, Description:STABLE PHARMACEUTICAL COMPOSITION OF SAXAGLIPTIN AND DAPAGLIFLOZIN

FIELD OF THE INVENTION

The present invention relates to stable pharmaceutical composition comprising Dapagliflozin and Saxagliptin, wherein Dapagliflozin and Saxagliptin are present in close contact with each other and its process for preparation.

BACKGROUND OF THE INVENTION

Type II diabetes is the most common form of diabetes accounting for 90% of diabetes cases. Over 100 million people worldwide have type-2 diabetes and the prevalence is increasing dramatically in both the developed and developing worlds. Type-II diabetes is a lifelong illness, which generally starts in middle age or later part of life, but can start at any age. Oral therapeutic options for the treatment of type II diabetes mellitus include compounds known as: sulfonylureas, thiazolidinediones, and alpha-glucosidase inhibitors. The active agents from each class are generally administered to patients alone. However, once monotherapy becomes inadequate, combination therapy is an attractive and rational course of action for treating hyperglycemia. The Fixed dose combination (FDC) are intended to improve patient compliance by providing two drugs with different modes of action in a single tablet.

Dapagliflozin is reported to inhibit subtype 2 of the sodium-glucose transport proteins (SGLT2), which is responsible for at least 90% of the glucose reabsorption in the kidney. Blocking this transporter causes blood glucose to be eliminated through the urine. In particular, dapagliflozin is indicated and currently being used for the treatment of type 2 diabetes and is marketed under the trade name Farxiga®.

Saxagliptin is a dipeptidyl peptidase IV (DPP-IV) inhibitor currently being used for the treatment of type 2 diabetes and is marketed under the trade name Onglyza®. In addition, fixed dose combination products of Saxagliptin with Metformin and Dapagliflozin are marketed under trade names Kombiglyze® XR and Qtern® respectively.

Saxagliptin is a labile compound which undergoes intramolecular cyclization leading to formation of a degradant known as cyclic amidine which is therapeutically inactive. Prior art states that rate of cyclization of saxagliptin increases when mixed with common excipients and during processing steps such as wet granulation, dry granulation and compression; and considering such compatibility issues with excipients and process, manufacturing of combination of saxagliptin with other therapeutic agents will become even more problematic. The solution disclosed in US8628799 to overcome these issues includes separation of saxagliptin from all excipients or other active agents. To achieve separation of saxagliptin multiple coating steps were used on inert core. Such an approach of multiple layering is cumbersome and complex process and additionally drug layering causes several issues such as content uniformity and assay because of non uniform coating which impacts the product quality. Hence, it is a major challenge in pharmaceutical industry to formulate a stable Saxagliptin with another therapeutic agent as a combination formulation using a less complex and viable process.

Similarly, US20140079778 discloses a coated tablet where drug tablet comprising a drug other than saxagliptin is coated with an active coating layer comprising saxagliptin and an amine compound such as glycine. Apart from these, several patent publications including WO2014096982, WO2014096983, WO2013179307, WO2014030051, WO2014122671, US20140072628, WO2015071887, WO2015071889 and WO2017060861 disclose pharmaceutical formulations of saxagliptin and/or its combination with other therapeutic agents.

However, still there remains an unmet need to prepare a stable pharmaceutical composition of Saxagliptin in combination with other therapeutic agent particularly Dapagliflozin.

The inventors of the present application surprisingly found that formulation comprising Saxagliptin and Dapagliflozin can be prepared without physically separating the active agents without increasing rate of cyclization of Saxagliptin and provides a pharmaceutical composition which remains stable for a longer period of time with very low rate of degradation and lower impurity formation particularly cyclic amidine impurity. In addition, the inventors found that Saxagliptin remains stable even when it is formulated by a conventional process of wet mixing of Saxagliptin and Dapagliflozin in contrast to the inevitable coating process for Saxagliptin mentioned in prior art. Hence, present invention provides a stable pharmaceutical composition with very low impurity content for a longer period of time which can be prepared by simple, cost effective, industrially feasible and commercially viable wet mixing method.

SUMMARY OF THE INVENTION
The present invention provides stable pharmaceutical composition comprising Dapagliflozin and Saxagliptin, wherein Dapagliflozin and Saxagliptin are present in close contact with each other.

One aspect of the present invention provides stable pharmaceutical composition comprising
(a) Dapagliflozin
(b) Saxagliptin and
(c) inert granules comprising one or more pharmaceutically acceptable excipient(s),
wherein Dapagliflozin and Saxagliptin are present in close contact with each other.

Another aspect of the present invention provides stable pharmaceutical composition comprising
(a) Dapagliflozin
(b) Saxagliptin and
(c) inert granules comprising one or more diluents(s) and one or more binder(s)
wherein Dapagliflozin and Saxagliptin are present in close contact with each other.

Another aspect of the present invention provides stable pharmaceutical composition comprising
(a) Dapagliflozin
(b) Saxagliptin and
(c) inert granules comprising one or more pharmaceutically acceptable excipient(s)
wherein Dapagliflozin and Saxagliptin are present in close contact with each other and wherein Dapagliflozin and Saxagliptin are wet mixed with inert granules.

Another aspect of the present invention is to provide process for preparation of a stable pharmaceutical composition comprising
(a) Granulating one or more pharmaceutical excipient(s) to prepare inert granules and
(b) Granulating Dapagliflozin and Saxagliptin with inert granules prepared in step (a),
wherein Dapagliflozin and saxagliptin are present in close contact with each other.

Another aspect of the present invention is to provide process for preparation of a stable pharmaceutical composition comprising
(a) Granulating one or more pharmaceutical excipient(s) to prepare inert granules and
(b) Wet granulating Dapagliflozin and Saxagliptin with inert granules prepared in step (a) with suitable solvent,
wherein Dapagliflozin and saxagliptin are present in close contact with each other.

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

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

The term “Saxagliptin” as used herein means Saxagliptin and its pharmaceutically acceptable salts in various solid state forms such as polymorphs, solvates and hydrates. Preferably, saxagliptin is saxagliptin hydrochloride dihydrate.

Similarly, the term “Dapagliflozin” as used herein means Dapagliflozin and its pharmaceutically acceptable salts or solvates in various solid state forms such as polymorphs, solvates and hydrates. Preferably, dapagliflozin is in amorphous form or dapagliflozin propylene glycol solvate.

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

The term “about” as used herein means plus or minus 30%, preferably 20%, most preferably 10%, of the numerical value of the number with which it is being used.

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

The term “inert granule” as used herein means granules, beads or pellets wherein Saxagliptin, Dapagliflozin or any other active pharmaceutical ingredient is not added during its process for preparation. The term excludes the active pharmaceutical ingredient which is adsorbed or absorbed inside the said first inert component after its preparation.

One embodiment of the present invention provides stable pharmaceutical composition comprising Dapagliflozin and Saxagliptin, wherein Dapagliflozin and Saxagliptin are present in close contact with each other.

A preferred embodiment of the present invention provides stable pharmaceutical composition comprising
(a) Dapagliflozin
(b) Saxagliptin and
(c) inert granules comprising one or more pharmaceutically acceptable excipient(s)
wherein Dapagliflozin and Saxagliptin are present in close contact with each other.

Another preferred embodiment of the present invention provides stable pharmaceutical composition comprising
(a) Dapagliflozin
(b) Saxagliptin and
(c) inert granules comprising one or more diluents(s) and one or more binder(s)
wherein Dapagliflozin and Saxagliptin are present in close contact with each other.

Another preferred embodiment of the present invention provides stable pharmaceutical composition comprising
(a) about 2-20 % w/w Dapagliflozin
(b) about 2-20 % w/w Saxagliptin and
(c) inert granules comprising about 60-85 % w/w of one or more diluents(s) and about 8-15 % w/w one or more binder(s)
wherein Dapagliflozin and Saxagliptin are present in close contact with each other.

Another preferred embodiment of the present invention provides stable pharmaceutical composition comprising
(a) about 6 % w/w Dapagliflozin
(b) about 4 % w/w Saxagliptin and
(c) inert granules comprising about 73 % w/w microcrystalline cellulose (MCC) and about 12 % w/w polyvinyl alcohol (PVA)
wherein Dapagliflozin and Saxagliptin are present in close contact with each other.

Pharmaceutical composition according to present invention can be prepared by any suitable method such as direct mixing, wet granulation or dry granulation. Preferably, pharmaceutical composition is prepared by wet granulation process.

Another embodiment of the present invention provides stable pharmaceutical composition comprising
(a) Dapagliflozin
(b) Saxagliptin and
(b) inert granules comprising one or more pharmaceutically acceptable excipient(s)
wherein Dapagliflozin and Saxagliptin are present in close contact with each other and wherein Dapagliflozin and Saxagliptin are wet mixed with inert granules.

Another embodiment of the present invention provides process for preparation of a stable pharmaceutical composition comprising
(a) Granulating one or more pharmaceutical excipient(s) to prepare inert granules and
(b) Granulating Dapagliflozin and Saxagliptin with inert granules prepared in step (a),
wherein Dapagliflozin and saxagliptin are present in close contact with each other.

Another preferred embodiment of the present invention provides process for preparation of a stable pharmaceutical composition comprising
(a) Granulating one or more pharmaceutical excipient(s) to prepare inert granules and
(b) Wet granulating Dapagliflozin and Saxagliptin with inert granules prepared in step (a) with suitable solvent,
wherein Dapagliflozin and saxagliptin are present in close contact with each other.

Another preferred embodiment of the present invention provides process for preparation of a stable pharmaceutical composition comprising
(a) Granulating one or more diluent and binder to prepare inert granules and
(b) Wet granulating Dapagliflozin and Saxagliptin with inert granules prepared in step (a) with suitable solvent,
wherein Dapagliflozin and saxagliptin are present in close contact with each other.

Another preferred embodiment of the present invention provides process for preparation of a stable pharmaceutical composition comprising
(a) Granulating MCC and PVA to prepare inert granules and
(b) Wet granulating Dapagliflozin and Saxagliptin with inert granules prepared in step a) with acetone,
wherein Dapagliflozin and saxagliptin are present in close contact with each other.

The inert granules according to the present invention may be prepared using known methods for granulation such as wet granulation by high shear granulation (Rapid mixer granulator/RMG) or fluidized bed granulation (FBG) or dry granulation using roller compactor etc. Preferably top spray method (FBG) is used. A dry mix is prepared from suitable amounts of one or more diluent and binder and is granulated using a spray solution (binder/granulating solution) prepared by dissolving binder into a suitable solvent to obtain inert granules.
Wet mixing of dapagliflozin and saxagliptin includes mixing with inert granules in RMG, granulating the blend using a suitable solvent.
The granules are further dried, optionally blended with lubricant and compressed to form tablet or filled into capsules or sachets.

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

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

Diluent according to present invention includes but not limited to powdered cellulose, microcrystalline cellulose (MCC), silicified microcrystalline cellulose, starch, pregelatinized starch, dibasic calcium phosphate, tribasic calcium phosphate, dibasic sodium phosphate, tribasic sodium phosphate, calcium carbonate, magnesium carbonate, calcium bicarbonate, magnesium bicarbonate magnesium oxide, calcium sulfate; sugars such as dextrose, lactose (monohydrate or anhydrous), fructose or sucrose, maltose maltodextrin; sugar alcohols such as mannitol, sorbitol, xylitol, lactitol, maltitol or erythritol; dextrin, kaolin and mixtures thereof. Preferably, microcrystalline cellulose is used as diluent. The diluents(s) may be present in an amount ranging from 50 % to 90 % w/w of the composition. Preferably, the diluents are present in an amount ranging from about 60-85 % w/w of the composition.

Binder according to present invention includes but not limited to polyvinyl alcohol (PVA), polyvinyl acetate, starch, pregelatinised starch; cellulose derivatives such as cellulose powder, microcrystalline cellulose, hydroxypropyl methylcellulose, ethyl cellulose, methyl cellulose, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, hydroxyethyl cellulose, carboxymethylcellulose sodium, carboxymethylcellulose calcium; carbomers, dextrin, gelatin, zein, shellac, polymethacrylates, povidone (PVP), copovidone, sodium alginate, alginic acid; gums such as xanthan gum, guar gum, locust bean gum, carrageenan, acacia, tragacanth, synthetic resins or mixtures thereof. Preferably, PVA is used. The binder may be present in an amount ranging from 0.5 % to 20 % w/w of the composition, preferably from about 8 % to 15 % by weight of the composition.
Binder used for preparation of inert granules can be present either in dry mix or dissolved/dispersed in a binder solution or both. Binder in dry mix may be present in an amount ranging from 1-10 % w/w of the composition, preferably 6 % w/w of the composition. Binder used in preparing a binder solution may be present in an amount ranging from 1-10 % w/w of the composition, preferably 6 % w/w of the composition.

Disintegrant(s) can be added in formulating inert granules or combined with the mixture of active agents or as a component at any other stage of preparation of present invention. Disintegrant according to present invention includes but not limited to carboxymethyl cellulose and its salt including sodium or calcium salt, cross-linked carboxymethyl cellulose sodium, cross-linked carboxymethyl cellulose calcium, cross-linked polyvinylpyrrolidone (crospovidone), microcrystalline or microfine or powdered cellulose, silicified microcrystalline cellulose, sodium alginate; starch derivatives such as maize starch, rice starch, pregelatinized starch; cross-linked N-vinyl-2-pyrrolidone ("CLPVP") (marketed under the trade names Polyplasdone® XL and Polyplasdone® XL-10), sodium starch glycollate, low substituted hydroxypropyl cellulose and mixtures thereof.

Granulating solvent can be used for preparation of inert granules and wet mixing of intimate mixture of dapagliflozin and saxagliptin with inert granules. Granulating solvent used in any of the said granulating step may be selected from water, isopropyl alcohol, ethanol, methanol, acetone, methylene chloride or mixtures thereof. Preferably, water is used for granulation solution for preparation of inert granules. Additionally, one or more acid(s) selected from hydrochloric acid (HCl), tartaric acid, citric acid, oxalic acid, succinic acid, fumaric acid and malic acid may be added to the granulating solution. The acid may be present in an amount ranging from about 0.05-10 % by weight of the composition. Preferably, 0.1-5 % by weight of the composition is used. Granulating/binder/spray solution according to the present invention is a mixture of any binder in the granulating solvent. Preferably, PVA is dissolved in water and/or hydrochloric acid to form a granulating/binder/spray solution. For wet mixing of intimate mixture of dapagliflozin and saxagliptin with inert granules, preferably acetone is used.

Lubricant according to present invention includes but not limited to metallic stearates such as magnesium stearate, calcium stearate, zinc stearate; stearic acid, sodium stearyl fumerate hydrogenated vegetable oil, hydrogenated castor oil, glyceryl palmitostearate, glyceryl behenate, polyethylene glycols, corn starch, sodium stearyl fumarate, sodium benzoate, mineral oil, talc and mixture thereof. Preferably, stearic acid is used. The lubricant may be present in an amount ranging from about 0.1 % to about 10 % by weight of the composition. Preferably, the lubricant may be present in an amount ranging from about 0.5 % to about 5 % by weight of the composition.

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

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

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

Stable solid oral composition according to the present invention comprises active ingredient Dapagliflozin in an amount of 2-20 % w/w, preferably about 6 % w/w of the composition. Saxagliptin is present in an amount of 2-20 % w/w, preferably about 4 % of the composition.

Solid oral composition according to present invention can be in the form of tablet, capsule, powder or sachet. Preferably solid oral composition according to present invention is a film-coated tablet.

The prepared film-coated tablet can be packaged into Alu-Alu blister pack or HDPE bottle. The packages Alu-Alu blister pack protected by a desiccant lining or HDPE bottle with 1 g, 2 g or 3g silica gel can be used.

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

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

Example 1

Sr. No Ingredients Qty.
mg/tab %w/w
Inert granules
1 Microcrystalline cellulose (MCC) 121.088 73.48
2 Polyvinyl alcohol (PVA) 10.000 6.07
Spray Solution
3 Polyvinyl alcohol 10.000 6.07
4 Hydrochloric acid (HCl) 0.333 0.20
5 Purified Water q.s. q.s.
Total 141.420
Mixture of dapagliflozin and saxagliptin
6 Saxagliptin hydrochloride dihydrate 6.149 3.73
7 Dapagliflozin 10.000 6.07
8 Acetone q.s. q.s.
Lubrication
9 Stearic acid 2.430 1.47
Total (core tablet) 160.000 97.09
Coating
10 Opadry Brown 20U565026 (HPMC/HPC based) 4.800 2.91
11 Isopropyl alcohol q.s. q.s.
12 Methylene chloride q.s. q.s.
Total (Coated tablet) 164.800 100.00

MCC and PVA were co-sifted through an appropriate mesh. A granulating solution was prepared by dissolving PVA in purified water and adding 0.1 N HCl to it. The dry mixture of MCC and PVA was granulated using the prepared granulating solution by Top spray granulation method in FBP to obtain inert granules. The prepared granules were dried and sifted. The granules were mixed with a mixture of Dapagliflozin and saxagliptin in RMG for an appropriate time period. The blend was further granulated with acetone to prepare granules. The prepared granules were dried and sized. The granules so obtained were mixed with stearic acid to prepare uniform blend which were further compressed into tablets. The tablets were coated with Opadry.
The tablets prepared according to example 1 were evaluated for content uniformity and stability by HPLC impurity profile.
Results of content uniformity by assay analysis of 10 sample units of prepared tablets indicated mean % drug content of 101 % (Dapagliflozin) and 98.2 % (Saxagliptin), % Relative standard deviation (RSD) of 1.09 (Dapagliflozin) and 0.91 (saxagliptin) and Acceptance value (AV) of 2.6 (Dapagliflozin) and 2.4 (Saxagliptin).
Tests for stability were conducted under 40°C and 75 % RH for 1 month. In addition, forced degradation study was conducted at 80°C for 1 hour and 4 hours. The results of HPLC analysis for cyclic amidine impurity is presented as Table 1. Non-detectable quantities of cyclic amidine impurity were found in initial tablets as well as tablets subjected to conditions of 1 Month 40ºC/75 % RH (HDPE bottle with 3 g silica gel) and Forced degradation under heat and moisture at 80ºC for 1 Hour as well as 4 Hours condition.

Table 1
Sr no. Stability conditions (Example 1) Cyclic amidine impurity (%)
1. Initial ND*
2. 40ºC/75 % RH for 1 Month (HDPE bottle with 3 g silica gel) ND*
3. Forced degradation under heat + moist at 80ºC for 1 Hour ND*
4. Forced degradation under heat + moist at 80ºC for 4 Hours ND*
*ND-Not detected
Claims:We claim:

1. A stable pharmaceutical composition comprising Dapagliflozin and Saxagliptin, wherein Dapagliflozin and Saxagliptin are present in close contact with each other.

2. The stable pharmaceutical composition according to claim 1, wherein the amount of Dapagliflozin is about 2-20 % w/w and amount of Saxagliptin is about 2-20 % w/w of the total composition.

3. The stable pharmaceutical composition according to claim 1 further comprising inert granules wherein inert granules comprise one or more pharmaceutically acceptable excipient(s).

4. The stable pharmaceutical composition according to claim 3, wherein pharmaceutically acceptable excipient is selected from one or more diluents(s) and one or more binder(s).

5. The stable pharmaceutical composition according to claim 4, wherein amount of diluent(s) is about 60-85 % w/w and amount of binder(s) is about 8-15 % w/w of total composition.

6. The stable pharmaceutical composition according to claim 5, wherein diluent is microcrystalline cellulose and binder is Polyvinyl alcohol.
7. A stable pharmaceutical composition comprising
(a) Dapagliflozin
(b) Saxagliptin and
(c) inert granules comprising one or more pharmaceutically acceptable excipient(s)
wherein Dapagliflozin and Saxagliptin are present in close contact with each other and wherein Dapagliflozin and Saxagliptin are wet mixed with inert granules.

8. A process for preparation of a stable pharmaceutical composition comprising
(a) Granulating one or more pharmaceutical excipient(s) to prepare inert
Granules and
(b) Granulating Dapagliflozin and Saxagliptin with inert granules prepared in step a) with suitable solvent,
wherein Dapagliflozin and saxagliptin are present in close contact with each other.

9. The process for preparation of a stable pharmaceutical composition according to claim 8, comprising
(a) Granulating one or more diluent and binder to prepare inert granules and
(b) Wet granulating Dapagliflozin and Saxagliptin with inert granules prepared in step a) with suitable solvent,
wherein Dapagliflozin and saxagliptin are present in close contact with each other.

10. The process for preparation of a stable pharmaceutical composition according to claim 9, comprising
(a) Granulating MCC and PVA to prepare inert granules and
(b) Wet granulating Dapagliflozin and Saxagliptin with inert granules prepared in step a) with acetone,
wherein Dapagliflozin and saxagliptin are present in close contact with each other.