Stable pharmaceutical composition containing dapagliflozin and sitagliptin and process for the preparation thereof

Abstract

A stable pharmaceutical composition for oral administration, comprising sitagliptin and dapagliflozin, wherein said active ingredients are substantially free of contact from each other. A process for the preparation of a stable pharmaceutical dosage form for oral administration, comprising: Step 1: Weigh sitagliptin hydrochloride monohydrate and Microcrystalline Cellulose and sieve; Step 2: Wet granulation Step 3: Drying the granules in fluid bed dryer; Step 4: Sizing the granules; Step 5: Weigh dapagliflozin base, lactose monohydrate, and sodium starch glycolate, premix them and sieve; Step 6: Mixing granules from step 4 with excipients from step 5; Step 7: Lubrication with magnesium stearate, and Step 8: Compression of the homogeneous powder obtained from step 7 under controlled humidity in mono-layer tablets in a rotary tabletting machine. An alternative process comprising the following steps: Step 1: Weigh sitagliptin hydrochloride monohydrate and Microcrystalline Cellulose and sieve; Step 2: Wet granulation Step 3: Drying the granules in fluid bed dryer; Step 4: Sizing the granules; Step 5: Weigh dapagliflozin base, lactose monohydrate, and hydroxypropylcellulose and sieve; Step 6: Dry granulation of second active ingredient and the intra-granular excipients of step 5 and mix; Step 7: Sizing the slugs or flakes obtained from step 6; Step 8: Pre-Mixing the granules from step 4 and step 7; Step 9: Weigh sodium starch glycolate and sieve; Step 10: Mixing; Step 11: Lubrication with magnesium stearate, and Step 12: Compression of the homogeneous powder obtained from step 11.

Description

[0001] STABLE PHARMACEUTICAL COMPOSITION CONTAINING DAPAGLIFLOZIN AND SITAGLIPTIN AND PROCESS FOR THE PREPARATION THEREOF

[0002] TECHNICAL FIELD OF THE INVENTION

[0003] The present invention relates to a stable pharmaceutical composition for oral administration, and in particular to a fixed-dose combination comprising a therapeutically effective quantity of sitagliptin or a pharmaceutically acceptable salt or derivative thereof, as a first active ingredient, and a therapeutically effective quantity of dapagliflozin or a pharmaceutically acceptable salt or derivative thereof, as a second active ingredient, in order to improve the stability, dissolution bioavailability and compatibility issues of both said active ingredients. Furthermore, the present invention relates to a process for the preparation of said pharmaceutical composition.

[0004] BACKGROUND OF THE INVENTION

[0005] Type 2 Diabetes is a condition in which blood sugar is too high because the body does not produce or use insulin normally. Several classes of type 2 diabetes medicines exist. Each class of medicine works in a different way to lower blood sugar. Sometimes combining medicines may increase the effectiveness of each individual medicine to lower blood sugar and control hyperglycemia.

[0006] A combination therapy of dipeptidyl peptidase-4 inhibitor (DPP-4) and sodium-glucose cotransportcr type 2 inhibitor (SGLT2) for the treatment of type 2 diabetes appears to be an attractive approach because the two drugs exert different and potentially complementary glucose- lowering effects.

[0007] Dipeptidyl peptidase-4 (DPP-4) inhibitors help reduce blood sugar levels but tend to have a very modest effect. Further, DPP-4 inhibitors cause the release of insulin when blood sugar is rising and limit the liver's ability to release glucose.

[0008] Sitagliptin belongs to dipeptidyl peptidase-4 (DPP-4) inhibitors class of medications. Sitagliptin is used along with diet and exercise and sometimes with other medications to lower blood sugar levels in adults with type 2 diabetes mellitus. It works by increasing the amounts of certain natural substances that lower blood sugar when it is high. The effect of this medication leads to glucose dependent increases in insulin and decreases in glucagon to improve control of blood sugar.

[0009] Sitagliptin phosphatei monohydrate is described chemically as 7-[(3R)-3-amino-l-oxo-4-(2,4,5- trifluorophenyl)butyl]-5,6,7,8-tetrahydro-3-(lrifluoromethyl)- l ,2,4-triazolo[4,3-a|pyrazine phosphate (1: 1) monohydrate. >

[0010] Sitagliptin phosphate monohydrate is a white to off-white, crystalline, non-hygroscopic powder. It is soluble in water and N,N-dimethyl formamide; slightly soluble in methanol; very slightly soluble in ethanol, acetone, and acetonitrile; and insoluble in isopropanol and isopropyl acetate.

[0011] Sitagliptin is commercially available under the brand name JanuviaI M(a film-coated tablet for oral administration), Each film-coated tablet of Januvia™ contains 32.13, 64.25, or 128.5 mg of sitagliptin phosphate monohydrate, which is equivalent to 25, 50, or 100 mg, respectively, of fice base and the following inactive ingredients: microcrystalline cellulose, anhydrous dibasic calcium > phosphate, croscarmellose sodium, magnesium stearate, and sodium stearyl fumarate. In addition, the film coating contains the following inactive ingredients: polyvinyl alcohol, polyethylene glycol, talc, titanium dioxide, red iron oxide, and yellow iron oxide. Sodium-glucose cotransporter 2 (SGLT2) inhibitors affect the blood-filtering functions in the kidneys by blocking the return of glucose to the bloodstream. As a result, glucose is removed in the urine. These medicines may reduce the risk of heart attack and stroke in people with a high risk of those conditions.

[0012] Dapagliflozin is an inhibitor of SGLT2. By inhibiting SGLT2, dapagliflozin reduces reabsorption of filtered glucose and lowers the renal threshold for glucose, and thereby increases urinary glucose excretion. Dapagliflozin also reduces sodium reabsorption and increases the deliver)' of sodium to the distal tubule. This may influence several physiological functions including, but not restricted to, lowering both pre- and afterload of the heart and downregulation of sympathetic activity. Dapagliflozin is described chemically as D-glucitol, l,5-anhydro-l-C-[4-chloro-3-[(4- ethoxyphenyl)methyl]phenyl]-, (I S)-, compounded with (2S)- 1 ,2 -propanediol, hydrate (1 : 1 :1). Dapagliflozin is commercially available under the brand name Forxiga™ ( a film-coated tablet for oral administration). Each tablet contains the equivalent of 5 mg dapagliflozin as dapagliflozin propanediol or the equivalent of 10 mg dapagliflozin as dapagliflozin propanediol, and the following inactive ingredients: microcrystalline cellulose, anhydrous lactose, crospovidone, silicon dioxide, and magnesium stearate. In addition, the film coating contains the following inactive ingredients: polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, and yellow iron oxide.

[0013] In combination with sitagliptin, Forxiga™ 10 mg provided statistically significant improvements in HbAlc, FPG, and a statistically significant reduction in body weight.

[0014] Various methods are already known for the industrial preparation of dosage forms comprising Sitagliptin and Dapagliflozin, due to their useful therapeutic properties. However, the prior art has encountered substantial difficulties in the production of a stable fixed-dose combination of a desirable bioavailability because of incompatibilities issues of said active ingredients. Although in the prior art there are various methods to provide an improved stable fixed-dose combination of Sitagliptin in combination with Dapagliflozin, there still exists the need for a pharmaceutical composition which overcomes the related stability problems and bioavailability of said active ingredients due to incompatibility issues. > " . ’ ’ ' t T SUMMARY OF THE INVENTION ' '

[0015] It is therefore, an object of the present invention to provide a stable solid pharmaceutical composition for oral administration comprising sitagliptin or a pharmaceutically acceptable salt or derivative thereof as a first active ingredient, and dapagliflozin or a pharmaceutically acceptable salt or derivative thereof as a second active ingredient, which is bioavailable, with sufficient shelf- life and good pharmacotechnical properties.

[0016] Moreover, it is another object of the present invention to provide a suitable process for the preparation of a stable immediate release fixed-dose combination for oral administration comprising a therapeutically effective quantity of sitagliptin or a pharmaceutically acceptable salt or derivative thereof as a first active ingredient, and dapagliflozin or a pharmaceutically acceptable salt or derivative thereof as a second active ingredient, which is cost effective and reproducible and overcomes the difficulties encountered in the production of said dosage form due to incompatibility issues of sitagliptin and dapagliflozin.

[0017] In accordance with the above objects of the present invention, a stable pharmaceutical composition for oral administration, and in particular a fixed-dose composition is provided comprising a therapeutically effective quantity of sitagliptin or a pharmaceutically acceptable salt, or derivative thereof, as a first active ingredient and a therapeutically effective quantity of dapagliflozin or a pharmaceutically acceptable salt or derivative thereof, as a second active ingredient, wherein said first and second active ingredients are substantially free of contact with each other, in order to improve stability and patient compliance with reduced amount of impurities of both said active ingredients in the finished dosage form. According to another embodiment of the present invention, a process for the preparation of a pharmaceutical dosage form for oral administration, and in particular a fixed-dose combination comprising a therapeutically effective quantity of sitagliptin or a pharmaceutically acceptable salt or derivative thereof as a first active ingredient, and a therapeutically effective quantity of Dapagliflozin or a pharmaceutically acceptable salt or derivative thereof, as a second active ingredient, wherein said first and second active ingredients are substantially free of contact with each other in order to improve stability and patient compliance with reduced amount of impurities of both said active ingredients in the finished dosage form, is provided, wherein said process comprises the following steps:

[0018] Step 1 : Dispensing and sieving of first active ingredient and intra-granular excipients: Weight individually the first active ingredient sitagliptin hydrochloride monohydrate and Microcrystalline Cellulose, as a diluent, and sieve through appropriate sieve;

[0019] Step 2: Wet granulation: in a high shear mixer granulator add individually the first active ingredient and the intra-granular excipients of step 1 , pre-mix them for suitable time, add in said high shear mixer granulator purified water as granulation liquid and granulate until a homogenized wet mixture is obtained;

[0020] Step 3: Drying: the granules comprising the first active ingredient obtained from step 2 arc dried in fluid bed dryer to appropriate loss on drying (LOD);

[0021] Step 4: Sizing: Pass the granules comprising the first active ingredient obtained from step 3 to an appropriate sieve; Step 5: Dispensing and sieving of second active ingredient and extra-granular excipients: Weigh individually the second active ingredient dapagliflozin base, lactose monohydrate as a diluent, and

[0022] • sodium starch glycolate, as a disintegrant, premix them geometrically for suitable time and sieve through appropriate sieve;

[0023] . Step 6: Mixing: In a suitable blender mix the granules comprising the first active ingredient obtained from step 4 with the extra-granular excipients from step 5 for appropriate time;

[0024] Step 7: Lubrication: Weight individually magnesium stearate, as a lubricant, sieve it through appropriate sieve and mix with the blend obtained from step 6 for appropriate time, and

[0025] Step 8: Compression: Compress the homogeneous powder obtained from step 7 under controlled humidity in mono-layer tablets in a rotary tabletting machine using appropriate punches.

[0026] According to a further embodiment of the present invention, a process for the preparation of a stable pharmaceutical dosage form for oral administration, and in particular a fixed-dose combination comprising a therapeutically effective quantity of sitagliptin or a pharmaceutically acceptable salt or derivative thereof as a first active ingredient, and a therapeutically effective quantity of Dapagliflozin or a pharmaceutically acceptable salt or derivative thereof, as a second active ingredient, wherein said first and second active ingredients arc substantially free of contact with each other, in order to improve stability and patient compliance with reduced amount of impurities of both said active ingredients in the finished dosage form, is provided, wherein said process comprises the following steps:

[0027] Step 1 : Dispensing and sieving of first active ingredient and intra-granular excipients: Weight individually the first active ingredient sitagliptin hydrochloride monohydrate and Microcrystalline Cellulose, as a diluent, and sieve through appropriate sieve;

[0028] Step 2: Wet granulation of first active ingredient: in a high shear mixer granulator add individually the first active ingredient and the intra-granular excipients of step 1, pre-mix them for suitable time, add in said high shear mixer granulator purified water as granulation liquid and granulate until a homogenized wet mixture is obtained;

[0029] Step 3: Drying: dry the granules comprising the first active ingredient obtained from step 2 in fluid bed dryer to appropriate loss on drying (LOD);

[0030] Step 4: Sizing: Pass the dried granules comprising the first active ingredient obtained from step 3 to an appropriate sieve;

[0031] Step 5: Dispensing-Sieving of second active ingredient and intra-granular excipients: Weigh individually the second active ingredient dapagliflozin base, lactose monohydrate, as a diluent and Hydroxypropylcellulose, as a binder and sieve through appropriate sieve;

[0032] Step 6: Dry granulation of second active ingredient: In a mixer add the second active ingredient and the intra-granular excipients of step 5 and mix for appropriate time and subsequently mechanically compress into slugs or compact into flakes by a roller compactor the obtained homogenous mixture;

[0033] Step 7: Sizing: Pass the slugs or flakes obtained from step 6 through an appropriate sieve;

[0034] Step 8: Pre-Mixing: In a blender add the granules comprising the first active ingredient prepared in step 4 and the granules comprising the second active ingredient obtained from step 7 and mix them for appropriate time;

[0035] Step 9: Dispensing-Sieving of extra-granular excipients: Weigh sodium starch glycolate, as a disintegrant, and sieve through appropriate sieve;

[0036] Step 10: Mixing: In a blender add the granules prepared from step 8 and the extra-granular excipients of step 9 and mix for appropriate time;

[0037] Step 11 : Lubrication: Weigh individually magnesium stearate, as a lubricant, sieve it through appropriate sieve and mix it with the blend of step 10 into a blender for appropriate time, and

[0038] Step 12: Compression: Compress the homogeneous powder obtained from step 11 under controlled humidity on a rotary tabletting machine using appropriate punches.

[0039] Further preferred embodiments of the present invention are defined in dependent claims 2 to 1 1, 13 and 15. Other objects and advantages of the present invention will become apparent to those skilled in the art in view of the following detailed description.

[0040] DETAILED DESCRIPTION OF THE INVENTION

[0041] For the purposes of the present invention, a pharmaceutical composition comprising sitagliptin or salts, or derivatives thereof and dapagliflozin or salts or derivatives thereof is considered to be “stable” if both said active ingredient degradate less or more slowly than they do on their own and / or in known pharmaceutical compositions during storage. An excipient is considered to be “incompatible” with sitagliptin or salts, or derivatives thereof and dapagliflozin or salts or derivatives thereof if it promotes the degradation of both said active ingredients, that is to say, if said active ingredients degrade more or faster in the presence of said excipient when compared with the degradation of said active ingredients on their own. The terms “incompatibility”, “compatible” and “compatibility” arc defined accordingly.

[0042] Both active ingredients contained in a dosage form are “bioavailable”, if when administered in a dosage form are released from the dosage form, absorbed and reach, at least the same, concentration levels in plasma as any of the marketed products individually containing the same quantity of the same active ingredient and intended for the same use.

[0043] Although the pharmaceutical composition may be in various forms, the preferred solid forms are tablets, capsules and caplets.

[0044] A major object of the present invention is to provide a stable immediate release fixed-dose formulation of Sitagliptin and Dapagliflozin which is simple to manufacture, cost effective, posses good pharmacotechnical properties and linearity.

[0045] Further, in the preparation of a fixed dose combination composition in a tablet form, it is very difficult to completely separate dapagliflozin and sitagliptin from each other. Even in case a bilayer tablet is formed, it is impossible to mechanically separate each active ingredient completely from each other. Moreover, a bilayer tablet machine is required in order to manufacture such tablets.

[0046] It has been surprisingly found that the object of the present invention is achieved by employing a manufacturing process for the fixed dose combination, in a mono-layer tablet dosage form, wherein the first and second active ingredients are substantially free of contact from each other, and both said active ingredients are not in direct physical contact with each other in order to increase the stability of the fixed-dose combination. Alternatively, the tablet may be a mono-layer tablet, wherein both said active ingredients are not in direct physical contact with each other and Sitagliptin is contained in first granules and Dapagliflozin is contained in second granules or blend and compressed together to a coated tablet.

[0047] The pharmaceutical compositions of the present invention may also contain one or more additional formulation ingredients selected from a wide variety of excipients. According to the desired properties of the composition, any number of ingredients may be selected, alone or in combination, based upon their known uses in preparation of solid dosage form compositions (tablet / capsule compositions).

[0048] Such. ingredients include, but are not limited to, fillers, diluents, binders, compression aids, disintegrants, glidants, lubricants, flavors, colorants, sweetener, film-coating agents, plasticizers and the like. ■ -. < ..

[0049] The optional excipients must be compatible with first active ingredient Dapagliflozin or salt, metabolite or derivative thereof and / or second active ingredient sitagliptin or salt thereof so that it does not interfere with them in the composition.

[0050] Moreover, any excipient may optionally be added to the above composition, provided that they arc compatible with the active ingredients of the composition, in order to overcome problems associated with unfavorable pharmacotechnical characteristics of these substances, and in order to increase the stability of the drug and the shelf-life of the pharmaceutical product, and provide a product exhibiting excellent bioavailability and palatability. Diluents may be selected from calcium carbonate, calcium phosphate dibasic, calcium phosphate tribasic. calcium sulfate, microcrystalline cellulose, microcrystalline silicified cellulose, powdered cellulose, dextrates, dextrose, dextrin, fructose, lactitol, lactose anhydrous, lactose monohydrate, lactose dihydrate, lactose trihydrate, mannitol, sorbitol, starch, pregelatinize starch, modified starch, sucrose, talc, xylitol, maltose, fructose, isomalt, maltodextrin, maltitol and the like. Diluents may be in the range of 10-90 by weight % of the total weight of the composition.

[0051] Binders may be selected from acacia, alginic acid, carbomer, carboxymethylcellulose calcium, carbomethylcellulose sodium, microcrystalline cellulose, powdered cellulose, ethyl cellulose, gelatin liquid glucose, guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose, ethyl cellulose, povidonemaltodextrin, methylcellulose, polydextrose, polyethylene oxide, sodium alginate, starch paste, com starch, pregelatinized starch, sucrose, tragacanth, low-substituted hydroxypropyl cellulose, glucose, sorbitol, lactose, dextrose. Binders may be in the range of 1-40 by weight % of the total weight o f the composition.

[0052] Disintegrants may be selected from alginic acid, carbon dioxide, carboxymethylcellulose calcium, carboxymethylcellulose sodium, microcrystalline cellulose, powdered cellulose, croscarmelose sodium, crospovidone, sodium docusate, gaur gum, hydroxypropyl cellulose, methylcellulose, polacrilin potassium, poloxamer, povidone, sodium alginate, sodium glycine carbonate, sodium laulyl sulfate (SLS), sodium starch glycolate, starch, pregelatinized starch, low-substituted hydroxypropyl cellulose and the like. Disintegrants may be in the range of 0.1 - 25 by weight % of the total weight of the composition.

[0053] Glidants may be selected from calcium silicate, calcium phosphate, metallic lauryl sulphatespowdered cellulose, starch, talc, colloidal silicon dioxide and the like. Glidants may be in the range of 0.01-2 weight % of the total weight of the composition.

[0054] Lubricants may be selected from magnesium stearate, stearic acid, sodium stearyl fumarate, magnesium lauryl sulphate, talc, polyethylene glycol, glyceryl behenate and the like. Lubricants may be in the range of 0.01-2 weight % of the total weight of the composition.

[0055] Suitable sweeteners may be selected from sugars such as sucrose, lactose and glucose; cyclamate and salts thereof; saccharin and salts thereof; aspartame and the like.

[0056] Flavouring agents may be selected from natural or synthetic flavours such as strawberry flavour, wild cherry flavour, green apple flavour, spearmint flavor, peppermint flavor and the like.

[0057] All percentages stated herein are weight percentages based on total composition weight, unless otherwise stated. The first and second active ingredients accordihg ’to the present invention may include any crystalline form, hydrate, co-crystal, salt, ester, solvate, enantiomer, diastereomer or derivative thereof.

[0058] According to the present invention the first active ingredient is preferable sitagliptin hydrochloride monohydrate and the second active ingredient is preferable Dapagliflozin base in amorphous form. Further, according to the present invention, the weight ratio of the first active ingredient Sitagliptin to the second active ingredient Dapagliflozin may be in the range from 1 : 1 to 20: 1 .

[0059] According to the present invention the manufacturing process used for the preparation of a pharmaceutical dosage form for oral administration, and in particular a fixed-dose combination comprising a therapeutically effective quantity of sitagliptin or a pharmaceutically acceptable salt or derivative thereof as a first active ingredient, and a therapeutically effective quantity of Dapagliflozin or a pharmaceutically acceptable salt or derivative thereof, as a second active ingredient, wherein said first and second active ingredients are substantially free of contact with each other in order to improve stability and patient compliance with reduced amount of impurities of both said active ingredients in the finished dosage form, comprises the following steps:

[0060] Step 1 : Dispensing and sieving of first active ingredient and intra-granular excipients: Weight individually the first active ingredient sitagliptin hydrochloride monohydrate and Microcrystalline Cellulose, as a diluent, and sieve through appropriate sieve;

[0061] Step 2: Wet granulation: in a high shear mixer granulator add individually the first active ingredient and the intra-granular excipients of step 1 , pre-mix them for suitable time, add in said high shear mixer granulator purified water as granulation liquid and granulate until a homogenized wet mixture is obtained;

[0062] Step 3: Drying: the granules comprising the first active ingredient obtained from step 2 are dried in fluid bed dryer to appropriate loss on drying (LOD);

[0063] Step 4: Sizing: Pass the granules comprising the first active ingredient obtained from step 3 to an appropriate sieve;

[0064] Step 5: Dispensing and sieving of second active ingredient and extra-granular excipients: Weigh individually the second active ingredient dapagliflozin base, lactose monohydrate as a diluent, and sodium starch glycolate, as a disintegrant, premix them geometrically for suitable time and sieve through appropriate sieve;

[0065] Step 6: Mixing: In a suitable blender mix the granules comprising the first active ingredient obtained from step 4 with the extra-granular excipients from step 5 for appropriate time;

[0066] Step 7: Lubrication: Weight individually magnesium stearate, as a lubricant, sieve it through appropriate sieve and mix with the blend obtained from step 6 for appropriate time, and

[0067] Step 8: Compression: Compress the homogeneous powder obtained from step 7 under controlled humidity in mono-layer tablets in a rotary tabletting machine using appropriate punches.

[0068] Step 9: Coating suspension: Prepare a suspension of coating material in purified water using a stainless-steel tank with a mixing device, and

[0069] Step 10: Film Coating: The tablets prepared from step 8 are sprayed with the coating suspension from step 9.

[0070] Alternatively, according to the present invention the manufacturing process used for the preparation of a stable pharmaceutical dosage form for oral administration, and in particular a fixed-dose combination comprising a therapeutically effective quantity of sitagliptin or a pharmaceutically acceptable salt or derivative thereof as a first active ingredient, and a therapeutically effective quantity of Dapagliflozin or a pharmaceutically acceptable salt or derivative thereof, as a second active ingredient, wherein said first and second active ingredients are substantially free of contact>,with each other, in order to improve stability and patientcompliance with reduced amount of impurities of both said active ingredients in the finished dosage form, comprises the following steps:

[0071] Step 1 : Dispensing and sieving of first active ingredient and intra-granular excipients: Weight individually the first active ingredient sitagliptin hydrochloride monohydrate and Microcrystalline Cellulose, as a diluent, and sieve through appropriate sieve;

[0072] Step 2: Wet granulation of first active ingredient: in a high shear mixer granulator add individually the first active ingredient and the intra-granular excipients of step 1 , pre-mix them for suitable time, add in said high shear mixer granulator purified water as granulation liquid and granulate until a homogenized wet mixture is obtained;

[0073] Step 3: Drying: dry the granules comprising the first active ingredient obtained from step 2 in fluid bed dryer to appropriate loss on drying (LOD); Step 4: Sizing: Pass the dried granules comprising the first active ingredient obtained from step 3 to an appropriate sieve;

[0074] Step 5: Dispensing-Sieving of second active ingredient and intra-granular excipients : Weigh individually the second active ingredient dapagliflozin base, lactose monohydrate, as a diluent and Hydroxy propylcellulose, as a binder and sieve through appropriate sieve;

[0075] Step 6: Dry granulation of second active ingredient: In a mixer add the second active ingredient and the intra-granular excipients of step 5 and mix for appropriate time and subsequently mechanically compress into slugs or compact into flakes by a roller compactor the obtained homogenous mixture;

[0076] Step 7: Sizing: Pass the slugs or flakes obtained from step 6 through an appropriate sieve;

[0077] Step 8: Pre-Mixing: In a blender add the granules comprising the first active ingredient prepared in step 4 and the granules comprising the second active ingredient obtained from step 7 and mix them for appropriate time;

[0078] Step 9: Dispensing-Sieving of extra-granular excipients: Weigh sodium starch glycolate, as a disintegrant, and sieve through appropriate sieve;

[0079] Step 10: Mixing: In a blender add the granules prepared from step 8 and the extra-granular excipients of step 9 and mix for appropriate time;

[0080] Step 11 : Lubrication: Weigh individually magnesium stearate, as a lubricant, sieve it through appropriate sieve and mix it with the blend of step 10 into a blender for appropriate time, and Step 12: Compression: Compress the homogeneous powder obtained from step 11 under controlled humidity on a rotary tabletting machine using appropriate punches.

[0081] Step 13: Coating suspension: Prepare a suspension of coating material in purified water using a stainless-steel tank with a mixing device.

[0082] Step 14: The tablets from step 12 are sprayed with the coating suspension from step 13.

[0083] The pharmaceutical compositions according to the present invention arc characterized by excellent pharmacotechnical properties, such as homogeneity, flowability and compressibility. Thanks to these properties, the solid dosage forms prepared by the process according to the present invention exhibit excellent technical characteristics including dissolution rate, hardness, stability and bioavailability.

[0084] One of the main objects of the present invention was to prepare a product with acceptable stability. For this reason, the mono-layer tablets of the present invention were exposed to normal and accelerated stability studies according to the current ICH guidelines.

[0085] The results showed that the stability of the present invention was good (e.g. total impurities were not increased throughout normal and accelerated conditions).

[0086] The selection of appropriate materials (excipients etc.) should be done carefully in order to avoid any incompatibility problems or non-compliance with EMA and FDA guidelines for inactive , ingredients.

[0087] The following examples illustrate preferred embodiments in accordance with the present invention without limiting the scope or spirit of the invention:

[0088] EXAMPLES

[0089] Compatibility studies of Sitagliptin and Dapagliflozin

[0090] Prior to evaluating the potential effects of inactive ingredients on the stability of the fixed-dose composition comprising sitagliptin and dapagliflozin, extensive compatibility studies were carried out for the identification of potential sitagliptin - dapagliflozin interactions. The compatibility studies performed revealed that when Sitagliptin and Dapagliflozin active ingredients are in direct contact with each other, even in various ratio, are incompatible. Degradation impurities were formed, and it was deemed necessary to achieve a stable formulation containing both active ingredients reducing as much as possible their direct contact.

[0091] Drug-drug interactions were monitored against related substances through stability indicating HPLC method.

[0092] Example 1: Compositions 1 - 3 according to the present invention.

[0093] TABLE 1 : Compositions 1 - 3 of the present invention.

[0094] For the purpose of stability profile evaluation of Sitagliptin - Dapagliflozin fixed-dose composition, compositions containing sitagliptin and dapagliflozin in direct contact with each other and at various ratio were prepared and were placed at accelerated conditions and elevated temperature for a time period of one month. The impurity profiles of the prepared compositions (compositions 1 -3 as presented in Table 1) were monitored at time period T=0 days and T=30 days and were placed at accelerated conditions, providing essential information of instability of Sitagliptin ad Dapagliflozin.

[0095] Unless otherwise indicated, all steps in this procedure were carried out at room temperature.

[0096] TABLE 2: Stability results of Compositions 1 - 3 of Example 1 at time period T = 0 days

[0097] The limit of known and unknown impurities for both active ingredients is not more than (NMT) 0.2%. The preparation of compositions 1 - 3 of Example I of the present invention was prepared according to the following process: Based on the desirable composition the appropriate quantity from each active ingredient was weighed, mixed for appropriate time, and transferred into an amber vial. For each composition, two vials were prepared with aim the first to be analyzed immediately after the direct contact of the two active ingredients and the second one after their exposure to accelerated conditions for a time period of 30 days, in order to identify if they are compatible.

[0098] The stability results of compositions 1 - 3 of Example 1 according to the present invention are presented in Table 2 and Table 3.

[0099] TABLE 3: Stability results of Compositions 1 - 3 of Example 1 at accelerated conditions and time period T = 30 days ( Temperature 40±2° C and relative humidity 75±5%.)

[0100] BRT = Below Reporting Threshold, and ND = Not Detected

[0101] Upon monitoring of sitagliptin and dapagliflozin compositions 1 - 3 of Example 1, the levels of degradation impurities arisen upon exposure to accelerated conditions (40°C ± 2°C / 75% ± 5% RH).

[0102] The above data reveal the incompatibility between two active ingredients.

[0103] Example 2 - Compositions 4 containing lOOmg Sitagliptin and lOmg Dapagliflozin

[0104] A series of compatibility studies were carried out, challenging the stability performance of sitagliptin and dapagliflozin with various excipients and at various ratio of both active ingredients with substantially no direct contact between both active ingredients. The following excipients were the most preferred excipients used in fixed-dose combination of sitagliptin and dapagliflozin according to the present invention and were subjected to evaluation: diluent such as microcrystalline cellulose, lactose monohydrate, disintegrant such as sodium starch glycolate, lubricant such as Magnesium stearate and coating such as Polyvinyl alcohol (PVA) based coating material. TABLE 4: Composition 4 of Example 2 containing Sitagliptin - Dapagliflozin lOOmg / l Omg of the present invention

[0105] Composition 4 of Example 2 of the present invention (TABLE 4) were prepared according to the following manufacturing process: The intragranular materials Sitagliptin HCl monohydrate and microcrystalline cellulose, were individually weighted and sieved through appropriate sieve. Subsequently, said intragranular materials were added in a high shear mixer granulator and premixed for suitable time and granulated by adding purified water as granulation liquid until a homogenized wet mixture is obtained. The granules thus formed comprising sitagliptin were dried in fluid bed dryer to appropriate LOD and then sized through suitable sieve. Further, all extra- granular materials such as Dapagliflozin base, lactose monohydrate and sodium starch glycolate were dispensed, and premixed geometrically for suitable time and sieved through appropriate sieve. Then, the previously formed granules from intragranular materials containing Sitagliptin and the mixture of the extra-granular materials were added in a suitable blender and mixed for suitable time. Further, lubricant such as magnesium stearate was added in said blender with the blend from intragranular and extra-granular materials and mixed for suitable time. The homogeneous powder obtained was compressed under controlled humidity on a rotary tabletting machine by using appropriate punches. Further, a suspension of coating material was prepared in purified water using a stainless-steel tank with a mixing device and the prepared tablets were sprayed with said coating suspension. ■'c

[0106] The generated results of said composition are provided in the table below (see Table 5).

[0107] The produced mono-layer tablets were tested for hardness, friability, disintegration, and water content. All tests were performed according to European Pharmacopoeia 5.1 and were well within the specifications. TABLE 5: Stability results of Composition 4 of Example 2 at T=0, at accelerated conditions and time period T - 3 Months and T=6 months (Temperature 40±2° C and relative humidity 75±5%.)

[0108] BRT = Below Reporting Threshold and ND = Not Detected

[0109] Example 3: Composition 5 according to the present invention as illustrated in Table 6 below

[0110] TAB LE 6: Composition 5 of Example 3 containing Sitagliptin - Dapagliflozin 25mg / 10mg of the present invention Tablets of the above composition 5 of Example 3 comprising Sitagliptin and Dapagliflozin according to the present invention were prepared according to the same manufacturing process as in composition 4 of Example 2 of the present invention. The produced tablets were tested for hardness, friability, disintegration, and water content. All tests were performed according to European Pharmacopoeia 5.1 and were well within the specifications. The stability test of composition 5 of Example 3 of the present invention was performed under the same conditions as in Table 7.

[0111] TABLE 7: Stability results of Composition 5 of Example 3 at T=0, at accelerated conditions and time period T = 3 Months and T=6 months (Temperature 40±2° C and relative humidity 75±5%.)

[0112] BRT = Below Reporting Threshold and ND = Not Detected

[0113] Example 4: Composition 6 according to the present invention as illustrated in Table 8 below

[0114] TABLE 8: Composition 6 of Example 4 containing Sitagliptin - Dapagliflozin 25mg / 10mg of the present invention Tablets of composition 6 of Example 4 comprising 25mg Sitagliptin and lOmg Dapagliflozin according to the present invention were prepared according to the following manufacturing process: The intragranular materials Sitagliptin HC1 monohydrate and microcrystalline cellulose, were individually weighted and sieved through appropriate sieve. Subsequently, said intragranular materials were added in a first high shear mixer granulator and premixed for suitable time and granulated by adding purified water as granulation liquid until a homogenized wet mixture is obtained. The granules thus formed (first granules) containing sitagliptin were dried in fluid bed dryer to appropriate LOD and then sized through suitable sieve.

[0115] Further, intragranular materials such as lactose monohydrate and Ilydroxypropylcellulose were weighted and sieved through appropriate sieve. Then Dapagliflozin base was weighted and mixed with lactose monohydrate and hydroxypropylcellulose in a second mixer for appropriate time. The obtained mixture was mechanically compressed (slugging) or compacted in flakes by roller compactor. Subsequently, the formed slugs or the flakes were sized through a suitable sieve and added in a suitable blender together with the first granules and mixed for appropriate time and second granules containing sitagliptin ana dapagliflozin were formed.

[0116] Further, all extra-granular materials such as sodium starch glycolate were dispensed and sieved through appropriate sieve. Then, the previously formed second granules from intragranular materials and the extra-granular material sodium starch glycolate were added in a suitable blender and mixed for suitable time. Further, lubricant such as magnesium stearate was added in said blender with the blend from intragranular and extra-granular materials and mixed for suitable time. The homogeneous powder thus obtained was compressed under controlled humidity on a rotary tablctting machine by using appropriate punches. Further, a suspension of coating material was prepared in purified water using a stainless-steel tank with a mixing device and the prepared tablets were sprayed with said coating suspension.

[0117] The produced tablets were tested for hardness, friability, disintegration, and water content. All tests were performed according to European Pharmacopoeia 5.1 and were well within the specifications.

[0118] The stability test of composition 6 of Example 4 o f the present invention was performed under the same conditions as in Table 5.

[0119] TABLE 9: Stability results of Composition 6 of Example 4 at T=0, at accelerated conditions and time period T = 3 Months and T=6 months (Temperature 40±2° C and relative humidity 75±5%.)

[0120] BRT = Below Reporting Threshold; ND=Not Detected, and BQL = Below Quantification Level

[0121] Therefore, the present inventors have developed a pharmaceutical composition, a fixed-dose combination, comprising Sitagliptin and Dapagliflozin with good stability for long-term use while exerting no adverse effects. According to the present invention, the storage-stable pharmaceutical composition comprising sitagliptin and dapagliflozin can be provided.

[0122] Further, the composition can be provided as a pharmaceutical composition capable of containing a usual single dose ( 25mg or 100 mg of sitagliptin and 5 mg or 10 mg of dapagliflozin) (e.g., tablets containing the usual doses of the respective tablets for monotherapy), and hence is favourable for compliance by the recipient. Further, sitagliptin and dapagliflozin can be easily used in combination for the treatment of type 2 diabetes mellitus:

[0123] • To improve glycaemic control when metformin and / or sulphonylurea (SU) and one of the mono-components of the new fixed-dose combination do not provide adequate glycaemic control,

[0124] • When already being treated with the free combination of dapagliflozin and sitagliptin.

[0125] While the present invention has been described with respect to the particular embodiments, it will be apparent to those skilled in the art that various changes and modifications may be made in the invention without departing from the spirit and scope thereof, as defined in the appended claims.

Claims

CLAIMS1 . A stable pharmaceutical composition for oral administration, and in particular a fixed-dose combination comprising a therapeutically effective quantity of sitagliptin or a pharmaceutically acceptable salt, or derivative thereof, as a first active ingredient and a therapeutically effective quantity of dapagliflozin or a pharmaceutically acceptable salt or derivative thereof, as a second active ingredient, wherein said first and second active ingredients are substantially free of contact from each other, in order to improve stability and patient compliance with reduced amount of impurities of both said active ingredients.

2. The pharmaceutical composition according to claim 1 , wherein the weight ratio of the first active ingredient Sitagliptin or salt and / or derivative thereof to the second active ingredient Dapagliflozin or salt and / or derivative thereof is in the range from 1 : 1 to 20: 1.

3. The pharmaceutical composition according to claim 1 , wherein said first active ingredient is sitagliptin hydrochloride monohydrate and said second active ingredient is dapagliflozin base.

4. The pharmaceutical composition according to any of the previous claims, wherein said fixed- dose combination is a mono-layer tablet.

5. The pharmaceutical composition according to any of the previous claims, wherein said first active ingredient is contained in granules comprising sitagliptin hydrochloride monohydrate as first active ingredient and microcrystalline cellulose as diluent.

6. The pharmaceutical composition according to any of the previous claims, wherein further comprises at least one pharmaceutically acceptable excipient, as diluent, selected from the list consisting of microcrystalline cellulose or lactose monohydratc in an amount from 10 to 90% by weight % of the total weight of the composition.

7. The pharmaceutical composition according to any of the previous claims, wherein it further comprises at least one pharmaceutically acceptable excipient as binder, selected from the group of hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, or povidone in an amount of 1 to 40% by weight % of the total weight of the composition.

8. The pharmaceutical composition according to any of the previous claims, wherein it further comprises at least one pharmaceutically acceptable excipient as disintegrant, such as sodium starch glycolate, croscarmellose sodium, crospovidone in an amount of 0.1 to 25% by weight % of the total weight of the composition.

9. The pharmaceutical composition according to any of the previous claims, wherein said pharmaceutical composition further comprises pharmaceutically acceptable additives selected from a group comprising of absorbents, acids, anticaking agents, glidants, anticoagulants, antimicrobials, antiseptics, diluents, binders, chelating agents, coating agents, colorants, pigments, dispersants, fillers, lubricants, plasticizers, stabilizers, sweeteners, disintegrants, surfactants, and their combinations thereof.

10. The pharmaceutical composition according to claim 2 or 3, wherein it further comprises microcrystalline cellulose and lactose monohydrate, as diluents, sodium starch glycolate as a disintegrant, magnesium stearate as a lubricant and optionally hydroxypropyl cellulose as a binder.

11. The pharmaceutical composition according to any of the previous claims, wherein said fixed- dose combination further comprises a coating, optionally a polyvinyl alcohol based coating.

12. A process for the preparation of a stable pharmaceutical dosage form for oral administration, and in particular a fixed-dose combination comprising a therapeutically effective quantity of sitagliptin or a pharmaceutically acceptable salt or derivative thereof as a first active ingredient, and a therapeutically effective quantity of Dapagliflozin or a pharmaceutically acceptable salt or derivative thereof, as a second active ingredient, wherein said first and second active ingredients are substantially free of contact with each other, in order to improve stability and patient compliance with reduced amount of impurities of both said active ingredients in the finished dosage form, wherein said process comprises the following steps:Step 1 : Dispensing and sieving of first active ingredient and intra-granular excipients: Weight individually the first active ingredient sitagliptin hydrochloride monohydrate and Microcrystalline Cellulose, as a diluent, and sieve through appropriate sieve;Step 2: Wet granulation: in a high shear mixer granulator add individually the first active ingredient and the intra-granular excipients of step 1, pre-mix them for suitable time, add in said high shear mixer granulator purified water as granulation liquid and granulate until a homogenized wet mixture is obtained;Step 3: Drying: the granules comprising the first active ingredient obtained from step 2 are dried in fluid bed dryer to appropriate loss on drying (LOD);Step 4: Sizing: Pass the granules comprising the first active ingredient obtained from step 3 to an appropriate sieve;Step 5: Dispensing and sieving of second active ingredient and extra-granular excipients: Weigh individually the second active ingredient dapagliflozin base, lactose monohydrate as a diluent, and sodium starch glycolate, as a disintegrant, premix them geometrically for suitable time and sieve through appropriate sieve;Step 6: Mixing: In a suitable blender mix the granules comprising the first active ingredient obtained from step 4 with the extra-granular excipients from step 5 for appropriate time;Step 7: Lubrication: Weight individually magnesium stearate, as a lubricant, sieve it through appropriate sieve and mix with the blend obtained from step 6 for appropriate time, andStep 8: Compression: Compress the homogeneous powder obtained from step 7 under controlled humidity in mono-layer tablets in a rotary tabletting machine using appropriate punches.

13. The process for the preparation of a pharmaceutical dosage form according to claim 12, wherein it further comprises two additional steps, namely:Step 9: Coating suspension: Prepare a suspension of coating material in purified water using a stainless-steel tank with a mixing device, andStep 10: Film Coating: The tablets prepared from step 8 are sprayed with the coating suspension from step 9.

14. A process for the preparation of a stable pharmaceutical dosage form for oral administration, and in particular a fixed-dose combination comprising a therapeutically effective quantity of sitagliptin or a pharmaceutically acceptable salt or derivative thereof as a first active ingredient, and a therapeutically effective quantity of Dapagliflozin or a pharmaceutically acceptable salt or derivative thereof, as a second active ingredient, wherein said first and second active ingredients are substantially free of contact with each other, in order to improve stability and patient compliance with reduced amount of impurities of both said active ingredients in the finished dosage form, wherein said process comprises the following steps:Step I : Dispensing and sieving of first active ingredient and intra-granular excipients: Weight individually the first active ingredient sitagliptin hydrochloride monohydrate and MicrocrystallineCellulose, as a diluent, and sieve through appropriate sieve;Step 2: Wet granulation of first active ingredient: in a high shear mixer granulator add individually the first active ingredient and the intra-granular excipients of step 1, pre-mix them for suitable time, add in said high shear mixer granulator purified water as granulation liquid and granulate until a homogenized wet mixture is obtained;Step 3: Drying: dry the granules comprising the first active ingredient obtained from step 2 in fluid bed dryer to appropriate loss on drying (LOD);Pass the dried granules comprising the first active ingredient obtained from step 3 to an appropriate sieve;Step 5: Dispensing-Sieving of second active ingredient and intra-granular excipients: Weigh individually the second active ingredient dapagliflozin base, lactose monohydrate, as a diluent and Hydroxypropylcellulose, as a binder and sieve through appropriate sieve;Step 6: Dry granulation of second, active ingredient: In a mixer add the second active ingredient and the intra-granular excipients of step 5 and mix for appropriate time and subsequently mechanically compress into slugs or compact into flakes by a roller compactor the obtained homogenous mixture;Step 7: Sizing: Pass the slugs or flakes obtained from step 6 through an appropriate sieve;Step 8: Pre-Mixing: In a blender add the granules comprising the first active ingredient prepared in step 4 and the granules comprising the second active ingredient obtained from step 7 and mix them for appropriate time;Step 9: Dispensing-Sieving of extra-granular excipients: Weigh sodium starch glycolate, as a disintegrant, and sieve through appropriate sieve;Step 10: Mixing: In a blender add the granules prepared from step 8 and the extra-granular excipients of step 9 and mix for appropriate time;11 Lubrication: Weigh individually magnesium stearate, as a lubricant, sieve it through appropriate sieve and mix it with the blend of step 10 into a blender for appropriate time, and Step 12: Compression: Compress the homogeneous powder obtained from step 11 under controlled humidity on a rotary tabletting machine using appropriate punches.

15. The process for the preparation of a pharmaceutical dosage form according to claim 14, wherein it further comprises two additional steps, namely:Step 13: Coating suspension: Prepare a suspension of coating material in purified water using a stainless-steel tank with a mixing device.Step 14: The tablets from step 12 Eire sprayed with the coating suspension from step 13.

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