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(12) INTERNATIONALAPPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date 27 August 2009 (27.08.2009) WO 2009/104080 A2 (51) International Patent Classification: CA, CH, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, A61K 31/137 (2006.01) EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, (21) International Application Number: KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, PCT/IB2009/000309 MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, (22) International Filing Date: NZ, OM, PG, PH, PL, PT, RO, RS, RU, SC, SD, SE, SG, 20 February 2009 (20.02.2009) SK, SL, SM, ST, SV, SY, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (25) Filing Language: English (84) Designated States (unless otherwise indicated, for every (26) Publication Language: English kind of regional protection available): ARIPO (BW, GH, (30) Priority Data: GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM, 61/030,141 20 February 2008 (20.02.2008) US ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), European (AT, BE, BG, CH, CY, CZ, DE, DK, EE, (71) Applicant (for all designated States except US): TAR- ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, GIA PHARMACEUTICALS [ILIlL]; Mishol Hama- MC, MK, MT, NL, NO, PL, PT, RO, SE, SI, SK, TR), galit, 17, 97277 Jerusalem (IL). OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, ML, MR, NE, SN, TD, TG). (72) Inventor; and (75) Inventor/Applicant (for US only): GLOZMAN, Sabina Published: [IL/IL]; Aliyah Street, 26, Naharya (IL). — without international search report and to be republished (81) Designated States (unless otherwise indicated, for every upon receipt of that report (Rule 48.2(g)) kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, (54) Title: CNS PHARMACEUTICAL COMPOSITIONS AND METHODS OF USE (57) Abstract: The present invention is directed to CNS pharmaceutical compositions and methods of use. The pharmaceutical compositions comprise a CNS active agent and preferably at least two vagal neuromodulators, one of which is a mechanoreceptor stimulator. The vagal neuromodulators are preferably in an amount sufficient to reduce a side-effect of the CNS active agent. The invention further encompasses a method of reducing CNS active agent side-effects. The method typically comprises administering the CNS active agent to a patient; and administering at least two vagal neuromodulators to the patient so that at least one neuro - modulator is administered or released after the CNS active agent is administered or released. CNS PHARMACEUTICAL COMPOSITIONS AND METHODS OF USE CROSS-REFERENCE TO RELATED APPLICATION [0001] This patent application is based on and claims the benefit of U.S. provisional patent application serial no. 61/030,141 filed on February 20, 2008, which is hereby incorporated herein by reference for all that it discloses. TECHNICAL FIELD [0002] The field of the invention relates to pharmaceutical compositions in general, more particularly, neuromodulator stimulators used in combination with a central nervous system (CNS) active agent. BACKGROUND ART [0003] Various pharmaceuticals, such as CNS active agents, undergo tachyphylaxis and cause severe side-effects that generally worsen with increasing doses. When administered alone, CNS active agents usually require large and increasing doses. Some classes of CNS active agents that require increasing doses include pain reducing drugs, selective serotonin re-uptake inhibitors, antidepressants, anti-convulsants, hypnotics, anesthetics, sedative agents, angiolytics, NSAIDs, xanthines, antipsychotics, appetite suppressants, sleep agents, antibiotics, antivirals, insulin resistance drugs, antihypertensives, and anti-asthma drugs. At high doses, many CNS active agents rapidly lose their effectiveness, induce pharmacologic tolerance, and cause increasingly severe side-effects. Lowering the dosage of the CNS active agent, however, does not address the problem because reducing the dosage to prior levels results in significantly lower efficacy. While combinations of centrally active agents have been tried to overcome the current disadvantages of single agent use, such combinations are not without their problems. Thus, there still exists a need for novel combinations of CNS active agents and neuromodulators to potentiate the pharmacological effect of the CNS active agent, reduce dose-dependent side-effects, avoid tolerance/tachyphylaxis problems, and overcome the resistance and noncompliance issues. In addition, given the extent of addictive drugs and drug abuse, there is a need for combinations that will allow the CNS active agent dosage to be reduced to such a degree that patients will not receive enough to enter the addictive/withdrawal cycle. DISCLOSURE OF INVENTION [0004] The present invention is directed to pharmaceutical compositions comprising a central nervous system (CNS) active agent and method of use. The compositions and method advantageously reduce a side effect of the CNS active agent. In a preferred embodiment, the compositions further comprise at least two vagal neuromodulators; and a pharmaceutically-acceptable vehicle, carrier or diluent. The vagal neuromodulators are in an amount sufficient to reduce a side-effect of the CNS active agent. Preferably, at least one of the vagal neuromodulators is a mechanoreceptor stimulator. Suitable mechanoreceptor stimulator may be selected from the group consisting of: mucomodulators and surfactants, e.g., guaifenesin (GUA). [0005] In addition, preferably that the vagal neuromodulators further comprise at least one chemoreceptor stimulator, and more preferably if at least one chemoreceptor stimulator is selected from the group consisting of: pH modulators, secretagouges, adrinomimetics, xanthines, cholecystokinins and gastric agonists, e.g., pseudophedrine (PSE). [0006] Advantageously, the present composition may further comprise a GABA modulator and/or a nociceptor stimulator. In an exemplary embodiment, the vagal neuromodulator comprises a vasoactive agent and the mechanoreceptor comprises a mucomodulator. [0007] In certain embodiments the mechanoreceptor stimulator is in a delayed form for co-synchronization with the CNS active agent. For example, in one formulation, the CNS active agent has a time to maximum concentration (Tmax) and the mechanoreceptor stimulator has a Tmax, the delay in the release of mechanoreceptor stimulator is equal to the Tmax of the CNS active agent minus the Tmax of the mechanoreceptor stimulator plus about 5 to about 30 minutes, more preferably plus about 10 to 20 minutes. [0008] In a preferred embodiment, at least one side-effect is reduced selected from the group consisting of: sedation, somnolence, sleepnece, memory impairment, amnesia, impairment of cognitive and learning function, ataxia, impaired night sleep/day alertness, impaired memory, impaired concentration, impaired appetite, drowsiness, hypotension, fatigue, kinetic disorders, catalepsy, movement disorders, bowel irritation and impaired reaction. Preferably the side-effect that is reduced is sedation. [0009] In an exemplary embodiment, the invention is direct to a composition comprising a central nervous system (CNS) active agent and at least two vagal neuromodulators, wherein the CNS active agent has a time to maximum concentration (Tmax) and the at least two vagal neuromodulators each have a Tmax, wherein the Tmax of the CNS active agent is greater than the Tmax of at least one vagal neuromodulator and the release of at least one vagal neuromodulator is delayed, the delay being equal to the Tmax of the CNS active agent minus the Tmax of the neuromodulator plus about 5 to about 30 minutes. Preferably, in this embodiment the at least two vagal neuromodulators comprise at least one mechanoreceptor stimulator and the mechanoreceptor stimulator is in a delayed release form. For example, the formulation of this embodiment may comprise GUA and PSE, wherein the GUA is released between about 10 and about 20 minutes after the CNS active agent. [0010] The invention is further directed to a method of reducing a side-effect of a CNS active agent. Preferably, the method comprises: administering the CNS active agent to a patient; and administering at least two vagal neuromodulators to the patient in an amount sufficient to reduce a side-effect of the CNS active agent. Particularly, at least one neuromodulator may be administered or released at least about 5 minutes after the CNS active agent is administered or released. In a specific embodiment, the neuromodulator is administered or released after the CNS active agent is administered or released, preferably within 30 minutes. In this embodiment the CNS agent maybe in an amount that is substantially the same as the conventially accepted effective dosage still have a reduction in at least one side-effect of the CNS. The at least two vagal neuromodulators may also comprise at least one mechanoreceptor stimulator as stated above, wherein the at least two vagal neuromodulators are in an amount sufficient to reduce the side-effect associated with the CNS active agent. Specifically, the release or the administration of the mechanoreceptor stimulator may be delayed. In this embodiment, the delay in the administration or release of mechanoreceptor stimulator is typically equal to the Tmax of the CNS active agent minus the Tmax of the mechanoreceptor stimulator plus about 5 to about 30 minutes. [0011] In an alternative embodiment, the invention the invention is directed to a method for reducing dependency or toxicity of an addictive central nervous system (CNS) active agent. The method comprises: administering to a patient between about 5 to about 80 percent, more preferably less than about 60%, and most preferably less than about 50% of the conventionally accepted effective dosage of the addictive CNS active agent for the desired treatment. The method further comprises administering to the patient at least two vagal neuromodulators in an amount sufficient to reduce the dosage of the addictive CNS active agent without reduction of efficacy.
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