A prolonged-release pharmaceutical composition comprising betahistine or salt thereof

Abstract

A prolonged release oral solid pharmaceutical composition comprising: 0.1 to 30 % by weight of Betahistine or a pharmaceutically acceptable salt thereof; 1 to 90 % by weight of one or more release controlling polymer; optionally other suitable pharmaceutically acceptable excipients; wherein said release controlling polymer comprises carbomer and processes thereof. The prolonged release oral solid pharmaceutical composition exhibits dissolution profile according to which more than about 35% by weight of Betahistine is dissolved in 1 hour and a constant release over 24 hours.

Description

[0001] A PROLONGED-RELEASE PHARMACEUTICAL COMPOSITION COMPRISING BETAHISTINE OR SALT THEREOF

[0002] FIELD OF INVENTION

[0003] The present invention relates to a pharmaceutical composition comprising Betahistine or a pharmaceutically acceptable salt thereof as an active agent, one or more pharmaceutically acceptable excipients, process of preparation thereof and method of using the same.

[0004] This invention specifically relates to a stable prolonged release pharmaceutical composition of Betahistine or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.

[0005] The invention also relates to the use of the said composition for the treatment of a vestibular disease or condition more particularly in the treatment of vertigo, tinnitus and hearing loss associated with Meniere's syndrome.

[0006] BACKGROUND OF THE INVENTION

[0007] Meniere's disease (MD) is a disease of the inner ear that is characterized by potentially severe and incapacitating episodes of vertigo, tinnitus, hearing loss, and a feeling of fullness in the ear.

[0008] Betahistine is an anti-vertigo medication. The IUPAC name of Betahistine is N- methyl-2-(pyridin-2-yl)ethanamine of the formula CsHnNi having following chemical structure:

[0009] (Formula I) The first marketing authorization in Europe for Betahistine dihydrochloride was in 1970 for balancing or alleviating vertigo, tinnitus, hearing loss and nausea symptoms associated with Meniere's disease. The treatment of Meniere's disease is a long-term treatment which encompasses a first initial oral treatment phase followed by a second maintained phase. Particularly, the first initial treatment phase involves the oral administration of 8-16 mg of Betahistine dihydrochloride three times per day; meanwhile the second maintained treatment phase involves the oral administration of 24-48 mg of Betahistine dihydrochloride without exceeding a total daily dose of 48 mg.

[0010] Conventional treatment with Betahistine immediate release tablets requires patient to take multiple single doses of medication throughout the day, it reduces comfort and adherence significantly. Adequate patient compliance is crucial for effectiveness of therapy, preventing complications and it is important for maintaining health and quality of life.

[0011] The occurrence of Meniere’s disease is considerably greater among older individuals compared to younger populations, thus minimizing the frequency of administration in the development of a new dosage form would be highly advantageous in older patients and in patients with difficulty in swallowing.

[0012] Betahistine dihydrochloride is available in the market as immediate release tablets in dosages of 8 mg, 16 mg, or 24 mg, as well as in an oral solution with a concentration of 8 mg / ml. Therefore, the indicated posology for the treatment of Meniere's disease encompasses two to four oral intakes per day depending on the dosage form. Hence, there is need for a prolonged release dosage form which can reduce the frequency of dose administration. Such pharmaceutical composition that requires less frequent daily administrations, yet sustains the drug's plasma levels for an extended period, is always advantageous. Considering the posology and multiple daily dose requirement for treatment of Meniere's disease (MD), multiple efforts have been made in the art to develop prolonged release dosage form of Betahistine or salts thereof which reduces frequency of daily intakes while maintaining the plasma levels of the active ingredient for a long period of time.

[0013] As per Biopharmaceutics Classification System, Betahistine is a class I drug and has high solubility and high permeability. Due to its extremely good solubility in water, hygroscopicity, and acidity, it is extremely difficult to formulate the active substance in a prolonged release dosage form.

[0014] Following patent / patent publications pertain to various formulations of Betahistine or a pharmaceutically acceptable salt thereof.

[0015] European patent application EP3431078A discloses a non-pulsatile 24 hours prolonged-release oral solid composition comprising a 48 mg amount of Betahistine dihydrochloride, or of a pharmaceutically acceptable salt thereof together with one or more pharmaceutically acceptable excipients or carriers, along with dissolution profile limitation. Wherein one or more hydrophilic matrix forming agents used is selected from the group consisting of cellulose derivative; noncellulose polysaccharide; polyvinylpyrrolidone; polyvinylacetate; polyvinyl alcohol; polyacrylic acid; hyaluronic acid, a salt of hyaluronic acid; polyethylene oxide; and mixtures thereof, wherein said one or more hydrophilic matrix forming agents are in an amount from 20% to 85%, more preferably from 50% to 55%, w / w of the composition. EP3431078A discloses wet granulation process as a preferred tablet manufacturing process. However, said composition releases less than 30% of Betahistine in 1 hour. As Betahistine is used for treatment in vertigo and other treatment where quick relief to patient is required followed by maintaining the drug concentration for longer period of time in blood. Accordingly, there is a need for providing a stable controlled release compositions comprising Betahistine with improved release profile. Indian patent application 2489 / MUM / 2011 discloses stable controlled release compositions comprising Betahistine or pharmaceutically acceptable salts thereof, polyethylene oxide and at least one adsorbent in a matrix. Wherein polyethylene oxide has an average molecular weight in the range of 900,000 to 80,00,000 and it is present from 10% to 70% by weight of the composition. 2489 / MUM / 2011 also discloses examples of controlled release tablets of Betahistine hydrochloride and 12 hours dissolution data thereof.

[0016] European patent application EP1493435A discloses controlled-release tablets of Betahistine comprising: a) A core comprising a granulate of Betahistine, an organic or inorganic acid and an hydrophilic polymer or mixtures of hydrophilic polymers; b) Optionally, a first coating layer comprising a hydrophilic polymer and a water insoluble excipient; c) Optionally, a second coating layer comprising hydrophilic polymers and colouring agents. wherein the hydrophilic polymers are selected from acrylic acid polymers or copolymers, starch polymeric derivatives, polyethylene glycols, alginates, cellulose, and derivatives (ethers, esters and salts), wherein the percentage of hydrophilic polymer ranges from 5 to 60%, based on the final weight of the tablet. Further said patent also discloses a process for the preparation of the tablets of Betahistine further comprising use of hydrophilic polymers and wet granulation process.

[0017] Chinese patent application CN107260708A discloses a dual-release preparation of Betahistine or its salt wherein said preparation consists of two parts: a common drug-containing rapid-release preparation and a sustained-release preparation, wherein said sustained-release material is selected from the group consisting of hydroxypropyl methylcellulose, hydroxypropyl cellulose, sodium alginate, sodium carboxymethyl cellulose, povidone, copovidone, polyvinyl alcohol, carboxyvinyl polyol, polypropylene alcohol, ethyl cellulose, hydroxyethyl cellulose, polyacrylic acid resin polymers, stearic acid, carnauba wax, glyceryl monostearate, stearyl alcohol, beeswax, xanthan gum, shellac, guar gum, pectin, chitosan, or a mixture of more than one thereof.

[0018] PCT publication W02000053162A discloses 16 to 48 mg controlled-release tablet of Betahistine or salt thereof and at least one hydrophilic polymer selected from the group consisting of acrylic acid polymers or co-polymers, polyethylene glycols, alginates, cellulose ethers and esters. It further discloses melt-granulation, wetgranulation or dry-granulation as the process of manufacturing.

[0019] In the prior art, sustained release compositions of Betahistine with various retardation mechanisms such as matrix based compositions have been used effectively to decrease the frequency of drug intake, but said compositions suffer from multiple disadvantages such as but not limited to: a) Release profile inconsistency: Not able to achieve high release (more than 35%) during initial one hour followed by maintaining sustained release for 24 hours period; b) Complex manufacturing process; c) Moisture related issues during formulation and stability; d) T ablet manufacturing defects such capping, lamination, poor tablet hardness or the like.

[0020] Hence, there is still a need to design pharmaceutical composition of Betahistine or a pharmaceutically acceptable salt thereof that have a) Release profile consistency b) Formulation stability c) Moisture control d) Cost effective and e) Patient compliance.

[0021] OBJECT OF THE INVENTION

[0022] It is an object of the present invention to overcome the drawbacks of the prior art It is another object of the present invention to provide a stable and effective prolonged release pharmaceutical formulation of Betahistine by overcoming the problems of prior art formulation.

[0023] It is a further object of the present invention to provide a novel prolonged release composition of Betahistine or a pharmaceutically acceptable salt thereof that overcomes above disadvantages and prolong the release till 24 hours while releasing more than 35% of Betahistine in 1 hour.

[0024] SUMMARY OF THE INVENTION

[0025] In one aspect, there is provided a prolonged release oral solid pharmaceutical composition comprising: a) Betahistine or a pharmaceutically acceptable salt thereof; b) One or more release controlling polymer; c) Optionally other suitable pharmaceutically acceptable excipients.

[0026] In another aspect, there is provided a prolonged release oral solid pharmaceutical composition of Betahistine or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients including diluent, binder, glidant, lubricant, stabilizer, release controlling polymer, solvent / vehicle, film coating agents or the like.

[0027] In another aspect, there is provided a prolonged release oral solid pharmaceutical composition comprising: a) Betahistine or a pharmaceutically acceptable salt thereof; b) One or more release controlling polymer; c) Optionally other suitable pharmaceutically acceptable excipients; and wherein said composition is in the form of monolayer tablet or bilayer tablet.

[0028] In another aspect, there is provided a prolonged release oral solid pharmaceutical composition comprising: a) Betahistine or a pharmaceutically acceptable salt thereof; b) One or more release controlling polymer; c) Optionally other suitable pharmaceutically acceptable excipients; wherein Betahistine or a pharmaceutically acceptable salt thereof is dissolved in binder solution. In another aspect, there is provided a prolonged release oral solid pharmaceutical composition comprising: a) Betahistine or a pharmaceutically acceptable salt thereof; b) One or more release controlling polymer; c) Optionally other suitable pharmaceutically acceptable excipients; wherein Betahistine or a pharmaceutically acceptable salt thereof is dissolved in binder solution; wherein one or more release controlling polymer is added in extra-granular part of the composition; and wherein said composition is in the form of monolayer tablet or bilayer tablet.

[0029] In another aspect, there is provided a prolonged release oral solid pharmaceutical composition comprising: a) Betahistine or a pharmaceutically acceptable salt thereof; b) One or more release controlling polymer; c) Optionally other suitable pharmaceutically acceptable excipients; wherein Betahistine or a pharmaceutically acceptable salt thereof is dissolved in binder solution; wherein one or more release controlling polymer is added in extra-granular part of the composition; and wherein the composition is prepared by suitable granulation process, preferably wet granulation.

[0030] In another aspect, there is provided a prolonged release oral solid pharmaceutical composition comprising: a) Betahistine or a pharmaceutically acceptable salt thereof; b) One or more release controlling polymer; c) Optionally other suitable pharmaceutically acceptable excipients; wherein Betahistine or a pharmaceutically acceptable salt thereof is dissolved in binder solution; wherein one or more release controlling polymer is added in extra-granular part of the composition; and wherein one or more release controlling polymer is preferably selected from group comprising of Hydroxypropyl Methylcellulose (HPMC), and carbopol (carbomer); wherein the composition is prepared by suitable granulation process, preferably wet granulation.

[0031] In another aspect, there is provided a prolonged release oral solid pharmaceutical composition comprising: a) 0.1 to 30% w / w of Betahistine or a pharmaceutically acceptable salt thereof; b) 10 to 95% w / w of diluent; c) 0.1 to 15% w / w of binder; d) 1 to 90% w / w of one or more release controlling polymer; e) Optionally other suitable pharmaceutically acceptable excipients; wherein Betahistine or a pharmaceutically acceptable salt thereof is optionally dissolved in binder solution.

[0032] In another aspect, there is provided a prolonged release oral solid pharmaceutical composition comprising: a) Betahistine or a pharmaceutically acceptable salt thereof; b) One or more release controlling polymer; c) Optionally other suitable pharmaceutically acceptable excipients; and wherein said composition is in the form of bilayer tablet; wherein

[0033] I] Immediate release layer / part comprising a) Betahistine or a pharmaceutically acceptable salt thereof; b) Optionally other suitable pharmaceutically acceptable excipients;

[0034] II] Prolonged release layer / part comprising a) Betahistine or a pharmaceutically acceptable salt thereof; b) One or more release controlling polymer; c) Optionally other suitable pharmaceutically acceptable excipients; and wherein Betahistine or a pharmaceutically acceptable salt thereof is dissolved in binder solution; and wherein one or more release controlling polymer is preferably selected from group comprising of Hydroxypropyl Methylcellulose (HPMC), and carbopol (carbomer).

[0035] In another aspect, there is provided a bilayer prolonged release oral solid pharmaceutical composition comprising:

[0036] I] Immediate release part comprising c) Betahistine or a pharmaceutically acceptable salt thereof; d) Optionally other suitable pharmaceutically acceptable excipients;

[0037] II] Prolonged release part comprising d) Betahistine or a pharmaceutically acceptable salt thereof; e) One or more release controlling polymer; f) Optionally other suitable pharmaceutically acceptable excipients; and wherein Betahistine or a pharmaceutically acceptable salt thereof is dissolved in binder solution; wherein one or more release controlling polymer is preferably selected from group comprising of Hydroxypropyl Methylcellulose (HPMC), and carbopol (carbomer); and wherein the Immediate release part and Prolonged release part is independently prepared by suitable granulation process such as wet granulation, dry granulation and direct compression or combination thereof.

[0038] The prolonged release oral solid pharmaceutical composition provided in the above aspects are optionally coated.

[0039] The prolonged release oral solid pharmaceutical composition provided in the above aspects exhibits dissolution profile according to which more than about 35% by weight of Betahistine is dissolved in 1 hour, wherein the dissolution profile is tested under one or more different pH conditions such as pH 6.8 phosphate buffer, 0.1 N hydrochloric acid and pH 4.5 acetate buffer. BRIEF DESCRIPTION OF ACCOMPANYING FIGURES

[0040] Figure 1 illustrates the dissolution profile comparison in pH 6.8 phosphate buffer of the formulation of Example 1 initial and after 6-month at 40°C, 75% RH in Alu- Alu packaging.

[0041] Figure 2 illustrates the dissolution profile comparison in pH 6.8 phosphate buffer of the formulation of Example 2 initial and after 6-month at 40°C, 75% RH in Alu- Alu packaging.

[0042] Figure 3 illustrates the dissolution profile comparison in pH 6.8 phosphate buffer of the formulation of Example 3 initial and after 6-month at 40°C, 75% RH in Alu- Alu packaging.

[0043] Figure 4 illustrates the dissolution profile comparison in pH 6.8 phosphate buffer of the formulation of Example 4 initial and after 6-month at 40°C, 75% RH in Alu- Alu packaging

[0044] DETAILED DESCRIPTION OF THE INVENTION

[0045] The term “composition”, as in solid pharmaceutical composition, is intended to encompass a drug product comprising Betahistine or its pharmaceutically acceptable salts, esters, solvates, polymorphs, enantiomers or mixtures thereof, and other inert ingredient(s) (pharmaceutically acceptable excipients). Such pharmaceutical compositions are synonymous with "formulation" and "dosage form". Pharmaceutical composition of the invention include, but is not limited to, granules, tablets, immediate release tablets, modified release tablet (prolonged, sustained, delayed), caplets and the like. Preferably, the pharmaceutical composition refers to immediate release tablets, modified release tablet or mixture thereof, which may be uncoated or film coated.

[0046] The term “excipient”, means a pharmacologically inactive component such as a diluent, binder, glidant, lubricant, stabilizer, and release controlling polymer, solvent / vehicle, and film coating agents or the like. The excipients that are useful in preparing a pharmaceutical composition are generally safe, non- toxic and are acceptable for veterinary as well as human pharmaceutical use. Reference to an excipient includes both one and more than one such excipient.

[0047] The term “Betahistine” is used in broad sense to include not only “Betahistine” per se but also its pharmaceutically acceptable salts, solvates, hydrates, enantiomers, derivatives, isomers, polymorphs, prodrugs thereof, and also its various crystalline and amorphous forms.

[0048] The term "pharmaceutically acceptable salt" refers to salts derived from a variety of organic and inorganic counter ions including dihydrochloride, hydrochloride, fumarate, maleate, phosphate, L-tartrate, citrate, acetate, oxalate, sulfate or the like. Preferably, Betahistine dihydrochloride is used.

[0049] The amount of Betahistine or salt thereof according to the invention may be present from about 0.1 to about 30% by weight based on total weight of the composition.

[0050] As used herein, the terms “about” and “approximately” should be understood to mean within an acceptable range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, “about” can mean ±30%, preferably up to ±20%, more preferably up to ±5%.

[0051] The term “prolonged release composition” refers to any composition which can provide drug release for extended time for more than 12 hours, 16 hours, or 20 hours or upto 24 hours. The term “modified or sustained or extended release pharmaceutical composition” can be used synonymously to prolonged release composition.

[0052] The term "treating" or "treatment" refers to obtaining desired pharmacological and / or physiological effect. The effect can be therapeutic, which includes achieving, partially or substantially, one or more of the following results: partially or totally reducing the extent of the disease, disorder or syndrome; ameliorating or improving a clinical symptom or indicator associated with the disorder or delaying, inhibiting or decreasing the likelihood of the progression of the disease, disorder or syndrome.

[0053] The term “stable” as used herein refers to formulations that substantially retain the label amount of the therapeutically active ingredient during storage for commercially relevant times, and the drug-related impurity contents in the formulations remain within the acceptable limit.

[0054] The use of the terms “a” and "an” and "the” and similar referents in the context of describing the invention (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context.

[0055] In another embodiment, there is provided a prolonged release oral solid pharmaceutical composition may include one or more pharmaceutically acceptable excipients selected from diluents, binders, stabilizers, disintegrants / superdisintegrants, lubricants, glidants, sweeteners, flavouring agents, coloring agents, antioxidants, surfactants / solubilizers, release controlling polymer(s), vehicle / solvents, plasticizers, suitable taste masking agents, or physical or co-processed mixture thereof.

[0056] The term "diluent" or "filler" as used herein is defined as an inert agent designed to increase the weight and / or the size of the pharmaceutical composition, for example in the case of a tablet. Examples of diluents according to present invention include, but not limited to group comprising of calcium carbonate, calcium phosphate, dibasic calcium phosphate, tribasic calcium sulfate, calcium carboxymethyl cellulose, cellulose, cellulose products such as microcrystalline cellulose and its salts, dextrin derivatives, dextrin, dextrose, fructose, lactitol, lactose, starches or modified starches, magnesium carbonate, magnesium oxide, maltitol, maltodextrins, maltose, mannitol, sorbitol, starch, sucrose, sugar, xylitol, erythritol and mixtures thereof. In an embodiment, the composition of the invention is one wherein the pharmaceutically acceptable excipients or carriers comprises one or more filler. The diluents according to present invention may be present in an amount from about 10% to about 95% by weight with respect to total weight of the pharmaceutical composition.

[0057] The term "binder" as used herein is defined as an agent able to bind particles which cannot be bound only by a compression force. The binder may be present in the form of a single compound or in the form of a mixture of compounds. Examples of Binders include, but not limited to group comprising of povidone such as povidone K-30LP, polyvinylpyrrolidone K30, methylcellulose polymers, hydroxyethyl cellulose, hydroxypropyl cellulose, L-hydroxypropyl cellulose (low substituted), hydroxypropylmethyl cellulose (HPMC), sodium carboxymethyl cellulose, carboxymethylene, carboxymethylhydroxyethyl cellulose and other cellulose derivatives, starches or modified starches and mixture thereof. The binder according to present invention may be present in an amount from about 0.1 to about 15% by weight with respect to total weight of the pharmaceutical composition.

[0058] The term “stabilizer” as used herein is defined as any substance that slows or retards the degradation or alteration of active ingredient. Examples of stabilizer include, but not limited to group comprising of alpha-hydroxyl carboxylic acid such as lactic acid, tartaric acid or citric acid, citric acid anhydrous and mixture thereof.

[0059] The term “release controlling polymer” is synonymous to term “hydrophilic polymer”. The term “hydrophilic polymer” as used herein is defined as any polymer which has more affinity towards aqueous medium. These polymers swell upon contact with aqueous medium and forms gel layer. The drug release from such hydrophilic polymer system involves diffusion of dissolved drug through gel layer and release of dissolved drug or drug particles through erosion or dissolution of the polymer gel layer. Examples of hydrophilic polymer include, but not limited to group comprising of cellulosic polymers such as methylcellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, sodium carboxy methyl cellulose, ethyl cellulose; non-cellulosic polymers such as sodium alginate, xanthan gum, carrageenan, guar gum, locus gum bean, chitosan; non- glyceryl behenate, stearic acid, carbopol or carbomer, Carbopol 71G NF, Carbopol 974P NF, Carbopol 97 IP NF, Carbopol 934P NF Eudragit, Eudragit E30, non-cellulosic polymers such as acrylic acid, copolymers of acrylic acid and mixture thereof.

[0060] In another embodiment, there is provided a prolonged release oral solid pharmaceutical composition can be prepared by a known conventional methods like wet granulation, direct compression, dry granulation, roller compaction or slugging or combination thereof.

[0061] In another embodiment, there is provided a prolonged release oral solid pharmaceutical composition comprising: a) 0.1 to 30 % by weight of Betahistine or a pharmaceutically acceptable salt thereof; b) I to 90 % by weight of one or more release controlling polymer; c) Optionally other suitable pharmaceutically acceptable excipients.

[0062] The present inventors have surprisingly found that inclusion of atleast one release controlling polymer such as carbopol, improves the release profile of the betahistidine from the composition. It ensures more than 35% release in the first hour and further constant release till 24 hours thereby resulting in a stable singledosage formulation.

[0063] In another embodiment, there is provided a process for producing prolonged release oral solid pharmaceutical composition which comprises steps of: a) sifting a diluent; b) mixing Betahistine or pharmaceutically acceptable salts thereof, binder, stabilizer in suitable solvent; c) granulating the “step a” with solution of “step b”; d) drying the granules obtained in “step c”; e) sifting further diluent, one or more glidant, lubricant and one or more release controlling polymer to form pre lubrication part; f) sifting and mixing dried granules of “step d” and pre lubrication part of “step e”; g) lubricating mixture of “step f’; h) compressing tablets; and i) optionally film coating said tablets; wherein said release controlling polymer comprises carbopol.

[0064] In a further embodiment of the present invention there is provided a prolonged release oral solid pharmaceutical composition comprising: a) Betahistine or a pharmaceutically acceptable salt thereof; b) One or more release controlling polymer; c) Optionally other suitable pharmaceutically acceptable excipients; wherein Betahistine or a pharmaceutically acceptable salt thereof is dissolved in binder solution; one or more release controlling polymer is added in extra-granular part of the composition; one or more release controlling polymer comprises carbopol; and the composition is prepared by suitable granulation process, preferably wet granulation.

[0065] In yet another embodiment there is provided a prolonged release oral solid pharmaceutical composition comprising: a) 0.1 to 30% w / w of Betahistine or a pharmaceutically acceptable salt thereof; b) 10 to 95% w / w of diluent; c) 0.1 to 15% w / w of binder; d) 1 to 90% w / w of one or more release controlling polymer; e) optionally other suitable pharmaceutically acceptable excipients; wherein Betahistine or a pharmaceutically acceptable salt thereof is optionally dissolved in binder solution; one or more release controlling polymer comprises carbopol.

[0066] In yet another embodiment there is provided a prolonged release oral solid pharmaceutical composition comprising: a) Betahistine or a pharmaceutically acceptable salt thereof; b) One or more release controlling polymer; c) Optionally other suitable pharmaceutically acceptable excipients; wherein said composition is in the form of bilayer tablet having an immediate release layer and a prolonged release layer; wherein

[0067] I] said immediate release layer comprises e) Betahistine or a pharmaceutically acceptable salt thereof; f) Optionally other suitable pharmaceutically acceptable excipients; and

[0068] II] said prolonged release layer comprises g) Betahistine or a pharmaceutically acceptable salt thereof; h) One or more release controlling polymer; i) Optionally other suitable pharmaceutically acceptable excipients; and wherein Betahistine or a pharmaceutically acceptable salt thereof is dissolved in binder solution; and wherein said release controlling polymer comprises carbopol.

[0069] In another embodiment, there is provided a process for producing a prolonged release oral solid pharmaceutical composition which comprises steps of:

[0070] I] Preparation of Immediate release part: a) sifting a diluent; b) dissolving Betahistine or pharmaceutically acceptable salts thereof, binder, stabilizer in suitable solvent; c) granulating the “step a” with solution of “step b”; d) drying the granules obtained in “step c”; e) sifting further diluent, one or more glidant, lubricant to form pre lubrication part; f) sifting and mixing dried granules of “step d” and pre lubrication part of “step e”; g) lubricating mixture of “step f’;

[0071] II] Preparation of prolonged release part: h) sifting a diluent; i) dissolving Betahistine or pharmaceutically acceptable salts thereof, binder, stabilizer in suitable solvent; j) granulating the “step h” with solution of “step i”; k) drying the granules obtained in “step j”; l) sifting the part of diluent, one or more glidant, lubricant and one or more release controlling polymer to form pre lubrication part; m) sifting and mixing dried granules of “step k” and pre lubrication part of “step 1”; n) lubricating mixture of “step m”; o) compressing tablets of IR part of “step g” and PR part of “step o” using suitable punches; p) optionally film coating said tablets; wherein said release controlling polymer comprises carbopol.

[0072] Film coating comprises coating the compressed tablets with polymers selected from ethylcellulose, cellulose acetate, cellulose acetate butyrate, pullulan, methacrylate copolymers available under the trade name of Eudragit (type RL, RS and NE30D), maltrin, an aminoalkyl methacrylate copolymer available under the trade name of Eudragit (type E100 or EPO), polyvinylacetal diethylaminoacetate, sodium chloride, sucrose, povidone and mixtures thereof. The polymers may be present in an amount from about 5 to about 70% w / w of the composition, preferably from about 10% w / w to about 40% w / w of the composition. Solvents can be selected but are not limited to water, methanol, ethanol, acetone, diacetone, polyols, polyethers, oils, esters, alkyl ketones, methylene chloride, isopropyl alcohol, butyl alcohol, methyl acetate, ethyl acetate, isopropyl acetate, castor oil, ethylene glycol monoethyl ether, diethylene glycol monobutyl ether, diethylene glycol monoethyl ether, dimethylsulfoxide, N,N-dimethylformamide, tetrahydrofuran, and any mixtures thereof.

[0073] In an embodiment, there is provided a method of using a prolonged release oral solid pharmaceutical composition comprising Betahistine or pharmaceutically acceptable salts thereof in the treatment of a vestibular disease or condition, preferably for use in the treatment of Meniere's disease, wherein the treatment comprises once-daily administration of the 24 hours prolonged-release oral solid composition.

[0074] In an embodiment, there is provided a method of treating a vestibular disease or condition, said method comprising administering once-daily the prolonged release oral solid pharmaceutical composition in accordance with the present invention.

[0075] The present invention is illustrated below by reference to the following examples. However, one skilled in the art will appreciate that the specific methods and results discussed are merely illustrative of the invention, and not to be construed as limiting the invention, as many variations thereof are possible without departing from the spirit and scope of the invention.

[0076] Examples of 48 mg prolonged release tablet of Betahistine or salt thereof are given below for reference purpose, hence it does not limit the scope of the present invention to 48 mg tablet. 16 mg, 24 mg & 32 mg prolonged release tablet of Betahistine or salt thereof can also be manufactured using the composition and process below. Example 1:

[0077] Table 1

[0078] Carbopol bi layer tablets

[0079] Procedure Immediate release part

[0080] Step 1: Sifting microcrystalline cellulose 102 through 30# sieve load in rapid mixer granulator and mixing for 5 mins.

[0081] Step 2: Dissolving the Betahistine Dihydrochloride, povidone K-30LP and citric acid anhydrous into purified water with continuous stirring till it dissolve.

[0082] Step 3: Granulating step-1 using Betahistine Dihydrochloride solution of step-2 into rapid mixer granulator.

[0083] Step 4: Drying the wet granules into dryer at 50-60°C till reaching desired LOD.

[0084] Step 5: Co-Sifting microcrystalline cellulose 112 and colloidal anhydrous silica Sifting talc through 30 # sieve.

[0085] Step 6: Sifting the dry granules of step- 4 through 30# sieve and adding Prelubrication of step-5 into it and mixing into blender for 15 mins.

[0086] Step 7: Sifting sodium stearyl fumarate through 60 # sieve and adding into step-6 and mixing for 3 mins.

[0087] Procedure Prolonged release part

[0088] Step 1: Sifting microcrystalline cellulose 102 through 30# sieve load in rapid mixer granulator and mixing for 5 Mins.

[0089] Step 2: Dissolving the Betahistine Dihydrochloride, povidone K-30LP and citric acid into purified water with continuous stirring till it dissolve

[0090] Step 3: Granulating step-1 using Betahistine Dihydrochloride solution of step-2 into rapid mixer granulator.

[0091] Step 4: Drying the wet granules into dryer at 50-60°C till reaching desired LOD. Step 5: Co-sifting microcrystalline cellulose 112 and Colloidal anhydrous silica, HPMC K 100 M premium CR, Carbopol 71G, talc, Through 30 # sieve.

[0092] Step 6: Sifting the dry granules of step- 4 through 30# sieve adding pre-lubrication of step-5 into it and mixing into blender for 15 mins.

[0093] 5 Step 7: Sifting sodium stearyl fumarate through 60 # sieve and adding in to step-6 and mixing for 3 min.

[0094] Step 8: Compressed tablets of immediate release part and prolonged release part of granules using suitable punches.

[0095] 10 Example 2

[0096] Carbopol mono layer Betahistine Dihydrochloride PR tablets 48 mg Following similar method as in example 1, the following 48mg tablets were prepared.

[0097] Table 2 Step 1: Sifting Microcrystalline Cellulose through 30# sieve load in rapid mixer granulator and mixing for 5 Mins.

[0098] Step 2: Dissolving the Betahistine Dihydrochloride, Povidone K-30LP and citric acid into purified water with continuous stirring till it dissolve. Step 3: Granulating step-1 using Betahistine Dihydrochloride solution of step-2 into rapid mixer granulator.

[0099] Step 4: Drying the wet granules into dryer at 50-60°C till reach desired LOD.

[0100] Step 5: Co-Sifting, Microcrystalline Cellulose 112 & Colloidal Anhydrous silica, HPMC K 100 M Premium CR, Polyethylene oxide, Talc through 30 # sieve. Step 6: Sifting the dry granules of step- 4 through 30# sieve Add Pre-lubrication of step-5 into it & mixing into blender for 15 mins.

[0101] Step 7: Sifting Sodium Stearyl Fumarate through 60 # sieve and adding in to step-

[0102] 6 and mixing for 3 min.

[0103] Step 8: Compressing tablets using suitable punches.

[0104] Example 3 - Betahistine Dihydrochloride prolonged release (PR) tablets 48 mg Table 3

[0105] HPMC - Carbopol bi layer tablets

[0106] QS: quantity sufficient

[0107] Procedure Immediate release part

[0108] Step 1: Sifting microcrystalline cellulose 102 through 30# sieve load in rapid mixer granulator and mixing for 5 mins. Step 2: Dissolving the Betahistine Dihydrochloride, povidone K-30LP and citric acid anhydrous into purified water with continuous stirring till it dissolve.

[0109] Step 3: Granulating step-1 using Betahistine Dihydrochloride solution of step-2 into rapid mixer granulator.

[0110] Step 4: Drying the wet granules into dryer at 50-60°C till reaching desired LOD. Step 5: Co-Sifting microcrystalline cellulose 112 and colloidal anhydrous silica Sifting talc through 30 # sieve.

[0111] Step 6: Sifting the dry granules of step- 4 through 30# sieve and adding Prelubrication of step-5 into it and mixing into blender for 15 mins.

[0112] Step 7: Sifting sodium stearyl fumarate through 60 # sieve and adding into step-6 and mixing for 3 mins.

[0113] Procedure Prolonged release part

[0114] Step 1: Sifting microcrystalline cellulose 102 through 30# sieve load in rapid mixer granulator and mixing for 5 Mins.

[0115] Step 2: Dissolving the Betahistine Dihydrochloride, povidone K-30LP and citric acid into purified water with continuous stirring till it dissolve

[0116] Step 3: Granulating step-1 using Betahistine Dihydrochloride solution of step-2 into rapid mixer granulator.

[0117] Step 4: Drying the wet granules into dryer at 50-60°C till reaching desired LOD.

[0118] Step 5: Co-sifting microcrystalline cellulose 112 and Colloidal anhydrous silica, HPMC K 100 M premium CR, Carbopol 71G, talc, Through 30 # sieve.

[0119] Step 6: Sifting the dry granules of step- 4 through 30# sieve adding pre-lubrication of step-5 into it and mixing into blender for 15 mins.

[0120] Step 7: Sifting sodium stearyl fumarate through 60 # sieve and adding in to step-6 and mixing for 3 min.

[0121] Step 8: Compressed tablets of immediate release part and prolonged release part of granules using suitable punches.

[0122] Example 4

[0123] Table 4

[0124] Carbopol - PEO bi layer tablets

[0125] The above formulation was prepared using similar process as in Example 3.

[0126] Example 7

[0127] The dissolution studies were performed with the above formulations.

[0128] Procedure - the following procedure was followed for the studies

[0129] Reagent, Chemical and Standard required:

[0130] 1. Potassium Dihydrogen phosphate (AR Grade)

[0131] 2. 1-Hexane Sulfonic Acid Sodium Salt Anhydrous (HPLC Grade)

[0132] 3. Ortho-phosphoric acid ( HPLC Grade)

[0133] 4. Acetonitrile (HPLC Grade)

[0134] 5. Water (HPLC Grade and Purified Grade)

[0135] Note: Alternate higher or same grade of chemicals, reagent and solvents can be used if found suitable

[0136] Points of emphasis:

[0137] 1. Sample preparation flasks should be properly stopper with lids to avoid solvent loss.

[0138] 2. Wash the column first with Water: Acetonitrile 50:50; %v / v for 30 minutes, and followed by Water: Acetonitrile 20: 80; %v / v for 30 minutes after each analysis and store the column in the final solvent mixture

[0139] 3. Use Water: Acetonitrile 50:50; %v / v as needle wash and as Rinsing solvent. 4. Keep the working standard at 105°C in oven for 3 hrs. Before use.

[0140] Carry out procedure using Ph.Eur Type-I dissolution apparatus. Use Basket stirring assembly and maintain following parameters.

[0141] Dissolution Parameters Conditions

[0142] Strength 48 mg / tablet

[0143] Media (1) 0.1 N Hydrochloric Acid

[0144] (2) pH 4.5 Acetate Buffer

[0145] (3) pH 6.8 Phosphate Buffer (QC Release Media)

[0146] Volume 900 mL

[0147] Dissolution apparatus Apparatus-I (Basket)

[0148] Agitation 100 RPM

[0149] Number of Units per Study 12 Tablets

[0150] Sampling Time 01, 02, 04, 08, 16 & 24 Hrs.

[0151] Temperature 37 °C ± 0.5 °C

[0152] Dissolution medium preparation:

[0153] 1. 0.1 N Hydrochloric acid :

[0154] 85 ml of Hydrochloric Acid is transferred in to 10000 ml of Water and mixed well.

[0155] 2. pH 4.5 Acetate Buffer :

[0156] 29.9 gm of sodium acetate trihydrate was dissolved in 10000 mL of water. pH adjusted to 4.5 ± 0.05 with Glacial acetic acid and mixed well.

[0157] 3. pH 6.8 Phosphate Buffer (QC Release Media): :

[0158] 2500 mL of 0.2 M potassium dihydrogen phosphate R and 1120 ml of 0.2 M sodium hydroxide solution were mixed, and diluted to 10000.0 mL with water, Adjusted pH to 6.8 ± 0.05 with 0.2 M sodium hydroxide solution and mixed well.

[0159] Diluent:

[0160] Use dissolution medium as diluent. Buffer preparation:

[0161] Dissolve 6.8 gm of Potassium Dihydrogen Orthophosphate & 1.0 gm 1 -Hexane Sulfonic Acid Sodium Salt anhydrous in 1000 mL of water and mix well. Adjust the pH of Solution to 2.7 with Orthophosphoric acid. Filter through 0.45p membrane filter.

[0162] Mobile phase preparation:

[0163] Prepare a degassed mixture of 900 volumes of Buffer and 100 volumes of Acetonitrile. Prepare it as per requirement.

[0164] Preparation of Standard stock solution:

[0165] Weigh accurately and transfer 52.00 mg of Betahistine Dihydrochloride Working Standard or Reference Standard into 100 mL volumetric flask. Add about 70 mL of Water and sonicate to dissolve, allow it to come at room temperature, dilute up to the mark with Water and mix well.

[0166] (about 480 pg / mL of Betahistine Dihydrochloride)

[0167] Standard solution preparation for 48 mg:

[0168] Dilute 5.0 ml of Standard stock solution to 50 ml with Dissolution medium and mix. (About 52.0 pg / mL of Betahistine Dihydrochloride).

[0169] Dissolution procedure (Sample solution):

[0170] Note: Use separate filter for each bowl.

[0171] Set parameters of instrument as described above and transfer 900 mL of dissolution medium into each of 12 different dissolution vessel. Place 1 tablet in each of 12 different vessel and operate apparatus for multitime point. At end of specified time point, withdraw solution from zone midway between surface of dissolution medium and top of rotating basket not less than 1 cm from vessel wall and replace 12 ml dissolution media after withdrawal of solution at each time point Filter solution through 0.45 pm Nylon filter, discarding at least first 5 mL of filtrate.

[0172] (About 53.33 pg / mL of Betahistine Dihydrochloride). Chromatographic parameters:

[0173] Liquid chromatograph is equipped with PDA detector or variable wavelength UV detector, injector and data processor.

[0174] Column Inertsil ODS-3V (150 x 4.6) mm, 5 pm

[0175] Column oven temperature 25°C

[0176] Sampler temperature 25°C

[0177] Detection wavelength 259 nm

[0178] Injection volume 10 pL

[0179] Flow rate 1.2 mL / minutes

[0180] Retention time About 3.5 minutes of Betahistine

[0181] Run time 6.0 minutes

[0182] Note: Retention time of Betahistine Dihydrochloride mentioned here is for reference purpose only & not to be considered as an acceptance criteria.

[0183] System suitability:

[0184] Inject five replicate injections of Standard solution into liquid chromatograph and record chromatograms. Relative standard deviation of area of Betahistine peak should not be more than 2.0%, Tailing factor Betahistine peak should not be more than 2.0 and Theoretical plate of Betahistine peak should not be less than 2000.

[0185] Procedure:

[0186] Inject single injection of Diluent as Blank solution, Sample solution into liquid chromatograph and record chromatograms. Calculate percentage of Betahistine Dihydrochloride dissolved in individual tablet using following formula.

[0187] The dissolution tests of the formulation of Example 1 at 6.8 pH was conducted after 6 month stability study at 40°C / 75%RH condition. The results are shown below: Table 5

[0188] Figure 1 illustrates the dissolution profile comparison in pH 6.8 phosphate buffer of the formulation of Example 1 initial and after 6-month at 40°C, 75% RH in Alu- Alu packaging.

[0189] The dissolution tests of the formulation of Example 2 at 6.8 pH was conducted after 6 month stability study at 40°C / 75%RH condition. The results are shown below :

[0190] Table 6 Figure 2 illustrates the dissolution profile comparison in pH 6.8 phosphate buffer of the formulation of Example 2 initial and after 6-month at 40°C, 75% RH in Alu- Alu packaging. The dissolution tests of the formulation of Example 3 at 6.8 pH was conducted after

[0191] 6 month stability study at 40°C / 75%RH condition. The results are shown below :

[0192] Table 7

[0193] Figure 3 illustrates the dissolution profile comparison in pH 6.8 phosphate buffer of the formulation of Example 3 initial and after 6-month at 40°C, 75% RH in Alu- Alu packaging.

[0194] The dissolution tests of the formulation of Example 4 at 6.8 pH was conducted after

[0195] 6 month stability study at 40°C / 75%RH condition. The results are shown below : Table 8

[0196] Figure 4 illustrates the dissolution profile comparison in pH 6.8 phosphate buffer of the formulation of Example 4 initial and after 6-month at 40°C, 75% RH in Alu- Alu packaging.

[0197] Example 8

[0198] The stability tests were performed with the above formulations

[0199] The stability tests of the formulation of Example 1 (Batch No. NE722 / 016-Alu-Alu) was conducted at Initial, Imonth, 3months, and at 6 month time period at accelerated condition (40°C / 75%RH) condition. The results are shown below :

[0200] Table 9

[0201] The stability tests of the formulation of Example 2 (Batch No. NE722 / 019-Alu-Alu) was conducted at Initial, Imonth, 3months, and at 6 month time period at accelerated condition (40°C / 75%RH) condition. The results are shown below : Table 10

[0202] The stability tests of the formulation of Example 3 (Batch No. NE722 / 012-Alu-Alu) was conducted at Initial, Imonth, 3months, and at 6 month time period at accelerated condition (40°C / 75%RH) condition. The results are shown below : Table 11 The stability tests of the formulation of Example 4 (Batch No. NE722 / 015-Alu-Alu) was conducted at Initial, Imonth, 3months, and at 6 month time period at accelerated condition (40°C / 75%RH) condition. The results are shown below : Table 12

[0203] Where 1) Impurity A is 2- Vinyl pyridine 2) Impurity B is 2-(pyridin-2-yl)ethanol

[0204] 3) Impurity-C is Nmethyl-2-(pyridin-2-yl)-N-[2-(pyridin-2-yl) ethyl] ethanamine

Claims

1. CLAIMS:

1. A prolonged release oral solid pharmaceutical composition comprising: a) 0.1 to 30 % by weight of Betahistine or a pharmaceutically acceptable salt thereof; b) I to 90 % by weight of one or more release controlling polymer; c) optionally other suitable pharmaceutically acceptable excipients; wherein said release controlling polymer comprises carbomer.

2. The prolonged release oral solid pharmaceutical composition as claimed in claim 1, wherein said pharmaceutically acceptable excipients is selected from diluents, binders, stabilizers, disintegrants / superdisintegrants, lubricants, glidants, sweeteners, flavouring agents, coloring agents, antioxidants, surfactants / solubilizers, release controlling polymer(s), vehicle / sol vents, plasticizers, and taste masking agents.

3. The prolonged release oral solid pharmaceutical composition as claimed in claim 1, wherein said release controlling polymer is selected from hydrophilic polymer.

4. The prolonged release oral solid pharmaceutical composition as claimed in claim 3, wherein said hydrophilic polymer is selected from the group comprising of cellulosic polymers such as methylcellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, sodium carboxy methyl cellulose, ethyl cellulose; non-cellulosic polymers such as sodium alginate, xanthan gum, carrageenan, guar gum, locus gum bean, chitosan; non-glyceryl behenate, stearic acid, carbopol or carbomer, non- cellulosic polymers such as acrylic acid, copolymers of acrylic acid and mixture thereof.

5. A process for producing prolonged release oral solid pharmaceutical composition said claimed in claim 2, said process comprising the steps of: a) sifting a diluent; b) mixing Betahistine or pharmaceutically acceptable salts thereof, binder, stabilizer in a solvent;c) granulating the “step a” with solution of “step b”; d) drying the granules obtained in “step c”; e) sifting further diluent, one or more glidant, lubricant and one or more release controlling polymer to form pre lubrication part; f) sifting and mixing dried granules of “step d” and pre lubrication part of “step e”; g) lubricating mixture of “step f’; h) compressing tablets; and i) optionally film coating said tablets.

6. A prolonged release oral solid pharmaceutical composition comprising: a) Betahistine or a pharmaceutically acceptable salt thereof; b) One or more release controlling polymer; c) Optionally other suitable pharmaceutically acceptable excipients; wherein Betahistine or a pharmaceutically acceptable salt thereof is dissolved in binder solution; one or more release controlling polymer is added in extra-granular part of the composition; one or more release controlling polymer comprises carbopol; and the composition is prepared by suitable granulation process, preferably wet granulation.

7. A prolonged release oral solid pharmaceutical composition comprising: a) 0.1 to 30% w / w of Betahistine or a pharmaceutically acceptable salt thereof; b) 10 to 95% w / w of diluent; c) 0.1 to 15% w / w of binder; d) 1 to 90% w / w of one or more release controlling polymer; e) Optionally other suitable pharmaceutically acceptable excipients; wherein Betahistine or a pharmaceutically acceptable salt thereof is optionally dissolved in binder solution; one or more release controlling polymer comprises carbopol.

8. A prolonged release oral solid pharmaceutical composition comprising: a) Betahistine or a pharmaceutically acceptable salt thereof; b) One or more release controlling polymer; c) Optionally other suitable pharmaceutically acceptable excipients; wherein said composition is in the form of bilayer tablet having an immediate release layer and a prolonged release layer; whereinI] said immediate release layer comprises a) Betahistine or a pharmaceutically acceptable salt thereof; b) Optionally other suitable pharmaceutically acceptable excipients; andII] said prolonged release layer comprises a) Betahistine or a pharmaceutically acceptable salt thereof; b) One or more release controlling polymer; c) Optionally other suitable pharmaceutically acceptable excipients; and wherein Betahistine or a pharmaceutically acceptable salt thereof is dissolved in binder solution; and wherein said release controlling polymer comprises carbopol.

9. A process for producing a prolonged release oral solid pharmaceutical composition, said process comprising: i) preparing an immediate release part and ii) preparing a prolonged release part, such that : said preparing an immediate release part comprises the steps of: a) sifting a diluent; b) dissolving Betahistine or pharmaceutically acceptable salts thereof, binder, stabilizer in suitable solvent; c) granulating the “step a” with solution of “step b”; d) drying the granules obtained in “step c”; e) sifting further diluent, one or more glidant, lubricant to form pre lubrication part; f) sifting and mixing dried granules of “step d” and pre lubrication part of “step e”;g) lubricating mixture of “step f’; and said preparing a prolonged release part comprises the steps of : h) sifting a diluent; i) dissolving Betahistine or pharmaceutically acceptable salts thereof, binder, stabilizer in suitable solvent; j) granulating the “step h” with solution of “step i”; k) drying the granules obtained in “step j”; l) sifting the part of diluent, one or more glidant, lubricant and one or more release controlling polymer to form pre lubrication part; m) sifting and mixing dried granules of “step k” and pre lubrication part of “step 1”; n) lubricating mixture of “step m”; o) compressing tablets of IR part of “step g” and PR part of “step o” using suitable punches; p) optionally film coating said tablets; wherein said release controlling polymer comprises carbopol.

10. A method of treating a vestibular disease or condition, said method comprising administering once-daily the prolonged release oral solid pharmaceutical composition as claimed in any of claim 1 to 8.

11. The method as claimed in claim 10, wherein said vestibular disease or condition is Meniere's disease.

12. Use of the prolonged release oral solid pharmaceutical composition as claimed in any of claim 1 to 8 for treating a vestibular disease or condition.

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