Anti-vertigo composition and its pharmaceutical composition

Abstract

The present invention relates to the use of levocloperastine for the treatment or prevention of dizziness, dizziness-related diseases, or symptoms associated therewith.Furthermore, the present invention relates to an oral pharmaceutical composition comprising levocloperastine and one or more pharmaceutical excipients, and a process for the preparation thereof.

Description

Technical Field

[0001] The present invention relates to a method for treating vertigo and / or one or more symptoms of vertigo or a disease associated with vertigo using levocloperastine. The present invention further relates to a composition comprising levocloperastine and its use for the treatment or prevention of one or more symptoms of vertigo or a disease associated with vertigo.

Background Art

[0002] Levocloperastine (I) is the levorotatory isomer of DL-cloperastine. Levocloperastine is used to reduce the strength and frequency of cough. The antihistamine, antiserotonin, and muscle relaxant properties of levocloperastine contribute to its overall effectiveness in the treatment of cough, bronchospasm, and related symptoms.

[0003] Figure 1

Chemical Formula

[0004] Peripheral vertigo is an abnormality in the information integration mechanism of the central nervous system caused by a sudden dysfunction of the balance nervous system that occurs in the vestibular nervous system, and is accompanied by various symptoms such as abnormal sensations of movement and posture, nystagmus, balance disorders, head deviation, nausea, vomiting, sweating, salivary secretion, and tachycardia. The proportion of peripheral vertigo patients is increasing.

[0005] The most common causes of peripheral vertigo are ear disorders or inner ear infections, such as benign paroxysmal positional vertigo (BPPV), vestibular neuritis, and Meniere's disease. BPPV is caused by calcium buildup in the inner ear canal, which can lead to brief episodes of dizziness lasting 20 seconds to 1 minute. It is usually caused by head trauma or head movement in certain positions. Vestibular neuritis is caused by an infection of the inner ear, which causes inflammation around the nerves that help with balance. This can result in severe episodes of peripheral vertigo lasting more than a day, sometimes accompanied by hearing loss. Meniere's disease (MD) is an inner ear disorder characterized by episodes of symptoms such as a spinning sensation (peripheral vertigo), ringing in the ear (tinnitus), hearing loss, and a feeling of fullness in the ear.

[0006] Meclizine, diphenhydramine, scopolamine, diazepam, lorazepam, betahistine, and cinnarizine are commonly used medications for peripheral vertigo, and current anti-vertigo drugs cause drowsiness. Furthermore, a faster onset of action is also desirable in patients with peripheral vertigo.

[0007] There is a need for an effective treatment of dizziness or dizziness-related disorders that avoids drowsiness, alleviates autonomic symptoms in a shorter period, and provides a faster onset of action. Patients suffering from peripheral vertigo require an effective treatment that can alleviate peripheral vertigo and associated autonomic symptoms such as nausea, vomiting, sweating, and tachycardia. This invention provides optimal patient compliance by offering rapid relief in a short time without administering sedatives to the patient. Objective of the present invention

[0008] The first object of the present invention is to provide a treatment for dizziness and / or prevention of one or more symptoms of dizziness or dizziness-related diseases using levocloperastine.

[0009] Another object of the present invention is to provide treatment and rapid relief for one or more symptoms of peripheral vertigo using levocloperastine.

[0010] Another object of the present invention is to use levocloperastine for the treatment of dizziness or clinical signs and symptoms associated with dizziness.

[0011] Another object of the present invention is to use levocloperastine for the treatment of dizziness, or clinical signs and symptoms associated with dizziness, or autonomic symptoms, or diseases associated with dizziness, within a shorter period of time compared to standard therapeutics used.

[0012] Another object of the present invention is to provide a pharmaceutical composition for use in the treatment of dizziness, or related clinical signs and symptoms, or autonomic nervous system-related symptoms, within a shorter period of time compared to standard therapeutics used.

[0013] Another object of the present invention is to provide a pharmaceutical composition of levocloperastine and its use for the treatment or prevention of one or more symptoms of dizziness. [Overview of the Initiative]

[0014] One embodiment of the present invention is the use of levocloperastine for the treatment of dizziness and / or for the prevention of one or more symptoms of dizziness.

[0015] Another embodiment of the present invention involves the use of levocloperastine for the treatment of peripheral vertigo and the clinical signs and symptoms of peripheral vertigo.

[0016] Another embodiment of the present invention is the administration of a therapeutically effective dose of levocloperastine for the treatment of dizziness and / or one or more symptoms of dizziness.

[0017] Another embodiment of the present invention is the administration of a therapeutically effective dose of levocloperastine for the treatment of peripheral vertigo.

[0018] Another embodiment of the present invention involves the use of levocloperastine for rapid relief of dizziness symptoms compared to existing standard treatments, as well as rapid relief of associated autonomic parasymptoms, which in turn greatly contributes to the treatment of dizziness patients and to improving their compliance.

[0019] Another embodiment of the present invention is a novel pharmaceutical composition comprising levocloperastine for use in the treatment of dizziness or one or more symptoms associated with dizziness.

[0020] Another embodiment of the present invention involves using levocloperastine for the treatment of dizziness or one or more symptoms associated with dizziness or related autonomic symptoms or diseases, within a shorter period of time compared to the standard therapeutic treatment used.

[0021] Another embodiment of the present invention is a method for treating dizziness and / or preventing one or more symptoms of dizziness or a dizziness-related disorder in a human subject, the method comprising administering to the subject a therapeutically effective amount of levocloperastine or a pharmaceutically acceptable salt thereof for a period shorter than that of the standard therapeutic therapy used.

[0022] Another embodiment of the present invention is a pharmaceutical composition for use in the treatment of dizziness or dizziness-related disorders or autonomic nervous system-related symptoms, within a shorter period of time compared to standard therapeutics used for the treatment of dizziness or dizziness-related disorders. [Modes for carrying out the invention]

[0023] The general and more specific embodiments of the invention described above, including the examples described below, are illustrative and do not limit the scope of the invention to the embodiments explicitly or specifically disclosed, nor do modifications and / or variations thereof that are obvious to those skilled in the art fall within the scope of the invention.

[0024] Unless otherwise defined, all technical and scientific terms used herein shall have the meanings that are commonly understood by those skilled in the art of the present invention.

[0025] Processes, methods, and techniques that are commonly used and routinely practiced in the field of the present invention and / or are readily understood by those skilled in the art are not described in detail for the sake of brevity.

[0026] As used throughout this specification, the term "levocromoperastine" includes the free base form and its pharmaceutically acceptable salts; the anhydrous form, solvates, hydrates, and co-crystalline forms thereof; and the crystalline and amorphous polymorphic forms thereof.

[0027] The term "patient or subject" means a human being in some disease state.

[0028] As used for the purposes of the invention, the term "pharmaceutical composition" means a composition in the form of tablets, capsules, solutions, and suspensions. The pharmaceutical composition includes levocromoperastine and one of more pharmaceutically acceptable excipients.

[0029] One embodiment of the present invention is the use of levocromoperastine or a pharmaceutically acceptable salt thereof for the treatment of dizziness and / or the prevention of one or more symptoms of dizziness.

[0030] Another embodiment of the present invention is the use of levocromoperastine or a pharmaceutically acceptable salt thereof for the treatment and / or prevention of one or more symptoms of dizziness or a disease associated with dizziness. Dizziness-related diseases include, but are not limited to, Meniere's disease and giddiness.

[0031] Another embodiment of the present invention is the use of levocromoperastine for the treatment of peripheral vertigo.

[0032] Another embodiment of the present invention is the use of levocromoperastine or a pharmaceutically acceptable salt thereof in the preparation of a pharmaceutically acceptable composition for use in the treatment of dizziness and / or the prevention of one or more symptoms of dizziness.

[0033] Another embodiment of the present invention is the administration of levocloperastine or a pharmaceutically acceptable salt thereof in a therapeutically effective dose for the treatment of dizziness and / or the prevention of one or more symptoms of dizziness.

[0034] Another embodiment of the present invention is a method for treating dizziness and / or preventing one or more symptoms of dizziness or a dizziness-related disorder in a human subject, the method comprising administering to the subject a therapeutically effective amount of levocloperastine or a pharmaceutically acceptable salt thereof.

[0035] Other embodiments of the present invention provide a method for treating one or more symptoms or diseases in a human subject that are related to peripheral vertigo, Meniere's disease, tinnitus, hearing loss, dizziness, paresthesia of movement and posture, nystagmus, balance disorders, vertigo, head deviation, nausea, vomiting, sweating, salivation and tachycardia, orthostatic intolerance and gait instability, unsteadiness, spinning sensation, tendency to fall, lift sensation, blackout, change of posture (lying down), bowing, getting up, driving, head movement (tilting, twisting), eye movement, or one or more related symptoms or diseases, wherein the method comprises administering to the subject a therapeutically effective amount of levocloperastine or a pharmaceutically acceptable salt thereof.

[0036] Another embodiment of the present invention involves using levocloperastine in human subjects for the treatment of dizziness and / or for the prevention of one or more symptoms of dizziness or a dizziness-related disorder.

[0037] Another embodiment of the present invention involves using levocloperastine in the preparation of a pharmaceutical composition for use in the treatment of dizziness and / or the prevention of one or more symptoms of dizziness or a dizziness-related disorder in a human subject.

[0038] Levocloperastine can be used to treat or prevent dizziness or dizziness-related disorders in a daily dose of 5 to 1000 mg, preferably about 5 to 500 mg, more preferably about 5 to 200 mg, or more preferably about 5 to 160 mg.

[0039] Levocloperastine can be administered as a single dose or in divided doses.

[0040] Levocloperastine can be administered daily in doses of approximately 5-80 mg once a day, approximately 5-40 mg twice a day, or approximately 3-30 mg three times a day.

[0041] Levocloperastine can be administered in daily doses of approximately 60-90 mg once a day, approximately 30-45 mg twice a day, or approximately 20-30 mg three times a day.

[0042] Levocloperastine can be administered in daily doses of approximately 70-120 mg once a day, approximately 35-60 mg twice a day, or approximately 25-40 mg three times a day.

[0043] Levocloperastine can be administered in daily doses of approximately 90-160 mg once a day, approximately 45-80 mg twice a day, or approximately 30-55 mg three times a day.

[0044] The actual dosage of levocloperastine can be calculated and adjusted according to the pharmaceutically acceptable salt used. For example, 35.4 mg of levocloperastine fendizoate is equivalent to 20 mg of levocloperastine HCl.

[0045] Another embodiment of the present invention involves using approximately 20-36 mg of levocloperastine or a pharmaceutically acceptable salt thereof three times a day for the treatment of dizziness or / or for the prevention of one or more symptoms of dizziness.

[0046] Another embodiment of the present invention involves using approximately 30-55 mg of levocloperastine or a pharmaceutically acceptable salt thereof twice daily for the treatment of dizziness or / or the prevention of one or more symptoms of dizziness.

[0047] Another embodiment of the present invention involves using approximately 60-110 mg of levocloperastine or a pharmaceutically acceptable salt thereof once daily for the treatment of dizziness or / or for the prevention of one or more symptoms of dizziness.

[0048] Another embodiment of the present invention involves using approximately 30-55 mg of levocloperastine or a pharmaceutically acceptable salt thereof three times a day for the treatment of dizziness or / or for the prevention of one or more symptoms of dizziness.

[0049] Another embodiment of the present invention involves using approximately 45-85 mg of levocloperastine or a pharmaceutically acceptable salt thereof twice daily for the treatment of dizziness or / or the prevention of one or more symptoms of dizziness.

[0050] Another embodiment of the present invention involves using approximately 90-160 mg of levocloperastine or a pharmaceutically acceptable salt thereof once daily for the treatment of dizziness or / or for the prevention of one or more symptoms of dizziness.

[0051] Another embodiment of the present invention is the use of levocloperastine for the treatment or prevention of dizziness or dizziness-related disorders, where the patient's dizziness symptoms are on a scale of 0 to 5.

[0052] The efficacy of levocloperastine in the treatment or prevention of dizziness or dizziness-related disorders has been evaluated as follows: improvement of dizziness symptoms based on the MVS score as the primary efficacy endpoint; improvement of quality of life (QoL) related to peripheral dizziness based on the NVI and IGA scores on a 5-point verbal rating scale assessed by the investigator (greatly improved, improved, slightly improved, not improved, worsened); improvement of tinnitus severity subjectively assessed by the THI on a 3-point categorical scale (yes / no / sometimes); and improvement of four autonomic parasymptoms (nausea, vomiting, sweating, and tachycardia) based on intensity assessed on a subjective 5-point VAS (0: absent, 1: moderate, 2: moderate, 3: strong, 4: very strong).

[0053] The MVS score is a 12-item composite score for measuring the severity of dizziness symptoms, defined as the average intensity of dizziness resulting from six (unprovoked) dizziness symptoms (orthostatic and gait instability, unsteadiness, spinning sensation, tendency to fall, upward sensation, blackout) and six triggers [changes in body position (lying down), lowering the head, getting up, driving a car / train, head movements (tilting, twisting), eye movements]. The intensity of each of the 12 individual symptoms is assessed by the patient using a 5-point VAS scale (0=absent, 1=low, 2=moderate, 3=severe, 4=very severe). The mean MVS, which is a measure of dizziness intensity, is calculated by adding up the scores of all 12 dizziness symptoms and dividing by 12. The scale is assessed directly by the patient.

[0054] The NVI is a 28-item questionnaire with a 5-point Likert scale (1: never; 2: rarely; 3: sometimes; 4: quite frequently; 5: always), and the total score ranges from 28 to 140. A higher score indicates greater functional impairment. It assesses seven cognitive domains: spatial perception, attention, temporal perception, memory, affect, visual / oculokinetic, and motor skills. The scale is administered by the patient.

[0055] The severity of tinnitus is measured using a subjective assessment of 25 questions on a categorical 3-point scale (yes / no / sometimes) as part of the THI (Tinnitus Inventory). The total score reflects the sum of all responses, with a maximum score of 100 indicating the greatest impact on daily functioning.

[0056] Levocloperastine exhibits highly selective CNS activity; therefore, it avoids central nervous system side effects such as sedation. Levocloperastine did not induce clinically relevant sedation at doses up to 450 times the therapeutic dose. Levocloperastine offers a faster onset of action and also avoids adverse events such as agitation and excitement. Because treatment with levocloperastine is not accompanied by any sedative effect, symptoms associated with dizziness are not masked, and surprisingly, levocloperastine shows improvement in dizziness and dizziness-related autonomic parasymptoms even without sedative properties.

[0057] Levocloperastine provides treatment for dizziness, peripheral vertigo, dizziness-related disorders, or autonomic parasymptoms within a shorter timeframe compared to standard treatments used. Levocloperastine achieves equivalent improvement in MVS scores with a shorter treatment duration compared to standard treatment. Equivalent improvement in the severity of autonomic parasymptoms is achieved with standard treatment after approximately 28 days of treatment, but with levocloperastine, this is achieved in only about 7 days of treatment, significantly reducing the treatment duration to about one-quarter of that of standard treatment. Levocloperastine results in rapid relief of dizziness or its symptoms and improvement in the severity of associated autonomic parasymptoms.

[0058] Without causing the clinically relevant sedative effects of levocloperastine, the faster onset and shorter duration of treatment aid in better patient compliance, better treatment adherence, and limited exercise / exercise restrictions in patients.

[0059] Another embodiment of the present invention is a method for treating dizziness in a human subject and / or preventing one or more symptoms of dizziness or autonomic symptomatic symptoms or diseases associated with dizziness, the method comprising administering to the subject a therapeutically effective amount of levocloperastine or a pharmaceutically acceptable salt thereof for a period shorter than that of the standard therapeutic therapy used.

[0060] Another embodiment of the present invention involves using a therapeutically effective amount of levocloperastine or a pharmaceutically acceptable salt thereof for the treatment of one or more symptoms or diseases related to peripheral vertigo, Meniere's disease, tinnitus, hearing loss, vertigo, paresthesia of movement and position, nystagmus, balance disorders, dizziness, head deviation, nausea, vomiting, sweating, salivation and tachycardia, orthostatic and gait instability, unsteadiness, spinning sensation, tendency to fall, upward sensation, blackout, changes in body position (lying down), lowering the head, getting up, driving, head movements (tilting, twisting), eye movements, or a related condition, for a shorter period than standard therapeutic treatment used.

[0061] Another embodiment of the present invention is a pharmaceutical composition for use in the treatment of dizziness or dizziness-related disorders or autonomic nervous system-related symptoms, within a shorter period of time compared to standard therapeutics used for the treatment of dizziness or dizziness-related disorders.

[0062] Another embodiment of the present invention is a pharmaceutical composition comprising levocloperastine or a pharmaceutically acceptable salt thereof for use in human subjects in the treatment of dizziness and / or in the prevention of one or more symptoms of dizziness or a disease associated with dizziness.

[0063] A pharmaceutically acceptable composition of levocloperastine may be suitable for oral, buccal, sublingual, transdermal, intravenous, intraperitoneal, intramuscular, or subcutaneous administration.

[0064] Another embodiment of the present invention is an oral pharmaceutical composition comprising levocloperastine for use in the treatment or prevention of dizziness or dizziness-related disorders.

[0065] Another embodiment of the present invention is an oral pharmaceutical composition comprising levocloperastine for use in the treatment or prevention of peripheral vertigo or diseases associated with peripheral vertigo.

[0066] Another embodiment of the present invention is a pharmaceutical composition comprising levocloperastine for use in the treatment of dizziness and / or the prevention of one or more symptoms of dizziness.

[0067] Pharmaceutical dosage forms for use in the treatment or prevention of dizziness or dizziness-related disorders may be, but are not limited to, solid or liquid oral dosage forms. Solid oral dosage forms may be, but are not limited to, tablets, capsules, granules, or powders, and liquid oral compositions may be, but are not limited to, solutions, syrups, suspensions, or emulsions.

[0068] Another embodiment of the present invention involves the use of levocloperastine for the treatment or prevention of dizziness or dizziness-related disorders, wherein the pharmaceutical composition used for the treatment or prevention of dizziness or dizziness-related disorders comprises levocloperastine and one or more pharmaceutically acceptable excipients, the composition being in the form of a liquid dosage form, the liquid dosage form being used for administration to pediatric and adult patients.

[0069] Another embodiment of the present invention involves the use of levocloperastine in a mixture with a conventional pharmaceutically acceptable carrier or diluent suitable for oral or parenteral administration, for the treatment of dizziness or dizziness-related disorders.

[0070] Another embodiment of the present invention is a stable oral pharmaceutical composition of levocloperastine and one or more pharmaceutically acceptable excipients, the composition being in the form of tablets, capsules, solutions, syrups, or suspensions.

[0071] Other embodiments of the present invention are stable oral pharmaceutical compositions comprising levocloperastine and one or more pharmaceutically acceptable excipients, the pharmaceutically acceptable excipients including, but not limited to, diluents, disintegrants, binders, lubricants, anti-adherents, plasticizers, colorants, opacifiers, chelating agents, glidants, fragrances, sweeteners, coatings, wetting agents, buffers, suspending agents, preservatives, surfactants, viscosity modifiers, osmotic pressure regulators, dust suppressants, adsorbents, antioxidants, wetting agents, solvents, polymers, soft gel capsules, hard gel capsules, or mixtures thereof.

[0072] The diluent or filler (excipient) is selected from, but is not limited to, the group including lactose monohydrate, corn starch, mannitol, anhydrous calcium hydrogen phosphate, crystalline cellulose, silicified MCC, corn starch, sucrose or other sugars or sugar derivatives, low-substituted HPC, pregelatinized starch or mixtures thereof, more preferably mannitol and crystalline cellulose. The excipient or filler may be present in a concentration of about 20% to about 80% by weight of the total weight of the composition.

[0073] The binder may be selected from, but is not limited to, pregelatinized starch, polyvinylpyrrolidone, vinylpyrrolidone-vinyl acetate copolymer, povidone, copovidone, hydroxypropyl methylcellulose, hydroxypropylcellulose, corn starch, crystalline cellulose, or mixtures thereof. The binder may be present in a concentration of about 0.5% to about 5% by weight of the total weight of the composition.

[0074] The disintegrant may be selected from the group including, but is not limited to, croscarmellose sodium, crospovidone, sodium starch glycolate, starch, corn starch, pregelatinized starch, or mixtures thereof. The disintegrant may be present in a concentration of about 1% to about 10% by weight of the total weight of the composition.

[0075] The lubricant can be selected from the group comprising agar, calcium stearate, ethyl oleate, ethyl laurate, glycerin, glyceryl palmitostearate, hydrogenated vegetable oil, magnesium oxide, magnesium stearate, sodium stearyl, sorbitol, stearic acid, talc, zinc stearate, or mixtures thereof. The lubricant may be present in a concentration of about 0.2% to about 2% by weight of the total weight of the composition.

[0076] The plasticizer may be selected from the group comprising acetyl tributyl citrate, acetyl triethyl citrate, benzyl benzoate, chlorobutanol, cellulose acetate phthalate compatible, dextrin, dibutyl phthalate, dibutyl sebacate, diethyl phthalate, dimethyl phthalate, glycerin, glycerin monostearate, hypromellose phthalate compatible, mannitol, liquid paraffin and lanolin alcohol, petrolatum and lanolin alcohol, polyethylene glycol, propylene glycol, pyrrolidone, sorbitol, triacetin, tributyl citrate, triethyl citrate, palmitic acid, polymethacrylate compatible, polyvinyl acetate phthalate, stearic acid, triethanolamine, or mixtures thereof.

[0077] The colorants may be selected from the group including Red No. 3 (erythrosine), Red No. 40 (Allura Red AC), Yellow No. 5 (tartrazine), Yellow No. 6 (Sunset Yellow), Blue No. 1 (Brilliant Blue), Blue No. 2 (Indigotine), Green No. 3 (Fast Green), iron oxide, or mixtures thereof.

[0078] The milking agent may be selected from the group comprising aluminum monostearate, calcium carbonate, calcium silicate, ceresin, titanium dioxide, zinc acetate, colorants, ethylene glycol palmitostearate, octyldodecanol, zinc stearate, or mixtures thereof.

[0079] The chelating agent may be selected from the group comprising calcium acetate, hydroxypropyl beta-dex, potassium citrate, citric acid, citric acid monohydrate, disodium edetate, edetate, malic acid, pentetic acid, phosphoric acid, sodium citrate dihydrate, dibasic sodium phosphate, monobasic sodium phosphate, tartaric acid, potassium citrate, fumaric acid, maltol, pentetic acid, or mixtures thereof.

[0080] The fluidizing agent can be selected from the group comprising colloidal silicon dioxide, magnesium silicate, starch, talc, tribasic calcium phosphate, stearic acid, palmitic acid, polyethylene glycol, carnauba wax, or mixtures thereof. The fluidizing agent may be present in a concentration of about 0% to about 2% by weight of the total weight of the composition.

[0081] The fragrance agent may be selected from the group comprising adipic acid, n-butyl lactate, confectionery sugar, citrate monohydrate, dibutyl sebacate, denatonium benzoate, ethyl acetate, ethyl lactate, ethyl maltol, ethyl vanillin, ethylcellulose, fructose, fumaric acid, leucine, malic acid, maltol, menthol, methionine, sodium glutamate, neohesperidin dihydrochalcone, neotame, sodium acetate, sodium lactate, triethyl citrate, tartaric acid, thaumatin, thymol, trehalose, vanilla, phosphoric acid, propionic acid, sodium propionate, or mixtures thereof.

[0082] The sweetener can be selected from the group comprising acesulfame potassium, aliterm, aspartame, glucose, erythritol, fructose, glucose solution, glycerin, inulin, isomalt, lactitol, maltitol, maltitol solution, maltose, mannitol, neohesperidin dihydrochalcone, neotame, saccharin, sodium saccharin, sodium cyclamate, sorbitol, sucralose, sucrose, compressible sugar, confectionery sugar, tagatose, thaumatin, trehalose, xylitol, or mixtures thereof.

[0083] The anti-adhesive can be selected from the group consisting of magnesium stearate, calcium stearate, leucine, colloidal silicon dioxide, talc, starch, microcrystalline cellulose, leucine, or mixtures thereof.

[0084] The polymer can be selected from the group comprising hydroxypropyl methylcellulose, polyethylene glycol, hydroxypropyl cellulose and its derivatives, polysorbate, Soluplus® (polyvinyl caprolactam-polyvinyl acetate-polyethylene), sodium carboxymethylcellulose, talc, titanium dioxide, simethicone, eudoragit, purified water, and colorants. The polymer is used in film coating materials. Alternatively, it can be used as an excipient and may be present in a concentration of about 1% to about 5% by weight of the total weight of the composition.

[0085] The surfactant can be selected from the group including anionic surfactants such as sodium lauryl sulfate and sodium doxate; cationic surfactants such as cetrimide; amphoteric surfactants such as N-dodecyl-N,N-dimethylbetaine; and nonionic surfactants such as sorbitan fatty acid esters, polysorbates, polyoxyethylene alkyl ethers, poloxamers, medium-chain triglycerides, polyoxylglycerides, polyoxyethylene castor oil derivatives, and combinations thereof. The surfactant can be present in a concentration of about 0% to about 5% by weight of the total weight of the composition.

[0086] The dust suppressant is cooking oil.

[0087] The adsorbent can be selected from the group including bone gelatin (type B), skin gelatin (type A), or mixtures thereof. Gelatin also functions as a suspending agent.

[0088] The solubilizer, emulsifier, or dispersant may be selected from the group including Tween80, Labrasol, HPMC, DOSS, Caproyl 909, Labrafac, Labrafil, Peceol, Transktol, Capmul MCM, Capmul PG-12, Captex 355, Gelucire, Lecithine, Vitamin E TOPS, or other acceptable solubilizers, emulsifiers, or dispersants.

[0089] The solvent can be selected from the group including purified water, water for injection, aromatic water, alcohol, glycerol, propylene glycol USP, ether (diethyl ether), polyethylene glycol and its derivatives, diethylene glycol monomethyl ether and its derivatives, dimethylacetamide, non-volatile oil-based plant sources, or mixtures thereof.

[0090] The humectant can be selected from the group comprising benzalkonium chloride, benzethonium chloride, cetylpyridinium chloride, sodium doxate, glycine, glycoflor, hypromellose, poloxamer, phospholipids, polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene stearate, sodium lauryl sulfate, sorbitan esters (sorbitan fatty acid esters), tricaprylin, or mixtures thereof.

[0091] The buffering agent can be selected from the group comprising adipic acid, ammonia solution, boric acid, calcium carbonate, calcium hydroxide, calcium lactate, calcium phosphate (tribasic), citric acid monohydrate, dibasic sodium phosphate, diethanolamine, glycine, maleic acid, malic acid, methionine, sodium glutamate, monoethanolamine, sodium glutamate, potassium citrate, sodium acetate, sodium borate, sodium carbonate, sodium citrate dihydrate, sodium hydroxide, sodium lactate, sodium phosphate (dibasic), sodium phosphate (monobasic), propionic acid, phosphoric acid, sodium bicarbonate, triethanolamine, or mixtures thereof.

[0092] The suspending agent may be selected from the group comprising acacia, agar, alginic acid, bentonite, carbomer, calcium stearate, calcium carboxymethylcellulose, sodium carboxymethylcellulose, carrageenan, crystalline cellulose, sodium carboxymethylcellulose, powdered cellulose, ceratonia, colloidal silicon dioxide, dextrin, gelatin, guar gum, hydrophobic colloidal silica, hydroxyethylcellulose, hydroxyethylmethylcellulose, hydroxypropylcellulose, hypromellose, kaolin, aluminum magnesium silicate, maltitol solution, medium-chain triglycerides, methylcellulose, phospholipids, polycarbophil, polyoxyethylene sorbitan fatty acid ester, potassium alginate, povidone, propylene glycol alginate, sodium alginate, saposite, sesame oil, sorbitan ester (sorbitan fatty acid ester), sucrose, tragacanth, vitamin E polyethylene glycol succinate, xanthan gum, ceratonia, hectorite, or mixtures thereof.

[0093] Viscosity modifiers can be selected from the group comprising acacia, agar, alginic acid, bentonite, calcium carboxymethylcellulose, sodium carboxymethylcellulose, carrageenan, ceratonia, cetostearyl alcohol, chitosan, colloidal silicon dioxide, cyclomethicone, ethylcellulose, gelatin, glycerin, glyceryl behenate, guar gum, hectorite, hydrophobic colloidal silica, hydroxyethylcellulose, hydroxyethylmethylcellulose, hydroxypropylcellulose, hydroxypropyl starch, hypromellose, magnesium aluminum silicate, maltodextrin, methylcellulose, myristyl alcohol, polydextrose, poly(methyl vinyl ether / maleic anhydride), polyvinyl alcohol, propylene glycol, propylene glycol alginate, saposite, sodium alginate, sodium chloride, starch, sulfobutyl ether β-cyclodextrin, tragacanth, xanthan gum, or mixtures thereof.

[0094] The preservatives include alcohol, benzalkonium chloride, benzethonium chloride, benzoic acid, benzyl alcohol, boric acid, bronopol, butylene glycol, butylhydroxyanisole, butylparaben, calcium acetate, calcium chloride, calcium lactate, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, citric acid monohydrate, cresol, dimethyl ether, ethylparaben, glycerin, hexetidine, imidourea, isopropyl alcohol, lactic acid, methylparaben, monothioglycerol, pentetic acid, and phenol. The following can be selected from the group comprising phenoxyethanol, phenylethyl alcohol, phenylmercury acetate, phenylmercury borate, phenylmercury nitrate, potassium benzoate, sodium pyrosulfite, potassium sorbate, propionic acid, propylene glycol, propyl gallate, propylparaben, sodium propylparaben, sodium acetate, sodium benzoate, sodium borate, sodium lactate, sodium disulfite, sodium propionate, sodium sulfite, sorbic acid, sulfur dioxide, thimerosal, sulfobutyl ether β-cyclodextrin, xylitol, EDTA, or mixtures thereof.

[0095] The antioxidant can be selected from the group comprising α / β / δ / γ tocopherol, ascorbic acid, ascorbyl palmitate, butylhydroxyanisole, butylhydroxytoluene, citric acid monohydrate, erythorbic acid, ethyl oleate, fumaric acid, malic acid, methionine, sodium pyrosulfite, propionic acid, propyl gallate, sodium ascorbate, sodium formaldehyde sulfoxylate, sodium disulfite, sodium sulfite, sodium bisulfite, sodium thiosulfate, sulfur dioxide, thymol, vitamin E polyethylene glycol succinate, monothioglycerol, phosphoric acid, or mixtures thereof.

[0096] The osmotic regulator can be selected from the group comprising glucose, glycerin, hydroxypropyl beta-dex, mannitol, potassium chloride, sodium chloride, or mixtures thereof.

[0097] The humectant can be selected from the group comprising ammonium alginate, butylene glycol, cyclomethicone, glycerin, polydextrose, propylene glycol, sodium hyaluronate, sodium lactate, sorbitol, or mixtures thereof.

[0098] Dicom DC SP (registered trademark) and F-Melt Type C (registered trademark) are used as excipients.

[0099] In one preferred embodiment of the present invention, the pharmaceutical composition comprises levocloperastine or a pharmaceutically acceptable salt thereof, wherein the composition is a tablet composition comprising, based on the total weight of the tablet composition, 1-5% levocloperastine, 20-80% diluent, 1-10% disintegrant, 0.5-5% binder, 0.2-2% lubricant, 0-2% fluidizing agent, and 0-5% surfactant.

[0100] In one preferred embodiment of the present invention, the pharmaceutical composition comprises levocloperastine or a pharmaceutically acceptable salt thereof, wherein the composition comprises 1-5% levocloperastine, 1-10% antioxidant, and 0.01-10% preservative, based on the total weight of the solution composition, further comprising a buffering agent, and optionally comprising a flavoring agent and a sweetener.

[0101] In another embodiment of the present invention, the pharmaceutical composition comprises levocloperastine or a pharmaceutically acceptable salt thereof, and the composition is a hard gel capsule composition comprising levocloperastine, a surfactant, a binder, a polymer, a diluent, and a solvent.

[0102] In another embodiment of the present invention, the pharmaceutical composition comprises levocloperastine or a pharmaceutically acceptable salt thereof, wherein the composition is a softgel capsule composition comprising levocloperastine, a solubilizer, a stabilizer, a lubricant, and optionally other excipients.

[0103] The pharmaceutical compositions described herein can be prepared by conventional techniques well known to those skilled in the art, such as wet granulation, dry granulation, and direct compression.

[0104] In one preferred embodiment, the present invention provides a process for preparing a stable pharmaceutical composition comprising levocloperastine or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients, the process comprising the following steps: 1) Mix levocloperastin or a salt thereof with a diluent and a disintegrant to obtain a mixture. 2) Disperse the binder in the solvent while stirring to obtain a binder solution. 3) In a granulator, the mixture obtained in step 1 is granulated together with the binder solution to obtain moist granules. The moist granules are then dried. 4) The dried granules are sorted, and a desired amount of lubricant is added to obtain smooth granules. 5) The smooth granules from step 6 are compressed to obtain compressed tablets. 6) Optionally, coat the compressed tablets with a coating solution.

[0105] In one preferred embodiment, the present invention provides a process for preparing a stable pharmaceutical composition comprising levocloperastine or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients, the process comprising the following steps: 1) Mix levocloperastin or a salt thereof with a diluent and a disintegrant to obtain a mixture. 2) Disperse the binder in the solvent while stirring to obtain a binder solution. 3) In a granulator, the mixture obtained in step 1 is granulated together with the binder solution to obtain moist granules. The moist granules are then dried. 4) The dried granules are sorted, and a desired amount of lubricant is added to obtain smooth granules. 5) Fill the smooth granules into capsules of a suitable size.

[0106] In one preferred embodiment, the present invention provides a process for preparing a stable pharmaceutical composition comprising levocloperastine or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients, the process comprising the following steps: 1) Mix levocloperastin or a salt thereof with a diluent and a disintegrant to obtain a mixture. 2) Mix the remaining excipients into the resulting mixture. 3) Mix the mixture from step 2 with the mixture from step 1. 4) The dried mixture is compressed to obtain tablets or filled into capsules. 5) Optionally, coat the compressed tablets.

[0107] In one preferred embodiment, the present invention provides a process for preparing a stable pharmaceutical composition comprising levocloperastine or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients, wherein the levocloperastine is mixed with a suitable pharmaceutically acceptable excipient and filled into a softgel capsule.

[0108] In one preferred embodiment, the present invention provides a process for preparing a stable pharmaceutical composition comprising levocloperastine or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients, wherein the levocloperastine or a pharmaceutically acceptable salt is subjected to a size reduction process to which buffers, suspending agents, antioxidants, preservatives, cosolvents, sweeteners, or flavoring agents are added to obtain a suspension dosage form.

[0109] In one preferred embodiment, the present invention provides a stable pharmaceutical composition comprising levocloperastine or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients, wherein the composition has a uniform content of 95% to 105%.

[0110] In one preferred embodiment, the present invention provides a stable pharmaceutical composition comprising levocloperastine or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients, wherein when the composition is subjected to a dissolution test using a paddle method at 50 rpm in 900 ml of purified water, the dissolution rate of levocloperastine is 90% or more in 45 minutes.

[0111] In further embodiments, the present invention provides a stable pharmaceutical composition comprising levocloperastine and one or more pharmaceutically acceptable excipients, the composition being in the form of a tablet, capsule, solution, or suspension, which can be used in adult and pediatric patients as a single-dose or divided-dose prescription for the treatment of vertigo, vertigo, Meniere's disease, and dizziness.

[0112] Examples

[0113] One or more general or specific embodiments are described in further detail in the following examples, but it is not intended in any way to limit the scope of the invention to the embodiments specifically disclosed. It will be readily apparent to those skilled in the art, in light of the teachings of the invention, that certain changes and modifications may be made without departing from the scope of the invention.

[0114] Example 1: Levocloperastine tablets JPEG0007837967000002.jpg125153 Tablet preparation process 1. Levocloperastin was mixed with a diluent and a disintegrant to obtain a mixture. 2. The binder was dispersed in the solvent while stirring to obtain a binder solution. 3. In a granulator, the mixture obtained in step 1 was granulated together with the binder solution. 4. The moist granules were dried in a fluidized bed dryer, and the dried granules were sieved. 5. The granules were mixed with a lubricant, compressed into tablets, and coated with a coating solution prepared by dissolving a film coating agent in a solvent.

[0115] Example 2: Levocloperastine Hard Gel Capsules JPEG0007837967000003.jpg90155 Capsule preparation process 1. Levocloperastin phendizoate was mixed with lactose monohydrate, corn starch, vinylpyrrolidone-vinyl acetate copolymer, and silicified MCC to obtain a mixture. 2. Polyvinylpyrrolidone was dispersed in the solvent while stirring to obtain a binder solution. 3. In a granulator, the mixture obtained in step 1 was granulated together with the binder solution. 4. The moist granules were dried in a fluidized bed dryer, and the dried granules were sieved. 5. The granules were mixed with sodium lauryl sulfate and polysorbate 80, and then filled into capsules.

[0116] Example 3: Levocloperastine softgel capsules JPEG0007837967000004.jpg66158 The levocloperastin fenzizoate and excipients listed in the table above were mixed and filled into softgel capsules.

[0117] Example 4: Levocloperastin solution JPEG0007837967000005.jpg88158 Solution preparation process 1. Pour purified water into an SS container. 2. Add preservatives, buffers, sweeteners, and antioxidants, and stir until a uniform mixture is formed. 3. Add levocloperastin, fragrance, and co-solvent, and stir until a homogeneous mixture is formed. 4. Add purified water to reach the final volume.

[0118] Example 5: Levocloperastin suspension JPEG0007837967000006.jpg114146 Suspension preparation process 1. Pour 60% of the purified water into the SS container. 2. Add preservatives, buffers, sweeteners, antioxidants, suspending agents, and flocculants, and stir until a uniform mixture is formed. 3. Add levocloperastin and stir until a uniform mixture is formed. 4. Add the fragrance agent and co-solvent, and stir until a homogeneous mixture is formed. 5. Add purified water to reach the final volume.

[0119] Example 6: Levocloperastin capsules JPEG0007837967000007.jpg90161 Capsule preparation process: Wet granulation method 1. Dimethylacetamide and Soluplus® were stirred in a glass container. 2. Levocloperastin phendizoate was added and stirred until a homogeneous mixture was obtained. 3. Dicom DC SP (registered trademark) was sieved through a #40 sieve and added to the above mixture, then stirred until a homogeneous mixture was achieved. 4. The mixture was granulated using a granulator. 5. The granules were dried in a 50°C hot air oven. 6. The dried granules were sifted through a #40 sieve and mixed with talc powder (sifted through an #80 sieve) and magnesium stearate (sifted through an #80 sieve). 7. The resulting mixture was filled into size "0" capsules.

[0120] Example 7: Levocloperastin capsules JPEG0007837967000008.jpg44156 Capsule preparation process: Dry mixing method Dicom DC SP® (#40 sieved), levocloperastin fendizoate (#40 sieved), talc powder (#80 sieved), and magnesium stearate (#80 sieved) were blended in a blender until a uniform mixture was formed, and then filled into size "0" capsules.

[0121] Example 8: Levocloperastine tablets JPEG0007837967000009.jpg50158 Tablet preparation process: Dry mixing method F-Melt Type C (registered trademark) (sieved through #40), levocloperastin fendizoate (sieved through #40), croscarmellose sodium (sieved through #40), and magnesium stearate (sieved through #80) were mixed in a blender until a homogeneous mixture was formed and compressed in an 8 / 32 or 9 / 32 concave punch.

[0122] Example 9: Levocloperastin HCl solution (20 mg / 0.1 mL) JPEG0007837967000010.jpg78150 Process for preparing levocloperastin HCl solution 1. Approximately 20% of the total required amount of purified water was placed in a glass container, polyethylene glycol 300 and polypropylene glycol were added, and the mixture was stirred until it became a uniform mixture. 2. Levocloperastin HCl was added and the mixture was stirred to obtain a homogeneous mixture. 3. Glycerin and hydroxypropyl methylcellulose E15 were added and stirred until a homogeneous mixture was formed. 4. The final volume was restored using purified water.

[0123] Example 10: Levocloperastin HCl solution (20 mg / 0.1 mL) JPEG0007837967000011.jpg79159 Process for preparing levocloperastin HCl solution 1. Approximately 10% of the total required amount of purified water was placed in a glass container, and polyethylene glycol 400, polypropylene glycol, dehydrated alcohol, and M-polyethylene glycol 350 were added and stirred until a homogeneous mixture was formed. 2. Levocloperastin HCl was added and the mixture was stirred to obtain a homogeneous mixture. 3. The final volume was supplemented with purified water. 4.0. The solution was filtered through a 45μ nylon filter.

[0124] Example 11: Treatment of peripheral vertigo: This study was designed as an open-label, two-treatment-group, active-controlled clinical trial in patients with peripheral vertigo. The trial included a screening phase, a randomization phase, and a treatment phase, as described below. • Screening phase (1st visit): -14 to -1 day • Baseline visit and randomization day (visit 2): Day 0 / 1 • Treatment phase: Day 1 to Day 28 • Completion of treatment (4th visit): Day 29 ± 2 days

[0125] Patients with peripheral vertigo who met the above eligibility criteria were identified, and final candidates were screened within 14 days prior to randomization. A total of 16 patients were randomly assigned to receive the investigational drug or the active control drug in a 3:1 ratio (12 patients on the investigational drug, 4 on the active control drug). The investigational drug was levocloperastine 20 mg orally three times daily for 28 days. At the sole discretion of the investigator and based on medical judgment, the active control drug (standard treatment) was administered to patients. Standard treatment included administering betahistine 16 mg tablets three times daily, or betahistine 16 mg tablets three times daily and acetazolamide 125 mg tablets twice daily, or cinnarizine 25 mg tablets three times daily.

[0126] MVS score: The mean change in MVS score from baseline score was compared between the two treatment groups. Absolute data and mean changes from baseline are shown in Table 1. [Table 1]

[0127] Levocloperastine is found to be equally effective compared to standard treatment in terms of the primary efficacy endpoint, namely the MVS score and similar trends, while also evaluating other secondary endpoints, such as NVI score, THI severity, and IGA.

[0128] Furthermore, the mean change in the composite score of autonomic nervous system-related symptoms from baseline was compared between the two treatment groups. The absolute data and mean change from baseline data are shown in Table 2 below.

[0129] Autonomic nervous system-related symptoms score [Table 2]

[0130] Research data confirm that levocloperastine can control autonomic parasymptoms more rapidly and significantly than existing standard therapies. While both treatments showed clinical improvement, levocloperastine was statistically superior to standard therapy in alleviating autonomic parasymptoms. Furthermore, as statistically shown in Tables 1 and 2, the drug demonstrated superior efficacy compared to standard treatment within a shorter timeframe. This study demonstrated desirable responses and good tolerability in all patients. Levocloperastine showed comparable efficacy to standard treatment.

Claims

1. A pharmaceutical composition for the treatment of dizziness and / or the prevention of one or more symptoms of dizziness or a disease related to dizziness, characterized by comprising levocloperastine or a pharmaceutically acceptable salt thereof.

2. The pharmaceutical composition according to claim 1, which is used to treat one or more symptoms or diseases related to peripheral vertigo, Meniere's disease, tinnitus, hearing loss, dizziness, abnormal sensations of movement and posture, nystagmus, balance disorders, dizziness, head deviation, nausea, vomiting, sweating, salivation and tachycardia, orthostatic intolerance and gait instability, unsteadiness, spinning sensation, tendency to fall, upward sensation, blackout, changes in posture, lowering the head, getting up, driving, head movements, eye movements, or related symptoms or diseases.

3. The pharmaceutical composition according to claim 1, wherein levocloperastine or a pharmaceutically acceptable salt thereof is administered in a daily dose of 10 to 1000 mg.

4. The pharmaceutical composition according to claim 1, wherein 60 to 90 mg of levocloperastine or a pharmaceutically acceptable salt thereof is administered once daily, or 30 to 45 mg twice daily, or 20 to 30 mg three times daily.

5. The pharmaceutical composition according to claim 1, wherein levocloperastine or a pharmaceutically acceptable salt thereof is administered at a dose of 70 to 120 mg once daily, or 35 to 60 mg twice daily, or 25 to 40 mg three times daily.

6. The pharmaceutical composition according to claim 1, wherein levocloperastine or a pharmaceutically acceptable salt thereof is administered at a dose of 90 to 160 mg once daily, or 45 to 80 mg twice daily, or 30 to 55 mg three times daily.

7. The pharmaceutical composition according to claim 1, wherein 20 to 36 mg of levocloperastine or a pharmaceutically acceptable salt thereof is administered three times a day.

8. The pharmaceutical composition provides treatment for dizziness or dizziness-related disorders or autonomic nervous system-related symptoms in a shorter period of time compared to standard therapeutic treatments used for the treatment of dizziness or dizziness-related disorders. The pharmaceutical composition according to claim 1, wherein the standard therapeutic therapy is selected from one or more of the following: betahistine 16 mg tablets three times a day, or betahistine 16 mg tablets three times a day and acetazolamide 125 mg tablets twice a day, or cinnarizine 25 mg tablets three times a day.

9. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is an oral composition.

10. The pharmaceutical composition according to claim 9, wherein the oral composition is a tablet, capsule, granule, powder, solution, syrup, emulsion, or suspension composition.

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