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WO 2014/115127 Al 31 July 20 14 (31.07.2014) W P O P C T (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2014/115127 Al 31 July 20 14 (31.07.2014) W P O P C T (51) International Patent Classification: AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, A61K 31/4425 (2006.01) A61P 37/00 (2006.01) BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, A61P 11/00 (2006.01) A61K 9/00 (2006.01) DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, A61P 29/00 (2006.01) HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, (21) International Application Number: MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, PCT/IB2014/058617 OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, (22) International Filing Date: SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, 28 January 2014 (28.01 .2014) TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (25) Filing Language: English (84) Designated States (unless otherwise indicated, for every (26) Publication Language: English kind of regional protection available): ARIPO (BW, GH, (30) Priority Data: GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, SZ, TZ, 354/CHE/2013 28 January 2013 (28.01.2013) IN UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, 355/CHE/2013 28 January 2013 (28.01.2013) IN TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, ΓΓ, LT, LU, LV, (71) Applicant: INCOZEN THERAPEUTICS PVT. LTD. MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, [IN/IN]; 450, Alexandria Knowledge Park, Phase I, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, Shameerpet, Hyderabad 500 078 (IN). KM, ML, MR, NE, SN, TD, TG). (72) Inventor: VAKKALANKA, Swaroop Kumar; c/o In- Published: cozen Therapeutics Pvt. Ltd., 450, Alexandria Knowledge — with international search report (Art. 21(3)) Park, Phase I, Shameerpet, Hyderabad 500078 (IN). (81) Designated States (unless otherwise indicated, for every kind of national protection available): AE, AG, AL, AM, - (54) Title: METHODS OF TREATING AUTOIMMUNE, RESPIRATORY AND INFLAMMATORY DISORDERS BY INHALA- o- TION OF ROFLUMILAST N-OXIDE (57) Abstract: The present disclosure relates to pharmaceutical compositions useful for (and to a method of) treating autoimmune, respiratory and/or inflammatory diseases and conditions. The method involves administering to a subject in need thereof roflumilast N-oxide by inhalation. The present disclosure particularly relates to the treatment of asthma and chronic obstructive pulmonary dis- ease (COPD) by administering roflumilast N-oxide by inhalation. METHODS OF TREATING AUTOIMMUNE, RESPIRATORY AND INFLAMMATORY DISORDERS BY INHALATION OF ROFLUMILAST N-OXIDE The present application claims the benefit of Indian Patent Application Nos. 354/CHE/2013, filed January 28, 2013, and 355/CHE/2013, filed January 28, 2013, each of which is hereby incorporated by reference in its entirety. FIELD OF THE INVENTION The present invention relates to a method of treating an autoimmune, respiratory and/or inflammatory disease or condition, such as asthma, COPD and other allergic and/or inflammatory disorders of the lung by pulmonary administration (e.g., by inhalation) of roflumilast N-oxide or a pharmaceutically acceptable salt thereof. The invention also relates to pharmaceutical compositions for use in the method. BACKGROUND OF THE INVENTION Autoimmune, respiratory and inflammatory diseases such as chronic obstructive pulmonary disorder (COPD) and asthma are chronic and often progressive diseases associated with a dysregulated or overactive immune system. Asthma is the most common chronic disease among children and also affects millions of adults. Some 235 million people worldwide suffer from this disease. COPD is a highly prevalent condition and a major cause of morbidity and mortality worldwide. As the disease progresses, patients with COPD may become prone to frequent exacerbations resulting in patient anxiety, worsening health status, lung function decline and increase in mortality rate. These episodes of worsening respiratory function lead to increases in health care utilization, hospital admissions and costs. Worse, frequent exacerbations are associated with a faster decline in lung function, thereby shortening life expectancy. In addition to COPD and Asthma, other allergic and/or inflammatory disorders of lung include diseases such as Cystic Fibrosis and Idiopathic pulmonary fibrosis (IPF). According to the recommendations of Global Initiative for Chronic Obstructive Lung Disease (GOLD), the first line therapy for COPD are long acting β-agonists, long acting muscarinic antagonist and inhalation corticosteroids. However, these drugs reduce the symptoms and exacerbations associated with the disease rather than targeting its molecular and cellular basis. Accordingly, there is still a need for further improvement in COPD therapy. Roflumilast (Daliresp®), a PDE4 inhibitor, is approved as an oral therapy in the U.S. to reduce the risk of COPD exacerbations in patients with severe COPD associated with chronic bronchitis and a history of exacerbations. In April 2010, the Pulmonary-Allergy Drugs Advisory Committee (PADAC) to the FDA voted 10 to 5 against approving roflumilast due to modest benefit and potential for adverse events. In March 2011, the FDA approved roflumilast with a narrower indication than had originally been pursued (namely, the treatment to reduce the risk of COPD exacerbations in patients with severe COPD associated with chronic bronchitis and a history of exacerbations). Roflumilast has been reported to have dose dependent toxicity, which limits the use of roflumilast at higher doses. The table below shows adverse events (AEs) that occurred in at least 2% of those receiving roflumilast and greater than placebo. Data obtained from the FDA label for Dalresp® (roflumilast) 08/13/13 R.W. Chapman et al., European Journal of Pharmacology, 571, 215-221 (2007), report experiments involving administration of roflumilast by inhalation to Brown Norway rats in an attempt to improve its therapeutic index. According to the label for Daliresp, roflumilast N-oxide is an active metabolite of roflumilast. International Publication Nos. WO 2001/90076 and WO 2011/163469, both of which are hereby incorporated by reference, disclose the preparation and certain uses of roflumilast N- oxide. Additional efficacy, preclinical and clinical information for roflumilast and roflumilast N-oxide is provided in A. Hatzelmann et al., Journal of Pharmacology and Experimental Therapeutics, 297, 267-279, 2001; Center For Drug Evaluation And Research Pharmacology Review(s) on Roflumilast (Application Number: 022522Origls000) available online on the U.S. FDA website; D.S. Bundschuh et al., Journal of Pharmacology and Experimental Therapeutics, 297, 280-290, 2001; Rabe et al., Br. J. Pharmacol., 16353-67, 2011; Zuzana Diamant et al., Pulmonary Pharmacology & Therapeutics 24, 4 (2011) 353; and S. Vollert et al., Diabetologia, 55, 2779-2788, 2012, each of which is hereby incorporated by reference. Despite currently available intervention therapies, respiratory disorders such as asthma and COPD remain a disease class with a significant unmet medical need. More effective therapies with fewer adverse events are needed. SUMMARY OF THE INVENTION The present invention provides a method of treating an autoimmune, respiratory and/or inflammatory disease and/or condition by pulmonary administration (e.g., by inhalation), an effective amount of roflumilast N-oxide or a pharmaceutically acceptable salt thereof. Without being bound by any particular theory, the inventors theorize that pulmonary administration of roflumilast N-oxide will result in lower plasma levels of roflumilast N- oxide and roflumilast and therefore fewer side effects than oral delivery of roflumilast. Furthermore, pulmonary delivery of roflumilast N-oxide has a broader therapeutic window than oral delivery of roflumilast. This permits a lower dosage of drug to be administered and/or a longer drug regimen with fewer adverse events. The disease or condition can be asthma, COPD, chronic obstructive bronchiolitis, chronic bronchitis, or allergic or non-allergic rhinitis. In a preferred embodiment, the disease or condition is asthma or COPD. The roflumilast N-oxide (or pharmaceutically acceptable salt thereof) can be administered by inhalation in the form of a dry powder, solution or suspension. In one embodiment, the roflumilast N-oxide is administered as a dry powder. In another embodiment, the roflumilast N-oxide is administered as a solution or suspension. The roflumilast N-oxide may be administered, for example, using a metered dose inhaler (MDI) or a dry powder inhaler (DPI). Alternatively, the roflumilast N-oxide may be administered with a nebulizer (e.g., an ultrasonic nebulizer). In one embodiment, the roflumilast N-oxide is administered as a single dose of about 5 g to about 2000 g. In another embodiment, the roflumilast N-oxide is administered as a single dose of about 20 g to about 1200 g. One or more doses of the roflumilast N-oxide may be administered a day. In yet another embodiment, the roflumilast N-oxide is administered as a single dose of about 50 µg to about 1000 ug, such as a single dose of about 100 µg to about 800 µg, for example, as a single dose of about 100 µg, about 200 µg, about 400 µg or about 600 µg. The present invention also relates to a pharmaceutical composition suitable for pulmonary administration (e.g., by inhalation) comprising roflumilast N-oxide and optionally one or more pharmaceutically acceptable carriers and/or excipients. The pharmaceutical composition may be used in the methods of treatment described herein, such as for the treatment of asthma or COPD. The pharmaceutical composition may be in the form of an inhalable dry powder comprising roflumilast N-oxide as an active ingredient and optionally particles of a physiologically acceptable, pharmacologically-inert solid carrier.
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