Oromucosal liquid compositions of betahistine or its pharmaceutically acceptable salt(s) and processes for preparation thereof

Abstract

The present invention provides pharmaceutical compositions comprising betahistine or its pharmaceutically acceptable salt(s) for oromucosal administration and their use in the treatment of inner ear disorders such as vestibular vertigo and Meniere's disease. In particular, the present invention provides oromucosal liquid compositions comprising betahistine or its pharmaceutically acceptable salt(s) and their use in the treatment of inner ear disorders such as vestibular vertigo and Meniere's disease.

Description

[0001] OROMUCOSAL LIQUID COMPOSITIONS OF BETAHISTINE OR ITS PHARMACEUTICALLY ACCEPTABLE SALT(S) AND PROCESSES FOR PREPARATION THEREOF

[0002] FIELD OF THE INVENTION

[0003] The present invention relates to pharmaceutical compositions or formulations comprising betahistine or its pharmaceutically acceptable salt(s) for oromucosal administration and their use in the treatment of inner ear disorders such as vestibular vertigo and Meniere's disease. In particular, the present invention relates to oromucosal liquid compositions comprising betahistine or its pharmaceutically acceptable salt(s) and their use in the treatment of inner ear disorders such as vestibular vertigo and Meniere's disease.

[0004] BACKGROUND OF THE INVENTION

[0005] Betahistine is an active agent belonging to the group of central nervous and vestibular system. The chemical name of betahistine is 2-[2-(methylamino)ethyl]pyridine and its chemical structure is as depicted below:

[0006] The compound betahistine is known since 1904 and it is described in the prior art such as Loffler, Ber. 37,161 (1904) and Walter et al. , J Am. Chem. Soc. 63, 2771 (1941).

[0007] Betahistine is an orally active histamine analog used in the treatment of vestibular vertigo and Meniere's disease such as dizziness, tinnitus, hearing loss and the sensation of pressure or pain in the affected ear. In humans, betahistine is usually administered orally in the form of tablets, usually two to three times a day, up to 6 times a day at maximum daily dose of 48 mg. The commercially or conventionally available dosage forms of betahistine (Vertin® manufactured by Abbott, India) include immediate release tablets containing 8 mg, 16 mg, and 24 mg and orally disintegrating strips containing 24 mg of betahistine.

[0008] Oral administration of tablets undergoes extensive first-pass metabolism in the liver and produce gastric irritation in patients with peptic ulcer. After absorption betahistine is rapidly and almost completely metabolized into 2-pyridylacetic acid (2-PAA; which has no pharmacological activity). Due to its very high first pass metabolism, the absolute bioavailability of orally administered betahistine is estimated to be around 1% (European Summary of Product Characteristics). Betahistine is known for its short plasma half-life (3-4 hours) which necessitates frequent administration and may lead to noncompliance, especially in elderly patients. Besides, the oral dosage forms can also cause gastric irritation.

[0009] Further, the solid dosage forms are usually difficult to swallow as it is, and therefore are usually taken with large quantity of water. In particular, it is often difficult for elderly people and infants to swallow the solid dosage forms. Moreover, solid preparations have the risk of accidentally blocking the respiratory tract or the risk of adhering to the esophagus. On the other hand, liquid dosage forms are easily administered to elderly people and infants.

[0010] EP0397025B1 discloses salts of betahistine and process for their preparation. It also discloses various dosage forms of betahistine fumarate including syrup, oral drops, sublingual tablets, chewable tablets, injectables, suppositories, dragees, and intranasal formulations besides tablets and controlled release tablets. However, it does not provide any pharmacokinetic data on the extent of absorption from the oral mucosa for sublingual tablets, nor does it teach compositions enabling absorption of betahistine solution from the intraoral mucosa to avoid first pass metabolism of the drug in the liver.

[0011] W02002087622 discloses an oral administration agent, especially an oral administration agent in the form of a film, having improved ease of taking and safety, comprising one drugcontaining layer and two water swellings. The water-swellable gel-forming layer contains a water- swellable gel-forming agent such as a cross-linked carboxyvinyl polymer, and a film-forming agent such as polyvinyl alcohol. There is no teaching whether these formulations enable absorption of betahistine from the intraoral mucosa. Further, no pharmacokinetic data on the extent of absorption of betahistine from the oral mucosa has been provided.

[0012] CN110664765 discloses betahistine sublingual tablets and process for its preparation. It also discloses that sublingual tablets avoid first pass effect when the dose of betahistine is reduced from 6 mg to 3 mg with Tmax of 0.3 to 0.6 hours. Further, the sublingual tablet of 3 mg strength provides efficacy of 95%, in comparison to the efficacy of the conventional tablet of 6 mg which provides efficacy of 77%. However, as betahistine and its salts have intensely bitter taste, effectively masking the bitter taste is not feasible in sublingual tablet dosage form.

[0013] WO2018141922 discloses a pharmaceutical composition for intranasal delivery to a human patient, comprising a solution or suspension of therapeutically effective amount of betahistine or a pharmaceutically acceptable salt thereof and a viscosity enhancing agent. It teaches that for nasal drug delivery, pH of the formulation is in the range of 5.0 to 5.5. However, a large number of patients do not prefer nasal drug delivery.

[0014] Thus, there remains an unmet need to provide an easy to administer oromucosal liquid formulations of betahistine or its pharmaceutically acceptable salt(s) to provide formulations demonstrating:

[0015] • Reduced first-pass metabolism,

[0016] • Provides significantly higher bioavailability of betahistine or its pharmaceutically acceptable salt(s), up to 11 times, preferably about 6 to 11 times as compared to the bioavailability of conventional betahistine tablets,

[0017] • Avoidance of first-pass metabolism,

[0018] • Enhanced therapeutic effect of betahistine or its pharmaceutically acceptable salt(s) with a significantly lower dose,

[0019] • Avoids gastric irritation, as compared to conventional oral tablets and intraoral tablet formulations of betahistine or its pharmaceutically acceptable salt(s).

[0020] OBJECTIVES OF THE INVENTION

[0021] The main objective of the present invention is to provide oromucosal liquid compositions comprising betahistine or its pharmaceutically acceptable salt(s) that circumvents first-pass metabolism in the liver, provide enhanced bioavailability, and significantly lower the dose leading to improved therapeutic response and minimizing side effects of betahistine tablets.

[0022] Another objective of the present invention is to provide aqueous oromucosal liquid compositions comprising betahistine or its pharmaceutically acceptable salt(s) that circumvents first-pass metabolism in the liver, provide enhanced bioavailability, and significantly lower the dose leading to improved therapeutic response and minimizing side effects of betahistine tablets.

[0023] Another objective of the present invention is to provide oromucosal liquid compositions of betahistine or its pharmaceutically acceptable salt(s), wherein the compositions absorbed into systemic circulation through the oral mucosa is high as compared to that absorbed from the commercially available oral tablets and intraoral tablet formulations disclosed in the prior art. Another objective of the present invention is to provide oromucosal liquid compositions of betahistine or its pharmaceutically acceptable salt(s), wherein the compositions produce significantly higher blood levels of the drug, up to 11 times, preferably about 6 to 11 times as compared to the blood levels produced by an equal dose of commercially available oral tablets and intraoral tablet formulations disclosed in the prior art.

[0024] Another objective of the present invention is to provide oromucosal liquid compositions of betahistine or its pharmaceutically acceptable salt(s) that provide therapeutic efficacy at much reduced dose of the drug as compared to conventional oral tablets.

[0025] Another objective of the present invention is to mask the bitter taste of betahistine or its pharmaceutically acceptable salt(s) so as to provide highly palatable compositions of betahistine or its pharmaceutically acceptable salt(s).

[0026] Another objective of the present invention is to provide processes for the preparation of oromucosal liquid compositions comprising the step of mixing betahistine or its pharmaceutically acceptable salt(s) with solvent or mixture of the solvent with co-solvent(s), one or more penetration enhancer(s), water, and optionally, one or more pharmaceutically acceptable excipient(s).

[0027] SUMMARY OF THE INVENTION

[0028] The present invention provides oromucosal liquid compositions of betahistine or its pharmaceutically acceptable salt(s) with solvent or mixture of solvent with co-solvent(s), one or more penetration enhancer(s), water, and overcoming drawbacks associated with oral tablets and sublingual tablet formulations disclosed and taught in the prior art.

[0029] The oromucosal liquid formulations of the present invention further provides enhanced bioavailability at less than half the dose of commercially available oral tablets and intraoral tablet formulations disclosed in the prior-art.

[0030] Benefits of oromucosal liquid compositions of betahistine or its pharmaceutically acceptable salt(s) as per the present invention are as follows:

[0031] • Reduced first-pass metabolism,

[0032] • Enhanced bioavailability: The comparative pK study of present invention versus that of conventional tablet demonstrates that the absorption of the drug from the novel sublingual solution is significantly higher blood levels of the drug, up to 11 times, preferably about 6 to 11 times that of conventional tablet,

[0033] • Enhanced bioavailability at a much lower dose leading to improved therapeutic response, • Minimized systemic side effects due to reduction of the therapeutic dose,

[0034] • Minimized gastric side effects since the drug is predominantly absorbed from the oral mucosa,

[0035] • Palatable taste, and

[0036] • Easy for the patient to administer and therefore high patient compliance.

[0037] The present invention provides oromucosal liquid compositions comprising betahistine or its pharmaceutically acceptable salt(s), wherein concentration of betahistine or its pharmaceutically acceptable salt(s) present in the composition is in the range from 0.05% w / v to 24% w / v, preferably from 0.25% w / v to 16% w / v, and most preferably from 2% w / v to 8% w / v.

[0038] The present invention provides aqueous oromucosal liquid compositions, comprising a) betahistine or its pharmaceutically acceptable salt(s), b) solvent or mixture of solvent with co-solvent(s), c) one or more penetration enhancer(s), d) optionally, one or more pharmaceutically acceptable excipient(s), wherein the pharmaceutically acceptable excipient(s) is selected from the group comprising antioxidant, mucoadhesive agent, surfactant, pH adjusting agent, buffering agent, flavoring agent, sweetener, and preservative, and e) water; wherein pH of the compositions is in the range of 1.5 to 4.0.

[0039] The present invention also discloses a method of treating inner ear disorders such as vestibular vertigo and Meniere's disease in a subject, comprising the step of administering to the subject an effective amount of the oromucosal liquid compositions of the present invention.

[0040] The composition(s) of the present invention surprisingly circumvents first-pass metabolism in the liver and significantly lowering the dose leading to improved therapeutic response.

[0041] In a feature of the present invention, a method of treating inner ear disorders such as vestibular vertigo and Meniere's disease in a subject is disclosed, comprising the step of administering to the subject the oromucosal liquid compositions of the present invention comprising betahistine or its pharmaceutically acceptable salt(s), wherein concentration of betahistine or its pharmaceutically acceptable salt(s) is from 0.05% w / v to 24% w / v, preferably from 0.25% w / v to 16% w / v, and most preferably from 2% w / v to 8% w / v. The present invention also provides processes for the preparation of oromucosal liquid compositions comprising the step of mixing betahistine or its pharmaceutically acceptable salt(s) with solvent or mixture of the solvent with co-solvent(s), one or more penetration enhancer(s), water, and optionally, one or more pharmaceutically acceptable excipient(s).

[0042] In a feature of the present invention, administration of the composition results in enhanced bioavailability of betahistine.

[0043] BRIEF DESCRIPTION OF ACCOMPANYING FIGURES

[0044] Figure - 1 illustrates betahistine pharmacokinetic (PK) study data in mammals (n=3).

[0045] Figure - 2 illustrates 2-Pyridylacetic acid (2 -PAA- inactive metabolite) PK study data in mammals (n=3).

[0046] Figure - 3 illustrates betahistine pharmacokinetic (PK) study data in mammals (n=9).

[0047] Figure - 4 illustrates 2-Pyridylacetic acid (2 -PAA- inactive metabolite) PK study data in mammals (n=9).

[0048] DETAILED DESCRIPTION OF THE INVENTION

[0049] The term "liquid compositions" as used herein is defined as a solution, suspension, emulsion or dispersion.

[0050] The term “oromucosal” as used herein refers to buccal, sublingual, buccomaxillary sublingual, gingival, buccogingival and palatal.

[0051] The term "mammal" as used herein is defined as a human or an animal such as monkeys, primates, dogs, cats, horses, cows, rabbits and the like.

[0052] The use of the terms "a" and "an" and "the" and similar references in the context of describing the invention (especially in the context of the claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context.

[0053] The term “v / v” as used herein refers to volume per volume, and the term “w / v” as used herein refers to weight per volume.

[0054] The present invention discloses an aqueous oromucosal liquid compositions, comprising: a) betahistine or its pharmaceutically acceptable salt(s); b) solvent or mixture of solvent with cosolvents); c) one or more penetration enhancer(s); d) optionally, one or more pharmaceutically acceptable excipient(s), wherein the pharmaceutically acceptable excipient(s) is selected from the group comprising antioxidant, mucoadhesive agent, surfactant, pH adjusting agent, buffering agent, flavoring agent, sweetener, and preservative; and e) water; wherein pH of the composition(s) is in the range of 1.5 to 4.0.

[0055] The pharmaceutically acceptable excipient(s) according to the present invention is selected from a group comprising antioxidant, mucoadhesive agent, surfactant, pH adjusting agent, buffering agent, flavoring agent, sweetener, and preservative.

[0056] The pharmaceutically acceptable salt(s) of betahistine according to the present invention are acid addition salts, wherein acid is selected from benzoic acid, cinnamic acid, L-(+)-lactic acid, S-(+)-mandelic acid, (+)-camphor-10-sulfonic acid, gluconic acid, L-(+)-ascorbic acid, ascorbic acid, palmitic acid, naphthalene- 1,5 -disulfonic acid, hexanoic acid, oleic acid, stearic acid, gentisic acid, octanoic acid, decanoic acid, nitric acid, orotic acid, mucic acid, alginic acid and acesulfamic acid, nicotinic acid, hydrochloric acid (mono or di), hydrobromic acid, embonic acid, (2S.3S)- dibenzoyltartaric acid, dibenzoyltartaric acid, sebacic acid, 1 -hydroxys-naphthoic acid, phosphoric acid, L-(+)-tartaric acid, lysinic acid, L-lysinic acid, D-(+)-malic acid, 4-methylbenzenesulfonic acid, ethanesulfonic acid, hydrogen bromide, sulfuric acid, acetic acid, propionic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, hippuric acid, lactic acid, mandelic acid, malonic acid, malic acid, tartaric acid, methanesulfonic acid, citric acid, lactic acid. Preferably, betahistine dihydrochloride is used in the present invention and any embodiment thereof.

[0057] The concentration of betahistine or its pharmaceutically acceptable salt(s) is present in the range from 0.05% w / v to 24% w / v of the composition, preferably in the range from 0.25% w / v to 16% w / v. Most preferably, the concentration of betahistine or its pharmaceutically acceptable salt(s) is present in the range from 2% w / v to 8% w / v of the composition.

[0058] The solvent or mixture of solvent with co-solvent(s) is selected from the group comprising lower chain alcohol(s) with C1-C5 carbon straight chain alcohol, preferably ethanol or isopropyl alcohol, glycerol, propylene glycol, polyethylene glycol (PEG 400), propylene carbonate, glycofurol, isopropyl myristate, isopropyl palmitate, dimethyl sulfoxide, triethyl citrate, dimethylacetamide, benzyl alcohol, N-methyl-pyrrolidone, ethyl acetate, cyclodextrins, hydroxypropyl betadex, polyoxyethylene castor oil derivatives, povidone, sulfobutylether-b- cyclodextrin, tricaprylin, triolein, glyceryl monostearate, d-alpha tocopherol polyethylene glycol 1000 succinate (vitamin E TPGS), macrogol (15)-hydroxystearate (solutol HS 15), polyoxyethylene-polyoxypropylene copolymer (poloxamer, pluronic), PEO-PLLA diblock copolymer, PEG-PLGA-PEG triblock copolymer, sorbitan esters (sorbitan fatty acid esters), polyoxyethylene fatty acid esters, diethylene glycol monoethyl ether (transcutol), or dimethyl isosorbide.

[0059] The solvent or mixture of solvent with co-solvent(s) is in the range of 20% w / v to 75% w / v of the composition, preferably in the range of 30% w / v to 60% w / v of the composition.

[0060] The one or more penetration enhancer(s) is selected from the group comprising lower chain alcohol(s) with C1-C5 carbon straight chain alcohol, preferably ethanol or isopropyl alcohol, sodium glycocholate, sodium deoxycholate, sodium taurocholate, sodium glycodeoxycholate, sodium taurodeoxycholate, myristic acid, cethylpyridinium chloride, hydroxylpropyl betadex, lysophosphatidylcholine, phosphatidylcholine, laurocapram (azone), cyclodextrin, sodium lauryl sulphate, polyoxyethylene-9-laurylether, polyoxythylene-20-cetylether, benzalkonium chloride, cetylpyridinium chloride, d-alpha tocopheryl polyethylene glycol 1000 succinate (vitamin E TPGS), caprylocaproyl poly oxy Iglyceri des, stearoyl macrogolglycerides, N-methyl-2- pyrrolidone, diethylene glycol monoethyl ether (transcutol), glycofurol, dimethyl isosorbide, dimethyl sulfoxide, or mixtures thereof.

[0061] The one or more penetration enhancer(s) is added in the range of 1% v / v to 35% v / v of the composition, preferably in the range of 5% v / v to 30% v / v of the composition.

[0062] In some embodiments of the present invention, the compositions may contain antioxidant. The antioxidant(s) is selected from the group comprising ascorbic acid, propyl gallate, sodium ascorbate, sodium metabisulphite, alpha tocopherol, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, citric acid monohydrate, or mixtures thereof.

[0063] In other embodiments of the present invention, the amount of antioxidant used for the preparation of oromucosal liquid compositions are in the range of 0.02% w / v to 5.0% w / v of the composition.

[0064] In other embodiments of the present invention, the compositions may contain a mucoadhesive agent. The mucoadhesive agent is selected from the group comprising polyacrylic polymers like carbopols, polycarbophil, carboxymethylcellulose, microcrystalline cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose (hypromellose), methylcellulose, poloxamers, pectin, xanthan gums, alginates, gelatin, chitosan, or mixtures thereof.

[0065] The present invention comprises mucoadhesive agent in the range of 0.02% w / v to 2.0% w / v of the composition, preferably in the range of 0.05% w / v to 1.0% w / v. In some embodiments of the present invention, the compositions may contain surfactant. The surfactant is selected from the group comprising polyoxyethylene (20) sorbitan monolaurate (Polysorbate 20 / Tween 20), polyoxyethylene (40) sorbitan monolaurate (Polysorbate 40 / Tween 40), polyoxyethylene (60) sorbitan monolaurate (Polysorbate 60 / Tween 60), polyoxyethylene (80) sorbitan monooleate (Polysorbate 80 / Tween 80), sorbitan monolaurate (Span 20), sorbitan monopalmitate (Span 40), sorbitan monostearate (Span 60), sorbitan monooleate (Span 80), polyethylene-polypropylene glycols, polyoxyethylene-stearates, polyoxyethylene monolauryl ether, alkylphenylpolyoxy-ethylene ethers (Triton-X), polyoxyethylene-polyoxypropylene copolymer, sodium lauryl sulfate, sodium dodecyl sulphate (SDS), butylene glycol, polyoxyl 35 castor oil, polyoxyl 40 hydrogenated castor oil, lecithin, polyoxyethylene-polyoxypropylene copolymers (Pluronics), or any mixtures thereof.

[0066] The surfactant is in the range of 0.2% w / v to 5.0% w / v of the composition, preferably in the range of 0.5% w / v to 2.0% w / v.

[0067] In some embodiments of the present invention, the compositions may contain pH adjusting agent. The pH adjusting agent is selected from the group comprising hydrochloric acid, glacial acetic acid, sodium citrate dihydrate, phosphoric acid, propionic acid, sulfuric acid, or mixtures thereof.

[0068] In some embodiments of the present invention, the compositions may contain buffering agent. The buffering agent is selected from the group comprising citric acid monohydrate, maleic acid, malic acid, potassium citrate, sodium acetate, sodium citrate dihydrate, or mixtures thereof.

[0069] The compositions of present invention may further contain auxiliary ingredient(s) selected from the group comprising flavoring agents, sweeteners known in the art. The flavoring agent of the present invention is selected from the group comprising menthol, peppermint oil, maltol, ethyl maltol, ethyl vanillin, vanillin, spearmint, strawberry, cherry, raspberry, wintergreen, watermelon, grape flavors, ecocool, or mixtures thereof.

[0070] The amount or concentration of flavoring agent is in the range of 0.05% w / v to 0.5% w / v of the composition.

[0071] The sweetener of the present invention is selected from the group comprising neotame, sucrose, alitame, acesulfame potassium, aspartame, trehalose, xylitol, sucralose, sorbitol, saccharin sodium, neohesperidin dihydrochalcone, mannitol, maltitol, lactitol, fructose, or mixtures thereof. The amount or concentration of sweetener is in the range of 0.1% w / v to 5.0% w / v of the composition.

[0072] The compositions may further contain preservative. The preservative is selected from the group comprising benzalkonium chloride, benzethonium chloride, benzoic acid, benzyl alcohol, bronopol, chlorobutanol, methylparaben, phenoxyethanol, phenylethyl alcohol, propylparaben, sodium benzoate, sorbic acid, or mixtures thereof.

[0073] The amount or concentration of preservative is in the range of 0.01% w / v to 2.0% w / v of the composition.

[0074] In the present invention, water is used in a quantity sufficient to make up the final volume of the compositions.

[0075] The pH of the compositions of the present invention are in the range of 1.5 to 4.0 and maintains the drug in a stable state during the entire shelf-life of the composition.

[0076] The oromucosal liquid compositions of the present invention circumvents first-pass metabolism in the liver, provide enhanced bioavailability, and significantly lowering the dose yet providing improved therapeutic response.

[0077] The oromucosal liquid compositions of the present invention are arrived at by combining betahistine or its pharmaceutically acceptable salt(s) with judiciously selected solvent or mixture of solvent with co-solvent(s), one or more penetration enhancer(s), and water, in carefully decided quantities at pH in the range of 1.5 to 4.0, and optionally in the presence of one or more pharmaceutically acceptable excipient(s) selected from the group comprising antioxidant, mucoadhesive agent, surfactant, pH adjusting agent, buffering agent, flavoring agent, sweetener, and preservative, to produce a synergy that surprisingly results in significantly higher absorption of drug through oromucosal route of administration, as compared to commercially available oral tablets and intraoral tablet formulations disclosed in the prior art.

[0078] The surprising results of the present invention are evident from the fact that compositions provide AUC up to 11 times, preferably about 6 to 11 times higher than the conventional tablets at equivalent dose. More preferably, AUC of the compositions is about 8 to 11 times higher than the conventional tablets at equivalent dose.

[0079] The compositions of the present invention exhibit high AUC, as compared with the commercially available oral tablets and intraoral tablet formulations disclosed in the prior art. The superior pharmacokinetic profile leads to reduction of the dose and yet provide superior therapeutic response. The results of the pharmacokinetic study confirm that the compositions as per the present invention (Example-4) provide formulation with AUC 81.109 hr*ng / mL in 3 animals. In comparison, the conventional tablet (Vertin®, Comparative Example 30) produces AUC of 7.045 hr*ng / mL in 3 animals (Figure 1). Moreover, the results of the pharmacokinetic study carried out in 9 animals reaffirm that the compositions as per the present invention (Example-4) provide formulation with AUC 100.077 hr*ng / mL. In comparison, the conventional tablet (Vertin®, Comparative Example 30) produces AUC of 8.995 hr*ng / mL in 9 animals (Figure 3).

[0080] The invention also provides a pharmaceutical product comprising oromucosal liquid compositions as described herein and a dispensing device, wherein the dispensing device is adapted for administering the compositions to intraoral mucosa in an accurate dose. For example, the device may comprise oromucosal pump so that the product can be administered in the form of oromucosal spray. Alternatively, the device may comprise another suitable oromucosal applicator. The pharmaceutical product may further comprise instruction for use, for example in the form of an insert or label.

[0081] The oromucosal liquid compositions of the present invention can be administered through oromucosal spray or any suitable oromucosal applicator. The oromucosal liquid compositions can be provided in multi dose container(s) or unit dose container, preferably in multi dose container(s).

[0082] Another embodiment of the present invention provides oromucosal liquid compositions comprising betahistine or its pharmaceutically acceptable salt(s) for the treatment of inner ear disorders such as vestibular vertigo and Meniere’s disease.

[0083] Further provided is a method of treating inner ear disorders such as vestibular vertigo and Meniere’s disease comprising administering to a subject in need thereof, oromucosal liquid compositions comprising betahistine or its pharmaceutically acceptable salt(s), wherein the concentration of betahistine or its pharmaceutically acceptable salt(s) is from 0.05% w / v to 24% w / v, preferably from 0.25% w / v to 16% w / v, and most preferably from 2% w / v to 8% w / v. The administration of the composition results in enhanced bioavailability of betahistine or its pharmaceutically acceptable salt(s).

[0084] Additionally provided is processes for the preparation of oromucosal liquid compositions comprising the step of mixing betahistine or its pharmaceutically acceptable salt(s) with solvent or mixture of solvent with co-solvent(s), one or more penetration enhancer(s), water, and optionally, one or more pharmaceutically acceptable excipient(s). Non-limiting examples of the composition of the present invention are provided below:

[0085] EXAMPLES:

[0086] Example 1

[0087] Process:

[0088] In a beaker, purified water (30% of the batch size) and betahistine dihydrochloride were added and stirred to get clear solution under nitrogen purging. Subsequently, propylene glycol, neotame, ecocool and absolute alcohol were added one by one under stirring to obtain clear solution. The obtained solution is then made up to 100% of the composition with purified water and pH of the solution was 3.50.

[0089] Example 2

[0090] Process:

[0091] In a beaker, purified water (30% of the batch size) and betahistine dihydrochloride were added and stirred to get clear solution under nitrogen purging. Subsequently, propylene glycol, neotame, ecocool and absolute alcohol were added one by one under stirring to obtain clear solution. The obtained solution is then made up to 100% of the composition with purified water and pH of the solution was 3.20.

[0092] Example 3

[0093] Process:

[0094] In a beaker, purified water (30% of the batch size) and betahistine dihydrochloride were added and stirred to get clear solution under nitrogen purging. Subsequently, propylene glycol, neotame, ecocool and absolute alcohol were added one by one under stirring to obtain clear solution. The obtained solution is then made up to 100% of the composition with purified water and pH of the solution was 2.30.

[0095] Example 4

[0096] Process:

[0097] In a beaker, purified water (30% of the batch size) and betahistine dihydrochloride were added and stirred to get clear solution under nitrogen purging. Subsequently, propylene glycol, neotame, ecocool and absolute alcohol were added one by one under stirring to obtain clear solution. The obtained solution is then made up to 100% of the composition with purified water and pH of the solution was 2.33.

[0098] Example 5

[0099] Process:

[0100] In a beaker, purified water (30% of the batch size) and betahistine dihydrochloride were added and stirred to get clear solution under nitrogen purging. Subsequently, propylene glycol, neotame, ecocool and absolute alcohol were added one by one under stirring to obtain clear solution. The obtained solution is then made up to 100% of the composition with purified water and pH of the solution was 2.24.

[0101] Example 6

[0102] Process:

[0103] In a beaker, purified water (30% of the batch size) and betahistine dihydrochloride were added and stirred to get clear solution under nitrogen purging. Subsequently, propylene glycol and absolute alcohol were added one by one under stirring to obtain clear solution. The obtained solution is then made up to 100% of the composition with purified water and pH of the solution was 1.90. Example 7

[0104] Process:

[0105] In a beaker, purified water (30% of the batch size) and betahistine dihydrochloride were added and stirred to get clear solution under nitrogen purging. Subsequently, propylene glycol, PEG 400, neotame, ecocool and absolute alcohol were added one by one under stirring to obtain clear solution. The obtained solution is then made up to 100% of the composition with purified water and pH of the solution was 2.52.

[0106] Example 8 Process:

[0107] In a beaker- 1, purified water (40% of the batch size) and betahistine dihydrochloride were added and stirred to get clear solution under nitrogen purging. Subsequently, neotame and ecocool were added one by one under stirring to obtain clear solution.

[0108] In a beaker-2, propylene glycol and hypromellose were added and stirred to get clear solution under nitrogen purging. The solution obtained is then transferred to beaker- 1 and stirred to get clear solution. Subsequently, absolute alcohol was added and then the composition is made up to 100% with purified water and pH of the solution was 2.54.

[0109] Example 9

[0110] Process:

[0111] In a beaker, purified water (30% of the batch size) and betahistine dihydrochloride were added and stirred to get clear solution under nitrogen purging. Subsequently, propylene glycol, benzyl alcohol, neotame, ecocool and absolute alcohol were added one by one under stirring to obtain clear solution. The obtained solution is then made up to 100% of the composition with purified water and pH of the solution was 2.00.

[0112] Example 10

[0113] Process:

[0114] In a beaker, purified water (30% of the batch size) and betahistine dihydrochloride were added and stirred to get clear solution under nitrogen purging. Subsequently, propylene glycol, aspartame, ecocool and absolute alcohol were added one by one under stirring to obtain clear solution. The obtained solution is then made up to 100% of the composition with purified water and pH of the solution was 2.10.

[0115] Example 11

[0116] Process:

[0117] In a beaker, purified water (30% of the batch size) and betahistine dihydrochloride were added and stirred to get clear solution under nitrogen purging. Subsequently, propylene glycol, aspartame, ecocool and absolute alcohol were added one by one under stirring to obtain clear solution. The obtained solution is then made up to 100% of the composition with purified water and pH of the solution was 2.00.

[0118] Example 12

[0119] Process:

[0120] In a beaker, purified water (35% of the batch size) and betahistine dihydrochloride were added and stirred to get clear solution under nitrogen purging. Subsequently, propylene glycol, aspartame, ecocool and glycofurol were added one by one under stirring to obtain clear solution. The obtained solution is then made up to 100% of the composition with purified water and pH of the solution was 2.34.

[0121] Example 13

[0122] Process:

[0123] In a beaker, purified water (40% of the batch size) and betahistine dihydrochloride were added and stirred to get clear solution under nitrogen purging. Subsequently, propylene glycol, aspartame, ecocool and glycofurol were added one by one under stirring to obtain clear solution. The obtained solution is then made up to 100% of the composition with purified water and pH of the solution was 2.60.

[0124] Example 14

[0125] Process:

[0126] In a beaker, purified water (35% of the batch size) and betahistine dihydrochloride were added and stirred to get clear solution under nitrogen purging. Subsequently, propylene glycol, aspartame, ecocool, sodium metabisulphite and absolute alcohol were added one by one under stirring to obtain clear solution. The obtained solution is then made up to 100% of the composition with purified water and pH of the solution was 2.20.

[0127] Example 15

[0128] Process:

[0129] In a beaker- 1, purified water (30% of the batch size) and betahistine dihydrochloride were added and stirred to get clear solution under nitrogen purging. Subsequently, propylene glycol and aspartame were added one by one under stirring to obtain clear solution.

[0130] In a beaker-2, absolute alcohol, menthol and butylated hydroxyanisole were added and stirred to get clear solution under nitrogen purging. The solution obtained is then transferred to beaker- 1 and stirred to get uniform solution. The obtained solution is then made up to 100% with purified water and pH of the solution was 2.37. Example 16

[0131] Process:

[0132] In a beaker- 1, purified water (30% of the batch size) and betahistine dihydrochloride were added and stirred to get clear solution under nitrogen purging. Subsequently, propylene glycol and ascorbic acid were added one by one under stirring to obtain clear solution.

[0133] In a beaker-2, transcutol, aspartame and menthol were added and stirred to get clear solution under nitrogen purging. The solution obtained is then transferred to beaker- 1 and stirred to get uniform solution. The solution obtained is then made up to 100% with purified water and pH of the solution was 2.04.

[0134] Example 17

[0135] Process:

[0136] In a beaker- 1, purified water (35% of the batch size) and betahistine dihydrochloride were added and stirred to get clear solution under nitrogen purging. Subsequently, propylene glycol, citric acid monohydrate and neotame were added one by one under stirring to obtain clear solution.

[0137] In a beaker-2, absolute alcohol, transcutol and menthol were added and stirred to get clear solution under nitrogen purging. The solution obtained is then transferred to beaker- 1 and stirred to get uniform solution. The obtained solution is then made up to 100% with purified water and pH of the solution was 2.14.

[0138] Example 18

[0139] Process:

[0140] In a beaker- 1, purified water (35% of the batch size) and betahistine dihydrochloride were added and stirred to get clear solution under nitrogen purging. Subsequently, neotame and ecocool were added one by one under stirring to obtain clear solution.

[0141] In a beaker-2, propylene glycol and hydroxypropyl cellulose were added and stirred to get clear solution. The solution obtained is then transferred to beaker- 1 and stirred to get uniform solution. To this uniform solution, absolute alcohol was added and made up to 100% of the composition with purified water and pH of the solution was 2.12.

[0142] Example 19

[0143] Process:

[0144] In a beaker- 1, purified water (40% of the batch size) and betahistine dihydrochloride were added and stirred to get clear solution under nitrogen purging. Subsequently, neotame and ecocool were added one by one under stirring to obtain clear solution.

[0145] In a beaker-2, propylene glycol and hydroxy ethyl cellulose were added and stirred to get clear solution under nitrogen purging. The solution obtained is then transferred to beaker- 1 and stirred to get uniform solution. To this uniform solution, absolute alcohol was added and made up to 100% of the composition with purified water and pH of the solution was 2.25.

[0146] Example 20

[0147] Process:

[0148] In a beaker- 1, purified water (40% of the batch size) and betahistine dihydrochloride were added and stirred to get clear solution under nitrogen purging. Subsequently, neotame and ecocool were added one by one under stirring to obtain clear solution.

[0149] In a beaker-2, propylene glycol and hydroxyethyl cellulose were added and stirred to get clear solution under nitrogen purging. The solution obtained is then transferred to beaker- 1 and stirred to get uniform solution. To this uniform solution, absolute alcohol was added and made up to 100% of the composition with purified water and pH of the solution was 2.40.

[0150] Example 21

[0151] Process:

[0152] In a beaker- 1, purified water (40% of the batch size) and betahistine dihydrochloride were added and stirred to get clear solution under nitrogen purging. Subsequently, neotame and ecocool were added one by one under stirring to obtain clear solution.

[0153] In a beaker-2, propylene glycol and hydroxyethyl cellulose were added and stirred to get clear solution under nitrogen purging. The solution obtained is then transferred to beaker- 1 and stirred to get uniform solution. To this uniform solution, absolute alcohol and dimethyl isosorbide were added, stirred to get clear solution and made up to 100% of the composition with purified water and pH of the solution was 2.52.

[0154] Example 22

[0155] Process:

[0156] In a beaker- 1, purified water (40% of the batch size) and betahistine dihydrochloride were added and stirred to get clear solution under nitrogen purging. Subsequently, neotame and ecocool were added one by one under stirring to obtain clear solution.

[0157] In a beaker-2, propylene glycol and hydroxyethyl cellulose were added and stirred to get clear solution under nitrogen purging. The solution obtained is then transferred to beaker- 1 and stirred to get uniform solution. To this uniform solution, absolute alcohol and Vitamin TPGS were added, stirred to get clear solution and made up to 100% of the composition with purified water and pH of the solution was 2.32.

[0158] Example 23

[0159] Process:

[0160] In a beaker, purified water (35% of the batch size) and betahistine dihydrochloride were added and stirred to get clear solution under nitrogen purging. Subsequently, propylene glycol, polyethylene glycol sorbitan monolaurate (Tween 20), neotame, ecocool and absolute alcohol were added one by one under stirring to obtain clear solution. The solution obtained is then made up to 100% of the composition with purified water and pH of the solution was 2.09.

[0161] Example 24

[0162] Process:

[0163] In a beaker, purified water (30% of the batch size) and betahistine dihydrochloride were added and stirred to get clear solution under nitrogen purging. Subsequently, propylene glycol and dimethyl isosorbide were added one by one under stirring to obtain clear solution. The solution obtained is then made up to 100% of the composition with purified water and pH of the solution was 1.79.

[0164] Example 25

[0165] Process:

[0166] In a beaker, purified water (30% of the batch size) and betahistine dihydrochloride were added and stirred to get clear solution under nitrogen purging. Subsequently, propylene glycol, neotame, ecocool and absolute alcohol were added one by one under stirring to obtain clear solution. The solution obtained is then made up to 100% of the composition with purified water and pH of the solution was 1.92.

[0167] Example 26

[0168] Process:

[0169] In a beaker- 1, purified water (40% of the batch size) and betahistine dihydrochloride were added and stirred to get clear solution under nitrogen purging. Subsequently, neotame and ecocool were added one by one under stirring to obtain clear solution.

[0170] In a beaker-2, propylene glycol and hydroxypropylmethyl cellulose were added and stirred to get clear solution under nitrogen purging. The solution obtained is then transferred to beaker- 1 and stirred to get uniform solution. To this uniform solution, absolute alcohol was added, stirred to get clear solution and made up to 100% of the composition with purified water and pH of the solution was 1.86.

[0171] Example 27

[0172] Process:

[0173] In a beaker, purified water (30% of the batch size) and betahistine dihydrochloride were added and stirred to get clear solution under nitrogen purging. Subsequently, propylene glycol, citric acid monohydrate, neotame, ecocool and absolute alcohol were added one by one under stirring to obtain clear solution. The solution obtained is then made up to 100% of the composition with purified water and pH of the solution was 1.73. Example 28

[0174] Process:

[0175] In a beaker- 1, purified water (30% of the batch size) and betahistine dihydrochloride were added and stirred to get clear solution under nitrogen purging. Subsequently, propylene glycol, neotame and ecocool were added one by one under stirring to obtain clear solution.

[0176] In a beaker-2, absolute alcohol and butylated hydroxyanisole were added and stirred to get clear solution under nitrogen purging. The solution obtained is then transferred to beaker- 1 and stirred to get clear solution. The obtained solution is then made up to 100% with purified water and pH of the solution was 1.74.

[0177] Example 29 Process:

[0178] In a beaker- 1, purified water (30% of the batch size) and betahistine dihydrochloride were added and stirred to get clear solution under nitrogen purging. Subsequently, propylene glycol, neotame and ecocool were added one by one under stirring to obtain clear solution.

[0179] In a beaker-2, absolute alcohol and butylated hydroxyanisole were added and stirred to get clear solution under nitrogen purging. The solution obtained is then transferred to beaker- 1 and stirred to get clear solution. The obtained solution is then made up to 100% with purified water and pH of the solution was 1.72.

[0180] Comparative Example-30 (Vertin® 8 mg tablet*)

[0181] Example 31 Process:

[0182] In a beaker- 1, purified water (20% of the batch size) and betahistine dihydrochloride were added and stirred to get clear solution under nitrogen purging. Subsequently, ecocool and aspartame were added under continuous stirring to obtain a clear solution.

[0183] In a beaker-2, purified water (10% of the batch size) and hypromellose were stirred to obtain clear solution under nitrogen purging and transferred the obtained solution to beaker-1. To this mixture, dimethyl isosorbide, glycofurol were added one by one to obtain clear solution. The obtained solution is then made up to 100% with purified water and pH of the solution was 2.58. Example 32

[0184] Process:

[0185] In a beaker- 1, purified water (25% of the batch size) and betahistine dihydrochloride were added and stirred to get clear solution under nitrogen purging. In a separate beaker, menthol was dissolved in transcutol to form a clear solution and transferred the obtained solution to beaker- 1. Subsequently, neotame and sodium glycocholate were added and stirred to obtain clear solution. The solution obtained is then made up to 100% with purified water and pH of the solution was 3.31.

[0186] Example 33

[0187] Process:

[0188] In a beaker- 1, purified water (20% of the batch size) and betahistine dihydrochloride were added and stirred to get clear solution under nitrogen purging. Menthol was dissolved in transcutol and added to beaker- 1. Subsequently, neotame was added and stirred to get clear solution.

[0189] In a beaker-2, purified water (10% of the batch size) and hypromellose were stirred to obtain clear solution under nitrogen purging and the obtained solution was then transferred to beaker- 1. To this mixture, tween 80 and absolute alcohol were added and stirred to provide clear solution. The solution obtained is then made up to 100% with purified water and pH of the solution was 2.28.

[0190] Example 34

[0191] Process:

[0192] In a beaker, purified water (25% of the batch size) and betahistine dihydrochloride were added and stirred to obtain a clear solution under nitrogen purging. Subsequently, transcutol, ecocool, aspartame, polyethylene glycol sorbitan monolaurate (Tween 80), and absolute alcohol were added one by one under stirring to obtain a clear solution. The solution obtained is then made up to 100% with purified water and pH of the solution was 2.48.

[0193] Example 35

[0194] Process:

[0195] In a beaker, purified water (25% of the batch size) and betahistine dihydrochloride were added and stirred to obtain a clear solution under nitrogen purging. Subsequently, propylene glycol, ecocool, aspartame, poloxamer, and absolute alcohol were added one by one under stirring to obtain a clear solution. The obtained solution is then made up to 100% with purified water and pH of the solution was 2.09.

[0196] The examples disclosed above are representative of the composition covered in the present invention. The scope of the present invention is not limited to any of these examples. The advantageous features provided by said representative composition(s) are also provided by all the composition(s) covered in the scope of the present invention.

[0197] Comparative pharmacokinetic study in mammals: A cross-over comparative pharmacokinetic study of betahistine sublingual solution 4% w / v and 8% w / v (Example 4 and 5 of the present invention) with the oral formulation available in the market (Comparative Example 30, Vertin® 8 mg) was carried out following single dose administration in mammals.

[0198] Detail experimental procedure for performing PK study with mammal / biological species

[0199] An open label, single dose and crossover pharmacokinetic study in male New Zealand White rabbits was conducted. Betahistine sublingual solution 4% w / v (Example 4 of the present invention) was administered below the tongue sublingually (8 mg dose per rabbit) using micropipette. The betahistine 8 mg tablet (Vertin® manufactured by Abbott, India) was administered orally as per the recommended method of dosing. A series of blood samples were collected from each rabbit at decided intervals and plasma was separated. Estimation of plasma concentrations of betahistine and its metabolite, 2-pyridylacetic acid (2-PAA) was performed using a LCMS / MS method. The pharmacokinetic parameters Cmax and AUC were derived using WinNonlin software.

[0200] Pharmacokinetic Parameters of Betahistine

[0201] Pharmacokinetic Parameters of 2-PAA (metabolite)

[0202] Results: Example 4 of the present invention provides 11 fold higher bioavailability of betahistine solution as compared to betahistine 8mg tablet, Comparative Example 30 (Vertin® manufactured by Abbott, India) (Figure 1). Also, concentrations of 2-pyridylacetic acid (i.e. 2-PAA), which is an inactive metabolite of betahistine, are lower in Example 4 of the present invention compared to Comparative Example 30 (Vertin® tablet) indicating lower metabolic degradation of the sublingual formulation. The above study was carried out on 3 animals. To confirm the above results, the experiment was repeated in larger number of animals i.e. n= 9. Results of which are presented hereunder:

[0203] Pharmacokinetic Parameters of Betahistine

[0204] Pharmacokinetic Parameters of 2-PAA (metabolite)

[0205] The results of the study carried out in larger number of animals indicates that 11 fold higher bioavailability of betahistine solution (Example 4) as compared to comparative Example 30 (Vertin® tablet) reaffirming the previous results of study carried out in 3 animals (Figure 3).

[0206] Further, in this study bioavailability of sublingual betahistine solution 8% (Example 5) was also compared with comparative Example 30 (Vertin® tablet). The results of this study also confirm that multi fold absorption of betahistine from Example 5 when compared with comparative Example 30 (Vertin® tablet) (Figure 3). The results of the same are given as under: Pharmacokinetic Parameters of Betahistine

[0207] Pharmacokinetic Parameters of 2-PAA (metabolite) In light of the above, the palatable oromucosal liquid compositions of betahistine or its pharmaceutically acceptable salt(s) of the present invention offers significant advantages over conventional tablet formulations, providing superior pharmacokinetic profile. These compositions represent a valuable advancement in the treatment of inner ear disorders such as vestibular vertigo and Meniere's disease.

[0208] Although the present invention has been described in considerable detail with reference to certain preferred embodiments thereof, other versions are possible. Moreover, it will be understood that the illustrations are for the purpose of describing exemplary embodiments of the invention and the same do not limit the scope of the present invention.

Claims

We claim:

1. An oromucosal liquid composition(s), comprising: a) betahistine or its pharmaceutically acceptable salt(s), b) solvent or mixture of solvent with co-solvent(s), c) one or more penetration enhancer(s), d) optionally, one or more pharmaceutically acceptable excipient(s), wherein the pharmaceutically acceptable excipient(s) is selected from the group comprising antioxidant, mucoadhesive agent, surfactant, pH adjusting agent, buffering agent, flavoring agent, sweetener, and preservative, and e) water; wherein pH of the composition(s) is in the range of 1.5 to 4.0.

2. The composition(s) as claimed in claim 1, wherein concentration of the betahistine or its pharmaceutically acceptable salt(s) present in the composition ranges from 0.05% w / v to 24.0% w / v.

3. The composition(s) as claimed in claim 1, wherein the solvent or mixture of solvent with cosolvents) is selected from the group comprising lower chain alcohol(s) having C1-C5 carbon straight chain, glycerol, propylene glycol, polyethylene glycol, propylene carbonate, glycofurol, isopropyl myristate, isopropyl palmitate, dimethyl sulfoxide, triethyl citrate, dimethyl acetamide, benzyl alcohol, N-methyl-pyrrolidone, ethyl acetate, cyclodextrins, hydroxypropyl betadex, polyoxyethylene castor oil derivatives, povidone, sulfobutylether-P- cyclodextrin, tricaprylin, triolein, glyceryl monostearate, d-alpha tocopherol polyethylene glycol 1000 succinate (vitamin E TPGS), macrogol (15)-hydroxystearate, polyoxyethylenepolyoxypropylene copolymer (poloxamer), PEO-PLLA diblock copolymer, PEG-PLGA-PEG triblock copolymer, sorbitan esters (sorbitan fatty acid esters), polyoxyethylene fatty acid esters, diethylene glycol monoethyl ether, or dimethyl isosorbide.

4. The composition(s) as claimed in claim 1 or 3, wherein concentration of the solvent or mixture of solvent with co-solvent(s) is in the range of 20% w / v to 75% w / v of the composition.

5. The composition(s) as claimed in claim 1, wherein the penetration enhancer(s) is selected from the group comprising lower chain alcohol(s) having C1-C5 carbon straight chain, sodium glycocholate, sodium deoxycholate, sodium taurocholate, sodium glycodeoxycholate, sodium taurodeoxycholate, myristic acid, cethylpyridinium chloride, hydroxylpropyl betadex,lysophosphatidylcholine, phosphatidylcholine, laurocapram, cyclodextrin, sodium lauryl sulphate, polyoxyethylene-9-laurylether, polyoxythylene-20-cetylether, benzalkonium chloride, cetylpyridinium chloride, d-alpha tocopheryl polyethylene glycol 1000 succinate (vitamin E TPGS), caprylocaproyl poly oxylglyceri des, stearoyl macrogolglycerides, N- methyl-2-pyrrolidone, diethylene glycol monoethyl ether, glycofurol, dimethyl isosorbide, dimethyl sulfoxide, or mixtures thereof.

6. The composition(s) as claimed in claim 1 or 5, wherein concentration of the penetration enhancer(s) is in the range from 1% v / v to 35% v / v of the composition.

7. The composition(s) as claimed in claim 1 , wherein the antioxidant is selected from the group comprising ascorbic acid, propyl gallate, sodium ascorbate, sodium metabisulphite, alpha tocopherol, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, citric acid monohydrate, or mixtures thereof.

8. The composition(s) as claimed in claim 1 or 7, wherein concentration of the antioxidant is in the range from 0.02% w / v to 5.0% w / v of the composition.

9. The composition(s) as claimed in claim 1 , wherein the mucoadhesive agent is selected from the group comprising polyacrylic polymers like carbopols, polycarbophil, carboxymethylcellulose, microcrystalline cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose (hypromellose), methylcellulose, poloxamers, pectin, xanthan gums, alginates, gelatin, chitosan, or mixtures thereof.

10. The composition(s) as claimed in claim 1 or 9, wherein concentration of the mucoadhesive agent is in the range from 0.02% w / v to 2.0% w / v of the composition.

11. The composition(s) as claimed in claim 1, wherein the surfactant is selected from the group comprising polyoxyethylene (20) sorbitan monolaurate, polyoxyethylene (40) sorbitan monolaurate, polyoxyethylene (60) sorbitan monolaurate, polyoxyethylene (80) sorbitan monooleate, sorbitan monolaurate (Span 20), sorbitan monopalmitate, sorbitan monostearate, sorbitan monooleate, polyethylene-polypropylene glycols, polyoxyethylene-stearates, polyoxyethylene monolauryl ether, alkylphenylpolyoxy-ethylene ethers, polyoxyethylenepolyoxypropylene copolymer, sodium lauryl sulfate, sodium dodecyl sulphate (SDS), butylene glycol, polyoxyl 35 castor oil, polyoxyl 40 hydrogenated castor oil, lecithin, polyoxyethylene-polyoxypropylene copolymers, or any mixtures thereof.

12. The composition(s) as claimed in claim 1 or 11, wherein concentration of the surfactant is in the range from 0.2% w / v to 5.0% w / v of the composition.

13. The composition(s) as claimed in claim 1, wherein the flavoring agent is selected from the group comprising menthol, peppermint oil, maltol, ethyl maltol, ethyl vanillin, vanillin, spearmint, strawberry, cherry, raspberry, wintergreen, watermelon, grape flavors, ecocool, or mixtures thereof.

14. The composition(s) as claimed in claim 1 or 13, wherein concentration of the flavoring agent is in the range from 0.05% w / v to 0.5% w / v of the composition.

15. The composition(s) as claimed in claim 1, wherein the sweetener is selected from the group comprising neotame, sucrose, alitame, acesulfame potassium, aspartame, trehalose, xylitol, sucralose, sorbitol, saccharin sodium, neohesperidin dihydrochalcone, mannitol, maltitol, lactitol, fructose, or mixtures thereof.

16. The composition(s) as claimed in claim 1 or 15, wherein concentration of the sweetener is in the range from 0.1% w / v to 5.0% w / v of the composition.

17. The composition(s) as claimed in claim 1, wherein the preservative is selected from the group comprising benzalkonium chloride, benzethonium chloride, benzoic acid, benzyl alcohol, bronopol, chlorobutanol, methylparaben, phenoxyethanol, phenylethyl alcohol, propylparaben, sodium benzoate, sorbic acid, or mixtures thereof.

18. The composition(s) as claimed in claim 1 or 17, wherein concentration of the preservative is in the range from 0.01% w / v to 2.0% w / v of the composition.

19. The composition(s) as claimed in claim 1, wherein the water is used in a quantity sufficient to make up the final volume of the compositions.

20. The composition(s) as claimed in any one of the preceding claims, wherein the bioavailability of betahistine or its pharmaceutically acceptable salt(s) is up to 11 times higher as compared to the conventional betahistine tablets.

21. The composition(s) as claimed in any one of the preceding claims, wherein the bioavailability of betahistine or its pharmaceutically acceptable salt(s) is about 6 to 11 times higher as compared to the conventional betahistine tablets.

22. A process(es) for preparing a composition(s) as claimed in claim 1, wherein the process(es) comprising the step of mixing betahistine or its pharmaceutically acceptable salt(s) withsolvent or mixture of the solvent with co-solvent(s), one or more penetration enhancer(s), water, and optionally, one or more pharmaceutically acceptable excipient(s).

23. A method of treating inner ear disorders such as vestibular vertigo and Meniere's disease in a subject, comprising the step of administering to the subject an effective amount of the oromucosal liquid composition(s) as claimed in claim 1.

24. The method as claimed in claim 23, wherein administration of the composition results in enhanced bioavailability of betahistine or its pharmaceutically acceptable salt(s).

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