JP2009520828A - Systems and methods for delivering corticosteroids - Google Patents

Abstract

The present invention relates to (1) an inhalable aqueous mixture comprising a corticosteroid and a solubility enhancer, and (2) a method and system for delivery of a corticosteroid comprising an inhalation nebulizer, the corticosteroid by the nebulizer Delivery of the aqueous mixture containing results in an improved pharmacokinetic profile and / or increased pulmonary deposition of corticosteroids when compared to conventional inhalation therapies. In certain embodiments, the invention provides an inhalable composition comprising no more than about 250 μg of a single corticosteroid, a solvent and a solubility enhancer, which composition is delivered to the subject via the device. A rate of increase of corticosteroid concentration in the device of about 5 μg / ml / min or less is achieved over administration of the corticosteroid via the device upon administration of the composition of It is substantially free of active pharmaceutical agents.

Description

FIELD OF THE INVENTION The present invention relates to (1) an inhalable aqueous mixture comprising a corticosteroid and a solubility enhancer, and (2) an inhalable nebulizer, which is conventional by delivery of the corticosteroid-containing aqueous mixture by a nebulizer. The present invention relates to methods and systems for the delivery of corticosteroids that result in an improved pharmacokinetic profile of corticosteroids and / or increased pulmonary deposition when compared to inhaled therapeutic agents.

Background of the Invention Inhaled corticosteroids are fundamental to long-term management of persistent asthma and are recommended in national guidelines for the treatment of young children diagnosed with asthma. Numerous clinical trials support its effectiveness and relative safety for children. It is also believed that early corticosteroid intervention may play an important role in reducing permanent lung damage and modifying the chronic and progressive nature of the disease.

  The use of inhaled corticosteroids in the treatment of asthma is substantial due to direct delivery to the site of action, the lung (as used herein, “lung” refers to either the right and left lung organs or both). Provide benefits. The purpose of inhaled corticosteroid therapy is to provide localized delivery of corticosteroids with immediate drug activity at the site of action. Inhaled corticosteroids are known to be well absorbed from the lungs. In fact, it can be assumed that substantially all of the drug available at the receptor site in the lung is absorbed. However, it is also known that current methods and formulations allow the majority of inhaled corticosteroid doses to be swallowed and available for oral absorption. Thus, depending on the particular method or system used, some corticosteroids are more likely to be deposited in the mouth and throat than in the lungs, which can cause adverse effects. In the oral delivery portion of an inhaled corticosteroid dose, bioavailability depends on the extent of absorption from the GI tract and first-pass metabolism in the liver. Because this oral component of corticosteroid drug delivery does not provide any beneficial therapeutic effect and increases the risk of systemic side effects, it is desirable that the oral bioavailability of inhaled corticosteroids be relatively low. Thus, for inhaled corticosteroids, high lung availability is more important than high oral bioavailability because the lung is the target organ.

  Thus, a delivery method or system that provides corticosteroids with high pulmonary availability has a greater potential for positive effects in the lung. An ideal system for providing inhaled corticosteroids can result in minimal oral delivery and a reduced number of doses, thereby reducing the likelihood of systemic adverse effects.

  Unfortunately, however, delivery of corticosteroids by inhalation often results in the deposition of corticosteroids away from the respiratory tract, such as the mouth, throat and esophagus. In general, the smaller the corticosteroid particle size, the longer the particles remain suspended in air, and the drug can be delivered further down the airway. Corticosteroids are delivered by inhalation using nebulizers, metered dose inhalers or dry powder inhalers. A major advantage of nebulizers over other methods of pulmonary delivery of corticosteroids is that the nebulizer can deliver higher doses more efficiently compared to other methods. However, the main concerns with nebulizers are increased cost, low portability, and the inconvenience of having to prepare the medication in advance, and the high time requirements for performing the treatment. Therefore, a method for improving the delivery of drugs such as corticosteroids by nebulization is desired.

  Both particle size and formulation affect the effectiveness of inhaled corticosteroids. The formulation of the drug has a significant impact on the delivery of the drug to the lung and thus has a significant impact on its effectiveness. Furthermore, it is believed that the most important considerations in drug delivery to the lung are the aerosol delivery vehicle and the size of the delivered particles.

  Inhalation of drug particles is known to be inconvenient as opposed to dissolved drug. Non-patent document 1 reports that particles having low solubility deposited on the mucus surface layer covering the lung airway and nasal passage move toward the pharynx by cilia. Such particles include large drug particles, which are deposited in the upper respiratory tract. When mucus, cells and debris from the nasal cavity and lungs come together in the pharynx, they are mixed with saliva and enter the gastrointestinal tract when swallowed. According to reports, this mechanism removes particles from the lung with a half-life of minutes to hours. Therefore, solubilization of slow-dissolving drugs such as corticosteroids (eg budesonide) takes little time. In contrast, particles deposited in pililess compartments such as the alveoli have a much longer residence time. Because it is difficult to make very small particles of corticosteroids for deep lung deposition, the majority of this inhaled suspension can be found in the upper and middle airways. However, making small droplets from a solution is much easier than making a solid suspension.

Cyclic 16,17-acetal (C ₂₅ H ₄ O ₆ ) of (R, S) -llβ, 16α, 17,21-tetrahydroxypregna-1,4-diene-3,20-dione with budesonide, butyraldehyde MW: 430.5) is used in particular for the treatment of bronchial disorders. Budesonide is a racemic compound consisting of a mixture of two diastereomers 22R and 22S and is commercially available as a mixture of two isomers (22R and 22S). It acts as an anti-inflammatory corticosteroid that exhibits potent glucocorticoid activity. Administration of budesonide is indicated for maintenance treatment of asthma and as preventive therapy in children.

  Because of its lipophilicity, budesonide as well as other lipophilic corticosteroids are practically insoluble in water but readily soluble in alcohol. A sufficient amount of the active substance can be dissolved by the use of solubilizers such as organic water-soluble alcohols. However, the solutions thus obtained are generally of limited stability for pharmaceutical use, since large amounts of active substance can disintegrate in a short time.

  Commercially available budesonide formulations are sold by AstraZeneca LP (Wilmington, DE) under the trademarks Entocort (R) EC, Pulmicort Repules (R), Rhinocort (R) Aqua, Rhinocort (R) Nasal Intalter (R) , And its common name. Pulmicort Respules® is a sterile aqueous suspension of micronized budesonide that is administered by inhalation using a nebulizer, particularly a compressed air driven jet nebulizer. The Rhinocort® Nasal Inhaler is a metered pressure aerosol unit that contains a suspension of micronized budesonide in a propellant mixture. Rhinocort® Aqua is an unscented metered manual pump spray formulation containing a suspension of micronized budesonide in an aqueous medium. Budesonide suspension formulations also have a tendency to rapidly form coarse floe during dispersion and redispersion, which can adversely affect dosage reproducibility. Budesonide also tends to deposit on the wall of the container from the suspension.

Accordingly, there is a need for systems and methods for delivering non-suspended formulations containing corticosteroids by nebulization. However, in view of this need, Pulmicort Resple® Suspension is the only currently approved therapy for the treatment of childhood asthma with budesonide by inhalation therapy. There is also a need for the availability of compositions, methods and systems for corticosteroids other than budesonide. Thus, a method that results in an improved pharmacokinetic profile of the delivered corticosteroid and / or increased pulmonary deposition compared to the pharmacokinetic profile of a suspension unit dose formulation containing a corticosteroid, or Providing a system can be a significant advance towards the field of corticosteroid inhalation therapy.
Brain et al., Bronchial Asthma, 2nd edition, E.I. B. Edited by Weis et al., Little Brown & Co. (1985), pp. 594-603

SUMMARY OF THE INVENTION In certain embodiments, the present invention provides an inhalable composition comprising no more than about 250 μg of a single corticosteroid, a solvent and a solubility enhancer, the composition being delivered via the device. Upon administration of the composition to a subject, a rate of increase in corticosteroid concentration in the device of about 5 μg / ml / min or less is achieved over administration of the corticosteroid through the device, the corticosteroid It is substantially free of active pharmaceutical agents other than steroids.

  In certain embodiments, the invention provides an inhalable composition wherein a rate of increase of corticosteroid concentration in the device of about 5 μg / ml / min or less is achieved over the first 3 minutes of administration.

  In certain embodiments, the present invention provides inhalable compositions wherein a rate of increase of corticosteroid concentration in the device of about 3.5 μg / ml / min or less is achieved over the first 3 minutes of administration. .

  In certain embodiments, the present invention provides inhalable compositions wherein a rate of increase of corticosteroid concentration in the device of about 5% / min or less is achieved over the first 3 minutes of administration.

  In certain embodiments, the present invention provides an inhalable composition wherein the solvent comprises water.

  In certain embodiments, the present invention provides that the solubility enhancer is propylene glycol, nonionic surfactant, tyloxapol, polysorbate 80, vitamin E-TPGS, macrogol-15-hydroxystearate, phospholipid, lecithin, purification and / Or enriched lecithin, phosphatidylcholine fraction extracted from lecithin, dimyristoylphosphatidylcholine (DMPC), dipalmitoylphosphatidylcholine (DPPC), distearoylphosphatidylcholine (DSPC), cyclodextrin and its derivatives, SAE-CD derivatives, SBE-α -CD, SBE-β-CD, SBE1-β-CD, SBE4-β-CD, SBE7-β-CD, SBE-γ-CD, dimethyl β-CD, hydroxypropyl-β-cyclodextrin, 2, -HP-β-CD, hydroxyethyl-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, hydroxyethyl-γ-cyclodextrin, dihydroxypropyl-β-cyclodextrin, glucosyl-α-cyclodextrin, glucosyl-β- Cyclodextrin, diglucosyl-β-cyclodextrin, maltosyl-α-cyclodextrin, maltosyl-β-cyclodextrin, maltosyl-γ-cyclodextrin, maltotriosyl-β-cyclodextrin, maltotriosyl-γ-cyclodextrin, dimaltosyl -Β-cyclodextrin, methyl-β-cyclodextrin, carboxyalkyl thioether derivative, ORG 26054, ORG 25969, hydroxypropylmethylcellulose, Provided is an inhalable composition selected from the group consisting of hydroxypropyl cellulose, polyvinyl pyrrolidone, vinyl acetate copolymer, vinyl pyrrolidone, sodium lauryl sulfate, dioctyl sodium sulfosuccinate, and combinations thereof. In certain embodiments, the solubility enhancer comprises SBE7-β-CD.

  In certain embodiments, the present invention provides an inhalable composition wherein the device is a nebulizer. In certain embodiments, the device is a Pari eFlow nebulizer.

  In certain embodiments, the present invention provides an inhalable composition comprising a corticosteroid at a nominal dosage of about 60 μg.

  In certain embodiments, the present invention provides an inhalable composition comprising a corticosteroid at a nominal dosage of about 120 μg.

  In certain embodiments, the present invention provides an inhalable composition comprising an effective amount of a single corticosteroid, a solvent and a solubility enhancer, which composition is delivered to a subject via a device. 60% of the rate of increase of corticosteroid concentration in the device achieved by the inhalable suspension comprising the corticosteroid without the solubility enhancer administered under the same conditions upon administration of the composition The following rates of increasing corticosteroid concentrations in the device are achieved and are substantially free of active pharmaceutical agents other than the corticosteroid.

  In certain embodiments, the invention provides that the rate of increase of corticosteroid concentration in the device is over the first 3 minutes of administration, during the second and third 1 minutes of administration, or at the third of administration. An inhalable composition is provided that is achieved in a minute.

  In certain embodiments, the invention provides an inhalable composition wherein administration of the composition through the device is achieved over 5 minutes and administration of the inhalable suspension is accomplished over 5 minutes. .

  In certain embodiments, the present invention provides an inhalable composition wherein the administration time of the composition through the device and the administration time of the inhalable suspension are the same.

  In certain embodiments, the present invention provides an inhalable composition wherein the administration time of the composition through the device differs from the administration time of the inhalable suspension.

  In certain embodiments, the invention provides an inhalable composition comprising about 40 μg, about 60 μg, about 120 μg, about 125 μg, about 240 μg, about 250 μg, about 500 μg, about 1000 μg, about 1500 μg, or about 2000 μg of corticosteroid. Offer things.

  In certain embodiments, the present invention provides an inhalable composition wherein the solvent comprises water.

  In certain embodiments, the present invention provides that the solubility enhancer is propylene glycol, nonionic surfactant, tyloxapol, polysorbate 80, vitamin E-TPGS, macrogol-15-hydroxystearate, phospholipid, lecithin, purification and / Or enriched lecithin, phosphatidylcholine fraction extracted from lecithin, dimyristoylphosphatidylcholine (DMPC), dipalmitoylphosphatidylcholine (DPPC), distearoylphosphatidylcholine (DSPC), cyclodextrin and its derivatives, SAE-CD derivatives, SBE-α -CD, SBE-β-CD, SBE1-β-CD, SBE4-β-CD, SBE7-β-CD, SBE-γ-CD, dimethyl β-CD, hydroxypropyl-β-cyclodextrin, 2, -HP-β-CD, hydroxyethyl-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, hydroxyethyl-γ-cyclodextrin, dihydroxypropyl-β-cyclodextrin, glucosyl-α-cyclodextrin, glucosyl-β- Cyclodextrin, diglucosyl-β-cyclodextrin, maltosyl-α-cyclodextrin, maltosyl-β-cyclodextrin, maltosyl-γ-cyclodextrin, maltotriosyl-β-cyclodextrin, maltotriosyl-γ-cyclodextrin, dimaltosyl -Β-cyclodextrin, methyl-β-cyclodextrin, carboxyalkyl thioether derivative, ORG 26054, ORG 25969, hydroxypropylmethylcellulose, Provided is an inhalable composition selected from the group consisting of hydroxypropyl cellulose, polyvinyl pyrrolidone, vinyl acetate copolymer, vinyl pyrrolidone, sodium lauryl sulfate, dioctyl sodium sulfosuccinate, and combinations thereof.

  In certain embodiments, the present invention provides an inhalable composition wherein the solubility enhancer comprises SBE7-β-CD.

  In certain embodiments, the present invention provides a device comprising a jet nebulizer, an ultrasonic nebulizer, a pulsating membrane nebulizer, a nebulizer having a vibrating mesh or plate with multiple holes, and a vibration generator and an aqueous chamber ( An inhalable composition selected from a nebulizer comprising an aqueous chamber) is provided.

  In certain embodiments, the present invention provides a method of making microparticles from an inhalable composition, the method comprising adding a solvent and a solubility enhancer to an effective amount of a single corticosteroid. Forming a composition (the composition is substantially free of an active pharmaceutical agent other than the corticosteroid), and activating a nebulizer to produce microparticles of the composition, the nebulizer Upon administration of the composition to a subject via an inhalable suspension comprising the corticosteroid without a solubility enhancer administered under the same conditions by the composition A rate of increase in corticosteroid concentration in the nebulizer that is 60% or less of the rate of increase in corticosteroid concentration in the nebulizer is achieved.

  In certain embodiments, the invention provides that the rate of increase of corticosteroid concentration in the device is over the first 3 minutes of administration, during the second and third 1 minutes of administration, or at the third of administration. Provides a method that can be achieved in a minute.

  In certain embodiments, the present invention provides a method wherein administration of the composition via a nebulizer is achieved over 5 minutes and administration of an inhalable suspension is achieved over 5 minutes.

  In certain embodiments, the present invention provides a method wherein the administration time of the composition through the nebulizer and the administration time of the inhalable suspension are the same.

  In certain embodiments, the present invention provides a method in which the administration time of the composition through the nebulizer differs from the administration time of the inhalable suspension.

  In certain embodiments, the invention provides that the composition comprises about 40 μg, about 60 μg, about 120 μg, about 125 μg, about 240 μg, about 250 μg, about 500 μg, about 1000 μg, about 1500 μg, or about 2000 μg of corticosteroid. A method of including is provided.

  In certain embodiments, the present invention provides a method wherein the solvent comprises water.

  In certain embodiments, the present invention provides that the solubility enhancer is propylene glycol, nonionic surfactant, tyloxapol, polysorbate 80, vitamin E-TPGS, macrogol-15-hydroxystearate, phospholipid, lecithin, purification and / Or enriched lecithin, phosphatidylcholine fraction extracted from lecithin, dimyristoylphosphatidylcholine (DMPC), dipalmitoylphosphatidylcholine (DPPC), distearoylphosphatidylcholine (DSPC), cyclodextrin and its derivatives, SAE-CD derivatives, SBE-α -CD, SBE-β-CD, SBE1-β-CD, SBE4-β-CD, SBE7-β-CD, SBE-γ-CD, dimethyl β-CD, hydroxypropyl-β-cyclodextrin, 2, -HP-β-CD, hydroxyethyl-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, hydroxyethyl-γ-cyclodextrin, dihydroxypropyl-β-cyclodextrin, glucosyl-α-cyclodextrin, glucosyl-β- Cyclodextrin, diglucosyl-β-cyclodextrin, maltosyl-α-cyclodextrin, maltosyl-β-cyclodextrin, maltosyl-γ-cyclodextrin, maltotriosyl-β-cyclodextrin, maltotriosyl-γ-cyclodextrin, dimaltosyl -Β-cyclodextrin, methyl-β-cyclodextrin, carboxyalkyl thioether derivative, ORG 26054, ORG 25969, hydroxypropylmethylcellulose, Provided is a process selected from the group consisting of hydroxypropyl cellulose, polyvinyl pyrrolidone, vinyl acetate copolymer, vinyl pyrrolidone, sodium lauryl sulfate, dioctyl sodium sulfosuccinate, and combinations thereof.

  In certain embodiments, the present invention provides a method wherein the solubility enhancer comprises SBE7-β-CD.

  In certain embodiments, the invention selects the nebulizer from a jet nebulizer, an ultrasonic nebulizer, a pulsating membrane nebulizer, a nebulizer having a vibrating mesh or plate with multiple holes, and a nebulizer comprising a vibration generator and an aqueous chamber Provide a way to be.

  In certain embodiments, the present invention provides an inhalation system for delivering a therapeutically effective dose of a single corticosteroid to a patient comprising: (a) a corticosteroid, a solvent and a solubility enhancer. An aqueous inhalation mixture comprising (the composition is substantially free of active pharmaceutical agents other than the corticosteroid), and (b) a nebulizer (on administration of the mixture to the subject via the nebulizer, Within the nebulizer that is 60% or less of the rate of increase of the corticosteroid concentration in the nebulizer achieved by the mixture with the inhalable suspension containing the corticosteroid without a solubility enhancer administered under the same conditions An increasing rate of corticosteroid concentration is achieved).

  In certain embodiments, the invention provides that the rate of increase of corticosteroid concentration in the device is over the first 3 minutes of administration, during the second and third 1 minutes of administration, or at the third of administration. An inhalation system that is achieved during a 1 minute period is provided.

  In certain embodiments, the invention provides an inhalation system wherein administration of the composition via a nebulizer is achieved over 5 minutes and administration of an inhalable suspension is achieved over 5 minutes.

  In certain embodiments, the present invention provides an inhalation system in which the administration time of the composition through the nebulizer is the same as the administration time of the inhalable suspension.

  In certain embodiments, the present invention provides an inhalation system in which the administration time of the composition through the nebulizer differs from the administration time of the inhalable suspension.

  In certain embodiments, the invention provides that the mixture comprises about 40 μg, about 60 μg, about 120 μg, about 125 μg, about 240 μg, about 250 μg, about 500 μg, about 1000 μg, about 1500 μg, or about 2000 μg of corticosteroid. Provide an inhalation system.

  In certain embodiments, the present invention provides an inhalation system where the solvent comprises water.

  In certain embodiments, the present invention provides that the solubility enhancer is propylene glycol, nonionic surfactant, tyloxapol, polysorbate 80, vitamin E-TPGS, macrogol-15-hydroxystearate, phospholipid, lecithin, purification and / Or enriched lecithin, phosphatidylcholine fraction extracted from lecithin, dimyristoylphosphatidylcholine (DMPC), dipalmitoylphosphatidylcholine (DPPC), distearoylphosphatidylcholine (DSPC), cyclodextrin and its derivatives, SAE-CD derivatives, SBE-α -CD, SBE-β-CD, SBE1-β-CD, SBE4-β-CD, SBE7-β-CD, SBE-γ-CD, dimethyl β-CD, hydroxypropyl-β-cyclodextrin, 2, -HP-β-CD, hydroxyethyl-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, hydroxyethyl-γ-cyclodextrin, dihydroxypropyl-β-cyclodextrin, glucosyl-α-cyclodextrin, glucosyl-β- Cyclodextrin, diglucosyl-β-cyclodextrin, maltosyl-α-cyclodextrin, maltosyl-β-cyclodextrin, maltosyl-γ-cyclodextrin, maltotriosyl-β-cyclodextrin, maltotriosyl-γ-cyclodextrin, dimaltosyl -Β-cyclodextrin, methyl-β-cyclodextrin, carboxyalkyl thioether derivative, ORG 26054, ORG 25969, hydroxypropylmethylcellulose, Provided is an inhalation system selected from the group consisting of hydroxypropyl cellulose, polyvinyl pyrrolidone, vinyl acetate copolymer, vinyl pyrrolidone, sodium lauryl sulfate, dioctyl sodium sulfosuccinate, and combinations thereof.

  In certain embodiments, the present invention provides an inhalation system wherein the solubility enhancer comprises SBE7-β-CD.

  In certain embodiments, the invention selects the nebulizer from a jet nebulizer, an ultrasonic nebulizer, a pulsating membrane nebulizer, a nebulizer having a vibrating mesh or plate with multiple holes, and a nebulizer comprising a vibration generator and an aqueous chamber An inhalation system is provided.

  In certain embodiments, the present invention provides a method for treating bronchoconstrictive disorder in a patient in need of treatment of bronchoconstrictive disorder, wherein the method comprises a solvent and a solubility enhancer in a certain amount. Forming a composition by adding to one corticosteroid, wherein the composition is substantially free of an active pharmaceutical agent other than the corticosteroid, as well as activating the nebulizer Wherein, upon administration of the composition to a subject via the nebulizer, the composition causes the inhalable suspension comprising the corticosteroid without a solubility enhancer administered under the same conditions. A rate of increase of corticosteroid concentration in the nebulizer that is 60% or less of the rate of increase of corticosteroid concentration in the nebulizer achieved by the turbidity is achieved.

  In certain embodiments, the invention provides that the rate of increase of corticosteroid concentration in the device is over the first 3 minutes of administration, during the second and third 1 minutes of administration, or at the third of administration. Provides a method that can be achieved in a minute.

  In certain embodiments, the present invention provides a method wherein administration of the composition via a nebulizer is achieved over 5 minutes and administration of an inhalable suspension is achieved over 5 minutes.

  In certain embodiments, the present invention provides a method wherein the administration time of the composition through the nebulizer and the administration time of the inhalable suspension are the same.

  In certain embodiments, the present invention provides a method in which the administration time of the composition through the nebulizer differs from the administration time of the inhalable suspension.

  In certain embodiments, the invention provides that the composition comprises about 40 μg, about 60 μg, about 120 μg, about 125 μg, about 240 μg, about 250 μg, about 500 μg, about 1000 μg, about 1500 μg, or about 2000 μg of corticosteroid. A method of including is provided.

  In certain embodiments, the present invention provides a method wherein the solvent comprises water.

  In certain embodiments, the present invention provides that the solubility enhancer is propylene glycol, nonionic surfactant, tyloxapol, polysorbate 80, vitamin E-TPGS, macrogol-15-hydroxystearate, phospholipid, lecithin, purification and / Or enriched lecithin, phosphatidylcholine fraction extracted from lecithin, dimyristoylphosphatidylcholine (DMPC), dipalmitoylphosphatidylcholine (DPPC), distearoylphosphatidylcholine (DSPC), cyclodextrin and its derivatives, SAE-CD derivatives, SBE-α -CD, SBE-β-CD, SBE1-β-CD, SBE4-β-CD, SBE7-β-CD, SBE-γ-CD, dimethyl β-CD, hydroxypropyl-β-cyclodextrin, 2, -HP-β-CD, hydroxyethyl-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, hydroxyethyl-γ-cyclodextrin, dihydroxypropyl-β-cyclodextrin, glucosyl-α-cyclodextrin, glucosyl-β- Cyclodextrin, diglucosyl-β-cyclodextrin, maltosyl-α-cyclodextrin, maltosyl-β-cyclodextrin, maltosyl-γ-cyclodextrin, maltotriosyl-β-cyclodextrin, maltotriosyl-γ-cyclodextrin, dimaltosyl -Β-cyclodextrin, methyl-β-cyclodextrin, carboxyalkyl thioether derivative, ORG 26054, ORG 25969, hydroxypropylmethylcellulose, Provided is a process selected from the group consisting of hydroxypropyl cellulose, polyvinyl pyrrolidone, vinyl acetate copolymer, vinyl pyrrolidone, sodium lauryl sulfate, dioctyl sodium sulfosuccinate, and combinations thereof.

  In certain embodiments, the present invention provides a method wherein the solubility enhancer comprises SBE7-β-CD.

  In certain embodiments, the present invention comprises a nebulizer comprising a jet nebulizer, an ultrasonic nebulizer, a pulsating membrane nebulizer, a nebulizer having a vibrating mesh or plate with multiple holes, and a vibration generator and an aqueous chamber. A method selected from nebulizers is provided.

  In certain embodiments, the invention provides that the bronchoconstrictive disorder comprises asthma, childhood asthma, bronchial asthma, allergic asthma, endogenous asthma, chronic obstructive pulmonary disease (COPD), chronic bronchitis and emphysema Provide a more selected method.

  In certain embodiments, the invention provides an inhalable composition comprising no more than about 250 μg budesonide, a solvent and a solubility enhancer, the composition comprising the composition to the subject via a device. Upon administration, an increasing rate of budesonide concentration in the device of about 5 μg / ml / min or less is achieved over administration of budesonide through the device, and is substantially free of active pharmaceutical agents other than the corticosteroid.

  In certain embodiments, the invention provides an inhalable composition wherein a rate of increase of budesonide concentration in the device of about 5 μg / ml / min or less is achieved over the first 3 minutes of administration.

  In certain embodiments, the present invention provides inhalable compositions wherein an increasing rate of budesonide concentration in the device of about 3.5 μg / ml / min or less is achieved over the first 3 minutes of administration.

  In certain embodiments, the present invention provides inhalable compositions wherein a rate of increasing budesonide concentration in the device of about 5% / min or less is achieved over the first 3 minutes of administration.

  In certain embodiments, the present invention provides an inhalable composition wherein the solvent comprises water.

  In certain embodiments, the present invention provides that the solubility enhancer is propylene glycol, nonionic surfactant, tyloxapol, polysorbate 80, vitamin E-TPGS, macrogol-15-hydroxystearate, phospholipid, lecithin, purification and / Or enriched lecithin, phosphatidylcholine fraction extracted from lecithin, dimyristoylphosphatidylcholine (DMPC), dipalmitoylphosphatidylcholine (DPPC), distearoylphosphatidylcholine (DSPC), cyclodextrin and its derivatives, SAE-CD derivatives, SBE-α -CD, SBE-β-CD, SBE1-β-CD, SBE4-β-CD, SBE7-β-CD, SBE-γ-CD, dimethyl β-CD, hydroxypropyl-β-cyclodextrin, 2, -HP-β-CD, hydroxyethyl-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, hydroxyethyl-γ-cyclodextrin, dihydroxypropyl-β-cyclodextrin, glucosyl-α-cyclodextrin, glucosyl-β- Cyclodextrin, diglucosyl-β-cyclodextrin, maltosyl-α-cyclodextrin, maltosyl-β-cyclodextrin, maltosyl-γ-cyclodextrin, maltotriosyl-β-cyclodextrin, maltotriosyl-γ-cyclodextrin, dimaltosyl -Β-cyclodextrin, methyl-β-cyclodextrin, carboxyalkyl thioether derivative, ORG 26054, ORG 25969, hydroxypropylmethylcellulose, Provided is an inhalable composition selected from the group consisting of hydroxypropyl cellulose, polyvinyl pyrrolidone, vinyl acetate copolymer, vinyl pyrrolidone, sodium lauryl sulfate, dioctyl sodium sulfosuccinate, and combinations thereof.

  In certain embodiments, the present invention provides an inhalable composition wherein the solubility enhancer comprises SBE7-β-CD.

  In certain embodiments, the present invention provides an inhalable composition wherein the device is a nebulizer.

  In certain embodiments, the present invention provides an inhalable composition wherein the device is a Pari eFlow nebulizer.

  In certain embodiments, the present invention provides an inhalable composition comprising budesonide at a nominal dosage of about 60 μg.

  In certain embodiments, the present invention provides an inhalable composition comprising budesonide at a nominal dosage of about 120 μg.

  In certain embodiments, the present invention provides an inhalable composition comprising an effective amount of budesonide, a solvent, and a solubility enhancer, the composition administering the composition to a subject via a device. The rate of increase of budesonide concentration in the device up to 60% of the rate of increase in budesonide concentration in the device achieved by an inhalable suspension containing budesonide without a solubility enhancer administered under the same conditions Is achieved and is substantially free of active pharmaceutical agents other than the corticosteroid.

  In certain embodiments, the invention provides that the rate of increase of budesonide concentration in the device is over the first 3 minutes of administration, during the second and third 1 minutes of administration, or the third 1 of administration. An inhalable composition is provided that is achieved during a minute.

  In certain embodiments, the invention provides an inhalable composition wherein administration of the composition through the device is achieved over 5 minutes and administration of the inhalable suspension is accomplished over 5 minutes. .

  In certain embodiments, the present invention provides an inhalable composition wherein the administration time of the composition through the device and the administration time of the inhalable suspension are the same.

  In certain embodiments, the present invention provides an inhalable composition wherein the administration time of the composition through the device differs from the administration time of the inhalable suspension.

  In certain embodiments, the invention provides an inhalable composition comprising about 40 μg, about 60 μg, about 120 μg, about 125 μg, about 240 μg, about 250 μg, about 500 μg, about 1000 μg, about 1500 μg, or about 2000 μg budesonide. provide.

  In certain embodiments, the present invention provides an inhalable composition wherein the solvent comprises water.

  In certain embodiments, the present invention provides that the solubility enhancer is propylene glycol, nonionic surfactant, tyloxapol, polysorbate 80, vitamin E-TPGS, macrogol-15-hydroxystearate, phospholipid, lecithin, purification and / Or enriched lecithin, phosphatidylcholine fraction extracted from lecithin, dimyristoylphosphatidylcholine (DMPC), dipalmitoylphosphatidylcholine (DPPC), distearoylphosphatidylcholine (DSPC), cyclodextrin and its derivatives, SAE-CD derivatives, SBE-α -CD, SBE-β-CD, SBE1-β-CD, SBE4-β-CD, SBE7-β-CD, SBE-γ-CD, dimethyl β-CD, hydroxypropyl-β-cyclodextrin, 2, -HP-β-CD, hydroxyethyl-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, hydroxyethyl-γ-cyclodextrin, dihydroxypropyl-β-cyclodextrin, glucosyl-α-cyclodextrin, glucosyl-β- Cyclodextrin, diglucosyl-β-cyclodextrin, maltosyl-α-cyclodextrin, maltosyl-β-cyclodextrin, maltosyl-γ-cyclodextrin, maltotriosyl-β-cyclodextrin, maltotriosyl-γ-cyclodextrin, dimaltosyl -Β-cyclodextrin, methyl-β-cyclodextrin, carboxyalkyl thioether derivative, ORG 26054, ORG 25969, hydroxypropylmethylcellulose, Provided is an inhalable composition selected from the group consisting of hydroxypropyl cellulose, polyvinyl pyrrolidone, vinyl acetate copolymer, vinyl pyrrolidone, sodium lauryl sulfate, dioctyl sodium sulfosuccinate, and combinations thereof.

  In certain embodiments, the present invention provides an inhalable composition wherein the solubility enhancer comprises SBE7-β-CD.

  In certain embodiments, the invention selects from a nebulizer comprising a jet nebulizer, an ultrasonic nebulizer, a pulsating membrane nebulizer, a nebulizer having a vibrating mesh or plate with multiple holes, and a vibration generator and an aqueous chamber. An inhalable composition is provided.

  In certain embodiments, the present invention provides a method of making microparticles from an inhalable composition, the method comprising forming the composition by adding a solubility enhancer to an effective amount of budesonide ( Wherein the composition is substantially free of an active pharmaceutical agent other than the corticosteroid) and actuating a nebulizer to produce microparticles of the composition, via the nebulizer Upon administration of the composition to a subject, the composition increases the budesonide concentration in the nebulizer achieved by an inhalable suspension comprising budesonide without a solubility enhancer administered under the same conditions An increasing rate of budesonide concentration in the nebulizer that is less than 60% of the rate is achieved.

In certain embodiments, the invention provides that the rate of increase of budesonide concentration in the device is over the first 3 minutes of administration, during the second and third 1 minutes of administration, or the third 1 of administration. Providing a method that can be achieved in minutes.

  In certain embodiments, the present invention provides a method wherein administration of the composition via a nebulizer is achieved over 5 minutes and administration of an inhalable suspension is achieved over 5 minutes.

  In certain embodiments, the present invention provides a method wherein the administration time of the composition through the nebulizer and the administration time of the inhalable suspension are the same.

  In certain embodiments, the present invention provides a method in which the administration time of the composition through the nebulizer differs from the administration time of the inhalable suspension.

  In certain embodiments, the invention provides a method wherein the composition comprises about 40 μg, about 60 μg, about 120 μg, about 125 μg, about 240 μg, about 250 μg, about 500 μg, about 1000 μg, about 1500 μg, or about 2000 μg budesonide. I will provide a.

  In certain embodiments, the present invention provides a method wherein the solvent comprises water.

  In certain embodiments, the present invention provides that the solubility enhancer is propylene glycol, nonionic surfactant, tyloxapol, polysorbate 80, vitamin E-TPGS, macrogol-15-hydroxystearate, phospholipid, lecithin, purification and / Or enriched lecithin, phosphatidylcholine fraction extracted from lecithin, dimyristoylphosphatidylcholine (DMPC), dipalmitoylphosphatidylcholine (DPPC), distearoylphosphatidylcholine (DSPC), cyclodextrin and its derivatives, SAE-CD derivatives, SBE-α -CD, SBE-β-CD, SBE1-β-CD, SBE4-β-CD, SBE7-β-CD, SBE-γ-CD, dimethyl β-CD, hydroxypropyl-β-cyclodextrin, 2, -HP-β-CD, hydroxyethyl-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, hydroxyethyl-γ-cyclodextrin, dihydroxypropyl-β-cyclodextrin, glucosyl-α-cyclodextrin, glucosyl-β- Cyclodextrin, diglucosyl-β-cyclodextrin, maltosyl-α-cyclodextrin, maltosyl-β-cyclodextrin, maltosyl-γ-cyclodextrin, maltotriosyl-β-cyclodextrin, maltotriosyl-γ-cyclodextrin, dimaltosyl -Β-cyclodextrin, methyl-β-cyclodextrin, carboxyalkyl thioether derivative, ORG 26054, ORG 25969, hydroxypropylmethylcellulose, Provided is a process selected from the group consisting of hydroxypropyl cellulose, polyvinyl pyrrolidone, vinyl acetate copolymer, vinyl pyrrolidone, sodium lauryl sulfate, dioctyl sodium sulfosuccinate, and combinations thereof.

  In certain embodiments, the present invention provides a method wherein the solubility enhancer comprises SBE7-β-CD.

  In certain embodiments, the invention selects from a nebulizer comprising a jet nebulizer, an ultrasonic nebulizer, a pulsating membrane nebulizer, a nebulizer having a vibrating mesh or plate with multiple holes, and a vibration generator and an aqueous chamber. Provide a way to be.

  In certain embodiments, the present invention provides an inhalation system for delivering a therapeutically effective dose of budesonide to a patient, the system comprising (a) an aqueous inhalation mixture comprising budesonide and a solubility enhancer, wherein the The composition is substantially free of an active pharmaceutical agent other than the corticosteroid), and (b) comprising a nebulizer, upon administration of the mixture to a subject via the nebulizer, An increase rate of budesonide concentration in the nebulizer of 60% or less of the increase rate of budesonide concentration in the nebulizer achieved by an inhalable suspension containing budesonide without a solubility enhancer administered under the same conditions is achieved. .

  In certain embodiments, the invention provides that the rate of increase of budesonide concentration in the device is over the first 3 minutes of administration, during the second and third 1 minutes of administration, or the third 1 of administration. Provide an inhalation system that is achieved during a minute.

  In certain embodiments, the invention provides an inhalation system wherein administration of the composition via a nebulizer is achieved over 5 minutes and administration of an inhalable suspension is achieved over 5 minutes.

  In certain embodiments, the present invention provides an inhalation system in which the administration time of the composition through the nebulizer is the same as the administration time of the inhalable suspension.

  In certain embodiments, the present invention provides an inhalation system in which the administration time of the composition through the nebulizer differs from the administration time of the inhalable suspension.

  In certain embodiments, the invention provides an inhalation system wherein the mixture comprises about 40 μg, about 60 μg, about 120 μg, about 125 μg, about 240 μg, about 250 μg, about 500 μg, about 1000 μg, about 1500 μg, or about 2000 μg budesonide. I will provide a.

  In certain embodiments, the present invention provides an inhalation system where the solvent comprises water.

  In certain embodiments, the present invention provides that the solubility enhancer is propylene glycol, nonionic surfactant, tyloxapol, polysorbate 80, vitamin E-TPGS, macrogol-15-hydroxystearate, phospholipid, lecithin, purification and / Or enriched lecithin, phosphatidylcholine fraction extracted from lecithin, dimyristoylphosphatidylcholine (DMPC), dipalmitoylphosphatidylcholine (DPPC), distearoylphosphatidylcholine (DSPC), cyclodextrin and its derivatives, SAE-CD derivatives, SBE-α -CD, SBE-β-CD, SBE1-β-CD, SBE4-β-CD, SBE7-β-CD, SBE-γ-CD, dimethyl β-CD, hydroxypropyl-β-cyclodextrin, 2, -HP-β-CD, hydroxyethyl-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, hydroxyethyl-γ-cyclodextrin, dihydroxypropyl-β-cyclodextrin, glucosyl-α-cyclodextrin, glucosyl-β- Cyclodextrin, diglucosyl-β-cyclodextrin, maltosyl-α-cyclodextrin, maltosyl-β-cyclodextrin, maltosyl-γ-cyclodextrin, maltotriosyl-β-cyclodextrin, maltotriosyl-γ-cyclodextrin, dimaltosyl -Β-cyclodextrin, methyl-β-cyclodextrin, carboxyalkyl thioether derivative, ORG 26054, ORG 25969, hydroxypropylmethylcellulose, Provided is an inhalation system selected from the group consisting of hydroxypropyl cellulose, polyvinyl pyrrolidone, vinyl acetate copolymer, vinyl pyrrolidone, sodium lauryl sulfate, dioctyl sodium sulfosuccinate, and combinations thereof.

  In certain embodiments, the present invention provides an inhalation system wherein the solubility enhancer comprises SBE7-β-CD.

  In certain embodiments, the invention selects from a nebulizer comprising a jet nebulizer, an ultrasonic nebulizer, a pulsating membrane nebulizer, a nebulizer having a vibrating mesh or plate with multiple holes, and a vibration generator and an aqueous chamber. An inhalation system is provided.

  In certain embodiments, the present invention provides a method for treating bronchoconstrictive disorder in a patient in need of treatment of bronchoconstrictive disorder, the method comprising adding a solubility enhancer to an amount of budesonide Forming a composition (wherein the composition is substantially free of an active pharmaceutical agent other than the corticosteroid) and actuating a nebulizer, wherein the nebulizer The concentration of budesonide in the nebulizer achieved by inhalable suspension comprising budesonide without a solubility enhancer administered under the same conditions upon administration of the composition to a subject via An increase rate of budesonide concentration in the nebulizer of 60% or less of the increase rate of is achieved.

  In certain embodiments, the invention provides that the rate of increase of budesonide concentration in the device is over the first 3 minutes of administration, during the second and third 1 minutes of administration, or the third 1 of administration. Providing a method that is accomplished during a minute.

  In certain embodiments, the present invention provides a method wherein administration of the composition via a nebulizer is achieved over 5 minutes and administration of an inhalable suspension is achieved over 5 minutes.

  In certain embodiments, the present invention provides a method wherein the administration time of the composition through the nebulizer and the administration time of the inhalable suspension are the same.

  In certain embodiments, the present invention provides a method in which the administration time of the composition through the nebulizer differs from the administration time of the inhalable suspension.

  In certain embodiments, the invention provides a method wherein the composition comprises about 40 μg, about 60 μg, about 120 μg, about 125 μg, about 240 μg, about 250 μg, about 500 μg, about 1000 μg, about 1500 μg, or about 2000 μg budesonide. I will provide a.

  In certain embodiments, the present invention provides a method wherein the solvent comprises water.

  In certain embodiments, the present invention provides that the solubility enhancer is propylene glycol, nonionic surfactant, tyloxapol, polysorbate 80, vitamin E-TPGS, macrogol-15-hydroxystearate, phospholipid, lecithin, purification and / Or enriched lecithin, phosphatidylcholine fraction extracted from lecithin, dimyristoylphosphatidylcholine (DMPC), dipalmitoylphosphatidylcholine (DPPC), distearoylphosphatidylcholine (DSPC), cyclodextrin and its derivatives, SAE-CD derivatives, SBE-α -CD, SBE-β-CD, SBE1-β-CD, SBE4-β-CD, SBE7-β-CD, SBE-γ-CD, dimethyl β-CD, hydroxypropyl-β-cyclodextrin, 2, -HP-β-CD, hydroxyethyl-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, hydroxyethyl-γ-cyclodextrin, dihydroxypropyl-β-cyclodextrin, glucosyl-α-cyclodextrin, glucosyl-β- Cyclodextrin, diglucosyl-β-cyclodextrin, maltosyl-α-cyclodextrin, maltosyl-β-cyclodextrin, maltosyl-γ-cyclodextrin, maltotriosyl-β-cyclodextrin, maltotriosyl-γ-cyclodextrin, dimaltosyl -Β-cyclodextrin, methyl-β-cyclodextrin, carboxyalkyl thioether derivative, ORG 26054, ORG 25969, hydroxypropylmethylcellulose, Provided is a process selected from the group consisting of hydroxypropyl cellulose, polyvinyl pyrrolidone, vinyl acetate copolymer, vinyl pyrrolidone, sodium lauryl sulfate, dioctyl sodium sulfosuccinate, and combinations thereof.

  In certain embodiments, the present invention provides a method wherein the solubility enhancer comprises SBE7-β-CD.

  In certain embodiments, the invention selects from a nebulizer comprising a jet nebulizer, an ultrasonic nebulizer, a pulsating membrane nebulizer, a nebulizer having a vibrating mesh or plate with multiple holes, and a vibration generator and an aqueous chamber. Provide a way to be.

  In certain embodiments, the invention provides that the bronchoconstrictive disorder comprises asthma, childhood asthma, bronchial asthma, allergic asthma, endogenous asthma, chronic obstructive pulmonary disease (COPD), chronic bronchitis and emphysema Provide a more selected method.

Detailed Description of the Invention The embodiments of the inhalable compositions, systems and methods disclosed herein will now be described in detail. Examples of embodiments are described in the Examples section below.

  Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the invention described herein belongs. All patents and patent publications mentioned herein are hereby incorporated by reference.

Specific Definitions As used herein, the terms “comprising”, “including”, “such as” and “for example” are open and non-limiting. It is used in a meaning.

  The term “about” is used interchangeably with the term “approximately”. As will be appreciated by those skilled in the art, the exact boundary of “about” depends on the components of the composition or other parameters. Illustratively, the use of the term “about” with respect to certain therapeutically effective pharmaceutical doses is also useful when values slightly outside the stated values, ie, values of + or −0.1% to 10% are also effective. To show that it is safe.

  “Administering under the same conditions” or “same conditions” as used herein means two or more methods and / or systems for corticosteroid delivery having one or more identical corticosteroid dosage conditions Say. Dosing conditions include, but are not limited to, the corticosteroid to be administered, the route of delivery of the corticosteroid, the time of administration, the nominal dosage administered to the subject, the number of doses administered, the volume of dose administered, and the corti It may be selected from the group consisting of the type of nebulizer used to deliver the costeroid, or any combination of the above administration conditions. In some embodiments, “under the same conditions” can mean that the corticosteroids administered are the same. In other embodiments, “under the same conditions” may mean that the delivery route of the corticosteroid is the same. In yet another embodiment, “under the same conditions” means that the administration time of the corticosteroid is the same. In yet other embodiments, “under the same conditions” means that the nominal dosage of the corticosteroid administered to the subject is the same. In still other embodiments, “under the same conditions” means that the number of doses administered is the same. In other embodiments, “under the same conditions” may mean that the administration time of the corticosteroid is the same, but the nominal dosage of the corticosteroid is different. In yet another embodiment, “under the same conditions” may mean that the administered corticosteroid is the same, but that the nominal dosage of the corticosteroid is different. In still other embodiments, "under the same conditions" means that the corticosteroid administered is the same, but the nominal dosage of corticosteroid and the type of nebulizer used to deliver the corticosteroid is different. Can mean. In yet another embodiment, “under the same conditions” may mean that the nominal dosage of the corticosteroid is the same, but the administration time of the corticosteroid is different. In other embodiments, “under the same conditions” means that the nominal dosage of the corticosteroid is the same, but the type of nebulizer used to deliver the corticosteroid and the delivery time are different. obtain. In yet other embodiments, `` under the same conditions '' means that the corticosteroid administered is the same, but the nominal dosage, the type of nebulizer used to deliver the corticosteroid, and the administration time are different. It can mean something.

“Bioavailability” refers to the weight percent of a corticosteroid dose such as budesonide delivered into the systemic circulation of the animal or human being tested. The total exposure (AUC _(0-∞) ) of the drug when administered intravenously is usually defined as 100% Bioavailable (F%).

“Plasma concentration” refers to the concentration of a corticosteroid, such as budesonide, in the plasma component of the blood of a subject or patient population. It will be appreciated that the concentration of corticosteroids such as plasma budesonide may differ significantly between subjects due to metabolic diversity and / or potential interaction with other therapeutic agents. According to one aspect of the invention, the concentration of corticosteroids such as plasma budesonide can vary from subject to subject. Similarly, the time under which the maximum plasma concentration (C _max ) or maximum plasma concentration (T _max ) is reached, or the area under the curve from time 0 to the last measurable concentration time (AUC _last ) or the area under the total plasma concentration time curve Values such as (AUC _(0-∞) ) may vary from subject to subject. Because of this diversity, the amount required to constitute a “therapeutically effective amount” of a corticosteroid, such as budesonide, can vary from subject to subject.

  "Bronchoconstrictive disorder" as used herein refers to any disease or condition that can cause bronchoconstriction or narrowing to appear in the body. Examples of bronchoconstrictive disorders include, but are not limited to, asthma, childhood asthma, bronchial asthma, allergic asthma, endogenous asthma, chronic obstructive pulmonary disease (COPD), chronic bronchitis, and emphysema.

  “Conventional inhalation corticosteroid therapy” or “corticosteroid-containing (including) inhalable suspension” as used herein refers to available suspension-based corticosteroid formulations, such as Asthma and / or chronic obstructive pulmonary disease (COPD) in combination with a commercially available Pulmicort® Respules (budesonide suspension) in combination with a nebulizer (preferably a jet nebulizer such as a Pari LC Jet Plus nebulizer) Alternatively, for the treatment of other bronchoconstrictive disorders, a therapeutically effective dosage for a given subject, population (s), or conventional dosages known to those skilled in the art (eg, the above-described commercial formulation, Pulmicort) (Registered Trademark) Respules is used at about 500 μg / day to 2000 μg / day) It says the door. In particular, the preferred budesonide suspension comparison is Pulmicort® Respules, which is 250 μg budesonide suspended in a 2 ml volume of aqueous phase in a unit dose ampoule or 2 ml in a unit dose ampoule. Commercial budesonide suspension containing any of 500 μg budesonide suspended in a volume of aqueous phase. Additional suspension-based corticosteroid preparations include beclomethasone dipropionate (Clenil®) and fluticasone propionate (Flyxide®), where the suspension-based corticosteroid The preparation is administered by inhalation nebulizer at a therapeutically effective dose or a conventional dose known to those of skill in the art.

  “Drug absorption” or “absorption” typically refers to the process of movement of a drug from the drug delivery site across the barrier into the blood vessel or into the site of action, eg, the lung capillaries of the alveoli. It is absorbed into the floor.

“Equal” or “equivalent” as used herein refers to two or more parameters or values having substantially the same value. As will be appreciated by those skilled in the art, the exact boundary of “equal” or “equivalent” depends on the specific parameter or value being analyzed. Illustratively, use of the term “equal” or “corresponding” as used herein encompasses values slightly outside the stated values, ie, + or −0.1% to 25%. . For example, in the context of the present invention, a C _max of 578.2 (pg / ml) is equal to a C _{max of} 556.74 pg / ml. Similarly, in another example, the C _max of 1195.3 (pg / ml) is equal to the C _{max of} 1114.83 pg / ml.

  “Inhalation nebulizer” as used herein refers to a device that converts dosages, compositions, formulations, suspensions and mixtures, etc. into a fine mist for delivery to the lungs.

  “Inhaled aqueous mixture”, “aqueous inhaled mixture” or “inhalable composition” as used herein generally refers to any aqueous (one inhaled) for inhaled delivery of an active agent other than a suspension. (Including partial aqueous). Examples of suitable aqueous mixtures or inhalable compositions include, but are not limited to, solutions, dispersions, nanoparticle dispersions, nanoparticle suspensions, emulsions, colloidal liquids, micelles or mixed micellar liquids, and liposomes. Liquid. Other suitable inhaled aqueous mixtures include suspensions to which a solubility enhancer has been added to increase the solubility of at least a portion of the initial suspension.

  In some embodiments of the present invention, an “inhalation aqueous mixture”, “aqueous inhalation mixture” or “inhalable composition” does not include nanodispersions and / or nanosuspensions. In other embodiments, the “inhaled aqueous mixture”, “aqueous inhaled mixture” or “inhalable composition” does not include micelles, mixed micelle liquids or liposome liquids. In still other embodiments, the “inhalation aqueous mixture”, “aqueous inhalation mixture” or “inhalable composition” does not include nanodispersions and / or nanosuspensions, micelles, mixed micelle liquids or liposome liquids. . In other embodiments, “inhalable compositions” include, but are not limited to, solutions, emulsions and colloidal fluids. In one embodiment, the inhalable composition is a solution comprising a corticosteroid such as budesonide and a solubility enhancer. In another embodiment, the inhalable composition is an emulsion comprising a corticosteroid such as budesonide and a solubility enhancer.

  “Local bioavailability” refers to the proportion of the total dose of a pharmacological agent that is bioavailable at the pharmacologically active site of the agent when the agent is administered to a patient by a particular delivery route. Local bioavailability is to be contrasted with systemic bioavailability (which is the proportion of the total dose of pharmacological agent administered that reaches the patient's systemic circulation). As a non-limiting example, local bioavailability of a drug delivered by inhalation refers to the proportion of the total dose of inhaled drug that is delivered to the lung upon administration by the inhalation delivery route.

  “Nominal dosage”, as used herein, refers to the pharmaceutically active agent (eg, corticosteroid) present in the inhaled dosage form prior to administration of the inhaled dosage form containing the pharmaceutically active agent. Refers to the total amount. Thus, as a non-limiting example, an aqueous inhalation mixture comprising budesonide at a nominal dosage of 120 μg / dose refers to an aqueous inhalation mixture comprising approximately 120 μg budesonide prior to administration of the aqueous inhalation mixture to a patient. Similarly, a unit dose ampoule comprising an inhalable suspension with 1000 μg corticosteroid (eg, budesonide) prior to administration is a delivery device for administration to a patient (the entire contents of the unit dose ampoule). For example, when in a nebulizer, it should have a nominal dosage of about 1000 μg / dose as used herein.

  “Pharmacokinetics” refers to factors that reflect the achievement and maintenance of drug concentration at the site of action.

  “Improvement of pharmacokinetic profile” as used herein refers, in some embodiments, to a site of drug action in one embodiment of a drug formulation (test formulation) compared to another drug formulation (reference formulation). Refers to a pharmacokinetic profile showing increased absorption or distribution. In other embodiments, the improvement in pharmacokinetic profile is achieved when the aqueous inhalation mixture is administered at a nominal dosage less than the inhalable suspension, as compared to the inhalable suspension. Administration results in a corresponding absorption or distribution at the site of drug action (eg, the absorption corresponding to a test formulation with a nominal dosage of 1: 2 relative to the reference product is a 2-fold improvement in pharmacokinetic profile). Equivalent absorption corresponding to the test formulation at a nominal dosage of 1: 3 is equal to a three-fold pharmacokinetic profile, and the absorption corresponding to a test formulation at a nominal dosage of 1: 4 is four times Such as equal to the pharmacokinetic profile). In other embodiments, the improvement in pharmacokinetic profile is the administration of an aqueous inhalation mixture when the aqueous inhalation mixture is administered at the same nominal dosage as the inhalable suspension compared to the inhalable suspension. Occurs when greater absorption or distribution occurs at the site of drug action. In other specific embodiments, the improvement in pharmacokinetic profile can be quantified based on an increase in absorption or distribution at the site of drug action of the aqueous inhalation mixture when compared to an inhalable suspension. For example, in certain embodiments, a two-fold improvement in pharmacokinetic profile indicates that administration of an aqueous inhalation mixture results in a numerical value representing the value of absorption or distribution at the drug action site of the aqueous inhalation mixture. Occurs when a pharmacokinetic profile is shown that is at least twice (2 ×) the value representing the value of absorption or distribution of the turbid at the site of drug action. In some embodiments, the inhalable suspension may be Pulmicort Respules®, which is a package insert included with Pulmicort Respules® commercial products (AstraZeneca LP, Wilmington Delaware, USA). Shows the pharmacokinetic profile as described in.

  In some embodiments of the invention, “enhanced pulmonary deposition” as used herein refers to one drug formulation (eg, an aqueous inhalation mixture) from another drug formulation (eg, inhalable). Refers to the pulmonary deposition of a compound that exhibits an increase in the total pulmonary deposition compared to the suspension. In some embodiments of the invention, “enhanced pulmonary deposition”, as used herein, refers to one drug formulation (eg, an aqueous inhalation mixture) and another drug formulation (eg, inhalable). Refers to intrapulmonary deposition of a compound that, when administered at a nominal dosage less than that of an inhalable suspension, exhibits substantially equivalent total lung deposition by an aqueous inhalation mixture compared to an inhalable suspension. In some embodiments, the inhalable suspension can be Pulmicort® Respules.

  As used herein, “respirable fraction” refers to the mass fraction of drug-containing particles having an aerodynamic diameter of less than about 5 μm exiting a nebulizer or a nebulizer mouthpiece. The respiratory fraction relates to the dose of drug exiting the nebulizer, not the nominal dose inside the nebulizer.

  “Solubility enhancer” as used herein includes methods that result in an increase in solubility with or without the action of chemicals. In certain embodiments, a “solubility enhancer” can refer to a chemical that increases the solubility of a second chemical compound (eg, active ingredient) in a solvent. In other embodiments, the chemical may also be a solvent for the second chemical compound. In yet other embodiments, the chemical is not a solvent for the second chemical compound. In yet other embodiments, the “solubility enhancer” is a formulation method that provides improved solubility without the action of chemicals as a means of increasing solubility, eg, to make nanoparticles dispersed in a solvent. It may refer to the use of a supercritical fluid fabrication method.

  “Substantially free” as used herein refers, in some embodiments, to a composition or mixture comprising a single therapeutically active agent. In certain embodiments, “substantially free” is a composition or mixture comprising a single therapeutically active agent that is free of measurable amounts of a second pharmaceutically active agent or treatment. A composition or mixture that does not contain a sufficient amount of a second pharmaceutically active agent to provide activity.

  A “therapeutically effective amount” or “effective amount” is the amount of a pharmaceutical agent that achieves a pharmacological effect. The term “therapeutically effective amount” includes, for example, a prophylactically effective amount. An “effective amount” of a corticosteroid, such as budesonide, is an amount effective to obtain a desired pharmacological effect or therapeutic improvement without undue adverse side effects. An effective amount of a corticosteroid, such as budesonide, is selected by one skilled in the art depending on the specific patient and the disease level. “Effective amount” or “therapeutically effective amount” is a variation in the metabolism of a corticosteroid such as budesonide, the subject's age, weight, general condition, condition being treated, severity of the condition being treated, prescription It will be understood that this may vary from subject to subject and from population to population, depending on the judgment of the attending physician.

  “Treat” or “treatment”, when used in the context of a bronchoconstrictive disorder, may have any treatment of a disorder or disease associated with bronchoconstriction, eg, a predisposition to the disorder or disease, Preventing the onset of the disorder or disease in a subject not yet diagnosed as having the disorder or disease; suppressing the disorder or disease (eg, stopping the development of the disorder or disease), It refers to alleviating the disorder or disease, causing regression of the disorder or disease, alleviating a condition caused by the disease or disorder, or suppressing symptoms of the disease or disorder. Thus, as used herein, the term “treatment” is used interchangeably with the term “prophylaxis or prevention”.

I. An inhalable composition comprising a corticosteroid that results in enhanced pulmonary deposition. An inhalable composition comprising a solubility enhancer capable of providing enhanced pulmonary deposition of corticosteroids is provided. In preferred embodiments, the inhalable compositions described herein may allow for enhanced lung deposition of the delivered corticosteroid compared to conventional inhaled corticosteroid therapy. Furthermore, it may be able to provide, inter alia, means for reducing the dosage required to produce a local therapeutic effect. Similarly, there is provided a method of making microparticles from an inhalable composition comprising adding a solvent and solubility enhancer to an effective amount of a corticosteroid and activating a nebulizer to create the microparticles. In other embodiments, the methods provided herein allow for enhanced pulmonary deposition of delivered corticosteroids compared to conventional therapeutic agents, and more particularly provide local therapeutic effects. Inhalable compositions that provide a means to reduce the dosage required for

  Also provided are methods and systems for the treatment of bronchoconstrictive disorders, such as asthma and / or chronic obstructive pulmonary disease (COPD), which are administered by inhalation in the form of a suspension. Compared to, it may allow delivery of corticosteroids with enhanced pulmonary deposition. Administration by the methods and systems described herein has the following advantages: increased pulmonary deposition of delivered corticosteroids; reduced nominal dosage of corticosteroids required to produce a local therapeutic effect A method for reducing the time required to administer an effective dose of a corticosteroid; to increase patient compliance with a treatment regimen that includes inhalation of nebulized corticosteroids Methods; methods for improving delivery of corticosteroids; methods for increasing the amount of corticosteroids deposited in the lung (eg bronchi and alveoli); or methods for reducing side effects associated with inhalation of corticosteroids Provide one or more of

  Certain embodiments of the invention relate to an inhalable composition comprising an effective amount of a corticosteroid, a solvent, and a solubility enhancer, which composition when administered to a subject via a nebulizer is in a mixture prior to administration. Based on the amount of corticosteroid, at least about 20% to about 55%, about 20% to about 50%, or about 20% to about 40% of intrapulmonary deposition (eg, bronchi and alveoli) is achieved. In certain embodiments, the inhalable composition comprises an effective amount of a single corticosteroid, a solvent and a solubility enhancer and is substantially free of active pharmaceutical agents other than the corticosteroid. In yet other embodiments, the composition can achieve at least about 20% to about 55% lung deposition based on the amount of corticosteroid in the mixture prior to administration. In other embodiments, the composition is such that at least 25% to about 45% lung deposition can be achieved based on the amount of corticosteroid in the mixture prior to administration. In certain embodiments, the composition is one in which at least about 25% lung deposition is achieved based on the amount of corticosteroid in the composition prior to administration. In other embodiments, the composition is one in which at least about 30% lung deposition is achieved based on the amount of corticosteroid in the composition prior to administration. In yet other embodiments, the composition achieves at least about 35% lung deposition based on the amount of corticosteroid in the composition prior to administration. In still other embodiments, the composition achieves at least about 40% lung deposition based on the amount of corticosteroid in the composition prior to administration. In other embodiments, the composition is one in which at least about 45% lung deposition is achieved based on the amount of corticosteroid in the composition prior to administration. In still other embodiments, the composition achieves at least about 55% lung deposition based on the amount of corticosteroid in the composition prior to administration. In one embodiment, the corticosteroid is budesonide. In another embodiment, the corticosteroid is either an individual diastereomer of budesonide or a mixture of two diastereomers of budesonide administered individually or together for therapeutic effect. In certain embodiments, the inhalable composition comprises an effective amount of a single corticosteroid and a solubility enhancer and is substantially free of active pharmaceutical agents other than the corticosteroid. In still other embodiments, the inhalable composition comprises an effective amount of budesonide, a solvent and a solubility enhancer, and is substantially free of active pharmaceutical agents other than budesonide.

  In certain embodiments of the invention, an inhalable composition comprising an effective amount of a corticosteroid, a solvent, and a solubility enhancer that can provide enhanced lung deposition is also at least about 60% when administered. Respirable fractions are achieved. In a more preferred embodiment of the invention, the composition also achieves a respiratory fraction of at least about 70% when administered. In an even more preferred embodiment of the present invention, the composition also achieves a respiratory fraction of at least about 80% when administered. In the most preferred embodiments of the invention, the composition also achieves a respiratory fraction of at least about 85% when administered. In certain embodiments, the inhalable composition comprises an effective amount of a single corticosteroid, a solvent and a solubility enhancer and is substantially free of active pharmaceutical agents other than the corticosteroid.

  In some embodiments of the invention, an inhalable composition comprising an effective amount of a corticosteroid, a solvent, and a solubility enhancer that can provide enhanced lung deposition is a corticosteroid in the pre-dose composition. An amount of about 15 to about 2000 μg of corticosteroid is included. In certain embodiments, the inhalable composition comprises an effective amount of a single corticosteroid, a solvent and a solubility enhancer and is substantially free of active pharmaceutical agents other than the corticosteroid. In other embodiments, an inhalable composition comprising an effective amount of a corticosteroid, a solvent, and a solubility enhancer that can provide enhanced lung deposition comprises an amount of corticosteroid in the pre-dose composition of about 250- Contains about 2000 μg of corticosteroid. In still other embodiments, an inhalable composition comprising an effective amount of a corticosteroid, a solvent, and a solubility enhancer that can provide enhanced pulmonary deposition comprises an amount of corticosteroid in the pre-dose composition of about 60 Contains about 1500 μg of corticosteroid. In yet other embodiments, an inhalable composition comprising an effective amount of a corticosteroid, a solvent, and a solubility enhancer that can provide enhanced pulmonary deposition comprises an amount of corticosteroid in the pre-dose composition of about 100. Contains about 1000 μg corticosteroid. In still other embodiments, an inhalable composition comprising an effective amount of a corticosteroid, a solvent, and a solubility enhancer that can provide enhanced pulmonary deposition comprises an amount of corticosteroid in the pre-dose composition of about 120. Contains about 1000 μg corticosteroid. In still other embodiments, an inhalable composition comprising an effective amount of a corticosteroid, a solvent, and a solubility enhancer that can provide enhanced pulmonary deposition comprises an amount of corticosteroid in the pre-dose composition of about Contains 125 to about 500 μg of corticosteroid. In certain embodiments, an inhalable composition comprising an effective amount of a corticosteroid, a solvent, and a solubility enhancer that can provide enhanced lung deposition comprises an amount of corticosteroid in the pre-dose composition of about 40 μg, About 60 μg, about 100 μg, about 120 μg, about 125 μg, about 240 μg, about 250 μg, about 500 μg, about 1000 μg, about 1500 μg, or about 2000 μg of corticosteroid. In one embodiment, the inhalable composition comprises about 40 μg of corticosteroid in the pre-administration composition. In another embodiment, the inhalable composition comprises a corticosteroid in the pre-dose composition in an amount of about 60 μg. In yet another embodiment, the inhalable composition comprises a corticosteroid amount of about 100 μg of the corticosteroid in the pre-administration composition. In yet another embodiment, the inhalable composition comprises about 120 μg of corticosteroid in the pre-administration composition. In yet another embodiment, the inhalable composition comprises a corticosteroid in the pre-dose composition in an amount of about 125 μg. In yet another embodiment, the inhalable composition comprises a corticosteroid amount of about 240 μg in the pre-dose composition. In yet another embodiment, the inhalable composition comprises a corticosteroid in the pre-administration composition that is less than about 250 μg of corticosteroid. In another embodiment, the inhalable composition comprises a corticosteroid in the pre-dose composition that is less than about 500 μg of corticosteroid. In one embodiment, the corticosteroid is budesonide. In another embodiment, the corticosteroid is either an individual diastereomer of budesonide or a mixture of two diastereomers of budesonide administered individually or together for therapeutic effect. In certain embodiments, the inhalable composition comprises an effective amount of a single corticosteroid and a solubility enhancer and is substantially free of active pharmaceutical agents other than the corticosteroid. In still other embodiments, the inhalable composition comprises an effective amount of budesonide and a solubility enhancer and is substantially free of active pharmaceutical agents other than budesonide.

  In certain embodiments, the inhalable composition comprises about 40 μg budesonide, a solvent and a solubility enhancer, wherein at least 15 μg budesonide intrapulmonary deposition is achieved when administered to a subject via a nebulizer. possible. In other specific embodiments, the inhalable composition comprises about 60 μg budesonide, a solvent and a solubility enhancer, and achieves at least 20 μg budesonide lung deposition when administered to a subject via a nebulizer. Can be a thing. In still other embodiments, the inhalable composition comprises about 120 μg budesonide, a solvent and a solubility enhancer, wherein at least 40 μg budesonide intrapulmonary deposition is achieved when administered to a subject via a nebulizer. It can be. In yet other embodiments, the inhalable composition comprises about 240 μg budesonide, a solvent, and a solubility enhancer, wherein at least 80 μg budesonide intrapulmonary deposition is achieved when administered to a subject via a nebulizer. It can be.

  In certain embodiments, the inhalable composition comprises about 40 μg budesonide, a solvent and a solubility enhancer, and when administered to a subject via a nebulizer, at least 13 μg budesonide is deposited in the lung, other than budesonide Of the active pharmaceutical agent. In other specific embodiments, the inhalable composition comprises about 60 μg budesonide, a solvent and a solubility enhancer, and when administered to a subject via a nebulizer, at least 20 μg budesonide in the lung is achieved; It may be substantially free of active pharmaceutical agents other than budesonide. In still other embodiments, the inhalable composition comprises about 120 μg budesonide, a solvent and a solubility enhancer, and when administered to a subject via a nebulizer, at least 40 μg budesonide is deposited in the lung, and budesonide It may be substantially free of other active pharmaceutical agents. In yet another embodiment, the inhalable composition comprises about 240 μg budesonide, a solvent and a solubility enhancer, and when administered to a subject via a nebulizer, at least 80 μg budesonide is deposited in the lung, and budesonide It may be substantially free of other active pharmaceutical agents.

  In some embodiments, inhalable compositions comprising suitable corticosteroids include, but are not limited to, solutions, dispersions, nanoparticle dispersions, emulsions, colloidal solutions, micelles or mixed micelle solutions, and liposomes. Liquid. In one embodiment, the aqueous inhalation mixture is a solution comprising a corticosteroid such as budesonide and a solubility enhancer. In another embodiment, the aqueous inhalation mixture is a mixed micelle solution comprising a corticosteroid such as budesonide and a solubility enhancer. In yet another embodiment, the aqueous inhalation mixture is a liposome solution comprising a corticosteroid such as budesonide and a solubility enhancer.

  In some embodiments of the invention, inhalable compositions comprising corticosteroids do not include nanodispersions and / or nanosuspensions. In other embodiments, inhalable compositions comprising corticosteroids do not include micelles, mixed micelle fluids or liposome fluids. In still other embodiments, inhalable compositions comprising corticosteroids do not include nanodispersions and / or nanosuspensions, micelles, mixed micelle fluids, or liposome fluids. In other embodiments, inhalable compositions include, but are not limited to, solutions, emulsions, and colloidal fluids. In one embodiment, the inhalable composition is a solution comprising a corticosteroid such as budesonide and a solubility enhancer. In another embodiment, the inhalable composition is an emulsion comprising a corticosteroid such as budesonide and a solubility enhancer.

  Corticosteroids useful in the inhalable compositions described herein include, but are not limited to, aldosterone, beclomethasone, betamethasone, budesonide, ciclesonide, clopredonol, cortisone, cortibazole, deoxycolton, desonide, desoxymeta Zon, dexamethasone, difluorocortron, fluchlorolone, flumethazone, flunisolide, fluocinolone, fluocinonide, fluocortin butyl, fluorocortisone, fluorocortron, fluorometholone, flulandrenolone, fluticasone, halcinonide, hydrocortisone, icomethasone, Prednisone, methylprednisolone, mometasone, parameterzone, prednisolone, prednisone, rofleponide, RPR 106541, thixcortol, triamcinolone, and their respective pharmaceutically acceptable derivatives. In a preferred embodiment, the corticosteroid is budesonide. In other preferred embodiments, the corticosteroid is either an individual diastereomer of budesonide or a mixture of two diastereomers of budesonide administered individually or together for therapeutic effect.

  In some embodiments of the inhalable compositions described herein, the inhalable composition is one that includes a solvent. In certain embodiments, the solvent is selected from the group comprising water, aqueous alcohol, propylene glycol or an aqueous organic solvent. In a preferred embodiment, the solvent is water.

  In other embodiments of the inhalable compositions described herein, the inhalable composition comprises a solubility enhancer. In some embodiments, 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 still other embodiments, the solubility enhancer can have a concentration (w / v) ranging from about 1% to about 10%. In a preferred embodiment, when the solubility enhancer is a cyclodextrin or cyclodextrin derivative such as SBE7-β-CD (Captisol®), the concentration (w / v) ranges from about 2% to about 10%. ). In one embodiment, the solubility enhancer may have a concentration (w / v) of about 2% when it is a cyclodextrin or cyclodextrin derivative, such as SBE7-β-CD (Captisol®). In another embodiment, the solubility enhancer may have a concentration (w / v) of about 5% when it is a cyclodextrin or cyclodextrin derivative, such as SBE7-β-CD (Captisol®). In yet another embodiment, the solubility enhancer can have a concentration (w / v) of about 7% when it is a cyclodextrin or cyclodextrin derivative, such as SBE7-β-CD (Captisol®). . In yet another embodiment, the solubility enhancer has a concentration (w / v) of about 10% when it is a cyclodextrin or cyclodextrin derivative, such as SBE7-β-CD (Captisol®). obtain.

  Chemicals that act as solubility improvers suitable for use in the present invention include, but are not limited to, propylene glycol, nonionic surfactants, phospholipids, cyclodextrins and their derivatives, and surface modifiers and / or stabilizers. Is mentioned. In other embodiments, the solubility enhancer is a formulation method that provides improved solubility without the action of chemicals as a means to increase solubility, e.g., a supercritical fluid for making nanoparticles dispersed in a solvent. This refers to the use of a production method.

  Additional solubility enhancers suitable for use in the inhalable compositions described herein are known in the art, eg, US Pat. Nos. 5,134,127, 5,145,684. Nos. 5,376,645, 6,241,969, and US Patent Application Publication Nos. 2005/0244339 and 2005/0008707, each of which is specifically incorporated herein by reference. Incorporated). Examples of suitable solubility improvers 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), US Pat. No. 5,134,127, ibid. Nos. 5,376,645 and 5,874,418, each of which is specifically incorporated herein by reference. In some embodiments, suitable cyclodextrins or cyclodextrin derivatives for use in the present invention include, but are not limited to, α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, SAE-CD derivatives (eg, , SBE-α-CD, SBE-β-CD, SBE1-β-CD, SBE4-β-CD, SBE7-β-CD (Captisol®) and SBE-γ-CD) (Cydex, Inc. Lenexa) , KS), hydroxyethyl, hydroxypropyl (eg 2- and 3-hydroxypropyl) and dihydroxypropyl ether, its corresponding mixed ether and further mixed ethers with methyl or ethyl groups, such as α-, β- and methyl of γ-cyclodextrin Droxyethyl, ethyl-hydroxyethyl and ethyl-hydroxypropyl ether; and the like, and maltosyl, glucosyl and maltotriosyl derivatives of α-, β- and γ-cyclodextrins (which contain one or more sugar residues such as glucosyl or Diglucosyl, maltosyl or dimaltosyl, as well as various mixtures thereof, which may include, for example, mixtures of maltosyl and dimaltosyl derivatives). Specific cyclodextrin derivatives for use herein include hydroxypropyl-β-cyclodextrin, hydroxyethyl-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, hydroxyethyl-γ-cyclodextrin, dihydroxy Propyl-β-cyclodextrin, glucosyl-α-cyclodextrin, glucosyl-β-cyclodextrin, diglucosyl-β-cyclodextrin, maltosyl-α-cyclodextrin, maltosyl-β-cyclodextrin, maltosyl-γ-cyclodextrin, malto Triosyl-β-cyclodextrin, maltotriosyl-γ-cyclodextrin, dimaltosyl-β-cyclodextrin, diethyl-β-cyclodextrin, glucosyl-α Cyclodextrin, glucosyl-β-cyclodextrin, diglucosyl-β-cyclodextrin, tri-O-methyl-β-cyclodextrin, tri-O-ethyl-β-cyclodextrin, tri-O-butyryl-O-cyclodextrin, Tri-O-valeryl-β-cyclodextrin, and di-O-hexanoyl-β-cyclodextrin, and methyl-β-cyclodextrin, and mixtures thereof, such as maltosyl-β-cyclodextrin / dimaltosyl-β-cyclodextrin Etc. Procedures for preparing such cyclodextrin derivatives are well known, for example, from US Pat. No. 5,024,998 and references incorporated by reference. Other cyclodextrins suitable for use in the present invention include carboxyalkyl thioether derivatives such as ORG 26054 and ORG 25969 (ORGANON (AKZO-NOBEL)), hydroxybutenyl ether derivatives (EASTMAN), sulfoalkyl-hydroxyalkyls Ether derivatives, sulfoalkyl-alkyl ether derivatives, and other derivatives such as US 2002/0128468, 2004/0106575, 2004/0109888 and 2004/0063663, or the United States Patents 6,610,671, 6,479,467, 6,660,804 or 6,509,323 (each of which is specifically described herein for reference) And the like described in the above).

  Hydroxypropyl-β-cyclodextrin is available from Research Diagnostics Inc. (Flanders, NJ). Exemplary hydroxypropyl-β-cyclodextrin products include Encapsin® (degree of substitution about 4) and Molecsol® (degree of substitution about 8); however, implementations involving other degrees of substitution Forms are also available and are within the scope of the present invention.

  Dimethylcyclodextrin is available from FLUKA Chemie (Buchs, CH) or Wacker (Iowa). Other derivatized cyclodextrins suitable for use in the present invention include water soluble derivatized cyclodextrins. Exemplary water-soluble derivatized cyclodextrins include carboxylated derivatives; sulfated derivatives; alkylated derivatives; hydroxyalkylated derivatives; methylated derivatives; and carboxy-β-cyclodextrins (eg, succinyl-β-cyclodextrin ( SCD)). All these materials can be made according to methods known in the art and / or are commercially available. Suitable derivatives of cyclodextrin, Modified Cyclodextrins: Scaffolds and Templates for Supramolecular Chemistry (Edit Christopher J.Easton, Stephen F.Lincoln, Imperial College Press, London, UK, 1999) and New Trends in Cyclodextrins and Derivatives (editing Dominique Duchene , Editions de Sante, Paris, France, 1991).

  Examples of nonionic surfactants that appear to have particularly good physiological compatibility for use in the present invention include tyloxapol, polysorbates such as, but not limited to, polyoxyethylene (20) sorbitan monolaurate, polyoxyethylene (20) sorbitan monopalmitate, polyoxyethylene (20) monostearate (available under the trademark Tween 20-40-60, etc.), Polysorbate 80, Polyethylene glycol 400; sodium lauryl sulfate; sorbitan laurate, sorbitan palmitate, Sorbitan stearate (available under the trademark Span 20-40-60, etc.), benzalkonium chloride, PPO-PEO block copolymer (Pluronics), Cremophor-EL, Bio Tamine E-TPGS (eg, d-α-tocopheryl-polyethylene glycol-1000-succinate), Solutol-HS-15, oleic acid PEO ester, stearic acid PEO ester, Triton-X100, Nonidet P-40, and macrogol hydroxy Stearate (such as macrogol-15-hydroxystearate).

  In some embodiments, nonionic surfactants suitable for use in the present invention are formulated into corticosteroids to form liposome preparations, micelles or mixed micelles. Methods for the preparation and characterization of liposomes and liposome preparations are known in the art. In many cases, when amphiphilic lipids are hydrated, multilamellar vesicles spontaneously form, but the formation of small unilamellar vesicles usually involves processes with significant energy input (eg, Sonication or high-pressure homogenization) is required. Additional methods for the preparation and characterization of liposomes are described, for example, in S.H. Vemuri et al. (Preparation and characterisation of liposomals as therapeutic delivery systems: a review. Pharm Act Helv. 1995, 70 (2): 95-111), U.S. Pat. Nos. 5,882,679 and 6,656,497, each of which is specifically incorporated herein by reference.

  In some cases, for example, micelles or mixed micelles can be formed by a surfactant, in which case a soluble insufficient active agent can be solubilized. In general, 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 because their structure, properties and behavior are very different from solids. The amphiphilic molecules that form micelles are usually associated temporarily. In micellar solutions, there is dynamic molecular exchange between micelle-forming amphiphiles and monomolecularly dispersed amphiphiles (which are also present in the solution). The portion of the drug molecule that is solubilized in such micelles or mixed micelles depends on the structure of these molecules as well as the surfactant used. For example, it is assumed that in particular nonpolar molecules are mainly localized within the colloidal structure, but polar substances are likely to be found on the surface of the structure. In one embodiment of a micellar solution or mixed micelle solution, the average micelle size can be less than about 200 nm (measured by photon correlation spectroscopy), such as from about 10 nm to about 100 nm. Especially preferred are micelles having an average diameter of about 10 nm to about 50 nm. Methods for making micelles and mixed micelles are known in the art, for example, US Pat. Nos. 5,747,066 and 6,906,042, each of which is specifically incorporated herein by reference. Incorporated by reference).

  Phospholipids are defined as amphiphile lipids containing phosphorus. Phospholipids chemically derived from phosphatidic acid are widely present and commonly used for pharmaceutical purposes. This acid is usually a (double) acylated glycerol-3-phosphate, whose fatty acid residues can be of different lengths. Examples of the phosphatidic acid derivative include phosphocholine or phosphatidylcholine (the phosphate group is further esterified with choline), phosphatidylethanolamine, phosphatidylinositol, and the like. Lecithin is a natural mixture of various phospholipids, usually with a high proportion of phosphatidylcholine. Depending on the specific source of lecithin and how it is extracted and / or enriched, such a mixture may also contain significant amounts of sterols, fatty acids, triglycerides and other substances.

  Additional phospholipids suitable for delivery by inhalation due to their physiological properties include in particular lecithin from natural sources (such as soja bean / soy bean or chicken egg yolk), preferably in hydrogenated form. Phospholipid mixtures extracted and / or released from lysolecithin and phospholipids (preferably using saturated fatty acid esters) prepared by purification, enrichment or partial synthesis. Of the phospholipid mixture, lecithin is particularly preferred. Medium to long-chain zwitterionic phospholipids prepared by enrichment or partial synthesis are mainly free of unsaturated bonds in the acyl chain and free of lysolecithin and peroxide. Examples of enriched or pure compounds are dimyristoyl phosphatidylcholine (DMPC), distearoyl phosphatidylcholine (DSPC) and dipalmitoyl phosphatidylcholine (DPPC). Of these, DMPC is more preferred at the present time. Alternatively, phospholipids with oleyl residues and phosphatidylglycerols without choline residues are suitable for some embodiments and applications of the present invention.

  In some embodiments, nonionic surfactants and phospholipids suitable for use in the present invention are incorporated into corticosteroids to form a colloidal structure. A colloidal solution is defined as a single phase system in which the colloidal material dispersed in the colloidal solution does not have the measurable physical properties normally associated with solid materials. Methods for making colloidal dispersions are known in the art and are described, for example, in US Pat. No. 6,653,319, which is specifically incorporated herein by reference. Yes.

Suitable surface modifiers for use in the present invention are known in the art, for example, U.S. Pat. Nos. 5,145,684, 5,510,118, 5,565,188, And 6,264,922, each of which is specifically incorporated herein by reference. Examples of surface modifiers and / or surface stabilizers suitable for use in the present invention include, but are not limited to, hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, sodium lauryl sulfate, dioctyl sulfosuccinate, gelatin, casein, lecithin (Phosphatide), dextran, gum arabic, cholesterol, tragacanth, stearic acid, benzalkonium chloride, calcium stearate, glycerol monostearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan ester, polyoxyethylene alkyl ether (for example , Macrogol ethers such as cetomacrogol 1000), polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid Ester (e.g., the commercially available Tween ^TM, for example, Tween ^{20 TM} and ^{Tween 80 TM (ICI Specialty Chemicals)} ), polyethylene glycols (e.g., Carbowaxs 3550 ^TM and ⁹³⁴ TM (Union Carbide)), polyoxyethylene stearates, colloidal Silicon dioxide, phosphate, carboxymethylcellulose calcium, sodium carboxymethylcellulose, methylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose phthalate, amorphous cellulose, magnesium magnesium silicate, triethanolamine, polyvinyl alcohol (PVA), ethylene oxide and formaldehyde 4- (1,1,3,3-teto Lamethylbutyl) -phenolic polymer (also known as tyloxapol, superion and triton), poloxamers (eg Pluronic F68 ^™ and F108 ^™ , which are block copolymers of ethylene oxide and propylene oxide), poloxamine (eg Tetronic 908 ^™ , Also known as Poloxamine 908 ^™ , which is a tetrafunctional block copolymer derived from the sequential addition of propylene oxide and ethylene oxide to ethylenediamine (BASF Wyandotte Corporation, Parsippany, NJ)), Tetronic 1508 ^™ ( T-1508) (BASF Wyandotte Corporation), Tri tons X-200 ^™ (which is an alkylaryl polyether sulfonate) (Rohm and Haas), Crodestas F-100 ^™ (which is a mixture of sucrose stearate and sucrose distearate) (Croda Inc. ), P-isononylphenoxypoly- (glycidol) (also known as Olin-10G ^™ or Surfactant 10 ^™ ) (Olin Chemicals, Tamford, Conn.), Crodestas SL-40. RTM. (Croda, Inc.), and SA9OHCO (which is C18H37CH2 (CON (CH3) -CH2 (CHOH) 4 (CH2OH) 2) (Eastman Kodak Co.), Decanoyl-N-methylglucamide, n-decyl. -Β-D-glucopyranoside, n-decyl-β-D-maltopyranoside, n-dodecyl-β-D-glucopyranoside, n-dodecyl-β-D-maltoside, heptanoyl-N-methylglucamide, n-heptyl-β -D-glucopyranoside, n-heptyl-β-D-thioglucoside, n-hexyl-β-D-glucopyranoside, nonanoyl-N-methylglucamide, n-noyl-β-D-glucopyranoside, octanoyl-N-methylgluca Mid, n-octyl-β-D-glucopyranoside, octyl β D-thioglucopyranoside, PEG-phospholipid, PEG-cholesterol, PEG-cholesterol derivative, PEG-vitamin A, PEG-vitamin E, lysozyme, random copolymer of vinylpyrrolidone and vinyl acetate, etc. (for example, hydroxypropylmethylcellulose, hydroxypropylcellulose) , Polyvinyl pyrrolidone, vinyl acetate copolymer, vinyl pyrrolidone, sodium lauryl sulfate and dioctyl sodium sulfosuccinate).

Other useful cationic stabilizers include, but are not limited to, cationic lipids, sulfonium, phosphonium and quaternary ammonium compounds such as stearyltrimethylammonium chloride, benzyl-di (2-chloroethyl) ethylammonium bromide, coconut trimethyl Ammonium chloride or bromide, coconut methyl dihydroxyethylammonium chloride or bromide, decyltriethylammonium chloride, decyldimethylhydroxyethylammonium chloride or bromide, C12-15 dimethylhydroxyethylammonium chloride or bromide, coconut dimethylhydroxyethylammonium chloride or bromide, myristyltrimethyl Ammonium methylsulf , Lauryldimethylbenzylammonium chloride or bromide, lauryldimethyl (ethenoxy) 4ammonium chloride or bromide, N-alkyl (C12-18) dimethylbenzylammonium chloride, N-alkyl (C14-18) dimethylbenzylammonium chloride, N- Tetradecylide methylbenzylammonium chloride monohydrate, dimethyldidecylammonium chloride, N-alkyl and (C12-14) dimethyl 1-naphthylmethylammonium chloride, trimethylammonium halide, alkyltrimethylammonium and dialkyldimethylammonium salts, lauryl Trimethylammonium chloride, ethoxylated alkyl (alkyl) amidoalkyldialkyla Monium salt and / or ethoxylated trialkylammonium salt, dialkylbenzenedialkylammonium chloride, N-didecyldimethylammonium chloride, N-tetradecyldimethylbenzylammonium chloride monohydrate, N-alkyl (C12-14) dimethyl 1- Naphtylmethylammonium chloride and dodecyldimethylbenzylammonium chloride, dialkylbenzenealkylammonium chloride, lauryltrimethylammonium chloride, alkylbenzylmethylammonium chloride, alkylbenzyl-dimethylammonium bromide, C12, C15, C17 trimethylammonium bromide, dodecylbenzyl-triethylammonium chloride Poly-diallyldimethyl Ammonium chloride (DADMAC), dimethylammonium chloride, alkyldimethylammonium halide, tricetylmethylammonium chloride, decyltrimethylammonium bromide, dodecyltriethylammonium bromide, tetradecyltrimethylammonium bromide, methyltrioctylammonium chloride (ALLIQUAT 336 ^™ ), POLYQUAT 10 ^TM , tetrabutylammonium bromide, benzyl-trimethylammonium bromide, choline ester (such as choline ester of fatty acid), benzalkonium chloride, stearalkonium chloride compound (such as stearyltrimonium chloride and distearyldimonium chloride), cetyl Pyridinium bromide or chloride, quaternary Halide salts of polyoxyethylalkylamines, Mirapol ^TM and ALKAQUAT ^TM (Alkaril Chemical Company), alkyl pyridinium salts, amines (alkylamines, dialkylamines, alkanolamines, polyethylenepolyamines, N, N-dialkylaminoalkyl acrylates, and vinyl pyridine ), Amine salts (such as laurylamine acetate, stearylamine acetate, alkylpyridinium and alkylimidazolium salts and amine oxides), imidoazolinium salts, protonated quaternary acrylamides, methylated quaternary polymers (poly [ Diallyldimethylammonium chloride] and poly- [N-methylvinylpyridinium chloride]), and Cationic guar and the like can be mentioned.

  In certain embodiments, the inhalable composition of the present invention comprises propylene glycol, nonionic surfactant, tyloxapol, polysorbate 80, vitamin E-TPGS, macrogol-15-hydroxystearate, phospholipid, lecithin, purified And / or enriched lecithin, phosphatidylcholine fraction extracted from lecithin, dimyristoylphosphatidylcholine (DMPC), dipalmitoylphosphatidylcholine (DPPC), distearoylphosphatidylcholine (DSPC), cyclodextrin and its derivatives, SAE-CD derivatives, SBE- α-CD, SBE-β-CD, SBE1-β-CD, SBE4-β-CD, SBE7-β-CD (Captisol (registered trademark)), SBE-γ-CD, dimethyl β-CD, hydroxy Lopyl-β-cyclodextrin, 2-HP-β-CD, hydroxyethyl-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, hydroxyethyl-γ-cyclodextrin, dihydroxypropyl-β-cyclodextrin, glucosyl-α -Cyclodextrin, glucosyl-β-cyclodextrin, diglucosyl-β-cyclodextrin, maltosyl-α-cyclodextrin, maltosyl-β-cyclodextrin, maltosyl-γ-cyclodextrin, maltotriosyl-β-cyclodextrin, maltotrio Sil-γ-cyclodextrin, dimaltosyl-β-cyclodextrin, methyl-β-cyclodextrin, carboxyalkyl thioether derivative, ORG 26054, ORG 25969, A solubility enhancer selected from the group consisting of droxypropylmethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, vinyl acetate copolymer, vinylpyrrolidone, sodium lauryl sulfate, dioctyl sodium sulfosuccinate, and combinations thereof. In certain embodiments, the solubility enhancer is SBE7-β-CD (Captisol®).

  In another specific embodiment, the inhalable composition of the invention comprises cyclodextrin and its derivatives, SAE-CD derivatives, SBE-α-CD, SBE-β-CD, SBE1-β-CD, SBE4-β. -CD, SBE7-β-CD (Captisol®), SBE-γ-CD, dimethyl β-CD, hydroxypropyl-β-cyclodextrin, 2-HP-β-CD, hydroxyethyl-β-cyclodextrin , Hydroxypropyl-γ-cyclodextrin, hydroxyethyl-γ-cyclodextrin, dihydroxypropyl-β-cyclodextrin, glucosyl-α-cyclodextrin, glucosyl-β-cyclodextrin, diglucosyl-β-cyclodextrin, maltosyl-α- Cyclodextrin, maltosyl-β-si Improved solubility selected from the group consisting of rhodextrin, maltosyl-γ-cyclodextrin, maltotriosyl-β-cyclodextrin, maltotriosyl-γ-cyclodextrin, dimaltosyl-β-cyclodextrin, methyl-β-cyclodextrin Contains agents. In certain embodiments, the solubility enhancer is SBE7-β-CD (Captisol®).

  In addition to an aqueous inhalation mixture or inhalable composition comprising a corticosteroid and a solubility enhancer, herein, in certain embodiments, an aqueous inhalation mixture or composition formulated by a method that provides improved solubility is provided. Similarly, it is envisaged that it is suitable for use in the invention disclosed herein. Thus, in the context of the present invention, a “solubility enhancer” includes an aqueous inhalation mixture formulated by a method that provides improved solubility with or without a chemical acting as a solubility enhancer. . An example of such a method is the preparation of a supercritical fluid. By such a method, corticosteroid compositions such as budesonide are processed into particles with a narrow particle size distribution (usually less than 200 nanometers wide) and an average hydrodynamic radius of the particles in the range of 50 nanometers to 700 nanometers. Is done. Nano-sized corticosteroid particles (such as budesonide particles) may be used in supercritical fluids (SCF) processes, such as rapid expansion of supercritical solutions (RESS), or supercritical fluid solutions. Processed using Solution Enhanced Dispersion of Supercritical fluids (SEDS), as well as any other technique involving supercritical fluids. The use of the SCF process to form particles is described in Parakodity, S .; Et al., Pharmaceutical Research 16: 976-985 (1999), and Bandi et al., Eur. J. et al. Pharm. Sci. 23: 159-168 (2004), US Pat. No. 6,576,264 and US Patent Application Publication No. 2003/0091513, each of which is specifically incorporated herein by reference. Yes. These methods allow the formation of micron and submicron sized particles having different morphologies depending on the method and parameters selected. Such nanoparticles can also be processed by spray drying, freeze drying, volume exclusion, and any other conventional particle reduction method.

  Furthermore, the desired form (e.g., amorphous, crystalline, segmented) can be achieved by appropriately adjusting the conditions of particle formation during precipitation or condensation by the method of producing nanometer sized particles (e.g., SCF). Racemate) may be possible. As a result of the selection of the desired particle form, sustained release of the selected medicament can be achieved. Using such a particle processing process, nanoparticulate material having high purity, low surface imperfection, low surface charge and low sedimentation rate is obtained. Due to the characteristics of the particles, adhesion and aggregation of the particles are suppressed, and sedimentation in the liquid dispersion is prevented. In addition, in processes such as SCF, certain pharmaceutical isomers can be separated, and such separation can contribute to enhanced activity, efficacy and extreme dose reduction of the pharmaceutical. In some cases, the separation of isomers also contributes to the reduction of side effects. With the method and system of the present invention, the aqueous inhalation mixture can be a composition processed into a powder form by any process, such as direct SCF in the recovery medium, spray drying, precipitation and volume exclusion, and thus The particulate compound is automatically made into a dispersion formulation. In some embodiments, this formulation may be the final formulation.

  In another embodiment of the invention, the inhalable composition further comprises the group consisting of a β2-adrenergic receptor agonist, a dopamine (D2) receptor agonist, an anticholinergic agent and a prophylactic therapeutic agent. It may comprise a second therapeutic agent of choice. In some embodiments of the invention, the second therapeutic agent is a β2-adrenergic receptor agonist selected from the group comprising albuterol, levalbuterol or a pharmaceutically acceptable derivative thereof. .

Β2-adrenergic receptor agonists for use in the inhalable compositions provided herein include, but are not limited to, albuterol (α-1-(((1,1-dimethylethyl) amino ) Methyl) -4-hydroxy-1,3-benzenedimethanol); bambuterol (5- (2-((1,1-dimethylethyl) amino) -1-hydroxyethyl) -1,3-phenylene dimethylcarbamate Ester); bitolterol (4-methylbenzoic acid 4- (2-((1,1-dimethylethyl) amino) -1-hydroxyethyl) -1,2-phenylene ester); broxaterol (3-bromo-α- ( ((1,1-dimethylethyl) amino) methyl) -5-isoxazolemethanol); isoproterenol (4- (1-hydro Cis-2-((1-methylethyl-) amino) ethyl) -1,2-benzene-diol); trimethquinol (1,2,3,4-tetrahydro-1-((3,4,5) -Trimethoxyphenyl) -methyl) -6,7-isoquinolinediol); clenbuterol (4-amino-3,5-dichloro-α-(((1,1-dimethyl (ethyldimethyl) ethyl) amino) methyl) benzenemethanol ); Fenoterol (5- (1-hydroxy-2-((2- (4-hydroxyphenyl) -1-methylethyl) amino) ethyl) -1,3-benzenediol); formoterol (2-hydroxy-5) -((L RS) -1-hydroxy-2-(((l RS) -2- (p-methoxyphenyl) -1-methylethyl) amino) ethyl) formanilide (R, R) -formoterol; Desformoterol ((R, R) or (S, S) -3-amino-4-hydroxy-α-(((2- (4-methoxyphenyl) -1- Methyl-ethyl) amino) methyl) benzenemethanol); hexoprenaline (4,4 '-(1,6-hexane-diyl) -bis (imino (1-hydroxy-2,1-ethanediyl))) bis-1,2 -Benzenediol); isoetarine (4- (1-hydroxy-2-((1-methylethyl) amino) butyl) -1,2-benzenediol); isoprenaline (4- (1-hydroxy-2-((1 -Methylethyl) amino) ethyl) -1,2-benzenediol); meta-proterenol (5- (1-hydroxy-2-((1-methylethyl) amino) ethyl) -1, -Benzenediol (d-iol)); picmeterol (4-amino-3,5-dichloro-α-(((6- (2- (2-pyridinyl) ethoxy) hexyl) -amino) methyl) benzenemethanol); Pyrbuterol (α-6-(((1,1-dimethylethyl) -amino) methyl) -3-hydroxy-2,6-pyridinemethanol); procaterol (((R ^* , S ^* )-(+-)- 8-hydroxy-5- (1-hydroxy-2-((1-methylethyl) amino) butyl) -2 (1H) quinolin-one); reproterol ((7- (3-((2- (3,5 -Dihydroxyphenyl) -2-hydroxyethyl) amino) -propyl) -3,7-dihydro-1,3-dimethyl-1H-purine-2,6-dione); limiterol (4- (hydroxy) -2-piperidinylmethyl) -1,2-benzenediol); salbutamol ((+-)-α-1-(((1,1-dimethylethyl) amino) methyl) -4-hydroxy-1,3 (Benzene) dimethanol); (R) -salbutamol; salmeterol ((+-)-4-hydroxy-α-1-(((6- (4-phenylbutoxy) hexyl) -amino) methyl) -1,3-benzenedimethanol); (R) -salmeterol; terbutaline (5- (2-((1,1-dimethylethyl) amino) -1-hydroxyethyl) -1,3-benzenediol); tubuterol (2-chloro-α-(((1,1-dimethylethyl) amino) methyl) benzenemethanol); and TA-2005 (8-hydroxy-5-((1R) 1-hydroxy -2- (N - ((1R) -2- (4- methoxyphenyl) -1-methylethyl) amino) ethyl) carbostyril hydrochloride) and the like.

  Albuterol sulfate α1 [(tert-butylamino) methyl] -4-hydroxy-m-xylene-α, α′-diol sulfate (2: 1) (salt) has the chemical formula (C13H21NO3) 2 · H2SO4. It is a relatively selective β2-adrenergic bronchodilator. Albuterol inhalation aerosols are indicated for the prevention and alleviation of bronchospasm in patients over 4 years of age with reversible obstructive airway disease and for prevention of exercise-induced bronchospasm in patients over 4 years of age. Albuterol inhalation solution is indicated for the relief of bronchospasm in patients over 2 years old with reversible obstructive airway disease and acute seizures of bronchospasm.

  (R) -a1-[[(1,1-dimethylethyl) amino] methyl] -4-hydroxy-1,3-benzenedimethanol hydrochloride, which is levalbuterol HCl, has the chemical formula C13H21NO3 · HCl, It is a relatively selective β2-adrenergic receptor agonist and the (R) -enantiomer of the drug albuterol. Xopenex (Levalbuterol HCl) Inhalation Solution is supplied in unit dose vials and does not require dilution prior to nebulization. Each 3 mL unit dosage vial is either 0.63 mg levalbuterol (as 0.73 mg levalbuterol HCl) or 1.25 mg levalbuterol (as 1.44 mg levalbuterol HCl). Sodium chloride for adjusting the degree, and sulfuric acid for adjusting 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 with reversible obstructive airway disease and adolescents aged 12 years and older.

  Dopamine (D2) receptor agonists include, but are not limited to, apomorphine ((r) 5,6,6a, 7-tetrahydro-6-methyl-4H-dibenzo [de, gluquinoline-10,11-diol) ); Bromocriptine ((5′.α.)-2-bromo-12′-hydroxy-2 ′-(1-methylethyl) -5 ′-(2-methylpropyl) ergotaman-3 ′, 6 ′, 18- Trion); cabergoline ((8-β) -N- (3- (dimethylamino) propyl) -N-((ethylamino) carbonyl-1) -6- (2-propenyl) ergoline-8-carboxamide); lisuride (N ′-((8-α-)-9,10-didehydro-6-methylergolin-8-yl) -N, N-diethylurea); pergolide ((8-β-) 8-((methylthio) methyl) -6-propylergoline); levodopa (3-hydroxy-L-tyrosine); pramipexole ((s) -4,5,6,7-tetrahydro-N6-propyl-2,6 -Benzothiazolediamine); quinpirole hydrochloride (trans-(-)-4aR-4,4a, 5,6,7,8,8a, 9-octahydro-5-propyl-1H-pyrazolo [3,4-g] Quinoline hydrochloride); ropinirole (4- (2- (dipropylamino) ethyl) -1,3-dihydro-2H-indol-2-one); and talipexol (5,6,7,8-tetrahydro-6- (2-propenyl) -4H-thiazolo [4,5-d] azepin-2-amine). Other dopamine D2 receptor agonists for use herein are disclosed in International Patent Application Publication No. WO 99/36095, the relevant disclosures of which are hereby incorporated by reference.

  Anti-cholinergic agents for use herein include, but are not limited to, ipratropium bromide, oxitropium bromide, methyl atropine nitrate, atropine methyl sulfate, ipratropium, belladonna extract, scopolamine, scopolamine methobromide (scopolamine method) ), Homatropine metobromide, hyoscyamine, isopriopramide, orphenadrine, benzalkonium chloride, tiotropium bromide and glycopyrronium bromide.

  Other active ingredients for use in the inhalable compositions described herein include, but are not limited to, IL-5 inhibitors such as US Pat. Nos. 5,668,110, 5,683, No. 983, No. 5,677,280, No. 6,071,910, and No. 5,654,276, each of which is incorporated herein by reference. IL-5 antisense modulators such as those disclosed in US Pat. No. 6,136,603 (the relevant disclosure of which is incorporated herein by reference); milrinone (1,6 -Dihydro-2-methyl-6-oxo- [3,4'-bipyridine] -5-carbonitrile); milrinone lactate; tryptase inhibitors such as US Pat. No. 5,525,623 Are disclosed herein); tachykinin receptor antagonists such as US Pat. Nos. 5,691,336, 5,877,191, 5,929. , 094, 5,750,549 and 5,780,467, each of which is incorporated herein by reference; leukotriene receptor antagonists such as Montelukast sodium (Singular, R- (E)]-1-[[[1- [3- [2- (7-chloro-2-quinolinyl) ethenyl] -phenyl] -3- [2- (I-hydroxy -1-methylethyl) -phenyl] -propyl] -thio] -methyl] cyclopropaneacetic acid, monosodium salt), such as 5-lipoxygenase inhibitors such as zileuton (Zy lo®, Abbott Laboratories, Abbott Park, IL) and the like, and anti-IgE antibodies such as Xolair (recombinant humanized anti-IgE monoclonal antibody (CGP 51901; IGE 025A; rhuMAb-E25), Genentech, Inc., South San Francisco, CA), and surface anesthetics such as lidocaine, N-arylamides, aminoalkylbenzoates, prilocaine, etidocaine, etc. (US Pat. Nos. 5,510,339, 5,631,267, and the like) No. 5,837,713 (the relevant disclosure of which is incorporated herein by reference).

  In some embodiments of the invention, the inhalable composition is administered to the patient no more than once a day. In other embodiments, the inhalable composition is administered to the patient no more than twice a day. In some embodiments of the invention, the composition is administered to the patient twice a day or more than twice a day. In yet other embodiments, the inhalable composition is administered to the patient no more than once a day in the evening.

  Another aspect of the invention is an inhalable composition comprising an effective amount of a corticosteroid, a solvent and a solubility enhancer, comprising an inhalable suspension comprising the corticosteroid administered under the same conditions In comparison, it relates to an inhalable composition in which a higher respiratory fraction is achieved. In certain embodiments, an inhalable composition comprising an effective amount of a corticosteroid, a solvent and a solubility enhancer is substantially free of active pharmaceutical agents other than corticosteroids. In a preferred embodiment of the invention, the inhalable composition achieves a respiratory fraction that is at least about 10% higher compared to an inhalable suspension comprising a corticosteroid administered under the same conditions. Is. In a more preferred embodiment of the invention, the inhalable composition achieves a respirable fraction that is at least about 15% higher compared to an inhalable suspension comprising a corticosteroid administered under the same conditions. Is. In a most preferred embodiment of the invention, the inhalable composition achieves a respirable fraction that is at least about 20% higher compared to an inhalable suspension comprising a corticosteroid administered under the same conditions. Is.

  In certain embodiments, an inhalable composition described herein comprising an effective amount of a corticosteroid, a solvent and a solubility enhancer comprises an inhalable suspension comprising a corticosteroid administered under the same conditions. A lung deposition that is at least about 5% higher than that of the product is achieved. In other embodiments, the inhalable composition is one that achieves at least about 10% higher lung deposition than an inhalable suspension comprising a corticosteroid administered under the same conditions. . In still other embodiments, the inhalable composition is one that achieves at least about 15% higher lung deposition compared to an inhalable suspension comprising a corticosteroid administered under the same conditions. is there. In yet other embodiments, the inhalable composition is one that achieves at least about 20% higher lung deposition compared to an inhalable suspension comprising a corticosteroid administered under the same conditions. is there. In yet another embodiment, the inhalable composition achieves at least about 25% higher lung deposition compared to an inhalable suspension comprising a corticosteroid administered under the same conditions. It is. In certain embodiments, an inhalable composition comprising an effective amount of a corticosteroid, a solvent and a solubility enhancer is substantially free of active pharmaceutical agents other than corticosteroids.

  In some embodiments of the invention, an inhalable composition comprising an effective amount of a corticosteroid, a solvent and a solubility enhancer is administered when administered at a nominal dosage less than an inhalable suspension. Compared to inhalable suspensions containing costeroids, approximately the same corticosteroid pulmonary deposition is achieved. In some embodiments of the invention, an inhalable composition, when administered at a nominal dosage less than an inhalable suspension, compared to an inhalable suspension comprising a corticosteroid, About 90% to 110% corticosteroid intrapulmonary deposition is achieved. In some embodiments of the invention, an inhalable composition, when administered at a nominal dosage less than an inhalable suspension, compared to an inhalable suspension comprising a corticosteroid, About 80% to 120% of corticosteroid intrapulmonary deposition is achieved. In some embodiments of the invention, an inhalable composition, when administered at a nominal dosage less than an inhalable suspension, compared to an inhalable suspension comprising a corticosteroid, About 70% to 130% of corticosteroid intrapulmonary deposition is achieved. In certain embodiments, an inhalable composition comprising an effective amount of a corticosteroid, a solvent and a solubility enhancer is substantially free of active pharmaceutical agents other than corticosteroids.

  In other embodiments of the invention, an inhalable composition comprising an effective amount of a corticosteroid, a solvent and a solubility enhancer also comprises an inhalable suspension comprising the corticosteroid administered under the same conditions. In comparison, a fine particle fraction of at least about 10% higher is achieved. In a more preferred embodiment of the invention, the inhalable composition also achieves a particulate fraction that is at least about 15% higher compared to an inhalable suspension comprising a corticosteroid administered under the same conditions. Is. In a most preferred embodiment of the invention, the inhalable composition achieves a particulate fraction that is at least about 20% higher than an inhalable suspension comprising a corticosteroid administered under the same conditions. Is. In certain embodiments, an inhalable composition comprising an effective amount of a corticosteroid, a solvent and a solubility enhancer is substantially free of active pharmaceutical agents other than corticosteroids.

  In certain embodiments, the compositions of the invention can also be administered using a pressurized metered dose inhaler (pMDI). A typical pMDI includes a propellant, a surfactant, and a drug in dissolved or suspended form. The device is portable and inexpensive and is designed to provide a constant volume whenever the drug is protected from light, oxygen or (of) moisture and administered. After complete propellant evaporation, a small spray particle size can be achieved. Using a more volatile propellant (evaporates faster), smaller particle sizes can be obtained. The most common technical challenge is the solubility of the drug in the propellant. Accordingly, the solubility enhancer of the present invention provides methods and systems for the effective administration of corticosteroids, β2-adrenergic receptor agonists or combinations thereof using MDI.

  In some embodiments of the invention, the nebulizer is a jet nebulizer, an ultrasonic nebulizer, a pulsating membrane nebulizer, a nebulizer having a vibrating mesh or plate with multiple holes, or a nebulizer comprising a vibration generator and an aqueous chamber. . In some embodiments of the present invention, the nebulizer is a Pari LC Jet Plus, Intertech, Baxter Misty-Neb, Hudson T-Updraft II, Hudson Ava-Neb, Ailos, Pari LCJet, DeVilbisNs, DeVilbisNs, DeVilbisPs. Neb (B), Hudson T-Updraft Neb-U-Mist, Pari-Jet 1460, and AeroTech with T-piece. In another particular embodiment, the nebulizer is a Pari eFlow nebulizer.

  In still other embodiments, the inhalable compositions of the invention are delivered in a significantly shorter time than conventional inhaled corticosteroid therapy. For example, the nebulization time of Pulmicort® Respules administered by a Pari LC Plus jet nebulizer typically takes at least 5-8 minutes and in some cases exceeds 10 minutes. In contrast, inhalable compositions comprising corticosteroids such as budesonide are not limited to a particular administration time, but in preferred embodiments are administered at a delivery time of less than about 5 minutes to less than about 1.5 minutes. obtain. In some embodiments, the delivery time can be about 5 minutes. In other embodiments, the delivery time can be less than about 5 minutes. In certain embodiments, the delivery time can be about 4.5 minutes. In other specific 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 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 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 specific 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 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.

  Another aspect of the invention relates to an inhalable composition comprising albuterol and a solubility enhancer, wherein enhanced lung deposition is achieved as compared to albuterol administered under the same conditions. One aspect of the present invention also relates to an inhalable composition comprising albuterol and a solubility enhancer, wherein an improved pharmacokinetic profile is achieved as compared to albuterol administered under the same conditions. . Also, one aspect of the present invention is an inhalable comprising an effective amount of albuterol comprising activating a Pari eFlow nebulizer and causing administration of albuterol in the lung when administered to a patient. The present invention relates to a method for producing fine particles from a composition. Also, another aspect of the present invention is an inhalation comprising an effective amount of albuterol, comprising activating a Pari eFlow nebulizer and causing an improvement in the albuterol pharmacokinetic profile when administered to a patient. The present invention relates to a method for producing fine particles from a possible composition. In some embodiments of the invention, the inhalable composition comprises a corticosteroid.

II. Another aspect of the invention relates to an inhalable composition comprising a corticosteroid, a solvent and a solubility enhancer that results in a decrease in the increase in the concentration of corticosteroid in the device. The composition has a corticosteroid concentration within the device of no more than about 5 μg / ml / min over administration of the corticosteroid via the device upon administration of the composition to the subject via the device. Achieve increasing speed. In certain embodiments, the composition is such that an increasing rate of corticosteroid concentration in the device of about 5 μg / ml / min or less is achieved over the first 3 minutes of administration. In another specific embodiment, the composition is such that a rate of increase of corticosteroid concentration in the device of about 3.5 μg / ml / min or less is achieved over the first 3 minutes of administration. In certain embodiments, the inhalable composition comprises no more than about 500 μg corticosteroid. In other specific embodiments, the inhalable composition comprises no more than about 250 μg corticosteroid. In other embodiments, the inhalable composition comprises no more than about 240 μg corticosteroid. In yet other embodiments, the inhalable composition comprises no more than about 120 μg of corticosteroid. In still other embodiments, the inhalable composition comprises no more than about 60 μg corticosteroid. In still other embodiments, the inhalable composition comprises no more than about 40 μg corticosteroid. In one embodiment, the corticosteroid is budesonide. In another embodiment, the corticosteroid is either an individual diastereomer of budesonide or a mixture of two diastereomers of budesonide administered individually or together for therapeutic effect. In certain embodiments, the inhalable composition comprises an effective amount of a single corticosteroid, a solvent and a solubility enhancer, and is substantially free of active pharmaceutical agents other than the corticosteroid. In still other embodiments, the inhalable composition comprises an effective amount of budesonide, a solvent and a solubility enhancer, and is substantially free of active pharmaceutical agents other than budesonide.

  In other specific embodiments, an inhalable composition comprising a corticosteroid, a solvent and a solubility enhancer has a rate of increase of corticosteroid concentration in the device of about 5% / min or less at the first 3 doses of administration. Is achieved over a period of minutes. In some embodiments of the invention, the corticosteroid is budesonide or a pharmaceutically acceptable derivative. In other specific embodiments, an inhalable composition comprising an effective amount of a corticosteroid, a solvent and a solubility enhancer is substantially free of active pharmaceutical agents other than the corticosteroid.

  In other specific embodiments, the inhalable composition comprises an effective amount of a corticosteroid, a solvent and a solubility enhancer, upon administration of the composition to a subject via a device. Within about 60% or less of the rate of increase of corticosteroid concentration in the device achieved by an inhalable suspension comprising the corticosteroid without a solubility enhancer administered under the same conditions The rate of increase of corticosteroid concentration is achieved.

  In one embodiment, the rate of increase of corticosteroid concentration in the device is achieved over the first 3 minutes of administration. In another embodiment, the rate of increase of corticosteroid concentration in the device is achieved during the second and third 1 minute of administration. In yet another embodiment, the rate of increase of corticosteroid concentration in the device is achieved during the third minute of administration. In certain embodiments, an inhalable composition comprising an effective amount of a corticosteroid, a solvent and a solubility enhancer is substantially free of active pharmaceutical agents other than corticosteroids. In some embodiments of the invention, the corticosteroid is budesonide or a pharmaceutically acceptable derivative.

  In one embodiment, the invention relates to an inhalable composition wherein administration of the composition through the device is achieved over 5 minutes and administration of the inhalable suspension is achieved over 5 minutes. In another embodiment, the invention relates to an inhalable composition wherein the administration time of the composition through the device and the administration time of the inhalable suspension are the same. In yet another embodiment, the invention relates to an inhalable composition wherein the administration time of the composition through the device differs from the administration time of the inhalable suspension.

  In one preferred embodiment of the invention, the composition also achieves a respiratory fraction of at least about 60% when administered. In a more preferred embodiment of the invention, the composition also achieves a respiratory fraction of at least about 70% when administered. In an even more preferred embodiment of the present invention, the composition also achieves a respiratory fraction of at least about 80% when administered. In the most preferred embodiments of the invention, the composition also achieves a respiratory fraction of at least about 85% when administered.

  In some embodiments of the invention, an inhalable comprising a corticosteroid, a solvent and a solubility enhancer that can achieve a rate of increase of the corticosteroid concentration in the device of about 5 μg / ml / min or less at the time of administration. The composition composition contains about 15 to about 500 μg of corticosteroid. In other embodiments, the inhalable composition comprises about 50 to about 500 μg of corticosteroid. In still other embodiments, the inhalable composition comprises about 60 to about 250 μg of corticosteroid. In still other embodiments, the composition comprises about 125 to about 500 μg of corticosteroid. In certain embodiments, the inhalable composition comprises about 40 μg, 60 μg, 120 μg, 125 μg, 240 μg, 250 μg, 500 μg, 1000 μg, 1500 μg or 2000 μg of corticosteroid. In one embodiment, the inhalable composition comprises a nominal dosage of about 40 μg of corticosteroid. In another embodiment, the inhalable composition comprises a nominal dosage of about 60 μg of corticosteroid. In yet another embodiment, the inhalable composition comprises a nominal dosage of about 100 μg of corticosteroid. In yet another embodiment, the inhalable composition comprises a nominal dosage of about 120 μg of corticosteroid. In yet another embodiment, the inhalable composition comprises a nominal dosage of about 125 μg of corticosteroid. In yet another embodiment, the inhalable composition comprises a nominal dosage of about 240 μg of corticosteroid. In yet another embodiment, the inhalable composition comprises a nominal dosage of less than about 250 μg of corticosteroid. In one embodiment, the corticosteroid is budesonide. In another embodiment, the corticosteroid is either an individual diastereomer of budesonide or a mixture of two diastereomers of budesonide administered individually or together for therapeutic effect. In certain embodiments, the inhalable composition comprises an effective amount of a single corticosteroid, a solvent and a solubility enhancer and is substantially free of active pharmaceutical agents other than the corticosteroid. In still other embodiments, the inhalable composition comprises an effective amount of budesonide, a solvent and a solubility enhancer, and is substantially free of active pharmaceutical agents other than budesonide.

  In some embodiments, inhalable compositions comprising suitable corticosteroids include, but are not limited to, solutions, dispersions, nanodispersions, emulsions, colloidal liquids, micelles or mixed micelle solutions, and liposome liquids. Can be mentioned. In one embodiment, the aqueous inhalation mixture is a solution comprising a corticosteroid such as budesonide and a solubility enhancer. In another embodiment, the aqueous inhalation mixture is a mixed micelle solution comprising a corticosteroid such as budesonide and a solubility enhancer. In yet another embodiment, the aqueous inhalation mixture is a liposome solution comprising a corticosteroid such as budesonide and a solubility enhancer.

  In some embodiments of the invention, inhalable compositions comprising corticosteroids do not include nanodispersions and / or nanosuspensions. In other embodiments, inhalable compositions comprising corticosteroids do not include micelles, mixed micelle fluids or liposome fluids. In still other embodiments, inhalable compositions comprising corticosteroids do not include nanodispersions and / or nanosuspensions, micelles, mixed micelle fluids, or liposome fluids. In other embodiments, inhalable compositions include, but are not limited to, solutions, emulsions and colloidal liquids. In one embodiment, the inhalable composition is a solution comprising a corticosteroid such as budesonide and a solubility enhancer. In another embodiment, the inhalable composition is an emulsion comprising a corticosteroid such as budesonide and a solubility enhancer.

  Corticosteroids useful in the inhalable compositions described herein include, but are not limited to, aldosterone, beclomethasone, betamethasone, budesonide, ciclesonide, clopredonol, cortisone, cortibazole, deoxycolton, desonide, desoxymeta Zon, dexamethasone, difluorocortron, fluchlorolone, flumethasone, flunisolide, fluocinolone, fluocinonide, fluocortin butyl, fluorocortisone, fluorocortron, fluorometholone, flulandrenolone, fluticasone, halcinonide, hydrocortisone, icomethasone, meprednisone, methyl Prednisolone, mometasone, parameterzone, prednisolone, prednisone, rofleponide, RPR 106541, thixocort Le, triamcinolone and derivatives of these may be the respective pharmaceutically acceptable thereof. In a preferred embodiment, the corticosteroid is budesonide. In other preferred embodiments, the corticosteroid is either an individual diastereomer of budesonide or a mixture of two diastereomers of budesonide administered individually or together for therapeutic effect.

  In certain embodiments, the systems and methods described herein include a solvent. In certain embodiments, the solvent is selected from the group consisting of water, water / ethanol mixtures, aqueous alcohols, propylene glycol or aqueous organic solvents, or combinations thereof. In certain embodiments, the solvent comprises water. In a preferred embodiment, the solvent is water.

  In other embodiments of the inhalable compositions described herein, the inhalable composition comprises a solubility enhancer. In some embodiments, 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 still other embodiments, the solubility enhancer can have a concentration (w / v) ranging from about 1% to about 10%. In a preferred embodiment, when the solubility enhancer is a cyclodextrin or cyclodextrin derivative such as SBE7-β-CD (Captisol®), the concentration (w / v) ranges from about 2% to about 10%. ). In one embodiment, the solubility enhancer may have a concentration (w / v) of about 2% when it is a cyclodextrin or cyclodextrin derivative, such as SBE7-β-CD (Captisol®). In another embodiment, the solubility enhancer may have a concentration (w / v) of about 5% when it is a cyclodextrin or cyclodextrin derivative, such as SBE7-β-CD (Captisol®). In yet another embodiment, the solubility enhancer can have a concentration (w / v) of about 7% when it is a cyclodextrin or cyclodextrin derivative, such as SBE7-β-CD (Captisol®). . In yet another embodiment, the solubility enhancer has a concentration (w / v) of about 10% when it is a cyclodextrin or cyclodextrin derivative, such as SBE7-β-CD (Captisol®). obtain.

  Chemicals that act as solubility improvers suitable for use in the present invention include, but are not limited to, propylene glycol, nonionic surfactants, phospholipids, cyclodextrins and their derivatives, and surface modifiers and / or stabilizers. Is mentioned. In other embodiments, the solubility enhancer is a formulation method that provides improved solubility without the action of chemicals as a means to increase solubility, e.g., a supercritical fluid for making nanoparticles dispersed in a solvent. This refers to the use of a production method.

  Additional solubility enhancers suitable for use in the inhalable compositions described herein are known in the art, eg, US Pat. Nos. 5,134,127, 5,145,684. Nos. 5,376,645, 6,241,969, and US Patent Application Publication Nos. 2005/0244339 and 2005/0008707, each of which is specifically incorporated herein by reference. Incorporated). Examples of suitable solubility improvers 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), US Pat. No. 5,134,127, ibid. Nos. 5,376,645 and 5,874,418, each of which is specifically incorporated herein by reference. In some embodiments, suitable cyclodextrins or cyclodextrin derivatives for use in the present invention include, but are not limited to:
α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, SAE-CD derivatives (for example, SBE-α-CD, SBE-β-CD, SBE1-β-CD, SBE4-β-CD, SBE7-β- CD (Captisol®), and SBE-γ-CD) (Cydex, Inc. Lenexa, KS), hydroxyethyl, hydroxypropyl (eg, 2- and 3-hydroxypropyl) and dihydroxypropyl ether, their corresponding Mixed ethers and further mixed ethers with methyl or ethyl groups, such as methyl hydroxyethyl, ethyl-hydroxyethyl and ethyl-hydroxypropyl ethers of α-, β- and γ-cyclodextrins; and α-, β- and γ-cyclodextri Of maltosyl, glucosyl and maltotriosyl derivatives of one or more sugar residues, such as glucosyl or diglucosyl, maltosyl or dimaltosyl, and various mixtures thereof, such as mixtures of maltosyl and dimaltosyl derivatives Possible). Specific cyclodextrin derivatives for use herein include hydroxypropyl-β-cyclodextrin, hydroxyethyl-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, hydroxyethyl-γ-cyclodextrin, dihydroxy Propyl-β-cyclodextrin, glucosyl-α-cyclodextrin, glucosyl-β-cyclodextrin, diglucosyl-β-cyclodextrin, maltosyl-α-cyclodextrin, maltosyl-β-cyclodextrin, maltosyl-γ-cyclodextrin, malto Triosyl-β-cyclodextrin, maltotriosyl-γ-cyclodextrin, dimaltosyl-β-cyclodextrin, diethyl-β-cyclodextrin, glucosyl-α Cyclodextrin, glucosyl-β-cyclodextrin, diglucosyl-β-cyclodextrin, tri-O-methyl-β-cyclodextrin, tri-O-ethyl-β-cyclodextrin, tri-O-butyryl-β-cyclodextrin, Tri-O-valeryl-β-cyclodextrin, and di-O-hexanoyl-β-cyclodextrin, and methyl-β-cyclodextrin, and mixtures thereof, such as maltosyl-β-cyclodextrin / dimaltosyl-β-cyclodextrin Is mentioned. Procedures for preparing such cyclodextrin derivatives are well known from US Pat. No. 5,024,998 and references incorporated therein by reference. Other cyclodextrins suitable for use in the present invention include carboxyalkyl thioether derivatives such as ORG 26054 and ORG 25969 (ORGANON (AKZO-NOBEL)), hydroxybutenyl ether derivatives (EASTMAN), sulfoalkyl-hydroxyalkyls Ether derivatives, sulfoalkyl-alkyl ether derivatives, and other derivatives such as US 2002/0128468, 2004/0106575, 2004/0109888 and 2004/0063663, or the United States Patent Nos. 6,610,671, 6,479,467, 6,660,804 or 6,509,323 (each of which is specifically described herein for reference) Like those described in to) incorporated in the book.

  Hydroxypropyl-β-cyclodextrin is available from Research Diagnostics Inc. (Flanders, NJ). Exemplary hydroxypropyl-β-cyclodextrin products include Encapsin® (degree of substitution about 4) and Molecsol® (degree of substitution about 8); however, implementations involving other degrees of substitution Forms are also available and are within the scope of the present invention.

  Dimethylcyclodextrin is available from FLUKA Chemie (Buchs, CH) or Wacker (Iowa). Other derivatized cyclodextrins suitable for use in the present invention include water soluble derivatized cyclodextrins. Exemplary water-soluble derivatized cyclodextrins include: carboxylated derivatives; sulfated derivatives; alkylated derivatives; hydroxyalkylated derivatives; methylated derivatives; SCD). All these materials can be made according to methods known in the art and / or are commercially available. Suitable derivatives of cyclodextrin, Modified Cyclodextrins: Scaffolds and Templates for Supramolecular Chemistry (Edit Christopher J.Easton, Stephen F.Lincoln, Imperial College Press, London, UK, 1999) and New Trends in Cyclodextrins and Derivatives (editing Dominique Duchene , Editions de Sante, Paris, France, 1991).

  Examples of nonionic surfactants that appear to have particularly good physiological compatibility for use in the present invention include tyloxapol, polysorbates such as, but not limited to, polyoxyethylene (20) sorbitan monolaurate, polyoxyethylene (20) sorbitan monopalmitate, polyoxyethylene (20) monostearate (available under the trademark Tween 20-40-60, etc.), Polysorbate 80, Polyethylene glycol 400; sodium lauryl sulfate; sorbitan laurate, sorbitan palmitate, Sorbitan stearate (available under the trademark Span 20-40-60, etc.), benzalkonium chloride, PPO-PEO block copolymer (Pluronics), Cremophor-EL, Bio Tamine E-TPGS (eg, d-α-tocopheryl-polyethylene glycol-1000-succinate), Solutol-HS-15, oleic acid PEO ester, stearic acid PEO ester, Triton-X100, Nonidet P-40, and macrogol hydroxy Stearate (such as macrogol-15-hydroxystearate).

  In some embodiments, nonionic surfactants suitable for use in the present invention are formulated into corticosteroids to form liposome preparations, micelles or mixed micelles. Methods for the preparation and characterization of liposomes and liposome preparations are known in the art. In many cases, when amphiphilic lipids are hydrated, multilamellar vesicles spontaneously form, but the formation of small unilamellar vesicles usually involves processes with significant energy input (eg, Sonication or high-pressure homogenization) is required. Additional methods for the preparation and characterization of liposomes are described, for example, in S.H. Vemuri et al. (Preparation and characterization of liposomals as therapeutic delivery systems: a review. Nos. 5,882,679 and 6,656,497, each of which is specifically incorporated herein by reference.

  In some cases, for example, micelles or mixed micelles can be formed by a surfactant, in which case a soluble insufficient active agent can be solubilized. In general, 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 because their structure, properties and behavior are very different from solids. The amphiphilic molecules that form micelles are usually associated temporarily. In micellar solutions, there is dynamic molecular exchange between micelle-forming amphiphiles and monomolecularly dispersed amphiphiles (which are also present in the solution). The portion of the drug molecule that is solubilized in such micelles or mixed micelles depends on the structure of these molecules as well as the surfactant used. For example, it is assumed that, for example, in particular, nonpolar molecules are mainly localized within the colloidal structure, but polar substances are likely to be found on the surface of the structure. In one embodiment of a micelle solution or mixed micelle solution, the average micelle size can be less than about 200 nm (measured by photon correlation spectroscopy), such as from about 10 nm to about 100 nm. Particularly preferred are micelles having an average diameter of about 10 to about 50 nm. Methods for making micelles and mixed micelles are known in the art, for example, US Pat. Nos. 5,747,066 and 6,906,042, each of which is specifically incorporated herein by reference. Incorporated by reference).

  Phospholipids are defined as amphiphile lipids containing phosphorus. Phospholipids chemically derived from phosphatidic acid are widely present and commonly used for pharmaceutical purposes. This acid is usually a (double) acylated glycerol-3-phosphate, whose fatty acid residues can be of different lengths. Examples of the phosphatidic acid derivative include phosphocholine or phosphatidylcholine (the phosphate group is further esterified with choline), phosphatidylethanolamine, phosphatidylinositol, and the like. Lecithin is a natural mixture of various phospholipids, usually with a high proportion of phosphatidylcholine. Depending on the specific source of lecithin and how it is extracted and / or enriched, such a mixture may also contain significant amounts of sterols, fatty acids, triglycerides and other substances.

  Additional phospholipids suitable for delivery by inhalation due to their physiological properties, especially extracted from natural sources (such as soy or chicken egg yolk) in the form of lecithin, preferably in hydrogenated form, and / or Or phospholipid mixtures released from lysolecithin, as well as phospholipids (preferably using saturated fatty acid esters) prepared by purification, enrichment or partial synthesis. Of the phospholipid mixture, lecithin is particularly preferred. Medium to long-chain zwitterionic phospholipids prepared by enrichment or partial synthesis are mainly free of unsaturated bonds in the acyl chain and free of lysolecithin and peroxide. Examples of enriched or pure compounds are dimyristoyl phosphatidylcholine (DMPC), distearoyl phosphatidylcholine (DSPC) and dipalmitoyl phosphatidylcholine (DPPC). Of these, DMPC is more preferred at the present time. Alternatively, phospholipids with oleyl residues and phosphatidylglycerols without choline residues are suitable for some embodiments and applications of the present invention.

  In some embodiments, nonionic surfactants and phospholipids suitable for use in the present invention are incorporated into corticosteroids to form a colloidal structure. A colloidal solution is defined as a single phase system in which the colloidal material dispersed in the colloidal solution does not have the measurable physical properties normally associated with solid materials. Methods for making colloidal dispersions are known in the art and are described, for example, in US Pat. No. 6,653,319, which is specifically incorporated herein by reference. Yes.

Suitable surface modifiers for use in the present invention are known in the art, for example, U.S. Pat. Nos. 5,145,684, 5,510,118, 5,565,188, And 6,264,922, each of which is specifically incorporated herein by reference. Examples of surface modifiers and / or surface stabilizers suitable for use in the present invention include, but are not limited to, hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, sodium lauryl sulfate, dioctyl sulfosuccinate, gelatin, casein, lecithin (Phosphatide), dextran, gum arabic, cholesterol, tragacanth, stearic acid, benzalkonium chloride, calcium stearate, glycerol monostearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan ester, polyoxyethylene alkyl ether (for example , Macrogol ethers such as cetomacrogol 1000), polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid Ester (e.g., the commercially available Tween ^TM, for example, Tween ^{20 TM} and ^{Tween 80 TM (ICI Specialty Chemicals)} ), polyethylene glycols (e.g., Carbowaxs 3550 ^TM and ⁹³⁴ TM (Union Carbide)), polyoxyethylene stearates, colloidal 4- with silicon dioxide, phosphates, calcium carboxymethylcellulose, sodium carboxymethylcellulose, methylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose phthalate, amorphous cellulose, magnesium magnesium silicate, triethanolamine, polyvinyl alcohol (PVA), ethylene oxide and formaldehyde (1,1,3 , 3-tetramethylbutyl) -phenol polymer (also known as tyloxapol, superion and triton), poloxamers (eg Pluronic F68 ^™ and F108 ^™ , which are block copolymers of ethylene oxide and propylene oxide), poloxamine (eg , Tetronic 908 ^™ , Poloxamine 908 ^™ , which is a tetrafunctional block copolymer derived from the sequential addition of propylene oxide and ethylene oxide to ethylenediamine (BASF Wyandotte Corporation, Parsippany, NJ)) , Tetronic 1508 ^TM (T-1508) (BASF Wyandotte Corporation) ), Tritons X-200 ^™ (which is an alkylaryl polyether sulfonate) (Rohm and Haas), Crodestas F-100 ^™ (which is a mixture of sucrose stearate and sucrose distearate) (Croda Inc. ), P-isononylphenoxypoly- (glycidol), (also known as Olin-IOG ^™ or Surfactant 10 ^™ ) (Olin Chemicals, Stamford, Conn.), Crodestas SL-40. RTM. (Croda, Inc.), and SA9OHCO (which is C18H37CH2 (CON (CH3) -CH2 (CHOH) 4 (CH2OH) 2) (Eastman Kodak Co.), Decanoyl-N-methylglucamide, n-decyl. -Β-D-glucopyranoside, n-decyl-β-D-maltopyranoside, n-dodecyl β-D-glucopyranoside, n-dodecyl-β-D-maltoside, heptanoyl-N-methylglucamide, n-heptyl-β- D-glucopyranoside, n-heptyl-β-D-thioglucoside, n-hexyl-β-D-glucopyranoside, nonanoyl-N-methylglucamide, n-noyl-β-D-glucopyranoside, octanoyl-N-methylglucamide N-octyl-β-D-glucopyranoside, octyl β-D -Thioglucopyranoside, PEG-phospholipid, PEG-cholesterol, PEG-cholesterol derivatives, PEG-vitamin A, PEG-vitamin E, lysozyme, random copolymers of vinylpyrrolidone and vinyl acetate (eg, hydroxypropylmethylcellulose, hydroxypropylcellulose, Polyvinyl pyrrolidone, vinyl acetate copolymer, vinyl pyrrolidone, sodium lauryl sulfate and dioctyl sodium sulfosuccinate).

Other useful cationic stabilizers include, but are not limited to, cationic lipids, sulfonium, phosphonium and quaternary ammonium compounds such as stearyltrimethylammonium chloride, benzyl-di (2-chloroethyl) ethylammonium bromide, coconut trimethyl Ammonium chloride or bromide, coconut methyl dihydroxyethylammonium chloride or bromide, decyltriethylammonium chloride, decyldimethylhydroxyethylammonium chloride or bromide, C12-15 dimethylhydroxyethylammonium chloride or bromide, coconut dimethylhydroxyethylammonium chloride or bromide, myristyltrimethyl Ammonium methylsulf , Lauryldimethylbenzylammonium chloride or bromide, lauryldimethyl (ethenoxy) 4ammonium chloride or bromide, N-alkyl (C12-18) dimethylbenzylammonium chloride, N-alkyl (C14-18) dimethylbenzylammonium chloride, N- Tetradecylide methylbenzylammonium chloride monohydrate, dimethyldidecylammonium chloride, N-alkyl and (C12-14) dimethyl 1-naphthylmethylammonium chloride, trimethylammonium halide, alkyltrimethylammonium and dialkyldimethylammonium salts, lauryl Trimethylammonium chloride, ethoxylated alkylamidoalkyldialkylammonium salt And / or ethoxylated trialkylammonium salt, dialkylbenzenedialkylammonium chloride, N-didecyldimethylammonium chloride, N-tetradecyldimethylbenzylammonium chloride monohydrate, N-alkyl (C12-14) dimethyl 1-naphthylmethyl Ammonium chloride and dodecyldimethylbenzylammonium chloride, dialkylbenzene alkylammonium chloride, lauryltrimethylammonium chloride, alkylbenzylmethylammonium chloride, alkylbenzyl-dimethylammonium bromide, C12, C15, C17 trimethylammonium bromide, dodecylbenzyl-triethylammonium chloride, poly -Diallyldimethylammonium Chloride (DADMAC), dimethylammonium chloride, alkyldimethylammonium halide, tricetylmethylammonium chloride, decyltrimethylammonium bromide, dodecyltriethylammonium bromide, tetradecyltrimethylammonium bromide, methyltrioctylammonium chloride (ALIQUAT 336 ^™ ), POLYQUAT 10 ^TM , tetrabutylammonium bromide, benzyl-trimethylammonium bromide, etc., choline esters (such as choline esters of fatty acids), benzalkonium chloride, stearalkonium chloride compounds (such as stearyltrimonium chloride and distearyldimonium chloride), cetylpyridinium Bromide or chloride, quaternized polyoxy Halide salts chill alkylamine, Mirapol ^TM and ALKAQUAT ^TM (Alkaril Chemical Company), alkyl pyridinium salts, amines (alkylamines, dialkylamines, alkanolamines, polyethylenepolyamines, N, etc. N- dialkylaminoalkyl acrylate and vinyl pyridine) Amine salts (such as laurylamine acetate, stearylamine acetate, alkylpyridinium and alkylimidazolium salts and amine oxides), imidoazolinium salts, protonated quaternary acrylamides, methylated quaternary polymers (poly [diallyldimethylammonium Chloride] and poly- [N-methylvinylpyridinium chloride]), and cationic guars -Is mentioned.

  In certain embodiments, the inhalable composition of the present invention comprises propylene glycol, nonionic surfactant, tyloxapol, polysorbate 80, vitamin E-TPGS, macrogol-15-hydroxystearate, phospholipid, lecithin, purified And / or enriched lecithin, phosphatidylcholine fraction extracted from lecithin, dimyristoylphosphatidylcholine (DMPC), dipalmitoylphosphatidylcholine (DPPC), distearoylphosphatidylcholine (DSPC), cyclodextrin and its derivatives, SAE-CD derivatives, SBE- α-CD, SBE-β-CD, SBE1-β-CD, SBE4-β-CD, SBE7-β-CD (Captisol (registered trademark)), SBE-γ-CD, dimethyl β-CD, hydroxy Lopyl-β-cyclodextrin, 2-HP-β-CD, hydroxyethyl-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, hydroxyethyl-γ-cyclodextrin, dihydroxypropyl-β-cyclodextrin, glucosyl-α -Cyclodextrin, glucosyl-β-cyclodextrin, diglucosyl-β-cyclodextrin, maltosyl-α-cyclodextrin, maltosyl-β-cyclodextrin, maltosyl-γ-cyclodextrin, maltotriosyl-β-cyclodextrin, maltotrio Sil-γ-cyclodextrin, dimaltosyl-β-cyclodextrin, methyl-β-cyclodextrin, carboxyalkyl thioether derivative, ORG 26054, ORG 25969, A solubility enhancer selected from the group consisting of droxypropylmethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, vinyl acetate copolymer, vinylpyrrolidone, sodium lauryl sulfate, dioctyl sodium sulfosuccinate, and combinations thereof. In certain embodiments, the solubility enhancer is SBE7-β-CD (Captisol®).

  In another specific embodiment, the inhalable composition of the invention comprises cyclodextrin and its derivatives, SAE-CD derivatives, SBE-α-CD, SBE-β-CD, SBE1-β-CD, SBE4-β. -CD, SBE7-β-CD (Captisol®), SBE-γ-CD, dimethyl β-CD, hydroxypropyl-β-cyclodextrin, 2-HP-β-CD, hydroxyethyl-β-cyclodextrin , Hydroxypropyl-γ-cyclodextrin, hydroxyethyl-γ-cyclodextrin, dihydroxypropyl-β-cyclodextrin, glucosyl-α-cyclodextrin, glucosyl-β-cyclodextrin, diglucosyl-β-cyclodextrin, maltosyl-α- Cyclodextrin, maltosyl-β-si Improved solubility selected from the group consisting of rhodextrin, maltosyl-γ-cyclodextrin, maltotriosyl-β-cyclodextrin, maltotriosyl-γ-cyclodextrin, dimaltosyl-β-cyclodextrin, methyl-β-cyclodextrin Contains agents. In another specific embodiment, the solubility enhancer is SBE7-β-CD (Captisol®).

  In addition to an aqueous inhalation mixture or inhalable composition comprising a corticosteroid and a solubility enhancer, herein also an aqueous inhalation mixture or composition formulated by a method that provides improved solubility is also disclosed herein. It is envisaged that it is suitable for use in the present invention. Thus, in the context of the present invention, a “solubility enhancer” includes an aqueous inhalation mixture formulated by a method that provides improved solubility with or without a chemical acting as a solubility enhancer. . An example of such a method is the preparation of a supercritical fluid. By such a method, corticosteroid compositions such as budesonide are processed into particles with a narrow particle size distribution (usually less than 200 nanometers wide) and an average hydrodynamic radius of the particles in the range of 50 nanometers to 700 nanometers. Is done. Nano-sized corticosteroid particles (such as budesonide particles) can be used in supercritical fluid (SCF) processes such as supercritical fluid rapid expansion (RESS), or supercritical fluid solution-enhanced dispersion (SEDS), as well as supercritical fluids. Are processed using any other technique involving. The use of the SCF process to form particles is described in Parakodity, S .; Et al., Pharmaceutical Research 16: 976-985 (1999), and Bandi et al., Eur. J. et al. Pharm. Sci. 23: 159-168 (2004), US Pat. No. 6,576,264 and US Patent Application Publication No. 2003/0091513, each of which is specifically incorporated herein by reference. Yes. These methods allow the formation of micron and submicron sized particles having different morphologies depending on the method and parameters selected. Such nanoparticles can also be processed by spray drying, freeze drying, volume exclusion, and any other conventional particle reduction method.

  Furthermore, the desired form (e.g., amorphous, crystalline, segmented) can be achieved by appropriately adjusting the conditions of particle formation during precipitation or condensation by the method of producing nanometer sized particles (e.g., SCF). Racemate) may be possible. As a result of the selection of the desired particle form, sustained release of the selected medicament can be achieved. Using such a particle processing process, nanoparticulate material having high purity, low surface imperfection, low surface charge and low sedimentation rate is obtained. Due to the characteristics of the particles, adhesion and aggregation of the particles are suppressed, and sedimentation in the liquid dispersion is prevented. In addition, in processes such as SCF, certain pharmaceutical isomers can be separated, and such separation can contribute to enhanced activity, efficacy and extreme dose reduction of the pharmaceutical. In some cases, the separation of isomers also contributes to the reduction of side effects. With the method and system of the present invention, the aqueous inhalation mixture can be a composition processed into a powder form by any process, such as direct SCF in the recovery medium, spray drying, precipitation and volume exclusion, and thus The particulate compound is automatically made into a dispersion formulation. In some embodiments, this formulation may be the final formulation.

  In some embodiments of the invention, the inhalable composition further comprises a second therapeutic agent selected from the group consisting of β2-adrenergic receptor agonists, prophylactic therapeutic agents, and anticholinergic agents. Contains drugs. In some embodiments of the invention, the β2-adrenergic receptor agonist is albuterol, levalbuterol or a pharmaceutically acceptable derivative.

  In some embodiments of the invention, the inhalable composition is administered to the patient no more than once a day. In other embodiments, the inhalable composition is administered to the patient no more than twice a day. In some embodiments of the invention, the composition is administered to the patient twice a day or more than twice a day. In yet other embodiments, the inhalable composition is administered to the patient no more than once a day in the evening.

  In some embodiments of the invention, the device is a nebulizer. In certain embodiments, the nebulizer is a jet nebulizer, an ultrasonic nebulizer, a pulsating membrane nebulizer, a nebulizer having a vibrating mesh or plate with multiple holes, or a nebulizer comprising a vibration generator and an aqueous chamber. In other specific embodiments of the invention, the nebulizer is a Pari LC Jet Plus, Intertech, Baxter Misty-Neb, Hudson T-Updraft II, Hudson Ava-Neb, Ailos, Pari LCNet, DeVilbNs, Pari LCJet, DeVilbNs. -Neb (B), Hudson T-Updraft Neb-U-Mist, Pari-Jet 1460, and AeroTech with T-piece. In another particular embodiment, the nebulizer is a Pari eFlow nebulizer.

III. Method of making microparticles from an inhalable composition comprising a corticosteroid that results in enhanced lung deposition The present invention further provides a method of making microparticles from an inhalable composition comprising a solvent and Adding a solubility enhancer to an effective amount of a corticosteroid, and activating a nebulizer to produce microparticles of the composition upon administration of the composition to a subject via the nebulizer And at least about 20% to about 40%, about 20% to about 50%, or about 20% to about 55% of pulmonary deposition (e.g., bronchial and Alveoli) is achieved. In certain embodiments, the inhalable composition comprises an effective amount of a single corticosteroid, a solvent and a solubility enhancer, and is substantially free of active pharmaceutical agents other than the corticosteroid. In some embodiments, the method is such that at least about 25% to about 45% lung deposition can be achieved based on the amount of corticosteroid in the mixture prior to administration. In other embodiments, the method 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 composition is one in which at least about 25% lung deposition is achieved based on the amount of corticosteroid in the composition prior to administration. In other embodiments, the composition is one in which at least about 30% lung deposition is achieved based on the amount of corticosteroid in the composition prior to administration. In yet other embodiments, the composition achieves at least about 35% lung deposition based on the amount of corticosteroid in the composition prior to administration. In yet other embodiments, the composition achieves at least about 40% lung deposition based on the amount of corticosteroid in the composition prior to administration. In other embodiments, the composition is one in which at least about 45% lung deposition is achieved based on the amount of corticosteroid in the composition prior to administration. In one embodiment, the corticosteroid is budesonide. In another embodiment, the corticosteroid is either an individual diastereomer of budesonide or a mixture of two diastereomers of budesonide administered individually or together for therapeutic effect. In certain embodiments, the inhalable composition comprises an effective amount of a single corticosteroid and a solubility enhancer and is substantially free of active pharmaceutical agents other than the corticosteroid. In still other embodiments, the inhalable composition comprises an effective amount of budesonide and a solubility enhancer and is substantially free of active pharmaceutical agents other than budesonide.

  In a preferred embodiment, the method of making microparticles from an inhalable composition also achieves a respiratory fraction of at least about 60% when administered. In a more preferred embodiment of the invention, the method also achieves at least about 70% respiratory fraction upon administration. In an even more preferred embodiment of the invention, the method also achieves at least about 80% respiratory fraction upon administration. In the most preferred embodiments of the invention, the method also achieves at least about 85% respiratory fraction upon administration.

  In some embodiments of the invention, the method of making microparticles from an inhalable composition comprising a corticosteroid comprises about 15 to about 2000 μg of corticosteroid in the pre-dose composition. In other embodiments, an inhalable composition comprising an effective amount of a corticosteroid, a solvent and a solubility enhancer that can provide enhanced lung deposition has an amount of corticosteroid in the pre-dose composition of about 250 to about Contains 2000 μg corticosteroid. In still other embodiments, an inhalable composition comprising an effective amount of a corticosteroid, a solvent and a solubility enhancer that can provide enhanced pulmonary deposition comprises an amount of corticosteroid in the pre-dose composition of about 60- Contains about 1500 μg of corticosteroid. In yet other embodiments, an inhalable composition comprising an effective amount of a corticosteroid, a solvent, and a solubility enhancer that can provide enhanced lung deposition comprises an amount of corticosteroid in the pre-dose composition of about 100 to Contains about 1000 μg of corticosteroid. In still other embodiments, an inhalable composition comprising an effective amount of a corticosteroid, a solvent, and a solubility enhancer that can provide enhanced lung deposition comprises an amount of corticosteroid in the pre-administration composition of about 120- Contains about 1000 μg of corticosteroid. In still other embodiments, an inhalable composition comprising an effective amount of a corticosteroid, a solvent, and a solubility enhancer that can provide enhanced lung deposition provides an amount of about 125 corticosteroid in the pre-dose composition. Contains about ~ 500 μg corticosteroid. In certain embodiments, an inhalable composition comprising an effective amount of a corticosteroid, a solvent and a solubility enhancer that can provide enhanced pulmonary deposition comprises an amount of corticosteroid in the pre-dose composition of about 40 μg, about 60 μg, about 100 μg, about 120 μg, about 125 μg, about 240 μg, about 250 μg, about 500 μg, about 1000 μg, about 1500 μg, or about 2000 μg of corticosteroid. In one embodiment, the inhalable composition comprises about 40 μg of corticosteroid in the pre-administration composition. In another embodiment, the inhalable composition comprises about 60 μg of corticosteroid in the pre-administration composition. In yet another embodiment, the inhalable composition comprises a corticosteroid amount of about 100 μg of the corticosteroid in the pre-administration composition. In yet another embodiment, the inhalable composition comprises about 120 μg of corticosteroid in the pre-administration composition. In yet another embodiment, the inhalable composition comprises a corticosteroid in the pre-dose composition in an amount of about 125 μg. In yet another embodiment, the inhalable composition comprises a corticosteroid amount of about 240 μg in the pre-dose composition. In yet another embodiment, the inhalable composition comprises a corticosteroid in the pre-administration composition that is less than about 250 μg of corticosteroid. In another embodiment, the inhalable composition comprises a corticosteroid in the pre-dose composition that is less than about 500 μg of corticosteroid. In one embodiment, the corticosteroid is budesonide. In another embodiment, the corticosteroid is either an individual diastereomer of budesonide or a mixture of two diastereomers of budesonide administered individually or together for therapeutic effect. In certain embodiments, the inhalable composition comprises an effective amount of a single corticosteroid, a solvent and a solubility enhancer and is substantially free of active pharmaceutical agents other than the corticosteroid. In still other embodiments, the inhalable composition comprises an effective amount of budesonide, a solvent and a solubility enhancer, and is substantially free of active pharmaceutical agents other than budesonide.

  In some embodiments, inhalable compositions comprising suitable corticosteroids include, but are not limited to, solutions, dispersions, nanodispersions, emulsions, colloidal liquids, micelles or mixed micelle solutions, and liposome liquids. Can be mentioned. In one embodiment, the aqueous inhalation mixture is a solution comprising a corticosteroid such as budesonide and a solubility enhancer. In another embodiment, the aqueous inhalation mixture is a mixed micelle solution comprising a corticosteroid such as budesonide and a solubility enhancer. In yet another embodiment, the aqueous inhalation mixture is a liposome solution comprising a corticosteroid such as budesonide and a solubility enhancer.

  In some embodiments of the invention, inhalable compositions comprising corticosteroids do not include nanodispersions and / or nanosuspensions. In other embodiments, inhalable compositions comprising corticosteroids do not include micelles, mixed micelle fluids or liposome fluids. In still other embodiments, inhalable compositions comprising corticosteroids do not include nanodispersions and / or nanosuspensions, micelles, mixed micelle fluids, or liposome fluids. In other embodiments, inhalable compositions include, but are not limited to, solutions, emulsions and colloidal liquids. In one embodiment, the inhalable composition is a solution comprising a corticosteroid such as budesonide and a solubility enhancer. In another embodiment, the inhalable composition is an emulsion comprising a corticosteroid such as budesonide and a solubility enhancer.

  Corticosteroids useful in the inhalable compositions described herein include, but are not limited to, aldosterone, beclomethasone, betamethasone, budesonide, ciclesonide, clopredonol, cortisone, cortibazole, deoxycolton, desonide, desoxymeta Zon, dexamethasone, difluorocortron, fluchlorolone, flumethasone, flunisolide, fluocinolone, fluocinonide, fluocortin butyl, fluorocortisone, fluorocortron, fluorometholone, flulandrenolone, fluticasone, halcinonide, hydrocortisone, icomethasone, meprednisone, methyl Prednisolone, mometasone, parameterzone, prednisolone, prednisone, rofleponide, RPR 106541, thixocort Le, triamcinolone and derivatives of these may be the respective pharmaceutically acceptable thereof. In a preferred embodiment, the corticosteroid is budesonide. In other preferred embodiments, the corticosteroid is either an individual diastereomer of budesonide or a mixture of two diastereomers of budesonide administered individually or together for therapeutic effect.

  In some embodiments of the inhalable compositions described herein, the inhalable composition is one that includes a solvent. In certain embodiments, the solvent is selected from the group comprising water, aqueous alcohol, propylene glycol or an aqueous organic solvent. In a preferred embodiment, the solvent is water.

  In other embodiments of the inhalable compositions described herein, the inhalable composition comprises a solubility enhancer. In some embodiments, 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 still other embodiments, the solubility enhancer can have a concentration (w / v) ranging from about 1% to about 10%. In a preferred embodiment, when the solubility enhancer is a cyclodextrin or cyclodextrin derivative such as SBE7-β-CD (Captisol®), the concentration (w / v) ranges from about 2% to about 10%. ). In one embodiment, the solubility enhancer may have a concentration (w / v) of about 2% when it is a cyclodextrin or cyclodextrin derivative, such as SBE7-β-CD (Captisol®). In another embodiment, the solubility enhancer may have a concentration (w / v) of about 5% when it is a cyclodextrin or cyclodextrin derivative, such as SBE7-β-CD (Captisol®). In yet another embodiment, the solubility enhancer has a concentration (w / v) of about 7% when it is a cyclodextrin or cyclodextrin derivative, eg, SBE7-β-CD (Captisol®). obtain. In yet another embodiment, the solubility enhancer has a concentration (w / v) of about 10% when it is a cyclodextrin or cyclodextrin derivative, such as SBE7-β-CD (Captisol®). obtain.

  In other embodiments, inhalable compositions for use in the methods of the invention further comprise a solubility enhancer. In certain embodiments, the solubility enhancer is propylene glycol, nonionic surfactant, tyloxapol, polysorbate 80, vitamin E-TPGS, macrogol-15-hydroxystearate, phospholipid, lecithin, purification and / or enrichment. Lecithin, phosphatidylcholine fraction extracted from lecithin, dimyristoylphosphatidylcholine (DMPC), dipalmitoylphosphatidylcholine (DPPC), distearoylphosphatidylcholine (DSPC), cyclodextrin and its derivatives, SAE-CD derivatives, SBE-α-CD, SBE -Β-CD, SBE1-β-CD, SBE4-β-CD, SBE7-β-CD (Captisol®), SBE-γ-CD, dimethyl β-CD, hydroxypropyl-β- Cyclodextrin, 2-HP-β-CD, hydroxyethyl-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, hydroxyethyl-γ-cyclodextrin, dihydroxypropyl-β-cyclodextrin, glucosyl-α-cyclodextrin, Glucosyl-β-cyclodextrin, diglucosyl-β-cyclodextrin, maltosyl-α-cyclodextrin, maltosyl-β-cyclodextrin, maltosyl-γ-cyclodextrin, maltotriosyl-β-cyclodextrin, maltotriosyl-γ- Cyclodextrin, dimaltosyl-β-cyclodextrin, methyl-β-cyclodextrin, carboxyalkyl thioether derivative, ORG 26054, ORG 25969, hydroxypro A chemical selected from the group consisting of pyrmethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, vinyl acetate copolymer, vinylpyrrolidone, sodium lauryl sulfate, dioctyl sodium sulfosuccinate, and combinations thereof. In a preferred embodiment, the solubility enhancer is SBE7-β-CD (Captisol®).

  In another specific embodiment, the inhalable composition of the invention comprises cyclodextrin and its derivatives, SAE-CD derivatives, SBE-α-CD, SBE-β-CD, SBE1-β-CD, SBE4-β. -CD, SBE7-β-CD (Captisol®), SBE-γ-CD, dimethyl β-CD, hydroxypropyl-β-cyclodextrin, 2-HP-β-CD, hydroxyethyl-β-cyclodextrin , Hydroxypropyl-γ-cyclodextrin, hydroxyethyl-γ-cyclodextrin, dihydroxypropyl-β-cyclodextrin, glucosyl-α-cyclodextrin, glucosyl-β-cyclodextrin, diglucosyl-β-cyclodextrin, maltosyl-α- Cyclodextrin, maltosyl-β-si Improved solubility selected from the group consisting of rhodextrin, maltosyl-γ-cyclodextrin, maltotriosyl-β-cyclodextrin, maltotriosyl-γ-cyclodextrin, dimaltosyl-β-cyclodextrin, methyl-β-cyclodextrin Contains agents. In another specific embodiment, the solubility enhancer is SBE7-β-CD (Captisol®).

  In addition to an aqueous inhalation mixture or inhalable composition comprising a corticosteroid and a solubility enhancer, herein also an aqueous inhalation mixture or composition formulated by a method that provides improved solubility is also disclosed herein. It is envisaged that it is suitable for use in the present invention. Thus, in the context of the present invention, a “solubility enhancer” includes an aqueous inhalation mixture formulated by a method that provides improved solubility with or without a chemical acting as a solubility enhancer. . An example of such a method is the preparation of a supercritical fluid. By such a method, corticosteroid compositions such as budesonide are processed into particles with a narrow particle size distribution (usually less than 200 nanometers wide) and an average hydrodynamic radius of the particles in the range of 50 nanometers to 700 nanometers. Is done. Nano-sized corticosteroid particles (such as budesonide particles) can be used in supercritical fluid (SCF) processes such as supercritical fluid rapid expansion (RESS), or supercritical fluid solution-enhanced dispersion (SEDS), as well as supercritical fluids. Are processed using any other technique involving. The use of the SCF process to form particles is described in Parakodity, S .; Et al., Pharmaceutical Research 16: 976-985 (1999), and Bandi et al., Eur. J. et al. Pharm. Sci. 23: 159-168 (2004), US Pat. No. 6,576,264 and US Patent Application Publication No. 2003/0091513, each of which is specifically incorporated herein by reference. Yes.

  In some embodiments of the invention, the inhalable composition for use in the methods of the invention further comprises the group consisting of a β2-adrenergic receptor agonist, a prophylactic therapeutic agent and an anticholinergic agent. A second therapeutic agent that is more selected. In other embodiments of the invention, the β2-adrenergic receptor agonist is albuterol, levalbuterol or a pharmaceutically acceptable derivative.

  In some embodiments of the invention, the methods of the invention comprise administering to an inhalable composition patient described herein no more than once a day. In other embodiments of the invention, the methods of the invention comprise administering to an inhalable composition patient as described herein twice or more than twice a day.

Any known inhalation nebulizer is suitable for use in the invention described herein. Such nebulizers include, for example, jet nebulizers, ultrasonic nebulizers, pulsatile membrane nebulizers, nebulizers having a vibrating mesh or plate with multiple holes, and nebulizers comprising a vibration generator and an aqueous chamber (eg, Pari eFlow®). )). Commercially available air-driven jet nebulizers, ultrasonic nebulizers or pulsatile membrane nebulizers suitable for use in the present invention include Aeroneb®, Aeroneb GO® (Aerogen, San Francisco, Calif.), Pari LC PLUS. (Registered trademark), Pari Boy® (registered trademark) N, and Pari Duraneb (registered trademark) (PARI Respiratory Equipment, Inc., Monterrey, CA), MicroAir (registered trademark) (Omron Healthcare, Inc, Vernon Hills, Illinois) Halolite (R) (Profile Therapeutics Inc, Boston, MA), Respirat (R) (Boehringer I gelheim Ingelheim, Germany), Aerodose (R) (Aerogen, Inc, Mountain View, CA), Omron Elite (R) (Omron Healthcare, Inc, Vernon Hills, Illinois), Omron Microre (R) , Inc, Vernon Hills, Illinois), Mabismist II® (Mabis Healthcare, Inc, Lake Forest, Illinois), Lumisscope® 6610, (The Lumicscope Company, Inc, East Brownswick, New Jersey) , Airsep Mystere®, (AirSep Corporation) ion, Buffalo, NY), Acorn-1 and Acorn-II (Vital Signs, Inc, Totowa, NJ), Aquawater (R) (Medical Industries America, Adel, Iowa), Ava-Neb (R) Hudson Respiratory Care Incorporated (Temecula, CA), Cirrus (registered trademark) (International Incorporated, Liverpool, New York), Dart (registered trademark) (Professional Medical Product registered in South Carolina, vD Aide (DeVilbiss Cor . Somerset, Pennsylvania), Downdraft® (Marquest, Englewood, Colorado), Fan Jet® (Marquest, Englewood, Colorado), MB-5 (Mefar, Bovezzo, Italy), Misty Neb (R) (Baxter, Valencia, CA), Salter 8900 (Salter Labs, Irvine, CA), Sidestream (R) (Medic-Aid, Sussex, UK), Updraft-II (R) Hudson Respiratory Care; Temecula, Calif., Whisper Jet® (Marquest Medical Products, Engle , Colorado), Airos® (Ailos Mediknsk Teknik, Karlstad, Sweden), Inspiron® (Intertech Resources, Inc., Bannockburn, Illinois), Optimist® (alInoc) , McAllen, Texas), Prodomo®, Spira® (Respiratory Care Center, Hemenlinna, Finland), AERx (Aradigm Corporation, Hayward, Calif.), Sonik® LDI NebulizerLab , Sacramento, California), as well as Swirler W Radio Aerosol System (AMICI, Inc., Spring City, PA).
Any of these and other known nebulizers can be used to deliver the aqueous inhalation mixture described in the present invention. In some embodiments, the nebulizer can be, for example, Pari GmbH (Starnberg, Germany), DeVilbiss Healthcare (Heston, Middlesex, UK), Healthdyne, Vital Signs, Baxter, Allied Health Care, Uvacare, Uvacare, H Omron, Bremed, AirSep, Luminscope, Mediana, Siemens, Aerogen, Mountain Medical, Aerosol Medical Ltd. (Colechester, Essex, UK), AFP Medical (Rugby, Warwickshire, UK), Bard Ltd. (Sunderland, UK), Carri-Med Ltd. (Dorking, UK), Plaem Nuiva (Brescia, Italy), Henleys Medical Supplements (London, UK), International (Berkshire, UK), Lifecare Hospital Supplements (Reillys, UK), Med-Aid. (West Sussex, UK), Medix Ltd. (Essex, UK), Sinclair Medical Ltd. (Surrey, UK) and many others.

  Other nebulizers suitable for use in the method and system described herein include, but are not limited to, jet nebulizers (optionally sold with a compressor), ultrasonic nebulizers, and the like. Exemplary jet nebulizers for use herein include: Pari LC plus / ProNeb, Pari LC plus / ProNeb Turbo, Pari LCPlus / Dura Neb 1000 & 2000 Pari LC plus / Walkhaler, Pari LC Pris Pari LC star, Omron Compair Air XL Portable Nebulizer System (NE-C18 and JetAir Disposable nebulizer), Omron Compreit Elite Compressor NebulizerNebulizer Ultra compressor comprising a Pari LC Plus or Pari LC Star nebulizer, Pulomo-aide, Pulmo-aide LT, Pulmo-aide traveler, Invacare Passport, Inspiration Healthdyne 626, Pulmo-Neb Traveler, DeVilbiss 646, Whisper Jet, AcornII, Misty-Neb , Allied Aerosol, Schuco Home Care, Lexan Plastic Pocket Neb, SideStream Hand Held Neb, Mobile Mist, Up-Draft, Up-Draft II, T Up-Draft, ISO-NE , Ava-Neb, Micro Mist, as well as PulmoMate.

  Exemplary ultrasound nebulizers for use herein include: MicroAir, UltraAir, Siemens Ultra Nebulizer 145, CompAir, Pulmosonic, Scout, 5003 Ultrasonic Neb, 5110 Ultrasonic. s Ultrasonic Nebulizer, Mediana Ultrasonic Nebulizer, Microstat Ultrasonic Nebulizer, and Mabismist Hand Held Ultrasonic Nebulizer. Other nebulizers for use herein, 5000 Electromagnetic Neb, 5001 Electromagnetic Neb 5002 Rotary Piston Neb, Lumineb I Piston Nebulizer 5500, Aeroneb Portable Nebulizer System, include Aerodose Inhaler, and AeroEclipse Breath Actuated Nebulizer. An exemplary nebulizer that includes a vibrating mesh or plate having multiple holes is described in R.C. Dhand, New Nebulizer Technology-Aerosol Generation by Using a Vibrating Mesh or Plate with Multiple Apertures, Long-Term Healthcare 3rd. 1-4 and Respiratory Care, 47: 1406-1416 (2002), the disclosures of each of which are incorporated herein by reference.

  Additional nebulizers suitable for use in the invention described herein include nebulizers comprising a vibration generator and an aqueous chamber. Such nebulizers are commercially available, for example, as Pari eFlow, US Pat. Nos. 6,962,151, 5,518,179, 5,261,601 and 5,152,456. (Each of which is specifically incorporated herein by reference).

  Parameters used in nebulization, such as flow rate, mesh membrane size, aerosol inhalation chamber size, mask size and material, valves and power supplies, etc., according to the principles of the present invention to maximize their use, It can vary with different types of aqueous inhalation mixtures or different types of corticosteroids.

  In addition to the nebulizer described above, atomizers are also suitable for the systems and methods described herein for delivery of aqueous inhalation solutions containing corticosteroids and solubility enhancers. Atomizers are known in the art, for example, U.S. Pat. Nos. 5,954,047, 6,026,808, 6,095,141 and 6,527,151 ( Each of which is specifically incorporated herein by reference).

  In certain embodiments of the invention, the nebulizer is a jet nebulizer, an ultrasonic nebulizer, a pulsating membrane nebulizer, a nebulizer having a vibrating mesh or plate with multiple holes, or a nebulizer comprising a vibration generator and an aqueous chamber. In some embodiments of the present invention, the nebulizer is a Pari LC Jet Plus, Intertech, Baxter Misty-Neb, Hudson T-Updraft II, Hudson Ava-Neb, Ailos, Pari LCJet, DeVilbisNs, DeVilbisNs, DeVilbisPs. Neb (B), Hudson T-Updraft Neb-U-Mist, Pari-Jet 1460, and AeroTech with T-piece. In another particular embodiment, the nebulizer is a Pari eFlow nebulizer.

IV. Another aspect of the present invention relates to a method for producing microparticles from an inhalable composition, wherein the method comprises the steps of: The method comprises the steps of forming the composition by adding a solvent and a solubility enhancer to an effective amount of a corticosteroid, and activating a nebulizer to produce microparticles of the composition, the nebulizer comprising Via the inhalable suspension comprising the corticosteroid without the solubility enhancer administered under the same conditions upon administration of the composition to a subject via A rate of increase in corticosteroid concentration in the device of about 60% or less of the rate of increase in corticosteroid concentration within is achieved. In certain embodiments, the method comprises an inhalable composition comprising a single corticosteroid substantially free of active pharmaceutical agents other than the corticosteroid.

  In certain embodiments, the rate of increase of corticosteroid concentration in the device is achieved over the first 3 minutes of administration. In other embodiments, the rate of increase of corticosteroid concentration in the device is achieved during the second and third 1 minute of administration. In yet other embodiments, the rate of increase of corticosteroid concentration in the device is achieved during the third minute of administration.

  In one embodiment, the invention relates to an inhalable composition wherein administration of the composition through the device is achieved over 5 minutes and administration of the inhalable suspension is achieved over 5 minutes. In another embodiment, the invention relates to an inhalable composition wherein the administration time of the composition through the device and the administration time of the inhalable suspension are the same. In yet another embodiment, the invention relates to an inhalable composition wherein the administration time of the composition through the device differs from the administration time of the inhalable suspension.

  In certain embodiments of the invention, an inhalable composition is also one that achieves a respiratory fraction of at least about 60% when administered. In a more preferred embodiment of the invention, the inhalable composition is also one which achieves at least about 70% respiratory fraction upon administration. In an even more preferred embodiment of the present invention, the inhalable composition is also one which achieves a respiratory fraction of at least about 80% when administered. In the most preferred embodiment of the invention, the inhalable composition is also one which achieves at least about 85% respiratory fraction upon administration.

  In some embodiments of the invention, the inhalable composition comprises about 15 to about 2000 μg of corticosteroid. In other embodiments, the composition comprises about 50 to about 2000 μg of corticosteroid. In yet other embodiments, the composition comprises about 60 to about 1500 μg of corticosteroid. In yet other embodiments, the composition comprises about 120 to about 1000 μg of corticosteroid. In still other embodiments, the composition comprises about 125 to about 500 μg of corticosteroid. In some embodiments of the invention, the composition comprises about 40, 60, 120, 125, 240, 250, 500, 1000, 1500 or 2000 μg of the corticosteroid. In some embodiments of the invention, the composition comprises a nominal dosage of about 60-2000 μg of the corticosteroid. In one embodiment, the inhalable composition comprises a nominal dosage of about 40 μg of corticosteroid. In another embodiment, the inhalable composition comprises a nominal dosage of about 60 μg of corticosteroid. In yet another embodiment, the inhalable composition comprises a nominal dosage of about 100 μg of corticosteroid. In yet another embodiment, the inhalable composition comprises a nominal dosage of about 120 μg of corticosteroid. In yet another embodiment, the inhalable composition comprises a nominal dosage of about 125 μg of corticosteroid. In yet another embodiment, the inhalable composition comprises a nominal dosage of about 240 μg of corticosteroid. In yet another embodiment, the inhalable composition comprises a nominal dosage of less than about 250 μg of corticosteroid. In one embodiment, the corticosteroid is budesonide. In another embodiment, the corticosteroid is either an individual diastereomer of budesonide or a mixture of two diastereomers of budesonide administered individually or together for therapeutic effect. In certain embodiments, the inhalable composition comprises an effective amount of a single corticosteroid, a solvent and a solubility enhancer and is substantially free of active pharmaceutical agents other than the corticosteroid. In still other embodiments, the inhalable composition comprises an effective amount of budesonide, a solvent and a solubility enhancer, and is substantially free of active pharmaceutical agents other than budesonide.

  In some embodiments, inhalable compositions comprising suitable corticosteroids include, but are not limited to, solutions, dispersions, nanodispersions, emulsions, colloidal liquids, micelles or mixed micelle solutions, and liposome liquids. Can be mentioned. In one embodiment, the aqueous inhalation mixture is a solution comprising a corticosteroid such as budesonide and a solubility enhancer. In another embodiment, the aqueous inhalation mixture is a mixed micelle solution comprising a corticosteroid such as budesonide and a solubility enhancer. In yet another embodiment, the aqueous inhalation mixture is a liposome solution comprising a corticosteroid such as budesonide and a solubility enhancer.

  In some embodiments of the invention, inhalable compositions comprising corticosteroids do not include nanodispersions and / or nanosuspensions. In other embodiments, inhalable compositions comprising corticosteroids do not include micelles, mixed micelle fluids or liposome fluids. In still other embodiments, inhalable compositions comprising corticosteroids do not include nanodispersions and / or nanosuspensions, micelles, mixed micelle fluids, or liposome fluids. In other embodiments, inhalable compositions include, but are not limited to, solutions, emulsions and colloidal liquids. In one embodiment, the inhalable composition is a solution comprising a corticosteroid such as budesonide and a solubility enhancer. In another embodiment, the inhalable composition is an emulsion comprising a corticosteroid such as budesonide and a solubility enhancer.

  Corticosteroids useful in the inhalable compositions described herein include, but are not limited to, aldosterone, beclomethasone, betamethasone, budesonide, ciclesonide, clopredonol, cortisone, cortibazole, deoxycolton, desonide, desoxymeta Zon, dexamethasone, difluorocortron, fluchlorolone, flumethasone, flunisolide, fluocinolone, fluocinonide, fluocortin butyl, fluorocortisone, fluorocortron, fluorometholone, flulandrenolone, fluticasone, halcinonide, hydrocortisone, icomethasone, meprednisone, methyl Prednisolone, mometasone, parameterzone, prednisolone, prednisone, rofleponide, RPR 106541, thixocort Le, triamcinolone and derivatives of these may be the respective pharmaceutically acceptable thereof. In a preferred embodiment, the corticosteroid is budesonide. In other preferred embodiments, the corticosteroid is either an individual diastereomer of budesonide or a mixture of two diastereomers of budesonide administered individually or together for therapeutic effect.

  In some embodiments of the inhalable compositions described herein, the inhalable composition is one that includes a solvent. In certain embodiments, the solvent is selected from the group comprising water, aqueous alcohol, propylene glycol or an aqueous organic solvent. In a preferred embodiment, the solvent is water.

  In other embodiments of the inhalable compositions described herein, the inhalable composition comprises a solubility enhancer. In some embodiments, 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 still other embodiments, the solubility enhancer can have a concentration (w / v) ranging from about 1% to about 10%. In a preferred embodiment, when the solubility enhancer is a cyclodextrin or cyclodextrin derivative, such as SBE7-β-CD (Captisol®), a concentration (w / w) ranging from about 2% to about 10%. v). In one embodiment, the solubility enhancer may have a concentration (w / v) of about 2% when it is a cyclodextrin or cyclodextrin derivative, such as SBE7-β-CD (Captisol®). In another embodiment, the solubility enhancer may have a concentration (w / v) of about 5% when it is a cyclodextrin or cyclodextrin derivative, such as SBE7-β-CD (Captisol®). In yet another embodiment, the solubility enhancer can have a concentration (w / v) of about 7% when it is a cyclodextrin or cyclodextrin derivative, such as SBE7-β-CD (Captisol®). . In yet another embodiment, the solubility enhancer has a concentration (w / v) of about 10% when it is a cyclodextrin or cyclodextrin derivative, such as SBE7-β-CD (Captisol®). obtain.

  In other embodiments, inhalable compositions for use in the methods of the invention further comprise a solubility enhancer. In certain embodiments, the solubility enhancer is propylene glycol, nonionic surfactant, tyloxapol, polysorbate 80, vitamin E-TPGS, macrogol-15-hydroxystearate, phospholipid, lecithin, purification and / or enrichment. Lecithin, phosphatidylcholine fraction extracted from lecithin, dimyristoylphosphatidylcholine (DMPC), dipalmitoylphosphatidylcholine (DPPC), distearoylphosphatidylcholine (DSPC), cyclodextrin and its derivatives, SAE-CD derivatives, SBE-α-CD, SBE -Β-CD, SBE1-β-CD, SBE4-β-CD, SBE7-β-CD (Captisol®), SBE-γ-CD, dimethyl β-CD, hydroxypropyl-β- Cyclodextrin, 2-HP-β-CD, hydroxyethyl-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, hydroxyethyl-γ-cyclodextrin, dihydroxypropyl-β-cyclodextrin, glucosyl-α-cyclodextrin, Glucosyl-β-cyclodextrin, diglucosyl-β-cyclodextrin, maltosyl-α-cyclodextrin, maltosyl-β-cyclodextrin, maltosyl-γ-cyclodextrin, maltotriosyl-β-cyclodextrin, maltotriosyl-γ- Cyclodextrin, methyl-β-cyclodextrin, carboxyalkyl thioether derivative, ORG 26054, ORG 25969, hydroxypropylmethylcellulose, hydroxypro Le cellulose, polyvinyl pyrrolidone, copolymers of vinyl acetate, vinyl pyrrolidone, sodium lauryl sulfate, dioctyl sodium sulfosuccinate, as well as chemicals that are selected from the group consisting of a combination thereof. In a preferred embodiment, the solubility enhancer is SBE7-β-CD (Captisol®).

  In another specific embodiment, the inhalable composition of the invention comprises cyclodextrin and its derivatives, SAE-CD derivatives, SBE-α-CD, SBΕ-β-CD, SBE1-β-CD, SBE4-β. -CD, SBE7-β-CD (Captisol®), SBE-γ-CD, dimethyl β-CD, hydroxypropyl-β-cyclodextrin, 2-HP-β-CD, hydroxyethyl-β-cyclodextrin , Hydroxypropyl-γ-cyclodextrin, hydroxyethyl-γ-cyclodextrin, dihydroxypropyl-β-cyclodextrin, glucosyl-α-cyclodextrin, glucosyl-β-cyclodextrin, diglucosyl-β-cyclodextrin, maltosyl-α- Cyclodextrin, maltosyl-β-si Improved solubility selected from the group consisting of rhodextrin, maltosyl-γ-cyclodextrin, maltotriosyl-β-cyclodextrin, maltotriosyl-γ-cyclodextrin, dimaltosyl-β-cyclodextrin, methyl-β-cyclodextrin Contains agents. In another specific embodiment, the solubility enhancer is SBE7-β-CD (Captisol®).

  In addition to an aqueous inhalation mixture or inhalable composition comprising a corticosteroid and a solubility enhancer, herein also an aqueous inhalation mixture or composition formulated by a method that provides improved solubility is also disclosed herein. It is envisaged that it is suitable for use in the present invention. Thus, in the context of the present invention, a “solubility enhancer” includes an aqueous inhalation mixture formulated by a method that provides improved solubility with or without a chemical acting as a solubility enhancer. . An example of such a method is the preparation of a supercritical fluid. By such a method, corticosteroid compositions such as budesonide are processed into particles with a narrow particle size distribution (usually less than 200 nanometers wide) and an average hydrodynamic radius of the particles in the range of 50 nanometers to 700 nanometers. Is done. Nano-sized corticosteroid particles (such as budesonide particles) can be used in supercritical fluid (SCF) processes such as supercritical fluid rapid expansion (RESS), or supercritical fluid solution-enhanced dispersion (SEDS), as well as supercritical fluids. Are processed using any other technique involving. The use of the SCF process to form particles is described in Parakodity, S .; Et al., Pharmaceutical Research 16: 976-985 (1999), and Bandi et al., Eur. J. et al. Pharm. Sci. 23: 159-168 (2004), US Pat. No. 6,576,264 and US Patent Application Publication No. 2003/0091513, each of which is specifically incorporated herein by reference. Yes. These methods allow the formation of micron and submicron sized particles having different morphologies depending on the method and parameters selected. These nanoparticles can also be processed by spray drying, freeze drying, volume exclusion and any other conventional particle reduction method.

  In some embodiments of the invention, the inhalable composition for use in the methods of the invention further comprises the group consisting of a β2-adrenergic receptor agonist, a prophylactic therapeutic agent and an anticholinergic agent. A second therapeutic agent that is more selected. In other embodiments of the invention, the β2-adrenergic receptor agonist is albuterol, levalbuterol or a pharmaceutically acceptable derivative.

  In some embodiments of the invention, the inhalable composition is administered to the patient no more than once a day. In other embodiments, the inhalable composition is administered to the patient no more than twice a day. In some embodiments of the invention, the composition is administered to the patient twice a day or more than twice a day. In yet other embodiments, the inhalable composition is administered to the patient no more than once a day in the evening.

  In certain embodiments of the invention, the device is a nebulizer. In other specific embodiments, the nebulizer is a jet nebulizer, an ultrasonic nebulizer, a pulsating membrane nebulizer, a nebulizer having a vibrating mesh or plate with multiple holes, or a nebulizer comprising a vibration generator and an aqueous chamber. In some embodiments of the present invention, the nebulizer is a Pari LC Jet Plus, Intertech, Baxter Misty-Neb, Hudson T-Updraft II, Hudson Ava-Neb, Ailos, Pari LCJet, DeVilbisNs, DeVilbisNs, DeVilbisPs. Neb (B), Hudson T-Updraft Neb-U-Mist, Pari-Jet 1460, and AeroTech with T-piece. In another particular embodiment, the nebulizer is a Pari eFlow nebulizer.

  Any known inhalation nebulizer is suitable for use in the invention described herein. Such nebulizers include, for example, jet nebulizers, ultrasonic nebulizers, pulsatile membrane nebulizers, nebulizers having a vibrating mesh or plate with multiple holes, and nebulizers comprising a vibration generator and an aqueous chamber (eg, Pari eFlow®). )). Commercially available air-driven jet nebulizers, ultrasonic nebulizers or pulsatile membrane nebulizers suitable for use in the present invention include Aeroneb®, Aeroneb GO® (Aerogen, San Francisco, Calif.), Pari LC PLUS. (Registered trademark), Pari Boy® N and Pari Duraneb (registered trademark) (PARI Respiratory Equipment, Inc., Monterrey, CA), MicroAir (registered trademark) (Omron Healthcare, Inc, Vernon Hills, Illinois) Halolite (R) (Profile Therapeutics Inc, Boston, MA), Respirat (R) (Boehring er Ingelheim Ingelheim, Germany), Aerodose (R) (Aerogen, Inc, Mountain View, CA), Omron Elite (R) (Omron Healthcare, Inc, Vernon Hills, Illinois), Omron Microa (R) Healthcare, Inc, Vernon Hills, Illinois), Mabismist II (R) (Mabis Healthcare, Inc, Lake Forest, Illinois), Lumisscope (R) 6610, (The Lumicscope Company, Inc, New York, New York) ), Airsep Mystere®, (AirSep corporation, Buffalo, NY), Acorn-1 and Acorn-II (Vital Signs, Inc, Totowa, NJ), Aquapower® (Medical Industries America, Adel, Iowa), Ava-Neb® Hudson Respiratory Care Incorporated (Temecula, CA), Cirrus (registered trademark) (International Incorporated, Liverpool, New York), Dart (registered trademark) (Professional Medical Product registered in South Carolina, vD Aide (De Vilbiss Corp. Somerset, Pennsylvania), Downdraft (R) (Marquest, Englewood, Colorado), Fan Jet (R) (Marquest, Englewood, Colorado), MB-5 (Mefar, Bovezzo, Italy), Misty Neb® (Baxter, Valencia, Calif.), Salter S900 (Salter Labs, Irvine, Calif.), Sidestream® (Medic-Aid, Sussex, UK), Uρdraft-II® ( Hudson Respiratory Care; Temecula, Calif., Whisper Jet® (Marquest Medical Products, Inc.) Gluwood, Colorado), Aiolos® (Ailos Medinnsk Teknik, Karlstad, Sweden), Inspiron® (Intertech Resources, Inc., Bannockburn, Illinois), Optimist® ed. , McAllen, Texas), Prodomo®, Spira® (Respiratory Care Center, Hemenlinna, Finland), AERx (Aradigm Corporation, Hayward, Calif.), Sonik® LDI Nebulizer (Evit Lit Sacramento, California, and Swirler W Radioaerosol System (AMICI, Inc., Spring City, PA).

  Any of these and other known nebulizers can be used to deliver the aqueous inhalation mixture described in the present invention. In some embodiments, the nebulizer can be, for example, Pari GmbH (Starnberg, Germany), DeVilbiss Healthcare (Heston, Middlesex, UK), Healthdyne, Vital Signs, Baxter, Allied Health Care, Uvacare, Uvacare, Omron, Bremed, AirSep, Luminscope, Mediana, Siemens, Aerogen, Mountain Medical, Aerosol Medical Ltd. (Colechester, Essex, UK), AFP Medical (Rugby, Warwickshire, UK), Bard Ltd. (Sunderland, UK), Carri-Med Ltd. (Dorking, UK), Plaem Nuiva (Brescia, Italy), Henleys Medical Supplements (London, UK), International (Berkshire, UK), Lifecare Hospital Supplements (Reillys, UK), Med-Aid. (West Sussex, UK), Medix Ltd. (Essex, UK), Sinclair Medical Ltd. (Surrey, UK) and many others.

  Other nebulizers suitable for use in the methods and systems described herein include, but are not limited to, jet nebulizers (optionally sold with a compressor), ultrasonic nebulizers, and the like. Exemplary jet nebulizers for use herein include: Pari LC plus / ProNeb, Pari LC plus / ProNeb Turbo, Pari LCPlus / Dura Neb 1000 & 2000 Pari LC plus / Walkhaler, Pari LC Pris Pari LC star, Omron Compair Air XL Portable Nebulizer System (NE-C18 and JetAir Disposable nebulizer), Omron Compreit Elite Compressor NebulizerNebulizer Ultra compressor comprising a Pari LC Plus or Pari LC Star nebulizer, Pulomo-aide, Pulmo-aide LT, Pulmo-aide traveler, Invacare Passport, Inspiration Healthdyne 626, Pulmo-Neb Traveler, DeVilbiss 646, Whisper Jet, AcornII, Misty-Neb , Allied aerosol, Schuco Home Care, Lexan Plastic Pocket Neb, SideStream Hand Held Neb, Mobile Mist, Up-Draft, Up-Draftll, T Up-Draft, ISO-NE , Ava-Neb, Micro Mist, as well as PulmoMate.

  Exemplary ultrasound nebulizers for use herein include: MicroAir, UltraAir, Siemens Ultra Nebulizer 145, CompAir, Pulmosonic, Scout, 5003 Ultrasonic Neb, 5110 Ultrasonic. s Ultrasonic Nebulizer, Mediana Ultrasonic Nebulizer, Microstat Ultrasonic Nebulizer, and Mabismist Hand Held Ultrasonic Nebulizer. Other nebulizers for use herein, 5000 Electromagnetic Neb, 5001 Electromagnetic Neb 5002 Rotary Piston Neb, Lumineb I Piston Nebulizer 5500, Aeroneb Portable Nebulizer System, include Aerodose Inhaler, and AeroEclipse Breath Actuated Nebulizer. An exemplary nebulizer that includes a vibrating mesh or plate having multiple holes is described in R.C. Dhand, New Nebulizer Technology-Aerosol Generation by Using a Vibrating Mesh or Plate with Multiple Apertures, Long-Term Healthcare 3rd. 1-4 and Respiratory Care, 47: 1406-1416 (2002), the disclosures of each of which are incorporated herein by reference.

  Additional nebulizers suitable for use in the invention described herein include nebulizers comprising a vibration generator and an aqueous chamber. Such nebulizers are commercially available, for example, as Pari eFlow, and are described in U.S. Pat. Each of which is specifically incorporated herein by reference).

  Parameters used in nebulization, such as flow rate, mesh membrane size, aerosol inhalation chamber size, mask size and material, valves and power supplies, etc., according to the principles of the present invention to maximize their use, It can vary with different types of aqueous inhalation mixtures or different types of corticosteroids.

  In addition to the nebulizer described above, atomizers are also suitable for the systems and methods described herein for delivery of aqueous inhalation solutions containing corticosteroids and solubility enhancers. Atomizers are known in the art, for example, U.S. Pat. Nos. 5,954,047, 6,026,808, 6,095,141 and 6,527,151 ( Each of which is specifically incorporated herein by reference).

VI. Corticosteroid Inhalation System for Providing Enhanced Lung Deposition Another aspect of the present invention is a therapeutically effective dose of corti comprising (a) an aqueous inhalation mixture comprising a corticosteroid and a solubility enhancer, and (b) a nebulizer. With respect to a system for delivering a costeroid to a patient, upon administration of the composition to a subject via the nebulizer, the system provides at least based on the amount of corticosteroid in the mixture prior to administration. About 20% to about 40%, about 20% to about 50%, or about 20% to about 55% of intrapulmonary deposition (eg, bronchi and alveoli) is achieved. In some embodiments, the system is such that at least about 25% to about 45% lung deposition can be achieved based on the amount of corticosteroid in the mixture prior to administration. In other embodiments, the system is such that at least 35% to about 40% lung deposition can be achieved based on the amount of corticosteroid in the mixture prior to administration. In certain embodiments, the system is one in which about 25% lung deposition is achieved based on the amount of corticosteroid in the mixture prior to administration. In other embodiments, the system is such that at least about 30% lung deposition is achieved based on the amount of corticosteroid in the mixture prior to administration. In still other embodiments, the system is such that at least about 35% lung deposition is achieved based on the amount of corticosteroid in the mixture prior to administration. In yet other embodiments, the system is such that at least about 40% lung deposition is achieved based on the amount of corticosteroid in the mixture prior to administration. In yet other embodiments, the system is such that at least about 45% lung deposition is achieved based on the amount of corticosteroid in the mixture prior to administration. In still other embodiments, the system is such that at least about 50% lung deposition is achieved based on the amount of corticosteroid in the mixture prior to administration. In yet 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. In another embodiment, the corticosteroid is either an individual diastereomer of budesonide or a mixture of two diastereomers of budesonide administered individually or together for therapeutic effect. In certain embodiments, the inhalable composition comprises an effective amount of a single corticosteroid and a solubility enhancer and is substantially free of active pharmaceutical agents other than the corticosteroid. In still other embodiments, the inhalable composition comprises an effective amount of budesonide and a solubility enhancer and is substantially free of active pharmaceutical agents other than budesonide.

  In certain embodiments of the invention, the system for delivering a therapeutically effective dose of a corticosteroid-containing aqueous inhalation mixture by the nebulizer provides at least about 60% respiratory fraction. In another embodiment, the system for delivering a therapeutically effective dose of a corticosteroid-containing aqueous inhalation mixture by the nebulizer provides at least about 75% respiratory fraction. In yet another embodiment, the system for delivering a therapeutically effective dose of an inhaled corticosteroid-containing mixture by the nebulizer provides at least about 80% respiratory fraction. In yet another embodiment, a system for delivering a therapeutically effective dose of a corticosteroid-containing aqueous inhalation mixture by the nebulizer provides at least about 85% respiratory fraction. In one embodiment, the corticosteroid is budesonide. In another embodiment, the corticosteroid is either an individual diastereomer of budesonide or a mixture of two diastereomers of budesonide administered individually or together for therapeutic effect. In certain embodiments, the inhalable composition comprises an effective amount of a single corticosteroid, a solvent and a solubility enhancer, and is substantially free of active pharmaceutical agents other than the corticosteroid. In still other embodiments, the inhalable composition comprises an effective amount of budesonide, a solvent and a solubility enhancer, and is substantially free of active pharmaceutical agents other than budesonide.

  In some embodiments of the invention, the system comprises an aqueous inhalation mixture comprising about 15 to about 2000 μg of corticosteroid in the pre-dose mixture. In other embodiments, the inhalation mixture comprises about 250 to about 2000 μg of corticosteroid in the pre-dose mixture. In still other embodiments, the inhalation mixture comprises about 60 to about 1500 μg of corticosteroid in the pre-dose mixture. In still other embodiments, the inhalation mixture comprises about 100 to about 1000 μg of corticosteroid in the pre-dose mixture. In yet other embodiments, the inhalation mixture comprises about 120 to about 1000 μg of corticosteroid in the pre-dose mixture. In still other embodiments, the inhalation mixture comprises about 125 to about 500 μg of corticosteroid in the pre-dose mixture. In certain embodiments, the inhalation mixture has a corticosteroid amount in the pre-dose mixture of about 40 μg, about 60 μg, about 100 μg, about 120 μg, about 125 μg, about 240 μg, about 250 μg, about 500 μg, about 1000 μg, about 1500 μg, or about 1500 μg. Contains 2000 μg corticosteroid. In one embodiment, the inhalation mixture comprises about 40 μg of corticosteroid in the pre-dose mixture. In another embodiment, the inhalation mixture comprises about 60 μg of corticosteroid in the pre-dose mixture. In yet another embodiment, the inhalation mixture comprises about 100 μg of corticosteroid in the pre-dose mixture. In yet another embodiment, the inhalation mixture comprises about 120 μg of corticosteroid in the pre-dose mixture. In yet another embodiment, the inhalation mixture comprises about 125 μg of corticosteroid in the pre-dose mixture. In yet another embodiment, the inhalation mixture comprises about 240 μg of corticosteroid in the pre-dose mixture. In yet another embodiment, the inhalation mixture comprises less than about 250 μg of corticosteroid in the pre-dose mixture. In one embodiment, the corticosteroid is budesonide. In another embodiment, the corticosteroid is either an individual diastereomer of budesonide or a mixture of two diastereomers of budesonide administered individually or together for therapeutic effect. In certain embodiments, the inhalable composition comprises an effective amount of a single corticosteroid and a solubility enhancer and is substantially free of active pharmaceutical agents other than the corticosteroid. In still other embodiments, the inhalable composition comprises an effective amount of budesonide and a solubility enhancer and is substantially free of active pharmaceutical agents other than budesonide.

  In some embodiments, suitable corticosteroid-containing aqueous inhalation mixtures include, but are not limited to, solutions, dispersions, nanodispersions, emulsions, colloidal liquids, micelles or mixed micelle solutions, and liposome liquids. In one embodiment, the aqueous inhalation mixture is a solution comprising a corticosteroid such as budesonide and a solubility enhancer. In another embodiment, the aqueous inhalation mixture is a mixed micelle solution comprising a corticosteroid such as budesonide and a solubility enhancer. In yet another embodiment, the aqueous inhalation mixture is a liposome solution comprising a corticosteroid such as budesonide and a solubility enhancer. In some embodiments of the invention, inhalable compositions comprising corticosteroids do not include nanodispersions and / or nanosuspensions. In other embodiments, inhalable compositions comprising corticosteroids do not include micelles, mixed micelle fluids or liposome fluids. In yet other embodiments, inhalable compositions comprising corticosteroids do not include nanodispersions and / or nanosuspensions, micelles, mixed micelle fluids or liposome fluids. In other embodiments, inhalable compositions include, but are not limited to, solutions, emulsions and colloidal liquids. In one embodiment, the inhalable composition is a solution comprising a corticosteroid such as budesonide and a solubility enhancer. In another embodiment, the inhalable composition is an emulsion comprising a corticosteroid such as budesonide and a solubility enhancer.

  Corticosteroids useful in the inhalation mixtures described herein include, but are not limited to, aldosterone, beclomethasone, betamethasone, budesonide, ciclesonide, clopredonol, cortisone, cortibazole, deoxycolton, desonide, desoxymethazone, dexamethasone , Difluorocortron, fluchlorolone, flumethasone, flunisolide, fluocinolone, fluocinonide, fluocortin butyl, fluorocortisone, fluorocortron, fluorometholone, flulandrenolone, fluticasone, harcinonide, hydrocortisone, icometazone, meprednisone, methylprednisolone, mometasone , Parameterzone, Prednisolone, Prednisone, Rofleponide, RPR 106541, Thixocortol, Riamushinoron, and each pharmaceutically acceptable derivative thereof. In a preferred embodiment, the corticosteroid is budesonide. In other preferred embodiments, the corticosteroid is either an individual diastereomer of budesonide or a mixture of two diastereomers of budesonide administered individually or together for therapeutic effect.

  In certain embodiments, the systems and methods described herein include a solvent. In certain embodiments, the solvent is selected from the group consisting of water, water / ethanol mixtures, aqueous alcohols, propylene glycol or aqueous organic solvents, or combinations thereof. In certain embodiments, the solvent comprises water. In a preferred embodiment, the solvent is water.

  In other embodiments of the inhalation mixtures described herein, the inhalation mixture includes a solubility enhancer. In some embodiments, 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 still other embodiments, the solubility enhancer can have a concentration (w / v) ranging from about 1% to about 10%. In a preferred embodiment, when the solubility enhancer is a cyclodextrin or cyclodextrin derivative such as SBE7-β-CD (Captisol®), the concentration (w / v) ranges from about 2% to about 10%. ). In one embodiment, the solubility enhancer may have a concentration (w / v) of about 2% when it is a cyclodextrin or cyclodextrin derivative, such as SBE7-β-CD (Captisol®). In another embodiment, the solubility enhancer may have a concentration (w / v) of about 5% when it is a cyclodextrin or cyclodextrin derivative, such as SBE7-β-CD (Captisol®). In yet another embodiment, the solubility enhancer can have a concentration (w / v) of about 7% when it is a cyclodextrin or cyclodextrin derivative, such as SBE7-β-CD (Captisol®). . In yet another embodiment, the solubility enhancer has a concentration (w / v) of about 10% when it is a cyclodextrin or cyclodextrin derivative, such as SBE7-β-CD (Captisol®). obtain.

  In other embodiments, the inhalation mixture for use in the methods of the present invention further comprises a solubility enhancer. In certain embodiments, the solubility enhancer is propylene glycol, nonionic surfactant, tyloxapol, polysorbate 80, vitamin E-TPGS, macrogol-15-hydroxystearate, phospholipid, lecithin, purification and / or enrichment. Lecithin, phosphatidylcholine fraction extracted from lecithin, dimyristoylphosphatidylcholine (DMPC), dipalmitoylphosphatidylcholine (DPPC), distearoylphosphatidylcholine (DSPC), cyclodextrin and its derivatives, SAE-CD derivatives, SBE-α-CD, SBE -Β-CD, SBE1-β-CD, SBE4-β-CD, SBE7-β-CD (Captisol®), SBE-γ-CD, dimethyl β-CD, hydroxypropyl-β- Cyclodextrin, 2-HP-β-CD, hydroxyethyl-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, hydroxyethyl-γ-cyclodextrin, dihydroxypropyl-β-cyclodextrin, glucosyl-α-cyclodextrin, Glucosyl-β-cyclodextrin, diglucosyl-β-cyclodextrin, maltosyl-α-cyclodextrin, maltosyl-β-cyclodextrin, maltosyl-γ-cyclodextrin, maltotriosyl-β-cyclodextrin, maltotriosyl-γ- Cyclodextrin, dimaltosyl-β-cyclodextrin, methyl-β-cyclodextrin, carboxyalkyl thioether derivative, ORG 26054, ORG 25969, hydroxypro A chemical selected from the group consisting of pyrmethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, vinyl acetate copolymer, vinylpyrrolidone, sodium lauryl sulfate, dioctyl sodium sulfosuccinate, and combinations thereof. In a preferred embodiment, the solubility enhancer is SBE7-β-CD (Captisol®).

  In another specific embodiment, the inhalable composition of the invention comprises cyclodextrin and its derivatives, SAE-CD derivatives, SBE-α-CD, SBE-β-CD, SBE1-β-CD, SBE4-β. -CD, SBE7-β-CD (Captisol®), SBE-γ-CD, dimethyl β-CD, hydroxypropyl-β-cyclodextrin, 2-HP-β-CD, hydroxyethyl-β-cyclodextrin , Hydroxypropyl-γ-cyclodextrin, hydroxyethyl-γ-cyclodextrin, dihydroxypropyl-β-cyclodextrin, glucosyl-α-cyclodextrin, glucosyl-β-cyclodextrin, diglucosyl-β-cyclodextrin, maltosyl-α- Cyclodextrin, maltosyl-β-si Improved solubility selected from the group consisting of rhodextrin, maltosyl-γ-cyclodextrin, maltotriosyl-β-cyclodextrin, maltotriosyl-γ-cyclodextrin, dimaltosyl-β-cyclodextrin, methyl-β-cyclodextrin Contains agents. In certain embodiments, the solubility enhancer is SBE7-β-CD (Captisol®).

  In addition to an aqueous inhalation mixture or inhalable composition comprising a corticosteroid and a solubility enhancer, herein also an aqueous inhalation mixture or composition formulated by a method that provides improved solubility is also disclosed herein. It is envisaged that it is suitable for use in the present invention. Thus, in the context of the present invention, a “solubility enhancer” includes an aqueous inhalation mixture formulated by a method that provides improved solubility with or without a chemical acting as a solubility enhancer. . An example of such a method is the preparation of a supercritical fluid. By such a method, corticosteroid compositions such as budesonide are processed into particles with a narrow particle size distribution (usually less than 200 nanometers wide) and an average hydrodynamic radius of the particles in the range of 50 nanometers to 700 nanometers. Is done. Nano-sized corticosteroid particles (such as budesonide particles) can be used in supercritical fluid (SCF) processes such as supercritical fluid rapid expansion (RESS), or supercritical fluid solution-enhanced dispersion (SEDS), as well as supercritical fluids. Are processed using any other technique involving. The use of the SCF process to form particles is described in Parakodity, S .; Et al., Pharmaceutical Research 16: 976-985 (1999), and Bandi et al., Eur. J. et al. Pharm. Sci. 23: 159-168 (2004), US Pat. No. 6,576,264 and US Patent Application Publication No. 2003/0091513, each of which is specifically incorporated herein by reference. Yes.

  In still other embodiments, the nebulizer is a jet nebulizer, an ultrasonic nebulizer, a pulsating membrane nebulizer, a nebulizer having a vibrating mesh or plate with multiple holes, or a nebulizer comprising a vibration generator and an aqueous chamber. In some embodiments of the present invention, the nebulizer is a Pari LC Jet Plus, Intertech, Baxter Misty-Neb, Hudson T-Updraft II, Hudson Ava-Neb, Ailos, Pari LCJet, DeVilbisNs, DeVilbisNs, DeVilbisPs. Neb (B), Hudson T-Updraft Neb-U-Mist, Pari-Jet 1460, and AeroTech with T-piece. In another particular embodiment, the nebulizer is a Pari eFlow nebulizer.

  One aspect of the invention relates to an inhalation system for delivering to a patient a therapeutically effective dose of a corticosteroid comprising (a) an inhalable aqueous mixture comprising a corticosteroid and a solubility enhancer, and (b) a nebulizer, During administration of the inhalable aqueous mixture through the nebulizer, the system allows cortis with enhanced pulmonary deposition compared to an inhalable suspension comprising a corticosteroid administered under the same conditions. Costeroids are delivered. In a preferred embodiment of the present invention, the system achieves a respirable fraction that is at least about 10% higher than an inhalable suspension comprising a corticosteroid administered under the same conditions. is there. In a more preferred embodiment of the invention, the system achieves a respiratory fraction that is at least about 15% higher than an inhalable suspension comprising a corticosteroid administered under the same conditions. is there. In a most preferred embodiment of the invention, the system is such that a respiratory fraction is achieved that is at least about 20% higher compared to an inhalable suspension comprising a corticosteroid administered under the same conditions. is there.

  In a preferred embodiment of the present invention, a system comprising an inhalable aqueous mixture comprising a corticosteroid and a solubility enhancer is compared to an inhalable suspension comprising a corticosteroid administered under the same conditions. At least about 5% higher intrapulmonary deposition is achieved. In another preferred embodiment of the present invention, a system comprising an inhalable aqueous mixture comprising a corticosteroid and a solubility enhancer is compared to an inhalable suspension comprising a corticosteroid administered under the same conditions. At least about 10% higher intrapulmonary deposition is achieved. In a more preferred embodiment of the invention, a system comprising an inhalable aqueous mixture comprising a corticosteroid and a solubility enhancer is compared to an inhalable suspension comprising a corticosteroid administered under the same conditions. At least about 15% higher intrapulmonary deposition is achieved. In another more preferred embodiment of the present invention, a system comprising an inhalable aqueous mixture comprising a corticosteroid and a solubility enhancer is compared to an inhalable suspension comprising a corticosteroid administered under the same conditions. Thus, at least about 20% higher intrapulmonary deposition is achieved. In a most preferred embodiment of the present invention, a system comprising an inhalable aqueous mixture comprising a corticosteroid and a solubility enhancer is compared to an inhalable suspension comprising a corticosteroid administered under the same conditions. At least about 25% higher intrapulmonary deposition is achieved.

  In some embodiments of the invention, a system comprising an inhalable aqueous mixture comprising a corticosteroid and a solubility enhancer is when the composition is administered at a nominal dosage that is less than an inhalable suspension. Compared to inhalable suspensions containing corticosteroids, approximately the same corticosteroid intrapulmonary deposition is achieved. In some embodiments of the invention, a system comprising an inhalable aqueous mixture comprising a corticosteroid and a solubility enhancer is about 90% to 110% as compared to an inhalable suspension comprising a corticosteroid. Corticosteroid intrapulmonary deposition is achieved. In some embodiments of the invention, a system comprising an inhalable aqueous mixture comprising a corticosteroid and a solubility enhancer is about 80% to 120% compared to an inhalable suspension comprising a corticosteroid. Corticosteroid intrapulmonary deposition is achieved. In some embodiments of the invention, a system comprising an inhalable aqueous mixture comprising a corticosteroid and a solubility enhancer is about 70% to 130% compared to an inhalable suspension comprising a corticosteroid. Corticosteroid intrapulmonary deposition is achieved.

  The system described herein allows an inhalable aqueous mixture containing a corticosteroid (eg, budesonide), a solvent and a solubility enhancer to be administered to an individual patient's clinical status, site and method of administration, administration, Considering the plan as well as other factors known to the practitioner, the active ingredient can be delivered in a manner that is delivered according to good medical practice. In human therapy, the systems and methods described herein maintain a therapeutically effective amount of a corticosteroid (eg, budesonide) at the site of action, thereby reducing or alleviating symptoms associated with bronchoconstrictive disorder. Corticosteroid-containing inhalable aqueous mixtures (eg, budesonide solution) can be delivered.

  In another embodiment, the inhalable aqueous mixture comprises a corticosteroid such as budesonide, wherein the inhalable aqueous mixture is no more than twice daily (bid) according to the methods described herein. Be administered. In yet another embodiment, the inhalable aqueous mixture comprises a corticosteroid such as budesonide, and the inhalable aqueous mixture is administered no more than once a day according to the methods described herein. In yet another embodiment, the inhalable aqueous mixture comprises a corticosteroid such as budesonide, and the inhalable aqueous mixture is administered no more than once a day in the evening.

  In yet other embodiments, the system of the invention can deliver a therapeutically effective amount of corticosteroid in a significantly shorter time than conventional inhaled corticosteroid therapy. For example, the nebulization time of Pulmicort® Respules administered by a Pari LC Plus jet nebulizer takes at least 5-8 minutes and in some cases over 10 minutes. In contrast, in the methods and systems of the invention, a therapeutically effective amount of a corticosteroid (such as budesonide) can be delivered at 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. In other embodiments, the delivery time can be less than about 5 minutes. In certain embodiments, the delivery time can be about 4.5 minutes. In other specific 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 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 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 specific 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 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.

  As previously mentioned, the nebulization time of Pulmicort® Repules administered by the Pari LC Plus jet nebulizer can exceed 10 minutes. This long administration time is very burdensome for the patient, especially when the patient is a pediatric patient. Thus, a system or method that can reduce the delivery time by inhalation of corticosteroids can increase patient compliance with treatment regimens. In contrast, in the methods and systems of the present invention, a therapeutically effective amount of a corticosteroid (such as budesonide) can be delivered at 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. In other embodiments, the delivery time can be less than about 5 minutes. In certain embodiments, the delivery time can be about 4.5 minutes. In other specific 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 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 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 specific 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 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.

  In yet another embodiment of the invention, the inhalation mixture for use in the method of the invention is further selected from the group consisting of β2-adrenergic receptor agonists, prophylactic therapeutic agents and anticholinergics. A second therapeutic agent. In other embodiments of the invention, the β2-adrenergic receptor agonist is albuterol, levalbuterol or a pharmaceutically acceptable derivative.

  Another aspect of the 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, wherein the inhalation mixture by the nebulizer Delivery of a corticosteroid with enhanced pulmonary deposition compared to albuterol administered under the same conditions by another nebulizer. One aspect of the invention also 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, wherein the inhalation by the nebulizer Delivery of the mixture delivers a corticosteroid with an improved pharmacokinetic profile compared to albuterol administered under the same conditions by another nebulizer. In some embodiments of the invention, the inhalable composition comprises a corticosteroid.

VII. Corticosteroid inhalation system that results in a decrease in the increase in corticosteroid concentration in the device Another aspect of the invention comprises (a) an aqueous inhalation mixture comprising a corticosteroid, a solvent and a solubility enhancer, and (b) a nebulizer. With respect to an inhalation system for delivering a therapeutically effective dose of a corticosteroid to a patient, the solubility administered by the system under the same conditions upon administration of the composition to a subject via the nebulizer A rate of increase of the corticosteroid concentration in the device of about 60% or less of the rate of increase of the corticosteroid concentration in the device achieved by the inhalable suspension comprising the corticosteroid without an enhancer is achieved. . In certain embodiments, the aqueous inhalation mixture comprises a single corticosteroid and is substantially free of active pharmaceutical agents other than the corticosteroid.

  In certain embodiments, the rate of increase of corticosteroid concentration in the device is achieved over the first 3 minutes of administration. In other embodiments, the rate of increase of corticosteroid concentration in the device is achieved during the second and third 1 minute of administration. In yet other embodiments, the rate of increase of corticosteroid concentration in the device is achieved during the third minute of administration.

  In one embodiment, the invention relates to an inhalable composition wherein administration of the composition through the device is achieved over 5 minutes and administration of the inhalable suspension is achieved over 5 minutes. In another embodiment, the invention relates to an inhalable composition wherein the administration time of the composition through the device and the administration time of the inhalable suspension are the same. In yet another embodiment, the invention relates to an inhalable composition wherein the administration time of the composition through the device differs from the administration time of the inhalable suspension.

  In certain embodiments of the invention, an inhalable composition is also one that achieves a respiratory fraction of at least about 60% when administered. In a more preferred embodiment of the invention, the inhalable composition is also one which achieves at least about 70% respiratory fraction upon administration. In an even more preferred embodiment of the present invention, the inhalable composition is also one which achieves a respiratory fraction of at least about 80% when administered. In the most preferred embodiment of the invention, the inhalable composition is also one which achieves at least about 85% respiratory fraction upon administration.

  In some embodiments of the invention, the system comprises an aqueous inhalation mixture comprising about 15 to about 2000 μg of corticosteroid. In other embodiments, the inhalation mixture comprises about 50 to about 2000 μg of corticosteroid. In still other embodiments, the inhalation mixture comprises about 60 to about 1500 μg of corticosteroid. In yet other embodiments, the inhalation mixture comprises about 100 to about 1000 μg of corticosteroid. In still other embodiments, the inhalation mixture comprises about 120 to about 1000 μg of corticosteroid. In still other embodiments, the inhalation mixture comprises about 125 to about 500 μg of corticosteroid. In certain embodiments, the inhalation mixture comprises about 40 μg, about 60 μg, about 100 μg, about 120 μg, about 125 μg, about 240 μg, about 250 μg, about 500 μg, about 1000 μg, about 1500 μg, or about 2000 μg of corticosteroid. In one embodiment, the inhalation mixture comprises a nominal dosage of about 40 μg of corticosteroid. In another embodiment, the inhalation mixture comprises a nominal dosage of about 60 μg of corticosteroid. In yet another embodiment, the inhalation mixture comprises a nominal dosage of about 100 μg of corticosteroid. In yet another embodiment, the inhalation mixture comprises a nominal dosage of about 120 μg of corticosteroid. In yet another embodiment, the inhalation mixture comprises a nominal dosage of about 125 μg of corticosteroid. In yet another embodiment, the inhalation mixture comprises a nominal dosage of about 240 μg of corticosteroid. In yet another embodiment, the inhalation mixture comprises a nominal dosage of less than about 250 μg of corticosteroid. In one embodiment, the corticosteroid is budesonide. In another embodiment, the corticosteroid is either an individual diastereomer of budesonide or a mixture of two diastereomers of budesonide administered individually or together for therapeutic effect. In certain embodiments, the inhalation mixture comprises an effective amount of a single corticosteroid, a solvent and a solubility enhancer, and is substantially free of active pharmaceutical agents other than the corticosteroid. In still other embodiments, the inhalation mixture comprises an effective amount of budesonide, a solvent and a solubility enhancer and is substantially free of active pharmaceutical agents other than budesonide.

  In some embodiments, suitable corticosteroid-containing aqueous inhalation mixtures include, but are not limited to, solutions, dispersions, nanodispersions, emulsions, colloidal liquids, micelles or mixed micelle solutions, and liposome liquids. In one embodiment, the aqueous inhalation mixture is a solution comprising a corticosteroid such as budesonide and a solubility enhancer. In another embodiment, the aqueous inhalation mixture is a mixed micelle solution comprising a corticosteroid such as budesonide and a solubility enhancer. In yet another embodiment, the aqueous inhalation mixture is a liposome solution comprising a corticosteroid such as budesonide and a solubility enhancer.

  In some embodiments of the invention, inhalable compositions comprising corticosteroids do not include nanodispersions and / or nanosuspensions. In other embodiments, inhalable compositions comprising corticosteroids do not include micelles, mixed micelle fluids or liposome fluids. In still other embodiments, inhalable compositions comprising corticosteroids do not include nanodispersions and / or nanosuspensions, micelles, mixed micelle fluids, or liposome fluids. In other embodiments, inhalable compositions include, but are not limited to, solutions, emulsions and colloidal liquids. In one embodiment, the inhalable composition is a solution comprising a corticosteroid such as budesonide and a solubility enhancer. In another embodiment, the inhalable composition is an emulsion comprising a corticosteroid such as budesonide and a solubility enhancer.

  Corticosteroids useful in the inhalation mixtures described herein include, but are not limited to, aldosterone, beclomethasone, betamethasone, budesonide, ciclesonide, clopredonol, cortisone, cortibazole, deoxycolton, desonide, desoxymethazone, dexamethasone , Difluorocortron, fluchlorolone, flumethasone, flunisolide, fluocinolone, fluocinonide, fluocortin butyl, fluorocortisone, fluorocortron, fluorometholone, flulandrenolone, fluticasone, harcinonide, hydrocortisone, icometazone, meprednisone, methylprednisolone, mometasone , Parameterzone, Prednisolone, Prednisone, Rofleponide, RPR 106541, Thixocortol, Riamushinoron, and each pharmaceutically acceptable derivative thereof. In a preferred embodiment, the corticosteroid is budesonide. In other preferred embodiments, the corticosteroid is either an individual diastereomer of budesonide or a mixture of two diastereomers of budesonide administered individually or together for therapeutic effect.

  In certain embodiments, the systems and methods described herein include a solvent. In certain embodiments, the solvent is selected from the group consisting of water, water / ethanol mixtures, aqueous alcohols, propylene glycol or aqueous organic solvents, or combinations thereof. In certain embodiments, the solvent comprises water. In a preferred embodiment, the solvent is water.

  In certain embodiments of the inhalation mixtures described herein, the inhalation mixture includes a solubility enhancer. In some embodiments, 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 still other embodiments, the solubility enhancer can have a concentration (w / v) ranging from about 1% to about 10%. In a preferred embodiment, when the solubility enhancer is a cyclodextrin or cyclodextrin derivative such as SBE7-β-CD (Captisol®), the concentration (w / v) ranges from about 2% to about 10%. ). In one embodiment, the solubility enhancer may have a concentration (w / v) of about 2% when it is a cyclodextrin or cyclodextrin derivative, such as SBE7-β-CD (Captisol®). In another embodiment, the solubility enhancer may have a concentration (w / v) of about 5% when it is a cyclodextrin or cyclodextrin derivative, such as SBE7-β-CD (Captisol®). In yet another embodiment, the solubility enhancer can have a concentration (w / v) of about 7% when it is a cyclodextrin or cyclodextrin derivative, such as SBE7-β-CD (Captisol®). . In yet another embodiment, the solubility enhancer has a concentration (w / v) of about 10% when it is a cyclodextrin or cyclodextrin derivative, such as SBE7-β-CD (Captisol®). obtain.

  In some embodiments of the invention, the solubility enhancer is propylene glycol, nonionic surfactant, tyloxapol, polysorbate 80, vitamin E-TPGS, macrogol-15-hydroxystearate, phospholipid, lecithin, purified and / Or enriched lecithin, phosphatidylcholine fraction extracted from lecithin, dimyristoylphosphatidylcholine (DMPC), dipalmitoylphosphatidylcholine (DPPC), distearoylphosphatidylcholine (DSPC), cyclodextrin and its derivatives, SAE-CD derivatives, SBE-α -CD, SBE-β-CD, SBE1-β-CD, SBE4-β-CD, SBE7-β-CD (Captisol®), SBE-γ-CD, dimethyl β-CD, hydroxypro -Β-cyclodextrin, 2-HP-β-CD, hydroxyethyl-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, hydroxyethyl-γ-cyclodextrin, dihydroxypropyl-β-cyclodextrin, glucosyl-α -Cyclodextrin, glucosyl-β-cyclodextrin, diglucosyl-β-cyclodextrin, maltosyl-α-cyclodextrin, maltosyl-β-cyclodextrin, maltosyl-γ-cyclodextrin, maltotriosyl-β-cyclodextrin, maltotrio Sil-γ-cyclodextrin, dimaltosyl-β-cyclodextrin, methyl-β-cyclodextrin, carboxyalkyl thioether derivative, ORG 26054, ORG 25969, hydro A chemical selected from the group consisting of xyloxymethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, vinyl acetate copolymer, vinylpyrrolidone, sodium lauryl sulfate, dioctyl sodium sulfosuccinate, and combinations thereof. In certain embodiments, the solubility enhancer is SBE7-β-CD (Captisol®).

  In another specific embodiment, the inhalable composition of the invention comprises cyclodextrin and its derivatives, SAE-CD derivatives, SBE-α-CD, SBE-β-CD, SBE1-β-CD, SBE4-β. -CD, SBE7-β-CD (Captisol®), SBE-γ-CD, dimethyl β-CD, hydroxypropyl-β-cyclodextrin, 2-HP-β-CD, hydroxyethyl-β-cyclodextrin , Hydroxypropyl-γ-cyclodextrin, hydroxyethyl-γ-cyclodextrin, dihydroxypropyl-β-cyclodextrin, glucosyl-α-cyclodextrin, glucosyl-β-cyclodextrin, diglucosyl-β-cyclodextrin, maltosyl-α- Cyclodextrin, maltosyl-β-si Improved solubility selected from the group consisting of rhodextrin, maltosyl-γ-cyclodextrin, maltotriosyl-β-cyclodextrin, maltotriosyl-γ-cyclodextrin, dimaltosyl-β-cyclodextrin, methyl-β-cyclodextrin Contains agents. In certain embodiments, the solubility enhancer is SBE7- / 8-CD (Captisol®).

  In addition to an aqueous inhalation mixture or inhalable composition comprising a corticosteroid and a solubility enhancer, herein also an aqueous inhalation mixture or composition formulated by a method that provides improved solubility is also disclosed herein. It is envisaged that it is suitable for use in the present invention. Thus, in the context of the present invention, a “solubility enhancer” includes an aqueous inhalation mixture formulated by a method that provides improved solubility with or without a chemical acting as a solubility enhancer. . An example of such a method is the preparation of a supercritical fluid. By such a method, corticosteroid compositions such as budesonide are processed into particles with a narrow particle size distribution (usually less than 200 nanometers wide) and an average hydrodynamic radius of the particles in the range of 50 nanometers to 700 nanometers. Is done. Nano-sized corticosteroid particles (such as budesonide particles) can be used in supercritical fluid (SCF) processes such as supercritical fluid rapid expansion (RESS), or supercritical fluid solution-enhanced dispersion (SEDS), as well as supercritical fluids. Are processed using any other technique involving. The use of the SCF process to form particles is described in Parakodity, S .; Et al., Pharmaceutical Research 16: 976-985 (1999), and Bandi et al., Eur. J. et al. Pharm. Sci. 23: 159-168 (2004), US Pat. No. 6,576,264 and US Patent Application Publication No. 2003/0091513, each of which is specifically incorporated herein by reference. Yes.

  In some embodiments of the invention, the composition further comprises a second therapeutic agent selected from the group consisting of β2-adrenergic receptor agonists, prophylactic therapeutic agents, and anticholinergic agents. Is included. In some embodiments of the invention, the β2-adrenergic receptor agonist is albuterol, levalbuterol or a pharmaceutically acceptable derivative.

  In another embodiment, the inhalable aqueous mixture comprises a corticosteroid such as budesonide, wherein the inhalable aqueous mixture is no more than twice daily (bid) according to the methods described herein. Be administered. In yet another embodiment, the inhalable aqueous mixture comprises a corticosteroid such as budesonide, and the inhalable aqueous mixture is administered no more than once a day according to the methods described herein. In yet another embodiment, the inhalable aqueous mixture comprises a corticosteroid such as budesonide, and the inhalable aqueous mixture is administered no more than once a day in the evening.

  In some embodiments of the invention, the nebulizer is a jet nebulizer, an ultrasonic nebulizer, a pulsating membrane nebulizer, a nebulizer having a vibrating mesh or plate with multiple holes, or a nebulizer comprising a vibration generator and an aqueous chamber. . In some embodiments of the present invention, the nebulizer is a Pari LC Jet Plus, Intertech, Baxter Misty-Neb, Hudson T-Updraft II, Hudson Ava-Neb, Ailos, Pari LCJet, DeVilbisNs, DeVilbisNs, DeVilbisPs. Neb (B), Hudson T-Updraft Neb-U-Mist, Pari-Jet 1460, and AeroTech with T-piece. In certain embodiments, the nebulizer is a Pari eFlow nebulizer.

VIII. Methods of treatment to achieve enhanced pulmonary deposition In other embodiments of the invention, methods are provided for the delivery of therapeutically effective doses of corticosteroids to a patient. In certain embodiments, the methods described herein include providing an inhalable aqueous mixture comprising a corticosteroid, a solvent and a solubility enhancer, and delivering the aqueous inhalation mixture by an inhalation nebulizer. Relates to the treatment of bronchoconstrictive disorders in patients.

  In certain embodiments, the present invention provides a method for treating a bronchoconstrictive disorder in a patient in need of treatment of a bronchoconstrictive disorder, the method comprising a solvent and a solubility enhancer in an amount of corti. Forming a mixture by adding to a costeroid, and activating a nebulizer, wherein upon administration of the mixture to a subject via the nebulizer, the method causes cortico in the mixture prior to administration. Based on the amount of steroid, at least about 20% to about 40%, about 20% to about 50%, or about 20% to about 55% intrapulmonary deposition (eg, bronchi and alveoli) can be achieved. In some embodiments, the method can achieve at least about 20% to about 35% lung deposition based on the amount of corticosteroid in the mixture prior to administration. In other embodiments, the method can achieve at least 20% to about 30% lung deposition based on the amount of corticosteroid in the mixture prior to administration. In certain embodiments, the method achieves about 25% lung deposition based on the amount of corticosteroid in the composition prior to administration. In other embodiments, the method achieves at least about 30% lung deposition based on the amount of corticosteroid in the composition prior to administration. In yet other embodiments, the method achieves at least about 35% lung deposition based on the amount of corticosteroid in the composition prior to administration. In yet other embodiments, the method achieves at least about 40% lung deposition based on the amount of corticosteroid in the composition prior to administration. In still other embodiments, the method achieves at least about 45% lung deposition based on the amount of corticosteroid in the composition prior to administration. In yet other embodiments, the method achieves at least about 50% lung deposition based on the amount of corticosteroid in the composition prior to administration. In other embodiments, the method achieves 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. In another embodiment, the corticosteroid is either an individual diastereomer of budesonide or a mixture of two diastereomers of budesonide administered individually or together for therapeutic effect. In certain embodiments, the inhalable composition comprises an effective amount of a single corticosteroid and a solubility enhancer and is substantially free of active pharmaceutical agents other than the corticosteroid. In still other embodiments, the inhalable composition comprises an effective amount of budesonide and a solubility enhancer and is substantially free of active pharmaceutical agents other than budesonide.

  In other embodiments of the invention, the method also achieves at least about 60% respiratory fraction when administered. In a more preferred embodiment of the invention, the method also achieves at least about 70% respiratory fraction upon administration. In an even more preferred embodiment of the invention, the method also achieves at least about 80% respiratory fraction when administered. In the most preferred embodiments of the invention, the method also achieves at least about 85% respiratory fraction upon administration. In one embodiment, the corticosteroid is budesonide. In another embodiment, the corticosteroid is either an individual diastereomer of budesonide or a mixture of two diastereomers of budesonide administered individually or together for therapeutic effect. In certain embodiments, the inhalable composition comprises an effective amount of a single corticosteroid and a solubility enhancer and is substantially free of active pharmaceutical agents other than the corticosteroid. In still other embodiments, the inhalable composition comprises an effective amount of budesonide and a solubility enhancer and is substantially free of active pharmaceutical agents other than budesonide.

  In certain embodiments, a method for treating bronchoconstrictive disorder includes delivery of an inhalable aqueous mixture comprising a corticosteroid. Corticosteroids useful in the present invention include, but are not limited to, aldosterone, beclomethasone, betamethasone, budesonide, ciclesonide, clopredonol, cortisone, cortibazole, deoxycorton, desonide, desoxymethasone, dexamethasone, difluorocortron, fluchlorolone. , Flumethasone, flunisolide, fluocinolone, fluocinonide, fluocortin butyl, fluorocortisone, fluorocortron, fluorometholone, flulandrenolone, fluticasone, halcinonide, hydrocortisone, icometazone, meprednisone, methylprednisolone, mometasone, parameterzone, prednisone, prednisone , Rofleponide, RPR 106541, Thixocortol, Triamcinolol , And the respective pharmaceutically acceptable derivatives thereof. In some embodiments, the corticosteroid is budesonide. In other embodiments, the corticosteroid is either an individual diastereomer of budesonide or a mixture of two diastereomers of budesonide administered individually or together for therapeutic effect.

  In some embodiments of the invention, the method of treatment comprises an aqueous inhalation mixture comprising about 15 to about 2000 μg of corticosteroid in the pre-dose mixture. In other embodiments, the inhalation mixture comprises about 250 to about 2000 μg of corticosteroid in the pre-dose mixture. In still other embodiments, the inhalation mixture comprises about 60 to about 1500 μg of corticosteroid in the pre-dose mixture. In still other embodiments, the inhalation mixture comprises about 100 to about 1000 μg of corticosteroid in the pre-dose mixture. In yet other embodiments, the inhalation mixture comprises about 120 to about 1000 μg of corticosteroid in the pre-dose mixture. In still other embodiments, the inhalation mixture comprises about 125 to about 500 μg of corticosteroid in the pre-dose mixture. In certain embodiments, the inhalation mixture has a corticosteroid amount in the pre-dose mixture of about 40 μg, about 60 μg, about 100 μg, about 120 μg, about 125 μg, about 240 μg, about 250 μg, about 500 μg, about 1000 μg, about 1500 μg, or about 1500 μg. Contains 2000 μg corticosteroid. In one embodiment, the inhalation mixture comprises about 40 μg of corticosteroid in the pre-dose mixture. In another embodiment, the inhalation mixture comprises about 60 μg of corticosteroid in the pre-dose mixture. In yet another embodiment, the inhalation mixture comprises about 100 μg of corticosteroid in the pre-dose mixture. In yet another embodiment, the inhalation mixture comprises about 120 μg of corticosteroid in the pre-dose mixture. In yet another embodiment, the inhalation mixture comprises about 125 μg of corticosteroid in the pre-dose mixture. In yet another embodiment, the inhalation mixture comprises about 240 μg of corticosteroid in the pre-dose mixture. In yet another embodiment, the inhalation mixture comprises less than about 250 μg of corticosteroid in the pre-dose mixture. In one embodiment, the corticosteroid is budesonide. In another embodiment, the corticosteroid is either an individual diastereomer of budesonide or a mixture of two diastereomers of budesonide administered individually or together for therapeutic effect. In certain embodiments, the inhalable composition comprises an effective amount of a single corticosteroid, a solvent and a solubility enhancer, and is substantially free of active pharmaceutical agents other than the corticosteroid. In still other embodiments, the inhalable composition comprises an effective amount of budesonide, a solvent and a solubility enhancer, and is substantially free of active pharmaceutical agents other than budesonide.

  In certain embodiments, the inhalation mixture comprises about 40 μg budesonide, a solvent and a solubility enhancer, and at least 13 μg budesonide intrapulmonary upon administration of the composition to the subject via the nebulizer. Deposition can be achieved. In another specific embodiment, the inhalation mixture comprises about 60 μg budesonide, a solvent and a solubility enhancer, and at least 20 μg budesonide upon administration of the composition to the subject via the nebulizer. Intrapulmonary deposition may be achieved. In still other embodiments, the inhalable composition comprises about 120 μg budesonide, a solvent and a solubility enhancer, and at least 40 μg budesonide upon administration of the composition to a subject via the nebulizer. Intrapulmonary deposition can be achieved. In still other embodiments, the inhalable composition comprises about 240 μg budesonide, a solvent and a solubility enhancer, and at least 80 μg budesonide upon administration of the composition to a subject via the nebulizer. Intrapulmonary deposition can be achieved.

  In certain embodiments, the inhalation mixture comprises about 40 μg budesonide, a solvent and a solubility enhancer, and at least 13 μg budesonide intrapulmonary upon administration of the composition to the subject via the nebulizer. Deposition can be achieved and the composition is substantially free of active pharmaceutical agents other than budesonide. In another specific embodiment, the inhalation mixture comprises about 60 μg budesonide, a solvent and a solubility enhancer, and at least 20 μg budesonide upon administration of the composition to the subject via the nebulizer. Intrapulmonary deposition can be achieved and the composition is substantially free of active pharmaceutical agents other than budesonide. In still other embodiments, the inhalable composition comprises about 120 μg budesonide, a solvent and a solubility enhancer, and at least 40 μg budesonide upon administration of the composition to a subject via the nebulizer. Intrapulmonary deposition can be achieved and the composition is substantially free of active pharmaceutical agents other than budesonide. In still other embodiments, the inhalable composition comprises about 240 μg budesonide, a solvent and a solubility enhancer, and at least 80 μg budesonide upon administration of the composition to a subject via the nebulizer. In the lung, and the composition is substantially free of active pharmaceutical agents other than budesonide.

  In some embodiments, suitable corticosteroid-containing aqueous inhalation mixtures include, but are not limited to, solutions, dispersions, nanodispersions, emulsions, colloidal liquids, micelles or mixed micelle solutions, and liposome liquids. In one embodiment, the aqueous inhalation mixture is a solution comprising a corticosteroid such as budesonide and a solubility enhancer. In another embodiment, the aqueous inhalation mixture is a mixed micelle solution comprising a corticosteroid such as budesonide and a solubility enhancer. In yet another embodiment, the aqueous inhalation mixture is a liposome solution comprising a corticosteroid such as budesonide and a solubility enhancer.

  In some embodiments of the invention, inhalable compositions comprising corticosteroids do not include nanodispersions and / or nanosuspensions. In other embodiments, inhalable compositions comprising corticosteroids do not include micelles, mixed micelle fluids or liposome fluids. In still other embodiments, inhalable compositions comprising corticosteroids do not include nanodispersions and / or nanosuspensions, micelles, mixed micelle fluids, or liposome fluids. In other embodiments, inhalable compositions include, but are not limited to, solutions, emulsions and colloidal liquids. In one embodiment, the inhalable composition is a solution comprising a corticosteroid such as budesonide and a solubility enhancer. In another embodiment, the inhalable composition is an emulsion comprising a corticosteroid such as budesonide and a solubility enhancer. In certain embodiments, the systems and methods described herein include a solvent. In certain embodiments, the solvent is selected from the group consisting of water, water / ethanol mixtures, aqueous alcohols, propylene glycol or aqueous organic solvents, or combinations thereof. In certain embodiments, the solvent comprises water. In a preferred embodiment, the solvent is water.

  In some embodiments, a method of treating bronchoconstrictive disorder includes delivery of an inhalable aqueous mixture comprising a corticosteroid and a solvent. In certain embodiments, the solvent is selected from the group consisting of water, aqueous alcohol, propylene glycol, or aqueous organic solvent. In a preferred embodiment, the solvent is water.

  In certain embodiments of the inhalation mixtures described herein, the inhalation mixture includes a solubility enhancer. In some embodiments, 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 still other embodiments, the solubility enhancer can have a concentration (w / v) ranging from about 1% to about 10%. In a preferred embodiment, when the solubility enhancer is a cyclodextrin or cyclodextrin derivative such as SBE7-β-CD (Captisol®), the concentration (w / v) ranges from about 2% to about 10%. ). In one embodiment, the solubility enhancer may have a concentration (w / v) of about 2% when it is a cyclodextrin or cyclodextrin derivative, such as SBE7-β-CD (Captisol®). In another embodiment, the solubility enhancer may have a concentration (w / v) of about 5% when it is a cyclodextrin or cyclodextrin derivative, such as SBE7-β-CD (Captisol®). In yet another embodiment, the solubility enhancer can have a concentration (w / v) of about 7% when it is a cyclodextrin or cyclodextrin derivative, such as SBE7-β-CD (Captisol®). . In yet another embodiment, the solubility enhancer has a concentration (w / v) of about 10% when it is a cyclodextrin or cyclodextrin derivative, such as SBE7-β-CD (Captisol®). obtain.

  In some embodiments of the invention, the method of treating bronchoconstrictive disorder includes delivery of an inhalable aqueous mixture comprising a corticosteroid and a solubility enhancer. In certain embodiments, the solubility enhancer is propylene glycol, nonionic surfactant, tyloxapol, polysorbate 80, vitamin E-TPGS, macrogol-15-hydroxystearate, phospholipid, lecithin, purification and / or enrichment. Lecithin, phosphatidylcholine fraction extracted from lecithin, dimyristoylphosphatidylcholine (DMPC), dipalmitoylphosphatidylcholine (DPPC), distearoylphosphatidylcholine (DSPC), cyclodextrin and its derivatives, SAE-CD derivatives, SBE-α-CD, SBE -Β-CD, SBE1-β-CD, SBE4-β-CD, SBE7-β-CD (Captisol®), SBE-γ-CD, dimethyl β-CD, hydroxypropyl-β- Cyclodextrin, 2-HP-β-CD, hydroxyethyl-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, hydroxyethyl-γ-cyclodextrin, dihydroxypropyl-β-cyclodextrin, glucosyl-α-cyclodextrin, Glucosyl-β-cyclodextrin, diglucosyl-β-cyclodextrin, maltosyl-α-cyclodextrin, maltosyl-β-cyclodextrin, maltosyl-γ-cyclodextrin, maltotriosyl-β-cyclodextrin, maltotriosyl-γ- Cyclodextrin, dimaltosyl-β-cyclodextrin, methyl-β-cyclodextrin, carboxyalkyl thioether derivative, ORG 26054, ORG 25969, hydroxypro A chemical selected from the group consisting of pyrmethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, vinyl acetate copolymer, vinylpyrrolidone, sodium lauryl sulfate, dioctyl sodium sulfosuccinate, and combinations thereof. In another embodiment, the solubility enhancer is SBE7-β-CD (Captisol®).

  In another specific embodiment, the inhalable composition of the invention comprises cyclodextrin and its derivatives, SAE-CD derivatives, SBE-α-CD, SBE-β-CD, SBE1-β-CD, SBE4-β. -CD, SBE7-β-CD (Captisol®), SBE-γ-CD, dimethyl β-CD, hydroxypropyl-β-cyclodextrin, 2-HP-β-CD, hydroxyethyl-β-cyclodextrin , Hydroxypropyl-γ-cyclodextrin, hydroxyethyl-γ-cyclodextrin, dihydroxypropyl-β-cyclodextrin, glucosyl-α-cyclodextrin, glucosyl-β-cyclodextrin, diglucosyl-β-cyclodextrin, maltosyl-α- Cyclodextrin, maltosyl-β-si Improved solubility selected from the group consisting of rhodextrin, maltosyl-γ-cyclodextrin, maltotriosyl-β-cyclodextrin, maltotriosyl-γ-cyclodextrin, dimaltosyl-β-cyclodextrin, methyl-β-cyclodextrin Contains agents. In certain embodiments, the solubility enhancer is SBE7-β-CD (Captisol®).

  In addition to an aqueous inhalation mixture or inhalable composition comprising a corticosteroid and a solubility enhancer, herein also an aqueous inhalation mixture or composition formulated by a method that provides improved solubility is also disclosed herein. It is envisaged that it is suitable for use in the present invention. Thus, in the context of the present invention, a “solubility enhancer” includes an aqueous inhalation mixture formulated by a method that provides improved solubility with or without a chemical acting as a solubility enhancer. . An example of such a method is the preparation of a supercritical fluid. By such a method, corticosteroid compositions such as budesonide are processed into particles with a narrow particle size distribution (usually less than 200 nanometers wide) and an average hydrodynamic radius of the particles in the range of 50 nanometers to 700 nanometers. Is done. Nano-sized corticosteroid particles (such as budesonide particles) can be used in supercritical fluid (SCF) processes such as supercritical fluid rapid expansion (RESS), or supercritical fluid solution-enhanced dispersion (SEDS), as well as supercritical fluids. Are processed using any other technique involving. The use of the SCF process to form particles is described in Parakodity, S .; Et al., Pharmaceutical Research 16: 976-985 (1999), and Bandi et al., Eur. J. et al. Pharm. Sci. 23: 159-168 (2004), US Pat. No. 6,576,264 and US Patent Application Publication No. 2003/0091513, each of which is specifically incorporated herein by reference. Yes.

  In some embodiments of the invention, the composition further comprises a second therapeutic agent selected from the group consisting of β2-adrenergic receptor agonists, prophylactic therapeutic agents, and anticholinergic agents. Is included. In some embodiments of the invention, the β2-adrenergic receptor agonist is albuterol, levalbuterol or a pharmaceutically acceptable derivative.

  In certain embodiments of the invention, the bronchoconstrictive disorder is from the group consisting of asthma, childhood asthma, bronchial asthma, allergic asthma, endogenous asthma, chronic obstructive pulmonary disease (COPD), chronic bronchitis and emphysema Selected.

  In another embodiment, the inhalable aqueous mixture comprises a corticosteroid such as budesonide, wherein the inhalable aqueous mixture is no more than twice daily (bid) according to the methods described herein. Be administered. In yet another embodiment, the inhalable aqueous mixture comprises a corticosteroid such as budesonide, and the inhalable aqueous mixture is administered no more than once a day according to the methods described herein. In yet another embodiment, the inhalable aqueous mixture comprises a corticosteroid such as budesonide, and the inhalable aqueous mixture is administered no more than once a day in the evening.

  In some embodiments of the invention, the nebulizer is a jet nebulizer, an ultrasonic nebulizer, a pulsating membrane nebulizer, a nebulizer having a vibrating mesh or plate with multiple holes, or a nebulizer comprising a vibration generator and an aqueous chamber. . In some embodiments of the present invention, the nebulizer is a Pari LC Jet Plus, Intertech, Baxter Misty-Neb, Hudson T-Updraft II, Hudson Ava-Neb, Ailos, Pari LCJet, DeVilbisNs, DeVilbisNs, DeVilbisPs. Neb (B), Hudson T-Updraft Neb-U-Mist, Pari-Jet 1460, and AeroTech with T-piece. In certain embodiments, the nebulizer is a Pari eFlow nebulizer.

  In still other embodiments, the present invention may provide a method for treating a bronchoconstrictive disorder in a patient, the method providing an inhalable aqueous mixture comprising a corticosteroid, a solvent and a solubility enhancer. About 10 corticosteroids delivered to the outside of the lung, for example, the mouth, esophagus and / or stomach, by delivering the aqueous inhalable mixture by inhalation nebulizer. % To about 30% or less. In one embodiment, the method can provide delivery of an inhalable aqueous mixture that is about 10% or less of the corticosteroid delivered outside the lung. In another embodiment, the method can provide delivery of an inhalable aqueous mixture that is about 15% or less of the corticosteroid delivered outside the lung. In yet another embodiment, the method can provide delivery of an inhalable aqueous mixture that has no more than about 20% corticosteroid delivered outside the lung. In yet another embodiment, the method may provide delivery of an inhalable aqueous mixture that has no more than about 25% corticosteroid delivered outside the lung. In yet another embodiment, the method can provide delivery of an inhalable aqueous mixture that is about 30% or less of the corticosteroid delivered to the exterior of the lung.

  In other embodiments, the invention provides a bronchoconstriction of a patient comprising providing an inhalable aqueous mixture comprising a corticosteroid, a solvent and a solubility enhancer, and delivering the aqueous inhalation mixture by an inhalation nebulizer. Methods for the prevention of sexual disorders can be provided. In another embodiment, the present invention provides a method for reducing the risk of side effects associated with corticosteroid inhalation therapy, as needed to obtain a therapeutic effect as compared to conventional inhaled corticosteroid therapy. A method can be provided in which the nominal dosage of corticosteroids taken is low. In one embodiment, the risk of side effects is reduced compared to conventional inhaled corticosteroid therapy.

IX. Method of treatment resulting in reduced increase in corticosteroid concentration in the device A further aspect of the invention relates to a method of treating a bronchoconstrictive disorder in a patient in need thereof, the method comprising a solvent and a solubility enhancer. Forming the composition by adding to the corticosteroid, and activating the nebulizer, wherein the composition is administered under the same conditions upon administration of the composition to the subject via the nebulizer. A rate of increase in corticosteroid concentration in the device of about 60% or less of the rate of increase in corticosteroid concentration in the device achieved by the inhalable suspension containing the corticosteroid without a solubility enhancer is achieved. Is done. In certain embodiments, the composition comprises a single corticosteroid and is substantially free of active pharmaceutical agents other than the corticosteroid. In other embodiments of the invention, the corticosteroid is budesonide or a pharmaceutically acceptable derivative. In still other embodiments, the corticosteroid is either an individual diastereomer of budesonide or a mixture of two diastereomers of budesonide administered individually or together for therapeutic effect.

  In certain embodiments, the rate of increase of corticosteroid concentration in the device is achieved over the first 3 minutes of administration. In other embodiments, the rate of increase of corticosteroid concentration in the device is achieved during the second and third 1 minute of administration. In yet other embodiments, the rate of increase of corticosteroid concentration in the device is achieved during the third minute of administration.

  In one embodiment, the invention relates to an inhalable composition wherein administration of the composition through the device is achieved over 5 minutes and administration of the inhalable suspension is achieved over 5 minutes. In another embodiment, the invention relates to an inhalable composition wherein the administration time of the composition through the device and the administration time of the inhalable suspension are the same. In yet another embodiment, the invention relates to an inhalable composition wherein the administration time of the composition through the device differs from the administration time of the inhalable suspension.

  In certain embodiments of the invention, an inhalable composition is also one that achieves a respiratory fraction of at least about 60% when administered. In a preferred embodiment of the present invention, the inhalable composition is also one that achieves a respiratory fraction of at least about 70% when administered. In a more preferred embodiment of the invention, the inhalable composition is also one which achieves at least about 80% respiratory fraction upon administration. In the most preferred embodiment of the invention, the inhalable composition is also one which achieves at least about 85% respiratory fraction upon administration.

  In some embodiments of the invention, the system comprises an aqueous inhalation mixture comprising about 15 to about 2000 μg of corticosteroid. In other embodiments, the inhalation mixture comprises about 50 to about 2000 μg of corticosteroid. In still other embodiments, the inhalation mixture comprises about 60 to about 1500 μg of corticosteroid. In yet other embodiments, the inhalation mixture comprises about 100 to about 1000 μg of corticosteroid. In still other embodiments, the inhalation mixture comprises about 120 to about 1000 μg of corticosteroid. In still other embodiments, the inhalation mixture comprises about 125 to about 500 μg of corticosteroid. In certain embodiments, the inhalation mixture comprises about 40 μg, about 60 μg, about 100 μg, about 120 μg, about 125 μg, about 240 μg, about 250 μg, about 500 μg, about 1000 μg, about 1500 μg, or about 2000 μg of corticosteroid. In one embodiment, the inhalation mixture comprises a nominal dosage of about 40 μg of corticosteroid. In another embodiment, the inhalation mixture comprises a nominal dosage of about 60 μg of corticosteroid. In yet another embodiment, the inhalation mixture comprises a nominal dosage of about 100 μg of corticosteroid. In yet another embodiment, the inhalation mixture comprises a nominal dosage of about 120 μg of corticosteroid. In yet another embodiment, the inhalation mixture comprises a nominal dosage of about 125 μg of corticosteroid. In yet another embodiment, the inhalation mixture comprises a nominal dosage of about 240 μg of corticosteroid. In yet another embodiment, the inhalation mixture comprises a nominal dosage of less than about 250 μg of corticosteroid. In other embodiments of the invention, the corticosteroid is budesonide or a pharmaceutically acceptable derivative. In other preferred embodiments, the corticosteroid is either an individual diastereomer of budesonide or a mixture of two diastereomers of budesonide administered individually or together for therapeutic effect.

  In some embodiments, suitable corticosteroid-containing aqueous inhalation mixtures include, but are not limited to, solutions, dispersions, nanodispersions, emulsions, colloidal liquids, micelles or mixed micelle solutions, and liposome liquids. In one embodiment, the aqueous inhalation mixture is a solution comprising a corticosteroid such as budesonide and a solubility enhancer. In another embodiment, the aqueous inhalation mixture is a mixed micelle solution comprising a corticosteroid such as budesonide and a solubility enhancer. In yet another embodiment, the aqueous inhalation mixture is a liposome solution comprising a corticosteroid such as budesonide and a solubility enhancer.

  In some embodiments of the invention, inhalable compositions comprising corticosteroids do not include nanodispersions and / or nanosuspensions. In other embodiments, inhalable compositions comprising corticosteroids do not include micelles, mixed micelle fluids or liposome fluids. In still other embodiments, inhalable compositions comprising corticosteroids do not include nanodispersions and / or nanosuspensions, micelles, mixed micelle fluids, or liposome fluids. In other embodiments, inhalable compositions include, but are not limited to, solutions, emulsions and colloidal liquids. In one embodiment, the inhalable composition is a solution comprising a corticosteroid such as budesonide and a solubility enhancer. In another embodiment, the inhalable composition is an emulsion comprising a corticosteroid such as budesonide and a solubility enhancer.

  In certain embodiments, the systems and methods described herein include a solvent. In certain embodiments, the solvent is selected from the group consisting of water, water / ethanol mixtures, aqueous alcohols, propylene glycol or aqueous organic solvents, or combinations thereof. In certain embodiments, the solvent comprises water. In a preferred embodiment, the solvent is water.

  In certain embodiments of the inhalation mixtures described herein, the inhalation mixture includes a solubility enhancer. In some embodiments, 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 still other embodiments, the solubility enhancer can have a concentration (w / v) ranging from about 1% to about 10%. In a preferred embodiment, when the solubility enhancer is a cyclodextrin or cyclodextrin derivative such as SBE7-β-CD (Captisol®), the concentration (w / v) ranges from about 2% to about 10%. ). In one embodiment, the solubility enhancer may have a concentration (w / v) of about 2% when it is a cyclodextrin or cyclodextrin derivative, such as SBE7-β-CD (Captisol®). In another embodiment, the solubility enhancer may have a concentration (w / v) of about 5% when it is a cyclodextrin or cyclodextrin derivative, such as SBE7-β-CD (Captisol®). In yet another embodiment, the solubility enhancer can have a concentration (w / v) of about 7% when it is a cyclodextrin or cyclodextrin derivative, such as SBE7-β-CD (Captisol®). . In yet another embodiment, the solubility enhancer has a concentration (w / v) of about 10% when it is a cyclodextrin or cyclodextrin derivative, such as SBE7-β-CD (Captisol®). obtain.

  In some embodiments of the invention, the solubility enhancer is propylene glycol, nonionic surfactant, tyloxapol, polysorbate 80, vitamin E-TPGS, macrogol-15-hydroxystearate, phospholipid, lecithin, purified and / Or enriched lecithin, phosphatidylcholine fraction extracted from lecithin, dimyristoylphosphatidylcholine (DMPC), dipalmitoylphosphatidylcholine (DPPC), distearoylphosphatidylcholine (DSPC), cyclodextrin and its derivatives, SAE-CD derivatives, SBE-α -CD, SBE-β-CD, SBE1-β-CD, SBE4-β-CD, SBE7-β-CD (Captisol®), SBE-γ-CD, dimethyl β-CD, hydroxypro -Β-cyclodextrin, 2-HP-β-CD, hydroxyethyl-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, hydroxyethyl-γ-cyclodextrin, dihydroxypropyl-β-cyclodextrin, glucosyl-α -Cyclodextrin, glucosyl-β-cyclodextrin, diglucosyl-β-cyclodextrin, maltosyl-α-cyclodextrin, maltosyl-β-cyclodextrin, maltosyl-γ-cyclodextrin, maltotriosyl-β-cyclodextrin, maltotrio Sil-γ-cyclodextrin, dimaltosyl-β-cyclodextrin, methyl-β-cyclodextrin, carboxyalkyl thioether derivative, ORG 26054, ORG 25969, hydro A chemical selected from the group consisting of xyloxymethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, vinyl acetate copolymer, vinylpyrrolidone, sodium lauryl sulfate, dioctyl sodium sulfosuccinate, and combinations thereof. In certain embodiments, the solubility enhancer is SBE7-β-CD (Captisol®).

  In another specific embodiment, the inhalable composition of the invention comprises cyclodextrin and its derivatives, SAE-CD derivatives, SBE-α-CD, SBE-β-CD, SBE1-β-CD, SBE4-β. -CD, SBE7-β-CD (Captisol®), SBE-γ-CD, dimethyl β-CD, hydroxypropyl-β-cyclodextrin, 2-HP-β-CD, hydroxyethyl-β-cyclodextrin , Hydroxypropyl-γ-cyclodextrin, dihydroxypropyl-β-cyclodextrin, glucosyl-α-cyclodextrin, glucosyl-β-cyclodextrin, diglucosyl-β-cyclodextrin, maltosyl-α-cyclodextrin, maltosyl-β-cyclo Dextrin, maltosyl-γ-cyclode Including string, maltotriosyl -β- cyclodextrin, maltotriosyl -γ- cyclodextrin, dimaltosyl -β- cyclodextrin, the solubility enhancer selected from the group consisting of methyl -β- cyclodextrin. In another specific embodiment, the solubility enhancer is SBE7-β-CD (Captisol®).

  In addition to an aqueous inhalation mixture or inhalable composition comprising a corticosteroid and a solubility enhancer, herein also an aqueous inhalation mixture or composition formulated by a method that provides improved solubility is also disclosed herein. It is envisaged that it is suitable for use in the present invention. Thus, in the context of the present invention, a “solubility enhancer” includes an aqueous inhalation mixture formulated by a method that provides improved solubility with or without a chemical acting as a solubility enhancer. . An example of such a method is the preparation of a supercritical fluid. By such a method, corticosteroid compositions such as budesonide are processed into particles with a narrow particle size distribution (usually less than 200 nanometers wide) and an average hydrodynamic radius of the particles in the range of 50 nanometers to 700 nanometers. Is done. Nano-sized corticosteroid particles (such as budesonide particles) can be used in supercritical fluid (SCF) processes such as supercritical fluid rapid expansion (RESS), or supercritical fluid solution-enhanced dispersion (SEDS), as well as supercritical fluids. Are processed using any other technique involving. The use of the SCF process to form particles is described in Parakodity, S .; Et al., Pharmaceutical Research 16: 976-985 (1999), and Bandi et al., Eur. J. et al. Pharm. Sci. 23: 159-168 (2004), US Pat. No. 6,576,264 and US Patent Application Publication No. 2003/0091513, each of which is specifically incorporated herein by reference. Yes.

  In some embodiments of the invention, the composition further comprises a second therapeutic agent selected from the group consisting of β2-adrenergic receptor agonists, prophylactic therapeutic agents, and anticholinergic agents. Is included. In some embodiments of the invention, the β2-adrenergic receptor agonist is albuterol, levalbuterol or a pharmaceutically acceptable derivative.

  In another embodiment, the inhalable aqueous mixture comprises a corticosteroid such as budesonide, wherein the inhalable aqueous mixture is no more than twice daily (bid) according to the methods described herein. Be administered. In yet another embodiment, the inhalable aqueous mixture comprises a corticosteroid such as budesonide, and the inhalable aqueous mixture is administered no more than once a day according to the methods described herein. In yet another embodiment, the inhalable aqueous mixture comprises a corticosteroid such as budesonide, and the inhalable aqueous mixture is administered no more than once a day in the evening.

  In some embodiments of the invention, the nebulizer is a jet nebulizer, an ultrasonic nebulizer, a pulsating membrane nebulizer, a nebulizer having a vibrating mesh or plate with multiple holes, or a nebulizer comprising a vibration generator and an aqueous chamber. . In some embodiments of the present invention, the nebulizer is a Pari LC Jet Plus, Intertech, Baxter Misty-Neb, Hudson T-Updraft II, Hudson Ava-Neb, Ailos, Pari LCJet, DeVilbisNs, DeVilbisNs, DeVilbisPs. Neb (B), Hudson T-Updraft Neb-U-Mist, Pari-Jet 1460, and AeroTech with T-piece. In certain embodiments, the nebulizer is a Pari eFlow nebulizer.

  In certain embodiments of the invention, the bronchoconstrictive disorder is from the group consisting of asthma, childhood asthma, bronchial asthma, allergic asthma, endogenous asthma, chronic obstructive pulmonary disease (COPD), chronic bronchitis and emphysema Selected.

X. Process for Producing the Inhalable Composition of the Invention Another aspect of the invention is a corticosteroid in the manufacture of an inhalable composition for treating or preventing a bronchoconstrictive disorder in a patient in need thereof. This includes the steps of adding a solvent and solubility enhancer to an amount of corticosteroid, and activating the nebulizer, whereby the amount of corticosteroid in the composition prior to administration. , At least about 25% lung deposition is achieved. In some embodiments of the invention, the composition also achieves a respiratory fraction of at least about 60% when administered. In certain embodiments, the inhalable composition comprises a single corticosteroid, a solvent and a solubility enhancer and is substantially free of active pharmaceutical agents other than the corticosteroid. In some embodiments, the corticosteroid is budesonide. In other embodiments, the corticosteroid is either an individual diastereomer of budesonide or a mixture of two diastereomers of budesonide administered individually or together for therapeutic effect.

  Another aspect of the invention is the use of a corticosteroid in the manufacture of an inhalable composition for treating a bronchoconstrictive disorder in a patient in need thereof, comprising a solvent and a solubility enhancer. Adding a quantity of corticosteroid as well as activating a nebulizer, the composition comprising a corticosteroid administered under the same conditions to deliver a therapeutically effective amount of said corticosteroid It relates to the use of corticosteroids, wherein at least about 5% higher intrapulmonary deposition is achieved compared to inhalable suspensions. In certain embodiments, the inhalable composition comprises a single corticosteroid, a solvent and a solubility enhancer and is substantially free of active pharmaceutical agents other than the corticosteroid.

  One aspect of the present invention also relates to the use of a corticosteroid in the manufacture of an inhalable composition for treating a bronchoconstrictive disorder in a patient in need thereof, comprising a solvent and a solubility enhancer. Adding to a quantity of corticosteroid, as well as activating a nebulizer, wherein the composition is more inhalable than an inhalable suspension to deliver a therapeutically effective amount of the corticosteroid. Nearly the same pulmonary deposition is achieved compared to inhalable suspensions containing corticosteroids when administered at lower nominal dosages. In certain embodiments, the inhalable composition comprises a single corticosteroid, a solvent and a solubility enhancer and is substantially free of active pharmaceutical agents other than the corticosteroid.

  In some embodiments of the invention, the system comprises an aqueous inhalation mixture comprising about 15 to about 2000 μg of corticosteroid and containing the corticosteroid. In other embodiments, the inhalation mixture comprises about 50 to about 2000 μg of corticosteroid. In still other embodiments, the inhalation mixture comprises about 60 to about 1500 μg of corticosteroid. In yet other embodiments, the inhalation mixture comprises about 100 to about 1000 μg of corticosteroid. In still other embodiments, the inhalation mixture comprises about 120 to about 1000 μg of corticosteroid. In still other embodiments, the inhalation mixture comprises about 125 to about 500 μg of corticosteroid. In certain embodiments, the inhalation mixture comprises about 40 μg, about 60 μg, about 100 μg, about 120 μg, about 125 μg, about 240 μg, about 250 μg, about 500 μg, about 1000 μg, about 1500 μg, or about 2000 μg of corticosteroid. In one embodiment, the inhalation mixture comprises a nominal dosage of about 40 μg of corticosteroid. In another embodiment, the inhalation mixture comprises a nominal dosage of about 60 μg of corticosteroid. In yet another embodiment, the inhalation mixture comprises a nominal dosage of about 100 μg of corticosteroid. In yet another embodiment, the inhalation mixture comprises a nominal dosage of about 120 μg of corticosteroid. In yet another embodiment, the inhalation mixture comprises a nominal dosage of about 125 μg of corticosteroid. In yet another embodiment, the inhalation mixture comprises a nominal dosage of about 240 μg of corticosteroid. In yet another embodiment, the inhalation mixture comprises a nominal dosage of less than about 250 μg of corticosteroid. In other embodiments of the invention, the corticosteroid is budesonide or a pharmaceutically acceptable derivative. In other preferred embodiments, the corticosteroid is either an individual diastereomer of budesonide or a mixture of two diastereomers of budesonide administered individually or together for therapeutic effect.

  In certain embodiments, the systems and methods described herein include a solvent. In certain embodiments, the solvent is selected from the group consisting of water, water / ethanol mixtures, aqueous alcohols, propylene glycol or aqueous organic solvents, or combinations thereof. In certain embodiments, the solvent comprises water. In a preferred embodiment, the solvent is water.

  In some embodiments of the invention, the solubility enhancer is propylene glycol, nonionic surfactant, tyloxapol, polysorbate 80, vitamin E-TPGS, macrogol-15-hydroxystearate, phospholipid, lecithin, purified and / Or enriched lecithin, phosphatidylcholine fraction extracted from lecithin, dimyristoylphosphatidylcholine (DMPC), dipalmitoylphosphatidylcholine (DPPC), distearoylphosphatidylcholine (DSPC), cyclodextrin and its derivatives, SAE-CD derivatives, SBE-α -CD, SBE-β-CD, SBE1-β-CD, SBE4-β-CD, SBE7-β-CD (Captisol®), SBE-γ-CD, dimethyl β-CD, hydroxypro -Β-cyclodextrin, 2-HP-β-CD, hydroxyethyl-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, hydroxyethyl-γ-cyclodextrin, dihydroxypropyl-β-cyclodextrin, glucosyl-α -Cyclodextrin, glucosyl-β-cyclodextrin, diglucosyl-β-cyclodextrin, maltosyl-α-cyclodextrin, maltosyl-β-cyclodextrin, maltosyl-γ-cyclodextrin, maltotriosyl-β-cyclodextrin, maltotrio Sil-γ-cyclodextrin, dimaltosyl-β-cyclodextrin, methyl-β-cyclodextrin, carboxyalkyl thioether derivative, ORG 26054, ORG 25969, hydro A chemical selected from the group consisting of xyloxymethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, vinyl acetate copolymer, vinylpyrrolidone, sodium lauryl sulfate, dioctyl sodium sulfosuccinate, and combinations thereof. In certain embodiments, the solubility enhancer is SBE7-β-CD (Captisol®).

  In another specific embodiment, the inhalable composition of the invention comprises cyclodextrin and its derivatives, SAE-CD derivatives, SBE-α-CD, SBE-β-CD, SBE1-β-CD, SBE4-β. -CD, SBE7-β-CD (Captisol®), SBE-γ-CD, dimethyl β-CD, hydroxypropyl-β-cyclodextrin, 2-HP-β-CD, hydroxyethyl-β-cyclodextrin , Hydroxypropyl-γ-cyclodextrin, hydroxyethyl-γ-cyclodextrin, dihydroxypropyl-β-cyclodextrin, glucosyl-α-cyclodextrin, glucosyl-β-cyclodextrin, diglucosyl-β-cyclodextrin, maltosyl-α- Cyclodextrin, maltosyl-β-si Improved solubility selected from the group consisting of rhodextrin, maltosyl-γ-cyclodextrin, maltotriosyl-β-cyclodextrin, maltotriosyl-γ-cyclodextrin, dimaltosyl-β-cyclodextrin, methyl-β-cyclodextrin Contains agents. In certain embodiments, the solubility enhancer is SBE7-β-CD (Captisol®).

  In addition to an aqueous inhalation mixture or inhalable composition comprising a corticosteroid and a solubility enhancer, herein also an aqueous inhalation mixture or composition formulated by a method that provides improved solubility is also disclosed herein. It is envisaged that it is suitable for use in the present invention. Thus, in the context of the present invention, a “solubility enhancer” includes an aqueous inhalation mixture formulated by a method that provides improved solubility with or without a chemical acting as a solubility enhancer. . An example of such a method is the preparation of a supercritical fluid. By such a method, corticosteroid compositions such as budesonide are processed into particles with a narrow particle size distribution (usually less than 200 nanometers wide) and an average hydrodynamic radius of the particles in the range of 50 nanometers to 700 nanometers. Is done. Nano-sized corticosteroid particles (such as budesonide particles) can be used in supercritical fluid (SCF) processes such as supercritical fluid rapid expansion (RESS), or supercritical fluid solution-enhanced dispersion (SEDS), as well as supercritical fluids. Are processed using any other technique involving. The use of the SCF process to form particles is described in Parakodity, S .; Et al., Pharmaceutical Research 16: 976-985 (1999), and Bandi et al., Eur. J. et al. Pharm. Sci. 23: 159-168 (2004), US Pat. No. 6,576,264 and US Patent Application Publication No. 2003/0091513, each of which is specifically incorporated herein by reference. Yes.

  In some embodiments of the invention, the nebulizer is a jet nebulizer, an ultrasonic nebulizer, a pulsating membrane nebulizer, a nebulizer having a vibrating mesh or plate with multiple holes, or a nebulizer comprising a vibration generator and an aqueous chamber. . In some embodiments of the present invention, the nebulizer is a Pari LC Jet Plus, Intertech, Baxter Misty-Neb, Hudson T-Updraft II, Hudson Ava-Neb, Ailos, Pari LCJet, DeVilbisNs, DeVilbisNs, DeVilbisPs. Neb (B), Hudson T-Updraft Neb-U-Mist, Pari-Jet 1460, and AeroTech with T-piece. In another particular embodiment, the nebulizer is a Pari eFlow nebulizer.

  In some embodiments of the invention, the composition further comprises a second therapeutic agent selected from the group consisting of β2-adrenergic receptor agonists, prophylactic therapeutic agents, and anticholinergic agents. Is included. In some embodiments of the invention, the β2-adrenergic receptor agonist is albuterol, levalbuterol or a pharmaceutically acceptable derivative.

  In some embodiments of the invention, the bronchoconstrictive disorder is a group consisting of asthma, childhood asthma, bronchial asthma, allergic asthma, endogenous asthma, chronic obstructive pulmonary disease (COPD), chronic bronchitis and emphysema More selected.

  In another embodiment, the inhalable composition comprises a corticosteroid such as budesonide, wherein the inhalable composition is administered no more than twice a day (bid) according to the methods described herein. Is done. In yet another aspect, the inhalable composition comprises a corticosteroid, such as budesonide, and the inhalable composition is administered no more than once daily according to the methods described herein. . In yet another embodiment, the inhalable composition comprises a corticosteroid such as budesonide, and the inhalable composition is administered no more than once a day in the evening.

XI. Method of treatment with improved pK profile A method and system for treating or preventing bronchoconstrictive disorders as described herein in a patient in need thereof, administered by inhalation in the form of a suspension Compared to corticosteroids, an improvement in the pharmacokinetic profile of the delivered corticosteroid can be provided. In a preferred embodiment, the methods and systems described herein for treating or preventing bronchoconstrictive disorders in patients in need thereof are delivered corticosteroids compared to conventional inhalation therapy. It may be possible to increase the local bioavailability of, and further provide a means for reducing the dosage required to produce a local therapeutic effect, among others. Similarly, bronchoconstrictive disorders (eg, asthma) that may allow for delivery of corticosteroids with improved pharmacokinetic properties compared to corticosteroids administered by inhalation in suspension form. There are provided methods and systems for the treatment of wherein the administration by the methods and systems described herein provides the following advantages: increased local bioavailability of the delivered corticosteroid; provides local therapeutic effects A method for reducing the nominal dosage of corticosteroids required for administration; A method for reducing the time required to administer an effective dose of corticosteroids; A nebulized corticosteroid For increasing patient compliance with treatment regimens, including inhalation of urine; improved delivery of corticosteroids That method; provides one or more methods of reducing the side effects associated with inhalation of and corticosteroids; pulmonary (e.g., bronchi and alveoli) methods for increasing the amount of corticosteroid to be deposited in the.

  In some embodiments, providing an aqueous inhalation mixture comprising a corticosteroid and a solubility enhancer by a method and system for treating or preventing bronchoconstrictive disorder in a patient in need thereof, and Delivery of an aqueous inhalation mixture via an inhalation nebulizer can provide a method for the treatment of bronchoconstrictive disorders in a patient, wherein the corticosteroid is administered at a nominal dosage of less than about 250 μg / dose. In one embodiment, the corticosteroid can be administered at a nominal dosage of less than about 240 μg / dose. In another embodiment, the corticosteroid can be administered at a nominal dosage of less than about 200 μg / dose. In yet another embodiment, the corticosteroid can be administered at a nominal dosage of less than about 150 μg / dose. In yet another embodiment, the corticosteroid can be administered at a nominal dosage of less than about 125 μg / dose. In another embodiment, the corticosteroid can be administered at a nominal dosage of about 120 μg / dose. In yet another embodiment, the corticosteroid can be administered at a nominal dosage of about 100 μg / dose. In yet another embodiment, the corticosteroid can be administered at a nominal dosage of about 60 μg / dose. In yet another embodiment, the corticosteroid can be administered at a nominal dosage of about 50 μg / dose. In yet another embodiment, the corticosteroid can be administered at a nominal dosage of about 40 μg / dose. In other specific embodiments of the methods described herein, the aqueous inhalation mixture is about 15 μg / dose to about 250 μg / dose, or about 40 μg / dose to about 250 μg / dose, or about 60 μg / dose to about 250 μg. / Dose, or about 40 μg / dose to about 200 μg / dose, or about 60 μg / dose to about 200 μg / dose, or about 40 μg / dose to about 150 μg / dose, or about 60 μg / dose to about 150 μg / dose, or about 40 μg. / Dose to about 125 μg / dose, or about 60 μg / dose to about 125 μg / dose, or about 40 μg / dose to about 100 μg / dose, or about 60 μg / dose to about 100 μg / dose, or about 25 μg / dose to about 50 μg / dose. A dose, or may include a nominal corticosteroid dosage ranging from about 25 μg / dose to about 60 μg / dose . In some embodiments, the corticosteroid is budesonide. In other embodiments, the corticosteroid is either an individual diastereomer of budesonide or a mixture of two diastereomers of budesonide administered individually or together for therapeutic effect.

  In other embodiments, an aqueous inhalation mixture comprising a single corticosteroid and a solubility enhancer is provided by a method and system for treating or preventing bronchoconstrictive disorders in patients in need thereof. And delivering the aqueous inhalation mixture by inhalation nebulizer, wherein the corticosteroid is administered at a nominal dosage of less than about 250 μg / dose, wherein the inhalation mixture substantially contains a pharmaceutically active agent other than the corticosteroid. A method can be provided for the treatment of bronchoconstrictive disorders in a patient that is not included. In one embodiment, the corticosteroid can be administered at a nominal dosage of less than about 240 μg / 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 a nominal dosage of less than about 200 μg / dose, and the inhalation mixture is substantially free of pharmaceutically active agents other than the corticosteroid. In yet another embodiment, the corticosteroid can be administered at a nominal dosage of less than about 150 μg / dose, and the inhalation mixture is substantially free of pharmaceutically active agents other than the corticosteroid. In yet another embodiment, the corticosteroid can be administered at a nominal dosage of less than about 125 μg / 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 a nominal dosage of 120 μg / dose, and the inhalation mixture is substantially free of pharmaceutically active agents other than the corticosteroid. In yet another embodiment, the corticosteroid can be administered at a nominal dosage of about 100 μg / dose, and the inhalation mixture is substantially free of pharmaceutically active agents other than the corticosteroid. In yet another embodiment, the corticosteroid can be administered at a nominal dosage of about 60 μg / dose, and the inhalation mixture is substantially free of pharmaceutically active agents other than the corticosteroid. In yet another embodiment, the corticosteroid can be administered at a nominal dosage of about 50 μg / 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 a nominal dosage of about 40 μg / dose, and the inhalation mixture is substantially free of pharmaceutically active agents other than the corticosteroid. In other specific embodiments of the methods described herein, the aqueous inhalation mixture is about 15 μg / dose to about 250 μg / dose, or about 40 μg / dose to about 250 μg / dose, or about 60 μg / dose to about 250 μg. / Dose, or about 40 μg / dose to about 200 μg / dose, or about 60 μg / dose to about 200 μg / dose, or about 40 μg / dose to about 150 μg / dose, or about 60 μg / dose to about 150 μg / dose, or about 40 μg. / Dose to about 125 μg / dose, or about 60 μg / dose to about 125 μg / dose, or about 40 μg / dose to about 100 μg / dose, or about 60 μg / dose to about 100 μg / dose, or about 25 μg / dose to about 50 μg / dose. A dose, or a nominal corticosteroid dosage in the range of about 25 μg / dose to about 60 μg / dose, The inhalation mixture is substantially free of pharmaceutically active agents other than corticosteroids. In some embodiments, the corticosteroid is budesonide. In other embodiments, the corticosteroid is either an individual diastereomer of budesonide or a mixture of two diastereomers of budesonide administered individually or together for therapeutic effect.

  In yet other embodiments, the systems and methods described herein provide for the delivery of an aqueous inhalation mixture comprising a corticosteroid, a solvent and a solubility enhancer, the delivery of the corticosteroid by conventional inhalation. Compared to corticosteroid delivery with type suspension-based therapeutics, the pharmacokinetic profile of corticosteroids is improved. In some embodiments, the corticosteroid is budesonide. In other embodiments, the corticosteroid is either an individual diastereomer of budesonide or a mixture of two diastereomers of budesonide administered individually or together for therapeutic effect.

  Corticosteroids useful in the present invention include, but are not limited to, aldosterone, beclomethasone, betamethasone, budesonide, ciclesonide, clopredonol, cortisone, cortibazole, deoxycorton, desonide, desoxymethasone, dexamethasone, difluorocortron, fluchlorolone. , Flumethasone, flunisolide, fluocinolone, fluocinonide, fluocortin butyl, fluorocortisone, fluorocortron, fluorometholone, flulandrenolone, fluticasone, halcinonide, hydrocortisone, icometazone, meprednisone, methylprednisolone, mometasone, parameterzone, prednisone, prednisone , Rofleponide, RPR 106541, Thixocortol, Triamcinolol , And the respective pharmaceutically acceptable derivatives thereof. In some embodiments, the corticosteroid is budesonide. In other embodiments, the corticosteroid is either an individual diastereomer of budesonide or a mixture of two diastereomers of budesonide administered individually or together for therapeutic effect.

  In another particular embodiment, the corticosteroid is selected from the group of corticosteroids that do not contain betamethasone in the previous paragraph.

  In another embodiment, the present invention involves corticosteroid inhalation therapy, which requires a lower nominal dosage of corticosteroid to obtain a therapeutic effect compared to conventional inhaled corticosteroid therapy. Methods can be provided for reducing the risk of side effects. In one embodiment, the risk of side effects is reduced when corticosteroids are administered at a nominal dosage of less than about 250 μg / dose compared to conventional inhaled corticosteroid therapy. In another embodiment, the risk of side effects is reduced compared to conventional inhaled corticosteroid therapy. In yet another embodiment, when the corticosteroid is administered at a nominal dosage of less than about 240 μg / dose, the risk of side effects is when the corticosteroid is administered at a nominal dosage of less than about 200 μg / dose. Reduced compared to conventional inhaled corticosteroid therapy. In yet another embodiment, the risk of side effects is reduced when corticosteroids are administered at a nominal dosage of less than about 150 μg / dose compared to conventional inhaled corticosteroid therapy. In yet another embodiment, the risk of side effects is reduced when corticosteroids are administered at a nominal dosage of less than about 125 μg / dose compared to conventional inhaled corticosteroid therapy. In yet another embodiment, the risk of side effects is reduced compared to conventional inhaled corticosteroid therapy. When the corticosteroid is administered at a nominal dosage of less than about 100 μg / dose, and in yet another embodiment, the risk of side effects is when the corticosteroid is administered at a nominal dosage of less than about 60 μg / dose. Reduced compared to conventional inhaled corticosteroid therapy. In yet another embodiment, the risk of side effects is reduced when corticosteroids are administered at a nominal dosage of less than about 50 μg / dose compared to conventional inhaled corticosteroid therapy. In some embodiments, the corticosteroid is budesonide administered at a nominal dosage of less than about 250 μg / dose. In other embodiments, the corticosteroid is budesonide administered at a nominal dosage of less than about 125 μg / dose. In still other embodiments, the corticosteroid is budesonide administered at a nominal dosage of about 120 μg / dose. In yet other embodiments, the corticosteroid is budesonide administered at a nominal dosage of about 60 μg / dose. In still other embodiments, the corticosteroid is budesonide administered at a nominal dosage of about 40 μg / dose.

  The systems and methods described herein provide for the delivery of an aqueous inhalation mixture comprising a corticosteroid and a solubility enhancer. In some embodiments, suitable aqueous inhalation mixtures comprising corticosteroids include, but are not limited to, solutions, dispersions, nanodispersions, emulsions, colloidal liquids, micelles or mixed micelle solutions, and liposome liquids. . In one embodiment, the aqueous inhalation mixture is a solution comprising a corticosteroid such as budesonide and a solubility enhancer. In another embodiment, the aqueous inhalation mixture is a mixed micelle solution comprising a corticosteroid such as budesonide and a solubility enhancer. In yet another embodiment, the aqueous inhalation mixture is a liposome solution comprising a corticosteroid such as budesonide and a solubility enhancer.

  In some embodiments of the invention, inhalable compositions comprising corticosteroids do not include nanodispersions and / or nanosuspensions. In other embodiments, inhalable compositions comprising corticosteroids do not include micelles, mixed micelle fluids or liposome fluids. In yet other embodiments, inhalable compositions comprising corticosteroids do not include nanodispersions and / or nanosuspensions, micelles, mixed micelle fluids or liposome fluids. In other embodiments, inhalable compositions include, but are not limited to, solutions, emulsions and colloidal liquids. In one embodiment, the inhalable composition is a solution comprising a corticosteroid such as budesonide and a solubility enhancer. In another embodiment, the inhalable composition is an emulsion comprising a corticosteroid such as budesonide and a solubility enhancer.

  The systems and methods described herein provide for the delivery of an aqueous inhalation mixture comprising a corticosteroid, a solvent and a solubility enhancer. In some embodiments, suitable aqueous inhalation mixtures comprising corticosteroids include, but are not limited to, solutions, dispersions, nanodispersions, emulsions, colloidal liquids, micelles or mixed micelle solutions, and liposome liquids. . In one embodiment, the aqueous inhalation mixture is a solution comprising a corticosteroid such as budesonide and a solubility enhancer. In another embodiment, the aqueous inhalation mixture is a mixed micelle solution comprising a corticosteroid such as budesonide and a solubility enhancer. In yet another embodiment, the aqueous inhalation mixture is a liposome solution comprising a corticosteroid such as budesonide and a solubility enhancer.

  In some embodiments of the invention, inhalable compositions comprising corticosteroids do not include nanodispersions and / or nanosuspensions. In other embodiments, inhalable compositions comprising corticosteroids do not include micelles, mixed micelle fluids or liposome fluids. In still other embodiments, inhalable compositions comprising corticosteroids do not include nanodispersions and / or nanosuspensions, micelles, mixed micelle fluids, or liposome fluids. In other embodiments, inhalable compositions include, but are not limited to, solutions, emulsions and colloidal liquids. In one embodiment, the inhalable composition is a solution comprising a corticosteroid such as budesonide and a solubility enhancer. In another embodiment, the inhalable composition is an emulsion comprising a corticosteroid such as budesonide and a solubility enhancer.

  In certain embodiments, the systems and methods described herein include a solvent. In certain embodiments, the solvent is selected from the group consisting of water, water / ethanol mixtures, aqueous alcohols, propylene glycol or aqueous organic solvents, or combinations thereof. In certain embodiments, the solvent comprises water. In a preferred embodiment, the solvent is water.

  In some embodiments of the systems and methods described herein, a corticosteroid-containing aqueous inhalation mixture further comprising a solubility enhancer is used. In some embodiments, 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 still other embodiments, the solubility enhancer can have a concentration (w / v) ranging from about 1% to about 10%. In a preferred embodiment, when the solubility enhancer is a cyclodextrin or cyclodextrin derivative such as SBE7-β-CD (Captisol®), the concentration (w / v) ranges from about 2% to about 10%. ). In one embodiment, the solubility enhancer may have a concentration (w / v) of about 2% when it is a cyclodextrin or cyclodextrin derivative, such as SBE7-β-CD (Captisol®). In another embodiment, the solubility enhancer may have a concentration (w / v) of about 5% when it is a cyclodextrin or cyclodextrin derivative, such as SBE7-β-CD (Captisol®). In yet another embodiment, the solubility enhancer can have a concentration (w / v) of about 7% when it is a cyclodextrin or cyclodextrin derivative, such as SBE7-β-CD (Captisol®). . In yet another embodiment, the solubility enhancer has a concentration (w / v) of about 10% when it is a cyclodextrin or cyclodextrin derivative, such as SBE7-β-CD (Captisol®). obtain.

  Chemicals that act as solubility improvers suitable for use in the present invention include, but are not limited to, propylene glycol, nonionic surfactants, phospholipids, cyclodextrins and their derivatives, and surface modifiers and / or stabilizers. Is mentioned. In other embodiments, the solubility enhancer is a formulation method that provides improved solubility without the action of chemicals as a means to increase solubility, e.g., a supercritical fluid for making nanoparticles dispersed in a solvent. This refers to the use of a production method.

  Additional solubility enhancers are known in the art, for example, U.S. Pat. Nos. 5,134,127, 5,145,684, 5,376,645, 6,241. , 969, and U.S. Patent Application Publication Nos. 2005/0244339 and 2005/0008707, each of which is specifically incorporated herein by reference. Examples of suitable solubility improvers 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), US Pat. No. 5,134,127, ibid. Nos. 5,376,645 and 5,874,418, each of which is specifically incorporated herein by reference. In some embodiments, suitable cyclodextrins or cyclodextrin derivatives for use in the present invention include, but are not limited to, α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, SAE-CD derivatives (eg, SBE-α-CD, SBE-β-CD, SBE1-β-CD, SBE4-β-CD, SBE7-β-CD (Captisol®), and SBE-γ-CD) (Cydex, Inc.). Lenexa, KS), hydroxyethyl, hydroxypropyl (eg 2- and 3-hydroxypropyl) and dihydroxypropyl ether, its corresponding mixed ether and further mixed ethers with methyl or ethyl groups, eg α-, β- And γ-cyclodextrin methyl Hydroxyethyl, ethyl-hydroxyethyl and ethyl-hydroxypropyl ether and the like; and maltosyl, glucosyl and maltotriosyl derivatives of α-, β- and γ-cyclodextrins (which contain one or more sugar residues such as glucosyl Or diglucosyl, maltosyl or dimaltosyl, as well as various mixtures thereof, such as those comprising a mixture of maltosyl and dimaltosyl derivatives). Specific cyclodextrin derivatives for use herein include hydroxypropyl-β-cyclodextrin, hydroxyethyl-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, hydroxyethyl-γ-cyclodextrin, dihydroxy Propyl-β-cyclodextrin, glucosyl-α-cyclodextrin, glucosyl-β-cyclodextrin, diglucosyl-β-cyclodextrin, maltosyl-α-cyclodextrin, maltosyl-β-cyclodextrin, maltosyl-γ-cyclodextrin, malto Triosyl-β-cyclodextrin, maltotriosyl-γ-cyclodextrin, dimaltosyl-β-cyclodextrin, diethyl-β-cyclodextrin, glucosyl-α Cyclodextrin, glucosyl-β-cyclodextrin, diglucosyl-β-cyclodextrin, tri-O-methyl-β-cyclodextrin, tri-O-ethyl-β-cyclodextrin, tri-O-butyryl-β-cyclodextrin, Tri-O-valeryl-β-cyclodextrin, and di-O-hexanoyl-β-cyclodextrin, and methyl-β-cyclodextrin, and mixtures thereof, such as maltosyl-β-cyclodextrin / dimaltosyl-β-cyclodextrin Etc. Procedures for preparing such cyclodextrin derivatives are well known from US Pat. No. 5,024,998 and references incorporated by reference. Other cyclodextrins suitable for use in the present invention include carboxyalkyl thioether derivatives such as ORG 26054 and ORG 25969 (ORGANON (AKZO-NOBEL)), hydroxybutenyl ether derivatives (EASTMAN), sulfoalkyl-hydroxyalkyls Ether derivatives, sulfoalkyl-alkyl ether derivatives, and other derivatives such as US 2002/0128468, 2004/0106575, 2004/0109888 and 2004/0063663, or the United States Patents 6,610,671, 6,479,467, 6,660,804 or 6,509,323 (each of which is specifically described herein for reference) And the like described in the above).

  Hydroxypropyl-β-cyclodextrin is available from Research Diagnostics Inc. (Flanders, NJ). Exemplary hydroxypropyl-β-cyclodextrin products include Encapsin® (degree of substitution about 4) and Molecsol® (degree of substitution about 8); however, implementations involving other degrees of substitution Forms are also available and are within the scope of the present invention.

  Dimethylcyclodextrin is available from FLUKA Chemie (Buchs, CH) or Wacker (Iowa). Other derivatized cyclodextrins suitable for use in the present invention include water soluble derivatized cyclodextrins. Exemplary water-soluble derivatized cyclodextrins include: carboxylated derivatives; sulfated derivatives; alkylated derivatives; hydroxyalkylated derivatives; methylated derivatives; SCD). All these materials can be made according to methods known in the art and / or are commercially available. Suitable derivatives of cyclodextrin, Modified Cyclodextrins: Scaffolds and Templates for Supramolecular Chemistry (Edit Christopher J.Easton, Stephen F.Lincoln, Imperial College Press, London, UK, 1999) and New Trends in Cyclodextrins and Derivatives (editing Dominique Duchene , Editions de Sante, Paris, France, 1991).

  Examples of nonionic surfactants that appear to have particularly good physiological compatibility for use in the present invention include tyloxapol, polysorbates such as, but not limited to, polyoxyethylene (20) sorbitan monolaurate, polyoxyethylene (20) sorbitan monopalmitate, polyoxyethylene (20) monostearate (available under the trademark Tween 20-40-60, etc.), Polysorbate 80, Polyethylene glycol 400; sodium lauryl sulfate; sorbitan laurate, sorbitan palmitate, Sorbitan stearate (available under the trademark Span 20-40-60, etc.), benzalkonium chloride, PPO-PEO block copolymer (Pluronics), Cremophor-EL, Bio Tamine E-TPGS (eg, d-α-tocopheryl-polyethylene glycol-1000-succinate), Solutol-HS-15, oleic acid PEO ester, stearic acid PEO ester, Triton-X100, Nonidet P-40, and macrogol hydroxy Stearate (such as macrogol-15-hydroxystearate).

  In some embodiments, nonionic surfactants suitable for use in the present invention are formulated into corticosteroids to form liposome preparations, micelles or mixed micelles. Methods for the preparation and characterization of liposomes and liposome preparations are known in the art. In many cases, when amphiphilic lipids are hydrated, multilamellar vesicles spontaneously form, but the formation of small unilamellar vesicles usually involves processes with significant energy input (eg, Sonication or high-pressure homogenization) is required. Additional methods for the preparation and characterization of liposomes are described, for example, in S.H. Vemuri et al. (Preparation and characterisation of liposomals as therapeutic delivery system: a review. Pharm Act Helv. 1995, 70 (2): 95-111); Nos. 5,882,679 and 6,656,497, each of which is specifically incorporated herein by reference.

  In some cases, for example, micelles or mixed micelles can be formed by a surfactant, in which case a soluble insufficient active agent can be solubilized. In general, 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 because their structure, properties and behavior are very different from solids. The amphiphilic molecules that form micelles are usually associated temporarily. In micellar solutions, there is dynamic molecular exchange between micelle-forming amphiphiles and monomolecularly dispersed amphiphiles (which are also present in the solution). The portion of the drug molecule that is solubilized in such micelles or mixed micelles depends on the structure of these molecules as well as the surfactant used. For example, it is assumed that in particular nonpolar molecules are mainly localized within the colloidal structure, but polar substances are likely to be found on the surface of the structure. In one embodiment of a micelle solution or mixed micelle solution, the average micelle size can be less than about 200 nm (measured by photon correlation spectroscopy), such as from about 10 nm to about 100 nm. Especially preferred are micelles having an average diameter of about 10 nm to about 50 nm. Methods for making micelles and mixed micelles are known in the art, for example, US Pat. Nos. 5,747,066 and 6,906,042, each of which is specifically incorporated herein by reference. Incorporated by reference).

  Phospholipids are defined as amphiphile lipids containing phosphorus. Phospholipids chemically derived from phosphatidic acid are widely present and commonly used for pharmaceutical purposes. This acid is usually a (double) acylated glycerol-3-phosphate, whose fatty acid residues can be of different lengths. Examples of the phosphatidic acid derivative include phosphocholine or phosphatidylcholine (the phosphate group is further esterified with choline), phosphatidylethanolamine, phosphatidylinositol, and the like. Lecithin is a natural mixture of various phospholipids, usually with a high proportion of phosphatidylcholine. Depending on the specific source of lecithin and how it is extracted and / or enriched, such a mixture may also contain significant amounts of sterols, fatty acids, triglycerides and other substances.

  Additional phospholipids suitable for delivery by inhalation due to their physiological properties, especially extracted from natural sources (such as soy or chicken egg yolk) in the form of lecithin, preferably in hydrogenated form, and / or Or phospholipid mixtures released from lysolecithin, as well as phospholipids (preferably using saturated fatty acid esters) prepared by purification, enrichment or partial synthesis. Of the phospholipid mixture, lecithin is particularly preferred. Medium to long-chain zwitterionic phospholipids prepared by enrichment or partial synthesis are mainly free of unsaturated bonds in the acyl chain and free of lysolecithin and peroxide. Examples of enriched or pure compounds are dimyristoyl phosphatidylcholine (DMPC), distearoyl phosphatidylcholine (DSPC) and dipalmitoyl phosphatidylcholine (DPPC). Of these, DMPC is more preferred at the present time. Alternatively, phospholipids with oleyl residues and phosphatidylglycerols without choline residues are suitable for some embodiments and applications of the present invention.

  In some embodiments, nonionic surfactants and phospholipids suitable for use in the present invention are incorporated into corticosteroids to form a colloidal structure. A colloidal solution is defined as a single phase system in which the colloidal material dispersed in the colloidal solution does not have the measurable physical properties normally associated with solid materials. Methods for making colloidal dispersions are known in the art and are described, for example, in US Pat. No. 6,653,319, which is specifically incorporated herein by reference. Yes.

Suitable surface modifiers for use in the present invention are known in the art, for example, U.S. Pat. Nos. 5,145,684, 5,510,118, 5,565,188, And 6,264,922, each of which is specifically incorporated herein by reference. Examples of surface modifiers and / or surface stabilizers suitable for use in the present invention include, but are not limited to, hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, sodium lauryl sulfate, dioctyl sulfosuccinate, gelatin, casein, lecithin (Phosphatide), dextran, gum arabic, cholesterol, tragacanth, stearic acid, benzalkonium chloride, calcium stearate, glycerol monostearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan ester, polyoxyethylene alkyl ether (for example , Macrogol ethers such as cetomacrogol 1000), polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid Steal (eg, commercially available Tween®, such as Tween 20® and Tween 80® (ICI Specialty Chemicals), polyethylene glycol (eg, Carbowax 3550® and 934®). ) (Union Carbide)), polyoxyethylene stearate, colloidal silicon dioxide, phosphate, carboxymethylcellulose calcium, sodium carboxymethylcellulose, methylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose phthalate, amorphous cellulose, aluminum magnesium silicate , Triethanolamine, polyvinyl alcohol (PVA), ethylene oxide and formal 4- (1,1,3,3-tetramethylbutyl) -phenolic polymers with hydrides (also known as tyloxapol, superion and triton), poloxamers (eg Pluronic F68® and F108®), These are also known as block copolymers of ethylene oxide and propylene oxide), poloxamines (eg Tetronic 908®, Poloxamine 908®, which are obtained by sequential addition of propylene oxide and ethylene oxide to ethylenediamine. Tetronic 1508® (T-1), which is a derived tetrafunctional block copolymer (BASF Wyandotte Corporation, Parsippany, NJ)) 508) (BASF Wyandotte Corporation), Tritons X-200® (which is an alkylaryl polyether sulfonate) (Rohm and Haas), Crodestas F-100®, (which is a sucrose steer) Rate and sucrose distearate) (Croda Inc. ), P-isononylphenoxypoly- (glycidol), (also known as Olin-1OG® or Surfactant 10®) (Olin Chemicals, Tamford, Conn.), Crodestas SL-40. RTM. (Croda, Inc.), and SA9OHCO (this is C ₁₈ H ₃₇ CH ₂ (CON (CH ₃ ) CH ₂ (CHOH) ₄ (CH ₂ OH) ₂ (Eastman Kodak Co.), Decanoyl-N-methylgluca) N-decyl-β-D-glucopyranoside, n-decyl-β-D-maltopyranoside, n-dodecyl-β-D-glucopyranoside, n-dodecyl-β-D-maltoside, heptanoyl-N-methylglucamide, n-heptyl-β-D-glucopyranoside, n-heptyl-β-D-thioglucoside, n-hexyl-β-D-glucopyranoside, nonanoyl-N-methylglucamide, n-noyl-β-D-glucopyranoside, octanoyl -N-methylglucamide, n-octyl-β-D-glucopyranoside, octyl β D-thioglucopyranoside, PEG-phospholipid, PEG-cholesterol, PEG-cholesterol derivative, PEG-vitamin A, PEG-vitamin E, lysozyme, random copolymer of vinylpyrrolidone and vinyl acetate, etc. (for example, hydroxypropylmethylcellulose, hydroxypropylcellulose) , Polyvinyl pyrrolidone, vinyl acetate copolymer, vinyl pyrrolidone, sodium lauryl sulfate and dioctyl sodium sulfosuccinate).

Other useful cationic stabilizers include, but are not limited to, cationic lipids, sulfonium, phosphonium, and quaternary ammonium compounds such as stearyltrimethylammonium chloride, benzyl-di (2-chloroethyl) ethylammonium bromide, coconut Trimethylammonium chloride or bromide, coconut methyldihydroxyethylammonium chloride or bromide, decyltriethylammonium chloride, decyldimethylhydroxyethylammonium chloride or bromide, _C12-15 dimethylhydroxyethylammonium chloride or bromide, coconut dimethylhydroxyethylammonium chloride or bromide, Myristyltrimethylammonium methylsulfur Feto, lauryl dimethyl benzyl ammonium chloride or bromide, lauryl dimethyl _{(ethenoxy) 4} ammonium chloride or bromide, N- alkyl _{(C 12 to 18)} dimethyl benzyl ammonium chloride, N- alkyl _{(C 14 to 18)} dimethylbenzyl ammonium chloride, N Tetradecylide methylbenzylammonium chloride monohydrate, dimethyldidecylammonium chloride, N-alkyl and ( _C12-14 ) dimethyl 1-naphthylmethylammonium chloride, trimethylammonium halide, alkyltrimethylammonium salt and dialkyldimethylammonium salt , Lauryltrimethylammonium chloride, ethoxylated alkylamidoalkyldialkylammonia Um salts and / or ethoxylated trialkyl ammonium salt, dialkyl benzene dialkyl ammonium chloride, N- didecyl dimethyl ammonium chloride, N- tetradecyl dimethyl benzyl ammonium chloride monohydrate, N- alkyl (C _{12 ~ 14)} dimethyl 1 - naphthylmethyl ammonium chloride and dodecyl dimethyl benzyl ammonium chloride, dialkyl benzenealkyl ammonium chloride, lauryl trimethyl ammonium chloride, alkylbenzyl methyl ammonium chloride, alkyl benzyl - dimethyl ammonium _{bromide, C 12, C 15, C} 17 trimethyl ammonium bromide, dodecyl benzyl -Triethylammonium chloride, poly-diallyldimethyl Ammonium chloride (DADMAC), dimethylammonium chloride, alkyldimethylammonium halide, tricetylmethylammonium chloride, decyltrimethylammonium bromide, dodecyltriethylammonium bromide, tetradecyltrimethylammonium bromide, methyltrioctylammonium chloride (ALIQUAT 336®) ), POLYQUAT 10 (registered trademark), tetrabutylammonium bromide, benzyl-trimethylammonium bromide, etc., choline esters (such as choline esters of fatty acids), benzalkonium chloride, stearalkonium chloride compounds (stearyltrimonium chloride and distearyl chloride) Dimonium, etc.), cetylpyridinium bromide or Chlorides, halide salts of quaternized polyoxyethylalkylamines, Mirapol® and ALKQUAT® (Alkaril Chemical Company), alkylpyridinium salts, amines (alkylamines, dialkylamines, alkanolamines, polyethylene polyamines, N, N-dialkylaminoalkyl acrylate and vinyl pyridine) amine salts (such as lauryl amine acetate, stearyl amine acetate, alkyl pyridinium salts and alkyl imidazolium salts and amine oxides), imidoazolinium salts, protonated quaternary acrylamide Methylated quaternary polymers (poly [diallyldimethylammonium chloride] and poly- [N-methylvinylpyridinium Chloride], etc.), and the like cationic guar.

  In addition to an aqueous inhalation mixture or inhalable composition comprising a corticosteroid and a solubility enhancer, herein also an aqueous inhalation mixture or composition formulated by a method that provides improved solubility is also disclosed herein. It is envisaged that it is suitable for use in the present invention. Thus, in the context of the present invention, a “solubility enhancer” includes an aqueous inhalation mixture formulated by a method that provides improved solubility with or without a chemical acting as a solubility enhancer. . An example of such a method is the preparation of a supercritical fluid. By such a method, corticosteroid compositions such as budesonide are processed into particles with a narrow particle size distribution (usually less than 200 nanometers wide) and an average hydrodynamic radius of the particles in the range of 50 nanometers to 700 nanometers. Is done. Nano-sized corticosteroid particles (such as budesonide particles) can be used in supercritical fluid (SCF) processes such as supercritical fluid rapid expansion (RESS), or supercritical fluid solution-enhanced dispersion (SEDS), as well as supercritical fluids. Are processed using any other technique involving. The use of the SCF process to form particles is described in Parakodity, S .; Et al., Pharmaceutical Research 16: 976-985 (1999), and Bandi et al., Eur. J. et al. Pharm. Sci. 23: 159-168 (2004), US Pat. No. 6,576,264 and US Patent Application Publication No. 2003/0091513, each of which is specifically incorporated herein by reference. Yes. These methods allow the formation of micron and submicron sized particles having different morphologies depending on the method and parameters selected. These nanoparticles can also be processed by spray drying, freeze drying, volume exclusion and any other conventional particle reduction method.

  Furthermore, the desired form (e.g., amorphous, crystalline, segmented) can be achieved by appropriately adjusting the conditions of particle formation during precipitation or condensation by the method of producing nanometer sized particles (e.g., SCF). Racemate) may be possible. As a result of the selection of the desired particle form, sustained release of the selected medicament can be achieved. Using such a particle processing process, nanoparticulate material having high purity, low surface imperfection, low surface charge and low sedimentation rate is obtained. Due to the characteristics of the particles, adhesion and aggregation of the particles are suppressed, and sedimentation in the liquid dispersion is prevented. In addition, in processes such as SCF, certain pharmaceutical isomers can be separated, and such separation can contribute to enhanced activity, efficacy and extreme dose reduction of the pharmaceutical. In some cases, the separation of isomers also contributes to the reduction of side effects. With the method and system of the present invention, the aqueous inhalation mixture can be a composition processed into a powder form by any process, such as direct SCF in the recovery medium, spray drying, precipitation and volume exclusion, and thus The particulate compound is automatically made into a dispersion formulation. In some embodiments, this formulation may be the final formulation.

  In some embodiments of the invention, the solubility enhancer is propylene glycol, nonionic surfactant, tyloxapol, polysorbate 80, vitamin E-TPGS, macrogol-15-hydroxystearate, phospholipid, lecithin, purified and / Or enriched lecithin, phosphatidylcholine fraction extracted from lecithin, dimyristoylphosphatidylcholine (DMPC), dipalmitoylphosphatidylcholine (DPPC), distearoylphosphatidylcholine (DSPC), cyclodextrin and its derivatives, SAE-CD derivatives, SBE-α -CD, SBE-β-CD, SBE1-β-CD, SBE4-β-CD, SBE7-β-CD (Captisol®), SBE-γ-CD, dimethyl β-CD, hydroxypro -Β-cyclodextrin, 2-HP-β-CD, hydroxyethyl-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, hydroxyethyl-γ-cyclodextrin, dihydroxypropyl-β-cyclodextrin, glucosyl-α -Cyclodextrin, glucosyl-β-cyclodextrin, diglucosyl-β-cyclodextrin, maltosyl-α-cyclodextrin, maltosyl-β-cyclodextrin, maltosyl-γ-cyclodextrin, maltotriosyl-β-cyclodextrin, maltotrio Sil-γ-cyclodextrin, dimaltosyl-β-cyclodextrin, methyl-β-cyclodextrin, carboxyalkyl thioether derivative, ORG 26054, ORG 25969, hydro A chemical selected from the group consisting of xyloxymethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, vinyl acetate copolymer, vinylpyrrolidone, sodium lauryl sulfate, dioctyl sodium sulfosuccinate, and combinations thereof. In certain embodiments, the solubility enhancer is SBE7-β-CD (Captisol®).

  In another specific embodiment, the inhalable composition of the invention comprises cyclodextrin and its derivatives, SAE-CD derivatives, SBE-α-CD, SBE-β-CD, SBE1-β-CD, SBE4-β. -CD, SBE7-β-CD (Captisol®), SBE-γ-CD, dimethyl β-CD, hydroxypropyl-β-cyclodextrin, 2-HP-β-CD, hydroxyethyl-β-cyclodextrin , Hydroxypropyl-γ-cyclodextrin, hydroxyethyl-γ-cyclodextrin, dihydroxypropyl-β-cyclodextrin, glucosyl-α-cyclodextrin, glucosyl-β-cyclodextrin, diglucosyl-β-cyclodextrin, maltosyl-α- Cyclodextrin, maltosyl-β-si Improved solubility selected from the group consisting of rhodextrin, maltosyl-γ-cyclodextrin, maltotriosyl-β-cyclodextrin, maltotriosyl-γ-cyclodextrin, dimaltosyl-β-cyclodextrin, methyl-β-cyclodextrin Contains agents. In certain embodiments, the solubility enhancer is SBE7-β-CD (Captisol®).

  Any known inhalation nebulizer is suitable for use in the invention described herein. Such nebulizers include, for example, jet nebulizers, ultrasonic nebulizers, pulsatile membrane nebulizers, nebulizers having a vibrating mesh or plate with multiple holes, and nebulizers comprising a vibration generator and an aqueous chamber (eg, Pari eFlow®). )). Commercially available air-driven jet nebulizers, ultrasonic nebulizers or pulsatile membrane nebulizers suitable for use in the present invention include Aeroneb®, Aeroneb GO® (Aerogen, San Francisco, Calif.), Pari LC PLUS ( (Registered trademark), Pari Boye (registered trademark) N, and Pari Duraneb (registered trademark) (PARI Respiratory Equipment, Inc., Monterrey, CA), MicroAir (registered trademark) (Omron Healthcare, Inc, Vernon Hills, Ill.) (Registered trademark) (Profile Therapeutics Inc, Boston, MA), Respirat (registered trademark) (Boehringer In gelheim Ingelheim, Germany), Aerodose (R) (Aerogen, Inc, Mountain View, CA), Omron Elite (R) (Omron Healthcare, Inc, Vernon Hills, Illinois), Omron Microre (R) , Inc, Vernon Hills, Illinois), Mabismist II® (Mabis Healthcare, Inc, Lake Forest, Illinois), Lumisscope® 6610, (The Lumicscope Company, Inc, East Brownswick, New Jersey) , Airsep Mystere®, (AirSep Corpo , Buffalo, NY), Acorn-1 and Acorn-II (Vital Signs, Inc, Totowa, NJ), Aquawater® (Medical Industries America, Adel, Iowa), Ava-Neb® Hudson Respiratory Care Incorporated (Temecula, CA), Cirrus (registered trademark) (International Incorporated, Liverpool, New York), Dart (registered trademark) (Professional Medical Products, South Carolina, P Aide (DeVilb ss Corp. Somerset, Pennsylvania), Downdraft® (Marquest, Englewood, Colorado), Fan Jet® (Marquest, Englewood, Colorado), MB-5 (Mefar, Bovezzo, Italy), Misty Neb (R) (Baxter, Valencia, CA), Salter 8900 (Salter Labs, Irvine, CA), Sidestream (R) (Medic-Aid, Sussex, UK), Updraft-II (R) Hudson Respiratory Care; Temecula, Calif., Whisper Jet® (Marquest Medical Products, Inc.) Gluwood, Colorado), Aiolos® (Ailos Medinnsk Teknik, Karlstad, Sweden), Inspiron® (Intertech Resources, Inc., Bannockburn, Illinois), Optimist® ed. McAllen, Texas, Prodomo®, Spira® (Respiratory Care Center, Hemenlinna, Finland), AERx (Aradigm Corporation, Hayward, Calif.), Sonik® LDI Nebulizer (Evit Lit Sacramento, California), and Swirler W Radioaerosol System (AMICI, Inc., Spring City, PA).

  Any of these and other known nebulizers can be used to deliver the aqueous inhalation mixture described in the present invention. In some embodiments, the nebulizer can be, for example, Pari GmbH (Starnberg, Germany), DeVilbiss Healthcare (Heston, Middlesex, UK), Healthdyne, Vital Signs, Baxter, Allied Health Care, Uvacare, Uvacare, Omron, Bremed, AirSep, Luminscope, Mediana, Siemens, Aerogen, Mountain Medical, Aerosol Medical Ltd. (Colechester, Essex, UK), AFP Medical (Rugby, Warwickshire, UK), Bard Ltd. (Sunderland, UK), Carri-Med Ltd. (Dorking, UK), Plaem Nuiva (Brescia, Italy), Henleys Medical Supplements (London, UK), International (Berkeshire, UK), LifecaTe Hospital Supplies (Reillys, UK), Med-Aid. (West Sussex, UK), Medix Ltd. (Essex, UK), Sinclair Medical Ltd. (Surrey, UK) and many others.

  Other nebulizers suitable for use in the methods and systems described herein include, but are not limited to, jet nebulizers (optionally sold with a compressor), ultrasonic nebulizers, and the like. Exemplary jet nebulizers for use herein include: Pari LC plus / ProNeb, Pari LC plus / ProNeb Turbo, Pari LCPIus / Dura Neb 1000 & 2000 Pari LC plus / Walkhaler, Pari LC Plus / Pari LC star, Omron Compair Air XL Portable Nebulizer System (NE-C18 and JetAir Disposable nebulizer), Omron Compreit Elite Compressor NebulizerNebulizer Ultra compressor comprising a Pari LC Plus or Pari LC Star nebulizer, Pulomo-aide, Pulmo-aide LT, Pulmo-aide traveler, Invacare Passport, Inspiration Healthdyne 626, Pulmo-Neb Traveler, DeVilbiss 646, Whisper Jet, AcornII, Misty-Neb , Allied Aerosol, Schuco Home Care, Lexan Plastic Pocket Neb, SideStream Hand Held Neb, Mobile Mist, Up-Draft, Up-Draft II, T Up-Draft, ISO-NE , Ava-Neb, Micro Mist, as well as PulmoMate.

  Exemplary ultrasound nebulizers for use herein include: MicroAir, UltraAir, Siemens Ultra Nebulizer 145, CompAir, Pulmosonic, Scout, 5003 Ultrasonic Neb, 5110 Ultrasonic. s Ultrasonic Nebulizer, Mediana Ultrasonic Nebulizer, Microstat Ultrasonic Nebulizer, and Mabismist Hand Held Ultrasonic Nebulizer. Other nebulizers for use herein, 5000 Electromagnetic Neb, 5001 Electromagnetic Neb 5002 Rotary Piston Neb, Lumineb I Piston Nebulizer 5500, Aeroneb Portable Nebulizer System, include Aerodose Inhaler and AeroEclipse Breath Actuated Nebulizer. An exemplary nebulizer that includes a vibrating mesh or plate having multiple holes is described in R.C. By Dhand (New Nebulizer Technology-Aerosol Generation by Using a Vibrating Mesh or Plate with Multiple Apertures, 4th, 4th, 4th, 4th, 4th, 4th, and 4th, 4th, 4th, 4th, and 4th, 4th, 4th, and 4th, 4th, 4) (The disclosures of each of which are incorporated herein by reference).

  Additional nebulizers suitable for use in the invention described herein include nebulizers comprising a vibration generator and an aqueous chamber. Such nebulizers are commercially available, for example, as Pari eFlow® and are disclosed in US Pat. Nos. 6,962,151, 5,518,179, 5,261,601 and No. 5,152,456, each of which is specifically incorporated herein by reference.

  Parameters used in nebulization, such as flow rate, mesh membrane size, aerosol inhalation chamber size, mask size and material, valves and power supplies, etc., according to the principles of the present invention to maximize their use, It can vary with different types of aqueous inhalation mixtures or different types of corticosteroids.

  In addition to the nebulizer described above, atomizers are also suitable for the systems and methods described herein for delivery of aqueous inhalation solutions containing corticosteroids and solubility enhancers. Atomizers are known in the art, for example, U.S. Pat. Nos. 5,954,047, 6,026,808, 6,095,141 and 6,527,151 ( Each of which is specifically incorporated herein by reference).

  In certain preferred embodiments, the methods and systems described herein include jet nebulizers, ultrasonic nebulizers, pulsatile membrane nebulizers, nebulizers having a vibrating mesh or plate with multiple holes, or vibration generators and aqueous A nebulizer selected from the group consisting of nebulizers with chambers. In some embodiments of the present invention, the nebulizer is a Pari LC Jet Plus, Intertech, Baxter Misty-Neb, Hudson T-Updraft II, Hudson Ava-Neb, Ailos, Pari LCJet, DeVilbisNs, DeVilbisNs, DeVilbisPs. Neb (B), Hudson T-Updraft Neb-U-Mist, Pari-Jet 1460, and AeroTech with T-piece. In another particular embodiment, the nebulizer is a Pari eFlow nebulizer.

  In other aspects of the invention, the methods and systems described herein may provide asthma, childhood asthma, bronchial asthma, allergic asthma, endogenous asthma, chronic obstructive pulmonary disease (COPD), chronic bronchitis, emphysema. Or a corticosteroid (eg, budesonide) for the treatment of a subject who has had or is expected to have a bronchoconstrictive disorder selected from the group consisting of any of the foregoing An aqueous inhalable mixture comprising can be delivered to a subject in a therapeutically effective amount.

  In yet other aspects of the invention, the methods and systems described herein comprise corticosteroids administered no more than twice daily (bid) in accordance with the methods and systems described herein. Contains an aqueous inhalation mixture. In yet another aspect, the aqueous inhalation mixture comprises a corticosteroid such as budesonide, and the aqueous inhalation mixture is administered twice daily according to the methods and systems described herein. In yet another aspect, the aqueous inhalation mixture comprises a corticosteroid such as budesonide, and the aqueous inhalation mixture is administered no more than once a day according to the methods and systems described herein. In yet another embodiment, the aqueous inhalation mixture comprises a corticosteroid, such as budesonide, and the aqueous inhalation mixture is administered once daily according to the methods and systems described herein. In yet another embodiment, the aqueous inhalation mixture comprises a corticosteroid such as budesonide, and the aqueous inhalation mixture is administered no more than once a day in the evening according to the methods and systems described herein.

  In other embodiments, the methods and systems described herein can further comprise administering an aqueous inhalation mixture comprising a corticosteroid in combination with one or more active agents. In some embodiments, the corticosteroid (eg, budesonide) is (a) a B2-adrenergic receptor agonist; (b) a dopamine (D2) receptor agonist; (c) a prophylactic agent such as a steroid. Shown herein in combination with one or more other drugs that are one or more active agents selected from the group consisting of (d) a surface anesthetic; or (e) an anticholinergic agent. It can be administered at the same time, before or after the inhalable composition.

  In another aspect of the invention, the systems and methods described herein can provide a more efficient dose of corticosteroid on a weight basis. In some embodiments, the corticosteroid dose provided in the aqueous inhalation mixture by the systems and methods described herein is significantly greater on a weight basis than conventional inhaled corticosteroid therapy. The amount can be absorbed into the patient's bloodstream. In certain embodiments, the systems and methods described herein can deliver an inhalation mixture comprising budesonide and a solubility enhancer. Here, the budesonide administered is on a weight basis greater than about 55%; or 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% is absorbed into the bloodstream.

  In still other embodiments, the methods and systems of the present invention allow a therapeutically effective amount of corticosteroid to be delivered in a significantly shorter time than conventional inhaled corticosteroid therapy. For example, the nebulization time of Pulmicort® Respules administered by a Pari LC Plus jet nebulizer takes at least 5-8 minutes and in some cases over 10 minutes. In contrast, in the methods and systems of the invention, a therapeutically effective amount of a corticosteroid (such as budesonide) can be delivered at 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. In other embodiments, the delivery time can be less than about 5 minutes. In certain embodiments, the delivery time can be about 4.5 minutes. In other specific 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 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 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 specific 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 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.

  In other embodiments, the methods and systems of the present invention can deliver a nominal dosage of substantially all of the corticosteroid in a significantly shorter time than conventional inhaled corticosteroid therapy. For example, the nebulization time of Pulmicort® Respules administered by a Pari LC Plus jet nebulizer takes at least 5-8 minutes and in some cases over 10 minutes. In contrast, in the methods and systems of the present invention, nominal dosages of corticosteroids (such as budesonide) can be delivered at 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. In other embodiments, 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 other specific embodiments, substantially all of the nominal dosage can be delivered in less than about 4.5 tan. In yet 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 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 in less than about 3.5 minutes. In 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. In certain embodiments, substantially all of the nominal dosage can be delivered in about 2.5 minutes. In other specific 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 in about 2 minutes. In 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.

  In other specific embodiments, the methods and systems of the present invention allow a therapeutically effective amount of corticosteroid to be delivered in a unit dose that contains less volume than conventional inhaled corticosteroid therapy. For example, the systems and methods of the present invention can deliver a therapeutically effective amount of a corticosteroid (such as budesonide) when the volume of the aqueous inhalation mixture is less than about 0.5 ml to less than 5 ml. In some embodiments, the volume of the aqueous inhalation mixture can be about 3.5 ml. In other embodiments, the volume of the aqueous inhalation mixture can be about 3.0 ml. In still other embodiments, the volume of the aqueous inhalation mixture can be about 2.5 ml. In still other embodiments, the volume of the aqueous inhalation mixture can be about 2.0 ml. In certain embodiments, the volume of the aqueous inhalation mixture can be about 1.5 ml. In other specific embodiments, the volume of the aqueous inhalation mixture can be about 1.0 ml. In a preferred embodiment, the volume of the aqueous inhalation mixture can be about 0.5 ml.

It will be understood that aspects of the methods and systems described herein may include any one or more or all of the advantages afforded by the present invention, and further embodiments are within the scope of the present invention. I want to be. For example, the methods and systems described herein provide an aqueous inhalation mixture containing a nominal dosage of corticosteroid and a solubility enhancer of about 60 μg / dose with an inhalation nebulizer at an inhalation mixture volume of about 0.5 ml. Wherein the delivery of the corticosteroid-containing aqueous mixture by the nebulizer is less than about 2 minutes, and the delivery of the corticosteroid-containing aqueous inhalation mixture by the nebulizer results in a C _max of about An inhalable containing corticosteroid when the aqueous inhalation mixture containing a nominal dosage of corticosteroid less than 100 μg / dose is about 60% of the nominal dosage of an inhalable suspension containing the corticosteroid improved pharmacokinetic profile resulting in equal such corticosteroids in C _max of Do suspension The above embodiments are merely examples of one embodiment of the invention that includes numerous aspects or variations and are not intended to limit the scope of the invention in any way.

A. Delivery of corticosteroids exhibiting improved pharmacokinetic profile The present invention also provides an aqueous inhalation mixture comprising a nominal dosage of corticosteroid and a solubility enhancer, and the aqueous inhalation mixture by an inhalation nebulizer A method or system for treating or preventing a bronchoconstrictive disorder in a patient can be provided that includes delivering. In such embodiments, the method provides for the delivery of a corticosteroid that exhibits an improved pharmacokinetic profile as compared to a suspension-based corticosteroid formulation administered under the same conditions. obtain.

  In certain embodiments, the methods and systems of the present invention, in certain embodiments, provide (a) an aqueous inhalation mixture comprising a nominal dosage of a corticosteroid and a solubility enhancer, and (b) corti. Treatment or prophylaxis of a bronchoconstrictive disorder in a patient in need thereof, comprising delivering an aqueous inhalation mixture comprising a costeroid by a nebulizer, administered by the method and system under the same conditions Compared to the pharmacokinetic profile of inhalable suspensions containing certain nominal dosages of corticosteroids (e.g., Pulmicort Repres®), aqueous inhalation mixtures comprising such nominal dosages of corticosteroids A treatment that results in an improvement in the pharmacokinetic profile of at least twice It is one which provides a prophylactic. In some embodiments, the inhalable aqueous mixture substantially reduces corticosteroids compared to inhalable suspensions containing conventional corticosteroids, even at significantly lower nominal dosages. Corresponding bioavailability can be shown. In other embodiments, increased bioavailability of corticosteroids when delivered at the same nominal dosage by an inhalable aqueous mixture compared to inhalable suspensions containing conventional corticosteroids. Can be shown. In certain embodiments, the ratio of the nominal dosage of corticosteroid in the aqueous inhalation mixture to the nominal dosage of corticosteroid in the inhalable suspension is about 0.01: 1. To about 1: 100.

  In other embodiments, the methods and systems of the invention provide (a) an aqueous inhalation mixture comprising a nominal dosage of a single corticosteroid and a solubility enhancer, and (b) comprises a corticosteroid. Treatment or prevention of a bronchoconstrictive disorder in a patient in need thereof, comprising delivering an aqueous inhalation mixture via a nebulizer, the nominal dosage administered by the method and system under the same conditions Compared to the pharmacokinetic profile of an inhalable suspension containing a certain amount of corticosteroid (eg, Palmicort Respules®), at least twice as much as the aqueous inhalation mixture containing the nominal dosage of corticosteroid Improved pharmacokinetic profile, wherein the inhalation mixture is It does not include the pharmaceutically active agents other than corticosteroid substantially, treatment or prevention can be provided. In some embodiments, the inhalable aqueous mixture substantially reduces corticosteroids compared to inhalable suspensions containing conventional corticosteroids, even at significantly lower nominal dosages. Corresponding bioavailability can be shown. In other embodiments, increased bioavailability of corticosteroids when delivered at the same nominal dosage by an inhalable aqueous mixture compared to inhalable suspensions containing conventional corticosteroids. Can be shown. In certain embodiments, the ratio of the nominal dosage of corticosteroid in the aqueous inhalation mixture to the nominal dosage of corticosteroid in the inhalable suspension is from about 0.01: 1 to about 1: 100. .

In certain embodiments, the corticosteroid-containing aqueous inhalation mixture delivered by the methods described herein is more than the C _{max of} a suspension-based corticosteroid formulation administered under the same conditions at the same nominal dosage. _Can also have a large C _max . In other embodiments, the corticosteroid-containing aqueous inhalation mixture delivered by the methods described herein is a suspension based corticosteroid formulation AUC _(last ) administered under the same conditions at the same nominal dosage. ₎ Having an AUC _(last) greater than. In still other embodiments, the corticosteroid-containing aqueous inhalation mixture delivered by the methods described herein is a suspension-based corticosteroid formulation AUC ₍₁ ) administered under the same conditions at the same nominal dosage. _Can have an AUC ₍₀ to _∞) greater than _{0 to ∞)} . In yet other embodiments, the corticosteroid-containing aqueous inhalation mixture delivered by the methods described herein has a T _{max that is} less than the T _max of the suspension corticosteroid formulation administered under the same conditions. It may have.

In other specific embodiments, the corticosteroid-containing aqueous inhalation mixture delivered by the methods described herein is a suspension-based cortico in which the nominal dosage of the aqueous inhalation mixture is administered under the same conditions. when less than nominal dosage of steroid, it may be one having a C _max which corresponds to the C _max of suspensions based corticosteroid formulations. In other embodiments, the corticosteroid-containing aqueous inhalation mixture delivered by the methods described herein is a suspension-based corticosteroid formulation wherein the nominal dosage of the aqueous inhalation mixture is administered under the same conditions The AUC _(last) corresponding to the AUC _(last) of the suspension-based corticosteroid preparation may be at a dose less than the nominal dosage of. In still other embodiments, the corticosteroid-containing aqueous inhalation mixture delivered by the methods described herein is a suspension-based corticosteroid in which the nominal dosage of the aqueous inhalation mixture is administered under the same conditions when less than nominal dosage of the formulation, can have the _{AUC (0 to ∞)} corresponding to _{AUC (0 to ∞)} of the suspension system corticosteroid preparations. In yet other embodiments, the corticosteroid-containing aqueous inhalation mixture delivered by the methods described herein is a suspension corticosteroid in which the nominal dosage of the aqueous inhalation mixture is administered under the same conditions. when less than nominal dosage of the formulation, can have the T _max is less than T _max of the suspension system corticosteroid preparations.

As mentioned above, increased exposure to corticosteroids with elevated plasma levels can lead to undesirable side effects. Therefore, lower corticosteroid doses are desired that can achieve the same or better therapeutic effects as observed with higher doses of conventional inhaled corticosteroid therapy. Such low doses can be achieved using the methods and systems described herein as a result of increased bioavailability of corticosteroids compared to inhalable suspensions containing conventional corticosteroids. . In accordance with the methods and systems described herein, certain nominal dosages of corticosteroids administered under the same conditions in an aqueous inhalation mixture comprising a nominal dosage of corticosteroids (eg, Pulmicort Responses®) Specific therapeutic parameters (eg, AUC _(0-∞) ) at least about 1.5 times (150%) to about 10 times (1000) compared to the pharmacokinetic profile of inhalable suspensions containing %)) Corticosteroids with an improved pharmacokinetic profile can be delivered, improving the pharmacokinetic profile. In certain embodiments, the ratio of the nominal dosage of corticosteroid in the aqueous inhalation mixture to the nominal dosage of corticosteroid in the inhalable suspension is about 0.01: 1 to about 1: 100. .

In other embodiments, the methods and systems described herein allow the nominal dosage of corticosteroid in the aqueous inhalation mixture to be at least the nominal dose of corticosteroid in a conventional inhalable suspension. When in the range of about 1: 1.5 to about 1:10, the corresponding bioavailability (eg, the corresponding AUC) compared to a conventional inhalable suspension containing a nominal dosage of corticosteroid. _An aqueous inhalation mixture containing a nominal dosage of corticosteroid can be delivered with an improvement in the pharmacokinetic profile including _(0-∞) ) and an improvement in the pharmacokinetic profile (from 1.5-fold An approximately 10-fold improvement in pharmacokinetic profile).

  In certain embodiments, the methods and systems of the present invention provide (a) an aqueous inhalation mixture comprising a nominal dosage of a corticosteroid and a solubility enhancer, and (b) an aqueous inhalation comprising a corticosteroid. Delivering the mixture by an inhalation nebulizer, the method and system comparing the pharmacokinetic profile of an inhalable suspension comprising a nominal dosage of corticosteroid administered under the same conditions, Treatment of bronchoconstrictive disorders in which an aqueous inhalation mixture containing the nominal dosage of corticosteroid with an improved pharmacokinetic profile from about 1.5 times (150%) to about 10 times (1000%) is delivered Can result in treatment or prevention in patients in need. In other embodiments, the inhalation mixture comprises a single corticosteroid and is substantially free of any other pharmaceutically active agent other than the corticosteroid. In one embodiment, an aqueous inhalation mixture comprising a nominal dosage of corticosteroid administered by the systems and methods described herein comprises a nominal dosage of corticosteroid administered under the same conditions. An improvement in pharmacokinetic profile of about 1.5 times (150%) to about 9 times (900%) can be delivered compared to conventional inhalable suspensions. In another embodiment, an aqueous inhalation mixture comprising a nominal dosage of corticosteroid administered by the systems and methods described herein comprises a nominal dosage of corticosteroid administered under the same conditions. Can have a pharmacokinetic profile improvement of about 1.5 times (150%) to about 8 times (800%) compared to conventional inhalable suspensions. In yet another embodiment, an aqueous inhalation mixture comprising a nominal dosage of corticosteroid administered by the systems and methods described herein, when administered under the same conditions, results in a nominal dosage of cortico Pharmacokinetic profile with improved pharmacokinetic profile ranging from about 1.5 times (150%) to about 7 times (700%) compared to conventional inhalable suspensions containing steroids It may have the improvement of. In yet another embodiment, an aqueous inhalation mixture comprising a nominal dosage of corticosteroid administered by the systems and methods described herein, when administered under the same conditions, Pharmacokinetics with improved pharmacokinetic profile ranging from about 1.5 times (150%) to about 6 times (600%) compared to conventional inhalable suspensions containing costeroids It can have a profile improvement. In one embodiment, an aqueous inhalation mixture comprising a nominal dosage of corticosteroid administered by the systems and methods described herein, when administered under the same conditions, will result in a nominal dosage of corticosteroid Of pharmacokinetic profile with an improvement in pharmacokinetic profile ranging from about 1.5 times (150%) to about 5 times (500%) compared to conventional inhalable suspensions containing It may have an improvement. In yet another embodiment, an aqueous inhalation mixture comprising a nominal dosage of corticosteroid administered by the systems and methods described herein, when administered under the same conditions, Pharmacokinetics with improved pharmacokinetic profile ranging from about 1.5 times (150%) to about 4 times (400%) compared to conventional inhalable suspensions containing costeroids It can have a profile improvement. In yet another embodiment, an aqueous inhalation mixture comprising a nominal dosage of corticosteroid administered by the systems and methods described herein, when administered under the same conditions, Pharmacokinetics with improved pharmacokinetic profile ranging from about 1.5 times (150%) to about 3 times (300%) compared to conventional inhalable suspensions containing costeroids It can have a profile improvement. In yet another embodiment, an aqueous inhalation mixture comprising a nominal dosage of corticosteroid administered by the systems and methods described herein is administered at a nominal dosage when administered under the same conditions. Pharmacokinetics with improved pharmacokinetic profile ranging from about 1.5 times (150%) to about 2 times (200%) compared to conventional inhalable suspensions containing corticosteroids May have an improved profile. In one embodiment, an aqueous inhalation mixture comprising a nominal dosage of corticosteroid administered by the systems and methods described herein, when administered under the same conditions, will result in a nominal dosage of corticosteroid Can have a pharmacokinetic profile improvement of about 2-fold (200%) compared to conventional inhalable suspensions containing. In another embodiment, an aqueous inhalation mixture comprising a nominal dosage of a corticosteroid administered by the systems and methods described herein, when administered under the same conditions, will result in a nominal dosage of cortico It can have a pharmacokinetic profile improvement of about 3 times (300%) compared to conventional inhalable suspensions containing steroids. In yet another embodiment, an aqueous inhalation mixture comprising a nominal dosage of corticosteroid administered by the systems and methods described herein, when administered under the same conditions, It can have about a 4-fold (400%) pharmacokinetic profile improvement compared to conventional inhalable suspensions containing costeroids. In yet another embodiment, an aqueous inhalation mixture comprising a nominal dosage of corticosteroid administered by the systems and methods described herein, when administered under the same conditions, It may have about a 5-fold (500%) pharmacokinetic profile improvement compared to conventional inhalable suspensions containing costeroids. In yet another embodiment, an aqueous inhalation mixture comprising a nominal dosage of corticosteroid administered by the systems and methods described herein is administered at a nominal dosage when administered under the same conditions. It can have a pharmacokinetic profile improvement of about 6 times (600%) compared to conventional inhalable suspensions containing corticosteroids.

  In other specific embodiments, an aqueous inhalation mixture comprising a nominal dosage of budesonide and a solubility enhancer is delivered by the systems and methods described herein and when administered under the same conditions, the nominal dosage Pharmacokinetics with improved pharmacokinetic profile ranging from at least about 2 times (200%) to about 6 times (600%) compared to conventional inhalable suspensions containing amounts of budesonide It has a profile improvement. In one embodiment, an aqueous inhalation mixture comprising a nominal dosage of budesonide administered by the systems and methods described herein includes a conventional dosage of budesonide when administered under the same conditions. It may have an approximately 2-fold (200%) pharmacokinetic profile improvement compared to a fresh inhalable suspension. In another embodiment, an aqueous inhalation mixture comprising a nominal dosage of budesonide administered by the systems and methods described herein includes a nominal dosage of budesonide when administered under the same conditions. It may have a pharmacokinetic profile improvement of about 3 times (300%) compared to a typical inhalable suspension. In yet another embodiment, an aqueous inhalation mixture comprising a nominal dosage of budesonide administered by the systems and methods described herein comprises a nominal dosage of budesonide when administered under the same conditions. It may have an approximately 4-fold (400%) pharmacokinetic profile improvement compared to conventional inhalable suspensions. In yet another embodiment, an aqueous inhalation mixture comprising a nominal dosage of budesonide administered by the systems and methods described herein comprises a nominal dosage of budesonide when administered under the same conditions. It may have about a 5-fold (500%) pharmacokinetic profile improvement compared to conventional inhalable suspensions. In yet another embodiment, an aqueous inhalation mixture comprising a nominal dosage of budesonide administered by the systems and methods described herein, when administered under the same conditions, produces a nominal dosage of budesonide. It may have a pharmacokinetic profile improvement of about 6 times (600%) compared to a conventional inhalable suspension containing.

  The methods and methods of the invention for treating or preventing bronchoconstrictive disorders in patients in need thereof by improving the pharmacokinetic profile of corticosteroids provided by the methods and systems described herein. When the system causes the corticosteroid-containing aqueous inhalable mixture to have a nominal dosage that is in the range of about 1: 1.5 to about 1:10 of the nominal dosage of an inhalable suspension containing the corticosteroid. A corticosteroid-containing aqueous inhalable mixture with bioavailability corresponding to the inhalable suspension containing the corticosteroid can be delivered. In one embodiment, the methods and systems of the invention comprise (1) providing an aqueous inhalation mixture comprising a corticosteroid and a solubility enhancer, and (2) delivering the aqueous inhalation mixture by an inhalation nebulizer; Delivery of the aqueous corticosteroid-containing mixture by the nebulizer allows the nominal dosage of the corticosteroid-containing aqueous inhalation mixture to be about 1: 1 of the nominal dosage of inhalable suspensions containing conventional corticosteroids. A treatment of bronchoconstrictive disorders that can result in a corresponding corticosteroid bioavailability when compared to an inhalable suspension comprising the corticosteroid when .5 to about 1:10. Treatment or prevention in the patient in need can be provided. In another embodiment, the corticosteroid-containing aqueous inhalation mixture administered by the systems and methods described herein includes a nominal dosage of the corticosteroid-containing aqueous inhalation mixture comprising a conventional corticosteroid When the nominal dosage of the inhalable suspension is from about 1: 1.5 to about 1: 9, the pharmacokinetic profile is improved as compared to the inhalable suspension comprising the corticosteroid. It may have. In yet another embodiment, the corticosteroid-containing aqueous inhalation mixture administered by the systems and methods described herein is such that the nominal dosage of the corticosteroid-containing aqueous inhalation mixture is a conventional corticosteroid. Improved pharmacokinetic profile when the nominal dosage of an inhalable suspension comprising is about 1: 1.5 to about 1: 8 compared to an inhalable suspension comprising the corticosteroid It may have. In yet another embodiment, the corticosteroid-containing aqueous inhalation mixture administered by the systems and methods described herein is such that the nominal dosage of the corticosteroid-containing aqueous inhalation mixture is a conventional corticosteroid. Improved pharmacokinetic profile when the nominal dosage of an inhalable suspension comprising is about 1: 1.5 to about 1: 7 compared to an inhalable suspension comprising the corticosteroid It may have. In yet another embodiment, the corticosteroid-containing aqueous inhalation mixture administered by the systems and methods described herein is such that the nominal dosage of the corticosteroid-containing aqueous inhalation mixture is a conventional corticosteroid. Improved pharmacokinetic profile when the nominal dosage of the inhalable suspension comprising is about 1: 1.5 to about 1: 6 compared to the inhalable suspension comprising the corticosteroid It may have. In one embodiment, the corticosteroid-containing aqueous inhalation mixture administered by the systems and methods described herein is an inhalation wherein the nominal dosage of the corticosteroid-containing aqueous inhalation mixture comprises a conventional corticosteroid. Having an improved pharmacokinetic profile as compared to an inhalable suspension comprising the corticosteroid when the nominal dosage of the possible suspension is from about 1: 1.5 to about 1: 5 Can be a thing. In yet another embodiment, the corticosteroid-containing aqueous inhalation mixture administered by the systems and methods described herein is such that the nominal dosage of the corticosteroid-containing aqueous inhalation mixture is a conventional corticosteroid. Improved pharmacokinetic profile when the nominal dosage of an inhalable suspension comprising is about 1: 1.5 to about 1: 4 compared to an inhalable suspension comprising the corticosteroid It may have. In yet another embodiment, the corticosteroid-containing aqueous inhalation mixture administered by the systems and methods described herein is such that the nominal dosage of the corticosteroid-containing aqueous inhalation mixture is a conventional corticosteroid. Improved pharmacokinetic profile when the nominal dosage of the inhalable suspension comprising is about 1: 1.5 to about 1: 3 compared to the inhalable suspension comprising the corticosteroid It may have. In yet another embodiment, the corticosteroid-containing aqueous inhalation mixture administered by the systems and methods described herein is such that the nominal dosage of the corticosteroid-containing aqueous inhalation mixture is a conventional corticosteroid. A pharmacokinetic profile of the inhalable suspension comprising about 0.1 to about 1: 2 of the nominal dosage of the inhalable suspension comprising It may have an improvement.

  In other embodiments, an aqueous inhalation mixture comprising a corticosteroid and a solubility enhancer is delivered by the systems and methods described herein, wherein the nominal dosage of the corticosteroid-containing aqueous inhalation mixture is conventional Pharmacokinetic profile when inhalable suspension containing corticosteroid is about 1: 2 to about 1:10 nominal dosage compared to inhalable suspension containing corticosteroid It has the improvement of. In yet other embodiments, an aqueous inhalation mixture comprising a corticosteroid and a solubility enhancer is delivered by the systems and methods described herein, wherein the nominal dosage of the corticosteroid-containing aqueous inhalation mixture is conventional Pharmacokinetics when the nominal dosage of an inhalable suspension containing a corticosteroid is about 1: 2 to about 1: 5 compared to an inhalable suspension containing the corticosteroid It has a profile improvement. In yet other embodiments, an aqueous inhalation mixture comprising a corticosteroid and a solubility enhancer is delivered by the systems and methods described herein, wherein the nominal dosage of the corticosteroid-containing aqueous inhalation mixture is conventional Pharmacokinetics when compared to an inhalable suspension containing a corticosteroid when the nominal dosage of an inhalable suspension containing a typical corticosteroid is about 1: 2 to about 1: 4 Have an improved profile. In yet other embodiments, an aqueous inhalation mixture comprising a corticosteroid and a solubility enhancer is delivered by the systems and methods described herein, wherein the nominal dosage of the corticosteroid-containing aqueous inhalation mixture is conventional Has an improved pharmacokinetic profile when it is about 1: 4 of the nominal dosage of an inhalable suspension containing a corticosteroid compared to an inhalable suspension containing the corticosteroid Is.

  In other specific embodiments, an aqueous inhalation mixture comprising budesonide and a solubility enhancer is delivered by the systems and methods described herein, wherein the nominal dosage of the aqueous inhalation mixture is conventional budesonide-containing inhalable When the nominal dosage of such a suspension is from about 1: 2 to about 1:10, it has an improved pharmacokinetic profile compared to the budesonide-containing inhalable suspension. In still other embodiments, an aqueous inhalation mixture comprising budesonide and a solubility enhancer is delivered by the systems and methods described herein, wherein the nominal dosage of the aqueous inhalation mixture is a conventional budesonide-containing inhalable When the nominal dosage of the suspension is about 1: 2 to about 1: 5, it has an improved pharmacokinetic profile as compared to the budesonide-containing inhalable suspension. In still other embodiments, an aqueous inhalation mixture comprising budesonide and a solubility enhancer is delivered by the systems and methods described herein, wherein the nominal dosage of the aqueous inhalation mixture is conventional budesonide-containing inhalable A nominal suspension dosage of from about 1: 2 to about 1: 4 has an improved pharmacokinetic profile as compared to the budesonide-containing inhalable suspension. In still other embodiments, an aqueous inhalation mixture comprising budesonide and a solubility enhancer is delivered by the systems and methods described herein, wherein the nominal dosage of the aqueous inhalation mixture is a conventional budesonide-containing inhalable When the nominal dosage of the suspension is about 1: 4, it has an improved pharmacokinetic profile as compared to the budesonide-containing inhalable suspension.

  In certain embodiments, the methods and systems of the present invention allow a therapeutically effective amount of corticosteroid to be delivered in a unit dose that contains less volume than conventional inhaled corticosteroid therapy. For example, the systems and methods of the present invention can deliver a therapeutically effective amount of a corticosteroid (such as budesonide) when the volume of the aqueous inhalation mixture is less than about 0.5 ml to less than 5 ml. In some embodiments, the volume of the aqueous inhalation mixture can be about 3.5 ml. In other embodiments, the volume of the aqueous inhalation mixture can be about 3.0 ml. In still other embodiments, the volume of the aqueous inhalation mixture can be about 2.5 ml. In still other embodiments, the volume of the aqueous inhalation mixture can be about 2.0 ml. In certain embodiments, the volume of the aqueous inhalation mixture can be about 1.5 ml. In other specific embodiments, the volume of the aqueous inhalation mixture can be about 1.0 ml. In a preferred embodiment, the volume of the aqueous inhalation mixture can be about 0.5 ml.

  In still other embodiments, the methods and systems of the present invention allow a therapeutically effective amount of corticosteroid to be delivered in a significantly shorter time than conventional inhaled corticosteroid therapy. For example, the nebulization time of Pulmicort® Respules administered by a Pari LC Plus jet nebulizer takes at least 5-8 minutes and in some cases over 10 minutes. In contrast, in the methods and systems of the invention, a therapeutically effective amount of a corticosteroid (such as budesonide) can be delivered at 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. In other embodiments, the delivery time can be less than about 5 minutes. In certain embodiments, the delivery time can be about 4.5 minutes. In other specific 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 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 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 specific 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 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.

  In other embodiments, the methods and systems of the present invention can deliver a nominal dosage of substantially all of the corticosteroid in a significantly shorter time than conventional inhaled corticosteroid therapy. For example, the nebulization time of Pulmicort® Respules administered by a Pari LC Plus jet nebulizer takes at least 5-8 minutes and in some cases over 10 minutes. In contrast, in the methods and systems of the invention, a therapeutically effective amount of a corticosteroid (such as budesonide) can be delivered at 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. In other embodiments, 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 other specific embodiments, substantially all of the nominal dosage can be delivered in less than about 4.5 minutes. In yet 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 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 in less than about 3.5 minutes. In 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. In certain embodiments, substantially all of the nominal dosage can be delivered in about 2.5 minutes. In other specific 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 in about 2 minutes. In 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.

B. C _max plasma levels According to the methods and systems described herein for treating or preventing bronchoconstrictive disorders in patients in need thereof, a corticosteroid-containing inhalation mixture is administered to a subject under the same conditions. The active ingredient having an increase in the C _max plasma value of the corticosteroid can be delivered in a manner that is delivered compared to a conventional inhaled corticosteroid suspension that is administered. In one example, when a conventional budesonide suspension is administered in a single dose using a Pari LC Plus® jet nebulizer in a 2.0 ml volume with a dosing time of about 5 minutes, the C _max plasma value is , Pharmacokinetic profiles are shown, ranging from about 556 ± 193 (pg / ml) to about 1114 ± 593 (pg / ml), respectively, at nominal dosages of 500 μg to 1000 μg. Using the systems and methods described herein, a single dose of budesonide + SBE7-β-CD inhalation solution having nominal dosages of 60 μg, 120 μg, and 240 μg was used with a ParieFlow Inhaler®, 0. When delivered in a volume of 5 ml with a delivery time of about 1.5 minutes, C _max plasma of about 227 ± 89 (pg / ml), about 578 ± 238 (pg / ml) and 1195 ± 811 (pg / ml), respectively. A value was obtained. FIG. 4 shows a graphical representation of the data used to obtain the above _Cmax plasma values.

In the second example, a conventional budesonide suspension (Pulmicort Respules®) was used twice a day for 7 days using a Pari LC Plus® jet nebulizer, with a volume of about 4 ml. When administered at a minute administration time, pharmacokinetic profiles with mean C _max plasma values of 319.6 ± 185 pg / ml and about 491.4 ± 207 pg / ml are shown at nominal dosages of 250 μg and 500 μg, respectively. It was. The same 250 μg and 500 μg of Pulmicort Respules® inhalation suspensions had C _max plasma geometric mean values of 270.5 pg / ml and 451.6 pg / ml, respectively. Using the system and method described herein, 60 μg of CBIS inhalation solution was used twice a day for 7 days using a Parie Flow Inhaler® in a 0.5 ml volume with a delivery time of about 1.5 minutes. Delivered a minimum C _max plasma value of about 186.4 pg / ml, a maximum C _max plasma value of about 779.4 pg / ml, and a geometric mean C _max value of about 362.2 pg / ml. Similarly, when 120 μg of CBIS inhalation solution was delivered twice daily for 7 days using a ParieFlow Inhaler® with a delivery time of about 1.5 minutes in a volume of 0.5 ml, the minimum C _max plasma value Was about 169.8 pg / ml, the maximum C _max plasma value was about 1160.4 pg / ml, and the geometric mean C _max value was about 516.9 pg / ml. FIG. 5 shows a graphical representation of data based on the above C _max plasma value.

Thus, conventional inhaled cortis containing a nominal dosage of corticosteroid administered under the same conditions by a method and system for treating or preventing bronchoconstrictive disorders in patients in need thereof. This results in the delivery of an inhalation mixture containing a nominal dosage of corticosteroid with an improved pharmacokinetic profile compared to a costeroid suspension. More specifically, in certain embodiments, the systems and methods described herein provide a microscopic dose of corticosteroid administered compared to conventional inhaled corticosteroid therapy administered under the same conditions. For corticosteroids normalized to corticosteroid dose per gram, an increase of at least about 1.5 to about 14-fold in C _max plasma values (measured on an individual basis) is provided. In certain embodiments, the systems and methods described herein provide cortico per microgram of corticosteroid administered compared to conventional inhaled corticosteroid therapy administered under the same conditions. At least about 1.5 times to about 13 times, about 1.5 times to about 12 times, about 1.5 times the C _max plasma value (measured on an individual basis) for corticosteroids normalized to steroid doses. Times to about 10 times, about 1.5 times to about 8 times, about 1.5 times to about 7.5 times, about 1.5 times to about 7 times, about 1.5 times to about 6.5 times, About 1.5 times to about 6.25 times, about 1.5 times to about 6 times, about 1.5 times to about 5.75 times, about 1.5 times to about 5.5 times, about 1.5 times A fold to about 5 fold increase, a 1.5 fold to about 4.75 fold increase, a 1.5 fold to 4.5 fold increase, a 1.5 fold to 4 fold increase is provided.

In other embodiments, cortico per microgram of corticosteroid administered by the methods and systems described herein for treating or preventing bronchoconstrictive disorders in patients in need thereof. Normalized to steroid dose, compared to conventional inhaled corticosteroid therapy administered under the same conditions, for corticosteroids considered between study patient populations (eg, geometric mean between study patient populations) As a result of at least about 4-fold to about 7-fold increase in C _max plasma values. In certain embodiments, conventional inhalation forms administered under the same conditions when normalized to a dose of corticosteroid per microgram of corticosteroid administered by the systems and methods described herein. Compared to corticosteroid therapy, C _max plasma levels are considered to be at least about 4 times to about 7 times, about 4 times to about 6.5 times, about 4 times to about 4 times for corticosteroids considered among study patient populations. 6.25 times, about 4 times to about 6 times, about 4 times to about 5.75 times, about 4 times to about 5.5 times, about 4 times to about 5 times, about 5 times to about 7 times, about There is an increase of 5.5 to about 7 times, about 6 to about 7 times.

In some embodiments, the C _max is significantly greater than the C _max plasma value exhibited by an inhalable suspension comprising a conventional corticosteroid administered at the same nominal dosage and under the same conditions It can be. In certain embodiments, C _max is about 1.5 times (150%) the C _max plasma value exhibited by an inhalable suspension containing the same nominal dosage of a conventional corticosteroid under the same conditions. ~ 14 times (1400%). In other embodiments, the C _max is about 1.5 times (150%) the C _max plasma value exhibited by an inhalable suspension containing the same nominal dosage of a conventional corticosteroid under the same conditions. ~ 12 times (1200%). In still other embodiments, the C _max is about 1.5 times (150%) the C _max plasma value exhibited by an inhalable suspension containing the same nominal dosage of a conventional corticosteroid under the same conditions. ) To about 10 times (1000%). In one embodiment, the C _max is at least about 12 times (1200%) the C _max plasma value exhibited by an inhalable suspension containing the same nominal dosage of a conventional corticosteroid under the same conditions. obtain. In other specific embodiments, the C _max is at least about 1000% (10-fold) greater than the C _max plasma value exhibited by an inhalable suspension comprising a conventional corticosteroid of the same nominal dosage under the same conditions. ) To about 1200% (12 times), about 1100% (11 times) to about 1200% (12 times), or about 1150% (11.5 times) to about 1200% (12 times). In other embodiments, improved pharmacokinetic profile, the C _max of C _max greater aqueous inhalation mixtures inhalable suspension at the same nominal dosage comprising a corticosteroid administered under the same conditions Including. In one embodiment, the C _max is at least about 1000% (10 times) greater than the C _max plasma value exhibited by an inhalable suspension comprising the same nominal dosage of a conventional corticosteroid under the same conditions. It can be. In other specific embodiments, the C _max is at least about 900% (9-fold) greater than the C _max plasma value exhibited by an inhalable suspension containing the same nominal dosage of a conventional corticosteroid under the same conditions. ) To about 1000% (10 times), about 925% (9.25 times) to about 1000% (10 times), or about 950% (9.5 times) to about 1000% (10 times) obtain. In another embodiment, the C _max is at least about 900% (9 times) greater than the C _max plasma value exhibited by an inhalable suspension comprising the same nominal dosage of a conventional corticosteroid under the same conditions. Can be a thing. In other specific embodiments, the C _max is at least about 800% (8-fold) greater than the C _max plasma value exhibited by an inhalable suspension comprising a conventional corticosteroid of the same nominal dosage under the same conditions. ) To about 900% (9 times), about 825% (8.25 times) to about 900% (9 times), or about 850% (8.5 times) to about 900% (9 times) obtain. In yet another embodiment, the C _max is at least about 800% (8 times) higher than the C _max plasma value exhibited by an inhalable suspension containing the same nominal dosage of a conventional corticosteroid under the same conditions. It can be big. In other specific embodiments, the C _max is at least about 700% (7-fold) greater than the C _max plasma value exhibited by an inhalable suspension containing the same nominal dosage of a conventional corticosteroid under the same conditions. ) To about 800% (8 times), about 725% (7.25 times) to about 800% (8 times), or about 750% (7.5 times) to about 800% (8 times) obtain. In yet another embodiment, the C _max is at least about 700% (7-fold) greater than the C _max plasma value exhibited by an inhalable suspension containing the same nominal dosage of a conventional corticosteroid under the same conditions. ) Can be big. In other specific embodiments, the C _max is at least about 600% (six times higher) than the C _max plasma value exhibited by an inhalable suspension containing the same nominal dosage of a conventional corticosteroid under the same conditions. ) To about 700% (7 times), about 625% (6.25 times) to about 700% (7 times), or about 650% (6.5 times) to about 700% (7 times) obtain. In one embodiment, the C _max is at least about 600% (6 times) greater than the C _{max of} an inhalable suspension comprising a corticosteroid. In other specific embodiments, the C _max is at least about 500% (5-fold) greater than the C _max plasma value exhibited by an inhalable suspension comprising a conventional corticosteroid of the same nominal dosage under the same conditions. ) To about 600% (6 times), about 525% (5.25 times) to about 600% (6 times), or about 550% (5.5 times) to about 600% (6 times) obtain. In another embodiment, the C _max is at least about 500% (5 times) greater than the C _{max of} an inhalable suspension comprising a corticosteroid. In other specific embodiments, the C _max is at least about 400% (4 times) greater than the C _max plasma value exhibited by an inhalable suspension containing the same nominal dosage of a conventional corticosteroid under the same conditions. ) To about 500% (5 times), about 425% (4.25 times) to about 500% (5 times), or about 450% (4.5 times) to about 500% (5 times) obtain. In yet another embodiment, the C _max is at least about 400% (4 times) greater than the C _{max of} an inhalable suspension comprising a corticosteroid. In other specific embodiments, the C _max is at least about 300% (3 times higher) than the C _max plasma value exhibited by an inhalable suspension comprising the same nominal dosage of a conventional corticosteroid under the same conditions. ) To about 400% (4 times), about 325% (3.25 times) to about 400% (4 times), or about 350% (3.5 times) to about 400% (4 times) obtain. In yet another embodiment, the C _max is at least about 300% (3 times) greater than the C _{max of} an inhalable suspension comprising a corticosteroid. In other specific embodiments, the C _max is at least about 200% (2 times) greater than the C _max plasma value exhibited by an inhalable suspension comprising the same nominal dosage of a conventional corticosteroid under the same conditions. ) To about 300% (3 times), about 225% (2.25 times) to about 300% (3 times), or about 250% (2.5 times) to about 300% (3 times) obtain. In yet another embodiment, the C _max is at least about 200% (2 times) greater than the C _{max of} an inhalable suspension comprising a corticosteroid. In other specific embodiments, the C _max is about 150% (1.5% of the C _max plasma value exhibited by an inhalable suspension containing the same nominal dosage of a conventional corticosteroid under the same conditions. Times) to about 200% (2 times) larger. In another embodiment, the C _max is at least about 150% (1.5 times) greater than the C _{max of} an inhalable suspension comprising a corticosteroid.

In other embodiments, C _max is indicated by an inhalable suspension comprising a conventional corticosteroid when the corticosteroid-containing aqueous inhalation mixture is administered under the same conditions at a lower nominal dosage. The C _max plasma value may be substantially equivalent. In one embodiment, the nominal dosage is about 1: 1.5 (ie, 1.5 times the pharmacokinetic profile) of the nominal dosage of inhalable suspensions containing conventional corticosteroids. Improvement) to about 1:10 (ie, a 10-fold improvement in pharmacokinetic profile). In another embodiment, the nominal dosage of the aqueous corticosteroid-containing inhalation mixture is from about 1: 1.5 to about 1: 9 of the nominal dosage of an inhalable suspension comprising a conventional corticosteroid. possible. In yet another embodiment, the nominal dosage of the corticosteroid-containing aqueous inhalation mixture is from about 1: 1.5 to about 1: 8 of the nominal dosage of an inhalable suspension comprising a conventional corticosteroid. It can be. In yet another embodiment, the nominal dosage of the corticosteroid-containing aqueous inhalation mixture is about 1: 1.5 to about 1: 7 of the nominal dosage of an inhalable suspension containing a conventional corticosteroid. It can be. In a further embodiment, the nominal dosage of the corticosteroid-containing aqueous inhalation mixture is from about 1: 1.5 to about 1: 6 of the nominal dosage of an inhalable suspension comprising a conventional corticosteroid. possible. In another embodiment, the nominal dosage of the corticosteroid-containing aqueous inhalation mixture can be about 1: 2 to about 1: 5 of the nominal dosage of an inhalable suspension containing a conventional corticosteroid. . In yet another embodiment, the nominal dosage of the corticosteroid-containing aqueous inhalation mixture is from about 1: 2 to about 1: 4 of the nominal dosage of an inhalable suspension comprising a conventional corticosteroid. obtain. In still other embodiments, the nominal dosage of the corticosteroid-containing aqueous inhalation mixture is from about 1: 2 to about 1: 3 of the nominal dosage of an inhalable suspension comprising a conventional corticosteroid. possible. In certain embodiments, the nominal dosage of an aqueous inhalation mixture containing corticosteroids can be about 1: 2 of the nominal dosage of an inhalable suspension containing conventional corticosteroids. In other specific embodiments, the nominal dosage of the corticosteroid-containing aqueous inhalation mixture can be about 1: 3 of the nominal dosage of an inhalable suspension containing a conventional corticosteroid. In other specific embodiments, the nominal dosage of the corticosteroid-containing aqueous inhalation mixture can be about 1: 4 of the nominal dosage of an inhalable suspension comprising a conventional corticosteroid. In yet other embodiments, the nominal dosage of the corticosteroid-containing aqueous inhalation mixture can be about 1: 5 of the nominal dosage of an inhalable suspension containing conventional corticosteroids. In still other embodiments, the nominal dosage of the corticosteroid-containing aqueous inhalation mixture can be about 1: 6 of the nominal dosage of an inhalable suspension containing a conventional corticosteroid. In yet other embodiments, the nominal dosage of the corticosteroid-containing aqueous inhalation mixture can be about 1: 7 of the nominal dosage of an inhalable suspension containing a conventional corticosteroid. In other embodiments, the nominal dosage of a corticosteroid-containing aqueous inhalation mixture can be about 1: 8 of the nominal dosage of an inhalable suspension containing a conventional corticosteroid. In yet other embodiments, the nominal dosage of the corticosteroid-containing aqueous inhalation mixture can be about 1: 9 of the nominal dosage of an inhalable suspension containing a conventional corticosteroid. In still other embodiments, the nominal dosage of the corticosteroid-containing aqueous inhalation mixture can be about 1:10 of the nominal dosage of an inhalable suspension containing a conventional corticosteroid.

C. AUC _(last) plasma levels According to the methods and systems described herein for treating or preventing bronchoconstrictive disorders in patients in need thereof, a corticosteroid-containing inhalation mixture is administered to a subject under the same conditions. Compared to conventional inhaled corticosteroid suspensions administered below, active ingredients with increased AUC _(last) plasma levels of corticosteroids can be delivered in a delivered manner. For example, when a conventional budesonide suspension is administered in a single dose using a Pari LC Plus® jet nebulizer in a 2.0 ml volume with a dosing time of about 5 minutes, the AUC _(last) plasma value Show pharmacokinetic profiles ranging from about 739 ± 220 (pg / h / ml) to about 1989 ± 379 (pg / h / ml), respectively, at nominal dosages of 500 μg to 1000 μg . Using the systems and methods described herein, budesonide + SBE7-β-CD inhalation solution with nominal dosages of 60 μg, 120 μg and 240 μg was used in a single dose using the ParieFlow Inhaler®, 0. Delivered in a 5 ml volume with a delivery time of about 1.5 minutes, about 179 ± 75 (pg / h / ml), about 569 ± 213 (pg / h / ml), and 1183 ± 328 (pg / h), respectively. / Ml) AUC _(last) plasma values were obtained. FIG. 4 shows a graphical representation of the data used to obtain the above AUC _(last) plasma values.

In the second example, a conventional budesonide suspension (Pulmicort Respules®) was used twice a day for 7 days using a Pari LC Plus® jet nebulizer with a volume of about 4 ml. Pharmacokinetic profile with mean AUC _(last) plasma values of 361.1 ± 212 pg / ml and about 811.1 ± 328 pg / ml, respectively, at nominal dosages of 250 μg and 500 μg when administered at a minute administration time It has been shown. The 250 μg and 500 μg Pulmicort Respules® inhalation suspensions had AUC _(last) plasma geometric mean values of 302.6 pg / ml and 735.1 pg / ml, respectively. Using the system and method described herein, 60 μg of CBIS inhalation solution was used twice a day for 7 days using a Parie Flow Inhaler® in a 0.5 ml volume with a delivery time of about 1.5 minutes. Delivered at a minimum AUC _(last) plasma value of about 106.4 pg / ml, a maximum AUC _(last) plasma value of about 463.1 pg / ml, and a geometric mean AUC _(last) value of about 293.7 pg / ml. there were. Similarly, when 120 μg of CBIS inhalation solution is delivered twice daily for 7 days using a ParieFlow Inhaler® with a delivery time of about 1.5 minutes in a volume of 0.5 ml, the minimum AUC _(last) The plasma value was about 168.2 pg / ml, the maximum AUC _(last) plasma value was about 1496.7 pg / ml, and the geometric mean AUC _(last) value was about 621.4 pg / ml. FIG. 5 shows a graphical representation of the data based on the above AUC _(last) plasma value.

Thus, compared to conventional inhaled corticosteroid suspensions administered under the same conditions by methods and systems for treating or preventing bronchoconstrictive disorders in patients in need thereof, the drug Delivery of an inhalation mixture containing corticosteroids with an improved kinetic profile results. More specifically, conventional inhalation forms administered under the same conditions when normalized to a dose of corticosteroid per microgram of corticosteroid administered by the systems and methods described herein. Compared to corticosteroid therapy, an increase in corticosteroid (measured on an individual basis) AUC _(last) plasma value of at least about 1.5- to about 10-fold results. In certain embodiments, the systems and methods described herein provide corticosteroids per microgram of corticosteroid administered compared to conventional inhaled corticosteroid therapy administered under the same conditions. For dose-normalized corticosteroids, at least about 1.5 to about 10 times, about 1.5 to about 9.5 times, about 1.5 to about AUC _(last) plasma values (measured on an individual basis), about 1.5 times to about 9 times, about 1.5 times to about 8.5 times, about 1.5 times to about 8 times, about 1.5 times to about 7.75 times, about 1.5 times to about 7.5 times, about 1.5 times to about 7.25 times, about 1.5 times to about 7 times, about 1.5 times to about 6.75 times, about 1.5 times to about 6.5 times About 1.5 times to about 6 times, about 1.5 times to about 5.75 times, about 1.5 times to about 5.5 times, about 1.5 times to about 5 times, about 1.5 times ~ About 4 An increase of .75 times, about 1.5 times to about 4.5 times, about 1.5 times to about 4 times.

In other embodiments, cortico per microgram of corticosteroid administered by the methods and systems described herein for treating or preventing bronchoconstrictive disorders in patients in need thereof. Normalized to steroid dose, compared to conventional inhaled corticosteroid therapy administered under the same conditions, for corticosteroids considered between study patient populations (eg, geometric mean between study patient populations) ) Results in an increase of at least about 4-fold to about 6-fold in AUC _(last) plasma values. In certain embodiments, conventional inhalation forms administered under the same conditions when normalized to a dose of corticosteroid per microgram of corticosteroid administered by the systems and methods described herein. Compared to corticosteroid therapy, at least about 4 to about 6 times, about 4 to about 5.75 times, about 4 times the AUC _(last) plasma value for corticosteroids considered among the study patient population To about 5.5 times, about 4 times to about 5.25 times, about 4 times to about 5 times, about 4.5 times to about 6 times, about 4.75 times to about 6 times, about 5 times to about There is a 6 fold increase of about 5.5 to about 6 fold.

In some embodiments, methods and systems for treating or preventing bronchoconstrictive disorders in patients in need thereof are conventional corticosteroids administered under the same conditions at the same nominal dosage. may be one that results in the _{AUC (last)} significantly than the plasma values greater _{AUC (last)} represented by the inhalable suspension comprising a. In certain embodiments, AUC _(last) is about 1.5 times the AUC _(last) plasma value exhibited by an inhalable suspension containing the same nominal dosage of a conventional corticosteroid under the same conditions. (150%) to about 10 times (1000%). In one embodiment, the AUC _(last) is at least about 1000% (10% ₎ greater than the AUC _(last) plasma value exhibited by an inhalable suspension comprising the same nominal dosage of a conventional corticosteroid under the same conditions. Times) can be large. In other specific embodiments, the AUC _(last) is at least about 900 greater than the AUC _(last) plasma value exhibited by an inhalable suspension comprising a conventional corticosteroid of the same nominal dosage under the same conditions. % (9 times) to about 1000% (10 times), about 925% (9.25 times) to about 1000% (10 times), or about 950% (9.5 times) to about 1000% (10 times) It can be big. In another embodiment, AUC _(last) is at least about 900% greater than the AUC _(last) plasma value exhibited by an inhalable suspension comprising the same nominal dosage of a conventional corticosteroid under the same conditions ( 9 times) can be large. In other specific embodiments, the AUC _(last) is at least about 800 greater than the AUC _(last) plasma value exhibited by an inhalable suspension comprising the same nominal dosage of a conventional corticosteroid under the same conditions. % (8 times) to about 900% (9 times), about 825% (8.25 times) to about 900% (9 times), or about 850% (8.5 times) to about 900% (9 times) It can be big. In yet another embodiment, AUC _(last) is at least about 800% greater than the AUC _(last) plasma value exhibited by an inhalable suspension comprising a conventional corticosteroid at the same nominal dosage under the same conditions. It can be (8 times) larger. In another specific embodiment, AUC _(last) is at least about 700 greater than the AUC _(last) plasma value exhibited by an inhalable suspension comprising a conventional corticosteroid of the same nominal dosage under the same conditions. % (7 times) to about 800% (8 times), about 725% (7.25 times) to about 800% (8 times), or about 750% (7.5 times) to about 800% (8 times) It can be big. In yet another embodiment, the AUC _(last) is at least about 700 greater than the AUC _(last) plasma value exhibited by an inhalable suspension comprising the same nominal dosage of a conventional corticosteroid under the same conditions. % (Seven times) larger. In other specific embodiments, the AUC _(last) is at least about 600 greater than the AUC _(last) plasma value exhibited by an inhalable suspension comprising the same nominal dosage of a conventional corticosteroid under the same conditions. % (6 times) to about 700% (7 times), about 625% (6.25 times) to about 700% (7 times), or about 650% (6.5 times) to about 700% (7 times) It can be big. In one embodiment, AUC _(last) is at least about 600% (6 times) greater than AUC _(last) of an inhalable suspension comprising a corticosteroid. In other specific embodiments, the AUC _(last) is at least about 500 greater than the AUC _(last) plasma value exhibited by an inhalable suspension comprising the same nominal dosage of a conventional corticosteroid under the same conditions. % (5 times) to about 600% (6 times), about 525% (5.25 times) to about 600% (6 times), or about 550% (5.5 times) to about 600% (6 times) It can be big. In another embodiment, AUC _(last) is at least about 500% (5 times) greater than AUC _(last) of an inhalable suspension comprising a corticosteroid. In other specific embodiments, the AUC _(last) is at least about 400 greater than the AUC _(last) plasma value exhibited by an inhalable suspension comprising the same nominal dosage of a conventional corticosteroid under the same conditions. % (4 times) to about 500% (5 times), about 425% (4.25 times) to about 500% (5 times), or about 450% (4.5 times) to about 500% (5 times) It can be big. In yet another embodiment, AUC _(last) is at least about 400% (4 times) greater than AUC _(last) of an inhalable suspension comprising a corticosteroid. In other specific embodiments, the AUC _(last) is at least about 300 greater than the AUC _(last) plasma value exhibited by an inhalable suspension comprising a conventional corticosteroid of the same nominal dosage under the same conditions. % (3 times) to about 400% (4 times), about 325% (3.25 times) to about 400% (4 times), or about 350% (3.5 times) to about 400% (4 times) It can be big. In yet another embodiment, AUC _(last) is at least about 300% (3 times) greater than AUC _(last) of an inhalable suspension comprising a corticosteroid. In other specific embodiments, the AUC _(last) is at least about 200 greater than the AUC _(last) plasma value exhibited by an inhalable suspension comprising the same nominal dosage of a conventional corticosteroid under the same conditions. % (2 times) to about 300% (3 times), about 225% (2.25 times) to about 300% (3 times), or about 250% (2.5 times) to about 300% (3 times) It can be big. In yet another embodiment, AUC _(last) is at least about 200% (2 times) greater than AUC _(last) of an inhalable suspension comprising a corticosteroid. In other specific embodiments, AUC _(last) is about 150% of the AUC _(last) plasma value exhibited by an inhalable suspension containing the same nominal dosage of a conventional corticosteroid under the same conditions. (1.5 times) to about 200% (2 times) larger. In another embodiment, AUC _(last) is at least about 150% (1.5 times) greater than AUC _(last) of an inhalable suspension comprising a corticosteroid.

In some embodiments, AUC _(last) is represented by an inhalable suspension comprising a conventional corticosteroid when an aqueous inhalation mixture is administered under the same conditions at a lower nominal dosage. AUC _(last) is substantially equal to the plasma value. In one embodiment, the nominal dosage is about 1: 1.5 (ie, 1.5 times the pharmacokinetic profile) of the nominal dosage of inhalable suspensions containing conventional corticosteroids. Improvement) to about 1:10 (ie, a 10-fold improvement in pharmacokinetic profile). In another embodiment, the nominal dosage of the aqueous corticosteroid-containing inhalation mixture is from about 1: 1.5 to about 1: 9 of the nominal dosage of an inhalable suspension comprising a conventional corticosteroid. possible. In yet another embodiment, the nominal dosage of the corticosteroid-containing aqueous inhalation mixture is from about 1: 1.5 to about 1: 8 of the nominal dosage of an inhalable suspension comprising a conventional corticosteroid. It can be. In yet another embodiment, the nominal dosage of the corticosteroid-containing aqueous inhalation mixture is about 1: 1.5 to about 1: 7 of the nominal dosage of an inhalable suspension containing a conventional corticosteroid. It can be. In a further embodiment, the nominal dosage of the corticosteroid-containing aqueous inhalation mixture is from about 1: 1.5 to about 1: 6 of the nominal dosage of an inhalable suspension comprising a conventional corticosteroid. possible. In another embodiment, the nominal dosage of the corticosteroid-containing aqueous inhalation mixture can be about 1: 2 to about 1: 5 of the nominal dosage of an inhalable suspension containing a conventional corticosteroid. . In yet another embodiment, the nominal dosage of the corticosteroid-containing aqueous inhalation mixture is from about 1: 2 to about 1: 4 of the nominal dosage of an inhalable suspension comprising a conventional corticosteroid. obtain. In still other embodiments, the nominal dosage of the corticosteroid-containing aqueous inhalation mixture is from about 1: 2 to about 1: 3 of the nominal dosage of an inhalable suspension comprising a conventional corticosteroid. possible. In certain embodiments, the nominal dosage of an aqueous inhalation mixture containing corticosteroids can be about 1: 2 of the nominal dosage of an inhalable suspension containing conventional corticosteroids. In other specific embodiments, the nominal dosage of the corticosteroid-containing aqueous inhalation mixture can be about 1: 3 of the nominal dosage of an inhalable suspension containing a conventional corticosteroid. In other specific embodiments, the nominal dosage of the corticosteroid-containing aqueous inhalation mixture can be about 1: 4 of the nominal dosage of an inhalable suspension comprising a conventional corticosteroid. In yet other embodiments, the nominal dosage of the corticosteroid-containing aqueous inhalation mixture can be about 1: 5 of the nominal dosage of an inhalable suspension containing conventional corticosteroids. In still other embodiments, the nominal dosage of the corticosteroid-containing aqueous inhalation mixture can be about 1: 6 of the nominal dosage of an inhalable suspension containing a conventional corticosteroid. In yet other embodiments, the nominal dosage of the corticosteroid-containing aqueous inhalation mixture can be about 1: 7 of the nominal dosage of an inhalable suspension containing a conventional corticosteroid. In other embodiments, the nominal dosage of a corticosteroid-containing aqueous inhalation mixture can be about 1: 8 of the nominal dosage of an inhalable suspension containing a conventional corticosteroid. In yet other embodiments, the nominal dosage of the corticosteroid-containing aqueous inhalation mixture can be about 1: 9 of the nominal dosage of an inhalable suspension containing a conventional corticosteroid. In still other embodiments, the nominal dosage of the corticosteroid-containing aqueous inhalation mixture can be about 1:10 of the nominal dosage of an inhalable suspension containing a conventional corticosteroid.

D. AUC _(0-∞) plasma levels A method and system as described herein for treating or preventing bronchoconstrictive disorder in a patient in need thereof, wherein the corticosteroid is administered to the subject under the same conditions. Compared to conventional inhaled corticosteroid suspensions administered in, the active ingredient having an increased AUC _(0-∞) plasma value of the corticosteroid can be delivered in a delivered manner. For example, when a conventional budesonide suspension is administered in a single dose using a Pari LC Plus® jet nebulizer in a volume of 2.0 ml with a dosing time of about 5 minutes, AUC _(0-∞) Pharmacokinetic profiles such that plasma values range from about 867 ± 216 (pg / h / ml) to about 2083 ± 394 (pg / h / ml), respectively, at nominal dosages of 500 μg to 1000 μg. Indicated. Using the systems and methods described herein, budesonide + SBE7-β-CD inhalation solution with nominal dosages of 60 μg, 120 μg and 240 μg was used in a single dose using the ParieFlow Inhaler®, 0. Delivered in a 5 ml volume with a delivery time of about 1.5 minutes, about 262 ± 125 (pg / h / ml), about 679 ± 201 (pg / h / ml), and about 1365 ± 313 (pg / h), respectively. h / ml) of AUC _(0-∞) was obtained. FIG. 4 shows a graphical representation of the data used to obtain the above AUC _(last) plasma values.

In the second example, a conventional budesonide suspension (Pulmicort Respules®) was used twice a day for 7 days using a Pari LC Plus® jet nebulizer with a volume of about 4 ml. Pharmacokinetics with mean AUC _(0-∞) plasma values of 472.3 ± 239 pg / ml and about 945.7 ± 363 pg / ml, respectively, at nominal dosages of 250 μg and 500 μg when administered at a minute administration time The target profile was shown. The 250 μg and 500 μg Palmicor Repres® inhalation suspensions had AUC _(0-∞) plasma geometric mean values of 413.0 pg / ml and 874.6 pg / ml, respectively. Using the system and method described herein, 60 μg of CBIS inhalation solution was used twice a day for 7 days using a Parie Flow Inhaler® in a 0.5 ml volume with a delivery time of about 1.5 minutes. Delivered with a minimum AUC _(0-∞) plasma value of about 156.5 pg / ml, a maximum AUC _(0-∞) plasma value of about 748.5 pg / ml, and a geometric mean AUC _(0-∞) value of about It was 396.1 pg / ml. Similarly, when 120 μg of CBIS inhalation solution is delivered twice daily for 7 days using a ParieFlow Inhaler® with a delivery time of about 1.5 minutes in a volume of 0.5 ml, a minimum AUC _{(0 ∞)} Plasma value was about 221.4 pg / ml, maximum AUC _(0-∞) plasma value was about 1863.7 pg / ml, and geometric mean AUC _(0-∞) value was about 752.2 pg / ml. FIG. 5 shows a graph display of data based on the above AUC _{(0 to ∞)} plasma value.

Thus, conventional inhaled corticosteroid suspensions administered under the same conditions by the methods and systems described herein for treating or preventing bronchoconstrictive disorders in patients in need thereof This results in the delivery of corticosteroids with an improved pharmacokinetic profile compared to products. More specifically, conventional inhalation forms administered under the same conditions when normalized to a dose of corticosteroid per microgram of corticosteroid administered by the systems and methods described herein. Compared to corticosteroid therapy, an AUC _(0-∞) plasma level of corticosteroid (measured on an individual basis) is at least about 1.5-fold to about 10-fold increased. In certain embodiments, the systems and methods described herein provide cortico per microgram of corticosteroid administered compared to conventional inhaled corticosteroid therapy administered under the same conditions. At least about 1.5 times to about 10 times, about 1.5 times to about 9.5 times the AUC _(0-∞) plasma value (measured on an individual basis ₎ for corticosteroids normalized to steroid doses. Times, about 1.5 times to about 9 times, about 1.5 times to about 8.5 times, about 1.5 times to about 8 times, about 1.5 times to about 7.75 times, about 1.5 times Times to about 7.5 times, about 1.5 times to about 7.25 times, about 1.5 times to about 7 times, about 1.5 times to about 6.75 times, about 1.5 times to about 6 times .5 times, about 1.5 times to about 6 times, about 1.5 times to about 5.75 times, about 1.5 times to about 5.5 times, about 1.5 times to about 5 times, about 1 .5 times to about 4 An increase of .75 times, about 1.5 times to about 4.5 times, about 1.5 times to about 4 times.

In other embodiments, cortico per microgram of corticosteroid administered according to the methods and systems described herein for treating or preventing bronchoconstrictive disorders in patients in need thereof. Normalized to steroid dose, compared to conventional inhaled corticosteroid therapy administered under the same conditions, for corticosteroids considered between study patient populations (eg, geometric mean between study patient populations) ) _{Results in} an increase in AUC _(0-∞) plasma levels of at least about 4-fold to about 6-fold. In certain embodiments, conventional inhalation forms administered under the same conditions when normalized to a dose of corticosteroid per microgram of corticosteroid administered by the systems and methods described herein. Compared to corticosteroid therapy, AUC _{(0 to ∞)} plasma values are at least about 4 to about 6 times, about 4 to about 5.75 times, about corticosteroids considered between study patient populations 4 times to about 5.5 times, about 4 times to about 5.25 times, about 4 times to about 5 times, about 4.5 times to about 6 times, about 4.75 times to about 6 times, about 5 times An increase of ˜about 6 times, or about 5.5 times to about 6 times.

In some embodiments, methods and systems for treating or preventing bronchoconstrictive disorders in patients in need thereof are conventional corticosteroids administered under the same conditions at the same nominal dosage. It may be one that results in the _{AUC (0 to ∞)} significantly greater than the plasma values _{AUC (0 to ∞)} represented by the inhalable suspension comprising a. In certain embodiments, AUC _(0-∞) is about the AUC _(0-∞) plasma value exhibited by an inhalable suspension containing the same nominal dosage of a conventional corticosteroid under the same conditions. It can be 1.5 times (150%) to about 10 times (1000%). In one embodiment, AUC _(0-∞) is at least about an AUC _(0-∞) plasma value exhibited by an inhalable suspension comprising the same nominal dosage of a conventional corticosteroid under the same conditions. It can be 1000% (10 times) larger. In another specific embodiment, AUC _(0-∞) is the AUC _(0-∞) plasma value exhibited by an inhalable suspension containing the same nominal dosage of a conventional corticosteroid under the same conditions. More than at least about 900% (9 times) to about 1000% (10 times), about 925% (9.25 times) to about 1000% (10 times), or about 950% (9.5 times) to about 1000% It can be (10 times) larger. In another embodiment, AUC _(0-∞) is at least greater than the AUC _(0-∞) plasma value exhibited by an inhalable suspension comprising the same nominal dosage of a conventional corticosteroid under the same conditions. It can be about 900% (9 times) larger. In another specific embodiment, AUC _(0-∞) is the AUC _(0-∞) plasma value exhibited by an inhalable suspension containing the same nominal dosage of a conventional corticosteroid under the same conditions. More than at least about 800% (8 times) to about 900% (9 times), about 825% (8.25 times) to about 900% (9 times), or about 850% (8.5 times) to about 900% It can be (9 times) larger. In yet another embodiment, AUC _(0-∞) is greater than the AUC _(0-∞) plasma value exhibited by an inhalable suspension containing the same nominal dosage of a conventional corticosteroid under the same conditions. It can be at least about 800% (8 times) larger. In another specific embodiment, AUC _(0-∞) is the AUC _(0-∞) plasma value exhibited by an inhalable suspension containing the same nominal dosage of a conventional corticosteroid under the same conditions. More at least about 700% (7 times) to about 800% (8 times), about 725% (7.25 times) to about 800% (8 times), or about 750% (7.5 times) to about 800% It can be (8 times) larger. In yet another embodiment, AUC _(0-∞) is an AUC _(0-∞) plasma value exhibited by an inhalable suspension containing the same nominal dosage of a conventional corticosteroid under the same conditions. It can be at least about 700% (seven times) larger. In another specific embodiment, AUC _(0-∞) is the AUC _(0-∞) plasma value exhibited by an inhalable suspension containing the same nominal dosage of a conventional corticosteroid under the same conditions. More than at least about 600% (6 times) to about 700% (7 times), about 625% (6.25 times) to about 700% (7 times), or about 650% (6.5 times) to about 700% It can be (seven times) larger. In one embodiment, the AUC _(0-∞) is at least about 600% (6 times) greater than the AUC _(0-∞) of the inhalable suspension comprising the corticosteroid. In another specific embodiment, AUC _(0-∞) is the AUC _(0-∞) plasma value exhibited by an inhalable suspension containing the same nominal dosage of a conventional corticosteroid under the same conditions. More at least about 500% (5 times) to about 600% (6 times), about 525% (5.25 times) to about 600% (6 times), or about 550% (5.5 times) to about 600% It can be (six times) larger. In another embodiment, AUC _(0-∞) is at least about 500% (5 times) greater than AUC _(0-∞) of an inhalable suspension comprising a corticosteroid. In other specific embodiments, AUC _(0-∞) is an AUC _(0-∞) plasma value exhibited by an inhalable suspension containing the same nominal dosage of a conventional corticosteroid under the same conditions. More than at least about 400% (4 times) to about 500% (5 times), about 425% (4.25 times) to about 500% (5 times), or about 450% (4.5 times) to about 500% It can be (5 times) larger. In yet another embodiment, AUC _(0-∞) is at least about 400% (4 times) greater than AUC _(0-∞) of an inhalable suspension comprising a corticosteroid. In other specific embodiments, AUC _(0-∞) is an AUC _(0-∞) plasma value exhibited by an inhalable suspension containing the same nominal dosage of a conventional corticosteroid under the same conditions. More than at least about 300% (3 times) to about 400% (4 times), about 325% (3.25 times) to about 400% (4 times), or about 350% (3.5 times) to about 400% (4 times) Larger. In yet another embodiment, AUC _(0-∞) is at least about 300% (3 times) greater than AUC _(0-∞) of an inhalable suspension comprising a corticosteroid. In other specific embodiments, AUC _(0-∞) is an AUC _(0-∞) plasma value exhibited by an inhalable suspension containing the same nominal dosage of a conventional corticosteroid under the same conditions. More than at least about 200% (2 times) to about 300% (3 times), about 225% (2.25 times) to about 300% (3 times), or about 250% (2.5 times) to about 300% It can be (three times) larger. In yet another embodiment, AUC _(0-∞) is at least about 200% (2 times) greater than AUC _(0-∞) of an inhalable suspension comprising a corticosteroid. In other specific embodiments, AUC _(0-∞) is an AUC _(0-∞) plasma value exhibited by an inhalable suspension containing the same nominal dosage of a conventional corticosteroid under the same conditions. From about 150% (1.5 times) to about 200% (2 times). In another embodiment, AUC _(0-∞) is at least about 150% (1.5-fold) greater than AUC _(0-∞) of an inhalable suspension comprising a corticosteroid.

In some embodiments, AUC _(0-∞) is administered by an inhalable suspension comprising a conventional corticosteroid when an aqueous inhalation mixture is administered under the same conditions at a lower nominal dosage. It is substantially equal to the indicated AUC _(0-∞) plasma value. In one embodiment, the nominal dosage is about 1: 1.5 (ie, 1.5 times the pharmacokinetic profile) of the nominal dosage of inhalable suspensions containing conventional corticosteroids. Improvement) to about 1:10 (ie, a 10-fold improvement in pharmacokinetic profile). In another embodiment, the nominal dosage of the aqueous corticosteroid-containing inhalation mixture is from about 1: 1.5 to about 1: 9 of the nominal dosage of an inhalable suspension comprising a conventional corticosteroid. possible. In yet another embodiment, the nominal dosage of the corticosteroid-containing aqueous inhalation mixture is from about 1: 1.5 to about 1: 8 of the nominal dosage of an inhalable suspension comprising a conventional corticosteroid. It can be. In yet another embodiment, the nominal dosage of the corticosteroid-containing aqueous inhalation mixture is about 1: 1.5 to about 1: 7 of the nominal dosage of an inhalable suspension containing a conventional corticosteroid. It can be. In a further embodiment, the nominal dosage of the corticosteroid-containing aqueous inhalation mixture is from about 1: 1.5 to about 1: 6 of the nominal dosage of an inhalable suspension comprising a conventional corticosteroid. possible. In another embodiment, the nominal dosage of the corticosteroid-containing aqueous inhalation mixture can be about 1: 2 to about 1: 5 of the nominal dosage of an inhalable suspension containing a conventional corticosteroid. . In yet another embodiment, the nominal dosage of the corticosteroid-containing aqueous inhalation mixture is from about 1: 2 to about 1: 4 of the nominal dosage of an inhalable suspension comprising a conventional corticosteroid. obtain. In still other embodiments, the nominal dosage of the corticosteroid-containing aqueous inhalation mixture is from about 1: 2 to about 1: 3 of the nominal dosage of an inhalable suspension comprising a conventional corticosteroid. possible. In certain embodiments, the nominal dosage of an aqueous inhalation mixture containing corticosteroids can be about 1: 2 of the nominal dosage of an inhalable suspension containing conventional corticosteroids. In other specific embodiments, the nominal dosage of the corticosteroid-containing aqueous inhalation mixture can be about 1: 3 of the nominal dosage of an inhalable suspension containing a conventional corticosteroid. In other specific embodiments, the nominal dosage of the corticosteroid-containing aqueous inhalation mixture can be about 1: 4 of the nominal dosage of an inhalable suspension comprising a conventional corticosteroid. In yet other embodiments, the nominal dosage of the corticosteroid-containing aqueous inhalation mixture can be about 1: 5 of the nominal dosage of an inhalable suspension containing conventional corticosteroids. In still other embodiments, the nominal dosage of the corticosteroid-containing aqueous inhalation mixture can be about 1: 6 of the nominal dosage of an inhalable suspension containing a conventional corticosteroid. In yet other embodiments, the nominal dosage of the corticosteroid-containing aqueous inhalation mixture can be about 1: 7 of the nominal dosage of an inhalable suspension containing a conventional corticosteroid. In other embodiments, the nominal dosage of a corticosteroid-containing aqueous inhalation mixture can be about 1: 8 of the nominal dosage of an inhalable suspension containing a conventional corticosteroid. In yet other embodiments, the nominal dosage of the corticosteroid-containing aqueous inhalation mixture can be about 1: 9 of the nominal dosage of an inhalable suspension containing a conventional corticosteroid. In still other embodiments, the nominal dosage of the corticosteroid-containing aqueous inhalation mixture can be about 1:10 of the nominal dosage of an inhalable suspension containing a conventional corticosteroid.

E. Reduction of T _max plasma levels The methods and systems described herein for treating or preventing bronchoconstrictive disorders in a patient in need thereof, allows corticosteroids to be administered to a subject at the same dose and under the same conditions. Compared to conventional inhaled corticosteroid suspensions administered below, active ingredients with a reduced T _max plasma value of corticosteroids can be delivered in a delivered manner. In one example, when a conventional budesonide suspension is administered in a single dose using a Pari LC Plus® jet nebulizer in a 2.0 ml volume with a dosing time of about 5 minutes, the T _max plasma value is The pharmacokinetic profile is shown to range from about 0.24 ± 0.25 (h) to about 0.23 ± 0.24 (h), respectively, at nominal dosages of 500 μg to 1000 μg. Using the systems and methods described herein, a single dose of budesonide + SBE7-β-CD inhalation solution having nominal dosages of 60 μg, 120 μg, and 240 μg was used with a ParieFlow Inhaler®, 0. Delivered in a 5 ml volume with a delivery time of about 1.5 minutes, about 0.11 ± 0.09 (h), 0.11 ± 0.09 (h), and 0.21 ± 0.24 ( h) T _max plasma values were obtained.

In the second example, a conventional budesonide suspension (Pulmicort Respules®) was used twice a day for 7 days using a Pari LC Plus® jet nebulizer, with a volume of about 4 ml. When administered at a minute administration time, the mean T _max plasma value is 0.22 ± 0.22 (h) with a nominal dose of 250 μg budesonide, with a minimum T _max plasma value of about 0.08 (h) and a maximum The T _m2x plasma value is about 0.75 (h), with a nominal dosage of 500 μg budesonide, the mean T _max plasma value is about 0.19 ± 0.19 (h), and the minimum T _max plasma value is A pharmacokinetic profile with about 0.08 (h) and a maximum T _max plasma value of about 0.75 (h) was shown. Using the system and method described herein, 60 μg of CBIS inhalation solution was used twice a day for 7 days using a Parie Flow Inhaler® in a 0.5 ml volume with a delivery time of about 1.5 minutes. Delivered at a minimum T _max plasma value of about 0.08 (h), a maximum T _max plasma value of about 0.25 (h), and an average T _max value of about 0.11 (h). Similarly, when 120 μg of CBIS inhalation solution was delivered twice daily for 7 days using a ParieFlow Inhaler® with a delivery time of about 1.5 minutes in a volume of 0.5 ml, the minimum T _max plasma value Was about 0.08 (h), the maximum T _max plasma value was about 0.50 (h), and the mean T _max value was about 0.14 (h). FIG. 5 shows a graphical representation of data based on the above T _max plasma value.

Thus, methods and systems for treating or preventing bronchoconstrictive disorders in patients in need thereof are inhalable comprising conventional corticosteroids administered under the same conditions at the same nominal dosage. It can be one that results in a T _max that is significantly less than the T _max plasma value exhibited by the suspension. In some embodiments, T _max is at least about 1/1 of the T _max plasma value exhibited by an inhalable suspension comprising a conventional corticosteroid administered at the same nominal dosage and under the same conditions. .5 to about 1/10. In certain embodiments, T _max is at least about 1/8 of the T _max plasma value exhibited by an inhalable suspension comprising a conventional corticosteroid administered at the same nominal dosage and under the same conditions. possible. In other specific embodiments, the T _max is at least about 1 / than the T _max plasma value exhibited by an inhalable suspension comprising a conventional corticosteroid administered under the same conditions at the same nominal dosage. It can be 6 times. In one such embodiment, T _max is at least about 1/4 of the T _max plasma value exhibited by an inhalable suspension comprising a conventional corticosteroid administered at the same nominal dosage and under the same conditions. possible. In another embodiment, the T _max is at least about 1/3 of the T _max plasma value exhibited by an inhalable suspension comprising a conventional corticosteroid administered at the same nominal dosage and under the same conditions. possible. In yet another embodiment, T _max is at least about 2 times faster than T _max plasma values exhibited by inhalable suspensions containing conventional corticosteroids administered under the same conditions at the same nominal dosage. (Fast). In still yet another embodiment, the T _max is at least about 1. greater than the T _max plasma value exhibited by an inhalable suspension comprising a conventional corticosteroid administered at the same nominal dosage and under the same conditions. It can be five times faster.

In some embodiments, T _max, T _max aqueous inhalation mixture, indicated by less when at nominal dosage is administered under the same conditions, inhalable suspensions comprising a conventional corticosteroid It can be less than the plasma value. In one embodiment, the nominal dosage is about 1: 1.5 (ie, 1.5 times the pharmacokinetic profile) of the nominal dosage of inhalable suspensions containing conventional corticosteroids. Improvement) to about 1:10 (ie, a 10-fold improvement in pharmacokinetic profile). In another embodiment, the nominal dosage of the aqueous corticosteroid-containing inhalation mixture is from about 1: 1.5 to about 1: 9 of the nominal dosage of an inhalable suspension comprising a conventional corticosteroid. possible. In yet another embodiment, the nominal dosage of the corticosteroid-containing aqueous inhalation mixture is from about 1: 1.5 to about 1: 8 of the nominal dosage of an inhalable suspension comprising a conventional corticosteroid. It can be. In yet another embodiment, the nominal dosage of the corticosteroid-containing aqueous inhalation mixture is about 1: 1.5 to about 1: 7 of the nominal dosage of an inhalable suspension containing a conventional corticosteroid. It can be. In a further embodiment, the nominal dosage of the corticosteroid-containing aqueous inhalation mixture is from about 1: 1.5 to about 1: 6 of the nominal dosage of an inhalable suspension comprising a conventional corticosteroid. possible. In another embodiment, the nominal dosage of the corticosteroid-containing aqueous inhalation mixture can be about 1: 2 to about 1: 5 of the nominal dosage of an inhalable suspension containing a conventional corticosteroid. . In yet another embodiment, the nominal dosage of the corticosteroid-containing aqueous inhalation mixture is from about 1: 2 to about 1: 4 of the nominal dosage of an inhalable suspension comprising a conventional corticosteroid. obtain. In still other embodiments, the nominal dosage of an aqueous inhalation mixture comprising a corticosteroid is about 1: 2 to about 1: 3 of the nominal dosage of an inhalable suspension comprising a conventional corticosteroid. It can be. In certain embodiments, the nominal dosage of an aqueous inhalation mixture containing corticosteroids can be about 1: 2 of the nominal dosage of an inhalable suspension containing conventional corticosteroids. In other specific embodiments, the nominal dosage of the corticosteroid-containing aqueous inhalation mixture can be about 1: 3 of the nominal dosage of an inhalable suspension containing a conventional corticosteroid. In other specific embodiments, the nominal dosage of the corticosteroid-containing aqueous inhalation mixture can be about 1: 4 of the nominal dosage of an inhalable suspension comprising a conventional corticosteroid. In yet other embodiments, the nominal dosage of the corticosteroid-containing aqueous inhalation mixture can be about 1: 5 of the nominal dosage of an inhalable suspension containing conventional corticosteroids. In still other embodiments, the nominal dosage of the corticosteroid-containing aqueous inhalation mixture can be about 1: 6 of the nominal dosage of an inhalable suspension containing a conventional corticosteroid. In yet other embodiments, the nominal dosage of the corticosteroid-containing aqueous inhalation mixture can be about 1: 7 of the nominal dosage of an inhalable suspension containing a conventional corticosteroid. In other embodiments, the nominal dosage of a corticosteroid-containing aqueous inhalation mixture can be about 1: 8 of the nominal dosage of an inhalable suspension containing a conventional corticosteroid. In yet other embodiments, the nominal dosage of the corticosteroid-containing aqueous inhalation mixture can be about 1: 9 of the nominal dosage of an inhalable suspension containing a conventional corticosteroid. In still other embodiments, the nominal dosage of the corticosteroid-containing aqueous inhalation mixture can be about 1:10 of the nominal dosage of an inhalable suspension containing a conventional corticosteroid.

XIlI. Dosage for Use in Methods and Systems for Treatment Corticosteroids (eg, budesonide) and improved solubility by methods and systems for treating or preventing bronchoconstrictive disorders in patients in need thereof An aqueous inhalation mixture containing the agent is delivered to the subject in accordance with good medical practice, taking into account the individual patient's clinical status, site and method of administration, dosage regimen, and other factors known to the medical practitioner. Can be delivered in such a manner. In human therapy, the methods described herein maintain a therapeutically effective amount of a corticosteroid (eg, budesonide) at the site of action, thereby reducing or alleviating symptoms associated with bronchoconstriction disorder A corticosteroid solution (eg, budesonide solution) can be delivered. In other embodiments, the aqueous inhalation mixture comprises a corticosteroid and a solubility enhancer and is substantially free of pharmaceutically active agents other than the corticosteroid.

  In other embodiments, the methods and systems described herein for treating or preventing bronchoconstrictive disorders in patients in need thereof, corticosteroids (eg, budesonide), solvents and solubility enhancement. An aqueous inhalation mixture containing the agent is delivered to the subject in accordance with good medical practice, taking into account the individual patient's clinical status, site and method of administration, dosage regimen, and other factors known to the medical practitioner. Can be delivered in such a manner. In human therapy, according to the methods described herein, the methods described herein maintain a therapeutically effective amount of a corticosteroid (eg, budesonide) at the site of action, thereby reducing bronchoconstrictive disorder. A corticosteroid solution (eg, budesonide solution) can be delivered in which the associated symptoms are reduced or alleviated. In other embodiments, the aqueous inhalation mixture includes a corticosteroid, a solvent, and a solubility enhancer, and is substantially free of pharmaceutically active agents other than the corticosteroid.

  In various embodiments of the methods and systems described herein above in Section XII, the methods and systems described herein for treating or preventing a bronchoconstrictive disorder in a patient in need thereof. To about 15 μg / dose to less than about 250 μg / dose, or from about 25 μg / dose to about 240 μg / dose, or a therapeutically effective amount of a corticosteroid administered by inhalation nebulizer to a subject, or About 200 μg / dose to about 240 μg / dose, or about 125 μg / dose to about 200 μg / dose, or about 150 μg / dose to about 200 μg / dose, or about 100 μg / dose to about 150 μg / dose, or about 100 μg / dose to about 125 μg / dose, or about 50 μg / dose to about 125 μg / dose, or about 60 μg / dose It can be delivered in nominal dosages ranging from dose to about 125 μg / dose, or from about 25 μg / dose to about 50 μg / dose. In one preferred embodiment, the corticosteroid is budesonide administered to a subject by inhalation nebulizer at a nominal dosage ranging from about 25 μg / dose to about 240 μg / dose. In one embodiment, the aqueous inhalation mixture comprises a corticosteroid such as budesonide, wherein the aqueous inhalation mixture is from about 60 μg / dose to less than about 250 μg / dose according to the methods and systems described herein. Administered at nominal dosage. In another embodiment, the aqueous inhalation mixture comprises a corticosteroid such as budesonide, the aqueous inhalation mixture at a nominal corticosteroid dosage of less than about 250 μg / dose according to the methods and systems described herein. Be administered. In yet another embodiment, the aqueous inhalation mixture comprises a corticosteroid such as budesonide, the aqueous inhalation mixture according to the methods and systems described herein at a nominal corticosteroid dosage of about 240 μg / dose. Be administered. In yet another embodiment, the aqueous inhalation mixture comprises a corticosteroid such as budesonide, the aqueous inhalation mixture at a nominal corticosteroid dosage of about 125 μg / dose according to the methods and systems described herein. Be administered. In yet another embodiment, the aqueous inhalation mixture comprises a corticosteroid such as budesonide, the aqueous inhalation mixture at a nominal dosage of about 120 μg / dose corticosteroid according to the methods and systems described herein. Be administered. In yet another embodiment, the aqueous inhalation mixture comprises a corticosteroid such as budesonide, the aqueous inhalation mixture according to the methods and systems described herein at a nominal dosage of about 60 μg / dose corticosteroid. Is administered. In yet another embodiment, the aqueous inhalation mixture comprises a corticosteroid such as budesonide, the aqueous inhalation mixture at a nominal dosage of about 40 μg / dose corticosteroid according to the methods and systems described herein. Be administered. In certain embodiments, the aqueous inhalation mixture comprises a single corticosteroid and is substantially free of pharmaceutically active agents other than the corticosteroid.

  In certain embodiments, a method and system for treating or preventing a bronchoconstrictive disorder in a patient in need thereof provides a therapeutically effective amount of a corticosteroid administered by an inhalation nebulizer to a subject. An aqueous inhalation mixture comprising can be delivered at a nominal dosage ranging from about 25 μg / dose to less than about 100 μg / dose, wherein the corticosteroid is from the group of betamethasone-free corticosteroids of the previous paragraph. Selected. In one such embodiment, the aqueous inhalation mixture comprises a corticosteroid such as budesonide, and the aqueous inhalation mixture is in a nominal corticosteroid dosage of less than about 100 μg / dose according to the methods and systems described herein. Be administered. In another embodiment, the aqueous inhalation mixture comprises a corticosteroid such as budesonide, and the aqueous inhalation mixture is administered at a nominal dosage of about 60 μg / dose corticosteroid according to the methods and systems described herein. Is done. In yet another embodiment, the aqueous inhalation mixture comprises a corticosteroid such as budesonide, the aqueous inhalation mixture at a nominal dosage of about 40 μg / dose corticosteroid according to the methods and systems described herein. Be administered. In certain embodiments, the aqueous inhalation mixture comprises a single corticosteroid and is substantially free of pharmaceutically active agents other than the corticosteroid.

  In some embodiments of the inhalable composition or aqueous inhalation mixture described herein, the inhalable composition or aqueous inhalation mixture includes a solvent. In certain embodiments, the solvent is selected from the group comprising water, aqueous alcohol, propylene glycol or an aqueous organic solvent. In a preferred embodiment, the solvent is water.

  In some embodiments of the systems and methods described herein, a corticosteroid-containing aqueous inhalation mixture further comprising a solubility enhancer is used. In some embodiments, 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 still other embodiments, the solubility enhancer can have a concentration (w / v) ranging from about 1% to about 10%. In a preferred embodiment, when the solubility enhancer is a cyclodextrin or cyclodextrin derivative such as SBE7-β-CD (Captisol®), the concentration (w / v) ranges from about 2% to about 10%. ). In one embodiment, the solubility enhancer may have a concentration (w / v) of about 2% when it is a cyclodextrin or cyclodextrin derivative, such as SBE7-β-CD (Captisol®). In another embodiment, the solubility enhancer may have a concentration (w / v) of about 5% when it is a cyclodextrin or cyclodextrin derivative, such as SBE7-β-CD (Captisol®). In yet another embodiment, the solubility enhancer can have a concentration (w / v) of about 7% when it is a cyclodextrin or cyclodextrin derivative, such as SBE7-β-CD (Captisol®). . In yet another embodiment, the solubility enhancer has a concentration (w / v) of about 10% when it is a cyclodextrin or cyclodextrin derivative, such as SBE7-β-CD (Captisol®). obtain.

  In certain embodiments, the aqueous inhalation mixture is propylene glycol, nonionic surfactant, tyloxapol, polysorbate 80, vitamin E-TPGS, macrogol-15-hydroxystearate, phospholipid, lecithin, purification and / or enrichment. Lecithin, phosphatidylcholine fraction extracted from lecithin, dimyristoylphosphatidylcholine (DMPC), dipalmitoylphosphatidylcholine (DPPC), distearoylphosphatidylcholine (DSPC), cyclodextrin and its derivatives, SAE-CD derivatives, SBE-α-CD, SBE -Β-CD, SBE1-β-CD, SBE4-β-CD, SBE7-β-CD (Captisol®), SBE-γ-CD, dimethyl β-CD, hydroxypropyl-β -Cyclodextrin, 2-HP-β-CD, hydroxyethyl-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, hydroxyethyl-γ-cyclodextrin, dihydroxypropyl-β-cyclodextrin, glucosyl-α-cyclodextrin , Glucosyl-β-cyclodextrin, diglucosyl-β-cyclodextrin, maltosyl-α-cyclodextrin, maltosyl-β-cyclodextrin, maltosyl-γ-cyclodextrin, maltotriosyl-β-cyclodextrin, maltotriosyl-γ -Cyclodextrin, dimaltosyl-β-cyclodextrin, methyl-β-cyclodextrin, carboxyalkyl thioether derivative, ORG 26054, ORG 25969, hydroxy A solubility improver selected from the group consisting of propylmethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, vinyl acetate copolymer, vinylpyrrolidone, sodium lauryl sulfate, dioctyl sodium sulfosuccinate, and combinations thereof. In certain embodiments, the solubility enhancer is SBE7-β-CD (Captisol®).

  In another specific embodiment, the inhalable composition of the invention comprises cyclodextrin and its derivatives, SAE-CD derivatives, SBE-α-CD, SBE-β-CD, SBE1-β-CD, SBE4-β. -CD, SBE7-β-CD (Captisol®), SBE-γ-CD, dimethyl β-CD, hydroxypropyl-β-cyclodextrin, 2-HP-β-CD, hydroxyethyl-β-cyclodextrin , Hydroxypropyl-γ-cyclodextrin, hydroxyethyl-γ-cyclodextrin, dihydroxypropyl-β-cyclodextrin, glucosyl-α-cyclodextrin, glucosyl-β-cyclodextrin, diglucosyl-β-cyclodextrin, maltosyl-α- Cyclodextrin, maltosyl-β-si Improved solubility selected from the group consisting of rhodextrin, maltosyl-γ-cyclodextrin, maltotriosyl-β-cyclodextrin, maltotriosyl-γ-cyclodextrin, dimaltosyl-β-cyclodextrin, methyl-β-cyclodextrin Contains agents. In certain embodiments, the solubility enhancer is SBE7-β-CD (Captisol®).

  In addition to an aqueous inhalation mixture or inhalable composition comprising a corticosteroid and a solubility enhancer, herein also an aqueous inhalation mixture or composition formulated by a method that provides improved solubility is also disclosed herein. It is envisaged that it is suitable for use in the present invention. Thus, in the context of the present invention, a “solubility enhancer” includes an aqueous inhalation mixture formulated by a method that provides improved solubility with or without a chemical acting as a solubility enhancer. . An example of such a method is the preparation of a supercritical fluid. By such a method, corticosteroid compositions such as budesonide are processed into particles with a narrow particle size distribution (usually less than 200 nanometers wide) and an average hydrodynamic radius of the particles in the range of 50 nanometers to 700 nanometers. Is done. Nano-sized corticosteroid particles (such as budesonide particles) can be used in supercritical fluid (SCF) processes such as supercritical fluid rapid expansion (RESS), or supercritical fluid solution-enhanced dispersion (SEDS), as well as supercritical fluids. Are processed using any other technique involving. The use of the SCF process to form particles is described in Parakodity, S .; Et al., Pharmaceutical Research 16: 976-985 (1999) and Bandi et al., Eur. J. et al. Pharm. Sci. 23: 159-168 (2004), US Pat. No. 6,576,264 and US Patent Application Publication No. 2003/0091513, each of which is specifically incorporated herein by reference. )It is described in.

  In another embodiment, the corticosteroid-containing aqueous inhalation mixture is administered no more than twice a day (bid) according to the methods and systems described herein. In yet another aspect, the aqueous inhalation mixture comprises a corticosteroid such as budesonide, and the aqueous inhalation mixture is administered twice daily according to the methods and systems described herein. In yet another aspect, the aqueous inhalation mixture comprises a corticosteroid such as budesonide, and the aqueous inhalation mixture is administered no more than once a day according to the methods and systems described herein. In yet another embodiment, the aqueous inhalation mixture comprises a corticosteroid such as budesonide, and the aqueous inhalation mixture is administered no more than once a day in the evening according to the methods and systems described herein.

  In certain embodiments, the methods and systems described herein can further comprise administering an aqueous inhalation mixture comprising a corticosteroid in combination with one or more active agents. In some embodiments, the corticosteroid (eg, budesonide) is (a) a B2-adrenergic receptor agonist; (b) a dopamine (D2) receptor agonist; (c) a prophylactic agent such as a steroid. Shown herein in combination with one or more other drugs that are one or more active agents selected from the group consisting of (d) a surface anesthetic; or (e) an anticholinergic agent. It can be administered at the same time, before or after the inhalable composition.

  Examples of active agent combinations that can be used in the methods and systems of the invention are shown below.

  B2-adrenergic receptor agonists for use in combination with the compositions provided herein include, but are not limited to, albuterol (α-1-(((1,1-dimethylethyl) amino) Methyl) -4-hydroxy-1,3-benzenedimethanol); bambuterol (dimethylcarbamic acid 5- (2-((1,1-dimethylethyl) amino) -1-hydroxyethyl) -1,3-phenylene ester ); Bitolterol (4-methylbenzoic acid 4- (2-((1,1-dimethylethyl) amino) -1-hydroxyethyl) -1,2-phenylene ester); broxaterol (3-bromo-α-(( (1,1-dimethylethyl) amino) methyl) -5-isoxazolemethanol); isoproterenol (4- (1-hydroxy-2-((1 -Methylethyl-) amino) ethyl) -1,2-benzene-diol); trimethquinol (1,2,3,4-tetrahydro-1-((3,4-, 5-trimethoxyphenyl) -methyl) ) -6,7-isoquinolinediol); clenbuterol (4-amino-3,5-dichloro-α-(((1,1-dimethylethyl) amino) methyl) benzenemethanol); fenoterol (5- (1-hydroxy -2-((2- (4-hydroxyphenyl) -1-methylethyl) amino) ethyl) -1,3-benzenediol); formoterol (2-hydroxy-5-((l RS) -I-hydroxy -2-(((l RS) -2- (p-methoxyphenyl) -1-methylethyl) amino) ethyl) formanilide); (R, R) -formoterol Desformoterol ((R, R) or (S, S) -3-amino-4-hydroxy-α-(((2- (4-methoxyphenyl) -1-methyl-ethyl) amino) methyl) benzenemethanol ); Hexoprenalin (4,4 ′-(1,6-hexane-diyl) -bis (imino (1-hydroxy-2,1-ethanediyl))) bis-1,2-benzenediol); isoethalin (4- ( 1-hydroxy-2-((1-methylethyl) amino) butyl) -1,2-benzenediol); isoprenaline (4- (1-hydroxy-2-((1-methylethyl) amino) ethyl) -1 , 2-benzenediol); meta-proterenol (5- (1-hydroxy-2-((1-methylethyl) amino) ethyl) -1,3-benzenediol); picumete (4-amino-3,5-dichloro-α-(((6- (2- (2-pyridinyl) ethoxy) hexyl) -amino) methyl) benzenemethanol); pyrbuterol (α-6-((( 1,1-dimethylethyl) -amino) methyl) -3-hydroxy-2,6-pyridinemethanol); procaterol (((R *, S *)-(+-)-8-hydroxy-5- (1- Hydroxy-2-((1-methylethyl) amino) butyl) -2 (1H) quinolin-one); reproterol ((7- (3-((2- (3,5-dihydroxyphenyl) -2-hydroxyethyl) ) Amino) -propyl) -3,7-dihydro-1,3-dimethyl-1H-purine-2,6-dione); limiterol (4- (hydroxy-2-piperidinylmethyl) -1,2-benzenedi Salbutamol ((+-)-α-1-(((1,1-dimethylethyl) amino) methyl) -4-hydroxy-1,3-benzenedimethanol); (R) -salbutamol; salmeterol ((+-)-4-hydroxy-α-1-(((6- (4-phenylbutoxy) hexyl) -amino) methyl) -1,3-benzenedimethanol); (R) -salmeterol; terbutaline ( 5- (2-((1,1-dimethylethyl) amino) -1-hydroxyethyl) -1,3-benzenediol); tubuterol (2-chloro-α-(((1,1-dimethylethyl) amino ) Methyl) benzenemethanol); and TA-2005 (8-hydroxy-5-((1R) -1-hydroxy-2- (N-((1R) -2- (4-methoxyphenyl)) 1-methylethyl) amino) ethyl) carbostyril hydrochloride) and the like.

  Dopamine (D2) receptor agonists include, but are not limited to, apomorphine ((r) 5,6,6a, 7-tetrahydro-6-methyl-4H-dibenzo [de, gluquinoline-10,11-diol) ); Bromocriptine ((5′.α.)-2-bromo-12′-hydroxy-2 ′-(1-methylethyl) -5 ′-(2-methylpropyl) ergotaman-3 ′, 6 ′, 18- Trion); cabergoline ((8-β) -N- (3- (dimethylamino) propyl) -N-((ethylamino) carbonyl-1) -6- (2-propenyl) ergoline-8-carboxamide); lisuride (N ′-((8-α-)-9,10-didehydro-6-methylergolin-8-yl) -N, N-diethylurea); pergolide ((8-β-) 8-((methylthio) methyl) -6-propylergoline); levodopa (3-hydroxy-L-tyrosine); pramipexole ((s) -4,5,6,7-tetrahydro-N6-propyl-2,6 -Benzothiazolediamine); quinpirole hydrochloride (trans-(-)-4aR-4,4a, 5,6,7,8,8a, 9-octahydro-5-propyl-1H-pyrazolo [3,4-g] Quinoline hydrochloride); ropinirole (4- (2- (dipropylamino) ethyl) -1,3-dihydro-2H-indol-2-one); and talipexol (5,6,7,8-tetrahydro-6- (2-propenyl) -4H-thiazolo [4,5-d] azepin-2-amine). Other dopamine D2 receptor agonists for use herein are disclosed in International Patent Application Publication No. WO 99/36095, the relevant disclosures of which are hereby incorporated by reference.

  Anticholinergics for use herein include, but are not limited to, ipratropium bromide, oxitropium bromide, atropine methyl nitrate, atropine methyl sulfate, ipratropium, belladonna extract, scopolamine, scopolamine methobromide, homatropin Metobromide, hyoscyamine, isopriopramide, orphenadrine, benzalkonium chloride, tiotropium bromide and glycopyrronium bromide.

  Other active ingredients for use in the combination therapy described herein include, but are not limited to, IL-5 inhibitors, such as US Pat. Nos. 5,668,110, 5,683,983, Disclosed in US Pat. Nos. 5,677,280, 6,071,910, and 5,654,276, each of which is incorporated herein by reference; IL -5 antisense modulators such as those disclosed in US Pat. No. 6,136,603 (the relevant disclosure of which is incorporated herein by reference); milrinone (1,6-dihydro- 2-methyl-6-oxo- [3,4'-bipyridine] -5-carbonitrile); milrinone lactate; tryptase inhibitors such as US Pat. No. 5,525,623 (this is for reference only) Tachykinin receptor antagonists, such as US Pat. Nos. 5,691,336, 5,877,191, 5,929, and the like, which are incorporated herein by reference. 094, 5,750,549 and 5,780,467, each of which is incorporated herein by reference; leukotriene receptor antagonists such as Montelukast sodium (Singular, R- (E)]-1-[[[1- [3- [2- (7-chloro-2-quinolinyl) ethenyl] -phenyl] -3- [2- (I-hydroxy- 1-methylethyl) -phenyl] -propyl] -thio] -methyl] cyclopropaneacetic acid, monosodium salt) and the like 5-lipoxygenase inhibitors such as zileuton (Zyflo ( ), Abbott Laboratories, Abbott Park, IL) and the like, and anti-IgE antibodies such as Xolair (recombinant humanized anti-IgE monoclonal antibody (CGP 51901; IGE 025A; rhuMAb-E25), Genentech, Inc., South. Francisco, CA), and surface anesthetics such as lidocaine, N-arylamides, aminoalkylbenzoates, prilocaine, etidocaine, etc. (US Pat. Nos. 5,510,339, 5,631,267 and 5). , 837,713 (the relevant disclosures of which are incorporated herein by reference).

XIV. Methods of Using Aqueous Inhalation Mixtures Containing Corticosteroids A method and system described herein above in Section XII treats a subject with an aqueous inhalation mixture containing a corticosteroid (eg, budesonide). Effective amount selected from the group consisting of asthma, childhood asthma, bronchial asthma, allergic asthma, endogenous asthma, chronic obstructive pulmonary disease (COPD), chronic bronchitis, emphysema, or any combination of the foregoing Have had a bronchoconstrictive disorder or can be delivered for treatment of a subject in whom the disorder is expected. In one embodiment, the bronchoconstrictive disorder is childhood asthma. In another embodiment, the bronchoconstrictive disorder is bronchial asthma. In yet another embodiment, the bronchoconstrictive disorder is chronic obstructive pulmonary disease (COPD).

  For a particular composition and method of administration, the actual dosage level of the corticosteroid-containing aqueous inhalation mixture described herein to obtain an amount of active ingredient effective to obtain the desired local therapeutic response is Can be different. The selected dosage level will therefore depend on the desired therapeutic effect, the desired duration of treatment and other factors.

XV. Pharmacokinetic Analysis Plasma in humans after administration of an aqueous inhalation solution containing a corticosteroid (such as budesonide) and a solubility enhancer using any standard pharmacokinetic protocol and by the systems and methods described herein. A concentration profile can be measured, thereby establishing whether the formulation meets the pharmacokinetic criteria set forth herein. By way of example and without limiting the type of protocol for use herein, a randomized single dose crossover study can be performed with a group of healthy adult human subjects. The number of subjects should be sufficient to provide sufficient variability control in the statistical analysis, typically about 8 or more, although a smaller number of groups may be sufficient for some purposes. possible. For example, a subject is administered a single dose (eg, 240 μg) of a test inhalation mixture containing a corticosteroid (such as budesonide) and a solubility enhancer at time zero. Blood samples are collected from each subject before administration (eg, 15 minutes before) and after administration at several intervals. For the purposes of the present invention, it is typically preferable to sample several times during the first hour and then sample at a lower frequency. Illustratively, blood samples may be taken 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 subject is used to test a second test formulation, it is advisable to allow a period of at least 10 days before administration of the second formulation. Plasma is separated from the blood sample by centrifugation, and the separated plasma is an effective high performance liquid chromatography / tandem mass analysis (LC / APCI-MS / MS) procedure for corticosteroids (such as budesonide). (E.g., Ramu et al., Journal of Chromatography B, 751: 49-59 (2001)). In other embodiments, data from a single subject can indicate an improvement in pharmacokinetic profile. In yet other embodiments, an appropriate in vitro model can be used to demonstrate improved pharmacokinetic profiles.

  Any aqueous inhalation mixture that provides the desired pharmacokinetic profile is suitable for administration by the systems and methods of the invention. An exemplary type of inhalation mixture that provides such a profile is a solution comprising a corticosteroid (such as budesonide) and a solubility enhancer.

  The following components, methods and procedures for carrying out the compositions, systems and processes disclosed herein correspond to those described above. The following procedure illustrates a specific embodiment of the method of delivery of the budesonide-containing aqueous inhalation mixture described herein and its pharmacokinetic profile. Methods, materials or excipients not specifically described in the following examples are within the scope of the present invention and will be apparent to those of skill in the art upon reference to the disclosure herein.

Example 1
A number of aqueous inhalation mixtures are prepared by draining the contents of one or more containers of commercially available Pulmicort Respules® (1000 μg budesonide / 2 mL suspension), per mL of Pulmicort Responses® 82.5 mg (corrected for water content) of Captisol® (CyDex, Inc., Lenexa, KS, USA) was added (distribution volume was 2.1 mL) and vortexed for 5-10 minutes. In addition to budesonide and water, Palmicor Repres® also contains the following ingredients that are considered inert: citric acid, sodium citrate, sodium chloride, disodium EDTA and polysorbate 80.

Example 2
As an alternative method of preparation of Example 1, a number of aqueous inhalation mixtures were placed in approximately 200 mg amounts of CAPTISOL® (CyDex, Inc., Lenexa, KS, USA) (corrected for water content) in two drum amber vials. Prepare by weighing in. Slowly squeeze the contents of two Pulmicort Respules® containers (0.5 mg / 2 mL) into the last possible drop of the deformable plastic container to contain a weighed amount of CAPTISOL Empty in each vial. Pulmicort Respules® is pre-stirred to resuspend the budesonide particles. Screw the vial into the vial, mix vigorously by vortexing and then cover with foil. The material can be kept refrigerated until use.

Example 3
Table 1 shows an exemplary formulation of an aqueous inhalation mixture comprising budesonide and a solubility enhancer used in the methods and systems described herein. As shown in the examples below, the aqueous inhalation mixture may further comprise excipients such as antioxidants, stabilizers and preservatives. The amount of various excipients used in the aqueous inhalation mixture is relative to the dosage administered and will be readily ascertainable by one skilled in the art.

実施例４
表２に、本明細書に記載の方法およびシステムにおいて使用されるブデソニドおよび溶解度向上剤を含む水性吸入混合物の例示的な製剤を示す。以下の実施例に示すように、水性吸入混合物は、さらに賦形剤、例えば、抗酸化剤、安定化剤および保存剤を含むものであり得る。水性吸入混合物に使用される種々の賦形剤の量は、投与される投薬量に相対的であり、当業者には容易に確認されよう。

Example 4
Table 2 shows an exemplary formulation of an aqueous inhalation mixture comprising budesonide and a solubility enhancer used in the methods and systems described herein. As shown in the examples below, the aqueous inhalation mixture may further comprise excipients such as antioxidants, stabilizers and preservatives. The amount of various excipients used in the aqueous inhalation mixture is relative to the dosage administered and will be readily ascertainable by one skilled in the art.

実施例５
表３に、ブデソニド含有水性吸入混合物およびＰｕｌｍｉｃｏｒｔ Ｒｅｓｐｕｌｅｓ（登録商標）の用量、ならびに前記用量を肺へ送達するために使用したネブライザデバイスを示す。投与Ａ〜Ｃは、実施例１に記載のようにして調製した水性吸入混合物を０．９％（ｗ／ｗ）生理食塩水で、以下のようにして希釈することにより調製した。投与Ａは、２５：７５の比で０．９％（ｗ／ｗ）生理食塩水により希釈し、投与Ｂは、５０：５０の比で０．９％（ｗ／ｗ）生理食塩水により希釈し、投与Ｃは希釈しなかった。ブデソニド＋ＳＢＥ７−β−ＣＤ（Ｃａｐｔｉｓｏｌ（登録商標））吸入溶液は、Ｐａｒｉ ｅＦｌｏｗ Ｉｎｈａｌｅｒ（登録商標）を使用し、０．５ｍｌの容量で約１．５分の送達時間で送達した。Ｐａｒｉ ｅＦＩｏｗ Ｉｎｈａｌｅｒ（登録商標）には、サイズ３０メッシュ膜および小型サイズのエーロゾルチャンバを取り付けた。Ｐｕｌｍｉｃｏｒｔ Ｒｅｓｐｕｌｅｓ（登録商標）は、Ｐａｒｉ ＬＣ Ｐｌｕｓ（登録商標）ジェットネブライザを使用し、２．０ｍｌの容量で約５分の投与時間で投与した。

Example 5
Table 3 shows the dose of budesonide-containing aqueous inhalation mixture and Pulmicort Respules® and the nebulizer device used to deliver the dose to the lung. Doses AC were prepared by diluting an aqueous inhalation mixture prepared as described in Example 1 with 0.9% (w / w) saline as follows. Administration A is diluted with 0.9% (w / w) saline in a 25:75 ratio, Administration B is diluted with 0.9% (w / w) saline in a 50:50 ratio Dosage C was not diluted. Budesonide + SBE7-β-CD (Captisol®) inhalation solution was delivered using a ParieFlow Inhaler® with a delivery time of about 1.5 minutes in a volume of 0.5 ml. The Pari eFIow Inhaler® was fitted with a size 30 mesh membrane and a small size aerosol chamber. Pulmicort Resples® was administered using a Pari LC Plus® jet nebulizer in a 2.0 ml volume with a dosing time of approximately 5 minutes.

実施例６
噴霧化による投薬形態の投与の前と後で、被験体においてガンマシンチグラフィ解析を行なうことにより臨床評価を行なった。本試験の目的は、ガンマシンチグラフィにより、ブデソニド懸濁物または溶解度向上剤を含む溶液の噴霧化後の、放射性標識ブデソニドの肺内沈着を調べることである。

Example 6
Prior to and after administration of the dosage form by nebulization, clinical evaluation was performed by performing gamma scintigraphy analysis in subjects. The purpose of this study is to examine the radiodeposition of radiolabeled budesonide in the lung after nebulization of a solution containing a suspension of budesonide or a solubility enhancer by gunmachigraphy.

  Table 4 summarizes the data regarding the percent lung deposition of doses AC delivered by the method described in Example 5. Percent lung deposition is the mean value of all subjects evaluated and was determined by quantification of scintigraphic data obtained at each dose. FIG. 1 shows the percentage of total pulmonary deposition and total oropharyngeal deposition of budesonide-containing inhalable compositions. FIG. 2 shows the total lung deposition of budesonide from scintigraphy data.

実施例７
表５に、実施例５に示す投与Ａ〜Ｅの単回用量送達後の、ブデソニドの薬物動態学的プロフィールの概要を示す。８例の健常男性をこの臨床試験に使用し、以下に示す値は、該臨床試験中に測定された各薬物動態学的パラメータの平均値である。図４に、投与Ａ〜Ｅの薬物動態学的プロフィールを得るために用いたデータのグラフ表示を示す。

Example 7
Table 5 summarizes the pharmacokinetic profile of budesonide after single dose delivery of doses AE shown in Example 5. Eight healthy men were used in this clinical study, and the values shown below are the mean values for each pharmacokinetic parameter measured during the clinical study. FIG. 4 shows a graphical representation of the data used to obtain the pharmacokinetic profiles for doses AE.

実施例８
表６に、実施例８に示す臨床試験に用いた試験投薬物の用量を示す（以下に詳細に記載）。試験投薬物には、２種類の試験製剤、吸入Ｃａｐｔｉｓｏｌ−Ｅｎａｂｌｅｄ（登録商標）Ｂｕｄｅｓｏｎｉｄｅ Ｉｎｈａｌａｔｉｏｎ Ｓｏｌｕｔｉｏｎ （ＣＢＩＳ）（処置ＡおよびＢ）ならびに２種類の参照製剤、吸入ブデソニド懸濁物（Ｐｕｌｍｉｃｏｒｔ Ｒｅｓｐｕｌｅｓ（登録商標））（処置ＣおよびＤ）を含め、前記試験投薬物の肺への送達には、ネブライザデバイスを使用した。

Example 8
Table 6 shows the doses of the test medication used in the clinical study shown in Example 8 (described in detail below). The test dosage includes two test formulations, inhaled Captisol-Enabled® Budesonide Inhalation Solution (CBIS) (treatment A and B) and two reference formulations, inhaled budesonide suspension (Pulmicort Respules®). )) A nebulizer device was used for delivery of the test medication to the lung, including (treatments C and D).

試験製剤および参照製剤の個々の成分を、表７に詳細に示す。

The individual components of the test and reference formulations are detailed in Table 7.

実施例９
表８に、実施例８に示す投与Ａ〜Ｄを伴う、単一施設、二重盲検、複数回投与、平行な群、プラセボ対照比較、二期間クロスオーバー試験後の、ブデソニドの薬物動態学的プロフィールの概要を示す。４８例の健常男性志願者をこの臨床試験に使用した。該試験に適格の各被験体に、無作為に以下の処置：処置Ａ（６０μｇのＣＢＩＳ溶液）、処置Ｂ（１２０μｇのＣＢＩＳ 溶液）、処置Ｃ（２５０μｇのＰｕｌｍｉｃｏｒｔ Ｒｅｓｐｕｌｅ Ｒｅｓｐｕｌｅ（登録商標）懸濁物（２５０μｇのＰｕｌｍｉｃｏｒｔ））、処置Ｄ（５００μｇのＰｕｌｍｉｃｏｒｔ Ｒｅｓｐｕｌｅ（登録商標）懸濁物（５００μｇのＰｕｌｍｉｃｏｒｔ））のうちの１つを行なった。被験体には、処置Ａ、Ｂ、ＣまたはＤを１日２回７日間行なった。各被験体には、２つの試験期間で、活性薬物およびプラセボを交代して与えた。表８に、臨床試験中、処置Ａ〜Ｄ投与に関する該試験で測定された各薬物動態学的パラメータの値を示す。

Example 9
Table 8 shows budesonide pharmacokinetics after single-center, double-blind, multiple-dose, parallel group, placebo-controlled comparison, two-period crossover study, with doses AD shown in Example 8. An overview of the target profile. Forty-eight healthy male volunteers were used in this clinical trial. Each subject eligible for the study was randomly assigned to the following treatments: Treatment A (60 μg CBIS solution), Treatment B (120 μg CBIS solution), Treatment C (250 μg of Palmicort Reply Restrain® suspension). (250 [mu] g of Pulmicort)), one of Treatment D (500 [mu] g of Pulmicort Resple (R) suspension (500 [mu] g of Pulmicort)). Subjects were treated A, B, C or D twice a day for 7 days. Each subject was given alternating active drug and placebo for two study periods. Table 8 shows the value of each pharmacokinetic parameter measured in the trial for treatments AD during the clinical trial.

実施例１０
実施例３および４に示す水性吸入混合物を患者集団に、実施例５に示した方法に従って送達する。Ｐｕｌｍｉｃｏｒｔ Ｒｅｓｐｕｌｅｓ（登録商標）を同様に、実施例５に示した方法に従って投与する。水性吸入溶液の薬物動態学的プロフィールは、Ｐｕｌｍｉｃｏｒｔ Ｒｅｓｐｕｌｅｓ（登録商標）の薬物動態学的プロフィールと比べて、薬物動態学的パラメータの向上を示す。例えば、水性吸入溶液は、Ｐｕｌｍｉｃｏｒｔ Ｒｅｓｐｕｌｅｓ（登録商標）と比べ、より大きいＣ_ｍａｘ、ＡＵＣ_{（ｌａｓｔ）}、ＡＵＣ_{（０〜∞）}の値および／またはより小さいＴ_ｍａｘ値を示す。同様に、水性吸入溶液は、より少ない投薬量で投与した場合、Ｐｕｌｍｉｃｏｒｔ Ｒｅｓｐｕｌｅｓ（登録商標）と比べると、等しいＱ_ｍａｘ、ＡＵＣ_{（ｌａｓｔ）}、ＡＵＣ_{（０〜∞）}の値を示す。

Example 10
The aqueous inhalation mixture shown in Examples 3 and 4 is delivered to the patient population according to the method shown in Example 5. Pulmicort Repres® is similarly administered according to the method set forth in Example 5. The pharmacokinetic profile of the aqueous inhalation solution shows an improvement in pharmacokinetic parameters compared to the pharmacokinetic profile of Pulmicort Respules®. For example, aqueous inhalation solutions exhibit higher C _max , AUC _(last) , AUC _(0-∞) values and / or smaller T _max values compared to Pulmicort Responses®. Similarly, aqueous inhalation solutions exhibit equal Q _max , AUC _(last) , AUC _(0-∞) values when administered at lower dosages when compared to Pulmicort Respules®.

Example 11
The aqueous inhalation mixture shown in Examples 1 and 2 is delivered to the patient population according to the method shown in Example 5. Pulmicort Respules® is administered according to the method set forth in Example 5 at nominal dosages ranging from 1000 μg / dose to 2500 μg / dose. The pharmacokinetic profile of the aqueous inhalation solution shows an improvement in pharmacokinetic parameters compared to the pharmacokinetic profile of Pulmicort Respules®. For example, aqueous inhalation solutions exhibit C _max , AUC _(last) , AUC _(0-∞) values substantially equal to Pulmicort Respules®, even though the nominal dosage administered is fairly small.

Example 12
Preparation and Use of Aqueous Inhalation Mixtures Containing Corticosteroid, Solubility-Enhancer and Albuterol Sulfate or Levalbuterol HCl (Xopenex) A citrate buffer (3 mM pH 4.5) is prepared as follows. Approximately 62.5 mg of citric acid is dissolved with water in one 100 ml volumetric flask to reach its volume. Approximately 87.7 mg of sodium citrate is dissolved with water in a separate 100 mL volumetric flask to that volume. In a beaker, add the sodium citrate solution to the citric acid solution until the pH is approximately 4.5.

  Approximately 10.4 mg budesonide and 1247 mg Captisol® (CyDex Inc.) are ground together with a mortar and pestle and transferred to a 10 mL flask. Buffer solution is added, the mixture vortexed, sonicated and an additional 1.4 mg budesonide is added. After shaking overnight, the solution is filtered through a 0.22 μm Durapore Millex-GV Millipore syringe filter unit. The resulting budesonide concentration is about 1 mg / ml. Approximately 0.5 ml of budesonide solution was added to either a unit dose of Proventil® (2.5 mg / 3 mL) or Xopenex® (1.25 mg / 3 mL), thereby adding to Example 5 A clear aqueous inhalation mixture is formed suitable for use in the inhalation nebulizer described.

Example 13
Preparation and use of an aqueous inhalation mixture containing corticosteroid, solubility enhancer and formoterol (FORADIL®; (formoterol fumarate inhalation powder)) 12 μg formoterol fumarate blended with 25 mg lactose The contents of one capsule containing is emptied into a vial and to this is added 3 ml of 3 mM citrate buffer (pH 4.5) prepared as described in Example 12. Vortex the contents of the vial to dissolve any solids present. The budesonide concentrate is prepared as described in Example 9 to a concentration of 1 mg / mL.

  Approximately 1 ml of budesonide solution is added to the formoterol fumarate buffer solution. This combination is a clear aqueous inhalation mixture suitable for use in the inhalation nebulizer described in Example 5.

Example 14
The aqueous inhalation mixture shown in Examples 12 and 13 is delivered to the patient population according to the method shown in Example 5. Pulmicort Repres® is similarly administered according to the method set forth in Example 5. The pharmacokinetic profile of the aqueous inhalation mixture shows an improvement in the pharmacokinetic parameters compared to the pharmacokinetic profile of Pulmicort Repres®. For example, an aqueous inhalation solution may have a higher C _max , AUC _(last) , AUC _(0-∞) value and / or a lower T _max when administered at the same nominal dosage compared to Pulmicort Respules®. Indicates the value. Similarly, aqueous inhalation solutions show equal C _max , AUC _(last) , AUC _(0-∞) values when administered at lower nominal dosages when compared to Pulmicort Respules®.

Example 15
Using a conventional cascade impactor for particle size in vitro testing, the following deposition characteristics are observed for both budesonide solutions and Pulse recoat suspensions. The budesonide solution was nebulized using a PARI eFlow device. The Pulmicort Resple suspension was nebulized using a PARI LC Plus nebulizer. These results were converted into pulmonary deposition efficiency using various definitions of pulmonary deposition as a function of the stage range (stage 3-7, stage 4-7, stage 5-7). Shown in Table 10 shows the ratio of lung deposition (shown as eFlow / Pari LC plus deposition ratio), depending on the stage range used for lung deposition (stage 3-7, stage 4-7, stage 5-7). Steps 3 to 7, Steps 4 to 7, or Steps 5 to 7 indicate the range of 1.2, 1.9 to 3.8, respectively. Fine particle fraction is defined as a particle size of less than 4.7 μm (Bosco AP et al. (2005); incorporated herein by reference in its entirety).

実施例１６
ＰＡＲＩ ＬＣ−ＰＬＵＳ ネブライザ内で３分の噴霧化時間の過程にわたって、ブデソニド濃度が増大する速度を、Ｃａｐｔｉｓｏｌ−Ｂｕｄｅｓｏｎｉｄｅ Ｉｎｈａｌａｔｉｏｎ Ｓｏｌｕｔｉｏｎ（ＣＢＩＳ）製剤（６０μｇ／０．５ｍｌのブデソニド濃度）およびＰｕｌｍｉｃｏｒｔ Ｒｅｓｐｕｌｅｓ（ＰＲ）製剤（２５０μｇ／２．０ｍｌのブデソニド濃度）について測定した。両方の製剤の試料を別々にプールし、３つの１ｍｌ試料を各プールから採取し、Ｃａｐｔｉｓｏｌ−Ｂｕｄｅｓｏｎｉｄｅ Ｉｎｈａｌａｔｉｏｎ Ｓｏｌｕｔｉｏｎ（ＣＢＩＳ）製剤およびＰｕｌｍｉｃｏｒｔ Ｒｅｓｐｕｌｅｓ（ＰＲ）製剤両方について、ｔ＝０の濃度を得た。試料採取による濃度変化を回避するため、各時点で３つの別々の実験を行なった：ｔ＝１（１分後噴霧化終了（ＣＢＩＳおよびＰＲでｎ＝３）、１ｍｌの試料をＬＣ−ＰＬＵＳネブライザから採取した；ｔ＝２（２分後噴霧化終了（ＣＢＩＳおよびＰＲでｎ＝３）、１ｍｌの試料をＬＣ−ＰＬＵＳネブライザから採取した；ｔ＝３（３分後噴霧化終了（ＣＢＩＳおよびＰＲでｎ＝３）、１ｍｌの試料をＬＣ−ＰＬＵＳネブライザから採取した。

Example 16
The rate of increase in budesonide concentration over the course of the nebulization time of 3 minutes in the PARI LC-PLUS nebulizer was compared to the Captisol-Budesonide Inhalation Solution (CBIS) formulation (60 μg / 0.5 ml budesonide concentration) and the Pulmicort Reples (PR). The formulation (250 μg / 2.0 ml budesonide concentration) was measured. Samples of both formulations were pooled separately and three 1 ml samples were taken from each pool to give a concentration of t = 0 for both Captisol-Budesonide Inhalation Solution (CBIS) and Palmicort Responses (PR) formulations. In order to avoid concentration changes due to sampling, three separate experiments were performed at each time point: t = 1 (end of nebulization after 1 minute (CBIS and PR n = 3), 1 ml of sample was LC-PLUS nebulizer T = 2 (end of nebulization after 2 minutes (CBIS and PR n = 3), 1 ml sample taken from LC-PLUS nebulizer; t = 3 (end of nebulization after 3 minutes (CBIS and PR) N = 3) A 1 ml sample was taken from the LC-PLUS nebulizer.

Example 17
Tables 11 and 12 show the Captisol-Budesonide Inhalation Solution (CBIS) and Pulmicort Responses (PR) formulation over the course of the 3 minute nebulization time inside the PARI LC-Plus nebulizer as measured by the method of Example 16. The result of the measurement of the increase rate in a density | concentration is shown. Three trials lasting 3 minutes were performed for both CBIS (CBIS 1-3) and Pulmicort Repres (PR 1-3). All CBIS solutions had a budesonide concentration of 60 μg / 0.5 ml. All of the Pulmicort Srepule formulations had a budesonide concentration of 250 μg / 2.0 ml.

表１１は、０、１、２および３分に測定した、３分の試行時間の過程にわたるネブライザデバイス内部のＣＢＩＳ製剤１〜３およびＰＲ製剤１〜３の濃度を示す。表１１に示されるように、ネブライザデバイス内部のＣＢＩＳ製剤１〜３およびＰＲ製剤１〜３の濃度は、試行開始時（ｔ＝０分）では１００％である。３分の噴霧化時間（ｔ＝３分）後、ネブライザデバイス内部のＣＢＩＳ製剤の濃度は、開始濃度の平均１０８％まで増大した。同一噴霧化時間（ｔ＝３分）中、ネブライザデバイス内部のＰｕｌｍｉｃｏｒｔ Ｒｅｓｐｕｌｅ製剤の濃度は、開始濃度の平均１２１％まで増大した。図６に、表１１に示したデータのグラフ表示を示す。

Table 11 shows the concentration of CBIS formulations 1-3 and PR formulations 1-3 within the nebulizer device over the course of a 3-minute trial time measured at 0, 1, 2, and 3 minutes. As shown in Table 11, the concentrations of CBIS formulations 1 to 3 and PR formulations 1 to 3 inside the nebulizer device are 100% at the start of trial (t = 0 minutes). After a 3 minute nebulization time (t = 3 minutes), the concentration of the CBIS formulation inside the nebulizer device increased to an average of 108% of the starting concentration. During the same nebulization time (t = 3 minutes), the concentration of the Pulmicort Repule formulation inside the nebulizer device increased to an average of 121% of the starting concentration. FIG. 6 shows a graphical representation of the data shown in Table 11.

表１２は、０、１、２および３分に測定した、３分の試行時間の過程にわたるネブライザデバイス内部のＣＢＩＳ製剤１〜３およびＰＲ製剤１〜３の濃度を示す。表１２に示されるように、ネブライザデバイス内部のＣＢＩＳ製剤１〜３の平均濃度は、実験開始時（ｔ＝０分）では１２２．８μｇ／ｍｌである。ネブライザデバイス内部のＰＲ製剤１〜３の平均濃度は、実験開始時（ｔ＝０分）では１１５．９７μｇ／ｍｌである。３分の噴霧化時間（ｔ＝３分）後、ネブライザデバイス内部のＣＢＩＳ製剤の平均濃度は、１３２．９７μｇ／ｍｌまで増大した。同一噴霧化時間（ｔ＝３分）中、ネブライザデバイス内部のＰｕｌｍｉｃｏｒｔ Ｒｅｓｐｕｌｅ製剤の平均濃度は、１４０．３６μｇ／ｍｌまで増大した。図７に、表１１に示したデータのグラフ表示を示す。

Table 12 shows the concentration of CBIS formulations 1-3 and PR formulations 1-3 within the nebulizer device over the course of a 3-minute trial time, measured at 0, 1, 2 and 3 minutes. As shown in Table 12, the average concentration of CBIS formulations 1 to 3 inside the nebulizer device is 122.8 μg / ml at the start of the experiment (t = 0 min). The average concentration of PR formulations 1 to 3 inside the nebulizer device is 115.97 μg / ml at the start of the experiment (t = 0 min). After a 3 minute nebulization time (t = 3 minutes), the average concentration of the CBIS formulation inside the nebulizer device increased to 132.97 μg / ml. During the same nebulization time (t = 3 minutes), the average concentration of the Pulmicort Repule formulation inside the nebulizer device increased to 140.36 μg / ml. FIG. 7 shows a graphical representation of the data shown in Table 11.

FIG. 1 shows the percentage of intrapulmonary and oropharyngeal deposition of an inhalable composition comprising budesonide. FIG. 2 shows total lung deposition of budesonide from scintigraphic data. FIG. 3 shows respiratory fractions (RF; particle size less than 5 μm) measured using different methodologies (laser diffraction 20 L / min, laser diffraction 28.3 L / min, and cascade impaction). Indicates percentage. FIG. 4 shows a summary of mean plasma concentrations after administration of a single dose of budesonide A-E. Dosing A is 60 μg of 99mTc-DTPA labeled budesonide + SBE7-β-CD inhalation solution delivered in a modified Pari® eFlow nebulizer. Dosing B is 120 μg of 99mTc-DTPA labeled budesonide + SBE7-β-CD inhalation solution delivered in a modified Pari® eFlow nebulizer. Dosing C is 240 μg of 99mTc-DTPA labeled budesonide + SBE7-β-CD inhalation solution delivered in a modified Pari® eFlow nebulizer. Dosing D is 500 μg budesonide suspension (Pulmicort Respules®) delivered with a Pari® LC Plus jet nebulizer. Dosing E is 1000 μg budesonide suspension (Pulmicort Respules®) delivered with a Pari® LC Plus jet nebulizer. FIG. 5 shows an overview of the mean plasma concentration after administration of budesonide twice daily for 7 days. Treatment A (−Δ−) is 60 μg Captisol-Enabled® Budesonide Inhalation Solution (CBIS) inhalation solution delivered in a Pari® eFlow nebulizer. Treatment B (-o-) is 120 [mu] g CBIS inhalation solution delivered with a Pari <(R)> eFlow nebulizer. Treatment C (-□-) is 250 μg budesonide suspension (Pulmicort Respules®) delivered with a Pari® LC Plus jet nebulizer. Treatment D (− ◇ −) is 500 μg budesonide suspension (Pulmicort Respules®) delivered with a Pari® LC Plus jet nebulizer. FIG. 6 is a graphical representation of the budesonide content (μg / ml) in the LC PLUS nebulizer in the Pulmicort Reples (250 μg / 2 ml budesonide) and CBIS (120 μg / ml budesonide) formulations at 0, 1, 2, 3 minutes after nebulization. Indicates. FIG. 7 shows the budesonide content in the LC PLUS nebulizer in the amount at t = 0 in the Palmicor Reples (250 μg / 2 ml budesonide) and CBIS (120 μg / ml budesonide) formulations at 0, 1, 2, 3 minutes after nebulization. %) Graph display.

Claims (104)

An inhalable composition comprising no more than about 250 μg of a single corticosteroid, a solvent and a solubility enhancer upon administration of the composition to a subject via a device, the composition comprising: Over the administration of the corticosteroid through the device, an increasing rate of the corticosteroid concentration in the device of about 5 μg / ml / min or less is achieved and the active pharmaceutical agent other than the corticosteroid is substantially free of Contains no inhalable composition. The composition of claim 1, wherein an increasing rate of the corticosteroid concentration in the device of about 5 μg / ml / min or less is achieved over the first 3 minutes of administration. The composition of claim 1, wherein the rate of increase of the single corticosteroid concentration in the device of about 3.5 μg / ml / min or less is achieved over the first 3 minutes of administration. The composition of claim 1, wherein an increasing rate of the single corticosteroid concentration in the device of about 5% / min or less is achieved over the first 3 minutes of administration. The composition of claim 1, wherein the solvent comprises water. The solubility enhancer is extracted from propylene glycol, nonionic surfactant, tyloxapol, polysorbate 80, vitamin E-TPGS, macrogol-15-hydroxystearate, phospholipid, lecithin, purified and / or enriched lecithin, lecithin Phosphatidylcholine fractions, dimyristoylphosphatidylcholine (DMPC), dipalmitoylphosphatidylcholine (DPPC), distearoylphosphatidylcholine (DSPC), cyclodextrin and its derivatives, SAE-CD derivatives, SBE-α-CD, SBE-β-CD, SBE1-β-CD, SBE4-β-CD, SBE7-β-CD, SBE-γ-CD, dimethyl β-CD, hydroxypropyl-β-cyclodextrin, 2-HP-β-CD, hydroxye -Β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, hydroxyethyl-γ-cyclodextrin, dihydroxypropyl-β-cyclodextrin, glucosyl-α-cyclodextrin, glucosyl-β-cyclodextrin, diglucosyl-β-cyclo Dextrin, maltosyl-α-cyclodextrin, maltosyl-β-cyclodextrin, maltosyl-γ-cyclodextrin, maltotriosyl-β-cyclodextrin, maltotriosyl-γ-cyclodextrin, dimaltosyl-β-cyclodextrin, methyl- β-cyclodextrin, carboxyalkyl thioether derivative, ORG 26054, ORG 25969, hydroxypropylmethylcellulose, hydroxypropylcellulose, The composition of claim 1, selected from the group consisting of polyvinylpyrrolidone, vinyl acetate copolymer, vinylpyrrolidone, sodium lauryl sulfate, dioctyl sodium sulfosuccinate, and combinations thereof. The composition of claim 1, wherein the solubility enhancer comprises SBE7-β-CD. The composition of claim 1, wherein the device is a nebulizer. The composition of claim 1, wherein the device is a Pari eFlow nebulizer. 2. The composition of claim 1, comprising the single corticosteroid at a nominal dosage of about 60 [mu] g. 2. The composition of claim 1, comprising the single corticosteroid at a nominal dosage of about 120 [mu] g. An inhalable composition comprising an effective amount of a single corticosteroid, a solvent and a solubility enhancer, the composition being the same upon administration to the subject via a device Less than 60% of the rate of increase of the corticosteroid concentration in the device achieved by an inhalable suspension comprising the corticosteroid without a solubility enhancer administered under conditions An inhalable composition that achieves an increased rate of costeroid concentration and is substantially free of active pharmaceutical agents other than the corticosteroid. The rate of increase of the single corticosteroid concentration in the device is over the first 3 minutes of administration, during the second and third 1 minutes of administration, or during the third 1 minute of administration 13. The composition of claim 12, wherein the composition is achieved. 13. The composition of claim 12, wherein administration of the composition through the device is achieved over 5 minutes and administration of the inhalable suspension is accomplished over 5 minutes. 15. The composition of claim 14, wherein the administration time of the composition through the device and the administration time of the inhalable suspension are the same. 15. The composition of claim 14, wherein the administration time of the composition through the device is different from the administration time of the inhalable suspension. 13. The composition of claim 12, comprising about 40 μg, about 60 μg, about 120 μg, about 125 μg, about 240 μg, about 250 μg, about 500 μg, about 1000 μg, about 1500 μg, or about 2000 μg of the corticosteroid. The composition of claim 12, wherein the solvent comprises water. The solubility enhancer is extracted from propylene glycol, nonionic surfactant, tyloxapol, polysorbate 80, vitamin E-TPGS, macrogol-15-hydroxystearate, phospholipid, lecithin, purified and / or enriched lecithin, lecithin Phosphatidylcholine fractions, dimyristoylphosphatidylcholine (DMPC), dipalmitoylphosphatidylcholine (DPPC), distearoylphosphatidylcholine (DSPC), cyclodextrin and its derivatives, SAE-CD derivatives, SBE-α-CD, SBE-β-CD, SBE1-β-CD, SBE4-β-CD, SBE7-β-CD, SBE-γ-CD, dimethyl β-CD, hydroxypropyl-β-cyclodextrin, 2-HP-β-CD, hydroxye -Β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, hydroxyethyl-γ-cyclodextrin, dihydroxypropyl-β-cyclodextrin, glucosyl-α-cyclodextrin, glucosyl-β-cyclodextrin, diglucosyl-β-cyclo Dextrin, maltosyl-α-cyclodextrin, maltosyl-β-cyclodextrin, maltosyl-γ-cyclodextrin, maltotriosyl-β-cyclodextrin, maltotriosyl-γ-cyclodextrin, dimaltosyl-β-cyclodextrin, methyl- β-cyclodextrin, carboxyalkyl thioether derivative, ORG 26054, ORG 25969, hydroxypropylmethylcellulose, hydroxypropylcellulose, 13. The composition of claim 12, wherein the composition is selected from the group consisting of polyvinyl pyrrolidone, vinyl acetate copolymer, vinyl pyrrolidone, sodium lauryl sulfate, dioctyl sodium sulfosuccinate, and combinations thereof. 13. The composition of claim 12, wherein the solubility enhancer comprises SBE7- [beta] -CD. 13. The device of claim 12, wherein the device is selected from a jet nebulizer, an ultrasonic nebulizer, a pulsating membrane nebulizer, a nebulizer having a vibrating mesh or plate with multiple holes, and a nebulizer comprising a vibration generator and an aqueous chamber. Composition. A method of making microparticles from an inhalable composition comprising:
Forming the composition by adding a solvent and a solubility enhancer to an effective amount of a single corticosteroid, the composition substantially comprising an active pharmaceutical agent other than the corticosteroid. Not including a step; and activating a nebulizer to produce microparticles of the composition;
Upon administration of the composition to a subject via the nebulizer, the composition is achieved by an inhalable suspension comprising the corticosteroid without a solubility enhancer administered under the same conditions. Achieving a rate of increase of the corticosteroid concentration in the nebulizer that is not more than 60% of the rate of increase of the corticosteroid concentration in the nebulizer
Method. The rate of increase of the single corticosteroid concentration in the device is over the first 3 minutes of administration, during the second and third 1 minutes of administration, or during the third 1 minute of administration 23. The method of claim 22, wherein the method is accomplished. 23. The method of claim 22, wherein administration of the composition through the nebulizer is achieved over 5 minutes and administration of the inhalable suspension is accomplished over 5 minutes. 25. The method of claim 24, wherein the administration time of the composition through the nebulizer and the administration time of the inhalable suspension are the same. 25. The method of claim 24, wherein the administration time of the composition through the nebulizer is different from the administration time of the inhalable suspension. The composition comprises about 40 μg, about 60 μg, about 120 μg, about 125 μg, about 240 μg, about 250 μg, about 500 μg, about 1000 μg, about 1500 μg, or about 2000 μg of the single corticosteroid. The method described. 24. The method of claim 22, wherein the solvent comprises water. The solubility enhancer is extracted from propylene glycol, nonionic surfactant, tyloxapol, polysorbate 80, vitamin E-TPGS, macrogol-15-hydroxystearate, phospholipid, lecithin, purified and / or enriched lecithin, lecithin Phosphatidylcholine fractions, dimyristoylphosphatidylcholine (DMPC), dipalmitoylphosphatidylcholine (DPPC), distearoylphosphatidylcholine (DSPC), cyclodextrin and its derivatives, SAE-CD derivatives, SBE-α-CD, SBE-β-CD, SBE1-β-CD, SBE4-β-CD, SBE7-β-CD, SBE-γ-CD, dimethyl β-CD, hydroxypropyl-β-cyclodextrin, 2-HP-β-CD, hydroxye -Β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, hydroxyethyl-γ-cyclodextrin, dihydroxypropyl-β-cyclodextrin, glucosyl-α-cyclodextrin, glucosyl-β-cyclodextrin, diglucosyl-β-cyclo Dextrin, maltosyl-α-cyclodextrin, maltosyl-β-cyclodextrin, maltosyl-γ-cyclodextrin, maltotriosyl-β-cyclodextrin, maltotriosyl-γ-cyclodextrin, dimaltosyl-β-cyclodextrin, methyl- β-cyclodextrin, carboxyalkyl thioether derivative, ORG 26054, ORG 25969, hydroxypropylmethylcellulose, hydroxypropylcellulose, 23. The method of claim 22, wherein the method is selected from the group consisting of polyvinyl pyrrolidone, vinyl acetate copolymer, vinyl pyrrolidone, sodium lauryl sulfate, dioctyl sodium sulfosuccinate, and combinations thereof. 30. The method of claim 29, wherein the solubility enhancer comprises SBE7- [beta] -CD. 23. The device of claim 22, wherein the device is selected from a jet nebulizer, an ultrasonic nebulizer, a pulsating membrane nebulizer, a nebulizer having a vibrating mesh or plate with multiple holes, and a nebulizer comprising a vibration generator and an aqueous chamber. Method. An inhalation system for delivering a therapeutically effective dose of a single corticosteroid to a patient comprising:
(A) an aqueous inhalation mixture comprising the corticosteroid, a solvent and a solubility enhancer, wherein the composition is substantially free of active pharmaceutical agents other than the corticosteroid; and (b) ) With nebulizer,
The nebulizer wherein upon administration of the mixture to a subject via the nebulizer, the mixture is achieved by an inhalable suspension comprising the corticosteroid without a solubility enhancer administered under the same conditions Achieving a rate of increase of the corticosteroid concentration in the nebulizer of 60% or less of the rate of increase of the corticosteroid concentration in
Inhalation system. The rate of increase of the single corticosteroid concentration in the device is over the first 3 minutes of administration, during the second and third 1 minutes of administration, or during the third 1 minute of administration 35. The system of claim 32, wherein the system is achieved. 33. The system of claim 32, wherein administration of the composition through the nebulizer is achieved over 5 minutes and administration of the inhalable suspension is accomplished over 5 minutes. 35. The system of claim 34, wherein the administration time of the composition through the nebulizer and the administration time of the inhalable suspension are the same. 35. The system of claim 34, wherein the administration time of the composition through the nebulizer is different from the administration time of the inhalable suspension. 33. The mixture of claim 32, wherein the mixture comprises about 40 μg, about 60 μg, about 120 μg, about 125 μg, about 240 μg, about 250 μg, about 500 μg, about 1000 μg, about 1500 μg, or about 2000 μg of the single corticosteroid. System. The system of claim 32, wherein the solvent comprises water. The solubility enhancer is extracted from propylene glycol, nonionic surfactant, tyloxapol, polysorbate 80, vitamin E-TPGS, macrogol-15-hydroxystearate, phospholipid, lecithin, purified and / or enriched lecithin, lecithin Phosphatidylcholine fractions, dimyristoylphosphatidylcholine (DMPC), dipalmitoylphosphatidylcholine (DPPC), distearoylphosphatidylcholine (DSPC), cyclodextrin and its derivatives, SAE-CD derivatives, SBE-α-CD, SBE-β-CD, SBE1-β-CD, SBE4-β-CD, SBE7-β-CD, SBE-γ-CD, dimethyl β-CD, hydroxypropyl-β-cyclodextrin, 2-HP-β-CD, hydroxye -Β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, hydroxyethyl-γ-cyclodextrin, dihydroxypropyl-β-cyclodextrin, glucosyl-α-cyclodextrin, glucosyl-β-cyclodextrin, diglucosyl-β-cyclo Dextrin, maltosyl-α-cyclodextrin, maltosyl-β-cyclodextrin, maltosyl-γ-cyclodextrin, maltotriosyl-β-cyclodextrin, maltotriosyl-γ-cyclodextrin, dimaltosyl-β-cyclodextrin, methyl- β-cyclodextrin, carboxyalkyl thioether derivative, ORG 26054, ORG 25969, hydroxypropylmethylcellulose, hydroxypropylcellulose, 33. The system of claim 32, selected from the group consisting of polyvinyl pyrrolidone, vinyl acetate copolymer, vinyl pyrrolidone, sodium lauryl sulfate, dioctyl sodium sulfosuccinate, and combinations thereof. 40. The system of claim 39, wherein the solubility enhancer comprises SBE7- [beta] -CD. 33. The nebulizer of claim 32, wherein the nebulizer is selected from a jet nebulizer, an ultrasonic nebulizer, a pulsating membrane nebulizer, a nebulizer having a vibrating mesh or plate with multiple holes, and a nebulizer comprising a vibration generator and an aqueous chamber. system. A method for treating bronchoconstrictive disorder in a patient in need of treatment for bronchoconstrictive disorder, the method comprising:
Forming a composition by adding a solvent and a solubility enhancer to an amount of a single corticosteroid, the composition substantially comprising an active pharmaceutical agent other than the corticosteroid Not including the steps; and actuating the nebulizer,
Upon administration of the composition to a subject via the nebulizer, the composition is achieved by an inhalable suspension comprising the corticosteroid without a solubility enhancer administered under the same conditions. Achieving a rate of increase of the corticosteroid concentration in the nebulizer that is 60% or less of the rate of increase of the corticosteroid concentration in the nebulizer;
Method. The rate of increase of the single corticosteroid concentration in the device is over the first 3 minutes of administration, during the second and third 1 minutes of administration, or during the third 1 minute of administration 43. The method of claim 42, wherein the method is accomplished. 43. The method of claim 42, wherein administration of the composition via the nebulizer is accomplished over 5 minutes and administration of the inhalable suspension is accomplished over 5 minutes. 45. The method of claim 44, wherein the administration time of the composition through the nebulizer and the administration time of the inhalable suspension are the same. 45. The method of claim 44, wherein the administration time of the composition through the nebulizer is different from the administration time of the inhalable suspension. The composition comprises about 40 μg, about 60 μg, about 120 μg, about 125 μg, about 240 μg, about 250 μg, about 500 μg, about 1000 μg, about 1500 μg, or about 2000 μg of the single corticosteroid. The method described. 43. The method of claim 42, wherein the solvent comprises water. The solubility enhancer is extracted from propylene glycol, nonionic surfactant, tyloxapol, polysorbate 80, vitamin E-TPGS, macrogol-15-hydroxystearate, phospholipid, lecithin, purified and / or enriched lecithin, lecithin Phosphatidylcholine fractions, dimyristoylphosphatidylcholine (DMPC), dipalmitoylphosphatidylcholine (DPPC), distearoylphosphatidylcholine (DSPC), cyclodextrin and its derivatives, SAE-CD derivatives, SBE-α-CD, SBE-β-CD, SBE1-β-CD, SBE4-β-CD, SBE7-β-CD, SBE-γ-CD, dimethyl β-CD, hydroxypropyl-β-cyclodextrin, 2-HP-β-CD, hydroxye -Β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, hydroxyethyl-γ-cyclodextrin, dihydroxypropyl-β-cyclodextrin, glucosyl-α-cyclodextrin, glucosyl-β-cyclodextrin, diglucosyl-β-cyclo Dextrin, maltosyl-α-cyclodextrin, maltosyl-β-cyclodextrin, maltosyl-γ-cyclodextrin, maltotriosyl-β-cyclodextrin, maltotriosyl-γ-cyclodextrin, dimaltosyl-β-cyclodextrin, methyl- β-cyclodextrin, carboxyalkyl thioether derivative, ORG 26054, ORG 25969, hydroxypropylmethylcellulose, hydroxypropylcellulose, 43. The method of claim 42, selected from the group consisting of polyvinyl pyrrolidone, vinyl acetate copolymer, vinyl pyrrolidone, sodium lauryl sulfate, dioctyl sodium sulfosuccinate, and combinations thereof. 50. The method of claim 49, wherein the solubility enhancer comprises SBE7- [beta] -CD. 43. The device of claim 42, wherein the device is selected from a jet nebulizer, an ultrasonic nebulizer, a pulsating membrane nebulizer, a nebulizer having a vibrating mesh or plate with multiple holes, and a nebulizer comprising a vibration generator and an aqueous chamber. Method. 43. The bronchoconstrictive disorder is selected from the group consisting of asthma, childhood asthma, bronchial asthma, allergic asthma, endogenous asthma, chronic obstructive pulmonary disease (COPD), chronic bronchitis and emphysema. The method described. An inhalable composition comprising about 250 μg or less of budesonide, a solvent and a solubility enhancer, wherein upon administration of the composition to a subject via a device, the composition passes through the device An inhalable composition that achieves an increasing rate of budesonide concentration in the device of about 5 μg / ml / min or less over administration of budesonide and is substantially free of active pharmaceutical agents other than the corticosteroid. 54. The composition of claim 53, wherein an increasing rate of the budesonide concentration in the device of about 5 [mu] g / ml / min or less is achieved over the first 3 minutes of administration. 55. The composition of claim 54, wherein an increasing rate of budesonide concentration in the device of about 3.5 [mu] g / ml / min or less is achieved over the first 3 minutes of administration. 54. The composition of claim 53, wherein an increasing rate of budesonide concentration in the device of about 5% / min or less is achieved over the first 3 minutes of administration. 54. The composition of claim 53, wherein the solvent comprises water. The solubility enhancer is extracted from propylene glycol, nonionic surfactant, tyloxapol, polysorbate 80, vitamin E-TPGS, macrogol-15-hydroxystearate, phospholipid, lecithin, purified and / or enriched lecithin, lecithin Phosphatidylcholine fractions, dimyristoylphosphatidylcholine (DMPC), dipalmitoylphosphatidylcholine (DPPC), distearoylphosphatidylcholine (DSPC), cyclodextrin and its derivatives, SAE-CD derivatives, SBE-α-CD, SBE-β-CD, SBE1-β-CD, SBE4-β-CD, SBE7-β-CD, SBE-γ-CD, dimethyl β-CD, hydroxypropyl-β-cyclodextrin, 2-HP-β-CD, hydroxye -Β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, hydroxyethyl-γ-cyclodextrin, dihydroxypropyl-β-cyclodextrin, glucosyl-α-cyclodextrin, glucosyl-β-cyclodextrin, diglucosyl-β-cyclo Dextrin, maltosyl-α-cyclodextrin, maltosyl-β-cyclodextrin, maltosyl-γ-cyclodextrin, maltotriosyl-β-cyclodextrin, maltotriosyl-γ-cyclodextrin, dimaltosyl-β-cyclodextrin, methyl- β-cyclodextrin, carboxyalkyl thioether derivative, ORG 26054, ORG 25969, hydroxypropylmethylcellulose, hydroxypropylcellulose, 54. The composition of claim 53, selected from the group consisting of polyvinyl pyrrolidone, vinyl acetate copolymer, vinyl pyrrolidone, sodium lauryl sulfate, dioctyl sodium sulfosuccinate, and combinations thereof. 59. The composition of claim 58, wherein the solubility enhancer comprises SBE7- [beta] -CD. 54. The composition of claim 53, wherein the device is a nebulizer. 61. The composition of claim 60, wherein the device is a Pari eFlow nebulizer. 54. The composition of claim 53, comprising budesonide in a nominal dosage of about 60 [mu] g. 54. The composition of claim 53, wherein budesonide is in a nominal dosage of about 120 [mu] g. An inhalable composition comprising an effective amount of budesonide, a solvent and a solubility enhancer, wherein when the composition is administered to a subject via a device, the composition is administered under the same conditions. Achieving an increase rate of budesonide concentration in the device of 60% or less of the increase rate of budesonide concentration in the device achieved by an inhalable suspension comprising budesonide without a solubility enhancer, and the corticosteroid An inhalable composition substantially free of any active pharmaceutical agent other than The rate of increase of budesonide concentration in the device is achieved over the first 3 minutes of administration, during the second and third 1 minutes of administration, or during the third 1 minute of administration. Item 65. The composition according to item 64. 65. The composition of claim 64, wherein administration of the composition through the device is achieved over 5 minutes and administration of the inhalable suspension is accomplished over 5 minutes. 68. The composition of claim 66, wherein the administration time of the composition through the device and the administration time of the inhalable suspension are the same. 68. The composition of claim 66, wherein the administration time of the composition through the device and the administration time of the inhalable suspension are different. 65. The composition of claim 64, wherein the composition comprises about 40 μg, about 60 μg, about 120 μg, about 125 μg, about 240 μg, about 250 μg, about 500 μg, about 1000 μg, about 1500 μg, or about 2000 μg budesonide. 65. The composition of claim 64, wherein the solvent comprises water. The solubility enhancer is extracted from propylene glycol, nonionic surfactant, tyloxapol, polysorbate 80, vitamin E-TPGS, macrogol-15-hydroxystearate, phospholipid, lecithin, purified and / or enriched lecithin, lecithin Phosphatidylcholine fractions, dimyristoylphosphatidylcholine (DMPC), dipalmitoylphosphatidylcholine (DPPC), distearoylphosphatidylcholine (DSPC), cyclodextrin and its derivatives, SAE-CD derivatives, SBE-α-CD, SBE-β-CD, SBE1-β-CD, SBE4-β-CD, SBE7-β-CD, SBE-γ-CD, dimethyl β-CD, hydroxypropyl-β-cyclodextrin, 2-HP-β-CD, hydroxye -Β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, hydroxyethyl-γ-cyclodextrin, dihydroxypropyl-β-cyclodextrin, glucosyl-α-cyclodextrin, glucosyl-β-cyclodextrin, diglucosyl-β-cyclo Dextrin, maltosyl-α-cyclodextrin, maltosyl-β-cyclodextrin, maltosyl-γ-cyclodextrin, maltotriosyl-β-cyclodextrin, maltotriosyl-γ-cyclodextrin, dimaltosyl-β-cyclodextrin, methyl- β-cyclodextrin, carboxyalkyl thioether derivative, ORG 26054, ORG 25969, hydroxypropylmethylcellulose, hydroxypropylcellulose, 65. The composition of claim 64, selected from the group consisting of polyvinyl pyrrolidone, vinyl acetate copolymer, vinyl pyrrolidone, sodium lauryl sulfate, dioctyl sodium sulfosuccinate, and combinations thereof. 72. The composition of claim 71, wherein the solubility enhancer comprises SBE7- [beta] -CD. 65. The device of claim 64, wherein the device is selected from a jet nebulizer, an ultrasonic nebulizer, a pulsating membrane nebulizer, a nebulizer having a vibrating mesh or plate with multiple holes, and a nebulizer comprising a vibration generator and an aqueous chamber. Composition. A method of making microparticles from an inhalable composition, the method comprising:
Forming a composition by adding a solubility enhancer to an effective amount of budesonide, the composition being substantially free of an active pharmaceutical agent other than budesonide; and operating the nebulizer And producing a fine particle of the composition,
Upon administration of the composition to a subject via the nebulizer, the composition is achieved by an inhalable suspension comprising budesonide without a solubility enhancer administered under the same conditions. Achieving an increase rate of budesonide concentration in the nebulizer of 60% or less of the increase rate of budesonide concentration in the nebulizer;
Method. The rate of increase of budesonide concentration in the device is achieved over the first 3 minutes of administration, during the second and third 1 minutes of administration, or during the third 1 minute of administration. Item 75. The method according to Item 74. 75. The method of claim 74, wherein administration of the composition via the nebulizer is accomplished over 5 minutes and administration of the inhalable suspension is accomplished over 5 minutes. 77. The method of claim 76, wherein the administration time of the composition through the nebulizer and the administration time of the inhalable suspension are the same. 77. The method of claim 76, wherein the administration time of the composition through the nebulizer is different from the administration time of the inhalable suspension. 75. The method of claim 74, wherein the composition comprises about 40 μg, about 60 μg, about 120 μg, about 125 μg, about 240 μg, about 250 μg, about 500 μg, about 1000 μg, about 1500 μg, or about 2000 μg budesonide. 75. The method of claim 74, wherein the solvent comprises water. The solubility enhancer is extracted from propylene glycol, nonionic surfactant, tyloxapol, polysorbate 80, vitamin E-TPGS, macrogol-15-hydroxystearate, phospholipid, lecithin, purified and / or enriched lecithin, lecithin Phosphatidylcholine fractions, dimyristoylphosphatidylcholine (DMPC), dipalmitoylphosphatidylcholine (DPPC), distearoylphosphatidylcholine (DSPC), cyclodextrin and its derivatives, SAE-CD derivatives, SBE-α-CD, SBE-β-CD, SBE1-β-CD, SBE4-β-CD, SBE7-β-CD, SBE-γ-CD, dimethyl β-CD, hydroxypropyl-β-cyclodextrin, 2-HP-β-CD, hydroxye -Β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, hydroxyethyl-γ-cyclodextrin, dihydroxypropyl-β-cyclodextrin, glucosyl-α-cyclodextrin, glucosyl-β-cyclodextrin, diglucosyl-β-cyclo Dextrin, maltosyl-α-cyclodextrin, maltosyl-β-cyclodextrin, maltosyl-γ-cyclodextrin, maltotriosyl-β-cyclodextrin, maltotriosyl-γ-cyclodextrin, dimaltosyl-β-cyclodextrin, methyl- β-cyclodextrin, carboxyalkyl thioether derivative, ORG 26054, ORG 25969, hydroxypropylmethylcellulose, hydroxypropylcellulose, 75. The method of claim 74, selected from the group consisting of polyvinylpyrrolidone, a copolymer of vinyl acetate, vinylpyrrolidone, sodium lauryl sulfate, dioctyl sodium sulfosuccinate, and combinations thereof. 82. The method of claim 81, wherein the solubility enhancer comprises SBE7- [beta] -CD. 75. The device of claim 74, wherein the device is selected from a jet nebulizer, an ultrasonic nebulizer, a pulsating membrane nebulizer, a nebulizer having a vibrating mesh or plate with multiple holes, and a nebulizer comprising a vibration generator and an aqueous chamber. Method. 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, the composition being substantially free of active pharmaceutical agents other than the corticosteroid; and (b) comprising a nebulizer;
Budesonide in the nebulizer wherein upon administration of the mixture to the subject via the nebulizer, the mixture is achieved by an inhalable suspension comprising budesonide without a solubility enhancer administered under the same conditions Achieving a budesonide concentration increase rate in the nebulizer that is 60% or less of the concentration increase rate;
Inhalation system. The rate of increase of budesonide concentration in the device is achieved over the first 3 minutes of administration, during the second and third 1 minutes of administration, or during the third 1 minute of administration. Item 84. The system according to Item 84. 85. The system of claim 84, wherein administration of the composition through the nebulizer is accomplished over 5 minutes and administration of the inhalable suspension is accomplished over 5 minutes. 87. The system of claim 86, wherein the administration time of the composition through the nebulizer and the administration time of the inhalable suspension are the same. 90. The system of claim 86, wherein the administration time of the composition through the nebulizer is different from the administration time of the inhalable suspension. 85. The system of claim 84, wherein the mixture comprises about 40 μg, about 60 μg, about 120 μg, about 125 μg, about 240 μg, about 250 μg, about 500 μg, about 1000 μg, about 1500 μg, or about 2000 μg budesonide. The system of claim 84, wherein the solvent comprises water. The solubility enhancer is extracted from propylene glycol, nonionic surfactant, tyloxapol, polysorbate 80, vitamin E-TPGS, macrogol-15-hydroxystearate, phospholipid, lecithin, purified and / or enriched lecithin, lecithin Phosphatidylcholine fractions, dimyristoylphosphatidylcholine (DMPC), dipalmitoylphosphatidylcholine (DPPC), distearoylphosphatidylcholine (DSPC), cyclodextrin and its derivatives, SAE-CD derivatives, SBE-α-CD, SBE-β-CD, SBE1-β-CD, SBE4-β-CD, SBE7-β-CD, SBE-γ-CD, dimethyl β-CD, hydroxypropyl-β-cyclodextrin, 2-HP-β-CD, hydroxye -Β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, hydroxyethyl-γ-cyclodextrin, dihydroxypropyl-β-cyclodextrin, glucosyl-α-cyclodextrin, glucosyl-β-cyclodextrin, diglucosyl-β-cyclo Dextrin, maltosyl-α-cyclodextrin, maltosyl-β-cyclodextrin, maltosyl-γ-cyclodextrin, maltotriosyl-β-cyclodextrin, maltotriosyl-γ-cyclodextrin, dimaltosyl-β-cyclodextrin, methyl- β-cyclodextrin, carboxyalkyl thioether derivative, ORG 26054, ORG 25969, hydroxypropylmethylcellulose, hydroxypropylcellulose, 85. The system of claim 84, selected from the group consisting of polyvinyl pyrrolidone, vinyl acetate copolymer, vinyl pyrrolidone, sodium lauryl sulfate, dioctyl sodium sulfosuccinate, and combinations thereof. 92. The system of claim 91, wherein the solubility enhancer comprises SBE7- [beta] -CD. 85. The device of claim 84, wherein the device is selected from a jet nebulizer, an ultrasonic nebulizer, a pulsating membrane nebulizer, a nebulizer having a vibrating mesh or plate with multiple holes, and a nebulizer comprising a vibration generator and an aqueous chamber. system. A method for treating bronchoconstrictive disorder in a patient in need of treatment for bronchoconstrictive disorder, the method comprising:
Forming a composition by adding a solubility enhancer to an amount of budesonide, the composition being substantially free of active pharmaceutical agents other than budesonide; and activating a nebulizer Including
In the nebulizer achieved upon administration of the composition to a subject via the nebulizer, wherein the composition is achieved by an inhalable suspension comprising budesonide without a solubility enhancer administered under the same conditions Achieving an increase rate of budesonide concentration in the nebulizer of 60% or less of the increase rate of budesonide concentration of
Method. The rate of increase of budesonide concentration in the device is achieved over the first 3 minutes of administration, during the second and third 1 minutes of administration, or during the third 1 minute of administration. 95. A method according to item 94. 95. The method of claim 94, wherein administration of the composition via the nebulizer is accomplished over 5 minutes and administration of the inhalable suspension is accomplished over 5 minutes. 99. The method of claim 96, wherein the administration time of the composition through the nebulizer is the same as the administration time of the inhalable suspension. 99. The method of claim 96, wherein the administration time of the composition through the nebulizer is different from the administration time of the inhalable suspension. 95. The method of claim 94, wherein the composition comprises about 40 μg, about 60 μg, about 120 μg, about 125 μg, about 240 μg, about 250 μg, about 500 μg, about 1000 μg, about 1500 μg, or about 2000 μg budesonide. 95. The method of claim 94, wherein the solvent comprises water. The solubility enhancer is extracted from propylene glycol, nonionic surfactant, tyloxapol, polysorbate 80, vitamin E-TPGS, macrogol-15-hydroxystearate, phospholipid, lecithin, purified and / or enriched lecithin, lecithin Phosphatidylcholine fractions, dimyristoylphosphatidylcholine (DMPC), dipalmitoylphosphatidylcholine (DPPC), distearoylphosphatidylcholine (DSPC), cyclodextrin and its derivatives, SAE-CD derivatives, SBE-α-CD, SBE-β-CD, SBE1-β-CD, SBE4-β-CD, SBE7-β-CD, SBE-γ-CD, dimethyl β-CD, hydroxypropyl-β-cyclodextrin, 2-HP-β-CD, hydroxye -Β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, hydroxyethyl-γ-cyclodextrin, dihydroxypropyl-β-cyclodextrin, glucosyl-α-cyclodextrin, glucosyl-β-cyclodextrin, diglucosyl-β-cyclo Dextrin, maltosyl-α-cyclodextrin, maltosyl-β-cyclodextrin, maltosyl-γ-cyclodextrin, maltotriosyl-β-cyclodextrin, maltotriosyl-γ-cyclodextrin, dimaltosyl-β-cyclodextrin, methyl- β-cyclodextrin, carboxyalkyl thioether derivative, ORG 26054, ORG 25969, hydroxypropylmethylcellulose, hydroxypropylcellulose, 95. The method of claim 94, selected from the group consisting of polyvinyl pyrrolidone, vinyl acetate copolymer, vinyl pyrrolidone, sodium lauryl sulfate, dioctyl sodium sulfosuccinate, and combinations thereof. 102. The method of claim 101, wherein the solubility enhancer comprises SBE7- [beta] -CD. 95. The device of claim 94, wherein the device is selected from a jet nebulizer, an ultrasonic nebulizer, a pulsating membrane nebulizer, a nebulizer having a vibrating mesh or plate with multiple holes, and a nebulizer comprising a vibration generator and an aqueous chamber. Method. 95. The bronchoconstrictive disorder is selected from the group consisting of asthma, childhood asthma, bronchial asthma, allergic asthma, endogenous asthma, chronic obstructive pulmonary disease (COPD), chronic bronchitis and emphysema. The method described.

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