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United States Patent (10) Patent No.: US 9,555,047 B2 Bodick Et Al

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United States Patent (10) Patent No.: US 9,555,047 B2 Bodick Et Al USO09555047B2 (12) United States Patent (10) Patent No.: US 9,555,047 B2 Bodick et al. (45) Date of Patent: Jan. 31, 2017 (54) CORTICOSTEROIDS FOR THE 7,153,520 B2 12/2006 Seo et al. TREATMENT OF JOINT PAN 7,261,529 B2 8/2007 Persyn et al. 7,758,778 B2 7/2010 Persyn et al. 8,828,440 B2 9/2014 Bodick et al. (71) Applicant: Flexion Therapeutics, Inc., Burlington, 2004/0105821 A1 6/2004 Bernstein et al. MA (US) 2004/0224030 A1 11, 2004 Shastri 2005/OO31549 A1 2/2005 Quay et al. (72) Inventors: Neil Bodick, Boston, MA (US); Robert 2005, 0043706 A1 2/2005 Eaton et al. C. Blanks. Auburndale, MA (US); 2005, OO69591 A1 3/2005 Bernstein et al. Anjali Kumar Belmont MA (US). 2007/0053990 A1 3/2007 Persyn et al. s s s 2007/0264343 A1 11/2007 Bernstein et al. Michael D. Clayman, Gloucester, MA 2008/0248122 A1 10/2008 Rashba-Step et al. (US); Mark Moran, Orinda, CA (US) 2008/0317805 A1 12/2008 McKay et al. 2009, OO35253 A1 2/2009 Wright et al. (73) Assignee: FLEXION THERAPEUTICS, INC., 38885.7 A. 358 A. al Burlington,s MA (US) 2010.006.3179 A1 3/2010 Atkinsonorne et al.............. A61K9/5031 (*) Notice: Subject to any disclaimer, the term of this 2011/0206773 A1 8, 2011 Lavik et al. 523,332 patent is extended or adjusted under 35 2012/0282298 A1 11/2012 Bodick et al. U.S.C. 154(b) by 0 days. 2012/0288534 A1 11/2012 Bodick et al. 2014/0242170 A1 8, 2014 Bodick et al. (21) Appl. No.: 14/461,883 2014/0356437 A1 12/2014 Bodick et al. y x- - - 9 (22) Filed: Aug. 18, 2014 FOREIGN PATENT DOCUMENTS (65) Prior Publication Data ES 66 A. 3E JP 2006-503865. A 2, 2006 US 2015/OO25050 A1 Jan. 22, 2015 WO WO95/13799 A1 5, 1995 WO WO-95.13799 A1 5, 1995 Related U.S. Application Data WO WO 99.12571 A1 3, 1999 WO WO O2,36168 5, 2002 (60) Division of application No. 13/422,994, filed on Mar. (Continued) 16, 2012, now Pat. No. 8,828,440, which is a continuation of application No. 13/198,168, filed on OTHER PUBLICATIONS Aug. 4, 2011, now abandoned. Hickey, T, et al., “Dexamethasone/PLGA microspheres for con (60) Provisional application No. 61/370,666, filed on Aug. tinuous delivery of an anti-inflammatory drug for implantable 4, 2010. medical devices'. Biomaterials, 23(7): 1649-1656 (2002). Horisawa, E., et al. "Prolonged anti-inflammatory action of DL (51) Int. Cl. lactide? glycolide copolymer nanospheres containing betamethasone A6 IK 9/14 (2006.01) Sodium phosphate for an intra-articular delivery system in antigen A 6LX 9/50 (2006.01) inst arthritic rabbit'. Pharmaceutical Research, 19(4):403-409 A6 IK3I/56 2006.O1 A 6LX 3/573 (2006.01)( ) Extended European Search Report in corresponding Application A6 IK 9/16 (2006.01) No. EP11815323.8, dated Dec. 17, 2013. Aly, M. N. S. “Intra-articular drug delivery: A fast growing A6 IK3I/58 (2006.01) approach”. Recent Patents on Drug Delivery & Formulation, A6 IK 9/00 (2006.01) Bentham Science Publishers Ltd., NL 2(3):231-237 (2008). A6 IK 47/34 (2006.01) (Continued) (52) U.S. Cl. CPC ............. A61K 31/58 (2013.01); A61K 9/0019 Primary Examiner Tigabu Kassa (2013.01); A61K 9/0024 (2013.01); A61K 9/14 (74), Attorney, Agent, or Firm — Cooley LLP. Ivor R. (2013.01); A61K 9/1641 (2013.01); A61 K Elrifi 9/1647 (2013.01); A61K 9/1694 (2013.01); (57) ABSTRACT A61 K3I/573 (2013.01); test." Corticosteroid microparticle formulations are provided for use for treating pain, including pain caused by inflammatory (58) Field Oof ClassificationSSCO SeaS h diseases Such as osteoarthritis or rheumatoid arthritis, and None for slowing, arresting or reversing structural damage to See application file for complete search history. tissues caused by an inflammatory disease, for example damage to articular and/or peri-articular tissues caused by (56) References Cited osteoarthritis or rheumatoid arthritis. Corticosteroid U.S. PATENT DOCUMENTS microparticle formulations are administered locally as a Sustained release dosage form (with or without an immediate 4.293,539 A 10, 1981 Ludwig et al. release component) that results in efficacy accompanied by 4,530,840 A * 7/1985 Tice ..................... A61sg clinically insignificant or no measurable effect on endog 6,214,387 B1 * 4/2001 Berde .................. 5' enous cortisol production. 424/426 9 Claims, 30 Drawing Sheets US 9,555,047 B2 Page 2 (56) References Cited La Rochelle et al. “Recovery of the Hypothalamic-Pituitary-Adre nal (HPA) Axis in Patients with Rheumatic Diseases Receiving FOREIGN PATENT DOCUMENTS Low-Dose Prednisone.” Am. J. Med. 95(1993):258-264. Lo et al. "Bone Marrow Lesions in the Knee are Associated with WO WO 2007/030545 A2 3, 2007 Increased Local Bone Density.” Arth. Rheum. 52.9(2005):2814 WO WO 2008,157.057 A2 12/2008 2821. WO WO 2009,026539 2, 2009 Lo et al. “The Ratio of Medial to Lateral Tibial Plateau Bone WO WO 2009,026539 A1 2, 2009 Mineral Density and Compartment-Specific Tibiofemoral WO WO 2009,15O136 A1 12/2009 Osteoarthritis.” OsteoArth. Cartilage. 14(2006):984–990. WO WO 2010/085.609 T 2010 Meibohm et al. “Mechanism-Based PK/PD Model for the WO WO 2011/084518 T/2011 WO WO 2012/O19009 A1 2, 2012 Lymphocytopenia Induced by Endogenous and Exogenous Corticosteroids.” Int. J. Clin. Pharmacol. Ther. 37.8(1999):367 376. OTHER PUBLICATIONS Morlocket al. “Erythropoietin Loaded Microspheres Prepared from Da Silva-Junior, A A et al., “Thermal behavior and stability of Biodegradable LPLG-PEO-LPLG Triblock Copolymers: Protein biodegradable spray-dried microparticles containing Stabilization and in-vitro Release Properties.” J. Control. Release. 56.1-3(1998): 105-115. triamcinolone'. International Journal of Pharmaceutics, Elsevier Rojas et al. “Microdialysis of Triamcinolone Acetonide in Rat BV, NL, 368(1-2):45-55 (2009). Muscle.” J. Pharm. Sci. 92.2(2003):394-397. Cilurzo, F. et al: “Design of Methylprednisolone Biodegradable van den Berg et al. “Synovial Mediators of Cartilage Damage and Microspheres Intended for Intra-articular Administration'. AAPS Pharmscitech, val. 9, No. 4, Nov. 14, 2008 (Nov. 14, 2008), pp. Repair in Osteoarthritis.” Osteoarthritis. Brandt et al., eds. Oxford: 1136-1142. Oxford University Press. 7.2.3 (2003): 147-155. Khaled K. A. et al., “Prednisolone-Loaded PLGA Microspheres. In Yeh. “The Stability of Insulin in Biodegradable Microparticles Vitro Characterization and In Vivo Application in Adjuvant-Induced Based on Blends of Lactide Polymers and Polyethylene Glycol.” J. Arthritis in Mice.” AAPS PharmSciTech., Jun. 19, 2010 (Jun. 19, Microencapsul. 17.6(2000):743-756. 2010), pp. 859-869. Zentner et al. “Biodegradable Block Copolymers for Delivery of Anderson et al. “Biodegradation and Biocompatibility of PLA and Proteins and Water-Insoluble Drugs.” J. Control. Release. PLGA Microspheres.” Adv. Drug Deliv Rev. 28(1997):5-24. 72(2001):203-215. Ayral et al. “Synovitis: A Potential Predictive Factor of Structural Aly, M. N. S., “Intra-Articular Drug Delivery: A Fast Growing Progression of Medial Tibiofemoral Knee Osteoarthritis—Results Approach.” Recent Patents on Drug Delivery & Formulation, vol. of a 1 Year Longitudinal Arthroscopic Study in 422 Patients.” 2(3): 231-237 (2008). OsteoArth. Cartilage. 13(2005):361-367. Bandi, N. et al., “Intratracheal budesonide-poly(lactide-co Bouissou et al. “Poly(lactic-co-glycolic acid) Microspheres.” Poly glycolide) microparticles reduce oxidative stress, VEGF expression, mers in Drug Delivery. Chapter 7(2006):81-99. and vascular leakage in a benzo(a)pyrene-fed mouse model.” Jour Cleek et al. “Microparticles of Poly(DL-lactic-co-glycolic acid)/ nal of Pharmacy and Pharmacology, vol. 57(7):851-860 (2005). poly(ethylene glycol) Blends for Controlled Drug Delivery.” J. Chaw, C.S. et al., “Water soluble betamethasone-loaded Control. Relase. 48(1997):259-268. poly(lactide-co-glycolide) hollow microparticles as a Sustained Coopman et al. “Identification of Cross-Reaction Patterns in Aller release dosage form.” Journal of Encapsulation, vol. 20(3):349-359 gic Contact Dermatitis from Topical Corticosteroids.” Br: J. Dermatol. 121 (1989):27-34. (2003). Derendorf et al. “Clinical PKPD Modelling as a Tool in Drug Cilurzo, F. et al., “Design of methylprednisolone biodegradable Development of Corticosteroids.” Int. J. Clin. Pharmacol. Ther. microspheres intended for intra-articular administration.” AAPS 35.10(1997):481-488. Pharmscitech, vol. 9(4): 136-1142 (2008). Derendorf et al. “Pharmacokinetics and Pharmacodynamics of Da Silva-Junior, A. A. et al., “Thermal behavior and stability of Glucocorticoid Suspensions After Intra-Articular Administration.” biodegradable spray-dried microparticles containing Clin. Pharmacol. Ther. 39.3(1986):313-317. triamcinolone.” International Journal of Pharmaceutics, vol. Eckstein et al. “Magnetic Resonance Imaging (MRI) of Articular 368(1-2):45-55 (2009). Cartilage in Knee Osteoarthritis (OA): Morphological Assessment.” Hickey, T. et al., “Dexamethasone/PLGA microspheres for continu OsteoArth. Cartilage. 14(2006): A46-A75. ous delivery of an anti-inflammatory drug for implantable medical Foti et al. “Contact Allergy to Topical Corticosteroids: Update and devices.” Biomaterials, vol. 23(7): 1649-1656 (2002). Review on Cross-Sensitization.” Recent Pat. Inflamm. Allergy Drug Horisawa, E., et al., “Prolonged anti-inflammatory action of DL Discov. 3.1(2009):33-39. lactide? glycolide copolymer nanospheres containing betamethasone Habib. "Systemic Effects of Intra-Articular Corticosteroids.” Clin. Sodium phosphate for an intra-articular delivery system in antigen Rheumatol. 28.7(2009):749-756. induced arthritic rabbit.” Pharmaceutical Research, vol. 19(4):403 Hepper et al. “The Efficacy and Duration of Intra-Articular 409 (2002). Corticosteroid Injection for Knee Osteoarthritis: A Systematic Jaraswekin, S. et al., “Effect of poly(lactide-co-glycolide) molecular Review of Level I Studies.” J.
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