USOO91 01663B2 (12) United States Patent (10) Patent No.: US 9,101,663 B2 Yacoby-Zeevi et al. (45) Date of Patent: *Aug. 11, 2015 (54) CONTINUOUS ADMINISTRATION OF DOPA 5,350,769 A 9, 1994 Kasai et al. DECARBOXYLASE INHIBITORS AND 5,861,423 A * 1/1999 Caldwell et al. .............. 514,351 5,877,176 A 3, 1999 Gross COMPOSITIONS FOR SAME 6,153,615 A 11/2000 Gross 6,166,083 A 12/2000 Barrett et al. (75) Inventors: Oron Yacoby-Zeevi, Bitsaron (IL); 6,245,917 B1 6/2001 Bosch et al. Mara Nemas, Gedera (IL) 6,274,168 B1 8/2001 Addicks et al. 6,348,965 B1 2/2002 Palladino et al. 6,500,867 B1 * 12/2002 Virkki et al. .................. 514,646 (73) Assignee: NeuroDerm, Ltd., Rehovot (IL) 6,620,432 B2 9, 2003 Addicks et al. 6,716.452 B1 4/2004 Piccariello et al. (*) Notice: Subject to any disclaimer, the term of this 6,878,529 B2 4/2005 Harrow et al. patent is extended or adjusted under 35 6,974,591 B2 12/2005 Kendrup et al. U.S.C. 154(b) by 0 days. 7.201923 B1 4/2007 van Lengerich 7,223,776 B2 5/2007 Surivet et al. This patent is Subject to a terminal dis 7,309,719 B1 12/2007 Aomatsu claimer. 7,479,498 B2 1/2009 Keller 7,560, 100 B2 7/2009 Pinchasi et al. 7,589.233 B2 9, 2009 Chandran (21) Appl. No.: 12/961,534 7,709,494 B2 5, 2010 Defossa et al. 7,863,336 B2 1/2011 Yacoby-Zeevi et al. (22) Filed: Dec. 7, 2010 8,058,243 B2 11/2011 Tyers et al. 8,173,840 B2 5, 2012 Chandran (65) Prior Publication Data 8, 193,243 B2 6/2012 Yacoby-Zeevi et al. 8,263,125 B2 9/2012 Vaya et al. US 2011 FO269833 A1 Nov. 3, 2011 2002fOO28799 A1 3/2002 Naylor et al. 2002.00990 13 A1 7/2002 Piccariello et al. 2003/01 19714 A1 6/2003 Naylor et al. Related U.S. Application Data (Continued) (63) Continuation of application No. 12/836,130, filed on Jul. 14, 2010, now Pat. No. 7,863,336, which is a FOREIGN PATENT DOCUMENTS continuation of application No. 12/781,357, filed on CN 101669925 A 3, 2010 May 17, 2010. DE 2838232 A1 3, 1979 (60) Provisional application No. 61/179,511, filed on May (Continued) 19, 2009. OTHER PUBLICATIONS (51) Int. Cl. AOIN33/02 (2006.01) Gordon, M., et al., (2007) “Intravenous Levodopa Administration in A6 IK3I/35 (2006.01) Humans Based on a Two-Compartment Kinetic Model” J. AOIN37/2 (2006.01) Neuroscience Methods 159: 300-307. AOIN 37/44 (2006.01) Hirano, et al., J. Biochem, 2008, vol. 144, No. 3, pp. 363-369. A 6LX3L/95 (2006.01) Mehlisch, et al., J. Clin. Pharmacol., 2002, vol. 42, pp. 904-911. A6 IK3I/24 (2006.01) Movement Disorders “Levodopa” (2002) 17: S23-S37. A6 IK 47/8 (2006.01) Nahata, et al., (2000) “Development of Two Stable Oral Suspensions A6 IK9/00 (2006.01) of Levodopa-Carbidopa for Children with Amblyopia.” J. Pediatric A6 IK3I/2 (2006.01) Opthal. & Strab. 37:333-337. A6 IK3I/98 (2006.01) (Continued) A 6LX3L/277 (2006.01) A6 IK 47/22 (2006.01) (52) U.S. Cl. Primary Examiner — Samira Jean-Louis CPC ............. A61K47/183 (2013.01); A61 K9/0019 (74) Attorney, Agent, or Firm — Goodwin Procter LLP (2013.01); A61 K3I/I2 (2013.01); A61 K 31/198 (2013.01); A61 K3I/277 (2013.01); A61K47/22 (2013.01) (57) ABSTRACT (58) Field of Classification Search Disclosed herein are compositions that include for example USPC .................................. 514/646,565, 567, 534 the arginine salt of carbidopa, and methods for treating neu See application file for complete search history. rological or movement diseases or disorders such as restless leg syndrome, Parkinson's disease, secondary parkinsonism, (56) References Cited Huntington's disease, Parkinson's like syndrome, PSP. MSA, U.S. PATENT DOCUMENTS ALS, Shy-Drager syndrome and conditions resulting from brain injury including carbon monoxide or manganese intoxi 3,936,495 A 2, 1976 Sullivan, Jr. cation, using Substantially continuous administration of car 4,241,082 A 12/1980 Baba et al. 4.409,233 A 10, 1983 Tsukada et al. bidopa or salt thereof together with administration of 4,642,316 A 2f1987 Fawzi et al. levodopa. 4,684.666 A 8, 1987 HaaS 4,826,875 A 5, 1989 Chies 4,963,568 A 10, 1990 Schoenleber et al. 9 Claims, 18 Drawing Sheets US 9,101,663 B2 Page 2 (56) References Cited Parkinson's Disease.” Expert Review of Neurotherapeutics, 6(10): 1403-1411. U.S. PATENT DOCUMENTS Olanow, C.W. (2008) "Levopoda Dopamine Replacement Strategies in Parkinson's Disease—Future Directions.” Movement Disorders, 2005.0053669 A1 3/2005 Friedl et al. 23:S613-S622. 2005, 0163850 A1 7/2005 Wong et al. Redenti, et al., Journal of Pharmaceutical Sciences, 2001, vol.90, No. 2005/0233945 A1 10/2005 Brown et al. 8, pp. 979-986. 2006,004 1014 A1 2/2006 Naylor et al. Tsumoto, K., et al., (2004) “Role of Arginine in Protein Refolding, 2006, O159751 A1 7/2006 Gogia et al. Solubilization, and Purification.” Biotechnol. Prog. 20:1301-1308. 2006/0241183 A1 10, 2006 Karoun “Duodopa Intestinal Gel.” retrieved from https://www.medicines. 2008/005.1459 A1 2/2008 Nyholm et al. org.uk/emc/medicine/20786/SPC/Duodopa--intestinal+gelicom 2008/0255235 A1 * 10/2008 Segrell .......................... 514,567 position (2013), 7 pages. 2010/0298428 A1 1 1/2010 Yacoby-Zeevi et al. "Pharmacokinetics of Levodopa/Carbidopa Infusion With and With 2012/0115823 A1 5, 2012 Price et al. out Oral Catechol-O-Methyl Transferase (COMT) Inhibitors 2013/0116215 A1 5, 2013 Coma et al. (DuoCOMT),” retrieved from URL://http://clinicaltrials.gov/ct2/ 2013,0123485 A1 5, 2013 Park et al. show/NCT00906828 (2010), 3 pages. 2013/025.305.6 A1 9, 2013 Nemas et al. International Search Report for PCT/IL2010/000400, mailed Jul. 29, 2013/0338143 Al 12/2013 Yacoby-Zeevi et al. 2010, 4 pages. 2014/0051755 A1 2/2014 Yacoby-Zeevi et al. 2014/0249228 A1 9/2014 Yacoby-Zeevi et al. International Search Report for PCT/IL2011/000881, mailed Apr. 3, 2014/0249229 A1 9/2014 Yacoby-Zeevi et al. 2012, 4 pages. 2014/0249230 A1 9/2014 Yacoby-Zeevi et al. International Search Report for PCT/IL2014/050261, mailed May 2014/0249231 A1 9/2014 Yacoby-Zeevi et al. 30, 2014, 5 pages. Nord, M. (2010) The Effect of Peripheral Enzyme Inhibitors on FOREIGN PATENT DOCUMENTS Levodopa Concentrations in Blood and CSF, Movement Disorders, 25(3): 363-367. EP 1077692 A1 2, 2001 Nyholm, D. (2012) "Levodopa Infusion Combined with Entacapone IN 244675 B 12/2010 or Tolcapone in Parkinson Disease: a Pilot Trial.” European Journal IN 251149 B 2, 2012 of Neurology, 19: 820-826. JP 54050700 A 4f1979 Written Opinion of the International Search Authority for PCT/ WO WO-0054773 A1 9, 2000 IL2010/000400 mailed Aug. 29, 2010, 8 pages. WO WO-01 01984 A1 1, 2001 Written Opinion of the International Search Authority for PCT/ WO WO-2005099678 A1 10/2005 IL2011/000881 mailed May 15, 2013, 6 pages. WO WO-2006/006929 A1 1, 2006 Written Opinion of the International Search Authority for PCT/ WO WO-2007.138O86 A1 12/2007 IL2014/050261 mailed May 30, 2014, 6 pages. WO WO-2010, 134074 A1 11, 2010 Yacoby-Zeevi, O., et al. (2010) “Markedly Enhanced Levodopa WO WO-2012/OO6959 A1 1, 2012 Pharmacokinetics from Continuous Subcutaneous Carbidopa WO WO-2012/066538 A1 5, 2012 Administration.” European Journal of Neurology, 17 (Suppl. 3): 52. Martinez et al., “Hypothesis: Can N-Acetylcysteine Be Beneficial in OTHER PUBLICATIONS Parkinson's Disease?”. Life Sciences, 64(15): 1253-1257 (1999). Nutt, J.G. (1997) “Motor Fluctuations. During Continuous Levodopa Pardo et al., “Ascorbic acid protects against levodopa-induced Infusions in Patients with Parkinson's Disease.” Movement Disor neurotoxicity on a catecholamine-rich human neuroblastoma cell ders, 12:285-292. line”. Mov Disord, 8(3):278-284 (1993) Abstract Only. Nyholm, D. (2006) “Enteral Levodopa/Carbidopa Gel Infusion for the Treatment of Motor Fluctuations and Dyskinesias in Advanced * cited by examiner U.S. Patent Aug. 11, 2015 Sheet 1 of 18 US 9,101,663 B2 Fig. 1A 0076+72 200 600 7oosoogoo U.S. Patent Aug. 11, 2015 Sheet 2 of 18 US 9,101,663 B2 Fig. 1B U.S. Patent Aug. 11, 2015 Sheet 3 of 18 US 9,101,663 B2 Fig. 1C 123 s Ooo 110,2030 o' 50 oilre-rrer rtrayers m/z U.S. Patent Aug. 11, 2015 Sheet 4 of 18 US 9,101,663 B2 Fig. 2A U.S. Patent Aug. 11, 2015 Sheet 5 of 18 US 9,101,663 B2 Fig. 2B 00°16)*** *******************&&&&&& 200 250 3OO 350 nz U.S. Patent Aug. 11, 2015 Sheet 6 of 18 US 9,101,663 B2 Fig. 2C © O.8 O.6 0.4 0.2 80 1OO 120 160 180 200 U.S. Patent Aug. 11, 2015 Sheet 7 of 18 US 9,101,663 B2 Fig. 3A E N E. 10 at QP 3. ?ts 1 {o. 3xwk-o-o-o-o-wrotsk M wks-Mo 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 Fig. 3B 1000 - 5 100 d E. 10 s 1 8 12 16 20 24 28 32 36 40 44 48 52 56 6O 64 68 U.S.