DESC:Field of the Invention:
The present invention relates to oral dosage forms comprising bead compositions of acotiamide, the said bead compositions comprising a core and at least one coat. The present invention provides a process for the preparation of such compositions and dosage forms.

Background of the Invention:
Acotiamide is an acetylcholinesterase inhibitor used in the treatment of treatment of postprandial fullness, upper abdominal bloating, and early satiation due to functional dyspepsia. Acotiamide hydrochloride hydrate is approved in Japan as 100 mg oral tablet (ACOFIDE®).

The usual daily recommended adult dosage of ACOFIDE® is 300 mg, which is achieved by orally administering 100 mg tablet three times daily before a meal. Acotiamide can be administered as a 300 mg unit composition, once daily, to avoid its frequent administration. This would improve patient compliance, especially with the elderly.

Indian application no. 201821038746 relates to sustained release floating tablets of acotiamide or pharmaceutically acceptable salts thereof.

Chinese Publication No. CN105769784 discloses an oral tablet of acotiamide hydrochloride trihydrate and a preparation method thereof.

Chinese Publication Numbers CN103610657, CN106511291 and CN103622929 disclose an acotiamide hydrochloride sustained release/controlled release tablets and a preparation method thereof.

Chinese Publication No. CN105476963 discloses slow-release acotiamide hydrochloride pellets. The said pellets are prepared by mixing acotiamide hydrochloride, and excipients like diluents and binders, and subjecting the mix to extrusion-spheronization or granulation to prepare drug pellets. In one aspect, sustained release pellets are prepared by extruding and spheronizing a mixture of drug, sustained release agents, and other excipients, to provide pellets. In another aspect a sustained release coat is provided on the drug pellets.

Indian Application No. 201841031139 relates to capsule compositions comprising: i) one or more immediate release or sustained release mini-tablets of acotiamide, and ii) delayed release compositions of a proton pump inhibitor. In one aspect, the said compositions may contain one or more sustained release mini-tablets of acotiamide and/or one or more delayed mini-tablets of proton pump inhibitors.

Indian Patent 309051 relates to dual drug releasing granules which can directly be compressed into a tablets or bilayer tablets to achieve varied combinations of drug release profiles, e.g. one as immediate release and other as extended release, in a single tablet form. In one aspect, the dual release tablet composition contain actives - acotiamide and proton-pump inhibitor(s). Such tablet compositions contain acotiamide in an extended release form and proton-pump inhibitor(s) in an immediate release form.

Prior art primarily uses tablet technology to address drug delivery of acotiamide. In the present invention, acotiamide is formulated as a multi-unit dosage form such as beads.

It has surprisingly been found that when the oral dosage forms of the present invention comprise acotiamide formulated in the form of bead compositions, the dosage forms successfully achieve all the desired characteristics, i.e.:
• provide distinct drug-release patterns of the active agent;
• provide flexibility in achieving the desired drug-release profiles of the active pharmaceutical agent (beads with different drug-release patterns by easily blended to provide the desired drug release);
• provide flexibility in achieving the required doses without formulation/process changes (bead compositions can easily divided into desired dose strengths);
• provide flexibility in design of combination dosage forms (bead compositions of acotiamide can be easily to be combined and co-delivered with other active agents)
• provide the desired stability

The present invention uses bead technology to provide compositions comprising acotiamide. Such compositions provide the desired drug release and stability.

Further, dosage forms comprising bead compositions of acotiamide exhibit the desired drug release and stability, even when designed for oral co-delivery with another active pharmaceutical agent.

OBJECTS OF THE INVENTION
An object of the present invention is to provide oral dosage forms comprising bead compositions of acotiamide.

Another object of the present invention is to provide oral dosage forms comprising bead compositions of acotiamide, wherein acotiamide exhibits immediate release.

Another object of the present invention is to provide oral dosage forms comprising bead compositions of acotiamide, wherein acotiamide exhibits modified release.

Yet another object of the present invention is to provide oral dosage forms comprising bead compositions of acotiamide, wherein the bead compositions comprise a core and at least one coat.

Yet another object of the present invention is to provide oral dosage forms comprising two or more bead compositions, wherein one of the bead composition comprises acotiamide, and wherein the bead composition exhibits immediate release of acotiamide.

Yet another object of the invention is to provide oral dosage forms comprising two or more bead compositions, wherein one of the bead composition comprises acotiamide, and wherein the bead composition exhibits modified release of acotiamide.

Yet another object of the invention is to provide oral dosage forms comprising beads of acotiamide as a first active agent, and at least one other active pharmaceutical agent.

Yet another object of the invention is to provide a process for preparation of such oral dosage forms comprising bead compositions of acotiamide.

SUMMARY OF THE INVENTION
The present invention provides oral dosage forms comprising bead compositions of acotiamide. The present invention provides a process for preparation of such dosage forms and bead compositions.

DETAILED DESCRIPTION OF THE INVENTION
The present invention provides oral dosage forms comprising bead compositions of acotiamide.

The term “active pharmaceutical agent” or “active agent” as used herein refers to an agent or drug which has a biological effect, and includes acotiamide or any other active pharmaceutical agent.

The term “acotiamide” as used herein includes acotiamide and its pharmaceutically acceptable salts, hydrates, esters, derivatives or solvates. One such example of a salt of acotiamide is acotiamide hydrochloride. “Acotiamide” can be crystalline and/or amorphous.

The term “bead” or “bead composition”, as used herein refers to small, free-flowing, particulates, which may optionally contain an active pharmaceutical agent. Beads may have a spherical or a nearly spherical (e.g., elliptical) shape.

“Inert core” as used herein refers to inactive beads or spheres which do not contain any active pharmaceutical agent.

“Active core” as used herein refers to core or spheres, which contain at least one active pharmaceutical agent. Active core may be comprised of an inert core coated with a drug coat. Alternatively, the active core may be in the form of a matrix containing at least one active pharmaceutical agent and at least one matrixing agent, and may be prepared by granulating and milling and/or by extruding and spheronizing, a composition containing at least one active pharmaceutical agent.

“Coat” as used herein refers to a layer or film applied on the core.

“Drug coat” as used herein refers to a coat comprising at least one active pharmaceutical agent.

“Modified Release Coat” as used herein refers to a coat comprising at least one coating agent, which when applied on an inert core, active core, drug coat, barrier coat, or any other coat, modulates drug release and provides extended release, sustained release, controlled release, prolonged release, delayed release, enteric release, timed release, pulsed release or a combination thereof.

“Barrier Coat” as used herein refers to a coat comprising at least one coating agent, which can be applied on the inert core, active core, drug coat, modified release coat, or any other coat. The barrier coat can be applied between a core and a coat, or between coats, or as a top-most coat, to provide a barrier. Barrier coat includes but is not limited to a film-coat, a seal coat, a taste-masking coat, a color coat, an aesthetic coat, a moisture-barrier coat, a light barrier coat, a stabilizer coat, or combination thereof.

The present invention provides bead compositions of acotiamide for oral administration.

Bead compositions of acotiamide may provide immediate release, extended release, sustained release, controlled release, prolonged release, delayed release, enteric release, timed release, pulsed release or a combination thereof, of acotiamide.

Bead compositions of acotiamide of the present invention comprise a core and a coat.

In an aspect, bead compositions of acotiamide comprise a core and a coat, wherein the core is an inert core.

Bead compositions of acotiamide may comprise an inert core and at least one coat.

Bead compositions of acotiamide may comprise an inert core, and at least one coat, wherein the coat is a drug coat comprising acotiamide.

In another embodiment, bead compositions of acotiamide comprise an inert core, at least one drug coat comprising acotiamide, and one or more barrier coats.

In another embodiment, bead compositions of acotiamide comprise an inert core, at least one drug coat comprising acotiamide, and one or more modified release coats.

In yet another embodiment, bead compositions of acotiamide comprise an inert core, at least one drug coat comprising acotiamide, one or more barrier coats, and one or more modified release coats.

In another aspect, bead compositions of acotiamide comprise a core and a coat, wherein the core is an active core.

In an embodiment, bead compositions comprise an active core containing acotiamide, and at least one coat.

In another embodiment, bead compositions comprise an active core containing one portion of acotiamide, and a drug coat containing a second portion of acotiamide.

In yet another embodiment, bead compositions comprise an active core comprising acotiamide, and a drug coat comprising acotiamide or other active pharmaceutical agent.

In another embodiment, bead compositions comprise an active core containing acotiamide, and at least one coat, wherein the coat is a barrier coat.

In another embodiment, bead compositions comprise an active core containing acotiamide, and at least one coat, wherein the coat is a modified release coat.

In another embodiment, bead compositions comprise an active core containing acotiamide, one or more barrier coats, and one or more modified release coats.

In another embodiment, bead compositions comprise an active core containing acotiamide, one or more drug coats, one or more barrier coats, and one or more modified release coats.

Bead compositions comprising acotiamide, can further be formulated as oral dosage forms such as capsules, tablets, sachets, or suspensions.

Oral dosage forms comprising bead compositions of acotiamide may provide immediate release, extended-release, sustained-release, controlled-release, prolonged release, delayed-release, enteric-release, timed-release, pulsed-release or a combination thereof, of acotiamide.

In an embodiment, the oral dosage forms of the present invention comprise two or more bead compositions, wherein at least one of the bead compositions comprises acotiamide, and the said bead composition exhibits immediate release of acotiamide.

In an embodiment, the oral dosage forms of the present invention comprise two or more bead compositions, wherein at least one of the bead compositions comprises acotiamide and the said bead composition exhibits modified release of acotiamide.

In another embodiment, the oral dosage forms of the present invention comprise two or more bead compositions, wherein one bead composition comprising acotiamide exhibits immediate release of acotiamide, and a second bead composition comprising acotiamide exhibits modified release of acotiamide.

Bead compositions of the present invention comprise acotiamide in concentrations ranging from about 25% to about 95%, preferably from 30% to about 95%, and more preferably from about 35% to about 95% by weight of the bead composition.

In an embodiment, the bead compositions provide high drug-loading of acotiamide, wherein the concentration of acotiamide may range from about 40% to about 95%, preferably from 45% to about 95%, and more preferably from about 50% to about 90% by weight of the bead composition.

In an embodiment, the bead compositions provide high drug-loading of acotiamide, wherein the concentration of acotiamide may range from about 55% to about 95%, preferably from 60% to about 95%, and more preferably from about 65% to about 90% by weight of the bead composition.

Inert core(s) is selected from sugar spheres, non-pareil seeds, microcrystalline cellulose (MCC) spheres, lactose spheres, mannitol-MCC spheres, lactose-MCC spheres, glass beads, silicon dioxide spheres, acidic buffer crystal, alkaline buffer crystal, or mixtures thereof.

In an aspect, bead compositions of acotiamide comprise inert core in concentrations ranging from about 5% to about 75%, preferably about 5% to about 70%, more preferably from about 5% to about 65% by weight of the bead composition.

In an embodiment, bead compositions provide a high drug-loading of acotiamide, the concentration of inert core may range from about 5% to about 60%, preferably about 5% to about 55%, more preferably from about 10% to about 50% by weight of the bead composition.

In an embodiment, bead compositions of acotiamide comprise inert core in concentrations ranging from about 5% to about 45%, preferably about 5% to about 40%, more preferably from about 5% to about 35% by weight of the bead composition.

In another aspect, the bead compositions comprise an active core comprising acotiamide and at least one excipient selected from matrixing agents, binders, diluents, disintegrants, plasticizers, antioxidants, pH modifying agents, surfactants, stabilizers, lubricants, glidants, coloring agents, taste-masking agents, or flavoring agents.

In an aspect, bead compositions of acotiamide comprise active core in concentrations ranging from about 25% to about 100%, preferably about 30% to about 100%, more preferably from about 40% to about 100% by weight of the bead composition.

In an aspect, bead compositions of acotiamide comprise a core, and at least one drug coat, wherein the drug coat comprises acotiamide.

In another embodiment, bead compositions of acotiamide comprise a core, and at least one drug coat, wherein the core comprises an inert core, and the drug coat comprises acotiamide.

In an aspect, bead compositions comprise acotiamide in concentrations ranging from about 50% to about 99%, preferably from about 60% to about 99%, and more preferably from about 70% to about 99% by weight of the drug coat.

In an aspect, the concentration of drug coat ranges from about 40% to about 95%, preferably from 45% to about 95%, and more preferably from about 50% to about 90% by weight of the bead composition.

In another embodiment, the bead compositions comprising acotiamide comprise a core, and one or more barrier coats.

Barrier coat(s) of the bead compositions comprise at least one coating agent in concentrations of about 50% to about 100% by weight of the barrier coat.

In another aspect, the concentration of barrier coat ranges from about 1% to about 25%, preferably from 1% to about 20%, and more preferably from about 1% to about 15% by weight of the bead composition.

In yet another embodiment, the bead compositions of acotiamide comprise a core, and one or more modified release coats.

Modified release coat(s) of bead compositions comprise at least one coating agent in concentrations of about 50% to about 100% by weight of the modified release coat.

In another aspect, the concentration of modified release coat ranges from about 1% to about 50%, preferably from 1% to about 45%, and more preferably from about 1% to about 40% by weight of the bead composition.

Coating agent(s) is selected from the group of cellulose ethers (such as methylcellulose (MC), hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), hydroxyethylcellulose (HEC), carboxymethylcellulose (CMC), ethyl cellulose (EC); cellulose esters (such as cellulose acetate (CA), cellulose acetate phthalate (CAP), cellulose acetate butyrate (CAB), hydroxypropyl methyl cellulose phthalate (HPMCP), hydroxypropyl methyl cellulose acetate succinate (HPMCAS); polyacrylic acid; polymethacrylates; polyvinyl alcohol and its copolymers; polyvinyl acetate and its copolymers; polyvinyl acetate phthalate, waxes, fatty acids, fatty alcohols, or mixtures thereof.

In an aspect, the inert core, active core, coat, drug coat, barrier coat, modified release coat, bead compositions, and/or dosage forms can further comprise at least one excipient selected from binders, diluents, disintegrants, plasticizers, antioxidants, pH modifying agents, surfactants, stabilizers, lubricants, glidants, coloring agent, taste-masking agent, or flavoring agent.

Binder(s) is present in concentrations from 0.1% to 40% by weight of the bead composition, and are selected from those known in the art such as HPMC, HPC, MC, HEC, polyvinylpyrrolidone (PVP), polyvinyl alcohol, waxes, fatty alcohols (such as stearyl alcohol, cetyl alcohol), waxes, polyethylene glycol, carbomer, gums (such as xanthan gum, guar gum, acacia, locust bean gum), alginates, polymethacrylates or mixtures thereof.

Diluent(s) is present in concentrations of 1% to 90% by weight of the bead composition, and are selected from those known in the art such as microcrystalline cellulose, CMC sodium, CMC calcium, starch, modified starch, pregelatinized starch, dextrin, dextran, maltodextrin, calcium phosphate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulfate, cyclodextrins, glucose, lactose, mannitol, sucrose, dextrose, sorbitol, fructose, sorbitol, compressible sugar, or mixtures thereof.

Disintegrant(s) is present in concentrations from 1% to 25% by weight of the bead composition and are selected from those known in the art such as sodium starch glycolate, crospovidone, low-substituted HPC, croscarmellose sodium, and croscarmellose calcium.

Matrixing agent is present in concentrations from 1% to 90% by weight of the bead composition, and is selected from the group of cellulose ethers (such as MC, HPMC, HPC, HEC, CMC, EC); cellulose esters (such as CA, CAP, CAB, HPMCP, HPMCAS); polyacrylic acid; polymethacrylates; polyvinyl alcohol and its copolymers; polyvinyl acetate and its copolymers; polyvinyl acetate phthalate, waxes, fatty acids, fatty alcohols, or mixtures thereof.

Plasticizer(s) is present in concentrations from ranging from 0.05% to 20% by weight of the coat and is selected from the group of triacetin, triethylcitrate, acetyltriethylcitrate, tributyl citrate, acetyltributylcitrate, diethyl phthalate, dibutylsebacate, diethylphthalate, polyethylene glycol, propylene glycol, miglyol, hydrogenated oils, oleic acid, acetylated mono- and di-glycerides, polysorbate, castor oil, or mixtures thereof.

Antioxidant(s) is present in concentrations from ranging from 0.05% to 5% by weight of the bead composition, and are selected from those known in the art. Preferably antioxidant(s) are selected from butylated hydroxyanisole, butylated hydroxytoluene, propyl gallate, sodium metabisulfite, sodium sulfite, sodium bisulfite, citric acid, ascorbic acid and mixtures thereof.

pH modifying agent(s) is present in concentrations from 0.1% to 20% by weight of the bead composition and are selected from those known in the art. The pH modifying agent(s) can be acidic or basic in nature. Preferable basic pH modifying agent(s) is selected from metal oxides (such as calcium oxide, magnesium oxide); hydroxides (such as sodium hydroxide, potassium hydroxide); carbonates (such as sodium carbonate, sodium bicarbonate, magnesium carbonate); acetates (such as sodium acetate);, silicates (such as sodium silicate); quaternary ammonium salts; and N-methyl-D-glucamine. Preferable acidic pH modifying agents are selected from mineral acid and organic acids such as hydrochloric, nitric, phosphoric, acetic, citric, succinic, sulfuric, fumaric, maleic, malic, benzoic, tartaric, methanesulfonic, naphthalenesulfonic, p-toluenesulfonic, lactic, and ascorbic acid, and glycine hydrochloride. The pH modifying agent can be a buffering agent like Tris buffer, acetate buffer, phosphate buffer, citrate buffer and tris-(hydroxymethyl) methyl ammonium chloride.

Surfactant(s) may be present in concentrations from 0.05% to 10% by weight of the bead composition and are selected from those known in the art. Preferable surfactants are selected from ionic surfactants, such as sodium lauryl sulphate, or non-ionic surfactants such as poloxamers, lecithins, esters of sorbitan and fatty acids (such as Span®), esters of polyoxyethylenesorbitan and fatty acids (such as Tween®), polyoxyethylated hydrogenated castor oil (such as Cremophor®), polyoxyethylene stearates (such as Brij®), dimethylpolysiloxane or any combination of the above mentioned surfactants.

Stabilizer(s) may be present in concentrations from 0.05% to 20% by weight of the bead composition and are selected from those known in the art such as polyols, phospholipids, amino acids, quaternary ammonium compounds, buffers, alkalizers, acidifiers, or surfactants.

Lubricant(s) may be present in concentrations from 0.25% to 5% by weight of the bead composition and are selected from those known in the art. Preferably lubricants are selected from magnesium stearate, calcium stearate, stearic acid, sodium stearyl fumarate, sodium benzoate, palmitic acid, talc, and glyceryl behenate.

Glidant(s) may be present in concentrations from about 0.1% to about 10% by weight of the composition and are selected from those known in the art such as colloidal silicon dioxide, hydrated silicon dioxide, light anhydrous silicic acid, aluminum silicate, titanium oxide, stearic acid, and talc.

Another aspect of the present invention relates to providing oral dosage forms for combination therapy comprising acotiamide and at least one other active pharmaceutical agent.

The other active pharmaceutical agent, to be used in combination with acotiamide, can be selected from the class of proton pump inhibitors (e.g. rabeprazole, lansoprazole, dexlansoprazole, omeprazole, esomeprazole, or pantoprazole); prokinetic agents (e.g. benzamide, cisapride, domperidone, itopride, mosapride, metoclopramide, prucalopride, renzapride, tegaserod, mitemcinal, levosulpiride, cinitapride, linaclotide); antibiotics (e.g. amoxicillin, clarithromycin, cephalexin, ciprofloxacin, levofloxacin, clindamycin, metronidazole, azithromycin, sulfamethoxazole, trimethoprim); antacids (e.g. aluminum hydroxide, calcium carbonate, magnesium hydroxide, sodium bicarbonate, simethicone); H2 antagonists (e.g. cimetidine, ranitidine, famotidine, nizatidine, roxatidine, lafutidine); antiflatulents (e.g. simethicone, lactase). The active pharmaceutical agent can be used as is or in the form of its pharmaceutically acceptable salt, hydrate, ester, derivative or solvate.

In a preferable embodiment, the other active pharmaceutical agent to be used in combination with acotiamide is a proton pump inhibitor and is selected from rabeprazole, pantoprazole, lansoprazole, dexlansoprazole, omeprazole, esomeprazole, or their pharmaceutically acceptable salts, hydrates, esters, derivatives or solvates.

Oral dosage forms for combination therapy comprise bead compositions of acotiamide, and at least one other active pharmaceutical agent.

Oral dosage forms for combination therapy comprising bead compositions of acotiamide and at least one other active pharmaceutical agent, can be in the form of capsules, tablets, sachets, or suspensions.

In an embodiment, oral dosage forms for combination therapy comprise bead compositions of acotiamide, and compositions of at least one other active pharmaceutical agent.

In another embodiment, oral dosage forms for combination therapy comprise bead compositions, wherein the bead compositions comprise acotiamide and at least one other active pharmaceutical agent.

In yet another embodiment, oral dosage forms for combination therapy comprise bead composition of acotiamide, and compositions of other active pharmaceutical agent, wherein the compositions of the other active pharmaceutical agent are in the form of powder, beads, pellets, granules, spheroids, particulates, mini-tablets, and/or micro-tablets.

In a preferred embodiment, oral dosage forms for combination therapy comprise bead compositions comprising acotiamide, and bead compositions comprising at least one other active pharmaceutical agent.

Compositions of the other active pharmaceutical agent may comprise one or more excipients selected from inert core, coating agents, diluents, binders, disintegrants, agents, matrixing agents, plasticizers, antioxidants, pH modifying agents, surfactants, stabilizers, lubricants, glidants, coloring agent, taste-masking agent, and flavoring agent.

Oral dosage forms for combination therapy, comprising bead compositions of acotiamide, and at least one other active pharmaceutical agent, may provide release profiles that are immediate, extended, sustained, controlled, prolonged, delayed, enteric, timed, pulsed or a combination thereof, of the other active pharmaceutical agent.

Process for preparing bead compositions comprises one or more of steps selected from sifting, blending, dissolving, dispersing, granulation (wet granulation, dry granulation, spray-dry granulation, fluid-bed granulation, melt granulation, melt-extrusion, co-milling or co-precipitation), extrusion, spheronization, coating, layering, drying, milling, screening, filling into capsules, and compressing.

Solvents may be used in the process for preparing bead compositions of acotiamide, said solvents which may be selected from water, alcohols, organic solvents, or mixtures thereof. Examples of such solvents include but are not limited to methanol, ethanol, isopropanol, dichloromethane, acetone, halogenated hydrocarbon, and ethylmethylketone.

Oral dosage forms comprising bead compositions of acotiamide can be packed in suitable packs such as blisters, strips, or bottle packs, which use packing materials such as PVC-PVDC, aluminum, polyvinyl chloride (PVC), polychlorotrifluroethylene (PCTFE), and cellulose polymers. The packs can be used with or without desiccants.

Oral dosage forms of acotiamide, comprising bead compositions of acotiamide, were characterized in terms of acotiamide content, acotiamide dug release and total impurities.

Acotiamide content (assay): Acotiamide content in the oral dosage forms or bead compositions, as determined by liquid chromatography, can range from about 90% to about 110%, preferably from about 92.5% to about 107.5%, and most preferably 95% to about 105% of the label claim.

Drug release study of acotiamide, from the oral dosage forms or bead compositions, was analyzed in 900ml of pH 4.5 acetate buffer, using USP Type II (paddle) apparatus at 100 rpm and 370C ± 0.50C. Drug release of acotiamide was expressed as average cumulative % drug release.

In an embodiment, the average cumulative % drug release of acotiamide, from oral dosage forms or bead compositions of the present invention, is from 80% to 100%, preferably from 85% to 100%, more preferably from 90% to 100%, and most preferably from about 95% to 100%, in 60 minutes.

In an embodiment, the average cumulative % drug release of acotiamide, from oral dosage forms or bead compositions of the present invention, is from 80% to 100%, preferably from 85% to 100%, more preferably from 90% to 100%, and most preferably from about 95% to 100%, in 45 minutes.

In an embodiment, the average cumulative % drug release of acotiamide, from oral dosage forms or bead compositions of the present invention, is from 80% to 100%, preferably from 85% to 100%, more preferably from 90% to 100%, and most preferably from about 95% to 100%, in 30 minutes.

In another embodiment, the average cumulative % drug release of acotiamide, from oral dosage forms or bead compositions of the present invention, is from 80% to 100%, preferably from 85% to 100%, more preferably from 90% to 100% and most preferably from 95% to 100%, in 10 minutes.

In another embodiment, the average cumulative % drug release of acotiamide, from oral dosage forms or bead compositions of the present invention, is from 0% to 40%, preferably from 0% to 30%, more preferably from 0% to 20%, and most preferably from 0% to 10%, in 1 hour.

In another embodiment, the average cumulative % drug release of acotiamide, from oral dosage forms or bead compositions of the present invention, is from 10% to 55%, preferably from 10% to 50%, more preferably from 15% to 45%, and most preferably from 15% to 40%, in 3 hours.

In another embodiment, the average cumulative % drug release of acotiamide, from oral dosage forms or bead compositions of the present invention, is from 40% to 100%, preferably from 40% to 95%, more preferably from 45% to 95%, and most preferably from 50% to 95%, in 5 hours.

In a preferred embodiment, the average cumulative % drug release of acotiamide, from oral dosage forms or bead compositions of the present invention, is from about 55% to about 75%, in 5 hours.

In another embodiment, the average cumulative % drug release of acotiamide, from oral dosage forms or bead compositions of the present invention, is from 60% to 100%, preferably from 65% to 100%, and more preferably from 70% to 100%, in 7 hours.

In another embodiment, the average cumulative % drug release of acotiamide, from oral dosage forms or bead compositions of the present invention, is from 70% to 100%, preferably from 75% to 100%, and more preferably from 80% to 100%, in 9 hours.

In yet another embodiment, the average cumulative % drug release of acotiamide, from oral dosage forms or bead compositions of the present invention, is from 75% to 100%, preferably from 80% to 100%, more preferably from 85% to 100%, and most preferably from 90% to 100%, in 12 hours.

Content of total impurities related to acotiamide, in oral dosage forms or bead compositions of the present invention, as determined by liquid chromatography, is from 0% to 5%, preferably from 0% to 4%, more preferably from 0% to 3%, and most preferably from 0% to 2.5%.

In an embodiment, the content of total impurities content related to acotiamide, in oral dosage forms or bead compositions of the present invention, is from 0% to 2%, preferably from 0% to 1.5%, more preferably from 0% to 1%, and more preferably from 0% to 0.5%.

Storage stability of the dosage forms or bead compositions of acotiamide was studied in one or more of the following conditions:
a. 400C and 75% relative humidity (RH)
b. 300C and 75% relative humidity (RH)
c. 250C and 60% relative humidity (RH)

After specific time-periods of storage, the dosage forms/bead compositions were analyzed for acotiamide content, total impurities, and drug release of acotiamide. In addition, for combination products, the forms/bead compositions were also analyzed for content, total impurities, and drug release for the other active agent(s).

The invention is now illustrated with non – limiting examples.

Example 1: Drug coated beads of acotiamide hydrochloride
Drug coated bead composition of acotiamide hydrochloride was prepared as follows (percentages were calculated by weight of drug coated beads):
a) Povidone (11.82%w/w) was added to a portion of purified water and dissolved under stirring to provide povidone solution.
b) Acotiamide hydrochloride (70.92%w/w) was added to a portion of purified water and stirred till a uniform dispersion is obtained.
c) Povidone solution from step a) was added to the acotiamide hydrochloride dispersion of step b).
d) Talc (1.18%w/w) was added to the dispersion of step c) and stirred for about 10-20 minutes.
e) Remaining quantity of purified water was added to the dispersion of step d), stirring continued for about 10-20 minutes, and dispersion filtered through ASTM # 100 sieve to obtain the coating solution.
f) Coating solution of step e) was sprayed on sugar spheres (ASTM 30-35 mesh) (16.08%w/w), in a fluid bed processor, using the following processing parameters: an inlet air temperature of about 300C to about 600C, a product temperature and an outlet air temperature of about 250C to about 500C, atomization air pressure of about 0.4-2.0 kg/cm2, and a fluidization flap open from about 10% to about 90%.
g) Beads from step f) were further dried at an inlet air temperature of about 400C to about 600C, till the beads showed a loss of drying (LOD) (at 1050C) of not more than 1.5%w/w.
h) Dried beads of step g) were sifted through ASTM # 12/20 and beads collected to provide immediate release bead composition of acotiamide hydrochloride.

Example 2: Film coated beads of acotiamide hydrochloride
2A. Drug coated bead composition of acotiamide was prepared as follows (percentages were calculated by weight of drug coated beads):
a) Povidone (8.69%w/w) was added to a portion of purified water and dissolved under stirring to provide povidone solution.
b) Acotiamide hydrochloride (74.44%w/w) was added to a portion of purified water and stirred till a uniform dispersion is obtained.
c) Povidone solution from step a) was added to the acotiamide hydrochloride dispersion of step b).
d) Remaining quantity of purified water was added to the dispersion of step c), stirring for about 10-20 minutes, and the dispersion filtered through ASTM # 100 sieve to obtain the drug coating solution.
e) Coating solution of step d) was sprayed on sugar spheres (ASTM 30-35 mesh) (16.87%w/w) in a fluid bed processor, and the beads dried, and sifted, using processing parameters similar to Example 1, to provide drug coated beads of acotiamide hydrochloride.

2B. Film-coated (Barrier Coated) bead composition of acotiamide was prepared as follows (percentages calculated by weight of film-coated beads):
a) HPMC (6cps) (3.72%w/w) was added a portion of purified water and stirred till a clear solution is obtained.
b) Ethyl cellulose (45cps) (1.86%w/w) was added to a portion of isopropyl alcohol and stirred till a clear solution is obtained.
c) HPMC solution of step a) was added to the ethyl cellulose solution of step b) and stirred till a clear solution is obtained.
d) Amount of purified water remaining and isopropyl alcohol was added to the dispersion of step e) and further stirred for about 10 – 20 minutes.
e) The dispersion was filtered through ASTM # 100 sieve to obtain the coating dispersion.
f) Drug coated beads of acotiamide hydrochloride of Example 2A (93.72%w/w) were sprayed with the coating dispersion of step e) in a fluid bed processor, using the following processing parameters: inlet air temperature of about 300C to about 500C, product temperature and an outlet air temperature of about 250C to about 450C, atomization air pressure of about 0.2-2.0 kg/cm2, and spray rate of about 1 – 30 g/min.
g) Beads from step f) were further dried at an inlet air temperature of about 400C to about 600C, till the beads showed a loss of drying (LOD) (at 1050C) of not more than 1.5%w/w.
h) Dried beads of step g) were sifted through ASTM # 10/20, beads collected and lubricated with talc (0.7%w/w) to provide immediate release, film-coated (barrier coated) bead composition of acotiamide hydrochloride.

Example 3: Extended release beads of acotiamide hydrochloride
Extended release coated (modified release coated) bead composition of acotiamide hydrochloride were prepared as follows (percentages were calculated by weight of extended release beads):
a) HPMC (6cps) (2.5%w/w) was added a portion of purified water and stirred till a clear solution is obtained.
b) Ethyl cellulose (45cps) (4.65%w/w) was added to a portion of isopropyl alcohol and stirred till a clear solution is obtained.
c) HPMC solution of step a) was added to the ethyl cellulose solution of step b) and stirred till a clear solution is obtained.
d) Triethyl citrate (0.36%w/w) was added into the solution of step c) and stirring was continued for 10-30 minutes.
e) Talc (0.71%w/w) was added to the solution of step d) and stirring was continued for 10 - 30 minutes.
f) Remaining amount of purified water and isopropyl alcohol was added to the dispersion of step e) and further stirred for about 10 - 20 minutes.
g) The dispersion was filtered through ASTM # 100 sieve to obtain the coating dispersion.
h) Drug coated beads of acotiamide hydrochloride of Example 1 (91.36%w/w) were sprayed with the coating dispersion of step (g) in a fluid bed processor, using the following processing parameters: inlet air temperature of about 300C-500C, product temperature and an outlet air temperature of about 250C to about 450C, atomization air pressure of about 0.2-2.0 kg/cm2, and spray rate of about 1 – 30 g/min.
i) Beads from step h) were further dried at an inlet air temperature of about 400C to about 600C, till the beads showed a loss of drying (LOD) (at 1050C) of not more than 1.5 %w/w.
j) Dried beads of step i) were sifted through ASTM # 10/20, beads collected and lubricated with talc (0.42%w/w), to provide extended release bead composition of acotiamide hydrochloride.

Example 4: Capsules of Acotiamide hydrochloride Extended Release Beads and Rabeprazole Delayed Release Beads
4A. Acotiamide hydrochloride extended release bead composition were prepared in accordance with Example 3.

4B. Rabeprazole delayed release beads were prepared by the following process (percentages were calculated by weight of delayed release beads):
a) HPMC (15cps) (4.0%w/w), sodium hydroxide (0.67%w/w) and rabeprazole sodium (13.33%w/w) were dissolved in purified water.
b) Light magnesium carbonate (1.33%w/w) and talc (2.0%w/w) were added to the solution of step b), filtered through ASTM # 100 sieve to obtain the drug coating dispersion.
c) Drug coating dispersion of step b) was sprayed on magnesium carbonate-HPMC coated non-pariel seeds (ASTM # 16-18) (43.99%w/w), using an inlet air temperature of about 400C-600C, bed temperature of about 400C-450C, outlet air temperature of about 300C- 500C, and atomization air pressure of about 1.0-2.0 kg/cm2.
d) Beads from step c) were further dried at about 300C-600C, till a loss of drying (LOD) (at 600C) of not more than 1.5%w/w, and sifted through ASTM # 14 to provide drug coated beads of rabeprazole sodium.
e) HPMC (15cps) (5.23%w/w) and magnesium carbonate (3.27%w/w) were added to purified water, and filtered through ASTM # 100 sieve.
f) Seal coating dispersion of step e) was sprayed on drug coated beads of rabeprazole sodium from step d), dried (using conditions similar to steps d) and e)), and sifted through ASTM # 14 sieve.
g) Methacrylic acid and ethyl acrylate copolymer (1:1) (18.45%w/w) (as a 30% dispersion), polyethylene glycol 6000 (1.85%w/w), talc (3.69%w/w), titanium dioxide (0.92%w/w) and ferric oxide (0.92%w/w), were dissolved/dispersed in purified water, and dispersion milled (colloid mill).
h) Sodium hydroxide (0.25%w/w) was dissolved in purified water and added to the dispersion of step h).
i) Enteric Coating dispersion of step i) was sprayed on seal coated beads of rabeprazole sodium from step g), dried using conditions similar to steps f) and g), and beads sifted through ASTM # 10/20 beads, to provide to provide enteric coated beads of rabeprazole sodium.
j) Talc (0.10%w/w) was sifted through ASTM # 20 sieve and blended with enteric coated beads of rabeprazole sodium of step r) to give delayed release bead composition of rabeprazole sodium.

4C. Acotiamide hydrochloride extended release beads of example 4A (equivalent to 300 mg of acotiamide hydrochloride) and rabeprazole delayed release beads of example 4B (equivalent to 20 mg of rabeprazole sodium) were mixed and filled in hard gelatin capsules of size 00.

Examples 5-7: Capsule Compositions of Acotiamide hydrochloride Beads, and Pantoprazole/Lansoprazole/Omeprazole Delayed Release Beads
Delayed release (DR) beads pantoprazole, lansoprazole, or omeprazole were prepared in accordance to Table 1, using processing steps similar to Example 4B.

Table 1: Composition of delayed release beads of pantoprazole, lansoprazole, and omeprazole
Ingredients %w/w of Delayed Release Beads
Example 5 Example 6 Example 7
Inert Core
Non Pariel Seeds #18-20 (MgCO3-HPMC Coated) 38.89 -- 36.21
Non Pariel Seeds #16-18 (MgCO3-HPMC Coated) -- 61.92 --
Drug Coat
Pantoprazole Sodium Sesquihydrate * 23.68 -- --
Lansoprazole -- 8.5 --
Omeprazole -- -- 22.22
HPMC (15 cps) 4.74 2.81 3.44
Talc 2.37 1.40 3.44
Colloidal silicon dioxide -- 0.28 --
Sodium hydroxide -- 2.21 3.02
Barrier Coat (Seal Coat)
HPMC (5 cps) 5.23 5.01 6.83
Light magnesium carbonate 1.74 -- --
Talc 0.52 0.5 0.70
Magnesium stearate -- 1.53
Modified Release Coat (Delayed Release Coat)
Methacrylic acid and ethyl acrylate copolymer (30% Dispersion) 16.2 12.4 17.03
Polyethylene glycol 6000 1.62 1.24 --
Polysorbate 80 -- -- 0.10
Glycerol monostearate 40 – 55 -- -- 0.84
Sodium hydroxide 0.22 0.16 --
Colloidal anhydrous silica 0.22 0.16 --
Talc 3.24 2.60 0.83
Titanium dioxide 0.80 0.56 0.51
Lake of indigo carmine 0.43 -- --
Barrier Coat (Top-Film Coat)
Hypromellose phthalate HP55 -- -- 2.90
Dibutyl sebacate -- -- 0.30
Lubrication
Talc 0.10 0.25 0.10

Acotiamide beads of examples 1, 2 or 3 (equivalent to the required dose) can be mixed with the required quantity of delayed release beads (equivalent to the required dose) of pantoprazole, lansoprazole, or omeprazole from examples 5, 6, or 7 respectively. The bead composition mixture can be filled into sachets, or filled in hard gelatin capsules of suitable size, or compressed into tablets, to give oral dosage forms.

Evaluation of Compositions
Drug Release:
Example 2: Drug release of immediate release (IR) beads of Example 2 was analyzed according to the ‘drug release study for acotiamide’. IR Beads of example 1 provided an average cumulative % drug release of about 98% of acotiamide in 60 minutes.
Example 4C: Drug release study results of the capsules of Example 4C are provided in Table 2.
• Drug release study of acotiamide was conducted according to the ‘drug release study for acotiamide’.
• Drug release of rabeprazole sodium, expressed in terms of average cumulative % drug release, was analyzed in 900ml of 0.1N HCl using USP Type I (Basket) at 100 rpm and 370C ± 0.50C for 2 hours (Acid stage), followed by 900ml of phosphate buffer pH 7.8 with 0.5%w/v of sodium lauryl sulphate, using USP Type I (basket) at 100prm and 370C ± 0.50C. In preferable compositions average cumulative % drug release in 0.1N HCl should be 0% to 15% at 2 hours, and in phosphate buffer pH 7.8 should be from 70% to 100% in at least 1 hour.

Table 2: Drug Release Study of Capsules of Example 4C
Time (hours) Average Cumulative % Drug Release Time (hours) Average Cumulative % Drug Release
Acotiamide Hydrochloride Rabeprazole Sodium
1 3 2
(Acid Stage) 2
3 31
5 63
7 86 1
(pH 7.8 Buffer Stage) 88
9 96
12 99

Storage Stability Study
Acotiamide compositions prepared in accordance with Example 4 were packed in aluminum blisters, and stored at the various storage conditions. Table 3 shows the results of the stability study of capsule compositions of example 4 containing acotiamide. The compositions were analyzed for acotiamide content and total acotiamide impurities at 3 month time point.

Table 3: Storage Stability of Acotiamide in Capsules of Example 4
Time Point / Condition Content of Acotiamide % Total Impurities related to Acotiamide
Initial 100.1 0.19
3 Months at 40°C/75% RH 95.9 0.11
3 Months at 30°C/75% RH 95.6 0.13
3 Months at 25°C/60% RH 96.4 0.14

Capsule dosage forms comprising bead compositions of acotiamide and beads of rabeprazole were prepared in accordance to example 4C, packed in aluminum blisters, and subjected to long-term storage stability studies at various time-points. Stability Study results are provided in Table 4.

Table 4: Storage stability results of capsules of Example 4C
Time Point [Months(M)] / Condition ? Content of Acotiamide (%) % Total Impurities (Acotiamide) % Drug Release
5 h 12 h
Acceptance Criteria ? 90%-110% 0% to 5% 40% to 100% 75% to 100%
Initial 100.1 0.19 63 99
6 M at 40°C/75% RH 100.2 0.19 69 102
12 M at 30°C/75% RH 100.7 0.20 70 102
12 M at 25°C/60% RH 100.7 0.20 69 98
Time Point [Months(M)] / Condition ? Content of Rabeprazole (%) % Total Impurities (Rabeprazole) % Drug Release
2 h (Acid) 1 h
(pH 7.8)
Acceptance Criteria ? 90%-110% 0% to 6% 0% to 15% 70% to 100%
Initial 105.5 0.71 2 91
12 M at 30°C/75% RH 100.1 4.34 6 82
12 M at 25°C/60% RH 106.0 1.43 3 94

As seen in Examples 1-7, compositions of the present invention, comprising beads of acotiamide, can be formulated into doge forms with different drug release patterns, dose strengths and drug combinations. As seen in Tables 2-4, bead compositions were able to achieve the desired drug release patterns including immediate release and modified release, and the desired stability of acotiamide.

Thus, the present invention provides simple and easily scalable compositions comprising beads of acotiamide. The compositions of the present invention can easily be adapted to provide different dosage forms, and varied drug release profiles, and are amenable to co-delivery with other active pharmaceutical agents in combination therapy. ,CLAIMS:

1. A dosage form for oral administration comprising bead compositions comprising acotiamide, wherein the bead composition comprises a core and at least one coat.

2. The bead composition as claimed in claim 1, wherein the core is an inert core.

3. The bead composition as claimed in claim 1, wherein the core is an active core.

4. The bead composition as claimed in claim 1, wherein the coat is selected from a drug coat, a barrier coat, a modified release coat, or a combination thereof.

5. The bead composition as claimed in claim 1, wherein acotiamide is 25% to 95% by weight of the bead composition.

6. The dosage form as claimed in claim 1, wherein the dosage form is in the form of capsules, tablets, sachets, or suspensions.

7. The dosage form as claimed in claim 6, wherein the dosage form further comprises at least one other active pharmaceutical agent.

8. The dosage form as claimed in claim 7, wherein the at least one other active agent is selected from a proton pump inhibitor, prokinetic agent, antibiotic, antacid, H2 antagonist, or antiflatulent.

9. The dosage form as claimed in claim 8, wherein the at least one other active agent is a proton pump inhibitor, and is selected from rabeprazole, pantoprazole, lansoprazole, dexlansoprazole, omeprazole, or esomeprazole.

10. The dosage form as claimed in claim 7, wherein the at least one other active agent is in the form of powder, beads, pellets, granules, spheroids, particulates, mini-tablets, or micro-tablets.