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WO 2012/040229 Al (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 _ . 29 March 2012 (29.03.2012) WO 2012/040229 Al (51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every A61K 9/14 (2006.01) A61K 31/16 (2006.01) kind of national protection available): AE, AG, AL, AM, A01N 37/18 (2006.01) AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, (21) International Application Number: DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, PCT/US201 1/052398 HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, (22) International Filing Date: KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, 20 September 201 1 (20.09.201 1) ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PE, PG, PH, PL, PT, QA, RO, RS, RU, (25) Filing Language: English RW, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, (26) Publication Language: English TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (30) Priority Data: 61/403,941 22 September 2010 (22.09.2010) US (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, (71) Applicant (for all designated States except US): MAP GM, KE, LR, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, PHARMACEUTICALS, INC. [US/US]; 2400 Bayshore ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, Parkway, Suite 200, Mountain View, CA 94043 (US). TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, (72) Inventors; and LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, (75) Inventors/ Applicants (for US only): WU, Libo [CN/US]; SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, 2400 Bayshore Parkway, Suite 200, Mountain View, CA GW, ML, MR, NE, SN, TD, TG). 94043 (US). WATANABE, Wiwik [US/US]; 2400 Bayshore Parkway, Suite 200, Mountain View, CA 94043 Published: (US). ZHANG, Jian [CN/US]; 2400 Bayshore Parkway, — with international search report (Art. 21(3)) Suite 200, Mountain View, CA 94043 (US). — before the expiration of the time limit for amending the (74) Agent: CHENG, Jennifer; Map Pharmaceuticals, Inc., claims and to be republished in the event of receipt of 2400 Bayshore Parkway, Suite 200, Mountain View, CA amendments (Rule 48.2(h)) 94043 (US). (54) Title: CORTICOSTEROID PARTICLES AND METHOD OF PRODUCTION Shape: ,/ \ ΰ t i > ( o Figure 1 © (57) Abstract: A new particle morphology of glucocorticosteroids is described. The forms have a particle morphology that is par ticularly well suited for use in an inhaled corticosteroid drug suspension formulation for delivery from a next generation nebulizer o device. Use of the new glucocorticosteroid particles enables enhanced drug delivery efficiency and increased residence time of the delivered drug in the lungs. New methods for producing glucocorticosteroid particles having these specific particle morphologies are also described. The methods provide a simplified, reproducible and scalable particle formation process that can produce gluco o corticosteroid particles having a narrow particle size and shape distribution, a low surface energy, a low aspect ratio, uniform par ticle morphology and a reduced specific surface area. CORTICOSTEROID PARTICLES AND METHOD OF PRODUCTION CROSS REFERENCE TO RELATED CASES [0001] This application claims the benefit of the United States Provisional Patent Application serial number 61/403,941, filed on September 22, 2010, the content of which is hereby incorporated by reference in its entirety. TECHNICAL FIELD OF THE INVENTION [0002] The invention relates generally to technologies for producing and administering particulate medicaments via oral pulmonary inhalation and, more particularly, to methods for producing glucocorticosteroid particles with enhanced physical properties that facilitate delivery via pulmonary inhalation techniques using nebulizer inhalation devices, as well as the glucocorticosteroid particles themselves. BACKGROUND OF THE INVENTION [0003] Respiratory disorders are pulmonary conditions characterized by airway inflammation, airway hyperresponsiveness, and reversible airway obstruction. During respiratory disorder episodes, afflicted individuals often experience labored breathing, wheezing, and coughing. These disorders may be treated by oral inhalation of medications such as beta adrenergic agonists or corticosteroids. [0004] Inhaled corticosteroids (ICS) are corticosteroid medicaments that are designed for application directly to the tissues of the respiratory tract. ICS medicaments are the preferred treatment for long-term control of mild persistent, moderate persistent, or severe persistent asthma symptoms in children, teens, and adults. Corticosteroids provide highly effective treatment for chronic inflammatory disorders through a common mechanism that includes down-regulating the production of many inflammatory cytokines, chemokines, enzymes, and cell- adhesion molecules as well as inhibiting the activity of inflammatory mediators. Barnes (2003) Ann Intern Med 139 :359-370. Corticosteroids also help control narrowing and inflammation in the bronchial tubes. The drugs used as ICS are very similar in action and use. Commercially available ICS medicaments include Aerobid (flunisolide, Roche), Azmacort (triamcinolone acetonide, Abbott), Flovent (fluticasone propionate, GlaxoSmithKline), Pulmicort (budesonide, AstraZeneca) and QVAR (beclomethasone dipropionate, TEVA Branded Pharmaceuticals). [0005] Delivery systems that can administer ICS medicaments include nebulizers, dry powder inhalers (DPIs), and pressurized metered-dose inhalers (pMDIs). Nebulizer devices are a preferred delivery system when breathing strength or coordination is challenging. This is particularly true for children, elderly patients and patients with compromised breathing ability. [0006] Drug formulations for oral inhalation delivery using nebulizers are aqueous solutions, dispersions or suspensions that are aerosolized and then inhaled. The aerosol comprises very fine droplets of the formulation dispersed in air. The droplets are necessarily less than about 5 microns in geometric diameter to provide respirable droplets that enable delivery of the aerosolized drug to the respiratory tract beyond the oropharynx upon inhalation. Aerosol generators, or nebulizers, apply mechanical shearing forces to the drug formulation by various means to break up the formulation surface or generate filament streams to form the droplets. Nebulizers typically use pneumatic, piezoelectric, ultrasonic, or electromechanical means to generate shearing forces. The nebulizers may also incorporate baffling mechanisms to remove larger, nonrespirable droplets from the aerosol. In use, the nebulized formulation is administered to the individual via a mouthpiece or mask. [0007] Traditional nebulizer devices, such as jet nebulizers, are commonly used for ICS delivery. However, these devices require extended administration time lasting up to 30 minutes, often resulting in low patient compliance. In addition, the uniformity of the delivered dose from jet nebulizers can be challenging especially for suspension-based formulations. A particular group of nebulizers, referred to herein as "next generation nebulizers", use meshes or membranes to produce fine droplet sprays. These devices are much more efficient at producing aerosols, and can significantly reduce administration time. The meshes/membranes in next generation nebulizers contain many apertures or pores that have diameters typically between 1 and 8 microns. The drug formulation is forced through the mesh apertures by piezoelectric or electromechanical "pumping" or, alternatively, the mesh is vibrated to reciprocate through a pool of the formulation, thereby generating multiple liquid filaments with diameters approximating the mesh apertures. The filaments breakup to form droplets with diameters approximating the diameters of mesh apertures. Next generation nebulizers which include, but are not limited to the AerX and Essence devices (Aradigm Coorp., Hayward, CA), the eFlow device (PARI Respiratory Equipment, Monterey, CA), the TouchSpray device (The Technology Partnership, Cambridge, UK), the Ineb and Myneb devices (Respironic, Andover, MA), the MicroAir device (Omron Healthcare, Inc., Vernon Hills, IL) and the Aeroneb device (Aerogen, San Francisco, CA) are very efficient aerosol generators that minimize the duration of administration. This is because next generation nebulizers can form aerosols that have a high proportion of respirable aerosol droplets, those with diameters much less than 4.7 microns mass median aerodynamic diameter (MMAD per compendial method USP 601), enabling quick and efficient delivery of the aerosolized drug to the respiratory tract. [0008] Use of next generation nebulizers to deliver a suspension-based medicament presents significant pharmaceutical formulation challenges in regard to the need to enhance both delivery efficiency to the lungs and drug residence time in the lungs. The first challenge is the efficient delivery of the drug particles to the lung. This is primarily determined by the size of the largest dimension of the aerosol droplet population. The mean diameter of the aerosol droplet size distribution generated by the nebulizer must not exceed 4.7 microns MMAD to penetrate to the lungs. The drug particles need to be substantially smaller, less than
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