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(12) Patent Application Publication (10) Pub. No.: US 2014/01994.17 A1 Knutsen Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2014/01994.17 A1 Knutsen Et Al US 2014O1994.17A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2014/01994.17 A1 Knutsen et al. (43) Pub. Date: Jul. 17, 2014 (54) ANTHSTAMINES COMBINED WITH Publication Classification DETARY SUPPLEMENTS FOR IMPROVED HEALTH (51) Int. C. A613 L/445 (2006.01) A2.3L 2/52 (2006.01) (75) Inventors: Lars Jacob Stray Knutsen, West A613 L/4045 (2006.01) Chester, PA (US); Judi Lois Knutsen, A61E36/84 (2006.01) Cambridge (GB) A613 L/4402 (2006.01) A613 L/405 (2006.01) (73) Assignee: Requis Pharmaceuticals Inc., West (52) U.S. C. Chester, PA (US) CPC ......... A61 K3I/4415 (2013.01); A61 K3I/4402 (2013.01); A61 K3I/405 (2013.01); A61 K (21) Appl. No.: 14/124,748 31/4045 (2013.01); A61K 36/84 (2013.01); A2.3L 2/52 (2013.01) (22) PCT Fled: Jun. 8, 2012 USPC ............................ 424/733; 514/357; 514/345 (86) PCT NO.: PCT/US12A41655 (57) ABSTRACT S371 (c)(1), The present invention provides combinations comprising a (2), (4) Date: Mar. 5, 2014 sedating antihistamine and selected indole-based natural products such as L-tryptophan, 5-hydroxytryptophan and melatonin, along with pharmaceutically acceptable calcium Related U.S. Application Data and magnesium salts and selected B vitamins. These combi (60) Provisional application No. 61/495,185, filed on Jun. nations are useful in providing a medicament for improving 9, 2011. sleep in mammals, especially humans. Patent Application Publication Jul. 17, 2014 US 2014/O1994.17 A1 DOXylamine PrOmethazine Diphenhydramine Figure 1: Examples of preferred antihistamine drugs L-Tryptophan 5-Hydroxytryptophan Melatonin Figure 2: Representative indole-based dietary supplements US 2014/O 1994.17 A1 Jul. 17, 2014 ANTHISTAMINES COMBINED WITH demonstrated the highest association with insomnia (Sutton, DIETARY SUPPLEMENTS FOR IMPROVED D. A., Moldofsky, H. and Badley, E. M. Insomnia and Health HEALTH Problems in Canadians, Sleep, 2001, 24, 665-670). Around 24% of the total Canadian population age 15 and older CROSS REFERENCE TO RELATED reported experiencing insomnia. As expected the prevalence APPLICATIONS of insomnia increased with age, from one fifth of those age 15 0001. This application is the US national application of to 24 years to slightly more than one third among those 75 PCT/US2012/041655, filed on Jun. 8, 2012 and which claims years and older. The presence of circulatory, digestive and priority to U.S. Provisional Application No. 61/495,185 filed respiratory disease, allergy, migraine, and rheumatic disor on Jun. 9, 2011, now expired, the disclosure of which is herein ders show the highest associations with insomnia together incorporated by reference in its entirety. with pain, life stress, and health dissatisfaction. These find ings emphasize the importance of recognizing and addressing FIELD OF THE INVENTION chronic physical health conditions, pain, and life stress issues 0002 The present invention is directed to novel combina in the diagnosis and treatment of insomnia. tions of sedating antihistamines and certain indole-based 0011. It is estimated that insomnia is responsible for over dietary Supplements, and to their use for improving the health S14 billion in direct healthcare costs each year in the United of human Subjects, including improving sleep, inducing States, and untold billions in lost productivity. Overall, it is restorative sleep function, the treatment of insomnia and believed that the direct and indirect costs attributable to other sleep-related problems such as issues with circadian insomnia exceed S100 billion per year in the USA alone rhythm, shift work disorder and jet lag. (Fullerton D. The economic impact of insomnia in managed care: A clearer picture emerges. American Journal of Man BACKGROUND OF INVENTION aged Care, 2006, 12, 246-252). In its initial stages, insomnia 0003 Antihistamine drugs, i.e. antagonists or inverseago occurs when predisposing factors, such as illness or pain, nists of the histamine H receptor have been known since the combine with precipitating or triggering factors, typically life 1940s and 1950s and have been utilized with success as stress and anxiety, to bring about issues with falling asleep, anti-allergy agents. These drugs have proved to be generally mid-nocturnal or early morning awakening or poor sleep safe in low dose and normal use. One of the observed side quality. Once insomnia begins, perpetuating factors, includ effects of these antihistamines has been sedation and there ing a range of largely ineffective compensatory behaviors fore a range of clinically well-proven antihistamine-based (e.g. daytime naps, sleeping in on weekends) and negative drugs are now available in many territories as over-the thoughts can create a vicious cycle, transforming an acute counter (OTC) sleep-aids, which are distinguished from pre problem into a more chronic one. Without intervention, inef scription sleep drugs by their milder effect, and their avail fective coping strategies can distort the individual’s sleep ability in most pharmaceutical markets without a wake cycle, while the negative thoughts about sleep trigger prescription. anxiety and create a self-fulfilling prophecy. If people believe 0004 Antihistamines which are established for use as they will not fall asleep, then it is likely they will be tense at anti-allergy agents and have a range of sedative effects and bedtime, and as a result can find it difficult to sleep, and therefore have potential use as sleep-aids include Cetirizine, pharmacological intervention will be required. Some patients Chlorpheniramine, Clemastine, Desloratadine, Dexchlor may be even embarrassed to visit their physician for Such an pheniramine, Dimenhydrinate, Dimetindene, Diphenhy issue or may have had bad experiences with early prescription dramine, Doxylamine, Ebastine, Embramine, Fexofenadine, sleep medicines. Therefore a significant market in non-pre Levocetirizine, Loratadine, Meclozine, Olopatadine, Phe Scription sleep aids has developed, especially in North niramine, Promethazine and Triprolidine. America. However, there is a constant need for novel and 0005 According to the fourth edition of the Diagnostic improved products as existing products have their problems. and Statistical Manual of Mental Disorders (DSM-IV-TR), 0012 Insomnia is associated with a number of health insomnia is characterized by one or more of these sleep com issues. In a 2007 review article (Roth, T. Insomnia: Defini plaints, which cause clinically significant impairment of day tion, Prevalence, Etiology, and Consequences, Journal of time functioning: Clinical Sleep Medicine, 2007, 3, (suppl.):S7-S10). It is con 0006 Difficulty initiating sleep cluded that chronic insomnia is highly prevalent and affects 0007 Difficulty maintaining sleep approximately 30% of the general US population. Insomnia 0008. Nonrestorative sleep impairs cognitive and physical functioning and is associated 0009. One of the functions of sleep is the maintenance, with a wide range of impaired daytime functions across a restoration, and repair of the body. Sleep is generally charac number of emotional, social, and physical domains. Com terized by anabolic activity (including building and remodel pared with good sleepers, people with persistent sleep distur ing) in muscle, bone, connective tissue, skin, and major bances are more prone to accidents, have higher rates of work organs including the brain. One result of this activity is res absenteeism, diminished job performance, decreased quality toration of function including physical and mental perfor of life, and increased health care utilization. Various risk mance Such as stamina, energy, and mental alertness. Lack of factors associated with increased prevalence of chronic sleep has consequences for daytime performance and when insomnia include older age, female gender, and co-morbid chronic, for mental health. medical and psychiatric conditions. Approximately 40% of 0010 Insomnia has been shown to be highly prevalent adults with insomnia also have a diagnosable psychiatric among the non-institutionalized Canadian population age 15 disorder—most notably depression. A co-morbid psychiatric and older. The disorder is associated with a very stressful life, disorder Such as depression or anxiety may be a consequence severe pain and dissatisfaction with one's health, these factors of as well as a risk factor for—disrupted sleep. US 2014/O 1994.17 A1 Jul. 17, 2014 0013 Therefore an inability to sleep is often a symptom of motor impairment (ataxia), flushed skin, blurred vision at stress, and ifuntreated can lead to severe anxiety and depres nearpoint owing to lack of accommodation (cycloplegia), sion. A lot of patients self-medicate when suffering from mild abnormal sensitivity to bright light (photophobia), difficulty and temporary insomnia, and one of the most-used OTC or concentrating, short-term memory loss, visual disturbances, general sale treatments is with antihistamines. The Subject irregular breathing, dizziness, irritability, itchy skin, confu matter of this invention is that the effect of these sleep-aids be Sion, decreased body temperature (in general, in the hands improved further with addition of indole-based dietary and/or feet), erectile dysfunction, and excitability. (see http:// Supplements including L-tryptophan, 5-hydroxytryptophan www.drugs.com/sfx/diphenhydramine-side-effects.html). (5-HTP) and melatonin to the antihistamine drug formula 0021. In the 1960, the antihistamine diphenhydramine tion. was found to inhibit reuptake of the important neurotransmit 0014.
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