Pharmaceutical compositions and methods for treating insomnia

Abstract

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

Description

Field of the Invention

[0001] The present invention relates to the field of practical medicine, namely, to the use of a pharmaceutical composition for treating, preventing and / or alleviating insomnia manifestations or symptoms thereof. SUMMARY OF THE INVENTION

[0003] Insomnia is often diagnosed by the presence of polysomnographic evidence of sleep disturbances such as long sleep latency, frequent nocturnal awakenings, or prolonged wakefulness or even frequent transient awakenings during sleep. Various population-based studies have shown that about 30-40% of various adult samples from different countries report one or more symptoms of insomnia: difficulty initiating sleep, difficulty maintaining sleep, waking up too early, and in some cases, sleep that is not restorative or of poor quality. In particular, insomnia has a very negative impact on vulnerable patient groups including active military personnel and veterans, patients with coexisting mental and medical disorders, patients in transitional periods of life such as menopause, and the elderly. Due to its chronicity, insomnia is associated with substantial impairment of personal quality of life such as a high rate of psychiatric comorbidities. Insomnia even poses greater health risks due to the increased incidence of daytime accidents.

[0004] Insomnia treatments 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 have risks of tolerance, dependence, memory impairment, depression, headache, dizziness, and drowsiness.

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

[0006] Inflammation can be defined as one of the immune responses used to protect living organisms from damage. The immune system can be triggered by various factors such as pathogens, cell damage and stress, which can induce acute or chronic inflammatory responses in organs including the brain, potentially leading to tissue damage or disease. Recent advances in neurobiological research provide increasing evidence that inflammation and neurodegenerative pathways play a relevant role in insomnia. Preclinical and clinical studies on insomnia have emphasized the 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 overactivated inflammatory signaling pathways including nuclear factor κB (NF-κB). Recent studies have shown that blocking the biological actions of cytokines IL-1 and TNF leads to a decrease in the amount of physiological NREM sleep or NREM sleep rebound after sleep deprivation. On the other hand, increasing the availability of those cytokines promotes the amount and intensity of NREM sleep and suppresses the amount of REM sleep. These findings identify both cytokines IL-1 and TNF as 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-regulating properties. The anti-inflammatory cytokines IL-4, IL-10, and IL-13 reportedly reduce the amount of NREM sleep in rabbits, whereas the pro-inflammatory cytokines IFN-γ, IL-2, IL-6, IL-15, and IL-18 have NREM sleep-promoting effects in animal models.

[0007] Ebastine is a second-generation H1-receptor antagonist, given orally once daily, for the treatment of symptoms of allergic rhinitis and chronic idiopathic urticaria. In addition to blocking H1-receptors, ebastine has other effects that contribute to its anti-allergic effects. In vitro and in vivo studies as well as clinical trials have shown the effects of ebastine on various inflammatory mediators. Ebastine significantly inhibits the release of prostaglandin D2 (PGD2) and leukotrienes C4 / D4 (LTC4 / D4) induced by anti-IgE. Ebastine also inhibits the release of cytokines including granulocyte-macrophage colony-stimulating factor (GM-CSF), tumor necrosis factor-a, and interleukin-8. Its metabolite, carebastine, inhibits the release of PGD2.

[0008] Alprazolam is one of the most widely used benzodiazepines for the treatment of generalized anxiety disorder and panic disorder. The neurochemical mechanisms underlying alprazolam's anxiolytic effects are not fully understood, but studies suggest that benzodiazepines enhance central nervous system GABAergic pre- and postsynaptic inhibition. In addition, alprazolam binds to both GABA and benzodiazepine receptors, each of which has GABA and benzodiazepine recognition sites, with GABA and related agents enhancing the specific binding of benzodiazepines. Therefore, alprazolam may exert its therapeutic anxiolytic effects by interacting with high-affinity binding sites on brain receptors. These benzodiazepine receptors interact with GABA receptors, enhancing the synaptic inhibitory effects of GABA. We hypothesize that alprazolam stabilizes the anti-inflammatory cytokines IL-4, IL-10, and IL-13 through its effects on GABA and benzodiazepine receptors on nervous system GABAergic pre- and postsynaptic inhibition. The antidepressant effects of alprazolam depend on its effects on 3 The effects of H-DHA binding suggest the ability to reduce beta-adrenergic receptor sensitivity, particularly when given chronically at higher doses. Studies have shown that alprazolam significantly reduces the length of REM periods and the frequency of REM bursts of activity and increases REM latency. We believe that the differential effects of alprazolam on REM latency relative to other benzodiazepines are of potential clinical importance.

[0009] Therefore, the unique combination of ebastine and alprazolam may be effective in the treatment of insomnia in terms of acting through multiple mechanisms of action.

[0010] The present invention includes a pharmaceutical composition comprising two active pharmaceutical ingredients. The pharmaceutical composition comprises a first active ingredient, which is ebastine, and a second active ingredient, which is alprazolam. If desired, the composition may comprise only ebastine and alprazolam as pharmaceutically active ingredients, for example, the composition may consist of only ebastine and alprazolam as pharmaceutically active ingredients. Pharmaceutically inactive materials, such as excipients, may also be present in the pharmaceutical composition.

[0011] In some embodiments of the invention, ebastine in the pharmaceutical composition is provided in an amount of about 5 mg to about 50 mg and alprazolam is provided in an amount of about 0.2 mg to about 2 mg.

[0012] The present invention also includes oral pharmaceutical dosage forms of the pharmaceutical composition, which are in solid, liquid or gel form. The oral pharmaceutical dosage form may contain only ebastine and alprazolam as pharmaceutically active ingredients. For example, the oral pharmaceutical dosage form may consist only of ebastine and alprazolam as pharmaceutically active ingredients, for example, only of ebastine and alprazolam optionally in combination with non-pharmaceutically active materials such as excipients, binders, etc.

[0013] The invention also includes the use of the composition, such as by oral dosage administered to a patient suffering from insomnia.

[0014] In some embodiments of the invention, an oral 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 an insomnia patient.

[0015] Embodiments include aspect 1, which is a pharmaceutical composition comprising: ebastine; alprazolam; and one or more pharmaceutically acceptable excipients.

[0016] Aspect 2 is the pharmaceutical composition of aspect 1, wherein the ebastine is present in the pharmaceutical composition in an amount of about 5 mg to about 50 mg.

[0017] Aspect 3 is the pharmaceutical composition of aspect 1 or 2, wherein the alprazolam is present in the pharmaceutical composition in an amount of about 0.2 mg to about 2 mg.

[0018] Aspect 4 is the pharmaceutical composition of any one of aspects 1-3, wherein the ebastine is present in the pharmaceutical composition in an amount of about 5 mg to about 25 mg.

[0019] Aspect 5 is the pharmaceutical composition of any one of aspects 1-4, wherein the alprazolam is present in the pharmaceutical composition in an amount of about 0.4 mg to about 2.0 mg.

[0020] Aspect 6 is the pharmaceutical composition of any one of aspects 1-5, wherein: the ebastine is present in the pharmaceutical composition in an amount of about 5 mg to about 50 mg; and the alprazolam is present in the pharmaceutical composition in an amount of about 0.2 mg to about 2 mg.

[0021] Aspect 7 is the pharmaceutical composition of any one of aspects 1-6, wherein: the ebastine is present in the pharmaceutical composition in an amount of about 5 mg to about 25 mg; and the alprazolam is present in the pharmaceutical composition in an amount of about 0.2 mg to about 2.0 mg.

[0022] Aspect 8 is the pharmaceutical composition of any one of aspects 1 to 7, wherein the pharmaceutical composition is formulated as an oral pharmaceutical dosage form.

[0023] Aspect 9 is the pharmaceutical composition of any one of aspect 8, wherein the oral dosage form is in solid form or liquid form or gel form.

[0024] Aspect 10 is a method comprising: administering a pharmaceutical composition to a patient; wherein the pharmaceutical composition comprises effective amounts of ebastine and alprazolam, and wherein the effective amounts together are sufficient to treat insomnia in the patient.

[0025] Aspect 11 is the method of aspect 10, wherein the pharmaceutical composition is administered to the patient in an oral solid or liquid form or in a gel form once or twice a day, or once every 2 or 3 or 4 days.

[0026] Aspect 12 is the method of any one of aspects 10-11, wherein the ebastine is present in the pharmaceutical composition in an amount of about 5 mg to about 50 mg.

[0027] Aspect 13 is the method of any one of aspects 10-12, wherein the alprazolam is present in the pharmaceutical composition in an amount of about 0.2 mg to about 2.0 mg.

[0028] Aspect 14 is the method of any one of aspects 10-13, wherein the ebastine is present in the pharmaceutical composition in an amount of about 5 mg to about 25 mg.

[0029] Aspect 15 is the method of any one of aspects 10-14, wherein the alprazolam is present in the pharmaceutical composition in an amount of about 0.2 mg to about 2.0 mg.

[0030] Aspect 16 is the method of any one of aspects 10-15, wherein: the ebastine is present in the pharmaceutical composition in an amount of about 5 mg to about 50 mg; and the alprazolam is present in the pharmaceutical composition in an amount of about 0.2 mg to about 2.0 mg.

[0031] Aspect 17 is the method of any one of aspects 10-16, wherein: the ebastine is present in the pharmaceutical composition in an amount of about 5 mg to about 25 mg; and the alprazolam is present in the pharmaceutical composition in an amount of about 0.2 mg to about 2.0 mg.

[0032] BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE ATTACHED DRAWING

[0033] Figure 1 Show the chemical structure of alprazolam; and

[0034] Figure 2 The chemical structure of ebastine is shown. DETAILED DESCRIPTION OF THE INVENTION

[0036] Through clinical practice, the inventors of the present invention have found that a pharmaceutical composition having an oral dosage form comprising the active agents ebastine and alprazolam is suitable for treating patients, such as humans, who suffer from insomnia and / or its symptoms (such as difficulty falling asleep, waking up at night, waking up too early, daytime fatigue / sleepiness, etc.).

[0037] The detailed description provided below is intended to illustrate the present embodiment and is not intended to represent the only form in which the present embodiment can be constructed or utilized. The description sets forth the functions of the embodiment and the sequence of steps for constructing and operating the embodiment. However, the same or equivalent functions and sequences can be implemented by different embodiments.

[0038] definition

[0039] As used in this specification, the following words and phrases are generally intended to have the meanings set forth below, unless the context of their use indicates otherwise.

[0040] As used herein, the term "alprazolam" refers to Figure 1 8-Chloro-1-methyl-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine is shown.

[0041] As used herein, the term "ebastine" refers to Figure 2 4-diphenylmethoxy-l-[3-(4-tert-butylbenzoyl)-propyl]piperidine is shown.

[0042] As used herein, "treating" or "treatment" means complete or incomplete cure, or it means that the symptoms of the underlying disease or related conditions are at least alleviated and / or delayed, and / or one or more basic cellular, physiological or biochemical causes or mechanisms that cause the symptoms are alleviated, delayed and / or eliminated. It should be understood that reduction or delay as used herein means relative to the state of an untreated disease, including the molecular state of an untreated disease, not just the physiological state of an untreated disease.

[0043] The term "effective amount" refers to an amount sufficient to affect treatment when administered to a mammal in need of such 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 condition, the mode of administration, etc., which can be easily determined by one of ordinary skill in the art. The pharmaceutical composition can be administered orally in a single dose or multiple doses. It can be administered in any one or more of capsules, tablets, gels, sprays, drops, solutions, suspensions, syrups, etc.

[0044] As used herein, the term "about" in the context of quantitative measurements means ±10% of the indicated amount. For example, for a range of ±10%, "about 2 mg" may mean 1.8-2.2 mg.

[0045] The pharmaceutical composition can be formulated for pharmaceutical use using methods known in the art, for example, Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems Tenth Edition (Loyd Allen, 2013) and Handbook of Pharmaceutical Manufacturing Formulations (Sarfaraz K, Niazi, Volumes 1-6). Thus, the combination of an active compound and a controlled or slow release matrix can be achieved.

[0046] Can easily prepare liquid or solid unit dosage form for oral administration, for example, mix with any one or more conventional ingredients, this conventional ingredient is such as dicalcium phosphate, magnesium aluminum silicate, magnesium stearate, calcium sulfate, starch, talcum, lactose, gum arabic, methylcellulose and as the function similar material of pharmaceutical excipient or carrier.Can optionally use sustained release preparation.In old or disordered experimenter, sustained release preparation may even be preferred.Can prepare capsule by pharmaceutical composition and inert pharmaceutical diluent mixing, and this mixture is inserted in the hard gelatin capsule with suitable size.If desired soft capsule, pharmaceutical composition and the slurry of acceptable plant, light petroleum or other inert oil can be encapsulated by forming gelatin capsule.

[0047] Suspension, syrup and elixir can be used for oral administration or fluid unit dosage form. Fluid preparations comprising oil can be used for oil-soluble forms. Vegetable oils such as corn oil, peanut oil or flower oil, for example, produce acceptable fluid preparations together with flavorings, sweeteners and any preservatives. Surfactant can be added to the water to form a syrup for fluid unit dosage. Hydroalcoholic pharmaceutical preparations such as elixir forms with acceptable sweeteners (such as sugar, saccharin or other non-nutritional sweeteners) and / or biological sweeteners and / or flavorings can be used.

[0048] The solid oral dosage form of the disclosure refers to the form of tablets, caplets, bilayer tablets, film-coated tablets, pills, capsules, etc. Tablets according to the disclosure can be prepared by any mixing and tableting techniques well known in the pharmaceutical preparation industry. In some embodiments, the dosage form is prepared by directly compressing the separately prepared sustained-release portion and the immediate-release portion with a punch and a die mounted on a rotary tablet press, spraying or compression molding or granulation, and then compressing.

[0049] The pharmaceutical composition provided according to the present disclosure is generally orally administrable. Therefore, the disclosure provides a pharmaceutical composition comprising a solid dispersion, the solid dispersion comprising ebastine and alprazolam as described herein and one or more pharmaceutically acceptable excipients or carriers, 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 in a manner well known in the pharmaceutical field (see, for example, Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems, Tenth Edition (Pharmaceutical Dosage Forms and Drug Delivery Systems Tenth) (Loyd Allen, 2013) and Handbook of Pharmaceutical Manufacturing Formulations (Sarfaraz K, Niazi, Vol. 1-6)).

[0050] The pharmaceutical composition may further include 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 tablets, the tablets may be uncoated or may be coated by known techniques, including microencapsulation to delay disintegration and absorption in the gastrointestinal tract, thereby providing a longer sustained effect. For example, a time-delay material, such as glyceryl monostearate or glyceryl distearate, may be used alone or together with wax. In embodiments, the pharmaceutical composition is formulated into tablets, caplets, pills or capsules for gastrointestinal absorption, such as being formulated to delay disintegration until the pharmaceutical composition is in the gastrointestinal tract of the patient. In embodiments, delayed disintegration is achieved using coatings.

[0051] In embodiments, the pharmaceutical composition may include synergistically effective amounts of ebastine and alprazolam, such as a) about 5 mg to 10 mg of ebastine and b) about 0.2 mg to 0.4 mg of alprazolam, or a) about 10 mg to 20 mg of ebastine and b) about 0.4 mg to 1.2 mg of alprazolam, or a) about 5 mg to 50 mg of ebastine and b) about 0.4 mg to 2.0 mg of alprazolam, or any amount of ebastine or alprazolam within these ranges. In embodiments, alprazolam is present in the pharmaceutical composition in a synergistically effective amount relative to the amount of ebastine, and may include a pharmaceutical composition comprising a) about up to and including any amount of 5 mg, 10 mg, 20 mg, 30 mg, 50 mg, or any amount within these ranges, and b) about up to and including any amount between 0.4 mg, 0.8 mg, 1.2 mg, 1.6 mg, 2 mg of alprazolam, or any amount within these ranges. For example, a composition comprising synergistically effective amounts of ebastine and alprazolam may comprise a) about 5 mg of ebastine and b) about 0.4 mg of alprazolam. In addition, for example, the composition of the present invention may comprise ebastine present in an amount of about 5 mg to about 50 mg and a synergistically effective amount of alprazolam in an amount of about 0.4 mg to about 2 mg. In embodiments, the synergistically effective amount may be such that the amount of ebastine present in the composition may be equal to, greater than, or less than the amount of alprazolam present in the composition. In embodiments, the synergistically effective amount may be such that ebastine is present in the pharmaceutical composition in an amount of at least 5 mg and alprazolam is present in the pharmaceutical composition in an amount of at least 0.4 mg. In embodiments, the synergistically effective amount may be such that the amount of ebastine present in the composition may be the same as the amount of alprazolam present in the composition, or 2 times, or 3 times, or 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 compositions of the invention may be used with any one or more methods of the invention disclosed herein or other methods using the compositions.

[0052] It should be understood that the amount of the pharmaceutical composition containing ebastine and alprazolam actually administered will generally be determined by the physician based on relevant circumstances, including the condition to be treated, the route of administration selected, the actual compounds administered and their relative activities, the age, weight and response of the individual patient, the severity of the patient's symptoms, etc.

[0053] The pharmaceutical compositions, pharmaceutical dosage forms, and tablets described herein containing ebastine and alprazolam are administered to patients suffering from insomnia by administration (such as oral administration) once a day, twice a day, up to four times a day, 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.

[0054] In an embodiment, a therapeutically effective daily dose of ebastine from about 5 mg to about 50 mg and an amount of alprazolam from about 0.2 mg to about 2 mg is administered to a patient.

[0055] In embodiments, the pharmaceutical dosage forms and tablets of the pharmaceutical compositions described herein containing ebastine (such as ebastine and alprazolam) are effective in reversing, reducing, alleviating and / or treating insomnia within about 1-8 weeks, such as within 1, 2, 3, 4, 5, 6, 7, or 8 weeks, or any range therebetween.

[0056] The following examples are illustrative and should not be construed as limiting the scope of the claimed subject matter.

[0057] Example 1

[0058] A 58-year-old male patient was treated with ebastine (20 mg once daily) for about 3 months for his persistent insomnia (difficulty falling asleep) and severe allergic rhinitis, but his insomnia did not improve and his allergic rhinitis only slightly improved. He then received a combination of ebastine (10 mg) and alprazolam (0.4 mg) once daily. After the 5th day of treatment, his insomnia improved by 50%, and after 14 days of treatment, he had no symptoms of insomnia and allergic rhinitis. He received the combination treatment for 3 months and never had any symptoms of insomnia and severe allergic rhinitis.

[0059] Example 2

[0060] A 48-year-old male patient was treated with alprazolam (0.8 mg twice daily) for 2 months for his chronic insomnia and depression, and he did not experience improvement. He was then switched to a combination of ebastine (10 mg) and alprazolam (0.4 mg) twice daily for 30 days. After the initial 14 days of this combination treatment, he no longer had insomnia and his depression improved by 80%. At the end of the 30-day treatment, the patient experienced approximately 7 hours of sleep per day and did not have any depressive symptoms.

[0061] Example 3

[0062] A 55-year-old male patient had been suffering from insomnia for more than 2 months before he started medication. He had been treated with zolpidem (10 mg daily for 1 month) and then eszopiclone (1 mg daily for 2 weeks) but could not tolerate the headache and dizziness side effects associated with those medications. After that, he was treated with a combination of azelastine (2 mg) and alprazolam (0.4 mg) daily for 1 week, but the combination was ineffective in eliminating his insomnia. He then switched to a combination of ebastine (20 mg) and alprazolam (0.8 mg) daily for 1 week, and his sleep latency decreased by 40%, sleep duration improved by 50%, and he did not complain of serious side effects. Starting from the 5th week of treatment with this new combination, he began to no longer experience insomnia. The combination of ebastine and alprazolam is effective for treating insomnia and has no intolerable side effects.

[0063] Example 4

[0064] A 43-year-old female patient had insomnia for more than 3 months. She was treated with eszopiclone (1 mg daily) for one week, but had to withdraw from the treatment because she could not tolerate the adverse effect of headache. After that, she was treated with a combination of ebastine (10 mg) and alprazolam (0.4 mg) daily. After 5 weeks of treatment, she had no insomnia, and the adverse effects of the drugs were well tolerated during the 5-week treatment period.

[0065] References

[0066] P. Van Cauwenberge, T. De Beider & Lien Sys, “A review of the second-generation antihistamine eszopiclone ebastine for the treatment of allergicdisorders”. Expert Opinion on Pharmacotherapy, 2004, 5:8, 1807-1813.

[0067] JD Lie, KN Tu, DD Shen and BM Wong, “PharmacologicalTreatment of Insomnia”. P&T, 2015, Vol 40, No. 11 759-771.

[0068] T. Roth, T. Roehrs, and R. Pies “Insomnia: pathophysiology andimplication for treatment”. Sleep Med Rev, 2007; 11, 71-79.

[0069] A. Qaseem, D. Kansagara, et al. “Management of Chronic InsomniaDisorder in Adults: A Clinical Practice Guideline From the American Collegeof Physicians”. Allergy 2008 63 (Suppl. 89): 1-20.

[0070] J. Sastre, “Ebastine in allergic rhinitis and chronic idiopathicurticaria”. Current Topics in Med. Chem. 2011, 11: 221-240.

[0071] L. Wiserman and D. Faulds, “Ebastine, A Review of its PharmacologicalProperties and Clinical Efficacy in the Treatment of Allergic Disorders”.Drugs 1996, 51(2): 260-277.

[0072] Mónica de la Peña Bravo, L. D. Serpero, et al, “Inflammatory proteinsin patients with obstructive sleep apnea, with and without daytimesleepiness”. Sleep Breath, 2007 Sep; 11(3): 177-85.

[0073] R. Nadeem, J. Molnar, et al., “Serum inflammatory markers inobstructive sleep apnea: a meta-analysis”, Journal of Clinic Sleep Med (2013)Oct 15; 9(10): 1003-12.

[0074] J. Gaines, A. N. Vgontzas, et al, “Inflammation mediates theassociation between visceral adiposity and obstructive sleep apnea inadolescents” Am J. Physiol. Endocrinol Metab., 2016 Nov 1, 311(5).

[0075] A Kales, E O Bixler, et al., “Alprazolam: effects on sleep andwithdrawal phenomena” J Clin Pharmacol. 1987, 27(7): 508-15

[0076] A. Kales, CR. Soldatos, et al.,” Diazepam: effects on sleep andwithdrawal phenomena” J Clin Psychopharmacol. 1988, 8(5): 340-6.

[0077] E.B. Mohns, “Discontinuation and withdrawal problems of alprazolam”West J Med. 1989, 151(3): 312

[0078] Loyd Allen, Ansel's Pharmaceutical Dosage Forms and Drug DeliverySystems, Tenth (2013).

[0079] Sarfaraz K. Niazi, Handbook of Pharmaceutical Manufacturing Formulations Volumes 1-6.

[0080] The present invention has been described with reference to specific embodiments having various features. Based on the disclosure provided above, it will be apparent to those skilled in the art that various modifications and variations may 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, based on the requirements and specifications of a given application or design, the disclosed features may be used alone, in any combination, or omitted. When an embodiment refers to "comprising" certain features, it will be understood that these embodiments may alternatively "consist of" or "consist essentially of" any one or more features. Any method disclosed herein may be used with any composition disclosed herein or with any other composition. Similarly, any disclosed composition may be used with any method disclosed herein or with any other method. Other embodiments of the present invention will be apparent to those skilled in the art in view of the specification and practice of the present invention.

[0081] It should be particularly noted that, in the case of providing a numerical range in this specification, each numerical value between the upper and lower limits of the range is also specifically disclosed. The upper and lower limits of these smaller ranges may also be independently included in the range or excluded. The singular forms "one", "an" and "the" include plural references unless the context clearly specifies otherwise. The description and embodiments are intended to be considered exemplary, and changes that do not deviate from the essence of the present invention fall within the scope of the present invention. In addition, all references cited in the disclosure are incorporated herein in their entirety by reference alone, and it is therefore intended to provide an effective way to supplement the disclosure of the invention, as well as to provide a background that details the level of ordinary skill in the art.

Claims

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

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

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

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

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

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

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

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

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

10. A method comprising: administering a pharmaceutical composition to a patient suffering from insomnia or symptoms thereof; The pharmaceutical composition comprises ebastine and alprazolam.

11. The method of claim 10, wherein the pharmaceutical composition is administered to the patient in an oral solid or liquid form once or twice daily, or once every 2, 3 or 4 days.

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

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

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

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

16. A pharmaceutical composition for treating insomnia or one or more symptoms thereof, wherein the pharmaceutical composition comprises a composition according to any one of claims 1 to 9 and / or the use relates to a method according to any one of claims 10 to 15.

17. A method comprising: administering a pharmaceutical composition to a patient suffering from insomnia or symptoms thereof; wherein the pharmaceutical composition comprises 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.

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