DESC:FORM 2

THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003

COMPLETE SPECIFICATION
(Section 10 and Rule 13)

IMMEDIATE RELEASE FORMULATIONS OF DAPAGLIFLOZIN AND METFORMIN HYDROCHLORIDE

AUROBINDO PHARMA LTD HAVING CORPORATE OFFICE AT
GALAXY, FLOORS: 22-24,
PLOT No.1, SURVEY No.83/1,
HYDERABAD KNOWLEDGE CITY,
RAIDURG PANMAKTHA,
RANGA REDDY DISTRICT,
HYDERABAD – 500 032,
TELANGANA, INDIA
AN INDIAN ORGANIZATION

The following specification particularly describes the invention and the manner in
which it is to be performed:

FIELD OF THE INVENTION

The present invention relates to immediate release pharmaceutical formulations comprising of dapagliflozin and metformin hydrochloride and a process of making such formulations.

BACKGROUND OF THE INVENTION

Dapagliflozin is a sodium-glucose transporter-2 inhibitor (SGLT2) and it was identified as a potent drug for treating type-2 diabetes mellitus. Metformin is the most widely used medication for diabetes taken by mouth.

Dapagliflozin and metformin drug combination is indicated in adults aged 18 years and older with type 2 diabetes mellitus as an adjunct to diet and exercise to improve glycaemic control;
a) in patients insufficiently controlled on their maximally tolerated dose of metformin alone
b) in combination with other medicinal products for the treatment of diabetes in patients insufficiently controlled with metformin and these medicinal products
c) in patients already being treated with the combination of dapagliflozin and metformin as separate tablets.

Xigduo® (Dapagliflozin propylene glycol Monohydrate/ Metformin Hydrochloride) immediate release tablet 5/850mg and 5/1000mg got approved on Jan 16, 2014 to AstraZeneca AB in the Europe market. Inactive ingredients of Xigduo tablet are Hydroxypropyl cellulose, Microcrystalline cellulose, Magnesium stearate, Sodium starch glycolate type A, Polyvinyl alcohol, Macrogol 3350, Talc, Titanium dioxide, Iron oxide yellow, Iron oxide red.

WO2008116179 A1 of BMS discloses the immediate release pharmaceutical formulation in the form selected from the group consisting of a tablet, a stock granulation and a capsule, comprising; a) dapagliflozin propylene glycol hydrate, wherein the dapagliflozin propylene glycol hydrate is present in an amount within the range of from about 0.1% to about 15% by weight of tablet or capsule fill; b) microcrystalline cellulose, wherein the microcrystalline cellulose is present in an amount sufficient to make the total weight of the tablet or capsule fill 100%; c) lactose, wherein the lactose is present in an amount within the range of from about 10% to about 30% by weight of tablet or capsule fill; d) crospovidone, wherein the crospovidone is present in an amount within the range of from about 3% to about 10% by weight of tablet or capsule fill; e) silicon dioxide, wherein the silicon dioxide is present in an amount within the range of from about 0.5% to about 4% by weight of tablet or capsule fill; and f) magnesium stearate, wherein the magnesium stearate is present in an amount within the range of from about 0.5% to about 2% by weight of tablet or capsule fill.

EP2498759B1 of ASTRAZENECA AB disclose that after several unsuccessful attempts, including dry granulation by roller compaction and traditional wet granulation, they found that the drug content uniformity & tablet hardness problems can be rectified by spraying a solution or a suspension comprising dapagliflozin or dapagliflozin (S) propylene glycol hydrate and a binder onto the metformin particles in a fluid bed equipment, thereby producing granules that have uniform dapagliflozin or dapagliflozin (S) propylene glycol hydrate content and good compaction properties. The good compaction properties of these granules are thought to result from the way the granules are formed during the spray granulation process together with the fact that this process makes it possible to use larger amounts of a binder than was possible in the earlier tested granulation processes. The way in which the granules are built up during the spray granulation process gives them suitable density/porosity and a suitable particle size distribution with little variation between batches. The granules also have superior flow properties. However, the said fluid bed granulation process is cumbersome as compared to traditional wet granulation in a rapid mixer granulator as it includes additional steps of dissolving drug/ excipients such as binder in a solvent and spraying the same onto another drug/ excipients continuously in a fluid bed processing equipment.

There are great challenges to a formulation scientist to design a desired formulation and process of dapagliflozin and metformin hydrochloride immediate release film coated tablets, due to the following reasons: -
(a) large difference in drug-to-drug ratio due to low dose of dapagliflozin and high dose of metformin,
(b) a big difference in physical properties between metformin hydrochloride and dapagliflozin;
(c) poor compaction properties of metformin hydrochloride, so difficulty in producing tablets having adequate tablet hardness;

Thus, there is a need to design a formulation and a process for producing of dapagliflozin and metformin hydrochloride immediate release film coated tablets having desirable/acceptable results in a simple and conventional method with desired tablet hardness, drug content uniformity, tablet disintegration and tablet dissolution.

SUMMARY OF THE INVENTION

In one aspect, the present invention provides an immediate release pharmaceutical formulation comprising: dapagliflozin; metformin hydrochloride; wherein the immediate release pharmaceutical formulation is devoid of disintegrant and the formulation disintegrates/dissolves within 30 minutes.

In another aspect, the present invention provides a process of preparing an immediate release pharmaceutical formulation comprising: dapagliflozin; metformin hydrochloride; wherein the immediate release pharmaceutical formulation is devoid of disintegrant and the formulation disintegrates/dissolves within 30 minutes.

In another aspect, the present invention provides an immediate release pharmaceutical formulation comprising: dapagliflozin; metformin hydrochloride; wherein the immediate release pharmaceutical formulation is devoid of disintegrant and the formulation is having a comparative drug content uniformity, tablet hardness, tablet disintegration and tablet dissolution results with that of respective results of commercially available dapagliflozin and metformin hydrochloride tablets.

In another aspect, the present invention provides an immediate release pharmaceutical formulation of dapagliflozin and metformin hydrochloride which can be used as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

DETAILED DESCRIPTION OF THE INVENTION

In one embodiment, an immediate release pharmaceutical formulation of present invention comprising of: dapagliflozin; metformin hydrochloride; a diluent; a binder and a lubricant; and atleast one pharmaceutically acceptable excipient; wherein the immediate release pharmaceutical formulation is devoid of disintegrant and the formulation disintegrates/dissolves within 30 minutes, more preferably within 15 minutes.

Examples of diluents or bulking agents or fillers suitable for use herein include, but are not limited to, cellulose derivatives, such as microcrystalline cellulose (MCC) or wood cellulose (including microcrystalline cellulose 302), lactose, lactose anhydrous, sucrose, dextrose, mannitol (including mannitol Pearlitol SO 200), fructose, xylitol, sorbitol, inorganic salts such as calcium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, dextrin/dextrates, maltodextrin, compressible sugars, and other known bulking agents or fillers, and/or mixtures of two or more thereof. In a preferred embodiment the diluent is lactose monohydrate.

Examples of binders suitable for use herein include, but are not limited to, methyl cellulose, carboxymethyl cellulose (including sodium carboxymethyl cellulose), hydroxypropyl cellulose (including HPC-SSL, HPC-SL, HPC-L, 25 HPC-EXF, HPC-ELF, etc.), polyvinyl pyrrolidone (PVP), hydroxypropyl methylcellulose (HPMC) (including hydroxypropyl methylcellulose 2208), lactose, gum acacia, gum arabic, gelatin, agar, ethyl cellulose, cellulose acetate, tragacanth, sodium alginate, pullulan, as well as a wax binder such as carnauba wax, paraffin, spermaceti, polyethylenes or microcrystalline wax, as well as other conventional binding agents and/or mixtures of two or more thereof. Preferred binders of the present invention are hydroxypropyl cellulose SSL, hydroxypropyl cellulose SL, hydroxypropyl cellulose ELF, polyvinyl alcohol-polyethylene glycol, and polyvinyl pyrrolidone.

Examples of lubricants suitable for use herein include, but are not limited to, magnesium stearate, zinc stearate, calcium stearate, talc, carnauba wax, stearic acid, palmitic acid, sodium stearyl fumarate sodium laurel sulfate, glyceryl palmitostearate, palmitic acid, myristic acid and hydrogenated vegetable oils and fats, as well as other known lubricants, and/or mixtures of two or more thereof. In a preferred embodiment the lubricant is magnesium stearate.

Examples of glidants and/or anti-adherents suitable for use herein include but are not limited to, silicon dioxide, colloidal silicon dioxide, magnesium silicate, magnesium trisilicate, talc, and other forms of silicon dioxide, such as aggregated silicates and hydrated silica.

In another embodiment, the dapagliflozin is present in the form of amorphous, crystalline form.

The term Dapagliflozin as used herein refers to dapagliflozin or its salts or hydrates or solvates, preferably in propylene glycol solvate form.

In another embodiment, an immediate release pharmaceutical formulation of present invention comprising of: amorphous dapagliflozin; metformin hydrochloride; a diluent; a binder and a lubricant; and atleast one pharmaceutically acceptable excipients; wherein the immediate release pharmaceutical formulation is devoid of disintegrant and the formulation disintegrates/dissolves within 30 minutes.

In another embodiment, an immediate release pharmaceutical formulation of present invention comprising of: amorphous dapagliflozin; metformin hydrochloride; lactose monohydrate; hydroxypropyl cellulose and magnesium stearate; and atleast one pharmaceutically acceptable excipients; wherein the immediate release pharmaceutical formulation is devoid of disintegrant and the formulation is a coated tablet which disintegrates/dissolves within 30 minutes.

A coated tablet of present invention can be prepared by conventional film coating materials and coating techniques. Examples of film coating material can be Opadry® II white, Opadry® II orange, Opadry® II brown, or Opadry® II yellow, or Opadry® Beige of Colorcon.

In another embodiment, an immediate release pharmaceutical formulation of present invention comprising of:
a) about 0.1-1% amorphous dapagliflozin;
b) about 60-80% metformin hydrochloride;
c) about 15-30% of lactose;
d) about 2-6% of hydroxypropylcellulose;
e) about 0.4-1% of magnesium stearate; with the proviso that the formulation is free from disintegrants and the % is based on the total weight of the composition.

The term “about” is used herein to mean approximately, roughly, around, or in the regions of. When the term "about" is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the numerical values set forth. In general, the term "about" is used herein to modify a numerical value above and below the stated value by a variance of 10 percent.

The term % or percent refers % w/w means weight based on the total weight of the composition.
In another embodiment, a process of preparing an immediate release tablet formulation of dapagliflozin and metformin hydrochloride comprising of:
a) mixing dapagliflozin, metformin hydrochloride and one or more pharmaceutically acceptable excipients selected from a diluent, a binder and combinations thereof;
b) granulating step (a) with solvent;
c) optionally blending dried granules of step (b) with atleast one extragranular pharmaceutically acceptable excipient selected from a diluent, a binder and combinations thereof;
d) lubricating the pre-lubricated blend;
e) compressing the lubricated blend into tablet cores.

In another embodiment, a process of making an immediate release pharmaceutical formulation devoid of disintegrant comprising of the following steps:
(a) mix dapagliflozin, metformin hydrochloride, a diluent, a binder;
(b) make granules of step-(a) mixture in rapid mixer granulator by adding a granulating solvent;
(c) dry the wet granules of step-(b);
(d) mix the dried granules of step-(c) with remaining batch quantities of diluent and lubricant;
(e) compress the composition of step (d) into a tablet; and
(f) coating the core tablet of step (e).
wherein the process does not involve dissolving or dispersing amorphous dapagliflozin and a binder in granulating solvent.

The granulating solvent can be water, non-aqueous solvents or a hydro-alcoholic mixture.

The immediate release formulations of the present invention would be subjected to the in-vitro dissolution studies as per USP monograph <711> which can be performed using USP Type 1 (Basket) or Type 2 (Paddle) dissolution apparatus at desired rpm.

In another embodiment, an immediate release pharmaceutical formulation of dapagliflozin and metformin hydrochloride can be used an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

The following examples are intended to serve as illustrations of the present invention only and do not restrict the scope of the invention in any manner whatsoever.

EXAMPLES

Comparative example-1:- As per example 10 of EP2498759B1.

S. No. Ingredients Quantity/tablet (mg)
1 Metformin Hydrochloride 500.00
2 Dapagliflozin (PG-solvate) 1.50
3 MCC PH102 138.80
4 L-HPC LH21 31.20
5 Hydroxypropylcellulose 15.60
8 Magnesium Stearate 7.1
Tablet weight (mg) 694.20

Manufacturing process: As per manufacturing process of example 10 of EP2498759B1:

Metformin granules were prepared with Hydroxypropylcellulose in High shear Mixer Granulator (RMG) and dapagliflozin granules were prepared by dry granulation (Compaction) process. Final lubricated blend was prepared by mixing both granules with extra-granular excipients (MCC PH102, L-HPC LH21), followed by lubrication with Magnesium Stearate. Tablets were compressed with the lubricated blend.

Comparative example-2:

S. No. Ingredients Quantity/tablet (mg)
1 Metformin Hydrochloride 1000.00
2 Amorphous dapagliflozin 5.00
3 Lactose Monohydrate 53.90
4 Hydroxy propyl cellulose 113.60
5 Magnesium Stearate 2.50
Granulating solvent
6 Purified Water Q.S.
Extra-granular materials
7 Lactose Monohydrate 236.00
8 Magnesium Stearate 9.00
Tablet weight (mg) 1420.00

Manufacturing process:
1.1 Milling & Sifting
1.1.1: Intra-granular materials (Metformin Hydrochloride, Dapagliflozin, Lactose Monohydrate, Hydroxypropylcellulose, Magnesium Stearate), were milled and sifted using suitable co-mill and sieve no.
1.2 Binder: Purified water was used as a binder solution;
1.3 Granulation: Material of step 1.1.1 was loaded in rapid mixer granulator (RMG) and granulation was done by using binder solution of step (1.2);
1.4 Drying: Granules formed in step (1.3) were dried at suitable temperature in rapid dryer;
1.5 Sifting and milling of dried granules: Dried granules of step (1.4) were sifted and milled and passed through suitable sieves;
1.6 Sifting of Extra-granular materials: Sifted lactose monohydrate and magnesium stearate through suitable sieves;
1.7 Pre-lubrication: Granules obtained in step 1.5 were pre-lubricated by using lactose monohydrate obtained in step 1.6
1.8 Lubrication: Added sifted magnesium stearate of step 1.6 to the material of step 1.7 in low shear blender and blended for a suitable time period.
1.9 Compression: Lubricated blend of step 1.8 was compressed using suitable tooling to form uncoated tablets.

Example 1: An immediate release pharmaceutical formulation of present invention.

S. No. Ingredients Quantity per unit (mg)
5 mg/850 mg 5mg/1000 mg
Intra-granular materials
1 Metformin Hydrochloride 850 1000
2 Amorphous dapagliflozin 5 5
3 Lactose Monohydrate 249.26 305
4 Hydroxypropylcellulose 53.12 62.5
5 Magnesium Stearate 2.12 2.5
Granulating solvent
6 Purified Water Q.S. Q.S.
Extra-granular materials
7 Lactose Monohydrate 40.60 36.00
8 Magnesium Stearate 7.65 9.00
Core Tablet weight 1207.75 1420.00
Coating
9 Opadry Beige* 36.23 --
10 Opadry Yellow** -- 42.60
11 Purified Water Q.S. Q.S.
Coated Tablet weight 1243.98 1462.60

* Opadry Beige contains polyvinyl alcohol, Talc, Titanium dioxide, Glycerol Monocaprylocaprate type I, sodium lauryl sulphate, Iron oxide yellow and Iron oxide red.
** Opadry Yellow contains polyvinyl alcohol, Talc, Titanium dioxide, Glycerol Monocaprylocaprate type I, Iron oxide yellow and sodium lauryl sulphate.

Manufacturing process:
1.1 Milling & Sifting
1.1.1: Intra-granular materials (Metformin Hydrochloride, Dapagliflozin, Lactose Monohydrate, Hydroxypropylcellulose, Magnesium Stearate), were milled and sifted using suitable co-mill and sieve no.
1.2 Binder: Purified water was used as a binder solution;
1.3 Granulation: Material of step 1.1.1 was loaded in RMG (rapid mixer granulator) and granulation was done by using binder solution of step (1.2);
1.4 Drying: Granules formed in step (1.3) were dried at suitable temperature in rapid dryer;
1.5 Sifting and milling of dried granules: Dried granules of step (1.4) were sifted and milled and passed through suitable sieves;
1.6 Sifting of Extra-granular materials: Sifted lactose monohydrate and magnesium stearate through suitable sieves;
1.7 Pre-lubrication: Granules obtained in step 1.5 were pre-lubricated by using lactose monohydrate obtained in step 1.6;
1.8 Lubrication: Added sifted magnesium stearate of step 1.6 to the material of step 1.7 in low shear blender and blended for suitable time period;
1.9 Compression: Lubricated blend of step 1.8 was compressed using suitable tooling to form uncoated tablets;
2. Film coating: Core tablets of step-1 were film coated with aqueous dispersion of Opadry yellow and Opadry Beige respectively.

Experimental data:

A. Comparative tablet parameters:

S. No Parameters Xigduo®
(Coated) Comparative example-2 (Uncoated) Comparative example-1 (Uncoated) Example 1 (Uncoated)
1 Hardness (Newton’s) 284-314 190-208 - 191-215
2 Disintegration Time
(’minutes ; ” Seconds) 12’20”-13’15” 19'10"-20'30" 11-12 13'40"-14'20"
3 Content uniformity (% RSD) 1 - 7.6 1.71

B. Comparative dissolution profile: pH 6.8 phosphate buffer, 900mL, Basket, 100 RPM

S. No Time (min) % Drug release (5/850mg)
XIGDUO® Example 1
Dapagliflozin Metformin HCl Dapagliflozin Metformin HCl
1 10 31 35 37 43
2 15 40 42 60 61
3 20 64 66 79 79
4 30 97 99 100 98
5 45 97 99 102 101
6 60 97 98 102 100

Sr. No Time (Min) % Drug release (5/1000mg)
XIGDUO® Comparative example-2 Example 1
Dapagliflozin Metformin HCl Dapagliflozin Metformin HCl Dapagliflozin Metformin HCl
1 10 35 38 22 30 33 37
2 15 55 59 43 49 50 54
3 20 74 78 55 64 66 69
4 30 95 99 72 74 95 93
5 45 96 99 81 84 104 103
6 60 96 100 94 94 105 103

Based on dissolution profile, it was surprisingly found that Example 1 results were comparable to dissolution profile of commercially available XIGDUO®.

C. Stability data:

Tablets of Example 1 were packed in a high-density polyethylene (HDPE) bottle and were subjected to accelerated stability testing at temperature 40°±2°C and relative humidity of 75%±5% for 6 months. The impurity profile is shown below:

Impurities / Related compounds Example 1
0 Months 3 Months 6 Months
Dapagliflozin related degradation Product
Dapagliflozin N-Oxide Not detected Not detected Not detected
Any individual known impurity Not detected Not detected Not detected
Total impurities Not detected Not detected Not detected
Metformin HCl related degradation Product
Dapagliflozin N-Oxide Not detected Not detected Not detected
Any individual known impurity Not detected Not detected Not detected
Total impurities Not detected Not detected Not detected

The present invention formulation clearly indicates excellent chemical stability upon storage at accelerated stability conditions at 40°±2°C and 75%±5% relative humidity for six months showed no evidence of any degradation products and no reduction in the content of active substance.

D. Comparative Bioequivalence Data: “Reference Product” [Xigduo® IR Tablets] Versus “Test Product” [Dapagliflozin and metformin Hydrochloride IR Tablets of Example 1]

Dapagliflozin
Parameters Acceptable limit T/R Ratio (Test - Example 1)
Cmax/AUCI 0-t /AUC 0-inf -Fed 80-125 Within the acceptable limit
Cmax/AUCI 0-t /AUC 0-inf -fasting 80-125 Within the acceptable limit
Metformin Hydrochloride
Cmax/AUCI 0-t /AUC 0-inf -Fed 80-125 Within the acceptable limit
Cmax/AUCI 0-t /AUC 0-inf -Fasting 80-125 Within the acceptable limit

Based on above T/R ratios, it was surprisingly found that Test product-Example 1 results were well within the acceptable limits and was bio-equivalent to the Reference product.

The inventors of present invention have unexpectedly found that an immediate release pharmaceutical formulation comprising: dapagliflozin; metformin hydrochloride; a diluent; a binder and a lubricant; wherein the immediate release pharmaceutical formulation is devoid of disintegrant and the formulation disintegrates/dissolves within 30 minutes.

The immediate release pharmaceutical formulation of the present invention shows a comparative drug content uniformity, tablet hardness, tablet disintegration and tablet dissolution results with that of respective results of commercially available dapagliflozin and metformin hydrochloride tablets.
,CLAIMS:We claim:

1. An immediate release tablet formulation comprising dapagliflozin, metformin hydrochloride and atleast one pharmaceutically acceptable excipient, wherein the formulation is devoid of disintegrant and at least 90% of dapagliflozin and metformin hydrochloride dissolves within 30 minutes.

2. The tablet formulation of claim 1, wherein dapagliflozin is in amorphous or crystalline form.

3. The tablet formulation of claim 1, wherein the pharmaceutically acceptable excipients are selected from a diluent, a binder, a lubricant and combinations thereof.

4. The tablet formulation of claim 3, wherein the diluent is selected from anhydrous lactose, lactose monohydrate, microcrystalline cellulose, corn starch, sorbitol, xylitol and mannitol or combination thereof.

5. The tablet formulation of claim 3, wherein the binder is selected from hydroxypropylcellulose, gelatin, cellulose derivatives, polyvinyl pyrrolidone, starch, or combination thereof and lubricant selected from magnesium stearate, stearic acid, magnesium lauryl sulphate, sodium stearyl fumarate or combination thereof.

6. The tablet formulation of claim 3 comprising
a) about 0.1-1% amorphous dapagliflozin;
b) about 60-80% metformin hydrochloride;
c) about 15-30% diluent;
d) about 2-6% binder;
e) about 0.4-1% lubricant.

7. The tablet formulation of claim 1, wherein at least 90% of dapagliflozin and metformin hydrochloride dissolves within 30 minutes in pH 6.8 phosphate buffer.

8. The tablet formulation of claim 1 shows a comparative bioavailability profile with that of commercially available dapagliflozin and metformin hydrochloride tablets 5mg/850, 5mg/1000mg.

9. A process of preparing an immediate release tablet formulation of dapagliflozin and metformin hydrochloride comprising of:
a) mixing dapagliflozin, metformin hydrochloride and one or more pharmaceutically acceptable excipients selected from a diluent, a binder and combinations thereof;
b) granulating step (a) with solvent;
c) optionally blending dried granules of step (b) with atleast one extragranular pharmaceutically acceptable excipient selected from a diluent, a binder and combinations thereof;
d) lubricating the pre-lubricated blend;
e) compressing the lubricated blend into tablet cores.

10. The tablet formulation of claim 9, wherein the granulating solvent is water or non-aqueous solvent or a hydro-alcoholic mixture or combination thereof.