DESC:F O R M 2

THE PATENTS ACT, 1970
(39 of 1970)
AND
THE PATENT RULES, 2003
COMPLETE SPECIFICATION
(See section 10; rule 13)

PHARMACEUTICAL COMPOSITION COMPRISING REMOGLIFLOZIN OR SALT OR ESTER THEREOF

GLENMARK PHARMACEUTIALS LIMITED of B/12 Mahalaxmi Chambers 22, Bhulabhai Desai Road, Mumbai, Maharashtra, India-400026

The following specification particularly describes the invention and the manner in which it is to be performed.

FIELD OF THE INVENTION
The invention relates to a pharmaceutical composition comprising remogliflozin or salt or ester thereof. In particular, the invention relates to an extended release pharmaceutical composition of remogliflozin or salt or ester thereof and a pharmaceutically acceptable excipient.

BACKGROUND OF THE INVENTION

Diabetes is becoming an increasing concern across the world as in 2007, approximately 246 million people were affected by the disease, with an additional 7 million people developing the disease each year. As per the one prediction in 2025, around 380 million people will have diabetes. Diabetes is a metabolic syndrome characterized by hyperglycemia, which results from an absolute deficiency in insulin secretion (type 1 diabetes) or from resistance to insulin action combined with an inadequate compensatory increase in insulin secretion (type 2 diabetes). Diabetes is associated with macro and micro complications such as retinopathy, nephropathy, and neuropathy. It highly desirable to adopt a healthier lifestyle, failing of which calls for chronic therapy with medicinal agents.

U.S. Patent No. 7,056,892 is directed to remogliflozin or salt thereof. U.S. Patent No. 7,084,123 is directed to remogliflozinetabonate or salt thereof. These patents also disclose the use of the drugs for prevention or treatment of disease associated with hyperglycemia. Another U.S. Patent No. 8,951,976 is directed to the use of remogliflozin or remogliflozinetabonate or salt thereof for treating disease associated with abnormal accumulation of liver lipids.

Dipeptidyl peptidase IV inhibitors, also known as gliptins, are a class of oral diabetes drugs that inhibit the enzyme DPP-IV which destroys hormone incretin. Incretin helps the body to regulate insulin secretion and glucose metabolism. The use of dipeptidyl peptidase IV inhibitors is very well known in the art, however recently it has been found that some dipeptidyl peptidase IV inhibitors were also able to provide benefit for refractory cases of abnormal accumulation of liver lipids.
U.S. Patent No. 6,699,871 discloses sitagliptin; U.S. Patent No. 6,166,063 discloses vildagliptin; U.S. Patent No. 6,395,767 is directed to saxagliptin; U.S. Patent No. 7,407,955 discloses linagliptin; U.S. Patent No. 7,807,689 discloses alogliptin and trelagliptin; U.S. Patent No. 7,345,180 discloses anagliptin; U.S. Patent No. 8,143,289 is directed to omarigliptin; and; U.S. Patent No. 7,879,848 is directed to gemigliptin. International Patent Publication No. WO2012/006398 discloses a combination immediate and delayed release delivery system for remogliflozinetabonate which provides a dosage form that has two distinct phases of release, a formulation that promotes immediate release of the compound upon ingestion and another formulation which delays the release of the compound.

Although several approaches have been reported in the art with respect to formulations comprising remogliflozin, there remains a substantial need in the art for new and improved pharmaceutical formulations of remogliflozin which exhibit advantageous effect on the treatment of type II diabetes mellitus. There also remains a need in the art for remogliflozin formulations that will rapidly achieve therapeutic drug levels, and maintain them over an extended period of time, thereby improving both clinical efficacy and patient compliance with the dosage regimen. The inventors of the present invention have invented a once daily formulation of remogliflozin or salt thereof for treatment of diabetes and its complications.

SUMMARY OF INVENTION

In first embodiment of the invention, there is provided an extended release pharmaceutical composition of remogliflozin or salt or ester thereof and a pharmaceutically acceptable excipient. In one embodiment, there is provided an extended release pharmaceutical composition of remogliflozin or salt or ester thereof and an extended release polymer and a pharmaceutically acceptable excipient.

In one embodiment the present invention is an extended release pharmaceutical composition, comprising:
(i) an extended release component comprising remogliflozin or salt or ester thereof; and
(ii) optionally, an immediate release component comprising remogliflozin or salt or ester thereof;
wherein the extended release component comprises:
(a) a first population of pellets having a first release rate profile; and
(b) a second population of pellets having a second release rate profile, the second release rate profile being different from the first release rate profile.

In another embodiment of the invention, there is provided an extended release pharmaceutical composition of remogliflozin or salt or ester thereof comprising the extended release component and optionally, immediate release component. In one embodiment, there is provided an extended release pharmaceutical composition of remogliflozin or salt or ester thereof comprising the extended release component and immediate release component.

In yet another embodiment of the invention, there is provided an extended release pharmaceutical composition of remogliflozin or salt or ester thereof comprising the extended release component and optionally, immediate release component, wherein the extended release component is contained in at least one population of pellets coated with a release controlling coating.

In yet another embodiment of the invention, there is provided an extended release pharmaceutical composition of remogliflozin or salt or ester thereof comprising the extended release component and optionally, immediate release component, wherein the extended release component is contained in (a) a first population of pellets coated with a release controlling coating and (b) a second population of pellets coated with a release controlling coating.

In yet another embodiment of the invention, there is provided an extended release pharmaceutical composition of remogliflozin or salt or ester thereof comprising the extended release component and optionally, immediate release component, wherein the extended release component is contained in (a) a first population of pellets coated with a release controlling coating and (b) a second population of pellets coated with a release controlling coating, and wherein the release controlling coating is specific to every pellet population and determines its rate of release.

In yet another embodiment of the invention, there is provided an extended release pharmaceutical composition of remogliflozin or salt or ester thereof comprising the extended release component and immediate release component, wherein the extended release component is contained in (a) a first population of pellets coated with a release controlling coating and (b) a second population of pellets coated with a release controlling coating.

In yet another embodiment of the invention, there is provided an extended release pharmaceutical composition of remogliflozin or salt or ester thereof comprising a first extended release pellet population (DR1), a second extended release pellet population (DR2), and immediate release pellet population (IR), wherein:

(a) the IR pellet population comprises an inert core, remogliflozin or salt or ester thereof in about 10 to 30% by weight of total amount of remogliflozin or salt or ester thereof in the composition and a pharmaceutically acceptable excipient, wherein the remogliflozin or salt or ester thereof and the pharmaceutically acceptable excipients are coated on inert core;

(b) the DR1 pellet population comprises an inert core, remogliflozin or salt or ester thereof in about 10 to 30% by weight of total amount of remogliflozin or salt or ester thereof in the composition and a pharmaceutically acceptable excipient, wherein the remogliflozin or salt or ester thereof and the pharmaceutically acceptable excipients are coated on inert core and wherein remogliflozin or salt or ester thereof coated inert core is further coated with a release controlling coating;

(c) the DR2 pellet population comprises an inert core, remogliflozin or salt or ester thereof in about 30 to 70% by weight of total amount of remogliflozin or salt or ester thereof in the composition and a pharmaceutically acceptable excipient, wherein the remogliflozin or salt or ester thereof and the pharmaceutically acceptable excipients are coated on inert core and wherein remogliflozin or salt or ester thereof coated inert core is further coated with a release controlling coating;
wherein the DR1 and DR2 pellet population have their own specific release rate profile.

In yet another embodiment of the invention, there is provided an extended release pharmaceutical composition of remogliflozin or salt or ester thereof comprising a first extended release pellet population (DR1), a second extended release pellet population (DR2), and immediate release pellet population (IR), wherein:

(a)the IR pellet population comprises an inert core, and a layer of remogliflozin or salt or ester thereofsurrounding the inert core, the IR pellet population contributing for about 10 to 30% by weight of total amount of remogliflozin or salt or ester thereof in the composition;
(b) the DR1 pellet population comprises an inert core, a layer of a first release controlling material surrounding the inert core, and a layer of remogliflozin or salt or ester thereof disposed between the inert core and the layer of first release controlling material, the DR1 pellet population contributing for about 10 to 30% by weight of total amount of remogliflozin or salt or ester thereof in the composition; and
(c) the DR2 pellet population comprises an inert core, a layer of second release controlling material surrounding the inert core, and a layer of remogliflozin or salt or ester thereof disposed between the inert core and the layer of second release controlling coating, the DR1 pellet population contributing for about 30 to 80% by weight of total amount of remogliflozin or salt or ester thereof in the composition;
wherein the DR1 pellet population and DR2 pellet population have their own specific release rate profile.

In yet another embodiment the present invention disclose, wherein the first release controlling material starts releasing remogliflozin or salt or ester thereof when pH is 5.5 or above; second release controlling starts releasing remogliflozin or salt or ester thereof when pH is 6.0 or above.

In yet another embodiment the present invention disclose an extended release pharmaceutical, wherein the first release controlling material and the second release controlling material are selected from a group comprising of hypromellose, ethylcellulose, polymethacrylates, a combination of hypromellose and polymethacrylates in a weight ratio of 1:1 to 1:15, a combination of hypromellose and ethylcellulose in a weight ratio of 1:1 to 1:15.

In yet another embodiment the present invention disclose an extended release pharmaceutical, the first release controlling material provided on the DR1 pellet population is different from the second release controlling material provided on the DR2 pellet population; or the first release controlling material provided on the DR1 pellet population is same as the second release controlling material provided on the DR2 pellet population, and an amount of release controlling material provided on the DR1 pellet population is different from an amount of release controlling material provided on the DR1 pellet population.

In yet another embodiment the present invention is an extended release pharmaceutical composition, comprising:
(i) an extended release component comprising remogliflozin or salt or ester thereof; and
(ii) optionally, an immediate release component comprising remogliflozin or salt or ester thereof;
the extended release component comprisesa population of pellets having:
an inert core;
a layer of remogliflozin or salt or ester thereof surrounding the inert core;
a layer of an enteric material surrounding the layer of remogliflozin or salt or ester thereof; and
a layer of a release controlling materialdisposed between the layer of remogliflozin or salt or ester thereof and the layer of enteric polymer.

In yet another embodiment of the invention, there is provided an extended release pharmaceutical composition of remogliflozin or salt or ester thereof comprising an extended release pellet population (ER) and an immediate release pellet population (IR), wherein:

(a) the IR pellet population comprises an inert core, remogliflozin or salt or ester thereof in about 10 to 30% by weight of total amount of remogliflozin or salt or ester thereof in the composition and a pharmaceutically acceptable excipient, wherein the remogliflozin or salt or ester thereof and the pharmaceutically acceptable excipients are coated on inert core;

(b) the ER pellet population comprises an inert core, remogliflozin or salt or ester thereof in about 60 to 90% by weight of total amount of remogliflozin or salt or ester thereof in the composition and a pharmaceutically acceptable excipient, wherein the remogliflozin or salt or ester thereof and the pharmaceutically acceptable excipients are coated on inert core, and wherein remogliflozin or salt or ester thereof coated inert core is further coated with a release controlling coating, wherein said release controlling coating is further coated with an enteric coating,

wherein the release controlling coating and the enteric coating have theirown specificrelease rate profile.

In yet another embodiment the present application discloses an extended release pharmaceutical composition, wherein the composition comprises an extended release (ER) pellet population and an immediate release (IR) pellet population, wherein:
(a) the IR pellet population comprises an inert core, and a layer of remogliflozin or salt or ester thereof surrounding the inert core, the IR pellet population contributing for about 10 to 40% by weight of total amount of remogliflozin or salt or ester thereof in the composition; and
(b) the ER pellet population comprises an inert core; a layer of remogliflozin or salt or ester thereof surrounding the inert core; a layer of an enteric material surrounding the layer of remogliflozin or salt or ester thereof; and a layer of a release controlling material disposed between the layer of remogliflozin or salt or ester thereof and the layer of enteric polymer, the ER pellet population contributing for about 60 to 90% by weight of total amount of remogliflozin or salt or ester thereof in the composition.

In yet another embodiment the present application discloses an extended release pharmaceutical composition, wherein the layer of enteric material begins to dissolve at pH 5.5 or above and exposes the layer of release controlling material.

In yet another embodiment the present application discloses an extended release pharmaceutical composition wherein the release controlling material starts releasing remogliflozin or salt or ester thereof when pH is 5.5.

In yet another embodiment of the invention, there is provided an extended release pharmaceutical composition of remogliflozin or salt or ester thereof, wherein it is released at a rate which results in reduction in frequency of side effects.

In yet another embodiment of the invention, there is provided an extended release pharmaceutical composition, wherein the composition is administered once a day.

In yet another embodiment of the invention, there is provided an extended release pharmaceutical composition, wherein the composition is for the treatment of diabetes such as type 1 and type 2 diabetes and complications associated with diabetes.

In yet another embodiment of the invention, there is provided a process of preparing an extended release pharmaceutical composition of remogliflozin or slat or ester thereof, wherein said process comprises steps of:
a. forming at least on population of remogliflozin containing pellet population,
b. coating each population of pellets with its own coating solution, and
c. incorporating the pellets into the suitable dosage form,

wherein the process optionally includes a process of forming immediate release pellet population, delayed release pellet population (DR1), delayed release pellet population (DR2), or extended release pellet population (ER1), wherein each population has specific release rate profile.
In another embodiment the present invention discloses a process for preparing an extended release pharmaceutical composition, comprising:
• preparing an extended release component comprising remogliflozin or salt or ester thereof; and
• optionally, preparing an immediate release component comprising remogliflozin or salt or ester thereof and mixing the same with the extended release component;
wherein preparing the extended release component comprises:
(a) preparing a first population of pellets having a first release rate profile;
(b) preparing a second population of pellets having a second release rate profile, the second release rate profile being different from the first release rate profile; and
(c) mixing the first population of pellets and the second population of pellets.

In yet another embodiment the present invention discloses a process for preparing an extended release pharmaceutical composition, comprising:
• preparing an extended release component comprising remogliflozin or salt or ester thereof; and
• optionally, preparing an immediate release component comprising remogliflozin or salt or ester thereof and mixing the same with the extended release component;
wherein preparing the extended release component comprises:
preparing a population of pellets having an inert core;
providing on the inert core a layer of remogliflozin or salt or ester thereof to obtain are mogliflozin coated inert core;
providing a layer of a release controlling material on the remogliflozin coated inert core to obtain release controlling material coated inert core; and
providing a layer of an enteric material on the release controlling material coated inert core to obtain the extended release component.

DETAIL DESCRIPTION OF INVENTION

SGLT2 is a member of the sodium glucose cotransporter family which are sodium-dependent glucose transport proteins. SGLT2 is the major cotransporter involved in glucose reabsorption in the kidney. SGLT2 inhibitors lead to a reduction in blood glucose levels. Therefore, SGLT2 inhibitors have potential use in the treatment of type 2 diabetes.

Remogliflozin (base) has been disclosed in PCT publication WO2001/016147 A1.

Remogliflozinetabonate is the pro-drug of remogliflozin. Remogliflozinetabonate also known as 5-methyl-4-[4-(1-methylethoxy)benzyl]-1-(1-methylethyl)-1H-pyrazol-3-yl-6-O-(ethoxycarbonyl)-ß -D-glucopyranoside has the following formula

US Patent 7,084,123 discloses Remogliflozinetabonate and its salts. Remogliflozinetabonate has the potential to be used as monotherapy for the treatment of type 2 diabetes mellitus. Remogliflozinetabonate has the potential to be used as monotherapy for the treatment of type 2 diabetes in human subjects suffering from diabetes. Efforts have been made to develop oral formulations of remogliflozin for the treatment of type 2 diabetes.

Although several approaches have been reported in the art with respect to formulations comprising remogliflozin, there remains a substantial need in the art for new and improved pharmaceutical formulations of remogliflozin which exhibit advantageous effect on the treatment of type 2 diabetes mellitus. The present invention discloses an extended release pharmaceutical composition of remogliflozin or salt or ester thereof, wherein it is released at a rate which results in reduction in frequency of side effects. There is provided an extended release pharmaceutical composition, wherein the composition is administered once a day. Also provided an extended release pharmaceutical composition, wherein the composition is for the treatment of diabetes such as type 1 and type 2 diabetes and complications associated with diabetes.

The terms used herein are defined as follows.

The term “diabetes” used herein refers to Type 1 diabetes or Type 2 diabetes.

The term "remogliflozin" as employed herein refers to remogliflozin, prodrug and salts thereof, in particular remogliflozinetabonate, including hydrates and solvates thereof, amorphous and crystalline forms thereof. Examples of salts include acid addition salts with mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid and the like, acid addition salts with organic acids such as formic acid, acetic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, propionic acid, citric acid, succinic acid, tartaric acid, fumaric acid, butyric acid, oxalic acid, malonic acid, maleic acid, lactic acid, malic acid, carbonic acid, glutamic acid, aspartic acid and the like, and salts with inorganic bases such as a sodium salt, a potassium salt and the like.

The term "immediate release population (IR)" used throughout the specification means the drug to dissolve in the gastrointestinal contents, with no intention of delaying or prolonging dissolution or absorption of drug.

The term "extended release (ER)" means the drug is formulated to make it available over an extended period after ingestion. This allows a reduction in dosing frequency compared to a drug presented as a conventional dosage form (e.g., as a solution or an immediate release dosage form).

The term “delayed release (DR)” means the drug is formulated to make it available after the dosage form is entered in specific region of intestine with specific pH. For example, DR1 coating of the invention release the drug at pH 5.5 of above and DR2 coating release the drug at pH 6 or above.
The term “excipient” used throughout the specification refers to a substance with which the drug may be combined to achieve a specific dosage form, formulation or composition for delivery to humans.

The term “release controlling polymer” is used for polymers which controls the release of remogliflozin or salt or ester thereof in such way to provide release over prolong period of time that is over 4hrs or 6hrs or 8hrs or 12hrs or 18hrs or 24hrs or 36hrs.

The present invention provides an extended release pharmaceutical composition of remogliflozin or salt or ester thereof comprising the extended release component and optionally, immediate release component. Additionally, there is provided an extended release pharmaceutical composition of remogliflozin or salt or ester thereof comprising the extended release component and immediate release component.

In one embodiment the present invention is an extended release pharmaceutical composition, comprising:
(i) an extended release component comprising remogliflozin or salt or ester thereof; and
(ii) optionally, an immediate release component comprising remogliflozin or salt or ester thereof;
the extended release component comprises:
(a) a first population of pellets having a first release rate profile; and
(b) a second population of pellets having a second release rate profile, the second release rate profile being different from the first release rate profile.

In an embodiment, there is provided an extended release pharmaceutical composition of remogliflozin or salt or ester thereof comprising the extended release component and optionally, immediate release component, wherein the extended release component is contained in at least one population of pellets coated with a release controlling coating.

In another embodiment, there is provided an extended release pharmaceutical composition of remogliflozin or salt or ester thereof comprising the extended release component and optionally, immediate release component, wherein the extended release component is contained in (a) a first population of pellets coated with a release controlling coating and (b) a second population of pellets coated with a release controlling coating.

In another embodiment, there is provided an extended release pharmaceutical composition of remogliflozin or salt or ester thereof comprising the extended release component and optionally, immediate release component, wherein the extended release component is contained in (a) a first population of pellets coated with a release controlling coating and (b) a second population of pellets coated with a release controlling coating, and wherein the release controlling coating is specific to every pellet population and determines its rate of release.

Additionally there is disclosed an extended release pharmaceutical composition of remogliflozin or salt or ester thereof comprising the extended release component and immediate release component, wherein the extended release component is contained in (a) a first population of pellets coated with a release controlling coating and (b) a second population of pellets coated with a release controlling coating.

Further, there is disclosed extended release pharmaceutical composition of remogliflozin or salt or ester thereof comprising a first extended release pellet population (DR1), a second extended release pellet population (DR2), and immediate release pellet population (IR), wherein:
(a) the IR pellet population comprises an inert core, remogliflozin or salt or ester thereof in about 10 to 30% by weight of total amount of remogliflozin or salt or ester thereof in the composition and a pharmaceutically acceptable excipient, wherein the remogliflozin or salt or ester thereof and the pharmaceutically acceptable excipients are coated on inert core;
(b) the DR1 pellet population comprises an inert core, remogliflozin or salt or ester thereof in about 10 to 30% by weight of total amount of remogliflozin or salt or ester thereof in the composition and a pharmaceutically acceptable excipient, wherein the remogliflozin or salt or ester thereof and the pharmaceutically acceptable excipients are coated on inert core and wherein remogliflozin or salt or ester thereof coated inert core is further coated with a release controlling coating;
(c) the DR2 pellet population comprises an inert core, remogliflozin or salt or ester thereof in about 30 to 70% by weight of total amount of remogliflozin or salt or ester thereof in the composition and a pharmaceutically acceptable excipient, wherein the remogliflozin or salt or ester thereof and the pharmaceutically acceptable excipients are coated on inert core and wherein remogliflozin or salt or ester thereof coated inert core is further coated with a release controlling coating;
wherein the DR1 and DR2 pellet population have their own specific release rate profile.

In yet another embodiment of the invention, there is provided an extended release pharmaceutical composition of remogliflozin or salt or ester thereof comprising a first extended release pellet population (DR1), a second extended release pellet population (DR2), and immediate release pellet population (IR), wherein:

(a) the IR pellet population comprises an inert core, and a layer of remogliflozin or salt or ester thereof surrounding the inert core, the IR pellet population contributing for about 10 to 30% by weight of total amount of remogliflozin or salt or ester thereof in the composition;
(b) the DR1 pellet population comprises an inert core, a layer of a first release controlling material surrounding the inert core, and a layer of remogliflozin or salt or ester thereof disposed between the inert core and the layer of first release controlling material, the DR1 pellet population contributing for about 10 to 30% by weight of total amount of remogliflozin or salt or ester thereof in the composition; and
(c) the DR2 pellet population comprises an inert core, a layer of second release controlling material surrounding the inert core, and a layer of remogliflozin or salt or ester thereof disposed between the inert core and the layer of second release controlling coating, the DR1 pellet population contributing for about 30 to 80% by weight of total amount of remogliflozin or salt or ester thereof in the composition;
wherein the DR1 pellet population and DR2 pellet population have their own specific release rate profile.

a layer of a release controlling material disposed between the layer of remogliflozin or salt or ester thereof and the layer of enteric polymer.

The remogliflozin or salt or ester thereof in the present invention is remogliflozinetabonate. The amount of remogliflozinetabonate in each pellet population is decided based upon the release profile. The pellet population pellets comprises about 10 to about 80% by weight of total amount of remogliflozin or salt or ester thereof in the composition. Alternatively, the IR population pellets comprises about 25%, or about 50% or about 75% by weight of total amount of remogliflozin or salt or ester thereof in the composition. In an embodiment, the pellet population comprises about 25mg or about 50mg or about 100mg or about 150mg, or about 200mg, or about 250mg of remogliflozin or salt or ester thereof.

The IR pellets of the each population comprises an inert carrier core, remogliflozin or salt or ester thereof and a pharmaceutically acceptable excipient, wherein the remogliflozin or salt or ester thereof and the pharmaceutically acceptable excipients are coated on inert core.

The inert carriers useful in the present invention may be selected from, but are not limited to, a group consisting of cellulose spheres (Celphere CP 305), silicon dioxide, starch and sugar spheres. The inert carrier is present in an amount of from about 15% to about 99% by weight, and preferably in an amount of from about 30% to about 80% by weight.

The remogliflozin or salt or ester thereof is applied or layered onto inert core by techniques known to one skilled in the art, such as drug layering, powder coating, extrusion/spheronization, roller compaction or granulation. Preferably, the introduction method is drug layering by spraying a suspension of topiramate and a pharmaceutically acceptable excipient onto the inert carrier.

The pharmaceutically acceptable excipients present in the IR pellet comprises of a binder selected from the group consisting of povidone, plasdone, hydroxypropyl methyl cellulose, hydroxypropyl cellulose and copovidone and suitable solvents. The solution or suspension of the remogliflozin or salt or ester thereof and the binder are coated on inert core. The binder is present in concentration ranging from about 1 to about 15% by weight of the composition.

Additionally in another embodiment, the inert core coated with remogliflozin is further coated with a barrier coat comprising a film coating agent. The coating agent used in barrier coat are those known in the prior art and to person skilled in the art.

Preferably the amount of remogliflozinetabonate in IR pellet population is about 10 to about 30% by weight of total amount of remogliflozin or salt or ester thereof in the composition. Alternatively, about 25% by weight of total amount of remogliflozin or salt or ester thereof is present in IR pellet population.

The invention composition also contains extended release pellet population. In an embodiment, the extended release population (ER1) is single pellet population coated with release controlling coating which further coated with enteric coating. In another embodiment, the extended release population is contained in two pellet populationviz DR1 and DR2 which are coated with release controlling coating giving a specific and different release rate profile.

In an embodiment, the IR pellets are coated with specific release controlling coating to form the extended release pellet population.

The extended release pellet population DR1 comprises an inert core, remogliflozin or salt or ester thereof in about 10 to 30% by weight of total amount of remogliflozin or salt or ester thereof in the composition and a pharmaceutically acceptable excipient, wherein the remogliflozin or salt or ester thereof and the pharmaceutically acceptable excipients are coated on inert core, and wherein remogliflozin or salt or ester thereof coated inert core is further coated with a release controlling coating. In another word, the DR1 pellet population is IR pellet population coated with a release controlling coating, wherein the coating release remogliflozin at or above pH 5.5.

The extended release pellet population DR2 comprises an inert core, remogliflozin or salt or ester thereof in about 30 to 70% by weight of total amount of remogliflozin or salt or ester thereof in the composition and a pharmaceutically acceptable excipient, wherein the remogliflozin or salt or ester thereof and the pharmaceutically acceptable excipients are coated on inert core and wherein remogliflozin or salt or ester thereof coated inert core is further coated with a release controlling coating. In another word, the DR2 pellet population is IR pellet population coated with a release controlling coating, wherein the coating release remogliflozin at or above pH 5.5.

In yet another embodiment the present invention disclose, wherein the first release controlling material starts releasing remogliflozin or salt or ester thereof when pH is 5.5 or above; second release controlling starts releasing remogliflozin or salt or ester thereof when pH is 6.0 or above

The release controlling coating comprises a release controlling polymer, a plasticizer, an anti-tacking agent and a surfactant/emulsifying agent. The release controlling polymer selected from the group, but not limited to, acrylic acid and methacrylic acid polymers and copolymers, methyl methacrylate copolymers, ethoxyethylmethacrylates, cyanoethyl methacrylate, poly(acrylic acid), poly(methacrylic acid), methacrylic acid alkylamide copolymer, poly(methyl methacrylate), polymethacrylate, poly(methyl methacrylate) copolymers, polyacrylamide, aminoalkyl methacrylate copolymer, poly(methacrylic acid anhydride), glycidyl methacrylate co-polymers, ammonioalkyl methacrylate copolymers, a copolymer synthesized from diethylaminoethyl methacrylate and other neutral methacrylic esters, also known as methacrylic acid copolymers or polymer methacrylates, commercially available as Eudragit (Rohm Pharma), ammonioalkyl methacrylate copolymer such as Eudragit.TM. RS and Eudragit.TM. RL, which are acrylic resins comprising copolymers of acrylic and methacrylic acid esters with a low content of quaternary ammonium groups, sodium carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, ethyl cellulose, carboxymethylamide, potassium methacrylatedivinylbenzene co-polymer, polymethylmethacrylate, polyvinylpyrrolidone, high-molecular weight polyvinylalcohols, methyl cellulose, vinyl acetate copolymers, hypromellose phthalate and combinations of any of the foregoing.

In another embodiment, the release controlling polymer is a glyceryl ester such as glycerylmonostearate, glycerylbehenate, glycerylpalmitostearate, lauroylmacrogol glyceride, stearoylmacrogol glyceride, or a combination of any of the foregoing. Other fatty and/or waxy release rate-controlling polymers include lauryl alcohol, myristyl alcohol, stearyl alcohol, cetyl alcohol, cetostearyl alcohol, palmitoyl alcohol, ouricury wax, hydrogenated vegetable oil, candelilla wax, esparto wax, stearic acid, paraffin wax, beeswax, glycowax, castor wax, and carnauba wax.

In still another embodiment, the release rate controlling polymer is eudragit or hydroxypropylmethyl cellulose phthalate, or ethyl cellulose or hydroxypropylmethyl cellulose combination thereof.

In still another embodiment, the release rate controlling polymer is eudragit L30 D55 or eudragit L100-55 or hypromellose phthalate. In still another embodiment, the release rate controlling polymer is eudragit L100 or eudragit L12.5. In still another embodiment, the release controlling polymer is eudragit L100 or eudragit L12.5 or hypromellose phthalate 50/55 or hypromellose or ethylcellulose or combination thereof. In still another embodiment, the release controlling polymer is combination of hypromellose and eudragit, wherein the weight ratio of hypromellose and eudragit ranges from about 1:1 to 1:15. In still another embodiment, the release controlling polymer is combination of hypromellose and ethylcellulose, wherein the weight ratio of hypromellose and eudragit ranges from about 1:1 to 1:15.In yet another embodiment the present invention disclose an extended release pharmaceutical, wherein the first release controlling material and the second release controlling material are selected from a group comprising of hypromellose, ethylcellulose, polymethacrylates, a combination of hypromellose and polymethacrylates in a weight ratio of 1:1 to 1:15, a combination of hypromellose and ethylcellulose in a weight ratio of 1:1 to 1:15.

In yet another embodiment the present invention disclose an extended release pharmaceutical, the first release controlling material provided on the DR1 pellet population is different from the second release controlling material provided on the DR2 pellet population; or the first release controlling material provided on the DR1 pellet population is same as the second release controlling material provided on the DR2 pellet population, and an amount of release controlling material provided on the DR1 pellet population is different from an amount of release controlling material provided on the DR1 pellet population.

In another embodiment, the composition has a concentration of release controlling polymer ranging from about 2-50%, or about 5-40%, or about 10-30%, or about 20-25% by weight of composition.

In still another embodiment, the concentration of release rate retarding polymer about 10%, or about 20%, or about 30%, or about 40%, or about 50%, or about 60%, or about 70%, or about 80%, or about 90% by weight of composition.

In yet another embodiment the present invention is an extended release pharmaceutical composition, comprising:
(i) an extended release component comprising remogliflozin or salt or ester thereof; and
(ii) optionally, an immediate release component comprising remogliflozin or salt or ester thereof;
the extended release component comprises a population of pellets having:
an inert core;
a layer of remogliflozin or salt or ester thereof surrounding the inert core;
a layer of an enteric material surrounding the layer of remogliflozin or salt or ester thereof; and
a layer of a release controlling material disposed between the layer of remogliflozin or salt or ester thereof and the layer of enteric polymer.

In another embodiment, the invention composition also contains extended release pellet population. In an embodiment, the extended release population (ER1) is single pellet population coated with release controlling coating which further coated with enteric coating, wherein the enteric coating begins to dissolve at pH 5.5 or above and exposes release controlling coating. The enteric coating comprises polymers selected from the group consisting of acrylic acid and methacrylic acid polymers and copolymers, methyl methacrylate copolymers, ethoxyethylmethacrylates, cyanoethyl methacrylate, poly(acrylic acid), poly(methacrylic acid), methacrylic acid alkylamide copolymer, poly(methyl methacrylate), polymethacrylate, poly(methyl methacrylate) copolymers, polyacrylamide, aminoalkyl methacrylate copolymer, poly(methacrylic acid anhydride), glycidyl methacrylate co-polymers, ammonioalkyl methacrylate copolymers, sodium carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, ethylcellulose, carboxymethylamide, potassium methacrylatedivinylbenzene co-polymer, polymethylmethacrylate, polyvinylpyrrolidone, high-molecular weight polyvinylalcohols, methyl cellulose, vinyl acetate copolymers, hypromellose phthalate and combinations of any of the foregoing.

The enteric coating further comprises plasticizer, basifying agent and solvent.
In another embodiment, there is provided an extended release pharmaceutical composition of remogliflozin or salt or ester thereof comprising an extended release pellet population (ER) and an immediate release pellet population (IR), wherein:
(a) the IR pellet population comprises an inert core, remogliflozin or salt or ester thereof in about 10 to 30% by weight of total amount of remogliflozin or salt or ester thereof in the composition and a pharmaceutically acceptable excipient, wherein the remogliflozin or salt or ester thereof and the pharmaceutically acceptable excipients are coated on inert core;
(b) the ER pellet population comprises an inert core, remogliflozin or salt or ester thereof in about 60 to 90% by weight of total amount of remogliflozin or salt or ester thereof in the composition and a pharmaceutically acceptable excipient, wherein the remogliflozin or salt or ester thereof and the pharmaceutically acceptable excipients are coated on inert core, and wherein remogliflozin or salt or ester thereof coated inert core is further coated with a release controlling coating, wherein said release controlling coating is further coated with an enteric coating,
wherein the release controlling coating and the enteric coating have their own specific release rate profile.

In another embodiment, the release controlling coating comprises of a release controlling polymer, a plasticizer and a surfactant and/or emulsifying agent.

In yet another embodiment the present application discloses an extended release pharmaceutical composition, wherein the composition comprises an extended release (ER) pellet population and an immediate release (IR) pellet population, wherein:
(a) the IR pellet population comprises an inert core, and a layer of remogliflozin or salt or ester thereof surrounding the inert core, the IR pellet population contributing for about 10 to 40% by weight of total amount of remogliflozin or salt or ester thereof in the composition; and
(b) the ER pellet population comprises an inert core; a layer of remogliflozin or salt or ester thereof surrounding the inert core; a layer of an enteric material surrounding the layer of remogliflozin or salt or ester thereof; and a layer of a release controlling material disposed between the layer of remogliflozin or salt or ester thereof and the layer of enteric polymer, the ER pellet population contributing for about 60 to 90% by weight of total amount of remogliflozin or salt or ester thereof in the composition.

In yet another embodiment the present application discloses an extended release pharmaceutical composition, wherein the layer of enteric material begins to dissolve at pH 5.5 or above and exposes the layer of release controlling material.

In yet another embodiment the present application discloses an extended release pharmaceutical composition wherein the release controlling material starts releasing remogliflozin or salt or ester thereof when pH is 5.5.

The pharmaceutical composition of the present invention exhibits delayed release, modified release, extended release or pulsatile release of remogliflozin or salt thereof. The pharmaceutical composition of the present invention exhibits delayed release, modified release, extended release or pulsatile release of remogliflozinetabonate.

More preferably, the composition of the present invention exhibits extended release of remogliflozin or salt thereof.

In an embodiment, the composition are meant for once a daily use.

In another aspect of the invention, the pharmaceutical composition is in the form of a tablet, capsule, pill, mini-tablets, solution, suspension and any other suitable dosage form which can be formulated to yield. In another embodiment, the invention dosage form has either functional or non-functional coating.

In another aspect of the invention, the pharmaceutical composition comprises a pharmaceutically acceptable excipients such as one or more of diluents, disintegrants, binders, bulking agents, anti-oxidants, buffering agents, colorants, flavoring agents, coating agents, anti-tacking agents, emulsifiers, surfactants, plasticizers, stabilizers, preservatives, lubricants, glidants, chelating agents.

Suitable binders are selected from, but not limited to, polyvinyl pyrrolidone, copolymers of vinyl pyrrolidone with other vinylderivatives, hydroxypropyl methylcellulose, methylcellulose, hydroxypropylcellulose, powdered acacia, gelatin, guar gum, carbomer such as carbopol, polymethacrylates and starch.

Suitable diluents include, but are not limited to, dicalcium phosphate dihydrate, calcium sulfate, lactose, sucrose, mannitol, sorbitol, cellulose, microcrystalline cellulose, kaolin, sodium chloride, dry starch, hydrolyzed starches, pregelatinized starch, silicone dioxide, titanium oxide and magnesium aluminum silicate.

Examples of suitable lubricants include stearic acid, magnesium stearate, sodium stearylfumarate, sodium lauryl sulphate, magnesium lauryl sulphate, fumaric acid, glycerylpalmitostearate, zinc stearate, calcium stearate, silica, talc, polyethylene glycol, paraffin or the mixtures thereof.

Example of suitable glidants include, but are not limited to, colloidal silicon dioxide, stearic acid, talk, aluminium silicate or the mixtures thereof.

Suitable disintegrants are selected from microcrystalline cellulose, low-substituted hydroxypropyl cellulose, alginic acid and alginates, modified starches, Sodium starch glycolate, sodium carboxy methyl cellulose, carboxymethyl cellulose calcium, polyvinylpyrrolidone, docusate sodium, guar gum or the mixtures thereof.

Suitable buffering agents may include, but are not limited to, one or more of a bicarbonate salt of alkali earth metal, amino acids, an acid salt of an amino acid, an alkali salt of an amino acid, and combinations of any of the foregoing.

Suitable plasticizers include, but are not limited to, one or more of diethyl phthalate, triethyl citrate, acetyl tributyl citrate, dibutyl phthalate, triacetin, propylene glycol, and polyethylene glycol. The solvents comprise one or more of dichloromethane, acetone, ethanol, methanol, isopropyl alcohol, water or mixture thereof.

Suitable sweeteners include aspartame, neotame, sucralose, sodium saccharine and the like.

Suitable anti-tacking agents may be selected from stearates; stearic acid; vegetable oil; waxes; a blend of magnesium stearate and sodium lauryl sulfate; sodium benzoate; sodium acetate, glycerylmonostearate and the like.

The surfactants and emulsifiers may be ionic or nonionic. Specific examples of surfactants and emulsifiers are such as poloxamers, polyethylene glycols, polyethylene glycol monostearate, polysorbates, sodium lauryl sulfate, polyethoxylated and hydrogenated castor oil, etc.
Moreover, the composition of the present invention may include stabilizers like gums, agar; taste masking agents like acrylic polymers, copolymers of acrylates, celluloses, resins; coloring agents like titanium dioxide, natural food colors, dyes suitable for food, drug and cosmetic applications.

There is additionally disclosed a process of preparing an extended release pharmaceutical composition of remogliflozin or slat or ester thereof, wherein said process comprises steps of:
a. forming at least on population of remogliflozin containing pellet population,
b. coating each population of pellets with its own coating solution,
c. incorporating the pellets into the suitable dosage form,

Wherein the process optionally includes a process of forming an immediate release pellet population, a delayed release pellet population (DR1), a delayed release pellet population (DR2), or an extended release pellet population (ER1), wherein each population has specific release rate profile.

In another embodiment the present invention discloses a process for preparing an extended release pharmaceutical composition, comprising:
• preparing an extended release component comprising remogliflozin or salt or ester thereof; and
• optionally, preparing an immediate release component comprising remogliflozin or salt or ester thereof and mixing the same with the extended release component;
wherein preparing the extended release component comprises:
(a) preparing a first population of pellets having a first release rate profile;
(b) preparing a second population of pellets having a second release rate profile, the second release rate profile being different from the first release rate profile; and
(c) mixing the first population of pellets and the second population of pellets.

In yet another embodiment the present invention discloses a process for preparing an extended release pharmaceutical composition, comprising:
• preparing an extended release component comprising remogliflozin or salt or ester thereof; and
• optionally, preparing an immediate release component comprising remogliflozin or salt or ester thereof and mixing the same with the extended release component;
wherein preparing the extended release component comprises:
preparing a population of pellets having an inert core;
providing on the inert core a layer of remogliflozin or salt or ester thereof to obtain are mogliflozin coated inert core;
providing a layer of a release controlling material on the remogliflozin coated inert core to obtain release controlling material coated inert core; and
providing a layer of an enteric material on the release controlling material coated inert core to obtain the extended release component.
EXAMPLES
EXAMPLE 1: Extended release formulation of RemogliflozinEtabonate.
IR Pellets
DRUG LOADING
Sr.No. Ingredients mg/cap % w/w
1 Celphere CP-305 (#030/#050 fraction) 52.808 45.840
2 RemogliflozinEtabonate 50.000 43.403
3 Povidone/Plasdone K29/32/HPMC/HPC/Copovidone 10.006 8.686
4 Purified Water/IPA/DCM/Acetone q.s
Total 112.814
BARRIER COAT
1 Drug Loaded Pellets 112.814 97.929
2 Opadry White YS-1-18202-A 2.386 2.071
3 Purified Water q.s
Total 115.200

FUNCTIONAL/DR COAT 1 (12% w/w)
1 IR Pellets 115.2 89.287
2 Eudragit L30 D55/ L 100-55 11.33 8.781
3 Triethyl Citrate/ATBC/ATEC/DibutylSebacate/Diethyl Pthallate/Plasacryl 1.132 0.877
4 GlycerylMonostearate 1.132 0.877
5 Polysorbate 80 0.228 0.177
6 Purified Water/IPA/DCM/Acetone q.s
Total 129.022
FUNCTIONAL/DR COAT 2 (12% w/w)
1 IR Pellets 230.400 89.286
2 Eudragit L100/ L 12.5 25.134 9.740
3 Triethyl Citrate/ATBC/ATEC/DibutylSebacate/Diethyl Pthallate 2.513 0.974
4 Purified Water/IPA/DCM/Acetone q.s
Total 258.047

Manufacturing process:
A. IR PELLETS
a. DRUG LAYERING
1. Sift the microcrystalline cellulose spheres pellets to get #030/040 mesh fraction.
2. Dissolve binder in purified water under stirring. Add to it RemogliflozinEtabonate slowly under stirring.
3. Load the sifted pellets of step 1 into FBP bowl and start spraying drug-binder dispersion over it using suitable process parameters.
4. After completion of drug loading process, dry the drug loaded pellets in FBP for 15 min.

b. SEAL/BARRIER COATING
1. Coating Dispersion: Add and dissolve under stirring Opadry White to purified water.
2. Load the drug loaded pellets into FBP Bowl. Spray the coating dispersion over DLP using suitable process parameters.
3. After completion of coating process, dry the drug loaded pellets in FBP for 15 min.
B. DELAYED RELEASE PELLETS 1 (DR1)
1. Heat purified water and add to it glycerylmonostearate followed by plasticizer followed by surfactant. Allow this emulsion to cool under stirring.
2. Add to step 1, Eudragit L 30 D 55 and continue stirring throughout the process.
3. Load the IR pellets (A) to FBP bowl. Spray the polymer dispersion of step 2 over IR pellets using suitable process parameters.
4. After completion of coating process, dry the drug loaded pellets in FBP for 15 min.
C. DELAYED RELEASE PELLETS 1 (DR1)
• Add plasticizer followed by polymer to purified water under stirring.
• Continue stirring throughout the process.
• Load the IR pellets (A) to FBP bowl. Spray the polymer dispersion of step 2 over IR pellets using suitable process parameters.
• After completion of coating process, dry the drug loaded pellets in FBP for 15 min.
D. PREPARATION OF FINAL CAPSULE DOSAGE FORM
The capsule is filled IR, DR1 and DR2 pellets to achieve the desired fill weight.

EXAMPLE 2: Extended release formulation of RemogliflozinEtabonate.
IR Pellets
DRUG LOADING
Sr.No. Ingredients mg/cap % w/w
1 Celphere CP-305 (#030/#050 fraction) 52.808 45.840
2 RemogliflozinEtabonate 50.000 43.403
3 Povidone/Plasdone K29/32/HPMC/HPC/Copovidone 10.006 8.686
4 Purified Water/IPA/DCM/Acetone q.s
Total 112.814
BARRIER COAT
1 Drug Loaded Pellets 112.814 97.929
2 Opadry White YS-1-18202-A 2.386 2.071
3 Purified Water q.s
Total 115.200
FUNCTIONAL/DR COAT 1 (12% w/w)
1 IR Pellets 115.2 89.286
2 Hypromellose Phthalate HP 50 / HP 55 11.52 8.929
3 Triethyl Citrate/ATBC/ATEC/DibutylSebacate/Diethyl Pthallate 1.152 0.893
4 GlycerylMonostearate 1.152 0.893
5 Purified Water/IPA/DCM/Acetone q.s
Total 129.024
FUNCTIONAL/DR COAT 2 (12% w/w)
1 IR Pellets 230.400 89.286
2 Eudragit L100/ L 12.5 12.567 4.870
3 Hypromelose K100M,K4M,K15M/Metolose 50/90/100 SH 12.567 4.870
4 Triethyl Citrate/ATBC/ATEC/DibutylSebacate/Diethyl Pthallate 2.514 0.974
5 Isopropyl Alcohol q.s
Total 258.048

Manufacturing process: The compositions of Example 2 are manufactured as per the process described in Example 1.

EXAMPLE 3: Extended release formulation of RemogliflozinEtabonate.

IR Pellets
DRUG LOADING
Sr.No. Ingredients mg/cap % w/w
1 Celphere CP-305 (#030/#050 fraction) 52.808 45.840
2 RemogliflozinEtabonate 50.000 43.403
3 Povidone/Plasdone K29/32/HPMC/HPC/Copovidone 10.006 8.686
4 Purified Water/IPA/DCM/Acetone q.s
Total 112.814
BARRIER COAT
1 Drug Loaded Pellets 112.814 97.929
2 Opadry White YS-1-18202-A 2.386 2.071
3 Purified Water q.s
Total 115.200

ER Pellets
FUNCTIONAL COAT (12% w/w)
1 IR Pellets 345.6 79.719
2 Eudragit L100/ L 12.5/HPMC Phthalate 50/55 17.28 3.986
3 Hypromelose K100M,K4M,K15M/Metolose 50/90/100 SH 17.28 3.986
4 Triethyl Citrate/ATBC/ATEC/DibutylSebacate/Diethyl Pthallate 3.456 0.797
5 PEG800/Polysorbate 80 3.456 0.797
6 Purified Water/IPA/DCM/Acetone q.s
Total 387.072
FUNCTIONAL/DR COAT (12% w/w)
7 Function ER Coated Pellets 387.072
8 Eudragit L30D55/ HPMC Phthalate 50/55 42.23 9.741
9 NaOH q.s
10 Triethyl Citrate/ATBC/ATEC/DibutylSebacate/Diethyl Pthallate 4.223 0.974
11 Purified Water/IPA/DCM/Acetone q.s
Total 433.525

Manufacturing process:
A. IR PELLETS
a. DRUG LAYERING
1. Sift the MCC pellets to get #030/040 mesh fraction
2. Dissolve binder in P. water under stirring. Add to it API slowly under stirring.
3. Load the sifted pellets of step 1 into FBP bowl and start spraying drug-binder dispersion over it using suitable process parameters.
4. After completion of drug loading process, dry the drug loaded pellets in FBP for 15 min.

b. SEAL/BARRIER COATING
1. Coating Dispersion: Add and dissolve under stirring Opadry White to P.W.
2. Load the drug loaded pellets into FBP Bowl. And Spray the coating dispersion over DLP using suitable process parameters.
3. After completion of coating process, dry the drug loaded pellets in FBP for 15 min.

B. EXTENDED RELEASE PELLETS (ER PELLETS)
a. FUNCTIONAL COAT
1. Add polymers followed by plasticizer followed by surfactant PW/solvent under stirring
2. Load the IR pellets of Step I to FBP bowl. Spray the polymer dispersion of step 1 over IR pellets using suitable process parameters.
3. After completion of coating process, dry the drug loaded pellets in FBP for 15 min.

b. DELAYED RELEASE COAT
1. Add polymers followed by plasticizer followed by surfactant PW/Solvent under stirring
2. Load the IR pellets of Step I to FBP bowl. Spray the polymer dispersion of step 1 over IR pellets using suitable process parameters.
3. After completion of coating process, dry the drug loaded pellets in FBP for 15 min.

C. PREPARATION OF FINAL CAPSULE DOSAGE FORM
The capsule is filled IR and ER pellets to achieve the desired fill weight.
EXAMPLE 4: Extended release formulation of RemogliflozinEtabonate.
IR Pellets
DRUG LOADING
Sr.No. Ingredients mg/cap % w/w
1 Celphere CP-305 (#030/#050 fraction) 52.808 45.840
2 RemogliflozinEtabonate 50.000 43.403
3 Povidone/Plasdone K29/32/HPMC/HPC/Copovidone 10.006 8.686
4 Purified Water/IPA/DCM/Acetone q.s
Total 112.814

BARRIER COAT
1 Drug Loaded Pellets 112.814 97.929
2 Opadry White YS-1-18202-A 2.386 2.071
3 Purified Water q.s
Total 115.200
ER Pellets
FUNCTIONAL COAT (12% w/w)
1 IR Pellets 345.6 79.719
2 Ethyl Cellulose 17.28 3.986
3 Hypromelose K100M,K4M,K15M/Metolose 50/90/100 SH 17.28 3.986
4 Triethyl Citrate/ATBC/ATEC/DibutylSebacate/Diethyl Pthallate 3.456 0.797
5 PEG800/Polysorbate 80 3.456 0.797
6 Purified Water/IPA/DCM/Acetone q.s
Total 387.072
FUNCTIONAL/DR COAT (12% w/w)
7 Function ER Coated Pellets 387.072
8 Eudragit L30D55/ HPMC Phthalate 50/55 42.23 9.741
9 NaOH q.s
10 Triethyl Citrate/ATBC/ATEC/DibutylSebacate/Diethyl Pthallate 4.223 0.974
11 Purified Water/IPA/DCM/Acetone q.s
Total 433.525

Manufacturing process: The compositions of Example 4 are manufactured as per the process described in Example 3.
Although the invention herein has been described with reference to particular embodiments, it is to be understood that these embodiments are merely illustrative of the principles and applications of the present invention. It is therefore to be understood that numerous modifications may be made to the illustrative embodiments and that other arrangements may be devised without departing from the spirit and scope of the present invention as described above.

All publications and patent applications cited in this application are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated herein by reference.
,CLAIMS:We Claim,

1. An extended release pharmaceutical composition, comprising:
i. an extended release component comprising remogliflozin or salt or ester thereof; and
ii. optionally, an immediate release component comprising remogliflozin or salt or ester thereof;
wherein, the extended release component comprises:
(a) a first population of pellets having a first release rate profile; and
(b) a second population of pellets having a second release rate profile, the second release rate profile being different from the first release rate profile.

2. The extended release pharmaceutical composition as claimed in claim 1, further comprising one or more pharmaceutically acceptable excipients selected from diluents, disintegrants, binders, bulking agents, anti-oxidants, emulsifiers, surfactants, plasticizers, stabilizers, preservatives, lubricants, glidants, and chelating agents.

3. The extended release pharmaceutical composition as claimed in claim 1, wherein the composition comprises a first delayed release (DR1) pellet population, a second delayed release (DR2) pellet population, and an immediate release (IR) pellet population, wherein:
(a) the IR pellet population comprises an inert core, and a layer of remogliflozin or salt or ester thereof surrounding the inert core, the IR pellet population contributing for about 10 to 30% by weight of total amount of remogliflozin or salt or ester thereof in the composition;
(b) the DR1 pellet population comprises an inert core, a layer of a first release controlling material surrounding the inert core, and a layer of remogliflozin or salt or ester thereof disposed between the inert core and the layer of first release controlling material, the DR1 pellet population contributing for about 10 to 30% by weight of total amount of remogliflozin or salt or ester thereof in the composition; and
(c) the DR2 pellet population comprises an inert core, a layer of second release controlling material surrounding the inert core, and a layer of remogliflozin or salt or ester thereof disposed between the inert core and the layer of second release controlling coating, the DR2 pellet population contributing for about 30 to 80% by weight of total amount of remogliflozin or salt or ester thereof in the composition;
wherein the DR1 pellet population and DR2 pellet population have their own specific release rate profile.

4. The extended release pharmaceutical composition as claimed in claim 3, wherein the first release controlling material starts releasing remogliflozin or salt or ester thereof when pH is 5.5 or above; second release controlling starts releasing remogliflozin or salt or ester thereof when pH is 6.0 or above.

5. The extended release pharmaceutical composition as claimed in claim 3, wherein the first release controlling material and the second release controlling material are selected from a group comprising of hypromellose, ethylcellulose, polymethacrylates, a combination of hypromellose and polymethacrylates in a weight ratio of 1:1 to 1:15, a combination of hypromellose and ethylcellulose in a weight ratio of 1:1 to 1:15.

6. The extended release pharmaceutical composition as claimed in claim 3, wherein the first release controlling material provided on the DR1 pellet population is different from the second release controlling material provided on the DR2 pellet population.

7. The extended release pharmaceutical composition as claimed in claim 3, wherein the first release controlling material provided on the DR1 pellet population is same as the second release controlling material provided on the DR2 pellet population, and an amount of release controlling material provided on the DR1 pellet population is different from an amount of release controlling material provided on the DR1 pellet population

8. An extended release pharmaceutical composition, comprising:
i. an extended release component comprising remogliflozin or salt or ester thereof; and
ii. optionally, an immediate release component comprising remogliflozin or salt or ester thereof;
the extended release component comprises a population of pellets having:
an inert core;
a layer of remogliflozin or salt or ester thereof surrounding the inert core;
a layer of an enteric material surrounding the layer of remogliflozin or salt or ester thereof; and
a layer of a release controlling material disposed between the layer of remogliflozin or salt or ester thereof and the layer of enteric polymer.

9. The extended release pharmaceutical composition as claimed in claim 7, further comprising one or more pharmaceutically acceptable excipients selected from release controlling polymer diluents, disintegrants, binders, bulking agents, anti-oxidants, emulsifiers, surfactants, plasticizers, stabilizers, preservatives, lubricants, glidants, and chelating agents.

10. The extended release pharmaceutical composition as claimed in claim 7, wherein the composition comprises an extended release (ER) pellet population and an immediate release (IR) pellet population, wherein:
(a) the IR pellet population comprises an inert core, and a layer of remogliflozin or salt or ester thereof surrounding the inert core, the IR pellet population contributing for about 10 to 40% by weight of total amount of remogliflozin or salt or ester thereof in the composition; and
(b) the ER pellet population comprises an inert core; a layer of remogliflozin or salt or ester thereof surrounding the inert core; a layer of an enteric material surrounding the layer of remogliflozin or salt or ester thereof; and a layer of a release controlling material disposed between the layer of remogliflozin or salt or ester thereof and the layer of enteric polymer, the ER pellet population contributing for about 60 to 90% by weight of total amount of remogliflozin or salt or ester thereof in the composition.

11. The extended release pharmaceutical composition as claimed in claim 7, wherein the layer of enteric material begins to dissolve at pH 5.5 or above and exposes the layer of release controlling material.

12. The extended release pharmaceutical composition as claimed in claim 7, wherein the release controlling material starts releasing remogliflozin or salt or ester thereof when pH is 5.5.

13. A process for preparing an extended release pharmaceutical composition as claimed in claim 1, comprising:
• preparing an extended release component comprising remogliflozin or salt or ester thereof; and
• optionally, preparing an immediate release component comprising remogliflozin or salt or ester thereof and mixing the same with the extended release component;
wherein preparing the extended release component comprises:
(a) preparing a first population of pellets having a first release rate profile;
(b) preparing a second population of pellets having a second release rate profile, the second release rate profile being different from the first release rate profile; and
(c) mixing the first population of pellets and the second population of pellets.

14. A process for preparing an extended release pharmaceutical composition as claimed in claim 7, comprising:
• preparing an extended release component comprising remogliflozin or salt or ester thereof; and
• optionally, preparing an immediate release component comprising remogliflozin or salt or ester thereof and mixing the same with the extended release component;
wherein preparing the extended release component comprises:
preparing a population of pellets having an inert core;
providing on the inert core a layer of remogliflozin or salt or ester thereof to obtain a remogliflozin coated inert core;
providing a layer of a release controlling material on the remogliflozin coated inert core to obtain release controlling material coated inert core; and
providing a layer of an enteric material on the release controlling material coated inert core to obtain the extended release component.