Novel pharmaceutical compositions and methods for the treatment of insomnia

Abstract

Pharmaceutical compositions comprising azelastine or a pharmaceutically acceptable salt of azelastine and melatonin are disclosed. Methods of using the pharmaceutical compositions to treat patients suffering from insomnia are also disclosed.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application is a continuation-in-part of U.S. patent application Ser. No. 16 / 382,885 filed on April 12, 2019, which is a continuation-in-part of U.S. patent application Ser. No. 16 / 884,459 filed on May 27, 2020, the disclosure of which is incorporated by reference in its entirety into this specification.

[0002] FIELD OF THE INVENTION

[0002] The present invention relates to the field of practical medicine, namely the use of pharmaceutical compositions for treating, preventing and / or alleviating the symptoms of insomnia or its symptoms. [Background technology]

[0003] Background of the Invention Insomnia is often diagnosed by the presence of polysomnographic evidence of sleep disturbances, such as long sleep latency, frequent nocturnal awakenings, or prolonged awakenings during sleep, as well as frequent transient awakenings. Population-based studies have shown that approximately 30–40% of adult samples from various countries report one or more of the following symptoms of insomnia: difficulty falling asleep, difficulty maintaining sleep, premature awakenings, and, in some cases, unrestorative or poor-quality sleep. In particular, insomnia significantly impacts vulnerable patient populations, including active and retired military personnel, patients with coexisting psychiatric and medical disorders, patients undergoing transitional periods such as menopause, and the elderly. Due to its chronic nature, insomnia is associated with substantial impairments in an individual's quality of life, including high rates of psychiatric comorbidity. Insomnia also poses even greater health risks due to increased daytime accident incidence.

[0004]

[0004] Treatments for insomnia include benzodiazepine receptor agonists such as triazolam, estazolam, zolpidem, zaleplon, and eszopiclone; melatonin agonists such as ramelteon; tricyclic antidepressants such as doxepin; and orexin receptor antagonists such as suvorexant. These drugs carry risks such as tolerance, dependence, memory impairment, depression, headache, dizziness, and somnolence.

[0005]

[0005] Clinically, there is an urgent need for new treatments for insomnia that have significantly fewer side effects and can be offered to a wider range of patients experiencing insomnia who have additional medical or psychiatric conditions.

[0006] Inflammation can be defined as an immune response that protects organisms from injury. The immune system can induce acute or chronic inflammatory responses in organs, including the brain, triggered by various factors, such as pathogens, cellular damage, and stress, which can lead to tissue damage or disease. Recent advances in neurobiological research have provided growing evidence that inflammatory and neurodegenerative pathways play a relevant role in insomnia. Preclinical and clinical studies on insomnia have highlighted increased production of inflammatory markers, such as interleukin (IL)-1, IL-6, tumor necrosis factor (TNF)-α, and interferon (IFN)-α and -γ, as well as overactivation of inflammatory signaling pathways, including nuclear factor kappa B (NF-κB). More recent studies have shown that blocking the biological actions of the cytokines IL-1 and TNF reduces physiological non-rapid eye movement (NREM) sleep levels or the rebound of non-rapid eye movement (NREM) sleep after sleep deprivation. On the other hand, increasing the availability of these cytokines promoted the amount and intensity of non-rapid eye movement (NREM) sleep and suppressed the amount of REM sleep. These findings established both IL-1 and TNF as cytokines involved in the homeostatic regulation of sleep. Other cytokines, including IFN, IL-2, IL-4, IL-6, IL-10, IL-13, IL-15, and IL-18, also appear to have some sleep-regulating properties. The anti-inflammatory cytokines IL-4, IL-10, and IL-13 reduce the amount of non-REM sleep in rabbits, whereas the pro-inflammatory cytokines IFN-γ, IL-2, IL-6, IL-15, and IL-18 have been reported to promote non-REM sleep in animal models.

[0007] Azelastine is pharmacologically classified as a second-generation antihistamine, a relatively selective, non-sedating competitive antagonist of H1 receptors for the treatment of allergic rhinitis and asthma. However, more uniquely, in addition to its antihistamine activity, its inhibition of proinflammatory mediators and mast cell-stabilizing effects position it as one of a new generation of dual-action anti-inflammatory drugs. Its ability to modify several other proinflammatory mediators, such as IL-1, IL-6, TNF-α, and INF-α, and to reduce the overactivation of the NF-κB inflammatory signaling pathway, may contribute to its mechanism of action as a potential treatment for insomnia. In vitro and in vivo studies, as well as clinical trials, support the dual effects of direct inhibition and stabilization of inflammatory cells. In vitro data indicate that azelastine's affinity for inhibiting mast cell degranulation may also reduce the release of other proinflammatory mediators, including leukotrienes and interleukin-1β, among others. Preclinical studies have shown that azelastine also directly antagonizes other proinflammatory mediators, such as tumor necrosis factor-α, leukotrienes, endothelin-1, and platelet-activating factor.

[0008] Melatonin is best known for its mediation of circadian variations in metabolism and reproductive capacity in light-sensitive species, its ability to influence ubiquitous circadian processes in organisms and cells, and its sleep-promoting activity. Each of these functions relies on circadian messages provided by pineal-derived melatonin rhythms in blood and cerebrospinal fluid. Melatonin is also highly effective as an antioxidant at the mitochondrial level and as an anti-inflammatory agent. Doses for circadian rhythm regulation via membrane receptors are typically lower than those used to combat free radicals, and this effect is independent of membrane receptors. High doses of melatonin are believed to be effective in alleviating the overproduction of inflammatory markers, such as interleukin (IL)-1, IL-6, and tumor necrosis factor (TNF)-α.

[0009]

[0009] Thus, the unique combination of azelastine (an antihistamine with anti-inflammatory properties) and melatonin may be effective in treating insomnia in that it operates via multiple mechanisms of action. Summary of the Invention [Means for solving the problem]

[0010] Summary of the Invention

[0010] The present invention includes a pharmaceutical composition comprising two active pharmaceutical ingredients, the first active ingredient being azelastine or a pharmaceutically acceptable salt of azelastine, and the second active ingredient being melatonin.

[0011]

[0011] In some embodiments of the present invention, the pharmaceutically acceptable salt of azelastine in the pharmaceutical composition is azelastine hydrochloride.

[0012]

[0012] In some embodiments of the present invention, azelastine hydrochloride (and / or other salts) in the pharmaceutical composition is provided in an amount of about 2 mg to about 10 mg, and melatonin is provided in an amount of about 2 mg to about 20 mg.

[0013] The present invention also includes oral pharmaceutical dosage forms of the pharmaceutical composition in solid, liquid, gel, or solution form.

[0014]

[0014] The present invention further includes the use of the composition by administration, such as oral administration, to a patient suffering from insomnia.

[0015]

[0015] In some embodiments of the present invention, an oral pharmaceutical dosage form of a pharmaceutical composition comprising azelastine hydrochloride (and / or other salts) in an amount of about 2 mg to about 10 mg and melatonin in an amount of about 2 mg to about 20 mg is administered to a patient suffering from insomnia.

[0016]

[0016] Embodiments include Aspect 1, which is a pharmaceutical composition comprising azelastine or a pharmaceutically acceptable salt of azelastine; melatonin; and one or more pharmaceutically acceptable excipients.

[0017]

[0017] Aspect 2 is the pharmaceutical composition of Aspect 1, wherein the azelastine or a pharmaceutically acceptable salt of azelastine is present in the pharmaceutical composition in an amount ranging from about 1 mg to about 10 mg.

[0018]

[0018] Aspect 3 is the pharmaceutical composition of Aspect 1 or 2, wherein the melatonin is present in the pharmaceutical composition in an amount ranging from about 2 mg to about 20 mg.

[0019]

[0019] Aspect 4 is the pharmaceutical composition of any one of Aspects 1 to 3, wherein the melatonin is present in the pharmaceutical composition in an amount ranging from about 2 mg to about 20 mg.

[0020]

[0020] Aspect 5 is a pharmaceutical composition of any of aspects 1 to 4, wherein azelastine or a pharmaceutically acceptable salt of azelastine is present in the pharmaceutical composition in an amount ranging from about 1 mg to about 10 mg; and melatonin is present in the pharmaceutical composition in an amount ranging from about 5 mg to about 20 mg.

[0021]

[0021] Aspect 6 is the pharmaceutical composition of any one of Aspects 1 to 5, wherein the pharmaceutically acceptable salt of azelastine is azelastine hydrochloride.

[0022]

[0022] Aspect 7 is the pharmaceutical composition of any one of Aspects 1 to 6, wherein the pharmaceutically acceptable salt of azelastine is azelastine hydrochloride.

[0023]

[0023] Aspect 8 is a pharmaceutical composition of any of Aspects 1 to 7, wherein the pharmaceutically acceptable salt of azelastine is azelastine hydrochloride, and wherein azelastine hydrochloride is present in the pharmaceutical composition in an amount of up to about 10 mg.

[0024]

[0024] Aspect 9 is the pharmaceutical composition of any of Aspects 1 to 8, wherein the azelastine hydrochloride is present in an amount ranging from about 1 mg to about 10 mg.

[0025]

[0025] Aspect 10 is the pharmaceutical composition of any one of Aspects 1 to 9, formulated as an oral pharmaceutical dosage form.

[0026]

[0026] Aspect 11 is the pharmaceutical composition of any of Aspects 1 to 10, wherein the oral pharmaceutical dosage form is in solid form or liquid form.

[0027]

[0027] Aspect 12 is a method comprising administering to a patient having insomnia or a symptom thereof a pharmaceutical composition, the pharmaceutical composition comprising azelastine or a pharmaceutically acceptable salt of azelastine and melatonin.

[0028]

[0028] Aspect 13 is the method of aspect 12, wherein the pharmaceutical composition is administered to the patient in oral solid or liquid form once or twice daily, or once every two, three, or four days.

[0029]

[0029] Aspect 14 is the method of Aspect 12 or 13, wherein the azelastine or a pharmaceutically acceptable salt of azelastine is present in the pharmaceutical composition in an amount ranging from about 1 mg to about 10 mg.

[0030]

[0030] Aspect 15 is the method of any of Aspects 12-14, wherein the melatonin is present in the pharmaceutical composition in an amount ranging from about 2 mg to about 20 mg.

[0031]

[0031] Aspect 16 is the method of any of Aspects 12-15, wherein the melatonin is present in the pharmaceutical composition in an amount ranging from about 2 mg to about 20 mg.

[0032]

[0032] Aspect 17 is the method of any of Aspects 12-16, wherein the azelastine or a pharmaceutically acceptable salt of azelastine is present in the pharmaceutical composition in an amount ranging from about 4 mg to about 10 mg.

[0033]

[0033] Aspect 18 is the method of any of Aspects 12-17, wherein the azelastine or a pharmaceutically acceptable salt of azelastine and melatonin are present in the pharmaceutical composition in synergistically effective amounts.

[0034] Aspect 19 is the method of any of Aspects 1-18, wherein the pharmaceutical composition is administered to the patient for a period of up to 8 weeks.

[0035] Aspect 20 is the method of any of Aspects 1 to 19, wherein the pharmaceutical composition is administered to the patient for a period of at least four weeks.

[0036]

[0036] Aspect 21 is the use of a pharmaceutical composition in the preparation of a medicament for treating a patient having insomnia or one or more symptoms thereof, wherein the pharmaceutical composition comprises a composition of any of claims 1 to 11 and / or the use comprises a method or method step of any of claims 12 to 20.

[0037]

[0037] Aspect 22 is a pharmaceutical composition for use in treating insomnia or one or more symptoms thereof, wherein the pharmaceutical composition comprises a composition of any of claims 1 to 11 and / or the use comprises a method or method steps of any of claims 12 to 20. DETAILED DESCRIPTION OF THE INVENTION

[0038] Detailed Description of the Invention

[0038] Through clinical practice, the inventors of the present invention have found that an oral dosage form of a pharmaceutical composition comprising an active agent, a salt form of azelastine, and melatonin is suitable for treating patients suffering from insomnia and / or its symptoms, such as difficulty falling asleep, waking up at night, waking up too early, daytime fatigue / sleepyness, etc.

[0039]

[0039] This application is related to the subject matter of International Applications Nos. PCT / US19 / 27293, PCT / US19 / 29885, PCT / US19 / 33359, PCT / US20 / 34735, PCT / US20 / 39916, PCT / US20 / 59846, and PCT / US21 / 44654, each of which is incorporated herein by reference in its entirety.

[0040]

[0040] The detailed description set forth below is intended to be a description of the example and is not intended to represent the only manner in which the example may be constructed or utilized. The description sets forth the functions of the example and the sequence of steps for constructing and operating the example. However, the same or equivalent functions and sequences may be accomplished by different examples.

[0041]

[0041] Definition

[0042] As used herein, the following words and phrases are generally intended to have the meanings set forth below, except to the extent that the context in which they are used indicates otherwise.

[0042]

[0043] As used herein, the term "melatonin" refers to N-acetyl-5-methoxytryptamine.

[0043]

[0044] As used herein, the term "azelastine" refers to azelastine free base or 4-(p-chlorobenzyl)-2-(hexahydro-1-methyl-1H-azepin-4-yl)-1-(2H)-phthalazinone. In certain embodiments, azelastine also includes any pharmaceutically acceptable salt, such as a hydrochloride or HCl salt. Preferably, in any embodiment of the invention as described herein, azelastine is in the form of its hydrochloride salt, as azelastine hydrochloride or azelastine HCl. More preferably, in any embodiment of the invention as described herein, references to amounts and dosage ranges of azelastine in a solid oral dosage form are to amounts and dosage ranges of azelastine hydrochloride.

[0044]

[0045] As used herein, "treat" or "treatment" means a complete or incomplete cure, or that the symptoms of the underlying or related disease are at least alleviated and / or delayed, and / or that one or more of the underlying cellular, physiological, or biochemical causes or mechanisms that cause the symptoms are alleviated, delayed, and / or eliminated. It should be understood that alleviated or delayed, as used in this context, refers to a comparison with the state of the untreated disease, including not only the physiological state of the untreated disease, but also the molecular state of the untreated disease.

[0045]

[0046] The term "effective amount," as defined below, refers to an amount sufficient to affect treatment when administered to a mammal in need of such treatment. The therapeutically effective amount varies depending on the patient to be treated, the patient's weight and age, the severity of the disease state, the method of administration, etc., and can be easily determined by one skilled in the art. The pharmaceutical composition can be administered orally in a single dose or multiple doses. Administration can be by any one or more of capsules, tablets, gels, sprays, drops, solutions, suspensions, syrups, etc.

[0046]

[0047] As used herein in connection with quantitative measurements, the term "about" means the indicated amount ±10%. For example, within a ±10% range, "about 2 mg" can mean 1.8 to 2.2 milligrams.

[0047]

[0048] Pharmaceutical compositions can be formulated for pharmaceutical use using methods known in the art, such as Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems Tenth (by Loyd Allen, 2013) and Handbook of Pharmaceutical Manufacturing Formulations (Volumes 1-6, by Sarfaraz K. Niazi). Thus, incorporation of active compounds and controlled-release or sustained-release matrices can be achieved.

[0048]

[0049] Either liquid or solid unit dosage forms can be easily prepared for oral administration, for example, by mixing with any one or more conventional ingredients, such as dibasic calcium phosphate, magnesium aluminum silicate, magnesium stearate, calcium sulfate, starch, talc, lactose, acacia, methylcellulose, and functionally similar materials as pharmaceutical excipients or carriers. A sustained-release formulation can optionally be used. For elderly or inconsistent subjects, a sustained-release formulation may even be preferred. Capsules can be formulated by mixing the pharmaceutical composition with an inert pharmaceutical diluent and inserting the mixture into a hard gelatin capsule of appropriate size. If soft capsules are desired, they can be encapsulated by forming a slurry of the pharmaceutical composition with an acceptable vegetable oil, light oil, or other inert oil into a gelatin capsule.

[0049]

[0050] Suspensions, syrups, and elixirs can be used for oral administration or in liquid unit dosage forms. Fluid preparations containing oils can be used in an oil-soluble form. Vegetable oils, such as corn oil, peanut oil, or flower essential oils, can be used with flavorings, sweeteners, and optional preservatives to form acceptable fluid preparations. Surfactants can be added to water to form liquid unit dose syrups. Hydroalcoholic pharmaceutical preparations can use acceptable sweeteners, such as sugar, saccharin, or other non-nutritive sweeteners, and / or biological sweeteners, and / or flavoring agents, for example, in the form of elixirs.

[0050]

[0051] The solid oral dosage formulation of the present disclosure refers to the form of a tablet, caplet, bilayer tablet, film-coated tablet, pill, or capsule. Tablets according to the present disclosure can be prepared by any mixing and tableting technique well known in the pharmaceutical formulation industry. In some examples, the dosage formulation is produced by directly compressing the prepared sustained-release portion and immediate-release portion, respectively, using punches and dies attached to a rotary tablet press, followed by ejection after compression, or by compaction or granulation.

[0051]

[0052] The pharmaceutical compositions provided according to the present disclosure can typically be administered orally. Thus, the present disclosure provides pharmaceutical compositions comprising a solid dispersion comprising azelastine and melatonin as described herein and one or more pharmaceutically acceptable excipients or carriers, including, but not limited to, inert solid diluents and fillers, diluents including sterile aqueous solutions and various organic solvents, penetration enhancers, solubilizers, disintegrants, lubricants, binders, glidants, adjuvants, and combinations thereof. Such compositions are prepared by methods well known in the pharmaceutical arts (see, for example, Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems, Tenth (by Loyd Allen, 2013) and Handbook of Pharmaceutical Manufacturing Formulations (Volumes 1-6, by Sarfaraz K. Niazi)).

[0052]

[0053] The pharmaceutical composition may further comprise pharmaceutical excipients, such as diluents, binders, fillers, glidants, disintegrants, lubricants, solubilizers, and combinations thereof. Some examples of suitable excipients are described herein. When the pharmaceutical composition is formulated into a tablet, the tablet may be uncoated or may be coated by known techniques, including microencapsulation, to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained action over an extended period of time. For example, a time-delay material, such as glyceryl monostearate or glyceryl distearate, alone or in combination with a wax, may be used. In embodiments, the pharmaceutical composition is formulated as a tablet, caplet, pill, or capsule for gastrointestinal absorption, e.g., formulated so that disintegration can be delayed until the pharmaceutical composition enters the patient's gastrointestinal tract. In embodiments, delayed disintegration is achieved using a coating.

[0053]

[0054] In embodiments, the pharmaceutical composition may contain synergistically effective amounts of azelastine and melatonin, for example, (a) about 1 mg to 10 mg of azelastine HCl (or other salt) and (b) about 2 mg to 20 mg of melatonin, or (a) about 2 mg to 6 mg of azelastine HCl (or other salt) and (b) about 4 mg to 10 mg of melatonin, or (a) about 2 mg to 4 mg of azelastine HCl (or other salt) and (b) about 4 mg to 6 mg of melatonin, or any amount of azelastine or melatonin within these ranges. In embodiments, melatonin is present in the pharmaceutical composition in a synergistically effective amount relative to the amount of azelastine or a pharmaceutically acceptable salt of azelastine, and may include pharmaceutical compositions containing (a) up to about 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, or 10 mg (inclusive), or any amount within any of these ranges, of azelastine, e.g., azelastine HCl, and (b) up to about 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, or 20 mg (inclusive), or any amount within any of these ranges, of melatonin. For example, a composition containing synergistically effective amounts of melatonin and azelastine may include (a) about 4 mg of azelastine HCl and (b) about 6 mg of melatonin. Further, for example, a composition of the present invention can include azelastine or a pharmaceutically acceptable salt of azelastine present in an amount ranging from about 2 mg to about 10 mg and a synergistically effective amount of melatonin in an amount ranging from about 2 mg to about 20 mg. In embodiments, a synergistically effective amount can be an amount such that the amount of azelastine HCl (or other salt) present in the composition is equal to, greater than, or less than the amount of melatonin present in the composition. In embodiments, a synergistically effective amount is an amount such that azelastine is present in the pharmaceutical composition in an amount of at least 1 mg and melatonin is present in an amount of at least 0.1 mg.In embodiments, a synergistically effective amount can be an amount such that the amount of azelastine HCl (and / or other salt) present in the composition is the same as, or 2 times, or 3 times, or 4 times, 5 times, 6 times, 7 times, 8 times, 9 times, 10 times, 15 times, 20 times, 25 times, 30 times, 35 times, 10 times, 15 times, or 50 times the amount of melatonin present in the composition, or vice versa. Any one or more of the compositions of the invention can be used in conjunction with any one or more of the methods of the invention disclosed herein or other methods using compositions.

[0054]

[0055] It will be understood that the amount of a pharmaceutical composition comprising azelastine HCl and melatonin actually administered will normally be determined by a physician in light of the relevant circumstances, including the condition to be treated, the selected route of administration, the actual compound administered and its relative activity, the age, weight, and response of the individual patient, and the severity of the patient's symptoms.

[0055]

[0056] Pharmaceutical compositions, pharmaceutical dosage forms, and tablets containing azelastine, such as azelastine HCl, as described herein, and melatonin are administered to a patient suffering from insomnia by oral administration once daily, twice daily, up to four times daily, once every other day, once weekly, twice weekly, three times weekly, four times weekly, or five times weekly, or any combination thereof.

[0056]

[0057] In embodiments, a patient is administered a pharmaceutical composition comprising a therapeutically effective daily dose of azelastine (eg, azelastine HCl) in the range of about 1 mg to about 10 mg and melatonin in an amount ranging from about 2 mg to about 10 mg.

[0057]

[0058] In embodiments, pharmaceutical dosage forms and tablets of pharmaceutical compositions comprising azelastine, such as azelastine HCl, and melatonin as described herein are effective in relieving, alleviating, mitigating, and / or treating insomnia for about 1 to 8 weeks, e.g., 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, or 8 weeks, or any range therebetween.

[0058]

[0059] The following examples are illustrative and should not be construed as limiting the scope of the claimed subject matter.

[0059]

[0060] Example 1

[0061] A 61-year-old female patient had suffered from chronic insomnia for over 18 months, with symptoms of difficulty falling asleep and waking up two or three times during sleep. She tried an over-the-counter antihistamine hypnotic for three days, followed by melatonin (10 mg daily) for three days, but these treatments were ineffective. She was treated with the antidepressant trazodone and later with doxepin, but her insomnia persisted. She was initially administered eszopiclone, which relieved her insomnia. However, she was unable to tolerate the headache side effect of eszopiclone, and her insomnia recurred when she stopped taking eszopiclone. She was then administered a synergistically effective combination of azelastine (4 mg daily) and melatonin (6 mg daily). In this treatment, the combination of azelastine and melatonin exerted a synergistic effect, resolving her insomnia after the third day of treatment, whereas melatonin alone had no effect on her insomnia. This treatment regimen was continued for 8 weeks, during which she experienced no side effects other than a mild metallic taste, and her insomnia did not recur.

[0060]

[0062] Example 2

[0063] A 52-year-old female patient had suffered from chronic insomnia for over six months. She had difficulty falling asleep and slept less than four hours per night. She initially tried melatonin (10 mg daily) without success. Eszopiclone was prescribed, which increased her sleep time to approximately six hours. However, two weeks after starting treatment, she experienced daytime dizziness and nausea, forcing her to discontinue eszopiclone. One week after stopping eszopiclone, her insomnia returned. She was given a synergistically effective combination of azelastine (4 mg) and melatonin (6 mg) daily. This treatment demonstrated a synergistic effect of the azelastine-melatonin combination, allowing her to sleep six to seven hours per night; melatonin alone was unsuccessful. The patient reported only a bitter taste and was very satisfied with the treatment.

[0061]

[0064] Example 3

[0065] A 47-year-old male patient had suffered from chronic insomnia for over four months. He had difficulty falling asleep and was only able to sleep 5–6 hours per night, which often caused daytime sleepiness and prevented him from performing his normal duties at work. Over a period of over three months, he had taken diazepam for seven days, zolpidem for seven days, and eszopiclone for two weeks to treat his insomnia. However, he was unable to tolerate these treatments due to the side effects of drowsiness, dizziness, and headache, which prevented him from performing his normal duties at work. He was administered a combination of azelastine (6 mg daily) and melatonin (6 mg daily). Three days after treatment, he was able to sleep 6–7 hours per day and did not experience daytime sleepiness, dizziness, or headache. He received treatment for six weeks without any intolerable side effects.

[0062]

[0066] References

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[0089] Loyd Allen, Ansel’s Pharmaceutical Dosage Forms and Drug Delivery Systems, Tenth (2013).

[0090] Sarfaraz K. Niazi, Handbook of Pharmaceutical Manufacturing Formulations Volumes 1-6.

[0063]

[0091] The present invention has been described with reference to specific embodiments having various features. In light of the foregoing disclosure, it will be apparent to those skilled in the art that various modifications and variations can be made in the practice of the present invention without departing from the scope or spirit of the invention. Those skilled in the art will recognize that the disclosed features may be used alone, in any combination, or omitted, depending on the requirements and specifications of a given application or design. When an embodiment is referred to as "comprising" particular features, it is understood that the embodiment may alternatively "consist of" or "consist essentially of" any one or more features. Any of the methods disclosed herein can be used with any of the compositions disclosed herein or with any other compositions. Similarly, any of the disclosed compositions can be used with any of the methods disclosed herein or with any other methods. Other embodiments of the present invention will be apparent to those skilled in the art from consideration of the specification and practice of the present invention.

[0064]

[0092] It should be noted that, in particular, when a range of values is provided herein, each value between the upper and lower limits of that range is also specifically disclosed. The upper and lower limits of these smaller ranges may independently be included or excluded within the range. The singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. It is intended that the specification and examples be considered exemplary in nature, and that variations that do not depart from the essence of the invention are within the scope of the invention. Furthermore, all references cited in this disclosure are individually incorporated herein by reference in their entirety, and are therefore intended to provide an efficient manner of supplementing the effective disclosure of the present invention as well as providing a background that will inform those skilled in the art.

Claims

1. azelastine or a pharmaceutically acceptable salt of azelastine; Melatonin; and one or more pharmaceutically acceptable excipients.

2. 10. The pharmaceutical composition of claim 1, wherein the azelastine or a pharmaceutically acceptable salt of the azelastine is present in the pharmaceutical composition in an amount ranging from about 1 mg to about 10 mg.

3. 10. The pharmaceutical composition of claim 1, wherein the melatonin is present in the pharmaceutical composition in an amount ranging from about 2 mg to about 20 mg.

4. 3. The pharmaceutical composition of claim 2, wherein the melatonin is present in the pharmaceutical composition in an amount ranging from about 2 mg to about 20 mg.

5. the azelastine or a pharmaceutically acceptable salt of the azelastine is present in the pharmaceutical composition in an amount ranging from about 1 mg to about 10 mg; and 10. The pharmaceutical composition of claim 1, wherein the melatonin is present in the pharmaceutical composition in an amount ranging from about 5 mg to about 20 mg.

6. 2. The pharmaceutical composition of claim 1, wherein the pharmaceutically acceptable salt of azelastine is azelastine hydrochloride.

7. 3. The pharmaceutical composition of claim 2, wherein the pharmaceutically acceptable salt of azelastine is azelastine hydrochloride.

8. 2. The pharmaceutical composition of claim 1, wherein the pharmaceutically acceptable salt of azelastine is azelastine hydrochloride, and wherein the azelastine hydrochloride is present in the pharmaceutical composition in an amount of up to about 10 mg.

9. 7. The pharmaceutical composition of claim 6, wherein the azelastine hydrochloride is present in an amount ranging from about 1 mg to about 10 mg.

10. 10. The pharmaceutical composition of claim 1, formulated as an oral pharmaceutical dosage form.

11. 11. The pharmaceutical composition of claim 10, wherein the oral pharmaceutical dosage form is in solid or liquid form.

12. 1. A method comprising administering a pharmaceutical composition to a patient suffering from insomnia or a symptom thereof, The method, wherein the pharmaceutical composition comprises azelastine or a pharmaceutically acceptable salt of azelastine and melatonin.

13. 13. The method of claim 12, wherein the pharmaceutical composition is administered to the patient in oral solid or liquid form once or twice daily or once every two, three, or four days.

14. 13. The method of claim 12, wherein the azelastine or a pharmaceutically acceptable salt of the azelastine is present in the pharmaceutical composition in an amount ranging from about 1 mg to about 10 mg.

15. 15. The method of claim 14, wherein the melatonin is present in the pharmaceutical composition in an amount ranging from about 2 mg to about 20 mg.

16. 13. The method of claim 12, wherein the melatonin is present in the pharmaceutical composition in an amount ranging from about 2 mg to about 20 mg.

17. 17. The method of claim 16, wherein the azelastine or a pharmaceutically acceptable salt of the azelastine is present in the pharmaceutical composition in an amount ranging from about 4 mg to about 10 mg.

18. 13. The method of claim 12, wherein the azelastine or a pharmaceutically acceptable salt of the azelastine and the melatonin are present in the pharmaceutical composition in synergistically effective amounts.

19. 13. The method of claim 12, wherein the pharmaceutical composition is administered to the patient for a period of up to 8 weeks.

20. 13. The method of claim 12, wherein the pharmaceutical composition is administered to the patient for a period of at least four weeks.

21. 21. Use of a pharmaceutical composition in the preparation of a medicament for treating a patient with insomnia or one or more symptoms thereof, said pharmaceutical composition comprising a composition according to any one of claims 1 to 11 and / or said use comprising any method or method step according to any one of claims 12 to 20.

22. 21. A pharmaceutical composition for use in the treatment of insomnia or one or more symptoms thereof, comprising a composition according to any one of claims 1 to 11, and / or said use comprising any method or method step according to any one of claims 12 to 20.

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