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WO 2013/169647 Al 14 November 2013 (14.11.2013) P O P C T

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WO 2013/169647 Al 14 November 2013 (14.11.2013) 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 2013/169647 Al 14 November 2013 (14.11.2013) P O P C T (51) International Patent Classification: (74) Agents: ELRIFI, Ivor, R. et al; Mintz Levin Cohn Ferris C07J 31/00 (2006.01) C07J 71/00 (2006.01) Glovsky And Popeo, P.C., One Financial Center, Boston, MA 021 11 (US). (21) International Application Number: PCT/US20 13/039694 (81) Designated States (unless otherwise indicated, for every kind of national protection available): AE, AG, AL, AM, (22) International Filing Date: AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, 6 May 2013 (06.05.2013) BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, (25) Filing Language: English 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, (26) Publication Language: English KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, (30) Priority Data: ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, 61/644,105 8 May 2012 (08.05.2012) US NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, 61/657,239 8 June 2012 (08.06.2012) US RW, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, 61/692,487 23 August 2012 (23.08.2012) US TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, 13/735,973 7 January 2013 (07.01 .2013) US ZM, ZW. 61/763,770 12 February 2013 (12.02.2013) US (84) Designated States (unless otherwise indicated, for every 61/788,5 19 15 March 2013 (15.03.2013) US kind of regional protection available): ARIPO (BW, GH, (71) Applicant: ACIEX THERAPEUTICS, INC. [US/US]; GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, SZ, TZ, 470 Atlantic Avenue, 4th Floor, Boston, MA 02210 (US). UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, (72) Inventors: CAVANAGH, Thomas; 57 Hunters Creek EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, Lane, New Canaan, CT 06840 (US). BARMAN, Shikha, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, P.; 19a Crosby Drive, Suite 200, Bedford, MA 0 1730 TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, (US). HAO, Tian; 290 School Street, Acton, MA 01720 ML, MR, NE, SN, TD, TG). (US). LELAND, Thomas, B.; 43 Vaughn Hill Road, Bolton, MA 01740 (US). THEKKEDATH, Ritesh, V.; Published: D/l 202 Panchratna, Anand Nagar, Manpada Road, Dom- — with international search report (Art. 21(3)) bivli (E). M.S. (IN). [Continued on next page] (54) Title: PREPARATIONS OF HYDROPHOBIC THERAPEUTIC AGENTS, METHODS OF MANUFACTURE AND USE THEREOF 2500 2000 ί I ' 1500 I o \ c 1000 500 * 20 25 30 35 40 45 2theta (degree) FIG. 31A o (57) Abstract: The present invention further provides method of preparing nanocrystals of a hydrophobic therapeutic agent such as fluticasone or triamcinolone, pharmaceutical compositions (e.g., topical or intranasal compositions) thereof and methods for treating o and/or preventing the signs and/or symptoms of disorders such as blepharitis, meibomian gland dysfunction or skin inflammation or a respiratory disease (e.g., asthma). WO 2013/169647 Al llll II II 11III III before the expiration of the time limit for amending the claims and to be republished in the event of receipt of amendments (Rule 48.2(h)) PREPARATIONS OF HYDROPHOBIC THERAPEUTIC AGENTS, METHODS OF MANUFACTURE AND USE THEREOF RELATED APPLICATIONS [0001] This application claims priority to, and the benefit of, U.S. provisional application Nos. 61/644,105, filed May 8, 2012; 61/657,239, filed June 8, 2012; 61/692,487, filed August 23, 2012, 61/763,770, filed February 12, 2013; and 61/788,519, filed March 15, 2013, and U.S. Non-provisional Application No. 13/735,973, filed January 7, 2013. The contents of each of these applications are hereby incorporated by reference in their entireties. FIELD OF THE INVENTION [0002] The present invention provides a method of manufacture of sterile nanocrystals of hydrophobic therapeutic agents (such as fluticasone propionate and triamcinolone acetonide) that are optimized to meet pharmaceutical standards of administration (e.g., topical or intranasal administration). BACKGROUND OF THE INVENTION [0003] Fluticasone Propionate [(6a,l ip,16a,17a)-6,9,-difluoro-l l-hydroxy-16- methyl-3-oxo-17-(l-oxopropoxy) androsta-l,4-diene-17-carbothioic acid, S-fluoromethyl ester], a synthetic fluorinated corticosteroid. The corticosteroids constitute a class of primarily synthetic steroids used as anti-inflammatory and antipruritic agents. Fluticasone Propionate (FP) has been commercialized as a corticosteroid to treat inflammation associated diseases such as allergic rhinitis, asthma and atopic dermatitis. The PK PD properties of this molecule have been well-established by its long standing use in humans. C H [0004] Chemically, fluticasone propionate is 25 3 1F30 5S. Fluticasone propionate has a molecular weight of 500.6. It is a white to off-white powder and is insoluble in water. Like other topical corticosteroids, fluticasone propionate has anti-inflammatory, antipruritic and vasoconstrictive properties. The mechanism of the anti-inflammatory activity of the topical steroids, in general, is unclear. However, corticosteroids are thought to act by the induction of phospholipase A2 inhibitory proteins, collectively called lipocortins. It is postulated that these proteins control the biosynthesis of potent mediators of inflammation such as prostaglandins and leukotrienes by inhibiting the release of their common precursor, arachidonic acid. Arachidonic acid is released from membrane phospholipids by phospholipase A2. The compound has potent anti inflammatory activity and is particularly useful for the treatment of respiratory disorders, particularly asthma. In vitro assays using human lung cytosol preparations have established fluticasone propionate as a human glucocorticoid receptor agonist with an affinity 18 times greater than dexamethasone, and almost twice that of beclomethasone- 17-monopropionate (BMP), the active metabolite of budesonide. [0005] Adverse reactions from the current marketed forms of fluticasone propionate include lymphatic signs and symptoms; cardiovascular palpitations; hypersensitivity reactions, including angioedema, skin rash, edema of the face and tongue, pruritus, urticaria, bronchospasm, wheezing, dyspnea, and anaphylaxis/anaphylactoid reactions; otitis media; tonsillitis; rhinorrhea/postnasal drip/nasal discharge; earache; cough; laryngitis; hoarseness/dysphonia; epistaxis; tonsillitis; nasal signs and symptoms; unspecified oropharyngeal plaques; ear, nose, and throat polyps; sneezing; pain in nasal sinuses; rhinitis; throat constriction; allergic ear, nose, and throat disorders; alteration or loss of sense of taste and/or smell; nasal septal perforation; blood in nasal mucosa; nasal ulcer; voice changes; fluid disturbances; weight gain; goiter; disorders of uric acid metabolism; appetite disturbances; irritation of the eyes; blurred vision; glaucoma; increased intraocular pressure and cataracts; keratitis and conjunctivitis; blepharoconjunctivitis; nausea and vomiting; abdominal pain; viral gastroenteritis; gastroenteritis/colitis; gastrointestinal infections; abdominal discomfort; diarrhea; constipation; appendicitis; dyspepsia and stomach disorder; abnormal liver function; injury; fever; tooth decay; dental problems; mouth irritation; mouth and tongue disorders; cholecystitis; lower respiratory infections; pneumonia; arthralgia and articular rheumatism; muscle cramps and spasms; fractures; wounds and lacerations; contusions and hematomas; burns; musculoskeletal inflammation; bone and cartilage disorders; pain in joint; sprain/strain; disorder/symptoms of neck; muscular soreness/pain; aches and pains; pain in limb; dizziness/giddiness; tremors; hypnagogic effects; compressed nerve syndromes; sleep disorders; paralysis of cranial nerves; migraine; nervousness; bronchitis; chest congestion and/or symptoms; malaise and fatigue; pain; edema and swelling; bacterial infections; fungal infections; mobility disorders; cysts, lumps, and masses; mood disorders; acute nasopharyngitis; dyspnea; irritation due to inhalant; urticaria; rash/skin eruption; disorders of sweat and sebum; sweating; photodermatitis; dermatitis and dermatosis; viral skin infections; eczema; fungal skin infections; pruritus; acne and folliculitis; burning; hypertrichosis; increased erythema; hives; folliculitis; hypopigmentation; perioral dermatitis; skin atrophy; striae; miliaria; pustular psoriasis; urinary infections; bacterial reproductive infections; dysmenorrhea; candidiasis of vagina; pelvic inflammatory disease; vaginitis/vulvovaginitis; and irregular menstrual cycle. [0006] The mechanism of action of Fluticasone of all commercial and investigative products is identical; penetration of the plasma membrane of the cell and subsequent binding of the molecule to the cytosolic glucocorticoid receptors, represented by two separate receptors GR-a and GR-β transcribed by a single gene. Of the two receptors, GR-a is implicated in the generation of anti-inflammatory responses. Other mechanisms of regulating inflammation are via protein - protein sequestration via binding to other pro-inflammatory transcription factors such as activator protein (AP -1), leading to the inhibition of the transcription of inflammatory genes. The GC-GR complex can also act indirectly via the induction of inhibitory proteins, for example ΙκΒ that suppresses NF-KB activity. Thus, anti-inflammatory effects also affect
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