EP4106732A1

EP4106732A1 - Pharmaceutical composition comprising dapagliflozin

Info

Publication number: EP4106732A1
Application number: EP21705529.2A
Authority: EP
Inventors: Mateusz Kaczmarek; Szymon Przerada; Julia Hrakovsky; Jakub DZIK
Original assignee: Zaklady Farmaceutyczne Polpharma SA
Current assignee: Zaklady Farmaceutyczne Polpharma SA
Priority date: 2020-02-21
Filing date: 2021-02-17
Publication date: 2022-12-28
Also published as: CA3169665A1; WO2021165316A1

Abstract

The present invention relates to a dapagliflozin granulate composition, which is suitable for preparing capsules or tablets. It also relates to a pharmaceutical dosage form for oral administration which comprises such granulate. The invention also relates to a method for the preparation of the dapagliflozin granulate and to the use of the dosage forms containing it for the treatment of diabetes mellitus.

Description

PHARMACEUTICAL COMPOSITION COMPRISING DAPAGLIFLOZIN

Technical field

The present invention relates to pharmaceutical compositions comprising the anti-diabetic drug dapagliflozin as active ingredient.

State of the art

The anti-diabetic drug dapagliflozin is a potent, competitive, reversible, highly selective and orally active inhibitor of the human sodium-glucose co-transporter 2 (SGLT2), which is the major transporter responsible for the renal glucose reabsorption. The structure of dapagliflozin is depicted below:

Dapagliflozin improves glycaemic control in patients with type 2 diabetes mellitus by reducing renal glucose reabsorption leading to urinary glucose excretion (glucuresis).

Dapagliflozin is marketed under the trademark Forxiga^® and is indicated for the treatment of insufficiently controlled type 2 diabetes mellitus in adults as an adjunct to diet and exercise, either as monotherapy or in combination with other antidiabetics. Forxiga^® is also indicated in adults for the treatment of insufficiently controlled type 1 diabetes mellitus as an adjunct to insulin.

Dapagliflozin is also available as fixed-dose combination dosage forms with other anti-diabetic drugs. Thus, the medicine Xigduo^® contains the combination of dapagliflozin and metformin and the medicine Qtern^® comprises dapagliflozin and saxagliptin. Forxiga^®, Xigduo^® and Qtern^® are available as film-coated tablets wherein dapagliflozin is in the form of dapagliflozin propanediol monohydrate, which is a crystalline solvate containing 1 :1 :1 ratio of dapagliflozin, (S)-(+)-1 ,2-propanediol and water.

The excipients in Forxiga^® tablet core are microcrystalline cellulose (diluent), anhydrous lactose (diluent), crospovidone (disintegrant), silicon dioxide (glidant) and magnesium stearate (lubricant). It is available as 5 mg and 10 mg strength tablets.

The international patent application W02008/002824-A1 discloses crystalline forms of dapagliflozin, which are all solvated or complex forms, namely, with (S)-1 ,2- propanediol and water (molar ratio 1 :1 :1), with (F?)-1 ,2-propanediol and water (molar ratio 1 :1 :1), with ethanol and water (molar ratio 1 :1 :2), with ethylene glycol and water (molar ratio 1 :1 :2), with L-proline (in molar ratios 1 :2 and 1 :1), with L-proline and water (in molar ratio 1 :1 :0.5) and with L-phenylalanine (in molar ratio 1 :1).

The international patent application W02008/116179-A1 discloses pharmaceutical formulations in the form of capsules and tablets comprising dapagliflozin or the crystalline dapagliflozin (R)- and (S)-1 ,2-propanediol hydrates. The formulations disclosed comprise a bulking agent (preferably microcrystalline cellulose and/or lactose monohydrate), a binder (preferably pregelatinized starch), a disintegrant (preferably, sodium starch glycolate, croscarmellose sodium and/or crospovidone), a lubricant (preferably, magnesium stearate) and a glidant (preferably, silicon dioxide and/or talc). It is disclosed that lactose is a particularly useful bulking agent for tablets and that croscarmellose sodium and/or crospovidone are particularly useful disintegrants for tablet formulations.

The international patent applications WO03/099836-A1 and W02004/063209- A2 disclose the preparation of non-solvated, free dapagliflozin, which is obtained as a glassy, non-crystalline substance.

The use of dapagliflozin in its free, non-solvated form, may have advantages, for example, fewer production steps by avoiding the need to prepare the propylene glycol solvate hydrate. Furthermore, the use of non-solvated form reduces the ingestion of extra-substances by the patients, namely, the propylene glycol accompanying the active substance, which is desirable in terms of safety.

The non-solvated dapagliflozin form is an amorphous substance. In general, the use of amorphous active ingredients might have advantages, for example, better solubility. In this case, however, it has been reported that amorphous dapagliflozin is hygroscopic and its use for preparing pharmaceutical forms entails difficulties such as low content uniformity, and poor storage stability and dissolution profile, which could lead to reduced bioavailability of the drug. Several proposals have been disclosed in the art for preparing dapagliflozin pharmaceutical compositions comprising non solvated amorphous dapagliflozin which try to overcome those difficulties.

The international patent application WO2012/163546-A1 discloses the preparation of a dapagliflozin/cyclodextrin inclusion complex, which is advantageous for preparing pharmaceutical formulations because it is non-hygroscopic, highly soluble and has high storage stability. The tablets prepared with complexed dapagliflozin comprise lactose monohydrate, microcrystalline cellulose, crospovidone, colloidal silica and magnesium stearate as excipients. The international patent application W02015/011113-A1 discloses pharmaceutical compositions containing amorphous dapagliflozin as solid dispersions and adsorbates, which have improved processability, content uniformity, stability and dissolution profile. The amorphous solid dispersions are prepared by dissolving dapagliflozin and one suitable polymer in a solvent, optionally spraying the solution onto a carrier, and subsequently evaporating the solvent. The adsorbates comprise amorphous dapagliflozin adsorbed onto the surface of a substrate, for example, microcrystalline cellulose, and are prepared by combining a solution of dapagliflozin with the substrate and subsequently removing the solvent. Tablets comprising said solid dispersions and adsorbates are disclosed, further containing additional excipients, for example, disintegrants such as croscarmellose sodium.

The international patent application WO2015/128853-A1 also discloses pharmaceutical compositions comprising dapagliflozin solid dispersions. Said solid dispersions may be prepared by a solvent method or by hot-melt extrusion method. In the solvent method, for example, a solution or dispersion comprising dapagliflozin and a carrier (such as polyethylene glycol, or hypromellose, for example) is provided, which is used for granulating a blend of one or more excipients, and the granules are then dried to obtain a solid dispersion of the drug loaded onto the excipients. Said granules may be mixed with additional extra-granular excipients, typically, a filler, a disintegrant, a glidant and a lubricant, and compressed into tablets.

The international patent application WO2016/161995-A1 discloses stabilized amorphous forms dapagliflozin in the form of solid dispersions or solid solutions with polymers, saccharides, oligosaccharides, polysaccharides or urea, which can be used in combination with pharmaceutical excipients for preparing stable pharmaceutical compositions, such as tablets. Said stabilized forms may be prepared by a dissolution process or by a melting process.

The international patent application WO2018/167589-A1 discloses stable pharmaceutical compositions comprising amorphous dapagliflozin and at least one surfactant.

The Indian patent application IN201621023508-A discloses stable pharmaceutical compositions comprising amorphous dapagliflozin wherein the water content of dapagliflozin is in the range from about 0.5% to about 5% by weight. Tablets are disclosed, prepared by dry granulation or by direct compression, comprising amorphous dapagliflozin, microcrystalline cellulose, anhydrous lactose, crospovidone and lubricants and/or glidants. Therefore, there is the need to provide dapagliflozin pharmaceutical compositions comprising dapagliflozin in free form, which are easy to prepare, which are stable, with good dissolution profile, which are readily bioavailable and which are safer due to having reduced number of excipients.

Object of the invention

The object of the present invention is a granulate composition comprising dapagliflozin.

Another aspect of the invention is a pharmaceutical dosage form comprising the dapagliflozin granulate.

Another aspect of the invention is a process for the preparation of the dapagliflozin granulate and the pharmaceutical dosage form comprising it.

Another aspect of the invention is the pharmaceutical dosage form comprising the dapagliflozin granulate for use in therapy, particularly, for the treatment of diabetes.

Description of the Drawings

Figure 1 represents the comparative profiles for mean plasma dapagliflozin concentration (ng/mL) vs. time (hours) after the administration of 10 mg dapagliflozin film-coated tablet of Example 1 (A) and commercial 10 mg Forxiga^® tablet (C), as disclosed in Example 6. The X-axis represents the time (in hours) and the Y-axis represents the blood concentration (in ng/mL).

Figure 2 represents the comparative profiles for mean plasma dapagliflozin concentration (ng/mL) vs. time (hours) after the administration of 10 mg dapagliflozin film-coated tablet of Example 2 (B) and commercial 10 mg Forxiga^® tablet (C), as disclosed in Example 6. The X-axis represents the time (in hours) and the Y-axis represents the blood concentration (in ng/mL).

Figure 3 represents the XRPD of samples of amorphous dapagliflozin, either without being subjected to any stress factor (pattern 0), or after compression at 3T for 2 s (pattern I), or after wetting with water and drying (pattern II), or after wetting with ethanol and drying (pattern III), as disclosed in Example 7. The X-axis represents the angle 2Q and the Y-axis the intensity.

Figure 4 represents the comparative X-ray powder diffraction (XRPD) patterns of a sample of the 10 mg strength film-coated tablet of Example 1 packed in aluminium blisters after 6 months storage at 40° C and 75% RH (pattern a1), a sample of placebo (pattern b1), a sample of amorphous dapagliflozin (pattern c) and a sample of crystalline dapagliflozin hydrate Form A (pattern d). The X-axis represents the angle 2Q and the Y-axis the intensity.

Figure 5 represents the comparative XRPD patterns of a sample of the 10 mg strength film-coated tablet of Example 1 packed in polychlorotrifluoroethylene (PCTFE) blisters after 6 months storage at 40° C and 75% RH (pattern a2), a sample of placebo (pattern b1), a sample of amorphous dapagliflozin (pattern c) and a sample of crystalline dapagliflozin hydrate Form A (pattern d). The X-axis represents the angle 2Q and the Y-axis the intensity.

Figure 6 represents the comparative XRPD patterns of a sample of the 10 mg strength film-coated tablet of Example 2 packed in aluminium blisters after 6 months storage at 40° C and 75% RH (pattern a3), a sample of placebo (pattern b2), a sample of amorphous dapagliflozin (pattern c) and a sample of crystalline dapagliflozin hydrate Form A (pattern d). The X-axis represents the angle 2Q and the Y-axis the intensity.

Figure 7 represents the comparative XRPD patterns of a sample of the 10 mg strength film-coated tablet of Example 2 packed in polychlorotrifluoroethylene (PCTFE) blisters after 6 months storage at 40° C and 75% RH (pattern a4), a sample of placebo (pattern b2), a sample of amorphous dapagliflozin (pattern c) and a sample of crystalline dapagliflozin hydrate Form A (pattern d). The X-axis represents the angle 2Q and the Y-axis the intensity.

Detailed description of the invention

The object of the present invention is a granulate composition for loading in capsules or for forming tablets, characterized in that the granulate composition essentially consists of: a) dapagliflozin; b) a filler selected from mannitol, microcrystalline cellulose and mixtures thereof; c) a glidant; and d) optionally, a lubricant.

The authors of the present invention have developed a dapagliflozin granulate which is suitable for preparing oral dosage forms for the administration of dapagliflozin in free, non-solvated form. Surprisingly, the dosage forms prepared with this granulate are highly soluble and bioavailable and have good storage stability, despite the fact of using amorphous dapagliflozin. The formulation developed is simple and does not require the use of complicated preparation procedures as those disclosed in the art for formulating amorphous dapagliflozin, in particular, it does not require the preparation of solid dispersions, adsorbates or complexed forms. Furthermore, the simple formulation developed does not require the presence of solubility enhancing excipients, such cyclodextrins or surfactants, but, conversely, it contains only a few excipients and, in particular, it does not require the use of any disintegrating agent.

Indeed, surprisingly, a tablet prepared with the granulate composition of the invention is bioequivalent to commercial Forxiga^® tablet despite the fact of using dapagliflozin in a non-crystalline, amorphous form and despite the fact of not containing any disintegrant, in particular, crospovidone, for example, which is present in Forxiga^® tablets.

Along the present description, as well as in the claims, the singular expressions, generally preceded by the articles “a”, “an” or “the”, are meant to include also the plural forms, unless the context clearly indicates otherwise. Furthermore, numeric values preceded by the term “about” are meant to include the exact stated value and also a certain variation around such value, namely a variation or ±5% of the stated amount. Numeric ranges defined by lower and upper endpoints are meant to include also said stated endpoints. The percentages disclosed (%, wt%) are always weight percentages.

The pharmaceutical excipients used for preparing the pharmaceutical composition of the present invention are well-known in the pharmaceutical formulation field and are described in many reference books and Pharmacopoeias, for example, in the book R.C. Rowe, P.J. Sheskey & M.E. Quinn, Handbook of Pharmaceutical Excipients, 6^th Edition, Pharmaceutical Press, 2009, and/or in the European Pharmacopoeia.

Granulate composition

The term “granulate composition” as used herein, also referred to, alternatively, as “dapagliflozin granulate” or simply “granulate” means a dry mixture of all the recited components, i.e. dapagliflozin, a filler, a glidant and optionally a lubricant, and may be the result of either simple dry mixing all those components, or may be obtained by conventional granulation processes, typically, by dry granulation of those components, or may be made by dry granulating one part of the components and mixing the obtained granules with the rest of components in powder form.

The granulate composition of the invention “essentially consists” of the recited components, i.e. dapagliflozin, a filler, a glidant and, optionally, a lubricant. This means that no other active ingredients and substantially no other pharmaceutical excipients are included in the dapagliflozin granulate; however, the expression “essentially consists” would still encompass the presence of certain minor additional excipients in so small amount that they do not have any effect on the properties of the granulate composition, for example, it still includes a small amount of another filler, typically in an amount equal to or less than 5 wt%, or less than 4 wt%, or less than 3 wt%, or less than 2 wt%, or less than 1 wt%, said filler can be, for example, calcium carbonate, dextrin, dextrose, fructose, or maltodextrin, among others; another example is a colouring agent, typically, in an amount equal to or less than 1 wt%, preferably less than 0.5 wt%, and still more preferably less than 0.1 wt%. Thus, alternatively, the object of the invention can be defined as a granulate composition for loading in capsules or for forming tablets, characterized in that the granulate composition consists of: a) dapagliflozin; b) a filler selected from mannitol, microcrystalline cellulose and mixtures thereof; c) a glidant; d) optionally, a lubricant; e) optionally, an additional filler in an amount equal to or less than 5 wt%, or less than 4 wt%, or less than 3 wt%, or less than 2 wt% or less than 1 wt%, preferably selected from calcium carbonate, dextrin, dextrose, fructose, maltodextrin and mixtures thereof; and f) optionally, a colouring agent.

In one embodiment, the granulate composition strictly consists of the recited components a) to d) only.

In one embodiment, the granulate composition of the invention has typically a moisture content of not more than 6 wt%, preferably not more 5 wt%, for example comprised between 0.5 wt% and 5 wt%, as measured by the loss on drying (LOD) method.

Dapagliflozin

Dapagliflozin is the International Nonproprietary Name (INN) assigned to the substance (1 S)-1 ,5-anhydro-1 -C-{4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl}-D-glucitol (CAS number 461432-26-8), which has the following structure:

The term “dapagliflozin”, as used in the present description and in the claims, means amorphous dapagliflozin. Amorphous dapagliflozin is a free, non-solvated form, wherein “non-solvated” term includes also non-hydrated forms.

An amorphous solid substance, as is well-recognized in the art, means that its molecules are not arranged in any repeating crystalline form. The term “amorphous” as used herein referred to dapagliflozin means that substantially all dapagliflozin is in amorphous state, and “substantially all” typically means that at least 80%, preferably at least 85%, still more preferably at least 90%, still more preferably at least 92%, still more preferably at least 94%, still more preferably at least 96%, still more preferably at least 98%, still more preferably at least 99%, and still more preferably about 100% of dapagliflozin is amorphous.

As is well-known in the art, amorphous dapagliflozin may be identified by X- ray powder diffraction (XRPD) analysis, namely, by the absence of peaks corresponding to crystalline portions. XRPD patterns of several samples of amorphous dapagliflozin are shown in Figure 3.

The proportion of dapagliflozin in the granulate composition is generally comprised between 1 wt% and 10 wt%.

In one embodiment, the proportion of dapagliflozin in the granulate composition is preferably comprised between 2 wt% and 10 wt%, more preferably comprised between 3 wt% and 8 wt%, still more preferably comprised between 4 wt% and 6 wt%, and still more preferably is about 5 wt%, referred to the total weight of the granulate.

In another embodiment, the proportion of dapagliflozin in the granulate composition is preferably comprised between 1 wt% and 5 wt%, and more preferably comprised between 1.5 wt% and 3 wt%, referred to the total weight of the granulate.

Amorphous dapagliflozin can be prepared, for example, as disclosed in the international patent application WO03/099836-A1 , or in the international patent application WO2017/221211 -A1 , for example.

As disclosed in Example 7, amorphous dapagliflozin was proven to be polymorphically stable and remained in the amorphous state despite being subjected to several stress factors during production process or during storage.

The use of non-solvated dapagliflozin may be advantageous in order to reduce the amount of superfluous, non-active substances accompanying dapagliflozin, such as propanediol in the commercial Forxiga^® tablets, which could potentially give rise to undesired effects or allergic reactions.

Thus, the 5 mg and 10 mg strength tablets prepared in Examples 1 and 2, according to the present invention, contain just 5 mg and 10 mg of the active substance, whereas commercial Forxiga^® tablets contain 6.15 mg and 12.30 mg, respectively, of the dapagliflozin propanediol monohydrate.

Filler The granulate composition of the present invention comprises a filler selected from mannitol, microcrystalline cellulose and mixtures thereof.

Both mannitol and microcrystalline cellulose are well-known pharmaceutical excipients, which are typically used as fillers (also known as diluents) in tablets and capsules.

Microcrystalline cellulose (MCC) is commercially available in different particle sizes and moisture grades, and all of them are suitable to be used in the composition of the invention. In general, the mean particle size of microcrystalline cellulose ranges from about 50 pm to about 180 pm.

For example, different commercially available grades of microcrystalline cellulose may be used, such as those available from the company Dupont under the trademark Avicel^® (for example, Avicel^® 101 , Avicel^® 102 or Avicel^® 200); or those available from the company JRS Pharma, under the trademark Vivapur^® (for example, Vivapur^® 101 or Vivapur^® 102); or those available from the company Pharmatrans SANAQ (for example, MCC Sanaq 101 , MCC Sanaq 102 or MCC Sanaq 200), among others.

Mannitol is also commercially available from different sources and in different particle sizes, which are all suitable for preparing the granulate of the invention. For example, the company Roquette provides mannitol with different particle sizes under the trademark Pearlitol^®.

The amount of filler in the dapagliflozin granulate is generally comprised between 80 wt% and 97 wt%, preferably comprised between 85 wt% and 96 wt%, and more preferably comprised between 90 wt% and 95 wt%, relative to the total weight of the granulate composition.

In one embodiment the filler is microcrystalline cellulose.

In one embodiment the filler is mannitol.

In one embodiment the filler is a mixture of microcrystalline cellulose and mannitol.

In one embodiment, the filler is selected from: (i) microcrystalline cellulose and (ii) a mixture of microcrystalline cellulose and mannitol.

When the composition comprises both microcrystalline cellulose and mannitol, the weight ratio MCC:mannitol is generally comprised between 5:1 and 1 :1 , preferably comprised between 4.5:1 and 2:1 , more preferably comprised between 4:1 and 3:1 , and still more preferably is about 3.5:1.

Glidant The granulate composition of the present invention comprises a glidant. Preferably, the glidant is selected from silicon dioxide, magnesium oxide, magnesium silicate, magnesium trisilicate, talc, and mixtures thereof, more preferably, the glidant is silicon dioxide.

The amount of glidant in the granulate composition of the invention is generally comprised between 0.1 wt% and 10 wt%, preferably comprised between 0.5 wt% and 5 wt%, referred to the total weight of the granulate.

In one embodiment, the amount of glidant is preferably comprised between 0.75 wt% and 3 wt%, more preferably comprised between 1 wt% and 2 wt%, and still more preferably is about 1.5 wt%, referred to the total weight of the dapagliflozin granulate.

In another embodiment, the amount of glidant is preferably comprised between 3 wt% and 5 wt%, more preferably comprised between 3.5 wt% and 4 wt%, referred to the total weight of the dapagliflozin granulate.

Lubricant

The granulate composition of the present invention may optionally comprise a lubricant. The lubricant may be selected from calcium stearate, glycerin monostearate, glyceryl behenate, glyceryl palmitostearate, hydrogenated castor oil, magnesium stearate, palmitic acid, sodium stearyl fumarate, stearic acid and zinc stearate, among others, and mixtures thereof. A preferred lubricant is magnesium stearate.

In one embodiment, the composition comprises a lubricant.

In one embodiment, the composition does not comprise any lubricant.

When the granulate composition is to be used for preparing a tablet, it preferably comprises a lubricant, as it helps to prevent adhesion of the tablet material to the surface of the dies and punches during tablet manufacturing.

Typically, the lubricant is added as the last step in the preparation of the granulate composition of the invention, generally by thoroughly dry mixing it with the previously prepared granules.

The amount of lubricant in the granulate, if present, is generally comprised between 0.1 wt% and 5 wt%, preferably comprised between 0.5 wt% and 3.5 wt%, referred to the total weight of the dapagliflozin granulate.

Pharmaceutical dosage form

Another aspect of the invention is a pharmaceutical dosage form comprising the dapagliflozin granulate. The pharmaceutical dosage form is preferably selected from a tablet and a capsule.

Alternatively, other dosage forms may be also suitable, for example, a mono dose sachet, wherein a therapeutically effective dose of the dapagliflozin granulate is loaded into individual dose sachet. In this case, the granulate composition may be administered with water or another suitable liquid, or it may also be swallowed directly.

In one embodiment, the dapagliflozin granulate of the invention is the sole component of the pharmaceutical dosage form, i.e. is the only component of the tablet core or of the capsule filling or of the sachet content. In other words, the tablet core or the capsule filling consists of the dapagliflozin granulate. The pharmaceutical dosage form thus obtained is a mono-drug dosage form, comprising dapagliflozin as the sole active ingredient.

In another embodiment, the dapagliflozin granulate of the invention is combined with a second active ingredient, typically in the form of a second granulate. Or, alternatively, the dapagliflozin granulate may be combined with more than one additional active ingredients, for example, with a second and a third active ingredients in the form of a second and a third granulate. The dapagliflozin granulate and the second and, optionally, further granulates may be mixed, to obtain a granulate blend which may be either compressed to form the tablet core or may be encapsulated in the capsule, or may be, alternatively, filled into a mono-dose sachet. Alternatively, the granulate combination may be compressed to form a bilayer or multilayer tablet. The pharmaceutical dosage form thus obtained is a fixed-dose combination and the tablet core or the capsule filling consists of the dapagliflozin granulate and the additional active ingredient or ingredients, preferably in the form of a second and further granulates.

Typically, the second and further active ingredients to be combined with dapagliflozin are also anti-diabetic drugs, for a combined treatment of diabetes mellitus.

In one embodiment, the second anti-diabetic drug to be combined with dapagliflozin is metformin, or a pharmaceutically acceptable salt thereof, preferably metformin hydrochloride.

According to this embodiment, the pharmaceutical dosage form consists of the dapagliflozin granulate and the metformin granulate.

In one embodiment the metformin granulate comprises metformin or a pharmaceutically acceptable salt thereof, preferably metformin hydrochloride, a filler, a binder and, optionally, a lubricant; preferably the metformin granulate consists of metformin or a pharmaceutically acceptable salt thereof, preferably metformin hydrochloride, a filler, a binder and, optionally, a lubricant.

Typically, the amount of metformin or a pharmaceutically acceptable salt thereof, preferably metformin hydrochloride, in the metformin granulate is generally comprised between 70 wt% and 90 wt%, preferably comprised between 75 wt% and 85 wt%.

The filler in the metformin granulate is preferably selected from microcrystalline cellulose, mannitol and mixtures thereof. In one embodiment the filler is microcrystalline cellulose. The amount of filler in the metformin granulate is generally comprised between 5 wt% and 25 wt%, preferably comprised between 5 wt% and 15 wt%.

The binder in the metformin granulate is typically selected from acacia, agar, alginic acid, carboxymethylcellulose sodium, copovidone, corn starch, pregelatinized starch, ethylcellulose, gelatin, guar gum, hydroxypropyl cellulose, hypromellose, methylcellulose, povidone, sodium alginate, sucrose and mixtures thereof, preferably is selected from copovidone, gelatin, hydroxypropyl cellulose, povidone and sucrose, and more preferably is copovidone. The amount of binder in the metformin granulate is generally comprised between 3 wt% and 15 wt%.

The metformin granulate composition of the present invention may optionally comprise a lubricant. The lubricant may be selected from calcium stearate, glycerin monostearate, glyceryl behenate, glyceryl palmitostearate, hydrogenated castor oil, magnesium stearate, palmitic acid, sodium stearyl fumarate, stearic acid and zinc stearate, among others, and mixtures thereof. A preferred lubricant is magnesium stearate. The amount of lubricant in the metformin granulate, if present, is generally comprised between 0.1 wt% and 5 wt%, preferably comprised between 0.5 wt% and 2 wt%, referred to the total weight of the dapagliflozin granulate.

When the mixture of dapagliflozin granulate and metformin granulate is to be used for preparing a tablet, it preferably comprises a lubricant. Preferably, the same lubricant is used for both granulates, and, typically, both amounts are combined and are added together as the last step in the preparation of the granulate mixture combining the lubricant and dry mixing it with the previously prepared metformin and dapagliflozin granulates.

In another embodiment, the second anti-diabetic drug to be combined with dapagliflozin is saxagliptin, or a pharmaceutically acceptable salt thereof, preferably saxagliptin hydrochloride. According to this embodiment, the pharmaceutical dosage form consists of the dapagliflozin granulate and the saxagliptin granulate.

In one embodiment the saxagliptin granulate comprises saxagliptin or a pharmaceutically acceptable salt thereof, preferably saxagliptin hydrochloride, a filler, a binder and, optionally, a lubricant; preferably the saxagliptin granulate consists of saxagliptin or a pharmaceutically acceptable salt thereof, preferably saxagliptin hydrochloride, a filler, a binder and, optionally, a lubricant. In another embodiment, the dapagliflozin granulate is combined with metformin or a pharmaceutically acceptable salt thereof, preferably metformin hydrochloride, and with saxagliptin, or a pharmaceutically acceptable salt thereof, preferably saxagliptin hydrochloride.

According to this embodiment, the pharmaceutical dosage form consists of the dapagliflozin granulate, the metformin granulate and the saxagliptin granulate.

In one embodiment, the pharmaceutical dosage form is a tablet.

The tablet core, as used herein, means the uncoated compressed tablet, which is directly obtained by compression of the granulate composition.

Said tablet core may be itself a plain, finished, uncoated tablet dosage form, or, alternatively, said tabled core may be coated with a film-coating layer to produce a film-coated tablet dosage form. In another embodiment, one or more coated or uncoated tablets may be loaded into a capsule, to prepare a capsule dosage form.

In one embodiment, the pharmaceutical dosage form is a film-coated tablet comprising the tablet core and a film-coating layer applied onto it.

The film-coating layer is not intended for providing any modified release of the active ingredient but, rather, the pharmaceutical composition of the invention is an immediate release formulation.

The function of the film-coating layer in the tablet, if present, is, for example, to improve product appearance, to make swallowing easier or improve the stability of the tablet.

Film coating, as is well-known in the art, involves the deposition, usually by spraying a liquid coating mixture, of a thin film of a polymer-based formulation onto the surface of the tablet core. Besides the film-coating polymer, the film-coating layer may also contain auxiliary excipients, such as anti-tacking agents, plasticizers and/or colorants. An anti-tacking agent is a substance able to reduce or prevent adhesion between particles. Plasticizers can be typically added to increase the flexibility of the coating.

Suitable film-forming polymers include, for example, hydroxypropyl methyl cellulose (hypromellose, HPMC), hydroxypropyl cellulose (HPC), polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA) or copovidone, for example. Solid grades of polyethylene glycol can be also used as film-coating polymer, or can be used as plasticizer in conjunction with a film-forming polymer. Other suitable plasticizers are propylene glycol, diethyl phthalate or triethyl citrate, for example, among others.

Common anti-tacking agents that can be added to the coating mixture are, for example, calcium silicate, magnesium silicate, colloidal silicon dioxide magnesium stearate, calcium stearate, magnesium oxide or talc.

Furthermore, the coating mixture may also comprise pharmaceutically acceptable colourants, for example, iron oxide pigments or titanium dioxide, among others.

Ready to use coating mixtures are also commercially available, for example, those sold under the trademark Opadry^® (Colorcon).

The weight of the coating layer generally amounts from about 3% to about 8% of the weight of the tablet core (i.e., before applying said coating layer).

In one embodiment, the pharmaceutical dosage form is a capsule.

The capsule filing means the composition encapsulated in the capsule shell.

The capsule is typically a hard capsule comprising a capsule shell made of gelatin and usually containing also other minor ingredients, such as water, plasticizers and colorants, for example. The hard capsule shell may alternatively be made of hypromellose. The capsule shells are available in different sizes.

The finished capsules are prepared by filling the capsule shells with the dapagliflozin granulate, optionally combined with a second active ingredient, following standard methods, well-known in the field.

Alternatively, the capsules may be filled with pre-prepared mini-tablets, rather than with the raw granulate composition. Thus, the dapagliflozin granulate is previously compressed to form the mini-tablets, which are then loaded into the capsule, as is also well-known in the art. The term mini-tablets means conventional tablets having a small- enough size to be loaded into a capsule, and whose size is adjusted according to the dosage or production requirements. Typically, the number of mini-tablets loaded in each capsule may range, for example, from 2 to 12, so the total dose is divided in smaller doses contained in each mini-tablet. Generally, all mini-tablets have the same amount of active ingredient, so the strength of the tablet can be adjusted by adding a convenient number of mini-tablets. For fixed-dose combinations, mini-tablets of each active ingredient may be combined inside the capsule, or mini-tablets of one component may be combined with a granulate composition of the second component, for example. Each tablet or each capsule dosage form contains a therapeutically effective amount of dapagliflozin.

For fixed-dose combination forms, each tablet or each capsule dosage form contains therapeutically effective combined amounts of dapagliflozin and of the second active ingredient.

For dapagliflozin mono-drug dosage forms, typically, each tablet or each capsule contains between 3 and 30 mg of dapagliflozin. In one embodiment, each tablet or each capsule contains about 5 mg of dapagliflozin. In another embodiment, each tablet or each capsule contains about 10 mg of dapagliflozin.

For fixed-dose combination dosage forms containing dapagliflozin and metformin, typically, each tablet or each capsule contains between 1.5 and 20 mg of dapagliflozin, preferably about 2.5 mg or about 5 mg or about 10 mg of dapagliflozin and between 400 and 1200 mg of metformin hydrochloride, preferably about 500 mg or about 850 mg or about 1000 mg of metformin hydrochloride. For example, the following dapagliflozin/metformin hydrochloride combinations may be used: 5 mg/500 mg, 5 mg/850 mg, 5 mg/1000 mg, 2.5 mg/500 mg, 2.5 mg/850 mg, 2.5 mg/1000 mg, 10 mg/500 mg, 10 mg/850 mg or 10 mg/1000 mg.

For fixed-dose combination dosage forms containing dapagliflozin and saxagliptin, typically, each tablet or each capsule contains between 1.5 and 20 mg of dapagliflozin, preferably about 5 mg or about 10 mg of dapagliflozin, and between 1.5 and 10 mg of saxagliptin, preferably about 5 mg of saxagliptin. For example, the following dapagliflozin/saxagliptin combinations may be used: 5 mg/5 mg and 10 mg/5 mg.

For fixed-dose combination dosage forms containing dapagliflozin, saxagliptin and metformin, typically, each tablet or each capsule contains between 1.5 and 20 mg of dapagliflozin, preferably about 2.5 mg or about 5 mg or about 10 mg of dapagliflozin, between 1.5 and 10 mg of saxagliptin, preferably about 2.5 mg or about 5 mg of saxagliptin, and between 400 and 1200 mg of metformin hydrochloride, preferably about 1000 mg of metformin hydrochloride. For example, the following dapagliflozin/saxagliptin/metformin hydrochloride combinations may be used: 2.5 mg/2.5 mg/1000 mg, 5 mg/2.5 mg/1000 mg, 5 mg/5 mg/1000 mg and 10 mg/5 mg/1000 mg.

The pharmaceutical dosage form, i.e., tablet or capsule, may be packed in blisters, typically in aluminium blisters. For example, one possible type of blister to be used is AL//OPA-AL-PVC blister (aluminium foil 20 pm//polyamide film 25 pm- aluminium foil 45 pm-polyvinyl chloride 60 pm film). Other suitable blisters are, for example, polychlorotrifluoroethylene (PCTFE) blisters.

Preparation of the granulate and the pharmaceutical dosage form

The preparation of the dapagliflozin granulate composition of the invention generally involves only dry methods, for example, simple milling, mixing and compressing steps, and does not involve, for example, the use of solvents. It does not involve any melting process either.

Thus, for example, a suitable process for preparing the granulate composition of the invention comprises the following steps: i) mixing dapagliflozin, 50-100%, preferably 60-100%, more preferably 70-100% of the filler, and 30-70%, preferably 40-60%, more preferably about 50% of the glidant, and dry-granulating this mixture; and ii) mixing the granules obtained in step i) with the rest of filler, if any, with the rest of glidant and, if present, with the lubricant.

The characteristics, proportions and different embodiments related to each of the ingredients employed in said process are as disclosed above under the ’’granulate composition” section.

In one embodiment, all the filler is added in step i), so the process for preparing the granulate composition comprises the following steps: i) mixing dapagliflozin, the filler, and 30-70%, preferably 40-60%, more preferably about 50% of the glidant, and dry-granulating this mixture; and ii) mixing the granules obtained in step i) with the rest of glidant and, if present, with the lubricant.

In particular, when the filler is a mixture of microcrystalline cellulose and mannitol, preferably all the filler is added in step i).

In another embodiment, only part of the filler is added in step i), so the process for preparing the granulate composition comprises the following steps: i) mixing dapagliflozin, 50-90%, preferably 60-85%, more preferably 70-80% of the filler, and 30-70%, preferably 40-60%, more preferably about 50% of the glidant, and dry-granulating this mixture; and ii) mixing the granules obtained in step i) with the rest of filler, with the rest of glidant and, if present, with the lubricant.

In particular, when the filler is microcrystalline cellulose alone, or mannitol alone, the filler is preferably added in two portions: intra- and extra-granularly. Step i) of the process comprises dry granulation. As is well-known in the art, in dry granulation, the powder particles are aggregated at high pressure, either by slugging, i.e., compressing the powder mixture in a large tablet, or by squeezing the powder mixture between two rollers {roller compaction) to produce a sheet (or ribbon). Said intermediate products are broken and milled to produce the granules. The milled granules are generally screened through a mesh of the desired size.

The size of the granules is not critical, and may be comprised, for example, between about 10 pm and about 1500 pm, preferably between about 50 pm and about 1000 pm.

In one embodiment, the dry granulation of step i) is performed by roller compaction.

In step ii) the granules obtained in step i) are mixed with extra-granular ingredients, i.e., the rest of filler, if any, the rest of glidant and, if present, the lubricant.

The dapagliflozin granulate can be used for preparing a pharmaceutical dosage form, namely, a tablet or a capsule. Alternatively, the dapagliflozin granulate may be loaded into mono-dose sachets. Typically, the granulate composition is either compressed to form a tablet core, or is loaded into a capsule. The tablet core may be optionally coated.

A suitable amount of dapagliflozin granulate is used for manufacturing each capsule or each tablet in order to obtain a pharmaceutical dosage form comprising a therapeutically effective dose of dapagliflozin.

Alternatively, for preparing a fixed-dose combination of dapagliflozin and a second and optionally further active ingredients, the dapagliflozin granulate is combined with the second and optionally further active ingredients, typically in the form of a second and further granulates.

The granulates of the second and optionally further active ingredients may be prepared either by dry granulation methods, similarly as disclosed above for dapagliflozin granulates, or may be prepared by wet-granulation methods, for example, fluidized-bed granulation, which are also well-known for the skilled in the art.

The granulates are either mixed to be compressed in a monolayer tablet or to be loaded into a capsule, or they are combined in a bilayer or multilayer tablet. For the preparation of fixed-dose, monolayer combination tablets, the lubricant comprised in the dapagliflozin granulate may alternatively be added later, after mixing the granulates, typically combined with the lubricant corresponding to the additional granulate, as the last step of the mixing process, just before compression. The tablets can be prepared using any conventional tablet press, for example, a rotary tablet press. The capsules may also be prepared using any conventional capsule-filling machine.

The preparation of film-coated tablets can be done using conventional techniques, generally by spraying a suitable coating mixture, as discussed above, onto the surface of the tablet (tablet core), in a coating machine.

The procedures employed for preparing the granulate composition and the dosage forms of the present invention are common, well-known procedures for the skilled in pharmaceutical technology, and are disclosed in recognized reference books in the field, for example, in Aulton’s Pharmaceutics. The design and manufacture of medicines, M.E. Aulton and K.M.G. Taylor, editors, Churchill Livingstone Elsevier, Fourth Edition, 2013; or in the book Remington Essentials of Pharmaceutics, L. Felton, editor, Pharmaceutical Press, 2013; or in the book Pharmaceutics. Basic principles and application to pharmacy practice. A.K. Dash, S. Singh, and J. Tolman, editors, Academic Press, Elsevier, 2014.

Use of the pharmaceutical dosage form

The oral pharmaceutical dosage form prepared with the dapagliflozin granulate according to the present invention comprising amorphous, non-solvated, dapagliflozin has good bioavailability and, in particular, the tablets are bioequivalent to the commercial Forxiga^® tablets, as discussed in Example 6. Therefore, it is suitable for the same therapeutic uses as the reference medicine.

Furthermore, the dapagliflozin granulate of the present invention, ready to be compressed into tablets or to be loaded into capsules, for example, is simple and does not require the preparation of any adsorbate, solid dispersion or cyclodextrin complex, for example, as stated in the prior art. Furthermore, as discussed in Example 9, surprisingly, the tablets prepared with this granulate show a shorter disintegration time than the reference product, despite the fact of not containing any disintegrating agent, such as crospovidone, which is present in Forxiga^® tablets.

This simple formulation allows for the preparation of dapagliflozin tablets having the same strength as the Forxiga^® tablets, but having less total weight, in particular, about 20% of mass reduction can be achieved. Thus, for example, the 5 mg film-coated tablets of Examples 1 and 2 have a weight of 104 mg, compared to 130 mg of the analogous Forxiga^® tablet, and the 10 mg film-coated tablets of Examples 1 and 2 have a weight of 208 mg, compared to 260 mg of the analogous Forxiga^® tablet. This fact may be advantageous in terms of patient compliance, especially for the geriatric patients and those with dysphagia, because, as less weight of composition is required for a given strength of active ingredient, the size of the dosage forms, both tablets and capsules, may be reduced.

Furthermore, this mass reduction achieved with the dapagliflozin composition of the present invention brings a particularly significant advantage for preparing fixed- dose combination products, i.e. comprising dapagliflozin and a further active ingredient, since such combination products obviously involve larger amount of product to be swallowed.

Additionally, the formulation developed does not contain lactose, which, conversely, is disclosed in the prior art as a particularly preferred filler for the formulation of dapagliflozin tablets. The avoidance of lactose can be an additional advantage for lactose-intolerant patients.

Furthermore, the composition of the present invention is highly stable, as shown in Example 8 in conditions of accelerated stability. In particular, film-coated tablets packed both in aluminium (Alu) blisters and in polychlorotrifluoroethylene (PCTFE) blisters fulfilled the stability requirements after 6 months storage at 40° C and 75% RFI. In this regard, it was surprisingly found that the dosage form according to the present invention is also stable when packed in more permeable packaging material, such as PCTFE blisters. This fact provides an additional advantage for manufacturing the product and reducing packaging costs.

For all the above reasons, the pharmaceutical dosage form prepared with the dapagliflozin granulate of the present invention is particularly suitable to be used in therapy, in particular, for the treatment of diabetes mellitus.

Therefore, another aspect of the invention is a pharmaceutical dosage form comprising the dapagliflozin granulate according to the invention, for use in therapy. In particular, the dosage form is suitable for use in the treatment of diabetes mellitus. It may be used for the treatment of type 2 diabetes mellitus, either as monotherapy or in addition to other medicinal products for the treatment of type 2 diabetes mellitus. It may also be used for the treatment of insufficiently controlled type I diabetes mellitus, as an adjunct to insulin.

The present invention includes the following embodiments:

1.- A granulate composition for loading in capsules or for forming tablets, characterized in that the granulate composition essentially consists of: a) dapagliflozin; b) a filler selected from mannitol, microcrystalline cellulose and mixtures thereof; c) a glidant; and d) optionally, a lubricant.

2.- The granulate composition according to embodiment 1 , characterized in that dapagliflozin is amorphous.

3.- The granulate composition according to embodiment 1 or 2, characterized in that the amount of dapagliflozin is comprised between 2 wt% and 10 wt%, preferably comprised between 3 wt% and 8 wt%, more preferably comprised between 4 wt% and 6 wt%, and still more preferably is about 5 wt%, referred to the total weight of the granulate composition.

4.- The granulate composition according to embodiment 1 or 2, characterized in that the amount of dapagliflozin is comprised between 1 wt% and 5 wt%, and preferably comprised between 1.5 wt% and 3 wt%, referred to the total weight of the granulate.

5.- The granulate composition according to any one of embodiments 1 to 4, characterized in that the amount of filler is comprised between 80 wt% and 97 wt%, preferably comprised between 85 wt% and 96 wt%, and more preferably comprised between 90 wt% and 95 wt%, relative to the total weight of the granulate composition.

6.- The granulate composition according to any one of embodiments 1 to 5, characterized in that the filler is microcrystalline cellulose.

7.- The granulate composition according to any one of embodiments 1 to 5, characterized in that the filler is a mixture of microcrystalline cellulose and mannitol, preferably wherein the weight ratio microcrystalline cellulose:mannitol is comprised between 5:1 and 1 :1 , preferably comprised between 4.5:1 and 2:1 , more preferably comprised between 4:1 and 3:1 , and still more preferably is about 3.5:1.

8.- The granulate composition according to any one of embodiments 1 to 5, characterized in that the filler is mannitol.

9.- The granulate composition according to any one of embodiments 1 to 8, characterized in that the glidant is selected from silicon dioxide, magnesium oxide, magnesium silicate, magnesium trisilicate, talc, and mixtures thereof; preferably, the glidant is silicon dioxide.

10.- The granulate composition according to any one of embodiments 1 to 9, characterized in that the amount of glidant is comprised between 0.1 wt% and 10 wt%, preferably comprised between 0.5 wt% and 5 wt%, referred to the total weight of the granulate composition.

11.- The granulate composition according to any one of embodiments 1 to 10, characterized in that the composition contains a lubricant.

12.- The granulate composition according to embodiment 11 , characterized in that the lubricant is selected from calcium stearate, glycerin monostearate, glyceryl behenate, glyceryl palmitostearate, hydrogenated castor oil, magnesium stearate, palmitic acid, sodium stearyl fumarate, stearic acid, zinc stearate, and mixtures thereof, preferably the lubricant is magnesium stearate.

13.- The granulate composition according to embodiments 11 or 12, characterized in that the amount of lubricant is comprised between 0.1 wt% and 5 wt%, preferably comprised between 0.5 wt% and 3.5 wt%, referred to the total weight of the granulate composition.

14.- A pharmaceutical dosage form comprising the granulate composition according to any one of embodiments 1 to 13.

15.- The pharmaceutical dosage form according to embodiment 14, characterized in that it is selected from a tablet and a capsule.

16.- The pharmaceutical dosage form according to embodiment 15, characterized in that the tablet core or the capsule filling consists of the granulate composition according to any one of embodiments 1 to 13.

17.- The pharmaceutical dosage form according to embodiment 15, characterized in that the tablet core or the capsule filling consists of the granulate composition according to any one of embodiments 1 to 13 and at least one additional active ingredient, preferably selected from metformin or a pharmaceutically acceptable salt thereof and saxagliptin or a pharmaceutically acceptable salt thereof, wherein said additional active ingredient is preferably in the form of a granulate.

18.- The pharmaceutical dosage form according to embodiment 17, characterized in that the tablet core or the capsule filling consists of the granulate composition according to any one of embodiments 1 to 13 and a further granulate selected from a metformin granulate, a saxagliptin granulate and a combination of a metformin granulate and a saxagliptin granulate.

19.- The pharmaceutical dosage form according to embodiment 18, characterized in that the tablet core or the capsule filling consists of the granulate composition according to any one of embodiments 1 to 13 and a metformin granulate.

20.- The pharmaceutical dosage form according to embodiment 19, characterized in that the metformin granulate consists of metformin hydrochloride; a filler selected from microcrystalline cellulose, mannitol, and mixtures thereof, and preferably is microcrystalline cellulose; a binder preferably selected from copovidone, gelatin, hydroxypropyl cellulose, povidone and sucrose, and preferably is copovidone; and optionally a lubricant, which is selected from calcium stearate, glycerin monostearate, glyceryl behenate, glyceryl palmitostearate, hydrogenated castor oil, magnesium stearate, palmitic acid, sodium stearyl fumarate, stearic acid, zinc stearate and mixtures thereof, preferably is magnesium stearate.

21.- The pharmaceutical dosage form according to embodiment 16, characterized in that each tablet or each capsule comprises between 3 and 30 mg of dapagliflozin, preferably each tablet or each capsule comprises about 5 mg of dapagliflozin or about 10 mg of dapagliflozin.

22.- The pharmaceutical dosage form according to any one of embodiments 19 or 20, characterized in that each tablet or each capsule comprises between 1 .5 and 20 mg of dapagliflozin, preferably about 2.5 mg or about 5 mg or about 10 mg of dapagliflozin and between 400 and 1200 mg of metformin hydrochloride, preferably about 500 mg or about 850 mg or about 1000 mg of metformin hydrochloride.

23.- The pharmaceutical dosage form according to any one of embodiments 15 to 22, characterized in that it is a capsule. 24.- The pharmaceutical dosage form according to any one of embodiments 15 to 22, characterized in that it is a tablet, preferably, a film-coated tablet.

25.- A process for preparing the granulate composition according to any one of embodiments 1 to 13, characterized in that it comprises the following steps: i) mixing dapagliflozin, 50-100%, preferably 60-100%, more preferably 70-100% of the filler, and 30-70%, preferably 40-60%, more preferably about 50% of the glidant, and dry-granulating this mixture; and ii) mixing the granules obtained in step i) with the rest of filler, if any, with the rest of glidant and, if present, with the lubricant.

26.- A process for preparing the granulate composition according to any of embodiments 1 to 13, characterized in that it comprises the following steps: i) mixing dapagliflozin, the filler, and 30-70%, preferably 40-60%, more preferably about 50% of the glidant, and dry-granulating this mixture; and ii) mixing the granules obtained in step i) with the rest of glidant and, if present, with the lubricant.

27.- A process for preparing the granulate composition according to any of embodiments 1 to 13, characterized in that it comprises the following steps: i) mixing dapagliflozin, 50-90%, preferably 60-85%, more preferably 70-80% of the filler, and 30-70%, preferably 40-60%, more preferably about 50% of the glidant, and dry-granulating this mixture; and ii) mixing the granules obtained in step i) with the rest of filler, with the rest of glidant and, if present, with the lubricant.

28.- The pharmaceutical dosage form according to any of embodiments 14 to 24 for use in therapy.

29.- The pharmaceutical dosage form for use according to embodiment 28, characterized in that is for the treatment of diabetes.

Examples

Example 1 Preparation of dapagliflozin tablets 5 mg and 10 mg strength dapagliflozin tablets were prepared using MCC as filler, with the ingredients listed in Table I:

Both, 5 mg and 10 mg strength tablets were prepared using the same procedure. For preparing the tablets, dapagliflozin, about 78% of microcrystalline cellulose (MCC), and half of the colloidal silicon dioxide were weighed, sieved and mixed. This mixture was dry-granulated in a roller compactor and the granules were milled and sieved. The obtained granules were then mixed with the extra-granular ingredients, i.e., the rest of colloidal silicon dioxide, the rest of MCC and magnesium stearate, and thoroughly blended. The obtained dapagliflozin granulate was compressed into tablets using rotary tablet press. The tablets were coated in a drum coater using the ready-to-use coating mixture (containing polyvinyl alcohol, titanium dioxide, macrogol 3350, talc and iron oxide yellow), to obtain the film-coated tablets. Example 2 Preparation of dapagliflozin tablets

5 mg and 10 mg strength dapagliflozin tablets were prepared using a mixture of MCC and mannitol as filler, with the ingredients listed in Table II:

Dapagliflozin, MCC, mannitol and half of the colloidal silicon dioxide were weighed, sieved and mixed. This mixture was dry- granulated in a roller compactor and the granules were milled and sieved. The obtained granules were then mixed with the extra-granular ingredients, i.e., the rest of colloidal silicon dioxide and magnesium stearate, and thoroughly blended. The obtained mixture was compressed into tablets using rotary tablet press. The tablets were coated in a drum coater using the ready-to- use coating mixture (containing polyvinyl alcohol, titanium dioxide, macrogol 3350, talc and iron oxide yellow), to obtain the film-coated tablets.

Example 3 Preparation of dapagliflozin capsules

5 mg and 10 mg strength dapagliflozin capsules were prepared using MCC as filler, with the same ingredients and proportions used for preparing the tablet cores of Example 1 , as listed in Table I. The dapagliflozin granulate was prepared with amorphous dapagliflozin, MCC, colloidal silicon dioxide and magnesium stearate, using an analogous procedure as the one described in Example 1 , and the obtained granulate was loaded in hard gelatin capsules, each comprising either 5 mg or 10 mg of dapagliflozin. Example 4 Preparation of dapagliflozin capsules

5 mg and 10 mg strength dapagliflozin capsules were prepared using MCC and mannitol as filler, with the same ingredients and proportions used for preparing the tablet cores of Example 2, as listed in Table II.

The dapagliflozin granulate was prepared with amorphous dapagliflozin, MCC, mannitol, colloidal silicon dioxide and magnesium stearate, using an analogous procedure as the one described in Example 2, and the obtained granulate was loaded in hard gelatin capsules, each comprising either 5 mg or 10 mg of dapagliflozin.

Example 5 Preparation of dapaqliflozin-metformin combination tablets A combination tablet comprising 5 mg dapagliflozin and 850 mg of metformin hydrochloride was prepared using the ingredients listed in Table III:

TABLE III

The dapagliflozin granulate was prepared as disclosed in Example 2, but the magnesium stearate was reserved.

The metformin granulate was prepared by conventional fluidized-bed granulation. Metformin hydrochloride and microcrystalline cellulose were first mixed, and this mixture was granulated by spraying the granulation fluid made of copovidone dissolved in purified water and the wet granules obtained were subsequently dried.

The dapagliflozin granulate and the metformin granulate were mixed and combined with 17 mg of magnesium stearate. The obtained mixture was compressed into tablets using rotary tablet press and oval shape punches. The tablets obtained were coated in a drum coater using 48 mg of ready-to-use coating mixture (containing polyvinyl alcohol, titanium dioxide, macrogol 3350, talc and iron oxide yellow), to obtain film-coated tablets of 1200 mg each.

Combined tablets containing 5 mg of dapagliflozin and 1000 mg of metformin hydrochloride were analogously prepared. The dapagliflozin granulate was prepared with the same ingredients and in the same way as disclosed above. The metformin granulate was also prepared analogously as disclosed above, by fluidized-bed granulation, but using 1000 mg of metformin hydrochloride, 128 mg of microcrystalline cellulose and 91 mg of copovidone. Both granulates were mixed, combined with 20 mg of magnesium stearate and compressed into tablets. The weight of each combined tablet was of 1338 mg. The tablets were coated with 54 mg of the coating mixture to obtain film-coated tablets of 1392 mg each. Example 6 Comparative bioavailabilitv study

The comparative bioavailability of the following dapagliflozin dosage forms was tested: - 10 mg strength dapagliflozin film-coated tablets of Example 1 (A)

10 mg strength dapagliflozin film-coated tablets of Example 2 (B)

10 mg strength Forxiga^® film-coated tablets (Comparative, C)

The comparative bioavailability/bioequivalence study was carried out in 15 healthy volunteers under fasting condition, who were administered a single dose of each treatment, separated by a 7-day washout period, and blood samples were collected for a period of 48 hours

The comparative bioavailability data (AUC, C_max and T_max) obtained for the tablet of Example 1 (treatment A) vs. Forxiga^® (treatment C) are shown in Table IV (A vs. C):

TABLE IV

Figure 1 represents the comparative profiles for mean plasma dapagliflozin concentration (ng/mL) vs. time (hours) for treatments A and C.

The comparative bioavailability data obtained for the tablet of Example 2 (treatment B) vs. Forxiga^® (treatment C) is shown in Table V (B vs. C):

TABLE V

The number of subjects included was 15 (n=15) in all cases. CV means the coefficient of variation. Figure 2 represents the comparative profiles for mean plasma dapagliflozin concentration (ng/mL) vs. time (hours) for treatments B and C.

It was surprisingly found that the composition according to the present invention, containing amorphous dapagliflozin, using a plain, simple formulation, without any disintegrant or solubility enhancer, was bioequivalent to Forxiga^®.

Example 7 Study to assess the polymorphic stability of amorphous dapaaliflozin in the pharmaceutical composition

The object of the study was to confirm that the amorphous form of dapagliflozin is not converted to crystalline dapagliflozin during production process or during storage.

Firstly, for assessing the potential influence of stress factors during the preparation of the pharmaceutical composition on the polymorphic stability of amorphous dapagliflozin, samples of amorphous dapagliflozin were subjected to the following treatments:

I. Compression (at 3 T, for 2 s) with a hydraulic press

II. Wetting with water, by mixing dapagliflozin and water in a mortar for 30 min, and subsequent drying at 40° C

III. Wetting with ethanol, by mixing dapagliflozin with ethanol in a mortar for 30 min, and subsequent drying at 40° C.

The polymorphic form of dapagliflozin before the treatments (sample 0), and after treatments I, II or III was assessed by XRPD. The results are shown in Figure 3. The X-axis represents the angle 2Q and the Y-axis the intensity. No change in the polymorphic form was observed after any of the treatments, i.e., dapagliflozin remained in the amorphous state, thus confirming the stability of the amorphous form.

Furthermore, the polymorphic stability of amorphous dapagliflozin within the composition was also assessed during stability tests of the pharmaceutical compositions, namely, after storage for 6 months at 40° C and 75% RH for the 10 mg strength film-coated tablets of Examples 1 and 2 packed in two different packaging material: aluminium (Alu) blisters and polychlorotrifluoroethylene (PCTFE) blisters.

The polymorphic stability was also assessed by XRPD. The following samples were analysed:

Comparative XRPD patterns are shown in Figures 4-7, wherein the X-axis represents the angle 2Q and the Y-axis the intensity. Figure 4 shows the comparative XRPD patterns of samples a1 , b1 , c and d.

Figure 5 shows the comparative XRPD patterns of samples a2, b1 , c and d. Figure 6 shows the comparative XRPD patters of samples a3, b2, c and d. Figure 7 shows the comparative XRPD patterns of samples a4, b2, c and d.

It could be determined that the only crystalline peaks in samples a1 , a2 a3 and a4 correspond to the same peaks of the excipients in the placebo formulations b1 and b2, and no additional peaks from crystalline dapagliflozin could be detected. Therefore, the 6 months stability study confirmed that dapagliflozin amorphous form present in the tablets does not convert into the crystalline hydrate Form A.

Example 8 Stability tests The stability of the tablets prepared in Example 1 and Example 2 (of 10 mg strength) was tested in an accelerated stability tests by measuring the active ingredient assay and the percentage of impurities at the beginning (initial) and after 6 months at 40° C and 75% RH (final) in two different packaging materials:

A: Aluminium (Alu) blisters - B: Polychlorotrifluoroethylene (PCTFE) blisters

The results are shown in Table VI:

Example 9 Comparative disintegration time of the tablets

The disintegration time of the 10 mg strength film-coated tablets of Examplel and Example 2, and of the analogous 10 mg strength commercial Forxiga^® tablets (“Comparative”) was measured according to the procedure disclosed in the European Pharmacopoeia (2.9.1 . Disintegration of Tablets and Capsules), in water at 37° C. The disintegration time (maximum for single unit) was measured at the beginning (initial) and after 6 months at 40° C and 75% RH (final).

Film-coated tablets of Example 1 and Example 2 were packed in two different packaging materials: - A: Aluminium (Alu) blisters

B: Polychlorotrifluoroethylene (PCTFE) blisters

Forxiga tablets (comparative) were packed in aluminium (Alu) blisters.

The results are shown in Table VII:

TABLE VII

Claims

1 A granulate composition for loading in capsules or for forming tablets, characterized in that the granulate composition essentially consists of: a) dapagliflozin; b) a filler selected from mannitol, microcrystalline cellulose and mixtures thereof; c) a glidant; and d) optionally, a lubricant.

2.- The granulate composition according to claim 1 , characterized in that dapagliflozin is amorphous.

3.- The granulate composition according to claim 1 or 2, characterized in that the amount of dapagliflozin is comprised between 2 wt% and 10 wt%, preferably comprised between 3 wt% and 8 wt%, more preferably comprised between 4 wt% and 6 wt%, and still more preferably is about 5 wt%, referred to the total weight of the granulate composition.

4.- The granulate composition according to any one of claims 1 to 3, characterized in that the amount of filler is comprised between 80 wt% and 97 wt%, preferably comprised between 85 wt% and 96 wt%, and more preferably comprised between 90 wt% and 95 wt%, relative to the total weight of the granulate composition.

5.- The granulate composition according to any one of claims 1 to 4, characterized in that the filler is microcrystalline cellulose.

6.- The granulate composition according to any one of claims 1 to 4, characterized in that the filler is a mixture of microcrystalline cellulose and mannitol, preferably wherein the weight ratio microcrystalline cellulose:mannitol is comprised between 5:1 and 1 :1 , preferably comprised between 4.5:1 and 2:1 , more preferably comprised between 4:1 and 3:1 , and still more preferably is about 3.5:1 .

7.- The granulate composition according to any one of claims 1 to 6, characterized in that the glidant is selected from silicon dioxide, magnesium oxide, magnesium silicate, magnesium trisilicate, talc, and mixtures thereof; preferably, the glidant is silicon dioxide.

1

8.- The granulate composition according to any one of claims 1 to 7, characterized in that the amount of glidant is comprised between 0.1 wt% and 10 wt%, preferably comprised between 0.5 wt% and 5 wt%, referred to the total weight of the granulate composition.

9.- The granulate composition according to any one of claims 1 to 8, characterized in that the composition contains a lubricant, which is preferably selected from calcium stearate, glycerin monostearate, glyceryl behenate, glyceryl palmitostearate, hydrogenated castor oil, magnesium stearate, palmitic acid, sodium stearyl fumarate, stearic acid, zinc stearate, and mixtures thereof, and more preferably is magnesium stearate.

10.- A pharmaceutical dosage form selected from a tablet and a capsule, wherein the tablet core or the capsule filling consists of the granulate composition according to any one of claims 1 to 9.

11 .- A pharmaceutical dosage form selected from a tablet and a capsule, wherein the tablet core or the capsule filling consists of the granulate composition according to any one of claims 1 to 9 and a metformin granulate.

12.- The pharmaceutical dosage form of claim 11 , characterized in that the metformin granulate consists of metformin hydrochloride, a filler selected from microcrystalline cellulose and mannitol, a binder and, optionally, a lubricant.

13.- The pharmaceutical dosage form according to claim 10, characterized in that each tablet or each capsule comprises between 3 and 30 mg of dapagliflozin, preferably each tablet or each capsule comprises about 5 mg of dapagliflozin or about 10 mg of dapagliflozin.

14.- The pharmaceutical dosage form according to claims 11 or 12, characterized in that each tablet or each capsule comprises between 1.5 and 20 mg of dapagliflozin, preferably about 2.5 mg or about 5 mg or about 10 mg of dapagliflozin and between 400 and 1200 mg of metformin hydrochloride, preferably about 500 mg or about 850 mg or about 1000 mg of metformin hydrochloride.

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15.- The pharmaceutical dosage form according to any one of claims 10 to 14, characterized in that it is a tablet, preferably, a film-coated tablet.

16.- A process for preparing the granulate composition according to any one of claims 1 to 9, characterized in that it comprises the following steps: i) mixing dapagliflozin, 50-100%, preferably 60-100%, more preferably 70-100% of the filler, and 30-70%, preferably 40-60%, more preferably about 50% of the glidant, and dry-granulating this mixture; and ii) mixing the granules obtained in step i) with the rest of filler, if any, with the rest of glidant and, if present, with the lubricant.

17.- The pharmaceutical dosage form according to any of claims 10 to 15 for use in therapy.

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