WO2020104955A1

WO2020104955A1 - Pharmaceutical compositions of acotiamide and proton pump inhibitor

Info

Publication number: WO2020104955A1
Application number: PCT/IB2019/059957
Authority: WO
Inventors: Yuvaneshwari KANAGASABAPATHY; HariHaran VENUGOPAL; Nidhish AYACHI; Rahul Prakash GANGWAL; Rajib Lochan MAHARANA; Prashant Popatrao RAUT; Saurabh Srivastava; Anup Avijit Choudhury; Rajeev Raghuvanshi
Original assignee: Dr. Reddy’S Laboratories Limited
Priority date: 2018-11-20
Filing date: 2019-11-20
Publication date: 2020-05-28

Abstract

The invention relates to pharmaceutical unit compositions comprising multi-particulate modified release compositions of acotiamide or pharmaceutically acceptable salt thereof and a preparation method thereof. The invention further relates to pharmaceutical unit compositions comprising modified release multi-particulate compositions of acotiamide or pharmaceutically acceptable salts thereof and delayed release compositions of a proton pump inhibitor or pharmaceutically acceptable salts thereof. Methods of preparing such compositions are also provided. The compositions can be administered once daily.

Description

PHARMACEUTICAL COMPOSITIONS OF ACOTIAMIDE AND PROTON

PUMP INHIBITOR

TECHNICAL FIELD OF THE INVENTION

The present specification relates to pharmaceutical unit compositions comprising multi-particulate modified release compositions of acotiamide. The specification also relates to pharmaceutical unit compositions comprising acotiamide and a proton pump inhibitor. Methods of preparing such compositions are also provided.

BACKGROUND OF THE INVENTION

Gastroesophageal reflux disease (GERD) is defined as the reflux of gastric contents into the esophagus causes symptoms severe enough to adversely affect quality of life. Functional dyspepsia (FD) is distinct from GERD is defined as conditions in which upper abdominal symptoms are present in the absence of any organic disease that may explain the symptoms. According to the Rome III criteria, the international diagnostic criteria, FD is defined as“a disease that started at least 6 months prior to diagnosis, showing at least one of the following symptoms for the last 3 months: bothersome postprandial fullness, early satiation, epigastric pain, epigastric burning; and there is no evidence of structural disease (including at upper endoscopy) that is likely to explain the symptoms.”

The cause of FD is not fully elucidated. The current assumption is that the symptoms are caused by the involvement of multiple factors including abnormal gastric emptying, gastric dysrhythmia, gastric hypersensitivity, hypersensitivity and motility disorder of the small intestine, impaired postprandial relaxation of the gastric fundus, vagus nerve disorder, enhanced acid sensitivity, psychological factors, and central nerve disorders. Acoti amide is a first-in-class drug that is used to treat functional dyspepsia (FD). Acotiamide is an acetylcholinesterase (AChE) inhibitor discovered by the Zeria Pharm. Acotiamide suppresses the degradation of acetylcholine (ACh) released from cholinergic nerve terminals by inhibiting AChE, thereby enhancing the ACh-induced contraction and motility of the gastric antmm and the gastric body. It is considered that acotiamide acts as an antagonist on muscarinic autoreceptors in the enteric nervous system and inhibits acetylcholinesterase activity.

US patent 5,981,557 discloses aminothiazole derivative, medicament containing the same, and intermediate for preparation of said compound. Also discloses method for the prevention and treatment of diseases caused by digestive dysmotility.

Acotiamide hydrochloride hydrate is approved in Japan as 100 mg oral tablet and marketed under brand name ACOFIDE® for the treatment of postprandial fullness, upper abdominal bloating, and early satiation due to functional dyspepsia. A favorable clinical course with acotiamide 100 mg three times daily was demonstrated with high symptom elimination rate for patients of FD.

The usual daily recommended adult dosage of ACOFIDE® is 300 mg, which is achieved by administering 100 mg tablet three times daily before a meal. It is given three times a day to maintain the plasma concentration. Frequent administration is a major drawback for acotiamide treatment. Currently there is no approved single 300 mg unit composition of acotiamide which could be administered once daily. Thus, there remains an unmet need for once daily single unit acotiamide composition which improves patient compliance and convenience on taking of 300 mg once instead of three times a day and maintain the plasma concentration as well.

Proton pump inhibitors (PPIs) are among the most widely prescribed and over-the-counter for heartburn, gastroesophageal reflux disease (GERD) and other upper gastrointestinal issues. Examples of proton pump inhibitors are include but not limited to lansoprazole, omeprazole, esomeprazole, rabeprazole, pantoprazole, leminoprazole, or an optically active isomer thereof, or a pharmaceutically acceptable salt thereof.

PPIs are often the first choice for treating FD. However, some patients need additional medication because of residual symptoms despite a certain level of benefit from the PPIs. For these patients, a combination of PPI and other agents has a possibly more beneficial effect than changing their medication. Currently, there is no approved combination dmg product available for aeotl amide and a proton pump inhibitor in a single composition. Thus, there remains an unmet need for once daily oral composition comprising combination of acotiamide and a PPI in a single composition, wherein the said composition may be effective for the management and treatment of FD, GERD, and other upper gastrointestinal issues or disorders.

IN 201721028736 disclosed direct compressible dual drug releasing pharmaceutical composition comprising extended release acotiamide and immediate release proton pump inhibitors. The microcapsule of acotiamide are compressed along with bare proton pump inhibitor to form a final tablet.

It is often difficult to prepare single unit composition of a suitable swallow able size when the composition is having relatively high amount of drug. Therefore a high drug load compositions are being preferred for such cases. However, compositions containing high dmg load are challenging to prepare, especially when they have a modified release profile. Therefore, there remains a need for improved pharmaceutical composition of acotiamide with improved patient compliance, reduced frequency of administration and should not to be too large to avoid swallowing difficulties.

Accordingly, the present invention provides once daily multi-particulate acotiamide compositions. The present inventors also surprisingly found that the modified release composition for once daily administration can also be combined with a delayed release proton pump inhibitor in the single unit composition. This represents a substantial improvement in patient compliance. Accordingly, the present invention also provides once daily pharmaceutical unit compositions comprising multi particulate compositions of acotiamide and a proton pump inhibitor combination.

OBJECT OF THE INVENTION

The present specification relates to multi-particulate pharmaceutical compositions of acotl amide.

In one aspect, the present specification relates to multi-particulate modified release compositions of acotl amide.

In another aspect, the present specification relates to multi-particulate sustained release and/or delayed release compositions of acotiamide.

In yet another aspect, the present specification relates to multi-particulate immediate release and sustained release and/or delayed release compositions of acotiamide.

In yet another aspect, the present specification relates to a pharmaceutical unit composition comprising: i) plurality of multi-particulate modified release compositions of acotiamide or pharmaceutically acceptable salts thereof, and one or more rate controlling polymers,

ii) optionally multi-particulate immediate release compositions of acotiamide or pharmaceutically acceptable salts thereof, wherein the said unit composition is administered once daily and the total dose of acotiamide or pharmaceutically acceptable salts thereof in the unit composition is 300 mg. In yet another aspect, the present specification relates to multi-particulate modified release compositions of acotiamide or pharmaceutically acceptable salts thereof, wherein acoti amide or pharmaceutically acceptable salts thereof is present in an amount of at least 45%, preferably at least 50%, more preferably at least 60% by weight of the total unit composition.

In yet another aspect the present specification relates to multi-particulate modified release compositions of acotiamide when subjected to in vitro changeover dissolution study exhibits following release profile: i) releases not more than 55% in 1 hour, in 900 ml of 0.0 IN HC1 medium at 100 rpm and 37°C using USP type I apparatus, and

ii) releases at least about 20% - 75% in 3 hours and not less than 50% in 9 hours, in 900 ml of pH 6.8 phosphate buffer medium saline with 0.5% Sodium laureth sulfate at 100 rpm and 37°C using USP type I apparatus.

In one aspect, the present specification relates to pharmaceutical unit composition comprising acotiamide and a proton pump inhibitor.

In another aspect, the present specification relates to once daily pharmaceutical unit composition comprising acotiamide and a proton pump inhibitor.

In one aspect, the present specification relates to a pharmaceutical unit composition comprising: i) plurality of multi-particulate immediate release and/or modified release compositions of acotiamide and one or more rate controlling polymer, and ii) delayed release compositions of a proton pump inhibitor.

In another aspect, the present specification relates to a pharmaceutical unit composition comprising: i) delayed release compositions of a proton pump inhibitor or pharmaceutically acceptable salts thereof,

ii) plurality of multi-particulate modified release compositions of acotiamide or pharmaceutically acceptable salts thereof and one or more rate controlling polymers,

iii) optionally multi-particulate immediate release compositions of acotiamide or pharmaceutically acceptable salts thereof,

wherein the said unit composition is administered once daily and the total dose of acotiamide or a pharmaceutically acceptable salts thereof in the unit composition is 300 mg.

In another aspect, the present specification relates to a pharmaceutical unit composition comprising: i) delayed release compositions of a proton pump inhibitor or a pharmaceutically acceptable salts thereof,

wherein the acotiamide or a pharmaceutically acceptable salts thereof is present in an amount of at least 50% by weight of the total multi-particulate acotiamide compositions.

In another aspect, the present specification relates to a capsule unit composition comprising: i) plurality of multi-particulate modified release compositions of acotiamide and one or more rate controlling polymer, and

ii) delayed release compositions of a proton pump inhibitor. In another aspect, the present specification relates to a capsule unit composition comprising: i) plurality of multi-particulate immediate release and sustained release and/or delayed release compositions of acotiamide, and

ii) delayed release compositions of a proton pump inhibitor.

In yet another aspect, the present specification relates to a capsule unit composition comprising: i) plurality of multi-particulate modified release compositions of acotiamide, wherein total dose of said compositions is 300 mg acotiamide and

ii) delayed release compositions of a proton pump inhibitor,

wherein the said capsule unit composition is administered once daily.

In another aspect, the present specification relates to a capsule unit composition comprising: i) delayed release compositions of a proton pump inhibitor or pharmaceutically acceptable salts thereof,

iii) optionally multi-particulate immediate release compositions of acotiamide or pharmaceutically acceptable salts,

wherein the unit composition when subjected to in vitro changeover dissolution study exhibits the following release profile of acotiamide or pharmaceutically acceptable salts thereof: i) releases not more than 55% in 1 hour, in 900 ml of 0.01N HC1 medium at 100 rpm and 37°C using USP type I apparatus, and

In another aspect, the present specification relates to a capsule unit composition comprising: i) one or more sustained release mini-tablets of acotiamide, wherein total dose of said combined mini-tablets is 300 mg acotiamide, and

ii) multi-particulate delayed release compositions of a proton pump inhibitor.

In another aspect, the present specification relates to a capsule unit composition comprising: i) four sustained release mini-tablets of acotiamide, wherein total dose of said combined mini-tablets is 300 mg acotiamide, and

ii) one delayed release mini-tablet of a proton pump inhibitor.

In another aspect, the present invention relates to a capsule unit composition comprising: i) one or more immediate release mini-tablets of acotiamide and one or more sustained release mini-tablets of acotiamide, wherein total dose of said combined mini-tablets is 300 mg acotiamide, and

ii) multi-particulate delayed release compositions of a proton pump inhibitor.

The present specification also relates to use of multi-particulate pharmaceutical compositions comprising acotiamide and a proton pump inhibitor for the treatment and/or management of functional dyspepsia, postprandial fullness in the functional dyspepsia, upper abdominal fullness, gastroesophageal reflux disease, and other upper gastrointestinal issues or disorders.

BRIEF DESCRIPTION OF FIGURES

Figure 1 : Dissolution profile of pharmaceutical unit compositions comprising multi particulate modified release Acotiamide HC1 hydrate at initial stage.

DESCRIPTION OF INVENTION

The present specification relates to multi-particulate pharmaceutical compositions of acotiamide.

In one aspect, the present specification relates to multi-particulate modified release compositions of acotiamide.

In yet another aspect, the present specification relates to a pharmaceutical unit composition comprising: i) plurality of multi-particulate modified release compositions of acotiamide or pharmaceutically acceptable salts thereof and one or more rate controlling polymers,

ii) optionally multi-particulate immediate release compositions of acotiamide or pharmaceutically acceptable salts thereof, wherein the said unit composition is administered once daily and the total dose of acotiamide or pharmaceutically acceptable salts thereof in the unit composition is 300 mg.

In yet another aspect, the present specification relates to multi-particulate modified release compositions of acotiamide or pharmaceutically acceptable salts thereof, wherein acoti amide or pharmaceutically acceptable salts thereof is present in an amount of at least 45%, preferably at least 50%, more preferably at least 60% by weight of the total unit composition.

In yet another aspect the present specification relates to multi-particulate modified release compositions of acotiamide when subjected to in vitro changeover dissolution study exhibits following release profile: ii) releases not more than 55% in 1 hour, in 900 ml of 0.0 IN HC1 medium at 100 rpm and 37°C using USP type I apparatus, and

In one aspect, the present specification relates to a pharmaceutical unit composition comprising: i) plurality of multi-particulate immediate release and/or modified release compositions of acotiamide and one or more rate controlling polymer, and ii) delayed release compositions of a proton pump inhibitor. In another aspect, the present specification relates to a pharmaceutical unit composition comprising: i) delayed release compositions of a proton pump inhibitor or pharmaceutically acceptable salts thereof,

wherein the said unit composition is administered once daily and the total dose of acotiamide or pharmaceutically acceptable salts thereof in the unit composition is 300 mg.

wherein the acotiamide or pharmaceutically acceptable salts thereof is present in an amount of at least 50% by weight of the total multi-particulate acotiamide compositions.

ii) delayed release compositions of a proton pump inhibitor.

In another aspect, the present specification relates to a capsule unit composition comprising: i) plurality of multi-particulate immediate release and sustained release and/or delayed release compositions of acotiamide, and

ii) delayed release compositions of a proton pump inhibitor.

ii) delayed release compositions of a proton pump inhibitor,

wherein the said capsule unit composition is administered once daily.

iii) optionally multi-particulate immediate release compositions of acotiamide or a pharmaceutically acceptable salts,

wherein the unit composition when subjected to in vitro changeover dissolution study exhibits the following release profile of acotiamide or pharmaceutically acceptable salts thereof: ii) releases not more than 55% in 1 hour, in 900 ml of 0.01N HC1 medium at 100 rpm and 37°C using USP type I apparatus, and

ii) multi-particulate delayed release compositions of a proton pump inhibitor.

ii) one delayed release mini-tablet of a proton pump inhibitor.

ii) multi-particulate delayed release compositions of a proton pump inhibitor.

The term“pharmaceutical composition” as used herein refers to oral dosage forms preferably in the form of tablets, capsules, sachets and the like. The dosage forms generally are prepared by using suitable pharmaceutically acceptable excipients. The unit composition refers to a single unit of such pharmaceutical compositions. The term“acotiamide” as used in the context of the present specification relates to the free base form, acid form, salt form, polymorphic crystalline or amorphous form, solvates, hydrates, ethers, esters, etc. Preferably acotiamide is present in the salt form, e.g. acotiamide hydrochloride or acotiamide hydrochloride hydrate. The therapeutic effective dose of acotiamide or pharmaceutically acceptable salts thereof is 50mg, lOOmg, 150mg, 200mg, 250mg, 300mg, 350mg and 400mg. A standard dose of 300 mg per day has been proven clinically effective for the treatment of functional dyspepsia.

The term“multi-particulate” or“multi-particulate compositions” can be, but not limited to mini-tablets, spheroids, pellets, granules, powders, microcapsules, multiple unit particles, and the like. Multi-particulate can be filled in but not limited to sachet, capsules and the like or can be further processed in the form of solid dosage forms. Solid dosage forms can be but not limited to tablets, bilayer tablets, inlay tablets, capsules and the like. The preferred“multi-particulate” compositions is mini -tablets or pellets. The term“mini-tablets” as used herein refers to small round or cylindrical tablets, typically 2 to 7 mm in diameter and are produced by tableting technology, typically rotary presses with minor modifications. The mini-tablets offer finished dosage form flexibility in that they can be delivered as capsules, sachets or compressed into larger tablets. The size/dimension of the mini-tablets are selected in such a way, that it can be accommodated in a capsule of a suitable size.

The term“immediate release” as used herein refers to immediate release of dmg from the compositions after administration. The“modified release” relates release of drug from the compositions wherein said release only occurs some times after the administration or for a prolonged period of time or to a specific target in the body. Modified release systems can be further classified as: delayed release, where dmg is released only at some point after the initial administration; extended release or sustained release :-prolongs the release at a controlled rate to reduce dosing frequency. These terms are also used by the pharmacopoeias and the FDA. Whilst immediate- release dosage forms are designed to give a fast onset of drug action, modifications in dmg release are often desirable to increase the stability, safety and efficacy of the dmg, to improve the therapeutic outcome of the drug treatment and/or to increase patient compliance and convenience of administration.

The term“once daily” as used herein refers to once in a day administration of the compositions to the subject in the need thereof. The once daily administration could be any time of the day before or after meal. The preferred mode of administration would be once a day before meal.

The term“proton pump inhibitors (PPIs)” as used herein refers to the compound that inhibits the gastric acid secretion by blocking the gastric H,K-ATPase (proton pump). Examples of proton pump inhibitors are include but not limited to lansoprazole, omeprazole, esomeprazole, rabeprazole, pantoprazole, leminoprazole, or an optically active isomer thereof, or a pharmaceutically acceptable salt thereof.

The term“changeover dissolution study” as used herein refers to the dissolution study which is performed by using USP Type I (Basket) apparatus with 100 RPM, and the dissolution methodology includes one acid stage followed by one buffer stage. Firstly in vitro dissolution was carried out in acid stage (900 ml of 0.0 IN HC1 solution, USP Type 1 apparatus at a speed of 100 rpm and 37°C) till 60 minutes, followed by buffer stage (900 ml of phosphate buffer solution having pH 6.8 with 05% sodium laureth sodium at a speed of 100 rpm and 37°C). Multi-particulate modified release acotiamide compositions of the present specification for once daily oral administration when subjected to a changeover dissolution study releases not more than 55% in lhour in acid stage, at least about 20% - 75% in 3 hours, and not less than 50% in 9 hours in buffer stage.

The term“pharmaceutically acceptable excipients” include, but not limited to, one or more of rate controlling polymers, diluents, disintegrants, binders, lubricants, glidants, acidifying agent, alkalizing agent, stabilizers, surfactants, sweetener, film coating materials, plasticizers, pigments, opacifiers, coloring agents and the like.

Suitable "rate controlling polymers" may include but not limited to one or more hydrophilic polymers, hydrophobic polymers, Natural polymers, bioadhesive polymer pH-dependent or pH-independent, enteric, degradable, non-degradable, enteric polymers, melt extmsion polymers and the like.

Suitable hydrophilic polymers may include one or more of cellulosic polymers/copolymers or its derivatives including, but not limited to methyl cellulose, hydroxypropyl methylcellulose (not limited to HPMC K4M, K-100, K-200), hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxyethyl methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose; polyacrylates, methyl acrylates, polyethylene oxides, polyethylene glycols, chitosan, gums, starch derivatives, polyurethanes, galactomannans, polysaccharides, polyalcohols, acrylic acid or acrylamide derivatives, and the like.

Suitable hydrophobic polymers include one or more of ethyl cellulose, glycerol palmitostearate, beeswax, glycowax, carnaubawax, hydrogenated vegetable oil, glycerol monostearate, stearylalcohol, glyceryl behenate, poly anhydrides, methyl acrylates and the like.

Natural polymers include but are not limited to proteins (e.g., hydrophilic proteins), such as pectin, zein, modified zein, casein, gelatin, gluten, semm albumin, or collagen, chitosan, oligosaccharides and polysaccharides such as cellulose, dextrans, tamarind seed polysaccharide, gellan, carrageenan, xanthan gum, gum Arabic; hyaluronic acid, polyhyaluronic acid, alginic acid, sodium alginate and the like.

Suitable bioadhesive polymers selected from but are not limited to polyamides, polycarbonates, polyalkylenes, polyalkylene glycols, polyalkylene oxides, polyalkylene terephthalates, polyvinyl alcohols, polyvinyl ethers, polyvinyl esters, polyvinyl halides, polyvinylpyrrolidone, polyglycolides, polysiloxanes, polyurethanes, polystyrene, polymers of acrylic and methacrylic esters, polylactides, poly(butyric acid), poly( valeric acid), poly(lactide-co-glycolide), poly anhydrides, polyorthoesters, poly(fumaric acid), poly(maleic acid), and blends and copolymers or mixtures thereof and the like.

Other rate controlling polymers suitable for use in the invention include, but are not limited to, cellulose acetate, cellulose propionate, cellulose acetate butyrate, cellulose acetate phthalate, carboxymethyl cellulose, cellulose triacetate, cellulose sulfate sodium salt, poly(methyl methacrylate), poly(ethyl methacrylate), poly(butyl methacrylate), poly(isobutyl methacrylate), poly(hexyl methacrylate), poly(isodecyl methacrylate), poly(lauryl methacrylate), poly(phenyl methacrylate), poly(methyl acrylate), poly(isopropyl acrylate), poly(isobutyl acrylate), poly(octadecyl acrylate) polyethylene, polypropylene, poly(ethylene glycol), poly(ethylene oxide), poly (ethylene terephthalate), polyvinyl acetate), polyvinyl chloride, polystyrene, polyvinyl pyrrol idone, polyvinylphenol, Polylactides, polyglycolides and copolymers thereof, poly(ethylene terephthalate), poly(butyric acid), poly(valeric acid), poly(lactide-co- caprolactone), poly[lactide-co- glycolide], polyanhydrides (e.g., poly(adipic anhydride)), polyorthoesters, blends and copolymers thereof and the like. Methacrylates can be but not limited to Eudragit® L; Eudragit® S; Eudragit® FS 30 D; Eudragit® L30D-55; and Eudragit® L100-55, Eudragit RL PO, Eudragit RL 100, Eudragit RL 30 D, Eudragit ® E, Eudragit ® NE and the like.

Suitable rate controlling polymer may include one or more enteric coatings are usually formulated with synthetic polymers that contain ionisable functional groups that render the polymer water soluble at a pH value.

All enteric polymers that remain intact at pH value lower than about 4.0 and dissolve at pH values higher than 4.0, preferably higher than 5.0, most preferably about 6.0, are considered useful as rate controlling agents for this composition. Suitable enteric polymers may include but not limited to one or more of Methyl acrylate -methacrylic acid copolymers, Cellulose acetate phthalate (CAP), Cellulose acetate succinate, Hydroxypropyl methyl cellulose phthalate, Hydroxypropyl methyl cellulose acetate succinate (hypromellose acetate succinate), Polyvinyl acetate phthalate (PVAP), Methyl methacrylate-methacrylic acid copolymers, Shellac, Cellulose acetate trimellitate, Sodium alginate, Zein, Hydroxyethyl ethyl cellulose phthalate, Cellulose acetate tetrahydrophtalate, Acrylic resin and the like.

Suitable melt extmsion polymers can be, but not limited to derivatised cellulose, poly(methacrylate) derivative, poly(ethylene-co-vinyl acetate), poly(ethylene), poly(vinyl acetate-co-methacrylic acid), epoxy resins and caprolactones, poly(ethylene oxide), poly(ethylene glycol) and others including various waxes, fats, lipid-based excipients, including the Gelucire®, Witepsol®, Labrafil® and the like.

In another aspect, the present invention relates to multi-particulate modified release composition of acoti amide and/or proton pump inhibitor one or more rate controlling polymers.

Suitable diluents, may be selected from, but not limited to the group consisting of different grades of starches, such as maize starch, potato starch, rice starch, wheat starch, pregelatinised starch, fully pregelatinised starch; cellulose derivatives, such as microcrystalline cellulose or silicified microcrystalline cellulose; sugar alcohols such as mannitol, erythritol, sorbitol, xylitol; monosaccharides like glucose; oligosaccharides like sucrose and lactose such as lactose monohydrate, lactose anhydrous, spray dried lactose or anhydrous lactose; calcium salts, such as calcium hydrogen phosphate; particularly preferably the fillers are selected from the group consisting of, microcrystalline cellulose, silicified microcrystalline cellulose, lactose monohydrate, spray dried lactose, and anhydrous lactose and the like. Suitable disintegrants may be selected from, but not limited to the group consisting of carmellose calcium, carboxymethylstarch sodium, croscarmellose sodium (cellulose carboxymethylether sodium salt, crosslinked), starch, modified starch such as pregelatinized starch, starch derivatives such as sodium starch glycolate, crosslinked polyvinylpyrrolidone (crospovidone), and low-substituted hydroxypropylcellulose, and disintegrating aids such as magnesium alumino- metasilicate and ion exchange resins like polacrilin potassium; particularly preferably the disintegrants are selected from the group consisting of sodium starch glycolate, croscarmellose sodium and crospovidone and the like.

Suitable binders may be selected from, but not limited to the group consisting of polyvinyl pyrrolidone (Povidone), polyvinyl alcohol, copolymers of vinylpyrrolidone with other vinyl derivatives (Copovidone), hydroxypropyl methylcellulose, methylcellulose, hydroxypropylcellulose, powdered acacia, gelatin, guar gum, carbomer such as carbopol, polymethacrylates and pregelatinized starch and the like.

Suitable lubricants may be selected from, but not limited to the group consisting of stearic acid, talc, glyceryl behenate, sodium stearyl fumarate and magnesium stearate; particularly preferably the lubricant is magnesium stearate and sodium stearyl fumarate and the like.

Suitable glidants, may be selected from, but not limited to the group consisting of colloidal silica, hydrophobic colloidal silica and magnesium trisilicate, such as talc and the like.

Composition may contain acidifying and alkalinizing agent. Acidifying agents can be selected from, but not limited to citric acid, succinic acid, fumaric acid, malic acid, maleic acid, glutaric acid, lactic acid and mixtures thereof and the like. Alkalizing agent can be selected from, but not limited to magnesium oxide, aluminium oxide, ammonium hydroxide, magaldrate, an alkali metal salt or alkaline earth metal salt, such as sodium bicarbonate, calcium carbonate or sodium citrate, an alkali metal hydroxide such as sodium hydroxide, potassium hydroxide or lithium hydroxide, or an alkaline earth metal hydroxide such as calcium hydroxide or magnesium hydroxide, with magnesium oxide or calcium carbonate and meglumine and the like.

Suitable surfactants as component can be selected from, but not limited to the group consisting of anionic surfactants, preferably sodium lauryl sulphate; polyethylene glycols (PEGs), preferably those PEGs having molecular weight in the range of about 2000 to 10000, more preferably PEG 3350, PEG 4000, PEG 6000, PEG 8000; Polysorbates, preferably Tween 20, Tween 80 or Span 80; fatty acid esters, preferably propylene glycol caprylates such as Capmul PG-8, Capryol 90; esters of glycerol and fatty acids, preferably glycerol oleates and caprylates (Capmul MCM); esters of polyethylene glycol and fatty acids, such as Labrasol and Solutol; castor oil ethoxylate (glycerol polyethylene glycol ricinoleate) such as Cremophor EL and Cremophor RH 40. More preferably the surfactant is selected from the group consisting of sodium lauryl sulphate; PEG 3350, PEG 4000, PEG 600 or, PEG 8000 and preferably PEG 6000; Tween 20 or Tween 80; and esters of polyethylene glycol and fatty acids, most preferably sodium lauryl sulphate and PEG 6000 and in particular sodium lauryl sulphate and the like.

Suitable sweeteners may be selected from, but not limited to the group consisting of aspartame, saccharin sodium, dipotassium glycyrrhizinate, aspartame, stevia, thaumatin, and the like.

Suitable film-forming agents and coating materials, if used, may include, but are not limited to hydroxypropyl methylcellulose (Hypromellose), hydroxypropyl cellulose, polyvinylalcohol, , methylcellulose, ethylcellulose, hydroxypropylmethyl cellulose phthalate, hydroxypropylmethyl cellulose acetate succinate, shellac, liquid glucose, hydroxyethyl cellulose, polyvinylpyrrolidone, copolymers of vinylpyrrolidone and vinylacetate such as Kollidon® VA64 BASF, copolymers of acrylic and/or methacrylic acid esters with trimethylammoniummethylacrylate, copolymers of dimethylaminomethacrylic acid and neutral methacrylic acid esters, polymers of methacrylic acid or methacrylic acid esters, copolymers of acrylic acid ethylester and methacrylic acid methyl ester, and copolymers of acrylic acid and acrylic acid methylester and the like.

Suitable plasticizers, if used, may include, but are not limited to polyethylene glycol, diethyl phthalate and glycerol. Preference is given to polyethylene glycol and the like.

In an aspect the multi-particulate composition of aeoti amide can be prepared by one or more of various methods, but not limited direct compression, wet granulation, dry granulation (roller compaction), solvent evaporation, hot melt granulation, hot melt extmsion, fluid bed granulation, spray drying, extrusion-spheronization and the like. Such processes are well known in the art.

In one aspect, the present specification relates to a pharmaceutical unit compositions comprising aeoti amide and a proton pump inhibitor.

In one aspect, the present specification relates to a pharmaceutical unit compositions comprising multi-particulate compositions of aeoti amide and a delayed release composition of a proton pump inhibitor.

In another aspect, the present invention relates to a capsule unit composition comprising: i) plurality of multi-particulate sustained release or delayed release compositions of acotiamide and one or more rate controlling polymers, and

ii) delayed release compositions of proton pump inhibitor. In an aspect, the present invention further relates to multi-particulate composition of acoti amide and proton pump inhibitors wherein proton pump inhibitors can be at least one selected from, but not limited to omeprazole, lansoprazole, dexlansoprazole, esomeprazole, pantoprazole, rabeprazole, ilaprazole and the like. The composition of the proton pump inhibitors are preferably in delayed release dosage forms. The delayed release dosage forms of proton pump inhibitors of the present specification releases minimal/ no release in the pH of stomach region. Such dosage form includes, are but not limited to tablets, mini-tablets, pellets, granules or other multi-particulates compositions.

In another aspect, the present invention further relates to a pharmaceutical unit composition comprising multi-particulate composition of acoti amide and a proton pump inhibitors wherein composition of acoti amide or proton pump inhibitors can be at least one or more of immediate release, sustained release or delayed release multi particulates. In order to achieve such release profile, the said compositions can be further coated with suitable film-forming agents and/or coating materials to form a subcoating or enteric coating. Such coating methods are well known in the art.

In an aspect, the present invention relates to a capsule unit composition comprising: i) four sustained release mini-tablets of acotiamide, wherein total dose of said combined mini-tablets is 300 mg acotiamide, and

ii) one delayed release mini-tablet of a proton pump inhibitor.

In another aspect, the present invention relates to a capsule unit composition comprising: i) four sustained release mini-tablets of acotiamide, wherein total dose of said combined mini-tablets is 300 mg acotiamide, and

ii) multi-particulate delayed release compositions of a proton pump inhibitor. In another aspect, the present invention relates to a capsule unit composition comprising: i) three sustained release mini-tablets of acotiamide, wherein total dose of said combined mini-tablets is 300 mg acotiamide, and

ii) multi-particulate delayed release compositions of a proton pump inhibitor.

In an aspect, the present invention relates to a capsule unit composition comprising: i) one or more immediate release mini-tablet of acotiamide and one or more sustained release mini-tablets of acotiamide, wherein total dose of said combined mini-tablets is 300 mg acotiamide, and

ii) one delayed release mini-tablet of a proton pump inhibitor.

In an aspect, the present invention relates to a bilayer or inlay tablet unit composition comprising: i) plurality of multi-particulate modified release compositions of acotiamide, and ii) delayed release compositions of proton pump inhibitor.

The multi-particulate compositions of acotiamide or pharmaceutically acceptable salt thereof are preferably in solid oral dosage forms, and having sustained/delayed profile and optionally immediate release profile. Examples of such multi-particulates compositions are being selected from one or more of mini-tablets, spheroids, pellets, granules, powders, microcapsules, multiple unit particles and mixtures thereof. The multi-particulate compositions of acotiamide of the present specification can be further formulated in to a suitable dosage forms like tablets, capsules, sachets and the like. The size/dimensions of the multi-particulate composition can be modified in such a way that it can be filled in the capsule of a suitable size. The multi-particulate modified release compositions of acoti amide further comprise one or more rate controlling polymers and one or more pharmaceutically acceptable excipients. The use of rate controlling polymer aids to achieve delayed/ sustained release profile. The modified release acoti amide compositions of the present specification are specifically designed to accommodate high dmg load and also to meet the recommended total daily dose of acoti amide or pharmaceutically acceptable salts thereof in a single unit dosage form along with the desired release profile. The term dmg load refers to amount of aeotiamide or its pharmaceutically acceptable salt thereof present in the formulation based on the total weight of the formulation. The modified release aeotiamide compositions of the present specification contains dmg load at least 45% (w/w), preferably more than 50% (w/w), preferably more than 60% (w/w).

The individual components of aeotiamide and proton pump inhibitor formulations of the present specification can be prepared by one or more of various methods, but not limited direct compression, wet granulation, dry granulation (roller compaction), solvent evaporation, hot melt granulation, hot melt extmsion, fluid bed granulation, spray drying, extmsion-spheronization and the like. Such processes are well known in the art.

The pharmaceutical unit composition comprising combination of aeotiamide and a proton pump inhibitor can be prepared by making the individual composition or components of aeotiamide or a proton pump inhibitor separately which can then be formulated in to a suitable dosage forms like tablets, capsules, sachets and the like. For example, the individual components can be filled in a capsule or a sachet. The size/dimensions of the multi-particulate composition can be modified in such a way that it can be filled in the capsule of a suitable size. Alternatively, the individual components can be further processed to form a bilayer tablet or inlay tablet. The pharmaceutical unit compositions of the present specification may be suitably packed in to any conventional pack like stick pack, blister pack, HDPE bottle or any other packaging well known in the art.

The pharmaceutical unit compositions comprising acotiamide or acotiamide and a proton pump inhibitor of the present specification can be used for the treatment and/or management of functional dyspepsia, postprandial fullness in the functional dyspepsia, upper abdominal fullness, gastroesophageal reflux disease, and other upper gastrointestinal issues or disorders.

The pharmaceutical unit compositions of the present specification is stable throughout the shelf life which can be established by subjecting the compositions to accelerated and long term stability studies.

The following examples will further describe certain specific aspects and embodiments of the invention in greater details and are not intended to limit the scope of invention.

EXAMPLES

Example 1: Multi -particulate pharmaceutical compositions of acotiamide.

Process:

1. Acoti amide along with other intra-granular excipients were granulated by using granulating fluid in a high shear granulator.

2. Granules obtained in step 1 were then dried, milled to a suitable sized.

3. The milled granules obtained in step 2 were lubricated with extra granular material and compressed in to mini -tablets.

4. Mini tablets obtained in step 3 were filled in capsule as per required therapeutic dose.

Example 2: Multi-particulate pharmaceutical compositions of proton pump inhibitor

Process:

1. Rabeprazole along with other intra-granular excipients were granulated by using granulating fluid in a high shear granulator.

2. Granules obtained in step 1 were then dried, milled to a suitable sized.

3. The milled granules obtained in step 2 were lubricated with extra-granular material and compressed in to tablets.

4. The tablets were subcoated and followed by enteric coated.

Example 3: Multi-particulate pharmaceutical compositions of proton pump inhibitor

Process: 1. Drug coating solution was prepared by dissolving dibasic sodium phosphate and Poysorbate 80 until it dissolved.

2. Then HPMC, Omeprazole Light magnesium carbonate, SLS, Mannitol were added in the drug coating solution and mixed well.

3. The mixture obtained in Step 2 was coated on sugar spheres in Fluidized Bed Processor.

4. The pellets obtained in step 3 were subcoated and followed by enteric coated.

Example 4: Multi-particulate pharmaceutical compositions of acotiamide and proton pump inhibitor

Some multi-particulate pharmaceutical combinations of acotiamide and a proton pump inhibitor as per the present specification are described below:

Process:

1. Multi-particulate pharmaceutical compositions of aeoti amide were prepared according to example 1.

2. Multi -particulate pharmaceutical compositions of a proton pump inhibitor were prepared according to example 2 or 3.

3. The compositions prepared in Step 1 & 2 were filled in a capsule.

Example 5 Stability Study:

The stability of the pharmaceutical unit composition comprising multi-particulate modified release compositions of aeoti amide as per the present specification was evaluated through accelerated stability studies. The composition prepared according to the formula and process of example If was subjected to stability study at 40 °C/75% RH. The compositions was found to be stable at accelerated conditions. Table 1 represents the study result data.

Table 1: Stability study of example If

Example 6

In-vitro dissolution study:

The release profile of the pharmaceutical unit composition comprising multi particulates modified release compositions of acotiamide as per the present specification was evaluated through in vitro dissolution studies. The unit composition was prepared according to the formula and process of example If, and was subjected to an in vitro dissolution study in a changeover dissolution medium at 100 rpm, 37°C by using USP type I apparatus. Table 2 represents the dissolution results data. Figure 1 represent the dissolution profile of acotiamide hydrochloride composition of example If at initial stage. The dissolution profile of the composition was also assessed after storage in accelerated stability condition (40 °C/75% RH) for 1 month and 3 months, the data is represented in table 2.

Table 2: Dissolution study of Example If

NMT - Not more than; NLT - Not less than

Example 7:

The release profile of the pharmaceutical unit composition comprising multi particulate modified release compositions of acotiamide and delayed release compositions of proton pump inhibitors as per the present specification was evaluated through in vitro dissolution studies. The unit composition was prepared according to the formula and process of example 4h, and was subjected to an in vitro dissolution study in a changeover dissolution medium at 100 rpm, 37°C by using USP type I apparatus. Table 3 represents the dissolution results data of acoti amide or pharmaceutically acceptable salts thereof in example 4h. Table 4 represents the dissolution results data of rabeprazole or pharmaceutically acceptable salts thereof.

Table 3: Dissolution study of acoti amide in example 4h

Table 4: Dissolution study of rabeprazole in example 4h

Claims

We Claim:

1. A pharmaceutical unit composition comprising:

i) plurality of multi-particulate modified release compositions of aeotiamide or pharmaceutically acceptable salts thereof and one or more rate controlling polymers,

ii) optionally multi-particulate immediate release compositions of aeotiamide or pharmaceutically acceptable salts thereof,

wherein the said unit composition is administered once daily.

2. The composition of claim 1, wherein the total dose of aeotiamide or pharmaceutically acceptable salts thereof in the unit composition is about 300 mg.

3. The composition of claim 1 , wherein aeotiamide or pharmaceutically acceptable salts thereof is present in an amount of at least 50% by weight of the total unit composition.

4. The composition of claim 1, wherein the unit composition is selected from capsule, tablet and sachet.

5. The composition of claim 1, wherein the unit composition is capsule.

6. The composition of claim 1, wherein the multi-particulate compositions of aeotiamide or pharmaceutically acceptable salts thereof are selected from one or more of mini-tablets, spheroids, pellets, granules, powders, microcapsules, multiple unit particles and mixtures thereof.

7. The composition of claim 1 , when subjected to in vitro changeover dissolution study exhibits following release profile:

i) releases not more than 55% in 1 hour, in 900 ml of 0.0 IN HC1 medium at 100 rpm and 37°C using USP type I apparatus, and

8. A pharmaceutical unit composition comprising:

i) delayed release compositions of a proton pump inhibitor or pharmaceutically acceptable salts thereof,

ii) plurality of multi-particulate modified release compositions of aeotiamide or pharmaceutically acceptable salts thereof and one or more rate controlling polymers,

iii) optionally multi-particulate immediate release compositions of aeotiamide or a pharmaceutically acceptable salts thereof,

wherein the said unit composition is administered once daily.

9. The composition of claim 8, wherein the proton pump inhibitor is selected from rabeprazole, omeprazole, esomeprazole, ilaprazole, lansoprazole, pantoprazole, leminoprazole or an optically active isomer thereof, or pharmaceutically acceptable salts thereof.

10. The composition of claim 8, wherein the proton pump inhibitor is selected from rabeprazole, omeprazole or an optically active isomer thereof, or pharmaceutically acceptable salts thereof.

11. The composition of claim 8, wherein the delayed release compositions of a proton pump inhibitor are selected from one or more of tablet, mini-tablets or pellets or granules.

12. The composition of claim 8, wherein the total dose of aeotiamide or pharmaceutically acceptable salts thereof in the unit composition is 300 mg.

13. The composition of claim 8, wherein the aeotiamide or pharmaceutically acceptable salts thereof is present in an amount of at least 50% by weight of the total multi particulate aeotiamide compositions.

14. The composition of claim 8, wherein the modified release compositions of aeotiamide are selected from sustained release, delayed release or mixtures thereof.

15. The composition as claimed in claim 8, wherein the multi -particulate compositions of acoti amide are selected from one or more of mini-tablets, spheroids, pellets, granules, powders, microcapsules, multiple unit particles and mixtures thereof.

16. The composition of claim 8, wherein the said acoti amide and proton pump inhibitor compositions are physically separated.

17. The composition of claim 8, wherein the unit composition is selected from capsule, tablet and sachet.

18. The composition of claim 8, wherein the unit composition is capsule.

19. The use of composition as claimed in claim 8, for the treatment and/or management of functional dyspepsia, postprandial fullness in the functional dyspepsia, upper abdominal fullness, gastroesophageal reflux disease, and other upper gastrointestinal issues or disorders.

20. A pharmaceutical unit composition of proton pump inhibitor and acoti amide or a pharmaceutically acceptable salts thereof, wherein the composition is prepared by the steps comprising:

i) preparing a delayed release compositions of a proton pump inhibitor, ii) preparing one more modified release mini-tablet compositions of acoti amide and optionally preparing immediate release mini-tablet compositions of acotiamide,

iii) filling the compositions of step (i) and step (ii) in a capsule.