Intranasal composition containing betahistine

Abstract

The present disclosure relates to a pharmaceutical composition comprising betahistine or a pharmaceutically acceptable salt thereof as an active agent for use in treating otolaryngologic or neurological disorders in a human subject by intranasal application. [Selected figure] Figure 3

Description

Technical Field

[0001] Cross - Reference to Related Applications This application claims the benefit of priority to U.S. Provisional Patent Application No. 62 / 453,931, filed on February 2, 2017, the content of which is hereby incorporated by reference in its entirety.

[0002] Field The present disclosure generally relates to pharmaceutical compositions comprising betahistine or a pharmaceutically acceptable salt thereof, and methods of using them, for example, in the treatment of otolaryngological or neurological disorders.

Background Art

[0003] Agents useful for treating vestibular disorders or alleviating the symptoms of vestibular disorders, such as histamine, are known to act via the histaminergic system. Histamine is a powerful bioactive substance that has been studied for nearly a century as an amine - acting neurotransmitter in the nervous system and as a local mediator in the gut, skin, and peripheral immune system, and in the brain. Betahistine is a structural analog of histamine with similar pharmacological properties but without the potentially serious side effects of histamine, such as anaphylactic reactions.

[0004] Betahistine is known to have therapeutic benefits in the treatment of vestibular vertigo, for example, in benign paroxysmal positional vertigo, vestibular neuritis, or Meniere's disease. The therapeutic effect of betahistine in Meniere's disease, a condition characterized by vertigo, tinnitus, hearing loss, and a sense of pressure or pain in the affected ear, has been evaluated in numerous clinical trials. However, the results of the clinical trials are controversial, and the general opinion of critics is that there is still not enough evidence to state whether betahistine has any effect on Meniere's disease. Betahistine is also known to have therapeutic benefits in vestibular rehabilitation, for example, a significant reduction in the time to recover postural stability and subjective visual vertical and head orientation in Meniere's disease patients after vestibular neurectomy.

[0005] Betahistine is also known to have a therapeutic effect in the treatment of neurological disorders such as obesity, attention deficit hyperactivity disorder, cerebrovascular disease / dementia, narcolepsy / sleep disorder, Parkinson's disease, poisoning, schizophrenia, Gilles de la Tourette syndrome, or Alzheimer's disease.

[0006] In humans, betahistine is usually administered orally in the form of tablets or solutions, usually 2 to 3 times a day, up to a maximum of 6 times a day. Betahistine is known for its short plasma half-life (3 to 4 hours), which requires frequent administration and can lead to non-compliance, especially in elderly patients. Furthermore, after oral administration, betahistine is readily and almost completely absorbed from all parts of the gastrointestinal tract. After absorption, the drug is rapidly and almost completely metabolized by monoamine oxidase to 2-pyridylacetic acid (2-PAA, which has no pharmacological activity). Due to the very high first-pass metabolism, the absolute bioavailability of orally administered betahistine is estimated to be approximately 1% (SmPC). Therefore, the plasma concentration of betahistine is very low.

[0007] Therefore, the strong first-pass effect after oral administration of betahistine limits the effectiveness of the compound in clinical practice and may actually require substantially higher doses to achieve more significant results. Therefore, there is a need to provide an improved pharmaceutical composition containing betahistine that increases effectiveness, allows for a reduction in frequency and / or daily dose, and provides a more rapid and prolonged effect, as well as a method of administering them for the treatment of otolaryngological or neurological disorders including inner ear dysfunction. SUMMARY OF THE INVENTION MEANS FOR SOLVING THE PROBLEM

[0008] In various embodiments, the present disclosure relates to a pharmaceutical composition for intranasal delivery to a human patient comprising a therapeutically effective amount of betahistine or a pharmaceutically acceptable salt thereof and a solution or suspension of a thickening agent.

[0009] In certain embodiments, the present disclosure relates to a pharmaceutical composition that, after single intranasal administration to a human, has a C max in the range of 80 to 125% of the following: about 640 pg / mL for a 5 mg betahistine dose, about 2000 pg / mL for a 10 mg betahistine dose, about 4000 pg / mL for a 20 mg betahistine dose, or about 10500 pg / mL for a 40 mg betahistine dose.

[0010] In certain embodiments, the present disclosure relates to a pharmaceutical composition that, after single intranasal administration to a human, has an AUC 0-last in the range of about 80% to 125% of the following: about 210 pg*hour / mL for a 5 mg betahistine dose, about 500 pg*hour / mL for a 10 mg betahistine dose, about 1600 pg*hour / mL for a 20 mg betahistine dose, or about 3500 pg*hour / mL for a 40 mg betahistine dose.

[0011] In certain embodiments, the present disclosure relates to a pharmaceutical composition that, after single intranasal administration to a human, has an AUC 0-inf in the range of about 80% to 125% of the following: about 275 pg*hour / mL for a 5 mg betahistine dose, about 700 pg*hour / mL for a 10 mg betahistine dose, about 1630 pg*hour / mL for a 20 mg betahistine dose, or about 3940 pg*hour / mL for a 40 mg betahistine dose.

[0012] In yet other embodiments, the present disclosure relates to a method of treating inner ear dysfunction or inner ear disorder, or a method of treating or alleviating the symptoms of inner ear disorder, or a method of increasing cochlear blood flow or cerebral blood flow in a subject, the method comprising intranasally administering to the subject any of the compositions disclosed herein. The present invention provides, for example, the following items. (Item 1) A pharmaceutical composition for intranasal delivery to a human patient, comprising a solution or suspension of a therapeutically effective amount of betahistine or a pharmaceutically acceptable salt thereof, and a thickening agent. (Item 2) The pharmaceutical composition according to Item 1, wherein after a single intranasal administration to a human, C of betahistine max is in the range of 80 to 125% of the following: about 640 pg / mL for a 5 mg betahistine dose, about 2000 pg / mL for a 10 mg betahistine dose, about 4000 pg / mL for a 20 mg betahistine dose, or about 10500 pg / mL for a 40 mg betahistine dose. (Item 3) The pharmaceutical composition according to Item 1 or 2, wherein after a single intranasal administration to a human, the AUC of betahistine 0-last is in the range of about 80% to 125% of the following: about 210 pg·hour / mL for a 5 mg betahistine dose, about 500 pg·hour / mL for a 10 mg betahistine dose, about 1600 pg·hour / mL for a 20 mg betahistine dose, or about 3500 pg·hour / mL for a 40 mg betahistine dose. (Item 4) The pharmaceutical composition according to any one of Items 1 to 3, wherein after a single intranasal administration to a human, the AUC of betahistine 0-inf is in the range of about 80% to 125% of the following: about 275 pg·hour / mL for a 5 mg betahistine dose, about 700 pg·hour / mL for a 10 mg betahistine dose, about 1630 pg·hour / mL for a 20 mg betahistine dose, or about 3940 pg·hour / mL for a 40 mg betahistine dose. (Item 5) The pharmaceutical composition according to any one of Items 1 to 4, wherein after a single intranasal administration to a human, the t of betahistine max is in the range of about 0.08 to 0.5 hours. (Item 6) The pharmaceutical composition according to any one of Items 1 to 5, wherein the betahistine or a pharmaceutically acceptable salt thereof is selected from the group consisting of betahistine free base, betahistine hydrochloride, betahistine fumarate, betahistine maleate, betahistine tartrate, betahistine citrate, betahistine succinate, betahistine phthalate, and betahistine mesylate. (Item 7) The pharmaceutical composition according to any one of Items 1 to 6, wherein the betahistine or a pharmaceutically acceptable salt thereof is betahistine dihydrochloride. (Item 8) The pharmaceutical composition according to any one of items 1 to 7, wherein the thickener is selected from the group consisting of polyvinylpyrrolidone, polyvinyl alcohol, methylcellulose, carboxymethylcellulose-Na, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyethylene oxide, carbopol, polyethylene glycol, propylene glycol, glycerin, alginate, carrageenan, pectins, maltodextrin, sodium starch glycolate, tragacanth gum, gum arabic, microcrystalline cellulose, and combinations thereof. (Item 9) The pharmaceutical composition according to item 8, wherein the thickener is polyvinylpyrrolidone. (Item 10) The pharmaceutical composition according to any one of items 1 to 9, further comprising one or more humectants. (Item 11) The pharmaceutical composition according to item 10, wherein the one or more humectants are selected from the group consisting of glycerin, ethylene glycol, propylene glycol, propylene glycol 400, hexylene glycol, butylene glycol, dextrose, glyceryl triacetate, polydextrose, glycerol, glyceryl triacetate, sorbitol, mannitol, and combinations thereof. (Item 12) The pharmaceutical composition according to item 11, wherein the one or more humectants are selected from the group consisting of glycerin, polyethylene glycol 400, and propylene glycol. (Item 13) The pharmaceutical composition according to any one of items 1 to 12, wherein the composition contains betahistine or a pharmaceutically acceptable salt thereof at a concentration of about 1 mg / mL to about 1000 mg / mL. (Item 14) The pharmaceutical composition according to item 13, wherein the composition contains betahistine or a pharmaceutically acceptable salt thereof at a concentration of about 10 mg / mL to about 400 mg / mL. (Item 15) The pharmaceutical composition according to any one of items 1 to 14, wherein the composition is in unit dosage form containing betahistine or a pharmaceutically acceptable salt thereof in an amount of about 5 mg to about 100 mg. (Item 16) The pharmaceutical composition according to any one of items 1 to 15, wherein the composition is in unit dosage form containing betahistine or a pharmaceutically acceptable salt thereof in an amount of about 5 mg, about 10 mg, about 20 mg, about 40 mg, or about 80 mg. (Item 17) The pharmaceutical composition according to any one of items 1 to 14, wherein the composition is in the form of a unit dose containing about 1 μL to about 1000 μL of the composition per unit dose. (Item 18) The pharmaceutical composition according to any one of items 1 to 17, wherein the composition can be administered as a spray or aerosol. (Item 19) The pharmaceutical composition according to any one of items 1 to 18, wherein the composition is an aqueous solution. (Item 20) The pharmaceutical composition according to any one of items 1 to 19, wherein the composition contains lipids. (Item 21) The pharmaceutical composition according to any one of items 1 to 20, further comprising at least one additional pharmaceutically active agent. (Item 22) The pharmaceutical composition according to item 21, wherein the at least one additional pharmaceutically active agent is a glutamate receptor antagonist. (Item 23) The C of betahistine in human plasma after single intranasal administration of the composition max is at least about 0.5 ng / mL, and the pharmaceutical composition according to any one of items 1 to 22. (Item 24) The C of betahistine in human plasma after single intranasal administration of the composition max is at least about 4 ng / mL, and the pharmaceutical composition according to any one of items 1 to 23. (Item 25) The pharmaceutical composition according to any one of items 1 to 24, wherein the single dose of the composition contains 20 mg or 40 mg of betahistine or a pharmaceutically acceptable salt thereof. (Item 26) The t of betahistine in human plasma after single intranasal administration of the composition max is about 0.08 hours or more, and the pharmaceutical composition according to any one of items 1 to 25. (Item 27) The t of betahistine in human plasma after single intranasal administration of the composition max is about 0.12 hours or more, and the pharmaceutical composition according to any one of items 1 to 26. (Item 28) The pharmaceutical composition according to any one of items 1 to 27, wherein the single dose of the composition contains 20 mg or 40 mg of betahistine or a pharmaceutically acceptable salt thereof. (Item 29) The AUC of betahistine in human plasma after single intranasal administration of the composition 0-last is at least about 0.2 hour*ng / mL, and the pharmaceutical composition according to any one of items 1 to 28. (Item 30) The AUC of betahistine in human plasma after single intranasal administration of the composition 0-last is at least about 1.5 hours*ng / mL, and the pharmaceutical composition according to any one of items 1 to 29. (Item 31) The pharmaceutical composition according to item 30, comprising 20 mg of betahistine or a pharmaceutically acceptable salt thereof as a single dose of the composition. (Item 32) The AUC of betahistine in human plasma after a single intranasal administration of the composition 0-last is at least about 3.0 hour*ng / mL, the pharmaceutical composition according to any one of items 1 to 31. (Item 33) The pharmaceutical composition according to item 33, comprising 40 mg of betahistine or a pharmaceutically acceptable salt thereof as a single dose of the composition. (Item 34) The pharmaceutical composition according to any one of items 1 to 33, further comprising at least one enzyme inhibitor or absorption promoter. (Item 35) A pharmaceutical combination comprising the pharmaceutical composition according to any one of items 1 to 34 and at least one enzyme inhibitor or absorption promoter. (Item 36) A method for treating inner ear disorders, vestibular disorders, neurotological disorders, otological disorders or neurological disorders, comprising intranasally administering the pharmaceutical composition according to any one of items 1 to 34 to a subject in need thereof. (Item 37) The method according to item 36, wherein the method is for treating vestibular disorders. (Item 38) The method according to item 37, wherein the vestibular disorder is vestibular vertigo or Meniere's disease. (Item 39) The method according to item 36, wherein the method is for treating inner ear disorders selected from tinnitus or hearing loss. (Item 40) A method for treating or alleviating symptoms of inner ear disorders, vestibular disorders, neurotological disorders, otological disorders, or neurological disorders, comprising intranasally administering the pharmaceutical composition according to any one of items 1 to 34 to a subject in need thereof. (Item 41) The method according to item 40, wherein the method is for treating or alleviating symptoms of vestibular disorders. (Item 42) The method according to item 41, wherein the symptoms of the inner ear disorder are hearing loss, tinnitus, nausea or dizziness. (Item 43) The method according to item 43, wherein the hearing loss is sudden hearing loss. (Item 44) A method of administering the pharmaceutical composition according to any one of items 1 to 34 to a subject in need thereof to facilitate vestibular rehabilitation. (Item 45) A method for preventing inner ear disorders, vestibular disorders, neurotological disorders, otological disorders or neurological disorders, comprising intranasally administering the pharmaceutical composition according to any one of items 1 to 34 to a subject in need thereof. (Item 46) The method according to item 45, wherein the method is for preventing vestibular disorders. (Item 47) The method according to item 46, wherein the vestibular disorder is vestibular vertigo or Meniere's disease. (Item 48) The method according to item 45, wherein the method is for the prevention of inner ear disorders selected from tinnitus or hearing loss. (Item 49) A method for increasing cochlear blood flow or vestibular blood flow in a subject, comprising intranasally administering the pharmaceutical composition according to any one of items 1 to 34 to a subject in need thereof. (Item 50) A method for treating obesity, weight gain, and / or eating disorders in a subject, comprising intranasally administering the pharmaceutical composition according to any one of items 1 to 34 to a subject in need thereof. (Item 51) A method for reducing weight gain in a subject, comprising intranasally administering the pharmaceutical composition according to any one of items 1 to 34 to a subject in need thereof. (Item 52) The method according to item 51, wherein the weight gain is induced by administration of an antipsychotic that acts on histamine receptors. (Item 53) The method according to item 52, wherein the antipsychotic is olanzapine. (Item 54) The method according to any one of items 36 to 53, wherein the composition is administered once a day, twice a day, three times a day, four times a day, five times a day, six times a day, seven times a day, eight times a day, nine times a day, or ten times a day. (Item 55) The method according to any one of items 36 to 54, wherein the total daily dose of the betahistine or a pharmaceutically acceptable salt thereof is about 0.01 mg / kg to about 20 mg / kg per body weight of a human patient. (Item 56) The method according to any one of items 36 to 55, wherein the total daily dose of the betahistine or a pharmaceutically acceptable salt thereof is about 1 to 200 mg. (Item 57) The method according to any one of items 36 to 56, wherein the total daily dose of the betahistine or a pharmaceutically acceptable salt thereof is 5 to 100 mg. (Item 58) The method according to any one of items 36 to 57, wherein the composition is administered in an amount of about 1 mg to about 100 mg of betahistine per unit dose in a unit dose containing the betahistine or a pharmaceutically acceptable salt thereof. (Item 59) A pharmaceutical composition according to any one of items 1 to 4, wherein the relative bioavailability of betahistine delivered intranasally is up to about 10 to 50 times higher than that of betahistine delivered orally after a single intranasal administration to humans.

Brief Description of the Drawings

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DETAILED DESCRIPTION OF THE INVENTION

[0014] The following terms are considered to be well understood by those skilled in the art, but the following definitions are provided to facilitate the description of the subject matter disclosed herein.

[0015] Throughout this specification, the terms "about" and / or "approximately" may be used with numerical values and / or ranges. The term "about" is understood to mean a value close to the recited value. For example, "about 40 [units]" means within ±25% of 40 (e.g., 30 - 50), within ±20%, within ±15%, within ±10%, within ±9%, within ±8%, within ±7%, within ±6%, within ±5%, within ±4%, within ±3%, within ±2%, within ±1%, within less than ±1%, or any other value or range of values therein or lower. In other contexts, the term "about" may refer to the intermediate value between adjacent values in a numerical series. Further, expressions such as "less than about [value]" or "greater than about [value]" should be understood in view of the definition of the term "about" provided herein. The terms "about" and "approximately" may be used interchangeably.

[0016] Throughout this specification, numerical ranges are provided for certain quantities. It should be understood that these ranges include all sub-ranges therein. Thus, the range "50 - 80" includes all possible ranges therein (e.g., 51 - 79, 52 - 78, 53 - 77, 54 - 76, 55 - 75, 60 - 70, etc.). Further, all values within a given range may be the endpoints of the ranges subsumed thereby (e.g., the range 50 - 80 includes ranges having endpoints such as 55 - 80, 50 - 75, etc.).

[0017] The term "a" or "an" refers to one or more of that entity. For example, "kinase inhibitor" refers to one or more kinase inhibitors or at least one kinase inhibitor. Thus, the terms "one, a (indefinite article)" (or "one, an (indefinite article)", "one or more", and "at least one" are used interchangeably herein. Further, a reference to "inhibitor" by the indefinite article "a" or "an" does not exclude the possibility of the presence of two or more inhibitors, unless the context clearly requires that only one inhibitor is present.

[0018] As used herein, as used in the specification and claims, the verb "comprising" and its conjugations are used in its non-limiting sense, meaning that items following the word are included but items not specifically recited are not excluded. The present invention may appropriately "comprise", "consist of", or "consist essentially of" the steps, elements, and / or reagents recited in the claims.

[0019] It should further be noted that the claims may be drafted to exclude optional elements. Accordingly, this statement is intended to serve as a precedent for using exclusive terms such as "alone", "only", etc. in connection with the recitation of claim elements or the use of "negative" limitations.

[0020] The terms "treating", "being treated", "treatment" or "treat" include the reduction or alleviation of at least one symptom associated with or caused by the condition, disorder or disease being treated. Treatment may be the alleviation of one or some symptoms of the disorder, or may be the complete eradication of the disorder or disease. Similarly, the term "preventing" refers to the partial or total prevention of symptoms by administering an active agent prior to the expected onset of such symptoms.

[0021] As used herein, the terms "subject", "individual" or "patient" are used interchangeably and refer to a vertebrate, preferably a mammal. Non-limiting examples include mice, dogs, rabbits, livestock, sport animals, pets, and humans.

[0022] As used herein, "therapeutically effective amount" or "effective amount" refers to an amount that produces the desired pharmacological and / or physiological effect on the condition. The effect may be prophylactic with respect to completely or partially preventing the condition or symptom, and / or may be therapeutic with respect to partial or complete cure of the condition and / or adverse effects resulting from the condition.

[0023] As used herein, the term "pharmaceutically acceptable salts of betahistine" refers to pharmaceutically acceptable acid addition salts of betahistine, particularly acid addition salts that are known to be non-toxic and commonly used in the field of pharmaceutical formulations. In one embodiment, the betahistine salt is an acid addition salt in which non-limiting examples of the acid are selected from the following: 1-hydroxy-2-naphthoic acid, 2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid, ascorbic acid (L), aspartic acid (L), benzenesulfonic acid, benzoic acid, borneol acid (+), borneol-10-sulfonic acid (+), capric acid (decanoic acid), caproic acid (hexanoic acid), caprylic acid (octanoic acid), carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecyl sulfate, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid (D), gluconic acid (D), glucuronic acid (D), glutamic acid, glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, isobutyric acid, lactic acid (DL), lactobionic acid, lauric acid, maleic acid, malic acid (-L), malonic acid, mandelic acid (DL), methanesulfonic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, nitric acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, propionic acid, pyroglutamic acid (-L), salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tartaric acid (+L), thiocyanic acid, toluenesulfonic acid (p), or undecylenic acid. In another embodiment, suitable betahistine salts also include, but are not limited to, hydrochloride, hydrobromide, hydroiodide, tartrate, mesylate, citrate, phosphate, acetate, pamoate / embonate, nitrate, lactate, sulfate, methyl sulfate, fumarate, oxalate, phthalate, maleate, and succinate. Further, the betahistine salt may be a mono-salt or a bis-salt. In one embodiment, the betahistine hydrochloride may be betahistine monohydrochloride or betahistine dihydrochloride.

[0024] In one embodiment of the present disclosure, betahistine or a pharmaceutically acceptable salt thereof is formulated in any form suitable for administration by various routes including nasal (e.g., solution, spray, drops, aerosol, gel, dry powder), oral (e.g., tablets, capsules, granules, syrups, elixirs, or powders), sublingual, buccal, parenteral (e.g., subcutaneous, intravenous, intramuscular, intrathecal, or intracapsular injection), or infusion techniques (e.g., sterile aqueous injection solutions, or non-aqueous solutions or suspensions), topical (e.g., drug-releasing skin patches, creams or ointments), intravaginal, by douche, transdermal, intradermal, intralung, intrauterine, by use of an aerosol, or rectally (e.g., suppositories, unit dosage forms containing a non-toxic, pharmaceutically acceptable vehicle or diluent). In one embodiment, betahistine or a pharmaceutically acceptable salt thereof is formulated in any form suitable for nasal administration or intranasal administration.

[0025] In one embodiment of the present disclosure, a pharmaceutical composition comprising betahistine hydrochloride is provided. In another embodiment, a pharmaceutical composition comprising betahistine monohydrochloride is provided. In another embodiment, a pharmaceutical composition comprising betahistine dihydrochloride is provided.

[0026] In one embodiment, the pharmaceutical composition comprises a specific polymorph of betahistine or a pharmaceutically acceptable salt thereof. In one embodiment, a pharmaceutical composition comprising a specific polymorph of betahistine or a pharmaceutically acceptable salt thereof is formulated in any form suitable for nasal or intranasal administration.

[0027] In one embodiment of the present disclosure, a pharmaceutical composition comprising betahistine or a pharmaceutically acceptable salt thereof is provided. In certain embodiments, the pharmaceutical compositions of the present disclosure comprise a solution or suspension of betahistine or a pharmaceutically acceptable salt thereof. In another embodiment, a pharmaceutical composition comprising betahistine or a pharmaceutically acceptable salt thereof and one or more viscosity agents or one or more pharmaceutically acceptable thickening agents is provided. Non-limiting examples of suitable viscosity agents or thickening agents include polyvinylpyrrolidone, polyvinyl alcohol, methylcellulose, carboxymethylcellulose-Na, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyethylene oxide, carbopol, polyethylene glycol, propylene glycol, glycerin, alginate, carrageenan, pectin, maltodextrin, sodium starch glycolate, tragacanth gum, gum arabic, microcrystalline cellulose and derivatives thereof. In one embodiment, the thickening agent is polyvinylpyrrolidone.

[0028] In another embodiment, the present disclosure relates to a pharmaceutical composition comprising betahistine or a pharmaceutically acceptable salt thereof and one or more viscosity agents, which is a nasal pharmaceutical composition. In one embodiment, one or more viscosity agents in the formulation for nasal administration enable the formulation to be retained at the application site for a length of time sufficient for betahistine or a pharmaceutically acceptable salt thereof to be absorbed. In another embodiment, the presence of one or more viscosity agents in the formulation for nasal administration does not prevent the formulation from being sprayed into the nasal cavity.

[0029] In one embodiment, the pharmaceutical composition of the present disclosure has a viscosity in the range of about 0.1 cps to about 1000 cps or about 1 cps to about 100 cps. In one embodiment, the viscosity of the pharmaceutical composition of the present disclosure is about 0.1 cps, about 0.5 cps, about 1 cps, about 5 cps, about 10 cps, about 15 cps, about 20 cps, about 25 cps, about 30 cps, about 40 cps, about 45 cps, about 50 cps, about 55 cps, about 60 cps, about 65 cps, about 70 cps, about 75 cps, about 80 cps, about 85 cps, about 90 cps, about 95 cps, about 100 cps, about 105 cps, about 110 cps, about 115 cps, about 120 cps, about 125 cps, about 130 cps, about 135 cps, about 140 cps, about 145 cps, about 150 cps, about 175 cps, about 200 cps, about 250 cps, about 300 cps, about 350 cps, about 400 cps, about 450 cps, about 500 cps, about 550 cps, about 600 cps, about 650 cps, about 700 cps, about 750 cps, about 800 cps, about 850 cps, about 900 cps, about 950 cps, or about 1000 cps. In one embodiment, the viscosity of the pharmaceutical composition described herein can be measured by the USP <911> viscosity method.

[0030] In one embodiment, the pharmaceutical composition of the present disclosure for nasal delivery has a viscosity of from about 0.5 cps to about 10.5 cps, from about 1 cps to about 10 cps, or from about 1 cps to about 7 cps. In one embodiment, the pharmaceutical composition of the present disclosure for nasal delivery has a viscosity of about 0.5 cps, about 0.6 cps, about 0.7 cps, about 0.8 cps, about 0.9 cps, about 1.0 cps, about 1.1 cps, about 1.2 cps, about 1.3 cps, about 1.4 cps, about 1.5 cps, about 1.6 cps, about 1.7 cps, about 1.8 cps, about 1.9 cps, about 2.0 cps, about 2.1 cps, about 2.2 cps, about 2.3 cps, about 2.4 cps, about 2.5 cps, about 2.6 cps, about 2.7 cps, about 2.8 cps, about 2.9 cps, about 3.0 cps, about 3.1 cps, about 3.2 cps, about 3.3 cps, about 3.4 cps, about 3.5 cps, about 3.6 cps, about 3.7 cps, about 3.8 cps, about 3.9 cps, about 4.0 cps, about 4.1 cps, about 4.2 cps, about 4.3 cps, about 4.4 cps, about 4.5 cps, about 4.6 cps, about 4.7 cps, about 4.8 cps, about 4.9 cps, about 5.0 cps, about 5.1 cps, about 5.2 cps, about 5.3 cps, about 5.4 cps, about 5.5 cps, about 5.6 cps, about 5.7 cps, about 5.8 cps, about 5.9 cps, about 6.0 cps, about 6.1 cps, about 6.2 cps, about 6.3 cps, about 6.4 cps, about 6.5 cps, about 6.6 cps, about 6.7 cps, about 6.8 cps, about 6.9 cps, about 7.0 cps, about 7.1 cps, about 7.2 cps, about 7.3 cps, about 7.4 cps, about 7.5 cps, about 7.6 cps, about 7.7 cps, about 7.8 cps, about 7.9 cps, about 8.0 cps, about 8.1 cps, about 8.2 cps, about 8.3 cps, about 8.4 cps, about 8.5 cps, about 8.6 cps, about 8.7 cps, about 8.8 cps, about 8.9 cps, about 9.0 cps, about 9.1 cps, about 9.2 cps, about 9.3 cps, about 9.4 cps, about 9.5 cps, about 9.6 cps, about 9.7 cps, about 9.8 cps, about 9.9 cps, about 10.0 cps, about 10.1 cps, about 10.2 cps, about 10.3 cps, about 10.4 cps, about 10.5 cps, or any range of viscosities between any of these values. In one embodiment, the pharmaceutical composition of the present disclosure for nasal delivery is in a nasal composition.In one embodiment, the viscosity of the pharmaceutical composition described herein can be measured by the USP <911> viscosity method.

[0031] In one embodiment, the pharmaceutical composition of the present disclosure includes one or more pharmaceutically acceptable humectants. Non-limiting examples of such humectants include glycerin, ethylene glycol, propylene glycol, propylene glycol 400, hexylene glycol, butylene glycol, dextrose, glyceryl triacetate, polydextrose, glycerol, glyceryl triacetate, sorbitol, and mannitol. In various embodiments, the pharmaceutical composition of the present disclosure may include a mixture of pharmaceutically acceptable humectants.

[0032] In one embodiment, the one or more humectants are selected from glycerin, polyethylene glycol 400, and propylene glycol. In one embodiment, the pharmaceutical composition of the present disclosure includes glycerin. In another embodiment, the pharmaceutical composition of the present disclosure includes polyethylene glycol 400. In other embodiments, the pharmaceutical composition of the present disclosure includes propylene glycol. In some embodiments, the pharmaceutical composition of the present disclosure includes glycerin, polyethylene glycol 400, and propylene glycol.

[0033] In one embodiment, the pharmaceutical composition of the present disclosure that includes one or more pharmaceutically acceptable humectants is a nasal pharmaceutical composition. In one embodiment, the one or more humectants in the nasal pharmaceutical composition for nasal administration moisturize the nasal mucosa, nasal tissue, and / or nasal membrane. In one embodiment, the one or more humectants in the nasal pharmaceutical composition for nasal administration reduce irritation in the nasal cavity after administration. In some embodiments, the nasal pharmaceutical composition of the present disclosure includes glycerin, polyethylene glycol 400, and propylene glycol.

[0034] In another embodiment, there is provided a pharmaceutical composition comprising betahistine or a pharmaceutically acceptable salt thereof, one or more thickening agents, and one or more humectants. In one embodiment, this pharmaceutical composition is a nasal pharmaceutical composition.

[0035] In one embodiment, the pharmaceutical composition of the present disclosure comprises one or more pharmaceutically acceptable carriers and / or one or more pharmaceutically acceptable excipients.

[0036] In one embodiment, the pharmaceutical composition of the present disclosure further comprises one or more additives including, but not limited to, preservatives, agents affecting osmotic pressure, complexing agents (e.g., sodium edetate, etc.), surfactants, agents affecting pH and tonicity, and sensory masking agents. In one embodiment, the pharmaceutical composition of the present disclosure for nasal delivery further comprises one or more additives including, but not limited to, preservatives, agents affecting osmotic pressure, complexing agents (e.g., sodium edetate, etc.), surfactants, agents affecting pH and tonicity, and sensory masking agents.

[0037] Non-limiting examples of additives and / or excipients include benzyl alcohol, benzalkonium chloride, sodium carboxymethylcellulose / crystalline cellulose, propylparaben, methylparaben, phenethyl alcohol, chlorobutanol, EDTA, ethanol, ascorbic acid, hydrochloric acid, sulfuric acid, sodium hydroxide, potassium phosphate, sodium phosphate, sodium citrate, sodium chloride, anhydrous dextrose, butylated hydroxyanisole, butylated hydroxytoluene, PEG400, PEG3500, polyoxyl 400 stearate, polysorbate 20, polysorbate 80, glycerin, propylene glycol, glyceryl triacetate, glycerol, ethylene glycol, sorbitol, mannitol, and alginates, carrageenan, pectins, tragacanth gum, gum arabic.

[0038] For the purposes of the present disclosure, a pharmaceutical composition comprising betahistine or a pharmaceutically acceptable salt thereof may be formulated in a preparation containing a pharmaceutically acceptable carrier, adjuvant and vehicle for administration by various means including oral, parenteral, by inhalation spray, topical or rectal. As used herein, the term parenteral includes subcutaneous, intravenous, intramuscular, and intraarterial injection using various injection techniques. As used herein, intraarterial and intravenous injection include administration through a catheter.

[0039] The pharmaceutical compositions disclosed herein may be formulated according to conventional procedures adapted to the desired route of administration. Thus, the pharmaceutical compositions of the present specification may take the form of suspensions, solutions or emulsions in oily or aqueous vehicles and may contain formulating agents such as suspending, stabilizing and / or dispersing agents. Alternatively, betahistine or a pharmaceutically acceptable salt thereof may be in powder form for constitution with a suitable vehicle, for example sterile pyrogen-free water, before use. Formulations suitable for each of these methods of administration may be found, for example, in Remington: The Science and Practice of Pharmacy, A. Gennaro, ed., 20th edition, Lippincott, Williams & Wilkins, Philadelphia, PA.

[0040] In one embodiment, pharmaceutically acceptable carriers are well known to those skilled in the art and include, but are not limited to, buffers, saline solutions, and water. In one embodiment, the pharmaceutically acceptable carrier includes a phosphate buffer or saline solution (e.g., 0.8% saline solution) of about 0.01 to about 0.1 M. In one embodiment, the buffer includes sodium dibasic phosphate and sodium monobasic phosphate. In such embodiments, the buffer agent adjusts the pH of the composition within a range suitable to allow for rapid absorption of betahistine through the nasal mucosa and to minimize irritation. For example, the pH may be controlled to fall within a range of about 4 to about 9, including a pH range of about 4, about 4.2, about 4.4, about 4.6, about 4.8, about 5, about 5.2, about 5.4, about 5.6, about 5.8, about 6, about 6.2, about 6.4, about 6.6, about 6.8, about 7, about 7.2, about 7.4, about 7.6, about 7.8, about 8, about 8.2, about 8.4, about 8.6, about 8.8, or about 9 (including any and all ranges between these values). In one embodiment, the pharmaceutical composition of the present disclosure has a pH value of about 5. In another embodiment, the pharmaceutical composition of the present disclosure having a pH value of about 5 exhibits improved solubility and stability of betahistine or a pharmaceutically acceptable salt thereof when compared to compositions having a higher pH value.

[0041] Such pharmaceutically acceptable carriers may be aqueous or non-aqueous solutions, suspensions, and emulsions. Examples of non-aqueous solvents suitable for use in the present application include, but are not limited to, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and organic esters for injection such as ethyl oleate.

[0042] Aqueous carriers suitable for use in the present application include, but are not limited to, water, alcoholic / aqueous solutions (such as ethanol / water), glycerol and / or glycerol / aqueous mixtures, emulsions or suspensions (including saline solutions and buffer media). Oral carriers can be elixirs, syrups, capsules, tablets, and the like.

[0043] Liquid carriers suitable for use in the present application can be used to prepare solutions, suspensions, or emulsions. The active ingredient may be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both, or a pharmaceutically acceptable oil or fat. The liquid carrier may contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickeners, coloring agents, viscosity regulators, stabilizers, or osmotic pressure regulators.

[0044] Examples of liquid carriers suitable for use in the present application include, but are not limited to, water (partially containing additives as described above, such as cellulose derivatives, preferably sodium carboxymethylcellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols such as glycols) and their derivatives, and oils (such as fractionated coconut oil and peanut oil). When the composition of the present invention is administered from a pressurized container (e.g., a pressurized metered dispenser), the liquid carrier for the pressurized composition disclosed herein may be a halogenated hydrocarbon, a hydrocarbon, carbon dioxide, or other pharmaceutically acceptable propellant.

[0045] Examples of solid carriers suitable for use in the present application (e.g., when the composition is provided as an intranasal dry powder) include, but are not limited to, inert substances such as lactose, starch, glucose, methylcellulose, magnesium stearate, dicalcium phosphate, and mannitol.

[0046] If some of the composition administered intranasally is ingested, flavoring agents and flavor enhancers can make the dosage form more palatable to the patient. Examples of common flavoring agents and flavor enhancers for pharmaceuticals that may be included in the composition and / or combination of the present invention include maltol, vanillin, ethyl vanillin, menthol, citric acid, fumaric acid, ethyl maltol, and tartaric acid.

[0047] In connection with the administration of a pharmaceutical composition, a sensory masking agent can be used to mask sensations for taste masking and / or odor masking. In one embodiment, the odor masking agent may include a fragrant aroma masking agent. In one embodiment, any known sensory masking agent known in the pharmaceutical literature may be contemplated.

[0048] The compositions of the present disclosure may also include dyes using any pharmaceutically acceptable coloring agent to improve their appearance in the liquid pharmaceutical compositions of the invention, wherein the components are dissolved or suspended in a liquid carrier such as water, vegetable oil, alcohol, polyethylene glycol, propylene glycol, or glycerin, and / or to facilitate the recognition of the product and the patient at the unit dose level.

[0049] For example, formulations for parenteral administration may include, as common excipients, sterile water or physiological saline, polyalkyl glycols such as polyethylene glycol, plant-derived oils, hydrogenated naphthalenes, and the like. In particular, biocompatible, biodegradable lactide polymers, lactide / glycolide copolymers, or polyoxyethylene-polyoxypropylene copolymers can be useful excipients for controlling the release of the active compound. Formulations for inhalation administration may contain, for example, lactose as an excipient, or an aqueous solution containing, for example, polyoxyethylene-9-lauryl ether, glycolic acid, and deoxycholate salts, or an oily solution for administration in the form of a nasal drop, or a gel for application in the nasal cavity. Formulations for parenteral administration may also include glycolate for oral administration, methoxysalicylate for rectal administration, or citric acid for vaginal administration.

[0050] Liquid pharmaceutical compositions and / or combinations may include an emulsifier for uniformly dispersing an active ingredient or other excipient that is insoluble in the liquid carrier throughout the composition and / or combination. Emulsifiers that may be useful in the liquid compositions and / or combinations of the present invention include, for example, gelatin, egg yolk, casein, cholesterol, gum arabic, tragacanth gum, chondrus rubber, pectin, methylcellulose, carbomer, cetostearyl alcohol, and cetyl alcohol.

[0051] Sweetening agents such as aspartame, lactose, sorbitol, saccharin, sodium saccharin, sucrose, aspartame, fructose, mannitol, and invert sugar may be added to improve the taste.

[0052] Preservatives and chelating agents, for example, alcohol, quaternary ammonium compounds such as benzethonium chloride, benzoxonium chloride, benzododecinium bromide, alkyltrimethylammonium bromide, cetrimonium bromide, benzalkonium chloride, phenylethyl alcohol, benzoic acid and its esters and salts, for example, C of 4-hydroxybenzoic acid 1-C7-alkyl esters, such as methyl 4-hydroxybenzoate, sodium methyl 4-hydroxybenzoate or propyl, butyl 4-hydroxybenzoate, butylated hydroxytoluene, butylated hydroxyanisole, cetylpyridinium chloride, cetrimide; parabens and derivatives, such as propylparaben or methylparaben; alkyl acids, such as potassium sorbate, sorbic acid, calcium sorbate, sodium sorbate; biguanides, such as chlorhexidine or its nasally acceptable salts, such as chlorhexidine gluconate, chlorhexidine acetate or chlorhexidine hydrochloride, 2-phenoxyethanol; boric acid; phenols, such as 4-chlorocresol, 4-chloroxylenol, dichlorophen or hexachlorophene, and chelating agents, such as ethylenediaminetetraacetic acid (EDTA) or ethylenediamine-N,N'-disuccinic acid (EDDS), may be added at levels safe for administration to improve storage stability.

[0053] The liquid composition and / or combination may also contain additives or excipients such as gluconic acid, lactic acid, citric acid or acetic acid, sodium gluconate, sodium lactate, sodium citrate, or sodium acetate. The choice of excipient and the amount used can be readily determined by the formulation scientist based on experience in the art and consideration of standard procedures and references.

[0054] The pharmaceutical composition and / or pharmaceutical combination of the present invention may be in the form of an aqueous suspension or an oily suspension. In one embodiment, the pharmaceutical composition and / or pharmaceutical combination of the present invention may be in the form of a sterile aqueous suspension or an oily suspension. This suspension may be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents. The sterile solution or suspension may be dissolved or dispersed in a non-toxic pharmaceutically acceptable diluent or solvent such as a solution in 1,3-butanediol, or may be prepared as a lyophilized powder for delivery as a dry powder. Acceptable vehicles and solvents that may be used include, among others, water, Ringer's solution, and isotonic saline. In addition, a sterile non-volatile oil may be conventionally used as a solvent or suspending medium. For this purpose, any non-irritating non-volatile oil, including synthetic monoglycerides or diglycerides, may be used.

[0055] Dosage forms include powders or liquids that can be administered via vaporization or aerosol, or as dry powders. Administration can be controlled through the use of a metered pump dispensing device known in the art.

[0056] In one embodiment of the present disclosure, betahistine or a pharmaceutically acceptable salt thereof can be formulated by any method suitable for nasal or intranasal administration. In one embodiment of the present disclosure, an intranasal pharmaceutical composition containing betahistine hydrochloride is provided. In another embodiment, an intranasal pharmaceutical composition containing betahistine monohydrochloride is provided. In another embodiment, an intranasal pharmaceutical composition containing betahistine dihydrochloride is provided.

[0057] In another embodiment, the intranasal pharmaceutical composition comprises betahistine free base. In another embodiment, the intranasal pharmaceutical composition is selected from betahistine hydrochloride, betahistine dihydrochloride, betahistine fumarate, betahistine maleate, betahistine tartrate, betahistine citrate, betahistine succinate, betahistine phthalate, betahistine mesylate, betahistine hydrobromide, betahistine hydroiodide, betahistine mesylate, betahistine phosphate, betahistine acetate, betahistine pamoate / embonate, betahistine nitrate, betahistine lactate, betahistine sulfate, betahistine methyl sulfate, betahistine oxalate, or any other pharmaceutically acceptable salt of betahistine disclosed herein or known in the art.

[0058] In one embodiment, to improve intranasal delivery and retention, betahistine or a pharmaceutically acceptable salt thereof may be encapsulated with cyclodextrin or formulated with other agents expected to promote delivery and retention within the nasal mucosa.

[0059] In one embodiment, the present disclosure provides a sustained or controlled release formulation of betahistine. For example, bioadhesive polymers have shown good potential for nasal formulations and can control the rate and extent of drug release. Further, the long contact time provided by the bioadhesive polymer at the absorption site can improve the bioavailability of the drug. Accordingly, nasal formulations containing bioadhesive polymers, such as chitosan microspheres, are contemplated by the present disclosure. Various biocompatible and biodegradable polymers that can be used to formulate sustained release nasal compositions include polyvinyl alcohol, chitosan, carbopol, alginate, hydroxypropyl methylcellulose, hydroxypropyl cellulose, starch, and gellan gum. In some embodiments, liposomal formulations can also be used to provide sustained release. In other embodiments, sustained release may be provided using intranasal microparticles or microspheres containing albumin, starch, dextran, and / or chitosan. These and other sustained transnasal drug delivery systems are reviewed by Ghori et al. (American Journal of Pharmacological Sciences, 2015, Vol. 3, No. 5, 110-119), which is hereby incorporated by reference in its entirety for all purposes.

[0060] In some embodiments, the controlled release nasal delivery system disclosed in U.S. Patent No. 8,574,622 (which is hereby incorporated by reference in its entirety for all purposes) can be used to provide sustained release of the active substance.

[0061] In some embodiments, formulations containing absorption enhancers may be used to provide sustained release. The goal of enhanced absorption in intranasal drug delivery is to facilitate or increase drug uptake. This can be achieved by extending the residence time to obtain a longer absorption time frame or by increasing penetration of the mucosal tissue. Enhanced absorption is achieved by mucoadhesion or in situ gelation for long residence times, sometimes a combination thereof, or by enhancing permeation by weakening cell junctions or increasing the fluidity of the membrane bilayer. Thus, formulations containing mucoadhesive excipients and / or in situ gelling agents may be used for intranasal delivery of betahistine. For example, in one embodiment, a sustained release formulation containing a mucoadhesive excipient such as carbomer, cellulose derivative, starch derivative, or chitosan may be used in the present invention.

[0062] In another embodiment, the sustained-release formulation is in the form of an in situ nasal gelation system comprising a stimulus-responsive polymer. Examples of stimulus-responsive polymers include polymers that change the rheological properties of a formulation that gels in situ upon contact with the nasal mucosa due to changes in temperature, pH, or ions. Examples of stimulus-responsive polymers or in situ gelling agents include, but are not limited to, poloxamers, pectin, and chitosan-based polymers. In one embodiment, the in situ gelation system may further comprise a mucoadhesive additive such as Carbopol 934P, chitosan, sodium carboxymethylcellulose (NaCMC), hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose, and methylpropylcellulose. In some embodiments, the nasal formulation comprising a stimulus-responsive polymer may further comprise, as needed, a mucoadhesive excipient, for example, those disclosed in Chonkar et al., Indian J Pharm Sci., 2015 Jul-Aug;77(4):367-375 (which is hereby incorporated by reference in its entirety for all purposes), and can be used as a sustained-release formulation for practicing the present invention. In other embodiments, mucoadhesive microspheres comprising betahistine dihydrochloride, disclosed in Philicheva et al. (International Journal of Drug Delivery, 2013, 5(4):389-401), which is hereby incorporated by reference in its entirety for all purposes, can be adapted for the nasal delivery of betahistine according to the present invention.

[0063] In some embodiments, formulations containing absorption promoters such as alkyl glycosides disclosed in US Patent Application Publication Nos. 2006 / 0045868, 2006 / 0045869, and 2008 / 0299079, or formulations containing a stearyl glycoside and sterol mixture derived from soybeans as an absorption promoter (Ando et al., Biological and Pharmaceutical Bulletin, 21(8), 862 - 865) may be used to provide sustained release, and each of these documents is hereby incorporated by reference in its entirety for all purposes. In some other embodiments, formulations containing sodium micelle glycocholate or sodium micelle glycocholate mixed with a fatty acid (e.g., linoleic acid) as an absorption promoter may be used as sustained release formulations. Other examples of absorption promoters include cyclodextrin, phospholipids, and chitosan.

[0064] Exemplary nasal formulations based on thermosetting polymers such as poloxamer are disclosed in Sharma et al. (Drug Dev Ind Pharm. 2014 Jul;40(7):869 - 78); Cho et al. (J Pharm Sci. 2011 Fcb;100(2):681 - 91); Choi et al. (Int Forum Allergy Rhinol. 2017 Jul;7(7):705 - 711); and Balakrishnan et al. (Molecules. 2015 Mar 4;20(3):4124 - 35), and each of these documents is hereby incorporated by reference in its entirety for all purposes. The formulations disclosed in these references can be adapted for the intranasal delivery of betahistine according to the present invention.

[0065] In one embodiment, the pharmaceutical composition of the present disclosure contains the components disclosed in Table 1. In another embodiment, the pharmaceutical composition of the present disclosure is substantially similar to the composition disclosed in Table 1. In one embodiment, the pharmaceutical composition of the present disclosure contains the components disclosed in Table 1 in various amounts of each component.

[0066]

Table 1

[0067] Pharmacokinetics In one embodiment, the pharmaceutical composition of the present disclosure provides C of betahistine detectable in human plasma concentration after a single administration of the pharmaceutical composition of the present disclosure. max In one embodiment, C of betahistine in human plasma concentration after a single administration of the pharmaceutical composition of the present disclosure max is at least about 0.2 ng / mL or at least about 0.5 ng / mL. In one embodiment, C max is measured after a single administration of about 1 mg to about 250 mg of betahistine or a pharmaceutically acceptable salt. In one embodiment, C max is measured after a single administration of about 5 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 150 mg, or about 200 mg of betahistine or a pharmaceutically acceptable salt. In other embodiments, C of a 5 mg betahistine dose administered intranasally max is about 80% to about 125% of about 640 pg / mL, about 80% to about 125% of about 2000 pg / mL for a 10 mg betahistine dose administered intranasally, about 80% to about 125% of about 4000 pg / mL for a 20 mg betahistine dose administered intranasally, and about 80% to about 125% of about 10500 pg / mL for a 40 mg betahistine dose administered intranasally. In other embodiments, C of a 5 mg betahistine dose administered intranasally max is about 80% to about 125% of about 230 to about 1260 pg / mL, about 80% to about 125% of about 790 to about 3470 pg / mL for a 10 mg betahistine dose administered intranasally, about 80% to about 125% of about 1900 to about 8300 pg / mL for a 20 mg betahistine dose administered intranasally, and about 80% to about 125% of about 8000 to about 16000 pg / mL for a 40 mg betahistine dose administered intranasally.

[0068] In one embodiment, C of a 5 mg betahistine dose administered intranasally max is in the range of about 80% to about 125% of about 500 pg / mL, 550 pg / mL, 600 pg / mL, 650 pg / mL, 700 pg / mL, 750 pg / mL, 800 pg / mL, 850 pg / mL, 900 pg / mL, 950 pg / mL, 1000 pg / mL, 1050 pg / mL, 1100 pg / mL, 1150 pg / mL, 1200 pg / mL, 1250 pg / mL, 1300 pg / mL, 1350 pg / mL, 1400 pg / mL, 1450 pg / mL, 1500 pg / mL, 1550 pg / mL, 1600 pg / mL, 1650 pg / mL, 1700 pg / mL, 1750 pg / mL, 1800 pg / mL, 1850 pg / mL, 1900 pg / mL, 1950 pg / mL, 2000 pg / mL, 2050 pg / mL, 2100 pg / mL, 2150 pg / mL, 2200 pg / mL, 2250 pg / mL, 2300 pg / mL, 2350 pg / mL, 2400 pg / mL, 2450 pg / mL, 2500 pg / mL, 2550 pg / mL, 2600 pg / mL, 2650 pg / mL, 2700 pg / mL, 2750 pg / mL, 2800 pg / mL, 2850 pg / mL, 2900 pg / mL, 2950 pg / mL, or about 3000 pg / mL.

[0069] In other embodiments, C of a 5 mg betahistine dose administered intranasally max is in the range of about 80% to about 125% of about 600 to about 3000 pg / mL, about 600 to about 2800 pg / mL, about 600 to about 2600 pg / mL, about 600 to about 2400 pg / mL, about 600 to about 2200 pg / mL, about 600 to about 2000 pg / mL, about 600 to about 1800 pg / mL, about 600 to about 1600 pg / mL, about 600 to about 1400 pg / mL, about 600 to about 1200 pg / mL, about 600 to about 1000 pg / mL, about 500 to about 2500 pg / mL, about 500 to about 2300 pg / mL, about 500 to about 2100 pg / mL, about 500 to about 1900 pg / mL, about 500 to about 1700 pg / mL, about 500 to about 1500 pg / mL, about 500 to about 1300 pg / mL, or about 500 to about 1100 pg / mL.

[0070] In one embodiment, C of a 10 mg betahistine dose administered intranasally max is in the range of about 80% to about 125% of about 1800 pg / mL, 2000 pg / mL, 2200 pg / mL, 2400 pg / mL, 2600 pg / mL, 2800 pg / mL, 3000 pg / mL, 3200 pg / mL, 3400 pg / mL, 3600 pg / mL, 3800 pg / mL, 4000 pg / mL, 4200 pg / mL, 4400 pg / mL, 4600 pg / mL, 4800 pg / mL, 5000 pg / mL, 5200 pg / mL, 5400 pg / mL, 5600 pg / mL, 5800 pg / mL, 6000 pg / mL, 6200 pg / mL, 6400 pg / mL, 6600 pg / mL, 6800 pg / mL, 7000 pg / mL, 7200 pg / mL, 7400 pg / mL, 7600 pg / mL, 7800 pg / mL, or about 8000 pg / mL.

[0071] In other embodiments, C of a 10 mg betahistine dose administered intranasally max is in the range of about 80% to about 125% of about 1800 to about 4500 pg / mL, about 2000 to about 5000 pg / mL, about 2200 to about 5500 pg / mL, about 2500 to about 5500 pg / mL, about 1600 to about 3000 pg / mL, about 1600 to about 3300 pg / mL, or about 1600 to about 3500 pg / mL. In one embodiment, C of a 20 mg betahistine dose administered intranasally max is in the range of about 80% to about 125% of about 3600 pg / mL, 3800 pg / mL, 4000 pg / mL, 4200 pg / mL, 4400 pg / mL, 4600 pg / mL, 4800 pg / mL, 5000 pg / mL, 5200 pg / mL, 5400 pg / mL, 5600 pg / mL, 5800 pg / mL, 6000 pg / mL, 6200 pg / mL, 6400 pg / mL, 6600 pg / mL, 6800 pg / mL, 7000 pg / mL, 7200 pg / mL, 7400 pg / mL, 7600 pg / mL, 7800 pg / mL, 8000 pg / mL, 8200 pg / mL, 8400 pg / mL, 8600 pg / mL, 8800 pg / mL, or 9000 pg / mL.

[0072] In other embodiments, C of a 20 mg betahistine dose administered intranasally maxis about 3000 to about 8000 pg / mL, about 3000 to about 7700 pg / mL, about 3000 to about 7500 pg / mL, about 3000 to about 7300 pg / mL, about 3000 to about 7100 pg / mL, about 3000 to about 6900 pg / mL, about 3000 to about 6700 pg / mL, about 3000 to about 6500 pg / mL, about 3000 to about 6300 pg / mL, about 3000 to about 6100 pg / mL, about 3000 to about 5800 pg / mL, about 3000 to about 5600 pg / mL, about 3000 to about 5400 pg / mL, about 3000 to about 5200 pg / mL, about 3000 to about 5000 pg / mL, about 3250 to about 8000 pg / mL, about 3250 to about 7750 pg / mL, about 3250 to about 7500 pg / mL, about 3250 to about 7250 pg / mL, about 3250 to about 7000 pg / mL, about 3250 to about 6800 pg / mL, about 3250 to about 6600 pg / mL, about 3250 to about 6400 pg / mL, about 3250 to about 6200 pg / mL, about 3250 to about 6000 pg / mL, about 3250 to about 5800 pg / mL, about 3250 to about 5600 pg / mL, about 3250 to about 5400 pg / mL, about 3250 to about 5200 pg / mL, about 3250 to about 5000 pg / mL, about 3250 to about 4800 pg / mL, about 3500 to about 8000 pg / mL, about 3500 to about 7800 pg / mL, about 3500 to about 7600 pg / mL, about 3500 to about 7400 pg / mL, about 3500 to about 7200 pg / mL, about 3500 to about 7000 pg / mL, about 3500 to about 6800 pg / mL, 3500 to about 6600 pg / mL, about 3500 to about 6400 pg / mL, about 3500 to about 6200 pg / mL, about 3500 to about 6000 pg / mL, about 3500 to about 5800 pg / mL, about 3500 to about 5600 pg / mL, about 3500 to about 5300 pg / mL, about 3500 to about 5100 pg / mL, about 3700 to about 7500 pg / mL, about 3700 to about 7200 pg / mL, about 3700 to about 7000 pg / mL, about 3700 to about 6800 pg / mL, about 3700 to about 6500 pg / mL, about 3700 to about 6300 pg / mL, about 3700 to about 6100 pg / mL, about 3700 to about 5900 pg / mL, about 3700 to about 5700 pg / mL, about 3700 to about 5500 pg / mL, about 3700 to about 5300 pg / mL,Or it is in the range of about 80% to about 125% of about 3700 to about 5100 pg / mL.

[0073] In one embodiment, C of a 40 mg betahistine dose administered intranasally max is in the range of about 80% to about 125% of about 8000 pg / mL, 8500 pg / mL, 9000 pg / mL, 9500 pg / mL, 9800 pg / mL, 10000 pg / mL, 10300 pg / mL, 10500 pg / mL, 10750 pg / mL, 11000 pg / mL, 11250 pg / mL, 11500 pg / mL, 11750 pg / mL, 12000 pg / mL, 12250 pg / mL, 12500 pg / mL, 12750 pg / mL, 13000 pg / mL, 13250 pg / mL, 13500 pg / mL, 13750 pg / mL, 14000 pg / mL, 14250 pg / mL, 14500 pg / mL, 14750 pg / mL, 15000 pg / mL, 15250 pg / mL, 15500 pg / mL, 15750 pg / mL, 16000 pg / mL, 16500 pg / mL, 17000 pg / mL, 17500 pg / mL, 18000 pg / mL, 18500 pg / mL, 19000 pg / mL, 19500 pg / mL, or 20000 pg / mL.

[0074] In other embodiments, C of a 40 mg betahistine dose administered intranasally maxis in the range of about 80% to about 125% of about 8,000 to about 20,000 pg / mL, about 8,000 to about 19,000 pg / mL, about 8,000 to about 18,500 pg / mL, about 8,000 to about 18,000 pg / mL, about 8,000 to about 17,500 pg / mL, about 8,000 to about 17,000 pg / mL, about 8,000 to about 16,500 pg / mL, about 8,000 to about 16,000 pg / mL, about 8,000 to about 15,500 pg / mL, about 8,000 to about 15,000 pg / mL, about 8,000 to about 14,500 pg / mL, about 8,000 to about 14,000 pg / mL, about 8,000 to about 13,500 pg / mL, about 8,000 to about 13,000 pg / mL, about 8,000 to about 12,500 pg / mL, about 9,000 to about 19,500 pg / mL, about 9,000 to about 19,000 pg / mL, about 9,000 to about 18,500 pg / mL, about 9,000 to about 18,000 pg / mL, about 9,000 to about 17,500 pg / mL, about 9,000 to about 17,000 pg / mL, about 9,000 to about 16,500 pg / mL, about 9,000 to about 16,000 pg / mL, about 9,000 to about 15,500 pg / mL, about 9,000 to about 15,000 pg / mL, about 9,000 to about 15,000 pg / mL, about 9,000 to about 14,500 pg / mL, about 9,000 to about 14,000 pg / mL, about 9,000 to about 13,500 pg / mL, about 9,000 to about 13,000 pg / mL, about 10,000 to about 18,500 pg / mL, about 10,000 to about 18,000 pg / mL, about 10,000 to about 17,500 pg / mL, about 10,000 to about 17,000 pg / mL, about 10,000 to about 16,500 pg / mL, about 10,000 to about 16,000 pg / mL, about 10,000 to about 15,500 pg / mL, about 10,000 to about 15,000 pg / mL, about 10,000 to about 14,500 pg / mL, or about 10,000 to about 14,000 pg / mL.

[0075] In one embodiment, C of a 60 mg dose of betahistine administered intranasally maxis in the range of about 80% to about 125% of about 14,000 pg / mL, 14,250 pg / mL, 14,500 pg / mL, 14,750 pg / mL, 15,000 pg / mL, 15,250 pg / mL, 15,500 pg / mL, 15,750 pg / mL, 16,000 pg / mL, 16,250 pg / mL, 16,500 pg / mL, 16,750 pg / mL, 17,000 pg / mL, 17,250 pg / mL, 17,500 pg / mL, 17,750 pg / mL, 18,000 pg / mL, 18,250 pg / mL, 18,500 pg / mL, or 19,000 pg / mL.

[0076] In other embodiments, C of a 60 mg betahistine dose administered intranasally max is in the range of about 80% to about 125% of about 13,500 to about 19,000 pg / mL, about 13,500 to about 18,500 pg / mL, about 13,500 to about 18,250 pg / mL, about 13,500 to about 18,000 pg / mL, about 13,500 to about 17,750 pg / mL, about 13,500 to about 17,500 pg / mL, about 13,500 to about 17,250 pg / mL, about 13,500 to about 17,000 pg / mL, about 13,500 to about 16,500 pg / mL, about 13,500 to about 16,000 pg / mL, about 14,000 to about 19,000 pg / mL, about 14,000 to about 18,500 pg / mL, about 14,000 to about 18,250 pg / mL, about 14,000 to about 18,000 pg / mL, about 14,000 to about 17,750 pg / mL, about 14,000 to about 17,500 pg / mL, about 14,000 to about 17,250 pg / mL, about 14,000 to about 17,000 pg / mL, about 14,000 to about 16,500 pg / mL, about 14,000 to about 16,000 pg / mL, about 14,500 to about 18,500 pg / mL, about 14,500 to about 18,250 pg / mL, about 14,500 to about 18,000 pg / mL, about 14,500 to about 17,750 pg / mL, about 14,500 to about 17,500 pg / mL, about 14,500 to about 17,250 pg / mL, about 14,500 to about 17,000 pg / mL, or about 14,500 to about 16,500 pg / mL.

[0077] In one embodiment, C of an 80 mg betahistine dose administered intranasally maxis in the range of about 80% to about 125% of about 18,000 pg / mL, 18,500 pg / mL, 19,000 pg / mL, 19,250 pg / mL, 19,500 pg / mL, 19,750 pg / mL, 20,000 pg / mL, 20,250 pg / mL, 20,500 pg / mL, 20,750 pg / mL, 21,000 pg / mL, 21,250 pg / mL, 21,500 pg / mL, 21,750 pg / mL, 22,000 pg / mL, 22,250 pg / mL, 22,500 pg / mL, 22,750 pg / mL, 23,000 pg / mL, 23,250 pg / mL, 23,500 pg / mL, 23,750 pg / mL, or 24,000 pg / mL.

[0078] In other embodiments, C of an 80 mg betahistine dose administered intranasally maxis in the range of about 80% to about 125% of about 18,000 to about 25,000 pg / mL, about 18,000 to about 24,500 pg / mL, about 18,000 to about 24,000 pg / mL, about 18,000 to about 23,750 pg / mL, about 18,000 to about 23,500 pg / mL, about 18,000 to about 23,250 pg / mL, about 18,000 to about 23,000 pg / mL, about 18,000 to about 22,750 pg / mL, about 18,000 to about 22,500 pg / mL, about 18,000 to about 22,250 pg / mL, about 18,000 to about 22,000 pg / mL, about 18,500 to about 25,000 pg / mL, about 18,500 to about 24,500 pg / mL, about 18,500 to about 24,000 pg / mL mL, about 18,500 to about 23,750 pg / mL, about 18,500 to about 23,500 pg / mL, about 18,500 to about 23,250 pg / mL, about 18,500 to about 23,000 pg / mL, about 18,500 to about 22,750 pg / mL, about 18,500 to about 22,500 pg / mL, about 18,500 to about 22,250 pg / mL, about 18,500 to about 22,000 pg / mL, about 19,000 to about 25,000 pg / mL, about 19,000 to about 24,500 pg / mL, about 19,000 to about 24,250 pg / mL, about 19,000 to about 24,000 pg / mL, about 19,000 to about 23,750 pg / mL, about 19,000 to about 23,500 pg / mL, about 19,000 to about 23,250 pg / mL, about 19,000 to about 23,000 pg / mL, about 19,000 to about 22,750 pg / mL, about 19,000 to about 22,500 pg / mL, about 19,000 to about 22,250 pg / mL, about 19,000 to about 22,000 pg / mL, about 19,500 to about 24,500 pg / mL, about 19,500 to about 24,250 pg / mL, about 19,500 to about 24,000 pg / mL, about 19,500 to about 23,750 pg / mL, about 19,500 to about 23,500 pg / mL, about 19,500 to about 23,250 pg / mL, about 19,500 to about 23,000 pg / mL, about 19,500 to about 22,750 pg / mL, about 19,500 to about 22,500 pg / mL, about 19,500 to about 22,250 pg / mL, or about 19,500 to about 22,000 pg / mL.

[0079] In one embodiment, the C of betahistine in the human plasma concentration after single administration of the intranasal pharmaceutical composition of the present disclosure maxis at least about 0.2 ng / mL or at least about 0.5 ng / mL. In one embodiment, the C of betahistine in the human plasma concentration after a single administration of the intranasal pharmaceutical composition of the present disclosure max is at least about 0.2 ng / mL, at least about 0.3 ng / mL, at least about 0.4 ng / mL, at least about 0.5 ng / mL, at least about 0.6 ng / mL, at least about 0.7 ng / mL, at least about 0.8 ng / mL, at least about 0.9 ng / mL, at least about 1 ng / mL, at least about 1.5 ng / mL, at least about 2 ng / mL, at least about 2.5 ng / mL, at least about 3 ng / mL, at least about 3.5 ng / mL, at least about 4 ng / mL, at least about 4.5 ng / mL, at least about 5 ng / mL, at least about 5.5 ng / mL, at least about 6 ng / mL, at least about 7.5 ng / mL, at least about 8 ng / mL, at least about 8.5 ng / mL, at least about 9 ng / mL, at least about 9.5 ng / mL, or at least about 10 ng / mL.

[0080] In one embodiment, the C of betahistine in the human plasma concentration after a single administration of the intranasal pharmaceutical composition of the present disclosure max is at least about 10 ng / mL, at least about 11 ng / mL, at least about 12 ng / mL, at least about 13 ng / mL, at least about 14 ng / mL, at least about 15 ng / mL, at least about 16 ng / mL, at least about 17 ng / mL, at least about 18 ng / mL, at least about 19 ng / mL, at least about 20 ng / mL, at least about 21 ng / mL, at least about 22 ng / mL, at least about 23 ng / mL, at least about 24 ng / mL, at least about 25 ng / mL, at least about 26 ng / mL, at least about 27 ng / mL, at least about 28 ng / mL, at least about 29 ng / mL, or at least about 30 ng / mL.

[0081] In one embodiment, the C of betahistine in the human plasma concentration after a single administration of the intranasal pharmaceutical composition of the present disclosure maxis at least about 3.5 ng / mL. In one embodiment, C of betahistine in human plasma concentration max is measured after a single administration of an intranasal pharmaceutical composition comprising from about 1 mg to about 200 mg of betahistine or a pharmaceutically acceptable salt. In one embodiment, C max is measured after a single intranasal dose administration of from about 5 mg, 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 21 mg, about 22 mg, about 23 mg, about 24 mg, about 25 mg, about 26 mg, about 27 mg, about 28 mg, about 29 mg, about 30 mg, about 31 mg, about 32 mg, about 33 mg, about 34 mg, about 35 mg, about 36 mg, about 37 mg, about 38 mg, about 39 mg, about 40 mg, about 41 mg, about 42 mg, about 43 mg, about 44 mg, about 45 mg, about 46 mg, about 47 mg, about 48 mg, about 49 mg, about 50 mg, about 51 mg, about 52 mg, about 53 mg, about 54 mg, about 55 mg, about 56 mg, about 57 mg, about 58 mg, about 59 mg, about 60 mg, about 61 mg, about 62 mg, about 63 mg, about 64 mg, about 65 mg, about 66 mg, about 67 mg, about 68 mg, about 69 mg, about 70 mg, about 71 mg, about 72 mg, about 73 mg, about 74 mg, about 75 mg, about 76 mg, about 77 mg, about 78 mg, about 79 mg, about 80 mg, about 81 mg, about 82 mg, about 83 mg, about 84 mg, about 85 mg, about 86 mg, about 87 mg, about 88 mg, about 89 mg, about 90 mg, about 91 mg, about 92 mg, about 93 mg, about 94 mg, about 95 mg, about 96 mg, about 97 mg, about 98 mg, about 99 mg, or about 100 mg of betahistine or a pharmaceutically acceptable salt thereof.

[0082] In one embodiment, C max is measured after a single intranasal administration of about 20 mg or about 40 mg of betahistine or a pharmaceutically acceptable salt. In another embodiment, C maxIt is measured after a single intranasal administration of about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 150 mg, or about 200 mg of betahistine or a pharmaceutically acceptable salt.

[0083] In one embodiment, the intranasal pharmaceutical composition of the present disclosure exhibits good tolerance and a dose-dependent increase in betahistine plasma concentration that is higher than that detectable after oral betahistine administration.

[0084] In one embodiment, the pharmaceutical composition of the present disclosure provides a t max in human plasma concentration of betahistine after a single administration of the pharmaceutical composition of the present disclosure. In one embodiment, the t max of betahistine in human plasma concentration after a single administration of the pharmaceutical composition of the present disclosure is about 0.05 hours or more, 0.06 hours or more, 0.07 hours or more, about 0.08 hours or more, about 0.09 hours, about 0.1 hours or more, about 0.11 hours or more, about 0.12 hours or more, about 0.13 hours or more, about 0.14 hours or more, about 0.15 hours or more, about 0.16 hours or more, about 0.17 hours or more, about 0.18 hours or more, about 0.19 hours or more, about 0.2 hours or more, about 0.25 hours or more, or about 0.3 hours or more. In one embodiment, t max is measured after a single administration of about 1 mg to about 250 mg of betahistine or a pharmaceutically acceptable salt. In one embodiment, t max is measured after a single administration of about 5 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 150 mg, or about 200 mg of betahistine or a pharmaceutically acceptable salt.

[0085] In one embodiment, the t maxis about 0.05 hours or more, 0.06 hours or more, 0.07 hours or more, about 0.08 hours or more, about 0.09 hours or more, about 0.1 hours or more, about 0.11 hours or more, about 0.12 hours or more, about 0.13 hours or more, about 0.14 hours or more, about 0.15 hours or more, about 0.16 hours or more, about 0.17 hours or more, about 0.18 hours or more, about 0.19 hours or more, about 0.2 hours or more, about 0.25 hours or more, or about 0.3 hours or more. In one embodiment, the t of betahistine in the human plasma concentration after a single administration of the intranasal pharmaceutical composition of the present disclosure max is about 0.09 hours or more, about 0.1 hours or more, about 0.11 hours or more, or about 0.12 hours or more.. In one embodiment, the t of betahistine in the human plasma concentration max is determined after a single administration of an intranasal pharmaceutical composition comprising about 1 mg to about 200 mg of betahistine or a pharmaceutically acceptable salt. In one embodiment, t maxIt is determined after a single intranasal administration of betahistine or a pharmaceutically acceptable salt thereof of about 5 mg, 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 21 mg, about 22 mg, about 23 mg, about 24 mg, about 25 mg, about 26 mg, about 27 mg, about 28 mg, about 29 mg, about 30 mg, about 31 mg, about 32 mg, about 33 mg, about 34 mg, about 35 mg, about 36 mg, about 37 mg, about 38 mg, about 39 mg, about 40 mg, about 41 mg, about 42 mg, about 43 mg, about 44 mg, about 45 mg, about 46 mg, about 47 mg, about 48 mg, about 49 mg, about 50 mg, about 51 mg, about 52 mg, about 53 mg, about 54 mg, about 55 mg, about 56 mg, about 57 mg, about 58 mg, about 59 mg, about 60 mg, about 61 mg, about 62 mg, about 63 mg, about 64 mg, about 65 mg, about 66 mg, about 67 mg, about 68 mg, about 69 mg, about 70 mg, about 71 mg, about 72 mg, about 73 mg, about 74 mg, about 75 mg, about 76 mg, about 77 mg, about 78 mg, about 79 mg, about 80 mg, about 81 mg, about 82 mg, about 83 mg, about 84 mg, about 85 mg, about 86 mg, about 87 mg, about 88 mg, about 89 mg, about 90 mg, about 91 mg, about 92 mg, about 93 mg, about 94 mg, about 95 mg, about 96 mg, about 97 mg, about 98 mg, about 99 mg, or about 100 mg.

[0086] In one embodiment, t max is determined after a single intranasal administration of about 20 mg or about 40 mg of betahistine or a pharmaceutically acceptable salt. In another embodiment, t max is determined after a single intranasal administration of about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 150 mg, or about 200 mg of betahistine or a pharmaceutically acceptable salt.

[0087] In one embodiment, the AUC of betahistine in the human plasma concentration after a single administration of the pharmaceutical composition of the present disclosure is at least about 50 hour*pg / mL, at least about 100 hour*pg / mL, at least about 200 hour*pg / mL, at least about 250 hour*pg / mL, at least about 300 hour*pg / mL, at least about 400 hr*pg / mL, at least about 500 hour*pg / mL, at least about 600 hour*pg / mL, at least about 700 hour*pg / mL, at least about 800 hour*pg / mL, at least about 900 hour*pg / mL, at least about 1000 hour*pg / mL, at least about 1100 hour*pg / mL, at least about 1200 hour*pg / mL, at least about 1300 hr*pg / mL, at least about 1400 hr*pg / mL, at least about 1500 hour*pg / mL, at least about 1600 hour*pg / mL, at least about 1700 hour*pg / mL, at least about 1800 hour*pg / mL, at least about 1900 hour*pg / mL, at least about 2000 hour*pg / mL, at least about 2100 hour*pg / mL, at least about 2200 hour*pg / mL, at least about 2300 hour*pg / mL, at least about 2400 hour*pg / mL, at least about 2500 hour*pg / mL, at least about 2600 hour*pg / mL, at least about 2700 hour*pg / mL, at least about 2800 hour*pg / mL, at least about 2900 hour*pg / mL, at least about 3000 hour*pg / mL, at least about 3100 hour*pg / mL, at least about 3200 hour*pg / mL, at least about 3300 hour*pg / mL, at least about 3400 hour*pg / mL or at least about 3500 hour*pg / mL. 0-last results in. In one embodiment, the AUC 0-last is measured after a single administration of about 1 mg to about 250 mg of betahistine or a pharmaceutically acceptable salt thereof.

[0088] In one embodiment, the AUC of betahistine in the human plasma concentration after a single administration of the intravenous pharmaceutical composition of the present disclosure 0-lastis at least about 0.05 hour*ng / mL, at least about 0.1 hour*ng / mL, at least about 0.2 hour*ng / mL, at least about 0.25 hour*ng / mL, at least about 0.3 hour*ng / mL, at least about 0.4 hour*ng / mL, at least about 0.5 hour*ng / mL, at least about 0.6 hour*ng / mL, at least about 0.7 hour*ng / mL, at least about 0.8 hour*ng / mL, at least about 0.9 hour*ng / mL, at least about 1.0 hour*ng / mL, at least about 1.1 hour*ng / mL, at least about 1.2 hour*ng / mL, at least about 1.3 hour*ng / mL, at least about 1.4 hour*ng / mL, at least about 1.5 hour*ng / mL, at least about 1.6 hour*ng / mL, at least about 1.7 hour*ng / mL, at least about 1.8 hour*ng / mL, at least about 1.9 hour*ng / mL, at least about 2.0 hour*ng / mL, at least about 2.1 hour*ng / mL, at least about 2.2 hour*ng / mL, at least about 2.3 hour*ng / mL, at least about 2.4 hour*ng / mL, at least about 2.5 hour*ng / mL, at least about 2.6 hour*ng / mL, at least about 2.7 hour*ng / mL, at least about 2.8 hour*ng / mL, at least about 2.9 hour*ng / mL, at least about 3.0 hour*ng / mL, at least about 3.1 hour*ng / mL, at least about 3.2 hour*ng / mL, at least about 3.3 hour*ng / mL, at least about 3.4 hour*ng / mL, at least about 3.5 hour*ng / mL, at least about 3.6 hour*ng / mL, at least about 3.7 hour*ng / mL, at least about 3.8 hour*ng / mL, at least about 3.9 hour*ng / mL, at least about 4.0 hour*ng / mL. In one embodiment, the AUC of betahistine in human plasma concentration after a single administration of the intravenous pharmaceutical composition of the present disclosure 0-last is at least about 1.5 hour*ng / mL or at least about 3.0 hour*ng / mL.

[0089] In one embodiment, the AUC of betahistine in human plasma concentration 0-lastis determined after a single administration of an intranasal pharmaceutical composition comprising about 1 mg to about 200 mg of betahistine or a pharmaceutically acceptable salt thereof. In one embodiment, the AUC 0-last is determined after a single intranasal administration of about 5 mg, 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 21 mg, about 22 mg, about 23 mg, about 24 mg, about 25 mg, about 26 mg, about 27 mg, about 28 mg, about 29 mg, about 30 mg, about 31 mg, about 32 mg, about 33 mg, about 34 mg, about 35 mg, about 36 mg, about 37 mg, about 38 mg, about 39 mg, about 40 mg, about 41 mg, about 42 mg, about 43 mg, about 44 mg, about 45 mg, about 46 mg, about 47 mg, about 48 mg, about 49 mg, about 50 mg, about 51 mg, about 52 mg, about 53 mg, about 54 mg, about 55 mg, about 56 mg, about 57 mg, about 58 mg, about 59 mg, about 60 mg, about 61 mg, about 62 mg, about 63 mg, about 64 mg, about 65 mg, about 66 mg, about 67 mg, about 68 mg, about 69 mg, about 70 mg, about 71 mg, about 72 mg, about 73 mg, about 74 mg, about 75 mg, about 76 mg, about 77 mg, about 78 mg, about 79 mg, about 80 mg, about 81 mg, about 82 mg, about 83 mg, about 84 mg, about 85 mg, about 86 mg, about 87 mg, about 88 mg, about 89 mg, about 90 mg, about 91 mg, about 92 mg, about 93 mg, about 94 mg, about 95 mg, about 96 mg, about 97 mg, about 98 mg, about 99 mg, or about 100 mg of betahistine or a pharmaceutically acceptable salt thereof. In one embodiment, the AUC 0-last is determined after a single intranasal administration of about 20 mg or about 40 mg of betahistine or a pharmaceutically acceptable salt. In another embodiment, the AUC 0-last is determined after a single intranasal administration of about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 150 mg, or about 200 mg of betahistine or a pharmaceutically acceptable salt.

[0090] In various embodiments, the AUC 0-lastis in the range of about 80% to 125% of about 210 pg*h / mL for a 5 mg dose of betahistine administered intranasally, about 80% to 125% of about 500 pg*h / mL for a 10 mg dose of betahistine administered intranasally, about 80% to 125% of about 1600 pg*h / mL for a 20 mg dose of betahistine administered intranasally, and about 80% to 125% of about 3500 pg*h / mL for a 40 mg dose of betahistine administered intranasally.

[0091] In some embodiments, the AUC for a 5 mg dose of betahistine administered intranasally 0-last is in the range of about 80% to about 125% of about 200 pg*h / mL, 300 pg*h / mL, 400 pg*h / mL, 500 pg*h / mL, 600 pg*h / mL, 700 pg*h / mL, 800 pg*h / mL, 900 pg*h / mL, 1000 pg*h / mL, 1100 pg*h / mL, 1200 pg*h / mL, 1300 pg*h / mL, 1400 pg*h / mL, or 1500 pg*h / mL.

[0092] In some other embodiments, the AUC for a 5 mg dose of betahistine administered intranasally 0-last is in the range of about 80% to about 125% of about 200 to about 500 pg*h / mL, about 200 to about 600 pg*h / mL, about 300 to about 700 pg*h / mL, about 400 to about 800 pg*h / mL, about 500 to about 1000 pg*h / mL, about 600 to about 1100 pg*h / mL, about 750 to about 1250 pg*h / mL, or about 800 to about 1400 pg*h / mL.

[0093] In some embodiments, the AUC for a 10 mg dose of betahistine administered intranasally 0-lastis in the range of about 80% to about 125% of about 500 pg*hour / mL, 600 pg*hour / mL, 700 pg*hour / mL, 800 pg*hour / mL, 900 pg*hour / mL, 1000 pg*hour / mL, 1100 pg*hour / mL, 1200 pg*hour / mL, 1300 pg*hour / mL, 1400 pg*hour / mL, or 1500 pg*hour / mL.

[0094] In some other embodiments, the AUC for a 10 mg betahistine dose administered intranasally 0-last is in the range of about 80% to about 125% of about 400 to about 800 pg*hour / mL, about 500 to about 800 pg*hour / mL, about 500 to about 900 pg*hour / mL, about 500 to about 1000 pg*hour / mL, about 500 to about 1200 pg*hour / mL, about 600 to about 1000 pg*hour / mL, about 600 to about 1100 pg*hour / mL, about 600 to about 1200 pg*hour / mL, about 700 to about 1100 pg*hour / mL, about 700 to about 1200 pg*hour / mL, about 800 to about 1300 pg*hour / mL, about 800 to about 1200 pg*hour / mL, or about 900 to about 1200 pg*hour / mL.

[0095] In some embodiments, the AUC for a 20 mg betahistine dose administered intranasally 0-last is in the range of about 80% to about 125% of about 1500 pg*hour / mL, 1600 pg*hour / mL, 1700 pg*hour / mL, 1800 pg*hour / mL, 1900 pg*hour / mL, 2000 pg*hour / mL, 2100 pg*hour / mL, 2200 pg*hour / mL, 2300 pg*hour / mL, 2400 pg*hour / mL, 2500 pg*hour / mL, 2600 pg*hour / mL, 2700 pg*hour / mL, 2800 pg*hour / mL, 2900 pg*hour / mL, or 3000 pg*hour / mL.

[0096] In some other embodiments, the AUC for a 20 mg betahistine dose administered intranasally 0-lastis in the range of about 80% to about 125% of about 1500 to about 2000 pg·h / mL, about 1500 to about 2200 pg·h / mL, about 1600 to about 2100 pg·h / mL, about 1700 to about 2200 pg·h / mL, about 1700 to about 2400 pg·h / mL, about 1800 to about 2400 pg·h / mL, about 1900 to about 2500 pg·h / mL, about 2000 to about 2500 pg·h / mL, about 2100 to about 2700 pg·h / mL, or about 2200 to about 2900 pg·h / mL.

[0097] In some embodiments, the AUC for a 40 mg dose of betahistine administered intranasally 0-last is in the range of about 80% to about 125% of about 3300 pg·h / mL, 3400 pg·h / mL, 3500 pg·h / mL, 3600 pg·h / mL, 3700 pg·h / mL, 3800 pg·h / mL, 3900 pg·h / mL, 4000 pg·h / mL, 4100 pg·h / mL, 4250 pg·h / mL, 4500 pg·h / mL, 4750 pg·h / mL, 5000 pg·h / mL, 5250 pg·h / mL, 5500 pg·h / mL, 5750 pg·h / mL, 6000 pg·h / mL, 6250 pg·h / mL, 6500 pg·h / mL, or 7000 pg·h / mL.

[0098] In some other embodiments, the AUC for a 40 mg dose of betahistine administered intranasally 0-last is in the range of about 80% to about 125% of about 3300 to about 3800 pg·h / mL, about 3300 to about 4000 pg·h / mL, about 3300 to about 4200 pg·h / mL, about 3300 to about 4500 pg·h / mL, about 3500 to about 4000 pg·h / mL, about 3500 to about 4200 pg·h / mL, about 3500 to about 4500 pg·h / mL, about 3750 to about 4250 pg·h / mL, about 3750 to about 4500 pg·h / mL, about 3750 to about 4750 pg·h / mL, about 4000 to about 5000 pg·h / mL, or about 4000 to about 5500 pg·h / mL.

[0099] In some embodiments, the AUC for a 60 mg dose of betahistine administered intranasally 0-last is in the range of about 80% to about 125% of about 5300 pg·h / mL, 5400 pg·h / mL, 5500 pg·h / mL, about 5750 pg·h / mL, 6000 pg·h / mL, 6250 pg·h / mL, 6500 pg·h / mL, 6750 pg·h / mL, 7000 pg·h / mL, 7250 pg·h / mL, 7500 pg·h / mL, 7750 pg·h / mL, or about 8000 pg·h / mL.

[0100] In some other embodiments, the AUC for a 60 mg dose of betahistine administered intranasally 0-last is in the range of about 80% to about 125% of about 5300 to about 5800 pg·h / mL, about 5400 to about 5900 pg·h / mL, about 5500 to about 6000 pg·h / mL, about 5400 to about 6200 pg·h / mL, about 5500 to about 6400 pg·h / mL, about 5500 to about 6700 pg·h / mL, about 5500 to about 6900 pg·h / mL, about 5700 to about 6300 pg·h / mL, about 5700 to about 6500 pg·h / mL, about 5700 to about 6700 pg·h / mL, about 5900 to about 6500 pg·h / mL, about 5900 to about 6700 pg·h / mL, about 6000 to about 7250 pg·h / mL, about 6000 to about 7000 pg·h / mL, about 6000 to about 7500 pg·h / mL.

[0101] In some embodiments, the AUC for an 80 mg dose of betahistine administered intranasally 0-last is in the range of about 80% to about 125% of about 7500 pg·h / mL, 7750 pg·h / mL, 8000 pg·h / mL, 8250 pg·h / mL, 8500 pg·h / mL, 8750 pg·h / mL, 9000 pg·h / mL, 9250 pg·h / mL, 9500 pg·h / mL, 9750 pg·h / mL, or 10000 pg·h / mL.

[0102] In some other embodiments, the AUC for an 80 mg dose of betahistine administered intranasally 0-last is in the range of about 80% to about 125% of about 7300 to about 8000 pg*h / mL, about 7500 to about 8200 pg*h / mL, about 7500 to about 8000 pg*h / mL, about 7500 to about 8500 pg*h / mL, about 7750 to about 8500 pg*h / mL, about 7750 to about 8750 pg*h / mL, about 8000 to about 8500 pg*h / mL, about 8000 to about 8750 pg*h / mL, about 8000 to about 9000 pg*h / mL, about 8250 to about 9000 pg*h / mL, about 8250 to about 8750 pg*h / mL, about 8250 to about 9250 pg*h / mL, about 8500 to about 9500 pg*h / mL, or about 8500 to about 9000 pg*h / mL.

[0103] In one embodiment, the pharmaceutical composition of the present disclosure has an AUC of betahistine in human plasma concentration after a single administration of the pharmaceutical composition of the present disclosure of at least about 100 hour*pg / mL, at least about 200 hour*pg / mL, at least about 250 hour*pg / mL, at least about 300 hour*pg / mL, at least about 400 hour*pg / mL, at least about 500 hour*pg / mL, at least about 600 hour*pg / mL, at least about 700 hour*pg / mL, at least about 800 hour*pg / mL, at least about 900 hour*pg / mL, at least about 1000 hour*pg / mL, at least about 1100 hour*pg / mL, at least about 1200 hour*pg / mL, at least about 1300 hour*pg / mL, at least about 1400 hour*pg / mL, at least about 1500 hour*pg / mL, at least about 1600 hour*pg / mL, at least about 1700 hour*pg / mL, at least about 1800 hour*pg / mL, at least about 1900 hour*pg / mL, at least about 2000 hour*pg / mL, at least about 2100 hour*pg / mL, at least about 2200 hour*pg / mL, at least about 2300 hour*pg / mL, at least about 2400 hour*pg / mL, at least about 2500 hour*pg / mL, at least about 2600 hour*pg / mL, at least about 2700 hour*pg / mL, at least about 2800 hour*pg / mL, at least about 2900 hour*pg / mL, at least about 3000 hour*pg / mL, at least about 3100 hour*pg / mL, at least about 3200 hour*pg / mL, at least about 3300 hour*pg / mL, at least about 3400 hour*pg / mL or at least about 3500 hour*pg / mL. 0-inf This results in. In one embodiment, the AUC 0-inf is measured after a single administration of about 1 mg to about 250 mg of betahistine or a pharmaceutically acceptable salt.

[0104] In one embodiment, the AUC of betahistine in human plasma concentration after a single administration of the intranasal pharmaceutical composition of the present disclosure 0-infis at least about 0.1 hour*ng / mL, at least about 0.2 hour*ng / mL, at least about 0.25 hour*ng / mL, at least about 0.3 hour*ng / mL, at least about 0.4 hour*ng / mL, at least about 0.5 hour*ng / mL, at least about 0.6 hour*ng / mL, at least about 0.7 hour*ng / mL, at least about 0.8 hour*ng / mL, at least about 0.9 hour*ng / mL, at least about 1.0 hour*ng / mL, at least about 1.1 hour*ng / mL, at least about 1.2 hour*ng / mL, at least about 1.3 hour*ng / mL, at least about 1.4 hour*ng / mL, at least about 1.5 hour*ng / mL, at least about 1.6 hour*ng / mL, at least about 1.7 hour*ng / mL, at least about 1.8 hour*ng / mL, at least about 1.9 hour*ng / mL, at least about 2.0 hour*ng / mL, at least about 2.1 hour*ng / mL, at least about 2.2 hour*ng / mL, at least about 2.3 hour*ng / mL, at least about 2.4 hour*ng / mL, at least about 2.5 hour*ng / mL, at least about 2.6 hour*ng / mL, at least about 2.7 hour*ng / mL, at least about 2.8 hour*ng / mL, at least about 2.9 hour*ng / mL, at least about 3.0 hour*ng / mL, at least about 3.1 hour*ng / mL, at least about 3.2 hour*ng / mL, at least about 3.3 hour*ng / mL, at least about 3.4 hour*ng / mL, at least about 3.5 hour*ng / mL, at least about 3.6 hour*ng / mL, at least about 3.7 hour*ng / mL, at least about 3.8 hour*ng / mL, at least about 3.9 hour*ng / mL, at least about 4.0 hour*ng / mL. In one embodiment, the AUC of betahistine in the human plasma concentration after a single administration of the intranasal pharmaceutical composition of the present disclosure 0-inf is at least about 1.5 hour*ng / mL or at least about 3.0 hour*ng / mL.

[0105] In one embodiment, the AUC of betahistine in the human plasma concentration 0-inf is determined after a single administration of an intranasal pharmaceutical composition comprising from about 1 mg to about 200 mg of betahistine or a pharmaceutically acceptable salt thereof. In one embodiment, the AUC0-inf is determined after single intranasal administration of about 5 mg, 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 21 mg, about 22 mg, about 23 mg, about 24 mg, about 25 mg, about 26 mg, about 27 mg, about 28 mg, about 29 mg, about 30 mg, about 31 mg, about 32 mg, about 33 mg, about 34 mg, about 35 mg, about 36 mg, about 37 mg, about 38 mg, about 39 mg, about 40 mg, about 41 mg, about 42 mg, about 43 mg, about 44 mg, about 45 mg, about 46 mg, about 47 mg, about 48 mg, about 49 mg, about 50 mg, about 51 mg, about 52 mg, about 53 mg, about 54 mg, about 55 mg, about 56 mg, about 57 mg, about 58 mg, about 59 mg, about 60 mg, about 61 mg, about 62 mg, about 63 mg, about 64 mg, about 65 mg, about 66 mg, about 67 mg, about 68 mg, about 69 mg, about 70 mg, about 71 mg, about 72 mg, about 73 mg, about 74 mg, about 75 mg, about 76 mg, about 77 mg, about 78 mg, about 79 mg, about 80 mg, about 81 mg, about 82 mg, about 83 mg, about 84 mg, about 85 mg, about 86 mg, about 87 mg, about 88 mg, about 89 mg, about 90 mg, about 91 mg, about 92 mg, about 93 mg, about 94 mg, about 95 mg, about 96 mg, about 97 mg, about 98 mg, about 99 mg, or about 100 mg of betahistine or a pharmaceutically acceptable salt thereof. In one embodiment, AUC 0-inf is determined after intranasal administration of about 20 mg or about 40 mg of betahistine or a pharmaceutically acceptable salt thereof. In another embodiment, AUC 0-inf is determined after intranasal administration of about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 150 mg, or about 200 mg of betahistine or a pharmaceutically acceptable salt thereof.

[0106] In various embodiments, the AUC of betahistine 0-infis in the range of about 80% to 125% of about 275 pg*hour / mL for a 5 mg betahistine dose administered intranasally, about 80% to 125% of about 700 pg*hour / mL for a 10 mg betahistine dose administered intranasally, about 80% to 125% of about 1630 pg*hour / mL for a 20 mg betahistine dose administered intranasally, and about 80% to 125% of about 2940 pg*hour / mL for a 40 mg betahistine dose administered intranasally.

[0107] In some embodiments, the AUC for a 5 mg betahistine dose administered intranasally 0-inf is in the range of about 80% to about 125% of about 250 pg*hour / mL, 275 pg*hour / mL, 300 pg*hour / mL, 350 pg*hour / mL, 400 pg*hour / mL, 450 pg*hour / mL, 500 pg*hour / mL, 600 pg*hour / mL, 700 pg*hour / mL, 800 pg*hour / mL, 900 pg*hour / mL, or 1000 pg*hour / mL.

[0108] In some other embodiments, the AUC of a 5 mg betahistine dose administered intranasally 0-inf is in the range of about 80% to about 125% of about 250 to about 350 pg*hour / mL, about 250 to about 500 pg*hour / mL, about 275 to about 375 pg*hour / mL, about 275 to about 475 pg*hour / mL, about 275 to about 575 pg*hour / mL, about 250 to 850 pg*hour / mL, about 300 to about 800 pg*hour / mL, about 300 to about 700 pg*hour / mL, about 400 to about 800 pg*hour / mL, about 500 to about 1000 pg*hour / mL, about 750 to about 1250 pg*hour / mL, or about 750 to about 1500 pg*hour / mL.

[0109] In some embodiments, the AUC of a 10 mg betahistine dose administered intranasally 0-infis in the range of about 80% to about 125% of about 650 pg·h / mL, about 700 pg·h / mL, about 800 pg·h / mL, about 900 pg·h / mL, about 1000 pg·h / mL, about 1250 pg·h / mL, about 1500 pg·h / mL, about 1750 pg·h / mL, or about 2000 pg·h / mL.

[0110] In some other embodiments, the AUC of a 10 mg betahistine dose administered intranasally 0-inf is in the range of about 80% to about 125% of about 650 to about 1000 pg·h / mL, about 650 to about 1250 pg·h / mL, about 700 to about 1400 pg·h / mL, about 700 to about 1200 pg·h / mL, about 700 to 1000 pg·h / mL, about 800 to about 1200 pg·h / mL, about 800 to about 1400 pg·h / mL, about 800 to about 1600 pg·h / mL, about 1000 to about 1500 pg·h / mL, or about 1000 to about 2000 pg·h / mL.

[0111] In some embodiments, the AUC of a 20 mg betahistine dose administered intranasally 0-inf is in the range of about 80% to about 125% of about 1600 pg·h / mL, about 1700 pg·h / mL, about 1800 pg·h / mL, about 1900 pg·h / mL, about 2000 pg·h / mL, about 2250 pg·h / mL, about 2500 pg·h / mL, about 2750 pg·h / mL, about 3000 pg·h / mL, or about 3500 pg·h / mL.

[0112] In some other embodiments, the AUC of a 20 mg betahistine dose administered intranasally 0-infis in the range of about 80% to about 125% of about 1600 to about 2000 pg*hour / mL, about 1600 to about 2200 pg*hour / mL, about 1600 to about 2400 pg*hour / mL, about 1600 to about 2600 pg*hour / mL, about 1800 to about 2400 pg*hour / mL, about 1800 to about 2600 pg*hour / mL, about 1800 to about 2800 pg*hour / mL, about 2000 to about 3000 pg*hour / mL, about 2000 to about 2500 pg*hour / mL, about 2000 to about 2800 pg*hour / mL, about 2250 to about 3250 pg*hour / mL, about 2250 to about 3000 pg*hour / mL, about 2500 to about 3500 pg*hour / mL, or about 2500 to about 3000 pg*hour / mL.

[0113] In some embodiments, the AUC of a 40 mg dose of betahistine administered intranasally 0-inf is in the range of about 80% to about 125% of about 2800 pg*hour / mL, about 2900 pg*hour / mL, about 2950 pg*hour / mL, about 3000 pg*hour / mL, about 3100 pg*hour / mL, about 3200 pg*hour / mL, about 3300 pg*hour / mL, about 3400 pg*hour / mL, about 3500 pg*hour / mL, about 3600 pg*hour / mL, about 3700 pg*hour / mL, about 3800 pg*hour / mL, about 3900 pg*hour / mL, about 4000 pg*hour / mL, about 4250 pg*hour / mL, about 4500 pg*hour / mL, about 4750 pg*hour / mL, about 5000 pg*hour / mL, about 5250 pg*hour / mL, about 5500 pg*hour / mL, about 5750 pg*hour / mL, or about 6000 pg*hour / mL.

[0114] In some other embodiments, the AUC of a 40 mg dose of betahistine administered intranasally 0-infis in the range of about 80% to about 125% of about 2800 to about 3300 pg*hour / mL, about 2800 to about 3500 pg*hour / mL, about 2800 to about 3800 pg*hour / mL, about 3000 to about 3500 pg*hour / mL, about 3500 to about 3750 pg*hour / mL, about 3000 to about 4000 pg*hour / mL, about 3250 to about 4250 pg*hour / mL, about 3250 to about 4500 pg*hour / mL, about 3500 to about 4500 pg*hour / mL, about 3500 to about 4000 pg*hour / mL, about 3750 to about 4750 pg*hour / mL, about 3750 to about 4500 pg*hour / mL, about 4000 to about 5000 pg*hour / mL, about 4500 to about 5500 pg*hour / mL, or about 5000 to about 6000 pg*hour / mL.

[0115] In some embodiments, the AUC of a 60 mg dose of betahistine administered intranasally 0-inf is in the range of about 80% to about 125% of about 5300 pg*hour / mL, 5400 pg*hour / mL, 5500 pg*hour / mL, about 5750 pg*hour / mL, 6000 pg*hour / mL, 6250 pg*hour / mL, 6500 pg*hour / mL, 6750 pg*hour / mL, 7000 pg*hour / mL, 7250 pg*hour / mL, 7500 pg*hour / mL, 7750 pg*hour / mL, or about 8000 pg*hour / mL.

[0116] In some other embodiments, the AUC of a 60 mg dose of betahistine administered intranasally 0-infis in the range of about 80% to about 125% of about 5300 to about 5800 pg·h / mL, about 5400 to about 5900 pg·h / mL, about 5500 to about 6000 pg·h / mL, about 5400 to about 6200 pg·h / mL, about 5500 to about 6400 pg·h / mL, about 5500 to about 6700 pg·h / mL, about 5500 to about 6900 pg·h / mL, about 5700 to about 6300 pg·h / mL, about 5700 to about 6500 pg·h / mL, about 5700 to about 6700 pg·h / mL, about 5900 to about 6500 pg·h / mL, about 5900 to about 6700 pg·h / mL, about 6000 to about 7250 pg·h / mL, about 6000 to about 7000 pg·h / mL, about 6000 to about 7500 pg·h / mL.

[0117] In some embodiments, the AUC of an 80 mg dose of betahistine administered intranasally 0-inf is in the range of about 80% to about 125% of about 7500 pg·h / mL, 7750 pg·h / mL, 8000 pg·h / mL, 8250 pg·h / mL, 8500 pg·h / mL, 8750 pg·h / mL, 9000 pg·h / mL, 9250 pg·h / mL, 9500 pg·h / mL, 9750 pg·h / mL, or 10000 pg·h / mL.

[0118] In some other embodiments, the AUC of an 80 mg dose of betahistine administered intranasally 0-inf is in the range of about 80% to about 125% of about 7300 to about 8000 pg·h / mL, about 7500 to about 8200 pg·h / mL, about 7500 to about 8000 pg·h / mL, about 7500 to about 8500 pg·h / mL, about 7750 to about 8500 pg·h / mL, about 7750 to about 8750 pg·h / mL, about 8000 to about 8500 pg·h / mL, about 8000 to about 8750 pg·h / mL, about 8000 to about 9000 pg·h / mL, about 8250 to about 9000 pg·h / mL, about 8250 to about 8750 pg·h / mL, about 8250 to about 9250 pg·h / mL, about 8500 to about 9500 pg·h / mL, or about 8500 to about 9000 pg·h / mL.

[0119] In one embodiment, the absolute bioavailability (%F) of betahistine administered intranasally is about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90%. In one embodiment, the absolute bioavailability (%F) of betahistine administered intranasally is about 30-80%, about 25-75%, about 20-60%, about 10-50%, about 30-60%, about 40-60%, about 40-70%, about 40-80%, or about 50-80%.

[0120] In one embodiment, the relative bioavailability (F) of 5 mg of betahistine administered intranasally rel) is about 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 times the oral bioavailability. In one embodiment, the relative bioavailability of 10 mg of betahistine administered intranasally is about 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, or 29 times the oral bioavailability. In one embodiment, the relative bioavailability of 20 mg of betahistine administered intranasally is about 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, or 42 times the oral bioavailability. In one embodiment, the relative bioavailability of 40 mg of betahistine administered intranasally is about 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, or 46 times the oral bioavailability. In one embodiment, the relative bioavailability of 60 mg of betahistine administered intranasally is about 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, or 70 times the oral bioavailability. In one embodiment, the relative bioavailability of 80 mg of betahistine administered intranasally is about 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, or 80 times the oral bioavailability. In one embodiment, the relative bioavailability of 100 mg of betahistine administered intranasally is about 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, or 90 times the oral bioavailability.

[0121] In one embodiment, the relative bioavailability of betahistine administered intranasally is about 10 to about 25 times, about 15 to about 30 times, about 20 to about 40 times, about 20 to about 30 times, about 20 to about 50 times, about 25 to about 40 times, about 25 to about 45 times, 25 to about 50 times, about 15 to about 45 times, or about 30 to about 60 times the oral bioavailability.

[0122] In one embodiment, the t 1 / 2 (apparent half-life) of betahistine determined based on a single administration of the pharmaceutical composition of the present disclosure is about 0.07 hours or more, about 0.08 hours or more, about 0.09 hours, about 0.1 hours or more, about 0.2 hours or more, about 0.3 hours or more, about 0.4 hours or more, about 0.5 hours or more, about 0.6 hours or more, about 0.6 hours or more, about 0.8 hours or more, about 0.9 hours or more, or about 1.0 hours or more. In one embodiment, t 1 / 2 is determined based on a single administration of about 1 mg to about 250 mg of betahistine or a pharmaceutically acceptable salt thereof. In one embodiment, t 1 / 2 is determined based on a single administration of about 5 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 150 mg, or about 200 mg of betahistine or a pharmaceutically acceptable salt.

[0123] In one embodiment, the t 1 / 2 (apparent half-life) of betahistine determined based on a single administration of the intranasal pharmaceutical composition of the present disclosure is about 0.07 hours or more, about 0.08 hours or more, about 0.09 hours or more, about 0.1 hours or more, about 0.2 hours or more, about 0.3 hours or more, about 0.4 hours or more, about 0.5 hours or more, about 0.6 hours or more, about 0.6 hours or more, about 0.8 hours or more, about 0.9 hours or more, or about 1.0 hours or more. In one embodiment, the t 1 / 2 of betahistine determined based on a single administration of the intranasal pharmaceutical composition of the present disclosure is about 0.4 hours or more or about 0.8 hours or more. In one embodiment, the t 1 / 2 of betahistine determined based on a single administration of the intranasal pharmaceutical composition of the present disclosure is about 0.5 hours or about 0.9 hours.

[0124] In one embodiment, t 1 / 2 is determined based on a single intranasal administration of about 1 mg to about 200 mg of betahistine or a pharmaceutically acceptable salt thereof. In one embodiment, t 1 / 2 is determined based on a single intranasal administration of about 5 mg, 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 21 mg, about 22 mg, about 23 mg, about 24 mg, about 25 mg, about 26 mg, about 27 mg, about 28 mg, about 29 mg, about 30 mg, about 31 mg, about 32 mg, about 33 mg, about 34 mg, about 35 mg, about 36 mg, about 37 mg, about 38 mg, about 39 mg, about 40 mg, about 41 mg, about 42 mg, about 43 mg, about 44 mg, about 45 mg, about 46 mg, about 47 mg, about 48 mg, about 49 mg, about 50 mg, about 51 mg, about 52 mg, about 53 mg, about 54 mg, about 55 mg, about 56 mg, about 57 mg, about 58 mg, about 59 mg, about 60 mg, about 61 mg, about 62 mg, about 63 mg, about 64 mg, about 65 mg, about 66 mg, about 67 mg, about 68 mg, about 69 mg, about 70 mg, about 71 mg, about 72 mg, about 73 mg, about 74 mg, about 75 mg, about 76 mg, about 77 mg, about 78 mg, about 79 mg, about 80 mg, about 81 mg, about 82 mg, about 83 mg, about 84 mg, about 85 mg, about 86 mg, about 87 mg, about 88 mg, about 89 mg, about 90 mg, about 91 mg, about 92 mg, about 93 mg, about 94 mg, about 95 mg, about 96 mg, about 97 mg, about 98 mg, about 99 mg, or about 100 mg of betahistine or a pharmaceutically acceptable salt thereof. In one embodiment, t 1 / 2 is determined based on a single intranasal administration of about 20 mg or about 40 mg of betahistine or a pharmaceutically acceptable salt. In another embodiment, t 1 / 2 is determined based on a single intranasal administration of about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 150 mg, or about 200 mg of betahistine or a pharmaceutically acceptable salt thereof.

[0125] In one embodiment, the pharmaceutical composition of the present disclosure results in a detectable C of 2-PAA (2-pyridyl lactic acid) in human plasma after a single administration of the pharmaceutical composition of the present disclosure. max In one embodiment, the C of 2-PAA in human plasma after a single administration of the pharmaceutical composition of the present disclosure is max at least about 15 ng / mL or at least about 50 ng / mL. In one embodiment, the C of 2-PAA is max measured after a single administration of about 1 mg to about 250 mg of betahistine or a pharmaceutically acceptable salt thereof. In one embodiment, the C of 2-PAA is max measured after a single administration of about 5 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 150 mg, or about 200 mg of betahistine or a pharmaceutically acceptable salt. In other embodiments, the C of 2-PAA for a 5 mg betahistine dose administered intranasally is max about 80% to about 125% of about 65 ng / ml, about 80% to about 125% of about 150 ng / ml for a 10 mg betahistine dose administered intranasally, about 80% to about 125% of about 370 ng / ml for a 20 mg betahistine dose administered intranasally, and about 80% to about 125% of about 520 ng / ml for a 40 mg betahistine dose administered intranasally. In other embodiments, the C of 2-PAA for a 5 mg betahistine dose administered intranasally is max about 80% to about 125% of about 16 to about 95 ng / ml, about 80% to about 125% of about 115 ng / ml to about 175 ng / ml for a 10 mg betahistine dose administered intranasally, about 80% to about 125% of about 250 to about 430 g / ml for a 20 mg betahistine dose administered intranasally, and about 80% to about 125% of about 290 to about 690 ng / ml for a 40 mg betahistine dose administered intranasally.

[0126] In one embodiment, the C of 2-PAA in human plasma after a single administration of the intranasal pharmaceutical composition of the present disclosure is maxis at least about 15 ng / mL or at least about 50 ng / mL. In one embodiment, the C of 2-PAA in the human plasma concentration after a single administration of the intranasal pharmaceutical composition of the present disclosure max is at least about 10 ng / mL, at least about 15 ng / mL, at least about 20 ng / mL, at least about 25 ng / mL, at least about 30 ng / mL, at least about 35 ng / mL, at least about 40 ng / mL, at least about 45 ng / mL, at least about 50 ng / mL, at least about 55 ng / mL, at least about 60 ng / mL, at least about 65 ng / mL, at least about 70 ng / mL, at least about 75 ng / mL, at least about 80 ng / mL, at least about 85 ng / mL, at least about 90 ng / mL, at least about 95 ng / mL, at least about 100 ng / mL, at least about 150 ng / mL, at least about 200 ng / mL, at least about 250 ng / mL, at least about 300 ng / mL, at least about 400 ng / mL, at least about 450 ng / mL, at least about 500 ng / mL, or at least about 550 ng / mL.

[0127] In one embodiment, the C of 2-PAA in the human plasma concentration after a single administration of the intranasal pharmaceutical composition of the present disclosure max is at least about 60 ng / mL. In one embodiment, the C of 2-PAA in the human plasma concentration max is measured after a single administration of an intranasal pharmaceutical composition containing about 1 mg to about 200 mg of betahistine or a pharmaceutically acceptable salt thereof. In one embodiment, the C of 2-PAA max is measured after a single intranasal administration of about 5 mg to about 100 mg of betahistine or a pharmaceutically acceptable salt thereof. In one embodiment, the C of 2-PAA max is measured after a single intranasal administration of about 20 mg to about 40 mg of betahistine or a pharmaceutically acceptable salt thereof. In another embodiment, the C of 2-PAA maxIt is measured after a single intranasal administration of about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 150 mg, or about 200 mg of betahistine or a pharmaceutically acceptable salt.

[0128] In one embodiment, the pharmaceutical composition of the present disclosure provides a t max of 2-PAA in human plasma concentration after a single administration of the pharmaceutical composition of the present disclosure. In one aspect, the t max of 2-PAA in human plasma concentration after a single administration of the pharmaceutical composition of the present disclosure is about 0.6 hours or more, about 0.7 hours or more, about 0.8 hours or more, about 0.9 hours or more, about 1 hour or more, about 1.1 hours or more, about 1.2 hours or more, about 1.25 hours or more, about 1.3 hours or more, about 1.4 hours or more, or about 1.5 hours or more. In one embodiment, t max is measured after a single administration of about 1 mg to about 250 mg of betahistine or a pharmaceutically acceptable salt. In one embodiment, t max is measured after a single administration of about 5 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, 90 mg, about 100 mg, about 150 mg, or about 200 mg of betahistine or a pharmaceutically acceptable salt.

[0129] In one embodiment, the t max of 2-PAA in human plasma concentration after a single administration of the intranasal pharmaceutical composition of the present disclosure is about 1.0 hour. In one embodiment, the t max of 2-PAA in human plasma concentration after a single administration of the intranasal pharmaceutical composition of the present disclosure is about 0.9 hours or more, about 1.0 hours or more, about 1.1 hours or more, or about 1.2 hours or more. In one embodiment, the t max of 2-PAA in human plasma concentration is determined after a single administration of an intranasal pharmaceutical composition containing about 1 mg to about 200 mg of betahistine or a pharmaceutically acceptable salt. In one embodiment, the t maxis determined after a single intranasal administration of about 5 mg to about 100 mg of betahistine or a pharmaceutically acceptable salt thereof. In one embodiment, the t of 2-PAA max is determined after a single intranasal administration of about 20 mg or about 40 mg of betahistine or a pharmaceutically acceptable salt thereof. In another embodiment, the t of 2-PAA max is determined after a single intranasal administration of about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 150 mg, or about 200 mg of betahistine or a pharmaceutically acceptable salt thereof.

[0130] In one embodiment, the AUC of 2-PAA in the human plasma concentration after a single administration of the pharmaceutical composition of the present disclosure is at least about 100 hour*ng / mL, at least about 200 hour*ng / mL, at least about 250 hour*ng / mL, at least about 300 hour*ng / mL, at least about 400 hour*ng / mL, at least about 500 hour*ng / mL, at least about 600 hour*ng / mL, at least about 700 hour*ng / mL, at least about 800 hour*ng / mL, at least about 900 hour*ng / mL, at least about 1000 hour*ng / mL, at least about 1100 hour*ng / mL, at least about 1200 hour*ng / mL, at least about 1300 hour*ng / mL, at least about 1400 hour*ng / mL, at least about 1500 hour*ng / mL, at least about 1600 hour*ng / mL, at least about 1700 hour*ng / mL, at least about 1800 hour*ng / mL, at least about 1900 hour*ng / mL, at least about 2000 hour*ng / mL, at least about 2100 hour*ng / mL, at least about 2200 hour*ng / mL, at least about 2300 hour*ng / mL, at least about 2400 hour*ng / mL, at least about 2500 hour*ng / mL, at least about 2600 hour*ng / mL, at least about 2700 hour*ng / mL, at least about 2800 hour*ng / mL, at least about 2900 hour*ng / mL, at least about 3000 hour*ng / mL, at least about 3100 hour*ng / mL, at least about 3200 hour*ng / mL, at least about 3300 hour*ng / mL, at least about 3400 hour*ng / mL, or at least about 3500 hour*ng / mL. 0-last is provided. In one embodiment, the AUC of 2-PAA 0-last is measured after a single administration of about 1 mg to about 200 mg of betahistine or a pharmaceutically acceptable salt thereof.

[0131] In one embodiment, the AUC of 2-PAA in the human plasma concentration 0-last is determined after a single administration of a nasal pharmaceutical composition containing about 1 mg to about 200 mg of betahistine or a pharmaceutically acceptable salt. In one embodiment, the AUC of 2-PAA 0-lastis determined after a single intranasal administration of about 5 mg to about 100 mg of betahistine or a pharmaceutically acceptable salt. In one embodiment, the AUC of 2-PAA 0-last is determined after a single intranasal administration of about 20 mg or about 40 mg of betahistine or a pharmaceutically acceptable salt. In another embodiment, the AUC of 2-PAA 0-last is determined after a single intranasal administration of about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 150 mg, or about 200 mg of betahistine or a pharmaceutically acceptable salt.

[0132] In various embodiments, the AUC of 2-PAA 0-last is in the range of about 80% to 125% of about 390 ng*h / mL for a 5 mg betahistine dose administered intranasally, about 80% to 125% of about 730 ng*h / mL for a 10 mg betahistine dose administered intranasally, about 80% to 125% of about 2000 ng*h / mL for a 20 mg betahistine dose administered intranasally, and about 80% to 125% of about 2800 ng*h / mL for a 40 mg betahistine dose administered intranasally.

[0133] In one embodiment, the pharmaceutical composition of the present disclosure has an AUC of 2-PAA in human plasma concentration after a single administration of the pharmaceutical composition of the present disclosure of at least about 100 hour*ng / mL, at least about 200 hour*ng / mL, at least about 250 hour*ng / mL, at least about 300 hour*ng / mL, at least about 400 hour*ng / mL, at least about 500 hour*ng / mL, at least about 600 hour*ng / mL, at least about 700 hour*ng / mL, at least about 800 hour*ng / mL, at least about 900 hour*ng / mL, at least about 1000 hour*ng / mL, at least about 1100 hour*ng / mL, at least about 1200 hour*ng / mL, at least about 1300 hour*ng / mL, at least about 1400 hour*ng / mL, at least about 1500 hour*ng / mL, at least about 1600 hour*ng / mL, at least about 1700 hour*ng / mL, at least about 1800 hour*ng / mL, at least about 1900 hour*ng / mL, at least about 2000 hour*ng / mL, at least about 2100 hour*ng / mL, at least about 2200 hour*ng / mL, at least about 2300 hour*ng / mL, at least about 2400 hour*ng / mL, at least about 2500 hour*ng / mL, at least about 2600 hour*ng / mL, at least about 2700 hour*ng / mL, at least about 2800 hour*ng / mL, at least about 2900 hour*ng / mL, at least about 3000 hour*ng / mL, at least about 3100 hour*ng / mL, at least about 3200 hour*ng / mL, at least about 3300 hour*ng / mL, at least about 3400 hour*ng / mL, or at least about 3500 hour*ng / mL. 0-inf is provided. In one embodiment, the AUC of 2-PAA 0-inf is measured after a single administration of about 1 mg to about 200 mg of betahistine or a pharmaceutically acceptable salt.

[0134] In one embodiment, the AUC of 2-PAA in human plasma concentration 0-inf is determined after a single administration of an intranasal pharmaceutical composition containing about 1 mg to about 200 mg of betahistine or a pharmaceutically acceptable salt. In one embodiment, the AUC of 2-PAA 0-infis determined after a single intranasal administration of about 5 mg to about 100 mg of betahistine or a pharmaceutically acceptable salt. In one embodiment, the AUC of 2-PAA 0-inf is determined after a single intranasal administration of about 20 mg or about 40 mg of betahistine or a pharmaceutically acceptable salt. In another embodiment, the AUC of 2-PAA 0-inf is determined after a single intranasal administration of about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 150 mg, or about 200 mg of betahistine or a pharmaceutically acceptable salt.

[0135] In various embodiments, the AUC of 2-PAA 0-inf is in the range of about 80% to 125% of about 430 ng*hour / mL for a 5 mg betahistine dose administered intranasally, about 80% to 125% of about 760 ng*hour / mL for a 10 mg betahistine dose administered intranasally, about 80% to 125% of about 2000 ng*hour / mL for a 20 mg betahistine dose administered intranasally, and about 80% to 125% of about 2900 ng*hour / mL for a 40 mg betahistine dose administered intranasally.

[0136] In one embodiment, the t of 2-PAA determined based on a single administration of the pharmaceutical composition of the present disclosure 1 / 2 (apparent half-life) is about 2.5 hours or more, about 2.6 hours or more, about 2.7 hours or more, about 2.8 hours or more, about 2.9 hours or more, about 3.0 hours or more, about 3.1 hours or more, about 3.2 hours or more, about 3.3 hours or more, about 3.4 hours or more, about 3.5 hours or more, about 3.6 hours or more, about 3.7 hours or more, about 3.8 hours or more, about 3.9 hours or more, about 4.0 hours or more, about 4.1 hours or more, about 4.2 hours or more, about 4.3 hours or more, about 4.4 hours or more, or about 4.5 hours or more. In one embodiment, the t of 2-PAA 1 / 2 is determined based on a single administration of about 1 mg to about 200 mg of betahistine or a pharmacologically acceptable salt thereof. In one embodiment, t 1 / 2is the t of 2-PAA determined based on a single administration of about 5 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 150 mg, or about 200 mg of betahistine or a pharmaceutically acceptable salt 1 / 2 is.

[0137] In one embodiment, the pharmaceutical composition of the present disclosure may be useful in a method for use in the treatment or prevention of vestibular disorders. In another embodiment, the pharmaceutical composition of the present disclosure may be useful in a method for use in the treatment or prevention of neurotological disorders. In some embodiments, the pharmaceutical composition of the present disclosure may be useful in a method for use in the treatment or prevention of otological and / or neurological disorders.

[0138] In one embodiment, the pharmaceutical composition of the present disclosure may be useful in a method for use in the treatment or prevention of inner ear dysfunction or inner ear disorders. In one embodiment, inner ear disorders include tinnitus, vestibular vertigo, Meniere's disease, inflammation or infection of the inner ear, autoimmune ear disorders, or hearing loss. In one embodiment, the pharmaceutical composition of the present disclosure may be useful in a method for use in the treatment or prevention of tinnitus, vestibular vertigo, Meniere's disease, and hearing loss. In one embodiment, the pharmaceutical composition of the present disclosure may be useful in the treatment of vestibular vertigo. In another embodiment, the pharmaceutical composition of the present disclosure may be useful for treating Meniere's disease. In one embodiment, vestibular vertigo may include benign paroxysmal positional vertigo, vestibular neuritis and other peripheral vestibular vertigo.

[0139] In one embodiment, the pharmaceutical composition of the present disclosure may be useful in a method for use in the treatment, prevention or prophylaxis of vertigo, vestibular vertigo, and / or vertigo attacks. In another embodiment, the pharmaceutical composition of the present disclosure may be useful for reducing vertigo, vestibular vertigo, and / or vertigo attacks, or reducing their symptoms.

[0140] In one embodiment, the pharmaceutical composition of the present disclosure may be useful in a method for use in the treatment or prevention of eustachian tube dysfunction.

[0141] In one embodiment, the pharmaceutical composition of the present disclosure may be useful for treating or alleviating the symptoms of inner ear disorders. In one embodiment, the symptoms of inner ear dysfunction and / or inner ear disorders include hearing loss (including acute hearing loss), tinnitus, nausea, and dizziness. In one embodiment, the pharmaceutical composition of the present disclosure may be useful for treating hearing loss. In another embodiment, the pharmaceutical composition of the present disclosure may be useful for the treatment of acute hearing loss.

[0142] In one embodiment, the pharmaceutical composition of the present disclosure may be useful as part of vestibular therapy. In some embodiments, the vestibular therapy is vestibular rehabilitation.

[0143] In one embodiment, the pharmaceutical composition of the present disclosure may be useful for vestibular rehabilitation. In one embodiment, the pharmaceutical composition of the present disclosure may be useful for treating inner ear disorders or their symptoms using or in addition to vestibular rehabilitation. In one embodiment, the pharmaceutical composition of the present disclosure may be useful for treating inner ear disorders or their symptoms to promote vestibular rehabilitation.

[0144] Without being bound by any theory, betahistine or a pharmaceutically acceptable salt thereof is thought to act as a partial H1 receptor (H1R) agonist and / or an inverse H3 receptor (H3R) antagonist. H1R and H3R, together with H2 receptor (H2R) and H4 receptor (H4R), are thought to be G-protein coupled receptor subtypes of histamine receptors, i.e., histamine-binding receptors.

[0145] Although not bound by any theory, the pharmaceutical compositions of the present disclosure can contribute to an increase in blood flow in the inner ear, such as in the cochlea and vestibular blood flow, and / or cerebral blood flow. In another embodiment, the pharmaceutical compositions of the present disclosure can increase histamine turnover in the central nervous system (CNS) and enhance histamine release, which can re-regulate neuronal activity in the vestibular nuclear complex on both sides of the vestibular system. In one embodiment, the pharmaceutical compositions of the present disclosure can inhibit the firing of neurons in the vestibular nucleus. In another embodiment, the pharmaceutical compositions of the present disclosure can contribute to the upregulation of histamine, which induces a general brain arousal that supports sensorimotor activity. In one embodiment, the pharmaceutical compositions of the present disclosure can facilitate vestibular compensation and / or central vestibular compensation.

[0146] In one embodiment, the pharmaceutical compositions of the present disclosure can be useful for treating histamine-regulated diseases or conditions. In another embodiment, the pharmaceutical compositions of the present disclosure can be useful for treating H1R-regulated diseases or conditions. In some embodiments, the pharmaceutical compositions of the present disclosure can be useful for treating H3R-regulated diseases or conditions.

[0147] In one embodiment, the pharmaceutical compositions of the present disclosure can be useful for treating obesity, eating disorders, cognitive impairment, attention deficit disorder, memory processes, dementia and cognitive impairment, such as Alzheimer's disease and attention deficit hyperactivity disorder, bipolar disorder, cognitive enhancement, cognitive impairment in mental disorders, memory impairment, learning disorders, dementia, mild cognitive impairment, migraine, mood and attention changes, motion sickness, narcolepsy, neuroinflammation, obsessive-compulsive disorder, Parkinson's disease, schizophrenia, depression, epilepsy, and seizures or convulsions; sleep disorders, such as narcolepsy, vestibular dysfunction, such as Meniere's disease, migraine, motion sickness, pain, drug abuse, depression, epilepsy, jet lag, arousal, Tourette syndrome, dizziness, etc., and cardiovascular disorders, such as acute myocardial infarction, cancer, such as skin cancer, medullary thyroid cancer and melanoma; respiratory disorders, such as asthma, gastrointestinal disorders, inflammation, and septic shock, diabetes, type II diabetes, insulin resistance syndrome, metabolic syndrome, polycystic ovary syndrome, syndrome X, etc.

[0148] In one embodiment, the pharmaceutical composition of the present disclosure may be useful for treating obesity, attention deficit hyperactivity disorder, cerebrovascular disease, dementia, narcolepsy, sleep disorder, Parkinson's disease, poisoning, schizophrenia, Gilles de la Tourette syndrome, and / or Alzheimer's disease.

[0149] In one embodiment, the pharmaceutical composition of the present disclosure may be useful for treating or reducing weight gain. In some embodiments, unwanted weight gain may be caused by the administration of certain drugs. For example, antipsychotics that act on histamine receptors such as olanzapine can induce weight gain (Barak et al., Journal of Psychopharmacology, 2016, Vol. 30(3) 237-241, which is hereby incorporated by reference in its entirety). Thus, in one embodiment, the present disclosure provides a method for reducing weight gain induced by an antipsychotic that acts on histamine receptors, which comprises intranasal administration of the pharmaceutical composition of the present disclosure.

[0150] In one embodiment of the present disclosure, betahistine or a pharmaceutically acceptable salt thereof can be administered to a subject in need thereof by nasal (e.g., solution, spray, drops, aerosol, gel), oral (e.g., tablet, capsule, granule, syrup, elixir, or powder), sublingual, buccal, parenteral (e.g., subcutaneous, intravenous, intramuscular, intrathecal, or intracapsular injection), or infusion techniques (e.g., as a sterile aqueous or non-aqueous solution or suspension), topical (e.g., drug-releasing skin patch, cream or ointment), intravaginal administration, by douche, transdermally, intradermally, into the lungs, intrauterinely, by use of an aerosol, or rectally (e.g., in a suppository, in a unit dosage form containing a non-toxic pharmaceutically acceptable vehicle or diluent). In one embodiment, betahistine or a pharmaceutically acceptable salt thereof is administered nasally. In one embodiment, betahistine or a pharmaceutically acceptable salt thereof is administered by intranasal delivery.

[0151] In one embodiment, intranasal delivery of the pharmaceutical compositions of the present disclosure is advantageous for enabling non-invasive systemic delivery. In another embodiment, intranasal delivery of the pharmaceutical compositions of the present disclosure avoids or reduces the first-pass metabolism of betahistine (as compared to oral betahistine). In one embodiment, intranasal delivery of the pharmaceutical compositions of the present disclosure avoids or reduces gastric side effects (as compared to oral betahistine). In another embodiment, intranasal delivery of the pharmaceutical compositions of the present disclosure is advantageous for achieving rapid onset of betahistine action.

[0152] In one embodiment, the pharmaceutical compositions of the present disclosure are administered intranasally as drops, sprays, gels, ointments, creams, powders or suspensions. In one embodiment, the pharmaceutical compositions of the present disclosure are administered nasally using a dispenser or device (e.g., a single-dose ampoule, metered spray, atomizer, nebulizer, pump, nasal pad, nasal sponge or hard gelatin capsule) or any other nasal administration method known in the pharmaceutical literature.

[0153] In one embodiment, devices for intranasal administration of the liquid pharmaceutical compositions of the present disclosure include pipettes (e.g., unit-dose pipettes); droppers including multi-dose droppers; nasal catheters; vaporizers; mechanical spray pumps including squeeze bottles, metered spray pumps for multi-dose, spray pumps for single or double dose, spray pumps for bidirectional multi-dose; gas-driven spray systems / atomizers and electric nebulizers / atomizers. In one embodiment, devices for intranasal administration of the powder pharmaceutical compositions of the present disclosure include mechanical powder sprays, breath-activated inhalers, and inhalers including breath-actuated bidirectional delivery devices. These devices are summarized in the review by Djupesland (Drug Deliv. and Transl. Res. (2013) 3:42-62), which is hereby incorporated by reference in its entirety.

[0154] In one embodiment, the pharmaceutical composition of the present disclosure is administered nasally at a fixed dose. In one embodiment, a metered nasal spray may be used to administer the pharmaceutical composition of the present disclosure. In another embodiment, the pharmaceutical composition of the present disclosure may be administered quantitatively using a metered nasal pump spray. In one embodiment, a metered spray pump may be used to administer the pharmaceutical composition of the present disclosure quantitatively.

[0155] In one embodiment, a pressurized metered-dose inhaler (pMDI) may be used to administer the pharmaceutical composition of the present disclosure quantitatively. In one embodiment, the pressurized nasal preparation of the present disclosure may be an aerosol preparation. Such an aerosol preparation may, in one embodiment, contain betahistine or a pharmaceutically acceptable salt thereof in a pressurized pack together with a suitable propellant such as hydrofluoroalkane (HFA), carbon dioxide, or other suitable propellants known in the art. The aerosol may also, in one embodiment, contain a surfactant such as lecithin. The dose of betahistine or a pharmaceutically acceptable salt thereof can be controlled by providing a metering valve.

[0156] In another embodiment, the pharmaceutical composition of the present disclosure is administered nasally by conventional means, for example, using a dropper, pipette, or spray.

[0157] In one embodiment, the topical pharmaceutical composition of the present disclosure may be provided in the form of a dry powder, for example, a powder mixture of a compound in a suitable powder base such as lactose, starch, a starch derivative such as hydroxypropylmethylcellulose, and polyvinylpyrrolidone (PVP). In one embodiment, the powder carrier will form a gel in the nasal cavity. The powder composition may be provided in unit dosage forms such as gelatin capsules or cartridges, or blister packs from which the powder can be administered by an inhaler.

[0158] For a formulation intended for administration to the respiratory tract containing an intranasal formulation, the particle size of the pharmaceutical composition at the time of application should be less than 100 microns, less than 50 microns, less than 25 microns, less than 20 microns, less than 20 microns, less than 15 microns, or less than 10 microns. In one embodiment, the particle size of the nasal pharmaceutical composition is less than 10 microns at the time of application. In one embodiment, the D 50 of the particle size of the nasal pharmaceutical composition is less than 10 microns at the time of application. In one embodiment, the D 90 of the particle size of the nasal pharmaceutical composition is less than 10 microns at the time of application.

[0159] In one embodiment, the intranasal pharmaceutical composition of the present disclosure in spray form provides a droplet size distribution Dv(50) of about 150 μm to about 300 μm, including about 160 μm, about 170 μm, about 180 μm, about 190 μm, about 200 μm, about 210 μm, about 220 μm, about 230 μm, about 240 μm, about 250 μm, about 260 μm, about 270 μm, about 280 μm, about 290 μm, or about 300 μm (including the entire range between any of these values), when tested at a firing distance of about 20 mm to about 50 mm with a firing force of about 5 kg, about 6 kg, or about 7 kg.

[0160] In one embodiment, the intranasal pharmaceutical composition of the present disclosure in spray form provides a droplet size distribution Dv(90) of about 380 μm to about 650 μm, including about 380 μm, about 390 μm, about 400 μm, about 400 μm, about 410 μm, about 420 μm, about 430 μm, about 440 μm, about 450 μm, about 460 μm, about 470 μm, about 480 μm, about 490 μm, about 500 μm, about 510 μm, about 520 μm, about 530 μm, about 540 μm, about 550 μm, about 560 μm, about 570 μm, about 580 μm, about 590 μm, about 600 μm, about 610 μm, about 620 μm, about 630 μm, about 640 μm, about 650 μm (including the entire range between any of these values), when tested at a firing distance of about 20 mm to about 50 mm with a firing force of about 5 kg, about 6 kg, or about 7 kg.

[0161] In one embodiment, the pharmaceutical composition of the present disclosure is administered once, twice, three times, four times, five times, six times, seven times, eight times, nine times, or ten times a day. In one embodiment, the pharmaceutical composition of the present disclosure is administered one or more times a day, and each dose administers a controlled amount, a measured amount, or a set amount of betahistine or a pharmaceutically acceptable salt thereof.

[0162] In one embodiment, the pharmaceutical composition of the present disclosure is nasally administered in a unit dose containing about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 mg of betahistine or a pharmaceutically acceptable salt thereof. For example, when a metered nasal spray is used, a single spray dose contains about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 mg of betahistine or a pharmaceutically acceptable salt thereof. In another embodiment, the present disclosure is nasally administered in a unit dose containing about 10, 15, 20, 25, 30, 35, 40, 45, or 50 mg of betahistine or a pharmaceutically acceptable salt thereof. In one embodiment, the present disclosure is nasally administered in a unit dose containing about 20 mg of betahistine or a pharmaceutically acceptable salt thereof.

[0163] In one embodiment, the pharmaceutical composition of the present disclosure is nasally administered in a unit dose containing about 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, or 200 mg of betahistine or a pharmaceutically acceptable salt thereof.

[0164] In one embodiment, the pharmaceutical composition of the present disclosure is administered nasally in unit doses or fixed doses that provide uniformity of the administered content with a relative standard deviation of less than 5.0%, less than 4.5%, less than 4.0%, less than 3.5%, less than 2.0%, less than 1.5%, less than 1.0%, or less than 0.5%.

[0165] In one embodiment, the intranasal pharmaceutical composition of the present disclosure is administered 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 times a day. In one embodiment, the intranasal pharmaceutical composition of the present disclosure is administered once a day, twice a day, three times a day, four times a day, five times a day, or six times a day, where each dose administers a controlled, measured, or set amount of betahistine or a pharmaceutically acceptable salt thereof. In some embodiments, the intranasal pharmaceutical composition of the present disclosure is administered three times a day. In some embodiments, the intranasal pharmaceutical composition of the present disclosure is administered up to six times a day.

[0166] In one embodiment, the intranasal pharmaceutical composition of the present disclosure is about 0.01 mg / kg, about 0.02 mg / kg, about 0.03 mg / kg, about 0.04 mg / kg, about 0.05 mg / kg, about 0.06 mg / kg, about 0.07 mg / kg, about 0.08 mg / kg, about 0.09 mg / kg, about 0.1 mg / kg, about 0.12 mg / kg, about 0.14 mg / kg, about 0.16 mg / kg, about 0.18 mg / kg, about 0.2 mg / kg, about 0.22 mg / kg, about 0.24 mg / kg, about 0.26 mg / kg, about 0.28 mg / kg, about 0.3 mg / kg, about 0.32 mg / kg, about 0.34 mg / kg, about 0.36 mg / kg, about 0.38 mg / kg, about 0.4 mg / kg, about 0.42 mg / kg, about 0.44 mg / kg, about 0.46 mg / kg, about 0.48 mg / kg, about 0.5 mg / kg, about 0.52 mg / kg, about 0.54 mg / kg, about 0.56 mg / kg, about 0.58 mg / kg, about 0.6 mg / kg, about 0.62 mg / kg, about 0.64 mg / kg, about 0.66 mg / kg, about 0.68 mg / kg, about 0.7 mg / kg, about 0.72 mg / kg, about 0.74 mg / kg, about 0.76 mg / kg, about 0.78 mg / kg, about 0.8 mg / kg, about 0.82 mg / kg, about 0.84 mg / kg, about 0.86 mg / kg, about 0.88 mg / kg, about 0.9 mg / kg, about 0.92 mg / kg, about 0.94 mg / kg, about 0.96 mg / kg, about 0.98 mg / kg, about 1.0 mg / kg, about 1.1 mg / kg, about 1.2 mg / kg, about 1.3 mg / kg, about 1.4 mg / kg, about 1.5 mg / kg, about 1.6 mg / kg, about 1.7 mg / kg, about 1.8 mg / kg, about 1.9 mg / kg, about 2 mg / kg, about 2.1 mg / kg, about 2.2 mg / kg, about 2.3 mg / kg, about 2.4 mg / kg, about 2.5 mg / kg, about 2.6 mg / kg, about 2.7 mg / kg, about 2.8 mg / kg, about 2.9 mg / kg, about 3 mg / kg, about 3.1 mg / kg, about 3.2 mg / kg, about 3.3 mg / kg, about 3.4 mg / kg, about 3.5 mg / kg, about 3.6 mg / kg, about 3.7 mg / kg, about 3.8 mg / kg, about 3.9 mg / kg, about 4 mg / kg, about 4.1 mg / kg, about 4.2 mg / kg, about 4.3 mg / kg, about 4.4 mg / kg, about 4.5 mg / kg, about 4.6 mg / kg, about 4.7 mg / kg, about 4.8 mg / kg, about 4.9 mg / kg, about 5 mg / kg, about 5.1 mg / kg, about 5.2 mg / kg, about 5.3 mg / kg, about 5.4 mg / kg, about 5.5 mg / kg, about 5.6 mg / kg, about 5.7 mg / kg, about 5.8 mg / kg, about 5.9 mg / kg, about 6 mg / kg, about 6.1 mg / kg, about 6.2 mg / kg, about 6.3 mg / kg, about 6.4 mg / kg, about 6.5 mg / kg, about 6.6 mg / kg, about 6.7 mg / kg, about 6.8 mg / kg, about 6.9 mg / kg, about 7 mg / kg, about 7.1 mg / kg, about 7.2 mg / kg, about 7.3 mg / kg, about 7.4 mg / kg, about 7.5 mg / kg, about 7.6 mg / kg, about 7.7 mg / kg, about 7.8 mg / kg, about 7.9 mg / kg, about 8 mg / kg, about 8.1 mg / kg, about 8.2 mg / kg, about 8.3 mg / kg, about 8.4 mg / kg, about 8.5 mg / kg, about 8.6 mg / kg, about 8.7 mg / kg, about 8.8 mg / kg, about 8.9 mg / kg, about 9 mg / kg, about 9.1 mg / kg, about 9.2 mg / kg, about 9.3 mg / kg, about 9.4 mg / kg, about 9.5 mg / kg, about 9.6 mg / kg, about 9.7 mg / kg, about 9.8 mg / kg, about 9.9 mg / kg, about 10 mg / kg, about 11.1 mg / kg, about 11.2 mg / kg, about 11.3 mg / kg, about 11.4 mg / kg, about 11.5 mg / kg, about 11.6 mg / kg, about 11.7 mg / kg, about 11.8 mg / kg, about 11.9 mg / kg, about 12 mg / kg, about 12.1 mg / kg, about 12.2 mg / kg, about 12.3 mg / kg, about 12.4 mg / kg, about 12.5 mg / kg, about 12.6 mg / kg, about 12.7 mg / kg, about 12.8 mg / kg, about 12.9 mg / kg, about 13 mg / kg, about 13.1 mg / kg, about 13.2 mg / kg, about 13.3 mg / kg, about 13.4 mg / kg, about 13.5 mg / kg, about 13.6 mg / kg, about 13.7 mg / kg, about 13.8 mg / kg, about 13.9 mg / kg, about 14 mg / kg, about 14.1 mg / kg, about 14.2 mg / kg, about 14.3 mg / kg, about 14.4 mg / kg, about 14.5 mg / kg, about 14.6 mg / kg, about 14.7 mg / kg, about 14.8 mg / kg, about 14.9 mg / kg, about 15 mg / kg, about 15.1 mg / kg, about 15.2 mg / kg, about 15.3 mg / kg, about 15.4 mg / kg, about 15.5 mg / kg, about 15.Administered to provide a daily dose of betahistine or a pharmaceutically acceptable salt thereof at about 0.01 mg / kg to about 20 mg / kg per kg of body weight of a human patient, including 6 mg / kg, about 15.7 mg / kg, about 15.8 mg / kg, about 15.9 mg / kg, about 16 mg / kg, about 16.1 mg / kg, about 16.2 mg / kg, about 16.3 mg / kg, about 16.4 mg / kg, about 16.5 mg / kg, about 16.6 mg / kg, about 16.7 mg / kg, about 16.8 mg / kg, about 16.9 mg / kg, about 17 mg / kg, about 17.1 mg / kg, about 17.2 mg / kg, about 17.3 mg / kg, about 17.4 mg / kg, about 17.5 mg / kg, about 17.6 mg / kg, about 17.7 mg / kg, about 17.8 mg / kg, about 17.9 mg / kg, about 18 mg / kg, about 18.1 mg / kg, about 18.2 mg / kg, about 18.3 mg / kg, about 18.4 mg / kg, about 18.5 mg / kg, about 18.6 mg / kg, about 18.7 mg / kg, about 18.8 mg / kg, about 18.9 mg / kg, about 19 mg / kg, about 19.1 mg / kg, about 19.2 mg / kg, about 19.3 mg / kg, about 19.4 mg / kg, about 19.5 mg / kg, about 19.6 mg / kg, about 19.7 mg / kg, about 19.8 mg / kg, about 19.9 mg / kg, or about 20 mg / kg (including the full range between any of these values).

[0167] In one embodiment, the intranasal pharmaceutical composition of the present disclosure is administered to provide a daily dose of about 1 mg to about 200 mg of betahistine or a pharmaceutically acceptable salt thereof per patient. In another embodiment, the intranasal pharmaceutical composition of the present disclosure is administered to provide a daily dose of about 5 mg to about 100 mg of betahistine or a pharmaceutically acceptable salt thereof.

[0168] In one embodiment, the intranasal pharmaceutical composition of the present disclosure comprises betahistine or a pharmaceutically acceptable salt thereof at a concentration of about 1 mg / mL to about 1000 mg / mL. In another embodiment, the intranasal pharmaceutical composition of the present disclosure comprises betahistine or a pharmaceutically acceptable salt thereof at a concentration of about 10 mg / mL, about 15 mg / mL, about 20 mg / mL, about 25 mg / mL, about 30 mg / mL, about 35 mg / mL, about 40 mg / mL, about 45 mg / mL, about 50 mg / mL, about 55 mg / mL, about 60 mg / mL, about 65 mg / mL, about 70 mg / mL, about 75 mg / mL, about 80 mg / mL, about 85 mg / mL, about 90 mg / mL, about 95 mg / mL, about 100 mg / mL, about 105 mg / mL, about 110 mg / mL, about 115 mg / mL, about 120 mg / mL, about 125 mg / mL, about 130 mg / mL, about 135 mg / mL, about 140 mg / mL, about 145 mg / mL, about 150 mg / mL, about 155 mg / mL, about 160 mg / mL, about 165 mg / mL, about 170 mg / mL, about 175 mg / mL, about 180 mg / mL, about 185 mg / mL, about 190 mg / mL, about 195 mg / mL, about 200 mg / mL, about 205 mg / mL, about 210 mg / mL, about 215 mg / mL, about 220 mg / mL, about 225 mg / mL, about 230 mg / mL, about 235 mg / mL, about 240 mg / mL, about 245 mg / mL, about 250 mg / mL, about 255 mg / mL, about 260 mg / mL, about 265 mg / mL, about 270 mg / mL, about 275 mg / mL, about 280 mg / mL, about 285 mg / mL, about 290 mg / mL, about 295 mg / mL, about 300 mg / mL, about 305 mg / mL, about 310 mg / mL, about 315 mg / mL, about 320 mg / mL, about 325 mg / mL, about 330 mg / mL, about 335 mg / mL, about 340 mg / mL, about 345 mg / mL, about 350 mg / mL, about 355 mg / mL, about 360 mg / mL, about 365 mg / mL, about 370 mg / mL, about 375 mg / mL, about 380 mg / mL, about 385 mg / mL, about 390 mg / mL, about 395 mg / mL, or about 400 mg / mL (including the entire range between any of these values), and comprises betahistine or a pharmaceutically acceptable salt thereof at a concentration of about 10 mg / mL to about 400 mg / mL.

[0169] In one embodiment, the intranasal pharmaceutical composition of the present disclosure comprises betahistine or a pharmaceutically acceptable salt thereof administered in a unit dose or a fixed dose of about 1 μL to about 1000 μL, including about 1 μL, about 10 μL, about 20 μL, about 30 μL, about 40 μL, about 50 μL, about 60 μL, about 70 μL, about 80 μL, about 90 μL, about 100 μL, about 110 μL, about 120 μL, about 130 μL, about 140 μL, about 150 μL, about 160 μL, about 170 μL, about 180 μL, about 190 μL, about 200 μL, about 210 μL, about 220 μL, about 230 μL, about 240 μL, about 250 μL, about 260 μL, about 270 μL, about 280 μL, about 290 μL, about 300 μL, about 310 μL, about 320 μL, about 330 μL, about 340 μL, about 350 μL, about 360 μL, about 370 μL, about 380 μL, about 390 μL, about 400 μL, about 410 μL, about 420 μL, about 430 μL, about 440 μL, about 450 μL, about 460 μL, about 470 μL, about 480 μL, about 490 μL, about 500 μL, about 510 μL, about 520 μL, about 530 μL, about 545 μL, about 550 μL, about 560 μL, about 570 μL, about 580 μL, about 590 μL, about 600 μL, about 610 μL, about 620 μL, about 630 μL, about 640 μL, about 650 μL, about 660 μL, about 670 μL, about 680 μL, about 690 μL, about 700 μL, about 710 μL, about 720 μL, about 730 μL, about 740 μL, about 750 μL, about 760 μL, about 770 μL, about 780 μL, about 790 μL, about 800 μL, about 810 μL, about 820 μL, about 830 μL, about 840 μL, about 850 μL, about 860 μL, about 870 μL, about 880 μL, about 890 μL, about 900 μL, about 910 μL, about 920 μL, about 930 μL, about 940 μL, about 950 μL, about 960 μL, about 970 μL, about 980 μL, about 990 μL, or about 1000 μL. In some embodiments, the intranasal pharmaceutical composition of the present disclosure comprises betahistine or a pharmaceutically acceptable salt thereof administered in a unit dose or a fixed dose of about 10 μL to about 200 μL. In another embodiment, the intranasal pharmaceutical composition of the present disclosure comprises betahistine or a pharmaceutically acceptable salt thereof administered in a unit dose or a fixed dose of about 10 μL to about 100 μL.

[0170] In one embodiment, the unit dose or fixed dose of the intranasal pharmaceutical composition of the present disclosure containing betahistine or a pharmaceutically acceptable substance may be administered at 1 unit dose or fixed dose at a time, 2 unit doses or fixed doses at a time, 3 unit doses or fixed doses at a time, or 4 unit doses or fixed doses at a time.

[0171] In one embodiment, the treatment cycle with the pharmaceutical composition of the present disclosure can be about 1 day to about 7 days, about 1 week to about 5 weeks, or about 1 month to about 12 months. In one embodiment, the treatment cycle with the intranasal pharmaceutical composition may be about 1 day to about 7 days, about 1 week to about 5 weeks, or about 1 month to about 12 months. In one embodiment, the treatment cycle with the intranasal pharmaceutical composition may be about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, or about 12 months. In one embodiment, the treatment cycle with the intranasal pharmaceutical composition may be about 3 months or about 6 months. In one embodiment, the treatment cycle using the intranasal pharmaceutical composition of the present disclosure may exceed 1 year. In another embodiment, the treatment cycle may exceed 1 year, exceed 1.5 years, exceed 2 years, exceed 2.5 years, exceed 3 years, exceed 4 years, or exceed 5 years. The appropriate duration of treatment with the pharmaceutical composition of the present disclosure can be determined by the patient's physician and can be used as directed.

[0172] In one embodiment, the pharmaceutical composition of the present disclosure is a solution, suspension, powder, or aerosol. In one embodiment, the pharmaceutical composition of the present disclosure is an aqueous solution.

[0173] In one embodiment, the pharmaceutical composition of the present disclosure can be administered in combination with at least one of an enzyme inhibitor or an absorption promoter. In one embodiment, the at least one enzyme inhibitor is selected from beta statin, amastatin, boroxine, borovaline, aprotinin, trypsin inhibitor, fusidic acid, and bile salts. In another embodiment, the at least one absorption promoter is selected from β-cyclodextrin, fusidic acid derivative (sodium taurodihydrofusidate), microspheres, liposomes, bile salts, laureth-9, saponin, BL-9, glycolate, chitosan, didecanoyl-L-phosphatidylcholine and lysophosphatidylcholine.

[0174] In one embodiment, the pharmaceutical composition of the present disclosure may further comprise at least one additional pharmaceutically active agent. In some embodiments, the at least one additional pharmaceutically active agent is a drug for treating vestibular disorders, neurotological disorders, otological and / or neurological disorders. In some embodiments, the at least one additional pharmaceutically active agent is a drug for treating inner ear dysfunction or inner ear disorders, and / or a drug for treating or alleviating the symptoms of inner ear disorders and dysfunctions.

[0175] In one embodiment, the at least one additional pharmaceutically active agent is selected from the group of glutamate receptor modulators. Non-limiting examples of glutamate receptor modulators include glutamate receptor antagonists, AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptor antagonists, and NMDA (N-methyl-D-aspartic acid) receptor antagonists. In one embodiment, the AMPA receptor antagonist includes 6-cyano-7-nitroquinoxaline-2,3-dione, 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo[f]quinoxaline-2,3-dione, 6,7-dinitroquinoxaline-2,3-dione, kynurenic acid, 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo-[f]quinoxaline, or combinations thereof.

[0176] In one embodiment, glutamate receptor antagonists including NMDA receptor antagonists are 1 - aminoadamantane, dextromethorphan, dextrorphan, ibogaine, ifenprodil, (S)-ketamine, (R)-ketamine, memantine, dizocilpine, gacyclidine, traxoprodil, D - 2 - amino - 5 - phosphonopentanoic acid, 3 - ((±)2 - carboxypiperazin - 4 - yl)-propyl - 1 - phosphonic acid, conantokin, 7 - chlorokynurenate, licostinel, nitric oxide, fencyclidine, riluzole, tiletamine, aptiganel, remacemide, 5,7 - dichlorokynurenic acid, kynurenic acid, 1 - aminocyclopropanecarboxylic acid, 2 - amino - 7 - phosphonoheptanoic acid, R - 2 - amino - 5 - phosphonopentanoate, 3 - [(R)-2 - carboxypiperazin - 4 - yl]-prop - 2 - enyl - 1 - phosphonic acid, (+)-(1S,2S)-1-(4 - hydroxy - phenyl)-2-(4 - hydroxy - 4 - phenylpiperidino)-1 - propanol, (1S,2S)-1-(4 - hydroxy - 3-(methoxyphenyl)-2-(4 - hydroxy - 4 - phenylpiperidino)-1 - propanol, (3R,4S)-3-(4-(4 - fluorophenyl)-4 - hydroxypiperidin - 1 - yl - )-chroman - 4,7 - diol, (1R * ,2R * )-1-(4 - hydroxy - 3 - methylphenyl)-2-(4-(4 - fluoro - phenyl)-4 - hydroxypiperidin - 1 - yl)-propane - 1 - ol - mesylate, or a combination thereof.

Example

[0177] Example 1: Sample Formulation An intranasal delivery formulation of a pharmaceutical composition according to the present disclosure containing betahistine dihydrochloride was supplied by Otifex Therapeutics and stored in a desiccator under ambient conditions until needed.

[0178] Formulations containing 10, 50 or 200 mg / mL of betahistine were prepared as follows.

[0179] A betahistine preparation of 10 mg / mL. 20 mg of benzalkonium chloride (heated to about 65 °C to aid movement) and 20 mg of disodium edetate were added to the same beaker and dissolved in about 10 mL of water for injection using a stirrer. 1 g of betahistine dihydrochloride was placed in a sterile plastic bottle, and 97.5 mg of dibasic sodium phosphate and 552.5 mg of monobasic sodium phosphate were added thereto. About 25 mL of water for injection was added to the bottle, and the resulting solution was thoroughly mixed. Next, 100 mg of glycerin, 1.25 g of polyvinylpyrrolidone, 3.75 g of polyethylene glycol 400, and 2 g of propylene glycol were added (using a small amount of water for movement). To the resulting mixture, the prepared benzalkonium chloride and disodium edetate solutions were added using about 10 mL of water for injection.

[0180] The pH of the resulting solution was adjusted to pH 5.0 by adding 3.88 mL of 1 M sodium hydroxide. After checking the pH of the solution, it was quantitatively transferred to a 100 mL volumetric flask using a small amount of water for injection.

[0181] Water for injection was added to obtain a 100 mL preparation. Re-check / adjusted the pH to 5.0, and the preparation was stored at 2 - 8 °C until needed.

[0182] The 10 mg / mL betahistine nasal preparation thus prepared contained the following components (all concentrations are shown as weight / weight unless otherwise specified): 1.0% betahistine dihydrochloride as the active substance, 0.1% glycerin, 3.75% polyethylene glycol 400, 2% propylene glycol as a humectant, 1.25% polyvinylpyrrolidone for viscosity and to increase nasal ciliary clearance, 0.02% disodium edetate as a preservative / stabilizer, 0.02% benzalkonium chloride as a preservative, 0.0975% dibasic sodium phosphate and 0.5525% monobasic sodium phosphate as buffers, 3.88 mL of 1 M sodium hydroxide to adjust the pH to 5.0, and water for injection (an appropriate amount) up to 100 mL as a solvent.

[0183] Betahistine formulations of 50 and 200 mg / mL. The required concentrations of betahistine dihydrochloride were 5.0 and 20.0% respectively, and the amounts of 5M sodium hydroxide were 4.38 mL and 10M sodium hydroxide were 9.3 mL respectively.

Table 2

[0184] Example 2: Evaluation of Safety and Pharmacokinetic Profile in Dogs The safety and pharmacokinetic profile of intranasal betahistine were first evaluated in a single-dose toxicity study in male and female beagle dogs (14 - 21 months old, body weight 8.2 - 11.8 kg). Both vehicle and test article were administered as a single dose of 100 μL delivery volume via a nasal spray pump (Aptar Classic Line) into both nostrils at all dose levels of 0 (vehicle), 4, 20 or 80 mg of betahistine dihydrochloride. Each treatment group consisted of 1 dog per sex. Animals were observed for 7 days and then allowed a 3-day washout period before being used in the repeated-dose study, where dogs were administered approximately 4-hourly 3 doses of 0 (vehicle), 12, 60 or 240 mg of betahistine dihydrochloride daily for 14 consecutive days.

[0185] For the toxicokinetic evaluation, blood samples were collected as follows: before dosing and at approximately 5, 15 and 30 minutes, 1, 2, 6, 24 and 168 hours after dosing during the single-dose phase, and before the first dose on test days 1, 8 and 14, and 2 hours after the 3rd dose on test days 1 and 14, and on test day 15 before necropsy. Plasma concentrations were measured by liquid chromatography tandem mass spectrometry (LC-MS / MS, SCIEX API 5000 for betahistine, SCIEX API 4000 for 2-pyridyl lactic acid (2-PAA)) using a validated method. Betahistine- 13CD3 dihydrochloride and 2-PAA-D4 hydrochloride were used as internal standards. The standard calibration range of betahistine (using 0.05 mL of plasma sample volume) was from 0.05 to 50 ng / mL, and the standard calibration range of 2-PAA was 1 to 1000 ng / mL. The limits of quantification were 0.05 ng / mL for betahistine and 1.0 ng / mL for 2-PAA.

[0186] In the case of betahistine, this method involved liquid-liquid extraction. In the case of 2-PAA, it involved protein precipitation. For betahistine, the plasma sample was extracted with an organic solvent under basic conditions. The organic phase was dried and reconstituted in a reconstitution solvent. For LC-MS / MS analysis, approximately 0.1 mL of the aqueous layer was transferred to a polypropylene vial. For 2-PAA, the plasma sample was precipitated with a mixture of organic solvents, the supernatant was diluted, and 0.12 mL was transferred to a polypropylene vial for LC-MS / MS analysis. Sample analysis was performed using reverse-phase chromatography.

[0187] Intranasal betahistine had good tolerance. After intranasal delivery of 80 mg of the test article at both the single-dose and repeated-dose (240 mg / day) stages of the test, test article-related clinical signs consisting of mild to moderate salivation were observed. Salivation after betahistine treatment has been previously reported to occur in dogs, but it was of a transient nature in this test and resolved rapidly. Body weight, clinical pathology, and gross necropsy findings were not remarkable. In this test, no treatment-related adverse microscopic findings were observed.

[0188] Betahistine was rapidly absorbed after single-dose intranasal administration, and peak concentration was observed at 5 minutes (T max ). Without being bound by any theory, T max at 5 minutes after administration suggests a rapid onset of the pharmacological activity of betahistine. The increase in C max was linearly related to the administered dose but not proportional. C maxReached 26, 81, and 248 ng / mL for the 4, 20, and 80 mg groups (mean for male and female animals). Concentrations decreased rapidly, exceeding 90% at the 1-hour time point. Quantifiable plasma concentrations were no longer observed at 2 or 6 hours in the 4 and 20 mg dose groups, but were observed up to the 24-hour time point in the 80 mg dose group. The 2-PAA metabolite, similar to its parent substance, rapidly appeared by the 5-minute time point and showed rapid formation at a similar rate across the evaluated dose levels (Figure 2). 2-PAA reached peak concentrations of 606, 2195, and 4615 ng / mL for the 4, 20, and 80 mg groups (mean for male and female animals) in the time range of 15 minutes to 1 hour. C max The increase in C was approximately dose-proportional between the 4 - 20 mg dose groups and less so between the 20 - 80 mg dose groups, indicating saturation of the elimination process beyond the 20 mg dose level. Following the peak level, 2-PAA generally decreased rapidly and almost linearly to the last measurable value at 24 hours post-administration.

[0189] In the repeated-dose evaluation, measurable levels of betahistine and 2-PAA were present in all collected samples from the 20 and 80 mg dose groups and in most samples from the 4 mg dose group. The increase in betahistine concentration across dose levels was less proportional at comparable plasma sampling times. Overall, betahistine was rapidly eliminated, but low plasma concentration levels could still be observed in trough samples from days 8 and 14 of the study, suggesting some maintenance despite low baseline levels.

[0190] The results of the single-dose and repeated-dose toxicology studies indicate that intranasal betahistine is achievable and results in rapid and meaningful systemic exposure. The treatment was well tolerated in dogs.

[0191] Example 3: Evaluation of Safety and Pharmacokinetic Profile in Humans The safety and pharmacokinetic profile of betahistine in the nasal cavity were further evaluated in a double-blind, randomized, placebo-controlled, single-dose escalating clinical trial involving a total of 32 healthy male and female volunteers. The main selection criteria were that the subjects had to be between 18 and 45 years old and had to show a body mass index within the range of 18 - 30 kg / m 2 Subjects were required to fast for 8 hours before the study drug administration and 2 hours after administration. Water was withheld from 1 hour before to 1 hour after the study drug administration.

[0192] Betahistine dihydrochloride was tested in 4 dose cohorts of 5, 10, 20, and 40 mg. In each cohort, 6 subjects received the active drug and 2 subjects received the corresponding placebo. Betahistine was supplied as 50 and 200 mg / mL solutions in HDPE bottles and spray pump packs (Aptar Classic Line) that delivered exactly 100 μL per actuation. The test drug was delivered to the right nostril of the subject while the subject was in the supine position. For the 5 and 20 mg doses, one application of 50 and 200 mg / mL was required respectively, while for the 10 and 40 mg doses, two applications of 50 and 200 mg / mL were required.

[0193] After administration on days 1, 4, and 7, serial blood samples were collected over 24 hours to determine the concentrations of betahistine and its main metabolite, 2-PAA, in plasma. Plasma samples were assayed for BH content using a validated procedure and method. Blood samples (6 mL) were collected into tubes containing K2EDTA, centrifuged at approximately 2000 g for 10 minutes at +4°C, and the resulting plasma was transferred to two clean, labeled 2 mL cryovials. All plasma samples were stored at -70°C or below until all samples were collected and sent as a single batch for analysis. Aliquots 1 and 2 were sent as separate shipments. Concentrations were determined using a validated method with liquid chromatography tandem mass spectrometry (LC-MS / MS, SCIEX API 5000 for betahistine and SCIEX API 4000 for 2-PAA). Betahistine - 13CD3 dihydrochloride and 2-PAA-D4 hydrochloride were used as internal standards. The standard calibration ranges for betahistine (using plasma sample volumes of 0.2 and 0.1 mL respectively) were 10 - 800 pg / mL, and for 2-PAA it was 2 - 2000 ng / mL. The limits of quantification were 10 pg / mL for betahistine and 2.0 ng / mL for 2-PAA.

[0194] In the case of betahistine, this method involved liquid-liquid extraction. In the case of 2-PAA, it involved protein precipitation. For betahistine, plasma samples were extracted with an organic solvent under basic conditions. The organic phase was dried and then reconstituted in a reconstitution solvent. For LC-MS / MS analysis, approximately 0.120 mL of the aqueous layer was transferred to a polypropylene vial. For 2-PAA, plasma samples were precipitated with a mixture of organic solvents, the supernatant was diluted, and 0.120 mL was transferred to a polypropylene vial for LC-MS / MS analysis. Sample analysis was performed using reverse-phase chromatography.

[0195] Treatment with betahistine at test doses of 5, 10, 20 and 40 mg was well tolerated. There were no differences between subjects treated with the active drug and those treated with placebo in hematology, biochemistry, urine tests, vital signs and electrocardiogram evaluations. The incidence of adverse events attributable to treatment was also similar in subjects of both groups, and there was no obvious dose-related trend in the incidence of adverse events in subjects treated with the active drug. The pharmacokinetic parameters of the systemic exposure of betahistine and 2-PAA increased with the dose level. For betahistine, the peak concentrations in plasma were 4.1 and 10.5 ng / mL at the two maximum doses (Figure 3), which is less than the C reported by Chen et al. (Xenobiotica, 2003, 3(12)3, 1261) of less than 0.5 ng / mL after oral administration of 24 mg of betahistine. maxSignificantly higher. The peak was achieved at approximately 10 minutes after administration. The peak concentrations of the metabolite 2-PAA were 370 and 519 ng / mL at the two maximum doses (Figure 4), which are similar to the levels reported by Vai et al. (Arzneimittelforschung, 2010, 60(7), 440) after oral administration of betahistine 16 mg (522 ng / mL). T max was reached after 1.2 hours, which is also similar to the results from studies using oral administration of betahistine 16 or 50 mg reported by Chen et al. (2003) at 1 hour and Moorthy et al. (Biopharm. Drug Dispos., 2015, 36(12), 429) at 1.5 hours.

[0196] For each subject who completed the study, the plasma concentration-time data of betahistine and 2-PAA were used for the calculation of the following pharmacokinetic parameters:

Table A-1

Table A-2

[0197] C, a parameter normalized by dose max / dose and AUC / dose were also calculated.

[0198] Summary of the determined pharmacokinetic parameters of betahistine determined by the treatments shown in Tables 3 - 4.

Table 3

[0199]

Table 4

[0200] The summary of the determined pharmacokinetic parameters of 2-PAA is shown in Tables 5 - 6.

Table 5

Table 6

[0201] From the above data in Tables 3 to 6, it is shown that the pharmacokinetic parameters of systemic exposure to betahistine and 2-PAA increased with the dose level. The graphical representation of the dose response suggests that the exposure of betahistine in this study from 5 to 40 mg is proportional to the dose over the betahistine dose range. For betahistine, the peak concentration is achieved within 5 to 20 minutes and the apparent half-life is less than 1 hour. For the metabolite 2-PAA, the peak concentration is achieved at about 1 to 1.25 hours (range of 20 minutes to 2 hours) after administration and the apparent half-life is about 4 hours.

[0202] In summary, the results from this study have shown that intranasal betahistine is well tolerated and, unlike oral administration, provides a quantifiable and meaningful plasma concentration of the active parent compound. The peak concentration is reached at about 10 minutes after administration, suggesting a rapid onset of action, which, without being bound by any theory, may be particularly useful therapeutically, for example, in cases of urgent medical needs. This experiment has shown for the first time that betahistine can be administered systemically, effectively and safely, non-invasively via the intranasal route.

[0203] Example 4: Uniformity of the administered content Formulations containing 10 and 200 mg / mL of betahistine were prepared according to Example 1 and Table 2, except that the pH value was adjusted to 5.5.

[0204] The formulations were filled into a 100 μL Aptar Classic Line pump spray and then dispensed into an appropriate volumetric flask and the volume was adjusted with a diluent. Tables 7 to 8 show the uniformity of the administered content.

Table 7

Table 8

[0205] Example 5: Evaluation of Pharmacokinetic Profile in Dogs In this study, the pharmacokinetic profile of betahistine after single administration to male and female beagle dogs (5 - 7 months old, body weight 5 - 11 kg, within 3 kg for each sex) was evaluated for three routes of administration: oral, intranasal, and intravenous.

[0206] On day 1 of the study, betahistine (BH) was orally administered at doses of 12 mg / kg, 24 mg / kg, or 48 mg / kg. Each treatment group included 8 animals (4 males and 4 females). For pharmacokinetic evaluation, plasma samples were collected before administration and at 5, 10, 20, and 30 minutes, 1, 2, 3, 6, and 24 hours after administration.

[0207] On day 8 of the study, the test betahistine composition was intranasally administered at a dose of 40 mg of betahistine dihydrochloride to animals that had received oral BH at a dose of 12 mg / kg. The test betahistine composition was intranasally administered at a dose of 80 mg of betahistine dihydrochloride to animals that had received oral BH at a dose of 24 mg / kg. And the test betahistine composition was intranasally administered at a dose of 120 mg of betahistine dihydrochloride to animals that had received oral BH at a dose of 48 mg / kg. The test betahistine composition was delivered intranasally as a single dose via an Aptar nasal spray pump device at total dose levels of 40, 80, and 120 mg of betahistine dihydrochloride. Plasma samples were collected before administration and then at 5, 10, 20, and 30 minutes, 1, 2, 3, 6, and 24 hours after administration.

[0208] On day 15 of the study, a bolus intravenous injection of betahistine at a dose of 0.44 mg / kg was administered to animals that had received oral BH at a dose of 12 mg / kg and the test betahistine composition intranasally at a dose of 40 mg of betahistine dihydrochloride. Plasma samples were taken before administration and at 5, 10, 20, and 30 minutes, 1, 2, 3, 6, and 24 hours after administration.

[0209] Using a validated method, plasma concentrations were measured by liquid chromatography tandem mass spectrometry (LC-MS / MS, SCIEX API 5000 for betahistine and SCIEX API 4000 for 2-pyridylacetic acid (2-PAA)). Betahistine 13CD3 dihydrochloride and 2-pyridyl lactic acid-D4 hydrochloride were used as internal standards respectively. With a plasma sample volume of 0.50 mL, the calibration range for betahistine was 0.05 - 250 ng / mL and for 2-PAA was 2.00 - 3000 ng / mL.

[0210] For the determination of betahistine, this method involved liquid-liquid extraction, and for 2-PAA, this method involved protein precipitation. Plasma samples were prepared for betahistine by extraction under basic conditions using an organic solvent, then the organic phase was dried, reconstituted, and transferred for LC / MS-MS analysis. For 2-PAA, plasma samples were precipitated with a mixture of organic solvents, the supernatant was dried, reconstituted, and transferred for LC / MS-MS analysis. Sample analysis was performed using reverse-phase chromatography.

[0211] Intranasal administration of betahistine was well tolerated in dogs. In the highest concentration betahistine group, salivation was observed in most animals, and sneezing occurred in 2 out of 8 animals at that dose level.

[0212] The plasma levels of betahistine and 2-PAA in the test animals were as shown in Tables 9 - 17.

Table 9

Table 10

Table 11

Table 12

Table 13

Table 14

Table 15

Table 16

Table 17

[0213] Figures 5 and 6 are graphs showing the median (Figure 5) and mean (Figure 6) of betahistine plasma concentration after intranasal administration of betahistine dihydrochloride at total doses of 40, 80, and 120 mg over time, with the values of male and female animals pooled over time. Figure 5, which is a graph based on the median, shows a dose-dependent increase in betahistine plasma concentration. In the graph based on the mean (Figure 6), the mean C of the 80 mg dose max appears to be higher than the mean C of the 120 mg dose max . This discrepancy is due to certain outlier values.

[0214] Figures 7 and 8 are graphs showing the median (Figure 7) and mean (Figure 8) of betahistine plasma concentration after oral administration of betahistine, with the values of male and female animals pooled over time.

[0215] Figures 9 and 10 are graphs showing the median (Figure 9) and mean (Figure 10) of betahistine plasma concentration after intravenous administration of betahistine, with the values of male and female animals pooled over time.

[0216] Tables 18 - 20 show a summary of pharmacokinetic parameters for betahistine (BH) after oral, intranasal, and intravenous administrations. Tables 21 - 23 show a summary of pharmacokinetic parameters for 2 - PAA after oral, intranasal, and intravenous administrations of betahistine.

Table 18

Table 19

Table 20

Table 21

Table 22

Table 23

[0217] Tables 24 and 25 show the absolute bioavailability (%F) of betahistine (BH) in dogs after oral and intranasal administration.

Table 24

Table 25

[0218] Table 26 shows the relative bioavailability (Frel) of betahistine (BH) administered intranasally compared to oral administration.

Table 26

[0219] Example 6: Relative Bioavailability of Betahistine by Intranasal Administration Compared to Oral Administration in Humans For the calculation of the relative bioavailability of intranasal betahistine compared to oral betahistine, the area under the concentration-time curve (AUC) determined in Example 3 was compared with the AUC determined in a study using oral betahistine in healthy volunteers described by Barak et al. (Journal of Psychopharmacology, 2016, Vol. 30(3) 237-241). Briefly, in this study, 48 healthy women were recruited and randomized to receive either 144 mg / day of betahistine (48 mg three times a day) or the corresponding placebo orally (i.e., by mouth) for 4 weeks. Their mean weights were 60.2 kg in the active treatment group (n = 24) and 59.8 kg in the placebo group (n = 24). The study drug (betahistine or the corresponding placebo) was administered at least 30 minutes before a meal. On day 8, 6 mL blood samples were taken at 8:00 am and then at 30, 60, 150, and 300 minutes thereafter. Plasma concentrations of betahistine and its metabolite 2-PAA were determined by high-performance liquid chromatography. The AUC (0-5h) was 121 pg*h / mL at a dose of approximately 0.8 mg / kg.

[0220] At the intranasal dose of 40 mg (or 0.57 mg / kg) in Example 3, an AUC of 3531 pg*h / mL was obtained (see Table 3).

[0221] Based on the AUC values for oral administration in the study by Barak et al. and the AUC values for intranasal administration from Example 3, the relative bioavailability of oral to intranasal administration (i.e., bioavailability by oral relative to intranasal) was approximately 2.4%, whereas the relative bioavailability of intranasal to oral (bioavailability by intranasal administration relative to oral) is summarized in the following table.

Table 27

[0222] Table 27 shows that the bioavailability by intranasal administration is 20 to 40 times higher than that by oral administration. When using relative bioavailability at an equivalent absolute dose (intranasal dose of 40 mg vs. oral dose of 48 mg), the magnification factor is 41.1x. The 0.8 mg / kg in the study by Barak et al. corresponds to the currently approved daily dose of 48 mg in a single administration. Patients received 48 mg administered three times a day, but due to rapid excretion, each dose is considered separately.

[0223] Incorporation by reference All references, articles, publications, patents, patent publications, and patent applications cited in this specification are hereby incorporated by reference in their entirety for all purposes. However, any reference to any reference, article, publication, patent, patent publication, and patent application cited in this specification shall not be construed as an admission that they are valid prior art or form a part of the common general knowledge in any country of the world, nor shall they be so interpreted in any form of suggestion.

Claims

Claim 1 A pharmaceutical composition for intranasal delivery to a human patient, comprising a solution or suspension containing betahistine dihydrochloride, a thickening agent, one or more humectants, and a buffering agent, wherein the pH of the pharmaceutical composition is from about 4.4 to about 6.4, the composition contains betahistine dihydrochloride at a concentration of from about 10 mg / mL to about 100 mg / mL, the thickening agent is selected from the group consisting of polyvinylpyrrolidone, polyvinyl alcohol, methylcellulose, carboxymethylcellulose - Na, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyethylene glycol (except polyethylene glycol 400), alginates, carrageenan, pectins, maltodextrin, sodium starch glycolate, tragacanth gum, gum arabic, microcrystalline cellulose, and combinations thereof, the one or more humectants are selected from the group consisting of glycerin, ethylene glycol, propylene glycol, polyethylene glycol 400, hexylene glycol, butylene glycol, dextrose, glyceryl triacetate, polydextrose, glyceryl triacetate, sorbitol, mannitol, and combinations thereof, a pharmaceutical composition. Claim 2 The pharmaceutical composition according to claim 1, wherein the pH of the pharmaceutical composition is about 4.4, about 4.8, about 5, about 5.2, about 5.4, about 5.6, about 5.8, about 6, about 6.2, or about 6.

4. Claim 3 The pharmaceutical composition according to claim 1, wherein the thickening agent is hydroxypropylmethylcellulose. Claim 4 (i) the composition contains an amount of betahistine dihydrochloride of from about 5 mg to about 100 mg, about 5 mg, about 10 mg, about 20 mg, about 40 mg, or about 80 mg, or (ii) the composition has a volume of from about 1 μL to about 1000 μL, The pharmaceutical composition according to any one of claims 1 to 3. Claim 5 (i) the composition can be administered as a spray or aerosol, or (ii) the composition is an aqueous solution, or (iii) the composition contains lipids, or (iv) the composition further contains at least one additional pharmaceutically active agent, or (v) the composition further contains at least one enzyme inhibitor or absorption enhancer, The pharmaceutical composition according to any one of claims 1 to 4. Claim 6 The pharmaceutical composition according to claim 5, wherein the at least one additional pharmaceutically active agent is a glutamate receptor antagonist.

7. The pharmaceutical composition according to any one of claims 1 to 6, wherein the composition contains 20 mg or 40 mg of betahistine dihydrochloride.

8. The pharmaceutical composition according to any one of claims 1 to 7 for use as a medicament.

9. The pharmaceutical composition according to any one of claims 1 to 7 for treating or alleviating symptoms of inner ear disorders, vestibular disorders, neurotological disorders, otological disorders or neurological disorders, or for preventing inner ear disorders, vestibular disorders, neurotological disorders, otological disorders or neurological disorders, wherein the composition is administered intranasally.

10. (i) the vestibular disorder is vestibular vertigo or Meniere's disease, or (ii) the inner ear disorder is selected from tinnitus or hearing loss, or (iii) the inner ear disorder has one or more symptoms selected from the group consisting of hearing loss, sudden hearing loss, tinnitus, nausea and vertigo, The pharmaceutical composition according to claim 9.

11. The pharmaceutical composition according to any one of claims 1 to 7 for facilitating vestibular rehabilitation.

12. The pharmaceutical composition according to any one of claims 1 to 7 for treating obesity, reducing weight gain, treating weight gain, and / or treating eating disorders, wherein the composition is administered intranasally.

13. The pharmaceutical composition according to claim 12, wherein the weight gain is induced by administration of an antipsychotic agent acting on histamine receptors.

14. The pharmaceutical composition according to claim 13, wherein the antipsychotic agent is olanzapine.

15. (i) the composition is administered once a day, twice a day, three times a day, four times a day, five times a day, six times a day, seven times a day, eight times a day, nine times a day, or ten times a day, and / or (ii) the total daily dose of betahistine dihydrochloride is about 0.01 mg / kg to about 20 mg / kg per kg of body weight of a human patient, The pharmaceutical composition according to any one of claims 8 to 14.

16. (i) the total daily dose of betahistine dihydrochloride is about 1 to 200 mg or about 5 to 100 mg, or (ii) the composition contains about 1 mg to about 100 mg of betahistine, The pharmaceutical composition according to any one of claims 8 to 14.

17. 10. The pharmaceutical composition of claim 1, wherein the viscosity increasing agent is polyvinylpyrrolidone.

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