Claims:We claim:
1. A pharmaceutical composition comprising a gastro-retentive dosage form of lurasidone.
2. The pharmaceutical composition according to claim 1, wherein the dosage form comprises lurasidone and a pharmaceutically acceptable excipient which helps for gastro-retention of the dosage form in stomach.
3. The pharmaceutical composition according to claim 1, wherein the dosage form gastric retention period is greater than 4 hours or greater than 6-8 hours, up to 12 hours, 16 hours or 24 hours.
4. The pharmaceutical composition according to claim 1, wherein the dosage form is prepared by using mechanisms like co-administration of drug or pharmaceutical excipients influencing gastric motility pattern and thereby delaying gastric emptying process, magnetic systems, mucoadhesive systems, size-increasing systems due to swelling or unfolding, density-controlled systems that either float on gastric contents or sediment, and combination systems.
5. The pharmaceutical composition according to claim 1, wherein the dosage form is used for treatment of schizophrenia, positive and negative symptoms of schizophrenia, major depressive episodes associated with bipolar I disorder, memory or learning dysfunctions caused by schizophrenia, senile dementia, attention deficit hyperactivity disorder, central nervous system disorder responsive to modulation of glutamate levels and other associated CNS disorders.
6. The pharmaceutical composition according to claim 1, wherein the dosage form is bioequivalent to the IR formulation.
7. The pharmaceutical composition according to claim 1, wherein the mean plasma concentration of the lurasidone after single dose administration exhibits a pharmacokinetic profile which is superior to that attainable by a product that is not a gastroretentive.
8. The pharmaceutical composition according to claim 1, wherein the dosage form comprises lurasidone in the range of about 1 mg to about 200 mg, preferably about 5mg- 160mg or more preferably 20-40mg.
9. The pharmaceutical composition according to claim 1, wherein the dosage form provides the mean AUC of plasma lurasidone is about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50% or more than about 50% greater than the mean AUC of plasma lurasidone provided by administration of the IR dosage form to the subject.
10. The pharmaceutical composition according to claim 1, wherein the dosage form provides Tmax about 2 hours (h) to 5 h, about 3 h to 5 h, about 4 h to 5 h, about 2 h to 6 h, about 3 h to 6 h, about 3 h to 5 h, about 3 h to 4 h, or about 4 h to 6 h. , Description:Lurasidone Pharmaceutical Compositions

FIELD OF THE INVENTION
The present invention relates to stabilized gastroretentive dosage form comprising lurasidone, processes for the preparation of such compositions and use thereof for treatment of schizophrenia, bipolar disorders or senile dementia.

BACKGROUND OF THE INVENTION
Lurasidone is a psychotropic agent belonging to the chemical class of benzoisothiazol derivatives. It is a dopaminergic (D2) and serotonin (5-HT2A) receptor antagonist and is disclosed in US5532372. Chemically, it is (3aR,4S,7R,7aS)-2-{(1R,2R)-2-[4-(1,2-benzisothiazol-3-yl)piperazin-1-ylmethyl] cyclohexylmethyl}hexahydro-4,7-methano -2H-isoindole-1,3-dione hydrochloride. It

A free form of lurasidone and an acid addition salt thereof are known to have psychotropic activities and are effective as therapeutic agents, particularly for schizophrenia or senile dementia, etc. Senile dementia is broadly classified into Alzheimer's dementia and cerebrovascular dementia, and it can be said that the two make up about 80% of senile dementia.

Lurasidone hydrochloride is marketed in various markets as immediate release tablet by Dainippon Sumitomo Pharma under the trade name Latuda®. Latuda® tablet contains 20 mg, 40 mg, 60 mg, 80 mg, or 120 mg of lurasidone hydrochloride.

Lurasidone hydrochloride has very low aqueous solubility (water: 0.224 mg/mL) and the bioavailability is estimated to be about 9% to 19%, therefore Lurasidone hydrochloride is expected to be BCS class II API. b) Various patents and patent applications like US7727553, US8729085, US9433620B2, WO2012123858 and WO2016012898 disclose various pharmaceutical preparations for oral administration intended to increase the solubility of lurasidone and release the drug faster.

Further, lurasidone must be taken with food (350 calories) which can be a difficult considering patient’s willingness to do so every day. Food increases pH of stomach upto 3.5 which may help to increase solubility and also residence time of drug in that pH (3.5) to increase bio-availability of the drug. It also lacks dose – response linearity. Cmax and AUC of the 20, 40, 80, 120 and 160 mg shows that 20 and 40 mg have similar kinetics and 80, 120 and 160 mg shows similar kinetics values. Further, there is an increase in side effects at doses above 80 mg but no significant increase in clinical efficacy.

Lurasidone is not uniformly absorbed throughout the gastrointestinal tract, and is predominantly absorbed from the stomach and the upper part of the intestine. In such instances, it is beneficial to develop gastroretentive dosage forms that are retained in the upper parts of the gastrointestinal tract for prolonged periods of time.

The objective of the present invention is to develop a gastroretentive dosage form of lurasidone that not only extends the release of lurasidone but also retains lurasidone in the upper parts of the gastrointestinal tract for a long period of time to overcome its decreased colonic absorption.

SUMMARY OF THE INVENTION
The present invention provides a pharmaceutical composition containing lurasidone as gastroretentive dosage form. When administered, the pharmaceutical composition is retained in the stomach for a longer period of time than an IR dosage form. While it is retained in the stomach, the pharmaceutical composition continuously releases lurasidone. Eventually, the pharmaceutical composition passes out of the stomach and into the small intestine where it may continue to release Lurasidone. Extending the period of time during which Lurasidone is released in the stomach effectively widens the absorption window associated with IR dosing, thereby increasing bioavailability.

Another aspect of the present invention provides a method of making a gastro-retentive dosage form of lurasidone, wherein gastro retention is achieved by various mechanisms like co-administration of drug or pharmaceutical excipients influencing gastric motility pattern and thereby delaying gastric emptying process, magnetic systems, mucoadhesive systems, size-increasing systems due to swelling or unfolding, density-controlled systems that either float on gastric contents or sediment, and combination systems.

An additional aspect of the invention provides a method of treating a condition or disorder in a subject that is responsive to lurasidone. The method includes orally administering to the subject once per day the pharmaceutical composition described above.

Another aspect of the invention provides a method of treating a condition or disorder in a subject that is responsive to Lurasidone, the method comprising orally administering to the subject a pharmaceutical composition once daily. The pharmaceutical composition comprises Lurasidone and one or more excipients.

DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to a gastroretentive dosage form comprising lurasidone and methods of manufacturing and usage. Suitable gastroretentive pharmaceutical compositions may be, for instance, floating pharmaceutical compositions, heavy pharmaceutical compositions, bioadhesive pharmaceutical compositions, expandable pharmaceutical compositions, pharmaceutical compositions which retain in the stomach due to their specific form and cannot pass through the pylorus into the duodenum and the like.

An aspect of the present invention provides a gastroretentive dosage form of lurasidone by various mechanisms like co-administration of drug or pharmaceutical excipients influencing gastric motility pattern and thereby delaying gastric emptying process, magnetic systems, mucoadhesive systems, size-increasing systems due to swelling or unfolding, density-controlled systems that either float on gastric contents or sediment, and combination systems.

The term “lurasidone,” as used herein, includes lurasidone and salts, polymorphs, hydrates, solvates, prodrugs, chelates, and complexes thereof.

The term “gastroretentive dosage form,” as used herein, refers to a dosage form which is capable of staying in the stomach for a prolonged period of time, and therefore is capable of releasing lurasidone in the stomach for a time period longer than when delivered as a conventional dosage form.

An aspect of the present invention provides a gastroretentive dosage form comprising lurasidone wherein the dosage form has a size or will expand in the stomach to a size that is too large to pass the pyloric sphincter.

An aspect of the present invention provides a gastroretentive dosage form comprising lurasidone and a hydrophilic swellable floating matrix system either alone or in combination with a bioadhesive system.

An aspect of the present invention provides a gastroretentive dosage form comprising lurasidone, one or more swellable polymers, optionally a pH modifier, and other pharmaceutically acceptable excipients.

An aspect of the present invention provides a gastroretentive dosage form comprising lurasidone by buoyant (floating) systems, wherein the systems have a density lower than that of the gastric fluids so that they remain floating in the stomach.

An aspect of the present invention provides a gastroretentive dosage form comprising lurasidone by hydrodynamically balanced systems (HBS), wherein buoyant materials are incorporate into the system enable the dosage form to float;

An aspect of the present invention provides a gastroretentive dosage form comprising lurasidone by effervescent systems, wherein gas-generating materials such as carbonates are incorporated in the dosage form. These materials react with gastric acid and produce carbon dioxide (gas), which allows the dosage form to float.

An aspect of the present invention provides a gastroretentive dosage form comprising lurasidone by raft systems, wherein gels such as alginate or HPMC gels are incorporated into the dosage form. These have a carbonate component and upon reaction with gastric acid, bubbles form in the gel, enabling floating.

An aspect of the present invention provides a gastroretentive dosage form comprising lurasidone floating drug delivery system (FDDS), wherein said FDDS comprising a particle having a hollow, gas-filled core bordered by a wall of at least one aqueous soluble, erodible, disintegrating or degradable polymer, said wall being surrounded by a coating comprising at least one active ingredient, wherein said coating comprises a polymer that swells upon contact with water.

An aspect of the present invention provides a gastroretentive dosage form comprising lurasidone by bioadhesive or mucoadhesive systems, wherein a bio/mucoadhesive agent is incorporate into the dosage enabling the device to adhere to the stomach (or other GI) walls, thus resisting gastric emptying.

The term “swellable polymers,” as used herein, refers to polymers that swell in the presence of gastric fluids. This swelling increases the size of the tablet to such an extent so as to provide retention of the tablet in the stomach of a patient. The swellable polymers that may be used in the present invention are selected from the group comprising cellulosic polymers, polyalkylene oxides, polysaccharides, acrylic acid polymers, vinyl pyrrolidone polymer, and combinations thereof Cellulosic polymers include methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, ethyl cellulose, sodium carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, and combinations thereof. Polyalkylene oxides include polyethylene oxide, such as that available under the trade name Polyox®. Polysaccharides include starch and starch-based polymers, chitosan, agar, alginates, carrageenan, furcellaran, guar gum, gum arabic, gum tragacanth, karaya gum, locust bean gum, pectin, dextran, gellan gum, rhamsan gum, welan gum, xanthan gum, propylene glycol alginate, hydroxypropyl guar, and combinations thereof. Vinyl pyrrolidone polymers include cross-linked polyvinylpyrrolidone and crospovidone.

According to one embodiment of the above aspect, the swellable polymers are selected from the group comprising cellulosic polymers, polyalkylene oxides, polysaccharides, acrylic acid polymers, vinyl pyrrolidone polymers, and combinations thereof.

According to another embodiment of the above aspect, the pH modifier is selected from the group comprising magnesium oxide, sodium acetate, trisodium citrate, meglumine, trisodium orthophosphate, sodium bicarbonate, sodium hydroxide, and combinations thereof.

The phrase "bioadhesive system" as used herein is designed to retain the drug and/or dosage form in the specific part of the body in order to provide the prolonged effect. Bioadhesive polymers have strong affinity with gastric mucosa and hence provide prolonged gastro retention, which favors for drug absorption.

Moreover, in-situ gelling agents in the formulation offer not only rigidity to the matrix, which prevents dose dumping, but also provides controlled mode of drug release in addition to hydrophilic gelling polymer. In general, in-situ gelation takes place by one or more combinations of mechanism such as thermal gelation, ionic gelation, pH induced gelation. The present invention involves the in-situ gelling agent selected from the categories of pH induced gelation and/or ionic gelation.

In-situ gelling agents are selected from a group consisting of gellan gum, sodium alginate, locust bean gum and other natural gums, cellulose esters, modified cellulose esters, acrylate, methacrylates copolymers, and co-block polymers of acrylates and acrylic acid derivatives preferably gellan gum and sodium alginate, ranging from 0.5% to 25% w/w of the total formulation.

Ionic agents are used to induce the gelation by exchange of ions preferably cations with the in-situ gelling agents. The ionic agents are selected from a group consisting of calcium chloride, calcium sulfate, calcium carbonate, calcium stearate, magnesium chloride, magnesium sulfate, magnesium carbonate, magnesium stearate, zinc chloride and zinc carbonate preferably calcium carbonate, calcium chloride and calcium stearate.

The gas generating agent used in the core of the gastric retention controlled drug delivery system of the present invention may include a single component that generates gas upon contact with the gastric fluid, or may include a gas generating couple. Gas generating components that may be used in the present invention include carbonates such as calcium carbonate, bicarbonates such as sodium or potassium bicarbonate, sulfites such as sodium sulfite, sodium bisulfite, or sodium metabisulfite, and the like. These salts may be used alone or in combination with an acid source as a gas generating couple. The acid source may be an edible organic acid, a salt of an edible organic acid, or mixtures thereof. Examples of organic acids that may be used include citric acid, malic acid, succinic acid, tartaric acid, fumaric acid, maleic acid, ascorbic acid, glutamic acid, and their salts, and mixtures thereof. The gas generating agent is used in an amount ranging from about 1% to about 50% by weight of the core, more preferably from about 1% to about 15% by weight of the core. Sodium bicarbonate is used as the preferred gas generating agent.

According to another embodiment of the above aspect, the pharmaceutically acceptable excipients are selected from the group comprising diluents, binders, disintegrants, lubricants/glidants, and combinations thereof.

In another embodiment, the gastric retained dosage form of lurasidone is a floating dosage form. Floatation of drug delivery systems as a gastroretentive mechanism has been widely used. These systems, also known as hydro-dynamically balanced, are buoyant on the gastric fluid and delay their emptying through the pyloric sphincter by swelling and expanding. Several approaches are currently used to prolong gastric retention time. These include floating drug delivery systems, also known as hydrodynamically balanced systems, swelling and expanding systems, polymeric bioadhesive systems, modified-shape systems, high-density systems, and other delayed gastric emptying systems. In another embodiment, a gastroretentive drug delivery system of lurasidone using the principles of buoyant preparation, wherein guar gum, xanthan gum, and hydroxypropyl methylcellulose are used in the dosage form for gel-forming properties, sodium bicarbonate is used as a gas-generating agent, citric acid or stearic acid is used. Another embodiment, a floating drug delivery system containing lurasidone, wherein the dosage form is prepared as a bilayer tablet comprising a drug-loading layer and a floating layer in a suitable ratio to provide a bulk density lower than that of gastric fluids to remain buoyant on the stomach contents. Buoyancy is a result of a reduction in matrix density. Floatable delivery systems have been designed as single and multiple-unit devices.

In one embodiment, a dosage form is formulated to have a dual-matrix configuration (“shell-and-core”) as described in US publication US 2003/0104062 (herein incorporated by reference). One matrix forms a core of polymeric material in which the lurasidone is dispersed and the other matrix forms a casing that surrounds and fully encases the core, the casing being of polymeric material that swells upon imbibition of water (and hence gastric fluid) to a size large enough to promote retention in the stomach during the fed mode, the shell and core being configured such that the drug contained in the core is released from the dosage form by diffusion through the shell. The shell is sufficient thickness and strength that it is not disrupted by the swelling and remains intact during substantially the entire period of drug release. The shell may or may not contain the lurasidone.

In another embodiment, the oral dosage form may be comprised of: 1) a plurality of immediate release, enteric coated beads containing lurasidone, dispersed in a hydrophilic polymer that swells unrestrained dimensionally in water; 2) a series of inserts, each containing a plurality of immediate release beads containing the lurasidone, and each comprised of a swellable hydrophilic polymeric matrix, wherein the inserts are stacked to provide pulses of lurasidone over an extended period of time; and 3) a swellable hydrophilic matrix comprised of two or more regions, each region containing a dose of lurasidone, wherein the regions vary in size and position within the matrix to effect pulsed release of the lurasidone over an extended period of time.

In another embodiment, a gastric-retentive dosage form of lurasidone is formulated as osmotic dosage forms such as an elementary osmotic dosage form or a push-pull osmotic pump.

In another embodiment, osmotic dosage forms comprising a drug compartment containing lurasidone and a pharmaceutically acceptable polymer hydrogel (maltodextrin, polyalkylene oxide, polyethylene oxide, carboxyalkylcellulose), contained within a bilayer interior wall and exterior wall and having a passageway, where the polymer exhibits an osmotic pressure gradient across the bilayer interior wall and exterior wall thereby imbibing fluid into the drug compartment to form a solution or a suspension comprising the drug that is hydrodynamically and osmotically delivered through a passageway from the dosage form. In certain embodiments, the dosage form further comprises a push displacement layer which expands to expel the drug from the dosage form. The interior wall of these dosage forms comprises a pore former which provides for increased permeability of the dosage form to water to compensate for the decrease in osmotic driving force that occurs as the osmagent and/or drug dissolves and is released from the dosage form. The dosage form exhibits a slow drug delivery until the osmotically-sensitive pore former dissolves or leaches from the inner wall. The eluted pore former caused the permeability of the inner wall to increase, which correspondingly caused the net permeability of the bilaminated inner wall-outer wall to increase over time.

In another embodiment, lurasidone is released from the dosage form by generating gas, which means for generating gas is surrounded by, for example, a semipermeable membrane. In operation, when the gas generating means imbibes water and/or aqueous biological fluids, the means for generating gas reacts and generates gas, thereby enlarging and expanding the at least one means for forcibly dispensing the lurasidone unidirectionally or multidirectionally. The means for generating a gas includes any compound or compounds, which can produce effervescence, such as for example, at least one solid acid compound and at least one solid basic compound, which in the presence of a fluid can react to form a gas, such as for example, carbon dioxide. Examples of acid compounds include organic acids such as malic, fumaric, tartaric, itaconic, maleic, citric, adipic, succinic and mesaconic, and inorganic acids such as sulfamic or phosphoric, also acid salts such as monosodium citrate, potassium acid tartrate and potassium bitartrate. The basic compounds include, for example, metal carbonates and bicarbonates salts, such as alkali metal carbonates and bicarbonates. The acid and base materials can be used in any convenient proportion from about 1 to about 200 parts of the at least one acid compound to the at least one basic compound or from about 1 to about 200 parts of the at least one basic compound to the at least one acid compound. The means for generating gas is known.

In another embodiment, a gastro-retentive dosage form of lurasidone is a capsule dosage form that allows for the extended release of lurasidone in the stomach and comprises: (a) at least one component that expands on contact with gastric juice and contains an agent capable of releasing carbon dioxide or nitrogen, lurasidone; (b) at least one hydrophilic membrane in the form of a sachet which contains component (a), expands by inflation, floats on the aqueous phase in the stomach and is permeable to gastric juice and; (c) capsule dosage form which contains components (a) and (b) and which disintegrates without delay in the stomach under the action of gastric juice. Component (a) may also contain a pharmaceutically acceptable hydrophilic swelling agent such as lower alkyl ethers of cellulose, starches, water-soluble aliphatic or cyclic poly-N-vinylamides, polyvinyl alcohols, polyacrylates, polymethacrylates, polyethylene glycols and mixtures thereof, as well as other materials used in the manufacture of pharmaceutical dosage forms.

In another embodiment, a gastro-retentive dosage form of lurasidone is mucoadhesive dosage form which remains in the patient's stomach following oral administration, which is substantially longer than the average residence time of a corresponding immediate release dosage form. In this embodiment, the mucoadhesive dosage form comprising lurasidone with at least mucoadhesive excipient, wherein the mucoadhesive dosage form maintains gastric retention for the time period during which the drug is released into the stomach. The mucoadhesive excipient of the present invention includes polyethylene glycol (PEG 8000), Tragacanth, polymethacrylate derivatives (Eudragit), polyethylene oxide (PEO) or combinations or copolymers thereof. The mucoadhesive excipient is generally used in an amount ranging from about 5% to about 20% by weight of the tablet composition.

A bioadhesive or mucoadhesive excipient is a natural or synthetic polymer capable of adhering to a biological membrane (bioadhesive polymer) or the mucous lining of the gastrointestinal tract (mucoadhesive polymer). Polycarbophil (polyacrylic acid cross-linked with divinylglycol) is a suitable polymer for encouraging adhesion of orally administered dosage forms to the gastric mucosa, thereby prolonging residence time for a system designed to slowly deliver drug to absorptive sites in the upper part of the gastrointestinal tract. Other suitable bioadhesive polymers which may be used in the present invention include chitosan, dextran sodium, poly-L-aspartic acid, polystyrene sulfonic acid, polyvinyl sulfate, polyglutamic acid, bovine serum albumin, ficoll, acidic (high isoelectric point) gelatin, polybrene, polyvinyl methyl imidazole, polygalactosamine, proteins (polyaminoacids) such as polylysine, polyomithine, polyquaternary compounds, prolamine, polyimine, diethylaminoethyldextran (DEAE), DEAE-imine, polyvinylpyridine, polyethylene pyrrolidone, polythiodiethyl aminomethylethylene (PTDAE), polyhistidine, DEAE-methacrylate, DEAE-acrylamide, poly-p- aminostyrene, polyoxethane, copolymethacrylates (e.g., copolymers of HPMA, N- (2-hydroxypropyl)-methacrylamide), Eudragit™ RL, Eudragit™ RS, polyamidoamines, cationic starches, DEAE-dextran and DEAE-cellulose. Chitosan can be employed as a chitosan salt (e.g., the glutamate, lactate, chloride or acetate salts) or as a chitosan derivative such as N-trimethyl chitosan chloride.

In another embodiment, a gastro-retention of the dosage form of lurasidone is achieved by providing a high density to the composition. High-density systems have a density greater than 1 g/mL, such as about 2-3 g/mL, are retained in the rugae of the stomach, and are capable of withstanding its peristaltic movements. Above a threshold density of about 2.4-2.8 g/mL, such systems can be retained in the lower part of the stomach. The components that can be used to manufacture high-density formulations according to the present invention include diluents such as barium sulphate, zinc oxide and titanium dioxide.

According to another embodiment of the above aspect, the dosage form is tablet, capsule, pellets, granules, suspension or a mixture thereof. The gastric retentive dosage form may be a single layer, bilayer, or multilayer tablet or it may be a capsule. Multilayer tablets include tablets having a shell-and-core configuration in which a core is fully encased by a shell. Tablets may also have a coating with or without the pharmaceutically active agent. The tablet comprises a gastric retentive layer which comprises lurasidone dispersed in a matrix comprised of at least one hydrophilic polymer which swells upon imbibition of fluid.

According to another embodiment of the above aspect, the tablets are prepared by the processes of direct compression, dry granulation, or wet granulation.

The tablets of the present invention comprise other pharmaceutically acceptable excipients that are routinely used and are selected from the group comprising diluents, binders, disintegrants, lubricants/glidants, and combinations thereof.

Suitable diluents are selected from the group comprising microcrystalline cellulose; silicified microcrystalline cellulose; lactose; glucose; natural, modified, or pregelatinized starch; mannitol; sorbitol; and combinations thereof.

Suitable binders are selected from the group comprising povidone, methyl cellulose, ethyl cellulose, low-substituted hydroxypropyl cellulose, hydroxypropyl methyl cellulose, acacia, guar gum, alginic acid, dextrin, maltodextrin, polyvinyl alcohol, gelatin, starch, and combinations thereof.

Suitable disintegrants are selected from the group comprising sodium carboxymethyl cellulose; low-substituted hydroxypropyl cellulose; carboxymethyl cellulose; calcium carboxymethyl cellulose; cross-linked polyvinyl pyrrolidone; microcrystalline cellulose; natural, modified, or pregelatinized starch; gums; and combinations thereof.

Suitable lubricants/glidants are selected from the group comprising colloidal silicon dioxide, talc, stearic acid, magnesium stearate, zinc stearate, calcium stearate, sodium stearyl fumarate, hydrogenated castor oil, and combinations thereof.

The tablets described herein may be prepared by conventional processes using commonly available equipment. The process may comprise direct compression, wet granulation, or dry granulation.
The tablets of the present invention may be further coated with one or more non-functional coatings. The coating may comprise one or more film-forming polymers and coating additives.

Examples of film-forming polymers include ethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, methylcellulose, carboxymethyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, cellulose acetate, hydroxypropyl methyl cellulose phthalate, cellulose acetate phthalate, cellulose acetate trimellitate, waxes, and methacrylic acid polymers such as Eudragit®. Alternatively, commercially available coating compositions comprising film-forming polymers marketed under various trade names, such as Opadry®, may also be used.

Coating additives may be selected from the group comprising binders, plasticizers, opacifiers, coloring agents, and lubricants.

Examples of plasticizers include acetylated triacetin, triethyl citrate, tributyl citrate, glycerol tributyrate, diacetylated monoglyceride, polyethylene glycols, propylene glycol, sesame oil, acetyl tributyl citrate, acetyl triethyl citrate, diethyl oxalate, diethyl phthalate, diethyl maleate, diethyl fumarate, dibutyl succinate, diethyl malonate, dioctyl phthalate, dibutyl sebacate, and combinations thereof.

Examples of opacifiers include titanium dioxide, talc, calcium carbonate, behenic acid, cetyl alcohol, and combinations thereof. Coloring agents include any FDA approved color for oral use.

Specific examples of solvents for granulation or coating include water, acetone, ethanol, methanol, isopropyl alcohol, methylene chloride, and combinations thereof.

These additional excipients are selected based on function and compatibility with the lurasidone gastro-retentive dosage described herein and may be found, for example in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, (Easton, Pa.: Mack Publishing Co 1975); Liberman, H. A. and Lachman, L., Eds., Pharmaceutical Dosage Forms (New York, N.Y.: Marcel Decker 1980); and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed (Lippincott Williams & Wilkins 1999), herein incorporated by reference in their entirety.

Coating may be performed by applying the coating composition as a solution, suspension, or blend using any conventional coating technique known in the art such as spray coating in a conventional coating pan or fluidized bed processor, dip coating, or compression coating

The tablets may be dispensed in packs made with usual packaging materials like high-density polyethylene (HDPE) bottles or blister packs. The package may additionally contain a desiccant.

Another aspect of the invention provides gastroretentive dosage form of lurasidone comprising of
a. a controlled release core comprising a lurasidone, a highly swellable polymer and a gas generating agent, said core being capable of swelling and achieving flotation rapidly while maintaining its physical integrity in gastrointestinal fluids for prolonged periods, and
b. a rapidly releasing coat composition comprising the same drug as in the core and pharmaceutically acceptable excipients, wherein the coating composition surrounds the core such that the system provides a biphasic release of the drug in gastrointestinal fluids.

Another aspect of the invention provides gastroretentive dosage form of lurasidone comprising of a hydrophilic swellable floating matrix system either alone or in combination with a bioadhesive system comprising:
a) lurasidone in an amount of 10% to 98% w/w;
b) hydrophilic polymers in an amount of 0.1% to 30% w/w;
c) in-situ gelling agents in an amount of 0.5% to 25% w/w and
d) superdisintegrants in an amount of 0.1% to 20% w/w of the total formulation.

Another aspect of the invention provides gastroretentive dosage form of lurasidone, wherein the dosage form comprises a sheet of hydratable polymer, the hydrated sheet being of a size which will not pass out of the stomach. Typically the hydrated sheet is at least 8 mm by 8 mm, perhaps at least 12 mm by 12 mm. The sheet is made by extrusion of a mix of lurasidone and polymer, along with other optional ingredients. The mix is preferably extruded as a shaped sheet, and for example takes the form of a roll. As it is extruded, the roll is cut to size. The cut roll may then be filled in a capsule. Upon swallowing, the capsule dissolves and the roll rehydrates and unrolls. Other configurations may be employed for the sheet of hydratable polymer, and for example it can be a folded sheet, or otherwise compacted.

Another aspect of the invention provides gastroretentive dosage form of lurasidone, wherein a first the outermost immediate-release layer comprising lurasidone dissolves and releases the active ingredient in the stomach. After that, the extended-release coating, due to insolubility or poor solubility in an aqueous medium, prevents an influx of water into the shell for a predetermined period of time and air entrapped in the shell helps in floating the shell. In some of the aspects, the shell is filled with one or more osmotic agent(s) in addition to the active ingredient that swells with the help of water, creating an osmotic pressure that helps in complete and pH-independent release of the active ingredient. After the immediate burst release, the release is only controlled by the composition and thickness of a coating. Once the release process is initiated, the shell may still float or remain buoyant for a certain period of time in the medium or it may sink and disintegrate. The gastroretentive dosage system of the present invention remains floating for more than 1 hour, in particular for more than 12 hours.

The term "shell", as used herein, refers to hard or soft gelatin capsules, wafers or any aerogels or foam materials which are hollow and have a cavity inside which can entrap air. These shells may be precoated with a dispersion (solution or suspension) of a hydrophilic polymer, e.g., hydroxypropylmethylcellulose, hydroxypropylcellulose, or hydroxyethylcellulose. This precoating may protect the shell from being degraded by gastric juice, which can affect the floating performance in the stomach. It may also avoid rupture of the shell or change of shape of the shell in the stomach for a longer period of time.

Another aspect of the invention provides gastroretentive dosage form of lurasidone, wherein the said dosage form comprising (a) a tablet comprising a therapeutically effective amount of lurasidone, a binder, and a pharmaceutically-acceptable gas-generating agent capable of releasing carbon dioxide upon contact with gastric juice, and (b) an expandable, hydrophilic, water-permeable and substantially gas-impermeable, membrane surrounding the tablet, wherein the membrane expands as a result of the release of carbon dioxide from the gas-generating agent upon contact with the gastric juice, whereby the dosage form becomes too large to pass into the patient's pyloric sphincter.

One embodiment of this invention can be seen as a gas generating inflatable system which is encapsulated in a hard gelatin dry-fill capsule. On contact with gastric fluid, the capsule dissolves to release a membrane pouch which contains the active ingredient lurasidone formulated with effervescent and rate controlling excipients. When water or gastric fluid penetrates the pouch, carbon dioxide is liberated from the tablet and this causes the pouch to inflate to a volume of up to about 20 mls. The gas-filled pouch is able to float on the aqueous phase and is retained in the stomach because it is too large to pass into the pyloric sphincter. The inflation of the pouch is a gradual process and carbon dioxide is released over a defined time period to maintain the inflation. Typically, the pouch remains inflated for a period of about 8-12 hours and can remain inflated for up to 24 hours or more. The period of inflation also reflects the gastric retention time. During its dwell time in the stomach, the lurasidone and carbidopa present in the tablet component are released slowly into the surrounding body fluid, preferably by diffusion, through the membrane of the pouch. Since gastric juice is always being transported further, the active ingredient passes continuously and over a prolonged period into the duodenum, where it is absorbed over an extended period. Once the gas generating formulation is depleted, the pouch deflates and flattens, becoming flexible enough to pass through the pylorus and hence empties from the stomach.

The invention may be further illustrated by the following examples, which are for illustrative purposes only and should not be construed as limiting the scope of the invention in any way.

EXAMPLES
Example 1: Muco-adhesive tablets
Sr. No. Ingredient Qty/tab
20 mg 40 mg
Drug layer
1 Lurasidone hydrochloride 20.000 40.000
2 Hydroxy propyl methyl cellulose K4 M 100.000 100.000
3 Lactose monohydrate 80.000 60.000
Placebo layer
4 Alginic acid 40.000 40.000
5 Polyethylene oxide (Polyox, WSR 303) 600.000 600.000
6 Hydroxy propyl methyl cellulose K100 M 190.000 190.000
7 Colloidal silicon dioxide 10.000 10.000
8 Magnesium sterate 10.000 10.000

The prepared tablet is capsule shaped with a dimension 18 x 8 mm
Example 2: Swelling tablet
Sr. No. Ingredient Qty/tab
20 mg 40 mg
Drug layer
1 Lurasidone hydrochloride 20.000 40.000
2 Hydroxy propyl methyl cellulose K4 M 100.000 100.000
3 Lactose monohydrate 80.000 60.000
Placebo layer
4 Polyethylene oxide (Polyox, WSR 303) 400.000 400.000
4 Polyethylene oxide (Polyox, WSR N80) 200.000 200.000
5 Hydroxy propyl methyl cellulose K100 M 180.000 180.000
6 Colloidal silicon dioxide 10.000 10.000
9 Magnesium sterate 10.000 10.000
The prepared tablet is capsule shaped with a dimension 18 x 8 mm. Tablet swells by more than 2 mm within 30 min so that it will not move out from pyloric sphincter.

Example 3: Larger shape tablet
Sr. No. Ingredient Qty/tab
20 mg 40 mg
Drug layer
1 Lurasidone hydrochloride 20.000 40.000
2 Hydroxy propyl methyl cellulose K4 M 150.000 150.000
3 Lactose monohydrate 130.000 110.000
Placebo layer
4 Polyethylene oxide (Polyox, WSR 303) 750.000 750.000
5 Hydroxy propyl methyl cellulose K100 M 320.000 320.000
6 Colloidal silicon dioxide 15.000 15.000
9 Magnesium stearate 15.000 15.000
The prepared tablet is capsule shaped with a dimension 20 x 10 mm.

Example 4: Floating unit dosage form tablet
Sr. No. Ingredient Qty/tab
20 mg 40 mg
Drug layer
1 Lurasidone hydrochloride 20.000 40.000
2 Hydroxy propyl methyl cellulose K4 M 100.000 100.000
3 Lactose monohydrate 80.000 60.000
Placebo layer
4 Polyethylene oxide (Polyox, WSR 303) 600.000 600.000
5 Hydroxy propyl methyl cellulose K100 M 190.000 190.000
6 Colloidal silicon dioxide 75.000 75.000
7 Citric acid monohydrate 8.330 8.330
8 Sodium bicarbonate 16.660 16.660
9 Magnesium sterate 10.000 10.000
The prepared tablet is capsule shaped with a dimension 20 x 10 mm. The tablets float within 30 min.

Example 5: Buffered powder
Sr. No. Ingredient Qty/tab
20 mg 40 mg
Drug layer
1 Lurasidone hydrochloride 20.000 40.000
2 Hydroxy propyl methyl cellulose K4 M 200.000 200.000
3 Lactose monohydrate 180.000 160.000
Buffering agent
4 Disodium hydrogen phosphate,12H2O 20.000 20.000
5 Potassium dihydrogen phosphate 20.000 20.000
6 Lactose monohydrate 400.000 400.000
7 Hydroxy propyl methyl cellulose E3 LV 20.000 20.000
8 Pregelatinized Starch 5.000 5.000
9 Magnesium sterate 10.000 10.000

Example 6: Buffered tablet
Sr. No. Ingredient Qty/tab
20 mg 40 mg
Drug layer
1 Lurasidone hydrochloride 20.000 40.000
2 Hydroxy propyl methyl cellulose K4 M 200.000 200.000
3 Lactose monohydrate 180.000 160.000
Buffering agent
4 Disodium hydrogen phosphate,12H2O 20.000 20.000
5 Potassium dihydrogen phosphate 20.000 20.000
6 Lactose monohydrate 400.000 400.000
7 Hydroxy propyl methyl cellulose E3 LV 20.000 20.000
8 Pregelatinized Starch 5.000 5.000
9 Magnesium sterate 10.000 10.000
Total weight of tablet 875.000 875.000

Examples 7-11:
Quantity (% w/w)
Ingredients Example 7 Example 8 Example 9 Example 10 Example 11
Lurasidone 25.00 30.00 43.00 33.00 20.00
Crospovidone 25.00 30.00 20.00 30.00 38.50
Hydroxypropyl methyl cellulose — 25.00 30.00 29.75 30.00
Kollidon?® SR 25.00 — — — —
Polyethylene oxide 20.00 — — — —
Maltodextrin — 10.00 — — —
Acrylic acid polymer 4.00 4.00 6.00 6.00 10.00
Magnesium oxide — — — 0.25 0.50
Magnesium stearate 1.00 1.00 1.00 1.00 1.00

Examples 12-17:
Quantity (% w/w)
Ingredients Example 12 Example 13 Example 14 Example 15 Example 16 Example 17
Lurasidone 50.00 10.00 33.00 25.00 33.00 40.00
Crospovidone 30.00 50.00 29.50 35.00 30.50 30.00
Hydroxypropyl methyl cellulose 15.00 20.00 27.50 25.00 28.50 25.00
Acrylic acid polymer 13.00 18.00 6.00 9.00 6.00 4.00
Magnesium oxide 1.00 1.00 3.00 5.00 — —
Sodium acetate — — — — 1.00 —
Trisodium citrate — — — — — 0.5
Magnesium stearate 1.00 1.00 1.00 1.00 1.00 0.5

In another embodiment, a gastro-retentive dosage form comprising lurasidone, wherein the dosage form stays in the stomach for a prolonged period of time, preferably more than 2 hours; and therefore is capable of releasing lurasidone in the stomach for a time period longer than when delivered as a conventional dosage form. In one more embodiment, gastro-retentive dosage of lurasidone stays in stomach more than 2 hours, preferably more than 3 hours, more preferably more than 4 hours, most preferably more than 5 hrs. In one more embodiment, gastro-retentive dosage of lurasidone stays in stomach more than about 2 hours, about 2.5 hours, about 3 hours, about 3.5 hours, about 4 hours, about 4.5 hours, about 5 hours, about 5.5 hours, about 6 hours, about 6.5 hours, about 7 hours, about 7.5 hours, about 8 hours, about 8.5 hours, about 9 hours, about 9.5 hours or about 10 hours.

In one embodiment, lurasidone gastro-retentive dosage forms gastric retention period is greater than 4 hours or greater than 6-8 hours, up to 12 hours, 16 hours or 24 hours.

In one embodiment, the lurasidone gastro-retentive dosage forms are used for the treatment of diseases and conditions described herein to a subject. In some embodiments, the lurasidone gastro-retentive dosage forms described herein treat treatment of schizophrenia, senile dementia and depressive episodes associated with bipolar I disorder. In another embodiment, the pharmaceutical composition of the present invention can be used for treatment of schizophrenia, positive and negative symptoms of schizophrenia, major depressive episodes associated with bipolar I disorder, memory or learning dysfunctions caused by schizophrenia, senile dementia, attention deficit hyperactivity disorder, central nervous system disorder responsive to modulation of glutamate levels and other associated CNS disorders. In addition, a method for treating any of the diseases or conditions described herein in a subject in need of such treatment, involves administration of lurasidone gastro-retentive dosage forms in therapeutically effective amounts to said subject.

The compositions of the invention may also contain one or more active ingredients in addition to the Lurasidone. The additional active ingredient may be another antipsychotic compound including benzisothiazol derivatives, or it may be an active ingredient having a different therapeutic activity like vitamins, antibiotics, cardiovascular agents, NSAIDs and like.

Dosages of lurasidone gastro-retentive dosage forms described can be determined by any suitable method. Maximum tolerated doses (MTD) and maximum response doses (MRD) for lurasidone can be determined via established animal and human experimental protocols as well as in the examples described herein. For example, toxicity and therapeutic efficacy of lurasidone can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, for determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The dose ratio between the toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio between LD50 and ED50. Lurasidone dosages exhibiting high therapeutic indices are of interest. The data obtained from cell culture assays and animal studies can be used in formulating a range of dosage for use in human. The dosage of such compounds lies preferably within a range of circulating concentrations that include the ED50 with minimal toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized.

In some embodiments, the amount of a given lurasidone gastro-retentive dosage form that corresponds to such an amount varies depending upon factors such as the particular lurasidone salt or solvate, disease condition and its severity, the identity (e.g., weight, sex) of the subject or host in need of treatment, but can nevertheless be determined according to the particular circumstances surrounding the case, including, e.g., the specific agent being administered, the liquid formulation type, the condition being treated, and the subject or host being treated.

In some embodiments, the lurasidone gastro-retentive dosage forms described herein are provided in a dose per day from about 1 mg to 200 mg, from about 5 mg to about 180 mg, from about 10 to about 160mg, from about 20 mg to about 120 mg of lurasidone. In certain embodiments, the lurasidone gastro-retentive dosage forms described herein are provided in a daily dose of about 10 mg, about 15 mg, about 20 mg, about 21 mg, about 22 mg, about 23 mg, about 24 mg, about 25 mg, about 26 mg, about 27 mg, about 28 mg, about 29 mg, about 30 mg, about 31 mg, about 32 mg, about 33 mg, about 34 mg, about 35 mg, about 36 mg, about 37 mg, about 38 mg, about 39 mg, about 40 mg, about 41 mg, about 42 mg, about 43 mg, about 44 mg, about 45 mg, about 46 mg, about 47 mg, about 48 mg, about 49 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, or any range derivable therein. The dose per day described herein can be given once per day or multiple times per day in the form of sub-doses given b.i.d., t.i.d., q.i.d., or the like where the number of sub-doses equal the dose per day. In further embodiments, the daily dosages appropriate for the lurasidone gastro-retentive dosage forms described herein are from about 0.01 to about 10 mg/kg per body weight.

In one embodiment, there is provided a gastroretentive dosage form wherein the mean plasma concentration of the lurasidone after single dose administration exhibits a pharmacokinetic profile which is superior to that attainable by a product that is not a gastroretentive product.

In one embodiment, there is provided a method for providing a therapeutic blood plasma concentration of lurasidone over a period of up to 24 hours resulting in improved pharmacological effect result which comprises administering orally to a patient in need thereof a lurasidone gastroretentive dosage form conducive to pharmacologically effective lurasidone blood plasma levels from about half an hour to about 24 hours.

In another embodiment, there is provided a method for eliminating sharp peaks in the therapeutic blood plasma concentration of lurasidone after administration of lurasidone to a patient in need thereof over a period of up to 24 hours with improved pharmacological ad therapeutic effect which comprises administering orally to a patient in need thereof lurasidone gastroretentive dosage form.

In further embodiments, the lurasidone gastro-retentive dosage forms are provided in a dosage that is similar, comparable or equivalent to a dosage of a known lurasidone formulation. In other embodiments, the lurasidone gastro-retentive dosage forms are provided in a dosage that provides similar, comparable or equivalent pharmacokinetic parameters (e.g., AUC, Cmax, Tmax, Cmax, T1/2) as a dosage of a known lurasidone tablet formulation. Similar, comparable or equivalent pharmacokinetic parameters, in some instances, refer to within 50% to 200%, 80% to 150%, 85% to 125%, 90% to 110%, or increments therein, of the given values. It should be recognized that the ranges can, but need not be symmetrical, e.g., 85% to 105%.

In another embodiment, the gastro-retentive dosage form of lurasidone provides a mean AUC of plasma lurasidone in the subject which is greater than the mean AUC of plasma lurasidone provided by an immediate release (IR) lurasidone dosage form, wherein the dose of lurasidone in the gastro-retentive dosage form is the same as or less than the dose in the IR dosage form. In another embodiment, the mean AUC of plasma lurasidone is about 10% to 50%, about 15% to about 30%, about 5% to 15%, about 5% to 20%, about 10% to 20%, about 10% to 25%, about 15% to 25%, about 20% to 25%, about 20% to 30%, about 20% to 40%, or about 30% to 40% greater than the AUC of plasma lurasidone provided by administration of the IR dosage form to the subject. In another embodiment, the mean AUC of plasma lurasidone is about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50% or more than about 50% greater than the mean AUC of plasma lurasidone provided by administration of the IR dosage form to the subject.

In another embodiment, the gastro-retentive dosage form of lurasidone provides a mean Tmax for plasma lurasidone in the subject who has been administered lurasidone in the gastro-retentive dosage form as described herein is greater than the mean Tmax of plasma lurasidone provided by an immediate release (IR) lurasidone dosage form, wherein the dose of lurasidone in the gastro-retentive dosage form is the same as the dose in the IR dosage form. In another embodiment, the mean Tmax for plasma lurasidone in the subject who has been administered lurasidone in the gastro-retentive dosage form as described herein is about 2 hours (h) to 5 h, about 3 h to 5 h, about 4 h to 5 h, about 2 h to 6 h, about 3 h to 6 h, about 3 h to 5 h, about 3 h to 4 h, or about 4 h to 6 h.

In another embodiment, the gastro-retentive dosage form of lurasidone shows enhanced bioavailability. In another embodiment, the gastro-retentive dosage form of lurasidone shows a reduced "food effect" as compared to lurasidone IR compositions. The compositions exhibit substantially similar oral bioavailability in fed and fasted subjects.

As used herein and in the appended claims, the singular forms "a", "an", and "the" include plural reference unless the context clearly dictates otherwise. Thus, for example, reference to "an excipient" is a reference to one or more excipients and equivalents thereof known to those skilled in the art, and so forth.

The term "about" is used to indicate that a value includes the standard level of error for the device or method being employed to determine the value. The use of the term "or" in the claims is used to mean "and/or" unless explicitly indicated to refer to alternatives only or the alternatives are mutually exclusive, although the disclosure supports a definition that refers to only alternatives and to "and/or." The terms "comprise," "have" and "include" are open-ended linking verbs. Any forms or tenses of one or more of these verbs, such as "comprises," "comprising," "has," "having," "includes" and "including," are also open-ended. For example, any method that "comprises," "has" or "includes" one or more steps is not limited to possessing only those one or more steps and also covers other unlisted steps.

Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of embodiments described herein, certain preferred methods, devices, and materials are now described.