US008729070B2 (12) United States Patent (10) Patent N0.: US 8,729,070 B2 Glozman (45) Date of Patent: May 20, 2014 (54) CNS PHARMACEUTICAL COMPOSITIONS FOREIGN PATENT DOCUMENTS AND METHODS OF USE GB 2 I66 651 5/1986 (75) Inventor: Sabina Glozman, Naharya (IL) OTHER PUBLICATIONS (73) Assignee: Targia Pharmaceuticals, Jerusalem (IL) Ashton H, Toxicity and adverse consequences of benzodiazepine use, ( * ) Notice: Subject to any disclaimer, the term of this Psychiatric Annals, 1995;25: 15 8-65 .* Eccles, Substitution of phenylephrine for pseudoephedrine as a nasal patent is extended or adjusted under 35 decongestant. An illogical way to control metamphetamine abuse. U.S.C. 154(b) by 468 days. British Journal ofClinical Pharmacology, 63:1, pp. 10-14, published online Nov. 20, 2006* (21) Appl.No.: 12/860,846 European Search Report for corresponding European Patent Appli cation No. 097115679 dated Jan. 18,2012. (22) Filed: Aug. 20, 2010 International Search Report for corresponding PCT Application No. PCT/IB2009/000309 dated Jul. 27, 2009. (65) Prior Publication Data Written Opinion of the International Searching Authority for corre US 2011/0054038 A1 Mar. 3, 2011 sponding PCT Application No. PCT/IB2009/000309 dated Jul. 27, 2009. International Preliminary Report on Patentability for corresponding Related US. Application Data PCT Application No. PCT/IB2009/000309 dated Aug. 24, 2010. (63) Continuation-in-part of application No. PCT/IB2009/000309, ?led on Feb. 20, 2009. * cited by examiner (60) Provisional application No. 61/030,141, ?led on Feb. 20,2008. Primary Examiner * Sreeni Padmanabhan Assistant Examiner * Svetlana M Ivanova (51) Int. Cl. (74) Attorney, Agent, or Firm * Rodney J. Fuller; Booth A61K31/55 (2006.01) Udall Fuller, PLC A61K31/155 (2006.01) A61K33/30 (2006.01) (57) ABSTRACT A61K31/19 (2006.01) (52) U.S.Cl. The present invention is directed to CNS pharmaceutical USPC ......... .. 514/220;514/221;514/635;514/718; compositions and methods of use. The pharmaceutical com 5 14/5 68 positions comprise a CNS active agent and preferably at least (58) Field of Classi?cation Search two vagal neuromodulators, one of which is a mechanorecep None tor stimulator. The vagal neuromodulators are preferably in See application ?le for complete search history. an amount su?icient to reduce a somnolence side-effect of the CNS active agent without changing its therapeutic ef?cacy/ (56) References Cited activity. The invention further encompasses a method of reducing CNS active agent side-effects. The method typically U.S. PATENT DOCUMENTS comprises oral administration of at least one CNS active agent to a patient at the conventionally accepted dose; and 6,833,377 B2 * 12/2004 Serdyuk ...................... .. 514/327 administration of at least two vagal neuromodulators to the 2002/0015713 A1 2/2002 Murdock et a1. 2004/0063628 A1 4/2004 Piccariello et al. patient so that at least one neuromodulator is administered or 2005/0008690 A1 1/2005 Miller released from dosage form after the CNS active agent is 2005/0031651 A1 2/2005 Gervais et al. administered and/or released. 2005/0267009 A1 12/2005 Deagle 2008/0020018 A1 1/2008 Moodley et al. 2009/0197958 A1 * 8/2009 Sastry et al. ................ .. 514/563 4 Claims, 7 Drawing Sheets U S. Patent May 20, 2014 Sheet 3 0f7 US 8,729,070 B2 Tablet AM Tabiet AM Tablet PM (white) (blue) (r052) Lurazepam GUA/PSE— Lurazepam » Day time": delayeck Bed time dusage immediate dcsage reiease US. 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Thus, there still exists a need for novel combinations of CNS active agents and neuromodulators to potentiate the CROSS-REFERENCE TO RELATED pharmacological effect of the CNS active agent, reduce dose APPLICATION dependent side-effects, avoid tolerance/tachyphylaxis prob lems, and overcome the resistance and noncompliance issues. This patent application is a continuation-in-part of Inter More speci?cally, there is a clinical need to develop “non national Application No. PCT/ 1 B2009/ 000309, ?led Feb. 20, sedating” GABA agonists for therapeutic activities where 2009, which is based on and claims the bene?t of US. Pro sedation-related side effect damages the quality of life and visional Patent Application Ser. No. 61/030,141 ?led on Feb. cognitive functioning of the patient, causing the patient to live 20, 2008, the contents of each of which are hereby incorpo most of the day in a daze and making it dangerous to drive rated herein by reference for all that it discloses. vehicles and operate machinery. However, attempts to develop these “non-sedative” benzodiazepines have failed as FIELD OF THE INVENTION the prior art teaches that sedation effects of benzodiazepine The present invention is directed to pharmaceutical com treatment are linked to the GABA-inhibiting therapeutic positions in general, and more particularly to vagal afferent activity. In addition, attempts have been made to develop neuromodulators used in combination with a central nervous non-sedating anxiolytic drugs by chemical modi?cation of system (CNS) active agent as an adjunctive to reduce side the active agent, but no benzodiazepine receptor partial ago effects associated with CNS agent without affecting its thera 20 nist has emerged as a viable alternative. peutic e?icacy. The optimal anxiolytic drug product will be capable of producing a robust anxiolytic action by having a more rapid BACKGROUND onset of action than current therapies while potentially reduc ing the number of side effects. This drug would be compa Various pharmaceuticals, such as CNS active agents cause 25 rable to benzodiazepines, but lacking their limiting side severe side-effects that generally worsen with increasing effects at therapeutic doses. This new drug would represent an doses. Some classes of CNS active agents that require important advancement in the treatment of anxiety disorders. increasing doses include pain reducing drugs, selective sero Even if it is possible that a new, chemically-modi?ed non tonin re-uptake inhibitors, antidepressants, anti-convulsants, sedative GABA agonist may be ?nally developed, there is an hypnotics, anesthetics, sedative agents, angiolytics, NSAIDs, 30 advantage in the utilization of a drug product combination xanthines, antipsychotics, appetite suppressants, sleep from known, approved, and available pharmaceutical ingre agents, antibiotics, antivirals, insulin resistance drugs, anti dients. Such an approach reduces the risk of potential hypertensives, and anti-asthma drugs. At high doses, many unknown toxicity, and the long term development investment CNS active agents rapidly lose their effectiveness, induce required of new pharmaceutical ingredients. pharmacologic tolerance, and cause increasingly severe side 35 In light of the prior art, the inventors surprisingly discov effects. Lowering the dose of the CNS active agent, however, ered that (1) the reduction of sedation-associated side effects does not address the problem because reducing the dose to of CNS active agents is possible using the conventional dos prior levels results in signi?cantly lower therapeutic ef?cacy. age of the CNS drug; (2) chemoreceptor stimulators (i.e. Combinations of centrally active agents have been used in pseudoephedrine (PSE) and other andrenergic receptor ago an effort to overcome the current disadvantages of single 40 nists) optimally reduce the side effects associated with a CNS agent use. In local anesthetic formulations, locally acting agent when a mechanoreceptor stimulator (i.e. guaifenesin adrenergic agonists, such as epinephrine, are known to (GUA)) is administered approximately 15 minutes after enhance the local activity of analgesic drugs and improve administration of the CNS agent and PSE; and (3) adminis therapeutic ef?cacy. For example, it has been demonstrated tration of GUA eliminates the need to use a very high dose of that a higher dosage of epinephrine potentiated the effects of osmoactive polymers (or other osmoactive agents) which can local anesthesia. (Morganroth et al. 2009). Furthermore, sev complicate formulation preparation and disturb the subject’ s eral selective (12 agonist drugs have been used in anesthesia, physiological osmotic balance. either alone or in combination, with various opiate or inhala tional anesthetics, and have been found to reduce the dose SUMMARY OF THE INVENTION requirement for opiates, halothane, or ketamine (Verstegen 50 1989; Nevalainen et al. 1989; Moens and Fargetton 1990). The present invention is directed to pharmaceutical com Additionally, US. Pat. No. 5,605,911 discloses the use of an positions comprising a central nervous system (CNS) active (12 agonist to block the neurotoxic effects, such as hallucina agent and method of use. The compositions and method tions and neuronal damage, of an NMDA antagonist. Simi advantageously reduce a side effect of the CNS active agent. larly, US. Pat. No. 6,562,855 teaches that co-administration 55 In a preferred embodiment, the compositions further com of an NMDA receptor antagonist and an (12 adrenergic ago prise at least two vagal neuromodulators; and a pharmaceu nist both potentiates the effects of anesthesia and diminishes tically-acceptable vehicle, carrier or diluent. The vagal neu the side effects compared to administration of anesthesia romodulators are in an amount suf?cient to reduce a side alone.