MXPA06007583A - Inhalant formulation containing sulfoalkyl ether cyclodextrin and corticosteroid prepared from a unit dose suspension - Google Patents

Abstract

An inhalable unit dose liquid formulation containing SAE-CD and corticosteroid is provided. The formulation is adapted for administration to a subject by nebulization with any known nebulizer. The formulation can be included in a kit. The formulation is administered as an aqueóus solution or concentrated composition. The formulation is employed in an improved nebulization system for administering corticosteroid by inhalation. SAE-CD present in the formulation significantly enhances the chemical stability of corticosteroid, such as budesonide. A method of administering the formulation by inhalation is provided. The formulation can also be administered by conventional nasal delivery apparatus. The formulation is prepared by mixing SAE-CD, in solid or liquid (dissolved) form, with an inhalable suspension-based unit dose formulation.

Description

IMHALANT FORMULATION CONTAINING SULFOALKYLL ETHER-CYCLODYLTRINE AND A CORTICOSTEROID PREPARED FROM A SUSPENSION FOR UNIT DOSE FIELD OF THE INVENTION The present invention relates to a method for administering, and a formulation for administering, sulfoalkyl ether-cyclodextrin (SAE-CD) and a corticosteroid, such as budesonide, by means of inhalation. The formulation is made by combining the SAE-CD with a unit dose formulation based on corticosteroid suspension. The invention also relates to methods for treating diseases and disorders of the lungs.

BACKGROUND OF THE INVENTION The delivery of a drug by means of inhalation allows the deposition of the drug in different sections of the respiratory tract, for example the throat, swallow, bronchi and alveoli. Generally, the smaller the particle size, the longer the particle will remain suspended in the air and the drug can be delivered further down the respiratory tract in the lungs. Corticosteroids are delivered by inhalation using nebulizers, metered dose inhalers or dry powder inhalers.

The main advantages of nebulizers over other pulmonary installation methods are that the cooperation of the patient is not required and it is easier to provide higher doses of medication. However, the main concerns about nebulizers are their increased cost, reduced portability and inconvenience of the need to prepare a medication in advance and the requirement of increased time to administer a treatment. A method for improving the administration of drugs, such as corticosteroids by means of nebulization, will be desired. Budesonide (16,17-cyclic acetal of (R, S) -llβ, 16a, 17,21-tetrahydroxypropylene-1,4-diene-3, 20-dione with butyraldehyde, C25H34 ?6, Pm: 430.5) is well known This is commercially provided as a mixture of two isomers (22R and 22S). Budesonide is an anti-inflammatory corticosteroid that exhibits potent glucocorticoid activity. The administration of budesonide is indicated for the combination treatment of asthma and as a prophylactic therapy in children. Commercial budesonide formulations are sold by AstraZeneca LP (Wilmington, DE) under the trademarks ENTOCORT EC1®, PULMICORT RESPÜLES ™, Rhinocort Aqua1 ^, Rhinocort Nasal Inhaler ™ and Pulmicort Turbuhaler ™ and under its generic name. PÜLMICORT RESPULESMR, which is an aqueous, sterile suspension of micronized or too-fine budesonide, is administered by means of inhalation using a nebulizer, in particular a jet nebulizer driven by compressed air that supplies from 2 to 18% of the mass of drug contained in the nominal charge. RHINOCORT NASAL INHALERMR is a metered dose pressurized aerosol unit containing a suspension of micronized budesonide in a mixture of propellant gases. RHINOCORT AQÜA ^ is a formulation for the spray with manual pump of measured doses without essence that contains a suspension of micronized budesonide in an aqueous medium. Suspensions should not be administered with an ultrasonic nebulizer. The desired properties of a liquid for nebulization generally include: 1) reduced viscosity; 2) a sterile medium; 3) reduced surface tension; 4) stability towards the mechanism of the nebulizer; 5) at a moderate pH of about 4-10; 6) ability to form droplets with a MMAD of < 5 μm or preferably < 3 μm; 7) the absence of irritant preservatives and stabilizing agents; 8) adequate tonicity. On the one hand, the suspensions have some advantages but on the other hand the solutions have other advantages. Smaldone et al [J. Aerosol Med. (1998), 11, 113-125) describe the results of a study on the in vitro determination of the distribution of masses and inhaled particles of a budesonide suspension. They conclude that 2% -18% of the nebulizer budesonide load was delivered from the suspension, which means that the supply of budesonide was incomplete resulting in a significant waste of drug. In the thirteen most efficient systems, the suspension can be nebulized well enough for delivery in the lower respiratory tract. Another study also demonstrated the highly variable efficacy of nebulization from one nebulizer to another. Barry et al (J. Allergy Clin. Immunol. (1998), 320-231) establish that this variability must be taken into account when treating patients with nebulized budesonide. Berg et al. (J. Aerosol Sci. (1998), 19 (7), 1101-1104) also report the highly variable efficacy of nebulizing the PULMICORT suspension from one nebulizer to the next. In addition, the average mass aerodynamic diameter (MMAD) of the nebulized droplets is highly variable from one nebulizer to the next. In general, suspensions are nebulized less efficiently than solutions, O'Riordan (Respiratory Care, (2002), 1305-1313). Inhaled corticosteroids are used in the treatment of asthma and are significantly beneficial because they are delivered directly to the site of action, the lungs. The goal of an inhaled corticosteroid is to provide a localized therapy with immediate activity of the drug in the lungs. Inhaled corticosteroids are suitably absorbed from the lungs. In fact, it can be assumed that all of the available drug in the receptor site in the lungs will be systematically absorbed. However, it is well known that using current methods and formulations, most of a dose of inhaled corticosteroids is swallowed and becomes available for oral absorption, resulting in undesired systemic effects. For inhaled corticosteroids, high lung availability is more important than high oral bioavailability because the lungs are the target organ, a product with high lung availability has greater potential to exert positive effects on the lungs. The ideal formulation of inhaled corticosteroids would provide a minimal oral supply thereby reducing the likelihood of adverse systemic effects. Most of the dose of corticosterpides delivered to the lungs is absorbed and is available systemically. For the portion of the dose of inhaled corticosteroids that is supplied by the oral route, bioavailability depends on the absorption of the Gl tract and the degree of metabolism of the first step in the liver. Since this oral component of the corticosteroid drug supply does not provide any therapeutic effect, beneficial but may increase systemic side effects, it is desirable that the oral bioavailability of the inhaled corticosteroid be relatively low. Both the size of the particles and the formulation influence the efficacy of an inhaled corticosteroid. The formulation of a drug has a significant impact on the supply of that drug to the lungs and, therefore, on its effectiveness. More important in the supply of the drug to the lungs are the aerosol vehicle and the size of the particles supplied. Additionally, a reduced degree of pulmonary deposition suggests a greater degree of oropharyngeal deposition. Due to a particular formulation used, some corticosteroids are more likely to be deposited in the mouth and throat and may cause adverse local effects. While the distribution of the receptor is the main determinant of bronchodilator efficiency, the size of the particles seems to be more important in determining the efficacy of an inhaled corticosteroid. The smaller airways have an internal perimeter of 2 micrometers (cmcm) or less. Thus, an inhaler with particles having an average aerodynamic diameter of 1 mcm must have a respirable fraction larger than an inhaler with particles having an average diameter of 3.5 to 4 mcm. For patients with obstructive pulmonary disease, all particles should ideally be no greater than 2 to 3 mcm. It is more likely that a particle that is small (less than 5 mcm) will be inhaled into the smaller airways of the lungs, thus improving efficacy. By contrast, particles that are larger than 5 mcm can be deposited in the mouth and throat, reducing both the proportion of particles that reach the lungs and potentially causing adverse local effects such as oral candidiasis and hoarseness (dysphonia). It is considered that the particles that have an average mass aerodynamic diameter (MMAD) close to 1 mcm have a higher respirable fraction per dose than those with a diameter of 3.5 cmcm or greater. An additional disadvantage for the nebulization of budesonide suspensions is the need to generate very small droplets, MMAD of about <3 μm. Since the nebulized droplets are too small, then the micronized budesonide should be even smaller or in the range of 0.5-2.0 μm and the particles should have a small particle size distribution. The generation of these particles is difficult. However, efforts have been made to improve the nebulization of budesonide suspensions with ultrasonic nebulizers through the use of submicron size particles (Keller et al. In Respiratory Drug Delivery VIII (2002), 197-206). A suspension of nanoparticles (0.1-1.0 μm) of the corticosteroid could be used to increase the proportion of respirable particles compared to a thicker suspension as in the PULMICORTMR suspension. No improvement was observed on PULMICORT1111 suspension (budesonide particle size of approximately 4.4 μm in suspension). In addition, there are concerns regarding the use of nanosuspensions because small particles (< 0.05 μm) can induce an allergic response in a subject. Sheffield Pharmaceuticals, Inc. (St. Louis, MO; "The Pharmacokinetics of Nebulized Nanocrystal Budesonide Suspension in Healthy Volunteers", Kraft et al., J. Clin. Pharmacol, (2004), 44: 67-72) has described the preparation and evaluation of UDB (budesonide in unit doses), which is a suspension-based formulation containing budesonide nanoparticles dispersed in a liquid medium. This product is being developed by MAP Pharmaceuticals, Inc. (Mountain View, California). It is known that the inhalation of drug particles contrary to a dissolved drug is disadvantageous. Brain et al. (Bronchial Asthma, 2nd Ed. (Ed. EB Weis et al., Little Brown &Co. (1985), pages 594-603) report that the less soluble particles that are deposited on the mucus mantle that covers the Pulmonary airways and nasal passages move into the pharynx through the cilia, which would include the larger drug particles deposited in the upper respiratory tract, mucus, cells and debris coming from the nasal cavities and lungs. They are found in the pharynx, mixed with saliva and enter the gastrointestinal tract when they are swallowed.Promised, by means of this mechanism, the particles are removed from the lungs with rests from minutes to hours.Therefore, there is little time for the solubilization of slowly dissolving drugs, such as budesonide In contrast, particles deposited in different compartments of cilia, such as alveoli, have in much longer residence times. Since it is difficult to generate very small budesonide particles for deep deposition in the lungs, a large amount of the inhaled suspension would probably be found in the upper to intermediate respiratory tract. However, it is much easier to generate small droplets from a solution than from a solids suspension. For these reasons, the nebulization of a solution containing budesonide should be preferred over that of a suspension. O'Riordan. { Respiratory Care (November 2002), 47 (11), 1305-1313) states that drugs can be delivered by means of nebulization of either solutions or suspensions, but that in general, the nebulization of a solution is preferred over that of a suspension. He states that ultrasonic nebulizers should not be used in suspensions and should only be used in solutions. O'Callaghan. { Thorax, (1990), 45, 109-111), Storr et al. { Arch. Dis. Child (1986), 61, 270-273) and Webb et al. { Arch. Dis. Child (1986), 61, 1108-1110) suggest that nebulization of corticosteroid solutions (particularly beclomethasone) may be preferred over suspensions because the latter may be inefficient if the nebulized particles are too large to enter. the lungs in therapeutically effective amounts. However, the data presented by O'Callaghan (J. Pharm. Pharmacol. (2002), 54, 565-569) on the nebulization of a flunisolide solution against a suspension showed that the two performed in a similar manner. Therefore, it can not be generalized that the nebulization of a solution is preferred over that of a suspension. Accordingly, there is a widely recognized need for a different formulation of a suspension comprising a corticosteroid for administration via nebulization. However, the unit dose formulation based on PULMICORTMR suspension is widely available and accepted in the field of inhalation therapy. It would be extensively beneficial for this field of therapy to provide a method to improve the administration of the unit dose formulation based on PULMICORTMR suspension., or more generally, of a unit dose formulation based on suspension containing a corticosteroid. However, the current approach in therapy with nebulizers is to administer higher concentrations of drug, to use solutions, preferably solutions based predominantly on water giving preference to non-aqueous solutions or suspensions or non-aqueous alcoholic or alcoholic, if possible, minimize the treatment time, synchronize the nebulization with the inhalation and administer smaller droplets for the deeper deposition of the drug in the lungs. Solutions containing corticosteroids for nebulization are known. There are a variety of different ways to prepare solutions for nebulization. These have generally been prepared by the addition of a cosolvent, surfactant or buffer. However, cosolvents, such as ethanol, polyethylene glycol and prene glycol are only tolerated in low amounts when administered by inhalation due to irritation of the respiratory tract. There are limits to the acceptable levels of these cosolvents in inhaled products. Typically, cosolvents make up less than about 35% by weight of the nebulized composition, although it is the total cosolvent dose as well as its concentration that determines these limits. The limits are established by the propensity of these solvents to either cause a local irritation of the lung tissue, to form hyperosmotic solutions that would attract fluid to the lungs and / or to intoxicate the patient. In addition, the more potent, hydrophobic therapeutic agents are not sufficiently soluble in these cosolvent mixtures. Saidi et al. (US Patent No. 6,241,969) describe the preparation of solutions containing corticosteroids for nasal and pulmonary delivery. The dissolved corticosteroids are present in a concentrated form, essentially non-aqueous for storage or in a water-based form, diluted for administration. Lintz et al. (AAPS Annual Meeting and Exposition, 2004) describe the preparation of liquid formulations containing budesonide, water, citrate salt, sodium chloride and alcohol, prene glycol and / or surfactant, such as Tween101, Pluronic101 or phospholipids with HLB values. between 10 and 20. An alternative approach for the administration of PULMICORT suspension is the administration of a liposomal formulation. Waldrep et al. { J. Aerosol Med. (1994), 7 (2), 135-145) were reportedly successful in the preparation of a liposomal formulation of budesonide and phosphatidylcholine derivatives. None of the formulations identified above has provided a method for improving the administration of a unit dose formulation based on a suspension containing a corticosteroid. Instead, the general approach of the technique has been to completely circumvent the formulation of a suspension by first preparing a liquid formulation that is then divided into multiple unit doses that are packaged for marketing and then sold for use. The solubilization of drugs by cyclodextrins and their derivatives is well known. Cyclodextrins are cyclic carbohydrates derived from starch. Unmodified cyclodextrins differ by the number of glucanose units attached in the cylindrical structure. The original cyclodextrins contain 6, 7 or 8 glucanose units and are referred to as a-, β- and β-cyclodextrin, respectively. Each cyclodextrin subunit has secondary hydroxyl groups at positions 2 and 3 and a primary hydroxyl group at position 6. Cyclodextrins can be represented as truncated cones, hollows with outer surfaces, hydrophilic and hydrophobic inner cavities. In aqueous solutions, these hydrophobic cavities provide a refuge for organic compounds, hydrophobic that can be adjusted in all or part of its structure within these cavities. This process, known as inclusion complexation, can result in apparent, increased water solubility and stability for the complexed drug. The complex is stabilized by hydrophobic interactions and does not include the formation of any covalent bonds. This dynamic and reversible equilibrium process can be described by Equations 1 and 2, where the amount in the complexed form is a function of the drug and cyclodextrin concentrations and the equilibrium or bond constant, Kb. When the cyclodextrin formulations they are administered by means of an injection into the bloodstream, the complex dissociates rapidly due to the effects of dilution and the nonspecific binding of the drug to the components of blood and tissue. Kb Drug + Cyclodextrin <; Complex Equation 1 [Complex] Kb = Equation 2 [Drug] [cyclodextrin] The binding constants of the cyclodextrin and an active agent can be determined by means of the equilibrium solubility technique (T. Higuchi et al in "Advances in Analytical Chemistry and Instrumentation Vol. 4"; CN Reilly ed.; John Wiley & amp; Sons, Inc., 1965, pages 117-212). Generally, the higher the concentration of cyclodextrin, the equilibrium process of Equations 1 and 2 is more changed to the formation of more complexes, which means that the concentration of the free drug is generally decreased by increasing the concentration of cyclodextrin in the solution.

It is known that the original, non-derivatized cyclodextrins interact with human tissues and extract cholesterol and other components of the membrane, particularly with the accumulation in the tubule cells of the kidneys, leading to toxic and sometimes fatal renal effects. The original cyclodextrins frequently exhibit a different affinity for some given substrate. For example, β-cyclodextrin frequently forms complexes with limited solubility, resulting in solubility curves of the Bs type. This behavior is known for a wide variety of steroids which imposes serious limitations towards the use of β-CD in liquid preparations. However, ß-CD does not adequately complex with a number of different classes of compounds. It has been shown for the ß-CD and the? -CD that the derivatization, for example alkylation, does not only result in a better water solubility of the derivatives compared to the original CD, but also changes the type of water curves. solubility of type Bs limiting to the more linear type A curve (Bernd W. Muller and Ulrich Brauns, "Change of Phase-Solubility Behavior by Gamma-Cyclodextrin Derivatization ", Pharmaceutical Research (1985) pages 309-310). The chemical modification of the original cyclodextrins (usually in the hydroxyl groups) has resulted in derivatives with improved safety while retaining or improving the capacity of complexation. Of the numerous derivatized cyclodextrins that have been prepared to date, only two appear to be commercially viable: 2-hydroxypropyl derivatives (HP-CD, neutral cyclodextrins which are developed commercially by Janssen and others) and the sulfoalkyl ether derivatives, such as sulfobutyl ether, (SBE-CD; anionic cyclodextrins which are developed by CyDex Inc). However, HP-ß-CD still has toxicity unlike SBE-CD.

Sulfobutyl ether-β-Cyclodextrin (Captisol ^ ®) U.S. Patent Nos. 5,376,645 and No. ,134,127 issued to Stella et al., US Patent No. 3,426,011 issued to Parmerter et al., La mers et al. (Red. Trav. Chim. Pays-Bas (1972), 91 (6), 733-742); Staerke (1971), 23 (5), 167-171) and Qu et al. { J. Inclusion Phenom. Macro Chem, (2002), 43, 213-221) describe cyclodextrins derivatized with sulfoalkyl ether. The references suggest that the SAE-CD must be adequate to solubilize a wide range of different compounds. A sulfobutyl ether derivative of beta-cyclodextrin (SBE-β-CD), in particular the derivative with an average of approximately 7 substituents per molecule of cyclodextrin (SBE7-β-CD), has been marketed by CyDex, Inc. as CAPTISOL ™ . The anionic sulfobutyl ether substituent dramatically improves the aqueous solubility of the original cyclodextrin. In addition, the presence of charges decreases the ability of the molecule to form complexes with cholesterol compared to the hydroxypropyl derivative. The non-covalent, reversible complexation of drugs with the cyclodextrin CAPTISOL ™ generally allows an increased solubility and stability of the drugs in aqueous solutions. While CAPTISOL ™ is a relatively new but well known cyclodextrin, its use in the preparation of solutions containing corticosteroids for nebulization has not been previously evaluated.

Hemolytic assays are generally used in the field of parenteral formulations to predict whether or not a particular formulation is likely to be unsuitable for injection into the bloodstream of a subject. If the formulation that is tested induces a significant amount of hemolysis, that formulation will generally be considered as unsuitable for administration to a subject. It is generally expected that a higher osmolality is associated with a higher hemolytic potential. As represented in FIGURE 1 (Thompson, D.O. Critique Reviews in Therapeutic Drug Carrier Systems, (1997), 14 (1), 1-104), the hemolytic behavior of CAPTISOL "11 is compared with the same for the original β-cyclodextrin, the commercially available hydroxypropyl derivatives, the cyclodextrin ENCAPSIN ™ 1 (degree of substitution ~ 3-4) and cyclodextrin MOLECUSOL1 ^ (degree of substitution ~ 7-8) and two other sulfobutyl ether derivatives, SBEl-ß-CD and SBE4-ß-CD. Unlike the other cyclodextrin derivatives, the sulfoalkyl ether derivatives (SAE-CD), in particular those such as CAPTISOL ^ (degree of substitution ~ 7) and SBE4-β-CD (substitution degree ~ 4), do not show essentially a hemolytic behavior and exhibit a substantially lower membrane damage potential than commercially available hydroxypropyl derivatives at concentrations typically used to solubilize pharmaceutical formulations. The range of concentrations depicted in the figure includes the concentrations typically used to solubilize pharmaceutical formulations when initially diluted in the bloodstream after injection. After oral administration, the SAE-CD does not undergo significant systemic absorption. The osmolality of a formulation is generally associated with its hemolytic potential; the higher the osmolality (or more hypertonic), the greater the hemolytic potential. Zannou et al. ("Osmotic properties of sulfobutyl ether and hydroxypropyl cyclodextrins", Pharma, Res. (2001), 18 (8), 1226-1231) compared the osmolality of solutions containing SBE-CD and HP-CD. As depicted in FIGURE 2, solutions containing SBE-CD have a higher osmolality than solutions containing HP-CD comprising similar concentrations of a cyclodextrin derivative. Thus, it is surprising that the SAE-CD exhibits a lower hemolysis than that of the HP-CD in equivalent concentrations, although the HP-CD has a lower osmolality. Methylated cyclodextrins have been prepared - and their hemolytic effect on human erythrocytes has been evaluated. It was found that these cyclodextrins cause a moderate to severe haemolysis (Jodal et al, Proc. 4th Int. Symp.Cyclodextrins, (1988), 421-425; Yoshida et al., Int. J. Pharm., (1988), 46 (3), 217-222). The administration of cyclodextrins in the lungs of a mammal may not be acceptable. In fact, there is a literature on the potential or observed toxicity of native cyclodextrins and cyclodextrin derivatives. The NTP Chemical Repository indicates that a-cyclodextrin can be dangerous through inhalation. Nimbalkar and collaborators. { Biotechnol. Appl. Biochem. (2001), 33, 123-125) warns about the pulmonary use of a complex of HP-β-CD / diacetyldapsona due to its initial effect that resides in retarding the cellular growth of lung cells. However, a variety of studies have been reported with reference to the use of cyclodextrins for inhalation although none has been commercialized. Studies suggest that different combinations of drug-cyclodextrin for inhaled or intranasal, optimal or even useful, specific formulations will be required. Attempts have been made to develop powders and solutions containing cyclodextrins for buccal, pulmonary and / or nasal delivery. U.S. Patent No. 5No. 914,122 issued to Otterbeck et al. Describes the preparation of stable solutions containing budesonide for nebulization. They demonstrate the preferred use of cyclodextrin, such as β-CD, β-CD or HP-β-CD and / or EDTA as a stabilizer. Cyclodextrin is also suggested as a solubilizer to increase the concentration of budesonide in solution. In each case, the longest period of useful life reported for any of its formulations is, in terms of acceptable retention of the active ingredient, of only three to six months. The previously issued US Patent Publication No. 20020055496 issued to McCoy et al. Describes essentially non-aqueous intraoral formulations containing HP-β-CD. The formulations can be administered with an aerosol, spray pump or propellant gas. Russian Patent No. 2180217 issued to Chuchalin describes a stable solution containing budesonide for inhalation. The solution comprises budesonide, propylene glycol, poly (ethylene oxide), succinic acid, Trilon B, nipazole, thiourea, water and optionally HP-β-CD. Müller et al. (Proceed, Int'l Symp.Control, Reí. Bioact. Mater. (1997), 24, 69-70) describe the results of a study on the preparation of budesonide microparticles by means of a dioxide process. supercritical carbon ASES (Aerosol Solvent Extraction System) for use in a dry powder inhaler. HP-ß-CD is suggested as a carrier for a powder. Müller et al. (North American patent) No. 6,407,079) describe pharmaceutical compositions containing HP-β-CD. They suggest that nasal administration of a solution containing the cyclodextrin is possible. The art recognizes that it may be necessary to evaluate structurally related variations of a particular type of cyclodextrin derivative in order to optimize the binding of a particular compound to that type of cyclodextrin derivative. However, it is often the case that there are no extreme differences in the binding of a particular compound with a first mode against a second mode of a particular cyclodextrin derivative. For example, cases where there are extreme differences in the binding of a therapeutic agent, particularly for a first cyclodextrin derivative against a structurally related second cyclodextrin derivative, are not common. When these situations exist, they are unexpected. Worth and collaborators. { 24th International Symposium on Controlled Relay of Bioactive Materials (1997)) describe the results of a study evaluating the usefulness of steroid / cyclodextrin complexes for pulmonary delivery. In joint comparisons, ß-CD, SBE7-ß-CD and HP-ß-CD were evaluated according to their ability to form inclusion complexes with beclomethasone dipropionate (BDP) and its active metabolite beclomethasone monopropionate (BMP). ). BMP was more readily solubilized with a cyclodextrin and the observed order of solubilization potency was: HP-β-CD (higher) > ß-CD > SBE7-ß-CD. In this way, the artisan would expect that the SAE-CD derivatives would not be as suitable for use in the solubilization of corticosteroids such as BMP or BDP. Although no results were reported regarding actual utility in an inhaled formulation, they suggested that BMP preferably that BDP would be a better alternative for the development of a nebulizer solution. Kinnarinen et al. { llth International Cyclodextrin Symposium CD, (2002)) describe the results of an in vitro lung deposition study of a budesonide /? - CD inclusion complex for inhalation of dry powder. No advantage was observed for the complexation with? -CD. Vozone and collaborators. { llth International Cyclodextrin Symposium CD, (2002)) describe the results of a study on the complexation of budesonide with β-cyclodextrin for use in inhaling dry powder. No difference was observed within the emitted doses of the cyclodextrin complex or a physical mixture of budesonide and the CD. But, a difference observed in the fine particle fraction of both formulations suggested that the use of a cyclodextrin complex for pulmonary drug delivery could increase the respirable fraction of the dry powder. Pinto and collaborators. { S. T. P. Pharma. Sciences (1999), 9 (3), 253-256) describe the results of a study on the use of HP-β-CD in an inhalable dry powder formulation for beclomethasone. HP-ß-CD was evaluated as a complex or a physical mixture with the drug in an in vitro deposition study of the dose emitted from a MICRO-HALER1111 inhalation device. The amount of respirable drug fraction was supposedly the highest with the complex and the lowest with the micronized drug alone. Rajewski et al. (J. Pharm. Sci. (1996), 85 (11), 1142-1169) provide a review of the pharmaceutical applications of cyclodextrins. In that review, they cite studies that evaluate the use of cyclodextrin complexes in dry powder inhalation systems. Shao and collaborators. { Eur. J. Pharm. Biopharm. (1994), 40, 283-288) reported the effectiveness of cyclodextrins as promoters of pulmonary absorption. The relative effectiveness of cyclodextrins in improving the pulmonary absorption of insulin, as measured by pharmacodynamics, and relative efficacy was classified as follows: dimethyl-β-cyclodextrin >; a-cyclodextrin > β-cyclodextrin > ? -cyclodextrin > hydroxypropyl-β-cyclodextrin. In view of this report, the artisan would expect that the water-soluble derivative of β-CD is less suitable for the delivery of compounds via the inhalation than the respective derivative of β-CD because the non-derivatized β-CD is more adequate than the non-derivatized? -CD. Williams and colleagues (Eur. J. Pharm. Biopharm. (March 1999), 47 (2), 145-52) reported the results of a study to determine the influence of the formulation technique for 2-hydroxypropyl-beta- Cyclodextrin (HP-β-CD) on the stability of aspirin in a pressurized, suspension-based metered dose inhaler formulation (pMDI) containing a hydrofluoroalkane (HFA) propellant gas. The HP-β-CD was formulated in a pMDI as a lyophilized inclusion complex or a physical mixture with aspirin. Aspirin in the lyophilized inclusion complex exhibited the most significant degree of degradation during storage for 6 months, whereas aspirin alone in the pMDI demonstrated a moderate degree of degradation. Aspirin formulated in the physical mixture exhibited the lowest degree of degradation. Supposedly, HP-ß-CD can be used to improve the stability of a chemically labile drug, but the stability of the drug can be affected by the method of preparation of the formulation. Gudmundsdottir et al. { Pharmazie (December 2001), 56 (12), 963-6) describe the results of a study in which midazolam was formulated in an aqueous buffer solution of sulfobutyl ether-β-cyclodextrin. The nasal spray was tested in healthy volunteers and compared with intravenous midazolam in an open-cross trial. The nasal formulation presumably approximates the intravenous form in the rate of absorption, concentration in the serum and effect of clinical sedation. No serious side effects were observed. Srichana and collaborators. { Breathe Med. (June 2001), 95 (6), 513-9) report the results of a study to develop a new carrier in dry powder aerosols. Two types of cyclodextrin were selected; gamma cyclodextrin (? -CD) and dimethyl-beta-cyclodextrin (DMCD) as carriers in dry powder formulations. Salbutamol was used as a model drug and a control formulation containing lactose and the drug was included. A two-stage Greenbury and Smith powder measurement device ("impinger") (TSI) was used to evaluate the efficacy of the supply of those dry powder formulations. From the results obtained, it was discovered that the formulation containing? -CD improved the drug supply to the lower stage of the TSI (deposition = 65%) much more than that of both formulations containing DMCD (50%) and the control formulation (40%) (P <0.05). The hemolysis of red blood cells incubated with the DMCD complex was higher than that obtained in the? -CD complex. The release of drug in both formulations containing β -CD and DMCD was rapid (more than 70% was released in 5 minutes) and almost all of the drug was released in 30 minutes. Van der Kuy et al. (Eur. J. Clin. Pharmacol. (November 1999), 55 (9), 677-80) report the results of the pharmacokinetic properties of two intranasal preparations of a formulation containing dihydroergotamine mesylate (DHEM). ) using a commercially available intranasal preparation. The formulations also contained randomly methylated-cyclodextrin (RAMEB). No statistically significant differences were found in the maximum concentration in the plasma (Cmax), time to reach the Cmax (tmax), area under the time-concentration curve in the plasma (AUC0-8 h), Frel (t = 8 h ) and Cmax / AUC (t = 8 h) for the three intranasal preparations. The results indicate that the pharmacokinetic properties of the intranasal preparations are not significantly different from the commercially available nasal spray. U.S. Patent No. 5,942,251 and No. ,756,483 issued to Merkus cover pharmaceutical compositions for the intranasal administration of dihydroergotamine, apomorphine and morphine comprising one of these pharmacologically active ingredients in combination with a cyclodextrin and / or a disaccharide and / or a polysaccharide and / or a sugar alcohol. U.S. Patent No. 5,955,454 describes a pharmaceutical preparation that is suitable for nasal administration containing a progestogen and a methylated β-cyclodextrin having a degree of substitution between 0.5 and 3.0. US Patent No. 5,977,070 issued to Piazza et al. Discloses a pharmaceutical composition for the nasal delivery of compounds that is useful for treating osteoporosis, comprising an effective amount of a truncated, physiologically active analog of PTH or PTHrp or a salt thereof. and an absorption enhancer selected from the group consisting of dimethyl-β-cyclodextrin. US Patent No. 6,436,902 issued to Backstrom et al. Describes compositions and methods for the pulmonary administration of a parathyroid hormone in the form of a dry powder which are suitable for inhalation in which at least 50% of the dry powder consists of (a ) particles that have a diameter of up to 10 microns; or (b) agglomerates of these particles. A dry powder inhaler device contains a preparation consisting of a dry powder comprising (i) a parathyroid hormone (PTH) and (ii) a substance that improves the absorption of PTH in the lower respiratory tract, wherein at least 50 % of (i) and (ii) consists of primary particles having a diameter of up to 10 microns and wherein the substance is selected from the group consisting of a salt of a fatty acid, a bile salt or a derivative thereof, a phospholipid and a cyclodextrin or a derivative thereof. U.S. Patent No. 6,518,239 issued to Kuo et al. Describes an aerosol, dispersible formulation comprising an active agent and a dipeptide or tripeptide for aerosolization to the lungs. The compositions may also include allegedly excipients / polymeric additives, for example polyvinylpyrrolidones, derivatized celluloses such as hydroxymethylcellulose, hydroxyethylcellulose and hydroxypropylmethylcellulose, Ficolls (a polymeric sugar), hydroxyethylstarch, dextrates (e.g., cyclodextrins, such as 2-hydroxypropyl). -β-cyclodextrin and sulfobutyl ether-β-cyclodextrin), polyethylene glycols and pectin. Nakate and collaborators. { Eur. J. Pharm. Biopharm. (March 2003), 55 (2), 147-54) describe the results of a study to determine the improvement of lung absorption of the cyclopeptide FK224 (low aqueous solubility) in rats when co-formulated with beta-cyclodextrin. The purpose of the study was to investigate the effect of pulmonary delivery on the systemic absorption of FK224 compared to other routes of administration and to determine the bioavailability (BA) of FK224 after pulmonary administration in rats using various dosage forms. After administration of an aqueous suspension, the bioavailability was reduced to 2.7% compared to 16.8% for the solution. However, it was discovered that β-cyclodextrin (β-CD) was an effective additive in relation to improving the solubility of FK224. The bioavailability of the aqueous suspension containing β-CD was increased to 19.2%. It was observed that both the C (max) and the AUC of FK224 were increased as the amount of β-CD increased. The profiles in the plasma showed a sustained absorption. They suggest that ß-CD is an extremely effective additive in relation to the improvement of pulmonary absorption of FK224. They also suggest that ß-CD or derivatives with varying degrees of aqueous solubility are potential carriers of drugs to control lung absorption. Kobayashi and collaborators. { Pharm. Res. (January 1996), 13 (1) 80-3) describe the results of a study on pulmonary delivery in rats of dry salmon calcitonin (sCT) powders containing absorption enhancers. After intratracheal administration of the dry powder of sCT and liquid preparations (solutions) to rats, the levels of sCT and the levels of calcium in the plasma were measured. Supposedly, the sCT in the dry powder and in the liquid was absorbed to almost the same degree. The absorption enhancers (oleic acid, lecithin, citric acid, taurocholic acid, dimethyl-β-cyclodextrin, octyl-β-D-glucoside) were much more effective in the dry powder than in the solution. Adjei and collaborators. { Pharm. Res. (February 1992), 9 (2), 244-9) describe the results of a study on the bioavailability of leuprolide acetate after nasal delivery and by inhalation to healthy rats and humans. The systemic delivery of leuprolide acetate, a hormone agonist releasing a luteinizing hormone (LHRH), was compared after administration by inhalation (i.h.) and intranasal (i.n.). The bioavailability i.n. in rats it was significantly increased by a-cyclodextrin (CD), EDTA and the volume of the solution. The absorption varied from 8 to 46% compared to the i.v. controls. Studies in healthy men were conducted with leuprolide acetate i.n. by means of spraying or aerosol for inhalation (i.h.) and subcutaneous (s.c.) and intravenous (i.v.) injection. The injection s.c. it was 94% bioavailable compared to i.v. The bioavailability i.n. averaged 2.4%, with significant variability from subject to subject. The supply by means of inhalation provided a slightly lower variability between subjects. The average Cmax with a dose of 1 mg of aerosol solution was 0.97 mg / ml, compared with 4.4 and 11.4 ng / ml for the suspension aerosols provided in bolus dosages of 1 and 2 mg, respectively. The average bioavailability of the suspension aerosols (28% in relation to the s.c. administration) was four times higher than that of the solution aerosol (6.6%). CyDex. { Cyclopedia (2002), 5 (1), 3) describes that SBE-CD is not toxic to rats in an inhaled aerosol composition when presented alone. They do not describe a nebulizable composition comprising a drug, in particular a corticosteroid and SBE-CD. When deciding whether to administer a suspension against a solution, one should also consider the type of nebulizer to be used. The two most common types of nebulizers are the ultrasonic nebulizer and the air-powered jet nebulizer. There are significant differences between the two. For example, jet nebulizers cool rather than heat the liquid in the reservoir, while ultrasonic nebulizers heat the liquid. While heating the solution in the reservoir can reduce the viscosity of the solution and increase droplet formation, excessive heating could lead to drug degradation. The ultrasonic nebulizer is quieter and provides a faster supply than the jet nebulizer, but ultrasonic nebulizers are more expensive and are not proposed for the administration of the spheroid currently available for nebulization. However, more importantly, ultrasonic nebulizers generally provide a significantly higher rate of administration than jet nebulizers. Patients with asthma are frequently treated with inhaled short-acting or long-acting ß2 agonists, inhaled anticholinergics and inhaled corticosteroids alone, sequentially or in combination. Combinations of inhaled corticosteroids and long-acting β2-agonists are known, for example budesonide plus formoterol or fluticasone plus salmeterol are available in a dry powder inhaler. However, there is no example of these combinations that is available as a solution for nebulization. The combination of the medications in one solution would reduce the time required to administer the medications separately. In summary, the technique suggests that, in some cases, the nebulization of solutions may be preferred over that of suspensions and that, in some cases, an ultrasonic nebulizer, vibrating screen, electronic mechanism or other aerosol treatment mechanism may be preferred over a nebulizer. Air-driven jet depending on the liquid formulations for nebulization that are compared. Although the technique describes formulations based on inhalable solutions containing a corticosteroid and cyclodextrin, the results of the technique are uncertain. In other words, the combination of a cyclodextrin with a drug does not suggest that another cyclodextrin may be adequate. The technique also does not suggest that an inhalable formulation of cyclodextrin-corticosteroid will have advantages over another inhalable formulation of cyclodextrin-corticosteroid. The need remains in the field for an inhalable formulation containing solution-based, aqueous, stabilized budesonide which does not require the addition of preservatives and which provides significant advantages over other inhalable formulations containing solution-based, aqueous, stabilized budesonide. There also remains a need for a method for improving the administration of suspension-based formulations containing budesonide by means of nebulization by converting the suspension to a solution. There is also a need to develop improved systems that can solubilize water insoluble drugs for nebulization and to minimize the levels of co-solvents needed to do this. The ideal system would consist of non-toxic ingredients and would be stable for long periods of storage at room temperature. When it is nebulized, it would produce respirable droplets in the range of less than 10 microns or less than 5 microns or less than 3 microns and a substantial portion of superfine aerosol in the range of less than about 1 micron. There remains a need for a method for improving the administration, by means of nebulization, of a unit dose formulation based on suspension. This method would reduce the total time of administration, increase the total amount of drug administered, reduce the amount of drug left in the nebulizer reservoir, increase the portion of the pulmonary deposition relative to the oropharyngeal deposition of the corticosteroid, and / or improve penetration. deep in the lungs of the corticosteroid compared to this administration, absent the improvement, of the unit dose formulation based on suspension.

BRIEF DESCRIPTION OF THE INVENTION The present invention seeks to overcome the disadvantages present in the known formulations. As such, an inhalable formulation based on derivatized cyclodextrin is provided, for example, based on sulfoalkyl ether-cyclodextrin (SAE-CD). The present formulation includes at least one corticosteroid as the main active agent. The present formulation can provide improved solubility and / or improved chemical, thermochemical, hydrolytic and / or photochemical stability of the active agent or other ingredients in the formulation. In addition, the present formulation may possess other advantages, for example, improved drug delivery, increased rate of drug administration, reduced treatment time, reduced toxicity, ease of preparation, sterility assurance, improved stability, improved bioabsorption, no requirement in Regarding the control of particle size, increased exit velocity, increased total exit, no concern for the growth of solid particles and / or no need to confirm the formation of a suspension, over other formulations based on inhalable solution or suspension containing a corticosteroid such as budesonide. The present inventors have unexpectedly discovered that SAE-CD is absorbed systemically after administration via inhalation. It is also removed from the lungs. The SAE-CD also forms complexes with corticosteroids in liquid, inhalable, aqueous formulations. The co-administration of the corticosteroid with the SAE-CD may result in increased output rate and total drug delivery compared to a control that excludes SAE-CD. A formulation containing the SAE-CD can be prepared with sufficient solubility and stability of the active agents for a commercial product. If necessary, the formulation containing the SAE-CD can be prepared as an aqueous, clear solution which can be filtered under sterile conditions through a filter having a pore size of 0.45 μm or less and which is stable and stable. Keep under a variety of storage conditions.

One aspect of the invention provides a liquid formulation comprising an effective amount of corticosteroid, such as budesonide and SAE-CD, wherein the SAE-CD is present in an amount sufficient to dissolve and stabilize the corticosteroid during storage. Another aspect of the invention provides a method for improving the administration of a corticosteroid to a subject by means of nebulization, the method comprising the steps of: providing a unit-based formulation in aqueous suspension comprising water and a corticosteroid in a unit dose. suspended in it; combining the suspension with a sufficient amount of SAE-CD for and for a sufficient period of time to solubilize the corticosteroid and form a solution; and administering the solution to the subject, wherein the amount of time required to administer a therapeutic dose of corticosteroid with the solution is less than the amount of time required to administer the same therapeutic dose of corticosteroid with the suspension under similar fogging conditions, or otherwise comparable. When administered with a nebulizer, a suspension for nebulization will provide a first rate of corticosteroid output under a first set of fogging conditions. However, when the SAE-CD is added to the suspension and mixed therein, a sufficient amount of the corticosteroid is dissolved to form a liquid formulation for nebulization that provides a higher corticosteroid exit velocity compared to the formulation that excludes SAE-CD when administered under substantially the same conditions. In one embodiment, the drug release rate of the formulation is increased over that of the suspension although the total volume of the nebulized composition, that is, the total volume of the solution emitted by the nebulizer, has not increased. In another embodiment, the SAE-CD is present in an amount sufficient to solubilize at least 50%, at least 75%, at least 90%, at least 95% or substantially all of the corticosteroid. In yet another embodiment, the SAE-CD is present in an amount sufficient to decrease the amount of insolubilized corticosteroid in the suspension-based formulation and to improve the administration of the suspension-based formulation via nebulization. In still another embodiment, the SAE-CD is present in an amount sufficient to solubilize enough corticosteroid in such a way that the suspension-based formulation to which the SAE-CD is added is converted to a solution, substantially clear solution (containing less 5% solid) or clear solution. It is possible that other components of the suspension-based formulation will not completely dissolve in, or can be separated from, the solution-based formulation containing the SAE-CD. According to another embodiment, a nebulizer loaded with a solution containing a corticosteroid / SAE-CD generates smaller droplets than the same nebulizer loaded with a solution containing a corticosteroid / HP-β-CD operated under otherwise similar conditions. As a result of the generation of smaller droplets, the system comprising the SAE-CD is improved over an otherwise similar system comprising HP-ß-CD, since the system based on SAE-CD will generate a greater proportion of droplets Breathable, will increase the portion of pulmonary deposition in relation to the oropharyngeal deposition of corticosteroid and allow deeper penetration into the lungs (supply). One aspect of the invention provides the use of a SAE-CD in a nebulizable unit dose liquid formulation. In one embodiment, the invention provides the use of a SAE-CD to convert a unit dose formulation based on a nebulizable corticosteroid-containing suspension to a nebulizable corticosteroid-containing liquid unit dose formulation. Specific embodiments of the invention include those in which: 1) the molar ratio of budesonide to SAE-CD is 0.5 to 0.0001 (1: 2 to 1: 10,000), 1: 1 to 1: 100, 1: 1 to 1: 10,000 or 0.1 to 0.03; 2) SAE-CD is sulfobutyl ether-4-ß-CD or sulfobutyl ether-7-ß-CD, sulfobutyl ether-6 -? - CD, sulfobutyl ether-4 -? - CD, sulfobutyl ether-3 to 8- ? -CD or sulfobutyl-5-α-CD ether; 3) SAE-CD is a compound of formula 1 or a mixture thereof; 4) the composition for nebulization further comprises a conventional preservative, an antioxidant, a buffering agent, an acidifying agent, a solubilizing agent, a complexing-improving agent, saline, an electrolyte, another therapeutic agent, an alkalizing agent, a tonicity modifier, a surface tension modifier, a viscosity modifier, a density modifier, a volatility modifier or a combination thereof; 5) the SAE-CD is present in an amount sufficient to provide a clear solution; 6) the composition for nebulization comprises at least 4.8 + 0.5% weight / volume of SAE-CD to provide a self-preserved formulation for a predetermined period of time; 7) the composition for nebulization has been purged with an inert gas before storage to remove substantially all of the oxygen contained in the formulation; 8) the corticosteroid, such as budesonide, has a greater bond with the SAE-CD than a conventional preservative that is present in the formulation; 9) the formulation has a shelf life of at least 6 months; 10) the composition for the nebulization further comprises a liquid carrier different from water; 11) the formulation has been prepared at a temperature of or higher than 5 ° C, of or higher than 25 ° C, of or greater than 35 ° C, of or higher than 45 ° C of or higher than 50 ° C; 12) the composition for nebulization comprises less than or about 21.5 ± 2% weight / weight of SAE-CD; and / or 13) the composition for nebulization is visibly clear when viewed with the naked eye. Specific embodiments of the methods for preparing a liquid formulation include those wherein: 1) the method further comprises the step of sterile filtering the formulation through a filtration medium having a pore size of 0.1 mire or higher; 2) the liquid formulation is sterilized by means of irradiation or autoclaving; 3) the nebulization solution is purged with nitrogen or argon or other pharmaceutically acceptable inert gas before storage in such a manner that a substantial portion of the oxygen dissolved in and / or in contact with the surface of the solution is removed. The invention provides a method for stabilizing a corticosteroid in an aqueous formulation containing a corticosteroid comprising the step of adding the SAE-CD to a suspension or solution-based formulation, aqueous containing a corticosteroid in an amount sufficient to reduce the Corticosteroid degradation rate compared to a control sample that excludes SAE-CD. The invention also provides a method for improving the administration of a unit dose formulation based on a suspension containing an aqueous, inhalable corticosteroid by means of nebulization, the method comprising the step of adding the SAE-CD to a formulation of unit doses based on suspension containing a corticosteroid, aqueous in an amount sufficient to solubilize the corticosteroid to constitute a unit dose formulation based on a solution containing a corticosteroid, aqueous, inhalable, the improvement comprises increasing the exit velocity and / or the grade of nebulized corticosteroid.

The invention provides a method for reducing the amount of time required to provide a therapeutically effective amount of corticosteroid to a subject by inhaling a composition containing a corticosteroid with a nebulizer, the method comprising the steps consisting of: SAE-CD in the composition in an amount sufficient to solubilize the corticosteroid to form a solution containing an aqueous, inhalable corticosteroid; and administering the solution to the subject by means of inhalation with a nebulizer, wherein the amount of time required to provide a therapeutically effective amount of corticosteroid to the subject with the solution is reduced compared to the amount of time required to provide a therapeutically effective amount. Effective of corticosteroid to the subject with a suspension containing a corticosteroid comprising the same amount or concentration of corticosteroid when the suspension and the solution are administered under otherwise similar fogging conditions. The invention also provides an inhalable composition comprising a water soluble? -CD derivative, a corticosteroid (either esterified or unesterified) and a liquid, aqueous medium. Another embodiment of the invention also provides an inhalable composition comprising a water-soluble β-CD derivative, a corticosteroid (non-esterified) and a liquid, aqueous medium. Also, the invention provides an improved system for administering an inhalable formulation containing a corticosteroid by means of inhalation, the improvement comprising including a SAE-CD in the inhalable formulation such that the SAE-CD is present in an amount sufficient to provide an increased rate of inhaled corticosteroid compared to administration of an inhalable control formulation that excludes SAE-CD but is otherwise administered under approximately the same conditions. The invention can be used to provide a system for the administration of a corticosteroid by means of inhalation, the system comprises an inhalation device, such as a nebulizer and a drug composition comprising a therapeutically effective amount of corticosteroid, liquid carrier and a SAE-CD present in an amount sufficient to solubilize the corticosteroid when presented to an aqueous environment, wherein the molar ratio of the corticosteroid to the SAE-CD is in the range of about 0.072 to 0.0001 or 0.063 to 0.003. During the operation, the system forms droplets having a MMAD in the range of about 1-8 μ or 3-8 μ. The corticosteroid is delivered at a rate of at least about 20-50 μg / minute, wherein this interval may increase or decrease according to the concentration of the corticosteroid in the nebulizer solution in the nebulizer reservoir. As a result of the use of SAE-CD-corticosteroid therapy with an inhalable solution for nebulization, one can expect advantages such as an improved drug supply, improved delivery especially to the peripheral or small airways facilitated by the finer aerosol produced , a potentially improved treatment of asymptomatic, nocturnal asthma and recovery from acute asthma attacks, increased drug delivery rate, reduced treatment time, improved formulation stability and / or improved patient tolerance compared to comparable corticosteroid therapy with an inhalable suspension for nebulization or a pressurized metered dose inhaler (pMDI) with chlorofluorocarbon (CFC) or hydrofluoroalkanes (HFA) containing a suspension. The invention can be employed in an equipment comprising SAE-CD, an aqueous carrier and a corticosteroid, wherein the equipment is adapted for the preparation of a nebulizable solution. The modalities of the team are detailed later. The invention provides the potential to adapt combination products to overcome incompatibilities with a suspension by means of other dosage forms of solutions. These and other aspects of this invention will be apparent with reference to the following detailed description, examples, claims and appended figures.

BRIEF DESCRIPTION OF THE FIGURES The following drawings are provided by way of illustration only and, thus, are not intended to limit the scope of the present invention. Figure 1 depicts a graph of the hemolytic behavior of CAPTISOL ^ compared to the same for the original β-cyclodextrin, the commercially available hydroxypropyl derivatives, ENCAPSINMR (degree of substitution -3-4) and MOLECUSOL ™ 1 (degree of substitution ~ 7-8) and two other sulfobutyl ether derivatives, SBEl-ß-CD and SBE4-ß-CD. Figure 2 depicts a graph of the osmolality of solutions containing SBE-CD of varying degrees of substitution and solutions containing HP-β-CD comprising similar concentrations of a cyclodextrin derivative.

Figure 3 depicts a graph of phase solubility of the (molar) concentration of cyclodextrin against the (molar) concentration of budesonide for β-CD, HP-β-CD and SBE7-β-CD. Figure 4 represents a schematic of the estimated percentage of composition for nebulization emitted from three different nebulizers (PARÍ LC PLUS1®, HUDSON UPDRAFT II NEB-U-MIST ™ and MYSTIQUEMR) for each of the four different compositions for nebulization (suspension PULMICORT RESPULESMR, 5% w / v solution of SBE7-ß-CD, 10% w / v solution of SBE7-ß-CD and 20% w / v solution of SBE7-ß-CD). Figures 5a-5b depict droplet size data for nebulization of solutions with a PARÍ LC PLUS1® nebulizer. Figure 6 represents droplet size data for nebulizing solutions with a HUDSON ÜPDRAFT II NEBUMIST ™ nebulizer. Figure 7 represents the droplet size data for the nebulization of solutions with a MYSTIQUE1® ultrasonic nebulizer. Figure 8 represents the comparative data of the size of the Dv50 droplets for the nebulization of a composition with the three nebulizers PARÍ LC PLUS1®, HUDSON UPDRAFT II NEBUMIST1 ^ and MYSTIQUE1111.

Figure 9 is a graph depicting the relationship between the SAE-CD concentration versus the SAE-CD exit velocity in several different foggers. Figures lOa-lOb represent the comparative data of droplet size for solutions for nebulization with the PARÍ LC PLUSm and MYSTIQUEm nebulizers of the PULMICORT RESPULES1® suspension and a SAE-CD solution based on modified PULMICORT RESPULESMR. Figure 11 represents a semilogarithmic diagram of the% initial concentration of the R and S isomers of budesonide in solutions with and without CAPTISOLMR versus time at 60 ° C in solution. Figure 12 represents a semilogarithmic diagram of the% initial concentration of budesonide against Lux-hours when the samples are exposed to fluorescent lamps. Figure 13 depicts a phase solubility diagram for fluticasone propionate in the presence of several different cyclodextrins. Figure 14 depicts a phase solubility diagram for mometasone furoate in the presence of several different cyclodextrins. Figure 15 depicts a phase solubility diagram for esterified and non-esterified fluticasone in the presence of SAE (5-6) -? - CD. Figure 16 depicts a bar scheme summarizing the aqueous solubility of beclomethasone dipropionate in the presence of various SAE-CD derivatives.

DETAILED DESCRIPTION OF THE INVENTION The formulation currently claimed overcomes many of the undesired properties of other formulations containing inhaled, aqueous, known solution-based or suspension-based corticosteroids. By including an SAE-CD in a liquid, inhalable formulation containing a corticosteroid, the corticosteroid is dissolved. Unexpectedly, nebulization of the corticosteroid is improved in both an air-powered jet nebulizer and an ultrasonic nebulizer. In addition, the corticosteroid exhibits greater stability in the presence of SAE-CD than in the absence of same The corticosteroid would be present in an amount sufficient for the administration of single or multiple doses. The SAE-CD would be present in an amount sufficient to solubilize the corticosteroid when both are placed in an aqueous carrier. The aqueous carrier would be present in an amount sufficient to aid in the dissolution of the corticosteroid and to form a solution for nebulization of sufficient volume and a sufficiently low viscosity to allow administration in single or multiple doses with a nebulizer. The SAE-CD would be present in solid form or in solution in the aqueous carrier. The corticosteroid would be present in the form of dry powder / particles or in suspension in the aqueous carrier. Air-powered jet nebulizers, ultrasonic or commercially available propellant membrane include AERONEB1 ^ (Aerogen, San Francisco, CA), PARÍ LC PLUS1®, PARÍ BOY * ® N and PARÍ DURANEB1® (PARÍ Respiratory Equipment, Inc., Monterey, CA), MICROAIRm (Omron Healthcare, Inc, Vernon Hills, Illinois), HALOLITEm (Profile Therapeutics Inc., Boston, MA), RESPIMAT1® (Boehringer Ingelheim Ingelheim, Germany) AERODOSE101 (Aerogen, Inc, Mountain View, CA), OMRON ELITEm (Omron Healthcare, Inc, Vernon Hills, Illinois), OMRON MICROAIRm (Omron Healthcare, Inc., Vernon Hills, Illinois), MABISMIST II ^ 1 (Mabis Healthcare, Inc., Lake Forest, Illinois), LUMISCOPE 6610 ™, (The Lumiscope Company, Inc., East Brunswick, New Jersey), AIRSEP MYSTIQUE ^, (AirSep Corporation, Buffalo, NY), ACORN-1 and ACORN-II (Vital Signs, Inc., Totowa, New Jersey), AQUATOWER1® (Medical Industries America, Adel, Iowa), AVA-NEB (Hudson Respiratory Care Incorporated, Temecula, California), CIRRUS (Intersurgical Incorporated, Liverpool, New York), DART (Professional Medical Products, Greenwood, South Carolina), DEVILBISS1111 PULMO AIDE (DeVilbiss Corp, Somerset, Pennsylvania), DOWNDRAFT1® (Marquest, Englewood, Colorado), FAN JET (Marquest, Englewood, Colorado ), MB-5 (Mefar, Bovezzo, Italy), MISTY NEBm (Baxter, Valencia, California), SALTER 8900 (Salter Labs, Arvin, California), SIDESTREAM1® (Medic-Aid, Sussex, UK), UPDRAFT-II1111 ( Hudson Respiratory Care; Temecula, California), WHISPER JETm (Marquest Medical Products, Englewood, Colorado), AIOLOS1® (Aiolos Medicnnsk Teknik, Karlstad, Sweden), INSPIRON (Intertech Resources, Inc., Bannockburn, Illinois), OPTIMIST5® (Unomedical Inc., McAllen , Texas), PRODOMO ^, SPIRA1111 (Respiratory Care Center, Hameenlinna, Finland), AERx1111 (Aradigm Corporation, Hayward, California), SONIK1® LDI Nebulizer (Evit Labs, Sacramento, California) and SWIRLER Radioaerosol System (AMICI, Inc., Spring City, PA). Any of these and other known nebulizers can be used to deliver the formulation of the invention, including but not limited to the following: Nebulizers that perform their function with liquid formulations that do not contain propellant gas are suitable for use with the compositions provided in this document. Nebulizers are available from, for example, Pari GmbH (Starnberg, Germany), DeVilbiss Healthcare (Heston, Middlesex, UK), Healthdyne, Vital Signs, Baxter, Allied Health Care, Invacare, Hudson, Omron, Bremed, AirSep, Luminscope, Medisana, Siemens, Aerogen, Mountain Medical, Aerosol Medical Ltd. (Colchester, Essex, UK), AFP Medical (Rugby, Warwickshire, UK), Bard Ltd. (Sunderland, ÜK), Carri-Med Ltd. (Dorking, UK) , Plaem Nuiva (Brescia, Italy), Henleys Medical Supplies (London, UK), Intersurgical (Berkshire, UK), Lifecare Hospital Supplies (Leies, UK), Medic-Aid Ltd. (West Sussex, UK), Medix Ltd. ( Essex, UK), Sinclair Medical Ltd. (Surrey, UK) and many others. Nebulizers for use in this document include, but are not limited to, jet nebulizers (optionally sold with compressors), ultrasonic nebulizers and other nebulizers. Exemplary jet nebulizers for use herein include Pari LC plus / ProNeb, Pari LC plus / ProNeb Turbo, Pari LC Plus / Dura Neb 1000 & 2000 Pari LC plus / Walkhaler, Pari LC plus / Pari Master, Pari LC star, Omron CompAir XL Portable Nebulizer System (nebulizers NE-C18 and JetAir Disposable), Omron in comparison with Elite Compressor Nebulizer System (nebulizer NE-C21 and Elite Air Reusable Nebulizer, Pari LC Plus or Pari LC Star with Proneb Ultra compressor, Pulomo-aide, Pulmo-aide LT, Pulmo-aide traveler, Invacare Passport, Inspiration Healthdyne 626, Pulmo-Neb Traverler, DeVilbiss 646, Whisper Jet, Acorn II, Misty-Neb, Allied Spray, Schuco Home Care, Lexan Plasic Pocet Neb, SideStream Hand Held Neb, Mobil Mist, Up-Draft, Up-Draft II, T Up-Draft, ISO-NEB, Ava-Neb, Micro Mist and PulmoMate The exemplary ultrasonic nebulizers for use in this document include MicroAir, UltraAir, Siemens Ultra Nebulizer 145, CompAir, Pulmosonic, Scout, 5003 Ultrasonic Neb, 5110 Ultrasonic Neb, 5004 Desk Ultrasonic Nebulizer, Mystique Ultrasonic, Lumiscope's Ultrasonic Nebulizer, Medisana Ultrasonic Nebulizer, Microstat Ultrasonic Nebulizer and Mabismist Hand Held Ultrasonic Nebulizer. Other nebulizers for use in this document include 5000 Electromagnetic Neb, 5001 Electromagnetic Neb 5002 Rotary Piston Neb, Lumineb I Piston Nebulizer 5500, Aeroneb Portable Nebulizer System, Aerodose Inhaler ™ and AeroEclipse Breath Actuated Nebulizer. The present invention provides formulations based on SAE-CD, wherein the SAE-CD is a compound of Formula 1: Formula 1 where: n is 4, 5 or 6; RI? R2? R3? R4 Rs / - Re / R7? d and P-9 are each, independently, -0- or a group -0- (C2-C6 alkylene) -S03_, wherein at least one of Ri to R9 is independently a group -0- (C2-C6 alkylene) -S03", preferably a group -0- (CH2) mS03 ~, wherein m is 2 to 6, preferably 2 to 4, (for example -OCH2CH2CH2S03 ~ or -OCH2CH2CH2CH2S03"); and Si, S2, S3, S4, S5, S6, S7, S8 and S9 are each, independently, a pharmaceutically acceptable cation including, for example, H +, alkali metals (eg Li +, Na +, K +), alkaline earth metals (for example, Ca + 2, Mg + 2), ammonium ions and amine cations such as the alkylamine cations of 1 to 6 carbon atoms, piperidine, pyrazine, alkanolamine of 1 to 6 carbon atoms and cycloalkanolamine of 4 to 8 carbon atoms. Exemplary embodiments of the SAE-CD derivative of the invention include derivatives of Formula II (SAEx-a-CD), wherein "x" ranges from 1 to 18; of Formula III (SAEy-ß-CD), where "y" varies from 1 to 21; and of Formula IV (SAEz -? - CD), where "z" varies from 1 to 24 such as: SAEx-a-CD SAEy-ß-CD SAEz -? - CD Name SEEx-a-CD SEEy-ß-CD SEEz -? - CD Sulfoetyl Ether-CD SPEx-a-CD SPEy-ß-CD SPEz -? - CD Sulfopropyl Ether-CD SBEx-a-CD SBEy-ß-CD SBEz -? - CD Sulfobutyl Ether-CD SPtEx-a-CD SPtEy-ß-CD SPtEz -? - CD Sulfopentyl Ether-CD SHEx-a-CD SHEy-ß-CD SHEz -? - CD Sulfohexyl Ether-CD "SAE" represents a sulfoalkyl ether substituent attached to a cyclodextrin. The values "x", "y" and "z" represent the average degree of substitution as defined herein in terms of the number of sulfoalkyl ether groups per CD molecule. The SAE-CD used is described in general terms in US Patents No. 5,376,645 and No. 5,134,127 issued to Stella et al., The full descriptions of which are incorporated by this act as a reference. U.S. Patent No. 3,426,011 issued to Parmerter et al. Discloses anionic cyclodextrin derivatives having sulfoalkyl ether substituents. Lammers and collaborators. { Recl. Trav. Chim. Pays-Bas (1972), 91 (6), 733-742); Staerke (1971), 23 (5), 167-171) and Qu et al. { J. Inclusion Phenom. Macro Chem. , (2002), 43, 213-221) describe cyclodextrins derivatized with sulfoalkyl ether. The North American Patent No. 6,153,746 issued to Shah et al. Describes a process for the preparation of sulfoalkyl ether-cyclodextrin derivatives. An SAE-CD can be developed according to the descriptions of Stella and collaborators, Parmerter and collaborators, Lammers and collaborators, Shah and collaborators or Qu and collaborators, and if it is processed to withdraw the main portion (> 50%) of the The original non-derivatized cyclodextrin is used according to the present invention. The SAE-CD may contain from 0% to less than 50% by weight of the original non-derivatized cyclodextrin. The terms "alkylene" and "alkyl", used herein (for example, in the group -O- (C2-C6 alkylene) S03 ~ or in the alkylamines), include divalent alkylene groups and monovalent, saturated and unsaturated alkyl groups (that is, they contain a double bond), linear, cyclic and branched, respectively. The term "alkanol" in this text likewise includes saturated, unsaturated, linear, cyclic and branched alkyl components of the alkanol groups, in which the hydroxyl groups may be located at any position in the alkyl portion. The term "cycloalkanol" includes substituted or unsubstituted cyclic alcohols (for example, by methyl or ethyl). One embodiment of the present invention provides compositions containing a mixture of cyclodextrin derivatives having the structure set forth in formula (I), wherein the total composition contains on average at least 1 and up to 3n + 6 portions of alkylsulfonic acid per molecule of cyclodextrin. The present invention also provides compositions containing an individual type of cyclodextrin derivative, or at least 50% of an individual type of cyclodextrin derivative. The invention also includes formulations containing cyclodextrin derivatives having a reduced or broad degree and high or low substitution. These combinations can be optimized as necessary to provide cyclodextrins having particular properties. The present invention also provides compositions containing a mixture of cyclodextrin derivatives wherein two or more different types of cyclodextrin derivatives are included in the composition. By different types, derivatized cyclodextrins are proposed with different types of functional groups, for example hydroxyalkyl and sulfoalkyl, and not the heterogeneous character of derivatized cyclodextrins due to their varying degrees of substitution. Each different, independent type may contain one or more functional groups, for example SBE-CD where the cyclodextrin ring has only functional groups sulfobutyl and hydroxypropyl-ethyl-β-CD where the cyclodextrin ring has both hydroxypropyl functional groups and ethyl functional groups . The amount of each type of cyclodextrin derivative present can be varied as desired to provide a mixture having the desired properties. Exemplary SAE-CD derivatives include SBE4-β-CD, SBE7-β-CD, SBEll-β-CD, SBE3.4 -? - CD, SBE4.2 -? - CD, SBE4.9 -? - CD, SBE5.2 -? - CD, SBE6.1 -? - CD, SBE7.5 -? - CD, SBE7.8 -? - CD and SBE5 -? - CD which correspond to SAE-CD derivatives of the formula I where n = 5, 5, 5 and 6; m is 4; and there are on average 4, 7, 11 and 5 sulfoalkyl ether substituents, respectively. Suitable SAE-CD derivatives also include those having an average DS of about 3 to about 8. These SAE-CD derivatives increase the solubility of poorly water soluble active agents to varying degrees. Since SAE-CD is a polyanionic cyclodextrin, it can be provided in different salt forms. Suitable counterions include organic or cationic atoms or molecules and inorganic, cationic atoms or molecules. The SAE-CD may include an individual type of counterion or a mixture of different counterions. The properties of the SAE-CD can be modified by changing the identity of the present counterion. For example, a first salt form of the SAE-CD may have a greater stabilizing and / or solubilizing potency of corticosteroids than a second salt form different from the SAE-CD. Similarly, a SAE-CD having a first degree of substitution may have a greater stabilization and / or solubilization potency of corticosteroids than a second SAE-CD having a different degree of substitution. The improved solubilization of one corticosteroid by one SAE-CD against another is demonstrated by the data in the following tables which represent the molar solubility for fluticasone propionate with different SAE-CDs in concentrations of approximately 0.03 to 0.12 M in such a way that the solubilization potency followed approximately this sort order over this SAE-CD concentration range: SBE5.2 -? - CD > SPE5.4 -? - CD > SBE6.1 -? - CD > SBE9.7 -? - CD »SBE7-a-CD > SBE6.7-ß-CD > SPE7-ß-CD. For mometasone furoate, the solubilization potency followed approximately this sort order over this SAE-CD concentration range: SBE9.7 -? - CD > SBE6.1 -? - CD > SBE5.2 -? - CD »SPE5.4 -? - CD > SBE7-a-CD > SBE6.7-ß-CD > SPE7-ß-CD. Differences were also observed for the binding of budesonide and triamcinolone with specific modalities of SAE-CD. According to the invention, a SAE-α-CD binds to a corticosteroid better than a SAE-β-CD. Also, a SAE-ß-CD is linked to a budesonide better than an SAE-a-CD. The data is summarized in FIGURES 13-14.

The solubility of the selected steroids increased by alpha-cyclodextrins The solubility of the selected steroids increased by the gamma-cyclodextrins The inventors have also discovered that the SAE -? - CD is particularly suitable for use in the formation of complexes of esterified and non-esterified corticosteroids compared to the complexation of the same corticosteroids with SAE-β-CD or SAE-α-CD. The above table also summarizes the phase solubility data depicted in FIGURE 15 for fluticasone and fluticasone propionate with several different SAE-α-CD species having a degree of substitution in the range of 5-10. The present inventors have discovered that SAE-α-CD is also much more effective in binding to a particular regioisomer of esterified corticosteroids than SAE-β-CD or SAE-α-CD. The procedure set forth in Example 18 details the comparative evaluation of the SAE-α-CD and SAE-β-CD link with a series of structurally related corticosteroid derivatives. The following table summarizes the results of a study comparing the SBEx -? - CD derivative link, where x represents the average degree of substitution, and a SBE-β-CD derivative with different forms of beclomethasone.

The research study shows that in the presence of SBE (3.4)? -CD (0.04M), all forms of beclomethasone were at or near their highest solubilities. B17P, the active metabolite of BDP, has the highest solubility of the esterified beclomethasone forms in any of the derivatized CDs. The results indicate that the SBE -? - CD forms complexes with beclomethasone dipropionate better than Captisol "11 or? -CD alone." Of the SAE-CD derivatives evaluated, the optimum degree of substitution of the SBE -? - CD that provides the greatest improvement in BDP solubility is DS = 3.4 and the solubility decreases almost linearly as the degree of substitution increases.This is true for both 24-hour and 5-day equilibrium times. of the solubilization of BDP with SAE-CD: SBE (3.4)? -CD> SBE (5.2)? -CD> SBE (6.1)? -CD> SBE (7.5)? - CD >? -CD > Captisol ™ (SBE7-ß-CD) .The data are summarized in FIGURE 16. Therefore, the present inventors have discovered that the SAE-α-CD cyclodextrin derivatives are unexpectedly better at the solubilization of corticosteroids than the derivatives of SAE-ß-CD In addition, formulations based on SAE -? - CD are suitable for use in inhalabl formulations it is contrary to the description of Worth and colleagues (previously), who suggest that SAE-CD derivatives are not suitable. By "complexed" it is proposed "that it is part of a complex clatrado or of inclusion with", that is, a complex therapeutic agent is part of a complex clatrado or of inclusion with a derivative of cyclodextrin. By "major portion" at least about 50% by weight is proposed. In this manner, a formulation according to the present invention can contain an active agent of which more than about 50% by weight is complexed with a cyclodextrin. The actual percentage of active agent that is complexed will vary according to the complex equilibrium constant that characterizes the complexation of a specific cyclodextrin with a specific active agent. The invention also includes embodiments wherein the active agent is not complexed with the cyclodextrin or wherein a minor portion of the active agent is complexed with the derivatized cyclodextrin. It should be noted that an SAE-CD, or any other derivatized, anionic cyclodextrin, can form one or more ionic bonds with a positively charged compound. This ionic association can occur however if the positively charged compound is complexed with the cyclodextrin either by means of inclusion in the cavity or the formation of a salt connection. The binding of a drug to the derivatized cyclodextrin can be improved by including an acid or a base together with the drug and the cyclodextrin. For example, the link of a basic drug with the cyclodextrin could be improved by including an acid together with the basic drug and the cyclodextrin. Likewise, the binding of an acid drug with cyclodextrin could be improved by including a base (alkaline material) together with the acid drug and the cyclodextrin. The binding of a neutral drug could be improved by including a basic compound, acid or other neutral compound together with the neutral drug and cyclodextrin. Suitable acidic compounds include organic and inorganic acids. Examples of inorganic acids are mineral acids, such as hydrochloric and hydrobromic acid. Other suitable acids include sulfuric acid, sulfonic acid, sulfenic acid and phosphoric acid. Examples of organic acids are aliphatic carboxylic acids, such as acetic acid, ascorbic acid, carbonic acid, citric acid, butyric acid, fumaric acid, glutaric acid, glycolic acid, α-ketoglutaric acid, lactic acid, malic acid, mevalonic acid, maleic acid, malonic acid, oxalic acid, pimelic acid, propionic acid, succinic acid, tartaric acid or tartronic acid. Carboxylic, aliphatic acids carrying one or more oxygenated substituents on the aliphatic chain are also useful. A combination of acids can be used. Suitable basic compounds include organic and inorganic bases. Suitable inorganic bases include ammonia, metal oxide and metal hydroxide. Suitable organic bases include primary amine, secondary amine, tertiary amine, imidazole, triazole, tetrazole, pyrazole, indole, diethanolamine, triethanolamine, diethanolamine, methylamine, tromethamine (TRIS), aromatic amine, unsaturated amine, primary thiol and secondary thiol. A combination of bases can be used. A derivatized, anionic cyclodextrin can complex or otherwise bind to an acid ionizable agent. As used herein, the term "ionizable agent with acid" is taken to refer to any compound that becomes or is ionized in the presence of an acid. An acid ionizable agent comprises at least one ionizable functional group with acid that is ionized when exposed to an acid or when placed in an acid medium. Exemplary ionizable acid functional groups include a primary amine, secondary amine, tertiary amine, quaternary amine, aromatic amine, unsaturated amine, primary thiol, secondary thiol, sulfonium, hydroxyl, enol and other groups known to those of ordinary experience in the chemical arts. The degree to which an acid-ionizable agent is bound by a non-covalent ionic bond against the formation of inclusion complexes can be determined spectrophotometrically using methods such as RMN1H, 13C NMR or circular dichroism, for example, and by analyzing the data from phase solubility for the ionizable agent with acid and the derivatized, anionic cyclodextrin. The architect of ordinary experience in the field will be able to use these conventional methods to approximate the amount of each type of bond that is occurring in the solution to determine whether the link between the species is occurring predominantly or not by the non-covalent ionic bond or the formation of inclusion complexes. An acid-ionizable agent that binds to a cyclodextrin derivatized by both media will generally exhibit a biphasic phase solubility curve. Under conditions where the non-covalent ionic bond predominates over the formation of inclusion complexes, the amount of inclusion complex formation, measured by means of NMR or circular dichroism, will be reduced although the phase solubility data indicate a significant link between the species under these conditions; moreover, the intrinsic solubility of the ionizable agent with acid, determined from the phase solubility data, will generally be higher than that expected under those conditions. As used herein, the term "non-covalent ionic bond" refers to a bond formed between an anionic species and a cationic species. The bond is not covalent in such a way that the two species together form a salt or an ion pair. An derivatized, anionic cyclodextrin provides the anionic species of the ion pair and the ionizable agent with acid provides the cationic species of the ion pair. Since a derivatized, anionic cyclodextrin is multivalent, an SAE-CD can form an ion pair with one or more acid-ionizable agents. The original cyclodextrins have limited water solubility compared to SAE-CD and HPCD. The non-derivatized a-CD has a solubility in water of about 14.5% w / v at saturation. The non-derivatized β-CD has a solubility in water of about 1.85% w / v at saturation. The non-derivatized? -CD has a solubility in water of about 23.2% w / v at saturation. The dimethyl-beta-cyclodextrin (DMCD) forms an aqueous solution at 43% w / w at saturation. The SAE-CD can be combined with one or more different cyclodextrins or cyclodextrin derivatives in the inhalable solution to solubilize the corticosteroid. Other water-soluble cyclodextrin derivatives which can be used according to the invention include hydroxyethyl ethers, hydroxypropyl ethers (including 2- and 3-hydroxypropyl ethers) and dihydroxypropyl ethers, their corresponding mixed ethers and additional ethers, mixed with methyl or ethyl groups, such as methyl-hydroxy-ethyl, ethyl-hydroxyethyl and ethyl-hydroxypropyl ethers of alpha-, beta- and gamma-cyclodextrin; and maltosyl, glucosyl and maltotriosyl derivatives of alpha-, beta- and gamma-cyclodextrin, which may contain one or more sugar residues, for example glucosyl or diglucosyl, maltosyl or dimaltosyl, as well as various mixtures thereof, example a mixture of maltosyl and dimaltosyl derivatives. Specific cyclodextrin derivatives for use herein include hydroxypropyl-beta-cyclodextrin, hydroxyethyl-beta-cyclodextrin, hydroxypropyl-gamma-cyclodextrin, hydroxyethyl-gamma-cyclodextrin, dihydroxypropyl-beta-cyclodextrin, glucosyl-alpha-cyclodextrin, glucosyl- beta-cyclodextrin, diglucosyl-beta-cyclodextrin, maltosyl-alpha-cyclodextrin, maltosyl-beta-cyclodextrin, maltosyl-gamma-cyclodextrin, maltotriosyl-beta-cyclodextrin, maltrotriosyl-gamma-cyclodextrin and dimaltosyl-beta-cyclodextrin and mixtures thereof such as maltosyl-beta-cyclodextrin / dimaltosyl-beta-cyclodextrin, as well as methyl-beta-cyclodextrin. The processes for preparing these cyclodextrin derivatives are well known, for example, from U.S. Patent No. 5,024,998 to Bodor dated June 18, 1991 and references cited therein. Other cyclodextrins suitable for use in the present invention include the carboxyalkyl thioether derivatives such as ORG 26054 and ORG 25969 made by ORGANON (AKZO-NOBEL), hydroxybutenyl ether derivatives made by EASTMAN, sulfoalkyl hydroxyalkyl ether derivatives, ether derivatives sulfoalkyl-alkyl and other derivatives as described in the previously assigned US Patent Application Publications No. 2002/0128468, No. 2004/0106575, No. 2004/0109888 and No. 2004/0063663 or US Patent No. 6,610,671, No. 6,479,467, No. 6,660,804 or No. 6,509,323. HP-ß-CD can be obtained from Research Diagnostics Inc. (Flanders, NJ). HP-ß-CD is available with different degrees of substitution. Exemplary products include ENCAPSIN1® (substitution grade ~ 4; HP4-β-CD) and MOLECUSOLME (substitution grade ~ 8; HP8-β-CD); however, modalities that include other degrees of substitution are also available. Since HPCD is not ionic, it is not available in salt form. Dimethylcyclodextrin is available from FLUKA Chemie (Buchs, CH) or Wacker (Iowa). Other derivatized cyclodextrins which are suitable in the invention include water-soluble derivatized cyclodextrins. Derivatized, water-soluble cyclodextrins, examples include carboxylated derivatives; sulfated derivatives; alkylated derivatives; hydroxyalkylated derivatives, methylated derivatives; and carboxy-β-cyclodextrins, for example succinyl-β-cyclodextrin (SCD) and 6-amino-6A-deoxy-N- (3-carboxypropyl) -β-cyclodextrin. All these materials can be made according to methods known in the prior art. Suitable derivatized cyclodextrins are described in Modified Cyclodextrins: Scaffolds and Templates for Supramolecular Chemistry (Eds. Christopher J. Easton, Stephen F. Lincoln, Imperial College Press, London, UK, 1999) and New Trends in Cyclodextrins and Derivatives (Ed. Dominique Duchene, Editions de Santé, Paris, France, 1991). The solutions of% p / p of sulfobutyl ether-β-cyclodextrin (CAPTISOLMR, CyDex Inc., substitution degree = 6.6), 2-hydroxypropyl-β-cyclodextrin (HP-β-CD, CERESTAR, degree of substitution = 5.5 ), succinylated β-cyclodextrin (S-CD, Cyclolab) and 2,6,6-di-o-methyl-β-cyclodextrin (DM-CD, Fluka) were prepared at their native pH or quenched as necessary. Sulfoalkyl ether-α-CD and sulfoalkyl ether-α-CD derivatives were obtained from CyDex, Inc. (Lenexa, KS) and The University of Kansas (Lawrence, KS). The amount of derivatized cyclodextrin that is required to provide the desired effect will vary according to the materials comprising the formulation. Different cyclodextrins are able to solubilize a corticosteroid to different degrees. FIGURE 3 represents a solubility curve of molar phases for budesonide with HP-β-CD, SBE7-β-CD and β-CD compared to water. The inventors have discovered that SAE-CD is superior to other cyclodextrins and cyclodextrin derivatives in the solubilization of budesonide. On a molar basis, SBE-β-CD is a better budesonide solubilizer than HP-β-CD. In addition, the solubilization power among the SAE-CD derivatives followed approximately this order of classification for budesonide over a range of SAE-CD concentration of 0.04 to 0.1 M: SBE5.2 -? - CD ~ SPE5.4-? -CD > SBE6.1 -? - CD > SBE7-a-CD > SBE9.7 -? - CD ~ SBE6.7-ß-CD > SPE7-ß-CD. For example, a 0.1 M concentration of SBE7-β-CD was able to solubilize a greater amount of budesonide than either β-CD or HP-β-CD. In addition, the nebulisable formulations containing SAE-CD provide a higher exit velocity for the corticosteroid by means of nebulization as compared to the? -CD or the HP-β-CD administered under otherwise similar conditions. It was unexpectedly discovered that the nebulization of Captisol1® solutions provides several advantages over other cyclodextrins. The droplets leaving the nebulizer are of a more advantageous size and the solutions of Captisol ™ are nebulized faster than similar solutions of other cyclodextrins. The following table shows that the average particle size (Dv50) of Captisol1® solutions is smaller than that of HP-ß-CD or? -CD. More importantly, as seen in the following table, Dv90 shows that the other cyclodextrins had a significant number of very large droplets. The data (size of the Malvern particles) were obtained for each formulation issued from a PARÍ LC PLUSMR nebulizer equipped with a PARÍ PRONEB ULTRA1® air compressor. The smaller size of the droplets is favored for an inhalable composition since it allows the deeper supply in the lungs of active agents, such as a corticosteroid.

This advantage is also shown in the output speed of these solutions. The following table shows that Captisol1® is emitted faster from the nebulizer and also to a greater degree than the other cyclodextrins, in this way the exit velocity of the nebulizer is greater when the Captisol1® is nebulized.

Nebulization stops when the sound changes (time for spraying) or no visible particles are produced. The SAE-CD's advantage (s) was demonstrated (demonstrated) in addition by preparing solutions containing budesonide dissolved in several cyclodextrins and by comparing its performance in nebulization with respect to the performance of commercial PULMICORT RESPULES1®, a formulation of unit doses based on commercially available suspension. The suspension obtained from several unit dose vials of PULMICORTMR was accumulated to constitute a unit dose formulation based on multiple dose suspension and an SAE-CD (specifically CAPTISOL1®), HP-β- or β-cyclodextrin powder was added to achieve a concentration of 0.25 mg / ml of budesonide solution. These solutions containing budesonide contained 5% w / v of Captisol ™ (P5C), 1% w / v of gamma-CD (Pl? CD) and 5% w / v of hydroxypropyl-beta-cyclodextrin (P5HP? CD). Each one was prepared at least 30 minutes before the whole test. The three formulations were colorless, clear solutions.

(Note: a solution of 250 mg / mL budesonide can not be achieved in a 5% w / v solution of? -cyclodextrin since it exhibits a "B" type solubility behavior). A 2 ml aliquot of the suspension or solution was placed in the same assembly of the Pari LC Plus® nebulizer and the amount of budesonide in the droplets emitted was determined by collecting them on a filter and measuring budesonide using the HPLC. As shown in the following table, the total exit velocity (μg of budesonide collected / time for spraying) for each suspension or solution.

The exit velocity is higher for the Captisol1® solution indicating that an equivalent amount of drug can be delivered in a shorter period of time. Under the conditions used, ß-CD is not adequate to solubilize an equivalent amount of corticosteroid due to the limited solubility of ß-CD in water. The present invention can be used with other aqueous formulations based on suspension, formulations that can be adapted for nasal delivery or pulmonary delivery. Exemplary suspension-based aqueous formulations include the formulation of UDB (Sheffield Pharmaceuticals, Inc.) VANCENASE AQ1® (aqueous suspension of beclomethasone dipropionate, Schering Corporation, Kenilworth, NJ), ATOMASE1® (aqueous suspension of beclomethasone dipropionate, Douglas Pharmaceuticals Ltd. Aukland, Australia), BECONASE1® (aqueous suspension of beclomethasone dipropionate, Glaxo Wellcome), NASACORT AQ1® (triamcinolone acetonide nasal spray, Aventis Pharmaceuticals), TRI-NASAL1® (aqueous suspension of triamcinolone acetonide, Muro Pharmaceuticals Inc.) and AEROBID-MMR, (spray for inhalation of flunisolide, Forest Pharmaceuticals), NASALIDE ^ and NASAREL1® (nasal spray of flunisolide, Ivax Corporation), FLONASE1® (fluticasone propionate, GlaxoSmithKine) and NASONEXMR (Mometasone furoate, Schering-Plow Corporation). The suspension-based formulation may comprise a corticosteroid present in particulate, microparticulate, nanoparticulate or nanocrystalline form. Accordingly, an SAE-CD can be used to improve the administration of a unit dose formulation based on corticosteroid suspension. In addition, the SAE-CD outperforms other cyclodextrin derivatives. According to one embodiment, a method of the invention is practiced as follows. The SAE-CD is mixed (in solid or liquid form) and a unit dose formulation based on suspension comprising a corticosteroid. The SAE-CD is present in an amount sufficient to increase the amount of solubilized corticosteroid, ie to decrease the amount of corticosteroid not solubilized in it. Prior to administration, the liquid can be optionally filtered under aseptic conditions or terminally sterilized. The liquid is then administered to a subject by means of inhalation using a nebulizer. As a result, the amount of drug the subject receives is higher than that which the subject would have received if a formulation based on unaltered suspension had been administered. According to another embodiment, the SAE-CD (in liquid form, as a ready-to-use liquid or as a concentrate) and a solid unit dose formulation comprising a corticosteroid are mixed to form a liquid formulation. The SAE-CD is present in an amount sufficient to solubilize a substantial portion of the corticosteroid. The liquid is then administered via inhalation using a nebulizer. According to another embodiment, the SAE-CD (in solid form) and a solid unit dose formulation comprising a corticosteroid are mixed to form a solid mixture to which a liquid, aqueous carrier is added in an amount sufficient to constitute a Nebulizable formulation. Mixing and / or heating are optionally employed with the addition of the liquid carrier to constitute the formulation. The SAE-CD is present in an amount sufficient to solubilize a substantial portion of the corticosteroid. The formulation is then administered via inhalation using a nebulizer. The size of the deposit varies from one type of nebulizer to another. The volume of the liquid formulation can be adjusted as necessary to provide the volume required for loading in the reservoir of a particular type or nebulizer mark. The volume can be adjusted by adding an additional liquid carrier or an additional solution containing SAE-CD. In general, a unit dose formulation based on single-use corticosteroid suspension contains about 0.125, 0.25, 0.5, 1.2, or about 0.125 to about 2 mg of corticosteroid suspended in about 50 μl to 10 ml of liquid carrier. Alternatively, the corticosteroid is present in a concentration of about 20 mcg to about 30 mg of corticosteroid per ml of suspension. As a result, approximately 10 to 500 mg of SAE-CD, preferably 10 to 250 mg of SAE-CD, or 10 to 300 mg of SAE-CD, which is in solid form or dissolved in a liquid carrier, is added to each ml. of the suspension in order to dissolve a substantial portion of the corticosteroid and to constitute a nebulizable unit dose liquid formulation which is then administered to a subject. In general, a unit dose formulation based on suspension of multiple uses of corticosteroid contains from about 0.125 to 2 mg per mL of corticosteroid suspended in 1 to 100 mL of liquid carrier. A multi-use formulation actually contains two or more unit doses of corticosteroid. The individual aliquots of unit doses are taken from a multi-use unit dose formulation, and the individual unit dose is typically administered one at a time to a subject. As a result, approximately 10 to 500 mg of SAE-CD, which is in solid form or dissolved in a liquid carrier, is added to each mL of the suspension in order to dissolve a substantial portion of the corticosteroid and to constitute a liquid dosage unit formulation. of multiple uses that is then administered to a subject in aliquots of individual, unit doses. A key aspect of the invention is that a unit dose formulation based on suspension is converted to a liquid unit dose formulation prior to pulmonary administration via inhalation (of a nebulized mist) to a subject. The conversion can take place in the same container in which the suspension is provided, in a different container or in the reservoir of a nebulizer. In order to constitute a liquid formulation, a substantial portion of the corticosteroid must be dissolved. As used with reference to the amount of dissolved corticosteroid, a "substantial portion" is at least 20% by weight, at least 30% by weight, at least 40% by weight or at least 20% by weight and less than 50% in weight of the corticosteroid. As used with reference to the amount of corticosteroid dissolved, a "major portion" is at least 50% by weight of the corticosteroid. It is well known that pharmacists working in the combination of pharmaceutical products can prepare, and do so, a unit dose formulation based on suspension comprising a corticosteroid. These pharmacists will now be able to prepare a unit dose, liquid, single-use or multiple-use formulation by employing a method described herein. Alternatively, a subject (patient) who is subjected to corticosteroid treatment can convert the suspension-based formulation to a liquid formulation of the invention by employing a method described herein. Instead of preparing the liquid formulation from the suspension in the pharmaceutical product, an equipment containing the suspension-based formulation and an SAE-CD can be prepared. The concentration of SAE-CD in solution can be expressed on a weight-to-weight or weight-to-volume basis; however, these two units are interconvertible. When a known weight of cyclodextrin dissolves in a known weight of water, the% w / w concentration of cyclodextrin is determined by dividing the weight of cyclodextrin in grams by the total weight (weight of cyclodextrin + water) in similar units and multiplying it per 100. When a known weight of cyclodextrin dissolves in a known total volume, the% p / v concentration of cyclodextrin is determined by dividing the weight of cyclodextrin in grams by the total volume in milliliters and multiplying by 100. The correlation between The two percentages of cyclodextrin concentration were determined experimentally by preparing several% w / w solutions of cyclodextrin and measuring the density of each with a pycnometer at 25 ° C. The density (g / mL) of each% w / w solution of CAPTISOL1® is presented in the following table.

The resulting linear relationship easily makes possible the conversion of the CAPTISOL1® concentrations expressed in% p / pa to that of% p / v by means of the following equation:% p / v = [(% p / p * slope) + intercept and] *% p / p where the values of the slope and intercept are determined from a linear regression of the density data in the table. For example, when using the above equation, a solution of 40% w / w of CAPTISOLMR would be equivalent to a solution of ~ 48.3% w / v of CAPTISOL1®. The performance of an inhalable solution of the invention in a nebulizer may depend on the viscosity of the solution in its reservoir, the solution for nebulization. The viscosity of an aqueous solution of SBE7-β-CD changes with respect to the concentration approximately as indicated in the table above. The viscosity of the inhalable composition can have an impact on the percentage of the composition for nebulization emitted from a nebulizer, the exit velocity of the nebulized corticosteroid and the droplet size distribution.

The amount of inhalable composition for nebulization, residual left in the nebulizer reservoir may be higher for solutions containing SAE-CD than for a suspension containing budesonide. For example, Figure 4 depicts a scheme of the assessed percentage of composition for nebulization emitted from three different nebulizers (PARÍ LC PLUS1®, HUDSON ÜPDRAFT II NEB-U-MIST1® and MYSTIQUE1®) for each of four different compositions for Misting (PULMICORT RESPULES1® suspension, 5% w / w solution of SBE7-ß-CD, 10% w / w solution of SBE7-ß-CD and 20% w / w solution of SBE7-ß-CD). The PULMICORT RESPULES1® suspension was used as the control. The PARÍ LC PLUS1®, MYSTIQUE1® and HUDSON1® nebulizers were used for comparison. The MYSTIQUE1® nebulizer was not adequate to nebulize the suspension and the concentrated SAE-CD solution (20% w / w) efficiently so that they were not evaluated with that nebulizer. The results suggest that, under the conditions under test, the nebulization of the PULMICORT RESPULE1® suspension results in a higher percentage of nebulized composition, which means that, with the suspension, less composition is left for the nebulization in the reservoir of the nebulizer when completing the nebulization compared to the solution. In some cases, nebulization of the suspension resulted in the largest percentage by weight of the total composition emitted by a nebulizer. In other words, under similar fogging conditions, the PARÍ LC PLUS1® and HUDSON1® nebulizers more efficiently reduced the volume of the suspension for nebulization than the solution for nebulization; however, this did not correspond to the total amount of drug emitted by the nebulizer. The exit velocity of a SAE-CD nebulization solution was compared to that of a suspension, each containing budesonide. A modified version of the method of Example 10 was followed to determine the exit velocity. The following tables summarize the observed data.

Data obtained using a PARÍ LC PLUS1® nebulizer equipped with an air compressor PARÍ PRONEB ULTRA1 MR Data obtained using an MYSTIQUE-iM1-R ultrasonic nebulizer All the above formulations contain approximately 250 μg / mL of budesonide. Samples identified as "P5C" contain 50 mg / mL (or approximately 5%) of SBE7-β-CD. The following table shows the exit velocity of the nebulizer for solutions containing several levels of SAE-CD.

Surprisingly, the nebulization of the solution containing SAE-CD provided a higher budesonide exit velocity than the nebulization of the PULMICORT RESPULES1® suspension although the nebulizer emitted a greater total amount of the suspension. Without being limited to a particular mechanism, it is believed that the nebulizer performs its function preferably with the water in the suspension preferably with the particles of the suspension causing thereby an increase in the molar concentration of budesonide in the suspension in the tank. Higher SAE-CD concentrations, greater than 25% w / v, led to slightly longer nebulization times and lower exit velocities once the viscosity exceeded an upper, approximate limit. Based on the above data, the concentrations of 21.5 + 5% w / w of SBE7-ß-CD was identified as the acceptable, upper, approximate level for the nebulizer under test, "acceptable" is defined as the highest concentration of SBE7 -β-CD that can be used without increasing to an excessive viscosity, which can adversely affect the nebulization time and the exit velocity. The upper limit, practical for the concentration of SAE-CD will vary between the formats of the nebulizers. The acceptable, higher concentration of SAE-CD in a liquid formulation for use in a nebulizer may vary according to the DS of the derivative, the alkyl chain length of the sulfoalkyl functional group and / or the CD ring size of the SAE-CD. For administration to the respiratory tract, particularly the lungs, a nebulizer is used to produce approximately sized droplets. Typically, the particle size of the droplet produced by a nebulizer for inhalation is in the range between about 0.5 to about 5 microns. If it is desired that the droplets reach the lower regions of the respiratory tract, ie the alveoli and the terminal bronchi, the preferred particle size range is between about 0.5 and about 2.5 microns. If it is desired that the droplets reach the upper respiratory tract, the preferred particle size range is between 2.5 microns and 5 microns. As noted above, the viscosity of the composition for nebulization can impact the size of the droplets and the size distribution of the droplets. For example, the present formulations tend to form larger droplets, in terms of the Dv 50, at the lowest concentrations and thus the lowest viscosity, of SAE-CD in the absence of budesonide. FIGURES 5a-5b depict droplet size data for the nebulization of inhalable compositions with a PARÍ LC PLUS1® nebulizer. For each of the figures, a MALVERN1® laser light scattering device (Mastersizer S, Malvern Instruments Ltd. Malvern, Worcs, U.K.) was used to measure the MMAD. FIGURE 5a represents the results obtained using solutions of? -CD of varying concentrations (5% w / v, 10% w / v and 20% w / v) in the absence of budesonide. The results indicate that the? -CD by itself would not have behaved acceptably in a nebulizer, since almost the entire mass of the solution is of an unacceptable range of droplet size. Even with extensive recycling and droplet size selection by a nebulizer, a β-CD-based nebulizer solution containing a corticosteroid would require an extremely long dosing period due to the low percentage of mass that is within the appropriate range of droplet size, especially since the -CD is not an effective budesonide solubilizer at the concentrations tested. In comparison, FIGURE 5b represents the results obtained using the same nebulizer with the PULMICORT RESPULES1® suspension or a modified solution PULMICORT RESPULES1® containing a SAE-CD of different concentrations (5% w / v, 10% w / v and 20% p / v). With each of these samples, a significant portion of the nebulized mass is of a respirable size range. In addition, the solutions containing SAE-CD apparently form droplets that are comparable in size with those of the nebulized suspension. Figure 6 represents droplet size data for the nebulization of inhalable compositions with a HUDSON UPDRAFT II NEBUMIST1® nebulizer loaded with the PÜLMICORT RESPULES "11 suspension or a solution containing SAE-CD in different concentrations (5% w / v, 10% w / v and 20% w / v). Compared to the PARÍ LC PLUS1® nebulizer, the NEB-U-MIST® nebulizer forms a slightly larger particle size distribution, a significant portion of the nebulized mass is still in the appropriate size range. Accordingly, the solution for nebulization made from the suspension and containing SAE-CD is suitable for use in a variety of different air-driven jet nebulizers. The package insert for the PULMICORT RESPULES1® suspension states that the suspension must not be nebulized with an ultrasonic nebulizer. Figure 7 represents the droplet size data for the nebulization of inhalable compositions with a MYSTIQUE1® ultrasonic nebulizer. The compositions include three different solutions containing SAE-CD. Unlike the suspension, the solution containing SAE-CD can be nebulized with an ultrasonic nebulizer. In this manner, the invention provides a method for improving the pulmonary delivery of a corticosteroid in a unit dose formulation based on suspension from an ultrasonic nebulizer, the method comprising the step of including a SAE-CD in the formulation in a sufficient amount. to decrease the amount of undissolved corticosteroid in the unit dose formulation based on suspension. The performance of the compositions for nebulization through a range of nebulizers is typically compared by comparing the Dv 50 of the droplet size distribution for the respective compositions. Figure 8 represents the comparative data of the size of the droplets Dv50 for the nebulization of an inhalable composition with the three nebulizers mentioned above. In each case, the solutions containing SAE-CD are suitable for administration by means of nebulization through a range of concentrations. In addition, the droplet size distribution can be partially controlled by adjusting the concentration of the SAE-CD. Figure 9 is a graph depicting the relationship between the concentration of SAE-CD versus the exit velocity of the SAE-CD in several different nebulizers with different sources of compressed air required for the specific assembly: the air-driven jet nebulizers RAINDROP-Rat1®, RAINDROP-Dog1®, PARÍ LC STAR-UNC1®, PARÍ LC STAR-Rat PARÍ LC PLUS1® and DEVILBISS PULMO AIDEMR. The nebulizers were used in a variety of assemblies including isolated exposure chambers as well as animal exposure chambers and / or individual exhibition masks. In general, the data show that the SAE-CD output increases with the increase in SAE-CD concentration. Depending on the nebulizer used, the conditions under which the nebulizer is operated and the concentration of SAE-CD in the solution, different maximum output speeds can be achieved. For example, the maximum output speed in the Raindrop-Dog assembly is a concentration of 250 mg / mL of CAPTISOL1®. Although the nebulization of the PULMICORT RESPULES1® suspension with an ultrasonic nebulizer is not recommended, this can be achieved. Figures lOa-lOb represent the comparative data of droplet size for solutions for nebulization with the PARÍ LC PLUS1® and MYSTIQUE1® nebulizers of the PULMICORT RESPULES1® suspension and a SAE-CD solution based on modified PULMICORT RESPULES1®. The PULMICORT RESPÜLES1® suspension with and without 5% w / v SBE7-β-CD was used as the test samples. The procedure of Example 12 was followed. FIGURE 10a represents the data of DvlO and Dv50 of the solutions conducted in the air-powered jet nebulizer PARÍ LC PLUS1® and FIGURE 10b represents the data of DvlO and Dv50 for the solutions conducted in the the MYSTIQUE1® ultrasonic nebulizer. In each case, the droplet size data for the two different solutions are comparable. Nevertheless, the exit velocity of budesonide for the two solutions was significantly different. However, the use of a SAE-CD in a composition for nebulization results in an increased exit velocity of budesonide regardless of the format of the nebulizer. Thus, the invention provides a method for increasing the exit velocity of a unit dose formulation based on a suspension containing a corticosteroid which is delivered by a nebulizer, the method comprising the step of including an SAE-CD in the formulation in an amount sufficient to increase the amount of corticosteroid dissolved in the formulation to constitute an altered formulation, the exit rate of the corticosteroid for the altered formulation is thereby greater than the exit rate of the corticosteroid for the suspension-based formulation . Corticosteroids that are useful in the present invention generally include any spheroid produced by the adrenal cortex, including glucocorticoids and mineralocorticoids and analogues and synthetic derivatives of naturally occurring corticosteroids that have anti-inflammatory activity. Suitable synthetic analogs include prodrugs, ester derivatives. Examples of corticosteroids that can be used in the compositions of the invention include aldosterone, beclomethasone, betamethasone, budesonide, ciclesonide (Altana Pharma AG), cloprednol, cortisone, cortivazole, deoxycortone, desonide, deoximetasone, dexamethasone, difluorocortolone, fluclorolone, flumethasone, flunisolide, fluocinolone, fluocinonide, butyl fluocortin, fluorocortisone, fluorocortolone, fluorometholone, flurandrenolone, fluticasone, halcinonide, hydrocortisone, icometasone, meprednisone, methylprednisolone, mometasone, parametasone, prednisolone, prednisone, rofleponide, RPR 106541, tixocortol, triamcinolone and their respective derivatives , pharmaceutically acceptable, such as beclomethasone dipropionate (anhydrous or monohydrate), beclomethasone monopropionate, dexamethasone 21-isonicotinate, fluticasone propionate, icometasone enbutate, tixocortol-21 pivalate and triamcinolone acetonide. Particularly preferred are compounds such as beclomethasone dipropionate, budesonide, flunisolide, fluticasone propionate, mometasone furoate and triamcinolone acetonide. Other corticosteroids are not yet marketed, but those that will be marketed after the filing of this application are considered useful in the present invention unless it is experimentally established otherwise that they are not suitable. The corticosteroid compound is present in the final diluted corticosteroid composition, designed for inhalation in an amount of about 1 μg / ml to about 10 mg / ml, from about 10 μg / ml to about 1 mg / ml or about 20 μg / ml to approximately 500 μg / ml. For example, the drug concentration may be between about 30 and 1000 μg / ml of triamcinolone acetonide and between about 50 and 2000 μg / ml for budesonide, depending on the volume to be administered. By following the preferred methods of the present invention, relatively high concentrations of the corticosteroid can be achieved in a water-based composition. Similarly, the corticosteroid compound is present in the final, diluted corticosteroid composition designed for nasal administration in an amount of about 50 μg / ml to about 10 mg / ml, from about 100 μg / ml to about 2 mg / ml or from about 300 μg / ml to about 1 mg / ml. For example, the drug concentration is between about 250 μg / ml and 1 mg / ml for triamcinolone acetonide and between about 400 μg / ml and 1.6 mg / ml for budesonide, depending on the volume to be administered. For the treatment of bronchial inflammation, the diluted corticosteroid composition is prepared as described herein. The corticosteroid for this treatment is preferably either beclomethasone dipropionate, betamethasone, budesonide, dexamethasone, flunisolide, fluticasone propionate, mometasone furoate or triamcinolone acetonide and is formulated at the concentrations set forth herein. The daily dose of the corticosteroid is generally about 0.05 to 10 mg depending on the drug and the disease, according to Physician's Desk Reference. The corticosteroid may be present in its neutral, ionic, salt, basic, acid, natural, synthetic, diastereomeric, isomeric, enantiomerically pure, racemic, solvate, anhydrous, hydrate, chelate, derivative, analogue, esterified, unesterified form or another common form. If an active agent is named in this document, all of these available forms are included. For example, all known forms of budesonide are considered within the scope of the invention. The formulation of the invention can be used to deliver two or more different active agents. Particular combinations of active agents can be provided by means of the present formulation. Some combinations of active agents include: 1) a first drug of a first therapeutic class and a second drug of the same therapeutic class; 2) a first drug of a first therapeutic class and a second drug different from a different therapeutic class; 3) a first drug having a first type of biological activity and a second different drug having approximately the same biological activity; 4) a first drug having a first type of biological activity and a second different drug having a second different type of biological activity. Exemplary combinations of active agents are described herein. A corticosteroid, such as budesonide, can be administered in combination with one or more different drugs. These other drugs include: an anticholinergic agent, B2 adrenoreceptor agonist, dopamine D2 receptor agonist. Adrenoreceptor B2 agonists for use in combination with the compositions provided herein include, but are not limited to, Albuterol (alpha 1 - (((1,1-dimethylethyl) amino) methyl) -4-hydroxy-1,3-benzenedimethanol); Bambuterol (5- (2- ((1,1-dimethylethyl) amino) -1-hydroxyethyl) -1,3-phenylenyl ester of dimethylcarbamic acid); Bitolterol (4- (2- ((1,1-dimethylethyl) amino) -1-hydroxyethyl) -1,2-phenylenyl ester of 4-methylbenzoic acid); Broxaterol (3-bromo-alpha- (((1,1-dimethylethyl) amino) methyl) -5-isoxazolemethanol); Isoproterenol (4- (1-hydroxy-2- ((1-methylethyl) amino) ethyl) -1,2-benzenediol); Trimethoquinol (1, 2, 3, 4-tetrahydro-1 - ((3, 4, 5-trimethoxyphenyl) -methyl) -6,7-isoquinolindiol); Clenbuterol (4-amino-3,5-dichloro-alpha- (((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- ((1RS) -l-hydroxy-2- (((1RS) -2- (p-methoxyphenyl) -1-methylethyl) amino) ethyl) formanilide); (R, R) -Formoterol; Desformoterol ((R, R) or (S, S) -3-amino-4-hydroxy-alpha- (((2- (4-methoxyphenyl) -1-methyl-ethyl) amino) methyl) -benzenemethanol); Hexoprenaline (4, 4 '- (1,6-hexane-diyl) -bis (imino (l-hydroxy-2, 1-ethanediyl))) bis-1,2-benzenediol); Isoetharine (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); Picumeterol (4-amino-3, 5-dichloro-alpha- (((6- (2- (2-pyridinyl) ethoxy) hexyl) -amino) ethyl) benzenemethanol); Pirbuterol (.alpha.sub.6- (((1,1-dimethylethyl) -amino) methyl) -3-hydroxy-2,6-pyridinemethanol); Procaterol (((R *, S *) - (. + -.) -8-hydroxy-5- (l-hydroxy-2- ((1-methylethyl) amino) butyl) -2 (ÍH) -quinolin-one ); Reproterol ((7- (3- ((2- (3,5-dihydroxyphenyl) -2-hydroxyethyl) amino) -propyl) -3,7-dihydro-1,3-dimethyl-1H-purine-2, 6-dione); Rimiterol (4- (hydroxy-2-piperidinylmethyl) -1,2-benzenediol); Salbutamol ((. + -.) - alpha 1 - (((1,1-dimethylethyl) amino) methyl) -4 -hydroxy-l, 3-benzenedimethanol); (R) -Salbutamol; Salmeterol ((. + -.) -4-hydroxy-.alpha1- (((6- (4-phenylbutoxy) hexyl) -amino) methyl) - 1,3-benzenedimethanol); (R) -Salmeterol; Terbutaline (5- (2- ((1,1-dimethylethyl) amino) -1-hydroxyethyl) -1,3-benzenediol); Tulobuterol (2-chloro-). alpha.- (((1,1-dimethylethyl) amino) -methyl) benzenemethanol) and TA-2005 (8-hydroxy-5- ((IR) -l-hydroxy-2- (N- ((IR) hydrochloride -2- (4-methoxyphenyl) -1-methylethyl) amino) ethyl) carbostyril.) Dopamine receptor agonists (D2) include, but are not limited to, Apomorphine ((r) -5,6, 6a, 7 -tetrahydro-6-methyl-4H-dibenzo [de, glqui nolin-10, 11-diol); Bromocriptine ((5 '.alpha.) -2-bromo-12' -hydroxy-2 '- (1-methylethyl) -5' - (2-methylpropyl) ergotaman-3 ', 6', 18-trione); Cabergoline ((8.beta.) -N- (3- (dimethylamino) propyl) -N- ((ethylamino) carbonyl) -6- (2-propenyl) ergoline-8-carboxamide); Lisuride (N '- ((8-alpha-) -9,10-didehydro-6-methylergolin-8-yl) -N, N-diethylurea); Pergolide ((8-beta-) -8- ((methylthio) methyl) -6-propylergoline); Levodopa (3-hydroxy-L-tyrosine); Pramipexole ((s) -4, 5, 6, 7-tetrahydro-N. Sup.6-propyl-2,6-benzothiazoldiamine); Quinpirole hydrochloride (trans- (-) -4aR-4, 4a, 5, 6, 7, 8, 8a, 9-octahydro-5-propyl-lH-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 described in International Patent Application Publication No. WO 99/36095, the relevant disclosure of which is hereby incorporated by reference. Anticholinergic agents for use herein include, but are not limited to, ipratropium bromide, oxitropium bromide, atropine methyl nitrate, atropine sulfate, ipratropium, beladone extract, scopolamide, scopolamine methobromide, homatropine metobromide. , hyoscyamine, isopriopramide, orphenadrine, benzalkonium chloride, tiotropium bromide and glycopyrronium bromide. In certain embodiments, the compositions contain an anticholinergic agent, such as ipratropium bromide or tiotropium bromide, at a concentration of about 5 μg / mL to about 5 mg / mL, or from about 50 μg / mL to about 200 μg / mL. . In other embodiments, the compositions for use in the methods described herein contain an anticholinergic agent, including ipratropium bromide and tiotropium bromide, at a concentration of about 83 μg / mL or about 167 μg / mL.

Other active ingredients for use herein in combination therapy include, but are not limited to, IL-5 inhibitors such as those described in U.S. Patent No. 5,668,110, No. 5,683,983, No. 5,677,280, No. 6,071,910 and No. 5,654,276, the relevant descriptions of which are incorporated by this act by way of reference; antisense modulators of IL-5 such as those described in US Patent No. 6,136,603, the relevant disclosure of which is incorporated by this act by way of reference; milrinone (1,6-dihydro-2-methyl-6-oxo- [3,4'-bipyridine] -5-carbonitrile); Milrinone lactate; Tryptase inhibitors such as those described in U.S. Patent No. 5,525,623, the relevant disclosure of which is incorporated by this act by way of reference; tachykinin receptor antagonists such as those described in U.S. Patent Nos. 5,691,336, No. 5,877,191, No. 5,929,094, No. 5,750,549 and No. 5,780,467, the relevant descriptions of which are incorporated by this act by way of reference; leukotriene receptor antagonists such as montelukast sodium (Singular1®, monosodium salt of R- (E)] -1- [[[1- [3- [2- (7-chloro-2-quinolinyl) ethenyl] phenyl]] -3- [2- (1-hydroxy-l-methylethyl) -phenyl] propyl] thio] ethyl] cyclopropanacetic acid), 5-lipoxygenase inhibitors such as zileuton (Zyflo1®, Abbott Laboratories, Abbott Park, III.) And antibodies Anti-IgE such as Xolair1® (recombinant humanized anti-IgE monoclonal antibody (CGP 51901; IGE 025A; rhuMAb-E25), Genentech, Inc., South San Francisco, Calif.) and topical anesthetics such as lidocaine, N-arylamide , aminoalkylbenzoate, prilocaine, etidocaine (U.S. Patent No. 5,510,339, No. 5,631,267 and No. 5,837,713, the relevant descriptions of which are incorporated by this act as a reference). The invention includes methods for the treatment, prevention or amelioration of one or more symptoms of bronchoconstrictive disorders. The method further includes administering one or more of (a), (b), (c) or (d) as follows: (a) a β2-adrenoreceptor agonist; (b) a dopamine receptor agonist (D2); (c) a therapeutic, prophylactic agent, such as a spheroid; or (d) an anticholinergic agent; simultaneously with, before or subsequent to the composition provided in this document. The embodiments of the present invention allow combinations to be prepared in a variety of ways: 1) Mix ready-to-use solutions of a β2 agonist such as levalbuterol or an anticholinergic agent such as ipatropium bromide with a ready-to-use solution of a corticosteroid in SAE-CD; 2) Mix ready-to-use solutions of a β2 agonist or an anticholinergic agent with a concentrated solution of a corticosteroid dissolved using SAE-CD; 3) Mix a ready-to-use solution of a β2 agonist or an anticholinergic agent with a substantially dry SAE-CD and a substantially dry corticosteroid; 4) Mix a ready-to-use solution of a β2 agonist or an anticholinergic agent with a substantially dry mixture of SAE-CD and a corticosteroid or more conveniently a pre-measured amount of the mixture in a unit package such as a capsule (pour one capsule in a ready-to-use solution); 5) Mix a ready-to-use solution of a corticosteroid such as budesonide with a long-acting or substantially dry short acting ß2 agonist and / or with a substantially dry anticholinergic agent such as ipatropium bromide or tiotropium bromide; 6) Dissolve a substantially dry β2 agonist and / or a substantially dry anticholinergic agent and a substantially dry SAE-CD plus a substantially dry corticosteroid. It is well understood by those of ordinary skill in the art that the above solutions or powders may optionally contain other ingredients such as buffers and / or tonicity adjusters and / or antimicrobial agents and / or additives or other excipients of this type as disclosed. in this document or as it is currently used in liquid formulations, inhalable to improve the output of the nebulizer. The dosage, use and administration of the therapeutic agents described in this document is generally proposed to follow the guidelines set forth in Physician's Desk Reference, 55th Edition (Thompson Healthcare, Montvale, NJ, 2005), the relevant description of which is incorporated by this act as a reference. The bronchoconstrictive disorder to be treated, prevented, or whose symptoms must be improved is associated with asthma, including, but not limited to, bronchial asthma, allergic asthma, and intrinsic asthma, for example delayed asthma or hypersensitivity of the airways.; and, particularly in modalities where an anticholinergic agent is used, other pulmonary, obstructive, chronic diseases (COPDs), including, but not limited to, chronic bronchitis, emphysema, and associated pulmonary heart (cardiac disease that follows lung disease and respiratory system) with pulmonary hypertension, hypertrophy of the right ventricle and heart failure of the right side. COPD is frequently associated with cigarette smoking, infections, environmental pollution and exposure to occupational dust. A formulation according to the invention will have a shelf life of not less than 6 months. In this case, the shelf life is determined only with respect to the increase in the amount of budesonide degradation byproducts or a reduction in the amount of budesonide remaining in the formulation. For example, for a formulation that has a shelf life of at least six months, the formulation will not demonstrate an unacceptable and substantial increase in the amount of degradation products during a storage period of at least six months. The criteria for an acceptable useful life period are established as necessary in accordance with a given product and its storage stability requirements. In other words, the amount of degradation products in a formulation having an acceptable shelf life will not increase beyond a predetermined value during the proposed storage period. On the other hand, the amount of degradation products of a formulation having an unacceptable shelf life will increase beyond the predetermined value during the proposed storage period. The method of Example 3 was followed to determine the stability of budesonide in the solution. The period of useful life was defined as the time for the loss of 10% power. Under the conditions under test, the power loss was of the first order. The shelf life of an Inhalation Solution of Budesonide Captisol Enablecf (a solution comprising budesonide and SBE7-β-CD) is greater than about 3 years at a pH between 4 and 5, ie approximately 90 months at pH 4.0 and about 108 months at pH 5.0 without the need to add any other stabilizer, such as EDTA, in water in the presence of approximately 5% weight / volume of SAE-CD. This period of useful life is greater than that reported by Otterbeck (US Patent No. 5,914,122, up to six weeks at pH 4.0-6.0 in water in the presence of EDTA, HP-β-CD and other additives). The inventors have also discovered that SAE-CD is capable of stabilizing budesonide isomers at different degrees. A study to determine if SB7-ß-CD stabilized budesonide solutions and if an isomer was preferably stabilized was conducted according to Example 13. Figure 11 is a semilogarithmic diagram of the% initial concentration at each time point for the samples stored at 60 ° C. The loss of budesonide was of the first order in each temperature. The following table shows the pseudo-first order rate constants calculated for each isomer at 60 ° C and 80 ° C.

SBE7-ß-CD stabilized both the R and S isomers of budesonide in solutions at both pH 4 and pH 6. The ratio with / without CAPTISOL1® of the rate constants was much less than 1 at all temperatures. SBE7-ß-CD had a greater effect on the stability of the isomer both R and S at pH 6 than at pH 4. At a given temperature, the ratio of rate constants with / without SBE7-ß-CD was lower at pH 6 that at pH 4. Although SBE7-β-CD stabilized both isomers, the S-isomer seems to be stabilized to a much greater degree than the R-isomer. At all temperatures and pHs tested, the ratio of rate constants to / without SBE7-ß-CD was lower for the S-isomer. The degree of stabilization affected by SBE7-ß-CD at 60 ° C is higher than at 80 ° C. An even greater degree of stabilization would be expected at 40 ° C and / or at room temperature (20-30 ° C). Samples of the above solutions were also placed in a chamber under a bank of fluorescent lights. The flasks were periodically removed and tested for the budesonide content. Figure 12 shows the semilogarithmic diagram of the% of the initial value that remained as a function of exposure to light (light intensity * time). As observed in the following table, SBE7-ß-CD significantly reduced the photodecomposition of budesonide. The loss of budesonide was of the first order and independent of pH.

The formulation of the invention can be provided as an equipment adapted to form an inhalable solution for nebulization. The equipment would comprise a corticosteroid, an SAE-CD, an aqueous carrier and optionally one or more different components. The corticosteroid and the SAE-CD can be provided together or separately in solid, suspended or dissolved form. After mixing the SAE-CD with a corticosteroid in the presence of an aqueous carrier, the solids will dissolve to form an inhalable solution preferably a suspension for nebulization. Each component can be provided in a single package or together with another component. For example, SAE-CD can be provided in an aqueous solution while budesonide is provided in solid, dry or suspended, wet form. Alternatively, SAE-CD is provided in dry form and budesonide is provided as an aqueous suspension, for example, PULMICORT RESPÜLES1®. The kit may instead comprise a mixture of a solid derivatized cyclodextrin and a solid corticosteroid and, optionally, at least one solid pharmaceutical excipient, such that a larger portion of the active agent does not form complexes with the derivatized cyclodextrin prior to reconstitution of the mixture with an aqueous carrier. Alternatively, the composition may comprise a solid mixture comprising the inclusion complex of a derivatized cyclodextrin and an active agent, wherein a larger portion of the active agent is complexed with the derivatized cyclodextrin prior to reconstitution of the solid mixture with an aqueous carrier. . Depending on the storage temperature of the equipment, the aqueous carrier may be a liquid or a frozen solid. In one embodiment, the equipment excludes the aqueous carrier during storage, but the aqueous carrier is added to the SAE-CD and the corticosteroid before use to form the solution for nebulization. The corticosteroid and the SAE-CD can be complexed and can be present in concentrated, aqueous form before the addition of the aqueous carrier, which is then added to bring the solution to a volume and the appropriate viscosity and concentration for nebulization. A reconstitutable formulation can be prepared according to any of the following processes. First a liquid formulation of the invention is prepared, then a solid is formed by lyophilization (freeze drying), spray drying, spray drying, anti-solvent precipitation, various processes using supercritical or near supercritical fluids or other known methods for those of ordinary experience in the field to make a solid for reconstitution.

A liquid vehicle included in a formulation of the invention comprises an aqueous liquid carrier, such as water, aqueous alcohol or an organic, aqueous solvent. Although not necessary, the formulation of the present invention may include a conventional preservative, antioxidant, buffering agent, acidifying agent, alkalizing agent, dye, solubility enhancing agent, complexing enhancing agent, electrolyte, glucose, stabilizer, modifier, tonicity, agent for volume increase, antifoam agent, oil, emulsifying agent, cryoprotectant, plasticizer, essences, sweeteners, tonicity modifier, surface tension modifier, viscosity modifier, density modifier, modifier of the Volatility, other excipients known to those of ordinary experience in the field for use in preserved formulations or a combination thereof. As used herein, the term "alkalizing agent" is intended to refer to a compound used to provide an alkaline medium, such as for the stability of the product. These compounds include, by way of example and without limitation, a solution of ammonia, ammonium carbonate, diethanolamine, monoethanolamine, potassium hydroxide, sodium borate, sodium carbonate, sodium bicarbonate, sodium hydroxide, triethanolamine, diethanolamine, base of organic amine, alkali amino acids and trolamine and other compounds known to those of ordinary experience in the field. As used herein, the term "acidifying agent" is intended to refer to a compound used to provide an acidic medium for the stability of the product. These compounds include, by way of example and without limitation, acetic acid, acidic amino acids, citric acid, fumaric acid and other alpha-hydroxy acids, hydrochloric acid, ascorbic acid, phosphoric acid, sulfuric acid, tartaric acid and nitric acid and other compounds known to those of ordinary experience in the field. The inclusion of a conventional preservative in the formulation based on inhalable solution is optional, since the formulation is self-preserved by the SAE-CD depending on its concentration in the solution. However, a conventional preservative may be additionally included in the formulation if desired. The preservatives can be used to inhibit microbial growth in the compositions. The amount of the preservative is generally that which is necessary to prevent microbial growth in the composition during a storage period of at least six months. As used herein, a conventional preservative is a compound used to reduce at least the rate at which bioburden is increased, but which preferably maintains bioburden preferably or reduces bioburden after contamination has occurred. These compounds include, by way of example and without limitation, benzalkonium chloride, benzethonium chloride, benzoic acid, benzyl alcohol, cetylpyridinium chloride, chlorobutanol, phenol, phenylethyl alcohol, phenylmercuric nitrate, phenylmercuric acetate, thimerosal, metacresol, myristylgamma chloride. - picolinium, potassium benzoate, potassium sorbate, potassium benzoate, sodium propionate, sorbic acid, thymol and methyl, ethyl, propyl or butyl parabens and other compounds known to those of ordinary experience in the field. As used herein, the term "antioxidant" is intended to refer to an agent that inhibits oxidation and is used in this manner to prevent deterioration of preparations by the oxidative process. These compounds include, by way of example and without limitation, acetone, potassium metabisulfite, potassium sulfite, ascorbic acid, ascorbyl palmitate, citric acid, butylated hydroxyanisole, butylated hydroxytoluene., hypophosphorous acid, monothioglycerol, propyl gallate, sodium ascorbate, sodium citrate, sodium sulfide, sodium sulfite, sodium bisulfite, sodium formaldehyde-sulfoxylate, thioglycolic acid, EDTA, pentetate and sodium metabisulfite and other known compounds for those people with ordinary experience in the field. As used herein, the term "buffering agent" is intended to refer to a compound used to resist the change in pH with the dilution or addition of acid or alkali. The buffers are used in the present compositions to adjust the pH to a range between about 2 and about 8, about 3 to about 7 or about 4 to about 5. These compounds include, by way of example and without limitation, acetic acid, acetate sodium, adipic acid, benzoic acid, sodium benzoate, boric acid, sodium borate, citric acid, glycine, maleic acid, monobasic sodium phosphate, dibasic sodium phosphate, HEPES, lactic acid, tartaric acid, potassium metaphosphate, potassium phosphate, sodium monobasic acetate, sodium bicarbonate, tris, sodium tartrate and anhydrous sodium citrate and dihydrate and other compounds known to those of ordinary experience in the field. Other buffers include a mixture of citric acid / phosphate, acetate, barbital, borate, Britton-Robinson, cacodylate, citrate, collidine, formate, maleate, Mcllvaine, phosphate, Prideaux-Ward, succinate, citrate-phosphate-borate (Teorell-Stanhagen ), veronal acetate, MES (2- (N-morpholino) ethanesulfonic acid), BIS-TRIS (bis (2-hydroxyethyl) imino-tris (hydroxymethyl) methane), ADA (N- (2-acetamido) -2- iminodiacetic), ACES (N- (carbamoylmethyl) -2-aminoethanesulfonaic acid), PIPES (piperazine-N, N'-bis (2-ethanesulfonic acid)), MOPSO (3- (N-morpholino) -2-hydroxypropanesulfonic acid) , BIS-TRIS PROPANE (1, 3-bis (tris (hydroxymethyl) methylamino) propane), BES (acid N, N-bis (2-hydroxyethyl) -2-aminoethanesulfonaic acid), MOPS (acid) 3- (N-morpholino) propanesulfonic), TES (N-tris (hydroxymethyl) methyl-2-aminoethanesulfonic acid), HEPES (N- (2-hydroxyethyl) piperazine-N '- (2-ethanesulfonic acid), DIPSO (3- (N, N-bis (2-hydroxyethyl) amino) -2-hydroxypropanesulfonic acid), MOBS (4- ( N-morpholino) -butanesulfonic acid), TAPSO (3- (N-tris (hydroxymethyl) methylamino) -2-hydroxypropanesulfonic acid), TRIZMA1® (tris (hydroxymethylaminomethane), HEPPSO (N- (2-hydroxyethyl) piperazine-N 'acid - (2-hydroxypropanesulfonic), POPSO (piperazin-N, N '-bis (2-hydroxypropanesulfonic acid)), TEA (triethanolamine), EPPS (N- (2-hydroxyethyl) piperazine-N '- (3-propanesulfonic), TRICINE (N-tris (hydroxymethyl) methylglycine), GLY-GLY (glycylglycine), BICIN (N, N-bis) (2-hydroxyethyl) glycine), HEPBS (N- (2-hydroxyethyl) piperazine-N '- (4-butanesulfonic acid)), TAPS (acid N-tris (hydroxymethyl) methyl-3-aminopropanesulfonic acid), AMPD (2-amino-2-methyl-1,3-propanediol) and / or any other buffer known to those skilled in the art. A complexing enhancing agent may be added to a formulation of the invention. When this agent is present, the cyclodextrin / active agent ratio can be changed. A complexing enhancing agent is a compound, or compounds, that improves (n) complexation of the active agent with the cyclodextrin. Suitable complexing improving agents include one or more pharmacologically inert water soluble polymers, hydroxy acids and other organic compounds typically used in liquid formulations to improve the complexation of a particular agent with cyclodextrins. Hydrophilic polymers can be used as complexing enhancing agents, solubility enhancers and / or water activity reducers to improve the performance of formulations containing a cyclodextrin. Loftsson has described a variety of polymers suitable for combined use with a cyclodextrin (derivatized or non-derivatized) to improve the performance and / or properties of the cyclodextrin. Suitable polymers are described in Pharmazie (2001), 56 (9), 746-747; International Journal of Pharmaceutics (2001), 212 (1), 29-40; Cyclodextrin: From Basic Research to Market, International Cyclodextrin Symposium, lOth, Ann Arbor, MI, United States, May 21-24, 2000 (2000), 10-15 (Wacker Biochem Corp .: Adrián, Mich.); PCT International Publication No. WO 9942111; Pharmazie, 53 (11), 733-740 (1998); Pharm. Technol. Eur., 9 (5), 26-34 (1997); J. Pharm. Sci. 85 (10), 1017-1025 (1996); European Patent Application EP0579435; Proceedings of the International Symposium on Cyclodextrins, 9th, Santiago de Comostela, Spain, May 31-June 3, 1998 (1999), 261-264 (Editor (s): Labandeira, J. J. Torres; Vila-Jato, J. L.

Kluwer Academic Publishers, Dordrecht, Neth); S. T. P. Pharma Sciences (1999), 9 (3), 237-242; ACS Symposium Series (1999), 737 (Polysaccharide Applications), 24-45; Pharmaceutical Research (1998), 15 (11), 1696-1701; Drug Development and Industrial Pharmacy (1998), 24 (4), 365-370; International Journal of Pharmaceutics (1998), 163 (1-2), 115-121; Book of Abstracts, 216th ACS National Meeting, Boston, August 23-27 (1998), CELL-016, American Chemical Society; Journal of Controlled Relay, (1997), 44/1 (95-99); Pharm. Res. (1997) 14 (11), S203; Investigative Ophthalmology & Visual Science, (1996), 37 (6), 1199-1203; Proceedings of the International Symposium on Controlled Relay of Bioactive Materials (1996), 23rd, 453-454; Drug Development and Industrial Pharmacy (1996), 22 (5), 401-405; Proceedings of the International Symposium on Cyclodextrins, 8th, Budapest, March 31-April 2, (1996), 373-376. (Editor (s): Szejtli, J.; Szente, L. Kluwer: Dordrecht, Neth.); Pharmaceutical Sciences (1996), 2 (6), 277-279; European Journal of Pharmaceutical Sciences, (1996) 4 (SUPPL.), S144; Third European Congress of Pharmaceutical Sciences Edinburgh, Scotland, UK 15-17 September 1996; Pharmazie, (1996), 51 (1), 39-42; Eur. J. Pharm. Sci. (1996), 4 (Sup.), S143; U.S. Patent Nos. 5,472,954 and No. 5,324,718; International Journal of Pharmaceutics (The Netherlands), (December 29, 1995) 126, 73-78; Abstracts of Papers of the American Chemical Society, (April 2, 1995) 209 (1), 33-CELL; European Journal of Pharmaceutical Sciences, (1994) 2, 297-301; Pharmaceutical Research (New York), (1994) 11 (10), S225; International Journal of Pharmaceutics (The Netherlands), (April 11, 1994) 104, 181-184 and International Journal of Pharmaceutics (1994), 110 (2), 169-77, the full descriptions of which are incorporated by this act as a reference. Other suitable polymers are well known excipients which are commonly used in the field of pharmaceutical formulations and are included in, for example, Remington's Pharmaceutical Sciences, 18th Edition, Alfonso R. Gennaro (editor), Mack Publishing Company, Easton, PA , 1990, pages 291-294; Alfred Martin, James Swarbrick and Arthur Commarata, Physical Pharmacy. Physical Chemical Principles in Pharmaceutical Sciences, 3rd edition (Lea & Febinger, Philadelphia, PA, 1983, pages 592-638); A. T. Florence and D. Altwood,. { Physicochemical Principles of Pharmacy, 2nd Edition, MacMillan Press, London, 1988, pages 281-334. The full descriptions of the references cited in this document are incorporated by this act as a reference. Still other suitable polymers include natural water-soluble polymers, water-soluble semi-synthetic polymers (such as water-soluble cellulose derivatives) and synthetic water-soluble polymers. Natural polymers include polysaccharides such as insulin, pectin, algin derivatives (e.g., sodium alginate) and agar and polypeptides such as casein and gelatin. Semi-synthetic polymers include cellulose derivatives such as methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, their mixed ethers such as hydroxypropyl methyl cellulose and other mixed ethers such as hydroxyethyl ethyl cellulose and hydroxypropyl ethyl cellulose, hydroxypropyl methyl cellulose phthalate and carboxymethyl cellulose and their salts, especially sodium carboxymethylcellulose. Synthetic polymers include polyoxyethylene derivatives (polyethylene glycols) and polyvinyl derivatives (polyvinyl alcohol, polyvinylpyrrolidone and polystyrene sulfonate) and various copolymers of acrylic acid (eg carbomer). Other natural, semi-synthetic and synthetic polymers not named in this document which meet the criteria of water solubility, pharmaceutical acceptability and pharmacological inactivity are likewise considered within the scope of the present invention. An emulsifying agent is proposed to refer to a compound that aids in the formation of an emulsion. An emulsifier can be used to moisten the corticosteroid and make it more suitable for dissolution. Emulsifiers for use herein include, but are not limited to, polyoxyethylene sorbitan fatty esters or polysorbates, including, but not limited to, polyethylene sorbitan monooleate (Polysorbate 8O1®), Polysorbate 201® (monolaurate) polyoxyethylene sorbitan (20)), Polysorbate 651® (polyoxyethylene sorbitan tristearate (20)), polyoxyethylene sorbitan monooleate (20), polyoxyethylene sorbitan monopalmitate (20), polyoxyethylene sorbitan monostearate (20); lecithins; alginic acid; sodium alginate; potassium alginate; ammonium alginate; calcium alginate; propane-1, 2-diol alginate; agar; carrageenan; carob gum, guar gum; tragacanth; acacia gum; xanthan gum; karaya gum; pectin; amidated pectin; ammonium phosphatides, microcrystalline cellulose; methylcellulose; hydroxypropylcellulose; hydroxypropylmethylcellulose; ethyl methyl cellulose; carboxymethylcellulose; sodium, potassium and calcium salts of fatty acids; mono- and diglycerides of fatty acids; esters of acetic acid of mono- and di-glycerides of fatty acids; lactic acid esters of mono- and di-glycerides of fatty acids; citric acid esters of mono- and di-glycerides of fatty acids; esters of tartaric acid of mono- and di-glycerides of fatty acids; esters of mono- and di-acetyltartaric acid of mono- and di-glycerides of fatty acids; mixed esters of acetic and tartaric acid of mono- and diglycerides of fatty acids; sucrose esters of fatty acids; sucroglycerides; polyglycerol esters of fatty acids; Polyglycerol esters of polycondensed fatty acids of castor oil; propane-1,2-diol esters of fatty acids; sodium stearoyl-2-lactate; calcium stearoyl-2-lactate; stearoyl tartrate; sorbitan monostearate; sorbitan tristearate; sorbitan monolaurate; sorbitan monooleate; sorbitan monopalmitate; quilaya extract; polyglycerol esters of dimerized fatty acids from soybean oil; soybean oil polymerized by oxidation; and pectin extract. As used herein, the term "stabilizer" is intended to refer to a compound used to stabilize the therapeutic agent against physical, chemical or biochemical processes that would reduce the therapeutic activity of the agent. Suitable stabilizers include, by way of example and without limitation, albumin, sialic acid, creatinine, glycine and other amino acids, niacinamide, sodium acetyl trimophonate, zinc oxide, sucrose, glucose, lactose, sorbitol, mannitol, glycerol, polyethylene glycols, caprylate. of sodium and sodium saccharin and other stabilizers known to those of ordinary experience in the field. As used in this document, the term "Tonicity modifier" is proposed to refer to a compound or compounds that can be used to adjust the tonicity of the liquid formulation. Suitable tonicity modifiers include glycerin, lactose, mannitol, dextrose, sodium chloride, sodium sulfate, sorbitol, trehalose, and other tonicity modifiers known to those of ordinary skill in the art. Other tonicity modifiers include agents for adjusting both organic and inorganic tonicity. Tonicity modifiers include, but are not limited to, ammonium carbonate, ammonium chloride, ammonium lactate, ammonium nitrate, ammonium phosphate, ammonium sulfate, ascorbic acid, sodium bismuth tartrate, boric acid, calcium, calcium disodium edetate, calcium gluconate, calcium lactate, citric acid, dextrose, diethanolamine, dimethyl sulfoxide, disodium edetate, trisodium edetate monohydrate, sodium fluorescein, fructose, galactose, glycerin, lactic acid, lactose, magnesium, magnesium sulfate, mannitol, polyethylene glycol, potassium acetate, potassium chlorate, potassium chloride, potassium iodide, potassium nitrate, potassium phosphate, potassium sulfate, propylene glycol, silver nitrate, sodium acetate, baking soda sodium, sodium bisphosphate, sodium bisulfite, sodium borate, sodium bromide, sodium cacodylate, sodium carbonate, sodium chloride, sodium citrate, sodium iodide, lactate sodium, sodium metabisulfite, sodium nitrate, sodium nitrite, sodium phosphate, sodium propionate, sodium succinate, sodium sulfate, sodium sulfite, sodium tartrate, sodium thiosulfate, sorbitol, sucrose, tartaric acid, triethanolamine, urea, urethane, uridine and zinc sulfate. In one embodiment, the tonicity of the liquid formulation approximates the tonicity of the tissues in the respiratory tract.

An osmotic agent can be used in the compositions to improve the overall comfort for the patient with the delivery of the corticosteroid composition. Osmotic agents can be added to adjust the tonicity of solutions containing SAE-CD. Osmolality is related to the concentration of SAE-CD in water. At SBE7-β-CD concentrations less than about 11-13% w / v, solutions are hypotonic or hypoosmotic with respect to blood and at SBE7-β-CD concentrations greater than about 11-13% w / v Solutions containing SBE7-ß-CD are hypertonic or hyperosmotic with respect to blood. When red blood cells are exposed to solutions that are hypo- or hypertonic, they can shrink or swell, which can lead to hemolysis. As noted above and in Figure 1, SBE-CD is less likely to induce hemolysis than other derivatized cyclodextrins. Suitable osmotic agents include any low molecular weight water soluble species that is pharmaceutically approved for pulmonary and nasal delivery, such as sodium chloride, lactose and glucose. The formulation of the invention may also include biological salt (s), potassium chloride or other electrolyte (s). As used herein, the term "antifoam agent" is intended to refer to a compound or compounds that prevent or reduce the amount of foam that is formed on the surface of the liquid formulation. Suitable defoaming agents include dimethicone, simethicone, octoxynol, ethanol and other antifoaming agents known to those of ordinary skill in the art. As used herein, the term "bulking agent" is intended to refer to a compound used to add bulk to the lyophilized product and / or to aid in the control of the properties of the formulation during lyophilization. These compounds include, by way of example and without limitation, dextran, trehalose, sucrose, polyvinylpyrrolidone, lactose, inositol, sorbitol, dimethyl sulfoxide, glycerol, albumin, calcium lactobionate and other compounds known to those of ordinary experience in the field. As used herein, the term "cryoprotectant" is intended to refer to a compound used to protect a therapeutic agent, active from physical or chemical degradation during lyophilization. These compounds include, by way of example and without limitation, dimethyl sulfoxide, glycerol, trehalose, propylene glycol, polyethylene glycol and other compounds known to those of ordinary skill in the art. A solubility enhancing agent can be added to the formulation of the invention. A solubility enhancing agent is a compound, or compounds, that improves the solubility of the active agent when they are in a liquid formulation. When this agent is present, the cyclodextrin / active agent ratio can be changed. Suitable solubility-enhancing agents include one or more organic solvents, detergents, soaps, surfactants and other organic compounds that are typically used in parenteral formulations to improve the solubility of a particular agent. Suitable organic solvents that can be used in the formulation include, for example, ethanol, glycerin, polyethylene glycols, propylene glycol, poloxomers and other solvents known to those of ordinary skill in the art. It should be understood that the compounds used in the field of pharmaceutical formulations generally serve a variety of functions or purposes. Thus, if a compound named in this document is mentioned only once or is used to define more than one term in this document, it should not be considered that its purpose or function is limited solely to that purpose or named function. An active agent contained within the present formulation may be present as its pharmaceutically acceptable salt. As used herein, "pharmaceutically acceptable salt" refers to derivatives of the described compounds wherein the active agent is modified by reacting it with an acid or a base as necessary to form an ionic bond pair. Examples of pharmaceutically acceptable salts include conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, of non-toxic organic or inorganic acids. Suitable non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfonic, sulfamic, phosphoric, nitric acid and other acids known to those of ordinary skill in the art. Salts prepared from organic acids such as amino acids, acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroximic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2 -acetoxibenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane-disulfonic, oxalic, isethionic and other acids known to those of ordinary experience in the field. The pharmaceutically acceptable salts of the present invention can be synthesized from the active, original agent containing a basic or acid portion by means of conventional chemical methods. Lists of other suitable salts are found in Remington's Pharmaceutical Sciences, 17a. ed., Mack Publishing Company, Easton, PA, 1985, the relevant description of which is incorporated by this act as a reference. The phrase "pharmaceutically acceptable" is used herein to refer to those compounds, materials, compositions and / or dosage forms that are suitable, within the scope of sound medical judgment, for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response or other problem or complication, commensurate with a reasonable benefit / risk ratio. As used herein, the term "patient" or "subject" is taken to refer to warm-blooded animals such as mammals, e.g., cats, dogs, mice, guinea pigs, horses, cows, sheep and humans. A formulation of the invention will comprise an active agent that is present in an effective amount.

By the term "effective amount" is meant the amount of active agent that is sufficient to produce the required or desired response or, in other words, the amount that is sufficient to produce a biological response, appreciable when administered to a subject. In view of the above description and the subsequent examples, a person of ordinary experience in the field will be able to practice the invention as claimed with proper experimentation. The foregoing will be better understood with reference to the following examples which detail certain procedures for the preparation of formulations according to the present invention. All references made to those examples are for the purpose of illustration. The following examples should not be considered as exhaustive, but only as illustrative of only some of the many embodiments contemplated by the present invention.

EXAMPLE 1 Exemplary formulations according to the invention were made according to the following general procedures. Method A The cyclodextrin is dissolved in water (or buffer) to form a solution containing a known concentration of cyclodextrin. This solution is mixed with an active agent in solid, suspension, gel, liquid, paste, powder or other form while mixing, optionally while heating to form an inhalable solution. Method B A known amount of substantially dry cyclodextrin is mixed with a known amount of a substantially dry active agent. A liquid is added to the mixture to form a suspension, gel, solution, syrup or paste while mixing, optionally while heating and optionally in the presence of one or more different excipients, to form an inhalable solution. Method C A known amount of substantially dry cyclodextrin is added to a suspension, gel, solution, syrup or paste comprising a known amount of active agent while mixing, optionally while heating and optionally in the presence of one or more different excipients, for form an inhalable solution. The methods of this example can be modified by the inclusion of a wetting agent in the composition to facilitate dissolution and the subsequent inclusion complexation of the corticosteroid.

A surfactant, soap, detergent or emulsifying agent can be used as a wetting agent. As noted in this document, other excipients typically incorporated in inhalable formulations are optionally included in the present formulations.

EXAMPLE 2 The MMD of nebulized solutions containing SBE7-β-CD and budesonide was determined as follows. The placebo solutions of three different cyclodextrins were prepared in different concentrations. Two ml of the solutions were added to a Pari LC Plus1® nebulizer cup supplied with air from a Pari Proneb Ultra1® compressor. The particle size of the emitted droplets was determined using a Malvern Mastersizer S laser light scattering instrument.

EXAMPLE 3 The stability of the liquid formulations containing SAE-CD was determined by means of CLAR chromatography of aliquots periodically extracted from the liquid in storage. The buffer solutions of citrate-phosphate (Mcllvaines) at a pH of 4, 5, 6, 7 or 8 were prepared by mixing several portions of 0.01 M citric acid with 0.02 M Na2HP04. These stock solutions contained 5% w / w of Captisol1®. Approximately 250 μg / mL of budesonide was dissolved in each buffer. The aliquots of the solutions were stored at 40 ° C, 50 ° C and 60 ° C. The control samples were stored at 5 ° C but are not reported here. The HPLC analysis of the samples was carried out initially and after 1, 2 and 3 months of storage. CLAR conditions included: EXAMPLE 4 The viscosity of the aqueous solutions containing SAE-CD was measured using a cone and plate viscometer. A Brookfield Programmable Rheometer III-III +, cone CPE-4 and plate CPE 40Y (Brookfield Engineering Laboratories, Middleboro, MA) were used to make the measurements in samples of 0.5 ml at 1, 2, 3, 5 and 10 rpm. The samples were rotated for approximately 5 revolutions before each measurement. This allowed the accurate rheological characterization of the samples. The temperature of all samples was equilibrated to 25 +/- 1 degree centigrade using a double wall viscometer cone supplied with water from a circulating, thermostatic, electronically controlled water bath (Model 8001, Fisher Scientific, Pittsburgh, PA). The viscometer was calibrated using 5 and 50 centipoises using calibration standards of silicon oil. The viscosity measurements were made at 5 or more rotation speeds to observe the slimming behavior per turn (viscosities that decrease as the rotation speed increases). Higher rotation speeds result in increased speeds of rotation.

EXAMPLE 5 The exit velocity of the nebulizer as a function of the concentration of SAE-CD was measured according to the following general procedure. The Nebulizer Output was tested using a Pari LC Plus1® Nebulizer with a Pari ProNeb Ultra Air1® Compressor (Minimum Nebulizer Volume = 2 mL, Maximum Nebulizer Volume = 8 mL) for solutions containing 43%, 21.5% , 10.75% and 5.15% w / w of SBE7-ß-CD. The percentage of sample emitted was calculated gravimetrically. The nebulizer cup was weighed before and after the nebulization was completed. The nebulization time was defined as the duration time when the nebulizer conduction was started up to the time of the first spray. The Nebulizer Output Speed was calculated by dividing the% Emitted with the Nebulization Time.

EXAMPLE 6 Preparation of an inhalable solution containing budesonide. A buffer solution containing 3 mM Citrate Buffer and 82 mM NaCl at pH 4.45 is prepared. ~ 12.5 grams of CAPTISOL1® were placed in a 250 ml volumetric flask. ~ 62.5 mg of budesonide were placed in the same flask. The flask was brought to a volume with the solution of 3 mM citrate buffer / 82 mM NaCl. The flask was suitably mixed in a centrifuge for 10 minutes and sonicated for 10 minutes. The flask was stirred over the weekend with a magnetic stirrer. Stirring was stopped after ~62 hours and the flask was centrifuged and sonicated again for 10 minutes each time. The solution was filtered through a Durapore Millex-GV Millipore 0.22 μm syringe filtration unit. Some of the first drops were discarded before filtering the rest of the solution in an amber glass jar with a screw cap with a Teflon coating. The concentration of the sample was ~ 237 μg / ml.

EXAMPLE 7 Preparation of an inhalable solution containing budesonide. Approximately 5 grams of CAPTISOL1® were placed in a volumetric flask with a capacity of 100 mL. ~ 26.3 mg of budesonide were placed in the same flask. The flask was brought to a volume with the solution of 3 mM citrate buffer / 82 mM NaCl. The mixture was suitably combined in a centrifuge for 10 minutes and sonicated for 10 minutes. The mixture was stirred overnight with a magnetic stirrer. Stirring was stopped after ~ 16 hours and the flask was centrifuged and sonicated again for 10 minutes each. The solution was filtered through a Durapore Millex-GV Millipore 0.22 μm syringe filtration unit. The first 5 drops were discarded before filtering the rest of the solution in an amber glass jar with a screw cap with Teflon coating. The sample was analyzed to be 233 μg budesonide / ml.

EXAMPLE 8 Preparation of an inhalable solution containing budesonide. The procedure of Example 7 was followed except that 12.5 g of CAPTISOL1®, 62.5 mg of budesonide and about 250 ml of buffer were used. Enough disodium EDTA was added to prepare a solution having an EDTA concentration of about 0.01 or 0.05% w / v EDTA.

EXAMPLE 9 Preparation of a solution containing SAE-CD and budesonide prepared from a PULMICORT RESPULES1® suspension. Method AA the contents of one or more packages of Pulmicort Respules1® (nominally 2 mL of the suspension), approximately 50 mg (corrected for the water content) of CAPTISOL1® per mL of Respule1® were added and mixed or shaken adequately during several minutes After resting for approximately 30 minutes to several hours, the solution was used as it was for the in vitro characterization. In addition to budesonide and water, the PÜLMICORT RESPULE1® (suspension) also contains the following inactive ingredients according to the label: citric acid, sodium citrate, sodium chloride, disodium EDTA and Polysorbate 801®. Method B Amounts of approximately 200 mg of CAPTISOL1® (corrected for water content) were weighed in amber-colored flasks of 54.7 g (2 drachms). In each vial containing the heavy amount of CAPTISOL1®, the contents of two Pulmicort Respules1® containers were poured (0.5 mg / 2 mL, Lot # 308016 Feb05) by gently pressing the deformable plastic container to the last possible drop.

The Respules1® containers were previously swirled to resuspend the budesonide particles. The vials are closed with screw caps, they are mixed vigorously by centrifuge and then wrapped with thin sheets of metal. The material is kept refrigerated until its use. The liquid, inhalable composition that is prepared according to any of these methods can be used in any known nebulizer. By converting the suspension to a liquid, an improvement in the supply of budesonide (a corticosteroid) is observed.

EXAMPLE 10 Other solutions according to the invention can be prepared as described below.

Concentrate A at a ratio of 1 to 4 with citrate buffer with saline at pH 4.5 (4 mM containing 109 mM sodium chloride) containing 5% w / v CAPTISOL1® in an anhydrous base. Filter the diluted concentrate through a Millipore Durapore Millex-GV 0.22 μm syringe filtration unit. Test the filtered solution by means of HPLC, then add complementary budesonide as necessary to provide a final solution concentration of approximately 250 μg / mL (± < 5%). • Dilute Concentrate B to a ratio of 1 to 4 with citrate buffer with saline at pH 4.5 (4 mM containing 109 mM sodium chloride) containing 5% w / v CAPTISOL1® in an anhydrous base. Filter the diluted concentrate through a Millipore syringe filtration unit Durapore Millex-GV 0.22 μm. Test the filtered solution by means of HPLC, then dilute further with citrate buffer with saline to pH 4.5 (3 mM containing 82 mM sodium chloride) as required to provide a final solution concentration of approximately 250 μg. / mL (± < 5%). This technique takes advantage of the excess of solid budesonide used to saturate the solution.

EXAMPLE 11 The clarity of the solutions was determined by visual inspection or by means of instruments. A clear solution is at least clear by visual inspection with the naked eye.

EXAMPLE 12 The following method was used to determine the performance of nebulization compositions emitted from a nebulizer according to FIGS. 10A-10B. Two ml of the test CD solution or Pulmicort1® suspension were accurately transferred by volumetric pipettes into a clean nebulizer cup before beginning each experiment. The test nebulizer was assembled and loaded with the test solution or suspension for inhalation according to the manufacturer's instructions. The end of the nozzle was placed at a height of approximately 18 cm from the platform of MALVERN MASTERSIZER1® to the midpoint of the tip of the nozzle of the nebulizer. A vacuum source was placed in a location opposite the nozzle separated by approximately 6 cm to recover the aerosol after calibration. The distance between the nozzle and the detector was approximately 8 cm. The center of the nozzle was leveled with the laser beam (or adjusted as appropriate, depending on the individual design of each nebulizer). The laser beam was passed through the center of the emitted cloud when the nebulizer was operated. The measurements were started manually after 15 seconds of nebulization. The data collection started when the occultation of the beam reached 10% and averaged over ,000 sweeps (30 seconds). The data of the intensity of light scattered on the rings of the detector were displayed using the "Standard-Wet" model. Channels 1 and 2 were removed due to a low relative humidity during the measurement to prevent beam guidance. The diameter in volume of the droplets defining 10, 50 was determined (median volume) and 90% of the accumulated volume subdivision (DvlO is the smaller size at which there is 10% of the volume of the material, Dv50 is the smaller size at which there is 50% of the volume of the material and Dv90 is the smaller size to which there is 90% of the volume of the material).

EXAMPLE 13 Solutions of budesonide with and without SBE7-β-CD were prepared at two different pHs (4 and 6) and stored at 2 different temperatures (60 ° C and 80 ° C). The citrate buffers (50 mM) in each pH value were prepared by mixing different portions of solutions of 50 mM citric acid and 50 M sodium citrate (tribasic, dihydrate). To achieve a budesonide concentration in the buffers without sufficient SBE7-β-CD for accurate measurement, budesonide was first dissolved in 100% ethyl alcohol. Then an aliquot of the ethanol / budesonide solution was added dropwise with stirring to each buffer solution. The theoretical budesonide concentration was 100 μg / mL with a final ethanolic content of 5% in each buffer. All the preparations and procedures of the solutions involving budesonide were performed in a dark room under red light. After stirring the solutions for 24 hours, both buffer solutions were filtered through Millipore Millex-GV 0.22 μm syringe filters to remove any solid that had precipitated (no significant amounts were observed) from the solutions. The final budesonide concentration was approximately 50 μg / mL. The solutions at both pH 4 and pH 6 were divided in two and solid SBE7-β-CD was added to one portion to create solutions with and without 1% w / v of SBE7-β-CD at each pH. Each solution was apportioned within individual amber-colored vials. Then they were placed in ovens at 60 ° C and at 80 ° C. The sample flasks were removed from the ovens and analyzed by means of the HPLC at 0, 96, 164 and 288 hours. The HPLC test conditions are summarized below.

Chromatographic Conditions (Adapted from Hou, S., Hindle, M., and Byron, P.R.A. Stablity-Indicating HPLC Assay Method for Budesonide.

Journal of Pharmaceutical and Biomedical Analysis, 2001, 24: 371-380) EXAMPLE 14 Preparation and use of a combination solution containing SAE-CD, budesonide and albuterol sulfate. A solution of budesonide is prepared according to EXAMPLE 9 (mix SAE-CD with PULMICORT RESPULES1® suspension) and added to 3 ml of a solution containing 2.5 mg of albuterol (the name recommended by the World Health Organization for the base of albuterol is salbutamol) provided as albuterol sulfate. The albuterol solution is commercially available, previously diluted and sold under the name PROVENTIL1® Inhalation Solution, 0.083% or prepared from a commercially available 0.5% concentrate (sold under the names: PROVENTIL1® Solution for Inhalation and Solution) for VENTOLIN1® Inhalation). To provide the required dose for children 2 to 12 years of age, the initial dosage should be based on body weight (0.1 to 0.15 mg / kg per dose), with a subsequent dosage titrated to achieve the desired clinical response. The dosage should not exceed 2.5 mg three to four times a day by nebulization. The appropriate volume of the 0.5% inhalation solution should be diluted in saline, normal, sterile to a total volume of 3 L before administration via nebulization. To provide 2.5 mg, 0.5 mL of the concentrate is diluted to 3 mL with saline, normal, sterile. Aqueous solutions of albuterol also contain benzalkonium chloride: and sulfuric acid is used to adjust the pH between 3 and 5. Alternatively, an aqueous solution of an appropriate albuterol resistance can be prepared from albuterol sulfate, USP with or Without the preservative added benzalkonium chloride and pH adjustment using sulfuric acid may also be unnecessary when combined with the corticosteroid solution. In addition, the volume containing the appropriate dose of corticosteroid can be decreased four times as described in the following example allowing the total volume to be lower and consequently the time of administration to decrease.

EXAMPLE 15 Preparation and use of a combination solution containing SAE-CD, budesonide and albuterol sulfate or levalbuterol HCl (Xopenex). A citrate buffer (3 mM pH 4.5) was prepared as follows. Approximately 62.5 mg of citric acid was dissolved in and brought to volume with water in a volumetric flask with a capacity of 100 L. Approximately 87.7 mg of sodium citrate was dissolved in and brought to volume with water in another volumetric flask with capacity for 100 mL. In a beaker, the sodium citrate solution was added to the citric acid solution until the pH was about 4.5. Approximately 10.4 mg of budesonide and 1247.4 mg of Captisol1® were ground together with a mortar and pestle and transferred to a flask with a capacity of 10 mL. The buffer solution was added and the mixture was swirled, sonicated and an additional 1.4 mg of budesonide was added. After stirring overnight, the solution was filtered through a Durapore Millex-GV Millipore 0.22 μm syringe filtration unit. The resulting concentration of budesonide was ~ 1 mg / ml.

Approximately 0.5 ml of the budesonide solution was added to a unit dose of either Proventil1® (2.5 mg / 3 ml) or Xopenex1® (1.25 mg / 3 ml) forming the liquid, clear, combination dosage form of the invention. The resulting mixture was kept essentially clear for a period of at least 17 days at room temperature under protected light conditions.

EXAMPLE 16 Preparation and use of a combination solution containing SAE-CD, budesonide and formoterol (FORADIL1® (powder for inhalation of formoterol fumarate)). The contents of a capsule containing 12 mcg of formoterol fumarate combined with 25 mg of lactose were poured into a vial to which 3 mL of 3 mM citrate buffer (pH 4.5) prepared as described in the previous example was added. The contents of the vial were swirled to dissolve the solids present. The budesonide concentrate was prepared as described in the previous example to provide a concentration of ~ 1 mg / ml. Approximately 1 ml of the budesonide solution was added to the buffered formoterol fumarate solution. The resulting solution remained essentially clear for a period of at least one month at room temperature under protected light conditions.

EXAMPLE 17 The clinical evaluation of a dosage form according to the invention was conducted by performing scintigraphy analysis on subjects before and after administration of the dosage form by means of nebulization. A single-center, four-way crossover study was conducted to compare the pulmonary supply of budesonide via the budesonide formulations Pulmicort Respules1® and Captisol-Enabled1® using a Pari LC1® air-powered jet nebulizer. The purpose of the study was to determine, by means of scintigraphy, the intrapulmonary deposition of radiolabeled budesonide after the nebulization of a budesonide suspension (Pulmicort Respules11®, Astra Zeneca, reference formulation) and a budesonide solution Captisol-Enabled1® ( test formulation) in voluntary, healthy men. The dosage was conducted using a Pari LC Plus1® air-driven jet nebulizer. The use of scintigraphy in conjunction with a radiolabelled study drug and / or vehicle is the standard technique for the quantitative assessment of lung deposition and clearance of inhaled drugs and / or vehicle. The dosage forms of the study consisted of: 1) 1 mg of Budesonide as 2 mL x 0.5 mg / mL of Pulmicort Respules1®; or 2) 1 mg of Budesonide as 2 mL x 0.5 mg / mL of Pulmicort Respules1® to which 7.5% w / v of Captisol1® had been added. Each subject received each of the four administrations of the radiolabeled Budesonide study in a nonrandomized manner. A non-randomized design was used for this study since the reference formulation (Pulmicort Respules1®) must be administered first to all subjects in order to determine the time for spraying (TTS)., for its acronym in English) . The TTS was different between the subjects. For subsequent administrations, the administered dose was controlled by means of the length of administration, expressed as a fraction of the time for the spray determined after administration of the reference formulation (ie 25% TTS, 50% TTS and 75% of TTS). It was expected that although the same concentration of budesonide would be nebulized for a shorter time, the amount of drug reaching the lungs of the volunteers would be essentially the same as the reference suspension for one of the bifurcations in the study. The scintigraphic images were acquired using a gamma camera immediately after completing the dosing of the volunteers. Comparison of the reference product image and the 25% TTS bifurcation indicated that a higher percentage of Respule1® budesonide was in the stomach and throat immediately after administration. In this way, a greater percentage of budesonide reached the lung tissue, target when Captisol1® was used to dissolve budesonide. This could reduce the unwanted side effects that are caused by the drug. One aspect of the method and dosage form of the invention thus provides an improved method for administering a unit dosage based on corticosteroid suspension, the method comprising the step of adding a sufficient amount of SAE-CD to convert the suspension to a clear solution and then administer the clear solution to a subject. As a result, the method of the invention provides an increased rate of administration as well as an increased, total, pulmonary delivery of the corticosteroid compared to the formulation based on initial unit dose suspension. EXAMPLE 18 Comparative evaluation of various forms of SAE-CD in the solubilization of corticosteroid derivatives. The solubility of beclomethasone dipropionate (BDP), 17-beclomethasone monopropionate was evaluated (B17P), 21-beclomethasone monopropionate (B21P) and beclomethasone (non-esterified) in solutions containing CAPTISOL MR and several SBEn? -CD. The BDP, B17P and B21P were obtained from Havione. Beclomethasone was obtained from Spectrum Chemicals. CAPTISOL1®, SBE (3.4)? -CD, SBE (5.23)? -CD and SBE (6.1)? -CD were provided by CyDex Inc. (Lenexa, KS). The? -CD was obtained from Wacker Chemical Co. The SBE (5.24)? -CD and the SBE (7.5)? -CD were provided by the University of Kansas. A 0.04 M solution of each selected CD was prepared. Each form of beclomethasone required 2 ml of CD solution, therefore 0.04 M solutions were prepared in volumetric flasks with a capacity of 20 or 25 mL in duplicate (N = 2). The following table indicates the amount of each CD used after counting the water content in each CD.

The beclomethasone forms were weighed in amounts exceeding anticipated solubilities directly in teapron-capped flasks of 54.7 g (2 drams). Typically, these amounts provided approximately 6 mg / mL of solids. Each vial then received 2 mL of the appropriate CD solution. The flasks were swirled and sonicated for approximately 10 minutes to assist in the wetting of the solids with the fluid. The vials were then wrapped in a thin sheet of aluminum to protect them from light and placed on a shaker-creating laboratory device for balance. The bottles were inspected periodically to ensure that the solids were being properly moistened and in contact with the fluid. The time points for sampling were 24 hours for all samples and 72 hours for BDP only. The solutions of SBE (6.1)? -CD were prepared to 0. 04, 0.08 and 0.1 M and SBE (5.23)? - CD solutions were prepared only at 0.04 and 0.08 M. Beclomethasone dipropionate was weighed in quantities exceeding the anticipated solubilities directly in the Teflon-coated screw-cap vials of 54.7 g (2 drachms). Typically, these amounts provided approximately 2 mg / mL of solids. Each vial then received 2 mL of the appropriate CD solution (N = 1). The flasks were swirled and sonicated for approximately 10 minutes to assist in the wetting of the solids with the fluid. The vials were then wrapped in a thin sheet of aluminum to protect them from light and placed in a laboratory tremor creator for a five-day equilibrium. The? -CD solutions were prepared at 0.01 and 0.02 M. Beclomethasone dipropionate was weighed in amounts exceeding anticipated solubilities directly in the Teflon-coated screw-cap vials of 54.7 g (2 drams). Typically, these amounts provided approximately 2 mg / mL of solids. Each vial then received 2 mLs of the? -CD solution (N = 2). A solution was also prepared to measure the intrinsic solubility of BDP using water with CLAR grade instead of CD. The samples were wrapped in a thin sheet of metal and placed on a tremor-producing laboratory device for five days.

At the end of the equilibrium time for each stage, the flasks were centrifuged and 1 ml of the supernatant was removed. The removed supernatant was then filtered using the Durapore PVDF 0.22 μm syringe filter (some of the first drops were discarded) and diluted with the mobile phase to an appropriate concentration within the standard curve. The samples were then analyzed by means of the HPLC to determine the concentration of the solubilized corticosteroid.

EXAMPLE 19 Preparation and use of a combination solution containing SAE-CD, budesonide and formoterol fumarate. The formoterol fumarate dry powder is combined with dry powder of Captisol1® which are appropriately sized to provide a uniformity of content in a weight ratio of 12 mcg formoterol fumarate / 100 mg of Captisol1®. An amount of the powder combination corresponding to a unit dose of formoterol fumarate is placed in a suitable individual unit dose container such as an HPMC capsule for later use or is added directly to a unit dose of suspension for inhalation of budesonide Pulmicort Respules1® (500 mcg / 2 mL), then mixed to achieve the dissolution of all solids (a clear solution) and placed in the reservoir of the nebulizer for administration.

EXAMPLE 20 Preparation and use of a combination solution containing SAE-CD, budesonide and ipratropium bromide. A solution of budesonide is prepared according to EXAMPLE 9 and is added to a solution of ipratropium bromide that is commercially available and sold under the name Unit Dose of Inhalation Solution ATROVENT1®. The Solution for Inhalation ATROVENT1® (ipratropium bromide) is 500 mcg (a unit dose vial) administered three to four times a day by oral inhalation, with doses separated by 6 to 8 hours. The unit dose vials of the ATROVENT1® inhalation solution contain 500 mcg of anhydrous ipratropium bromide in 2.5 ml of a saline solution, isotonic, preservative-free, sterile, the pH is adjusted to 3.4 (3 to 4) with acid hydrochloric. In addition, the volume containing the appropriate dose of corticosteroid can be lowered four times as described in the previous example (budesonide concentrate ~ 1 mg / mL) allowing the total volume to be lower and consequently the time of administration to decrease.

The foregoing is a detailed description of the particular embodiments of the invention. It will be appreciated that, although the specific embodiments of the invention have been described in this document for purposes of illustration, various modifications may be made without departing from the spirit and scope of the invention. Accordingly, the invention is not limited except by the appended claims. All the modalities described and claimed in this document can be elaborated and executed without undue experimentation in view of the present description.

Claims (33)

1. A method for providing the administration of a unit dose formulation based on suspension containing a corticosteroid, inhalable to a subject by means of nebulization, the method is characterized in that it comprises the steps consisting in: providing in a unit dose a formulation based in aqueous suspension comprising water and a corticosteroid suspended therein; combining the suspension with an amount of SAE-CD sufficient for and for a period of time sufficient to increase the amount of corticosteroid solubilized in the formulation to constitute an altered formulation; and administering the altered formulation to the subject.

2. The method according to claim 1, characterized in that it further comprises one or more therapeutic agents independently selected from each occurrence of the group consisting of a B2 adrenoreceptor agonist, a dopamine receptor agonist (D2), topical anesthetic, agent anticholinergic, inhibitor of IL-5, antisense modulator of IL-5, milrinone (1,6-dihydro-2-methyl-6-oxo- [3,4'-bipyridine] -5-carbonitrile); Milrinone lactate; Trypta inhibitor, tachykinin receptor antagonist, leukotriene receptor antagonists, 5-lipoxygenase inhibitor and anti-IgE antibody.

The method according to claim 2, characterized in that the adrenoreceptor agonist B2 is selected from the group consisting of Albuterol (alpha 1 - (((1,1-dimethylethyl) amino) methyl) -4-hydroxy-1,3 -benzenedimethanol); Bambuterol (5- (2 - ((1, 1-dimethylethyl) amino) -1-hydroxyethyl) -1,3-phenylenyl ester of dimethylcarbamic acid); Bitolterol (4- (2- ((1,1-dimethylethyl) amino) -1-hydroxyethyl) -1,2-phenylenyl ester of 4-methylbenzoic acid); Broxaterol (3-bromo-alpha- (((1,1-dimethylethyl) amino) methyl) -5-isoxazolemethanol); Isoproterenol (4- (1-hydroxy-2- ((1-methylethyl) amino) ethyl) -1,2-benzenediol); Trimethoquinol (1, 2, 3, 4-tetrahydro-1 - ((3, 4, 5-trimethoxyphenyl) -methyl) -6,7-isoquinolindiol); Clenbuterol (4-amino-3,5-dichloro-alpha- (((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- ((1RS) -l-hydroxy-2- (((1RS) -2- (p-methoxyphenyl) -1-methylethyl) amino) ethyl) formanilide); (R, R) -Formoterol; Desformoterol ((R, R) or (S, S) -3-amino-4-hydroxy-alpha- (((2- (4-methoxyphenyl) -1-methyl-ethyl) amino) methyl) -benzenemethanol); Hexoprenaline (4, 4 '- (1,6-hexane-diyl) -bis (imino (l-hydroxy-2, 1-ethanediyl))) bis-1,2-benzenediol); Isoetharine (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); Picumeterol (4-amino-3,5-dichloro-alpha- (((6- (2- (2-pyridinyl) ethoxy) hexyl) -amino) methyl) benzenemethanol); Pirbuterol (alpha 6 - (((1,1-dimethylethyl) -amino) methyl) -3-hydroxy-2,6-pyridinemethanol); Procaterol (((R *, S *) - (+/-) -8-hydroxy-5- (l-hydroxy-2- ((1-methylethyl) amino) butyl) -2 (ÍH) -quinolin-one); Reproterol ((7- (3- ((2- (3,5-dihydroxyphenyl) -2-hydroxyethyl) amino) -propyl) -3,7-dihydro-l, 3-dimethyl-lH-purine-2,6 -dione); Rimiterol (4- (hydroxy-2-piperidinylmethyl) -1,2-benzenediol); Salbutamol ((+/-) -alpha1- (((1,1-dimethylethyl) amino) methyl) -4-hydroxy -l, 3-benzenedimethanol); (R) -Salbutamol; Salmeterol ((+/-) -4-hydroxy-alpha 1 - (((6- (4-phenylbutoxy) hexyl) -amino) methyl) -1, 3- benzenedimethanol); (R) -Salmeterol; Terbutaline (5- (2- ((1,1-dimethylethyl) amino) -1-hydroxyethyl) -1,3-benzenediol); Tulobuterol (2-chloro-alpha- ((( 1, 1-dimethylethyl) amino) -methyl) benzenemethanol) and TA-2005 (8-hydroxy-5- ((IR) -l-hydroxy-2- (N- ((IR) -2- (4- methoxyphenyl) -1-methylethyl) -amino) ethyl) carbostyril) 4.

The method according to claim 2, characterized in that the dopamine receptor agonist (D2) is selected from the group consisting of Apomorphine ((r) -5, 6, 6a, 7-tetrahydro-6-methyl-4H-dibenzo [de, g] quinolih-10, 11-diol); Bromocriptine ((5'alpha) -2-bromo-12 '-hydroxy-2' - (1-methylethyl) -5 '- (2-methylpropyl) -ergotaman-3', 6 ', 18-trione); Cabergoline ((8-beta) -N- (3- (dimethylamino) propyl) -N- ((ethylamino) carbonyl) -6- (2-propenyl) ergoline-8-carboxamide); Lisuride (N '- ((8-alpha-) -9,10-didehydro-6-methylergolin-8-yl) -N, N-diethylurea); Pergolide ((8-beta-) -8- ((methylthio) methyl) -6-propylergoline); Levodopa (3-hydroxy-L-tyrosine); Pramipexole ((s) -4, 5, 6, 7-tetrahydro-N6-propyl-2,6-benzothiazoldiamine); Quinopyrol 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).

The method according to claim 2, characterized in that the anticholinergic agent is selected from the group consisting of ipratropium bromide, oxitropium bromide, atropine methyl nitrate, atropine sulfate, ipratropium, belladonna extract, scopolamine, methobromide of scopolamine, homatropine metobromide, hyoscyamine, isopriopramide, orphenadrine, benzalkonium chloride, tiotropium bromide and glycopyrronium bromide.

The method according to claim 1, characterized in that the topical anesthetic is selected from the group consisting of lidocaine, N-arylamide, aminoalkylbenzoate, prilocaine and etidocaine.

The method according to claim 1, characterized in that the corticosteroid is selected from the group consisting of aldosterone, beclomethasone, betamethasone, budesonide, ciclesonide, cloprednol, cortisone, cortivazole, desoxicortone, desonide, deoximetasone, dexamethasone, difluorocortolone, fluclorolone, Flumetasone, flunisolide, fluocinolone, fluocinonide, butyl fluocortin, fluorocortisone, fluorocortolone, fluorometholone, flurandrenolone, fluticasone, halcinonide, hydrocortisone, icometasone, meprednisone, methylprednisolone, mometasone, parametasone, prednisolone, prednisone, rofleponide, RPR 106541, tixocortol, triamcinolone and their respective pharmaceutically acceptable derivatives.

8. The method according to claim 7, characterized in that the corticosteroid derivative is selected from the group consisting of beclomethasone dipropionate, beclomethasone monopropionate, dexamethasone 21-isonicotinate, fluticasone propionate, icometasone enbutate, 21-pivalate tixocortol and triamcinolone acetonide.

The method according to claim 1, characterized in that the corticosteroid is selected from the group consisting of beclomethasone dipropionate, budesonide, flunisolide, fluticasone propionate, mometasone furoate and triamcinolone acetonide.

The method according to claim 1, characterized in that the SAE-CD is present in an amount sufficient to solubilize at least 90% of the corticosteroid.

The method according to claim 1, characterized in that the SAE-CD is present in an amount sufficient to solubilize at least 95% of the corticosteroid.

The method according to claim 11, characterized in that the SAE-CD is present in an amount sufficient to solubilize enough corticosteroid in such a way that the solution-based formulation is a substantially clear solution containing less than 5% by weight of solid corticosteroid 13.

The method according to claim 1, characterized in that the molar ratio of the corticosteroid to the SAE-CD is in the range of about 1: 2 to about 1: 10,000.

The method according to claim 1, characterized in that the solution-based formulation further comprises a conventional preservative, antioxidant, buffering agent, acidifying agent, solubilizing agent, dye, complexing enhancing agent, saline, electrolyte, another therapeutic agent, alkalizing agent, tonicity modifier, surface tension modifier, viscosity modifier, density modifier, volatility modifier, antifoaming agent, flavoring agent, sweetener, hydrophilic polymer or a combination thereof.

15. The method according to claim 1, characterized in that the solution-based formulation has a shelf life of at least 6 months.

16. The method according to claim 1, characterized in that it also comprises a liquid carrier different from water.

17. The method according to claim 1, characterized in that the formulation comprises less than or about 21.5% ± 5% w / w of SAE-CD.

18. The method according to claim 1, characterized in that the SAE-CD is present in an amount sufficient to dissolve at least 50% by weight of the corticosteroid.

19. A method for preparing a nebulisable corticosteroid-containing, liquid unit dose formulation comprising the steps of: providing a unit dose formulation based on suspension comprising an aqueous liquid carrier and a corticosteroid suspended therein; wherein the corticosteroid is present in a concentration of about 20 mcg to about 30 mg of corticosteroid per ml of suspension; and mixing the SAE-CD with the unit dose formulation based on suspension to constitute a liquid, nebulizable unit dose formulation, wherein the SAE-CD is present in an amount sufficient to solubilize at least a larger portion of the corticosteroid.

The method according to claim 19, characterized in that the SAE-CD is present in the liquid formulation in a concentration of about 10 to about 500 mg of SAE-CD per ml of liquid formulation.

21. The method according to claim 19, characterized in that the molar ratio of corticosteroid to SAE-CD is in the range of about 1: 1 to about 1: 10,000.

22. Equipment adapted for the preparation of a unit dose, inhalable liquid formulation, the kit is characterized in that it comprises: a first composition comprising a unit dose formulation based on suspension comprising a corticosteroid suspended within an aqueous carrier; and a second separate composition comprising an SAE-CD, wherein the SAE-CD is present in an amount sufficient to increase the amount of corticosteroid dissolved when the first and second compositions are mixed; wherein the first and / or second compositions optionally comprise one or more different components.

23. The equipment according to claim 22, characterized in that the second composition is a dry solid, wet solid, semi-solid or glass.

24. The equipment according to claim 22, characterized in that the second composition comprises a liquid carrier.

25. The kit according to claim 22, characterized in that the unit dose liquid formulation further comprises one or more therapeutic agents independently selected at each occurrence from the group consisting of a β2-adrenoreceptor agonist, a dopamine receptor agonist (D2). ), anticholinergic agent, topical anesthetic, IL-5 inhibitor, IL-5 antisense modulator, milrinone (1,6-dihydro-2-methyl-6-oxo- [3,4'-bipyridin] -5-carbonitrile); Milrinone lactate; Tryptase inhibitor, tachykinin receptor antagonist, leukotriene receptor antagonist, 5-lipoxygenase inhibitor and anti-IgE antibody.

26. The kit according to claim 25, characterized in that the β2-adrenoreceptor agonist is selected from the group consisting of Albuterol (alpha 1 - (((1,1-dimethylethyl) amino) methyl) -4-hydroxy-1,3. -benzenedimethanol); Bambuterol (5- (2- ((1,1-dimethylethyl) amino) -1-hydroxyethyl) -1,3-phenylenyl ester of dimethylcarbamic acid); Bitolterol (4- (2- ((1,1-dimethylethyl) amino) -1-hydroxyethyl) -1,2-phenylenyl ester of 4-methylbenzoic acid); Broxaterol (3-bromo-alpha- (((1,1-dimethylethyl) amino) methyl) -5-isoxazolemethanol); Isoproterenol (4- (l-hydroxy-2- ((1-methylethyl) amino) ethyl) -1,2-benzenediol), - trimethoquinol (1,2,3,4-tetrahydro-1 - (3,4,5) -trimethoxyphenyl) -methyl) -6,7-isoquinolindiol); Clenbuterol (4-amino-3,5-dichloro-alpha- (((1,1-dimethylethyl) amino) methyl) -benzenemethanol); Fenoterol (5- (1-hydroxy-2- ((2- (4-hydroxyphenyl) -1- ethylethyl) amino) ethyl) -1,3-benzenediol); Formoterol (2-hydroxy-5- ((1RS) -l-hydroxy-2- (((1RS) -2- (p-methoxyphenyl) -1-methylethyl) amino) ethyl) formanilide); (R, R) -Formoterol; Desformoterol ((R, R) or (S, S) -3-amino-4-hydroxy-alpha- (((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); Isoetharine (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); Picumeterol (4-amino-3,5-dichloro-alpha- (((6- (2- (2-pyridinyl) ethoxy) hexyl) -amino) methyl) benzenemethanol); Pirbuterol (alpha 6 - (((1,1-dimethylethyl) -amino) methyl) -3-hydroxy-2,6-pyridinemethanol); Procaterol (((R *, S *) - (+/-) -8-hydroxy-5- (l-hydroxy-2- ((1-methylethyl) amino) butyl) -2 (ÍH) -quinolin-one); Reproterol ((7- (3- ((2- (3,5-dihydroxyphenyl) -2-hydroxyethyl) amino) -propyl) -3,7-dihydro-1,3-dimethyl-lH-purine-2,6 -dione); Rimiterol (4- (hydroxy-2-piperidinylmethyl) -1,2-benzenediol); Salbutamol ((+/-) -alpha1- (((1,1-dimethylethyl) amino) methyl) -4-hydroxy -1,3-benzenedimethanol); (R) -Salbutamol; Salmeterol ((+/-) -4-hydroxy-alpha 1 - (((6- (4-phenylbutoxy) hexyl) amino) methyl) -1,3-benzenedimethanol ); (R) -Salmeterol; Terbutaline (5- (2- ((1,1-dimethylethyl) amino) -1-hydroxyethyl) -1,3-benzenediol); Tulobuterol (2-chloro-alpha- (((1 , 1-dimethylethyl) amino) -methyl) benzenemethanol) and TA-2005 (8-hydroxy-5- ((IR) -l-hydroxy-2- (N- ((IR) -2- (4-methoxyphenyl ) -1-methylethyl) amino) ethyl) carbostyril 27.

The equipment according to claim 25, characterized in that the dopamine receptor agonist (D2) is selected from the group consisting of Apomorphine ester ((r) -5,6,6a, 7-tetrahydro-6-methyl-4H-dibenzo [de, g] -quinolin-10,11-diol); Bromocriptine ((5 'alpha) -2-bromo-12' -hydroxy-2 '- (1-methylethyl) -5' - (2-methylpropyl) ergotaman-3 ', 6', 18-trione); Cabergoline ((8-beta) -N- (3- (dimethylamino) propyl) -N- ((ethylamino) carbonyl) -6- (2-propenyl) ergoline-8-carboxamide); Lisuride (N '- ((8-alpha-) -9,10-didehydro-6-methylergolin-8-yl) -N, N-diethylurea); Pergolide ((8-beta-) -8- ((methylthio) methyl) -6-propylergoline); Levodopa (3-hydroxy-L-tyrosine); Pramipexole ((s) -4, 5, 6, 7-tetrahydro-N6-propyl-2,6-benzothiazoldiamine); Quinopyrol 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).

The equipment according to claim 25, characterized in that the anticholinergic agent is selected from the group consisting of ipratropium bromide, oxitropium bromide, atropine methyl nitrate, atropine sulfate, ipratropium, belladonna extract, scopolamide, methobromide of scopolamine, homatropine metobromide, hyoscyamine, isopriopramide, orphenadrine, benzalkonium chloride, tiotropium bromide and glycopyrronium bromide.

29. The kit according to claim 25, characterized in that the topical anesthetic is selected from the group consisting of lidocaine, N-arylamide, aminoalkyl benzoate, prilocaine and ethidocaine.

30. The kit according to claim 22, characterized in that the corticosteroid is selected from the group consisting of aldosterone, beclomethasone, betamethasone, budesonide, ciclesonide, cloprednol, cortisone, cortivazole, desoxicortone, desonide, deoximetasone, dexamethasone, difluorocortolone, fluclorolone, Flumetasone, flunisolide, fluocinolone, fluocinonide, butyl fluocortin, fluorocortisone, fluorocortolone, fluorometholone, flurandrenolone, fluticasone, halcinonide, hydrocortisone, icometasone, meprednisone, methylprednisolone, mometasone, parametasone, prednisolone, prednisone, rofleponide, RPR 106541, tixocortol, triamcinolone and their respective pharmaceutically acceptable derivatives.

31. The kit according to claim 30, characterized in that the corticosteroid derivative is selected from the group consisting of beclomethasone dipropionate., beclomethasone monopropionate, dexamethasone 21-isonicotinate, fluticasone propionate, icometasone enbutate, 21-tixocortol pivalate and triamcinolone acetonide.

32. The kit according to claim 22, characterized in that the corticosteroid is selected from the group consisting of beclomethasone dipropionate, budesonide, flunisolide, fluticasone propionate, mometasone furoate and triamcinolone acetonide.

33. The invention according to any of the preceding claims, characterized in that the cyclodextrin is a compound of the Formula 1: Formula 1 where: n is 4, 5 or 6; Ri R2, 3, 4A R5, R? R7, Rs and R9 are each, independently, -O- or a group -O- (alkylene) C2-C6) -S03", wherein at least one of Ri-R9 is independently a group -O- (C2-C6 alkylene) -S03 ~, a group -O- (CH2) mS03 ~, where m is 2 to 6, -0CH2CH2CH2S03"or -0CH2CH2CH2CH2S03"; and S2, S3, S4, S5, S6, S7, Ss and S9 are each, independently, a pharmaceutically acceptable cation.