WO2015009776A1 - Low dose corticosteroid microemulsion compositions and methods of treatments thereof - Google Patents

Abstract

This invention relates to steroidal solutions for the preparation of medicaments and drug products useful for treating diseases of the upper and lower airway passages. Various embodiments of the present invention provide mometasone furoate microemulsions that are suitable for inhalation and can be used for the treatment of diseases of the upper and/or lower airway passages.

Description

LOW DOSE CORTICOSTEROID MICROEMULSION COMPOSITIONS AND METHODS OF TREATMENTS THEREOF

[0001] FIELD OF THE INVENTION

[0002] This invention relates to low dose steroidal microemulsion compositions for the preparation of medicaments and drug products useful for treating diseases of the upper and lower airway passages.

[0003] BACKGROUND OF THE INVENTION

[0004] Rhinitis impairs the quality of life of more than 400 million people worldwide (Greiner AN, et al. Lancet. 2011 ; 378:21 12-2122.). Its symptoms, including congestion, runny noses, and post nasal drip, along with comorbid conditions of upper respiratory infections, sleep apnea, asthma, rhinosinusitis, and nasal polyps cause a loss of approximately 3.5 million work days and 2 million school days each year (Wallace DV, et al. J Allergy Clin Immunol. 2008; 122(2 suppl):S l-S84.). The symptoms increase fatigue and irritability, reduce attention span and learning ability, and impair activities of daily living. Thus rhinitis reduces productivity at work and reduces participation in leisure events with friends and family.

[0005] Other than allergy avoidance, the most effective treatments of rhinitis are intranasal corticosteroids. These anti-inflammatory agents are formulated as suspensions and delivered locally. Within the nasal cavity, they reduce cytokine and inflammatory cell infiltration, reduce endothelial and epithelial permeability, decrease the response of the mucous glands to stimulation, and reduce nasal hyperactivity, Side effects from these treatments are minor and limited to local irritation. Although corticosteroids could cause suppression of the hypothalamic-pituitary-adrenocortical (HPA) axis leading to growth suppression, they are minimal because intranasal delivery of these suspensions results in low systemic blood levels.

[0006] Several corticosteroids have been successfully formulated as aqueous suspensions. NASONEX ® (mometasone furoate), BECONASE® AQ

(beclamethasone dipropionate), NASACORT® AQ (triamcinolone acetonide), RHINOCORT® Aqua (budesonide), and FLONASE® (fluticasone propionate) are marketed nasal formulations in which the active pharmaceutical agents (APA) are suspended in a vehicle. However, there is a need for even greater efficacy than the current aqueous suspensions can provide. Many patients continue to be symptomatic despite treatment. Almost 74% of patients reported taking multiple therapies to achieve symptom control (Demoly P, et al. Allergy.2002; 57(6):546-554) Further, many experience bouts of severe symptoms while on therapy (Valovirta E, et al. Curr Opin Allergy Clin Immunol. 2008; 8: 1-9. Loh CY, et al. Allergy. 2004;59(11): 1 168-1 172). One approach to improving therapy would be to deliver the APA in dissolved form, instead of delivering a suspension formulation. A solubilized APA would be able to skip the dissolution step and be ready to permeate and act. More rapid permeation is especially important in the nasal cavity because permeation competes with mucociliary clearance, a defense that removes foreign formulation from the nasal cavity (Na L, Mao S, Wang J, Sun W. Comparison of different absorption enhancers on the intranasal absorption of isosorbide dinitrate in rats; Int J Pharm 2010 Jul 3.; Tas C, Ozkan CK, Savaser A, Ozkan Y, Tasdemir U, Altunay H. Nasal administration of metoclopramide from different dosage forms: in vitro, ex vivo, and in vivo evaluation. Drug Deliv 2009 Apr; 16(3): 167-75.). A solubilized APA could therefore have more potent local action. However, an already solubilized compound could also enter the blood stream more easily, increasing the risk of systemic exposure and HPA axis suppression. Therefore, it is desirable to deliver a lower dose of a solubilized corticosteroid, compared to the suspension products, in order to minimize the risk of systemic exposure and HPA axis suppression. Importantly, the solubilized lower dose must have the same or improved efficacy as the suspension product.

[0007] Because of their poor solubility, solvents, co-solvents, and surfactants must be used to solubilize corticosteroids. These solubilizing excipients also have the potential to increase local irritation. Further it is unknown how the amount of these excipients, in combination with a given level of the APA, could affect local efficacy, systemic exposure, or irritation. The spray characteristics of the final formulation must be such that it also deposits into the therapeutically beneficial portion of the nasal cavity. Thus it would be desirable to provide a corticosteroid dissolved in a formulation with excipient(s) whose amounts have been optimized to deliver to the therapeutically beneficial portions of the nasal cavity, provide high local efficacy, low systemic exposure, and negligible local irritation when delivered intranasally. [0008] U.S. Patent No. 6,241,969 teaches aqueous solution formulations of corticosteroids for nasal or pulmonary delivery which comprise at least 50% by weight of an ethoxylated derivative of vitamin E. U.S. Pat. Nos. 4,782,047 and 4,983,595 show aqueous formulations of steroids for nasal administration that contains propylene glycol, PEG 400, and polysorbate 20 as co-solvents. U.S. patent application

2006/0045850 teaches aqueous solution formulations of corticosteroids for nasal delivery comprising an inclusion complex between the steroid and a cyclodextrin, a co- solvent, and a chelating agent. WO 2010/042701 discloses aqueous microemulsion formulations containing a steroid, a surfactant, and oil. A need exists to provide a microemulsion formulation suitable for inhalation that includes a significantly lower dose of a solubilized corticosteroid active pharmaceutical agent (APA) that is similarly, or more efficacious than current suspension and solution formulations, has an acceptable safety profile, and does not irritate the mucosa.

[0009] Inhaled corticosteriods are also used to treat asthma. Asthma is an inflammatory disease of the airways that is characterized by airflow obstruction and bronchospasm. One way that corticosteriods can be delivered to the lung is via a nebulizer. This treatment is preferred in special populations such as children and the elderly who cannot coordinate hand breath maneuvers.

[0010] SUMMARY OF THE INVENTION

[0011] .The present invention provides for pharmaceutical compositions comprising a corticosteroid microemulsion suitable for inhalation, wherein the concentration of the solubilized corticosteroid is from about 1 microgram/g ("mcg/g") of the composition to about 30 mcg/g of the composition. The solvent used for the microemulsion system is aqueous. Suitable corticosteroids include but are not limited to mometasone furoate (MF), fluticasone propionate, fluticasone furoate, budesonide, triamcinolone acetonide, prednisolone, beclomethasone dipropionate, ciclesonide and flunisolide and any salts, polymorphs, hydrates or solvates thereof.

[0012] Various embodiments of the present invention provide for

pharmaceutical compositions comprising a corticosteroid microemulsion suitable for inhalation, wherein the concentration of the corticosteroid is from about 1 mcg/g of the composition to about 30 mcg/g of the composition. Alternatively, the concentration of the corticosteroid may be from about 2 mcg/g of the composition to about 20 mcg/g of the composition, from about 5 mcg/g of the composition to about 10 mcg/g of the composition, or about 8 mcg/g of the composition.

[0013] Various compositions of the present invention are comprised of at least one surfactant and at least one oil. The surfactant is present in an amount from about 0.01 to about 10% by weight or from about 1% to about 2% by weight. The oil is present in an amount from about 0.01 to about 5% by weight or from about 0.05% to 0.5% by weight. Surprisingly, significantly reducing the levels of excipients used in the microemulsion to solubilize the corticosteroid led to enhanced efficacy that is not tied to bioavailability.

[0014] Various compositions of the present invention may include at least one pH modifying agent. Suitable pH modifying agents include, but are not limited to: citric acid, sodium citrate dehydrate, phosphate buffers, borate buffers, and acetate buffers.

[0015] Various compositions of the present invention may include at least one additional active pharmaceutical agent (APA). Suitable additional APAs include decongestants, antihistamines, and combinations thereof. A particularly useful additional APA is a decongestant, such as oxymetazoline.

[0016] Other embodiments of the present invention provide pharmaceutical drug products that comprise an inhalation device and a microemulsion suitable for inhalation comprising a corticosteroid in a microemulsion in a concentration from about 1 mcg/g of the composition to about 30 mcg/g of the composition. Other useful concentrations of the corticosteroid may be from about 2 mcg/g to about 20 mcg/g or from about 5 mcg/g of the composition to about 10 mcg/g of the composition, or about 8 mcg/g of the composition. Useful inhalation devices include a nasal spray pump or soft mist inhaler. Another embodiment of the present invention provides a method of administering the drug product by applying the inhalation device to each nostril of the nose and actuating the inhalation device at least once to each nostril to deliver the solution to the nasal cavity.

[0017] Still other embodiments of the present invention provide methods of treating allergic rhinitis which comprise administering a corticosteroid microemulsion suitable for inhalation once daily to the upper airway passages; wherein the total daily dose of the corticosteroid is from about 0.8 meg to about 12 meg. Such amounts are useful to treat seasonal or perennial allergic rhinitis. [0018] Other embodiments of the present invention provide methods of treating nasal polyps including administering a corticosteroid microemulsion suitable for inhalation once or twice daily to the upper airway passages; wherein the total daily dose of corticosteroid is from about 0.8 meg to about 12 meg.

[0019] Additional embodiments of the present invention provide methods of treating an airway disease which comprises administering a corticosteroid

microemulsion suitable for inhalation once daily to the upper or lower airway passages; wherein the total daily dose of mometasone furoate is from about 0.8 meg to about 12 meg. Airway diseases that may be treated with this method include asthma, chronic obstructive pulmonary disease, sinusitis, allergic rhinitis, rhinosinusitis, and/or nasal polyps and combinations thereof.

[0020] Still other embodiments provide methods of treating a corticosteroid- responsive disease of the upper or lower airway passages in patients afflicted with said disease, which comprises administering to the surfaces of the passages of the patients a therapeutically effective amount of a corticosteroid microemulsion effective for treating the disease. The microemulsion may be administered once a day and may contain from about 0.8 meg to about 12 meg of a corticosteroid.

[0021] Various other embodiments provide pharmaceutical compositions that comprise a microemulsion suitable for inhalation which comprises a corticosteroid; a surfactant; an oil; and water.

[0022] Multiple embodiments provide pharmaceutical compositions which comprise a microemulsion suitable for inhalation that comprises a corticosteroid in a concentration from about 1 mcg/g to about 30 mcg/g; at least one surfactant in a concentration from about 0.01 to about 10%; at least one oil in a concentration from about 0.01 to about 5%; and water.

[0023] Other embodiments provide a pharmaceutical composition comprising an aqueous solution suitable for inhalation comprising a corticosteroid; at least one surfactant with a hydrophilic-lipophilic balance (HLB) value from about 11 to about 17, at least one oil comprising a fatty acid carbon chain length of C6-C22 fatty acid; and water.

BRIEF DESCRIPTION OF DRAWINGS [0024] FIGURE 1 : In vivo human deposition of mometasone furoate suspension

[0025] FIGURE 2: Pharmacodynamic Response of Allergic Dogs to Placebo,

Suspension and Microemulsion formulations of mometasone furoate

[0026] FIGURE 3 : Healthy Human Pharmacokinetic data

[0027] FIGURE 4: Pharmacodynamic Response of Asthmatic Dogs to Placebo

Solution, Budesonide and Microemulsion formulations of mometasone Furoate delivered by nebulizer

DETAILED DESCRIPTION

[0028] The present invention provides for pharmaceutical compositions comprising a corticosteroid microemulsion suitable for inhalation, wherein the concentration of the solubilized corticosteroid is from about 1 microgram (mcg)/g of the composition to about 30 mcg/g of the composition. The solvent used for the microemulsion system is aqueous. Suitable corticosteroids include but are not limited to mometasone furoate (MF), fluticasone propionate, fluticasone furoate, budesonide, triamcinolone acetonide, prednisolone, beclomethasone dipropionate, ciclesonide and flunisolide. Surprisingly, significantly reducing the levels of excipients used in the microemulsion to solubilize the corticosteroid led to enhanced efficacy that is not tied to bioavailability.

[0029] Various embodiments of the present invention provide pharmaceutical drug products that comprise an inhalation device and a microemulsion suitable for inhalation comprising a corticosteroid in a microemulsion in a concentration from about 1 mcg/g of the composition to about 30 mcg/g of the composition. Other useful concentrations of the corticosteroid may be from about 2 mcg/g of the composition to about 20 mcg/g of the composition or from about 5 mcg/g of the composition to about 10 mcg/g of the composition, or about 8 mcg/g of the composition. Useful inhalation devices include a nasal spray pump or soft mist inhaler. Another embodiment of the present invention provides a method of administering the drug product by applying the inhalation device to each nostril of the nose and actuating the inhalation device at least once to each nostril to deliver the solution to the nasal cavity.

[0030] Still other embodiments of the present invention provide methods of treating allergic rhinitis which comprise administering a corticosteroid microemulsion suitable for inhalation once daily to the upper airway passages; wherein the total daily dose of the corticosteroid is from about 0.8 meg to about 12 meg. Such amounts are useful to treat seasonal or perennial allergic rhinitis.

[0031] Other embodiments of the present invention provide methods of treating nasal polyposis including administering a corticosteroid microemulsion suitable for inhalation once or twice daily to the upper airway passages; wherein the total daily dose of corticosteroid is from about 0.8 meg to about 12 meg.

[0032] Additional embodiments of the present invention provide methods of treating an airway disease which comprises administering a corticosteroid

microemulsion suitable for inhalation once daily to the upper or lower airway passages; wherein the total daily dose of the corticosteroid is from about 0.8 meg to about 12 meg. Airway diseases that may be treated with this method include asthma, chronic obstructive pulmonary disease, sinusitis, allergic rhinitis, rhinosinusitis, and/or nasal polyposis and combinations thereof.

[0033] Still other embodiments provide methods of treating a corticosteroid- responsive disease of the upper or lower airway passages in patients afflicted with said disease, which comprises administering to the surfaces of the passages of the patients a therapeutically effective amount of a corticosteroid microemulsion effective for treating the disease. The microemulsion may be administered once a day and may contain from about 0.8 meg to about 12 meg of a corticosteroid.

[0034] Various other embodiments provide pharmaceutical compositions that comprise a microemulsion suitable for inhalation which comprises a corticosteroid; a surfactant; an oil; and water.

[0035] Multiple embodiments provide pharmaceutical compositions which comprise a microemulsion suitable for inhalation that comprises a corticosteroid in a concentration from about 1 mcg/g of the composition to about 30 mcg/g of the composition; at least one surfactant in a concentration from about 0.01 to about 10%; at least one oil in a concentration from about 0.01 to about 5%; and water.

[0036] Other embodiments provide a pharmaceutical composition comprising an aqueous solution suitable for inhalation comprising a corticosteroid; at least one surfactant with a hydrophilic-lipophilic balance (HLB) value from about 11 to about 17, optionally at least one oil comprising a fatty acid carbon chain length of C6-C22 fatty acid; and water.

[0037] Other embodiments of the present invention provide pharmaceutical drug products that comprise an inhalation device and a microemulsion suitable for inhalation comprising mometasone furoate, fluticasone propionate, fluticasone furoate, budesonide, prednisolone, beclomethasone dipropionate, ciclesonide, or flunisolide in a concentration from about 1 mcg/g to about 30 mcg/g. Other useful concentrations of the mometasone furoate, fluticasone propionate, fluticasone furoate, budesonide, prednisolone, beclomethasone dipropionate, ciclesonide, or flunisolide may be from about 2 mcg/g to about 20 mcg/g or from about 5 mcg/g to about 10 mcg/g, or about 8 mcg/g. Useful inhalation devices include a nasal spray pump or soft mist inhaler. Another embodiment of the present invention provides a method of administering the drug product by applying the inhalation device to each nostril of the nose and actuating the inhalation device at least once to each nostril to deliver the microemulsion to the nasal cavity.

[0038] Still other embodiments of the present invention provide methods of treating allergic rhinitis which comprise administering a corticosteroid microemulsion comprising mometasone furoate, fluticasone propionate, fluticasone furoate, budesonide, prednisolone, beclomethasone dipropionate, ciclesonide, or flunisolide suitable for inhalation once daily to the upper airway passages; wherein the total daily dose of the corticosteroid is from about 0.8 meg to about 12 meg. Such amounts are useful to treat seasonal or perennial allergic rhinitis.

[0039] Another embodiment of the present invention provides methods of treating asthma which comprise administering a corticosteroid microemulsion comprising mometasone furoate via a nebulizer. Preferred nebulizers include an ultrasonic nebulizer, jet nebulizer and/or vibrating mesh nebulizer.

[0040] Other embodiments of the present invention provide methods of treating nasal polyposis including administering a corticosteroid microemulsion comprising mometasone furoate, fluticasone propionate, fluticasone furoate, budesonide, prednisolone, beclomethasone dipropionate, ciclesonide, or flunisolide suitable for inhalation once or twice daily to the upper airway passages; wherein the total daily dose of corticosteroid is from about 0.8 meg to about 12 meg. [0041] Additional embodiments of the present invention provide methods of treating an airway disease which comprises administering a corticosteroid

microemulsion comprising mometasone furoate, fluticasone propionate, fluticasone furoate, budesonide, prednisolone, beclomethasone dipropionate, ciclesonide, or flunisolide suitable for inhalation once daily to the upper or lower airway passages; wherein the total daily dose of the corticosteroid is from about 0.8 meg to about 12 meg. Airway diseases that may be treated with this method include asthma, chronic obstructive pulmonary disease, sinusitis, allergic rhinitis, rhinosinusitis, and/or nasal polyposis and combinations thereof.

[0042] Still other embodiments provide methods of treating a corticosteroid- responsive disease of the upper or lower airway passages in patients afflicted with said disease, which comprises administering to the surfaces of the passages of the patients a therapeutically effective amount of a corticosteroid microemulsion comprising mometasone furoate, fluticasone propionate, fluticasone furoate, budesonide, prednisolone, beclomethasone dipropionate, ciclesonide, or flunisolide, which is effective for treating the disease. The microemulsion may be administered once a day and may contain from about 0.8 meg to about 12 meg of a corticosteroid.

[0043] Various other embodiments provide pharmaceutical compositions that comprise a microemulsion suitable for inhalation which comprises mometasone furoate, fluticasone propionate, fluticasone furoate, budesonide, prednisolone, beclomethasone dipropionate, ciclesonide, or flunisolide; a surfactant; an oil; and water.

[0044] Multiple embodiments provide pharmaceutical compositions which comprise a microemulsion suitable for inhalation comprising mometasone furoate, fluticasone propionate, fluticasone furoate, budesonide, prednisolone, beclomethasone dipropionate, ciclesonide, or flunisolide in a concentration from about 1 mcg/g of the composition to about 30 mcg/g of the composition; at least one surfactant in a concentration from about 0.01 to about 10%; at least one oil in a concentration from about 0.01 to about 5%; and water.

[0045] Other embodiments provide a pharmaceutical composition comprising an aqueous solution suitable for inhalation comprising mometasone furoate, fluticasone propionate, fluticasone furoate, budesonide, prednisolone, beclomethasone dipropionate, ciclesonide, or flunisolide; at least one surfactant with a hydrophilic- lipophilic balance (HLB) value from about 11 to about 17, at least one oil comprising a fatty acid carbon chain length of C6-C22 fatty acid; and water.

[0046] Other embodiments of the present invention provide pharmaceutical drug products that comprise an inhalation device and a microemulsion suitable for inhalation comprising mometasone furoate, in a concentration from about 1 mcg/g of the composition to about 30 mcg/g of the composition. Other useful concentrations of the mometasone furoate may be from about 2 mcg/g of the composition to about 20 mcg/g of the composition or from about 5 mcg/g of the composition to about 10 mcg/g of the composition, or about 8 mcg/g of the composition. Useful inhalation devices include a nasal spray pump or soft mist inhaler. Another embodiment of the present invention provides a method of administering the drug product by applying the inhalation device to each nostril of the nose and actuating the inhalation device at least once to each nostril to deliver the solution to the nasal cavity.

[0047] Still other embodiments of the present invention provide methods of treating allergic rhinitis which comprise administering a microemulsion comprising mometasone furoate, suitable for inhalation once daily to the upper airway passages; wherein the total daily dose of mometasone furoate is from about 0.8 meg to about 12 meg. Such amounts are useful to treat seasonal or perennial allergic rhinitis.

[0048] Other embodiments of the present invention provide methods of treating nasal polyposis including administering a corticosteroid microemulsion comprising mometasone furoate suitable for inhalation once or twice daily to the upper airway passages; wherein the total daily dose of mometasone furoate is from about 0.8 meg to about 12 meg.

[0049] Additional embodiments of the present invention provide methods of treating an airway disease which comprises administering a corticosteroid

microemulsion comprising mometasone furoate, suitable for inhalation once daily to the upper or lower airway passages; wherein the total daily dose of mometasone furoate is from about 0.8 meg to about 12 meg. Airway diseases that may be treated with this method include asthma, chronic obstructive pulmonary disease, sinusitis, allergic rhinitis, rhinosinusitis, and/or nasal polyposis and combinations thereof. [0050] Still other embodiments provide methods of treating a corticosteroid- responsive disease of the upper or lower airway passages in patients afflicted with said disease, which comprises administering to the surfaces of the passages of the patients a therapeutically effective amount of a corticosteroid microemulsion comprising mometasone furoate, which is effective for treating the disease. The microemulsion may be administered once a day and may contain from about 0.8 meg to about 12 meg of mometasone furoate.

[0051] Various other embodiments provide pharmaceutical compositions that comprise a microemulsion suitable for inhalation which comprises mometasone furoate; a surfactant; an oil; and water.

[0052] Multiple embodiments provide pharmaceutical compositions which comprise a microemulsion suitable for inhalation comprising mometasone furoate, fluticasone propionate, fluticasone furoate, budesonide, prednisolone, beclomethasone dipropionate, ciclesonide, or flunisolide in a concentration from about 1 mcg/g of the composition to about 30 mcg/g of the composition; at least one surfactant in a concentration from about 0.01 to about 10%; at least one oil in a concentration from about 0.01 to about 5%; and water.

[0053] Other embodiments provide a pharmaceutical composition comprising an aqueous solution suitable for inhalation comprising mometasone furoate, fluticasone propionate, fluticasone furoate, budesonide, prednisolone, beclomethasone

dipropionate, ciclesonide, or flunisolide; at least one surfactant with a hydrophilic- lipophilic balance (HLB) value from about 11 to about 17, optionally at least one oil comprising a fatty acid carbon chain length of C6-C22 fatty acid; and water.

[0054] Various compositions of the present invention may comprise at least one surfactant. Suitable concentration for surfactants will vary depending on the amount of other excipients and corticosteroid used. The surfactant may be present in an amount from about 0.01 to about 10% by weight, from about 0.5 to about 5% by weight, or from about 1% to about 2% by weight.

[0055] Suitable surfactants include, but are not limited to, medium chain mono- and diglyceride sold as IMWITOR® (S) by Sasol; distilled acetylated monoglyceride sold as MYVACET® 9-45 by Eastman Chemical Company; long chain monoglyceride sold as PECEOL® (GLYCERYL MONOOLEATE), MAISINE® (GLYCERYL MONOLINOLEATE) (S) by Gattefosse; propylene glycol monocaprylate sold as CAPRYOL® 90 (S) by Gattefosse; propylene glycol caprylate sold as CAPYROL® PGMC (S) by Gattefosse; diethylene glycol monoethyl ether sold as TRANSCUTOL® (S) by Gattefosse; macrogol- 15 -hydroxystearate sold as SOLUTOL® HS-15 by BASF (also known as Polyethylene glycol (15)-hydroxystearate) ; polyoxylglycerides sold as GELUCIRE® 33/01,39/01,43/01,44/14,50/13 by Gattefosse; polyoxyl 40 hydrogenated castor oil sold as CREMOPHOR® RH40 by BASF; polyoxyl 35 castor oil sold as CREMOPHOR® EL by BASF; d-a-tocopheryl polyethylene glycol 1000 succinate sold as VITAMIN E TPGS® by Eastman Kodak; PEG 300 linoleic glyceride sold as LABRAFIL® M-2125CS by Gattefosse; PEG 400 caprylic/capric glyceride sold as LABRASOL® by Gattefosse; PEG 300 oleic glyceride sold as LABRAFIL® M- 1944CS by Gattefosse; PEG 300 caprylic/capric glyceride sold as SOFTIGEN® 767 by Gattefosse; polyethylene oxide/poly-(propyleneoxide)/poly (ethyleneoxide) triblock copolymers sold as Poloxamers/Pluronics by BASF; polyoxyethylene 20 sorbitan monooleate sold as TWEEN® 20/TWEEN® 80 (Polysorbate 20, Polysorbate 80) by Sigma; Sorbiton monooleate sold as SPAN® 20/SPAN® 80 by ICI Americas, Inc; macrogol-glycerolhydroxystearat (DAB) or polyoxyethylenglyceroltrihydroxystearat (DAC) and combinations thereof. Macrogol- 15 -hydroxystearate and polysorbate 80 are particularly preferred surfactants. Macrogol- 15 -hydroxystearate is the most preferred surfactant.

[0056] Various compositions of the present invention may comprise at least one oil, wherein the oil is a medium- or long-chain triglyceride. Suitable concentration for the oil will vary depending on the amount of other excipients and corticosteroid used. The oil may be present in an amount from about 0.01 to about 5% by weight or from about 0.05% to 0.5% by weight. The oil may be a medium-chain triglyceride or a long- chain triglyceride.

[0057] Suitable medium-chain triglycerides include, but are not limited to: caprylic and capric acid triglycerides sold as propylene glycol dicaprylate/dicaprate sold as MIGLYOL® 840 by Sasol and CAPMUL® 200 (S) by Abitech; MIGLYOL® 812/MIGLYOL® 810 by Sasol North America; of caprylic and capric acid linoleic acid triglycerides sold as MYGLYOL® 818 by Sasol North America; trigylceride from coconut oil sold as CAPTEX® 300/CAPTEX® 850 by Abitech Corp; caprylic/caprylic triglyceride sold as CAPTEX® 355 by Abitech Corp; caprylic/caprylic/lauric triglyceride sold as CAPTEX® 350 by Abitech Corp; caprylic/caprylic/linoleic triglyceride sold as CAPTEX® 810 by Abitech Corp; caprylic/caprylic/stearic triglyceride sold as CAPTEX® SBE by Abitech Corp; tricaprylic/Caprylic triglyceride ester sold as NEOBEE® M-5 by Stephan and combinations thereof. MIGLYOL® 812 is the most preferred medium-chain triglyceride.

[0058] Suitable long-chain triglycerides include, but are not limited to, soybean oil sold as SUPER-REFINED® Soy Bean oil USP by Croda; corn oil sold as SUPER- REFINED® Corn Oil NF® by Croda; cottonseed oil sold as SUPER-REFINED® Cottenseed oil by Croda; olive oil sold as SUPER-REFINED® Olive Oil NF® by Croda; peanut oil sold as SUPER-REFINED® Peanut Oil BF by Croda; safflower oil sold as SUPER-REFINED® Safflower Oil USP by Croda; sesame oil sold as SUPER- REFINED® Sesame Oil NF® by Croda; shark liver oil sold as; SUPER-REFINED® Shark Liver Oil by Croda; castor oil; monounsaturated omega-9 fatty acid sold as Oleic acid by Croda; peppermint oil; hydrogenated palm oil sold as SOFTISAN® 154 by Sasol and combinations thereof.

[0059] Other embodiments provide a pharmaceutical composition comprising a microemulsion suitable for inhalation comprising a corticosteroid; at least one surfactant with a hydrophilic-lipophilic balance (HLB) value from about 11 to about 17, at least one oil comprising a fatty acid carbon chain length of C6-C22; and water.

[0060] Other embodiments provide a pharmaceutical composition comprising a microemulsion suitable for inhalation comprising mometasone furoate; at least one surfactant with a hydrophilic-lipophilic balance (HLB) value from about 11 to about 17, at least one oil comprising a fatty acid carbon chain length of C6-C22; and water.

[0061] A preferred embodiment provides a pharmaceutical composition comprising a microemulsion suitable for inhalation comprising mometasone furoate; Macrogol-15-hydroxystearate, MIGLYOL® 812; and water.

[0062] When the compositions of the invention are intended for application to sensitive mucosal membranes, it may be desirable to adjust the pH to a relatively neutral value, using an acid or base, unless the natural pH already is suitable. In general, pH values about 3 to about 8 are preferred for tissue compatibility; the exact values chosen should also promote chemical and physical stability of the composition. Various compositions of the present invention may include at least one pH modifying agent to assist with maintenance of selected pH values; typical buffers are well known in the art and include, without limitation thereto, acetate, phosphate, citrate, and borate salt systems.

[0063] Other embodiments of the present invention provide for pharmaceutical compositions which include combinations of a corticosteroid and at least one additional APA, including decongestants, and antihistamines. More particularly, useful combinations of APAs include mometasone furoate and oxymetazoline, mometasone furoate and an antihistamine such as azelastine or olopatadine.

[0064] One particularly useful combination is mometasone furoate with a decongestant. Examples of suitable decongestants include 1-desoxyephedrine, ephedrine, ephedrine hydrochloride, ephedrine sulfate, naphazoline, naphazoline hydrochloride, oxymetazoline and pharmaceutically acceptable salts thereof, oxymetazoline hydrochloride, phenylephrine, phenylpropanolamine, menazoline, phenylephrine hydrochloride, propylhexedrine, xylometazoline and xylometazoline hydrochloride. Oxymetazoline is a preferred decongestant.

[0065] Useful effective total daily amounts of oxymetazoline include from about

5 to about 5000 micrograms ("mcg")/day, from about 5 to about 2000 meg/day, about 12.5 to about 1000 meg/day, about 25 to aboutlOOO meg/day, about 12.5 to about 800 meg/day, about 12.5 to about 600 meg/day, about 25 to about 500 meg/day, 25 to about 400 micrograms, about 50 to about 500, about 50 to about 300 meg/day, from about 50 to about 200 micrograms, from about 100 to about 300 meg/day, about 100 meg/day or about 200 meg/day or about 300 meg/day in single or divided doses. The total daily dose includes the total amount of drug delivered to both nostrils. Each nostril may receive 1 or 2 sprays.

[0066] Other embodiments of the present invention provide pharmaceutical drug products that comprise an inhalation device and a microemulsion for inhalation comprising mometasone furoate in solution in a concentration from about 1 mcg/g to about 30 mcg/g. Other useful concentrations of mometasone furoate may be from about 2 mcg/g to about 20 mcg/g, from about 5 mcg/g to about 10 mcg/g, or about 8 mcg/g. Useful inhalation devices include a nasal spray, soft mist inhaler, and pressurized metered dose inhaler. Another embodiment of the present invention provides a method of administering the drug product by applying the inhalation device to each nostril of the nose and actuating the inhalation device at least once to each nostril to deliver the microemulsion to the nasal cavity.

[0067] Still other embodiments of the present invention provide methods of treating allergic rhinitis which comprise administering a corticosteroid microemulsion suitable for inhalation once daily to the upper airway passages; wherein the total daily dose of corticosteroid is from about 0.8 meg to about 12 micrograms. Such amounts are useful to treat seasonal or perennial allergic rhinitis. Further embodiments provide methods of treating allergic rhinitis which comprise administering a corticosteroid microemulsion comprising mometasone furoate, fluticasone propionate, fluticasone furoate, budesonide, prednisolone, beclomethasone dipropionate, ciclesonide, or flunisolide suitable for inhalation once daily to the upper airway passages; wherein the total daily dose of corticosteroid is from about 0.8 meg to about 12 micrograms. Such amounts are useful to treat seasonal or perennial allergic rhinitis. Another embodiment of the present invention provide methods of treating allergic rhinitis which comprise administering a corticosteroid microemulsion comprising mometasone furoate, suitable for inhalation once daily to the upper airway passages; wherein the total daily dose of mometasone furoate is from about 0.8 meg to about 12 micrograms. Such amounts are useful to treat seasonal or perennial allergic rhinitis.

[0068] Other embodiments of the present invention provide methods of treating nasal polyposis including administering a corticosteroid microemulsion suitable for inhalation once or twice daily to the upper airway passages; wherein the total daily dose of corticosteroid is from about 0.8 meg to about 12 micrograms. Other embodiments of the present invention provide methods of treating nasal polyposis including

administering a corticosteroid microemulsion comprising mometasone furoate, fluticasone propionate, fluticasone furoate, budesonide, prednisolone, beclomethasone dipropionate, ciclesonide, or flunisolide suitable for inhalation once or twice daily to the upper airway passages; wherein the total daily dose of corticosteroid is from about 0.8 meg to about 12 micrograms. Other embodiments of the present invention provide methods of treating nasal polyposis including administering a mometasone furoate microemulsion suitable for inhalation once or twice daily to the upper airway passages; wherein the total daily dose of mometasone furoate is from about 0.8 meg to about 12 micrograms of mometasone furoate.

[0069] Additional embodiments of the present invention provide methods of treating an airway disease which comprises administering a corticosteroid

microemulsion suitable for inhalation once daily to the upper or lower airway passages; wherein the total daily dose of corticosteroid is from about 0.8 meg to about 12 micrograms. Additional embodiments of the present invention provide methods of treating an airway disease which comprises administering a corticosteroid

microemulsion comprising mometasone furoate, fluticasone propionate, fluticasone furoate, budesonide, prednisolone, beclomethasone dipropionate, ciclesonide, or flunisolide suitable for inhalation once daily to the upper or lower airway passages; wherein the total daily dose of corticosteroid is from about 0.8 meg to about 12 micrograms. Additional embodiments of the present invention provide methods of treating an airway disease which comprises administering a mometasone furoate microemulsion suitable for inhalation once daily to the upper or lower airway passages; wherein the total daily dose of mometasone furoate is from about 0.8 meg to about 12 micrograms of mometasone furoate. Airway diseases that may be treated with this method include asthma, chronic obstructive pulmonary disease, sinusitis, allergic rhinitis and/or nasal polyposis and combinations thereof.

[0070] Still other embodiments provide methods of treating a corticosteroid- responsive disease of the upper or lower airway passages in patients afflicted with said disease, which comprises administering to the surfaces of the passages of the patients a therapeutically effective amount of a microemulsion of a corticosteroid effective for treating the disease. The microemulsion may be administered once a day and may contain from about 0.8 meg to about 12 meg of corticosteroid. Other embodiments provide methods of treating a corticosteroid-responsive disease of the upper or lower airway passages in patients afflicted with said disease, which comprises administering to the surfaces of the passages of the patients a therapeutically effective amount of a microemulsion comprising mometasone furoate, fluticasone propionate, fluticasone furoate, budesonide, prednisolone, beclomethasone dipropionate, ciclesonide, or flunisolide effective for treating the disease. The microemulsion may be administered once a day and may contain from about 0.8 meg to about 12 meg of corticosteroid. Still other embodiments provide methods of treating a corticosteroid-responsive disease of the upper or lower airway passages in patients afflicted with said disease, which comprises administering to the surfaces of the passages of the patients a therapeutically effective amount of a microemulsion of mometasone furoate effective for treating the disease. The microemulsion may be administered once a day and may contain from about 0.8 meg to about 12 meg of mometasone furoate.

[0071] Various other embodiments provide pharmaceutical compositions that comprise a microemulsion suitable for inhalation which comprises mometasone furoate; a surfactant; an oil; and water. The solution may be a microemulsion or a micellar formulation.

[0072] Multiple embodiments provide pharmaceutical compositions which comprise a microemulsion suitable for inhalation that comprises mometasone furoate in a concentration from about 1 mcg/g of the composition to about 30 mcg/g of the composition; at least one surfactant in a concentration from about 0.01 to about 10%; at least one oil in a concentration from about 0.01 to about 5%; and water.

[0073] Dosing may be one, two, three or four times daily. Particularly suitable dosing administration is either once daily or twice daily.

[0074] Based on the judgment of the attending clinician, the amount of corticosteroid administered and the treatment regimen used will, of course, be dependent on the age, sex and medical history of the patient being treated, the severity of the specific asthmatic or non-malignant pulmonary disease condition and the tolerance of patient to the treatment regimen as evidenced by local toxicity (e.g., nasal irritation and/or bleeding) and by systemic side-effects (e.g. Cortisol level). Cortisol (also referred to as hydrocortisone) is the major natural glucocorticosteroid elaborated by the adrenal cortex.

[0075] Suitable diseases that can be treated include corticosteroid-responsive disease of the airway passage ways and lungs which includes those allergic, non- allergic and/or inflammatory diseases of the upper or lower airway passages or of the lungs which are treatable by administering corticosteroids such as mometasone furoate. Typical corticosteroid-responsive diseases include allergic and non-allergic rhinitis, nasal polyps, chronic obstructive pulmonary disease (COPD) as well as non-malignant proliferative and inflammatory diseases of the airways passages and lungs. [0076] The invention is also useful in treating allergic and non-allergic rhinitis as well as non-malignant proliferative and/or inflammatory disease of the airway passages and lungs. Exemplary allergic or inflammatory conditions of the upper and lower airway passages which can be treated or relieved according to various embodiments of the present invention include nasal symptoms associated with allergic rhinitis, such as seasonal allergic rhinitis, intermittent allergic rhinitis, persistent allergic rhinitis and/or perennial allergic rhinitis as well as congestion in moderate to severe seasonal allergic rhinitis patients. Other conditions that may be treated or prevented include corticosteroid responsive diseases, nasal polyps, asthma, chronic obstructive pulmonary disease (COPD), rhinovirus, rhinosinusitis including acute rhinosinusitis and chronic rhinosinusitis, congestion, total nasal symptoms

(stuffiness/congestion, rhinorrhea, nasal itching, sneezing) and non-nasal symptoms (itchy/burning eyes, tearing/watery eyes, redness of the eyes, itching of the ears/palate) and nasal blockage associated with sinusitis, fungal induced sinusitis, and bacterial based sinusitis.

[0077] The term "allergic rhinitis" as used herein means any allergic reaction of the nasal mucosa and includes hay fever (seasonal allergic rhinitis) and perennial rhinitis (non-seasonal allergic rhinitis) which are characterized by seasonal or perennial sneezing, rhinorrhea, nasal congestion, pruritis and eye itching, redness and tearing.

[0078] The term "non-allergic rhinitis" as used herein means eosinophilic nonallergic rhinitis which is found in patients with negative skin tests and those who have numerous eosinophils in their nasal secretions.

[0079] The term "asthma" as used herein includes any asthmatic condition marked by recurrent attacks of paroxysmal dyspnea (i.e., "reversible obstructive airway passage disease") with wheezing due to spasmodic contraction of the bronchi (so called "bronchospasm"). Asthmatic conditions which may be treated or even prevented in accordance with this invention include allergic asthma and bronchial allergy characterized by manifestations in sensitized persons provoked by a variety of factors including exercise, especially vigorous exercise ("exercise-induced bronchospasm"), irritant particles (pollen, dust, cotton, cat dander) as well as mild to moderate asthma, chronic asthma, severe chronic asthma, severe and unstable asthma, nocturnal asthma, and psychological stresses. The invention is particularly useful in preventing the onset of asthma in mammals e.g., humans afflicted with reversible obstructive disease of the lower airway passages and lungs as well as exercise-induced bronchospasm.

[0080] The term "non-malignant proliferative and/or inflammatory disease" as used herein in reference to the pulmonary system means one or more of (1) alveolitis, such as extrinsic allergic alveolitis, and drug toxicity such as caused by, e.g. cytotoxic and/or alkylating agents; (2) vasculitis such as Wegener's granulomatosis, allergic granulomatosis, pulmonary hemangiomatosis and idiopathic pulmonary fibrosis, chronic eosinophilic pneumonia, eosinophilic granuloma and sarcoidoses.

[0081] The term "surfactant" as used herein refers to a compound that lowers the surface tension of a liquid, the interfacial tension between two liquids, or the interfacial tension between a liquid and a solid.

[0082] The term "oil" as used herein refers to a medium-chain or long-chain triglycerides.

[0083] The phrase "therapeutically effective amount" means that amount of a medicament which when administered supplies an amount of one or more

pharmaceutically active agents contained therein to provide a therapeutic benefit in the treatment or management of a disease or disease state.

[0084] Administration may be accomplished utilizing inhalation devices including but not limited to a metered pump-spray device or a soft mist inhaler.

Microemulsions may be administered intranasally by inserting an appropriate device (such as a nasal spray bottle and actuator used to deliver NASONEX® Nasal Spray) into each nostril. Active drug is then expelled from the nasal spray device. Efficacy can be generally assessed in a double blind fashion by a reduction in nasal and non-nasal symptoms (e.g., sneezing, itching, congestion, and discharge). Other objective measurements (e.g., nasal peak flow and resistance) can be used as supportive indices of efficacy. Any suitable pump spray may be used, such as pump sprays used for NASONEX ® or AFRTN ®, as sold by Merck.

[0085] Administering mometasone furoate to the surfaces of the airways of asthmatic patients can maximize the therapeutic index. The term "therapeutic index", as used herein, means the ratio of local efficacy to systemic safety.

[0086] A "soft-mist" inhaler is a multi-dose, metered aerosol delivery device typically used to deliver aqueous based solution medicaments to the lungs via oral inhalation. The aerosol plume that they create is both slow in velocity and lasts for approximately 6x that of a typical pMDI (e.g. typically 1-2 sec. vs. milliseconds). An example of such a device would be Boehringer Ingelheim's (BI) RESPIMAT® which is currently used to deliver ipatropium bromide to the lungs.

[0087] The mometasone furoate administered to treat disease of the upper or lower airway passages may be used as monotherapy or as adjuvant therapy with for example cromolyn sodium or nedocromil sodium (available from Fisons);

bronchodilators such as albuterol (available from Merck under the PROVENTIL® tradename) or oxymetazoline (available as AFRTN® from Merck).

[0088] Compositions of multiple embodiments of the present invention may include, inter alia, water, auxiliaries and/or one or more of the excipients, such as: suspending agents, e.g., microcrystalline cellulose, sodium carboxymethylcellulose, hydroxpropyl-methyl cellulose; humectants, e.g. glycerin and propylene glycol; acids, bases or buffer substances for adjusting the pH, e.g., citric acid, sodium citrate, phosphoric acid, sodium phosphate as well as mixtures of citrate and phosphate buffers; surfactants, e.g. polysorbate 80; and antimicrobial preservatives, e.g., benzalkonium chloride, phenylethyl alcohol and potassium sorbate.

[0089] The compositions may contain any of a number of optional components, such as humectants, preservatives, antioxidants, chelating agents and aromatic substances. Humectants, which are hygroscopic materials such as glycerin, a polyethylene or other glycol, a polysaccharide and the like act to inhibit water loss from the composition and may add moisturizing qualities. Useful aromatic substances include camphor, menthol, eucalyptol and the like, flavors and fragrances.

Preservatives are typically incorporated to establish and maintain a freedom from pathogenic organisms; representative components include benzyl alcohol,

methylparaben, propylparaben, butylparaben, chlorobutanol, phenethyl alcohol (which also is a fragrance additive), phenyl mercuric acetate and benzalkonium chloride.

[0090] Certain aspects of the invention are further described in the following examples. The descriptions of the embodiments of the invention have been presented for purpose of illustration and description. They are not intended to be exhaustive or to limit the invention to the precise forms disclosed, and obviously many modifications and variations are possible in light of the above teaching. [0091] Percentages are expressed on a weight basis, unless the context clearly indicates otherwise. The mention of any specific drug substance in this specification or in the claims is intended to encompass not only the base drug, but also

pharmaceutically acceptable salts, esters, hydrates and other forms of the drug. Where a particular salt or other form of a drug is mentioned, it is contemplated that other salts or forms can be substituted.

[0092] EXAMPLES

[0093] Example 1; Control Formulation

[0094] A commercial control suspension formulation was used for comparison purposes. It contained 500 mcg/g of mometasone furoate, delivered by a 100 mcL spray pump for a spray dose of 50 meg/spray. This formulation will be referred to as Formulation #1.

[0095] Example 2; Surfactant/Oil ratio selection

[0096] SOLUTOL® HS 15 and MIGLYOL® 812 were chosen as the surfactant and oil system for the compositions in the following examples, based on the solubility of mometasone furoate in this surfactant/oil system. SOLUTOL® HS 15, was melted at 65 °C, and mixed with MIGLYOL® 812 at ratios of 1 : 1 to 8: 1, or with no MIGLYOL® 812. Water was then added in the amount of 94 - 98%, to complete the composition. Visual assessment found that the formulation was not translucent and therefore no longer a microemulsion at SOLUTOL®: MIGLYOL® ratios less than 3 : 1. Further solubility studies were conducted and found that MIGLYOL® 812 doubled the MF solubility over SOLUTOL® on a per gram basis. For that reason, it is desirable to use as much MIGLYOL® 812 as possible, while maintaining a microemulsion. A

SOLUTOL®: MIGLYOL® ratio of 4: 1 was chosen.

[0097] Example 3; Deposition Study

The control formulation and a microemulsion of the same concentration of mometasone furoate were spiked with radioactivity and sprayed into the nasal cavities of 12 healthy patients. The microemulsion formulation had been prepared by mixing 5% MIGLYOL® 812 with 20% SOLUTOL®, which had been warmed at 65°C.

Mometasone furoate was mixed for 10 minutes, and then water was added to complete the formulation. [0098] As shown in Figure 1, regional deposition in the anterior and posterior nasal cavities, olfactory region, nasopharynx, and lungs/swallowed were similar, despite the differences in formulation. Further, the in vitro spray characteristics of droplet size, spray pattern, and plume geometry were similar.

Example 4; Microemulsion Formulations

[0099] Various MF microemulsion formulations were prepared containing a designated amount of anhydrous mometasone furoate, surfactant, oil, and water. All formulations contained a preservative. Each formulation was buffered to a pH of about 4.5 with a buffering system.

[00100] Formulations were prepared by dissolving the preservatives and buffering agents in 10% of the water. SOLUTOL® HS 15 was warmed in a 65°C water bath for at least 2 hours. The surfactant and MIGLYOL® 812 (ratio 4: 1) were measured and then mixed at 65°C for 10 minutes. The water containing buffer and preservative water was added to the surfactant/ MIGLYOL® mixture to form the microemulsion. Water was then added to achieve full volume placebo. The placebo needed to make an active solution was measured out. Anhydrous mometasone furoate was added to the placebo and mixed for at least 4 hours using a stir bar.

SOLUTOL®HS 15 was the surfactant used to prepare formulations A through Q and Polysorbate 80 was the surfactant used to prepare formulation batch R. Table 1 summarizes the compositions of each microemulsion manufactured.

[00101] Table 1A: Microemulsion formulations

Formulation Surfactant

MF (mcg/g) % Saturation Oil (%) Batch # (%)

A 500 89 20 5

B 125 82 5.39 1.35

C 125 25 20 5

D 31.25 87 1.4 0.35

E 62.50 89 2.72 0.68

F 125.0 85 5.39 1.35

G 31.25 22 5.39 1.35

H 62.50 44 5.39 1.35 I 4 12 1.4 0.35

J 12 33 1.4 0.35

K 18 7 10 2.5

L 29 1 1 10 2.5

M 8 24 1.4 0.35

N 8 — 1.4 0.35

0 8 3 12.5 3.125

P 17 49 1.4 0.35

Q 2 6 1.4 0.35

R 8 24 1.4 0.35

[00102] 1 "able IB: Microemulsion formulations (Via Nebulizer)

[00103] The percent saturation is equal to the concentration of mometasone furoate in solution divided by the maximum solubility of MF in solution. A lower amount of surfactant and oil yields a higher percent saturation.

[00104] Formulations (17 g) were packaged in the NASONEX® bottle with a 100 mcL (microliter) VP3 pump and actuator. For all experiments, animals received two sprays into each nostril, for a total of 400 mcL. The dose, in meg is therefore the concentration multiplied by 0.4 (or divided by 2.5).

[00105] Example 5: Healthy Dog Pharmacokinetic Studies

[00106] Pharmacokinetic studies in healthy dogs were performed to determine the dose (s)/vehicle(s) to match the pharmacokinetics and systemic exposure of MF from the commercial NASONEX^® suspension nasal spray to a MF microemulsion delivered by the same device as used for NASONEX®. The design and methods of the study are detailed below. [00107] Study Design

[00108] On the day of dosing n=6-8 male beagle dogs per arm were sprayed with the test formulation, two sprays into each nostril. Blood samples (~2 mL) were collected via a cephalic or peripheral vein into chilled pre-labeled Vacutainer® tubes containing K2-EDTA at 0 hr (pre-dose), 0.083, 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, and 24 hour post-dose. All samples were chilled in an ice water bath after collection and during processing to plasma. Within 60 minutes of collection, the samples were centrifuged for approximately 10 min at -2000 g in a refrigerated centrifuge maintained at ~4°C. The resultant plasma (at least 1 mL) were separated, transferred to plastic tubes, and stored at approximately -70°C pending analysis. Plasma samples were shipped on dry ice for analysis.

[00109] The study conducted in healthy beagle dogs consisted of four phases. The first phase of the study was used to compare the absorption of a microemulsion formulation to the suspension at the same dose. Control Formulation #1 and microemulsion Formulation A were used for this arm of the study.

[00110] The second phase determined how the amount of the solubilizing excipients impacted the pharmacokinetics. Formulations B and C were used for this second arm of the study.

[00111] The third phase assessed how the percent saturation and

dose/concentration affected the pharmacokinetics of the formulation. Microemulsion Formulations D, E, F, G, and H were used for the third arm of the study.

[00112] For the fourth phase, a linear regression model (Minitab Version 15, Minitab Inc., State College, PA) was used to create an equation between the geometric mean of the area of the curve of each arm and the MF concentration and percent saturation. After creating the model, the dose to match the commercial suspension was calculated for two surfactant / oil ratios: 1.4% /0.35% and 10% / 2.5%. These doses calculated using the linear regression model to match the 500 meg suspension were bracketed at each surfactant/oil level and tested in healthy dogs. Microemulsion Formulations I, J, K, and L were used for this part of the study.

[00113] Results of Healthy Dog Pharmacokinetic Study The results of the healthy dog pharmacokinetic study are summarized in Table 2. The first arm of the study illustrated that a suspension (Control #1) and a microemulsion (Formulation A) have significantly different pharmacokinetic profiles. The microemulsion formulation had a similar T_max, and a much larger C_max and AUC. The second phase, looking at the impact of solubilizing excipients on

pharmacokinetics, gave the surprising result that the formulations with the same amount of active ingredient but lower amount of solubilizing excipients (Formulation B versus Formulation C) led to higher C_max and AUC values. The third phase found a similar trend at lower concentrations of active (Formulations D-H) such that we developed an equation of pharmacokinetics AUC as a function of the concentration of drug and the percent saturation. An equation of the pharmacokinetics AUC as a function of the formulation components was also developed based on solubility.

[00114] Finally, a linear regression model was created to determine the microemulsion formulation that would match the commercial suspension at two different surfactant/oil levels (1.4%/0.35% and 10%/2.5%). This equation was solved for the concentrations and then those concentrations were bracketed and tested experimentally (Formulations I-L) to calculate the concentrations that would match the suspension at different excipient levels. It was determined that a formulation containing either (1) 7.7mcg/g MF in 1.4% SOLUTOL® HS-15 and 0.35%

MIGLYOL® 812 or (2) 17.4 mcg/g MF in 10% SOLUTOL® HS-15 and 2.5%

MIGLYOL® 812 met these requirements. These calculated values were used to determine the formulations to be tested in the allergic dog study.

Table 2: Pharmacokinetic data (geometric means) in healthy dogs from different single dose intranasal mometasone furoate formulations

Actual MF

Formulation

concentration N Tma Cmax AUC No.

(mcg/g)

Control #1 500.0 8 0.50 27 (66) 44.27 (80)

A 463.72 8 0.38 481.57 (57) 885.33 (78)

B 1 14.40 6 0.38 409.62 (40) 384.75 (64) c 130.84 5 0.25 184.68 (82) 170.6 (56)

D 30.29 8 0.25 114.53 (62) 164.88 (41)

E 61.52 8 0.38 346.63 (117) 338.41 (26)

F 1 18.76 8 0.25 281.69 (55) 428.13 (50)

G 30.19 8 0.38 103.36 (78) 158.65 (37)

H 60.70 8 0.50 113.67 (89) 185.64 (70)

I 4.05 8 0.25 23.53 (72) 16 (67)

J 11.65 8 0.38 71.95 (73) 77.33 (62)

K 17.89 8 0.25 39.45 (42) 47.28 (40)

L 28.63 8 0.25 92.42 (58) 107.42 (54)

[00115] Example 6; Allergic Dog Pharmacodynamic Studies

[00116] Allergic dogs were dosed with nasal sprays to assess the effect of vehicle, dose, and number of treatment days on pharmacodynamics. The beagles were immunized by subcutaneous injection with ragweed (RW) and inhalation of the allergen as puppies to develop allergic immune responses. These dogs developed increased nasal congestion and inflammation following a RW challenge in the nose. Dogs (n = 6; 6 per treatment group) with these pre-existing nasal and airway allergic responses were utilized in the study. Each dog served as its own control until formulation O, when three animals were replaced, and used through the end of the study.

[00117] Nasal dosing, for 7 days as listed in Tables 3 and 4, was achieved by delivering 2 sprays into each nare (50 mcL/spray) into each animal while they were awake. During dosing, the dog's head was elevated slightly to ensure a proper delivery of the compound without dripping out of the nose.

[00118] Dogs were challenged with Ambrosia artemisifolia (ragweed) one hour after the last treatment.

[00119] Acoustic rhinometery was used to measure nasal cavity volume of the anesthetized dogs using an Eccovision Acoustic Rhinometry System (Hood

Laboratories, Inc., Pembroke, MA). Briefly, a wave tube containing a spark sound generator was connected with the nasal cavity using a plastic nose piece. Measurements were taken prior to RW challenge, and 0, 15, 30, 45, 60, 90, 1440 minutes post-challenge.

[00120] Blood samples (~2 mL) were collected via a cephalic or peripheral vein into chilled pre-labeled Vacutainer® tubes containing K2-EDTA at 0 hour (pre-dose), 0.083, 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, and 24 hour post-dose. All samples were chilled in and ice water bath after collection and during processing to plasma. Within 60 minutes of collection, the samples were centrifuged for approximately 10 minutes at -2000 g in a refrigerated centrifuge maintained at ~4°C. The resultant plasma (at least 1 mL) were separated, transferred to plastic tubes, and stored at approximately -70°C pending analysis. Plasma samples were shipped on dry ice for analysis.

[00121] Results of Allergic Dog Pharmacodynamic Study

[00122] The results of the allergic dog pharmacodynamics study are summarized in Tables 3 and 4. Formulations K and M were manufactured based on the linear regression model values calculated based on the healthy dog study and were supposed to match the pharmacokinetics of the commercial suspension, Control #1. These formulations both had slightly higher C_max and AUC values than the commercial suspension.

[00123] Table 3: Pharmacokinetic data (geometric means) in allergic dogs from 1^st dose of 7 days of dosing

Actual MF

Formulation

concentration N Tmax Cmax AUC No.

(mcg/g)

Control #1 500.0 6 0.50 15.14 (90) 33.08 (51)

A 486.52 6 0.25 432.56 (96) 636.42 (90)

K 17.90 6 0.25 102.82 (44) 73.42 (32)

M (l) 8.50 6 0.25 66.14 (66) 63.24 (58)

N 7.80 6 0.50 54.82 (38) 88.17 (34)

M (2) 8.50 6 0.25 47.98 (46) 58.91 (44)

D 31.0 6 0.25 132.79 (84) 178.88 (89)

M

8.27 6 0.375 21.23 (79) 40.32 (92)

(1 spray/nare)

0 8.5 6 0.50 21.58 (71) 36.29 (55)

Q 2.1 6 0.25 12.91 (93) 10.07 (65)

[00124] Table 4 shows the data on change in nasal cavity volume after treatment with the intranasal formulation for 7 days and then stimulation by an allergy for 1.5 hours. The AUC Nasal Cavity Volume is the percent reduction in nasal cavity volume after being stimulated by the ragweed allergy up to 1.5 hours (maximum AUC is 100% x 1.5 hours = 1.5).

[00125] Table 4: Pharmacodynamics at 7 Days of Dosing

Formulation Number N AUC Nasal Cavity Volume (Geometric

Mean)

No Treatment 6 0.74 (9)

Control #1 6 1.21 (10)

A 6 1.19 (5)

K 2 1.28 (6)

N 2 1.12 (2)

M (l) 2 1.46 (1)

M (2) 6 1.44 (7)

D 6 1.26 (10)

M (1 spray/nostril) 6 1.44 (8)

0 6 1.38 (8)

Q 6 1.31 (13)

R (Polysorbate 80 surfactant) 6 1.40 (6)

The microemulsion formulations with lower excipients and a lower dose (Formulations K and M) had greater efficacy in ragweed sensitized dogs than a microemulsion with the same pharmacokinetics, but higher dose and higher excipients (Formulation A).

Figure 2 illustrates the pharmacodynamics response of the allergic dogs after seven days of treatment with a microemulsion placebo, a suspension of mometasone furoate (Control 1), and several doses of mometasone furoate in the microemulsion formulation. As seen in Figure 2, after seven days of treatment, allergic dogs treated with a microemulsion containing 8 mcg/g of mometasone furoate showed statistically significantly better efficacy in maintaining initial nasal cavity volume, than placebo, the suspension of mometasone furoate in suspension (Control) and a microemulsion that contained 2 mcg/g of mometasone furoate. In addition, the microemulsion containing 8 mcg/g (Formulation M) of mometasone furoate surprisingly showed statistically significantly better efficacy in maintaining initial nasal cavity volume than a similar microemulsion that contained the same excipients but had a higher amount

(Formulation D, 31 mcg/g) of mometasone furoate, which was unexpected. In addition, Formulation A, which had a higher dose of mometasone furoate and a higher level of excipients, had a lower efficacy than formulation M (8 mcg/g), which was also unexpected.

Example 7; Healthy Humans Pharmacokinetic Study

[00126] Pharmacokinetic studies in healthy humans were performed to determine how the MF microemulsions performed in humans.

[00127] Study Design

[00128] The study was a crossover study with n=12 healthy patients enrolled. The study was designed to compare the pharmacokinetics of three (3) microemulsion formulations of various doses with a 200 meg nasal suspension. Table 5 details the composition of the formulations used in the study.

[00129]

Table 5: Formulations used in Healthy Human Pharmacokinetic Study

[00130] Results

[00131] Figure 3 illustrates the Healthy Human Pharmacokinetic data. Table 6 shows the mean data in tabular format.

[00132] Table 6: Healthy Human Pharmacokinetic data

[00133] Formulations D and I were both run in dogs and humans. The ratio of the two in dogs averaged 10.30, and the ratio of those two arms in humans averaged 10.43.

[00134] Example 8; Allergic Dog Pharmacodynamic Studies (Via Nebulizer) [00135] Allergic dogs were dosed with a nebulizer to assess the effect of vehicle and dose on pharmacodynamics. The beagles were immunized by subcutaneous injection with ragweed (RW) and inhalation of the allergen as puppies to develop allergic immune responses. These dogs display many features of asthma that are similar to the human disease such as bronchoconstriction and inflammation in the lung. Dogs (n = 6; 6 per treatment group) with these pre-existing airway allergic responses were utilized in the study. Each dog served as its own control.

[00136] Each dog was dosed by a jet nebulizer twice a day for 14 days as listed in table 7 (5 mL/treatment) while the dog was awake. Each dog was dosed via an individual face mask that is connected to an individual nebulizer. The nebulizer was run until all material was delivered to the dog.

[00137] Dogs were challenged with Ambrosia artemisifolia (ragweed) one hour after the last treatment.

[00138] In order to measure bronchoconstriction, airflow and tidal volume were measured using a pneumotach (3719 series [0-100 1/min]; Hans Rudolph) and a differential pressure transducer (Validyne) located in front of the endotracheal tube. An esophageal balloon catheter placed in the esophagus and connected to a differential pressure transducer (Validyne) was used to determine transpulmonary pressure.

Pulmonary resistance and dynamic lung compliance were calculated from the simultaneous measurement of transpulmonary pressure, tidal volume, and respiratory flow using a custom designed software acquisition system (EMKA Technologies). Dogs were challenged with RW by inhalation using a Hospitak nebulizer that is connected to the end of the endo-tracheal tube while the dogs are being ventilated (15 breaths/minute, ±10%). A fixed concentration of RW (0.5 mg/ml solution in nebulizer, , ±10%) was continuously nebulized and administered for five minutes (±10%), changes in pulmonary resistance and dynamic lung compliance were measured until the peak response was reached (typically recording continues for 10 to 15 min post RW challenge).

[00139] Blood samples (~2 mL) were collected via a cephalic or peripheral vein into chilled pre-labeled Vacutainer® tubes containing K2-EDTA at 0 hour (pre-dose), 0.083, 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, and 24 hour post-dose. All samples were chilled in and ice water bath after collection and during processing to plasma. Within 60 minutes of collection, the samples were centrifuged for approximately 10 minutes at -2000 g in a refrigerated centrifuge maintained at ~4°C. The resultant plasma (at least 1 mL) were separated, transferred to plastic tubes, frozen and sent to PPD Laboratory for analysis.

[00140] Results of Allergic Dog Pharmacodynamic (Via Nebulizer) Study

[00141] The results of the allergic dog pharmacodynamics study are summarized in tables 7 and 8. Pharmacokinetic data was not generated for budesonide.

[00142] Table 7: Pharmacokinetic data (geometric means) in allerigc dogs (via nebulizer) from 1^st dose of 14 days of dosing

[00143] Table 8 shows the data on bronchoconstriction after treatment with the formulation via jet nebulizer for 14 days and then exposure to allergen for 5 minutes. Lower values indicate better efficacy of formulation.

[00144] Table 8: Pharmacodynamics at 14 days of Dosing (Via Nebulizer)

The microemulsion formulation with lower excipients (Formulation Neb-D) shows a similar efficacy to budesonide (Formulation Neb-B) despite a much lower deposited dose. Both Microemulsion formulations showed a significant improvement in bronchoconstriction over the Vehicle (Formulation Neb-A).

Claims

WHAT IS CLAIMED IS:

1. A corticosteroid composition suitable for inhalation comprising: a corticosteroid in an amount from about 1 mcg/mg to about 30 mcg/mg; a surfactant in the amount of about 0 to 10%; and an oil in the amount of about 0 to 5%.

2. The composition of claim 1 wherein the corticosteroid comprises mometasone furoate, fluticasone propionate, fluticasone furoate, budesonide, triamcinolone acetonide, prednisolone, beclomethasone dipropionate, ciclesonide and flunisolide.

3. The composition of claim 2 wherein the corticosteroid comprises mometasone furoate.

4. The composition of claim 1 wherein the corticosteroid is in an amount from about 2 meg/ to about 20 mcg/mg.

5. The composition of claim 4 wherein the corticosteroid is in an amount from 5 mcg/mg to about 10 mc/mg.

6. The composition of claim 1 wherein the surfactant comprises SOLUTOL® HS-15, Polysorbate 80, and combinations thereof.

7. The composition of claim 1 wherein the oil is MIGLYOL® 812.

8. The composition of claim 1 wherein the surfactant to oil ratio is 4 to 1.

9. The composition of claim 1 wherein the optional pH modifying agent comprises citric acid, sodium citrate dehydrate, phosphate buffers, acetate buffers, sodium borate and combinations thereof.

10. The composition of claim 1 wherein the corticosteroid is mometasone furoate in an amount from about 2 mcg/mg to about 20 mcg/mg, the surfactant is SOLUTOL® HS-15, the oil is MIGLYOL® 812, and wherein further the surfactant to oil ratio is 4 to 1.

1 1. A pharmaceutical drug product comprising an inhalation device and composition suitable for inhalation wherein said corticosteroid composition comprises: a corticosteroid in an amount from about 1 mcg/mg to about 30 mg/mg; a surfactant in the amount of about 0 to 10%; an oil in the amount of 0 to 5%; and water.

12. The drug product of claim 11, wherein the corticosteroid comprises mometasone furoate, fluticasone propionate, fluticasone furoate, budesonide, triamcinolone acetonide, prednisolone, beclomethasone dipropionate, ciclesonide and flunisolide.

13. The drug product of claim 12, wherein the corticosteroid is mometasone furoate.

14. The drug product of claim 13, wherein the inhalation device is a nasal spray device.

15. A method of treating allergic rhinitis comprising administering a corticosteroid composition suitable for inhalation to a subject once daily, wherein said corticosteroid composition comprises: an corticosteroid in an amount from about 1 mcg/mg to about 30 mg/mg; a surfactant in the amount of about 0 to 10%; an oil in the amount of about 0 to 5%; and water.

16. The method of claim 15, wherein the corticosteroid comprises mometasone furoate, fluticasone propionate, fluticasone furoate, budesonide, triamcinolone acetonide, prednisolone, beclomethasone dipropionate, ciclesonide and flunisolide.

17. The method of claim 16, wherein the corticosteroid is mometasone furoate.