(12) United States Patent (10) Patent No.: US 9,308,234 B2 Arnold Et Al

(12) United States Patent (10) Patent No.: US 9,308,234 B2 Arnold Et Al

USOO93O8234B2 (12) United States Patent (10) Patent No.: US 9,308,234 B2 Arnold et al. (45) Date of Patent: Apr. 12, 2016 (54) METHODS AND COMPOSITIONS FOR (56) References Cited TREATING MIUCOSAL TISSUE DISORDERS U.S. PATENT DOCUMENTS (71) Applicant: The University of North Carolina at 2,606,903. A 8, 1952 Ruskin Chapel Hill, Chapel Hill, NC (US) 2,822.317 A 2f1958 Gulesich et al. 4.324,778 A 4, 1982 Davis 4,578,390 A 3, 1986 Jensen et al. (72) Inventors: Roland R. Arnold, Chapel Hill, NC 4,617, 187 A 10/1986 Okuyama et al. (US); David C. Henke, Chapel Hill, NC 4,670471 A 6, 1987 Clark (US) 4,686,235 A 8/1987 Chang et al. 4,707,354 A 11/1987 Garlen et al. 4,822,816 A 4, 1989 Markham (73) Assignee: The University of North Carolina at 4,861,783 A 8, 1989 Ackerman et al. Chapel Hill, Chapel Hill, NC (US) 4,968,716 A 11/1990 Markham 4,975,272 A 12/1990 Voyt 5,021,452 A 6, 1991 Labbé (*) Notice: Subject to any disclaimer, the term of this 5,070,085 A 12/1991 Markham patent is extended or adjusted under 35 5,078,129 A 1/1992 Kleinberg et al. U.S.C. 154(b) by 0 days. 5,238,683 A 8/1993 Crystal 5,281, 196 A 1/1994 SultenfuSS 5,304,724 A 4, 1994 Newton (21) Appl. No.: 14/446,192 5,612.208 A 3, 1997 Nakanishi et al. 5,626,883. A 5, 1997 Paul 5,824,693. A 10/1998 Goldberg (22) Filed: Jul. 29, 2014 5,869,116 A 2, 1999 Yoo 5,876,700 A 3/1999 Boucher, Jr. et al. (65) Prior Publication Data 5,989,521 A 1 1/1999 Crystal 6,228,347 B1 5, 2001. Hersh US 2015/OO 10654 A1 Jan. 8, 2015 6,492,328 B2 12/2002 Lehrer et al. 6,495,170 B1 12/2002 Smit et al. 6,603,012 B2 8, 2003 Belloni et al. 6,655,385 B1 12/2003 Curti et al. Related U.S. Application Data 6,705,316 B2 3/2004 Blythe et al. 6,723,703 B2 4/2004 Gaston et al. (63) Continuation of application No. 7,129,035 B2 10/2006 Goldstein et al. PCT/US2013/067307, filed on Oct. 29, 2013. 7,179,791 B2 2/2007 Stamler et al. 7,572,251 B1 8, 2009 Davison et al. (60) Provisional application No. 61/719,804, filed on Oct. 7,591,999 B2 9/2009 Matsuyama et al. 29, 2012. (Continued) (51) Int. Cl. FOREIGN PATENT DOCUMENTS A6 IK38/00 (2006.01) AU 200231.0351 A1 12/2002 A6 IK38/06 (2006.01) AU 20O2345757 A1 12/2002 A6 IK3I/98 (2006.01) A 6LX3L/375 (2006.01) (Continued) A6 IK 45/06 (2006.01) A6 IK33/10 (2006.01) OTHER PUBLICATIONS A6 IK9/00 (2006.01) A6 IK38/40 (2006.01) Fitzpatrick et al. Glutathione Oxidation is Associated With Airway A6 IK38/44 (2006.01) Macrophage Functional Impairment in Children With Severe AOIN I/02 (2006.01) Asthma, Pediatr Res. Feb. 2011; 69(2): 154-159.* A6 IK33/00 (2006.01) (Continued) (52) U.S. Cl. CPC ............ A6 IK38/063 (2013.01); A0IN I/0226 (2013.01); A61 K9/006 (2013.01); A61 K9/008 Primary Examiner — Karlheinz, R Skowronek (2013.01); A61 K9/0031 (2013.01); A61 K Assistant Examiner — Sergio Coffa 9/0034 (2013.01); A61 K9/0075 (2013.01); A6 IK3I/198 (2013.01); A61 K3I/375 (74) Attorney, Agent, or Firm — Myers Bigel & Sibley, P.A. (2013.01); A61 K33/00 (2013.01); A61 K33/10 (2013.01); A61 K38/40 (2013.01); A61 K 38/443 (2013.01); A61K 45/06 (2013.01); C12Y (57) ABSTRACT 101/03004 (2013.01); C12Y III/01007 The present invention provides compositions and formula (2013.01); C12Y302/01011 (2013.01); C12Y tions comprising glutathione with or without thiocyanate and 302/01017 (2013.01); C12Y302/01059 methods of use thereof to treat diseases and disorders in (2013.01) mucosal/epithelial tissue. (58) Field of Classification Search None See application file for complete search history. 26 Claims, 11 Drawing Sheets US 9,308.234 B2 Page 2 (56) References Cited CN 101.491495 B 6, 2012 CN 101.384288 B 9, 2012 U.S. PATENT DOCUMENTS CN 1021009004 B 4/2013 DE 2845484 A1 4, 1980 7,790,762 B2 9/2010 Day et al. DE 1993.5763 A1 2/2001 8,022,082 B2 9/2011 Zierenberg DE 102004.035113 A1 2/2006 8,067,441 B2 11/2011 Gil et al. DE 60212837 T2 6, 2007 8,202,525 B2 6/2012 Crain et al. DE 2120.1110.0034 U1 7, 2012 8,211,628 B2 7/2012 Thatte et al. EP O 326 826 A1 8, 1989 8,217,006 B2 7/2012 Stamler et al. EP O 494405 A2 7, 1992 8,217,033 B2 7/2012 Gizurarson EP O 494405 B1 10, 1996 8,221.329 B2 7/2012 Hartings et al. EP O 494405 B2 4, 2000 8,267,084 B2 9/2012 Kwok EP 1 250 143 A2 10, 2002 8,327,843 B2 12/2012 Warden et al. EP O 938 331 B1 12/2002 2003/0082101 A1 5/2003 Taylor et al. EP 1282 416 A2 2/2003 2003. 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