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WO2009102814A2 - Formulation d'amphotéricine b liquide n'irritant pas les muqueuses, et procédé pour traiter une mucosite non invasive induite par champignon - Google Patents

Formulation d'amphotéricine b liquide n'irritant pas les muqueuses, et procédé pour traiter une mucosite non invasive induite par champignon Download PDF

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Publication number
WO2009102814A2
WO2009102814A2 PCT/US2009/033832 US2009033832W WO2009102814A2 WO 2009102814 A2 WO2009102814 A2 WO 2009102814A2 US 2009033832 W US2009033832 W US 2009033832W WO 2009102814 A2 WO2009102814 A2 WO 2009102814A2
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Prior art keywords
composition
amphotericin
mucoadministration
subject
sodium phosphate
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PCT/US2009/033832
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English (en)
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WO2009102814A3 (fr
Inventor
Francis E. O'donnell
Donald Deroo
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Accentia Biopharmaceuticals, Inc.
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Publication of WO2009102814A2 publication Critical patent/WO2009102814A2/fr
Publication of WO2009102814A3 publication Critical patent/WO2009102814A3/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0043—Nose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/009—Sachets, pouches characterised by the material or function of the envelope
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1611—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics

Definitions

  • Mucositis the inflammation of mucosal tissue, is a serious medical problem that affects millions of people worldwide. For example, conservative estimates indicate that between 20 and 40 million Americans suffer from chronic rhinosinusitis, an inflammation of the nasal cavity and/or paranasal sinuses.
  • the present invention provides universally non-irritative compositions for mucoadministration.
  • the present invention is based, at least in part, on compositions and methods which cause no or negligible burning when mucoadministered to a subject.
  • the present invention provides mucosally non-irritative compositions and methods useful for treating mucositis. Such compositions will allow for the rmicoadministration of amphotericin B to a larger, more comprehensive population of subjects than the population that currently tolerates conventional formulations. Accordingly, in one aspect, the present invention provides a composition for mucoadministration.
  • the composition generally includes a mucosally non-irritative mixture of amphotericin B and a pharmaceutically acceptable carrier, e.g., a universally mucosally non-irritative mixture.
  • a pharmaceutically acceptable carrier e.g., a universally mucosally non-irritative mixture.
  • the composition is a liquid formulation, such as an aqueous suspension.
  • the pharmaceutically acceptable carrier includes sodium phosphate dibasic and sodium phosphate monobasic.
  • the composition includes amphotericin B in an amount of between about 0.27% and about 0.50% by weight of the total composition.
  • the composition also includes water as an aqueous suspension.
  • the amphotericin B can be present in an amount of about 0.01% by weight of the total composition.
  • the pharmaceutically acceptable carrier includes sodium phosphate dibasic, sodium phosphate monobasic and water.
  • the present invention provides a composition for mucoadministration which includes between about 0.27% and about 0.50% by weight amphotericin B; between about 45% and about 70% by weight sodium phosphate dibasic; and between about 30% and about 55% by weight sodium phosphate monobasic.
  • the composition is a powder.
  • the composition is suitable for incorporation into a solution or suspension.
  • the composition can be in a solid form, wherein the solid form is suitable for incorporation into a solution or suspension.
  • the present invention provides a composition for mucoadministration which includes amphotericin B; sodium phosphate dibasic; sodium phosphate monobasic; and at least about 96.25% by weight water.
  • the composition can include about 0.01% by weight amphotericin B; about 1.59% by weight sodium phosphate dibasic; about 0.96% by weight sodium phosphate monobasic; and about 97.44% by weight water.
  • the present invention provides a composition consisting essentially of amphotericin B, sodium phosphate dibasic, sodium phosphate monobasic and water.
  • the composition is free or essentially free of propylene glycol. In other embodiments, the composition is free or essentially free of sodium metabisulfate. In still other embodiments, the composition is free or essentially free of carboxymethylcellulose sodium. In other embodiments, the composition is free or essentially free of methylparaben. In yet other embodiments, the composition is free or essentially free of propylparaben. In yet other embodiments, the composition is free or essentially free of desoxycholate, e.g., sodium desoxycholate (also referred to as sodium deoxycholate). In some embodiments, the compositions of the present invention provide a low maximum plasma concentration upon direct mucoadministration.
  • compositions of the present invention are at least about 90% stable for up to 18 months under a nitrogen atmosphere. In some embodiments, the compositions of the present invention are at least about 95% stable for up to 18 months under a nitrogen atmosphere. In some embodiments, the compositions of the present invention are at least about 20% more stable under a nitrogen atmosphere than under an oxygen atmosphere.
  • the liquid compositions of the present invention are at least about 80% stable for up to 18 months under an inert gas atmosphere (e.g., nitrogen or other inert gas such as argon, helium, carbon dioxide). In some embodiments, the compositions of the present invention are at least about 84% stable for up to 18 months under an inert gas atmosphere (e.g., nitrogen or other inert gas such as argon, helium, carbon dioxide). In some embodiments, the compositions of the present invention are at least about 50% more stable under an inert gas atmosphere (e.g., nitrogen or other inert gas such as argon, helium, carbon dioxide) than under an oxygen atmosphere for up to 18 months.
  • an inert gas atmosphere e.g., nitrogen or other inert gas such as argon, helium, carbon dioxide
  • the present invention provides a method of treating a subject having non-invasive fungus-induced mucositis.
  • the method generally includes mucoadministering any composition as described herein.
  • the method includes non-irritatively mucoadministering a composition comprising amphotericin B and a pharmaceutically acceptable carrier.
  • the composition is administered in an amount, at a frequency, and for a duration effective to reduce or eliminate the non-invasive fungus- induced mucositis.
  • the subject is a mammal, such as a human.
  • the method includes identifying the subject as suffering from non- invasive fungus-induced mucositis prior to mucoadministration.
  • U.S. Patent No. 6,416,955 by Dr. Jens Ponikau et al. and assigned to the Mayo Foundation For Medical Education And Research, describes methods for determining whether or not a sinusitis condition in a patient is non-invasive fungus-induced rhinosinusitis (the contents of which is incorporated herein by reference in its entirety).
  • the non-invasive fungus-induced mucositis is non-invasive fungus-induced rhinosinusitis, e.g., non-invasive fungus-induced rhinosinusitis with polyp formation or polypoid change and/or chronic non-invasive fungus-induced rhinosinusitis.
  • the method includes administering a composition wherein the pharmaceutically acceptable carrier comprises sterile water.
  • mucoadministration includes irrigating the nasal-paranasal anatomy of the subject with a liquid form of the composition.
  • mucoadministration includes applying an aerosol form of the composition to the nasal-paranasal anatomy of the subject.
  • mucoadministration includes spraying the composition (e.g., by pump spray) into the nasal-paranasal anatomy of the subject.
  • mucoadministration includes applying drops of the composition into the nasal-paranasal anatomy of the subject.
  • the composition includes between about 50 ⁇ g and about
  • the composition includes about 100 ⁇ g of Amphotericin B per milliliter of sterile water.
  • the effective amount includes about 5 mL to about 100 mL of the composition per nostril of the subject.
  • an effective amount comprises about 20 niL of the composition per nostril of the subject.
  • the compositions of the present invention include about 100 ⁇ g of amphotericin B per milliliter of aqueous carrier and about 20 ml of the composition is administered to a subject in each nostril twice daily.
  • mucoadministration is achieved via a pump spray. Accordingly, in some embodiments, mucoadministration includes from 1 to 4 pumps per nostril, e.g., 3 pumps per nostril. In some embodiments, the pump dispenses between about 50 ⁇ L and about 200 ⁇ L of the composition, e.g., about 100 ⁇ L of the composition. In some embodiments, the effective frequency of mucoadministration is from about four times a day to about once every other week. In other embodiments, the effective frequency of mucoadministration is from about three times a day to about once a week. In still other embodiments, the effective frequency of mucoadministration is from about one to four times a day, e.g., three times a day. In still other embodiments, the effective frequency of mucoadministration is more frequent than once a day. In some embodiments, the effective duration is greater than about 30 days. In other embodiments, the effective duration is greater than about 60 days.
  • polyposis is improved in the subject.
  • sinus inflammation is improved in the subject.
  • the present invention provides a method for reducing eosinophil in a subject.
  • the method can generally include non-irritatively mucoadministering a composition comprising amphotericin B and a pharmaceutically acceptable carrier.
  • the present invention provides a method for reducing the amount of major basic protein m the mucosa of a subject.
  • the method can generally include non- irritatively mucoadministering a composition comprising amphotericin B and a pharmaceutically acceptable carrier.
  • the present invention provides a method for preparing a mucosally non-irritative liquid amphotericin B composition for storage, comprising: providing a suspension of amphotericin B in de-oxygenated water; and placing the suspension in a sealed container under an inert atmosphere (e.g., nitrogen or another inert gas such as argon or helium).
  • an inert atmosphere e.g., nitrogen or another inert gas such as argon or helium
  • the container is opaque or light-proof.
  • the method further comprises storing the composition in the sealed container for a period of time selected from the group consisting of at least one month, at least 2 months, at least 3 months, at least 6 months, at least 9 months, at least 12 months, and at least 18 months.
  • the de-oxygenated amphotericin B suspension may be provided, for example, by introducing nitrogen or another inert gas (such as argon or helium) into a volume of water
  • the suspension is mixed during and/or after deoxygenation.
  • Mixing can be carried out, for example, by agitation, static mixing, or utilization of an impeller.
  • Introduction of the inert gas may be carried out under room temperature and normal atmospheric pressure; however, dissolved oxygen may be reduced further by introducing the inert gas under vacuum conditions.
  • Figure 1 is a graph depicting the plasma concentration of exemplary amphotericin B formulations of the present invention in Gottingen minipigs.
  • Figure 2 is a graph of plasma concentration of amphotericin B in Gottingen minpigs at day-135, administered intravenously (LV.) or by mucoadministration (see Example 3).
  • Figure 3 is a graph of plasma concentration of amphotericin B, based on dosages, in Gottingen minipigs at day-1, day-44, day-92, day-135, and day-179 (see Example 3 and Tables 2A-2C).
  • Figure 4 is a graph depicting the stabilities of exemplary liquid amphotericin B compositions of the present invention during storage at room temperature over an 18- month period (see Example 6 and Table 5). Stability is expressed as a percentage of label claim.
  • the present invention is directed to methods and compositions for treating and preventing non-invasive fungus-induced mucositis.
  • the present invention provides compositions including a mucosally non-irritative mixture of an anti-fungal agent, such as amphotericin B, and a pharmaceutically acceptable carrier.
  • Such compositions can be non-irritatively mucoadministered to prevent, reduce, or eliminate chronic non-invasive fungus-induced mucositis conditions.
  • non-irritative and “non-irritatively” refer to compositions and methods which exhibit no or negligible burning, stinging, itching or otherwise uncomfortable sensations when mucoadministered. In some embodiments, non-irritative compositions and methods also exhibit no or negligible odor, taste or aftertaste.
  • the term "universally,” when used in reference to non-irritative compositions and methods, refers to instances where at least 90% of the subjects to which a composition is administered experience no or negligible burning, stinging, etc. In some embodiments, the term universally includes instances where at least 95% of the subjects experience no or negligible burning, stinging, etc. In other embodiments, the term universally includes instances where 100% of the subjects experience no or negligible burning, stinging, etc.
  • the term “free or essentially free of any component” refers to the presence of the component in an amount less than that which would render the component mucosally irritative. In some embodiments, the term “free or essentially free of any component refers to less than about 3% of the component being present in a composition, e.g., a solid composition. In other embodiments, the term “free or essentially free of any component refers to less than about 2% of the component being present in a composition, e.g., a solid composition.
  • the term “free or essentially free of any component refers to less than about 1% of the component being present in a composition, e.g., a solid composition, hi still other embodiments, the term “free or essentially free of any component refers to less than about 0.5% of the component being present in a composition, e.g., a solid or liquid composition. In some embodiments, the term “free or essentially free of any component refers to less than about 0.1% of the component being present in a composition, e.g., a liquid composition.
  • low plasma concentration refers to a concentration which is significantly less than a toxic concentration.
  • low plasma concentration refers to a concentration at least 25% less than a toxic concentration.
  • low plasma concentration refers to a concentration at least 30% less than a toxic concentration.
  • low plasma concentration refers to a concentration at least 35% less than a toxic concentration.
  • low plasma concentration refers to a concentration at least 50% less than a toxic concentration.
  • low plasma concentration refers to a concentration at least 65% less than a toxic concentration.
  • Treatment is defined as the application or administration of a therapeutic agent to a subject who has a disorder, e.g., chronic noninvasive fungus-induced rhinosinusitis as described herein, with the purpose to cure, heal, alleviate, delay, relieve, alter, remedy, ameliorate, improve or affect the disease or disorder, or symptoms of the disease or disorder.
  • treatment or “treating” is also used herein in the context of administering agents prophylactically.
  • effective dose or “effective dosage” is defined as an amount sufficient to achieve or at least partially achieve the desired effect.
  • therapeutically effective dose is defined as an amount sufficient to cure or at least partially arrest the disease and its complications in a subject already suffering from the disease.
  • subject refers to animals such as mammals, including, but not limited to, humans, primates, cows, sheep, goats, horses, pigs, dogs, cats, rabbits, guinea pigs, rats, mice or other bovine, ovine, equine, canine, feline, rodent or murine species.
  • mucositis refers to inflammation of a mucus membrane.
  • a non-invasive fungus-induced mucositis refers to an inflammation of any mucosal tissue induced by a non-invasive fungal organism.
  • mucosal tissue include, without limitation, the mucosa of the mouth, gut, nasal passages, paranasal sinuses, airways of the lung, trachea, middle ear, eustachian tube, vagina, and urethra.
  • Typical inflammations of the mucous membranes include, but are not limited to, chronic non-invasive fungus-induced rhinosinusitis, chronic otitis media, chronic colitis, and Crohn's disease and chronic asthma symptoms.
  • non-invasive fungus-induced rhinosinusitis includes any nasal-paranasal mucositis condition having a non-invasive fungal etiology.
  • chronic refers to afflictions present for at least three months. It is to be understood that afflictions that are treated as described herein and become asymptomatic can be classified as chronic. Thus, chronic afflictions can be symptomatic or asymptomatic.
  • mucosal tissue e.g., chronic non-invasive fungus-induced rhinosinusitis
  • an inflammation of a mucosal tissue can be determined using methods described, e.g., in U.S. Patent No. 6,555,566, the entire contents of which are hereby incorporated by this reference.
  • stable and “stability” as used herein in reference to the active agent (e.g., amphotericin B or other anti-fungal agent) used in the solid and liquid compositions of the present invention means the active agent maintains at least about 80%, and preferably about 84% to 100% of its chemical integrity upon storage at room temperature for at least 2 months, at least 3 months, at least 6 months, at least 9 months, at least 12 months, at least 18 months, or at least 24 months. See Examples 5 and 6.
  • the data herein show that exemplary solid and liquid compositions of the present invention exhibit about 20% to about 50% greater stability under an inert gas atmosphere (e.g., nitrogen atmosphere) than under an oxygen atmosphere.
  • the chemical integrity can be determined by measuring the active agent (e.g., amphotericin B) content in a high-performance liquid chromatography (HPLC) assay, or by other assays effective in determining chemical concentration.
  • HPLC high-performance liquid chromatography
  • inert gas inert atmosphere
  • inert gas atmosphere is intended to refer to a gas or gaseous mixture that contains little or no oxygen and primarily consists of non-reactive gases or gases that have a high threshold before they react. Examples include nitrogen, argon, helium, and carbon dioxide. Preferably, the inert gas is nitrogen. Preferably, the gas is pure and of medical grade.
  • a pharmaceutically acceptable carrier includes more than one such carrier.
  • a reference to “an inert gas” includes more than one such gas.
  • an anti-fungal agent includes more than one such agent (e.g., amphotericin B and one or more other anti-fungal agents).
  • the terms “comprising”, “consisting of and “consisting essentially of are defined according to their standard meaning.
  • the te ⁇ ns may be substituted for one another herein in order to attach the specific meaning associated with each term.
  • Numerous values and ranges are recited in connection with various embodiments of the present invention, e.g., amount of amphotericin B. It is to be understood that all values and ranges which fall between the values and ranges listed are intended to be encompassed by the present invention unless stated otherwise.
  • compositions of the present invention are provided.
  • compositions of the invention are solid formulations that can be reconstituted into a liquid composition immediately prior to use.
  • Other embodiments of the composition of the invention are the resulting reconstituted liquid compositions.
  • Some conventional liquid compositions of amphotericin B include components (e.g., propylene glycol, sodium metabisulfate, carboxymethylcellulose sodium, etc.) which act to maintain the stability of the composition and the efficacy of the amphotericin B.
  • components e.g., propylene glycol, sodium metabisulfate, carboxymethylcellulose sodium, etc.
  • solid formulations of the present invention can remain stable and maintain their efficacy for longer than conventional liquid compositions. Water can then be added immediately prior to use to form a liquid composition suitable for mucoadministration.
  • the present invention is also based, at least in part, on the discovery that agents typically used to aid in dissolution of active ingredients may not be necessary in mucoadministered formulations.
  • Some conventional liquid compositions of amphotericin B, e.g., FUNGIZONE include components (e.g., deoxycholate salts) which act to increase the solubility of the active ingredient in liquid, e.g., distilled water. Accordingly, again without wishing to be bound by any particular theory, it is believed that the formulations of the present invention can be used in the treatment of non-invasive fungus induced mucositis without the necessity of an agent which aids dissolution.
  • the present invention is also based, at least in part, on the discovery of formulations for mucoadministration that are not irritating to the mucosa. Without wishing to be bound by any particular theory, it is believed that the removal of certain agents, e.g., agents conventionally used to maintain the stability of a composition and the efficacy and solubility of the amphotericin B also removes many of the irritative properties of the formulation. Accordingly, in some aspects, the present invention provides a composition for mucoadministration including a mucosally non-irritative mixture of amphotericin B and a pharmaceutically acceptable carrier. In some embodiments, the mixture is a universally mucosally non-irritative mixture.
  • compositions of the invention are liquid amphotericin B formulations having improved stability relative to conventional liquid compositions of amphotericin B.
  • an aqueous vehicle such as sterile water
  • it is added to the solid formulation to form a liquid composition that is both suitable for mucoadministration and stable for storage.
  • exemplary liquid compositions of the present invention exhibit about 50% greater stability under an inert gas atmosphere (e.g., nitrogen atmosphere) than under an oxygen atmosphere.
  • the liquid compositions of the invention are prepared to be non-irritative.
  • the present invention provides a liquid composition for mucoadministration including a mucosally non-irritative mixture of amphotericin B and a pharmaceutically acceptable carrier.
  • the mixture is a universally mucosally non-irritative mixture.
  • Solid and liquid compositions of the present invention generally include a pharmaceutically acceptable carrier.
  • the pharmaceutically acceptable carrier can be a solid vehicle.
  • powders, capsules or tablets can contain amphotericin B in a form suitable for dissolution and subsequent non-irritative mucoadministration.
  • the composition is a powder.
  • pharmaceutically acceptable solid vehicles include, but are not limited to, gelatin, starch, sugar, or bentonite.
  • the amphotericin B is present in an amount of between about 0.27% and about 0.50% by weight of the composition.
  • amphotericin B can be present in an amount of about 0.27%, 0.28%, 0.29%, 0.30%, 0.31%, 0.32%, 0.33%, 0.34%, 0.35%, 0.36%, 0.37%, 0.38%, 0.39%, 0.40%, 0.41%, 0.42%. 0.43%, 0.44%, 0.45%, 0.46%, 0.47%, 0.48%, 0.49% or 0.50%. Additional amounts of amphotericin B are also suitable for the compositions of the present invention, provided that the formulation is non-irritative and not toxic.
  • the pharmaceutically acceptable carrier includes buffering agents.
  • buffering agent refers to one or more components which are added to a composition in order to adjust or maintain the pH of the composition.
  • Suitable buffering agents are known to the skilled artisan and include, but are not limited to phosphates, carbonates, borates, lactates, acetates, and citrates, and combinations thereof, particularly alkali metal or alkaline metal salts of these agents. It is to be understood that buffering agents useful for the present invention are non-irritative. In some embodiments, the buffering agents are sodium phosphate buffering agents.
  • the pharmaceutically acceptable carrier includes sodium phosphate dibasic and/or sodium phosphate monobasic.
  • the sodium phosphate dibasic is present in an amount of between about 45% and about 70% by weight; e.g., about 45%, 50%. 55%, 60%, 65%, or 70%.
  • the sodium phosphate monobasic is present in an amount of between about 30% and about 55%, e.g., about 30%, 35%, 40%, 45%, 50% or 55%.
  • compositions of the present invention include sodium phosphate dibasic in an amount of about 62%. In some embodiments, the compositions of the present invention include sodium phosphate monobasic in an amount of about 37%.
  • the pharmaceutically acceptable carrier is a buffering agent or a mixture of buffering agents. In some embodiments, the pharmaceutically acceptable carrier is only buffering agent or a mixture of buffering agents. In some embodiments, the pharmaceutically acceptable carrier includes a buffering agent or a mixture of buffering agents and sterile water. In some embodiments, the pharmaceutically acceptable carrier includes only a buffering agent or a mixture of buffering agents and sterile water.
  • compositions for mucoadministration that include between about 0.27% and about 0.50% by weight amphotericin B; between about 60% and about 65% by weight sodium phosphate dibasic; and between about 35% and about 40% by weight sodium phosphate monobasic.
  • the solid form is suitable for incorporation into a solution or suspension.
  • water e.g., sterile water
  • Such a solution or suspension would be suitable for non-irritative mucoadministration.
  • compositions of the present invention generally include a pharmaceutically acceptable carrier.
  • the pharmaceutically acceptable carrier can be an aqueous vehicle, e.g., any liquid solution capable of dissolving an antifungal agent and is not toxic to the particular individual receiving the formulation.
  • examples of pharmaceutically acceptable aqueous vehicles include, but are not limited to, saline, water, and acetic acid.
  • pharmaceutically acceptable aqueous vehicles are sterile.
  • the pharmaceutically acceptable carrier includes sterile water. It is to be understood that additional aqueous vehicles are also suitable for the compositions of the present invention, provided that they are non-irritative and not toxic.
  • the composition is a liquid.
  • the composition includes water, e.g., sterile water.
  • the composition includes saline.
  • the saline or water used in amphotericin B formulations of the present invention is sterile.
  • the present invention provides compositions which include amphotericin B, sodium phosphate dibasic, sodium phosphate monobasic, and at least 96.25% by weight water, e.g., sterile water.
  • compositions of the present invention include at least 96.50% by weight water.
  • compositions of the present invention include at least 96.75% by weight water.
  • compositions of the present invention include at least 97.00% by weight water. In some embodiments, compositions of the present invention include at least 97.25% by weight water. In some embodiments, e.g., where the composition is in liquid form, the amphotericin B is present in an amount of about 0.01% by weight of the total composition. In some embodiments, e.g., where the composition is in liquid form, the sodium phosphate dibasic is present in an amount of about 1.59% by weight of the total composition. In some embodiments, e.g., where the composition is in liquid form, the sodium phosphate monobasic is present in an amount of amount of about 0.96% by weight of the total composition. In some embodiments, e.g. , where the composition is in liquid form, water is present in an amount of amount of about 97.44% by weight of the total composition.
  • the present invention provides compositions for mucoadministration that include amphotericin B; sodium phosphate dibasic; sodium phosphate monobasic; and at least about 96.25% by weight water, e.g., compositions that include about 0.01% by weight amphotericin B; about 1.59% by weight sodium phosphate dibasic; about 0.96% by weight sodium phosphate monobasic; and about 97.44% by weight water.
  • compositions of the present invention consist essentially of amphotericin B, sodium phosphate dibasic, and sodium phosphate monobasic. In some aspects, the compositions of the present invention consist essentially of amphotericin B, sodium phosphate dibasic, sodium phosphate monobasic and water.
  • a formulation containing an antifungal agent can be in any form provided the formulation can be non-irritatively mucoadministered to a mammal in an amount, at a frequency, and for a duration effective to prevent, reduce, or eliminate a non-invasive fungus-induced mucositis.
  • a formulation within the scope of the invention can be in the form of a solid, liquid, and/or aerosol including, without limitation, powders, crystalline substances, gels, pastes, ointments, salves, creams, solutions, suspensions, partial liquids, sprays, nebulae, mists, atomized vapors, tinctures, pills, capsules, tablets, and gelcaps.
  • compositions and methods of the present invention include amphotericin B and one or more additional ingredients.
  • Additional ingredients include, but are not limited to, additional antifungal agents, steroids, mucolytic agents, antibacterial agents, anti-inflammatory agents, immunosuppressants, dilators, vaso-constrictors, decongestants, leukotriene inhibitors, anticholinergics, anti-histamines, therapeutic compounds, compounds known to be effective for inhibiting the gag reflex of a mammal, and combinations thereof.
  • the compositions of the present invention are free or essentially free of components that may be irritative to the mucosa, e.g., the nasal- paranasal mucosa.
  • the compositions of the present invention are free or essentially free of solvent, e.g., propylene glycol.
  • the compositions of the present invention are free or essentially free of antioxidants, e.g., sodium metabisulfate.
  • the compositions of the present invention are free or essentially free of a thickening or suspending agent, e.g., carboxymethylcellulose sodium.
  • compositions of the present invention are free or essentially free of antimicrobials, e.g., methylparaben and/or propylparaben.
  • compositions of the present invention are free or essentially free of bile salts and/or emulsifiers, e.g., deoxycholate salts such as sodium deoxycholate.
  • compositions of the present invention are free or essentially free of combinations or mixtures of one or more solvents ⁇ e.g., propylene glycol), antioxidants (e.g., sodium metabisulfate), thickening or suspending agents (e.g., carboxymethylcellulose sodium), antimicrobials (e.g., methylparaben and/or propylparaben), bile salts and/or emulsifiers (e.g., deoxycholate salts).
  • solvents e.g., propylene glycol
  • antioxidants e.g., sodium metabisulfate
  • thickening or suspending agents e.g., carboxymethylcellulose sodium
  • antimicrobials e.g., methylparaben and/or propylparaben
  • bile salts and/or emulsifiers e.g., deoxycholate salts.
  • the solid and liquid compositions of the present invention are stable over a desired period of time.
  • the compositions of the present invention are at least 95% stable over 3 months, hi some embodiments, the compositions of the present invention are at least 95% stable over 6 months, hi some embodiments, the compositions of the present invention are at least 95% stable over 9 months.
  • the compositions of the present invention are at least 95% stable over 12 months.
  • the compositions of the present invention are at least 90% stable over 18 months.
  • the compositions of the present invention are at least 95% stable over 18 months.
  • the compositions of the present invention are at least 99% stable over 18 months.
  • compositions of the present invention may be enhanced by storage and/or preparation under an inert (e.g., nitrogen) atmosphere. Accordingly, in some embodiments, the compositions of the present invention are at least about 10% more stable under a nitrogen atmosphere than under an oxygen atmosphere. In some embodiments, the compositions of the present invention are at least about 15% more stable under a nitrogen atmosphere than under an oxygen atmosphere, hi some embodiments, the compositions of the present invention are at least about 20% more stable under a nitrogen atmosphere than under an oxygen atmosphere.
  • an inert e.g., nitrogen
  • the liquid compositions of the present invention are at least about 80% stable for up to 18 months or longer under an inert gas atmosphere (e.g., nitrogen or other inert gas such as argon, helium, carbon dioxide). In some embodiments, the compositions of the present invention are at least about 84% stable for up to 18 months or longer under an inert gas atmosphere (e.g., nitrogen or other inert gas such as argon, helium, carbon dioxide). In some embodiments, the compositions of the present invention are at least about 50% more stable under an inert gas atmosphere (e.g., nitrogen or other inert gas such as argon, helium, carbon dioxide) than under an oxygen atmosphere for up to 18 months or longer.
  • an inert gas atmosphere e.g., nitrogen or other inert gas such as argon, helium, carbon dioxide
  • an oxygen atmosphere for up to 18 months or longer.
  • the compositions of the present invention provide a low plasma concentration of antifungal agent.
  • the plasma concentration does not exceed about 25ng/mL when administered in a dosage of about 0.11 mg/kg per day.
  • the plasma concentration does not exceed about 20 ng/mL when administered in a dosage of about 0.11 mg/kg per day.
  • the plasma concentration does not exceed about 15 ng/mL when administered in a dosage of about 0.11 mg/kg per day.
  • the plasma concentration does not exceed about 10 ng/mL when administered in a dosage of about 0.11 mg/kg per day.
  • compositions of the present invention include antifungal agents other than amphotericin B.
  • Suitable antifungal agents include, but are not limited to, flucytosine, ketoconazole, miconazole, itraconazole, fluconazole, griseofulvin, clotrimazole, econazole, terconazole, butoconazole, oxiconazole, sulconazole, saperconazole, voriconazole, ciclopirox olamine, haloprogin, tolnaftate, naftifme, terbinafine hydrochloride, morpholines, nystatin, natamycin, butenafine, undecylenic acid, Whitefield's ointment, propionic acid, and caprylic acid.
  • compositions of the present invention can include a non-irritative mixture of itraconazole and a pharmaceutically acceptable carrier.
  • the antifungal agent of the composition used in the present invention includes at least one agent selected from the group consisting of: methyl and propyl parabens, sodium benzoate, benzyl alcohol, potassium sorbate, sodium metabisulf ⁇ te, thimerasol, hydrogen peroxide, sodium perborate, polyquad, polyhexamethylene, sodium silver chloride, polyquaternium-1, chlorobutanol, benzylalkonium chloride or quaternary ammonium salts.
  • Quaternary ammonium salts include compounds of the following formula:
  • N has a valency of 5;
  • R 1 , R 2 , R "5 , R 4 are the same or different and are independently chosen from H, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, an acyl group, or a thioacyl group; and X is an anion, preferably a halogen.
  • the quaternary ammonium salt is cetylpyridinium chloride.
  • the compositions of the present invention further include one or more polysaccharide degrading enzymes.
  • polysaccharide degrading enzyme refers to an enzyme that cleaves glycosidic bonds. Without wishing to be bound by any particular theory, it is believed that such an enzyme would cleave the glycosidic bonds of polysaccharides present in mucus and, thereby aid in breaking up thick secretions, e.g., by reducing the viscosity of mucus.
  • Examples of a polysaccharide degrading enzyme include, but are not limited to, ⁇ -glucosidase, pullulanase, neuraminidase and hyaluronidase. In a particular embodiment, the polysaccharide degrading enzyme is hyaluronidase.
  • the present invention provides coadministration of a mucosally non-irritative antifungal formulation and a polysaccharide degrading enzyme.
  • the polysaccharide degrading enzyme can be, e.g., any polysaccharide degrading enzyme listed above.
  • the polysaccharide degrading enzyme is hyaluronidase.
  • compositions of the present invention include an amount of amphotericin B or other antifungal agent which can be mucoadministered to a subject at a frequency and for a duration effective to treat or prevent non-invasive fungus- induced mucositis.
  • An effective amount of amphotericin B or other antifungal or composition including amphotericin B can be any amount that reduces, prevents, or eliminates non-invasive fungus-induced mucositis upon mucoadministration in a subject without producing significant toxicity to the subject.
  • an effective amount can be any amount greater than or equal to the minimum inhibitory concentration (MlC) for a fungal organism or isolate present within a particular individual's mucus that does not induce significant toxicity to the individual upon mucoadministration.
  • the effective amount can vary depending upon the specific fungal organism or isolate since certain organisms and isolates are more or less susceptible to particular antifungal agents.
  • Such effective amounts can be dete ⁇ nined using commonly available or easily ascertainable information involving antifungal effectiveness concentrations, animal toxicity concentrations, and tissue permeability rates. Using the information provided herein, such effective amounts also can be determined by routine experimentation in vitro or in vivo.
  • a patient having a non-invasive fungus-induced mucositis condition can receive direct mucoadministration of an antifungal agent in an amount close to the MIC calculated from in vitro analysis. If the patient fails to respond, then the amount can be increased by, for example, ten fold. After receiving this higher concentration, the patient can be monitored for both responsiveness to the treatment and toxicity symptoms, and adjustments made accordingly.
  • an effective amount can be about 0.01 ng to about 1000 mg per kg of body weight of the mammal per administration when mucoadministered.
  • an effective amount can be a volume of about 0.01 mL to about 1 liter per nostril per administration of a solution containing about 0.01 mg of amphotericin B per liter to about 1000 mg of amphotericin B per liter.
  • compositions of the present invention can include 0.01 mg, 0.10 mg, 0.25 mg, 0.50 mg, 0.75 mg, 1.0 mg, 5 mg, 10 mg, 25 mg, 50 mg, 75 mg, 100 mg, 250 mg, 500 mg, 750 mg, or 1000 mg of amphotericin B per liter of liquid carrier.
  • Exemplary volumes of such solutions to be administered can include 0.01 mL, 0.10 mL, 0.25 mL, 0.50 mL, 0.75 mL, 1.0 mL, 5 mL, 10 mL, 25 mL, 50 mL, 75 mL, 100 mL, 250 mL, 500 mL, 750 mL, or 1 L.
  • the composition includes between about 50 ⁇ g and about 1000 ⁇ g per milliliter of sterile water, e.g., between about 100 ⁇ g and about 500 ⁇ g per milliliter of sterile water. In some embodiments, the composition includes about 100 ⁇ g of Amphotericin B per milliliter of sterile water. In other embodiments, the effective amount includes about 5 mL to about 100 mL of the composition per nostril of the subject. In still other embodiments, an effective amount comprises about 20 mL of the composition per nostril of the subject. In some embodiments, about 0.01 mL to about IL of the composition is administered to each nostril of the subject. In some embodiments, about 0.01 mL to about 5 mL of the composition is administered to each nostril of the subject.
  • mucoadministration is achieved via a pump spray. Accordingly, in some embodiments, mucoadministration includes from 1 to 4 pumps per nostril, e.g., 3 pumps per nostril. In some embodiments, the pump dispenses between about 50 ⁇ L and about 200 ⁇ L of the composition, e.g., about 100 ⁇ L of the composition. In other embodiments, an effective amount is 20 mL per nostril per administration (e.g., two to four times daily) of an irrigation solution containing about 100 mg of amphotericin B per liter of saline or water. In some embodiments, about 0.01 mL to about I L of the composition is administered to each nostril of the subject by a pump spray.
  • about 0.01 mL to about 5 mL of the composition is administered to each nostril of the subject by a pump spray.
  • Any effective amount of amphotericin B described herein may be used provided that it is ⁇ rucosally non-irritative and not toxic to the subject.
  • the effective amount can remain constant or can be adjusted as a sliding scale or variable dose depending on the individual's response to treatment. It is to be understood that the volume administered can be administered in one single event or in multiple events. For example, 20 mL per nostril of an irrigation solution containing about 100 mg of amphotericin B per liter of saline or water can be administered as a continuous irrigation, wash or spray of the entire 20 mL.
  • administration can include two or more sequential applications of a portion of the exemplary 20 mL (e.g., 2 washes/sprays of 1OmL each, 4 washes/sprays of 5 mL each, etc.). It is also to be understood that, when a volume is administered via two or more sequential applications, each application need not be equivalent to the previous application. For example, 20 mL of a formulation can be administered via 1 wash/spray of 10 mL followed by 2 washes/sprays of 5 mL each.
  • a nonirritative composition of the present invention having a concentration of between about 50 ⁇ g/ml (amphotericin B/liquid carrier, e.g., sterile water) and about 1000 ⁇ g/ml, e.g., between about 100 ⁇ g/ml and about 500 ⁇ g/ml, can be administered by a pump from one to four times daily (e.g., three times daily).
  • Each pump can have a volume of between about 50 ⁇ L and about 200 ⁇ L, e.g., a volume of about 100 ⁇ L.
  • each single mucoadministration event can include from one to four pumps per nostril, e.g., three pumps per nostril.
  • the frequency of mucoadministration can be any frequency that reduces, prevents (delays onset of), or eliminates non-invasive fungus-induced mucositis in a mammal without producing significant toxicity to the mammal.
  • the frequency of mucoadministration can be from about four times a day to about once a month, or more specifically, from about twice a day to about once a week.
  • the frequency of mucoadministration can be four times a day, three times a day, two times a day, once a day, every other day, every third day, twice a week, once a week, once every two weeks, once ever ⁇ ' three weeks, or once a month.
  • the frequency of mucoadministration can remain constant or can be variable during the duration of treatment.
  • the first three doses may occur within day one at a frequency of three times a day, but the next four doses may be administered at a frequency of twice a day, once a day, etc.
  • the effective amount various factors can influence the actual frequency of mucoadministration used for a particular application.
  • the effective amount, duration of treatment, combination of other antifungal agents, site of administration, degree of inflammation, and the anatomical configuration of the treated area may require an increase or decrease in mucoadministration frequency.
  • An effective duration for antifungal agent mucoadministration can be any duration that reduces, prevents, or eliminates non-invasive fungus-induced mucositis in a mammal without producing significant toxicity to the mammal.
  • the effective duration can vary from several days to several weeks, months, or years.
  • the effective duration for the treatment of non-invasive fungus-induced mucositis can range in duration from several days to several months. Once the antifungal applications are stopped, however, non-invasive fungus-induced mucositis may return.
  • the effective duration for the prevention of non-invasive fungus-induced mucositis can last in some cases for as long as the individual is alive.
  • an effective duration is at least 7 days.
  • an effective duration is at least 14 days.
  • an effective duration is at least 30 days, 60 days, 90 days, 3 months, 6 months, 9 months, 1 year or more.
  • an effective duration can vary with the frequency of amphotericin B administration, effective amount, combination of amphotericin B with other agents (e.g., other antifungal agents), site of administration, degree of inflammation, and anatomical configuration of the treated area.
  • agents e.g., other antifungal agents
  • diagnostic algorithm methods can be devised to determine or reflect appropriate effective doses, durations, and frequencies without any undue experimentation.
  • the present invention provides a method for preparing a mucosally non-irritative anti-fungal composition for storage, comprising: providing a suspension of amphotericin B or other anti-fungal agent in de-oxygenated water; and placing the suspension in a sealed container under an inert atmosphere (e.g., nitrogen or another inert gas such as argon or helium).
  • an inert atmosphere e.g., nitrogen or another inert gas such as argon or helium
  • the container is opaque or light- proof.
  • the method further comprises storing the composition in the sealed container for a period of time selected from the group consisting of at least one month, at least 2 months, at least 3 months, at least 6 months, at least 9 months, at least 12 months, and at least 18 months.
  • the de-oxygenated amphotericin B suspension may be provided, for example, by introducing nitrogen or another inert gas (such as argon or helium) into a volume of water (e.g., sparging) for a time sufficient to deoxygenate the water (partially or fully); and combining amphotericin B with the volume of water during or after deoxygenation, to form a suspension.
  • the suspension is mixed during and/or after deoxygenation. Mixing can be carried out, for example, by agitation, static mixing, or utilization of an impeller.
  • Introduction of the inert gas may be earned out under room temperature and normal atmospheric pressure; however, dissolved oxygen may be reduced further by introducing the inert gas under vacuum conditions. Steps in the method of the invention can be carried out in an automated, high-throughput fashion.
  • the sealed containers may be any suitably clean (sterile) vessels such as vials.
  • the sealed containers can be constructed of one or more suitable materials, such as glass, polymers, plastics, resins, polysaccharides, silica or silica-based materials, carbon, metals and alloys, or membranes.
  • suitable materials such as glass, polymers, plastics, resins, polysaccharides, silica or silica-based materials, carbon, metals and alloys, or membranes.
  • suitable materials such as glass, polymers, plastics, resins, polysaccharides, silica or silica-based materials, carbon, metals and alloys, or membranes.
  • Other examples include polacryloylmorpholide, silica, controlled pore glass (CPG), polystyrene, polystyrene/latex, polyethylene, polyamide, carboxyl modified teflon, nylon and nitrocellulose.
  • the container is a disposable thermoplastic material.
  • suitable materials will be
  • the sealed containers are made essentially of foil. In some embodiments, the sealed containers are pharmaceutical "blister packs". In some embodiments, the sealed containers have a casing that can be perforated at at least one point by a sharp object to gain access to the liquid composition, without completely destroying the container. In some embodiments, the sealed containers are pre-filled delivery devices for mucoadministration of the liquid composition contained therein, or function as reservoirs for the delivery of the active agent in delivery devices such as inhalers. The sealed container is opened, or access to the liquid composition is otherwise gained, prior to mucoadministration.
  • the present invention provides methods for treating non-invasive fungus-induced mucositis.
  • the method generally includes the mucoadministration of any of the compositions provided herein to a subject.
  • the non -irritative compositions of the present invention are suitable for administration to the mucosa (e.g., for mucoadministration to the nasal-paranasal cavities).
  • the composition of the present invention is administered in an amount, at a frequency, and for a duration effective to reduce or eliminate the non-invasive fungus- induced mucositis.
  • eosinophils In general, most, if not all, individuals have fungal organisms living in their mucus. Normally, most individuals tolerate these non-invasive organisms and live normal disease-free lives. Some individuals do not tolerate these fungal organisms and begin to mount an immune response against them. As the immune response progresses, eosinophils accumulate within the local tissue. This accumulation of eosinophils can contribute to the formation of obstructive tissue masses (e.g., polyps and polypoid structures) as well as the transmigration of activated eosinophils from the tissue (inside the body) to the mucus (outside the body). These obstructive tissue masses appear to prevent normal cavity clearance and thus can facilitate additional fungal growth.
  • obstructive tissue masses e.g., polyps and polypoid structures
  • Eosinophil granules contain many toxic molecules such as eosinophil cationic protein (ECP), eosinophil peroxidase (EPO), and major basic protein (MBP). Upon release, these toxic molecules can damage both the targeted foreign microorganisms (e.g., fungus) as well as self tissues.
  • ECP eosinophil cationic protein
  • EPO eosinophil peroxidase
  • MBP major basic protein
  • the degree of damage caused by eosinophil accumulation and eosinophil degranulation varies significantly from slight inflammatory pain and discomfort to major structural abnormalities such as tissue and bone destruction and the formation of polyps, polypoid structures, and other tumors.
  • the present invention provides methods and compositions to reduce the amount of eosinophil and/or MBP in the mucosa of a subject.
  • the methods and compositions can be any of those described herein. It is noted that fungal organisms may be observed within the tissue under extreme mucositis conditions of tissue and bone destruction simply because the barrier (i.e., epithelium) between the inside and outside of the body has been destroyed or damaged. In these situations, the mere observed presence of a small number of fungal organisms within a localized area of tissue damage does not deter from the fact that the affliction is a non-invasive fungus-induced mucositis and not an infection.
  • Any fungal organism living in the mucus of a mammal can be a non-invasive fungal organism that is capable of inducing mucositis since it is the mere presence of the organism in an intolerant individual's mucus that causes inflammation.
  • Exemplary fungal organisms include, but are not limited to, Absidia, Aspergillus flavus, Aspergillus fumigatus, Aspergillus glaucus, Aspergillus nidulans, Aspergillus versicolor, Alternaria, Basidiobolus, Bipolaris, Candida albicans, Candida lypolytica, Candida parapsilosis, Cladosporium, Conidiobolus, Cunninahamella, Curvularia, Dreschlera, Exserohilum, Fusarium, Malbranchia, Paecilomvces, Penicillium, Pseudallescheria, Rhizopus, Schizophylum, Sporothrix, Acremonium
  • the present invention provides non -irritative methods and compositions that reduce the presence of fungal organisms within mucus to a level and for a period of time such that the characteristic inflammatory responses and resulting damages associated with mucositis are stopped, treated, or prevented ⁇ e.g., onset delayed). Mucosa from any mucosal tissue can be treated with the compositions of the present invention.
  • mucosal tissue examples include, but are not limited to, the mucosa of the mouth, gut, nasal passages, paranasal sinuses, airways of the lung, trachea, middle ear, eustachian tube, vagina, and urethra.
  • the mucosa treated in the present invention is from the nasal passages and/or paranasal sinuses.
  • the present invention provides methods for non-irritatively mucoadministering any of the compositions described herein to the nasal-paranasal cavities.
  • Mucosal tissue lines both the nasal cavity and the paranasal sinuses, and generally comprises an epithelial layer, connective tissue, and mucus glands.
  • a layer of mucus normally covers the mucosa.
  • Mucus secreted from mucosa serves to trap particles and to prevent dehydration of the nasal and paranasal tissues that are otherwise exposed to air.
  • the mucus is normally transported by cilia toward the nasopharynx and then swallowed.
  • the mucoadministration of an agent, e.g., to the nasal-paranasal anatomies can be any type of administration that places the agent in contact with mucus, e.g., direct or indirect mucoadministration.
  • the mucoadministration of a composition of the present invention is direct mucoadministration.
  • Direct mucoadministration to the nasal-paranasal anatomies can include, without limitation, nasal irrigations, nasal sprays, nasal drops, nasal inhalations, and nasal packs with, for example, saturated gauze provided the administered agent contacts nasal-paranasal mucus prior to crossing epithelium.
  • injections into the nasal-paranasal cavities using, for example, a needle or catheter tube is considered a direct mucoadministration provided the administered agent contacts nasal-paranasal mucus after leaving the needle or catheter tube and prior to crossing epithelium.
  • Any device can be used to directly mucoadminister an agent to the nasal-paranasal anatomy including, without limitation, a syringe, bulb, inhaler, canister, spray can, nebulizer, dropper, and mask.
  • a 20 mL bulb can be used to irrigate the nasal-paranasal anatomy with a liquid form of a formulation containing an antifungal agent.
  • a liquid form of a formulation can be stored at -2O 0 C, 0 0 C, or room temperature. If stored below room temperature, the formulation typically is warmed prior to application to the nasal/paranasal cavities.
  • the subject had a nasal surgery before said mucoadministration. In other embodiments, the subject was nasal surgery-free before said mucoadministration.
  • the compositions and methods of the present invention are useful for both subjects who have undergone nasal surgery as well as subjects who have never had nasal surgery.
  • mucoadministration begins during a period noncoincident with an intraoperative period, said intraoperative period being the time during a nasal surgery.
  • compositions of the present invention are useful for the treatment of any noninvasive fungus-induced musositis conditions.
  • Typical such conditions generally involve inflammations of the mucous membranes which include, but are not limited to, chronic non-invasive fungus-induced rhinosinusitis, chronic otitis media, chronic colitis, and Crohn's disease and chronic asthma symptoms.
  • the present invention provides methods for treating noninvasive fungus-induced rhinosinusitis.
  • Individuals suffering from rhinosinusitis can be identified using methods commonly known in the art.
  • Symptoms of rhinosinusitis include, without limitation, nasal airway obstruction, loss of smell, facial pain, head ache, post nasal drip, and rhinorrhea.
  • the presence of thick mucus or the visual identification of nasal or paranasal obstruction with mucus or polyps often indicates a rhinosinusitis condition.
  • the presence of nasal polyps is not a risk factor for rhinosinusitis, but rather an end stage of chronic inflammation.
  • Nasal polyps are outgrowths from the nasal-paranasal mucosa that are typically smooth, gelatinous, semitranslucent, round or pear shaped, and pale.
  • the mass of a nasal polyp is composed mainly of edematous fluid with sparse fibrous cells and a few mucous glands.
  • the surface epithelium of nasal and paranasal polyps generally reveals squamous metaplasia.
  • Eosinophils are usually present in polyps in moderate to large numbers, and it is now known that nasal polyp fluid contains greater than normal concentrations of IgA, IgE, IgG, and IgM antibodies as well as abnormally high concentrations of IL- 5, a cytokine that contributes to eosinophil activation and survival.
  • the present invention provides compositions and methods for non-irritatively treating a subject at risk for developing non-invasive fungus-induced mucositis.
  • a second formulation can include, without limitation, antifungal agents, mucolytic agents, antibacterial agents, antiinflammatory agents, immunosuppressants, dilators, vaso-constrictors, decongestants, steroids, anti-cholinergics, leukotriene inhibitors, antihistamines, therapeutic compounds, and combinations thereof.
  • this second formulation can be administered to a mammal by any route.
  • oral, intraperitoneal, intradermal, intravenous, subcutaneous, intramuscular, topical, intranasal, and intrabronchial administration can be used to deliver a second formulation to a mammal.
  • the present invention also provides a method for treating and preventing (e.g., delaying onset of) asthma using compositions as described herein.
  • Asthma can be characterized by a paradoxical narrowing of the bronchi (lung passageways) such that breathing becomes difficult.
  • Individuals suffering from asthma can exhibit symptoms such as wheezing, difficulty breathing (particularly exhaling air), dyspnea, and tightness in the chest.
  • Factors that can exacerbate asthma include rapid changes in temperature or humidity, allergies, upper respiratory infections, exercise, stress, and smoking.
  • Individuals suffering from asthma can be identified using any of the known methods in the art.
  • individuals at risk for developing chronic asthma can be prophylactically treated by mucoadministering an antifungal agent to at least a portion of the airways in an amount, at a frequency, and for a duration effective to prevent asthma symptoms.
  • an antifungal agent to at least a portion of the airways in an amount, at a frequency, and for a duration effective to prevent asthma symptoms.
  • prophylactic treatments can be similar to the methods and materials described herein for the prophylactic treatment of non-invasive fungus-induced rhinosinusitis.
  • a suspension of FUNGIZONE includes not only amphotericin B, but also sodium phosphate dibasic, sodium phosphate monobasic, and sodium desoxycholate.
  • Conventional amphotericin B formulations may also include, for example, carboxymethylcellulose sodium, sodium metabisulfite, propylene glycol, methylparaben, and propylparaben,
  • a composition of the present invention is produced by mixing amphotericin B, sodium phosphate dibasic, and sodium phosphate monobasic, e.g., in the ratios provided below.
  • amphotericin B for example 6.0 mg of amphotericin B, 956.5 mg sodium phosphate dibasic, and 577.5 mg sodium phosphate monobasic, can be mixed and placed into a foil laminate sachet. This mixture can then be reconstituted with sterile water immediately prior to use.
  • 58.5 ml sterile water can be added to provide a composition with a final amphotericin B concentration of 100 ⁇ g/ml.
  • compositions One Amphotericin B composition formulation (“Suspension”) and an exemplary composition of the present invention made from the powder formulation (“Powder”) of the present invention are listed below in Table 1. Percentages are listed for both the dry formulation (prior to the addition of sterile water) and the liquid formulations.
  • a conventional suspension of FUNGIZONE in water typically includes 50 mg Amphotericin B, 41 mg sodium desoxycholate and 20.2 mg sodium phosphates as a buffer.
  • a 7-day pilot study to evaluate the feasibility of repeated nasal lavage administrations of phosphate buffer, placebo and 5x drug to Gottingen mini pigs was performed.
  • One treatment group of two female Gottingen mini-pig swine were administered a composition formulated from the "Powder" formulation as described in Example 1 , at a dose concentration of 5 times the human dose.
  • a second group of two females were administered a placebo (sodium phosphate dibasic, sodium phosphate monobasic, calcium carbonate, Yellow #5 lake, and water).
  • a third group of two females received the vehicle control, sodium phosphate dibasic, sodium phosphate monobasic, and water.
  • the powder formulation, placebo, or vehicle was administered via nasal lavage, twice per day at approximately the time each day, approximately 6 hours apart, for 7 consecutive days.
  • the volume for the respective treatments was normalized against a standard weight of 70 kg.
  • the volume per nare was calculated as 2OmL x [weight animal (kg)]/[70 kg].
  • a complete physical examination was conducted on all animals pretest. Observations for mortality, morbidity, injury, and the availability of food and water were conducted twice daily for all animals. Clinical observations were conducted daily, approximately 2 hours following the first dose. Observations were made and recorded during each dose administration to document if the animal struggled and the severity of struggling. In turn, the approximate loss of dosing material, if any, during administration was recorded.
  • Body weights were measured and recorded prior to randomization on Day- 1 and at the end of the study. Blood samples for clinical pathology evaluations were collected from all animals on Day 7 prior to the terminal necropsy. At study termination (Day 8), necropsy examinations were performed, organ weights were recorded, and selected tissues were collected and preserved.
  • the three treatment groups consisted of four female and four male Gottingen mini-pig swine, and were administered a composition formulated from the "Powder" formulation as described in Example 1, at dose concentrations of IX, 5X and 1OX the human dose, respectively.
  • the powder formulation was administered via nasal lavage, twice per day at approximately the time each day, approximately 6 hours apart, for 180 consecutive days.
  • the volume for the respective treatments was normalized against a standard weight of 70 kg.
  • the volume per nare was calculated as 2OmL x [weight animal (kg)]/[70 kg].
  • compositions used in the present example maintained a low plasma level, e.g., as shown by the sample collected on day 135.
  • Figure 2 show data at sampling day-135.
  • "Sinunase" in Figure 2 refers to mucoadministered amphotericin B (in this case, nasal lavage).
  • Figure 3 and Tables 2A- 2C show plasma concentrations of amphotericin B on day-1, day-44, day-92, day-135, and day-179. Accordingly, exemplary compositions of the present invention are able to provide low absorption of Amphotericin B upon administration, e.g., administration over an extended time period.
  • Example 4 Non-lrritatively Treating and Preventing Non-Invasive Fungus-Induced Rhinosinusitis in Human Patients Rhinosinusitis patients were studied to evaluate the use of the compositions as prepared in Example 1 to treat non-invasive fungus-induced rhinosinusitis.
  • Diagnostic analysis showed that the patients had the following criteria prior to the study: (1) symptoms with a duration of greater than 12 weeks; (2) presence of observable disease within the nasal-paranasal anatomy as evidenced by a CT scan, (e.g., at least 5 mm mucosal thickening in at least 1 maxillary sinus at the level of the middle meatus); (3) endoscopy to exclude presence of polyps that are stage 4 in middle meatus and document presence of inflammation, such as polypoid thickening of the mucosa, discolored mucus or edema of the middle meatus or ethmoid area; and optionally (4) a history of at least 1 prior maxillary sinus surgery for CS consisting of antrostomy with or without polypectomy greater than or equal to 6 months prior to randomization.
  • a CT scan e.g., at least 5 mm mucosal thickening in at least 1 maxillary sinus at the level of the middle meatus
  • endoscopy to exclude presence of polyps
  • diagnostic analysis may show the presence of allergic mucus as evidenced by histologic evaluation of a surgical specimen and/or the presence of fungal organisms within nasal-paranasal mucus as evidenced by the ability to culture fungal organisms from a mucus sample.
  • the patients were administered about 20 niL of the solution per nostril (approximately one to three sprays per nostril), two to four times daily for at least three months.
  • the concentration of the amphotericin B solution was 100 mg per liter of sterile water.
  • Stage 0 no evidence of disease
  • Stage 1 polypoid changes/polyps seen by endoscopy only
  • Stage 2 polyps in the middle meatus
  • Stage 3 polyps filling the nasal cavity.
  • Patient Symptom Evaluation Stage -2 very bad/much worse
  • Stage -1 bad/worse
  • Stage 0 baseline/no change
  • Stage 1 good/improved
  • Stage 2 very good/free of symptoms.
  • compositions of the invention and the placebo provided an improvement in polyposis by endoscopy in about 50% of patients and improvement in sinus inflammation by CT scan in approximately 50% of patients.
  • B compositions are non-irritative and can be used to effectively treat non-invasive fungus-induced rhinosinusitis. As shown by the results in Table 3, there were statistically significant improvements in all measured symptoms of non-invasive fungus-induced rhinosinusitis.
  • ACC-05-01 Phase 3 (Amphotericin B arm) changes from baseline to 16-weeks (population is Intent to Treat) mean change from baseline to std. p-value (paired t-test, WiScoxon
  • AmphoB s6 face pain 147 -0.782 1.57 2.70E-08
  • AmphoB s7 face press 147 -0.891 1.59 4.27E-09
  • 3.34E-10 AmphoB s10 anosmia 146 -0.568 1.54 4.45E-06
  • amphotericin B composition used in the study demonstrated a 2-4% incidence of nasal burning compared to a 15-20% incidence of burning and irritation in previous compositions. As shown in Table 4 below, after the 16- week administration of
  • Amphotericin B solution subjects generally experienced extremely low levels of treatment-related adverse events.
  • the study conclusions showed that there was no statistically-significant difference in symptoms suggestive of inflammation or irritation following nasal administration of the active solution relative to placebo.
  • extremely low rates of adverse events were observed in the key symptoms of nasal congestion, discomfort, dryness, inflammation, oedema, polyps, turbinate abnormalities. dermatitis, or rash.
  • Diabetes mellitus 0 1 (0 70%) 1 (0 30%)
  • Nervous system disorders 21 (14 10%) 20 (13 20%) 41 (13 60%)
  • Bladder disorder 1 (0 70%) 0 1 (0 30%)
  • Dyspnoea exertional 1 (0 70%) 0 1 (0 30%)
  • Epistaxis 8 (5 40%) 6 (3 90%) 14 (4 70%)
  • Nasal septum disorder 1 (0 70%) 0 1 (0 30%)
  • Nasal turbinate abnormality 0 1 (0 70%) 1 (0 30%)
  • Pharyngolaryngeal pain 9 (6 00%) 4 (2 60%) 13 (4 30%)
  • Pulmonary congestion 1 (0 70%) 2 (1 30%) 3 (1 00%)
  • Rhinitis allergic 6 (4 00%) 2 (1 30%) 8 (2 70%)
  • Rhinorrhoea 5 (3 40%) 6 (3 90%) 1 1 (3 70%)
  • Throat lesion 1 (0.70%) 1 (0.70%) 2 (0.70%)
  • Urticaria 1 (0.70%) 0 1 (0.30%)
  • the total number of AEs counts all AEs for patients. At each level of patient summarization, a patient is counted once if the patient reported one or more events. Percentages are based on the number of patients in each treatment group.
  • the stability of the powder compositions (regular and anhydrous) of the present invention was measured via high-performance liquid chromatography (HPLC) after the compositions were stored for an 18-month period under an oxygen atmosphere (regular composition only) and under a nitrogen atmosphere. Results were calculated as percent area under the HPLC curve. The results show that the regular powder formulation was about 93% stable under nitrogen and the anhydrous powder formulation was about 98% stable under nitrogen. This is in contrast to the regular powder formulation under oxygen, which was about 74% stable. Accordingly, the data shows that exemplary compositions of the present invention exhibit about 20% greater stability under a nitrogen atmosphere than under an oxygen atmosphere.
  • a primary mechanism of Amphotericin B degradation is oxidation, particularly in the presence of water.
  • a relatively stable suspension of Amphotericin B in water can be prepared by removing dissolved oxygen from the suspension. The process can be carried out as follows:
  • a volume of water is sparged with medical grade nitrogen with mixing for approximately 15 minutes at room temperature and pressure.
  • the flow rate of nitrogen is maintained at approximately 1 standard volume per minute per 1-10 volumes of water.
  • the suspension is allowed to mix and further deoxygenate for an additional 5-10 minutes.
  • the suspension is transferred to an airtight, light- proof container(s) under medical grade nitrogen.
  • Dissolved oxygen may be further reduced by nitrogen sparging under vacuum conditions instead of atmospheric pressure.
  • the stability of the liquid compositions of the present invention was measured via HPLC after the compositions were stored for an 18-month period under an oxygen atmosphere or under a nitrogen atmosphere at room temperature.
  • each liquid composition is expressed as a percentage of the value claimed on the label of the commercially available amphotericin B product.
  • aqueous suspensions (IX and 10X) were each about 84% stable under nitrogen. This is in contrast to the aqueous suspension under oxygen, which was about 34% stable. Accordingly, the data show that exemplary liquid compositions of the present invention exhibit about 50% greater stability under a nitrogen atmosphere than under an oxygen atmosphere.
  • Patients may have had recent nasal surgery, may be using topical and systemic steroid therapy and/or may be using an antibiotic nasal irrigation in addition to the compositions of the invention. Additionally, patients may have other diseases, e.g., asthma and/or colitis.
  • a patient diagnosed with non-invasive fungus-induced rhinosinusitis who has undergone sinus surgery previously will be instructed to mucoadminister amphotericin B twice a day using a composition as described in Example 1 or 6. After an extended period of time, e.g., nine months, the patient will undergo sinus surgery for further improvement. During the surgery mucosal biopsies will be collected and the eosinophil count will be compared to those obtained from biopsies collected from the patient during a surgery prior to the amphotericin B treatment. It is expected that the eosinophil count in the mucosal biopsies from the sinuses will be diminished to less than about 5%.
  • frontal sinus biopsy will not be diminished to less than 5% because it is sometimes difficult to mucoadminister a formulation to the frontal sinus due to frontal sinus obstruction. It is expected, however, that all properly treated areas will show diminished eosinophil counts.
  • a patient with no history or symptoms of chronic rhinosinusitis who exhibits significant asthma symptoms will be treated with an amphotericin B formulation prepared as described in Example 1 or 6. 20 mL of the formulation will be mucoadministered in each nostril at least two times daily for an extended period of time ⁇ e.g., at least about two weeks). It is expected that the patient will report no or few episodes of shortness of breath and no wheezing during the treatment period.
  • the patient will exhibit improved pulmonary function, improved forced vital capacity (FVC) of the lung, an increased forced expiratory volume in 1 second (FEVl), improved maximal forced expiratory flow (FEFmax), and/or improved maximum voluntary ventilation (MVV). It is expected that the results will demonstrate that chronic asthma symptoms can be treated and prevented by mucoadministering the compositions of the present invention to the airways.
  • FVC forced vital capacity
  • FEVl forced expiratory volume in 1 second
  • FEFmax improved maximal forced expiratory flow
  • MVV maximum voluntary ventilation

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Abstract

La présente invention concerne des compositions liquides et des procédés pour un traitement non irritant et la prévention d'une mucosite induite non invasive par un champignon. Plus particulièrement, l'invention implique des compositions liquides comprenant un mélange n'irritant pas les muqueuses d'amphotéricine B et d'un support de qualité pharmaceutique. De telles compositions peuvent être administrées par l’intermédiaire des muqueuses de manière non irritante pour empêcher, réduire ou éliminer des conditions de mucosite non invasive chronique induite par champignon. Dans certains modes de réalisation, les compositions sont stockées dans un contenant étanchéifié dans une atmosphère de gaz inerte (par exemple de l'azote) avant administration par l’intermédiaire des muqueuses, ce qui fournit une stabilité améliorée. D'autres aspects de l'invention sont des contenants étanchéifiés contenant une composition liquide qui comporte un mélange n'irritant pas les muqueuses d'amphotéricine B; un support de qualité pharmaceutique, et un espace libre de gaz inerte, comme de l'azote pur de qualité médicale.
PCT/US2009/033832 2008-02-11 2009-02-11 Formulation d'amphotéricine b liquide n'irritant pas les muqueuses, et procédé pour traiter une mucosite non invasive induite par champignon WO2009102814A2 (fr)

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US4707470A (en) * 1985-05-17 1987-11-17 Smithkline Beckman Corporation Polyene antibiotic emulsion formulation
GB8919172D0 (en) * 1989-08-23 1989-10-04 Univ Nottingham Useful composition
WO2001001955A1 (fr) * 1999-07-02 2001-01-11 Janssen Pharmaceutica N.V. Formulation comprenant un antifongique, a administrer par voie nasale
US20070286813A1 (en) * 2006-06-09 2007-12-13 Toutounghi Camille Nasal formulation

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