(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(19) World Intellectual Property Organization _
`International Bureau
`
`in
`
`(43) International Publication Date
`31 December 2008 (31.12.2008)
`
` ' |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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`(10) International Publication Number
`
`WO 2009/003199 A1
`
`(51) International Patent Classification:
`A0lN 43/04 (2006.01)
`A6lK 31/715 (2006.01)
`
`(74) Agent: MATOS, Rick; Innovar, Llc, PO. Box 250647,
`Plano, TX 75025-0647 (US).
`
`(21) International Application Number:
`PCT/US2008/068872
`
`(22) International Filing Date:
`
`30 June 2008 (30.06.2008)
`
`(25) Filing Language:
`
`(26) Publication Language:
`
`English
`
`English
`
`(30) Priority Data:
`PCT/US07/723 87
`PCT/US07/72422
`
`28 June 2007 (28.06.2007)
`29 June 2007 (29.06.2007)
`
`US
`US
`
`(71) Applicant (for all designated States except US): CYDEX
`PHARIVIACEUTICALS, INC. [US/US]; 10513 W. 84th
`Terrace, Lenexa, KS 66214 (US).
`
`(72) Inventors; and
`(75) Inventors/Applicants (for US only): PIPKIN, James, D.
`[US/US]; 4500 Woodland Dr., Lawrence, KS 66049 (US).
`ZIMMERER, Rupert, O. [US/US]; 1162 North 1100 Rd.,
`Lawrence, KS 66047 (US). SIEBERT, John, M. [US/US];
`26840 W. 108th St., Olathe, KS 66061-7470 (US).
`
`(81) Designated States (unless otherwise indicated, for every
`kind of national protection available): AE, AG, AL, AM,
`AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, CA,
`CH, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE,
`EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID,
`IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC,
`LK, LR, LS, LT, LU, LY, MA, MD, ME, MG, MK, MN,
`MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PG, PH,
`PL, PT, RO, RS, RU, SC, SD, SE, SG, SK, SL, SM, SV,
`SY, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN,
`ZA, ZM, ZW.
`
`(84) Designated States (unless otherwise indicated, for every
`kind of regional protection available): ARIPO (BW, GH,
`GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM,
`ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM),
`European (AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI,
`FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, MC, MT, NL,
`NO, PL, PT, RO, SE, SI, SK, TR), OAPI (BF, BJ, CF, CG,
`CI, CM, GA, GN, GQ, GW, ML, MR, NE, SN, TD, TG).
`
`Published:
`
`with international search report
`
`(54) Title: NASAL AND OPHTHALMIC DELIVERY OF AQUEOUS CORTICOSTEROID SOLUTIONS
`
`FIG. 6E
`
`Tearing/Watering Eyes Symptom Score
`Change From Baseline
`
`
`
`
`
`ChangefromBaseline
`
`-0.7
`
`-0.8
`
`—O—CE—Budesonide
`
`—I— Rhinocort Aqua
`
`- A- Placebo
`
`6
`
`8
`
`10
`
`12
`
`
`
`009/003199A1||||||||||||||ll|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
`
`(\l (57) Abstract: The present invention is directed to methods of treating nasal and/or ophthalmic diseases, symptoms, or disorders
`that are therapeutically responsive to corticosteroid therapy by delivering aqueous solution formulations comprising a corticosteroid
`to nasal and ophthalmic tissues. The invention is also directed to methods, systems, devices, and compositions for delivering aqueous
`solution formulations comprising a corticosteroid and an antihistamine to nasal and ophthalmic tissues. watering eyes
`
`0 W
`
`000001
`
`ARGENTUM PHARM. 1022
`
`ARGENTUM PHARM. 1022
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`000001
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`

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`WO 2009/003199
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`PCT /US2008/068872
`
`- 1 -
`
`Nasal and Ophthalmic Delivery of Aqueous Corticosteroid
`
`Solutions
`
`FIELD OF THE INVENTION
`
`The present invention is directed to methods of treating nasal and/or ophthalmic
`
`diseases, symptoms, or disorders that are therapeutically responsive to corticosteroid
`
`therapy by delivering aqueous solution formulations comprising a corticosteroid to nasal
`
`5
`
`and ophthalmic tissues. The invention is also directed to methods, systems, devices, and
`
`compositions for delivering aqueous solution formulations comprising a corticosteroid and
`
`an antihistamine to nasal and ophthalmic tissues.
`
`BACKGROUND OF THE INVENTION
`
`The nasal administration of drugs allows for their deposition to the nose, sinuses,
`
`10
`
`and other nasal cavities. Intranasal administration of drugs such as corticosteroids and
`
`antihistamines may be used to treat nasal symptoms including seasonal allergic rhinitis,
`
`perennial allergic rhinitis, perennial non-allergic rhinitis, nasal polyps, as well as
`
`prevention of post surgical polyps, chronic sinusitis, recurrent sinusitis, asthma, grass
`
`pollen rhinitis, hay fever, snoring, cluster headache, and other diseases and disorders.
`
`15
`
`The ophthalmic administration of drugs allows for their deposition to the eye,
`
`including the ocular mucosa, eye surface, cornea, conjuctiva, sclera, and posterior eye
`
`parts such as the retina, choroid, and vitreous and optic nerves, as well as tissues
`
`surrounding the eye. Ophthalmic administration of drugs such as corticosteroids and
`
`antihistamines may be used
`
`to
`
`treat ocular symptoms
`
`including conjunctivitis,
`
`20
`
`inflammation of tissue(s) in the eye, dry eye, filamentary keratitis, delayed tear clearance,
`
`pain, keratoconjunctival dryness, keratoconjunctivitis sicca, lesions/tumors of the eye,
`
`infectious processes of the eye, bacterial infections, viral infections, glaucoma, uveitis,
`
`diabetic retinopathy, eye trauma, blepharitis, blepharoconjunctivitis, and other diseases or
`
`disorders.
`
`25
`
`Aqueous formulations containing a corticosteroid and a solubilizing agent have
`
`been prepared: Saidi et al. (U.S. Patent No. 6,241,969); Keller et al. (Respiratory Drug
`
`000002
`
`

`
`WO 2009/003199
`
`PCT /US2008/068872
`
`- 2 -
`
`Delivery IX (2004) 221-231); Lintz et al. (AAPS Annual Meeting and Exposition,
`
`Baltimore, Nov. 8, 2004; Poster Mll28); Schueepp et al. (ATS 99th International
`
`Conference, Seattle, May 16th-2ls\ 2003; poster 1607); Russian Patent No. 2180217 to
`
`Chuchalin; U.S. Publication No. 2006/0045850; and Waldrep et al. (J. Aerosol Med.
`
`5
`
`(1994), 7(2), 135-145); PCT International Publications No. WO 06/108556, No. WO
`
`03/35030, and No. WO 06/37246 and European Publications No. EP1894559 and No.
`
`EPl 712220 to PARI Pharma GmbH.
`
`Cyclodextrins have been included in nasal or ophthalmic compositions: Kaur et al.
`
`(Curr. Drug Deliv. (2004), 1(4), 351-360); Shimpi et al. (Acta Pharm. (2005), 55(2), 139-
`
`10
`
`56); Viegas et al. (U.S. Patents No. 6,136,334, No. 5,587,175, and No. 5,958,443); Pate et
`
`al. (U.S. Patent No. 5,977,180); Loftsson et al. (Acta Ophthalmol. Scand. (2002), 80(2),
`
`144-50).
`
`Underivatized and derivatized cyclodextrins can be used to prepare aqueous
`
`formulations containing a corticosteroid: U.S. Patents No. 5,376,645 and No. 5,134,127 to
`
`15
`
`Stella et al.; U.S. Patent No. 5,914,122 to Otterbeck et al.; Worth et al. (24th International
`
`Symposium on Controlled Release of Bioactive Materials (1997)); Kinnarinen et al. (11th
`
`International Cyclodextrin Symposium CD, (2002)); U.S. Patent No. 5,472,954; U.S.
`
`patent No. 5,089,482; Zimmerer et al. in Respiratory Drug Delivery IX (2004) 461 - 464);
`
`Singh et al. (U.S. Patents No. 7,128,928 and No. 6,696,426); Loftsson (U.S. Patents No.
`
`20
`
`7,115,586, No. 5,472,954, and No. 5,324,718); Chang et al. (U.S. Patent No. 6,969,706);
`
`Beck et al. (U.S. Patents No. 6,723,353 and No. 6,358,935); Buchanan et al. (U.S. Patent
`
`No. 6,610,671); Pitha (U.S. Patents No. 6,576,261 and No. 5,935,941); Kis (U.S. Patent
`
`No. 6,468,548); Muller et al. (U.S. Patent No. 6,407,079); Wiebe et al. (U.S. Patent No.
`
`5,739,121); Guy (U.S. Patent No. 5,576,311); Babcock et al. (U.S. Patent No. 5,538,721);
`
`25
`
`Folkman et al. (U.S. Patent No. 5,227,372); Lipari (U.S. Patent No. 4,383,992); PCT
`
`International Publication No. WO 2004/087043 to Sun Pharmaceutical Industries Ltd.;
`
`Saari et al. (Graefes Arch. Clin. Exp. Ophthalmol. (2006), 244(5), 620-6); Kristinsson et
`
`al. (Invest. Ophthalmol. Vis. Sci. (1996), 37(6), 1199-203); Usayapant et al. (Pharm. Res.
`
`(1991), 8(12), 1495-9); Bary et al. (Eur. J. Pharm. Biopharm. (2000), 50(2), 237-244);
`
`30 U.S. Publication No. 2006/0193783; U.S. Publication No. 2002/0198174; European
`
`Publication No. EP 0435682; Lyons et al. (abstract in AAPS Annual Meeting and
`
`Exposition, Denver, CO USA, October 1-25, 2001); Amselem et al. (U.S. Patent No.
`
`5,747,061).
`
`000003
`
`

`
`WO 2009/003199
`
`PCT /US2008/068872
`
`- 3 -
`
`Sulfoalkyl ether cyclodextrin derivatives can be used to prepare aqueous
`
`formulations containing a corticosteroid: U.S. Publication No. 2007 /0020336; U.S.
`
`Publication No. 2006/0120967; U.S. Publication No. 2002/0150616 to Van de Cruys; U.S.
`
`Publications No. 20070249572, No. 20070197487, No. 20070197486, No. 20070191599,
`
`5 No. 20070191327; No. 20070191323, No. 20070185066, No. 20070178050, No.
`
`20070178049, and No. 20070160542 and PCT International Publications No. WO
`
`07/95342, No. WO 07/95341, No. WO 07/95339, No. WO 07/75963, No. WO 07/75859,
`
`No. WO 07/75801, No. WO 07/75800, No. WO 07/75799, and No. WO 07/75798 to Hill;
`
`U.S. Publications No. 20070202054, No. 20070020299, No. 20070020298, and No.
`
`10
`
`20070020196, and PCT International Publications No. WO 08/05692, No. WO 08/05691,
`
`No. WO 08/05053, No. WO 05/065651, No. WO 05/065649, No. WO 05/065435 to
`
`Pipkin et al.; U.S. Publication No. 20060120967 and No. 20060045850 to Namburi et al.;
`
`and U.S. Publications No. 2005085446 and No. 20070049552 to Babu.
`
`Corticosteroid-containing formulations for ophthalmic use have been described:
`
`15
`
`Pflugfelder et al. (U.S. Patent No. 6,153,607), Sackeyfio et al. (U.S. Patent No.
`
`6,995,815), Guo et al. (U.S. Patent Nos. 6,548,078 and 6,217,895), Sher (U.S. Patent No.
`
`6,117,907), Clarke et al. (U.S. Patent Nos.5,358,943 and 4,945,089), Schwartz (U.S.
`
`Patent Nos. 5,212,168 and 4,904,649), and Saidi et al. (U.S. Patent No. 6,241,969).
`
`The nasal and/or ophthalmic delivery of an aqueous solution formulation
`
`20
`
`comprising a corticosteroid as a therapeutic agent alone or in combination with another
`
`therapeutic agent, such as an antihistamine, for the treatment of allergy-related disorders
`
`or symptoms would be useful and especially desirable if it could provide an improved
`
`clinical benefit over the delivery of other formulations, such as suspension-based
`
`formulations.
`
`25
`
`SUMMARY OF THE INVENTION
`
`The invention provides a method of treating, preventing or ameliorating in a
`
`subject a corticosteroid-responsive disease or disorder, meaning a disease or disorder in a
`
`subject that can be treated with a therapeutically effective amount of corticosteroid to
`
`provide a clinical or therapeutic benefit to the subject.
`
`In some embodiments, the
`
`30
`
`corticosteroid-responsive disease or disorder is a disease, disorder, symptom, or condition
`
`of the nose or eye.
`
`000004
`
`

`
`WO 2009/003199
`
`PCT /US2008/068872
`
`- 4 -
`
`The invention provides a method for treating an allergic symptom or disorder in a
`
`subject in need thereof, comprising:
`
`nasally administering to the subject a corticosteroid solution compnsmg a
`
`therapeutically effective amount of a corticosteroid, SAE-CD, and a pharmaceutically
`
`5
`
`acceptable aqueous liquid carrier,
`
`wherein the corticosteroid solution provides more rapid relief from an allergic
`
`symptom or disorder compared to a corticosteroid suspension at the same unit dose.
`
`In some embodiments, the allergic symptom or disorder includes a non-nasal
`
`symptom selected from the group consisting of itchy/gritty eyes, tearing/watery eyes,
`
`10
`
`red/burning eyes, itchy eyes and palate, and combinations thereof.
`
`The invention also provides a method for treating an ocular symptom or disorder in
`
`a subject in need thereof, comprising:
`
`nasally administering to the subject a corticosteroid solution compnsmg a
`
`therapeutically effective amount of a corticosteroid, SAE-CD, and a pharmaceutically
`
`15
`
`acceptable aqueous liquid carrier,
`
`wherein the ocular symptom or disorder is itchy/gritty eyes, tearing/watery eyes,
`
`red/burning eyes, or a combination thereof.
`
`The invention also provides a system for treating an allergic symptom or disorder
`
`in a subject in need thereof, comprising:
`
`20
`
`a corticosteroid solution comprising a therapeutically effective amount of a
`
`corticosteroid, a thereapeutically effective amount of an antihistamine, SAE-CD, and a
`
`pharmaceutically acceptable aqueous liquid carrier, and
`
`a metered dose device for nasal administration of the corticosteroid solution to the
`
`subject, wherein the corticosteroid solution is provided in the device.
`
`25
`
`In some embodiments, the system is for treating an ocular symptom or disorder in
`
`a subject in need thereof.
`
`The invention also provides a metered dose device for nasal administration
`
`comprising a corticosteroid solution comprising a therapeutically effective amount of a
`
`corticosteroid, a therapeutically effective amount of an antihistamine, SAE-CD, and a
`
`30
`
`pharmaceutically acceptable aqueous liquid carrier.
`
`000005
`
`

`
`WO 2009/003199
`
`PCT /US2008/068872
`
`- 5 -
`
`In some embodiments, the invention provides a method for treating a nasal
`
`symptom or disorder in a subject in need thereof, comprising:
`
`nasally administering to the subject a corticosteroid solution compnsmg a
`
`therapeutically effective amount of a corticosteroid, SAE-CD, and a pharmaceutically
`
`5
`
`acceptable aqueous liquid carrier,
`
`wherein the nasal symptom or disorder is selected from the group consisting of:
`
`acute or chronic rhinitis, nasal polyps, post surgical nasal polyps, snoring, cluster
`
`headache, and combinations thereof.
`
`In some embodiments of the method for treating a nasal symptom or disorder in a
`
`10
`
`subject in need thereof, the symptom or disorder is instead selected from the group
`
`consisting of obstructive sleep apnea, eustachian tube dysfunction, serous otitis media,
`
`sleep disturbances, daytime somnolesence, nasal furuncles, epistaxis, wounds of the nasal
`
`or sinunasal mucosa, dry nose syndrome, nasal bleeding, and combinations thereof.
`
`The invention also provides a method for treating an allergic symptom or disorder
`
`15
`
`in a subject in need thereof, comprising:
`
`ophthalmically administering to the subject a corticosteroid solution comprising a
`
`therapeutically effective amount of a corticosteroid, SAE-CD, and a pharmaceutically
`
`acceptable aqueous liquid carrier,
`
`wherein the corticosteroid solution provides more rapid relief from an allergic
`
`20
`
`symptom or disorder compared to a corticosteroid suspension at the same unit dose.
`
`The invention also provides a method for treating ocular inflammation in a subject
`
`in need thereof, comprising:
`
`ophthalmically administering to the subject a corticosteroid solution comprising a
`
`therapeutically effective amount of a corticosteroid, SAE-CD, and a pharmaceutically
`
`25
`
`acceptable aqueous liquid carrier,
`
`wherein the corticosteroid solution provides a more rapid reduction m ocular
`
`inflammation compared with a corticosteroid suspension at the same unit dose.
`
`The invention also provides a system for treating an allergic symptom or disorder
`
`in a subject in need thereof, comprising:
`
`000006
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`

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`WO 2009/003199
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`PCT /US2008/068872
`
`- 6 -
`
`a corticosteroid solution compnsmg a therapeutically effective amount of a
`
`corticosteroid, a thereapeutically effective amount of an antihistamine, SAE-CD, and a
`
`pharmaceutically acceptable aqueous liquid carrier, and
`
`a device for ophthalmic administration of the corticosteroid solution to the subject,
`
`5 wherein the corticosteroid solution is provided in the device.
`
`The invention also provides a device for ophthalmic adminstration comprising a
`
`corticosteroid solution comprising a therapeutically effective amount of a corticosteroid, a
`
`therapeutically effective amount of an antihistamine, SAE-CD, and a pharmaceutically
`
`acceptable aqueous liquid carrier.
`
`10
`
`The administration device can be: 1) a metered dose device such as a atomizer,
`
`sprayer, pump spray, dropper, squeeze tube, squeeze bottle, pipette, ampule, nasal cannula,
`
`metered dose device, nasal spray inhaler, nasal continuous positive air pressure device, or
`
`breath actuated bi-directional delivery device; or 2) a device for ophthalmic administration
`
`such as a dropper, drop dispensing package, tube, eye spray device, or eye wash unit. The
`
`15
`
`device can be adapted to to emit 10 µl to 500 µl of corticosteroid solution per unit dose.
`
`The device can also comprise a nozzle, wherein the nozzle comprises a valve, and the
`
`valve provides a release of a volume of 25 µl to 260 µl per unit dose through the nozzle
`
`upon operation of the device.
`
`In some embodiments,
`
`the corticosteroid
`
`is beclomethasone dipropionate,
`
`20
`
`beclomethasone monopropionate, betamethasone, budesonide, ciclesonide, desisobutyryl(cid:173)
`
`ciclesonide, dexamethasone, flunisolide, fluticasone propionate, fluticasone furoate,
`
`mometasone furoate, triamcinolone acetonide, or a combination thereof.
`
`The invention also includes embodiments wherein the corticosteroid solution
`
`further comprises one or more additional therapeutically effective agents, such as an anti-
`
`25
`
`IgE antibody, antibiotic agent, anticholinergic agent, antifungal agent, anti-inflammatory
`
`agent, anti-infective agent, antihistamine agent, analgesic agent, decongestant,
`
`expectorant, antitussive agent, antimicrobial agent, leukotriene receptor antagonist, or a
`
`combination thereof. Specific embodiments of these additional therapeutically effective
`
`agents can be selected from those disclosed herein or others suitable for nasal or
`
`30
`
`ophthalmic administration and for treatment of diseases, disorders or symptoms of the
`
`nose or eye.
`
`000007
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`

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`WO 2009/003199
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`PCT /US2008/068872
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`- 7 -
`
`In
`
`some embodiments,
`
`the method
`
`further compnses administering a
`
`therapeutically effective amount of an antihistamine.
`
`In some embodiments, the
`
`antihistamine
`
`is diphenhydramine, clemastine, chlorpheniramine, brompheniramine,
`
`dexchlorpheniramine, dexbrompheniramine,
`
`triprolidine, doxylamine,
`
`tripelennamine,
`
`5
`
`heptadine, carbinoaxime, bromdiphenhydramine, hydroxyzine, pyrilamine, acrivastine,
`
`AHR-11325, phenindamine, astemizole, azatadine, azelastine, cetirizine, ebastine,
`
`fexofenadine, ketotifen, lodoxine, loratadine, descarboethoxyloratadine, levocabastine,
`
`mequitazine, oxatomide, setastine, tazifyline, temelastine, terfenadine, tripelennamine,
`
`terfenadine carboxylate, phenyltoloxamine, pheniramine, or a combination thereof.
`
`In
`
`10
`
`some embodiments, the antihistamine is care bas tine, efletirizine, mapinastine, antazoline,
`
`bilastine, bepotastine besilate,
`
`rupatadine, emedastine,
`
`tecastemizole, epinastine,
`
`levocetirizine, mizolastine, noberastine, norastemizole, olopatadine, or a combination
`
`thereof. In some embodiments the antihistamine is azelastine. In some embodiments, the
`
`antihistamine is azelastine, wherein the azelastine is present at an amount of about 30 µg
`
`15
`
`to about 275 µg per unit dose.
`
`In some embodiments, the antihistamine is azelastine,
`
`wherein the azelastine is present at a concentration of 0.5 to 10 mg/mL.
`
`In some
`
`embodiments, the antihistamine is olopatadine. In some embodiments, the antihistamine
`
`is azelastine, wherein the olopatadine is present at an amount of about 330 µg to about
`
`2660 µg per unit dose. In some embodiments, the antihistamine is azelastine, wherein the
`
`20
`
`olopatadine is present at a concentration of 1 to 15 mg/mL. In some embodiments, the
`
`antihistamine is cetirizine. In some embodiments, the antihistamine is cetirizine, wherein
`
`the cetirizine is present at an amount of about 0.25 mg to about 4.4 mg per unit dose. In
`
`some embodiments, the antihistamine is cetirizine, wherein the cetirizine is present at a
`
`concentration of 0.25 to 4.4 mg/mL.
`
`25
`
`In some embodiments, the administering of the corticosteroid solution is performed
`
`once or twice daily.
`
`In some embodiments, the allergic symptom or disorder is or further includes a
`
`nasal symptom, non-nasal symptom, allergic rhinitis, seasonal allergic rhinitis, perennial
`
`allergic rhinitis, perennial non-allergic rhinitis, grass pollen rhinitis, have fever, nasal
`
`30
`
`polyps, or a combination thereof. In some embodiments, the allergic symptom or disorder
`
`is or further includes ocular symptom, bacterial rhinitis, fungal rhinitis, viral rhinitis,
`
`000008
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`WO 2009/003199
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`PCT /US2008/068872
`
`- 8 -
`
`atrophic rhinitis, vasomotor rhinitis, blocked nose, nasal congestion, or a combination
`
`thereof.
`
`In some embodiments, the nasal symptom is rhinorrhea, nasal congestion, nasal
`
`itchiness, sneezing, nasal obstruction, or a combination thereof.
`
`5
`
`In some embodiments, the non-nasal symptom is itchy/gritty eyes, tearing/watery
`
`eyes, red/burning eyes, itchy ears and palate, or a combination thereof.
`
`In some embodiments, the corticosteroid is budesonide. In some embodiments, the
`
`corticosteroid is budesonide, wherein the budesonide is present at an amount of about 5 µg
`
`to about 500 µg per unit dose. In some embodiments, the corticosteroid is budesonide,
`
`10 wherein the budesonide is present at a concentration of 40 to 2000 µg/mL.
`
`In some embodiments, the corticosteroid is fluticasone propionate.
`
`In some embodiments, the corticosteroid is fluticasone furoate.
`
`In some embodiments, the corticosteroid is mometasone furoate.
`
`In some embodiments, the molar ratio of the SAE-CD to the corticosteroid is 1: 1 or
`
`15
`
`greater. In some embodiments, the molar ratio of the SAE-CD to an additional therapeutic
`
`agent is 1: 1 or greater.
`
`In some embodiments, the molar ratio of the SAE-CD to an
`
`antihistamine is greater than 2: 1.
`
`Some embodiments of the invention includes those wherein the corticosteroid
`
`solution comprises: 1) a corticosteroid, such as budesonide, fluticasone propionate,
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`20
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`fluticasone furoate, mometasone furoate, ciclesonide, or a combination thereof; and 2)
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`another therapeutically effective agent, such as azelastine, olopatadine, cetirizine,
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`loratadine, desloratadine, azithromycin, voriconazole, or a combination thereof.
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`In some embodiments, the aqueous liquid carrier comprises water, buffer, alcohol, organic
`
`solvent, glycerin, propylene glycol, poly(ethylene glycol), poloxamer, surfactant or a
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`25
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`combination thereof.
`
`In some embodiments, the aqueous liquid carrier comprises
`
`povidone, polyol or a combination thereof.
`
`Some embodiments of the invention also provide a unit dose of a therapeutic
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`corticosteroid
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`solution
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`compnsmg:
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`about 32 µg
`
`of budesonide; SAE-CD;
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`pharmaceutically acceptable aqueous liquid carrier; disodium edetate of about 0.005 to
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`30
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`about 0.1 % by weight of the unit dose; and potassium sorbate of about 0.05 to about 0.2%
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`by weight of the unit dose, and wherein the corticosteroid solution is suitable for nasal
`
`administration to a subject in need thereof.
`
`Some embodiments of the invention also provide a method of treating preventing
`
`or ameliorating in a subject a corticosteroid-responsive disease or disorder, the method
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`5
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`comprising metering into the nose of the subject a therapeutically effective amount of
`
`budesonide that is less than about 320 µg per day, delivered as 8 or more unit doses,
`
`wherein each unit dose consists of about 32 µg of budesonide; SAE-CD; disodium edetate
`
`of about 0.005 to about 0.1 % by weight of the unit dose; potassium sorbate of about 0.05
`
`to about 0.2% by weight of the unit dose; and a pharmaceutically acceptable aqueous
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`10
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`liquid carrier.
`
`In some embodiments, the corticosteroid solution has a pH of about 3.5 to about 5
`
`or about about 4.2 to about 4.6.
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`In some embodiments, the SAE-CD is a compound, or mixture of compounds, of
`
`the Formula 1:
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`15
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`20
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`25
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`30
`
`wherein:
`
`Formula 1
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`n is 4, 5 or 6;
`Ri, Rz, R3, Ri, Rs, R6, R1, Rs and R9 are each, independently, -0- or a-O-(C2 - C6
`alkylene)-S03- group, wherein at least one of R 1 - R9 is independently a -O-(C2 -
`C6 alkylene)-S03- group, a -O-(CH2)mS03- group wherein mis 2 to 6,
`-
`-OCH2CH2CH2S03 -, or-OCH2CH2CH2CH2S03 ); and
`
`Si, S2, S3, S4, Ss, S6, S1, Ss and S9 are each, independently, a pharmaceutically acceptable
`
`cation.
`
`In some embodiments, the corticosteroid solution further comprises one or more
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`35
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`pharmaceutically acceptable excipients, such as a preservative, an antioxidant, a buffering
`
`agent, an acidifying agent, an alkalizing agent, a solubility-enhancing agent, a
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`complexation-enhancing agent, a diluent, an electrolyte, glucose, a stabilizer, a bulking
`
`agent, an antifoaming agent, an oil, an emulsifying agent, flavor, sweetener, a taste(cid:173)
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`masking agent, a tonicity modifier, a surface tension modifier, a viscosity modifier, a
`
`density modifier, or a combination thereof.
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`5
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`In some embodiments, the SAE-CD is present at a concentration of about 10 to
`
`about 500 mg/mL of corticosteroid solution, and/or the SAE-CD is present in an amount
`
`of 100 µg to 1000 mg per unit dose.
`
`The invention includes all combinations of the embodiments and aspects disclosed
`
`herein. Accordingly, the invention includes the embodiments and aspects specifically
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`10
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`disclosed, broadly disclosed, or narrowly disclosed herein, as well as combinations thereof
`
`and subcombinations of the individual elements of said embodiments and aspects.
`
`These and other aspects of this invention will be apparent upon reference to the
`
`following detailed description, examples, claims and attached figures.
`
`BRIEF DESCRIPTION OF THE FIGURES
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`15
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`The following drawings are given by way of illustration only, and thus are not
`
`intended to limit the scope of the present invention.
`
`FIG.
`
`lA depicts a phase solubility graph of the concentration (molar) of
`
`cyclodextrin versus the concentration (molar) of budesonide for y-CD, HP-~-CD and
`
`SBE7-~-CD.
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`20
`
`FIG. lB depicts a phase solubility graph for budesonide concentration (M) versus
`
`cyclodextrin concentration (M) for various SBG-y-CD species and CAPTISOL.
`
`FIG. 2 depicts a phase solubility diagram for fluticasone propionate in the presence
`
`of several different cyclodextrins.
`
`FIG. 3 depicts a phase solubility diagram for mometasone furoate in the presence
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`25
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`of several different cyclodextrins.
`
`FIG. 4 depicts a phase solubility diagram for esterified and non-esterified
`
`fluticasone in the presence of SAE(5-6)-y-CD.
`
`FIG. 5 depicts a bar chart summarizing the aqueous solubility of beclomethasone
`
`dipropionate in the presence of various SAE-CD derivatives.
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`30
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`FIGS. 6A to 6F depict charts detailing the results of a clinical study conducted
`
`according to Example 33.
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`FIG. 7 depicts a graphical summary of the study protocol of Example 33.
`
`FIG. 8A depicts a chart the TNSS change from baseline with onset of action for
`
`the first three time points in the study of Example 33.
`
`FIG. 8B depicts a chart the TNNSS change from baseline with onset of action for
`
`5
`
`the first three time points in the study of Example 33.
`
`FIGS. 9A-9C depict the results of the effect that the three solutions of Example 33
`
`have on the EEC-QOLQ as determined using the Quality of Life Questionnaire.
`
`FIGS. 1 OA-1 OC depict charts of the pH rate profile for degradation of azelastine in
`
`the presence or absence of SAE-CD at varying temperatures and pH's: FIG. lOA-
`
`10 Azelastine pH Rate Profile Area % (25°C), 0.5mg/mL azelastine HCl in 3mM citrate @
`
`pH 4, 5, & 6; with and without 1.75% CAPTISOL, Stored in 25°C Stability Chamber;
`
`FIG. lOB- Azelastine pH Rate Profile Area% (40°C), 0.5mg/mL azelastine HCl in 3mM
`
`citrate @ pH 4, 5, & 6; with and without 1.75% CAPTISOL, Stored in 40°C Stability
`
`Chamber; FIG. lOC- Azelastine pH Rate Profile Area % (60°C), 0.5mg/mL azelastine
`
`15 HCl in 3mM citrate@ pH 4, 5, & 6; with and without 1.75% CAPTISOL, Stored in 60°C
`
`Stability Chamber.
`
`FIGS.
`
`llA and llB depict phase solubility diagrams for budesonide in the
`
`presence of varying amounts of azelastine hydrochloride and fixed amounts of SBE-~-CD
`
`or SBE-y-CD.
`
`20
`
`FIGS. 12A-12C depict charts the TNSS, TOSS, and TSS, respectively, change
`
`from baseline with onset of action for the first three time points in the study of Example 34
`
`using budesonide and azelastine.
`
`FIGS. 13A-13B depict charts detailing the changes in ocular pressure of rabbits
`
`treated according to Example 41.
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`25
`
`DETAILED DESCRIPTION OF THE INVENTION
`
`The present invention is directed to methods of treating nasal and/or ophthalmic
`
`diseases, symptoms, or disorders that are therapeutically responsive to corticosteroid
`
`therapy by delivering aqueous solution formulations comprising a corticosteroid to nasal
`
`and ophthalmic tissues. The invention is also directed to methods, systems, devices, and
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`30
`
`compositions for delivering aqueous solution formulations comprising a corticosteroid and
`
`an antihistamine to nasal and ophthalmic tissues. The systems of the invention comprise
`
`an administration device, and a composition of the invention. The composition of the
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`invention 1s a corticosteroid solution compnsmg a corticosteroid and SAE-CD. The
`
`composition can be a nasal or non-nasal composition or an ophthalmic composition. In
`
`some embodiments, a non-nasal composition excludes an inhalable composition for
`
`pulmonary delivery.
`
`5
`
`By including SAE-CD in a liquid composition containing corticosteroid, the
`
`corticosteroid is dissolved. The corticosteroid exhibits greater stability in the presence of
`
`SAE-CD than it does in its absence. When a second active agent is present, the second
`
`active agent can also exhibit greater stability in the presence of SAE-CD than it does in its
`
`absence.
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`10
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`The methods, systems, devices, and compositions of the invention can provide an
`
`enhanced pharmacokinetic profile over a
`
`suspens10n
`
`formulation
`
`compnsmg
`
`approximately the same amount of a therapeutic agent and delivered under substantially
`
`the same conditions. The therapeutic agent is a corticosteroid alone or a corticosteroid
`
`combined with one or more additional therapeutic agents. As such, one or more
`
`15
`
`therapeutic agents in the methods, systems, devices, and compositions of the invention can
`
`demonstrate an enhanced pharmacokinetic profile when compared with the same
`
`therapeutic agent or agents
`
`in a suspension formulation.
`
`The
`
`term "enhanced
`
`pharmacokinetic profile" is taken to mean a higher AUC (e.g. AUC1ast or AUCco-700)) per
`
`µg of therapeutic agent delivered or administered, a higher Cmax per µg of therapeutic
`
`20
`
`agent delivered or administered, increased bioavailability, absorption or distribution of the
`
`therapeutic agent at the site of delivery, a shorter Tmax, or a longer Tmax. The methods,
`
`systems, devices, and compositions of the invention can also provide other enhancements
`
`over a suspension-based formulation, such as enhanced drug delivery, increased rate of
`
`drug administration, reduced treatment time, reduced toxicity,
`
`improved stability,
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`25
`
`enhanced bioabsorption, increased output rate, increased total output, reduced side effects
`
`associated with the therapeutic agent, increased nasal cavity deposition, increased
`
`paranasal sinus cavity deposition, increased ocular deposition, improved quality of life,
`
`reduced mucociliary clearance, reduced ocular clearance, and/or improved patient
`
`compliance.
`
`30
`
`Alternatively, the methods, systems, devices, and compositions of the invention
`
`provide substantially the same pharmacokinetic profile or an enhanced pharmacokinetic
`
`profile over a suspension formulation comprising a higher amount of therapeutic agent and
`
`delivered under substantially the same conditions.
`
`The therapeutic agent in the
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`formulation can be present at a dose that is less than about 80%, less than about 70%, less
`
`than about 60% less than about 50%, less than about 40%, less than about 20%, or less
`
`than about 10% of that in the suspension.
`
`The amount and/or concentration of SAE-CD in the composition can be varied as
`
`5
`
`needed or as described herein to provide a composition that possesses a desired physical
`
`property, provide therapeutic effectiveness in subjects to which the composition is
`
`administered, and/or achieve a desired performance in an administration device. SAE-CD
`
`can be present in an amount sufficient to solubilize and/or stabilize the therapeutic agent
`
`when the SAE-CD and therapeutic agent