WO2007075798A2 - Méthodes et systèmes d'administration de corticostéroïdes à dépôt pulmonaire accru - Google Patents

Méthodes et systèmes d'administration de corticostéroïdes à dépôt pulmonaire accru Download PDF

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WO2007075798A2
WO2007075798A2 PCT/US2006/048628 US2006048628W WO2007075798A2 WO 2007075798 A2 WO2007075798 A2 WO 2007075798A2 US 2006048628 W US2006048628 W US 2006048628W WO 2007075798 A2 WO2007075798 A2 WO 2007075798A2
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Prior art keywords
cyclodextrin
corticosteroid
composition
administration
nebulizer
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PCT/US2006/048628
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English (en)
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WO2007075798A9 (fr
WO2007075798A3 (fr
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Malcolm R. Hill
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Tika Lakemedel Ab
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Priority to JP2008547495A priority Critical patent/JP2009520821A/ja
Priority to EP06848786A priority patent/EP1971349A2/fr
Publication of WO2007075798A2 publication Critical patent/WO2007075798A2/fr
Publication of WO2007075798A9 publication Critical patent/WO2007075798A9/fr
Publication of WO2007075798A3 publication Critical patent/WO2007075798A3/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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
    • 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
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/716—Glucans
    • A61K31/724—Cyclodextrins
    • 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
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/0078—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a nebulizer such as a jet nebulizer, ultrasonic nebulizer, e.g. in the form of aqueous drug solutions or dispersions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/08—Bronchodilators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/38—Drugs for disorders of the endocrine system of the suprarenal hormones
    • A61P5/40—Mineralocorticosteroids, e.g. aldosterone; Drugs increasing or potentiating the activity of mineralocorticosteroids

Definitions

  • the system also achieves at least about 80% or at least about 85% respirable fraction upon administration.
  • the nebulizer is selected from the group consisting of a jet nebulizer, an ultrasonic nebulizer, a pulsating membrane nebulizer, a nebulizer comprising a vibrating mesh or plate with multiple apertures, or a nebulizer comprising a vibration generator and an aqueous chamber.
  • the amount of the corticosteroid in the composition prior to administration is a nominal dosage of less than about 250 ug, about 120 ug, about 60 ug or about 40 ug.
  • the solubility enhancer is selected from the group consisting of propylene glycol, non-ionic surfactants, tyloxapol, polysorbate 8O 7 vitamin E-TPGS, macrogol-15-hydroxystearate, phospholipids, lecithin, purified and/or enriched lecithin, phosphatidylcholine fractions extracted from lecithin, dimyristoyl phosphatidylcholine (DMPC), dipalmitoyl phosphatidylcholine (DPPC), distearoyl phosphatidylcholine (DSPC), cyclodextrins and derivatives thereof, S AE-CD derivatives, SBE- ⁇ -CD, SBE-/3- CD, SBEl -/3-CD, SBE4-0-CD, SBE7-/3-CD, SBE- ⁇ -CD, dimethyl /S-CD, hydroxypropyl-/3-cyclodextrin, 2-HP- /S-CD, hydroxye
  • the solvent comprises water.
  • the solubility enhancer is selected from the group consisting of propylene glycol, non-ionic surfactants, tyloxapol, polysorbate 80, vitamin E-TPGS, macrogol-15-hydroxystearate, phospholipids, lecithin, purified and/or enriched lecithin, phosphatidylcholine fractions extracted from lecithin, dimyristoyl phosphatidylcholine (DMPC), dipalmitoyl phosphatidylcholine (DPPC), distearoyl phosphatidylcholine (DSPC), cyclodextrins and derivatives thereof, SAE-CD derivatives, SBE-osCD, SBE- ⁇ -CD, SBEl-P-CD, SBE4-
  • the mixture further comprises a second therapeutic agent selected from the group consisting of a beta2-adrenoreceptor agonist, a prophylactic therapeutic, and an anticholinergic agent.
  • the beta2-adrenoreceptor agonist is albuterol, levalbuterol or a pharmaceutical acceptable derivative.
  • the bronchoconstrictive disorder is selected from the group consisting of asthma, pediatric asthma, bronchial asthma, allergic asthma, intrinsic asthma, chronic obstructive pulmonary disease (COPD), chronic bronchitis, and emphysema.
  • the mixture is administered to a patient not more than once a day, twice a day or more than twice a day.
  • the composition comprises about 60, about 120, about 125, about 240, about 250, about 500, about 1000, about 1500, or about 2000 ⁇ g of budesonide.
  • the nebulizer is selected from the group consisting of a jet nebulizer, an ultrasonic nebulizer, a pulsating membrane nebulizer, a nebulize ⁇ comprising a vibrating mesh or plate with multiple apertures, or a nebulizer comprising a vibration generator and an aqueous chamber.
  • administration through the nebulizer has a delivery time of less than about 5, less than about 4, less than about 3, less than about 2, or less than about 1.5 minutes.
  • the amount of budesonide in the composition prior to administration is a nominal dosage of less than about 250 ug, about 120 ug, about 60 ug or about 40 ug.
  • the composition further comprises a second therapeutic agent selected from the group consisting of a beta2-adrenoreceptor agonist, a prophylactic therapeutic, and an anti-cholinergic agent.
  • a second therapeutic agent selected from the group consisting of a beta2-adrenoreceptor agonist, a prophylactic therapeutic, and an anti-cholinergic agent.
  • the beta2- adrenoreceptor agonist is albuterol, levalbuterol or a pharmaceutical acceptable derivative.
  • the present invention provides an inhalable composition
  • an inhalable composition comprising about 240 ⁇ g budesonide, a solvent and a solubility enhancer, wherein upon administration of the composition to a subject through a nebulizer, the composition achieves lung deposition of at least 80 ⁇ g of budesonide
  • the solvent comprises water.
  • the solubility enhancer is selected from the group consisting of propylene glycol, non-ionic surfactants, tyloxapol, polysorbate 80, vitamin E-TPGS, macrogol-15-hydroxystearate, phospholipids, lecithin, purified and/or enriched lecithin, phosphatidylcholine fractions extracted from lecithin, dimyristoyl phosphatidylcholine (DMPC), dipalmitoyl phosphatidylcholine (DPPC), distearoyl phosphatidylcholine (DSPC), cyclodextrins and derivatives thereof, SAE-CD derivatives, SBE- ⁇ -CD, SBE-/3-CD, SBEl - ⁇ -CD, SB ⁇ A- ⁇ -CD, SBE7-/3-CD, SBE- ⁇ -CD, dimethyl ⁇ - CD, hydroxypropyl-Z-t-cyclodextrin, 2-
  • the present invention provides an inhalation system for delivering a therapeutically effective dose of budesonide to a patient comprising: (a) an aqueous inhalation mixture comprising budesonide and a solubility enhancer, and (b) a nebulizer, whereby upon administration of the composition to a subject through said nebulizer, the system achieves at least about 35% lung deposition based on the amount of budesonide in the mixture prior to administration. In certain embodiments, the system achieves at least about 40% lung deposition based on the amount of budesonide in the mixture prior to administration. In certain embodiments, the system also achieves at least about 80% or at least about 85% respirable fraction upon administration.
  • the method also achieves at least about 80% or at least about 85% respirable fraction upon administration.
  • the mixture comprises about 60, about 120, about 125, about 240, about 250, about 500, about 1000, about 1500, or about 2000 ⁇ g of budesonide.
  • the amount of budesonide in the composition prior to administration is a nominal dosage of less than about 250 ug, about 120 ug, about 60 ug or about 40 ug.
  • under the same conditions can mean that the corticosteroid that is administered is the same. In other embodiments, “under the same conditions” can mean that the route of delivery of the corticosteroid is the same. In yet other embodiments, “under the same conditions” means that the time of administration of the corticosteroid is the same. In still other embodiments, “under the same conditions” means that the nominal dosage of the corticosteroid administered to the subject is the same. In yet still other embodiments, “under the same conditions” means that the number of doses administered is the same. In other embodiments, “under the same conditions” can mean that the time of administration for the corticosteroid is the same, but the nominal dosage of the corticosteroid is different.
  • Inhaled aqueous mixture generally refer to any aqueous (including partially aqueous) dosage form for the inhaled delivery of an active agent other than a suspension.
  • suitable aqueous mixtures or inhalable compositions include, but are not limited to, solutions, dispersions, nanoparticulate dispersions, nanoparticulate suspensions, emulsions, colloidal liquids, micelle or mixed micelle liquids, and liposomal liquids.
  • Other suitable inhaled aqueous mixtures also include suspensions to which solubility enhancers have been added and at least part of the initial suspension has increased solubility.
  • inhaled aqueous mixture "aqueous inhalation mixture,” or
  • the inhalable composition is a solution comprising a corticosteroid, such as budesonide, and a solubility enhancer.
  • the inhalable composition is an emulsion comprising a corticosteroid, such as budesonide, and a solubility enhancer.
  • budesonide prior to administration, should have a nominal dosage, as used herein, of about 1000 ⁇ g/dose if the entire contents of the unit dose ampoule is put into a delivery device, e.g. a nebulize, for administration to a patient.
  • a delivery device e.g. a nebulize
  • Enhanced pharmacokinetic profile refers to a pharmacokinetic profile wherein one drug formulation (test formulation) displays increased absorption or distribution at the drug's site of action as compared to another drug formulation (reference formulation).
  • an enhanced pharmacokinetic profile can be quantified on the basis of the increase in absorption or distribution at the drug's site of action of a aqueous inhalation mixture as compared to a inhalable suspension.
  • a two-fold enhanced pharmacokinetic profile results when administration of an aqueous inhalation mixture displays a pharmacokinetic profile wherein the numerical values representing the absorption or distribution at the drug's site of action values of the aqueous .inhalation mixture are at least twice (2X) the numerical values representing the absorption or distribution at the drug's site of action values of an inhalable suspension.
  • “enhanced lung deposition,” as used herein, refers to lung deposition of a compound wherein one drug formulation (e.g. aqueous inhalation mixture) displays increased total lung deposition as compared to another drug formulation (e.g. inhalable suspension).
  • the inhalable suspension can be Pulmicort® Respules.
  • an effect amount or “a therapeutically effective amount” can vary from subject to subject, and population to population, due to variation in metabolism of a corticosteroid, such as budesonide, age, weight, general condition of the subject, the condition being treated, the severity of the condition being treated, and the judgment of the prescribing physician.
  • a corticosteroid such as budesonide
  • the inhalable composition comprises an amount of corticosteroid in the composition prior to administration of about 40 ⁇ g of a corticosteroid. In another embodiment, the inhalable composition comprises an amount of corticosteroid in the composition prior to administration of about of 60 ⁇ g of a corticosteroid. In still another embodiment, the inhalable composition comprises an amount of corticosteroid in the composition prior to administration of about 100 ⁇ g of a corticosteroid. In yet another embodiment, the inhalable composition comprises an amount of corticosteroid in the composition prior to administration of about 120 ⁇ g of a corticosteroid.
  • the corticosteroid is budesonide wherein the budesonide is eitheT an individual diastereome ⁇ or a mixture of the two diastereomers administered individually or together for a therapeutic effect.
  • the inhalable compositions comprise an effective amount of a single corticosteroid, and a solubility enhancer and are substantially free of active pharmaceutical agents other than corticosteroid.
  • the inhalable compositions comprises an effective amount of budesonide, and a solubility enhancer and are substantially free of active pharmaceutical agents other than the budesonide.
  • suitable inhalable compositions comprising a corticosteroid include, but are not limited to, solutions, dispersions, nanoparticulate dispersions, emulsions, colloidal liquids, micelle or mixed micelle solutions, and liposomal liquids.
  • the aqueous inhalation mixture is a solution comprising a corticosteroid, such as budesonide, and a solubility enhancer.
  • the aqueous inhalation mixture is a mixed micelle solution comprising a corticosteroid, such as budesonide, and a solubility enhancer.
  • the aqueous inhalation mixture is a liposomal solution comprising a corticosteroid, such as budesonide, and a solubility enhancer.
  • the inhalable composition is a solution comprising a corticosteroid, such as budesonide, and a solubility enhancer.
  • the inhalable composition is an emulsion comprising a corticosteroid, such as budesonide, and a solubility enhancer.
  • suitable cyclodextrins or cyclodextrin derivatives for use in the present invention include, but are not limited to, a- cyclodextrins, /3-cyclodextrins, ⁇ -cyclodextrins, SAE-CD derivatives (e.g., SBE- ⁇ -CD, SBE- ⁇ -CD, SBEl - ⁇ - CD, SBE4-/3-CD, SBE7-/3-CD (Captisol®), and SBE- ⁇ -CD) (Cydex, Inc.
  • SAE-CD derivatives e.g., SBE- ⁇ -CD, SBE- ⁇ -CD, SBEl - ⁇ - CD, SBE4-/3-CD, SBE7-/3-CD (Captisol®), and SBE- ⁇ -CD
  • Examples for enriched or pure compounds are dimyristoyl phosphatidyl choline (DMPC), distearoyl phosphatidyl choline (DSPC) and dipalmitoyl phosphatidyl choline (DPPC).
  • DMPC dimyristoyl phosphatidyl choline
  • DSPC distearoyl phosphatidyl choline
  • DPPC dipalmitoyl phosphatidyl choline
  • DMPC dimyristoyl phosphatidyl choline
  • DSPC distearoyl phosphatidyl choline
  • DPPC dipalmitoyl phosphatidyl choline
  • phospholipids with oleyl residues and phosphatidyl glycerol without choline residue are suitable for some embodiments and applications of the invention.
  • the processes for producing nanometer sized particles can permit selection of a desired morphology (e.g., amorphous, crystalline, resolved racemic) by appropriate adjustment of the conditions for particle formation during precipitation or condensation. As a consequence of selection of the desired particle form, extended release of the selected medicament can be achieved.
  • These particle fabrication processes are used to obtain nanoparticulates that have high purity, low surface imperfections, low surface charges and low sedimentation rates. Such particle features inhibit particle cohesion, agglomeration and also prevent settling in liquid dispersions. Additionally, because processes such as SCF can separate isomers of certain medicaments, such separation could contribute to the medicament's enhanced activity, effectiveness as well as extreme dose reduction.
  • an aqueous inhalation mixture can be a composition fabricated into a powdered form by any process including SCF, spray drying, precipitation and volume exclusion, directly into a collection media, wherein the particulate compound is thus automatically generated into a dispersed formulation.
  • this formulation can be the final formulation.
  • the inhalable composition can further comprise a second therapeutic agent selected from the group consisting of a beta2-adrenoreceptor agonist, a dopamine (D2) receptor agonist, an anti-cholinergic agent, and a prophylactic therapeutic.
  • second therapeutic agent is a beta2-adrenoreceptor agonist selected from the group comprising albuterol, levalbuterol or pharmaceutical acceptable derivatives thereof.
  • Albuterol inhalation aerosol is indicated for the prevention and relief of bronchospasm in patients 4 years of age and older with reversible obstructive airway disease and for the prevention of exercise-induced bronchospasm in patients 4 years of age and older.
  • Albuterol inhalation solution is indicated for the relief of bronchospasm in patients 2 years of age or older with reversible obstructive airway disease and acute attacks of bronchospasm.
  • Levalbuterol HCl (R)-al-[[(l,l- dimethylethyl)ami ⁇ o]methyl]-4-hydroxy-l,3-benzenedimethanol hydrochloride, having chemistry formula as C13H21NO3-HC1, a relatively selective beta2-adrenergic receptor agonist and is the (R)-enantio ⁇ ner of the drug albuterol.
  • Xopenex (levalbuterol HCl) Inhalation Solution is supplied in unit-dose vials and requires nodilution before by nebulization.
  • Each 3 mL unit-dose vial contains either 0.63 mg of levalbuterol (as 0.73 mg of levalbute ⁇ ol HCl) or 1.25 rng of levalbuterol (as 1.44 mg of levalbuterol HCl), sodium chloride to adjust tonicity, and sulfuric acid to adjust the pH to 4.0 (3.3 to 4.5).
  • Xopenex (levalbuterol HCl) Inhalation Solution is indicated for the treatment or prevention of bronchospasm in adults and adolescents 12 years of age and older with reversible obstructive airway disease.
  • IL-5 inhibitors such as those disclosed in U. S. Patents No. 5,668,110, No. 5,683,983, No. 5,677,280, No. 6,071,910 and No. 5,654,276, each of which is incorporated by reference herein; anti-sense modulators of IL-5 such as those disclosed in U. S. Pat. No. 6,136,603, the relevant disclosure of which is hereby incorporated by reference; milrinone (1, 6-dihydro-2-methyl-6-oxo-[3, 4'-bipyridine]-5-carbonitrile); milrinone lactate; tryptase inhibitors such as those disclosed in U.
  • the inhalable composition is administered to a patient not more than once a day. In other embodiments, the inhalable composition is administered to a patient not more than twice a day. In some embodiments of this invention, the composition is administered to a patient twice a day or more than twice a day. In still other embodiments, the inhalable composition is administered to a patient not more than once a day in the evening.
  • the inhalable composition achieves at least about 10% higher lung deposition compared to an inhalable suspension comprising the corticosteroid administered under the same conditions. In still other embodiments, the inhalable composition achieves at least about 15% higher lung deposition compared to an inhalable suspension comprising the corticosteroid administered under the same conditions. In yet other embodiments, the inhalable composition achieves at least about 20% higher lung deposition compared to an inhalable suspension comprising the corticosteroid administered under the same conditions. In still yet other embodiments, the inhalable composition achieves at least about 25% higher lung deposition compared to an inhalable suspension comprising the corticosteroid administered under the same conditions. In certain embodiments, the inhalable compositions comprising an effective amount of a corticosteroid, a solvent and a solubility enhancer are substantially free of active pharmaceutical agents other than corticosteroids.
  • the inhalable compositions comprising an effective amount of a corticosteroid, a solvent and a solubility enhancer achieves about the same lung deposition of the corticosteroid as compared to an inhalable suspension comprising the corticosteroid, wherein the composition is administered at a lower nominal dosage than the inhalable suspension.
  • the inhalable composition achieves about 90% to 110% lung deposition of the corticosteroid as compared to an inhalable suspension comprising the corticosteroid, wherein the composition is administered at a lower nominal dosage than the inhalable suspension.
  • the inhalable composition achieves about 80% to 120% lung deposition of the corticosteroid as compared to an inhalable suspension comprising the corticosteroid, ⁇ vhe ⁇ ein the composition is administered at a lower nominal dosage than the inhalable suspension. In some embodiments of this invention, the inhalable composition achieves about 70% to 130% lung deposition of the corticosteroid as compared to an inhalable suspension comprising the corticosteroid, wherein the composition is administered at a lower nominal dosage than the inhalable suspension. In certain embodiments, the inhalable compositions comprising an effective amount of a corticosteroid, a solvent and a solubility enhancer are substantially free of active pharmaceutical agents other than corticosteroids.
  • compositions of the present invention can also be administered with a pressurized metered dose inhaler (pMDI).
  • pMDI pressurized metered dose inhaler
  • a typical pMDI comprises a propellant, surfactant, and a drug in dissolved or suspended form.
  • the device is designed to be portable and inexpensive as well as protecting the drug from light, oxygen, of moisture, and providing constant metering volume upon administration. Small spray particle size can be achieved after complete propellant evaporation. More volatile propellant used (evaporates faster), smaller particle size can be achieved. The most common technical difficulty is the drug's solubility in propellant. Therefore, solubility enhancers of this invention provide methods and systems for effective administration of corticosteroid, beta2-adrenreceptor agonist, or their combination using MDI.
  • the nebulizer is selected from the group consisting of Pari LC Jet Plus, Intertech, Baxter Misty-Neb, Hudson T- Updraft II, Hudson Ava-Neb, Aiolos, Pari LC Jet, DeVilbiss Pulmo-Neb, Hudson Iso-Neb (B), Hudson T- Updraft Neb-U-Mist, Pari-Jet 1460, and AeroTech with T-piece.
  • the nebulizer is a Pari eFlow nebulizer.
  • the composition achieves a rate of increasing concentration of the corticosteroid inside the device of about 3.5 ⁇ g/ml per minute or less over the first three minutes of administration.
  • the inhalable compositions comprise about 500 ⁇ g or less of a corticosteroid.
  • the inhalable compositions comprise about 250 ⁇ g or less of a corticosteroid.
  • the inhalable compositions comprise about 240 ⁇ g or less of a corticosteroid.
  • the inhalable compositions comprise about 120 ⁇ g or less of a corticosteroid.
  • the inhalable compositions comprise about 60 ⁇ g or less of a corticosteroid.
  • the rate of increasing concentration of the corticosteroid inside the device is achieved over the first 3 minutes of administration. In another embodiment, the rate of increasing concentration of the corticosteroid inside the device is achieved during the second and third minute of administration. In still another embodiment, the rate of increasing concentration of the corticosteroid inside the device is achieved during the third minute of administration.
  • the inhalable compositions comprising an effective amount of a corticosteroid, a solvent and a solubility enhancer are substantially free of active pharmaceutical agents other than corticosteroids.
  • the corticosteroid is budesonide or a pharmaceutical acceptable derivative.
  • the inhalable compositions comprising corticosteroid, a solvent and a solubility enhancer composition which can achieve a rate of increasing concentration of the corticosteroid inside the device of about 5 ⁇ g/ml per minute or less over the timeof administration comprise about 15 to about 500 ⁇ g of a corticosteroid.
  • the inhalable composition comprises about 50 to about 500 ⁇ g of a corticosteroid.
  • the inhalable composition comprises about 60 to about 250 ⁇ g of a corticosteroid.
  • the composition comprises about 125 to about 500 ⁇ g of a corticosteroid.
  • the inhalable composition comprises about 40, 60, 120, 125, 240, 250, 500, 1000, 1500, or 2000 ⁇ g of a corticosteroid. In one embodiment, the inhalable composition comprises nominal dosage about of about 40 ⁇ g of a corticosteroid. In another embodiment, the inhalable composition comprises nominal dosage about of about 60 ⁇ g of a corticosteroid. In yet another embodiment, the inhalable composition comprises nominal dosage about of about 100 ⁇ g of a corticosteroid. In still yet another embodiment, the inhalable composition comprises nominal dosage about of about 120 ⁇ g of a corticosteroid. In still another embodiment, the inhalable composition comprises nominal dosage about of about 125 ⁇ g of a corticosteroid.
  • inhalable compositions comprising a corticosteroid do not include nano-dispersions and/or nano-suspensions. In other embodiments, inhalable compositions comprising a corticosteroid do not include micelle, mixed-micelle liquids or liposomal liquids. In still other embodiments, inhalable compositions comprising a corticosteroid do not include nano-dispersions and/or nano-suspensions, micelle, mixed-micelle liquids or liposomal liquids. In other embodiments, inhalable compositions, include but are not limited to, solutions, emulsions, and colloidal liquids.
  • the inhalable composition is a solution comprising a corticosteroid, such as budesonide, and a solubility enhancer.
  • the inhalable composition is an emulsion comprising a corticosteroid, such as budesonide, and a solubility enhancer.
  • corticosteroids that are useful in the inhalable compositions described herein included, but are not limited to, aldosterone, beclomethasone, betamethasone, budesonide, ciclesonide, cloprednol, cortisone, cortivazol, deoxycortone, desonide, desoximetasone, dexamethasone, difluorocortolone, fluclorolone, flumethasone, flunisolide, fluocinolone, fluocinonide, fluocortin butyl, fluorocortisone, fluorocortolone, fluorometholone, fturandrenolone, fluticasone, halcinonide, hydrocortisone, icomethasone, meprednisone, methylprednisolone, mometasone, paramethasone, prednisolone, prednisone, rofleponide, RPR 106541,
  • the corticosteroid is budesonide. In other preferred embodiments, the corticosteroid is budesonide wherein the budesonide is either an individual diastereomer or a mixture of the two diastereomers administered individually or together for a therapeutic effect.
  • the systems and methods described herein comprise a solvent.
  • the solvent is selected from the group consisting of water, water/ethanol mixture, aqueous alcohol, propylene glycol, or aqueous organic, solvent, or combinations thereof.
  • the solvent comprises water.
  • the solvent is water.
  • the inhalable composition comprises a solubility enhancer.
  • the solubility enhancer can have a concentration (w/v) ranging from about 0.001 % to about 25%. In other embodiments, the solubility enhancer can have a concentration (w/v) ranging from about 0.01% to about 20%. In still other embodiments, the solubility enhancer can have a concentration (w/v) ranging from about 0.1% to about 15%. In yet other embodiments, the solubility enhancer can have a concentration (w/v) ranging from about 1% to about 10%.
  • KS Lenexa, KS
  • hydroxyethyl, hydroxypropyl (including 2-and 3-hydroxypropyl) and dihydroxypropyl ethers their corresponding mixed ethers and further mixed ethers with methyl or ethyl groups, such as methylhydroxyethyl, ethyl-hydroxyethyl and ethyl- hydroxypropyl ethers of os-, ⁇ - and ⁇ -cyclodextrin; and the maltosyl, glucosyl and maltotriosyl derivatives of a-, ⁇ - and ⁇ -cyclodextrin, which may contain one or more sugar residues, e. g.
  • micelles or mixed micelles may be formed by the surfactants, in which poorly soluble active agents can be solubilized.
  • micelles are understood as substantially spherical structures formed by the spontaneous and dynamic association of amphophilic molecules, such as surfactants.
  • Mixed micelles are micelles composed of different types of amphiphilic molecules. Both micelles and mixed micelles should not be understood as solid particles, as their structure, properties and behavior are much different from solids.
  • the amphiphilic molecules which form the micelles usually associate temporarily. In a micellar solution, there is a dynamic exchange of molecules between the micelle-forming amphiphile and monomolecularly dispersed amphiphiles which are also present in the solution.
  • corticosteroid compositions such as budesonide
  • budesonide particles are fabricated into particles with narrow particle size distribution (usually less than 200 nanometers spread) with a mean particle hydrodynamic radius in the range of 50 nanometers to 700 nanometers.
  • the nano-sized corticosteroid particles, such as budesonide particles are fabricated using Supercritical Fluids (SCF) processes including Rapid Expansion of Supercritical Solutions (RESS), or Solution Enhanced Dispersion of Supercritical fluids (SEDS), as well as any other techniques involving supercritical fluids.
  • SCF Supercritical Fluids
  • RESS Rapid Expansion of Supercritical Solutions
  • SEDS Solution Enhanced Dispersion of Supercritical fluids
  • the inhalable compositions comprising an effective amount of a single corticosteroid, a solvent and a solubility enhancer and are substantially free of active pharmaceutical agents other than corticosteroids.
  • the methods can achieve at least about 25% to about 45% lung deposition based on the amount of corticosteroid in the mixture prior to administration.
  • the methods can achieve at least 35% to about 40% ⁇ lung deposition based on the amount of corticosteroid in the mixture prior to administration.
  • the composition achieves at least about 25% lung deposition based on the amount of corticosteroid in the composition prior to administration.
  • the methods of generating fine particles from an inhalable composition comprising a corticosteroid comprise an amount of corticosteroid in the composition prior to administration of about 15 to about 2000 ⁇ g of a corticosteroid.
  • the inhalable compositions comprising an effective amount of a corticosteroid, a solvent, and a solubility enhancer which can provide enhanced lung deposition comprise an amount of corticosteroid in the composition prior to administration of about 250 to about 2000 ⁇ g of a corticosteroid.
  • the inhalable compositions comprise an effective amount of a single corticosteroid, a solvent and a solubility enhancer and are substantially free of active pharmaceutical agents other than corticosteroid.
  • the inhalable compositions comprises an effective amount of a budesonide, a solvent and a solubility enhancer and are substantially free of active pharmaceutical agents other than the budesonide.
  • suitable inhalable compositions comprising a corticosteroid include, but are not limited to, solutions, dispersions, nano-dispersions, emulsions, colloidal liquids, micelle or mixed micelle solutions, and liposomal liquids.
  • the inhalable composition is a solution comprising a corticosteroid, such as budesonide, and a solubility enhancer.
  • the inhalable composition is an emulsion comprising a corticosteroid, such as budesonide, and a solubility enhancer.
  • corticosteroids that are useful in the inhalable compositions described herein included, but are not limited to, aldosterone, beclomethasone, betamethasone, budesonide, ciclesonide, cloprednol, cortisone, cortivazol, deoxycortone, desonide, desoximetasone, dexamethasone, difluorocortolone, fluclorolone, flumethasone, flunisolide, fluocinolone, fluocinonide, fiuocortin butyl, fluorocortisone, fluorocortolone, fluorometholone, flurandrenolone, fluticasone, halcinonide, hydrocortisone, icomethasone, meprednisone, methylpredm'solone, mometasone, paramethasone, prednisolone, prednisone, rofleponide, RPR 106541,
  • the inhalable composition comprises a solvent.
  • the solvent is selected from the group comprising water, aqueous alcohol, propylene glycol, or aqueous organic solvent.
  • the solvent is water.
  • the inhalable composition comprises a solubility enhancer.
  • the solubility enhancer can have a concentration (w/v) ranging from about 0.001% to about 25%. In other embodiments, the solubility enhancer can have a concentration (w/v) ranging from about 0.01% to about 20%. In still other embodiments, the solubility enhancer can have a concentration (w/v) ranging from about 0.1% to about 15%. In yet other embodiments, the solubility enhancer can have a concentration (w/v) ranging from about 1% to about 10%.
  • the solubility enhancer can have a concentration (w/v) of about 10% when the solubility enhancer is a cyclodextrin or cyclodextrin derivative,e.g. SBE7-/3-CD (Captisol®).
  • aqueous inhalation mixtures or inhalable composition comprising a corticosteroid and a solubility enhancer
  • aqueous inhalation mixtures or compositions formulated by methods which provide enhanced solubility are likewise suitable for use in the presently disclosed invention.
  • a "solubility enhancer” includes aqueous inhalation mixtures formulated by methods which provide enhanced solubility with or without a chemical agent acting as a solubility enhancer. Such methods include, e.g., the preparation of supercritical fluids.
  • the nebulizers are available from, e.g., Pan GmbH (Stamberg, Germany), DeVilbiss Healthcare (Heston, Middlesex, UK), Healthdyne, Vital Signs, Baxter, Allied Health Care, Invacare, Hudson, Omron, Bremed, AirSep, Luminscope, Medisana, Siemens, Aerogen, Mountain Medical, Aerosol Medical Ltd. (Colchester, Essex, UK), AFP Medical (Rugby, Warwickshire, UK), Bard Ltd. (Sunderland, UK), Carri-Med Ltd.
  • nebulizers suitable for use in the methods and systems describe herein include, but are not limited to, jet nebulizers (optionally sold with compressors), ultrasonic nebulizers, and others.
  • Exemplary jet nebulizers for use herein include Pari LC plus/ProNeb, Pan LC plus/ProNeb Turbo, Pan LCPlus/Dura Neb 1000 & 2000 Pari LC plus/Walkhaler, Pari LC plus/Pari Master, Pari LC star, Omron CompAir XL Portable Nebulizer System (NE-C 18 and JetAir Disposable nebulizer), Omron compare Elite Compressor Nebulizer System (NE-C21 and Elite Air Reusable Nebulizer, Pari LC Plus or Pari LC Star nebulizer with Proneb Ultra compressor, Pulomo- aide, Pulmo-aide LT, Pulmo-aide traveler, Invacare Passport, Inspiration Healthdyne 626, Pulm
  • nebulizers suitable for use in the presently described invention include nebulizers comprising a vibration generator and an aqueous chamber.
  • nebulizers are sold commercially as, e.g., Pari eFlow, and are described in U.S. Patent Nos. 6,962,151, 5,518,179, 5,261,601, and 5,152,456, each of which is specifically incorporated by reference herein.
  • nebulization such as flow rate, mesh membrane size, aerosol inhalation chamber size, mask size and materials, valves, and power source may be varied in accordance with the principles of the present invention to maximize their use with different types and aqueous inhalation mixtures or different types of corticosteroids.
  • the nebulizer is a jet nebulizer, an ultrasonic nebulizer, a pulsating membrane nebulizer, a nebulizer with a vibrating mesh or plate with multiple apertures, or a nebulizer comprising a vibration generator and an aqueous chamber.
  • Another aspect of this invention relates to a method of generating fine particles from an inhalable composition
  • a method of generating fine particles from an inhalable composition comprising forming the composition by adding a solvent and a solubility enhancer to an effective amount of corticosteroid, and operating a nebulizer to produce fine particles of said composition, wherein upon administration of the composition to a subject through the nebulizer, the composition achieves rate of increasing concentration of the corticosteroid inside the device of about 60% or less of a rate of increasing concentration of the corticosteroid inside the device achieved by an inhalable suspension comprising the corticosteroid without a solubility enhancer administered under the same conditions.
  • the methods comprise an inhalable composition comprising a single corticosteroid that is substantially free of active pharmaceutical agents other than the corticosteroid.
  • the rate of increasing concentration of the corticosteroid inside the device is achieved over the first 3 minutes of administration. In other embodiments, the rate of increasing concentration of the corticosteroid inside the device is achieved during the second and third minute of administration. In still other embodiments, the rate of increasing concentration of the corticosteroid inside the device is achieved during the third minute of administration.
  • the invention relates to an inhalable composition wherein administration of the composition through the device is achieved over five minutes or less, and administration of the inhalable suspension is achieved over five minutes or less.
  • the invention relates to an inhalable composition wherein the time of administration of the composition through the device and the time of administration of the inhalable suspension are the same.
  • the invention relates to an inhalable composition wherein the time of administration of the composition through the device and the time of administration of the inhalable suspension are different.
  • the inhalable composition also achieves at least about 60% respirable fraction upon administration. In a more preferred embodiment of this invention, the inhalable composition also achieves at least about 70% respirable fraction upon administration. In a still more preferred embodiment of this invention, the inhalable composition also achieves at least about 80% respirable fraction upon administration. In the most preferred embodiment of this invention, the inhalable composition also achieves at least about 85% respirable fraction upon administration
  • the inhalable composition comprises about 15 to about 2000 ⁇ g of a corticosteroid. In other embodiments, the composition comprises about 50 to about 2000 ⁇ g of a corticosteroid. In still other embodiments, the composition comprises about 60 to about 1500 ⁇ g of a corticosteroid. In yet other embodiments, the composition comprises about 120 to about 1000 ⁇ g of a corticosteroid. In yet still other embodiments, the composition comprises about 125 to about 500 ⁇ g of a corticosteroid. In some embodiments of this invention, the composition comprises about 40, 60, 120, 125, 240, 250, 500, 1000, 1500, or 2000 ⁇ g of said corticosteroid.
  • the nebulizers are available from, e.g., Pan GmbH (Stamberg, Germany), DeVilbiss Healthcare (Heston, Middlesex, UK), Healthdyne, Vital Signs, Baxter, Allied Health Care, Invacare, Hudson, Omron, Bremed, AirSep, Luminscope, Medisana, Siemens, Aerogen, Mountain Medical, Aerosol Medical Ltd. (Colchester, Essex, UK), AFP Medical (Rugby, Warwickshire, UK), Bard Ltd. (Sunderland, UK), Carri-Med Ltd.
  • Exemplary ultrasonic nebulizers for use herein include MicroAir, UltraAir, Siemens Ultra Nebulizer 145, CompAir, Pulmosonic, Scout, 5003 Ultrasonic Neb, 5110 Ultrasonic Neb, 5004 Desk Ultrasonic Nebulizer, Mystique Ultrasonic, Lumiscope's Ultrasonic Nebulizer, Medisana Ultrasonic Nebulizer, Microstat Ultrasonic Nebulizer, and Mabismist Hand Held Ultrasonic Nebulizer.
  • Another aspect of this invention relates to a system for delivering a therapeutically effective dose of a corticosteroid to a patient comprising (a) an aqueous inhalation mixture comprising the corticosteroid and a solubility enhancer, and (b) a nebulizer, whereby upon administration of the composition to a subject through a nebulizer, the system achieves at least about 20% to about 40%, between about 20% to about 50%, or between about 20% to about 55% lung deposition e.g., bronchi and alveoli, based on the amount of corticosteroid in the mixture prior to administration.
  • lung deposition e.g., bronchi and alveoli
  • the system can achieve at least about 25% to about 45% lung deposition based on the amount of corticosteroid in the mixture prior to administration. In other embodiments, the system can achieve at least 35% to about 40% lung deposition based on the amount of corticosteroid in the mixture prior to administration. In certain embodiments, the system achieves about 25% lung deposition based on the amount of corticosteroid in the mixture prior to administration. In other embodiments, the system achieves at least about 30% lung deposition based on the amount of corticosteroid in the mixture prior to administration. In still other embodiments, the system achieves at least about 35% lung deposition based on the amount of corticosteroid in the mixture prior to administration.
  • the system achieves at least about 40% lung deposition based on the amount of corticosteroid in the mixture prior to administration. In still other embodiments, the system achieves at least about 45% lung deposition based on the amount of corticosteroid in the mixture prior to administration. In yet still other embodiments, the system achieves at least about 50% lung deposition based on the amount of corticosteroid in the mixture prior to administration. In still another embodiment, the system achieves at least about 40% to about 55% lung deposition based on the amount of corticosteroid in the mixture prior to administration. In one embodiment, the corticosteroid is budesonide.
  • the inhalation mixture comprises an amount of corticosteroid in mixture prior to administration of about 125 ⁇ g of a corticosteroid. In still another embodiment, the inhalation mixture comprises an amount of corticosteroid in mixture prior to administration of about 240 ⁇ g of a corticosteroid. In still yet another embodiment, the inhalation mixture comprises an amount of corticosteroid in mixture prior to administration of less than about 250 ⁇ g of a corticosteroid. In one embodiment, the corticosteroid is budesonide.
  • the corticosteroid is budesonide wherein the budesonide is either an individual diastereomer or a mixture of the two diastereomers administered individually or together for a therapeutic effect.
  • the inhalable compositions comprise an effective amount of a single corticosteroid,and a solubility enhancer and are substantially free of active pharmaceutical agents other than corticosteroid.
  • the inhalable compositions comprises an effective amount of a budesonide,and a solubility enhancer and are substantially free of active pharmaceutical agents other than the budesonide.
  • the aqueous inhalation mixture is a liposomal solution comprising a corticosteroid, such as budesonide, and a solubility enhancer.
  • inhalable compositions comprising a corticosteroid do not include nano-dispersions and/or nano-suspensions.
  • inhalable compositions comprising a corticosteroid do not include micelle, mixed-micelle liquids or liposomal liquids.
  • inhalable compositions comprising a corticosteroid do not include nano- dispersions and/or nano-suspensions, micelle, mixed-micelle liquids or liposomal liquids.
  • corticosteroids that are useful in the inhalation mixtures described herein included, but are not limited to, aldosterone, beclomethasone, betamethasone, budesonide, ciclesonide, cloprednol, cortisone, cortivazol, deoxycortone, desonide, desoximetasone, dexamethasone, difluorocortolone, fluclorolone, flumethasone, flunisolide, fluocinolone, fluocinonide, fluocortin butyl, fluorocortisone, fluorocortolone, fluorometholone, flurandre ⁇ olone, fluticasone, halci ⁇ onide, hydrocortisone, icomethasone, meprednisone, methylprednisolone, mometasone, paramethasone, prednisolone, prednisone, rofleponide, RPR 1065
  • the inhalation mixture comprises a solubility enhancer.
  • the solubility enhancer can have a concentration (w/v) ranging from about 0.001% to about 25%. In other embodiments, the solubility enhancer can have a concentration (w/v) ranging from about 0.01% to about 20%. In still other embodiments, the solubility enhancer can have a concentration (w/v) ranging from about 0.1% to about 15%. In yet other embodiments, the solubility enhancer can have a concentration (w/v) ranging from about 1% to about 10%.
  • the solubility enhancer can have a concentration (w/v) ranging from about 2% to about 10% when the solubility enhancer is a cyclodextrin or cyclodextrin derivative,e.g. SBE7-/3-CD (Captisol®). In one embodiment, the solubility enhancer can have a concentration (w/v) of about 2% when the solubility enhancer is a cyclodextrin or cyclodextrin derivative.e.g. SBE7- / 8-CD (Captisol®).
  • the solubility enhancer can have a concentration (w/v) of about 5% when the solubility enhancer is a cyclodextrin or cyclodextrin derivative.e.g. SBE7-/3-CD (Captisol®). In yet another embodiment, the solubility enhancer can have a concentration (w/v) about 7% when the solubility enhancer is a cyclodextrin or cyclodextrin derivative.e.g. SBE7-/3-CD (Captisol®).
  • the solubility enhancer can have a concentration (w/v) of about 10% when the solubility enhancer is a cyclodextrin or cyclodextrin derivative.e.g. SBE7-/3-CD (Captisol®).
  • the inhalation mixture for use in the present methods further comprises a solubility enhancer.
  • the solubility enhancer is a chemical agent selected from the group consisting of propylene glycol, non-ionic surfactants, tyloxapol, polysorbate 80, vitamin E-TPGS, macrogol-15-hydroxystearate, phospholipids, lecithin, purified and/or enriched lecithin, phosphatidylcholine fractions extracted from lecithin, dimyristoyl phosphatidylcholine (DMPC), dipalmitoyl phosphatidylcholine (DPPC), distearoyl phosphatidylcholine (DSPC), cyclodextrins and derivatives thereof, SAE-CD derivatives, SBE- ⁇ -CD, SBE-/3-CD, SBEl - ⁇ -CD, SB ⁇ A- ⁇ -CD, SBE7-/3-CD (Captisol®), SBE- ⁇ -CD
  • aqueous inhalation mixtures or inhalable composition comprising a corticosteroid and a solubility enhancer
  • aqueous inhalation mixtures or compositions formulated by methods which provide enhanced solubility are likewise suitable for use in the presently disclosed invention.
  • a "solubility enhancer” includes aqueous inhalation mixtures formulated by methods which provide enhanced solubility with or without a chemical agent acting as a solubility enhancer. Such methods include, e.g., the preparation of supercritical fluids.
  • the nebulizer is a jet nebulizer, an ultrasonic nebulizer, a pulsating membrane nebulizer, a nebulizer with a vibrating mesh or plate with multiple apertures, or a nebulizer comprising a vibration generator and an aqueous chamber.
  • the nebulizer is selected from the group consisting of Pan LC Jet Plus, Intertech, Baxter Misty-Neb, Hudson T- Updraft II, Hudson Ava-Neb, Aiolos, Pan LC Jet, DeVilbiss Pulmo-Neb, Hudson Iso-Neb (B), Hudson T- Updraft Neb-U-Mist, Pari-Jet 1460, and AeroTech with T-piece.
  • the nebulizer is a Pan eFlow nebulizer.
  • An aspect of this invention relates to an inhalation system for delivering a therapeutically effective dose of a corticosteroid to a patient comprising (a) an inhalable aqueous mixture comprising the corticosteroid and a solubility enhancer, and (b) a nebulizer, whereby upon administration of said inhalable aqueous mixture through said nebulizer, the system delivers an enhanced lung deposition of the corticosteroid as compared to an inhalable suspension comprising a corticosteroid administered under the same conditions.
  • the system achieves at least about 10% higher respirable fraction compared to an inhalable suspension comprising the corticosteroid administered under the same conditions.
  • the system achieves at least about 15% higher respirable fraction compared to an inhalable suspension comprising the corticosteroid administered under the same conditions. In the most preferred embodiment of this invention, the system achieves at least about 20% higher respirable fraction compared to an inhalable suspension comprising the corticosteroid administered under the same conditions.
  • the system comprising an inhalable aqueous mixture comprising a corticosteroid and a solubility enhancer achieves at least about 15% higher lung deposition compared to an inhalable suspension comprising the corticosteroid administered under the same conditions.
  • the system comprising an inhalable aqueous mixture comprising a corticosteroid and a solubility enhancer achieves at least about 20% higher lung deposition compared to an inhalable suspension comprising the corticosteroid administered under the same conditions.
  • the system comprising an inhalable aqueous mixture comprising a corticosteroid and a solubility enhancer achieves about the same lung deposition of the corticosteroid as compared to an inhalable suspension comprising the corticosteroid, wherein the composition is administered at a lower nominal dosage than the inhalable suspension.
  • the system comprising an inhalable aqueous mixture comprising a corticosteroid and a solubility enhancer achieves about 90% to 110% lung deposition of the corticosteroid as compared to an inhalable suspension comprising the corticosteroid.
  • the delivery time can be about 4.5 minutes. In certain other embodiments, the delivery time can be less than about 4.5 minutes. In still other embodiments, the delivery time can be about 4 minutes. In yet other embodiments, the delivery time can be less than about 4 minutes. In still yet other embodiments, the delivery time can be about 3.5 minutes. In other embodiments, the delivery time can be less than about 3.5 minutes. In yet still other embodiments, the delivery time can be about 3 minutes. In other embodiments, the delivery time can be less than about 3 minutes. In certain embodiments, the delivery time can be about 2.5 minutes. In other certain embodiments, the delivery time can be less than about 2.5 minutes. In still other embodiments, the delivery time can be about 2 minutes. In yet still other embodiments, the delivery time can be less than about 2 minutes. In a preferred embodiment, the delivery time can be about 1.5 minutes. In a more preferred embodiment, the delivery time can be less than about 1.5 minutes.
  • the nebulization time for Pulmicort® Respules administered by a Pan LC Plus jet nebulizer can take in excess of 10 minutes. This prolonged administration time is very burdensome on the patient, especially when the patient is a pediatric patient.
  • a system or method that can reduce the time of delivery of a corticosteroid by inhalation can increase the patient's compliance with the therapeutic regimen.
  • the methods and systems of the present invention can deliver a therapeutically effective amount of a corticosteroid, such as a budesonide, over a delivery time of less than about 5 minutes to less than about 1.5 minutes. In some embodiments, the delivery time can be about 5 minutes.
  • the delivery time can be less than about 5 minutes. In certain embodiments, the delivery time can be about 4.5 minutes. In certain other embodiments, the delivery time can be less than about 4.5 minutes. In still other embodiments, the delivery time can be about 4 minutes. In yet other embodiments, the delivery time can be less than about 4 minutes. In still yet other embodiments, the delivery time can be about 3.5 minutes. In other embodiments, the delivery time can be less than about 3.5 minutes. In yet still other embodiments, the delivery time can be about 3 minutes. In other embodiments, the delivery time can be less than about 3 minutes. In certain embodiments, the delivery time can be about 2.5 minutes. In other certain embodiments, the delivery time can be less than about 2.5 minutes.
  • the inhalation mixture for use in the present methods further comprises a second therapeutic agent selected from the group consisting of a beta2-adrenoreceptor agonist, a prophylactic therapeutic, and an anticholinergic agent.
  • a second therapeutic agent selected from the group consisting of a beta2-adrenoreceptor agonist, a prophylactic therapeutic, and an anticholinergic agent.
  • the beta2-adrenoreceptor agonist is albuterol, levalbuterol or a pharmaceutical acceptable derivative.
  • an aspect of this invention relates to an inhalation system for delivering a therapeutically effective dose of albuterol to a patient comprising (a) an aqueous inhalation mixture comprising albuterol, and (b) a Pan eFlow nebulizer, whereby delivering said inhalation mixture by said nebulizer delivers an enhanced pharmacokinetic profile of the corticosteroid as compared to albuterol administered with another nebulizer under the same conditions.
  • the inhalable composition comprises a corticosteroid.
  • Corticosteroid within a Device Another aspect of this invention relates to an inhalation system for delivering a therapeutically effective dose of a corticosteroid to a patient comprising (a) an aqueous inhalation mixture comprising the corticosteroid, a solvent and a solubility enhancer, and (b) a nebulizer, whereby upon administration of the composition to a subject through a nebulizer, the system achieves rate of increasing concentration of the corticosteroid inside the device of about 60% or less or a rate of increasing concentration of the corticosteroid inside the device achieved by an inhalable suspension comprising the corticosteroid without a solubility- enhancer administered under the same conditions.
  • the aqueous inhalation mixture comprises a single corticosteroid and is substantially free of active pharmaceutical agents other than the corticosteroid.
  • the invention relates to an inhalable composition wherein administration of the composition through the device is achieved over five minutes or less, and administration of the inhalable suspension is achieved over five minutes or less.
  • the invention relates to an inhalable composition wherein the rime of administration of the composition through the device and the time of administration of the inhalable suspension are the same.
  • the invention relates to an inhalable composition wherein the time of administration of the composition through the device and the time of administration of the inhalable suspension are different.
  • the system comprises an aqueous inhalation mixture comprising about 15 to about 2000 ⁇ g of a corticosteroid.
  • the inhalation mixture comprises about 50 to about 2000 ⁇ g of a corticosteroid.
  • the inhalation mixtures comprise about 60 to about 1500 ⁇ g of a corticosteroid.
  • the inhalation mixtures comprise about 100 to about 1000 ⁇ g of a corticosteroid.
  • the inhalation mixtures comprising comprise about 120 to about 1000 ⁇ g of a corticosteroid.
  • the inhalation mixtures comprise about 125 to about 500 ⁇ g of a corticosteroid. In certain embodiments, the inhalation mixtures comprise about 40, 60, 100, 120, 125, 240, 250, 500, 1000, 1500, or 2000 ⁇ g of a corticosteroid. In one embodiment, the inhalation mixture comprises a nominal dosage of about 40 ⁇ g of a corticosteroid. In another embodiment, the inhalation mixture comprises a nominal dosage of about 60 ⁇ g of a corticosteroid. In yet another embodiment, the inhalation mixture comprises a nominal dosage of about 100 ⁇ g of a corticosteroid.
  • the corticosteroid is budesonide wherein the budesonide is either an individual diastereomer or a mixture of the two diastereomers administered individually or together for a therapeutic effect.
  • the inhalation mixtures comprise an effective amount of a single corticosteroid, a solvent and a solubility enhancer and are substantially free of active pharmaceutical agents other than corticosteroid.
  • the inhalation mixtures comprise an effective amount of a budesonide, a solvent and a solubility enhancer and are substantially free of active pharmaceutical agents other than the budesonide.
  • inhalable compositions comprising a corticosteroid do not include nano-dispersions and/or nano-suspensions. In other embodiments, inhalable compositions comprising a corticosteroid do not include micelle, mixed-micelle liquids or liposomal liquids. In still other embodiments, inhalable compositions comprising a corticosteroid do not include nano-dispersions and/or nano-suspensions, micelle, mixed-micelle liquids or liposomal liquids. In other embodiments, inhalable compositions, include but are not_ limited ⁇ tQv solutions, emulsions,-and colloidal liquids.
  • the inhalable composition is, a solution comprising a corticosteroid, such as .budesonide, and a solubility enhancer.
  • the inhalable composition is an emulsion comprising a corticosteroid,- such as budesonide, and a solubility enhancer
  • the corticosteroid is budesonide. In other preferred embodiments, the corticosteroid is budesonide wherein the budesonide is either an individual diastereomer or a mixture of the two diastereomers administered individually or together for a therapeutic effect. [00209]
  • the systems and methods described herein comprise a solvent.
  • the solvent is selected from the group consisting of water, water/ethanol mixture, aqueous alcohol, propylene glycol, or aqueous organic solvent, or combinations thereof.
  • the solvent comprises water.
  • the solvent is water.
  • the inhalation mixture comprises a solubility enhancer.
  • the solubility enhancer can have a concentration (w/v) ranging from about 0.001% to about 25%. In other embodiments, the solubility enhancer can have a concentration (w/v) ranging from about 0.01% to about 20%. In still other embodiments, the solubility enhancer can have a concentration (w/v) ranging from about 0.1% to about 15%. In yet other embodiments, the solubility enhancer can have a concentration (w/v) ranging from about 1% to about 10%.
  • the solubility enhancer can have a concentration (w/v) of about 5% when the solubility enhancer is a cyclodextrin or cyclodextrin derivative.e.g. SBE7-/3-CD (Captisol®). In yet another embodiment, the solubility enhancer can have a concentration (w/v) about 7% when the solubility enhancer is a cyclodextrin or cyclodextrin derivative,e.g. SB ⁇ ,7 ⁇ -CD (Captisol®).
  • the solubility enhancer can have a concentration (w/v) of about 10% when the solubility enhancer is a cyclodextrin or cyclodextrin derivative,e.g. SBE7-)3-CD (Captisol®).
  • the inhalable compositions of the present invention comprise a solubility enhancer selected from the group consisting of cyclodextrins and derivatives thereof, SAE-CD derivatives, SBE- ⁇ -CD, SBE-/3-CD, SBEl - ⁇ -CD, SBE4-/ ⁇ -CD, SBE7-/J-CD (Captisol®), SBE- ⁇ CD, dimethyl ⁇ -CD, hydroxypropyl-/3-cyclodextrin, 2-HP-/3-CD, hydroxyethyl-/3-cyclodextrin, hydroxypropyl- ⁇ -cyclodextrin, hydroxyethyl- ⁇ -cyclodextrin, dihydroxypropy1-/3-cyclodextrin, glucosyl-cfrcyclodextrin, g1ucosyl-/3- cyclodextrin, diglucosyl-jS-cycIodextrin, maltosyl-
  • SAE-CD derivatives SBE
  • aqueous inhalation mixtures or inhalable composition comprising a corticosteroid and a solubility enhancer
  • aqueous inhalation mixtures or compositions formulated by methods which provide enhanced solubility are likewise suitable for use in the presently disclosed invention.
  • a "solubility enhancer” includes aqueous inhalation mixtures formulated by methods which provide enhanced solubility with or without a chemical agent acting as a solubility enhancer. Such methods include, e.g., the preparation of supercritical fluids.
  • corticosteroid compositions such as budesonide
  • budesonide particles are fabricated into particles with narrow particle size distribution (usually less than 200 nanometers spread) with a mean particle hydrodynamic radius in the range of 50 nanometers to 700 nanometers.
  • the nano-sized corticosteroid particles, such as budesonide particles are fabricated using Supercritical Fluids (SCF) processes including Rapid Expansion of Supercritical Solutions (RESS), or Solution Enhanced Dispersion of Supercritical fluids (SEDS), as well as any other techniques involving supercritical fluids.
  • SCF Supercritical Fluids
  • RESS Rapid Expansion of Supercritical Solutions
  • SEDS Solution Enhanced Dispersion of Supercritical fluids
  • the composition further comprises a second therapeutic agent selected from the group consisting of a beta2-adrenoreceptor agonist, a prophylactic therapeutic, and an anticholinergic agent.
  • a beta2-adrenoreceptor agonist is albuterol, levalbuterol or a pharmaceutical acceptable derivative.
  • the nebulizer is a jet nebulizer, an ultrasonic nebulizer, a pulsating membrane nebulizer, a nebulizer with a vibrating mesh or plate with multiple apertures, or a nebulizer comprising a vibration generator and an aqueous chamber.
  • the nebulizer is selected from the group consisting of Pan LC Jet Plus, Intertech, Baxter Misty-Neb, Hudson T- Updraft II, Hudson Ava-Neb, Aiolos, Pari LC Jet, DeVilbiss Pulmo-Neb, Hudson Iso-Neb (B), Hudson T- Updraft Neb-U-Mist, Pari-Jet 1460, and AeroTech with T-piece.
  • the nebulizer is a Pari eFlow nebulizer.
  • VUI Methods of Treatment to Achieve Enhanced Lung Deposition
  • methods are provided for the delivery of a therapeutically effective dose of a corticosteroid to a patient.
  • the methods described herein are directed to the treatment of a bronchoconstrictive disorder in a patient comprising providing an inhalable aqueous mixture comprising a corticosteroid, a solvent and a solubility enhancer and delivering the aqueous inhalation mixture via an inhalation nebulizer.
  • the present invention can provide a method fo ⁇ the treatment of a bronchoconstrictive disorder in a patient in need of treatment thereof comprising forming a mixture by adding a solvent and a solubility enhancer to an amount of corticosteroid and operating a nebulizer, wherein upon administration of the mixture to a subject through the nebulizer, the methods can achieves at least about 20% to about 40%, between about 20% to about 50%, or between about 20% to about 55% lung deposition e.g., bronchi and alveoli, based on the amount of corticosteroid in the mixture prior to administration.
  • the methods achieve at least about 40% lung deposition based on the amount of corticosteroid in the composition prior to administration. In yet still other embodiments, the methods achieve at least about 45% lung deposition based on the amount of corticosteroid in the composition prior to administration. In still yet other embodiments, the methods achieve at least about 50% lung deposition based on the amount of corticosteroid in the composition prior to administration. In other embodiments, the methods achieve at least about 40% to about 55% lung deposition based on the amount of corticosteroid in the composition prior to administration. In one embodiment, the corticosteroid is budesonide.
  • the methods also achieve at least about 60% respirable fraction upon administration. In more preferred embodiments of this invention, the methods also achieve at least about 70% respirable fraction upon administration. In still more preferred embodiments of this invention, the methods also achieve at least about 80% respirable fraction upon administration. In the most preferred embodiments of this invention, the methods also achieve at least about 85% respirabie fraction upon administration.
  • the corticosteroid is budesonide. In another embodiment, the corticosteroid is budesonide wherein the budesonide is either an individual diastereomer or a mixture of the two diastereomers administered individually or together fo ⁇ a therapeutic effect.
  • the inhalable compositions comprise an effective amount of a single corticosteroid, and a solubility enhancer and are substantially free of active pharmaceutical agents other than corticosteroid. In still other embodiments, the inhalable compositions comprises an effective amount of a budesonide, and a solubility enhancer and are substantially free of active pharmaceutical agents other than the budesonide.
  • the methods of treatment of a bronchoconstrictive disorder comprise the delivery of an inhalable aqueous mixture comprising a corticosteroid.
  • the corticosteroids that are useful is in the present invention include, but are not limited to, aldosterone, beclomethasone, betamethasone, budesonide, ciclesonide, cloprednol, cortisone, cortivazol, deoxycortone, desonide, desoximetasone, dexamethasone, difluorocortolone, fluclorolone, flumethasone, flunisolide, fluocinolone, fluocinonide, fluocortin butyl, fluorocortisone, fluorocortolone, fluorometholone, flurandrenolone, fluticasone, halcinonide, hydrocortisone, icomethasone, meprednisone, methylprednisolone, mom
  • the corticosteroid is budesonide. In other embodiments, the corticosteroid is budesonide wherein the budesonide is either an individual diastereomer or a mixture of the two diastereomers administered individually or together for a therapeutic effect.
  • the methods of treatment comprise an aqueous inhalation mixture comprising an amount of corticosteroid in mixture prior to administration of about 15 to about 2000 ⁇ g of a corticosteroid.
  • the inhalation mixtures comprise an amount of corticosteroid in mixture prior to administration of about 250 to about 2000 ⁇ g of a corticosteroid.
  • the inhalation mixtures comprise an amount of corticosteroid in mixture prior to administration of about 60 to about 1500 ⁇ g of a corticosteroid.
  • the inhalation mixtures comprise an amount of corticosteroid in mixture prior to administration of about 100 to about 1000 ⁇ g of a corticosteroid.
  • the inhalation mixtures comprise an amount of corticosteroid in mixture prior to administration of about 120 to about 1000 ⁇ g of a corticosteroid. In yet still other embodiments, the inhalation mixtures comprise an amount of corticosteroid in mixture prior to administration of about 125 to about 500 ⁇ g of a corticosteroid. In certain embodiments, the inhalation mixtures comprise an amount of corticosteroid in mixture
  • the inhalation mixture comprises an amount of corticosteroid in mixture prior to administration of about 40 ⁇ g of a corticosteroid. In another embodiment, the inhalation mixture comprises an amount of corticosteroid in mixture prior to administration of about 60 ⁇ g of a corticosteroid. In still another embodiment, the inhalation mixture comprises an amount of corticosteroid in mixture prior to administration of about 100 ⁇ g of a corticosteroid.
  • the inhalable mixtures can comprise about 40 ⁇ g budesonide, a solvent and a solubility enhancer, wherein upon administration of the composition to a subject through a nebulizer, the composition achieves lung deposition of at least 13 ⁇ g of budesonide. In certain other embodiments, the inhalable mixtures can comprise about 60 ⁇ g budesonide, a solvent and a solubility enhancer, wherein upon administration of the composition to a subject through a nebulizer, the composition achieves lung deposition of at least 20 ⁇ g of budesonide.
  • the inhalable composition can comprise about 120 ⁇ g budesonide, a solvent and a solubility enhancer, wherein upon administration of the composition to a subject through a nebulizer, the composition achieves lung deposition of at least 40 ⁇ g of budesonide.
  • the inhalable composition can comprise about 240 ⁇ g budesonide, a solvent and a solubility enhancer, wherein upon administration of the composition to a subject through a nebulizer, the composition achieves lung deposition of at least 80 ⁇ g of budesonide.
  • the inhalable mixtures can comprise about 40 ⁇ g budesonide, a solvent and a solubility enhancer, wherein upon administration of the composition to a subject through a nebulizer, the composition achieves lung deposition of at least 13 ⁇ g of budesonide, wherein the composition is substantially free of active pharmaceutical agents other than the budeso ⁇ ide.
  • the inhalable composition can comprise about 240 ⁇ g budesonide, a solvent and a solubility enhancer, wherein upon administration of the composition to a subject through a nebulizer, the composition achieves lung deposition of at least 80 ⁇ g of budesonide, wherein the composition is substantially free of active pharmaceutical agents other than the budesonide.
  • suitable aqueous inhalation mixture comprising a corticosteroid include, but are not limited to, solutions, dispersions, nano-dispersions, emulsions, colloidal liquids, micelle or mixed micelle solutions, and liposomal liquids.
  • the aqueous inhalation mixture is a solution comprising a corticosteroid, such as budesonide, and a solubility enhancer.
  • the aqueous inhalation mixture is a mixed micelle solution comprising a corticosteroid, such as budesonide, and a solubility enhancer.
  • the aqueous inhalation mixture is a liposomal solution comprising a corticosteroid, such as budesonide, and a solubility enhancer.
  • inhalable compositions comprising a corticosteroid do not include nano-dispersions and/or nano-suspensions. In other embodiments, inhalable compositions comprising a corticosteroid do not include micelle, mixed-micelle liquids or liposomal liquids. In still othe ⁇ embodiments, inhalable compositions comprising a corticosteroid do not include nano-dispersions and/or nano-suspensions, micelle, mixed-micelle liquids or liposomal liquids. In other embodiments, inhalable compositions, include but are not limited to, solutions, emulsions, and colloidal liquids.
  • the inhalation mixture comprises a solubility enhancer.
  • the solubility enhancer can have a concentration (w/v) ranging from about 0.001% to about 25%. In other embodiments, the solubility enhancer can have a concentration (w/v) ranging from about 0.01% to about 20%. In still other embodiments, the solubility enhancer can have a concentration (w/v) ranging from about 0.1% to about 15%. In yet other embodiments, the solubility enhancer can have a concentration (w/v) ranging from about 1% to about 10%.
  • the solubility enhancer can have a concentration (w/v) ranging from about 2% to about 10% when the solubility enhancer is a cyclodextrin or • cyclodextrin derivative,e.g. SBE7-/3-CD (Captisol®). In one embodiment, the solubility enhancer can have a concentration (w/v) of about 2% when the solubility enhancer is a cyclodextrin or cyclodextrin derivative,e.g. SBE7-/3-CD (Captisol®).
  • the solubility enhancer can have a concentration (w/v) of about 10% when the solubility enhancer is a cyclodextrin or cyclodextrin derivative,e.g. SBE7-/3-CD (Captisol®).
  • the methods of treatment of a bronchoconstrictive disorder comprise the delivery of an inhalable aqueous mixture comprising a corticosteroid and a solubility enhancer.
  • the solubility enhancer is a chemical agent selected from the group consisting of propylene glycol, non-ionic surfactants, tyloxapol, polysorbate 80, vitamin E-TPGS, macrogol-15- hydroxystearate, phospholipids, lecithin, purified and/or enriched lecithin, phosphatidylcholine fractions extracted from lecithin, dimyristoyl phosphatidylcholine (DMPC), dipalmitoyl phosphatidylcholine (DPPC), distearoyl phosphatidylcholine (DSPC), cyclodextrins and derivatives thereof, SAE-CD derivatives, SBE- ⁇ -CD, SBE-0-CD, SBEl -0-CD, S
  • the inhalable compositions of the present invention comprise a solubility enhancer selected from the group consisting of cyclodextrins and derivatives thereof, SAE-CD derivatives, SBE- ⁇ -CD, SBE-/3-CD, SBEl -/3-CD, SBE4- / 3-CD, SBE7-/3-CD (Captisol®), SBE- ⁇ -CD, dimethyl ⁇ -CD, hydroxypropyl- ⁇ -cyclodextrin, 2-HP- ⁇ -CD, hydroxyethyl-jS-cyclodextrin, hydroxypropyl-Y-cyclodextrin, hydroxyethyl- ⁇ -cyclodextrin, dihydroxypro ⁇ yl-/?-cyclodextrin, glucosyl- ⁇ -cyclodextrin, glucosyl-/3- cyclodextri ⁇ , diglucosyl-jS-cyclodexrrin, maltosyl-os
  • SAE-CD derivatives SBE
  • the composition further comprises a second therapeutic agent selected from the group consisting of a beta2-adrenoreceptor agonist, a prophylactic therapeutic, and an anticholinergic agent.
  • a beta2-adrenoreceptor agonist is albuterol, levalbuterol or a pharmaceutical acceptable derivative.
  • the bronchoconstrictive disorder is selected from the group consisting of asthma, pediatric asthma, bronchial asthma, allergic asthma, intrinsic asthma, chronic obstructive pulmonary disease (COPD), chronic bronchitis, and emphysema.
  • COPD chronic obstructive pulmonary disease
  • the inhalable aqueous mixture comprises a corticosteroid, such as budesonide, wherein the inhalable aqueous mixture is administered according to the methods described herein no more than twice a day (b.i.d).
  • the inhalable aqueous mixture comprises a corticosteroid, such as budesonide, wherein the inhalable aqueous mixture is administered according to the methods described herein no more than once a day.
  • the inhalable aqueous mixture comprises a corticosteroid, such as budesonide, wherein the inhalable aqueous mixture is administered no more than once a day in the evening.
  • the nebulizer is a jet nebulizer, an ultrasonic nebulizer, a pulsating membrane nebulizer, a nebulizer with a vibrating mesh or plate with multiple apertures, or a nebulizer comprising a vibration generator and an aqueous chamber.
  • the nebulizer is selected from the group consisting of Pan LC Jet Plus, Intertech, Baxter Misty-Neb, Hudson T- Updraft H, Hudson Ava-Neb, Aiolos, Pan LC Jet, DeVilbiss Pulmo-Neb, Hudson Iso-Neb (B), Hudson T- Updraft Neb-U-Mist, Pari-Jet 1460, and AeroTech with T-piece.
  • the nebulizer is a Pari eFlow nebulizer.
  • the present invention can provide a method for the treatment of a bronchoconstrictive disorder in a patient comprising providing an inhalable aqueous mixture comprising a corticosteroid, a solvent and a solubility enhancer and delivering the aqueous inhalation mixture via an inhalation nebulizer, wherein the delivery of the inhalable aqueous mixture provides that no more than about 10% to about 30% of the corticosteroid is delivered outside of the lung, e.g., in the mouth, esophagus, and/or stomach.
  • the method can provide the delivery of an inhalable aqueous mixture wherein no more than about 10% of the corticosteroid is delivered outside of the lung. In another embodiment, the method can provide the delivery of an inhalable aqueous mixture wherein no more than about 15% of the corticosteroid is delivered outside of the lung. In yet another embodiment, the method can provide the delivery of an inhalable aqueous mixture wherein no more than about 20% of the corticosteroid is delivered outside of the lung. In still another embodiment, the method can provide the. delivery of an inhalable aqueous mixture wherein no more than about 25% of the corticosteroid is delivered outside of the lung. In yet another embodiment, the method can provide the delivery of an inhalable aqueous mixture wherein no more than about 30% of the corticosteroid is delivered outside of the lung.
  • the present invention can provide a method for the prophylaxis of a bronchoconstrictive disorder in a patient comprising providing an inhalable aqueous mixture comprising a corticosteroid, a solvent and a solubility enhancer and delivering the aqueous inhalation mixture via an inhalation nebulizer.
  • the present invention can provide a method for reducing the risk of side effects associated with corticosteroid inhalation therapy whereby a lower nominal dosage of the corticosteroid is required to achieve a therapeutic effect as compared to conventional inhalable corticosteroid therapies.
  • the risk of side effects is lowered compared to conventional inhalable corticosteroid therapies.
  • the composition comprises a single corticosteroid and is substantially free of active pharmaceutical agents other than the corticosteroid.
  • the corticosteroid is budesonide or a pharmaceutical acceptable derivative.
  • the corticosteroid is budesonide wherein the budesonide is either an individual diastereomer or a mixture of the two diastereomers administered individually or together for a therapeutic effect.
  • the rate of increasing concentration of the corticosteroid inside the device is achieved over the first 3 minutes of administration.
  • the Tate of increasing concentration of the corticosteroid inside the device is achieved during the second and third minute of administration.
  • the rate of increasing concentration of the corticosteroid inside the device is achieved during the third minute of administration.
  • the invention relates to an inhalable composition wherein administration of the composition through the device is achieved over five minutes or less, and administration of the inhalable suspension is achieved over five minutes or less.
  • the invention relates to an inhalable composition wherein the time of administration of the composition through the device and the time of administration of the inhalable suspension are the same.
  • the invention relates to an inhalable composition wherein the time of administration of the composition through the device and the time of administration of the inhalable suspension are different.
  • the inhalable composition also achieves at least about 60% respirable fraction upon administration. In a preferred embodiment of this invention, the inhalable composition also achieves at least about 70% respirable fraction upon administration. In a more preferred embodiment of this invention, the inhalable composition also achieves at least about 80% respirable fraction upon administration. In the most preferred embodiment of this invention, the inhalable composition also achieves at least about 85% ⁇ espi ⁇ able fraction upon administration.
  • the inhalation mixtures comprise about 125 to about 500 ⁇ g of a corticosteroid. In certain embodiments, the inhalation mixtures comprise about 40, 60, 100, 120, 125, 240, 250, 500, 1000, 1500, or .2000 ⁇ g of a corticosteroid. In one embodiment, the inhalation mixture comprises a nominal dosage of about 40 ⁇ g of a corticosteroid. In another embodiment, the inhalation mixture comprises a nominal dosage of about 60 ⁇ g of a corticosteroid. In still another embodiment, the inhalation mixture comprises a nominal dosage of about 100 ⁇ g of a corticosteroid.
  • the inhalation mixture comprises a nominal dosage of about 120 ⁇ g of a corticosteroid.
  • the inhalation mixture comprises a nominal dosage of about 125 ⁇ g of a corticosteroid.
  • the inhalation mixture comprises a nominal dosage of about 240 ⁇ g of a corticosteroid.
  • the inhalation mixture comprises a nominal dosage of less than about 250 ⁇ g of a corticosteroid.
  • the corticosteroid is budesonide or a pharmaceutical acceptable derivative.
  • the corticosteroid is budesonide wherein the budesonide is either an individual diastereomer or a mixture of the two diastereomers administered individually or together for a therapeutic effect.
  • the inhalation mixture comprises a solubility enhancer.
  • the solubility enhancer can have a concentration (w/v) ranging from about 0.001% to about 25%. In other embodiments, the solubility enhancer can have a concentration (w/v) ranging from about 0.01% to about 20%. In still other embodiments, the solubility enhancer can have a concentration (w/v) ranging from about 0.1% to about 15%. In yet other embodiments, the solubility enhancer can have a concentration (w/v) ranging from about 1% to about 10%.
  • the solubility enhancer can have a concentration (w/v) ranging from about 2% to about 10% when the solubility enhancer is a cyclodextrin or cyclodextrin derivative,e.g. SBE7-/3-CD (Captisol®). In one embodiment, the solubility enhancer can have a concentration (w/v) of about 2% when the solubility enhancer is a cyclodextrin or cyclodextrin derivative,e.g. SBE7-/3-CD (Captisol®).
  • the solubility enhancer can have a concentration (w/v) of about 5% when the solubility enhancer is a cyclodextrin or cyclodextrin derivative.e.g. SBE7-/J-CD (Captisol®). In yet another embodiment, the solubility enhancer can have a concentration (w/v) about 7% when the solubility enhancer is a cyclodextrin or cyclodextrin derivative,e.g. SBE7-/3-CD (Captisol®).
  • the solubility enhancer can have a concentration (w/v) of about 10% when the solubility enhancer is a cyclodextrin or cyclodextrin derivative.e.g. SBE7-/3-CD (Captisol®).
  • aqueous inhalation mixtures or inhalable composition comprising a corticosteroid and a solubility enhancer
  • aqueous inhalation mixtures or compositions formulated by methods which provide enhanced solubility are likewise suitable for use in the presently disclosed invention.
  • a "solubility enhancer” includes aqueous inhalation mixtures formulated by methods which provide enhanced solubility with or without a chemical agent acting as a solubility enhancer. Such methods include, e.g., the preparation of supercritical fluids.
  • corticosteroid compositions such as budesonide
  • budesonide particles are fabricated into particles with narrow particle size distribution (usually less than 200 nanometers spread) with a mean particle hydrodynamic radius in the range of 50 nanometers to 700 nanometers.
  • the nano-sized corticosteroid particles, such as budesonide particles are fabricated using Supercritical Fluids (SCF) processes including Rapid Expansion of Supercritical Solutions (RESS), or Solution Enhanced Dispersion of Supercritical fluids (SEDS), as well as any other techniques involving supercritical fluids.
  • SCF Supercritical Fluids
  • RESS Rapid Expansion of Supercritical Solutions
  • SEDS Solution Enhanced Dispersion of Supercritical fluids
  • the nebulizer is selected from the group consisting of Pari LC Jet Plus, Intertech, Baxter Misty-Neb, Hudson T- Updraft II, Hudson Ava-Neb, Aiolos, Pari LC Jet, DeVilbiss Pulmo-Neb, Hudson Iso-Neb (B), Hudson T- Updraft Neb-U-Mist, Pari-Jet 1460, and AeroTech with T-piece.
  • the nebulizer is a Pari eFlow nebulizer.
  • the bro ⁇ choconstrictive disorder is selected from the group consisting of asthma, pediatric asthma, bronchial asthma, allergic asthma, intrinsic asthma, chronic obstructive pulmonary disease (COPD), chronic bronchitis, and emphysema.
  • Another aspect of this invention relates to use of a corticosteroid in the manufacture of an inhalable composition for the treatment or prophylaxis of a bronchoconstrictive disorder in a patient in need of treatment thereof, comprising adding a solvent and a solubility enhancer to an amount of corticosteroid and operating a nebulizer, wherein the composition achieves at least about 25% lung deposition based on the amount of corticosteroid in the composition prior to administration. In some embodiments of this invention, the composition also achieves at least about 60% respirable fraction upon administration.
  • the inhalable compositions comprise a single corticosteroid, a solvent and a solubility enhancer and are substantially free of active pharmaceutical agents other than corticosteroids.
  • the corticosteroid is budesonide.
  • the corticosteroid is budesonide wherein the budesonide is either an individual diastereomer o ⁇ a mixture of the two diastereomers administered individually or together for a therapeutic effect.
  • An aspect of this invention also relates to use of a corticosteroid in the manufacture of an inhalable composition for the treatment of a bronchoconstrictive disorder in a patient in need of treatment thereof, comprising adding a solvent and a solubility enhancer to an amount of corticosteroid and operating a nebulizer, wherein the composition achieves about the same lung . deposition compared to an inhalable suspension comprising the corticosteroid, wherein the composition is administered at a lower nominal dosage than the inhalable suspension to deliver a therapeutically effective amount of said corticosteroid.
  • the inhalable compositions comprise a single corticosteroid, a solvent and a solubility enhancer and are substantially free of active pharmaceutical agents other than corticosteroids.
  • the inhalation mixtures comprise about 125 to about 500 ⁇ g of a corticosteroid. In certain embodiments, the inhalation mixtures comprise about 40, 60, 100, 120, 125, 240, 250, 500, 1000, 1500, or 2000 ⁇ g of a corticosteroid. In one embodiment, the inhalation mixture comprises a nominal dosage of about 40 ⁇ g of a corticosteroid. In another embodiment, the inhalation mixture comprises a nominal dosage of about 60 ⁇ g of a corticosteroid. In still another embodiment, the inhalation mixture comprises a nominal dosage of about 100 ⁇ g of a corticosteroid.
  • the inhalation mixture comprises a nominal dosage of about 120 ⁇ g of a corticosteroid. In yet still another embodiment, the inhalation mixture comprises a nominal dosage of about 125 ⁇ g of a corticosteroid. In still another embodiment, the inhalation mixture comprises a nominal dosage of about 240 ⁇ g of a corticosteroid. In still yet another embodiment, the inhalation mixture comprises a nominal dosage of less than about 250 ⁇ g of a corticosteroid. In other embodiments of this invention, the corticosteroid is budesonide or a pharmaceutical acceptable derivative. In other preferred embodiments, the corticosteroid is budesonide wherein the budesonide is either an individual diastereomer or a mixture of the two diastereomers administered individually or together for a therapeutic effect.
  • the systems and methods described herein comprise a solvent.
  • the solvent is selected from the group consisting of water, water/ethanol mixture, aqueous alcohol, propylene glycol, or aqueous organic solvent, or combinations thereof.
  • the solvent comprises water.
  • the solvent is water.
  • the solubility enhancer is a chemical agent selected from the group consisting of propylene glycol, non-ionic surfactants, tyloxapol, polysorbate 80, vitamin E-TPGS, macrogol-15-hydroxystea ⁇ ate, phospholipids, lecithin, purified and/or enriched lecithin, phosphatidylcholine fractions extracted from lecithin, dimyristoyl phosphatidylcholine (DMPC), dipalmitoyl phosphatidylcholine (DPPC), distearoyl phosphatidylcholine (DSPC), cyclodextrins and derivatives thereof, SAE-CD derivatives, SBE- ⁇ -CD, SBB- ⁇ -CD, SBEl - ⁇ -CD, SBE4-/3-CD, SBE7-/3-CD (Captisol®), SBE- ⁇ -CD, dimethyl ⁇ -CO, hydroxypropyl-/3-cyclodextr
  • the inhalable compositions of the present invention comprises a solubility enhancer is selected from the group consisting of cyclodextrins and derivatives thereof, SAE-CD. derivatives, SBE- ⁇ -CD, SBE-/3-CD, SBEl - ⁇ -CD, SBE4-/3-CD, SBE7-£-CD (Captisol®), SBE- ⁇ -CD, dimethyl ⁇ -CD, hydroxypropyl-/3-cyclodextrin, 2-HP-j3-CD, hydroxyethyl-/?-cyclodextrin, hydroxypropyl- ⁇ -cyclodextrin, hydroxyethyl- ⁇ -cyclodextrin, dihydroxypropyl- ⁇ -cyclodextrin, glucosyl- ⁇ -cyclodextrin, glucosyl-/3- cyclodextrin, diglucosyl- ⁇ -cyclodextrin, maltosyl- ⁇ -cyclod
  • aqueous inhalation mixtures or inhalable composition comprising a corticosteroid and a solubility enhancer
  • aqueous inhalation mixtures or compositions formulated by methods which provide enhanced solubility are likewise suitable for use in the presently disclosed invention.
  • a "solubility enhancer” includes aqueous inhalation mixtures formulated by methods which provide enhanced solubility with or without a chemical agent acting as a solubility enhancer. Such methods include, e.g., the preparation of supercritical fluids.
  • corticosteroid compositions such as budesonide
  • budesonide particles are fabricated into particles with narrow particle size distribution (usually less than 200 nanometers spread) with a mean particle hydrodynamic radius in the range of f 50 nanometers to 700 nanometers.
  • SCF Supercritical Fluids
  • RESS Rapid Expansion of Supercritical Solutions
  • SEDS Solution Enhanced Dispersion of Supercritical fluids
  • the bronchoconstrictive disorder is selected from the group consisting of asthma, pediatric asthma, bronchial asthma, allergic asthma, intrinsic asthma, chronic obstructive pulmonary disease (COPD), chronic bronchitis, and emphysema.
  • the methods and systems for the treatment or prophylaxis of a bronchoconstrictive disorder in a patient in need thereof can provide a method for the treatment of a bronchoconstrictive disorder in a patient comprising providing an aqueous inhalation mixture comprising a corticosteroid and a solubility enhancer and delivering the aqueous inhalation mixture with an inhalation nebulizer wherein the corticosteroid is administered at nominal dosage of less than about 250 ⁇ g/dose.
  • the corticosteroid can be administered at nominal dosage of less than about 240 ⁇ g/dose.
  • the corticosteroid can be administered at nominal dosage of less than about 200 ⁇ g/dose.
  • the corticosteroid can be administered at nominal dosage of less than about 150 ⁇ g/dose. In still another embodiment, the corticosteroid can be administered at nominal dosage of less than about 125 ⁇ g/dose. In another embodiment, the corticosteroid can be administered at nominal dosage of about 120 ⁇ g/dose. In yet still anther embodiment, the corticosteroid can be administered at nominal dosage of about 100 ⁇ g/dose. In yet another embodiment, the corticosteroid can be administered at nominal dosage of about 60 ⁇ g/dose. In yet still another embodiment, the corticosteroid can be administered at nominal dosage of about 50 ⁇ g/dose. In still another embodiment, the corticosteroid can be administered at nominal dosage of about 40 ⁇ g/dose.
  • the aqueous inhalation mixture can comprise a corticosteroid nominal dosage ranging from about 15 ⁇ g/dose to about 250 ⁇ g/dose, or about 40 ⁇ g/dose to about 250 ⁇ g/dose, or about 60 ⁇ g/dose to about 250 ⁇ g/dose, or about 40 ⁇ g/dose to about 200 ⁇ g/dose, or about 60 ⁇ g/dose to about 200 ⁇ g/dose, or about 40 ⁇ g/dose to about 150 ⁇ g/dose, or about 60 ⁇ g/dose to about 150 ⁇ g/dose, or about 40 ⁇ g/dose to about 125 ⁇ g/dose, or about 60 ⁇ g/dose to about 125 ⁇ g/dose, or about 40 ⁇ g/dose to about 100 ⁇ g/dose, or about 60 ⁇ g/dose to about 100 ⁇ g/dose, or about 25 ⁇ g/dose to about 50 ⁇ g/dose, or about 25 ⁇ g/dose to about 60 ⁇ g/dose
  • the corticosteroid is budesonide. In other embodiments, the corticosteroid is budesonide wherein the budesonide is either an individual diastereomer or a mixture of the two diastereomers administered individually or together for a therapeutic effect.
  • the methods and systems for the treatment or prophylaxis of a bronchoconstrictive disorder in a patient in need thereof can provide a method for the treatment of a branchoconstrictive disorder in a patient comprising providing an aqueous inhalation mixture comprising a single corticosteroid and a solubility enhancer and delivering the aqueous inhalation mixture with an inhalation nebulizer wherein the corticosteroid is administered at nominal dosage of less than about 250 ⁇ g/dose and the inhalation mixture is substantially free of pharmaceutically active agents other than the corticosteroid.
  • the corticosteroid can be administered at nominal dosage of less than about 240 ⁇ g/dose and the inhalation mixture is substantially free of pharmaceutically active agents other than the corticosteroid.
  • the corticosteroid can be administered at nominal dosage of less than about 200 ⁇ g/dose and the inhalation mixture is substantially free of pharmaceutically active agents other than the corticosteroid.
  • the corticosteroid can be administered at nominal dosage of less than about 150 ⁇ g/dose and the inhalation mixture is substantially free of pharmaceutically active agents other than the corticosteroid.
  • the corticosteroid can be administered at nominal dosage of about 60 ⁇ g/dose and the inhalation mixture is substantially free of pharmaceutically active agents other than the corticosteroid. In yet still another embodiment, the corticosteroid can be administered at nominal dosage of about 50 ⁇ g/dose and the inhalation mixture is substantially free of pharmaceutically active agents other than the corticosteroid. In another embodiment, the corticosteroid can be administered at nominal dosage of about 40 ⁇ g/dose and the inhalation mixture is substantially free of pharmaceutically active agents other than the corticosteroid.
  • the aqueous inhalation mixture can comprise a corticosteroid nominal dosage ranging from about 15 ⁇ g/dose to about 250 ⁇ g/dose, or about 40 ⁇ g/dose to about 250 ⁇ g/dose, or about 60 ⁇ g/dose to about 250 ⁇ g/dose, or about 40 ⁇ g/dose to about 200 ⁇ g/dose, or about 60 ⁇ g/dose to about 200 ⁇ g/dose, or about 40 ⁇ g/dose to about 150 ⁇ g/dose, or about 60 ⁇ g/dose.
  • the corticosteroid is budesonide. In other embodiments, the corticosteroid is budesonide wherein the budesonide is either an individual diastereomer or a mixture of the two diastereomers administered individually or together for a therapeutic effect, tnjjjsefciaiij
  • the present invention can provide a method for reducing the risk of side effects associated with corticosteroid inhalation therapy whereby a lower nominal dosage of the corticosteroid is required to achieve a therapeutic effect as compared to conventional inhalable corticosteroid therapies.
  • the risk of side effects is lowered compared to conventional inhalable corticosteroid therapies wherein the corticosteroid is administered at nominal dosage of less than about 250 ⁇ g/dose.
  • the risk of side effects is lowered compared to conventional inhalable corticosteroid therapies wherein the corticosteroid is administered at nominal dosage of less than about 125 ⁇ g/dose. In still yet another embodiment, the risk of side effects is lowered compared to conventional inhalable corticosteroid therapies wherein the corticosteroid is administered at nominal dosage of less than about 100 ⁇ g/dose. In yet still another embodiment, the risk of side effects is lowered compared to conventional inhalable corticosteroid therapies wherein the corticosteroid is administered at nominal dosage of less than about 60 ⁇ g/dose.
  • the risk of side effects is lowered compared to conventional inhalable corticosteroid therapies wherein the corticosteroid is administered at nominal dosage of less than about 50 ⁇ g/dose.
  • the corticosteroid is budesonide administered at nominal dosage of less than about 250 ⁇ g/dose.
  • the corticosteroid is budesonide administered at nominal dosage of less than about 125 ⁇ g/dose.
  • the corticosteroid is budesonide administered at nominal dosage of about 120 ⁇ g/dose.
  • the corticosteroid is budesonide administered at nominal dosage of about 60 ⁇ g/dose.
  • the corticosteroid is budesonide administered at nominal dosage of about 40 ⁇ g/dose.
  • aqueous inhalation mixture comprising a corticosteroid and a solubility enhancer.
  • suitable aqueous inhalation mixtures comprising a corticosteroid include, but are not limited to, solutions, dispersions, nano-dispersions, emulsions, colloidal liquids, micelle or mixed micelle solutions, and liposomal liquids.
  • the aqueous inhalation mixture is a solution comprising a corticosteroid, such as budesonide, and a solubility enhancer.
  • inhalable compositions comprising a corticosteroid do not include nano-dispersions and/or nano-suspensions. In other embodiments, inhalable compositions comprising a corticosteroid do not include micelle, mixed-micelle liquids or liposomal liquids. In still other embodiments, inhalable compositions comprising a corticosteroid do not include nano-dispersions and/or nano-suspensions, micelle, mixed-micelle liquids or liposomal liquids. In other- embodiments, inhalable; compositions, iincl ⁇ de .b ⁇ t'are.notJimited-it ⁇ jisoluti ⁇ nsjehiulsionSy and colloidal.liquids. In one embodiment.ithe!
  • aqueous inhalation mixture comprising a corticosteroid, a solvent and a solubility enhancer.
  • suitable aqueous inhalation mixtures comprising a corticosteroid include, but are not limited to, solutions, dispersions, nano- dispersions, emulsions, colloidal liquids, micelle or mixed micelle solutions, and liposomal liquids.
  • the aqueous inhalation mixture is a solution comprising a corticosteroid, such as budesonide, and a solubility enhancer.
  • inhalable compositions comprising a corticosteroid do not include nano-dispersions and/or nano-suspensions. In other embodiments, inhalable compositions comprising a corticosteroid do not include micelle, mixed-micelle liquids or liposomal liquids. In still other embodiments, inhalable compositions comprising a. corticosteroid do not include nano-dispersions and/or nano-suspensions, micelle, mixed-micelle liquids or liposomal liquids.
  • Jhtfbthfr emb ⁇ dime,nts' ⁇ inhalat>Te 'compositions, include-but sre not limited to, solutions, emulsio ⁇ a solution comprising a ⁇ c ⁇ rtic ⁇ ' ster ⁇ id ⁇ is' ⁇ ch ' ⁇ a ' s'b ' ⁇ desonidei and a s61 ⁇ Biliry : enhancer.
  • emulsio ⁇ a solution comprising a ⁇ c ⁇ rtic ⁇ ' ster ⁇ id ⁇ is' ⁇ ch ' ⁇ a ' s'b ' ⁇ desonidei and a s61 ⁇ Biliry : enhancer.
  • the systems and methods described herein comprise a solvent.
  • the solvent is selected from the group consisting of water, water/ethanol mixture, aqueous alcohol, propylene glycol, or aqueous organic solvent, or combinations thereof.
  • the solvent comprises water.
  • the solvent is water.
  • the solubility enhancer can have a concentration (w/v) ranging from about 2% to about 10% when the solubility enhancer is a cyclodextrin or cyclodextrin derivative,e.g. SBE7-/3-CD (Captisol®). In one embodiment, the solubility enhancer can have a concentration (w/v) of about 2% when the solubility enhancer is a cyclodextrin or cyclodextrin derivative,e.g. SBE7-/9-CD (Captisol®).
  • solubility enhancers suitable for use in the present invention include, but are not limited to, propylene glycol, non-ionic surfactants, phospholipids, cyclodextrins and derivatives thereof, and surface modifiers and/or stabilizers.
  • solubility enhancers refer to a formulation method which provides enhanced solubility without a chemical agent acting as the means to increase solubility, e.g. the use of super critical fluid production methods to generate nanoparticles for dispersion in a solvent.
  • solubility enhancers are known in the art and are described in, e.g., U.S. Patent Nos. 5,134,127, 5,145,684, 5,376,645, 6,241,969 and U.S. Pub. Appl. Nos. 2005/0244339 and 2005/0008707, each of which is specifically incorporated by reference herein.
  • suitable solubility enhancers are described below.
  • Suitable cyclodextrins and derivatives for use in the present invention are described in the art, for example, Challa et al., AAPS PharmSciTech 6(2): E329-E357 (2005), U.S. Patent Nos. 5,134,127, 5,376,645, 5,874,418, each of which is specifically incorporated by reference herein.
  • suitable cyclodextrins or cyclodextrin derivatives for use in the present invention include, but are not limited to, a- cyclodextrins, /3-cyciodextrins, ⁇ cyclodextrins, SAE-CD derivatives (e.g., SBE- ⁇ -CD, SBE-0-CD, SBEl - ⁇ - CD, SBE4-0-CD, SBE7-/3-CD (Captisol®), and SBE- ⁇ CD) (Cydex, Inc.
  • SAE-CD derivatives e.g., SBE- ⁇ -CD, SBE-0-CD, SBEl - ⁇ - CD, SBE4-0-CD, SBE7-/3-CD (Captisol®), and SBE- ⁇ CD
  • KS Lenexa, KS
  • hydroxy ⁇ thyl, hydroxypropyl (including 2-and 3-hydroxypropyl) and dihydroxypropyl ethers their corresponding mixed ethers and further mixed ethers with methyl or ethyl groups, such as methylhydroxyethyl, ethyl-hydroxyethyl and ethyl- hydroxypropyl ethers of a-, ⁇ - and ⁇ -cyclodextrin; and the maltosyl, glucosyl and maltotriosyl derivatives of a-, ⁇ - and 7-cyclodextrin, which may contain one or more sugar residues, e. g.
  • glucosyl or diglucosyl maltosyl or dimaltosyl, as well as various mixtures thereof, e. g. a mixture of maltosyl and dimaltosyl derivatives.
  • Specific cyclodextrin derivatives for use herein include hydroxypropyl-/3-cyclodextrin, hydroxyethyl-/3-cyclodextrin, hydroxypropyl- ⁇ -cyclodextrin, hydroxyethyl- ⁇ -cyclodextrin, dihydroxypropyl-/3- cyclodextrin, glucosyl- ⁇ t-cyclodextrin, glucosyl-/3-cyclodextrin, diglucosyl-j3-cyclodextrin, maltosyl- ⁇ - cyclodextrin, maltosyl-jS-cyclodextrin, maltosyl- ⁇ -cyclodextrin, maItotriosyl-/3-cyclod
  • Hydroxypropyl-/$-cycIodextrin can be obtained from Research Diagnostics Inc. (Flanders, NJ).
  • Exemplary hydroxypropyl-/3-cyclodextri ⁇ products include Encapsin® (degree of substitution ⁇ 4) and Molecusol® (degree of substitution ⁇ 8); however, embodiments including other degrees of substitution are also available and are within the scope of the present invention.
  • Dimethyl cyclodextrins are available from FLUKA Chemie (Buchs, CH) or Wacker (Iowa).
  • Other derivatized cyclodextrins suitable for use in the invention include water soluble derivatized cyclodextrins.
  • Exemplary water-soluble derivatized cyclodextrins include carboxylated derivatives; sulfated derivatives; alkylated derivatives; hydroxyalkylated derivatives; methylated derivatives; and carboxy-j3-cyclodextrins, e. g., succinyl-/?- cyclodextrin (SCD). All of these materials can be made according to methods known in the art and/or are available commercially.
  • Suitable derivatized cyclodextrins are disclosed in Modified Cyclodextrins: Scaffolds and Templates for Supramolecular Chemistry (Eds. Christopher J. Easton, Stephen F. Lincoln, Imperial College Press, London, UK, 1999) and New Trends in Cyclodextrins and Derivatives (Ed. Anthony Duchene, Editions de Sante, Paris, France, 1991).
  • the non-ionic surfactants suitable for use in the present invention are formulated with the corticosteroid to form liposome preparations, micelles or mixed micelles.
  • Methods for the preparations and characterization of liposomes and liposome preparations are known in the art. Often, multi-lamellar vesicles will form spontaneously when amphophilic lipids are hydrated, whereas the formation of small unilamellar vesicles usually requires a process involving substantial energy input, such as ultrasonication or high pressure homogenization. Further methods for preparing and characterizing liposomes have been described, for example, by S. Vemuri et al.
  • micelles or mixed micelles may be formed by the surfactants, in which poorly soluble active agents can be solubilized.
  • micelles are understood as substantially spherical structures formed by the spontaneous and dynamic association of amphiphilic molecules, such as surfactants.
  • Mixed micelles are micelles composed of different types of amphiphilic molecules. Both micelles and mixed micelles should not be understood as solid particles, as their structure, properties and behavior are much different from solids.
  • the amphiphilic molecules which form the micelles usually associate temporarily. In a micellar solution, there is a dynamic exchange of molecules between the micelle-forming amphiphile and monomolecularly dispersed amphiphiles which are also present in the solution.
  • the position of the drug molecules which are solublized in such micelles or mixed micelles depends on the structure of these molecules as well as the surfactants used. For example, it is to be assumed that particularly non-polar molecules are localized mainly inside the colloidal structures, whereas polar substances are more likely to be found on the surface.
  • the average size of the micelles may be less than about 200 nm (as measured by photon correlation spectroscopy), such as from about 10 nm to about 100 nm. Particularly preferred are micelles with average diameters of about 10 to about 50 nm.
  • Phospholipids are defined as amphiphile lipids which contain phosphorus. Phospholipids which are chemically derived from phosphatidic acid occur widely and are also commonly used for pharmaceutical purposes. This acid is a usually (doubly) acylatcd glycerol-3-phosphate in which the fatty acid residues may be of different length.
  • the derivatives of phosphatide acid include, for example, the phosphocholines or phosphatidylcholines, in which the phosphate group is additionally esterified with choline, furthermore phosphatidyl ethanolamines, phosphatidyl inositols, etc.
  • Lecithins are natural mixtures of various phospholipids which usually have a high proportion of phosphatidyl cholines. Depending on the source of a particular lecithin and its method of extraction and/or enrichment, these mixtures may also comprise significant amounts of sterols, fatty acids, tryglycerides and other substances.
  • Examples for enriched or pure compounds are dimyristoyl phosphatidyl choline (DMPC), distearoyl phosphatidyl choline (DSPC) and dipalmitoyl phosphatidyl choline (DPPC).
  • DMPC dimyristoyl phosphatidyl choline
  • DSPC distearoyl phosphatidyl choline
  • DPPC dipalmitoyl phosphatidyl choline
  • DMPC dimyristoyl phosphatidyl choline
  • DSPC distearoyl phosphatidyl choline
  • DPPC dipalmitoyl phosphatidyl choline
  • phospholipids with oleyl residues and phosphatidyl glycerol without choline residue are suitable for some embodiments and applications of the invention.
  • the non-ionic surfactants and phospholipids suitable for use in the present invention are formulated with the corticosteroid to form colloidal structures.
  • Colloidal solutions are defined as mono-phasic systems wherein the colloidal material dispersed within the colloidal solution does not have the measurable physical properties usually associated with a solid material. Methods of producing colloidal dispersions are known in the art, for example as described in U.S. Patent No. 6,653,319, which is specifically incorporated by reference herein.
  • Examples of surface modifiers and/or surface stabilizers suitable for use in the present invention include, but are not limited to, hydroxypropyl methylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, sodium lauryl sulfate, dioctylsulfosuccinate, gelatin, casein, lecithin (phosphatides), dextran, gum acacia, cholesterol, tragacanth, stearic acid, benzalkonium chloride, calcium stearate, glycerol monostearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters, polyoxyethylene alkyl ethers (e.g., macrogol ethers such as cetomacrogol 1000), polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters (e.g., the commercially available Tweens ® , e.g., Tween 20 ® and Tween 80 ®
  • corticosteroid compositions such as budesonide
  • budesonide particles are fabricated into particles with narrow particle size distribution (usually less than 200 nanometers spread) with a mean particle hydrodynamic radius in the range of 50 nanometers to 700 nanometers.
  • SCF Supercritical Fluids
  • RESS Rapid Expansion of Supercritical Solutions
  • SEDS Solution Enhanced Dispersion of Supercritical fluids
  • the processes for producing nanometer sized particles can permit selection of a desired morphology (e.g., amorphous, crystalline, resolved racemic) by appropriate adjustment of the conditions for particle formation during precipitation or condensation. As a consequence of selection of the desired particle form, extended release of the selected medicament can be achieved.
  • These particle fabrication processes are used to obtain nanoparticulates that have high purity, low surface imperfections, low surface charges and low sedimentation rates. Such particle features inhibit particle cohesion, agglomeration and also prevent settling in liquid dispersions. Additionally, because processes such as SCF can separate isomers of certain medicaments, such separation could contribute to the medicament's enhanced activity, effectiveness as well as extreme dose reduction.
  • an aqueous inhalation mixture can be a composition fabricated into a powdered form by any process including SCF, spray drying, precipitation and volume exclusion, directly into a collection media, wherein the particulate compound is thus automatically generated into a dispersed formulation.
  • this formulation can be the final formulation.
  • the solubility enhancer is a chemical agent selected from the group consisting of propylene glycol, non-ionic surfactants, tyloxapol, polysorbate 80, vitamin E-TPGS, macrogol-15-hydroxystearate, phospholipids, lecithin, purified and/or enriched lecithin, phosphatidylcholine fractions extracted from lecithin, dimyristoyl phosphatidylcholine (DMPC), dipalmitoyl phosphatidylcholine (DPPC), distearoyl phosphatidylcholine (DSPC), cyclodextrins and derivatives thereof, SAE-CD derivatives, SBE-ct-CD, SBE-/3-CD, SBE1-0-CD, SBE4-/3-CD, SBE7-/3-CD (Captisol®), SBE-rCD, dimethyl /J-CD, hydroxypropyl-(3-cyclodextrin
  • the inhalable compositions of the present invention comprise a solubility enhancer selected from the group consisting of cyclodextrins and derivatives thereof, SAE-CD derivatives, SBE-ct-CD, SBE- ⁇ -CD, SBE1-/S-CD, SBE4-j3-CD, SBE7-/3-CD (Captisol®), SBE- ⁇ -CD, dimethyl /S-CD, hydroxypropyl-/£-cyclodextrin, 2-HP-/8-CD, hydroxyethyI-/3-cyclodextrin, hydroxypropyl-T-cyclodextrin, hydroxyethyl- ⁇ -cyclodextrin, dihydroxy ⁇ ropyl-/3-cyclodextrin, glucosyl- ⁇ -cyclodextrin, glucosyl-/3- cyclodextrin, diglucosyl-jS-cyclodextrin, maltosyl-c
  • SAE-CD derivatives SBE
  • any known inhalation nebulizer is suitable for use in the presently described invention.
  • nebulizers include, e.g., jet nebulizers, ultrasonic nebulizers, pulsating membrane nebulizers, nebulizers with a vibrating mesh or plate with multiple apertures, and nebulizers comprising a vibration generator and an aqueous chamber (e.g., Pari eFlow ® ).
  • nebulizers for use herein include 5000 Electromagnetic Neb, 5001 Electromagnetic Neb 5002 Rotary Piston Neb, Lumineb I Piston Nebulizer 5500, Aeroneb Portable Nebulizer System, Aerodose Inhaler, and AeroEclipse Breath Actuated Nebulizer.
  • Exemplary nebulizers comprising a vibrating mesh or plate with multiple apertures are described by R. Dhand, (New Nebuliser Technology — Aerosol Generation by Using a Vibrating Mesh or Plate with Multiple Apertures, Long-Term Healthcare Strategies 2003, (July 2003), p. 1-4) and Respiratory Care, 47: 1406-1416 (2002), the entire disclosure of each of which is hereby incorporated by reference.
  • nebulization such as flow rate, mesh membrane size, aerosol inhalation chamber size, mask size and materials, valves, and power source may be varied in accordance with the principles of the present invention to maximize their use with different types and aqueous inhalation mixtures or different types of corticosteroids.
  • Atomizers are also suitable for the systems and methods described herein for the delivery of an aqueous inhalation solution comprising a corticosteroid and a solubility enhancer.
  • Atomizers are known in the art and are described in, for example, U.S. Patent Nos. 5,954,047, 6,026,808, 6,095,141 and 6,527,151, each of which is specifically incorporated by reference.
  • the nebulizer is selected from the group consisting of Pan LC Jet Plus, Intertech, Baxter Misty-Neb, Hudson T-Updraft II, Hudson Ava-Neb, Aiolos, Pan LC Jet, DeVilbiss Pulmo-Neb, Hudson Iso-Neb (B), Hudson T-Updraft Neb-U-Mist, Pari-Jet 1460, and AeroTech with T-piece.
  • the nebulizer is a Pari eFlow nebulizer.
  • the methods and systems described herein can deliver an aqueous inhalable mixture comprising a corticosteroid, e.g. budesonide, to a subject in therapeutically effective amount for the treatment of a subject that has had or is anticipating a bronchoconstrictive- disorder selected from the group consisting of asthma, pediatric asthma, bronchial asthma, allergic asthma, intrinsic asthma, chronic obstructive pulmonary disease (COPD), chronic bronchitis, emphysema, or a combination of any of the above.
  • a corticosteroid e.g. budesonide
  • COPD chronic obstructive pulmonary disease
  • the aqueous inhalation mixture comprises a corticosteroid, such as budesonide, wherein the aqueous inhalation mixture is administered according to the methods and systems described herein once a day.
  • the aqueous inhalation mixture comprises a corticosteroid, such as budesonide, wherein the aqueous inhalation mixture is administered according to the methods and systems described herein not more than once a day in the evening.
  • the methods and systems described herein can further include administering aqueous inhalation mixtures comprising a corticosteroid in combination with one or more active agents.
  • the corticosteroid e.g., budesonide
  • the corticosteroid can be administered in combination with one or more other drugs one or more active agents selected from the group consisting of: (a) a B2-adrenoreceptor agonist; (b) a dopamine (D2) receptor agonist; (c) a prophylactic therapeutic, such as a steroid; (d) a topical anesthetic; or (e) an anti-cholinergic agent; either simultaneously with, prior to or subsequent to the inhalable composition provided herein.
  • active agents selected from the group consisting of: (a) a B2-adrenoreceptor agonist; (b) a dopamine (D2) receptor agonist; (c) a prophylactic therapeutic, such as a steroid; (d) a topical anes
  • the systems and methods described herein can deliver an inhalation mixture comprising budesonide and a solubility enhancer wheTein greater than greater than about 55%; or greater than about 50%; or greater than about 45%; or greater than about 40%; or greater than about 35%; or greater than about 30%; or greater than about 25%; or greater than about 20% of the budesonide dosed by weight is absorbed into the bloodstream.
  • a solubility enhancer wheTein greater than greater than about 55%; or greater than about 50%; or greater than about 45%; or greater than about 40%; or greater than about 35%; or greater than about 30%; or greater than about 25%; or greater than about 20% of the budesonide dosed by weight is absorbed into the bloodstream.
  • the methods and systems of the present invention can deliver a therapeutically effective amount of a corticosteroid in a significantly shorter period of time than conventional inhalable corticosteroid therapies.
  • the nebulization time for Pulmicort ® Respules administered by a Pari LC Plus jet nebulizer takes at least 5 minutes to 8 minutes, and in some cases in excess of 10 minutes.
  • the methods and systems of the present invention can deliver a therapeutically effective amount of a corticosteroid, such as a budesonide, over a delivery time of less than about 5 minutes to less than about 1.5 minutes. In some embodiments, the delivery time can be about 5 minutes.
  • the delivery time can be less than about 5 minutes. In certain embodiments, the delivery time can be about 4.5 minutes. In certain other embodiments, the delivery time can be less than about 4.5 minutes. In still other embodiments, the delivery time can be about 4 minutes. In yet other embodiments, the delivery time can be less than about 4 minutes. In still yet other embodiments, the delivery time can be about 3.5 minutes. In other embodiments, the delivery time can be less than about 3.5 minutes. In yet still other embodiments, the delivery time can be about 3 minutes. In other embodiments, the delivery time can be less than about 3 minutes. In certain embodiments, the delivery time can be about 2.5 minutes. In other certain embodiments, the delivery time can be less than about 2.5 minutes.
  • the delivery time can be about 2 minutes. In yet still other embodiments, the delivery time can be less than about 2 minutes. In a preferred embodiment, the delivery time can be about 1.5 minutes. In a more preferred embodiment, the delivery time can be less than about 1.5 minutes.
  • the methods and systems of the present invention can deliver substantially all of the nominal dosage of a corticosteroid in a significantly shorter period of time than conventional inhalable corticosteroid therapies.
  • the nebulization time for Pulmicort ® Respules administered by a Pari LC Plus jet nebulizer takes at least 5 minutes to 8 minutes, and in some cases in excess of 10 minutes.
  • the methods and systems of the present invention can deliver an nominal dosage of a corticosteroid, such as a budesonide, over a delivery time of less than about 5 minutes to less than about 1.5 minutes. In some embodiments, substantially all of the nominal dosage can be delivered in about 5 minutes.
  • substantially all of the nominal dosage can be delivered in less than about 5 minutes. In certain embodiments, substantially all of the nominal dosage can be delivered in about 4.5 minutes. In certain other embodiments, substantially all of the nominal dosage can be delivered in than about 4.5 minutes. In still other embodiments, substantially all of the nominal dosage can be delivered in about 4 minutes. In yet other embodiments, substantially all of the nominal dosage can be delivered in less than about 4 minutes. In still yet other embodiments, substantially all of the nominal dosage can be delivered in about 3.5 minutes. In other embodiments, substantially all of the nominal dosage can be delivered than about 3.5 minutes. In yet still other embodiments, substantially all of the nominal dosage can be delivered in about 3 minutes. In other embodiments, substantially all of the nominal dosage can be delivered in less than about 3 minutes.
  • substantially all of the nominal dosage can be delivered in about 2.5 minutes. In other certain embodiments, substantially all of the nominal dosage can be delivered in less than about 2.5 minutes. In still other embodiments, substantially all of the nominal dosage can be delivered about 2 minutes. In yet still other embodiments, substantially all of the nominal dosage can be delivered in less than about 2 minutes. In a preferred embodiment, substantially all of the nominal dosage can be delivered in about 1.5 minutes. In a more preferred embodiment, substantially all of the nominal dosage can be delivered in less than about 1.5 minutes.
  • the volume of the aqueous inhalation mixture can be about 2.5 mis. In yet other embodiments, the volume of the aqueous inhalation mixture can be about 2.0 mis. In certain embodiments, the volume of the aqueous inhalation mixture can be about 1.5 mis. In other certain embodiments, the volume of the aqueous inhalation mixture can be about 1.0 mis. In a preferred embodiment, the volume of the aqueous inhalation mixture can be about 0.5 mis.
  • the methods and systems described herein can comprise one or more of any or all of the advantages provided by the present invention, and additional embodiments are within the scope of the invention.
  • the methods and systems described herein can provide an aqueous inhalation mixture comprising a corticosteroid in a nominal dosage of about 60 ⁇ g/dose and a solubility enhancer with a volume of the inhalation mixture of about 0.5 mis and an inhalable nebulizer, wherein the delivery of the aqueous mixture comprising the corticosteroid by the nebulizer is less than about 2 minutes, and wherein the delivery of the aqueous inhalation mixture comprising the corticosteroid by the nebulizer results in an enhanced pharmacokinetic profile of the corticosteroid such that the Cm ax is equal to the C m3x of a inhalable suspension comprising a corticosteroid when the aqueous inhalation mixture comprising the cortico
  • the present invention can also provide a method or system for the treatment or prophylaxis of a bronchoconstrictive disorder in a patient comprising providing an aqueous inhalation mixture comprising a nominal dosage of a corticosteroid and a solubility enhancer and delivering the aqueous inhalation mixture via an inhalation nebulizer.
  • the methods can provide the delivery of the corticosteroid displaying an enhanced pharmacokinetic profile as compared to a suspension-based corticosteroid formulation, administered under the same conditions.
  • the methods and systems of the present invention can provide for treatment or prophylaxis of a bronchoconstrictive disorder in a patient in need thereof comprising (a) providing an aqueous inhalation mixture comprising a nominal dosage of a corticosteroid and a solubility enhancer and (b) delivering the aqueous inhalation mixture comprising the corticosteroid with the nebulizer, whereby the methods and systems provide at least a two-fold enhanced pharmacokinetic profile of the aqueous inhalation mixture comprising a nominal dosage of a corticosteroid as compared to the pharmacokinetic profile of an inhalable suspension comprising a nominal dosage of a corticosteroid, e.g.
  • the inhalable aqueous mixtures can display substantially equivalent bioavailability for the corticosteroid as compared to conventional inhalable suspensions comprising a corticosteroid, while using significantly lower nominal dosages.
  • the inhalable aqueous mixtures can display increased bioavailability of the corticosteroid as compared to conventional inhalable suspensions comprising a corticosteroid when delivered at the same nominal dosage.
  • the ratio of the nominal dosage of the corticosteroid in the aqueous inhalation mixture to the nominal dosage the corticosteroid in the inhalable suspension is from about 0.01 :1 to about 1 :100.
  • the aqueous inhalation mixture comprising a corticosteroid delivered by the methods described herein can have a C 103x greater than the C 013x of a suspension-based corticosteroid formulation administered at the same nominal dosage under the same conditions.
  • the aqueous inhalation mixture comprising a corticosteroid delivered by the methods described herein can have an AUC ⁇ t) greater than the AUC ⁇ of a suspension-based corticosteroid formulation administered at the same nominal dosage under the same conditions.
  • the aqueous inhalation mixture comprising a corticosteroid delivered by the method described herein can have an AUC (0 .o $ greater than the AUC (O-0 ⁇ of a suspension-based corticosteroid formulation administered at the same nominal dosage under the same conditions.
  • the aqueous inhalation mixture comprising a corticosteroid delivered by the method described herein can have a T n Q x less than the T m3x of a suspension-based corticosteroid formulation administered under the same conditions.
  • the aqueous inhalation mixture comprising a corticosteroid delivered by the methods described herein can have a C n ⁇ x equivalent to the C m3x of a suspension-based corticosteroid formulation wherein the nominal dosage of the aqueous inhalation mixture is lower than the nominal dosage of the suspension-based corticosteroid formulation administered under the same conditions.
  • the aqueous inhalation mixture comprising a corticosteroid delivered by the methods described herein can have an AUC (I33I) equivalent to the AUC ( i ast) of a suspension-based corticosteroid formulation wherein the nominal dosage of the aqueous inhalation mixture is lower than the nominal dosage of the suspension-based corticosteroid formulation administered under the same conditions.
  • the aqueous inhalation mixture comprising a corticosteroid delivered by the method described herein can have an AUC(o-c $ equivalent to the of a suspension-based corticosteroid formulation wherein the nominal dosage of the aqueous inhalation mixture is lower than the nominal dosage of the suspension-based corticosteroid formulation administered under the same conditions.
  • the aqueous inhalation mixture comprising a corticosteroid delivered by the method described herein can have a T max less than the Tma x of a suspension- based corticosteroid formulation wherein the nominal dosage of the aqueous inhalation mixture is lower than the nominal dosage of the suspension-based corticosteroid formulation administered under the same conditions.
  • the methods and system described herein can deliver a corticosteroid with an enhanced pharmacokinetic profile of the aqueous inhalation mixture comprising a nominal dosage of a corticosteroid as compared to the pharmacokinetic profile of an inhalable suspension comprising a nominal dosage of a corticosteroid, e.g. Pulmicort Respules ® , administered under the same conditions in a range of between at least about 1.5 fold (150%) to about 10 fold (1000%) the specified therapeutic parameter (e.g., AUC (0 .c_ ) ) to provide an enhanced pharmacokinetic profile.
  • the ratio of the nominal dosage of the corticosteroid in the aqueous inhalation mixture to the nominal dosage the corticosteroid in the inhalable suspension is from about 0.01:1 to about 1:100.
  • the methods and system described herein can deliver an aqueous inhalation mixture comprising a nominal dosage of a corticosteroid with an enhanced pharmacokinetic profile comprising an equivalent bioavailability (e.g., equivalent compared to conventional inhalable suspensions comprising a nominal dosage of a corticosteroid wherein the nominal dosage of the corticosteroid in the aqueous inhalation mixtures is in a range of between at least about 1 :1.5 to about 1 :10 the nominal dose of the corticosteroid in conventional inhalable suspension to provide an enhanced pharmacokinetic profile (1.5 fold to about 10 fold enhanced pharmacokinetic profile).
  • an equivalent bioavailability e.g., equivalent compared to conventional inhalable suspensions comprising a nominal dosage of a corticosteroid wherein the nominal dosage of the corticosteroid in the aqueous inhalation mixtures is in a range of between at least about 1 :1.5 to about 1 :10 the nominal dose of the corticosteroid in conventional in
  • the methods and systems of the present invention can provide for treatment or prophylaxis of a bronchoconstrictive disorder in a patient in need thereof comprising (a) providing an aqueous inhalation mixture comprising a nominal dosage of a corticosteroid and a solubility enhancer and (b) delivering the aqueous inhalation mixture comprising the corticosteroid with an inhalation nebulizer, whereby the methods and systems deliver about a 1.5 fold (150%) to about a 10 fold (1000%) enhanced pharmacokinetic profile of the aqueous inhalation mixture comprising the nominal dosage of the corticosteroid as compared to the pharmacokinetic profile of an inhalable suspension comprising a nominal dosage of a corticosteroid administered under the same conditions.
  • the aqueous inhalation mixture comprising nominal dosage of a corticosteroid administered by the systems and method described herein can deliver about a 1.5 fold (150%) and about a 8 fold (800%) have an enhanced pharmacokinetic profile compared to conventional inhalable suspensions comprising a nominal dosage of a corticosteroid administered under the same conditions.
  • the aqueous inhalation mixture comprising a nominal dosage of a corticosteroid administered by the systems and method described herein can have an enhanced pharmacokinetic profile compared to conventional inhalable suspensions comprising a nominal dosage of corticosteroid in a range of between about a 1.5 fold (150%) and about a 6 fold (600%) enhanced pharmacokinetic profile when administered under the same conditions.
  • the aqueous inhalation mixture comprising a nominal dosage of a corticosteroid administered by the systems and method described herein can have an enhanced pharmacokinetic profile compared to conventional inhalable suspensions comprising a nominal dosage of a corticosteroid in a range of between about a 1.5 fold (150%) and about a 5 fold (500%) enhanced pharmacokinetic profile when administered under the same conditions.
  • the aqueous inhalation mixture comprising a nominal dosage of a corticosteroid administered by the systems and method described herein can have an enhanced pharmacokinetic profile compared to conventional inhalable suspensions comprising a nominal dosage of a corticosteroid in a range of between about a 1.5 fold (150%) and about a 4 fold (400%) enhanced pharmacokinetic profile when administered under the same conditions.
  • the aqueous inhalation mixture comprising a nominal dosage of a corticosteroid administered by the systems and method described herein can have an enhanced pharmacokinetic profile compared to conventional inhalable suspensions comprising a nominal dosage of a corticosteroid in a range of between about a 1.5 fold (150%) and about a 3 fold (300%) enhanced pharmacokinetic profile when administered under the same conditions.
  • the aqueous inhalation mixture comprising a nominal dosage of a corticosteroid administered by the systems and method described herein can have an enhanced pharmacokinetic profile compared to conventional inhalable suspensions comprising a nominal dosage of a corticosteroid in a range of between about a 1.5 fold (150%) and about a 2 fold (200%) enhanced pharmacokinetic profile when administered under the same conditions.
  • the aqueous inhalation mixture comprising a nominal dosage of a corticosteroid administered by the systems and method described herein can have an enhanced pharmacokinetic profile compared to conventional inhalable suspensions comprising a nominal dosage of a corticosteroid of about 2 fold (200%) when administered under the same conditions.
  • the aqueous inhalation mixture comprising a nominal dosage of a corticosteroid administered by the systems and method described herein can have an enhanced pharmacokinetic profile compared to conventional inhalable suspensions comprising a nominal dosage of a corticosteroid of about 3 fold (300%) when administered under the same conditions.
  • the aqueous inhalation mixture comprising a nominal dosage of a corticosteroid administered by the systems and method described herein can have an enhanced pharmacokinetic profile compared to conventional inhalable suspensions comprising a nominal dosage of a corticosteroid of about 4 fold (400%) when administered under the same conditions.
  • the aqueous inhalation mixture comprising a nominal dosage of a corticosteroid administered by the systems and method described herein can have an enhanced pharmacokinetic profile compared to conventional inhalable suspensions comprising a nominal dosage of a corticosteroid of about 5 fold (500%) when administered under the same conditions.
  • the aqueous inhalation mixture comprising a nominal dosage of a corticosteroid administered by the systems and method described herein can have an enhanced pharmacokinetic profile compared to conventional inhalable suspensions comprising a nominal dosage of a corticosteroid of about 6 fold (600%) when administered under the same conditions.
  • an aqueous inhalation mixture comprising a nominal dosage of budesonide and a solubility enhancer is delivered by the systems and method described herein and has an enhanced pharmacokinetic profile compared to conventional inhalable suspensions comprising a nominal dosage of budesonide in a range of between at least about a 2 fold (200%) and about a 6 fold (600%) enhanced pharmacokinetic profile when administered under the same conditions.
  • the aqueous inhalation mixture comprising a nominal dosage of budesonide administered by the systems and method described herein can have an enhanced pharmacokinetic profile compared to conventional inhalable suspensions comprising a nominal dosage of budesonide of about 2 fold (200%) when administered under the same conditions.
  • the aqueous inhalation mixture comprising a nominal dosage.of budesonide administered by the systems and method described herein can have an enhanced pharmacokinetic profile compared to conventional inhalable suspensions comprising a nominal dosage of budesonide of about 3 fold (300%) when administered under the same conditions.
  • the aqueous inhalation mixture comprising a nominal dosage of budesonide administered by the systems and method described herein can have an enhanced pharmacokinetic profile compared to conventional inhalable suspensions comprising a nominal dosage of budesonide of about 4 fold (400%) when administered under the same conditions.
  • the aqueous inhalation mixture comprising a nominal dosage of budesonide administered by the systems and method described herein can have an enhanced pharmacokinetic profile compared to conventional inhalable suspensions comprising a nominal dosage of budesonide of about 5 fold (500%) when administered under the same conditions.
  • the present methods and systems fo ⁇ the treatment or prophylaxis of a bronchoconstrictive disorder in a patient in need thereof can deliver an aqueous inhalable mixture comprising a corticosteroid with the equivalent bioavailability as a inhalable suspension comprising of a corticosteroid wherein the aqueous inhalable mixture comprising a corticosteroid has a nominal dosage in a range of between about 1 :1.5 to about 1:10 the nominal dosage of the inhalable suspension comprising a corticosteroid.
  • the methods and systems of the present invention can provide for treatment or prophylaxis of a bronchoconstrictive disorder in a patient in need thereof comprising (1) providing an aqueous inhalation mixture comprising a corticosteroid and a solubility enhancer and (2) delivering the aqueous inhalation mixture with a inhalation nebulizer, wherein the delivery of the aqueous mixture comprising the corticosteroid by the nebulizer can result in equivalent bioavailability of the corticosteroid as compared to conventional inhalable suspensions comprising a corticosteroid wherein the nominal dosage of the aqueous inhalation mixture comprising a corticosteroid is about 1 :1.5 to about 1:10 the nominal dosage of the inhalable suspension comprising a corticosteroid.
  • the aqueous inhalation mixture comprising a corticosteroid administered by the systems and method described herein can have an enhanced pharmacokinetic profile compared to conventional inhalable suspensions comprising a corticosteroid wherein the nominal dosage of the aqueous inhalation mixture comprising a corticosteroid is about 1:1.5 to about 1 :9 the nominal dosage of the inhalable suspension comprising a corticosteroid.
  • the aqueous inhalation mixture comprising a corticosteroid administered by the systems and method described herein can have an " enhanced pharmacokinetic profile compared to conventional inhalable suspensions comprising a corticosteroid wherein the nominal dosage of the aqueous inhalation mixture comprising a corticosteroid is about 1:1.5 to about 1:8 the nominal dosage of the inhalable suspension comprising a corticosteroid.
  • the aqueous inhalation mixture comprising a corticosteroid administered by the systems and method described herein can have an enhanced pharmacokinetic profile compared to conventional inhalable suspensions comprising a corticosteroid wherein the nominal dosage of the aqueous inhalation mixture comprising a corticosteroid is about 1:1.5 to about 1:7 the nominal dosage of the inhalable suspension comprising a corticosteroid.
  • the aqueous inhalation mixture comprising a corticosteroid administered by the systems and method described herein can have an enhanced pharmacokinetic profile compared to conventional inhalable suspensions comprising a corticosteroid wherein the nominal dosage of the aqueous inhalation mixture comprising a corticosteroid is about 1:1.5 to about 1:6 the nominal dosage of the inhalable suspension comprising a corticosteroid.
  • the aqueous inhalation mixture comprising a corticosteroid administered by the systems and method described herein can have an enhanced pharmacokinetic profile compared to conventional inhalable suspensions comprising a corticosteroid wherein the nominal dosage of the aqueous inhalation mixture comprising a corticosteroid is about 1:1.5 and about 1:5 the nominal dosage of the inhalable suspension comprising a corticosteroid.
  • the aqueous inhalation mixture comprising a corticosteroid administered by the systems and method described herein can have an enhanced pharmacokinetic profile compared to conventional inhalable suspensions comprising a corticosteroid wherein the nominal dosage of the aqueous inhalation mixture comprising a corticosteroid is about 1 : 1.5 to about 1 :4 the nominal dosage of the inhalable suspension comprising a corticosteroid.
  • the aqueous inhalation mixture comprising a corticosteroid administered by the systems and method described herein can have an enhanced pharmacokinetic profile compared to conventional inhalable suspensions comprising a corticosteroid wherein the nominal dosage of the aqueous inhalation mixture comprising a corticosteroid is about 1:1.5 to about 1:3 the nominal dosage of the inhalable suspension comprising a corticosteroid.
  • the aqueous inhalation mixture comprising a corticosteroid administered by the systems and method described herein can have an enhanced pharmacokinetic profile compared to conventional inhalable suspensions comprising a corticosteroid wherein the nominal dosage of the aqueous inhalation mixture comprising a corticosteroid is about 1:1.5 and about 1 :2 the nominal dosage of the inhalable suspension comprising a corticosteroid.
  • an aqueous inhalation mixture comprising a corticosteroid and a solubility enhancer is delivered by the systems and method described herein and has an enhanced pharmacokinetic profile compared to conventional inhalable suspensions comprising a corticosteroid wherein the nominal dosage of the aqueous inhalation mixture comprising a corticosteroid is about 1 :2 to about 1: 10 the nominal dosage of the inhalable suspension comprising a corticosteroid
  • an aqueous inhalation mixture comprising a corticosteroid and a solubility enhancer is delivered by the systems and method described herein and has an enhanced pharmacokinetic profile compared to conventional inhalable suspensions comprising a corticosteroid wherein the nominal dosage of the aqueous inhalation mixture comprising a corticosteroid is about 1 :2 to about 1 :5 the nominal dosage of the inhalable suspension comprising a corticosteroid.
  • an aqueous inhalation mixture comprising a corticosteroid and a solubility enhancer is delivered by the systems and method described herein and has an enhanced pharmacokinetic profile compared to conventional inhalable suspensions comprising a corticosteroid wherein the nominal dosage of the aqueous inhalation mixture comprising a corticosteroid is about 1 :2 to about 1 :4 the nominal dosage of the inhalable suspension comprising a corticosteroid.
  • an aqueous inhalation mixture comprising a corticosteroid and a solubility enhancer is delivered by the systems and method described herein and has an enhanced pharmacokinetic profile compared to conventional inhalable suspensions comprising a corticosteroid wherein the nominal dosage of the aqueous inhalation mixture comprising a corticosteroid is about 1 :4 the nominal dosage of the inhalable suspension comprising a corticosteroid.
  • an aqueous inhalation mixture comprising budesonide and a solubility enhancer is delivered by the systems and method described herein and has an enhanced pharmacokinetic profile compared to conventional inhalable suspensions comprising budesonide wherein the nominal dosage of the aqueous inhalation mixture is about 1 :2 to about 1 :10 the nominal dosage of the inhalable suspension comprising budesonide.
  • an aqueous inhalation mixture comprising budesonide and a solubility enhancer is delivered by the systems and method described herein and has an enhanced pharmacokinetic profile compared to conventional inhalable suspensions comprising budesonide wherein the nominal dosage of the aqueous inhalation mixture is about 1:2 to about 1 :5 the nominal dosage of the inhalable suspension comprising budesonide.
  • an aqueous inhalation mixture comprising budesonide and a solubility enhancer is delivered by the systems and method described herein and has an enhanced pharmacokinetic profile compared to conventional inhalable suspensions comprising budesonide wherein the nominal dosage of the aqueous inhalation mixture is about 1 :2 to about 1 :4 the nominal dosage of the inhalable suspension comprising budesonide.
  • an aqueous inhalation mixture comprising budesonide and a solubility enhancer is delivered by the systems and method described he ⁇ ein and has an enhanced pharmacokinetic profile compared to conventional inhalable suspensions comprising budesonide wherein the nominal dosage of the aqueous inhalation mixture is about 1 :4 the nominal dosage of the inhalable suspension comprising budesonide.
  • the volume of the aqueous inhalation mixture can be about 2.5 mis. In yet other embodiments, the volume of the aqueous inhalation mixture can be about 2.0 mis. In certain embodiments, the volume of the aqueous inhalation mixture can be about 1.5 mis. In other certain embodiments, the volume of the aqueous inhalation mixture can be about 1.0 mis. In a preferred embodiment, the volume of the aqueous inhalation mixture can be about 0.5 mis.
  • the methods and systems of the present invention can deliver a therapeutically effective amount of a corticosteroid in a significantly shorter period of time than conventional inhalable corticosteroid therapies.
  • the nebulization time for Pulmicort ® Respules administered by a Pan LC Plus jet nebulizer takes at least 5 minutes to 8 minutes, and in some cases in excess of 10 minutes.
  • the methods and systems of the present invention can deliver a therapeutically effective amount of a corticosteroid, such as a budesonide, over a delivery time of less than about 5 minutes to less than about 1.5 minutes. In some embodiments, the delivery time can be about 5 minutes.
  • the delivery time can be less than about 5 minutes. In certain embodiments, the delivery time can be about 4.5 minutes. In certain other embodiments, the delivery time can be less than about 4.5 minutes. In still other embodiments, the delivery time can be about 4 minutes. In yet other embodiments, the delivery time can be less than about 4 minutes. In still yet other embodiments, the delivery time can be about 3.5 minutes. In other embodiments, the delivery time can be less than about 3.5 minutes. In yet still other embodiments, the delivery time can be about 3 minutes. In other embodiments, the delivery time can be less than about 3 minutes. In certain embodiments, the delivery time can be about 2.5 minutes. In other certain embodiments, the delivery time can be less than about 2.5 minutes.
  • the delivery time can be about 2 minutes. In yet still other embodiments, the delivery time can be less than about 2 minutes. In a preferred embodiment, the delivery time can be about 1.5 minutes. In a more preferred embodiment, the delivery time can be less than about 1.5 minutes.
  • the methods and systems of the present invention can deliver substantially all of the nominal dosage of a corticosteroid in a significantly shorter period of time than conventional inhalable corticosteroid therapies.
  • the nebulization time for Pulmicort ® Respules administered by a Pan LC Plus jet nebulizer takes at least 5 minutes to 8 minutes, and in some cases in excess of 10 minutes.
  • the methods and systems of the present invention can deliver substantially all of the nominal dosage of a corticosteroid, such as a budesonide, over a delivery time of less than about 5 minutes to less than about 1.5 minutes. In some embodiments, substantially all of the nominal dosage can be delivered in about 5 minutes.
  • substantially all of the nominal dosage can be delivered in less than about 5 minutes. In certain embodiments, substantially all of the nominal dosage can be delivered in about 4.5 minutes. In certain other embodiments, substantially all of the nominal dosage can be delivered in than about 4.5 minutes. In still other embodiments, substantially all of the nominal dosage can be delivered in about 4 minutes. In yet other embodiments, substantially all of the nominal dosage can be delivered in less than about 4 minutes. In still yet other embodiments, substantially all of the nominal dosage can be delivered in about 3.5 minutes. In other embodiments, substantially all of the nominal dosage can be delivered than about 3.5 minutes. In yet still other embodiments, substantially all of the nominal dosage can be delivered in about 3 minutes. In other embodiments, substantially all of the nominal dosage can be delivered in less than about 3 minutes.
  • substantially all of the nominal dosage can be delivered in about 2.5 minutes. In other certain embodiments, substantially all of the nominal dosage can be delivered in less than about 2.5 minutes. In still other embodiments, substantially all of the nominal dosage can be delivered about 2 minutes. In yet still other embodiments, substantially all of the nominal dosage can be delivered in less than about 2 minutes. In a preferred embodiment, substantially all of the nominal dosage can be delivered in about 1.5 minutes. In a more preferred embodiment, substantially all of the nominal dosage can be delivered in less than about 1.5 minutes.
  • the methods and systems for the treatment or prophylaxis of a bronchoconstrictive disorder in a patient in need thereof described herein can deliver an inhalation mixture comprising corticosteroid to the subject in a manner wherein the active is delivered having an increased C max blood plasma value of the corticosteroid as compared to conventional inhalable corticosteroid suspensions administered under the same conditions.
  • budesonide + SBE7-/J-CD inhalation solutions having nominal dosages of 60 ⁇ g, 120 ⁇ g, and 240 ⁇ g delivered in a single dose using a Pan eFlow Inhaler ® in a 0.5 ml volume with a delive ⁇ y time of about 1.5 minutes had C 1113x blood plasma values of about 227 ⁇ 89 (pg/ml), about 578 ⁇ 238 (pg/ml), and 1195 ⁇ 811 (pg/ml), respectively.
  • FIG. 4 provides a graphic representation of the data used to generate the aforementioned Cma x blood plasma values.
  • a 60 ⁇ g CBIS inhalation solution delivered twice daily for seven days using a Pan eFlow Inhaler ® in a 0.5 ml volume with a delivery time of about 1.5 minutes had a minimum Q n3x blood plasma value of about 186.4 pg/ml, a maximum C n , a ⁇ blood plasma value of about 779.4 pg/ml, and geometric mean C max values of about 362.2 pg/ml.
  • a 120 ⁇ g CBIS inhalation solution delivered twice daily for seven days using a Pan eFlow Inhaler ® in a 0.5 ml volume with a delivery time of about 1.5 minutes had a minimum C m3x blood plasma value of about 169.8 pg/ml, a maximum C n13x blood plasma value of about 1160.4 pg/ml, and geometric mean C n ⁇ values of about 516.9 pg/ml.
  • FIG. 5 provides a graphic representation of the data upon which the aforementioned C m3x blood plasma values were based.
  • the methods and systems for the treatment or prophylaxis of a bronchoconstrictive disorder in a patient in need thereof provide the delivery of an inhalation mixture comprising a nominal dosage of a corticosteroid having an enhanced pharmacokinetic profile as compared to conventional inhalable corticosteroid suspensions comprising a nominal dosage of a corticosteroid administered under the same conditions.
  • the systems and methods described herein provide at least about 1.5 fold to about 14 fold increase in C 1113x blood plasma values (as determined on an individual basis) for a corticosteroid normalized for dose of corticosteroid per microgram of corticosteroid administered, as compared to conventional inhalable corticosteroid therapies administered under the same conditions.
  • the systems and methods described herein provide at least about 4 fold to about 7 fold, about 4 fold to about 6.5 fold, about 4 fold to about 6.25 fold, about 4 fold to about 6 fold, about 4 fold to about 5.75 fold, about 4 fold to about 5.5 fold, about 4 fold to about 5 fold, about 5 fold to about 7 fold, about 5.5 fold to about 7 fold, about 6 fold to about 7 fold increase in C 013x blood plasma values for a corticosteroid taken across a studied patient population, normalized for dose of corticosteroid per microgram of corticosteroid administered, as compared to conventional inhalable corticosteroid therapies administered under the same conditions.
  • the C n ⁇ x can be significantly greater than the C 13x blood plasma values exhibited by conventional inhalable suspensions comprising a corticosteroid administered at the same nominal dosage under the same conditions.
  • the C n _ ⁇ can be from about 1.5 fold (150%) to about 14 fold (1400%) the C n ⁇ x blood plasma values exhibited by conventional inhalable suspensions comprising a corticosteroid at the same nominal dosage under the same conditions.
  • the C m3x can be from about 1.5 fold (150%) to about 12 fold (1200%) the C n ⁇ x blood plasma values exhibited by conventional inhalable suspensions comprising a corticosteroid at the same nominal dosage under the same conditions.
  • the C 103x can be from about 1.5 fold (150%) to about 10 fold (1000%) the C max blood plasma values exhibited by conventional inhalable suspensions comprising a corticosteroid at the same nominal dosage under the same conditions.
  • the Cm 2x can be at least about 12 fold (1200%) the C 1J12x blood plasma values exhibited by conventional inhalable suspensions comprising a corticosteroid at the same nominal dosage under the same conditions.
  • the C 103x can be at least about 1000% (10 fold) to about 1200% (12 fold) , about 1100% (11 fold) to about 1200% (12 fold), or about 1 150% (11.5 fold) to about 1200% (12 fold) greater than the C n ⁇ x blood plasma values exhibited by conventional inhalable suspensions comprising a corticosteroid at the same nominal dosage under the same conditions.
  • the enhanced pharmacokinetic profile comprises a Ci 0x for the aqueous inhalation mixture that is greater than the Q 10x of the inhalable suspension comprising a corticosteroid, administered at the same nominal dosage under the same conditions.
  • the C n ⁇ x can be at least about 1000% (10 fold) greater than the C n ⁇ x blood plasma values exhibited by conventional inhalable suspensions comprising a corticosteroid at the same nominal dosage under the same conditions. In certain other embodiments, the C n ⁇ x can be at least about 900% (9 fold) to about 1000% (10 fold), about 925% (9.25 fold) to about 1000% (10 fold), or about 950% (9.5 fold) to about 1000% (10 fold) greater than the C 1113x blood plasma values exhibited by conventional inhalable suspensions comprising a corticosteroid at the same nominal dosage under the same conditions.
  • the C 013x can be at least about 900% (9 fold) greater than the C nw x blood plasma values exhibited by conventional inhalable suspensions comprising a corticosteroid at the same nominal dosage under the same conditions.
  • the C max can be at least about 800% (8 fold) to about 900% (9 fold) , about 825% (8.25 fold) to about 900% (9 fold), or about 850% (8.5 fold) to about 900% (9 fold) greater than the C 102x blood plasma values exhibited by conventional inhalable suspensions comprising a corticosteroid at the same nominal dosage under the same conditions.
  • the C m1x can be at least about 800% (8 fold) greater than the C mx blood plasma values exhibited by conventional inhalable suspensions comprising a corticosteroid at the same nominal dosage under the same conditions.
  • the C 013x can be at least about 700% (7 fold) to about 800% (8 fold) , about 725% (7.25 fold) to about 800% (8 fold), or about 750% (7.5 fold) to about 800% (8 fold) greater than the Q n ⁇ blood plasma values exhibited by conventional inhalable suspensions comprising a corticosteroid at the same nominal dosage under the same conditions.
  • the C m0x can be at least about 700% (7 fold) greater than the C ma ⁇ blood plasma values exhibited by conventional inhalable suspensions comprising a corticosteroid at the same nominal dosage under the same conditions.
  • the C m3x can be at least about 600% (6 fold) to about 700% (7 fold) , about 625% (6.25 fold) to about 700% (7 fold), or about 650% (6.5 fold) to about 700% (7 fold) greater than the C m3x blood plasma values exhibited by conventional inhalable suspensions comprising a corticosteroid at the same nominal dosage under the same conditions.
  • the C max is at least about 500% (5 fold) greater than the C 103x of the inhalable suspension comprising a corticosteroid.
  • the C 102x can be at least about 400% (4 fold) to about 500% (5 fold) , about 425% (4.25 fold) to about 500% (5 fold), or about 450% (4.5 fold) to about 500% (5 fold) greater than the C n ,-- blood plasma values exhibited by conventional inhalable suspensions comprising a corticosteroid at the same nominal dosage under the same conditions.
  • the C n13x is at least about 400% (4 fold) greater than the C n13x of the inhalable suspension comprising a corticosteroid.
  • the C m2x can be at least about 300% (3 fold) to about 400% (4 fold) , about 325% (3.25 fold) to about 400% (4 fold), or about 350% (3.5 fold) to about 400% (4 fold) greater than the C 011x blood plasma values exhibited by conventional inhalable suspensions comprising a corticosteroid at the same nominal dosage under the same conditions.
  • the C 110x is at least about 300% (3 fold) greater than the C m3x of the inhalable suspension comprising a corticosteroid.
  • the C 103x can be at least about 200% (2 fold) to about 300% (3 fold) , about 225% (2.25 fold) to about 300% (3 fold), or about 250% (2.5 fold) to about 300% (3 fold) greater than the C 11 I ax blood plasma values exhibited by conventional inhalable suspensions comprising a corticosteroid at the same nominal dosage under the same conditions.
  • the Q n3x is at least about 200% (2 fold) greater than the C 1113x of the inhalable suspension comprising a corticosteroid.
  • the C n ⁇ x can be at about 150% (1.5 fold) to about 200% (2 fold) greater than the C m3x blood plasma values exhibited by conventional inhalable suspensions comprising a corticosteroid at the same nominal dosage under the same conditions.
  • the C max is at least about 150% (1.5 fold) greater than the C n13x of the inhalable suspension comprising a corticosteroid.
  • the C n ⁇ can be substantially equivalent to the C max blood plasma values exhibited by conventional inhalable suspensions comprising a corticosteroid wherein the aqueous inhalation mixture comprising a corticosteroid is administered at a lower nominal dosage under the same conditions.
  • the nominal dosage can be about 1 :1.5 (i.e., 1.5 fold enhanced pharmacokinetic profile) to about 1 :10 (i.e., 10 fold enhanced pharmacokinetic profile) the nominal dosage of the conventional inhalable suspensions comprising a corticosteroid.
  • the nominal dosage of the aqueous inhalation mixture comprising a corticosteroid can be about 1:1.5 to about 1:9 of the nominal dosage of the conventional inhalable suspensions comprising a corticosteroid.
  • the nominal dosage of the aqueous inhalation mixture comprising a corticosteroid can be about 1 :1.5 to about 1:8 the nominal dosage of the conventional inhalable suspensions comprising a corticosteroid.
  • the nominal dosage of the aqueous inhalation mixture comprising a corticosteroid can be about 1 :1.5 to about 1:7 the nominal dosage of the conventional inhalable suspensions comprising a corticosteroid. In an additional embodiment, the nominal dosage of the aqueous inhalation mixture comprising a corticosteroid can be about 1:1.5 to about 1:6 the nominal dosage of the conventional inhalable suspensions comprising a corticosteroid. In another embodiment, the nominal dosage of the aqueous inhalation mixture comprising a corticosteroid can be about 1:2 to about 1:5 the nominal dosage of the conventional inhalable suspensions comprising a corticosteroid.
  • the nominal dosage of the aqueous inhalation mixture comprising a corticosteroid can be about 1 :2 to about 1 :4 the nominal dosage of the conventional inhalable suspensions comprising a corticosteroid. In still yet other embodiments, the nominal dosage of the aqueous inhalation mixture comprising a corticosteroid can be about 1 :2 to about 1 :3 the nominal dosage of the conventional inhalable suspensions comprising a corticosteroid. In certain embodiments, the nominal dosage of the aqueous inhalation mixture comprising a corticosteroid can be about 1:2 the nominal dosage of the conventional inhalable suspensions comprising a corticosteroid.
  • the nominal dosage of the aqueous inhalation mixture comprising a corticosteroid can be about 1 :3 the nominal dosage of the conventional inhalable suspensions comprising a corticosteroid. In other certain embodiments, the nominal dosage of the aqueous inhalation mixture comprising a corticosteroid can be about 1 :4 the nominal dosage of the conventional inhalable suspensions comprising a corticosteroid. In still other embodiments, the nominal dosage of the aqueous inhalation mixture comprising a corticosteroid can be about 1 :5 the nominal dosage of the conventional inhalable suspensions comprising a corticosteroid.
  • the nominal dosage of the aqueous inhalation mixture comprising a corticosteroid can be about 1 :6 the nominal dosage of the conventional inhalable suspensions comprising a corticosteroid. In still yet other embodiments, the nominal dosage of the aqueous inhalation mixture comprising a corticosteroid can be about 1 :7 the nominal dosage of the conventional inhalable suspensions comprising a corticosteroid. In other embodiments, the nominal dosage of the aqueous inhalation mixture comprising a corticosteroid can be about 1:8 the nominal dosage of the conventional inhalable suspensions comprising a corticosteroid.
  • the nominal dosage of the aqueous inhalation mixture comprising a corticosteroid can be about 1 :9 the nominal dosage of the conventional inhalable suspensions comprising a corticosteroid. In yet still other embodiments, the nominal dosage of the aqueous inhalation mixture comprising a corticosteroid can be about 1 :10 the nominal dosage of the conventional inhalable suspensions comprising a corticosteroid.
  • the methods and systems for the treatment or prophylaxis of a bronchoconstrictive disorder in a patient in need thereof described herein can deliver of an inhalation mixture comprising a corticosteroid to the subject in a manner wherein the active is delivered having an increased AUC (I351) blood plasma value of the corticosteroid as compared to conventional inhalable corticosteroid suspensions administered under the same conditions.
  • AUC AUC
  • budesonide + SBE7-/3-CD inhalation solutions having nominal dosages of 60 ⁇ g, 120 ⁇ g, and 240 ⁇ g delivered in a single dose using a Pari eFlow Inhaler ® in a 0.5 ml volume with a delivery time of about 1.5 minutes had AUC 035 ,) blood plasma values of about 179 ⁇ 75 (pg/h/ml), about 569 ⁇ 213 (pg/h/ml), and 1183 ⁇ 328 (pg/h/ml), respectively.
  • FIG. 4 provides a graphic representation of the data used to generate the aforementioned AUC ⁇ t) blood plasma values.
  • a 60 ⁇ g CBIS inhalation solution delivered twice daily for seven days using a Pari eFlow Inhaler ® in a 0.5 ml volume with a delivery time of about 1.5 minutes had a minimum AUC (I35 , ) blood plasma value of about 106.4 pg/ml, a maximum AUQ ⁇ s ,) blood plasma value of about 463.1 pg/ml, and geometric mean AUC ( Ia 31) values of about
  • FIG. 5 provides a graphic representation of the data upon which the aforementioned AUC (I35 , ) blood plasma values were based.
  • the methods and systems for the treatment or prophylaxis of a bronchoconstrictive disorder in a patient in need thereof provide the delivery of an inhalation mixture comprising a corticosteroid having an enhanced pharmacokinetic profile as compared to conventional inhalable corticosteroid suspensions administered under the same conditions. More specifically, the systems and methods described herein provide at least about 1.5 fold to about 10 fold increase in AUQns t) blood plasma values for a corticosteroid (as determined on an individual basis), normalized for dose of corticosteroid per microgram of corticosteroid administered, as compared to conventional inhalable corticosteroid therapies administered under the same conditions.
  • the systems and methods described herein provide at least about 1.5 fold to about 10 fold, about 1.5 fold to about 9.5 fold, about 1.5 fold to about 9 fold, about 1.5 fold to about 8.5 fold, about 1.5 fold to about 8 fold, about 1.5 fold to about 7.75 fold, about 1.5 fold to about 7.5 fold, about 1.5 fold to about 7.25 fold, about 1.5 fold to about 7 fold, about 1.5 fold to about 6.75 fold, about 1.5 fold to about 6.5 fold, about 1.5 fold to about 6 fold, about 1.5 fold to about 5.75 fold, about 1.5 fold to about 5.5 fold, about 1.5 fold to about 5 fold, about 1.5 fold to about 4.75 fold, about 1.5 fold to about 4.5 fold, about 1.5 fold to about 4 fold increase in blood plasma values (as determined on an individual basis) for a corticosteroid normalized for dose of corticosteroid per microgram of corticosteroid administered, as compared to conventional inhalable corticosteroid therapies administered under the same condition.
  • the methods and systems for the treatment or prophylaxis of a bronchoconstrictive disorder in a patient in need thereof described herein provide at least a about 4 fold to about a 6 fold increase in AUQh 5 ,) blood plasma values for a corticosteroid taken across a studied patient population, normalized for dose of corticosteroid per microgram of corticosteroid administered, as compared to conventional inhalable corticosteroid therapies administered under the same conditions, for example as determined using the geometric mean across a studied patient population.
  • the systems and methods described herein provide at least about 4 fold to about 6 fold, about 4 fold to about 5.75 fold, about 4 fold to about 5.5 fold, about 4 fold to about 5.25 fold, about 4 fold to about 5 fold, about 4.5 fold to about 6 fold, about 4.75 fold to about 6 fold, about 5 fold to about 6 fold, about 5.5 fold to about 6 fold increase in AUC (Ia ,, ) blood plasma values for a corticosteroid taken across a studied patient population, normalized for dose of corticosteroid per microgram of corticosteroid administered, as compared to conventional inhalable corticosteroid therapies administered under the same conditions.
  • AUC Ia ,,
  • the methods and systems for the treatment or prophylaxis of a bronchoconstrictive disorder in a patient in need thereof can provide a AUC ⁇ , ) that is significantly greater than the AUC( I a,,) blood plasma values exhibited by conventional inhalable suspensions comprising a corticosteroid administered at the same nominal dosage under the same conditions.
  • the AUC (Ia51) can be from about 1.5 fold (150%) to about 10 fold (1000%) the AUC ⁇ , ) blood plasma values exhibited by conventional inhalable suspensions comprising a corticosteroid at the same nominal dosage under the same conditions.
  • the AUC (tel ) can be at least about 1000% (10 fold) greater than the AUCji as flblood plasma values exhibited by conventional inhalable suspensions comprising a corticosteroid at the same nominal dosage under the same conditions.
  • the AUC (Ia5 , ) can be at least about 900% (9 fold) to about 1000% (10 fold) , about 925% (9.25 fold) to about 1000% (10 fold), or about 950% (9.5 fold) to about 1000% (10 fold) greater than the AUC 03S , ) blood plasma values exhibited by conventional inhalable suspensions comprising a corticosteroid at the same nominal dosage under the same conditions.
  • the AUC (I a 51) can be at least about 900% (9 fold) greater than the AUC ⁇ Q blood plasma values exhibited by conventional inhalable suspensions comprising a corticosteroid at the same nominal dosage under the same conditions.
  • the AUC (I2St) can be at least about 800% (8 fold) to about 900% (9 fold) , about 825% (8.25 fold) to about 900% (9 fold), or about 850% (8.5 fold) to about 900% (9 fold) greater than the AUC (Ia51) blood plasma values exhibited by conventional inhalable suspensions comprising a corticosteroid at the same nominal dosage under the same conditions.
  • the AUC ( ia S t) can be at least about 800% (8 fold) greater than the AUQ t ⁇ ) blood plasma values exhibited by conventional inhalable suspensions comprising a corticosteroid at the same nominal dosage under the same conditions.
  • the AUC ( i ast ) can be at least about 700% (7 fold) to about 800% (8 fold) , about 725% (7.25 fold) to about 800% (8 fold), or about 750% (7.5 fold) to about 800% (8 fold) greater than the AUC (I3Jt) blood plasma values exhibited by conventional inhalable suspensions comprising a corticosteroid at the same nominal dosage under the same conditions.
  • the AUC (I3St) can be at least about 700% (7 fold) greater than the AUQ ⁇ , ) blood plasma values exhibited by conventional inhalable suspensions comprising a corticosteroid at the same nominal dosage under the same conditions.
  • the AUC ( ⁇ s1) can be at least about 600% (6 fold) to about 700% (7 fold) , about 625% (6.25 fold) to about 700% (7 fold), or about 650% (6.5 fold) to about 700% (7 fold) greater than the AUC(Ia 51) blood plasma values exhibited by conventional inhalable suspensions comprising a corticosteroid at the same nominal dosage under the same conditions.
  • the AUC (hS , ) is at least about 600% (6 fold) greater than the AUQ UM) of the inhalable suspension comprising a corticosteroid, tn certain other embodiments, the AUC (I2S t) can be at least about 500% (5 fold) to about 600% (6 fold) , about 525% (5.25 fold) to about 600% (6 fold), or about 550% (5.5 fold) to about 600% (6 fold) greater than the AUC (I3 St ) blood plasma values exhibited by conventional inhalable suspensions comprising a corticosteroid at the same nominal dosage under the same conditions.
  • the AUC (Ia51) is at least about 500% (5 fold) greater than the AUC( Ia5I ) of the inhalable suspension comprising a corticosteroid.
  • the AUC ( iaso can be at least about 400% (4 fold) to about 500% (5 fold) , about 425% (4.25 fold) to about 500% (5 fold), or about 450% (4.5 fold) to about 500% (5 fold) greater than the AUC (I350 blood plasma values exhibited by conventional inhalable suspensions comprising a corticosteroid at the same nominal dosage under the same conditions.
  • the AUC( Ia5 , ) is at least about 400% (4 fold) greater than the AUC (Ia5I) of the inhalable suspension comprising a corticosteroid.
  • the AUQi as o can be at least about 300% (3 fold) to about 400% (4 fold) , about 325% (3.25 fold) to about 400% (4 fold), or about 350% (3.5 fold) to about 400% (4 fold) greater than the AUC (I83 , ) blood plasma values exhibited by conventional inhalable suspensions comprising a corticosteroid at the same nominal dosage under the same conditions.
  • the AUC (I35 ,) is at least about 300% (3 fold) greater than the AUC (I351) of the inhalable suspension comprising a corticosteroid.
  • the AUC( I05 , ) can be at least about 200% (2 fold) to about 300% (3 fold) . about 225% (2.25 fold) to about 300% (3 fold), or about 250% (2.5 fold) to about 300% (3 fold) greater than the AUC( ⁇ 31 ) blood plasma values exhibited by conventional inhalable suspensions comprising a corticosteroid at the same nominal dosage under the same conditions.
  • the AUC (I25 , ) is at least about 200% (2 fold) greater than the AUC (I25 , ) of the inhalable suspension comprising a corticosteroid. In certain other embodiments, the AUC (I25 , ) can be at about 150% (1.5 fold) to about 200% (2 fold) greater than the AUC ⁇ Q blood plasma values exhibited by conventional inhalable suspensions comprising a corticosteroid at the same nominal dosage under the same conditions. In another embodiment, the AUC (Ia5 , ) is at least about 150% (1.5 fold) greater than the AUC ( i ast) of the inhalable suspension comprising a corticosteroid.
  • the AUC ⁇ j can be substantially equal to the AUC ⁇ st ) blood plasma values exhibited by conventional inhalable suspensions comprising a corticosteroid wherein the aqueous inhalation mixture is administered at a lower nominal dosage under the same conditions.
  • the nominal dosage can be about 1 :1.5 (i.e., 1.5 fold enhanced pharmacokinetic profile) to about 1:10 (i.e., 10 fold enhanced pharmacokinetic profile) the nominal dosage of the conventional inhalable suspensions comprising a corticosteroid.
  • the nominal dosage of the aqueous inhalation mixture comprising a corticosteroid can be about 1:1.5 to about 1:9 of the nominal dosage of the conventional inhalable suspensions • comprising a corticosteroid. In yet another embodiment, the nominal dosage of the aqueous inhalation mixture comprising a corticosteroid can be about 1:1.5 to about 1:8 the nominal dosage of the conventional inhalable suspensions comprising a corticosteroid. In still another embodiment, the nominal dosage of the aqueous inhalation mixture comprising a corticosteroid can be about 1:1.5 to about 1:7 the nominal dosage of the conventional inhalable suspensions comprising a corticosteroid.
  • the nominal dosage of the aqueous inhalation mixture comprising a corticosteroid can be about 1 :1.5 to about 1 :6 the nominal dosage of the conventional inhalable suspensions comprising a corticosteroid.
  • the nominal dosage of the aqueous inhalation mixture comprising a corticosteroid can be about 1:2 to about 1:5 the nominal dosage of the conventional inhalable suspensions comprising a corticosteroid.
  • the nominal dosage of the aqueous inhalation mixture comprising a corticosteroid can be about 1:2 to about 1 :4 the nominal dosage of the conventional inhalable suspensions comprising a corticosteroid.
  • the nominal dosage of the aqueous inhalation mixture comprising a corticosteroid can be about 1 :7 the nominal dosage of the conventional inhalable suspensions comprising a corticosteroid. In other embodiments, the nominal dosage of the aqueous inhalation mixture comprising a corticosteroid can be about 1 :8 the nominal dosage of the conventional inhalable suspensions comprising a corticosteroid. In still other embodiments, the nominal dosage of the aqueous inhalation mixture comprising a corticosteroid can be about 1:9 the nominal dosage of the conventional inhalable suspensions comprising a corticosteroid. In yet still other embodiments, the nominal dosage of the aqueous inhalation mixture comprising a corticosteroid can be about 1:10 the nominal dosage of the conventional inhalable suspensions comprising a corticosteroid.
  • the methods and systems for the treatment or prophylaxis of a bronchoconstrictive disorder in a patient in need thereof described herein can deliver a corticosteroid to the subject in a manner wherein the active is delivered having an increased AUQo-o ⁇ blood plasma value of the corticosteroid as compared to conventional inhalable corticosteroid suspensions administered under the same conditions.
  • conventional budesonide suspensions administered in a single dose using a Pan LC Plus ® jet nebulizer in a 2.0 ml volume with an administration time of about 5 minutes display pharmacokinetic profiles such that the AUC ( o-e») blood plasma values ranges from about 867 ⁇ 216 (pg/h/ml) to about 2083 ⁇ 394 (pg/h/ml) with nominal dosages of 500 ⁇ g to 1000 ⁇ g, respectfully.
  • budesonide + SBE7- ⁇ -CD inhalation solutions having nominal dosages of 60 ⁇ g, 120 ⁇ g, and 240 ⁇ g delivered in a single dose using a Pari eFlow Inhaler ® in a 0.5 ml volume with a delivery time of about 1.5 minutes had AUC (O -CO) blood plasma values were about 262 ⁇ 125 (pg/h/ml), about 679 ⁇ 201 (pg/h/ml), and 1365 ⁇ 313 (pg/h/ml), respectively.
  • FIG. 4 provides a graphic representation of the data used to generate the . aforementioned AUC (I35 , ) blood plasma values.
  • a 60 ⁇ g CBIS inhalation solution delivered twice daily for seven days using a Pari eFlow Inhaler ® in a 0.5 ml volume with a delivery time of about 1.5 minutes had a minimum AUC ( o.o°) blood plasma value of about 156.5 pg/ml, a maximum AUC( O . ⁇ blood plasma value of about 748.5 pg/ml, and geometric mean AUC (O - O0) values of about
  • FIG. 5 provides a graphic representation of the data upon which the aforementioned AUC(o__3 blood plasma values were based.
  • the methods and systems for the treatment or prophylaxis of a bronchoconstrictive disorder in a patient in need thereof described herein provide the delivery of a corticosteroid having an enhanced pharmacokinetic profile as compared to conventional inhalable corticosteroid suspensions administered under the same conditions. More specifically, the systems and methods described herein provide at least about 1.5 fold to about 10 fold increase in AUC (0 .o $ blood plasma values for a corticosteroid (as determined on an individual basis), normalized for dose of corticosteroid per microgram of corticosteroid administered, as compared to conventional inhalable corticosteroid therapies administered under the same conditions.
  • the systems and methods described herein provide at least about 1.5 fold to about 10 fold, about 1.5 fold to about 9.5 fold, about 1.5 fold to about 9 fold, about 1.5 fold to about 8.5 fold, about 1.5 fold to about 8 fold, about 1.5 fold to about 7.75 fold, about 1.5 fold to about 7.5 fold, about 1.5 fold to about 7.25 fold, about 1.5 fold to about 7 fold, about 1.5 fold to about 6.75 fold, about 1.5 fold to about 6.5 fold, about 1.5 fold to about 6 fold, about 1.5 fold to about 5.75 fold, about 1.5 fold to about 5.5 fold, about 1.5 fold to about 5 fold, about 1.5 fold to about 4.75 fold, about 1.5 fold to about 4.5 fold, about 1.5 fold to about 4 fold increase in blood plasma values (as determined on an individual basis) for a corticosteroid normalized for dose of corticosteroid per microgram of corticosteroid administered, as compared to conventional inhalable corticosteroid therapies administered under the same condition.
  • the methods and systems for the treatment or prophylaxis of a bronchoconstrictive disorder in a patient in need thereof described herein provide at least a about 4 fold to about a 6 fold increase in AUC( O-0 ⁇ blood plasma values for a corticosteroid taken across a studied patient population, normalized for dose of corticosteroid per microgram of corticosteroid administered, as compared to conventional inhalable corticosteroid therapies administered under the same conditions, for example as determined using the geometric mean across a studied patient population.
  • the systems and methods described herein provide at least about 4 fold to about 6 fold, about 4 fold to about 5.75 fold, about 4 fold to about 5.5 fold, about 4 fold to about 5.25 fold, about 4 fold to about 5 fold, about 4.5 fold to about 6 fold, about 4.75 fold to about 6 fold, about 5 fold to about 6 fold, or about 5.5 fold to about 6 fold increase in AUQo-oj blood plasma values for a corticosteroid taken across a studied patient population, normalized for dose of corticosteroid per microgram of corticosteroid administered, as compared to conventional inhalable corticosteroid therapies administered under the same conditions.
  • the methods and systems for the treatment or prophylaxis of a bronchoconstrictive disorder in a patient in need thereof can provide a AUC ( o. « ) that is significantly greater than the AUC ( o.o j blood plasma values exhibited by conventional inhalable suspensions comprising a corticosteroid administered at the same nominal dosage under the same conditions.
  • the AUC ⁇ . ⁇ can be from about 1.5 fold (150%) to about 10 fold (1000%) the AUC (0-o$ blood plasma values exhibited by conventional inhalable suspensions comprising a corticosteroid at the same nominal dosage under the same conditions.
  • the AUC (O- OC j can be at least about 800% (8 fold) greater than the AUC (O-05) blood plasma values exhibited by conventional inhalable suspensions comprising a corticosteroid at the same nominal dosage under the same conditions.
  • the AUC (0 .c_) can be at least about 700% (7 fold) to about 800% (8 fold) , about 725% (7.25 fold) to about 800% (8 fold), or about 750% (7.5 fold) to about 800% (8 fold) greater than the blood plasma values exhibited by conventional inhalable suspensions comprising a corticosteroid at the same nominal dosage under the same conditions.
  • the AUC (O-0 J is at least about 600% (6 fold) greater than the AUQo-o) of the inhalable suspension comprising a corticosteroid.
  • the AUC ⁇ can be at least about 500% (5 fold) to about 600% (6 fold) , about 525% (5.25 fold) to about 600% (6 fold), or about 550% (5.5 fold) to about 600% (6 fold) greater than the AUC ( o. ⁇ ) blood plasma values exhibited by conventional inhalable suspensions comprising a corticosteroid at the same nominal dosage under the same conditions.
  • the is at least about 500% (5 fold) greater than the AUC (O-0 ) of the inhalable suspension comprising a corticosteroid.
  • the AUC (0 .oc ) is at least about 400% (4 fold) greater than the AUC ( o- ⁇ 4 of the inhalable suspension comprising a corticosteroid.
  • the AUC (0 -- $ is at least about 300% (3 fold) greater than the AUC ( o-o $ of the inhalable suspension comprising a corticosteroid.
  • the AUC M can be at least about 200% (2 fold) to about 300% (3 fold) , about 225% (2.25 fold) to about 300% (3 fold), or about 250% (2.5 fold) to about 300% (3 fold) greater than the AUCy ⁇ blood plasma values exhibited by conventional inhalable suspensions comprising a corticosteroid at the same nominal dosage under the same conditions.
  • the AUC ( o- ⁇ ⁇ can be at about 150% (1.5 fold) to about 200% (2 fold) greater than the AUC (0 .txj blood plasma values exhibited by conventional inhalable suspensions comprising a corticosteroid at the same nominal dosage under the same conditions.
  • the AUC ⁇ o.o ⁇ is at least about 150% (1.5 fold) greater than the AUC( O -O) of the inhalable suspension comprising a corticosteroid.
  • the ALfQo. ⁇ can be substantially equal to the AUQo- ⁇ j blood plasma values exhibited by conventional inhalable suspensions comprising a corticosteroid wherein the aqueous inhalation mixture is administered at a lower nominal dosage under the same conditions.
  • the nominal dosage can be about 1:1.5 (i.e., 1.5 fold enhanced pharmacokinetic profile) to about l:10 (i.e., 10 fold enhanced pharmacokinetic profile) the nominal dosage of the conventional inhalable suspensions comprising a corticosteroid.
  • the nominal dosage of the aqueous inhalation mixture comprising a corticosteroid can be about 1:1.5 to about 1 :9 of the nominal dosage of the conventional inhalable suspensions comprising a corticosteroid. In yet another embodiment, the nominal dosage of the aqueous inhalation mixture comprising a corticosteroid can be about 1 :1.5 to about 1 :8 the nominal dosage of the conventional inhalable suspensions comprising a corticosteroid. In still another embodiment, the nominal dosage of the aqueous inhalation mixture comprising a corticosteroid can be about 1:1.5 to about 1:7 the nominal dosage of the conventional inhalable suspensions comprising a corticosteroid.
  • the nominal dosage of the aqueous inhalation mixture comprising a corticosteroid can be about 1 :2 to about 1:3 the nominal dosage of the conventional inhalable suspensions comprising a corticosteroid. In certain embodiments, the nominal dosage of the aqueous inhalation mixture comprising a corticosteroid can be about 1 :2 the nominal dosage of the conventional inhalable suspensions comprising a corticosteroid. In certain other embodiments, the nominal dosage of the aqueous inhalation mixture comprising a corticosteroid can be about 1 :3 the nominal dosage of the conventional inhalable suspensions comprising a corticosteroid.
  • the nominal dosage of the aqueous inhalation mixture comprising a corticosteroid can be about 1 :4 the nominal dosage of the conventional inhalable suspensions comprising a corticosteroid. In still other embodiments, the nominal dosage of the aqueous inhalation mixture comprising a corticosteroid can be about 1 :5 the nominal dosage of the conventional inhalable suspensions comprising a corticosteroid. In yet still other embodiments, the nominal dosage of the aqueous inhalation mixture comprising a corticosteroid can be about 1 :6 the nominal dosage of the conventional inhalable suspensions comprising a corticosteroid.
  • the nominal dosage of the aqueous inhalation mixture comprising a corticosteroid can be about 1 :7 the nominal dosage of the conventional inhalable suspensions comprising a corticosteroid. In other embodiments, the nominal dosage of the aqueous inhalation mixture comprising a corticosteroid can be about 1:8 the nominal dosage of the conventional inhalable suspensions comprising a corticosteroid. In still other embodiments, the nominal dosage of the aqueous inhalation mixture comprising a corticosteroid can be about 1 :9 the nominal dosage of the conventional inhalable suspensions comprising a corticosteroid. In yet still other embodiments, the nominal dosage of the aqueous inhalation mixture comprising a corticosteroid can be about 1 :10 the nominal dosage of the conventional inhalable suspensions comprising a corticosteroid.
  • the methods and systems for the treatment or prophylaxis of a bronchoconstrictive disorder in a patient in need thereof described herein can deliver a corticosteroid to the subject in a manner wherein the active is delivered having a decreased T m3x blood plasma value of the corticosteroid as compared to conventional inhalable corticosteroid suspensions administered at the same dose under the same conditions.
  • conventional budesonide suspensions administered in a single dose using a Pari LC Plus ® jet nebulizer in a 2.0 ml volume with an administration time of about 5 minutes display pharmacokinetic profiles such that the T n ⁇ x blood plasma values ranges from about 0.24 ⁇ 0.25 (h) to about 0.23 ⁇ 0.24 (h) with nominal dosages of 500 ⁇ g to 1000 ⁇ g, respectfully.
  • budesonide + SBE7-J3-CD inhalation solutions having nominal dosages of 60 ⁇ g, 120 ⁇ g, and 240 ⁇ g delivered in a single dose using a Pari eFlow Inhaler ® in a 0.5 ml volume with a delivery time of about 1.5 minutes had T max blood plasma values of about 0.11 ⁇ 0.09 (h), 0.11 ⁇ 0.09 (h), and 0.2hfc 0.24 (h), respectively.
  • a 60 ⁇ g CBIS inhalation solution delivered twice daily for seven days using a Pari eFlow Inhaler ® in a 0.5 ml volume with a delivery time of about 1.5 minutes had a minimum T m3x blood plasma value of about 0.08 (h), a maximum T 1113x blood plasma value of about 0.25 (h), and mean T 1J13x values of about 0.11 (h).
  • FIG. 5 provides a graphic representation of the data upon which the aforementioned T n13x blood plasma values were based.
  • the methods and systems for the treatment or prophylaxis of a bronchoconstrictive disorder in a patient in need thereof can provide a T m11x that is significantly less than the T 1113x blood plasma values exhibited by conventional inhalable suspensions comprising a corticosteroid administered at the same nominal dosage under the same conditions.
  • the T n ⁇ x can be at least about 1.5 fold to about 10 fold less than the T n ⁇ x blood plasma values exhibited by conventional inhalable suspensions comprising a corticosteroid administered at the same nominal dosage under the same conditions.
  • the T 1113x can be at least about 8 fold less than the T 1113x blood plasma values exhibited by conventional inhalable suspensions comprising a corticosteroid administered at the same nominal dosage under the same conditions.
  • the T 103x can be at least about 6 fold less than the T 1113x blood plasma values exhibited by conventional inhalable suspensions comprising a corticosteroid administered at the same nominal dosage under the same conditions.
  • the T max can be at least about 4 fold less than the T m31 blood plasma values exhibited by conventional inhalable suspensions comprising a corticosteroid administered at the same nominal dosage under the same conditions.
  • the T m3x can be at least about 3 fold less than the T n13x blood plasma values exhibited by conventional inhalable suspensions comprising a corticosteroid administered at the same nominal dosage under the same conditions.
  • the T n ⁇ x can be at least about 2 fold faster than the T 1113x blood plasma values exhibited by conventional inhalable suspensions comprising a corticosteroid administered at the same nominal dosage under the same conditions.
  • the T 1112x can be at least about 1.5 fold faster than the T max blood plasma values exhibited by conventional inhalable suspensions comprising a corticosteroid administered at the same nominal dosage under the same conditions.
  • the T n ⁇ x can be less than the T m3x blood plasma values exhibited by conventional inhalable suspensions comprising a corticosteroid wherein the aqueous inhalation mixture is administered at a lower nominal dosage under the same conditions.
  • the nominal dosage can be about 1:1.5 (i.e., 1.5 fold enhanced pharmacokinetic profile) to about 1:10 (i.e., 10 fold enhanced pharmacokinetic profile) the nominal dosage of the conventional inhalable suspensions comprising a corticosteroid.
  • the nominal dosage of the aqueous inhalation mixture comprising a corticosteroid can be about 1:1.5 to about 1:9 of the nominal dosage of the conventional inhalable suspensions comprising a corticosteroid. In yet another embodiment, the nominal dosage of the aqueous inhalation mixture comprising a corticosteroid can be about 1:1.5 to about 1:8 the nominal dosage of the conventional inhalable suspensions comprising a corticosteroid. In still another embodiment, the nominal dosage of the aqueous inhalation mixture comprising a corticosteroid can be about 1:1.5 to about 1 :7 the nominal dosage of the conventional inhalable suspensions comprising a corticosteroid.
  • the nominal dosage of the aqueous inhalation mixture comprising a corticosteroid can be about 1:1.5 to about 1:6 the nominal dosage of the conventional inhalable suspensions comprising a corticosteroid. In another embodiment, the nominal dosage of the aqueous inhalation mixture comprising a corticosteroid can be about 1:2 to about 1:5 the nominal dosage of the conventional inhalable suspensions comprising a corticosteroid. In still another embodiment, the nominal dosage of the aqueous inhalation mixture comprising a corticosteroid can be about 1:2 to about 1 :4 the nominal dosage of the conventional inhalable suspensions comprising a corticosteroid.
  • the nominal dosage of the aqueous inhalation mixture comprising a corticosteroid can be about 1:2 to about 1:3 the nominal dosage of the conventional inhalable suspensions comprising a corticosteroid. In certain embodiments, the nominal dosage of the aqueous inhalation mixture comprising a corticosteroid can be about 1 :2 the nominal dosage of the conventional inhalable suspensions comprising a corticosteroid. In certain other embodiments, the nominal dosage of the aqueous inhalation mixture comprising a corticosteroid can be about 1 :3 the nominal dosage of the conventional inhalable suspensions comprising a corticosteroid.
  • the nominal dosage of the aqueous inhalation mixture comprising a corticosteroid can be about 1 :4 the nominal dosage of the conventional inhalable suspensions comprising a corticosteroid. In still other embodiments, the nominal dosage of the aqueous inhalation mixture comprising a corticosteroid can be about 1:5 the nominal dosage of the conventional inhalable suspensions comprising a corticosteroid. In yet still other embodiments, the nominal dosage of the aqueous inhalation mixture comprising a corticosteroid can be about 1 :6 the nominal dosage of the conventional inhalable suspensions comprising a corticosteroid.
  • the nominal dosage of the aqueous inhalation mixture comprising a corticosteroid can be about 1 :7 the nominal dosage of the conventional inhalable suspensions comprising a corticosteroid. In other embodiments, the nominal dosage of the aqueous inhalation mixture comprising a corticosteroid can be about 1 :8 the nominal dosage of the conventional inhalable suspensions comprising a corticosteroid. In still other embodiments, the nominal dosage of the aqueous inhalation mixture comprising a corticosteroid can be about 1 :9 the nominal dosage of the conventional inhalable suspensions comprising a corticosteroid. In yet still other embodiments, the nominal dosage of the aqueous inhalation mixture comprising a corticosteroid can be about 1:10 the nominal dosage of the conventional inhalable suspensions comprising a corticosteroid.
  • the methods and systems for the treatment or prophylaxis of a bronchoconstricrjve disorder in a patient in need thereof can deliver an aqueous inhalation mixture comprising a corticosteroid, e.g., budesonide, and a solubility enhancer to the subject in a manner wherein the active is delivered in accordance with good medical practice, talcing into account the clinical condition of the individual patient, the site and method of administration, scheduling of administration, and other factors known to medical practitioners.
  • a corticosteroid e.g., budesonide
  • solubility enhancer e.g., a solubility enhancer
  • the methods described herein can deliver corticosteroid solutions, e.g., a budesonide solution, that maintain a therapeutically effective amount of the corticosteroid, e.g., budesonide, at the site of action which reduces or mitigates symptoms related to bronchoconstrictive disorders.
  • the aqueous inhalation mixture comprises a corticosteroid and a solubility enhancer, wherein the inhalation mixture is substantially free of pharmaceutically active agents other than a corticosteroid.
  • the methods and systems for the treatment or prophylaxis of a bronchoconstrictive disorder in a patient in need thereof described herein can deliver an aqueous inhalation mixture comprising a corticosteroid, e.g., budesonide, a solvent, and a solubility enhancer to the subject in a manner wherein the active is delivered in accordance with good medical practice, taking into account the clinical condition of the individual patient, the site and method of administration, scheduling of administration, and other factors known to medical practitioners.
  • a corticosteroid e.g., budesonide
  • solvent e.g., a solvent
  • solubility enhancer e.g., a solubility enhancer
  • the methods described herein can deliver corticosteroid solutions, e.g., a budesonide solution, that maintain a therapeutically effective amount of the corticosteroid, e.g., budesonide, at the site of action which reduces or mitigates symptoms related to bronchoconstrictive disorders.
  • the aqueous inhalation mixture comprises a corticosteroid, a solvent, and a solubility enhancer, wherein the inhalation mixture is substantially free of pharmaceutically active agents other than a corticosteroid.
  • the methods and systems for the treatment or prophylaxis of a bronchoconstrictive disorder in a patient in need thereof described herein can deliver an aqueous inhalation mixture comprising a therapeutically effective amount of a corticosteroid administered to a subject via an inhalation nebulizer at a nominal dosage in the range of about 15 ⁇ g/dose to less than about 250 ⁇ g/dose, or from about 25 ⁇ g/dose to about 240 ⁇ g/dose, or from about 200 ⁇ g/dose to about 240 ⁇ g/dose, or from about 125 ⁇ g/dose to about 200 ⁇ g/dose, or from about 150 ⁇ g/dose to about 200 ⁇ g/dose, or from about 100 ⁇ g/dose to about 150 ⁇ g/dose, or from about 100 ⁇ g/dose to about 125 ⁇ g/dose, or from about 50 ⁇ g/dose to about 125 ⁇ g//
  • the corticosteroid is budesonide administered to a subject via an inhalation nebulizer at a nominal dosage in the range of about 25 ⁇ g/dose to about 240 ⁇ g/dose.
  • the aqueous inhalation mixture comprises a corticosteroid, such as budesonide, wherein the aqueous inhalation mixture is administered according to the methods and systems described herein with a nominal dosage of the corticosteroid of about 60 ⁇ g/dose to less than about 250 ⁇ g/dose.
  • the aqueous inhalation mixture comprises a corticosteroid, such as budesonide, wherein the aqueous inhalation mixture is administered according to the methods and systems described herein with a nominal dosage of the corticosteroid of less than about 250 ⁇ g/dose.
  • the aqueous inhalation mixture comprises a corticosteroid, such as budesonide, wherein the aqueous inhalation mixture is administered according to the methods and systems described herein with a nominal dosage of the corticosteroid of about 240 ⁇ g/dose.
  • the aqueous inhalation mixture comprises a corticosteroid, such as budesonide, wherein the aqueous inhalation mixture is administered according to the methods and systems described herein with a nominal dosage of the corticosteroid of about 125 ⁇ g/dose.
  • the aqueous inhalation mixture comprises a corticosteroid, such as budesonide, wherein the aqueous inhalation mixture is administered according to the methods and systems described herein with a nominal dosage of the corticosteroid of about 120 ⁇ g/dose.
  • the aqueous inhalation mixture comprises a corticosteroid, such as budesonide, wherein the aqueous inhalation mixture is administered according to the methods and systems described herein with a nominal dosage of the corticosteroid of about 60 ⁇ g/dose.
  • the aqueous inhalation mixture comprises a corticosteroid, such as budesonide, wherein the aqueous inhalation mixture is administered according to the methods and systems described herein with a nominal dosage of the corticosteroid of about 40 ⁇ g/dose.
  • the aqueous inhalation mixture comprises a single corticosteroid and is substantially free of pharmaceutically active agents other than the corticosteroid.
  • the methods and systems for the treatment or prophylaxis of a bronchoconstrictive disorder in a patient in need thereof can deliver an aqueous inhalation mixture comprising a therapeutic'ally effective amount of a corticosteroid administered to a subject via an inhalation nebulizer _at_a nominal dosage in the_range of about 25 ⁇ g/dose to less than about 100 ⁇ g/dose wherein the the corticosteroid is selected -group of corticosteroids in the foregoing paragraph not including the betamethasone.;
  • the aqueous inhalation mixture comprises a corticosteroid, such as budesonide, wherein the aqueous inhalation mixture is administered according to the methods and systems described herein with a nominal dosage of the corticosteroid of less than about 100 ⁇ g/dose.
  • the aqueous inhalation mixture comprises a corticosteroid, such as budesonide, wherein the aqueous inhalation mixture is administered according to the methods and systems described herein with a nominal dosage of the corticosteroid of about 60 ⁇ g/dose.
  • the aqueous inhalation mixture comprises a corticosteroid, such as budesonide, wherein the aqueous inhalation mixture is administered according to the methods and systems described herein with a nominal dosage of the corticosteroid of about 40 ⁇ g/dose.
  • the aqueous inhalation mixture comprises a single corticosteroid and is substantially free of pharmaceutically active agents other than the corticosteroid.
  • the inhalable composition or aqueous inhalation mixture comprises a solvent.
  • the solvent is selected from the group comprising water, aqueous alcohol, propylene glycol, or aqueous organic solvent.
  • the solvent is water.
  • a corticosteroid-containing aqueous inhalation mixture which further comprises a solubility enhancer.
  • the solubility enhancer can have a concentration (w/v) ranging from about 0.001 % to about 25%. In other embodiments, the solubility enhancer can have a concentration (w/v) ranging from about 0.01% to about 20%. In still other embodiments, the solubility enhancer can have a concentration (w/v) ranging from about 0.1% to about 15%. In yet other embodiments, the solubility enhancer can have a concentration (w/v) ranging from about 1% to about 10%.
  • the solubility enhancer can have a concentration (w/v) ranging from about 2% to about 10% when the solubility enhancer is a cyclodextrin or cyclodextrin derivative,e.g. SBE7-/3-CD (Captisol®). In one embodiment, the solubility enhancer can have a concentration (w/v) of about 2% when the solubility enhancer is a cyclodextrin or cyclodextrin derivative,e.g. SBE7-/3-CD (Captisol®).
  • the solubility enhancer can have a concentration (w/v) of about 5% when the solubility enhancer is a cyclodextrin or cyclodextrin derivative.e.g. SBE7-/J-CD (Captisol®). In yet another embodiment, the solubility enhancer can have a concentration (w/v) about 7% when the solubility enhancer is a cyclodextrin or cyclodextrin derivative,e.g. SBE7-/3-CD (Captisol®).
  • the solubility enhancer can have a concentration (w/v) of about 10% when the solubility enhancer is a cyclodextrin or cyclodextrin derivative.e.g. SBE7-/ ⁇ -CD (Captisol®).
  • the aqueous inhalation mixture comprises a solubility enhancer selected from the group consisting of propylene glycol, non-ionic surfactants, tyloxapol, polysorbate 80, vitamin E-TPGS, macrogol- 15-hydroxystearate, phospholipids, lecithin, purified and/or enriched lecithin, phosphatidylcholine fractions extracted from lecithin, dimyristoyl phosphatidylcholine (DMPC), dipalmitoyl phosphatidylcholine (DPPC), distearoyl phosphatidylcholine (DSPC), cyclodextrins and derivatives thereof, SAE-CD derivatives, SBE-QJ-CD, SBB- ⁇ -CD, SBEl -/J-CD, SBEA- ⁇ -CD, SBE7-/S-CD (Captisol®), SBE- ⁇ -CD, dimethyl /J-CD, hydroxypropyl-
  • a solubility enhancer
  • the inhalable compositions of the present invention comprise a solubility enhancer selected from the group consisting of cyclodextrins and derivatives thereof, SAE-CD derivatives, SBE- ⁇ -CD, SBE-/3-CD, SBEl-jS-CD, SBE4-/3-CD, SBE7-/3-CD (Captisol®), SBE- ⁇ -CD, dimethyl /3-CD, hydroxypropyl- ⁇ -cyclodextrin, 2-HP-/5-CD, hydroxyethyl-jS-cyclodextrin, hydroxypropyl-7-cyclodextrin, hydroxyethyl- ⁇ -cyclodextrin, dihydroxypro ⁇ yl-/3-cyclodextrin, glucosyl- ⁇ -cyclodextrin, glucosyl-/3- cyclodextrin, diglucosyl- ⁇ -cyclodextrin, maltosyl- ⁇ -cyclodextrin
  • aqueous inhalation mixtures or inhalable composition comprising a corticosteroid and a solubility enhancer
  • aqueous inhalation mixtures or compositions formulated by methods which provide enhanced solubility arc likewise suitable for use in the presently disclosed invention.
  • a "solubility enhancer” includes aqueous inhalation mixtures formulated by methods which provide enhanced solubility with or without a chemical agent acting as a solubility enhancer. Such methods include, e.g., the preparation of supercritical fluids.
  • the aqueous inhalation mixture comprising a corticosteroid is administered according to the methods and systems described herein not more than twice a day (b.i.d).
  • the aqueous inhalation mixture comprises a corticosteroid, such as budesonide, wherein the aqueous inhalation mixture is administered according to the methods and systems described herein twice a day.
  • the aqueous inhalation mixture comprises a corticosteroid, such as budesonide, wherein the aqueous inhalation mixture is administered according to the methods and systems described herein not more than once a day.
  • the aqueous inhalation mixture comprises a corticosteroid, such as budesonide, wherein the aqueous inhalation mixture is administered according to the methods and systems described herein not more than once a day in the evening.
  • a corticosteroid such as budesonide
  • the methods and systems described herein can further include administering aqueous inhalation mixtures comprising a corticosteroid in combination with one or more active agents.
  • the corticosteroid e.g., budesonide
  • the corticosteroid can be administered in combination with one or more other drugs one or more active agents selected from the group consisting of: (a) a B2-adrenoreceptor agonist; (b) a dopamine (D2) receptor agonist; (c) a prophylactic therapeutic, such as a steroid; (d) a topical anesthetic; or (e) an anti-cholinergic agent; either simultaneously with, prior to or subsequent to the inhalable composition provided herein.
  • active agents selected from the group consisting of: (a) a B2-adrenoreceptor agonist; (b) a dopamine (D2) receptor agonist; (c) a prophylactic therapeutic, such as a steroid; (d) a topical anes
  • B2-Adrenoreceptor agonists for use in combination with the compositions provided herein include, but are not limited to, Albuterol ( ⁇ s-l-(((l, 1-dimethylethyl) amino) methyl)-4-hydroxy-l, 3-benzenedimethanol); Bambuterol (dimethylcarbamic acid 5-(2-((l,l-dimethyIethyI)amino)-l-hydroxyethyl)-l, 3-phenyleneester); Bitolterol (4-methylbenzoic acid4-(2-((l , 1-dimethylethyl) amino)- l-hydroxyethyl)-l, 2-phenyleneester); Broxaterol (3-bromo-alpha-(((l, 1 -dimethylethyl) amino) methyl)-5-isoxazole ⁇ nethanol); Isoproterenol (4-(l- hydroxy-2-((l-methylethyl-
  • Dopamine (D2) receptor agonists include, but are not limited to, Apomorphine ( (r)- 5,6, 6a, 7- tet ⁇ ahydro-6-methyl ⁇ 4H-dibenzo [de,glquinoline-10, 11-diol); Bromocriptine ( (5'.
  • Anti-cholinergic agents for use herein include, but are not limited to, ipratropium bromide, oxitropium bromide, atropine methyl nitrate, atropine sulfate, ipratropium, belladonna extract, scopolamine, scopolamine methobromide, homatropine rnethobromide, hyoscyamine, isopriopramide, orphenadrine, benzalkonium chloride, tiotropium bromide and glycopyrronium bromide.
  • IL-5 inhibitors such as those disclosed in U. S. Patents No. 5,668,110, No. 5,683,983, No. 5,677,280, No. 6,071,910 and No. 5,654,276, each of which is incorporated by reference herein; anti-sense modulators of IL-5 such as those disclosed in U. S. Pat. No. 6,136,603, the relevant disclosure of which is hereby incorporated by reference; milrinone (1, 6-dihydro-2-methyl-6-oxo-[3, 4'-bipyridine]-5-carbonitrile); milrinone lactate; tryptase inhibitors such as those disclosed in U. S. Pat.
  • tachykinin receptor antagonists such as those disclosed in U. S. Patents No. 5,691,336, No. 5,877,191, No. 5,929,094, No. 5,750,549 and No.
  • a bronchoconstrictive disorder selected from the group consisting of asthma, pediatric asthma, bronchial asthma, allergic asthma, intrinsic asthma, chronic obstructive pulmonary disease (COPD), chronic bronchitis, emphysema, or a combination of any of the above.
  • the bronchoconstrictive disorder is pediatric asthma.
  • the bronchoconstrictive disorder is bronchial asthma.
  • the bronchoconstrictive disorder is chronic obstructive pulmonary disease (COPD).
  • aqueous inhalation mixtures comprising a corticosteroid described herein may be varied to obtain an amount of active ingredient that is effective to obtain a desired local therapeutic response for a particular composition and method of administration.
  • the selected dosage level therefore depends upon the desired therapeutic effect, on the desired duration of treatment, and other factors.
  • Any standard pharmacokinetic protocol can be used to determine blood plasma concentration profile in humans following administration of an aqueous inhalation solution comprising a corticosteroid, such as a budesonide, and a solubility enhancer by the systems and methods described herein, and thereby establish whether that formulation meets the pharmacokinetic criteria set out herein.
  • a corticosteroid such as a budesonide
  • solubility enhancer a solubility enhancer
  • subject receives administration at time zero a single dose (e.g., 240 ⁇ g) of a test inhalation mixture comprising a corticosteroid, such as a budesonide, and a solubility enhancer.
  • Blood samples are collected from each subject prior to administration (e.g., 15 minutes) and at several intervals after administration. For the present purpose it is typically preferred to take several samples within the first hour and to sample less frequently thereafter.
  • blood samples could be collected at 5, 10, 20, 30, 45, and 60 minutes after administration, and then at 2, 4, 8, and 12 hours after administration. If the same subjects are to be used for study of a second test formulation, a period of at least 10 days should elapse before administration of the second formulation.
  • Plasma is separated from the blood samples by centrifugation and the separated plasma is analyzed for a corticosteroid, such as a budesonide, by a validated high performance liquid chromatography/tandem weight spectrometry (LC/APCI-MS/MS) procedure such as, for example, Ramu et al., Journal of Chromatography B, 751:49-59 (2001).
  • LC/APCI-MS/MS liquid chromatography/tandem weight spectrometry
  • data from a single subject may be indicative of an enhanced pharmacokinetic profile.
  • appropriate in vitro models may be used to demonstrate enhanced pharmacokinetic profiles.
  • Any aqueous inhalable mixture giving the desired pharmacokinetic profile is suitable for administration according to the present systems and methods.
  • exemplary types of inhalable mixtures giving such profiles are solutions comprising a corticosteroid, such as a budesonide, and a solubility enhancer.
  • compositions, systems and methods disclosed herein correspond to that described above.
  • procedures below describe specific embodiments of methods of delivery of an aqueous inhalation mixture comprising budesonide as described herein and pharmacokinetic profiles thereof.
  • Methods, materials, or excipients which are not specifically described in the following examples are within the scope of the invention and will be apparent to those skilled in the art with reference to the disclosure herein.
  • aqueous inhalation mixtures were prepared by discharging the contents of one or more containers of commercially available Pulmicort Respules ® (1000 ⁇ g budesonide per 2 mL of the suspension), and 82.5 mg (corrected for water content) of Captisol ® (CyDex, Inc., Lenexa, KS, USA) was added per mL of Pulmicort Respules ® (dispensed volume was 2.1 mL) and vortexed for 5-10 minutes.
  • the Pulmicort Respules ® also contain the following ingredients which are believed to be inactive: citric acid, sodium citrate, sodium chloride, disodium EDTA, and polysorbate 80.
  • Example 1 As an alternative method of preparation to Example 1, multiple aqueous inhalation mixtures are prepared by weighing approximately 200 mg amounts of CAPTISOL ® (CyDex, Inc., Lenexa, KS, USA) (corrected for water content) into 2-dram amber vials. Into each vial containing the weighed amount of CAPTISOL, the contents of two Pulmicort Respules ® containers (0.5 mg/2 mL) are emptied by gently squeezing the deformable plastic container to the last possible drop. The Pulmicort Respules ® are previously swirled to re-suspend the bud ⁇ sonide particles. The vials are screw capped, mixed vigorously by vortex and then foil wrapped. The material can be kept refrigerated until use.
  • CAPTISOL ® CyDex, Inc., Lenexa, KS, USA
  • Table 1 provides exemplary formulations of aqueous inhalation mixtures comprising budesonide and a solubility enhancer which are used in the methods and systems described herein.
  • the aqueous inhalation mixtures can further comprise excipients, e.g., antioxidants, stabilizing agents, and preservatives.
  • excipients e.g., antioxidants, stabilizing agents, and preservatives.
  • the amount of the various excipients to be used in the aqueous inhalation mixture will be relative to the dosage to be administered and will be readily ascertained by a person having ordinary skill in the art.
  • aqueous inhalation mixtures comprising budesonide and Pulmicort Respules ® , and the nebulizer devices used for the delivery to the lung of said doses.
  • Administrations A-C were prepared by diluting the aqueous inhalation mixtures prepared as described in Example 1 with 0.9% (w/w) saline in the following manner: Administration A was diluted at a 25:75 ratio with 0.9% (w/w) saline; Administration B was diluted at a 50:50 ratio with 0.9% (w/w) saline; and Administration C was not diluted.
  • Table 5 Set forth in Table 5 is the summary of the pharmacokinetic profiles for budesonide following a single dose delivery of Administrations A to E as set forth in Example 5. Eight (8) healthy males were used in this clinical study and the values presented below are the mean values for each of the pharmacokinetic parameters measured during the clinical study.
  • FIG. 4 provides a graphic representation of the data used to generate the pharmacokinetic profiles for Administrations A to E.
  • Table 8 Set forth in Table 8 is the summary of the pharmacokinetic profiles for budesonide following a single- centre, double-blind, multiple dose, parallel group, placebo controlled, two period crossover study involving Administrations A to D as set forth in Example 8.
  • Forty-eight (48) healthy male volunteers were used in this clinical study.
  • Each subject that qualified for the study was randomized to receive one of the following treatments: Treatment A (60 ⁇ g CBIS solution), Treatment B (120 ⁇ g CBlS solution), Treatment C (250 ⁇ g Pulmicort Respule Respule ® suspension (250 ⁇ g Pulmioort)), Treatment D (500 ⁇ g Pulmicort Respule ® suspension (500 ⁇ g Pulmicort)).
  • the Subjects received Treatment A, B, C or D twice daily for seven days.
  • Each subject received active drug and placebo crossed over two study periods.
  • Table 8 provides the values for each of the pharmacokinetic parameters measured in the study for the administration of Treatments A-D during the clinical
  • aqueous inhalation mixtures set forth in Examples 3 and 4 a ⁇ e delivered to a patient population according the methods set forth in Example 5.
  • Pulmicort Respules ® is likewise administered according the methods set forth in Example 5.
  • the pharmacokinetic profile of the aqueous inhalation solutions will exhibit enhanced pharmacokinetic parameters as compared to the pharmacokinetic profile of the Pulmicort Respules ® .
  • the aqueous inhalation solutions will display greater C max , AUQo- ⁇ j values and/or lower T max values as compared to Pulmicort Respules ® .
  • the aqueous inhalation solutions will display equal C m a ⁇ , AUC (I35 ,), and AUC j o. ⁇ values as compared to Pulmicort Respules ® if administered at a lower dosage.
  • aqueous inhalation mixtures set forth in Examples 1 and 2 are delivered to a patient population according the methods set forth in Example 5.
  • Pulmicort Respules ® at a nominal dosages ranging from 1000 ⁇ g/dose up to 2500 ⁇ g/dose, are administered according the methods set forth in Example 5.
  • the pharmacokinetic profile of the aqueous inhalation solutions will exhibit enhanced pharmacokinetic parameters as compared to the pharmacokinetic profile of the Pulmicort Respules ® .
  • a citrate buffer (3 mM pH 4.5) is prepared as follows. Approximately 62.5 mg of citric acid is dissolved in and brought to volume with water in one 100 ml volumetric flask. Approximately 87.7 mg of sodium citrate is dissolved in and brought to volume with water in another 100 mL volumetric flask. In a beaker, the sodium citrate solution is added to the citric acid solution until the pH is approximately 4.5.
  • budesonide Approximately 10.4 mg of budesonide and 1247 mg of Captisol ® (CyDex Inc.) are ground together with a mortar and pestle and transferred to a 10 mL flask. Buffer solution is added, and the mixture is vortexed, sonicated and an additional 1.4 mg budesonide is added. After shaking overnight, the solution is filtered through a 0.22 ⁇ m Durapore Millex-GV Millipore syringe filter unit. The resulting budesonide concentration is about 1 mg/ml.
  • Approximately 0.5 ml of the budesonide solution is added to a unit dose of either Proventil ® (2.5 mg/3 mL) or Xopenex ® (1.25 mg/3 mL) thereby forming a clear aqueous inhalation mixture suitable for use in an inhalation nebulizer as described in Example 5.
  • the aqueous inhalation mixtures set forth in Examples 12 and 13 are delivered to a patient population according the methods set forth in Example 5.
  • Pulmicort Respules ® is likewise administered according the methods set forth in Example 5.
  • the pharmacokinetic profile of the aqueous inhalation mixtures will exhibit enhanced pharmacokinetic parameters as compared to the pharmacokinetic profile of the Pulmicort Respules ® .
  • the aqueous inhalation solutions will display greater C m3x , AUC (I351) , AUQo- ⁇ ⁇ values and/or lower T 1J13x values as compared to Pulmicort Respules ® if administered at the same nominal dosage.
  • the aqueous inhalation solutions will display equal C n ⁇ x , AUQi ast) , and AUC(o- ⁇ * values as compared to Pulmicort Respules ® if administered at a lower nominal dosage.
  • Table 10 shows that dependent on the stage range used for pulmonary deposition (stage 3-7, stage 4-7, stage 5-7) the ratio of pulmonary deposition (expressed as the ratio of eFlow/Pari LC plus depositions) Tanges from 1.2, 1.9 to 3.8 for stage 3-7, stage 4-7 or stage 5-7, respectively.
  • Fine particle fraction is defined as particle sizes less than 4.7 ⁇ m (Bosco AP et al., In Vitro Estimation of In Vivo Jet Nebulizer Efficiency Using Actual and Simulated Tidal Breathing Patterns, Journal of Aerosol Medicine 18(4): 427-38 (2005); herein incorporated by reference in its entirety).

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Abstract

La présente invention concerne des méthodes et des systèmes d'administration d'un corticostéroïde, lesquels systèmes comprennent (1) un mélange aqueux inhalable, composé d'un corticostéroïde et d'un agent améliorant la solubilité, et (2) un nébuliseur pour inhalation, l'administration du mélange aqueux contenant le corticostéroïde au moyen du nébuliseur permettant d'obtenir un meilleur profil pharmacocinétique du corticostéroïde par rapport à des traitements par inhalation classiques.
PCT/US2006/048628 2005-12-20 2006-12-19 Méthodes et systèmes d'administration de corticostéroïdes à dépôt pulmonaire accru WO2007075798A2 (fr)

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DK3151836T3 (da) * 2014-03-28 2023-04-03 Univ Liege Sammensætning omfattende cyclodextrin og budesonidderivater til anvendelse til behandling og profylakse af lungeinflammationer
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US11672781B2 (en) 2018-05-07 2023-06-13 Prana Biosciences Inc Metaxalone formulations
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CN113491677A (zh) * 2020-03-18 2021-10-12 迪斯凯威（深圳）新药发展有限公司 一类药用抗病毒药物吸入剂新型制剂及制备方法
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WO2007075798A9 (fr) 2007-08-23
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WO2007075963A3 (fr) 2008-11-27
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