DESC:FIELD OF INVENTION

The present invention relates to stable oral pharmaceutical compositions comprising Dapagliflozin and one or more pharmaceutically acceptable excipients and process for their preparation.

BACKGROUND

Dapagliflozin is chemically known as (2S,3R,4R,5S,6R)-2-[4- chloro-3-(4-ethoxybenzyl)phenyl]-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol which can be characterized by the following chemical formula:

Dapagliflozin being approved as Farxiga® in US and Forxiga® / Edistride® in EU, is an orally active sodium-glucose co-transporter-2 (SGLT2) inhibitor and is used in the treatment of patients with Type 2 diabetes. By inhibiting the transporter protein SGLT2 in the kidneys, dapagliflozin reduces renal glucose reabsorption, leading to urinary glucose excretion and reduction in blood glucose levels.

US patent no. 6,515,117 discloses the compound Dapagliflozin and its process for preparation. PCT publication no. WO 2008/002824 discloses crystalline solvates of Dapagliflozin particularly, dapagliflozin propylene glycol and/or its hydrate in crystalline form and its process of preparation. PCT publication no. WO 2008/116179 discloses immediate release pharmaceutical composition comprising Dapagliflozin or Dapagliflozin propylene glycol with one or more other excipients.

The active ingredient of the approved product Farxiga® is Dapagliflozin propylene glycol hydrate. The active ingredient has been explored in various solid state forms such as crystalline Dapagliflozin (or propylene glycol hydrate or other pharmaceutically acceptable solvates thereof), amorphous Dapagliflozin (or propylene glycol hydrate or other pharmaceutically acceptable solvates thereof) and co-crystals of Dapagliflozin or Dapagliflozin propylene glycol hydrate.

It is reported that Dapagliflozin is hygroscopic in nature and thus it absorbs water and forms sticky lumps causing difficulty in handling and processing ultimately leading to content uniformity problems in formulating a solid dosage form. Besides these, dapagliflozin shows polymorphic instability on exposure to heat and moisture which leads to storage and processing issues for formulation.

PCT publication no. WO 2013/079501 discloses crystalline dapagliflozin hydrate where Dapagliflozin is present in substantially pure crystalline form and its pharmaceutical composition. PCT publication no. WO 2012/163546 discloses pharmaceutical compositions comprising Dapagliflozin and cyclodextrin preferably as an inclusion complex with an objective to provide Dapagliflozin in a non-hygroscopic form having high solubility, high permeability and showing high storage stability. PCT publication no. WO 2015/011113, WO 2015/104658 and WO 2015/128853 disclose amorphous solid dispersion of dapagliflozin with one or more excipients and adsorbate comprising amorphous dapagliflozin adsorbed onto the surface of an adsorbate where Dapagliflozin is more stable, has superior solubility and has better processing abilities. US 2015/0307540 discloses an amorphous form of Dapagliflozin 1, 2-propanediol or hydrates and its solid dispersion.

Despite several solid oral dosage forms available in the art, there remains an unmet need to develop a stable pharmaceutical dosage form using Dapagliflozin more particularly in an amorphous form. It was surprisingly found by the inventors of the application that Dapagliflozin was stable in the formulation of present invention which can be stored at ambient conditions of storage and also achieves polymorph stability.

SUMMARY OF THE INVENTION

One aspect of the present invention is to provide a stable solid oral composition comprising (a) dapagliflozin, optionally one or more pharmaceutical excipient(s) and (b) inert granules comprising one or more diluent(s), one or more binder(s) and optionally one or more pharmaceutical excipient(s), wherein said inert granules are substantially free of dapagliflozin.

Another aspect of the present invention is to provide a stable solid oral composition comprising (a) amorphous dapagliflozin, optionally one or more pharmaceutical excipient(s) and (b) inert granules comprising one or more diluents(s), one or more binder(s) and optionally one or more pharmaceutical excipient(s), wherein said inert granules are substantially free of dapagliflozin.

Another aspect of the present invention is to provide process for preparation of a stable solid oral composition comprising:
a) Granulating one or more diluents(s), one or more binder(s) and optionally one or more pharmaceutical excipient(s) to prepare inert granules,
b) Mixing Dapagliflozin and optionally one or more excipient(s) to the said inert granules prepared in step (a), wherein said inert granules are substantially free of Dapagliflozin.

Figures
Fig 1: XRPD data of Dapagliflozin tablets prepared by Example 1 initial.
Fig 2: XRPD data of Dapagliflozin tablets prepared by Example 1 after 2 months of storage at 40°C/75% RH in HDPE bottle packaging.
Fig 3: XRPD data of Dapagliflozin tablets prepared by Example 1 after 6 months of storage at 40°C/75% RH in HDPE bottle packaging.

DETAIL DESCRIPTION OF THE INVENTION

The following paragraphs detail various embodiments of the invention. For the avoidance of doubt, it is specifically intended that any particular feature(s) described individually in any one of these paragraphs (or part thereof) may be combined with one or more other features described in one or more of the remaining paragraphs (or part thereof). In other words, it is explicitly intended that the features described below individually in each paragraph (or part thereof) represent important aspects of the invention that may be taken in isolation and combined with other important aspects of the invention described elsewhere within this specification as a whole, and including the examples and figures. The skilled person will appreciate that the invention extends to such combinations of features and that these have not been recited in detail here in the interests of brevity.

The use of the terms “a” and "an” and "the” and similar referents in the context of describing the invention (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context.

The term “Dapagliflozin” as used herein means Dapagliflozin as a free base. Dapagliflozin may be in amorphous form, crystalline form, a mixture thereof or co- crystals with suitable co-formers. Preferably, Dapagliflozin base is in amorphous form.

Suitable co-former according to present invention, includes but not limited to oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, fumaric acid, citric acid, terephthalic acid, pyroglutamic acid, mandelic acid, ascorbic acid, tartaric acid, benzoic acid and its derivatives such as p-amino benzoic acid and p-chloro benzoic acid and the like.

The term “substantially free” as used herein means less than 10% of Dapagliflozin is present in the inert granules. Preferably, less than 5%, most preferably less than 1% of Dapagliflozin is present in the inert granules.

The term “w/w” as used herein means weight of component by total weight of composition, unless specified otherwise.

The term “adding” “added” “mixing” “mixed” “blended” and “blending” as used herein are to be interpreted inclusively, unless the context requires otherwise. That is, the use of these words may imply mixing, adding or blending one or more excipient(s) with each other or with inert granules or with Dapagliflozin to form mixture or blend.

First embodiment of the present invention is to provide a stable solid oral composition comprising (a) dapagliflozin, optionally one or more pharmaceutical excipient(s) and (b) inert granules comprising one or more diluents(s), one or more binder(s) and optionally one or more pharmaceutical excipient(s), wherein said inert granules are substantially free of dapagliflozin.

A preferred embodiment of the present invention is to provide a stable solid oral composition comprising (a) dapagliflozin, disintegrant, glidant and lubricant, (b) inert granules comprising diluent, disintegrant and binder, wherein said inert granules are substantially free of dapagliflozin.

The particle size, D90 of dapagliflozin as used herein, ranges from 5µ to 500µ, preferably from 10µ to 250µ, more preferably from 10µ to 50µ, most preferably 30µ.
Particle size and its distribution can be determined by any suitable method from methods such as Sieve analysis, sedimentation, Light scattering, Acoustic methods, X-ray scattering, electron microscopy, Raman spectroscopy, Laser diffraction and other conventional methods known to those of skill in the art. Various instruments offering particle size measurement such as Malvern Mastersizer, Malvern Zetasizer and others may be used.

Another preferred embodiment of the present invention is to provide a stable solid oral composition comprising (a) 1-10 % dapagliflozin, 1-5 % disintegrant, 1-5 % glidant and 0.1-2 % lubricant, (b) inert granules comprising 80-85% diluent, 1-5 % disintegrant and 1-5 % binder, wherein said inert granules are substantially free of dapagliflozin.

Another preferred embodiment of the present invention is to provide a stable solid oral composition comprising (a) dapagliflozin, Crospovidone, colloidal silicon dioxide and magnesium stearate, (b) inert granules comprising Lactose anhydrous, microcrystalline cellulose, Crospovidone and PVP K-30, wherein said inert granules are substantially free of dapagliflozin.

In a preferred embodiment of the present invention, dapagliflozin used is in an amorphous form.

Another preferred embodiment of the present invention is to provide a stable solid oral composition comprising (a) 4.77 % amorphous dapagliflozin, 1.94 % Crospovidone, 1.46 % colloidal silicon dioxide and 0.73 % magnesium stearate, (b) inert granules comprising 19.6 % Lactose anhydrous, 63.8 % microcrystalline cellulose, 1.94 % Crospovidone and 3 % PVP K-30, wherein said inert granules are substantially free of dapagliflozin.

According to the present invention, inert granules are prepared by mixing one or more diluents(s), preferably lactose anhydrous and microcrystalline cellulose with one or more disintegrant(s), preferably crospovidone and granulating the prepared mixture with aqueous or non aqueous solution of binder, preferably aqueous solution of PVP K-30. The inert granules so prepared are blended with the extragranular component containing Dapagliflozin and one or more pharmaceutical excipient(s).

The extragranular component is prepared by mixing Dapagliflozin with one or more disintegrant(s) preferably Crospovidone, one or more glidant(s) preferably colloidal silicon dioxide and one or more lubricant(s) preferably magnesium stearate.

Another embodiment of the present invention is to provide process for preparation of a stable solid oral composition comprising:
a) Granulating one or more diluents(s), one or more binder(s) and optionally one or more pharmaceutical excipient(s) to prepare inert granules,
b) Mixing Dapagliflozin and optionally one or more excipient(s) to the said inert granules prepared in step (a), wherein said inert granules are substantially free of Dapagliflozin.

A preferred embodiment of present invention provides a process for preparation of a composition comprising:
a) Granulating one or more diluents(s), one or more binder, and optionally one or more disintegrant(s) to prepare inert granules
b) Mixing Dapagliflozin and one or more disintegrant, one or more glidant, one or more lubricant with said inert granules prepared in step (a)
c) Compressing the blend/mixture obtained in step (b)
d) Optionally, coating the compressed tablet of step (c).

Pharmaceutical excipient according to present invention comprises diluent, binder, disintegrant, lubricant, glidant and the like.

Compositions according to present invention may optionally further comprise one or more stabilizer, anti oxidant, coloring agent and the like. Example and suitable amount of said optional excipient is known to a skilled person or as given in Handbook of pharmaceutical excipients (sixth edition, 2009).

Diluent according to present invention includes but not limited to powdered cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, starch, pregelatinized starch, dibasic calcium phosphate, tribasic calcium phosphate, dibasic sodium phosphate, tribasic sodium phosphate, calcium carbonate, magnesium carbonate, calcium bicarbonate, magnesium bicarbonate magnesium oxide, calcium sulfate; sugars such as dextrose, lactose (monohydrate or anhydrous), fructose or sucrose, maltose maltodextrin; sugar alcohols such as mannitol, sorbitol, xylitol, lactitol, maltitol or erythritol; dextrin, kaolin and mixtures thereof. Preferably, lactose anhydrous and microcrystalline cellulose are used. The diluents(s) may be present in an amount ranging from 50 % to 90 % by weight of the composition. Preferably, the diluents are present in an amount ranging from 80-85 % w/w of the total weight of the composition.

Binder according to present invention includes but not limited to polyvinyl alcohol, polyvinyl acetate, starch, pregelatinised starch; cellulose derivatives such as cellulose powder, microcrystalline cellulose, hydroxypropyl methylcellulose, ethyl cellulose, methyl cellulose, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, hydroxyethyl cellulose, carboxymethylcellulose sodium, carboxymethylcellulose calcium; carbomers, dextrin, gelatin, zein, shellac, polymethacrylates, povidone (PVP), copovidone, sodium alginate, alginic acid; gums such as xanthan gum, guar gum, locust bean gum, carrageenan, acacia, tragacanth, synthetic resins or mixtures thereof. Preferably, PVP-K30 is used. The binder may be present in an amount ranging from 0.5 % to 10 % by weight of the composition, preferably from 1 % to 5 % by weight of the composition.

Disintegrant according to present invention includes but not limited to carboxymethyl cellulose and its salt including sodium or calcium salt, cross-linked carboxymethyl cellulose sodium, cross-linked carboxymethyl cellulose calcium, cross-linked polyvinylpyrrolidone (crospovidone), microcrystalline or microfine or powdered cellulose, silicified microcrystalline cellulose, sodium alginate; starch derivatives such as maize starch, rice starch, pregelatinized starch; cross-linked N-vinyl-2-pyrrolidone ("CLPVP") (marketed under the trade names Polyplasdone® XL and Polyplasdone® XL-10), sodium starch glycollate, low substituted hydroxypropyl cellulose and mixtures thereof. Preferably, cross-linked polyvinylpyrrolidone (crospovidone) is used. Pharmaceutical composition comprises disintegrant in the amount of 0.2 % to 10 % by weight of the total composition. The disintegrant can be divided equally or unequally into intragranular and extragranular portions. Preferably, the pharmaceutical composition may comprise of 1 - 5 % disintegrant intragranular and 1 – 5 % disintegrant extragranular of the total weight of the composition

Granulating solvent may be selected from water, isopropyl alcohol, ethanol, methanol, acetone, methylene chloride or mixtures thereof. Preferably, water is used. Granulating solution according to the present invention is a mixture of any binder in the granulating solvent. Preferably, PVP K-30 is dissolved in water to form a granulating solution.

Stabilizer according to present invention includes but not limited to ascorbic acid, ascorbic palmitate, Vitamin E, butylated hydroxyanisole, butylated hydroxy toluene, hypophosphorous acid, monothioglycerol, propyl gallate, sodium ascorbate, sodium bisulfite, sodium formaldehyde sulfoxylate, citric acid, tartaric acid, succinic acid amino acids such as leucine, arginine, glycine, cysteine and the like; sodium metalbisulfite and mixture thereof. The stabilizer may be present in an amount ranging from 0.1% to 20% by weight of the composition.

Anti-oxidant according to present invention includes but not limited to butylated hydroxanisole, sodium ascorbate, butylated hydroxytoluene, sodium metabisulfate, malic acid, citric acid, ascorbic acid; and mixtures thereof. The anti-oxidant may be present in an amount ranging from 0.01 to 3% by weight of the composition.

Lubricant according to present invention includes but not limited to metallic stearates such as magnesium stearate, calcium stearate, zinc stearate; stearic acid, sodium stearyl fumerate hydrogenated vegetable oil, hydrogenated castor oil, glyceryl palmitostearate, glyceryl behenate, polyethylene glycols, corn starch, sodium stearyl fumarate, sodium benzoate, mineral oil, talc and mixture thereof. Preferably, magnesium stearate is used. The lubricant may be present in an amount ranging from about 0.1 % to about 10 % by weight of the composition. Preferably, the lubricant may be present in an amount ranging from about 0.1 % to about 2 % by weight of the composition.

Glidant according to present invention includes but not limited to talc, colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch, tribasic calcium phosphate or mixture thereof. Preferably, colloidal silicon dioxide is used. The glidant may be present in an amount ranging from about 0.1 % to about 10 % by weight of the composition. Preferably, the glidant may be present in an amount ranging from about 1 % to about 5 % by weight of the composition.

Coating agent according to the present invention includes cellulose derivatives such as hydroxypropyl methylcellulose (hypromellose), hydroxypropyl cellulose, ethyl cellulose, methyl cellulose; polyvinyl compounds such as polyvinyl alcohol, polyvinyl pyrrolidone (povidone), polyvinyl acetal diethylaminoacetate, polyvinyl acetate; acrylate derivatives such as aminoalkyl methacrylate copolymer RS, ethyl acrylate-methyl methacrylate copolymer; saccharides such as sucrose, Mannitol and the mixture thereof. Preferably, polyvinyl alcohol based coating is used.

The coating material may further include plasticizers such as polyethylene glycols, propylene glycol, dibutyl phthalate, dibutyl sebacate, glycerin fatty acid esters, sucrose fatty acid esters, castor oil, triethyl citrate, triacetin; a lubricant/glidant such as stearic acid, magnesium or calcium stearate, talc; coloring agent such as iron (II) oxide, iron (III) oxide or titanium oxide.

Stable solid oral composition according to the present invention comprises active ingredient Dapagliflozin in an amount of 2-20 %, preferably about 5 % w/w of the total weight of the composition.
Solid oral composition according to present invention can be in the form of tablet, capsule, powder or sachet. Preferably solid oral composition according to present invention is a film-coated tablet.

Another embodiment of present invention provides use of the composition prepared according to present invention for treatment of Type II Diabetes Mellitus.

The invention will be further illustrated by the following examples, however, without restricting its scope to these embodiments.

Example 1
Sr. No. Ingredients % w/w

Inert granules
1. Lactose Anhydrous 19.26
2. Microcrystalline cellulose 63.8
3. Crospovidone 1.94
4. Povidone K-30 3.00
5. Water q.s.
Extragranular material
6. Dapagliflozin (amorphous) 4.77
7. Crospovidone 1.94
8. Aerosil 1.46
9. Magnesium stearate 0.73
Coating
10. Opadry (PVA based) 3.10
Total 100.00

Lactose anhydrous, microcrystalline cellulose and Crospovidone were sifted through a 40# sieve and mixed in high shear mixer for sufficient time. The mixture of excipients was granulated in Rapid Mixer Granulating bowl using binder solution containing Povidone K-30 in water to obtain inert granules. The inert granules were then dried in rapid dryer and sized through appropriate sieve. Extragranular material containing amorphous Dapagliflozin, crospovidone, colloidal silicon dioxide (aerosil) and magnesium stearate was sifted though suitable sieve and blended with the inert granules for sufficient time to obtain the blended material. The final blend material was compressed using rotary machine to obtain tablets. The tablets prepared were further film coated with OPADRY® (PVA based) coating material containing polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc and yellow iron oxide to obtain film coated tablets.

The tablets were characterized by XRPD data and HPLC impurity profile for the evaluation of chemical and polymorphic stability of amorphous Dapagliflozin in the prepared formulation. The result of HPLC analysis shows that the total impurity in the tablets was not greater than 0.6 % initially as well after 6 months of storage at 40°C/75% RH in HDPE bottle packaging.

XRPD graph of the prepared formulation initially, after 2 Months and 6 Months storage at 40°C/75% RH is shown in Fig. 1, Fig. 2 and Fig. 3 respectively. It can be observed that there was no change in the XRPD data initially as well as after 6 Months storage at 40°C/75% RH in HDPE bottle packaging.

Assay and water content analysis was performed for the tablets of Example 1. % purity and % water content initially as well as after 6 months of storage at 40°C/75% RH in HDPE bottle packaging was measured. % purity was found to be within the acceptable range of 90 to 110 % initially as well as after stability. Water content was found to be below the acceptable limit of not more than 8.0 % initially as well as after stability. The results indicate that amorphous Dapagliflozin when formulated according to the present invention, remains stable chemically as well as polymorphically.

Alternative compositions comprising Dapagliflozin can be prepared by solid dispersion technique in order to obtain a polymorphically and chemically stable solid oral composition. Illustrative example 2 provides Dapagliflozin solid dispersion prepared by Top spray granulation method.

Example 2 (Solid dispersion)
Sr. No Ingredients % w/w
Dry mix
1 Lactose anhydrous 47.72
2 Microcrystalline cellulose 30.18
3 Croscarmellose sodium 4.22
Binder solution
4 Dapagliflozin(Amorphous) 3.59
5 Povidone K-25 2.7
6 Isopropyl alcohol q.s
Extragranular material
7 Microcrystalline cellulose 4.32
8 Ferric oxide Yellow 0.10
9 Croscarmellose sodium 2.53
10 Colloidal Silicon Dioxide 0.85
11 Magnesium stearate 0.97
Coating
12 Opadry (PVA based) 2.88
Total 100.00

Lactose anhydrous, microcrystalline cellulose and croscarmellose sodium were sifted and mixed thoroughly to prepare dry mix. Binder solution was prepared by dissolving Dapagliflozin and Povidone K25 in isopropyl alcohol. The prepared dry mix was granulated in a fluid Bed Processor using the binder solution and dried. The granules were sized through appropriate sieve. The extragranular ingredients namely microcrystalline cellulose, ferric oxide yellow, croscarmellose sodium and colloidal silicon dioxide were sifted through appropriate sieve and blended properly with the prepared granules. The prepared blend of granules comprising dapagliflozin and extragranular material were further lubricated with Magnesium stearate to obtain the final blend which was compressed using rotary machine to obtain tablets. The tablets were further film coated with OPADRY® (PVA based) coating material containing polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc and yellow iron oxide to obtain film coated tablets.

The stable oral composition comprising Dapagliflozin prepared according to the present invention can be further combined with additional one or more orally active ingredient including biguanides such as metformin and phenformin; sulfonylurea such as glimepiride and gliclazide; Dipeptidyl peptidase-4 inhibitors such as saxagliptin, linagliptin, alogliptin, sitagliptin and thiazolidinedione such as rosiglitazone and pioglitazone for improving glycemic control in adults with type 2 diabetes mellitus. The stable oral composition comprising Dapagliflozin and another additional therapeutic agent preferably Metformin can be formulated into a stable bilayer or monolayer composition.
,CLAIMS:We claim:

1. A stable solid oral composition comprising
(a) dapagliflozin and optionally one or more pharmaceutical excipient(s) and
(b) inert granules comprising one or more diluents(s), one or more binder(s) and optionally one or more pharmaceutical excipient(s), wherein said inert granules are substantially free of dapagliflozin.

2. The stable solid oral composition according to claim 1, wherein pharmaceutical excipient(s) of (a) is selected from disintegrant, glidant and lubricant.

3. The stable solid oral composition according to claim 2, wherein disintegrant is crospovidone, glidant is colloidal silicon dioxide and lubricant is magnesium stearate.

4. The stable solid oral composition according to claim 1, wherein pharmaceutical excipients of (b) comprises of disintegrant.

5. The stable solid oral composition according to claim 1, comprising
(a) 1-10 % dapagliflozin and pharmaceutical excipient(s) comprising of 1-5 % disintegrant, 1-5 % glidant and 0.1-2 % lubricant and
(b) inert granules comprising 50-90% diluent, 1-5 % binder and pharmaceutical excipient comprising of 1-5 % disintegrant.

6. The stable solid oral composition according to claim 1, comprising
(a) dapagliflozin and pharmaceutical excipient(s) comprising of crospovidone, colloidal silicon dioxide and magnesium stearate and
(b) inert granules comprising diluent selected from Lactose anhydrous, microcrystalline cellulose or combination thereof; binder is polyvinyl pyrrolidone; and crospovidone.

7. The stable solid oral composition according to claim 6, wherein dapagliflozin is in amorphous form.

8. The stable solid oral composition according to claim 6, comprising
(a) 4.77 % amorphous dapagliflozin, 1.94 % Crospovidone, 1.46 % colloidal silicon dioxide and 0.73 % magnesium stearate and
(b) inert granules comprising 19.6 % Lactose anhydrous, 63.8 % microcrystalline cellulose, 1.94 % Crospovidone and 3 % polyvinylpyrrolidone.

9. A process for preparation of a stable solid oral composition comprising:
(a) Granulating one or more diluents(s), one or more binder(s) and optionally one or more pharmaceutical excipient(s) to prepare inert granules,
(b) Mixing Dapagliflozin and optionally one or more excipient(s) to the said inert granules prepared in step (a), wherein said inert granules are substantially free of Dapagliflozin.

10. A stable solid oral composition comprising Dapagliflozin, inert granules and one or more pharmaceutically acceptable excipients(s) as described with reference to the examples provided in the specification.