Filed of the invention:
The present invention relates to stable pharmaceutical compositions of Sodium Glucose Co-Transporter-2 inhibitor. Specifically the invention relates to stable pharmaceutical compositions of Canagliflozin and method of preparing them.
Background of invention:
Gliflozin drugs are a class of medications that inhibit reabsorption of glucose in the kidney and therefore lower blood sugar. They act by inhibiting sodium-glucose transport protein 2 (SGLT2), and are therefore also called SGLT2 inhibitors. Gliflozins are used in the treatment of type [I diabetes mellitus (T2DM). Canagliflozin is member of this class first marketed for the treatment of type 2 diabetes mellitus by Janssen Pharma in USA under the brand name ofInvokana®.
Chemically Canagliflozin is (IS)-1,5-anhydro-1 -[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]-D-glucitol and it is marketed in the form of hemihydrate. Structurally canagliflozin hemihydrate is:
Canagliflozin is marketed (under Invokana® brand) as film-coated tablets containing combination of microcrystalline cellulose and lactose as diluents, hydroxylpropyl cellulose as binder, croscarmellose sodium as disintegrant, and magnesium stearate as lubricant in the core tablet.

Polymorphic forms of a drug substance have different chemical and physical properties, including melting point, chemical reactivity, apparent solubility, dissolution rate, optical and mechanical properties, vapor pressure, and density. These properties can have a direct effect on the ability to process and/or manufacture the drug substance and the drug product, as well as on drug product stability, dissolution, and bioavailability. As per the USFDA Guideline "ANDAs: Pharmaceutical Solid polymorphism" FDA and all other Regulatory agencies has made requirement for study of polymorph conversion during manufacturing and shelf-life of finished product, as the conversion will adversely affect stability, dissolution and bioavailability of finished product.
Canagliflozin exist in different polymorphs, there is always possibility of polymorph conversion during manufacturing of finished product and also during shelf-life. Hence, this need to be monitored during finished product manufacturing and also shelf-life. As per EMA Assessment report for Invokana®, it disclosed that Canagliflozin shows Polymorphism and most stable Form is hemihydrate form (Form I) and unstable form is Amorphous form (Form II). Form I is (hemihydrate form) is used in the manufacture of the finished product. So the commercial product of Invokana® contains stable Form I.
U.S. Patent No. 7,943,788 disclose many compounds including Canagliflozin and its salts for treatment of diabetes mellitus or diabetic complications such as diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, obesity, and delayed wound healing. It also discloses canagliflozin and its salts may be used in combination with other agents like PKC inhibitors and/or ACE inhibitors for treatment of diabetic complications.
U.S. Patent No. 7,943,582 discloses stable crystalline hemihydrate form and also discloses that amorphous form is obtained via the process disclosed in WO 2005/012326 patent publication which is not easy to isolate, filter and handle in the commercial scale. It also discloses that crystalline hemihydrate form is more stable than amorphous. Crystalline hemihydrate form is characterized by FTIR, Thermogravimetric Analysis (TGA) and X-Ray Powder Diffraction methods.

U.S. Patent Publication Nos. 20120115799;-US20130338087 and 2015000524 disclose marketed composition .of Invokana®. It discloses formulations containing canagliflozin hemihydrate form and also discloses wet granulation by fluid bed/direct mixture process for preparation of pharmaceutical dosage forms. It also discloses in all the examples that combination of microcrystalline cellulose and lactose or silicifled microcrystalline cellulose and lactose as diluents in equal ratio. Further discloses compositions containing combination of two diluents (silicified microcrystalline cellulose/ microcrystalline cellulose and lactose) showed good bioavailability.
U.S. Patent Publication No. 20130052266 discloses composition of canagliflozin tablets. It discloses formulations containing canagliflozin hemihydrate form and also discloses wet granulation by high-shear granulator process for preparation of tablet dosage form. It also discloses D-mannitol is preferred diluent and combination of sodium stearyl fumarate and talc as lubricants are preferred to achieve good compressibility of tablets.
U.S. Patent Publication No. 20160083374 discloses stable amorphous form of canagliflozin and also discloses amorphous solid dispersion of canagliflozin containing canagliflozin and polymer . selected from hydroxypropylmethyl cellulose acetate succinate (HPMC-AS), hydroxypropylmethyl cellulose (HPMC), methacrylic acid copolymers, polyvinyl pyrrolidone (PVP).
U.S. Patent Publication No. 20160002275 discloses, canagliflozin complex with-an adsorbent selected from activated carbon, silica gel, ionic or non-ionic polymer, a cyclodextrin or derivatives.-These complexes are used for the preparation of canagliflozin amorphous form.
WO2016030502 Publication discloses non-stoichiometric hydrate forms and amorphous form of Canagliflozin and also discloses formulations containing these forms. It also discloses that formulations should be prepared by dry process. It further discloses tablet manufacturing process should be done in low Relative Humidity (less than 40%, preferably less than 20%) conditions instead of normal GM.P conditions of 60% Relative Humidity to control polymorphic conversion

of canagliflozin during manufacturing process. It further discloses that the excipients should be dried before use.in the formulation.. Tt further discloses that water activity is very important for polymorphic conversion and stable formulations should contain less than 0.4% of water activity. The disclosed formulations in this application contain two disintegrants. The examples disclosed in this application use two types of disintegrants (low substituted hydroxypropyl cellulose and Croscarmellose sodium/Crospovidone) to achieve dissolution.
Chinese Publication No. 103655539 discloses canagliflozin oral solid composition containing average particle size of canagliflozin is 2.5 -30u and the canagliflozin is in amorphous form. It discloses that particle size is very important for meeting quality parameters like hardness and dissolution. The tablet dosage form containing optimized particle size of 2.5 -30u is only achieved quality parameters and higher particle size did not achieve quality parameters. It also discloses combination of two diluents (microcrystalline cellulose and lactose) in the compositions.
WO 2017036389 discloses solid dispersion of canagliflozin containing amorphous canagliflozin, wherein the solid dispersion is prepared by dissolving canagliflozin, auxiliary excipient, organic solvent, heating the solution and evaporating/drying the solution to form solid dispersion.-Also discloses that the obtained solid dispersion is in amorphous form and shows very good dissolution and stability.
Indian Application No. 0946/CHE/2015 discloses amorphous solid dispersion of canagliflozin with Hydroxypropyl cellulose as carrier. Also discloses process for preparing solid dispersion comprising mixing canagliflozin, pharmaceutical excipient and organic solvent, removing the organic solvent to obtain amorphous solid dispersion of canagliflozin.
Chinese Publication No. 105769803 discloses solid dispersion of canagliflozin with water soluble solid carrier. Also discloses process for preparing solid dispersion comprising mixing canagliflozin; water soluble solid carrier, pharmaceutical excipients, organic solvent and heating the mixture to obtain solution and then drying the solution to form solid dispersion.

Chinese Publication No. 106606489 disclose solid dispersion of canagliflozin containing canagliflozin, solid carrier like povidone and other pharmaceutically.acceptable excipients. Also discloses process for preparing solid dispersion comprising dissolving canagliflozin, solid carrier in a solvent and removing the solvent to form solid dispersion.
WO 2016041530 publication discloses complex of canagliflozin with cyciodextrin and its process for preparing complex.
Chinese Publication No. 104586795 disclose solid dispersion of canagliflozin containing hydroxypropyl cellulose as carrier material.
Chinese Publication No. 104382859 disclose solid dispersion of canagliflozin containing canagliflozin, crystal inhibitor and filler in the ratio of 10: 0 5 to 10: 0.5 to 20.
The above prior arts disclose various formulations of canagliflozin containing two diluents or two disintegrants or solid dispersion process with various types of excipients in order to get good bioavailability, compressibility and dissolution and also use dry conditions during manufacturing process (less than 40% Relative Humidity). Dry conditions mentioned in the prior art requires additional manufacturing facility/equipment. Solid dispersion compositions disclosed in the prior-art require organic solvents and additional step of heating and followed drying/evaporating compared to normal routine manufacturing process. None of the above prior arts disclosed simple formulations containing one diluent, one disintegrant, without using organic solvents and simple process. Hence, there is a need to develop simple. formulation and process for canagliflozin solid oral dosage form.
Summary of the invention:
In one embodiment, the present invention provides stable pharmaceutical composition comprising canagliflozin, one diluent, one disintegrant and one or more pharmaceutically acceptable excipients.

In another embodiment, the present invention provides process for preparing stable pharmaceutical composition of canagliflozin, wherein the process is dry granulation process.
Detailed description of the invention:
In one aspect of the present invention provides stable pharmaceutical composition of canagliflozin comprising one diluent, one disintegrant, and one or more pharmaceutically acceptable excipients.
In another aspect of the present invention provides process for preparing canagliflozin composition, wherein the process is dry granulation process.
"Stable" according to the present invention is defined as the there is no polymorphic conversion of canagliflozin or its salt thereof from one polymorphic form to another polymorphic form or from amorphous form to polymorphic form or from polymorphic form to amorphous form during manufacturing and shelf-life of finished product. Alternatively "Stable" may also be defined as polymorphic form or amorphous form used as starting material in the pharmaceutical composition remain maintains the same form during manufacturing and shelf-life of finished - product.
"One diluent" according to the present invention is defined as only one diluent is used instead of two diluents disclosed in prior-art.
One diluent that may be used according to the present invention is selected from the group consisting of microcrystalline cellulose, mannitol, lactose, starch, maize starch, wheat starch, potato starch, pregelatinized starch, calcium hydrogen phosphate, calcium silicate, sorbitol, sucrose, dicalcium phosphate. Preferably single diluent is microcrystalline cellulose and mannitol. Diluent is present in an amount of about l0%-45% w/w.
"One disintegrant" according to the present invention is defined as only one disintegrant is used instead of two disintegrants disclosed in prior-art.
Single disintegrant that may be used according to the present invention is selected from the group consisting of sodium starch glycolate, Crospovidone, low substituted hydroxypropyl

cellulose, croscarmeltose sodium, croscarmellose potassium, starch, silicified microcrystalline cellulose, polacriiin potassium. Preferably single disintegrant is croscarmellose sodium. Disintegrant is present in an amount of about l%-20% w/w.
One or more pharmaceutical^ acceptable excipients according to the present invention are selected from the group of binder, glidant, lubricant etc.
Suitable binders that may be used according to the present invention are selected from the group consisting of povidone, microcrystalline cellulose, alginic acid, starch, potato starch, wheat . starch, corn starch, hydroxy propyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, gelatin and combinations thereof. Preferably the binder is microcrystalline cellulose and starch. Binder is present in an amount of about l%-25% w/w.
Suitable lubricants that may be used according to the present invention are selected from the group consisting of stearic acid, magnesium stearate, sodium stearyl fumarate, fumaric acid, - calcium stearate, hydrogenated vegetable oil, stearic acid, glyceryl behenate, and combinations thereof. Preferably lubricant is magnesium stearate. Lubricant is present in an amount of about 0.5%-4.0% w/w.
Suitable glidants that may be used according to the present invention are selected from the group consisting of calcium phosphate tribasic, powdered cellulose, colloidal silicon dioxide, magnesium oxide, magnesium silicate, magnesium trisilicate, starch, talc and combinations thereof. Preferably glidant is colloidal silicon dioxide. Glidant is present in an amount of about 0.5%-4.0% w/w.
The stable pharmaceutical composition of the present invention comprises either crystalline or amorphous form of canagliflozin or its salt thereof. Preferably the pharmaceutical composition contains amorphous form of canagliflozin.
The stable pharmaceutical composition of the present invention may be compressed into tablets, filled into capsules or filled into sachets.

The tablets of the present invention may be film-coated. Film-coating polymers used according to the present invention are selected from hydroxypropyl methylcellulose, polyvinyl alcohol, hydroxypropyl cellulose and combination thereof.
In another aspect of the present invention provides stable pharmaceutical composition comprising canagliflozin in an amount of about 40-60% w/w, one diluent in an amount of about 10-45% w/w, one disintegrant in an amount of about 1-20% w/w, and one or more pharmaceutically acceptable excipients.
In another aspect of the present invention provides stable pharmaceutical composition comprising canagliflozin in an amount of about 40-60% w/w, one diluent in an amount of about 10-45% w/w, one disintegrant in an amount of about 1-20% w/w, binder in an amount of about 1 -25% w/w, lubricant in an amount of about 0.5 to 4.0 % w/w, glidant in an amount of about 0.5-4.0 % w/w.
The % weight by weight as mentioned in the specification is based on the total weight of the composition.
In another aspect of the present invention provides use of stable pharmaceutical composition of canagliflozin for the treatment of diabetes mellitus.
In another aspect of the present invention provides stable pharmaceutical composition of canagliflozin can be co-administered with any other pharmaceutically acceptable active ingredient.
In another aspect, the stable pharmaceutical composition of the present invention is prepared by:.
a) Mixing canagliflozin with at least one excipient
b) granulate the mixture of step a) using dry granulation to form granules,
c) blending granules of step b) with other inactive ingredients
d) compress the blend of step c) into tablets or fill into capsules/sachets
The dry granulation process according to the present invention is prepared either by roller compaction or slugging and de-slugging process.

In .another aspect, the stable pharmaceutical composition of present invention is prepared by:
a) Mixing canagliflozin, diluent, disintegrant, optionally glidant and optionally lubricant . b) granulate the mixture of step a) using dry granulation to form granules,
c) blending granules of step b) with optionally diluent, optionally disintegrant, optionally glidant and lubricant
d) compress the blend of step c) into tablets or fill into capsules/sachets
The invention is further illustrated by following non-limiting examples:
Manufacturing process:
a) Sifting: Sifted Canagliflozin, microcrystalline cellulose, "Croscarrriellose sodium, Colloidal Silicon Dioxide through # 20 sieve and Magnesium stearate through # 30 sieve

. b) Dry blending: Transferred sifted canagliflozin, microcrystalline cellulose, Croscarmellose sodium, Colloidal Silicon Dioxide, Magnesium stearate into blender and blended for 10 minutes
c) Dry Granulation: Granulated step b) blend using roller compacter to form granules
d) Blending: Blended granules of step c) with extragranular quantities of microcrystalline
cellulose, Croscarmellose sodium, Colloidal Silicon Dioxide, into blender and blended for 10
minutes
e) Lubrication: Added Magnesium stearate in the blend of step d) and blended for 5 minutes
f) Compression: Compressed the blend of step e) into tablets
g) Film coating: Film coated the tablets using aqueous solution of Opadry white
The tablets of Example 1 are packed in HDPE bottle and analyzed for polymorphic conversion by X-ray diffraction using the method described in US 7943582 patent and the results of the same are given below in Table 1:
From the above data it is evident that there is no form conversion for Example 1 tablets at initial and tablets stored at 40°C/75%RH for 3 months.
Also Example 1 tablets are analyzed for dissolution profile in USP Type 2 Apparatus, 600ml, 75rpm using 0.75 % sodium lauryl sulfate (SLS) in water as dissolution medium and results are given in Table 2.
From the above results it is evident that composition with one diluent and one disintegrant produces similar dissolution profile to that of Reference Product.

The tablets of Example 2 are packed in HDPE bottle and are analyzed for polymorphic conversion by X-ray diffraction using the method described in US 7943582 patent and the results of the same are given below in Table 3:

From the above data it is evident that there is no polymorphic form conversion for Example 2 tablets at initial and tablets stored at 40°C/75%RH for 6 months.
Also Example 2 tablets are analyzed for dissolution profile in USP Type 2 Apparatus, 600ml, 75rpm using 0.75 % sodium lauryl sulfate (SLS) in water as dissolution medium and results are given in Table 4.
From the above results it is evident that composition with one diluent and one disintegrant produces similar dissolution profile to that of Reference Product.

Manufacturing process:
a) Sifting: Sifted Canagliflozin, microcrystalline cellulose and Croscarmellose sodium through # 20 sieve
b) Blending: Transferred sifted canagliflozin, microcrystalline cellulose, Croscarmellose sodium into rapid mixer granulator and blended for 5 minutes
c) Wet Granulation: Granulated step b) blend with purified water and dried the granules
d) Blending: Blended granules of step c) with extragranular quantities of microcrystalline
cellulose, Croscarmellose sodium, Colloidal Silicon Dioxide, into blender and blended for 10
minutes
e) Lubrication: Added Magnesium stearate in the blend of step d) and blended for 5 minutes •
f) Compression: Compressed the blend of step e) into tablets

g) Film coating: Film coated the tablets using aqueous solution of Opadry white
The tablets of Comparative Example 1 are packed in HDPE bottle and analyzed for polymorphic conversion by X-ray diffraction using the method described in US 7943582 patent and the results of the same are given below in Table 5:
From the above data it is observed that polymorphic form conversion was observed when the composition prepared using wet granulation process, whereas the composition prepared using dry granulation process as mentioned in Examples 1 and 2 did not show any polymorphic conversion.

We Claim:
1. Stable pharmaceutical composition of Canagliflozin, wherein the composition comprises canagliflozin, one diluent, one disintegrant and one or more pharmaceutically acceptable excipients.
2. Stable pharmaceutical composition of Canagliflozin according to Claim 1, wherein one or more pharmaceutically acceptable excipients are selected from binder, lubricant and glidant.
3. Stable pharmaceutical composition of Canagliflozin according to Claim 1, wherein canagliflozin is present in an amount of about 40-60% w/w, one diluent is present in an amount of about 10-45% w/w, one disintegrant is present in an amount of about 1-20% w/w, and one or more pharmaceutically acceptable excipients.
4. Stable pharmaceutical composition of Canagliflozin according to Claim 1, wherein canagliflozin is present in an amount of about 40-60% w/w, one diluent is present in an amount of about 10-45% w/w, one disintegrant is present in an amount of about 1-20% w/w,. binder is present in an amount of about 1-25% w/w, lubricant is present in an amount of about 0.5 to 4.0 % w/w and glidant is present in amount of about 0.5- 4.0 % w/w.
5. A process for preparing stable pharmaceutical composition of Canagliflozin, wherein the process is dry granulation process.
6. A process according to Claim 5, wherein dry granulation process is prepared by roller compaction or slugging and de-slugging process.
7. A process according to Claim 5, wherein the process comprises:

a) Mix canagliflozin with at least one excipient
b) granulate the mixture of step a) using dry granulation to form granules,

c) blend granules of step b) with other inactive ingredients
d) compress the blend of step c) into tablets or fill into capsules/sachets.

8. Stable pharmaceutical composition of Canagliflozin comprises one diluent, one disintegrant and one or more pharmaceutically acceptable excipients, wherein the composition is prepared by dry granulation process.
9. Stable pharmaceutical composition of Canagliflozin according to Claim 8, wherein canagliflozin is present in an amount of about 40-60% w/w, one diluent is present in an amount of about 10-45% w/w, one disintegrant is present in an amount of about 1-20% w/w, and one or more pharmaceutically acceptable excipients.