WO2023158424A1

WO2023158424A1 - Novel pharmaceutical compositions and methods for treatment of insomnia

Info

Publication number: WO2023158424A1
Application number: PCT/US2022/016545
Authority: WO
Inventors: Jianmin Wang; Fengyuan Jia
Original assignee: LA PharmaTech Inc
Current assignee: LA PharmaTech Inc
Priority date: 2022-02-16
Filing date: 2022-02-16
Publication date: 2023-08-24
Anticipated expiration: 2024-08-16
Also published as: EP4478887A1; CN119012916A; JP2025526852A

Abstract

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

Description

NOVEL PHARMACEUTICAL COMPOSITIONS AND METHODS FOR TREATMENT OF INSOMNIA

CROSS-REFERENCE TO RELATED APPLICATIONS

[001] The present application is a Continuation in Part application of U.S. Patent

Application No. 16/884,459 filed on May 27, 2020, which application is a Continuation in Part application of U.S. Patent Application No. 16/382,885 filed on April 12, 2019, the disclosure of which is hereby incorporated by reference herein in its entirety.

FIELD OF THE INVENTION

[002] The invention relates to the field of practical medicine, namely, to the use of pharmaceutical compositions for treating, preventing, and/or alleviating manifestations of insomnia or symptoms thereof.

BACKGROUND OF THE INVENTION

[003] Insomnia is often diagnosed through the presence of polysomnographic evidence of disturbed sleep, such as a long sleep latency, frequent nocturnal awakenings, or prolonged periods of wakefulness during the sleep period or even frequent transient arousals. Various population-based studies show that approximately 30-40% of a variety of adult samples drawn from different countries report one or more of the symptoms of insomnia: difficulty initiating sleep, difficulty maintaining sleep, waking up too early, and in some cases, nonrestorative or poor quality of sleep. Particularly, insomnia has a very negative impact on vulnerable patient groups, including active military personnel and veterans, patients with coexisting psychiatric and medical disorders, those in life transitions such as menopause, and elderly persons. Due to its chronicity, insomnia is associated with substantial impairments in an individual’s quality of life such as a high rate of psychiatric comorbidities. Insomnia even poses a greater health risk due to the increased occurrence of daytime accidents.

[004] Treatments for insomnia include benzodiazepine receptor agonists, such as triazolam, estazolam, zolpidem, zaleplon, eszopiclone, etc.; melatonin agonists, such as ramelteon; tricyclic antidepressants, such as doxepin; orexin receptor antagonists, such as suvorexant. These drugs do carry risks of tolerance, dependence, memory impairment, depression, headache, dizziness, somnolence, and so on. [005] Clinically, new treatments for insomnia are urgently needed that have significantly fewer side effects and can be provided to a wider range of patients experiencing insomnia who have additional medical or mental conditions.

[006] Inflammation can be defined as one of the immune responses for protecting living organisms from damage. The immune system can be triggered by various factors such as pathogens, damage to cells, and stress that may induce acute or chronic inflammatory responses in organs including the brain, potentially leading to tissue damage or disease. The latest advancements in neurobiological research provide increasing evidence that inflammatory and neurodegenerative pathways play a relevant role in insomnia. Preclinical and clinical studies on insomnia highlighted an increased production of inflammatory markers, such as interleukin (IL)-l, IL-6, tumor necrosis factor (TNF)-a and interferon (INF)- a and y, and overactivated inflammatory signaling pathways including nuclear factor kappa B (NF-KB). More recent studies have shown that blocking the biological actions of the cytokines IL-1 and TNF resulted in a reduction of physiological NREM sleep amount or NREM sleep rebound after sleep deprivation. On the other hand, increasing the availability of those cytokines promoted NREM sleep amount and intensity and suppressed REM sleep amount. These findings established both cytokines, IL-1 and TNF, as substances 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 regulatory properties. The anti-inflammatory cytokines IL-4, IL- 10, and IL- 13 have been reported to attenuate NREM sleep amount in rabbits, while the pro-inflammatory acting cytokines IFN-y, IL-2, IL-6, IL-15, and IL-18 have NREM sleep-promoting actions in animal models.

[007] Azelastine is classified pharmacologically as a second-generation antihistamine and is a relatively selective, non-sedative, competitive antagonist at Hi receptors for treatment of allergic rhinitis and asthma. But, more uniquely, its inhibition of inflammatory mediators and its mast cell stabilizing effects, in addition to its antihistaminic activity, place it among the new generation of dual-acting anti-inflammatory drugs. Its ability to modify several other mediators of inflammation, such as IL-1, IL-6, TNF-a and INF-a, and to reduce overactivation of the NF-KB inflammatory signaling pathway might contribute to its mechanism of action for potential treatment of 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 inhibition of mast cell degranulation may also decrease the release of other inflammatory mediators, including leukotrienes and interleukin- ip, among others. Preclinical studies show that azelastine also directly antagonizes other mediators of inflammation, such as tumor necrosis factor-a, leukotrienes, endothelin-1, and platelet-activating factor.

[008] Melatonin is best known for its mediation of circannual variations in metabolism and reproductive competence in photosensitive species, its ability to influence circadian processes that are ubiquitous in organisms and in cells, and its sleep promoting activity. Each of these functions relies on the circadian message provided by the pineal-derived blood and cerebrospinal fluid melatonin rhythms. Melatonin is also highly effective as an antioxidant at the mitochondrial level and also an anti-inflammatory agent. The doses for membrane receptor-mediated circadian rhythm regulation are usually lower than those used for defeating free radicals, an action that is membrane receptor independent. High doses of melatonin are believed to be effective in alleviating overproduction of inflammatory markers, such as interleukin (IL)-l, IL-6, tumor necrosis factor (TNF)-a.

[009] Therefore, a unique combination of azelastine (antihistamine agent with antiinflammatory activities) with melatonin would potentially be, in terms of working through multimechanisms of actions, effective in the treatment of insomnia.

SUMMARY OF THE INVENTION

[0010] The present invention includes a pharmaceutical composition that comprises two active pharmaceutical ingredients. This pharmaceutical composition comprises the first active ingredient that is azelastine or a pharmaceutically acceptable salt of azelastine and the second active ingredient that is melatonin.

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

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

[0013] The present invention also includes an oral pharmaceutical dosage form of the pharmaceutical composition that is a solid, liquid, gel, or solution form.

[0014] The present invention further includes use of the composition, such as by oral dosage, through administration to patients with insomnia. [0015] In some embodiments of this invention, an oral pharmaceutical dosage form of the pharmaceutical composition containing azelastine hydrochloride (and/or other salt thereof) 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 patients with insomnia.

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

[0018] Aspect 3 is the pharmaceutical composition of Aspect 1 or 2 wherein the melatonin is present in the pharmaceutical composition in an amount in the range of about 2 mg to about

20 mg.

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

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

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

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

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

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

[0025] Aspect 10 is the pharmaceutical composition of any of Aspects 1-9, wherein the pharmaceutical composition is formulated as an oral pharmaceutical dosage form. [0026] Aspect 11 is the pharmaceutical composition of any of Aspects 1-10, wherein the oral pharmaceutical dosage form is a solid form or a liquid form.

[0027] Aspect 12 is a method comprising: administering a pharmaceutical composition to a patient having insomnia or symptoms thereof; wherein the pharmaceutical composition comprises azelastine or a pharmaceutically acceptable salt of azelastine and melatonin.

[0028] Aspect 13 is the method of Aspect 12, wherein the pharmaceutical composition is administered once or twice a day, or once every 2 or 3 or 4 days to the patient in an oral solid or liquid form.

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

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

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

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

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

[0034] Aspect 19 is the method 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 1-19, wherein the pharmaceutical composition is administered to the patient for a period of at least 4 weeks.

[0036] Aspect 21 is use of a pharmaceutical composition in the preparation of a medicament for treating a patient having insomnia or one or more symptom thereof, wherein the pharmaceutical composition comprises the composition of any of claims 1-11, and/or the use involves any of the methods or method steps of claims 12-20. [0037] Aspect 22 is a pharmaceutical composition for use in treating insomnia or one or more symptom thereof, wherein the pharmaceutical comprises the composition of any of claims 1-11 and/or the use involves any of the methods or method steps of claims 12-20.

DETAILED DESCRIPTION OF THE INVENTION

[0038] Through clinical practice, the inventors of the present invention found that a pharmaceutical composition with oral dosage forms comprising the active agents, a salt form of azelastine and melatonin, is suitable for treating patients suffering from insomnia and/or symptoms thereof, such as difficulty falling asleep, waking up during the night, waking up too early, daytime tiredness/sleepiness, etc.

[0039] The present application is related by subject matter to International Patent Application Nos. PCT/US 19/27293, PCT/US 19/29885, PCT/US19/33359, PCT/US20/34735, PCT/US20/39916, PCT/US20/59846, and PCT/US21/44654, each of which are hereby incorporated by reference herein in their entireties.

[0040] The detailed description provided below is intended as a description of the present examples and is not intended to represent the only forms in which the present 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] Definitions

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

[0043] As used herein, the term “melatonin” refers to N-acetyl-5-methoxy tryptamine.

[0044] As used herein, the term “azelastine” refers to azelastine free base, or 4-(p- Chlorobenzyl)-2-(hexahydro- 1 -methyl- lH-azepin-4-yl)- 1 -(2H)-phthalazinone. In certain embodiments, azelastine also includes any pharmaceutically acceptable salt, such as the hydrochloride or HC1 salt. Preferably, in any embodiments of the invention as described herein, azelastine is in the form of its hydrochloride salt, as azelastine hydrochloride or azelastine HC1. More preferably, in any embodiment of the invention as described herein, reference to the amounts and dosage ranges of azelastine in the solid oral dosage forms are to the amounts and dosage ranges of azelastine hydrochloride. [0045] As used herein, “treating” or “treatment” means complete cure or incomplete cure, or it means that the symptoms of the underlying disease or associated conditions are at least reduced and/or delayed, and/or that one or more of the underlying cellular, physiological, or biochemical causes or mechanisms causing the symptoms are reduced, delayed and/or eliminated. It is understood that reduced or delayed, as used in this context, means relative to the state of the untreated disease, including the molecular state of the untreated disease, not just the physiological state of the untreated disease.

[0046] The term “effective amount” refers to an amount that is sufficient to affect treatment, as defined below, when administered to a mammal in need of such treatment. The therapeutically effective amount will vary depending upon the patient being treated, the weight and age of the patient, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art. The pharmaceutical compositions may be administered in either single or multiple doses by oral administration. Administration may be by way of any one or more of capsule, tablet, gel, spray, drops, solution, suspensions, syrups, or the like.

[0047] The term “about” used herein in the context of quantitative measurements means the indicated amount ±10%. For example, with a ±10% range, “about 2 mg” can mean 1.8-2.2 mg. [0048] The pharmaceutical compositions may be formulated for pharmaceutical use using methods known in the art, 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). Accordingly, incorporation of the active compounds and a controlled, or slow release matrix may be implemented.

[0049] Either fluid or solid unit dosage forms can be readily prepared for oral administration, for example, admixed with any one or more of conventional ingredients such as dicalcium phosphate, magnesium aluminum silicate, magnesium stearate, calcium sulfate, starch, talc, lactose, acacia, methyl cellulose and functionally similar materials as pharmaceutical excipients or carriers. A sustained release formulation may optionally be used. In older or incoherent subjects sustained release formulations may even be preferred. Capsules may be formulated by mixing the pharmaceutical composition with a pharmaceutical diluent which is inert and inserting this mixture into a hard gelatin capsule having the appropriate size. If soft capsules are desired, a slurry of the pharmaceutical composition with an acceptable vegetable, light petroleum or other inert oil can be encapsulated by forming into a gelatin capsule.

[0050] Suspensions, syrups and elixirs may be used for oral administration or fluid unit dosage forms. A fluid preparation including oil may be used for oil soluble forms. A vegetable oil such as com oil, peanut oil or a flower oil, for example, together with flavoring agents, sweeteners and any preservatives produces an acceptable fluid preparation. A surfactant may be added to water to form a syrup for fluid unit dosages. Hydro-alcoholic pharmaceutical preparations may be used having an acceptable sweetener, such as sugar, saccharin or other non-nutritive sweetener, and/or a biological sweetener and/or a flavoring agent, such as in the form of an elixir.

[0051] The solid oral dosage formulation of this disclosure means a form of tablets, caplets, bi-layer tablets, film-coated tablets, pills, capsules, or the like. Tablets in accordance with this disclosure can be prepared by any mixing and tableting techniques that are well known in the pharmaceutical formulation industry. In some examples, the dosage formulation is fabricated by direct compressing the respectively prepared sustained-release portion and the immediate-release portion by punches and dies fitted to a rotary tableting press, ejection or compression molding or granulation followed by compression.

[0052] The pharmaceutical compositions provided in accordance with the present disclosure can be typically administered orally. This disclosure therefore provides pharmaceutical compositions that comprise 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 solution and various organic solvents, permeation enhancers, solubilizers, disintegrants, lubricants, binders, glidants, adjuvants, and combinations thereof. Such compositions are prepared in a manner well known in the pharmaceutical arts (see, e.g., 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)).

[0053] The pharmaceutical compositions 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 compositions are formulated into tablets, tablets may be uncoated or may be coated by known techniques including microencapsulation to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax may be employed. In embodiments, the pharmaceutical compositions are formulated as tablets, caplets, pills, or capsules for gastrointestinal absorption, such as formulated to be capable of delaying disintegration until the pharmaceutical composition is in the gastrointestinal tract of a patient. In embodiments, delaying disintegration is achieved using a coating.

[0054] In embodiments, the pharmaceutical compositions can comprise synergistically effective amounts of azelastine and melatonin, such as a) about 1 mg to 10 mg of azelastine HC1 (or other salt thereof) and b) about 2 mg to 20 mg of melatonin or a) about 2 mg to 6 mg of azelastine HC1 (or other salt thereof) and b) about 4 mg to 10 mg of melatonin or a) about 2 mg to 4 mg of azelastine HC1 (or other salt thereof) and b) about 4 mg to 6 mg of melatonin, or any amount of azelastine or melatonin within these ranges. In embodiments, the melatonin is present in the pharmaceutical composition in a synergistically effective amount relative to the amount of azelastine or the pharmaceutically acceptable salt of azelastine and can include pharmaceutical compositions comprising a) about up to and including any of 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg,

7 mg 8 mg, 9 mg, or 10 mg azelastine, such as azelastine HC1, or any amount within any of these ranges and b) about up to and including any of between 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 melatonin, or any amount within any of these ranges. For example, the compositions comprising synergistically effective amounts of melatonin and azelastine can comprise a) about 4 mg of azelastine HC1 and b) about 6 mg of melatonin. Further, for example, compositions of the invention can comprise azelastine or a pharmaceutically acceptable salt of azelastine present in an amount in the range of about 2 mg to about 10 mg and a synergistically effective amount of melatonin in an amount in the range of about 2 mg to about 20 mg. In embodiments, the synergistically effective amounts can be such that the amount of azelastine HC1 (or other salt thereof) present in the composition can be equal to, more than, or less than the amount of melatonin present in the composition. In embodiments, the synergistically effective amounts are such that the 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, the synergistically effective amounts can be such that the amount of azelastine HC1 (and/or other salt thereof) present in the composition can be the same as, or 2 times as much, or 3 times as much, or 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 10, 15, or 50 times as much as the amount of melatonin present in the composition, or vice versa. Any one or more of the compositions of the invention can be used with any one or more the methods of the invention disclosed herein, or other methods of using the compositions.

[0055] It will be understood, that the amount of the pharmaceutical composition containing azelastine HC1 and melatonin actually administered usually will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered and its relative activity, the age, weight and response of the individual patient, the severity of the patient's symptoms, and the like.

[0056] The pharmaceutical compositions, pharmaceutical dosage forms, and tablets containing azelastine, such as azelastine HC1, and melatonin as described herein are administered to a patient suffering from insomnia, by administration (such as oral administration) once daily, twice daily, up to four times a day, once every other day, once a week, two times a week, three times a week, four times a week, or five times a week, or combinations thereof.

[0057] In embodiments, patients are administered the pharmaceutical composition(s) with a therapeutic effective daily dosage of azelastine (such as azelastine HC1) in the range of about 1 mg to about 10 mg and melatonin in an amount in the range of about 2 mg to about 10 mg.

[0058] In embodiments, the pharmaceutical dosage forms and tablets of pharmaceutical compositions containing azelastine, such as azelastine HC1, and melatonin as described herein are effective in reversing, reducing, alleviating, and/or treating insomnia in about 1-8 weeks, such as within 1, 2, 3, 4, 5, 6, 7, or 8 weeks, or any range in between.

[0059] The following Examples are illustrative and should not be interpreted to limit the scope of the claimed subject matter.

[0060] Example 1

[0061] A 61 -year-old female patient had chronic insomnia for more than 18 months with symptoms including difficulty in falling asleep and two to three awakenings during the sleep period. She tried OTC antihistamine sleeping pills for 3 days, and then melatonin (10 mg daily) for 3 days and they were ineffective in the treatment of her insomnia. She was treated with antidepressant trazodone and later with doxepin, but her insomnia still persisted. After she was provided with eszopiclone, her insomnia was eliminated after initial treatments, but she could not tolerate the side effect of headaches caused by eszopiclone and her insomnia returned after she stopped taking eszopiclone. Then she was provided with a combination of synergistically effective amounts of azelastine (4 mg daily) and melatonin (6 mg daily). With this treatment, the combination of azelastine and melatonin had a synergistic effect, and her insomnia disappeared after the 3rd day of the treatment, whereas melatonin alone was ineffective for her insomnia. This treatment regimen lasted for 8 weeks and she experienced no side effects except a mild metallic taste, and her insomnia has not returned.

[0062] Example 2

[0063] A 52-year-old female patient had chronic insomnia for more than 6 months. She had difficulty of falling asleep and slept for less than 4 hours every night. She tried melatonin (10 mg daily) as an initial treatment but had no success. She was prescribed with eszopiclone and her sleeping time increased to around 6 hours, but she experienced dizziness and nausea during the daytime after 2 weeks of treatment and she had to stop taking eszopiclone. Then after a week of taking no eszopiclone, she started to experience insomnia again. She was provided with the combination of synergistically effective amounts of azelastine (4 mg) with melatonin (6 mg), daily. With this treatment, the combination of azelastine and melatonin had a synergistic effect, and she can sleep for 6-7 hours daily, whereas with melatonin alone there was no success. With experiencing only bitter taste, this patient has been very satisfied with this treatment.

[0064] Example 3

[0065] A 47-year-old male patient had chronic insomnia for more than 4 months. He had difficulty falling asleep and slept for 5 to 6 hours every night which caused sleepiness during the daytime and very often prevented him from carrying out his regular tasks at work. Over a period of 3 months, to treat his insomnia, he took diazepam for 7 days, and then zolpidem for 7 days, and then eszopiclone for 2 weeks but he could not tolerate these treatments because of the side effects of drowsiness, dizziness and headache because those side effects prevented him from carrying out his regular task at work as his insomnia did. He was provided with the combination of azelastine (6 mg daily) with melatonin (6 mg daily). After three days of the treatment he could sleep for 6-7 hours a day and experienced no drowsiness, dizziness or headache during the day. He was on the treatment for 6 weeks with no complaints of intolerable side effects.

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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.

[0091] The present invention has been described with reference to particular embodiments having various features. In light of the disclosure provided above, 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. One skilled in the art will recognize that the disclosed features may be used singularly, in any combination, or omitted based on the requirements and specifications of a given application or design. When an embodiment refers to “comprising” certain features, it is to be understood that the embodiments can alternatively “consist of’ or “consist essentially of’ any one or more of the features. Any of the methods disclosed herein can be used with any of the compositions disclosed herein or with any other compositions. Likewise, any of the disclosed compositions can be used with any of the methods disclosed herein or with any other methods. Other embodiments of the invention will be apparent to those skilled in the art from consideration of the specification and practice of the invention.

[0092] It is noted in particular that where a range of values is provided in this specification, 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 in the range as well. 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 as exemplary in nature and that variations that do not depart from the essence of the invention fall within the scope of the invention. Further, all of the references cited in this disclosure are each individually incorporated by reference herein in their entireties and as such are intended to provide an efficient way of supplementing the enabling disclosure of this invention as well as provide background detailing the level of ordinary skill in the art.

Claims

1. A pharmaceutical composition, comprising: azelastine or a pharmaceutically acceptable salt of azelastine; melatonin; and one or more pharmaceutically acceptable excipients.

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

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

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

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

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

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

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

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

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

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

12. A method comprising: administering a pharmaceutical composition to a patient having insomnia or symptoms thereof; wherein the pharmaceutical composition comprises azelastine or a pharmaceutically acceptable salt of azelastine and melatonin.

13. The method of claim 12, wherein the pharmaceutical composition is administered once or twice a day, or once every 2 or 3 or 4 days to the patient in an oral solid or liquid form.

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

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

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

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

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

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

20. The method of claim 12, wherein the pharmaceutical composition is administered to the patient for a period of at least 4 weeks.

21. Use of a pharmaceutical composition in the preparation of a medicament for treating a patient having insomnia or one or more symptom thereof, wherein the pharmaceutical composition comprises the composition of any of claims 1-11, and/or the use involves any of the methods or method steps of claims 12-20.

22. A pharmaceutical composition for use in treating insomnia or one or more symptom thereof, wherein the pharmaceutical comprises the composition of any of claims 1-11 and/or the use involves any of the methods or method steps of claims 12-20.