Pharmaceutical compositions and methods for treating insomnia

Abstract

Disclosed is a pharmaceutical composition comprising ebastine and alprazolam. Also disclosed is a method of using a pharmaceutical composition for treating a patient suffering from insomnia.

Description

Technical Field

[0001] Field of the Invention The present invention relates to the field of clinical medicine, namely, the use of pharmaceutical compositions for treating, preventing, and / or alleviating the symptoms or signs of insomnia.

Background Art

[0002] Summary of the Invention Insomnia is often diagnosed by the presence of polysomnographic evidence of sleep disorders such as long sleep latency, frequent nocturnal awakenings, or long periods of wakefulness during sleep time, and even frequent transient awakenings. Various population-based studies have shown that about 30-40% of various adult samples from various countries report one or more of the following symptoms of insomnia: difficulty falling asleep, difficulty maintaining sleep, early morning awakening, and in some cases, poor sleep recovery or reduced quality. In particular, insomnia has a very adverse effect on patients in vulnerable positions, including active-duty military personnel and veterans, patients with co-existing mental and medical disorders, people in transitional periods of life such as menopause, and the elderly. Since insomnia is chronic, it causes considerable functional impairment in the quality of an individual's life, such as a high co-morbidity rate of mental disorders. Insomnia also poses an even greater health risk as it increases the occurrence of accidents during the day.

[0003] Treatments for insomnia include benzodiazepine receptor agonists such as triazolam, estazolam, zolpidem, zaleplon, eszopiclone, etc.; melatonin agonists such as ramelteon, etc.; tricyclic antidepressants such as doxepin, etc.; orexin receptor antagonists such as suvorexant, etc. These drugs are associated with risks such as tolerance, dependence, memory impairment, depression, headache, dizziness, and drowsiness.

[0004] Clinically, there is an urgent need for new treatments for insomnia that have significantly fewer side effects and can be provided to a wide range of patients suffering from insomnia who have another medical or mental condition.

[0005] Inflammation can be defined as one of the immune responses to defend the body from damage. The immune system can be triggered by various factors such as pathogens, cell damage, and stress, which may induce acute or chronic inflammatory reactions in organs including the brain, leading to tissue damage or diseases. Recent advances in neurobiological research have provided increasing evidence that inflammation and neurodegenerative pathways are involved 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 (INF)-α and γ, as well as overactivation of inflammatory signaling pathways including nuclear factor κB (NF-κB). More recent studies have shown that blocking the biological actions of cytokines IL-1 and TNF results in a decrease in the amount of physiological non-rapid eye movement (NREM) sleep, or NREM sleep rebound after sleep deprivation. On the other hand, enhancing the availability of these cytokines promoted the amount and intensity of NREM sleep and suppressed the amount of rapid eye movement (REM) sleep. These findings have demonstrated that both cytokines IL-1 and TNF are substances involved in the regulation of sleep homeostasis. 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. Anti-inflammatory cytokines IL-4, IL-10, and IL-13 have been reported to attenuate the amount of NREM sleep in rabbits, while pro-inflammatory cytokines IFN-γ, IL-2, IL-6, IL-15, and IL-18 have NREM sleep-promoting effects in animal models.

[0006] Ebastine is a second-generation H1 receptor antagonist, administered orally once daily, and indicated for the treatment of the symptoms of allergic rhinitis and chronic idiopathic urticaria. In addition to blocking the H1 receptor, ebastine also has other effects that contribute to its anti-allergic effect. In vitro and in vivo studies as well as clinical trials have shown the effects of ebastine on various mediators of inflammation. Ebastine significantly inhibits the anti-IgE-induced release of prostaglandin D2 (PGD2) and leukotriene C4 / D4 (LTC4 / D4). Ebastine also suppressed the release of cytokines including granulocyte macrophage colony-stimulating factor (GM-CSF), tumor necrosis factor-α, and interleukin-8. Its metabolite, carebastine, inhibits the release of PGD2.

[0007] Alprazolam is one of the most widely prescribed benzodiazepines for the treatment of general anxiety and panic disorder. The neurochemical mechanism of the anxiolytic effect of alprazolam is not fully understood, but studies have shown that benzodiazepines enhance presynaptic and postsynaptic inhibition of GABAergic synapses in the central nervous system. Also, alprazolam binds to both GABA and benzodiazepine receptors, and each receptor has recognition sites for both GABA and benzodiazepine, and GABA and related drugs enhance the specific binding of benzodiazepine. Therefore, alprazolam may exert its therapeutic anxiolytic effect through interaction with high-affinity binding sites of receptors in the brain. These benzodiazepine receptors interact with GABA receptors to enhance the synaptic inhibitory effect of GABA. The inventor has hypothesized that the effect of alprazolam, the presynaptic and postsynaptic inhibition of GABAergic synapses in the nervous system via GABA and benzodiazepine receptors, stabilizes anti-inflammatory cytokines IL-4, IL-10, and IL-13. The antidepressant effect of alprazolam is, 3Based on its effect on H-DHA binding and showing the ability to reduce the sensitivity of β-adrenergic receptors, especially when administered chronically at high doses. Studies have shown that alprazolam significantly reduces the length of the REM period and the frequency of REM burst activity, as well as increases REM latency. The inventor believes that the different effects of alprazolam and other benzodiazepines on REM latency may be clinically important.

Summary of the Invention

Problems to be Solved by the Invention

[0008] Therefore, the specific combination of ebastine and alprazolam may be effective in the treatment of insomnia in that it acts through multiple mechanisms of action.

Means for Solving the Problems

[0009] The present invention includes a pharmaceutical composition containing two active pharmaceutical ingredients. This pharmaceutical composition includes a first active ingredient which is ebastine and a second active ingredient which is alprazolam. Optionally, this composition may contain only ebastine and alprazolam as the pharmaceutically active ingredients. For example, this composition may consist only of ebastine and alprazolam as the pharmaceutically active ingredients. Pharmaceutically inactive materials such as excipients may also be present in the pharmaceutical composition.

[0010] In some embodiments of the present invention, the ebastine in the pharmaceutical composition is provided in an amount of about 5 mg to about 50 mg, and the alprazolam is provided in an amount of about 0.2 mg to about 2 mg.

[0011] The present invention also includes an oral pharmaceutical dosage form of the pharmaceutical composition which is in the form of a solid, liquid, or gel. The oral pharmaceutical dosage form may contain only ebastine and alprazolam as the pharmaceutically active ingredients. For example, the oral pharmaceutical dosage form may consist only of ebastine and alprazolam as the pharmaceutically active ingredients, and may optionally combine only ebastine and alprazolam with pharmaceutically inactive materials such as excipients, binders, etc.

[0012] The present invention further includes the use of a composition, such as an oral administration, by administration to patients with insomnia.

[0013] In some embodiments of the present invention, an oral pharmaceutical dosage form of a pharmaceutical composition containing ebastine in an amount of about 5 mg to about 50 mg and alprazolam in an amount of about 0.2 mg to about 2 mg is administered to patients with insomnia.

[0014] Embodiments include aspect 1 which is a pharmaceutical composition comprising ebastine; alprazolam; and one or more pharmaceutically acceptable excipients.

[0015] Aspect 2 is the pharmaceutical composition of aspect 1, wherein ebastine is present in the pharmaceutical composition in an amount in the range of about 5 mg to about 50 mg.

[0016] Aspect 3 is the pharmaceutical composition of aspect 1 or 2, wherein alprazolam is present in the pharmaceutical composition in an amount in the range of about 0.2 mg to about 2 mg.

[0017] Aspect 4 is the pharmaceutical composition of any one of aspects 1 to 3, wherein ebastine is present in the pharmaceutical composition in an amount in the range of about 5 mg to about 25 mg.

[0018] Aspect 5 is the pharmaceutical composition of any one of aspects 1 to 4, wherein alprazolam is present in the pharmaceutical composition in an amount in the range of about 0.4 mg to about 2.0 mg.

[0019] Aspect 6 is the pharmaceutical composition of any one of aspects 1 to 5, wherein ebastine is present in the pharmaceutical composition in an amount in the range of about 5 mg to about 50 mg; and alprazolam is present in the pharmaceutical composition in an amount in the range of about 0.2 mg to about 2 mg.

[0020] Aspect 7 is the pharmaceutical composition of any one of aspects 1 to 6, wherein ebastine is present in the pharmaceutical composition in an amount in the range of about 5 mg to about 25 mg; and alprazolam is present in the pharmaceutical composition in an amount in the range of about 0.2 mg to about 2.0 mg.

[0021] Aspect 8 is a pharmaceutical composition according to any one of Aspects 1 to 7, formulated as an oral pharmaceutical dosage form.

[0022] Aspect 9 is a pharmaceutical composition according to any one of Aspects 8, wherein the oral pharmaceutical dosage form is in solid form or liquid form or gel form.

[0023] Aspect 10 is a method comprising administering a pharmaceutical composition to a patient; wherein the pharmaceutical composition comprises an effective amount of ebastine and alprazolam; and the combined effective amount is sufficient to treat insomnia in the patient.

[0024] Aspect 11 is a method according to Aspect 10, wherein the pharmaceutical composition is administered to the patient once or twice a day, or once every two days or three days or four days, in oral solid or liquid form or gel form.

[0025] Aspect 12 is a method according to any one of Aspects 10 to 11, wherein ebastine is present in the pharmaceutical composition in an amount in the range of about 5 mg to about 50 mg.

[0026] Aspect 13 is a method according to any one of Aspects 10 to 12, wherein alprazolam is present in the pharmaceutical composition in an amount in the range of about 0.2 mg to about 2.0 mg.

[0027] Aspect 14 is a method according to any one of Aspects 10 to 13, wherein ebastine is present in the pharmaceutical composition in an amount in the range of about 5 mg to about 25 mg.

[0028] Aspect 15 is a method according to any one of Aspects 10 to 14, wherein alprazolam is present in the pharmaceutical composition in an amount in the range of about 0.2 mg to about 2.0 mg.

[0029] Aspect 16 is a method according to any one of Aspects 10 to 15, wherein ebastine is present in the pharmaceutical composition in an amount in the range of about 5 mg to about 50 mg; and alprazolam is present in the pharmaceutical composition in an amount in the range of about 0.2 mg to about 2.0 mg.

[0030] Aspect 17 is any of the methods of aspects 10 to 16, wherein ebastine is present in the pharmaceutical composition in an amount in the range of about 5 mg to about 25 mg; and alprazolam is present in the pharmaceutical composition in an amount in the range of about 0.2 mg to about 2.0 mg. BRIEF DESCRIPTION OF THE DRAWINGS

[0031]

Figure 1

Figure 2

[0032] Detailed Description of the Invention Through clinical practice, the inventors of the present invention have found that an oral dosage form pharmaceutical composition containing the active agents ebastine and alprazolam is suitable for the treatment of patients, such as humans, suffering from insomnia and / or its symptoms, for example, difficulty falling asleep, nocturnal awakening, early morning awakening, daytime fatigue / sleepiness, etc.

[0033] The detailed description provided below is intended as a description of the present examples and is not intended to represent the only form in which the present examples can be constructed or utilized. This description describes the functions of the examples and a series of steps for constructing and operating the examples. However, the same or equivalent functions and sequences may be realized by different examples.

[0034] Definitions As used herein, the following words and phrases are generally intended to have the meanings described below, unless the context in which they are used indicates otherwise.

[0035] As used herein, the term "alprazolam" refers to 8-chloro-1-methyl-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine as shown in FIG. 1.

[0036] As used herein, the term "ebastine" refers to 4-diphenylmethoxy-1-[3-(4-tert-butylbenzoyl)-propyl]piperidine as shown in Figure 2.

[0037] As used herein, "treating" or "treatment" means complete or incomplete cure, or at least reduction and / or delay of the symptoms of the underlying disease or related condition, and / or reduction, delay, and / or elimination of one or more of the cellular, physiological, or biochemical causes or mechanisms underlying the symptoms. As used in this context, reduction or delay is understood to mean in relation to the untreated disease state, including both the physiological state and the molecular state of the untreated disease.

[0038] The term "effective amount" refers to an amount sufficient to affect treatment when administered to a mammal in need of treatment, as defined below. The therapeutically effective amount will vary depending on the patient being treated, the patient's weight and age, the severity of the disease state, the method of administration, etc., but can be readily determined by one of ordinary skill in the art. The pharmaceutical composition can be administered either as a single dose or in multiple doses by oral administration. Administration can be by means of any one or more of capsules, tablets, gels, sprays, drops, solutions, suspensions, syrups, etc.

[0039] As used herein in the context of quantitative measurements, the term "about" means ±10% of the indicated amount. For example, in the range of ±10%, "about 2 mg" can mean 1.8 - 2.2 mg.

[0040] The pharmaceutical composition can be formulated for pharmaceutical use using methods known in the art, such as Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems, 10th Edition (by Loyd Allen, 2013) and Handbook of Pharmaceutical Manufacturing Formulations (Volumes 1 - 6, by Sarfaraz K. Niazi). Thus, incorporation of the active compound and a controlled or sustained release matrix can be carried out.

[0041] Either a fluid or solid unit dosage form can be readily prepared for oral administration by mixing any one or more of conventional ingredients, such as dicalcium phosphate, magnesium aluminum silicate, magnesium stearate, calcium sulfate, starch, talc, lactose, acacia, methylcellulose, and functionally similar materials, as pharmaceutical excipients or carriers. Sustained release formulations can be optionally used. In elderly or inconsistent subjects, sustained release formulations may be preferred. Capsules can be formulated by mixing the pharmaceutical composition with an inert pharmaceutical diluent and inserting this mixture into hard gelatin capsules of appropriate size. If soft capsules are desired, the pharmaceutical composition slurry containing an acceptable vegetable oil, light mineral oil, or other inert oil can be encapsulated by forming it into gelatin capsules.

[0042] Suspending agents, syrups, and elixirs can be used for oral administration or in fluid unit dosage forms. For oil-soluble forms, fluid formulations containing oil can be used. Vegetable oils such as corn oil, peanut oil, or flower essential oils can be used together with, for example, flavoring agents, sweetening agents, and any preservatives to obtain acceptable fluid formulations. Surfactants can be added to water to form fluid unit doses of syrups. Hydroalcoholic pharmaceutical preparations having acceptable sweetening agents such as sugar, saccharin, or other non-nutritive sweeteners, and / or biological sweeteners, and / or flavoring agents can be used in the form of elixirs, etc.

[0043] The solid oral dosage forms of the present disclosure mean forms such as tablets, caplets, bilayer tablets, film-coated tablets, pills, capsules, etc. Tablets according to the present disclosure can be prepared by any mixing and tableting techniques well known in the pharmaceutical industry. In some examples, the dosage forms are prepared by directly compressing the prepared sustained-release portion and immediate-release portion with punches and dies attached to a rotary tablet molding machine, injection or compression molding, or compression following granulation.

[0044] The pharmaceutical compositions provided according to the present disclosure can usually be administered orally. Accordingly, the present disclosure provides a pharmaceutical composition comprising a solid dispersion containing ebastine and alprazolam described herein, and one or more pharmaceutically acceptable excipients or carriers including, but not limited to, inert solid diluents and fillers, diluents such as sterile aqueous solutions and various organic solvents, penetration enhancers, solubilizing agents, disintegrants, lubricants, binders, flow promoters, adjuvants, and combinations thereof. Such compositions are prepared by methods well known in the pharmaceutical field (see, for example, Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems, 10th Edition (by Loyd Allen, 2013) and Handbook of Pharmaceutical Manufacturing Formulations (Volumes 1 - 6, by Sarfaraz K. Niazi)).

[0045] The pharmaceutical composition may further comprise pharmaceutical excipients such as diluents, binders, fillers, glidants, disintegrants, lubricants, solubilizing agents, and combinations thereof. Some examples of suitable excipients are described herein. When formulating the pharmaceutical composition into tablets, the tablets may or may not be coated, or may be coated by known techniques including microencapsulation to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained action over a long period. For example, a time-delay material such as glyceryl monostearate or glyceryl distearate can be used alone or together with wax. In embodiments, the pharmaceutical composition is formulated as tablets, caplets, pills, or capsules for gastrointestinal absorption, for example, formulated such that the pharmaceutical composition can delay disintegration until it enters the patient's gastrointestinal tract. In embodiments, the delay in disintegration is achieved using a coating.

[0046] In certain embodiments, the pharmaceutical composition comprises a synergistically effective amount of ebastine and alprazolam, for example, a) from about 5 mg to 10 mg of ebastine and b) from about 0.2 mg to 0.4 mg of alprazolam, or a) from about 10 mg to 20 mg of ebastine and b) from about 0.4 mg to 1.2 mg of alprazolam, or a) from about 5 mg to 50 mg of ebastine and b) from about 0.4 mg to 2.0 mg of alprazolam, or any amount of ebastine or alprazolam within these ranges may be included. In certain embodiments, alprazolam is present in the pharmaceutical composition in a synergistically effective amount relative to the amount of ebastine, and the pharmaceutical composition may comprise a) from about 5 mg, 10 mg, 20 mg, 30 mg, 50 mg or less, or any amount within these ranges of ebastine, and b) from about 0.4 mg, 0.8 mg, 1.2 mg, 1.6 mg, 2 mg or less, or any amount within these ranges of alprazolam. For example, a composition comprising a synergistically effective amount of ebastine and alprazolam may comprise a) about 5 mg of ebastine and b) about 0.4 mg of alprazolam. Further, for example, the compositions of the present invention may comprise ebastine present in an amount in the range of about 5 mg to about 50 mg, and a synergistically effective amount of alprazolam in an amount in the range of about 0.4 mg to about 2 mg. In certain embodiments, the synergistically effective amount may be such that the amount of ebastine present in the composition may be equal to, more than, or less than the amount of alprazolam present in the composition. In certain embodiments, the synergistically effective amount is such that ebastine is present in the pharmaceutical composition in an amount of at least 5 mg and alprazolam is present in an amount of at least 0.4 mg. In certain embodiments, the synergistically effective amount may be such that the amount of ebastine present in the composition is the same as, or 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 10, 15, or 50 times the amount of alprazolam present in the composition, or vice versa. Any one or more of the compositions of the present invention can be used with any one or more of the methods of the present invention disclosed herein, or with other methods of using the compositions.

[0047] The amount of the pharmaceutical composition containing ebastine and alprazolam actually administered will usually be determined by a physician considering relevant circumstances including the condition being treated, the selected route of administration, the actual compounds administered and their relative activities, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.

[0048] The pharmaceutical compositions, pharmaceutical dosage forms, and tablets containing ebastine and alprazolam described herein are administered to patients suffering from insomnia once a day, twice a day, up to four times a day, once every other day, once a week, twice a week, three times a week, four times a week, or five times a week, or a combination thereof (such as oral administration).

[0049] In various embodiments, the patient is administered a pharmaceutical composition comprising from about 5 mg to about 50 mg of ebastine and from about 0.2 mg to about 2 mg of alprazolam in a therapeutically effective daily dose.

[0050] In various embodiments, as described herein, the pharmaceutical dosage forms and tablets of pharmaceutical compositions containing ebastine, for example, ebastine and alprazolam, are effective to reverse, reduce, alleviate, and / or treat insomnia for about 1 to 8 weeks, for example, 1, 2, 3, 4, 5, 6, 7, or 8 weeks, or any range therebetween.

Example

[0051] The following examples are illustrative and should not be construed as limiting the scope of the claimed subject matter.

[0052] Example 1 A 58-year-old male patient had been treated with ebastine (20 mg once daily) for about three months for persistent insomnia (difficulty falling asleep) associated with severe allergic rhinitis. However, the insomnia did not improve, and the allergic rhinitis only improved slightly. Subsequently, he received treatment with a combination of ebastine (10 mg) and alprazolam (0.4 mg) once daily. After the 5th day of treatment, his insomnia improved by 50%. After 14 days of treatment, he had no symptoms of insomnia or allergic rhinitis. He received this combination treatment for three months, and the symptoms of insomnia and severe allergic rhinitis completely disappeared.

[0053] Example 2 A 48-year-old male patient had been treated with alprazolam (0.8 mg twice daily) for two months for chronic insomnia associated with depression, but no improvement was seen. Subsequently, he switched to treatment with a combination of ebastine (10 mg) and alprazolam (0.4 mg) twice daily, and the treatment continued for 30 days. Fourteen days after the first treatment with the combination, the insomnia disappeared and the depression improved by 80%. At the end of 30 days of treatment, the patient had a sleep time of about 7 hours per day, and the symptoms of depression were also no longer seen.

[0054] Example 3 A 55-year-old male patient had suffered from insomnia for more than two months before receiving medication. He had been treated with zolpidem (10 mg daily for one month) and then eszopiclone (1 mg daily for two weeks), but he could not tolerate the side effects of headache and dizziness associated with these drugs. Subsequently, he received treatment with a combination of azelastine (2 mg) and alprazolam (0.4 mg) daily for one week, but this combination had no effect on eliminating insomnia. Then he switched to treatment with a combination of ebastine (20 mg) and alprazolam (0.8 mg) daily for one week. As a result, the sleep latency decreased by 40%, the sleep time improved by 50%, and there were no complaints of severe side effects. From the 5th week of this new combination treatment, the insomnia began to disappear. The combination of ebastine and alprazolam is effective in treating insomnia without intolerable side effects.

[0055] Example 4 A 43-year-old female patient had suffered from insomnia for over three months. She was treated with eszopiclone (1 mg per day) for one week, but had to discontinue the treatment because she could not tolerate the adverse reaction of headache. Subsequently, she received a treatment combining ebastine (10 mg) and alprazolam (0.4 mg) daily. After five weeks of treatment, the insomnia disappeared, and during the five-week treatment, she could well tolerate the drug adverse reactions.

[0056] References P. Van Cauwenberge, T. De Belder & Lien Sys, “A review of the second-generation antihistamine eszopiclone ebastine for the treatment of allergic disorders”. Expert Opinion on Pharmacotherapy, 2004; 5:8, 1807-1813. J. D. Lie, K. N. Tu, D. D. Shen and B. M. Wong, “Pharmacological Treatment of Insomnia”. P&T, 2015, Vol 40, No. 11 759-771. T. Roth, T. Roehrs, and R. Pies “Insomnia: pathophysiology and implication for treatment”. Sleep Med Rev, 2007; 11, 71-79. A. Qaseem, D. Kansagara, et al. “Management of Chronic Insomnia Disorder in Adults: A Clinical Practice Guideline From the American College of Physicians”. Allergy 2008 63(Suppl. 89):1-20. J. Sastre, “Ebastine in allergic rhinitis and chronic idiopathic urticaria”. Current Topics in Med. Chem. 2011, 11: 221-240. L. Wiserman and D. Faulds, “Ebastine, A Review of its Pharmacological Properties and Clinical Efficacy in the Treatment of Allergic Disorders”. Drugs 1996, 51(2): 260-277. Monica de la Pena Bravo, L. D. Serpero, et al, “Inflammatory proteins in patients with obstructive sleep apnea with and without daytime sleepiness”. Sleep Breath, 2007 Sep;11(3):177-85. R. Nadeem, J. Molnar, et al., “Serum inflammatory markers in obstructive sleep apnea: a meta-analysis”, Journal of Clinic Sleep Med (2013) Oct 15; 9(10):1003-12. J. Gaines, A. N. Vgontzas, et al, “Inflammation mediates the association between visceral adiposity and obstructive sleep apnea in adolescents” Am J. Physiol. Endocrinol Metab., 2016 Nov 1; 311(5). A Kales, E O Bixler, et al., “Alprazolam: effects on sleep and withdrawal phenomena” J Clin Pharmacol. 1987, 27(7): 508-15 A. Kales, CR. Soldatos, et al.,” Diazepam: effects on sleep and withdrawal phenomena” J Clin Psychopharmacol. 1988, 8(5): 340-6. E.B. Mohns, “Discontinuation and withdrawal problems of alprazolam” West J Med. 1989,151(3): 312 Loyd Allen, Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems, Tenth (2013). Sarfaraz K. Niazi, Handbook of Pharmaceutical Manufacturing Formulations Volumes 1-6.

[0057] The present invention has been described with reference to specific embodiments having various features. In view 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 present invention. Those skilled in the art will recognize that the disclosed features can be used alone, in any combination, or omitted, based on a given application or design requirements and specifications. When an embodiment refers to a certain feature as "comprising", it should be understood that alternative 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 composition. Similarly, any of the compositions disclosed herein can be used with any of the methods disclosed herein or with any other method. Other embodiments of the present invention will be apparent to those skilled in the art from the specification and consideration of the practice of the present invention.

[0058] It should be particularly noted that 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 can also be included in or excluded from the range, separately. The singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise. The specification and examples are considered to be illustrative in nature, and modifications that do not depart from the essence of the present invention are intended to be within the scope of the present invention. Further, all references cited in this disclosure are hereby incorporated by reference in their entirety, each individually, and thus provide an efficient way to supplement the disclosed embodiments of the present invention and provide a background that details the ordinary level of skill in the art.

Claims

1. Ebastine; Alprazolam; and one or more pharmaceutically acceptable excipients A pharmaceutical composition comprising.

2. The pharmaceutical composition according to claim 1, wherein the ebastine is present in the pharmaceutical composition in an amount in the range of about 5 mg to about 50 mg.

3. The pharmaceutical composition according to claim 1, wherein the ebastine is present in the pharmaceutical composition in an amount in the range of about 5 mg to about 25 mg.

4. The pharmaceutical composition according to claim 1, wherein the alprazolam is present in the pharmaceutical composition in an amount in the range of about 0.2 mg to about 2 mg.

5. The pharmaceutical composition according to claim 2, wherein the alprazolam is present in the pharmaceutical composition in an amount in the range of about 0.2 mg to about 2 mg.

6. The ebastine is present in the pharmaceutical composition in an amount in the range of about 5 mg to about 50 mg; The alprazolam is present in the pharmaceutical composition in an amount in the range of about 0.2 mg to about 2 mg, The pharmaceutical composition according to claim 1.

7. The ebastine is present in the pharmaceutical composition in an amount in the range of about 5 mg to about 25 mg; The alprazolam is present in the pharmaceutical composition in an amount in the range of about 0.2 mg to about 2 mg, The pharmaceutical composition according to claim 1.

8. The pharmaceutical composition according to claim 1, formulated as an oral pharmaceutical dosage form.

9. The pharmaceutical composition according to claim 8, wherein the oral pharmaceutical dosage form is in solid form or liquid form or gel form.

10. A method comprising administering a pharmaceutical composition to a patient having insomnia or symptoms thereof; The method, wherein the pharmaceutical composition comprises ebastine and alprazolam.

11. The method according to claim 10, wherein the pharmaceutical composition is administered to the patient once or twice a day, or once every two days or three days or four days, in oral solid or liquid form.

12. The method according to claim 10, wherein the ebastine is present in the pharmaceutical composition in an amount in the range of about 5 mg to about 50 mg.

13. The method according to claim 12, wherein the alprazolam is present in the pharmaceutical composition in an amount in the range of about 0.2 mg to about 2 mg.

14. The method according to claim 10, wherein the alprazolam is present in the pharmaceutical composition in an amount in the range of about 0.2 mg to about 2 mg.

15. The method according to claim 10, wherein the ebastine and the alprazolam are present in the pharmaceutical composition in synergistically effective amounts.

16. A pharmaceutical composition for use in the treatment of insomnia or one or more of its symptoms, the pharmaceutical composition comprising the composition according to claim 1.

17. A method comprising administering a pharmaceutical composition to a patient having insomnia or a symptom thereof; The method, wherein the pharmaceutical composition comprises ebastine in an amount in the range of about 5 mg to about 50 mg and alprazolam in an amount in the range of about 0.2 mg to about 2 mg.