caused by Aspergillus fumigatus, Aspergillus flavus, Aspergillus niger, Aspergillus terreus, Candida albicans, Candida glabrata, Candida krusei, Candida parapsilosis, Candida tropicalis, Fusarium spp., Fusarium solani, Scedosporium apiospermum, Candida lusitaniae or Candida guilliermondii.

[0016] In certain embodiments, the fungal infection is invasive aspergillosis, candidemia or esophageal candidiasis.

[0017] In certain embodiments, the subject suffers from a reactive airways disorder, hi certain embodiments, the reactive airways disorder is asthma, chronic obstructive pulmonary disease (COPD) or a bronchial infection.

[0018] In certain embodiments, the subject is immunocompromised, hi certain embodiments, the immunocompromise is caused by factors including patients with neutropenia, hematopoietic stem cell transplantation (HSCT), solid organ transplantation, long-term therapy with high-dose corticosteroids, hematological malignancies, cytotoxic therapy, advanced acquired immune deficiency syndrome (AIDS), chronic granulomatous disease, and liver failure.

[0019] In certain embodiments, administration is at least once daily. In other embodiments, administration is at least twice daily.

[0020] In a particular embodiment, the voriconazole or salt thereof is voriconazole inhalation powder.

[0021] In certain embodiments, the present invention encompasses compositions and methods for increasing pulmonary delivery of voriconazole in a subject in need thereof, comprising administering voriconazole or a salt thereof to the subject by inhalation while minimizing systemic absorption and reducing drug-drug interactions. In certain embodiments, the reduced drug-drug interaction is an interaction with a CYP3A inhibitor. In certain embodiments, the method comprising administering voriconazole or a salt thereof to the subject by inhalation reduces or avoids drug interactions in a subject who is co-administered a drug that is metabolized by the cytochrome CYP3a enzyme. Thus, in certain embodiments, administering a therapeutic amount of voriconazole or a salt thereof to a subject by inhalation minimizes or overcomes drug-drug interactions associated with administering voriconazole orally or systemically (e.g., by IV injection).

[0022] In another embodiment, the invention encompasses compositions and methods for increasing pulmonary delivery of voriconazole in a subject in need thereof, the methods comprising administering to the subject by inhalation voriconazole or a salt thereof in an amount of about 10 mg to about 200 mg, preferably about 20 mg to about 80 mg, wherein delivery of voriconazole to the lung by inhalation results in about a 50-fold greater relative concentration in the lung compared to oral administration of voriconazole about 12 hours following administration.

[0023] In various embodiments, the amount of voriconazole or a salt thereof administered to a subject is about 1 mg, 2 mg, 4 mg, 6 mg, 8 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg or about 200 mg.

[0024] In various embodiments, the amount of voriconazole or a salt thereof is administered to the subject in a dosage form, e.g., a capsule, comprising about 1 mg, 2 mg, 4 mg, 6 mg, 8 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, or about 200 mg of voriconazole or a salt thereof. In certain embodiments, the dosage form is administered multiple times, e.g., about once a day, twice a day, three times a day, four times a day, five times a day, six times a day, seven times a day, eight times a day, nine times a day, or ten times a day.

[0025] In certain embodiments, the administration of voriconazole or a salt thereof comprises an amount of about 10 mg to about 120 mg, preferably about 40 mg to about 80 mg, and most preferably about 40 mg or about 80 mg. The administration of voriconazole or a salt thereof is about once a day, twice a day, three times a day, four times a day, or five times a day.

[0026] In various embodiments, delivery of voriconazole to the lung by inhalation results in a relative concentration in the lung that is about 10-fold to about 200-fold higher, preferably about 10-fold, 20-fold, 30-fold, 40-fold, 50-fold, 60-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, and most preferably about 50-fold higher, compared to oral administration of voriconazole about 12 hours following administration. In various embodiments, the higher relative concentration in the lung compared to oral administration of voriconazole is about 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, or about 12 hours following administration.

[0027] In certain embodiments, delivery of voriconazole to the lungs results in about a 100-fold higher relative concentration in the lungs compared to oral administration of voriconazole.

[0028] In certain embodiments, delivery of voriconazole to the lungs results in an approximately 200-fold higher relative concentration in the lungs compared to oral administration of voriconazole.

[0029] In certain embodiments, the subject is suffering from a fungal infection caused by Aspergillus fumigatus, Aspergillus flavus, Aspergillus niger, Aspergillus terreus, Candida albicans, Candida glabrata, Candida krusei, Candida parapsilosis, Candida tropicalis, Fusarium spp., Fusarium solani, Scedosporium apiospermum, Candida lusitaniae or Candida guilliermondii.

[0030] In certain embodiments, the subject is suffering from a fungal infection caused by invasive aspergillosis, candidemia or esophageal candidiasis.

[0031] In certain embodiments, the subject is immunocompromised.

[0032] In certain embodiments, the immune deficiency is caused by factors including patients with neutropenia, hematopoietic stem cell transplantation (HSCT), solid organ transplantation, long-term therapy with high-dose corticosteroids, hematological malignancies, cytotoxic therapy, advanced acquired immune deficiency syndrome (AIDS), chronic granulomatous disease, and liver failure.

[0033] In certain embodiments, administration is at least once daily. In other embodiments, administration is at least twice daily.

[0034] In a particular embodiment, the voriconazole or salt thereof is voriconazole inhalation powder.

[0035] In certain embodiments, the administration of voriconazole or a salt thereof comprises an amount of about 10 mg to about 120 mg. In certain embodiments, the administration of voriconazole or a salt thereof comprises an amount of about 40 mg to about 80 mg. In certain embodiments, the administration of voriconazole or a salt thereof comprises an amount of about 80 mg.

[0036] In a particular embodiment, the voriconazole or salt thereof is voriconazole inhalation powder.

[0037] In another embodiment, the invention encompasses methods and compositions for reducing systemic circulation of voriconazole compared to oral administration of voriconazole, comprising administering voriconazole or a salt thereof by inhalation to a subject in an amount of about 20 mg to about 80 mg, wherein administration by inhalation achieves a maximum circulating plasma concentration of voriconazole of less than 1,000 ng / mL.

[0038] In certain embodiments, the maximum circulating plasma concentration of voriconazole is less than 500 ng / mL.In certain embodiments, the maximum circulating plasma concentration of voriconazole is less than 300 ng / mL.

[0039] In various embodiments, the amount of voriconazole or a salt thereof administered to a subject is about 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, or about 200 mg. In certain embodiments, the amount of voriconazole or a pharma- ceutically acceptable salt thereof is about 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, 60, 62, 64, 66, 68, 70, 72, 74, 76, 78, or about 80 mg.

[0040] In certain embodiments, the administration of voriconazole or a salt thereof comprises an amount of about 10 mg to about 120 mg, preferably about 40 mg to about 80 mg, and most preferably about 40 mg or about 80 mg. The administration of voriconazole or a salt thereof is about once a day, twice a day, three times a day, four times a day, or five times a day.

[0041] In a particular embodiment, the voriconazole or salt thereof is voriconazole inhalation powder.

[0042] In various embodiments, the maximum circulating plasma concentration of voriconazole is less than about 1000 ng / mL, 900 ng / mL, 800 ng / mL, 700 ng / mL, 600 ng / mL, 500 ng / mL, 400 ng / mL, 300 ng / mL, 200 ng / mL, or less than 100 ng / mL.

[0043] In certain embodiments, the maximum circulating plasma concentration of voriconazole is less than 500 ng / mL.In certain embodiments, the maximum circulating plasma concentration of voriconazole is less than 300 ng / mL.

[0044] In certain embodiments, the fungal infection is caused by Aspergillus fumigatus, Aspergillus flavus, Aspergillus niger, Aspergillus terreus, Candida albicans, Candida glabrata, Candida krusei, Candida parapsilosis, Candida tropicalis, Fusarium spp., Fusarium solani, Scedosporium apiospermum, Candida lusitaniae or Candida guilliermondii.

[0045] In certain embodiments, the fungal infection is invasive aspergillosis, candidemia or esophageal candidiasis.

[0046] In certain embodiments, the subject is immunocompromised.

[0047] In certain embodiments, the immune deficiency is caused by factors including patients with neutropenia, hematopoietic stem cell transplantation (HSCT), solid organ transplantation, long-term therapy with high-dose corticosteroids, hematological malignancies, cytotoxic therapy, advanced acquired immune deficiency syndrome (AIDS), chronic granulomatous disease, and liver failure.

[0048] In certain embodiments, administration is at least once daily. In certain embodiments, administration is at least twice daily.

[0049] In a particular embodiment, the voriconazole or salt thereof is voriconazole inhalation powder.

[0050] In certain embodiments, the administration of voriconazole or a salt thereof comprises an amount of about 10 mg to about 120 mg. In certain embodiments, the administration of voriconazole or a salt thereof comprises an amount of about 40 mg to about 80 mg. In certain embodiments, the administration of voriconazole or a salt thereof comprises an amount of about 80 mg.

[0051] In a particular embodiment, the voriconazole or salt thereof is voriconazole inhalation powder. [Brief description of the drawings]

[0052] [Figure 1] A theoretical diagram of drug deposition of voriconazole following oral administration (left, 200 mg) and inhaled administration (right, 40-80 mg) is shown. This illustration shows that inhaled administration of voriconazole deposits a higher percentage of drug in the lungs, with lower gastrointestinal and systemic exposure, compared to the oral route of administration. [Figure 2A] Voriconazole plasma concentration time plots for all SAD and MAD subjects; semi-logarithm after a single inhaled dose (SAD and MAD cohorts combined). Voriconazole (mean + SD) concentration time plots after a single inhalation. [Figure 2B] Voriconazole plasma concentration time plot for extensive metabolizers only; semi-logarithmic scale shown. [Diagram 3] 1 shows voriconazole plasma concentration time plots for CYP2C19 good and poor metabolizers. Voriconazole (individual or mean [+SD]) plasma concentration time plots following a single inhalation of the VIP dose on day 1, including good metabolizers (EM) and poor metabolizers (PM); SAD and MAD cohorts combined. [Figure 4] Figure 1 shows voriconazole plasma concentration time plots for 40 mg and 80 mg on days 1 and 7. Voriconazole (mean + SD) plasma concentration time plots for 40 mg and 80 mg dose 1 (day 1) and dose 13 (day 7) overlay graphs (normal metabolizers only; semi-log). [Diagram 5] Log-log plots of dose vs. PK parameters in all subjects (Figures 5A and 5B: Panel A) and in normal metabolizers only (Figures 5A and 5B: Panel B) are shown. Figure 5A shows Cmax and Figure 5B shows AUCtau. Log-log plots of dose vs. PK parameters of voriconazole on Day 1 and Dose 13 (Day 7) for Cmax (Figure 5A) and AUCtau (Figure 5B). Panel A includes all subjects and Panel B includes normal metabolizers only. [Figure 6] FIG. 1 shows characterization of a voriconazole / mannitol (95:5 w / w) mixture by XRPD which showed a crystalline solid. [Figure 7] 1 shows SEM-EDX of a 50:50 mixture confirming the suitability of the thin film freezing (TFF) process with voriconazole phase separated from mannitol. [Figure 8] FIG. 1 shows an exemplary schematic diagram of a manufacturing protocol. [Figure 9] Mean (+SD) voriconazole plasma concentrations versus time by dose level, SAD-All Subjects (log-linear axis) are shown. [Figure 10] Mean (+SD) voriconazole plasma concentrations versus time by dose level, SAD-CYP2C19 normal metabolizers only (log-linear axis) are shown. [Figure 11] MAD, mean (±SD) voriconazole concentrations after the first and last dose from all subjects across all dose levels are shown. [Figure 12] MAD, all dose levels: Mean (±SD) voriconazole concentrations after the first and last doses from normal metabolizers only are shown. [Figure 13] 1 shows the mean voriconazole systemic exposure following single doses of 40 mg and 80 mg voriconazole inhalation powder in TFF-V1-001 and TFF-V1-002. [Figure 14] 1 shows the mean voriconazole systemic exposure following 40 mg and 80 mg repeat dose voriconazole inhalation powder in TFF-V1-001 and TFF-V1-002. [Figure 15] 1 shows that tacrolimus levels / dosages remain unchanged following administration of inhaled voriconazole supporting the notion of a reduced drug-drug interaction using inhalable voriconazole. [Figure 16] FIG. 1 shows stabilization of lung function following administration of inhalable voriconazole. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0053] definition Unless otherwise defined herein, scientific and technical terms used in this application shall have the meanings commonly understood by those of ordinary skill in the art. Generally, the nomenclature used in connection with, and techniques of, chemistry, molecular biology, cell and cancer biology, immunology, microbiology, pharmacology, and protein and nucleic acid chemistry described herein are well known and commonly used in the art.

[0054] As used herein, the following terms have the meanings ascribed to them unless specified otherwise.

[0055] "About" when referring to a value includes the stated value + / - 10% of the stated value. For example, about 50% includes a range of 45% to 55%, while about 20 molar equivalents includes a range of 18 to 22 molar equivalents. Thus, when referring to a range, "about" refers to each of the stated values ​​+ / - 10% of the stated value at each endpoint of the range. For example, a ratio of about 1 to about 3 (weight / weight) includes a range of 0.9 to 3.3.

[0056] It will be understood that throughout this specification the word "comprise" or variations such as "comprises" or "comprising" imply the inclusion of a stated integer (or component) or group of integers (or components) but not the exclusion of any other integer (or component) or group of integers (or components).

[0057] The singular forms "a," "an," and "the" include plurals unless the context clearly dictates otherwise.

[0058] The term "including" is used to mean "including but not limited to." "Including" and "including but not limited to" are used interchangeably.

[0059] The terms "patient," "subject," and "individual" can be used interchangeably and refer to either a human or a non-human animal. These terms include mammals such as humans, primates, livestock animals (e.g., cows, pigs), pets (e.g., dogs, cats), and rodents (e.g., mice and rats). The term "mammal" refers to any mammalian species, such as humans, mice, rats, dogs, cats, hamsters, guinea pigs, rabbits, farm animals, etc.

[0060] Also provided are pharma- ceutically acceptable salts and tautomeric forms of the compounds described herein. "Pharmaceutically acceptable" or "physiologically acceptable" refers to compounds, salts, compositions, dosage forms, and other materials that are useful in the preparation of pharmaceutical compositions suitable for veterinary or human pharmaceutical use.

[0061] The term "pharmaceutically acceptable salts" refers to salts that retain the biological effectiveness and properties of voriconazole and are not biologically or otherwise undesirable. "Pharmaceutically acceptable salts" or "physiologically acceptable salts" include, for example, salts with inorganic acids and salts with organic acids. Those skilled in the art will recognize various synthesis methods that can be used to prepare non-toxic pharmaceutically acceptable addition salts. Pharmaceutically acceptable acid addition salts can be prepared from non-toxic inorganic and organic acids. Pharmaceutically acceptable salts can be synthesized from the parent compound that contains a basic or acidic moiety by conventional chemical methods. A list of suitable salts can be found in Remington's Pharmaceutical Sciences, 17, pp. 171-175, 1997. thEd., (Mack Publishing Company, Easton, 1985), p. 1418, Berge et al., J. Pharm. Sci., 1977, 66(1), 1-19 and Stahl et al., Handbook of Pharmaceutical Salts: Properties, Selection, and Use, (Wiley, 2002). Non-limiting examples of pharma- ceutically acceptable salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogen-phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioxide, and the like. Examples of suitable pharma- ceutically acceptable salts include benzoate, hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, methylsulfonate, propylsulfonate, besylate, xylenesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, gamma-hydroxybutyrate, glycolate, tartrate, and mandelate. A list of other suitable pharma- ceutically acceptable salts can be found in Remington: The Science and Practice of Pharmacy, vol. 21. st Edition, Lippincott Williams and Wilkins, Philadelphia, Pa., 2006.

[0062] Voriconazole or a pharma- ceutically acceptable salt thereof may contain one or more asymmetric centers and thus may give rise to enantiomers, diastereomers and other stereoisomeric forms, which may be defined in terms of absolute stereochemistry as (R)- or (S)-, or with respect to amino acids as (D)- or (L)-. The present disclosure is intended to include all such possible isomers, as well as their racemic and optically pure forms. Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents or resolved using conventional techniques, e.g., chromatography and fractional crystallization. Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from suitable optically pure precursors or resolution of the racemates (or racemates of salts or derivatives) using, e.g., chiral high pressure liquid chromatography (HPLC). It is understood that this embodiment encompasses, but is not limited to, specific diastereomerically or enantiomerically enriched forms. Where no chirality is specified, it is understood that this embodiment is directed to either a specific diastereomerically or enantiomerically enriched form, or a racemic or scalemic mixture of such compound(s). As used herein, a "scalemic mixture" is a mixture of stereoisomers in a ratio other than 1:1.

[0063] "Racemate" refers to a mixture of enantiomers. The mixture may contain equal or unequal amounts of each enantiomer.

[0064] "Stereoisomer" and "stereoisomers" refer to the difference in chirality of one or more stereocenters. Stereoisomers include enantiomers and diastereomers. Voriconazole may exist in stereoisomeric forms if they possess one or more asymmetric centers, or double bonds with asymmetric substitution, and therefore can be produced as individual stereoisomers or mixtures. Unless otherwise indicated, the present specification is intended to include individual stereoisomers and mixtures. Methods for the determination of stereochemistry and separation of stereoisomers are well known in the art (see, for example, Chapter 4 of Advanced Organic Chemistry, 4th ed., J. March, John Wiley and Sons, New York, 1992).

[0065] The present invention generally encompasses compositions and methods comprising voriconazole or a pharma- ceutically acceptable salt thereof produced in nanocrystalline form using thin film freezing. In various embodiments, the present invention includes a dry powder formulation, referred to herein as "voriconazole dry powder," that can be inhaled, for example, using a dry powder inhaler, and is well tolerated as a daily regimen, preferably twice daily.

[0066] In various embodiments, the inventors have demonstrated that the claimed compositions and methods, including voriconazole inhalation powder at doses up to 80 mg twice daily, provide lower plasma exposure (e.g., C max , AUC) which they have found to provide therapeutic benefit to patients.

[0067] In various embodiments, compositions and methods comprising voriconazole inhalation powder can act as a therapeutic agent in the treatment of invasive fungal infections, for example, in critically ill patient populations, to overcome the extensive drug-drug interactions (DDIs) with oral or intravenous administration of voriconazole.

[0068] The potential for DDIs with voriconazole stems from its being an inhibitor of four of the CYP 450 enzymes (e.g., CYP2B6, CYP2C9, CYP2C19, and CYP3A) that are responsible for the metabolism of approximately 67% of currently marketed drugs. Table 1 shows the Ki and two oral C max The literature values ​​for C and the C values ​​observed in this study for voriconazole inhalation powder at the 80 mg dose are max Indicates the value. [Table 1]

[0069] CYP Ki was CYP2B6 (Ki<0.5 μM), CYP2C9 (Ki=2.79 μM), CYP2C19 (Ki=5.1 μM) and CYP3A (Ki=0.66 μM), and the PK data is shown in Table 2. [Table 2]

[0070] Tables 3 and 4 show the pharmacokinetic parameters after single and multiple dose administration, respectively. [Table 3] [Table 4]

[0071] The present invention further encompasses compositions and methods comprising voriconazole inhalation powder that reduce or avoid drug-drug interactions (DDIs). In certain embodiments, inhalation delivery of voriconazole inhalation powder does not affect the absorption and metabolism of drugs that are metabolized by CYP 450 enzymes in the GI epithelium, such as tacrolimus, an important immunosuppressant used after solid organ transplantation and metabolized by CYP3A5.

[0072] In other embodiments, compositions and methods comprising voriconazole inhalation powder containing a dose of up to about 80 mg avoid or reduce the potential for systemic / hepatic DDIs based on metabolism by CYP 450 enzymes, including, for example, CYP2C19 and CYP2C9.

[0073] In other embodiments, compositions and methods comprising voriconazole inhalation powder provide a lower systemic concentration of circulating voriconazole compared to oral administration. In certain embodiments, compositions and methods comprising voriconazole inhalation powder provide a systemic exposure after an inhalation dose of 80 mg that is lower than the therapeutic trough concentration of 1.7 μg / mL in plasma, which is required after oral administration to ensure successful treatment against invasive fungal infections. However, at this trough concentration, there are significant clinical DDIs, such as with tacrolimus, which are important in ensuring that organ rejection does not occur. Thus, the inventors have surprisingly found that the lower exposure following systemic administration of voriconazole inhalation powder after inhalation at high concentrations into the lungs provides a superior alternative to oral administration, for example in the case of patients with lung transplants.

[0074] In other embodiments, compositions and methods comprising voriconazole inhalation powder include a dose of about 10 mg to about 80 mg, for example, about 10, 20, 30, 40, 50, 60, 70 or about 80 mg of voriconazole or a pharma- ceutically acceptable salt thereof.

[0075] In other embodiments, compositions and methods comprising voriconazole inhalation powder exhibit a dose-proportional increase in exposure following single and repeated administration, with drug clearance being relatively consistent at steady state; C values ​​ranging from about 141 L / h to about 121 L / h for 10 mg and 80 mg, respectively. Lss / F In various embodiments, the C for an 80 mg inhaled dose is max was approximately 227 ng / mL, compared with 2310 ng / mL for the 200 mg oral dose.

[0076] In certain embodiments, compositions and methods comprising voriconazole inhalation powder provide less voriconazole to reach the systemic circulation for a given mg dose by the inhalation route than by the oral route. However, this does not mean that inhaled voriconazole is not effective against invasive aspergillosis. In various embodiments, compositions and methods comprising voriconazole inhalation powder provide a concentration on the airway surface available directly to the lung tissue of about 1600 μg / mL (80,000 μg / 50 mL), considering 50% deposition of inhaled voriconazole and a lung surface area of ​​50 mL, which is sufficient to treat all wild-type and resistant mutants of Aspergillus. Thus, compositions and methods comprising voriconazole inhalation powder provide lower exposure to systemic voriconazole by the inhalation route, thus enabling prevention and treatment and improving outcomes in lung transplant recipients.

[0077] In other embodiments, compositions and methods comprising voriconazole inhalation powder provide a temporary reservoir of voriconazole in the lungs, including a longer t1 / 2 at the 40 mg and 80 mg doses, leading to a longer half-life due to continued absorption from this drug reserve within the dosing interval.

[0078] In other embodiments, compositions and methods comprising voriconazole inhalation powder can be used as a primary prevention or treatment option, for example, in immune-compromised individuals undergoing hematopoietic stem cell transplants and individuals with lung transplants to avoid DDIs associated with other therapeutic agents being administered.

[0079] In other embodiments, compositions and methods comprising voriconazole inhalation powder provide prophylaxis to immunocompromised individuals, improving the risk-benefit ratio by using a less systemically available drug, such as compositions and methods comprising voriconazole inhalation powder.

[0080] In various embodiments, voriconazole inhalation powder can be used as an alternative to oral voriconazole treatment. In other embodiments, compositions and methods comprising voriconazole inhalation powder avoid or reduce limitations associated with oral or intravenous administration of voriconazole, including systemic side effects, multi-organ toxicity, multiple potential DDIs, and, for all antifungal agents, concerns about the emergence of antifungal resistance after long-term treatment.

[0081] In other embodiments, compositions and methods comprising voriconazole inhalation powder include delivery of voriconazole directly to the infected organ (e.g., lung), conveying the advantage of more effectively treating infection in the lungs and reducing progression to systemic invasive aspergillosis.

[0082] Formulation of Voriconazole Inhalation Powder Compositions comprising voriconazole inhalation powder include finished drug products that include a drug-device combination intended to deliver voriconazole drug products formulated as dry powder to the lungs via the oral inhalation route of administration. In certain embodiments, the formulated voriconazole inhalation powder is provided in a capsule, e.g., a hard two-piece HPMC capsule (e.g., size 3) for administration using a commercially available dry powder inhaler (DPI) device. In certain embodiments, voriconazole inhalation powder is available as a 10 mg voriconazole capsule that can be inserted directly into a DPI. In certain embodiments, a capsule-based DPI device (e.g., RS00 Model 8 Monodose) manufactured by Plastiape SpA (Osnago, Italy) is used to administer the voriconazole inhalation powder. In various embodiments, to achieve a therapeutic level of voriconazole, one or more 10 mg doses can be administered, e.g., one 10 mg dose, two 10 mg doses, three 10 mg doses, four 10 mg doses, five 10 mg doses, six 10 mg doses, seven 10 mg doses, eight 10 mg doses or more, to achieve an appropriate amount of voriconazole.

[0083] In one embodiment, the voriconazole inhalation powder is composed of 95:5% w / w voriconazole / mannitol in a capsule, for example a hard two-piece HPMC capsule (eg size 3).

[0084] Table 5 below provides illustrative embodiments of voriconazole inhalation powder formulations of the present invention. [Table 5]

[0085] In another embodiment, the voriconazole inhalation powder formulation consists of TFF processed voriconazole and leucine dry blended with magnesium stearate (93.1:4.9:2% w / w voriconazole / leucine / magnesium stearate) in a capsule (e.g., size 3).

[0086] Table 6 below provides another illustrative embodiment of a voriconazole inhalation powder formulation of the present invention. [Table 6]

[0087] Formulation screening was initially performed for voriconazole using a variety of excipients (bulking agents, disaggregating agents, and hydrophobic agents). The mixtures were aerosolized using a Plastiape RS01 (high resistance, low resistance, and low resistance with a longer mouthpiece) and evaluated using a Malvern Spraytec Laser Diffraction (LD) analyzer. Aerodynamic particle size parameters were estimated. Table 7 summarizes the excipients evaluated in conjunction with voriconazole. [Table 7]

[0088] Characterization of the voriconazole / mannitol (95:5 w / w) mixture by XRPD showed a crystalline solid as shown in Figure 6. SEM-EDX of the 50:50 mixture confirmed the suitability of the thin film freezing (TFF) process with voriconazole phase separated from mannitol (see Figure 7).

[0089] Excipients and adjuvants that may be used in the present invention are generally defined for the purposes of this application as compounds that enhance the efficiency and / or efficacy of an active agent. It is possible to have more than one excipient, adjuvant, or even active agent in a given formulation. Non-limiting examples of additional agents that may be included in the solution to be made according to the present invention include surfactants, bulking agents, stabilizers, polymers, protease inhibitors, antioxidants, and absorption enhancers. Excipients can be selected and added to either the drug / organic mixture or the aqueous solution either before or after the drug particles are formed to allow the drug particles to be homogenously mixed for proper administration. Suitable excipients include polymers, absorption enhancers, solubility enhancers, dissolution rate enhancers, stability enhancers, bioadhesives, controlled release agents, flow aids, and processing aids. More specifically, suitable excipients include cellulose ethers, acrylic acid polymers, and bile salts. Other suitable excipients are described in detail in the Handbook of Pharmaceutical Excipients, published jointly by the American Pharmaceutical Association and The Pharmaceutical Society of Great Britain, the Pharmaceutical Press, 1986, the relevant portions of which are incorporated herein by reference. Such excipients are commercially available and / or can be prepared by techniques known in the art.

[0090] Excipients can also be selected, alone or in combination, to modify the intended function of the active ingredient by improving flux or bioavailability, or to control or delay the release of the active ingredient. Specific non-limiting examples include Span 80, Tween 80, Brij 35, Brij 98, Pluronic, sucroester 7, sucroester 11, sucroester 15, sodium lauryl sulfate, oleic acid, laureth-9, laureth-8, lauric acid, vitamin E TPGS, Gelucire 50 / 13, Gelucire 53 / 10, Labrafil, dipalmitoyl phosphadityl choline, glycolic acid and salts, deoxycholic acid and salts, sodium fusidate, cyclodextrin, polyethylene glycol, Labrasol, polyvinyl alcohol, polyvinylpyrrolidone, and tyloxapol, cellulose derivatives, and polyethoxylated castor oil derivatives. The process of the present invention can be used to modify the morphology of active ingredients, resulting in highly porous particles and respirable aggregates.

[0091] Inhalers and nebulizers Delivery of voriconazole inhalation powder to the lungs can be accomplished through any suitable delivery means, including a nebulizer, a dry powder inhaler, or a metered dose inhaler. Those skilled in the art of pulmonary delivery will understand the details of operating such devices. More information on the operation of such devices can also be found, for example, in "The Mechanics of Inhaled Pharmaceutical Aerosols: An Introduction", by WH Inlay, Academic Press, 2001, and "Inhalation Aerosols" edited by AJ Hickey, Marcel Dekker, New York, 1996, both of which are incorporated herein by reference.

[0092] In certain embodiments, the Plastiape Monodose RS00 high resistance device is used with voriconazole inhalation powders including Plastiape RS01 high and medium resistance devices, and the RS00 high resistance device. In certain embodiments, the RS00 high resistance device has demonstrated consistent performance as a function of pressure drop through the device. In other embodiments, a capsule-based DPI device (e.g., RS00 Model 8 Monodose [RS00-0601212V1-M.8] manufactured by Plastiape) is used to administer the voriconazole inhalation powder.

[0093] Those skilled in the art will recognize that the performance of the DPI itself is a combination of the drug, capsule, and characteristics of the DPI device itself. In certain embodiments, the DPI device uses incoming air to efficiently empty the capsule (e.g., a hard two-piece size 3 capsule), while the centrifugal spin rotation action maximizes aerosolization of the powder formulation. The device is designed to be a small, lightweight, and high-resistance device.

[0094] Manufacturing Process Development The thin film freezing (TFF) process involves the rapid freezing of a solution of drug substance and excipients on a cryogenically cooled solid surface. This process has been shown to produce low-density pharmaceutical powders composed of porous nanostructured aggregate particles. TFF processed powders are highly respirable when aerosolized in a commercially available dry powder inhaler (e.g., Plastiape Monodose). The TFF process is designed to achieve a powder with low-density nanostructured morphology. A flow diagram of the manufacturing process for voriconazole inhalation powder is shown in Figure 8.

[0095] Voriconazole can be made, for example, using the following synthetic procedures using commercially available reagents and starting materials. [ka]

[0096] Voriconazole has two chiral centers and therefore there are four possible stereoisomers, namely voriconazole (I), its enantiomer (II), and two diastereomers III and IV (racemic mixture #2S, 3S / 2R, 3R). Their chemical structures are shown below. [ka]

[0097] A high yield diastereoselective process for the formation of (2R,3S)-2-(2,4-difluro-phenyl)-3-(5-fluoro-4-pyrimidinyl)-1(1H-1,2,4-triazol-1-yl) 2-butanol has been developed. Enantiomer (II) is controlled in the finished product specification with a limit of NMT 0.13% by HPLC. Diastereomers (III) and (IV) are controlled in the VOC1 (above) intermediate specification as diastereomeric impurities (i.e., racemic mixture 2S,3S / 2R,3R) with NMT of related substances 0.5% by HPLC. It has been determined that voriconazole is consistently the (2R,3S) isomer, with the remaining stereoisomeric enantiomers (II) and diastereomers (III and IV) being controlled in the drug substance.

[0098] Solution concentrations, freezing temperatures and lyophilization cycles (including shelf temperature and hold time / heat ramp rate) are systematically varied to identify critical process parameters. Voriconazole was dissolved in acetonitrile and mannitol was dissolved in water by continuous stirring. The organic and aqueous phases were combined with continuous stirring to form a co-solvent mixture. The final solutions (total volumes 2.0-3.7 L) consisted of 50:50 acetonitrile:water (v:v) containing 10-30 mg / mL total solids. A summary is shown in Table 8. [Table 8]

[0099] The solution was then frozen by dropwise application from a height of approximately 10 cm via an eight-channel pump head onto a rotating (e.g., 20 rpm) cryogenic steel surface (pre-cooled to approximately -150°C with liquid nitrogen) to produce a thin film. The frozen film was detached from the steel surface by a scraper and collected in a pre-cooled stainless steel tray.

[0100] Once sufficient frozen material (0.7-1.2 L) was collected to fill a tray, the tray was rapidly transferred to a three shelf freeze dryer with a shelf temperature pre-cooled to approximately -55 °C. The freeze drying cycle began when all three trays were filled with frozen material (total volume 2-3.7 L) and placed in the freeze dryer. The solvent was allowed to sublime over approximately 60-65 hours at a final chamber pressure of approximately 100 mTorr while the shelf temperature was gradually increased from approximately -40 °C to approximately +25 °C.

[0101] Ambient air was delivered to the freeze-drying chamber to equilibrate to atmospheric pressure, after which the dried powder was removed from the freeze-dryer and then stored at room temperature in double LDPE bags tied with cable ties with desiccant between the bags.

[0102] Voriconazole inhalation powder was loaded into capsules (e.g., size 3 HPMC capsules) and aerosolized using a Plastiape RS01 low resistance dry powder inhaler, and aerodynamic performance was tested using a Next Generation Impactor (NGI). EXAMPLES

[0103] Example 1 Pharmacokinetic analysis of voriconazole inhaled powder following oral inhalation administration using a high resistance inhaler device, Plastiape Monodose RS00, to healthy adults in a residential clinic setting to ensure continuous subject monitoring.

[0104] The first part consisted of a SAD regimen in four escalating dose cohorts (Part 1); following demonstration of safety and tolerability in these subjects as assessed by the medical monitor and an independent Data Safety Monitoring Board (DSMB) at each dose level, Part 2 of the study began as a MAD regimen (13 doses delivered BID over 7 days) across the four escalating dose cohorts. All cohorts in Part 1 (SAD) were completed sequentially, and Part 2 (MAD) dosing began following establishment of safety of the total daily administered dose in the SAD part (i.e., dosing of 10 mg / kg BID in the MAD part began when 20 mg / kg / day in the SAD part was shown to be safe).

[0105] An independent, medically certified DSMB oversaw the study and was charged with reviewing the open-label safety data in order to recommend to the sponsor whether to escalate dosing, stop the trial, or take additional steps to enhance subject safety.

[0106] Eligible healthy volunteers received single ascending doses (SAD-Part A) and multiple ascending doses (MAD-Part B) of voriconazole inhalation powder taken BID for 7 days. The objective of this study was to evaluate the safety and PK profile of single escalating doses of voriconazole inhalation powder versus placebo. Safety, including physical examinations, clinical tests, visual examinations, and ECG measurements, were performed throughout the course of dosing in both the SAD and MAD parts.

[0107] A total of 33 study subjects participated in Part A (SAD). Four cohorts of 8 study subjects (6 active drug, 2 placebo) were studied at escalating doses from 10 to 80 mg. In addition to safety evaluations, samples were collected for PK evaluation over 24 hours at each dose level. Thirty-two subjects participated in Part B (MAD) and received multiple doses of the same dose level. Subjects received a total of 13 doses, administered BID (every 12 hours). The MAD portion of the study was initiated after safety results from SAD dose level 2 were reviewed and progression was approved by the principal investigator and TFF medical monitor. Pharmacokinetic samples were collected centrally after the first and last dose administration.

[0108] In all study subjects, voriconazole plasma concentrations were measured after each dose administration. Figure 9 shows the mean concentrations ± standard deviation (SD) for each of the dose levels, and PK parameters from each dose level are shown in Table 9. [Table 9]

[0109] These data suggest that pulmonary delivery of voriconazole results in very rapid absorption, with maximum concentrations (C max ) Plasma concentrations were relatively low compared to IV and oral dosing, likely a factor of the low doses given. Voriconazole concentrations were well below those associated with voriconazole-related AEs.

[0110] Voriconazole is primarily metabolized by CYP2C19, and voriconazole pharmacokinetics is known to be influenced by gene expression of this enzyme. Allelic profiling was performed for CYP2C19 in all study subjects, and one poor metabolizer was identified and enrolled in the 80 mg group. Table 10 and Figure 10 provide a summary of the pharmacokinetics from these doses excluding the poor metabolizer. [Table 10]

[0111] Voriconazole is also known to exhibit nonlinear PK. The nonlinearity appears to be both dose- and time-related. However, the available literature does not provide PK at doses as low as those administered in this study to determine the doses associated with nonlinearity. Review of PK results from normal metabolizers only suggests linearity continues through the 40 mg dose, with nonlinearity above 40 mg.

[0112] Focused sample collection was performed after the first and last dose from BID (every 12 hours) administration of voriconazole. Mean (±SD) measurements from both Dose 1 and Dose 13 are provided in FIG.

[0113] Of the two subjects in the 20 mg cohort, one due to withdrawal of consent and one due to an AE. In total, four of the six subjects randomized to active drug provided the PK results summarized herein in the 20 mg BID group.

[0114] A summary of the PK parameters estimated from the first and last doses (doses 1 and 13, respectively) is provided in Table 11. Half-lives were very short for the 10, 20, and 40 mg cohorts, suggesting the absence of accumulation. max and the area under the concentration-time curve from 0 to 12 hours (AUC (0-12) ) values ​​support that premise. As can be seen from the SAD, voriconazole pharmacokinetics appear to be linear up to and including 40 mg; the PK summary for dose 1 and dose 13 is consistent with that.

[0115] Dosing above 40 mg (e.g., 80 mg) suggests the introduction of nonlinearity. PK exposure at dose 1 shows a less than proportional increase when compared to other doses. However, continued dosing shows an extension of voriconazole half-life and a more than proportional increase in overall exposure compared to other doses after dose 13. This observation is consistent with what is known about voriconazole PK after oral and IV administration. [Table 11]

[0116] Two subjects enrolled in this portion of the study were identified as poor metabolizers. Both subjects were part of the 20 mg BID cohort. Figure 12 shows the mean concentrations for normal metabolizers only. Two subjects in the 20 mg BID group were identified as normal metabolizers from dose 1, and three subjects were identified as normal metabolizers from dose 13 (one of the normal metabolizer subjects had all voriconazole concentrations below the quantifiable limit from dose 1). [Table 12]

[0117] Example 2 Additional studies conducted to estimate the safety, tolerability, and PK of voriconazole inhaled powder in adult subjects with asthma are ongoing with preliminary data included herein. The study involves two cohorts of eight subjects each randomized in a 3:1 ratio (6 active and 2 placebo) to receive seven doses (over 3.5 days) of either 40 mg or 80 mg voriconazole inhaled powder or placebo.

[0118] Plasma PK was estimated from serial blood draws after Dose 1 (Day 1) and Dose 7 (Day 4). Treatment stopping rules were included for individual subjects.

[0119] The mean quality control concentration data (40 mg and 80 mg voriconazole inhalation powder) on days 1 and 4 from individuals in cohorts 1 and 2 were compared to the mean concentration times from the 40 mg and 80 mg cohorts from Example 1. The MAD and SAD cohorts from Example 1 were combined without separating the poor and good metabolizers of CYP2C19, and a comparison to day 1 shows similar peak levels and clearance of voriconazole systemic exposure through 4-6 hours between subjects with reactive airway disease and healthy subjects from a single dose of 40 mg and 80 mg (Figure 13). The difference in mean concentrations observed at 6 hours and thereafter may be related to differences in CYP2C19 genetics between the four cohort populations. Note that the 6 hour time point for the 40 mg TFF-V1-002 cohort was a single subject above the LLOQ, while the other five were at the BLQ and were assigned a value of 0 for the generation of the average.

[0120] The voriconazole mean systemic exposure for both 40 mg and 80 mg cohorts from both studies was plotted. Voriconazole inhalation powder was administered BID for 3.5 days (7 doses) in Example 1 and BID for 6.5 days (13 doses) in Example 2. The mean systemic exposure after repeated dosing at both dose levels was similar. The 80 mg cohort mean in Example 2 was slightly higher at 354 ng / mL compared to 281 ng / mL, but the standard deviations (not shown) clearly overlapped, suggesting no statistical difference (Figure 14). Semi-log plots for three of the four cohorts (excluding Example 2 at 40 mg) suggest similar absorption and clearance rates of voriconazole into the systemic circulation for either the 40 mg or 80 mg doses after repeated dosing between subjects with reactive airway disease and healthy subjects. The differences observed in terminal phase clearance in the 40 mg cohort on day 4 in Example 2 may be related to CYP genetics.

[0121] Comparative Example 1 The PK of voriconazole presented herein represents systemically administered voriconazole (e.g., oral or IV). Voriconazole PK has been characterized in healthy subjects, special populations, and patients. Voriconazole exhibits non-linear dose-dependent behavior due to saturation of metabolism. There is a greater than proportional increase in exposure with increasing dose. Accumulation results with multiple dose administration. A summary of exposure following single and multiple dose administration from both IV and oral administration is shown in Table 13. [Table 13]

[0122] Based on population PK analysis of pooled data in healthy subjects (N=207), the oral bioavailability of voriconazole is estimated to be 96% (coefficient of variation, CV 13%). Bioequivalence between the 200 mg tablet and the 40 mg / mL oral suspension was established.

[0123] Maximum plasma concentration (C max ) is achieved 1 to 2 hours after dosing. When multiple doses of voriconazole are administered with a high-fat meal, the mean C max and AUCτ are reduced by 34% and 24%, respectively, when administered as a tablet and by 58% and 37%, respectively, when administered as an oral suspension.

[0124] In healthy subjects, voriconazole absorption is not affected by concomitant administration of oral ranitidine, cimetidine, or omeprazole, which are known to increase gastric pH.

[0125] Distribution from oral or IV administration The steady-state volume of distribution of voriconazole was estimated to be 4.6 L / kg, suggesting extensive distribution to tissues. Plasma protein binding was estimated to be 58% and was shown to be independent of plasma concentrations achieved following single and multiple oral doses of 200 mg or 300 mg (approximate range: 0.9-15 μg / mL). Varying degrees of hepatic and renal impairment do not affect voriconazole protein binding.

[0126] After 3 days of treatment (2 doses of 6 mg / kg IV q12h, followed by 4 mg / kg IV q12h), voriconazole concentrations were measured in both plasma and bronchoalveolar lavage (BAL) samples. Measurements are performed in airway epithelial lining fluid (ELF) and alveolar macrophages (AM) 4, 8, and 12 hours after the final voriconazole dose. The results, shown in Table 14, show substantially higher concentrations in BAL and AM when compared to plasma, and MICs of Aspergillus sp. 90 This shows that the number of cases far exceeds the number of cases reported. [Table 14]

[0127] Another study reviewed the use of prophylactic voriconazole use in lung transplant patients and determined the matching plasma and ELF concentrations at 2, 4, or 8 weeks post-transplant. Patients received 6 mg / kg IV q12h x 2 doses followed by 200 mg orally BID for approximately 4 months. A total of 12 lung transplant patients were included in this estimate and the results are shown in Table 15. In all cases, voriconazole concentrations in lung ELF exceeded those in plasma, with a mean (SD) ELF:plasma ratio of 11. [Table 15]

[0128] Comparative Example 2 1 From inhalation of VFEND IV solution when nebulized: Voriconazole has been administered by inhalation (e.g., nebulization) with concentrations determined in plasma and BAL. In a small study, inhaled voriconazole 40 mg BID for 2 days was compared to oral voriconazole 400 mg BID on day 1 and 200 mg BID on day 2. Blood samples were taken 15, 30, and 60 minutes after dosing on day 1, and BAL and blood samples were taken 12 hours after the last dose. Voriconazole was measured in ELF and plasma from these samples. Concentrations determined from ELF and plasma determinations on day 2 are shown in Table 16. Concentrations from 40 mg inhalation were much lower in both ELF and plasma, as expected. However, ELF:plasma ratios were higher for inhaled administration (median ratio=21) when compared to the oral route (median ratio=8). ELF:plasma ratios after oral dosing are consistent with the results presented in Table 16. [Table 16]

[0129] metabolism In vitro studies have shown that voriconazole is metabolized by human hepatic CP450 enzymes, CYP2C19, CYP2C9, and CYP3A4. In vivo studies have shown that CYP2C19 is significantly involved in the metabolism of voriconazole. This enzyme exhibits genetic polymorphism, which can add to the variability in metabolism and PK. Allelic polymorphisms of wild-type CYP2C19*1 (mainly CYP2C19*2, CYP2C19*3 [inactive allele], and CYP2C19*17 [hyperactive allele]) exist for CYP2C19 expression, and approximately 3-5% of European and 15-20% of Asian populations are poor metabolizers without CYP2C19 function (diplotype expression of CYP2C19*2 / *2, CYP2C19*2 / *3, or CYP2C19*3 / *3).

[0130] The major metabolite of voriconazole is the N-oxide, which accounts for 72% of the circulating radiolabeled metabolites in plasma. This metabolite has minimal antifungal activity and therefore does not contribute to the overall efficacy of voriconazole.

[0131] excretion Voriconazole is eliminated via hepatic metabolism, with less than 2% of the excreted dose remaining unchanged in the urine. Following administration of a single radiolabeled dose of either oral or IV voriconazole, prior to multiple oral or IV dosing, approximately 80%-83% of the radioactivity is recovered in the urine. The majority of the total radioactivity (>94%) is excreted in the first 96 hours after both oral and IV dosing.

[0132] As a result of non-linear PK, the terminal half-life of voriconazole is dose-dependent and therefore not useful for predicting voriconazole accumulation or elimination.

[0133] Drug interactions: Effect of other drugs on voriconazole pharmacokinetics Voriconazole is metabolized by the human hepatic cytochrome P450 enzymes CYP2C19, CYP2C9, and CYP3A4. Results of in vitro metabolism studies indicate that the affinity of voriconazole is highest for CYP2C19, followed by CYP2C9, and much lower for CYP3A4. Inhibitors or inducers of these three enzymes may increase or decrease voriconazole systemic exposure (plasma concentration), respectively.

[0134] Significant reductions in voriconazole concentrations can be expected when coadministered with rifampin, ritonavir, St. John's wort, carbamazepine, or long-acting barbiturates, all of which are considered contraindicated with voriconazole.

[0135] Drug interactions: Effect of voriconazole on the pharmacokinetics of other drugs Voriconazole, an azole antifungal compound, belongs to a group of drugs known to be strong CYP3A inhibitors. Voriconazole is no exception. In vitro studies have shown that voriconazole inhibits the metabolic activity of CYP2C19, CYP2C9, and CYP3A4. In vitro studies have also shown that voriconazole N-oxide, the major metabolite of voriconazole, inhibits the metabolic activity of CYP2C9 and CYP3A4. Thus, voriconazole has the potential to have significant interactions with other drugs.

[0136] Voriconazole is contraindicated with the following CYP3A4 substrates because it may increase concentrations of these drugs to potentially dangerous levels: sirolimus, terfenidine, atemizole, cisapride, pimozide, quinidine, everolimus, and ergot alkaloids.

[0137] Voriconazole is expected to increase the exposure of the following medications and downward dose adjustments may be necessary: ​​alfentanil, fentanyl, oxycodone, methadone, cyclosporine, tacrolimus, warfarin / coumarin, statin drugs, benzodiazepines, calcium channel blockers (e.g., nifendipine, felodipine, nicardipine), sulfonylureas (e.g., tolbutamide, glipizide, glyburide), vinca alkaloids, omeprazole and some nonsteroidal anti-inflammatory drugs (NSAIDs, ibuprofen, diclofenac).

[0138] Two-way interaction Some interactions may affect both voriconazole and another co-administered drug.

[0139] Voriconazole is contraindicated with rifabutin (a CYP3A4 inducer and substrate) and efavirenz (a CYP3A4 inhibitor / inducer and substrate) based on the effects of each drug on each other.

[0140] Phenytoin, a CYP2C9 substrate and CYP inducer, requires frequent monitoring of both phenytoin and voriconazole. Lower than usual doses of phenytoin and higher than usual doses of voriconazole may be required. When oral contraceptives and voriconazole are given together, each may increase concentrations of the other. Monitoring for AEs related to either oral contraceptives or voriconazole is recommended.

[0141] Pharmacodynamics in humans The primary PD endpoint with voriconazole is cure of infection. The use of voriconazole may also be associated with several safety factors, including hepatotoxicity and neurotoxicity.

[0142] The VFEND product information states that PK / PD analysis of patient data from 6 of 10 clinical trials (N=280) failed to detect a positive association between mean, maximum, or minimum plasma voriconazole concentrations and efficacy. However, PK / PD analysis of data from all 10 clinical trials (N=1121) identified a positive association between plasma voriconazole concentrations and rates of both liver function test abnormalities and visual disturbances.

[0143] Relationship of Voriconazole Concentration to Antifungal Efficacy and Toxicity. A meta-analysis was performed across 21 studies with 1158 patients treated with either IV or oral therapy. Trough plasma voriconazole concentrations were determined in these patients and evaluated for antifungal efficacy and toxicity. The analysis found that trough concentrations >0.5 μg / mL resulted in significantly higher antifungal efficacy, but reconsideration of results suggested that >1.0 μg / mL may be a better indicator. An increased risk of hepatotoxicity was found with trough voriconazole concentrations >3.0 μg / mL, and concentrations >4.0 μg / mL were associated with an increased risk of neurotoxicity. Other publications have suggested that plasma concentrations of 1.0-2.0 μg / mL are necessary to ensure a higher success rate, but these studies were based on smaller numbers of patients. Therapeutic drug monitoring is the standard of care with systemic voriconazole, and phase 2 and 3 trials of inhaled voriconazole will be planned.

[0144] Example 3 Pharmacokinetic / Pharmacodynamic Summary The PK of voriconazole inhalation powder has been summarized from the completed Phase 1 study discussed in Example 1. Oral and IV voriconazole PK has been summarized from a variety of literature sources and the VFEND prescribing information. Twice daily dosing is appropriate for oral and IV routes of drug administration and is expected for the inhaled route.

[0145] Lung ELF voriconazole concentrations measured after IV or oral administration are 8-11 times higher (on average) than simultaneously collected plasma concentrations. Small studies conducted with nebulized voriconazole for inhalation have shown efficacy at lower doses than IV or oral administration. Nebulized voriconazole provides higher ELF:plasma ratios when compared to IV or oral voriconazole, suggesting the potential for lower doses with targeted delivery for pulmonary fungal infections. These lower doses may provide greater safety for voriconazole, potentially reducing the chance of achieving plasma voriconazole concentrations associated with hepatic and neurotoxicity.

[0146] Therapeutic drug monitoring can reduce the incidence of voriconazole-related AEs. CYP2C19 genetic screening can also enhance optimal antifungal therapy.

[0147] All references cited herein, including patents, patent applications, papers, textbooks, etc., and references cited herein are incorporated herein by reference in their entirety unless they have already been cited. Comparative Examples 1 and 2 were compiled based on publicly available information.

[0148] The foregoing description is deemed sufficient to enable one skilled in the art to practice the present invention. The foregoing description and examples detail certain preferred embodiments of the present invention and set forth the best mode contemplated by the inventors. However, no matter how detailed the foregoing appears in text, it will be understood that the invention can be practiced in many ways and that the invention should be construed in accordance with the appended claims and any equivalents thereof.

Claims

1. 1. A method of treating a fungal infection in a subject in need thereof, said method comprising administering to said subject by inhalation voriconazole or a salt thereof in an amount of about 20 mg to about 80 mg, said administration by inhalation achieving a maximum circulating plasma concentration of voriconazole of less than 1,000 ng / mL.

2. 2. The method of claim 1, wherein the maximum circulating plasma concentration of voriconazole is less than 500 ng / mL.

3. 2. The method of claim 1, wherein the maximum circulating plasma concentration of voriconazole is less than 300 ng / mL.

4. 2. The method of claim 1, wherein the fungal infection is caused by Aspergillus fumigatus, Aspergillus flavus, Aspergillus niger, Aspergillus terreus, Candida albicans, Candida glabrata, Candida krusei, Candida parapsilosis, Candida tropicalis, Fusarium spp., Fusarium solani, Scedosporium apiospermum, Candida lusitaniae or Candida guilliermondii.

5. 2. The method of claim 1, wherein the fungal infection is invasive aspergillosis, candidemia or esophageal candidiasis.

6. The method of claim 1 , wherein the subject is suffering from a reactive airway disorder.

7. 7. The method of claim 6, wherein the reactive airway disorder is chronic obstructive pulmonary disease (COPD).

8. The method of claim 1 , wherein the subject is immunocompromised.

9. 9. The method of claim 8, wherein the immune deficiency is caused by factors including patients with neutropenia, hematopoietic stem cell transplantation (HSCT), solid organ transplantation, long-term therapy with high-dose corticosteroids, hematological malignancies, cytotoxic therapy, advanced acquired immune deficiency syndrome (AIDS), chronic granulomatous disease, and liver failure.

10. 10. The method of claim 1, wherein the administration is at least once daily.

11. 10. The method of claim 1, wherein the administration is at least twice daily.

12. 10. The method of claim 1, wherein the administration of voriconazole or a salt thereof comprises an amount of about 40 mg to about 120 mg.

13. 10. The method of claim 1, wherein the administration of voriconazole or a salt thereof comprises an amount of about 60 mg to about 80 mg.

14. 2. The method of claim 1, wherein the administration of voriconazole or a salt thereof comprises an amount of about 80 mg.

15. 2. The method of claim 1, wherein the voriconazole or salt thereof is voriconazole inhalation powder.

16. 1. A method of increasing pulmonary delivery of voriconazole in a subject in need thereof, the method comprising administering to the subject by inhalation voriconazole or a salt thereof in an amount of from about 20 mg to about 80 mg, wherein the delivery of voriconazole to the lung by inhalation results in about a 50-fold greater relative concentration in the lung compared to oral administration of voriconazole about 12 hours following administration.

17. 17. The method of claim 16, wherein delivery of the voriconazole to the lungs results in about a 100-fold greater relative concentration in the lungs as compared to oral administration of the voriconazole.

18. 17. The method of claim 16, wherein delivery of the voriconazole to the lungs results in about a 200-fold greater relative concentration in the lungs as compared to oral administration of the voriconazole.

19. The target is Aspergillus fumigatus, Aspergillus flavus, Aspergillus niger, Aspergillus terreus, Candida albicans, Candida glabrata, Candida krusei, Candida parapsilosis, Candida tropicalis, Fusarium spp.

17. The method of claim 16, wherein the patient is suffering from a fungal infection caused by Fusarium solani, Scedosporium apiospermum, Candida lusitaniae or Candida guilliermondii.

20. 13. The method of claim 12, wherein the subject is suffering from a fungal infection caused by invasive aspergillosis, candidemia or esophageal candidiasis.

21. 17. The method of claim 16, wherein the subject is immunocompromised.

22. 22. The method of claim 21, wherein the immune deficiency is caused by factors including patients with neutropenia, hematopoietic stem cell transplantation (HSCT), solid organ transplantation, long-term therapy with high-dose corticosteroids, hematological malignancies, cytotoxic therapy, advanced acquired immune deficiency syndrome (AIDS), chronic granulomatous disease, and liver failure.

23. 17. The method of claim 16, wherein the administration is at least once daily.

24. 17. The method of claim 16, wherein the administration is at least twice daily.

25. 17. The method of claim 16, wherein the administration of voriconazole or a salt thereof comprises an amount of about 40 mg to about 80 mg.

26. 17. The method of claim 16, wherein the administration of voriconazole or a salt thereof comprises an amount of about 60 mg to about 120 mg.

27. 17. The method of claim 16, wherein the administration of voriconazole or a salt thereof comprises an amount of about 80 mg.

28. 17. The method of claim 16, wherein the voriconazole or salt thereof is voriconazole inhalation powder.

29. 1. A method for reducing systemic circulation of voriconazole compared to oral administration of voriconazole, comprising administering voriconazole or a salt thereof by inhalation to a subject in an amount of about 20 mg to about 80 mg, wherein said administration by inhalation achieves a maximum circulating plasma concentration of voriconazole of less than 1,000 ng / mL.

30. 30. The method of claim 29, wherein the maximum circulating plasma concentration of voriconazole is less than 500 ng / mL.

31. 30. The method of claim 29, wherein the maximum circulating plasma concentration of voriconazole is less than 300 ng / mL.

32. 30. The method of claim 29, wherein the fungal infection is caused by Aspergillus fumigatus, Aspergillus flavus, Aspergillus niger, Aspergillus terreus, Candida albicans, Candida glabrata, Candida krusei, Candida parapsilosis, Candida tropicalis, Fusarium spp., Fusarium solani, Scedosporium apiospermum, Candida lusitaniae or Candida guilliermondii.

33. 30. The method of claim 29, wherein the fungal infection is invasive aspergillosis, candidemia or esophageal candidiasis.

34. 30. The method of claim 29, wherein the subject is immunocompromised.

35. 35. The method of claim 34, wherein the immune deficiency is caused by factors including patients with neutropenia, hematopoietic stem cell transplantation (HSCT), solid organ transplantation, long-term therapy with high-dose corticosteroids, hematological malignancies, cytotoxic therapy, advanced acquired immune deficiency syndrome (AIDS), chronic granulomatous disease, and liver failure.

36. 30. The method of claim 29, wherein the administration is at least once daily.

37. 30. The method of claim 29, wherein the administration is at least twice daily.

38. 30. The method of claim 29, wherein the administration of voriconazole or a salt thereof comprises an amount of about 40 mg to about 120 mg.

39. 30. The method of claim 29, wherein the administration of voriconazole or a salt thereof comprises an amount of about 60 mg to about 80 mg.

40. 30. The method of claim 29, wherein the administration of voriconazole or a salt thereof comprises an amount of about 80 mg.

41. 2. The method of claim 1, wherein the voriconazole or salt thereof is voriconazole inhalation powder.

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