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(12) Patent Application Publication (10) Pub. No.: US 2011/0054038A1 Glozman (43) Pub

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(12) Patent Application Publication (10) Pub. No.: US 2011/0054038A1 Glozman (43) Pub US 20110054038A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2011/0054038A1 Glozman (43) Pub. Date: Mar. 3, 2011 (54) CNS PHARMACEUTICAL COMPOSITIONS Publication Classification AND METHODS OF USE (51) Int. Cl. A63L/38 (2006.01) (75) Inventor: Sabina Glozman, Naharya (IL) A6II 3/09 (2006.01) A6IP 25/00 (2006.01) (73) Assignee: TARGIA (52) U.S. Cl. ......................................... 514/653: 514/718 PHARMACEUTICALS, (57) ABSTRACT Jerusalem (IL) The present invention is directed- 0 to CNS pharmaceutical compositions and methods of use. The pharmaceutical com (21) Appl. No.: 12/860,846 positions comprise a CNS active agent and preferably at least two vagal neuromodulators, one of which is a mechanorecep (22) Filed: Aug. 20, 2010 tor stimulator. The vagal neuromodulators are preferably in an amount Sufficient to reduce a Somnolence side-effect of the O O CNS active agent without changing its therapeutic efficacy/ Related U.S. Application Data activity. The invention further encompasses a method of (63) Continuation-in-part of application No. PCT/IB2009/ reducing CNS active agent side-effects. The method typically 000309 filed on Feb. 20, 2009. comprises oral administration of at least one CNS active s s agent to a patient at the conventionally accepted dose; and administration of at least two vagal neuromodulators to the (60) Provisional application No. 61/030,141, filed on Feb. patient so that at least one neuromodulator is administered or 20, 2008, provisional application No. 61/030,131, released from dosage form after the CNS active agent is filed on Feb. 20, 2008. administered and/or released. Patent Application Publication Mar. 3, 2011 Sheet 1 of 7 US 2011/0054038A1 (IoIoO93ueIo)9ON19?qeL Patent Application Publication Mar. 3, 2011 Sheet 2 of 7 US 2011/0054038A1 FIG 2 Tablet 1 Tablet 2 Tablet 3 (white) (blue) (rose) Alprazolam GUA/PSE- Alprazolam - Daytime delayed- Bedtime dosage immidiate dosage release Patent Application Publication Mar. 3, 2011 Sheet 3 of 7 US 2011/0054038A1 Tablet AM Tablet AM Tablet PM (white) (blue) (rose) Lorazepam GUA/PSE- Lorazepam - Daytime delayed- Bedtime dosage immidiate dosage release Patent Application Publication Mar. 3, 2011 Sheet 4 of 7 US 2011/0054038A1 FIG. 4 Patent Application Publication Mar. 3, 2011 Sheet 5 of 7 US 2011/0054038A1 FIG. 5 Primary Goal: Post dose Sedation, post dose alertness API - active pharmaceutical ingredients - alprazolam or lorazepam PLAC - Placebo NMI - Neuromodulator 1 - Pseudoephedrine NM2 - Neuromodulator 2- Guaifenesin -- -- - API-PLAC Visit I API+NMI+NM2(synchronized) synchronized) Two weeks washout API.--NMI-NM2 API-PLAC Visit 2 (synchronized) (synchronized) TimePoints 0 h 3h 6h Oh 8:00 900 0:S 2S 4:00 55 95 2030 A preparations, A A A A A A breakfast A L unch 'st ose Tests Tests (API+ NM) Tests Tests Home 2'nd dose (NM2) Patent Application Publication Mar. 3, 2011 Sheet 6 of 7 US 2011/0054038A1 |deelsesunziarzan ||deelsesunzºnºwn º?%,deepsunuomonpes? 9(OIH znajo, :uofferntuno;mae, sunoux,sulunumdaarseaun?eno,abereay 9 ag "deasy au eno . Patent Application Publication Mar. 3, 2011 Sheet 7 of 7 US 2011/0054038A1 FIG. 7 Primary Goal: Efficacy of Combined Formulation (Post Trial anxiety symptoms) Secondary Goal: Quality of Life, post dose Sedation, post dose alertness Visit I Visit 2 API-PLCB (synchronized) Treatment treatment wit Visit 4 API- active pharmaceutical ingredients - alprazolam or lorazepam PLAC - Placebo NMI - Neuromodulator 1 - Pseudoephedrine NM2-Neuromodulator 2 - Guaifenesin US 2011/0054038 A1 Mar. 3, 2011 CNS PHARMACEUTICAL COMPOSITIONS the minimal effective dose of a variety of CNS active agents, AND METHODS OF USE which in turn reduces the associated side effects. 0006 Such combinations, however, are not without their CROSS-REFERENCE TO RELATED problems. Thus, there still exists a need for novel combina APPLICATION tions of CNS active agents and neuromodulators to potentiate the pharmacological effect of the CNS active agent, reduce 0001. This patent application is a continuation-in-part of dose-dependent side-effects, avoid tolerance/tachyphylaxis International Application No. PCT/1B2009/000309, filed problems, and overcome the resistance and noncompliance Feb. 20, 2009, which is based on and claims the benefit of issues. U.S. Provisional Patent Application Ser. No. 61/030,141 filed 0007 More specifically, there is a clinical need to develop on Feb. 20, 2008, the contents of each of which are hereby “non-sedating GABA agonists for therapeutic activities incorporated herein by reference for all that it discloses. where sedation-related side effect damages the quality of life and cognitive functioning of the patient, causing the patient to FIELD OF THE INVENTION live most of the day in a daZe and making it dangerous to drive vehicles and operate machinery. However, attempts to 0002 The present invention is directed to pharmaceutical develop these “non-sedative' benzodiazepines have failed as compositions in general, and more particularly to vagal affer the prior art teaches that sedation effects of benzodiazepine ent neuromodulators used in combination with a central ner treatment are linked to the GABA-inhibiting therapeutic Vous system (CNS) active agent as an adjunctive to reduce activity. In addition, attempts have been made to develop side effects associated with CNS agent without affecting its non-sedating anxiolytic drugs by chemical modification of therapeutic efficacy. the active agent, but no benzodiazepine receptor partial ago nist has emerged as a viable alternative. BACKGROUND 0008. The optimal anxiolytic drug product will be capable 0003 Various pharmaceuticals, such as CNS active agents of producing a robust anxiolytic action by having a more cause severe side-effects that generally worsen with increas rapid onset of action than current therapies while potentially ing doses. Some classes of CNS active agents that require reducing the number of side effects. This drug would be increasing doses include pain reducing drugs, selective sero comparable to benzodiazepines, but lacking their limiting tonin re-uptake inhibitors, antidepressants, anti-convulsants, side effects at therapeutic doses. This new drug would repre hypnotics, anesthetics, sedative agents, angiolytics, NSAIDs, sent an important advancement in the treatment of anxiety Xanthines, antipsychotics, appetite Suppressants, sleep disorders. Even if it is possible that a new, chemically-modi agents, antibiotics, antivirals, insulin resistance drugs, anti fied non-sedative GABA agonist may be finally developed, hypertensives, and anti-asthma drugs. At high doses, many there is an advantage in the utilization of a drug product CNS active agents rapidly lose their effectiveness, induce combination from known, approved, and available pharma pharmacologic tolerance, and cause increasingly severe side ceutical ingredients. Such an approach reduces the risk of effects. Lowering the dose of the CNS active agent, however, potential unknown toxicity, and the long term development does not address the problem because reducing the dose to investment required of new pharmaceutical ingredients. prior levels results in significantly lower therapeutic efficacy. 0009. In light of the prior art, the inventors surprisingly 0004 Combinations of centrally active agents have been discovered that (1) the reduction of sedation-associated side used in an effort to overcome the current disadvantages of effects of CNS active agents is possible using the conven single agent use. In local anesthetic formulations, locally tional dosage of the CNS drug; (2) chemoreceptor stimulators acting adrenergic agonists, such as epinephrine, are known to (i.e. pseudoephedrine (PSE) and other andrenergic receptor enhance the local activity of analgesic drugs and improve agonists) optimally reduce the side effects associated with a therapeutic efficacy. For example, it has been demonstrated CNS agent when a mechanoreceptor stimulator (i.e. guaifen that a higher dosage of epinephrine potentiated the effects of esin (GUA)) is administered approximately 15 minutes after local anesthesia. (Morganroth et al. 2009). Furthermore, sev administration of the CNS agent and PSE; and (3) adminis eral selective 6.2 agonist drugs have been used in anesthesia, tration of GUA eliminates the need to use a very high dose of either alone or in combination, with various opiate or inhala oSmoactive polymers (or other osmoactive agents) which can tional anesthetics, and have been found to reduce the dose complicate formulation preparation and disturb the Subject's requirement for opiates, halothane, or ketamine (Verstegen physiological osmotic balance. 1989; Nevalainen et al. 1989; Moens and Fargetton 1990). Additionally, U.S. Pat. No. 5,605,911 discloses the use of an SUMMARY OF THE INVENTION 6.2 agonist to block the neurotoxic effects, such as hallucina 0010. The present invention is directed to pharmaceutical tions and neuronal damage, of an NMDA antagonist. Simi compositions comprising a central nervous system (CNS) larly, U.S. Pat. No. 6,562,855 teaches that co-administration active agent and method of use. The compositions and of an NMDA receptor antagonist and an (12 adrenergicago method advantageously reduce a side effect of the CNS active nist both potentiates the effects of anesthesia and diminishes agent. In a preferred embodiment, the compositions further the side effects compared to administration of anesthesia comprise at least two vagal neuromodulators; and a pharma alone. ceutically-acceptable
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