US 2006OO63810A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2006/0063810 A1 Vergez et al. (43) Pub. Date: Mar. 23, 2006 (54) COMBINATION TREATMENT FOR Publication Classification IMPARED MOTOR FUNCTION IN PARKINSON'S DISEASE (51) Int. Cl. A61K 31/452 (2006.01) (76) Inventors: Juan A. Vergez, Buenos Aires (AR); A61K 31/343 (2006.01) Alan B. Lanier, Raleigh, NC (US); A61K 3III.37 (2006.01) Ethel C. Feleder, Buenos Aires (AR); (52) U.S. Cl. ........................... 514/321; 514/469; 514/649 Glenn A. Meyer, Wilmington, NC (US); Marcelo A. Ricci, Buenos Aires (AR); Joaquina Faour, Buenos Aires (57) ABSTRACT (AR) The invention provides a method, and dosage form therefor, Correspondence Address: of treating impaired motor function associated with Parkin INNOVAR, LLC Son's disease, anti-Parkinson's drug treatment, e.g. L-Dopa PO BOX 250647 therapy, and/or dementia associated with Parkinson's dis ease. The invention includes the combined administration of PLANO, TX 75025 (US) an NMDA receptor antagonist and an antidepressant, e.g., the combination of amantadine and citalopram or Venlafax (21) Appl. No.: 11/215,797 ine, or an NMDA receptor antagonist and an anxiolytic (22) Filed: Aug. 30, 2005 agent, e.g., amantadine and buspirone or traZOdone, for the amelioration of undesired tremors, akinesia, dyskinesia, or Related U.S. Application Data bradykinesia associated with one or more different disorders or diseases. The drugs can be included in a single dosage (63) Continuation-in-part of application No. PCT/CR04/ form. One embodiment includes a combination dosage form 00003, filed on Mar. 5, 2004. containing each drug in controlled release forms. Another embodiment includes a combination dosage form providing (60) Provisional application No. 60/452,077, filed on Mar. a controlled release of an NMDA receptor antagonist and a 5, 2003. Provisional application No. 60/452,055, filed rapid release of a neuroactive agent after administration to a on Mar. 5, 2003. Subject. Patent Application Publication Mar. 23, 2006 Sheet 1 of 4 US 2006/0063810 A1 FIG. 1 Approximate Amantadine Release O 5 10 15 20 25 30 Time (h) Patent Application Publication Mar. 23, 2006 Sheet 2 of 4 US 2006/0063810 A1 FIG. 2 UPDRS II: PATIENTS 1-4 and A-D 90 1 2 3 4 5 6 7 Visit No. -0-UPDRS IIl Subject 1 -- UPDRS IIl Subject 2 UPDRS III Subject 3 -la. UPDRS Il Subject 4 --UPDRS IIl Subject A -o-UPDRS IIl Subject B --UPDRS Il Subject C -UPDRS IIl Subject D Patent Application Publication Mar. 23, 2006 Sheet 3 of 4 US 2006/0063810 A1 FIG. 3 UPDRS IV: SUBJECTS 1-4 and A-D 1 2 3 4 5 & 7 Visit No. --UPDRS IV Subject 1 -0-UPDRSM Subject 2 UPDRS IV Subject 3 .x. UPDRSM Subject 4 -k-UPDRS IV Subject A -o-UPDRSM Subject B -- UPDRS IV Subject C -UPDRS IV Subject D Patent Application Publication Mar. 23, 2006 Sheet 4 of 4 US 2006/0063810 A1 FIG. 4 influence of Amantadine-Citalopram as Add-on Therapy (N=28 Patients +/- Std. Error) i 1 4 10 Weeks of Therapy US 2006/OO6381.0 A1 Mar. 23, 2006 COMBINATION TREATMENT FOR IMPARED SSRI antidepressants concomitant with anti-Parkinson drug MOTOR FUNCTION IN PARKINSON'S DISEASE therapy actually worSens motor impairment. 0006 Korsgaard et al. (Clin. Neuropharmacol., (1986), CROSS-REFERENCE TO EARLIER FILED 9(1), 52-7) report that citalopram has no significant effect in APPLICATIONS treating tardive dyskinesia or Parkinsonism. 0001. The present application is a continuation-in-part of 0007 Rampello et al. (Clin. Neuropharmacol., (January and claims the benefit of priority of PCT International Patent February 2002), 25(1), 21-24) report that when combined Application No. PCT/CR04/00003 filed Mar. 5, 2004, which with levodopa, citalopram induces an improvement of motor claims the benefit of priority of U.S. Provisional Application performance, in particular of Subscores 23 and 31 of Unified for Patent No. 60/452,077 filed Mar. 5, 2003, the entire Parkinson's Disease Rating Scale both in depressed and in disclosures of which are hereby incorporated by reference. nondepressed patients with Parkinson's disease. FIELD OF THE INVENTION 0008 Osmotic devices and other sustained/extended release devices containing citalopram are known in the art. 0002 This invention pertains to a method, and dosage Such devices have been disclosed by, for example, Kuhrts, form therefore, of treating impaired motor function associ in U.S. Patent Application Publication No. 2002/0098239, ated with Parkinson's disease, anti-Parkinson's drug treat which discloses a Sustained release device and Suggests ment, and/or dementia associated with Parkinson's disease. citalopram as a drug Suitable for use in the device. Masters, More particularly, it pertains to the combined oral admin in U.S. Patent Application Publication No. 2002/0106410, istration of an NMDA receptor antagonist and a neuroactive discloses a controlled release device, and Suggests citalo agent for the treatment of impaired motor function. pram as a drug Suitable for use in the device. Elema et al., in U.S. Patent Application Publication No. 2002/0160050, BACKGROUND OF THE INVENTION disclose a melt granulated modified release dosage form and 0.003 Antidepressants are widely known for use in treat claim citalopram as a drug used in the device. Chopra et al., ing depression in different disease States. Antidepressant use in U.S. Patent Application Publication No. 2003/0003151, in the treatment of depression associated with Parkinson's disclose a controlled release dosage form having a com disease, Alzheimer's disease and various types of dementia pressed core and claim citalopram as a drug used in the is well known. Many patients have reportedly been admin device. istered an antidepressant while also receiving anti-Parkin 0009 BIOVAIL(R) is reportedly currently developing a Sons, anti-Alzheimer's or anti-dementia drug therapy. Vari controlled release dosage form containing citalopram for the ous Scientific publications and patents Specifically mention treatment of depression; however, this product does not the use of citalopram in treating depression associated with include amantadine. these disorders. However, citalopram is not generally known for its use in the treatment of tremors associated with these 0010 Buspirone, a 5-HT1A agonist, is a recognized disorders. anxiolytic agent. BuSpirone is primarily active in dopamin ergic pathways. It has the properties of both a dopamine 0004 Citalopram, an SSRI antidepressant that is selec agonist and antagonist. Buspirone is commercially available tive for the 5HT1 receptor, is available commercially in immediate release tablet or Solution form under the trade under the trademark BUSPARTM in rapid release tablet form. marks CELEXATM and LEXAPROTM (s-citalopram enanti 0011 Buspirone (BUS) has been evaluated for its effect omer). Citalopram has been used, with intermittent Success, on motor disorders associated with Parkinson's disease or in combination with other drugs for treating depression in levodopa therapy; however, results have been mixed and patients with Parkinson's disease. Heinonen et al. (Drug contradictory. Bonifati et al. (Clin. Neuropharmacol., (1994 Safety, (July 1998), 19(1), 11-22) disclose the combined February), 17(1), 73-82) report mixed results in the treat administration of citalopram with Selegiline (deprenyl). ment of levodopa induced dyskinesia by administration of They disclose the administration of Selective Serotonin buspirone. Ross (Med. Hypotheses, (1987 March), 22(3), reuptake inhibitors (SSRIs), such as citalopram, to Parkin 321-8) suggests that the treatment of movement disorders Son's patients undergoing treatment with Selegiline. Rihmer with buspirone should be further evaluated. Hammerstad et et al. (International J. Psychiatry in Clin. Prac., (June al. (Clin. Neuropharmacol., (1986), 9(6), 556-560) report 2000), 4(2), 123-125) disclose the results of a study evalu that buspirone is ineffective in the treatment of Parkinson's ating the combined administration of Selegiline and citalo disease. Ludwig et al. (Clin. Neuropharmacol., (1986), 9(4), pram for the treatment of depression in patients with Par 373-8) report that at normal therapeutic (anti-anxiolytic) kinson's disease. Linasazoro (Parkinsonism & Related levels, buSpirone was no different than placebo in terms of Disorders, (April 2000), 6(2), 111-113) disclose the results its effect on dyskinesia. The combined use of an NMDA-RA of a case history wherein addition of citalopram to the and an anxiolytic agent, Such as buspirone, for the treatment anti-Parkinson's drug regime of a single patient actually of motor disorderS has not been disclosed. worsened her motor Symptoms. 0012 Trazodone (TRZ) is indicated for the treatment of 0005 Dell'Agnello et al. (Clin. Neuropharmacol., (July depression and is a classified as a triazolopyridine anxi August 2001), 24(4), 221-227) disclose the results of a study olytic/anti-depressant, psychotropic agent or a Serotonin evaluating the effect of SSRIs on the extrapyramidal symp antagonist reuptake inhibitor (SARI). TRZ is described in toms associated with Parkinson's disease. They report that U.S. Pat. No. 4,215,104 and No. 4,258,027. It is available SSRI's do not significantly worsen extrapyramidal Symp commercially in immediate release form under the trade tomatology and may ameliorate depression in patients with marks DESYRELTM, BENEFICATTM, BIMARANTM, Parkinson's disease. Other reports Suggest that the use of DEPRAXTM, DESIRELTM, MANEGANTM, MOLI US 2006/OO6381.0 A1 Mar. 23, 2006 PAXINTM, PRAGMARELTM, SIDERILTM, TAXAGONTM, Parkinson's disease. The Husbands et al. patent discloses THOMBRANTM, TRAZALONTM, TRAZOLANTM, TRA that “It should also be understood that the present invention ZONILTM and TRITTICOTM. The combined use of traZ is intended to include all methods of, and reasons for, odone with Selegiline in the treatment of depression asso inducing cognition enhancement in a mammal by adminis ciated with Parkinson's disease has been Suggested.