WO2023113488A1

WO2023113488A1 - Pharmaceutical combination which has improved convenience for internal use through size reduction for formulation comprising dapagliflozin and sitagliptin and preparing method thereof

Info

Publication number: WO2023113488A1
Application number: PCT/KR2022/020427
Authority: WO
Inventors: Ji Soo Seo; Min Soo Kim; Shin Jung Park
Original assignee: Chong Kun Dang Corp
Current assignee: Chong Kun Dang Corp
Priority date: 2021-12-16
Filing date: 2022-12-15
Publication date: 2023-06-22
Anticipated expiration: 2024-06-16
Also published as: KR20230091684A

Abstract

Provided are a pharmaceutical combination comprising dapagliflozin and sitagliptin and a preparation method thereof.

Description

PHARMACEUTICAL COMBINATION WHICH HAS IMPROVED CONVENIENCE FOR INTERNAL USE THROUGH SIZE REDUCTION FOR FORMULATION COMPRISING DAPAGLIFLOZIN AND SITAGLIPTIN AND PREPARING METHOD THEREOF

The present invention relates to a pharmaceutical combination comprising dapagliflozin and sitagliptin and a preparing method thereof, specifically, a pharmaceutical combination comprising, as main ingredients, dapagliflozin, which is an SGLT2 inhibitor that inhibits resorption of glucose, and sitagliptin, which is a DPP4 inhibitor that controls insulin secretion.

Dapagliflozin inhibits sodium-glucose cotransporter 2 (SGLT2) in the proximal renal tubules to reduce the resorption of glucose filtered at the tubular lumen, and lower the renal threshold for glucose (RTG).

Sitagliptin is a dipeptidyl peptidase-4 (DPP-4) based drug, and it controls blood glucose by inhibiting the breakdown of the gastrointestinal hormone called incretin so that incretin, which regulates insulin and glucagon, functions well in the body. It is known that the oral administration of sitagliptin to type 2 diabetes patients significantly reduces the HbA1c level and reduces fasting blood glucose and postprandial blood glucose secretion.

For the blood glucose control and the reduction of side effects in diabetes, one or more antidiabetic drugs are often administered in combination. In particular, dapagliflozin and sitagliptin are effective in the treatment of diabetes and other diseases, and their pharmaceutical combinations have very high clinical usefulness.

However, considering the total weight of the representative tablets comprising each main ingredient of dapagliflozin and sitagliptin, when pharmaceutical combinations are prepared to include each main ingredient, the total weight of the main ingredient and the excipient is increased and the size of the tablet is increased accordingly. As a result, the drug compliance of the patients is decreased.

Therefore, it is necessary to develop a pharmaceutical combination that can reduce the tablet size, improve the drug release, and secure stability.

[Prior Arts]

[Patent Document]

(Patent Document D1) KR 2016-0111237

The purpose of the present invention is to increase the patient's convenience for internal use in providing a pharmaceutical combination comprising diabetes therapies, dapagliflozin and sitagliptin, as main ingredients. Specifically, when a pharmaceutical combination is prepared in the form of a single-layer tablet by using the wet granulation method according to the present invention, the patient's convenience for internal use can be increased by significantly reducing the tablet size, compared with the case where Forxiga TM tablet (260 mg) and Januvia TM tablet (416.1 mg) are used to prepare a bilayer tablet by the dry granulation method.

Another purpose of the present invention is to improve the drug release of dapagliflozin and sitagliptin in providing a pharmaceutical combination comprising diabetes therapies, dapagliflozin and sitagliptin, as main ingredients.

Another purpose of the present invention is to secure stability under severe (60±2℃) conditions and accelerated open (40±2℃, 75±5%) conditions in providing a pharmaceutical combination comprising diabetes therapies, dapagliflozin and sitagliptin, as main ingredients.

The technical solutions described below are disclosed to solve the technical problems above.

According to an aspect of the present invention, there is provided a pharmaceutical combination comprising dapagliflozin or a pharmaceutically acceptable salt thereof, or a hydrate thereof; and sitagliptin or a pharmaceutically acceptable salt thereof, or a hydrate thereof, as main ingredients, wherein the main ingredients are included 35% to 50% by weight based on the total weight of the whole pharmaceutical combination.

According to another aspect of the present invention, there is provided a preparation method of the pharmaceutical combination, the preparation method comprising: preparing a binding solution by dissolving a binder in a solvent; preparing a mixing part by mixing dapagliflozin or a pharmaceutically acceptable salt thereof, or a hydrate thereof, sitagliptin or a pharmaceutically acceptable salt thereof, or a hydrate thereof, an excipient, and a disintegrant; preparing granulated product by mixing the mixing part and the binding solution, and kneading and granulating the resulting mixture; preparing a dry product by drying the granulated product; and deagglomerating the dry product; and homogeneously mixing the deagglomerated product, an excipient, and a disintegrant, and a lubricant.

The pharmaceutical combination according to one aspect of the present invention can increase the patient's convenience for internal use by reducing the size of the tablet, improve the drug release (improving drug release rate and decreasing drug release difference), and provide a pharmaceutical combination having stability secured under severe (60±2℃) conditions and accelerated open (40±2℃, 75±5%) conditions.

Specifically, the pharmaceutical combination according to one aspect of the present invention can be prepared as a single-layer tablet to significantly reduce the tablet size in order to increase the patient's convenience for internal use and at the same time, to improve the drug release, and decrease the drug release difference.

In addition, the pharmaceutical combination according to one aspect of the present invention minimized the generation of impurities under severe (60±2℃) conditions and accelerated open (40±2℃, 75±5%) conditions and showed content of pharmaceutical combination that was similar to that of the control drugs (Forxiga ^TMtablet and Januvia^TM tablet), and so a pharmaceutical combination having excellent stability can be provided.

The effects of the present invention are not limited to the above-mentioned effects, and various effects may be included within the range that is obvious to those skilled in the art from the description below.

Hereinafter, the Specification of the present application is described in more details.

The Specification of the present application is described specifically. The terms used in the present invention have been selected as widely used general terms as possible in consideration of the functions in the present invention, but they may vary according to the intention or precedent of those skilled in the art, the emergence of new technologies and the like. In addition, in certain cases, there is also a term arbitrarily selected by the applicant, in which case the meaning will be described in detail in the detailed description of the invention. Therefore, the terms used in the present invention should be defined based on the meanings of the terms and the contents throughout the present invention, rather than the names of the simple terms.

Unless defined otherwise, all terms used herein, including technical or scientific terms, have the same meaning as commonly understood by one of ordinary skill in the art. Terms such as those defined in the commonly used dictionaries should be construed as having meanings consistent with the meanings in the context of the related art and shall not be construed in ideal or excessively formal meanings unless expressly defined in this application.

The numerical range includes the numerical values defined in the range. All maximum numerical limits given throughout this Specification include all lower numerical limits as if the lower numerical limits were clearly written. All minimum numerical limits given throughout this Specification include all higher numerical limitations as if the higher numerical limit were clearly written. All numerical limitations given throughout this Specification will include all better numerical ranges within the broader numerical range, as if the narrower numerical limitations were clearly written.

Hereinafter, each description and embodiment disclosed in the present invention may also be applied to other descriptions and embodiments for each. Therefore, all combinations of the various elements disclosed herein fall within the scope of the present invention. In addition, the scope of the present invention is not considered as being limited by the specific descriptions described below.

Expressions such as "comprising," used in the Specification of the present application, should be understood as open-ended terms that include the possibility of including other embodiments, unless mentioned particularly differently in a phrase or sentence in which the expression is included.

When the inventors of the present invention were conducted research and development to develop a pharmaceutical combination comprising diabetes therapies, dapagliflozin and sitagliptin, as main ingredients, since the flowability of sitagliptin was not good and a large amount of additives were necessary in direct tableting, the granulation method was applied. In particular, the wet granulation method was applied to prepare a single-layer tablet with two pharmaceuticals drugs (Forxiga ^TMtablet and Januvia^TM tablet), and it was confirmed that the pharmaceutical combination according to the present invention can increase the patient's convenience for internal use by reducing the size of the tablet, show improved drug release behavior, and secure stability under severe (60±2℃) conditions and accelerated open (40±2℃, 75±5%) conditions in order to be efficiently used as a diabetes therapy. Therefore, the present invention was completed.

Hereinafter, the present invention is described in details.

Pharmaceutical combination

To solve the technical problem above, the present invention provides the technical solution described below.

In the present invention, dapagliflozin, which is a main ingredient, is an SGLT2 inhibitor represented by Chemical formula 1 below, and the compound name is (2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxybenzyl)phenyl]-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol.

[Chemical formula 1]

In the present invention, sitagliptin, which is a main ingredient, is a DDP4 inhibitor represented by Chemical formula 2 below, and the compound name is (R)-3-amino-1-(3-(trifluoromethyl)-5,6-diphadro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-4-(2,4,5-trifluorophenyl)butane-1-one.

[Chemical formula 2]

In the present invention, the term "pharmaceutically acceptable salt" includes pharmaceutically acceptable inorganic acids, organic acids, or salts derived from bases. The term "hydrate" means a compound of the present invention or a pharmaceutically acceptable salt thereof comprising a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces.

In the present invention, a pharmaceutically acceptable salt of dapagliflozin or a hydrate thereof may be dapagliflozin bis L-proline, dapagliflozin citric acid or a dapagliflozin propanediol hydrate.

In the present invention, a pharmaceutically acceptable salt of sitagliptin or a hydrate thereof may be a sitagliptin phosphate salt or a sitagliptin phosphate hydrate.

In the present invention, the pharmaceutical combination may be a formulation of a tablet form, specifically, the tablet may be a single-layer tablet as a single formulation.

In the present invention, the single-layer tablet may be a film coated tablets coated with a film coating material. At that time, any film coating materials that can be used in the preparation of coated tablets in the field of pharmacy may be applied without limitation, and specifically, the film coating material may be Opadry, but not limited thereto.

In the present invention, the single-layer tablet may be prepared by the wet granulation method, and specifically, the single-layer tablet may comprise main ingredients in an amount of 40% to 45% by weight based on the total weight of the whole single-layer tablet, but is not limited thereto.

Specifically, a single-layer tablet prepared by the wet granulation method may be a single formation of which weight is reduced by about 45% in comparison with pharmaceutical combination of Forxiga ^TMtablet and Januvia^TM tablet prepared by the dry granulation method and which has advantages of increasing the patient's convenience for internal use, improving the release of the main ingredients, dapagliflozin and sitagliptin, and at the same time, decreasing the release difference.

In the present invention, the pharmaceutical combination may comprise at least one pharmaceutical additive consisting of an excipient, disintegrant, binder and lubricant, but is not limited thereto.

In the present invention, the pharmaceutical combination may comprise an excipient in an amount of 45% to 50% by weight based on the total weight of the pharmaceutical combination, but is not limited thereto.

In the present invention, the pharmaceutical combination may comprise a disintegrant in an amount of 1% to 5% by weight based on the total weight of the pharmaceutical combination, but is not limited thereto.

In the present invention, the pharmaceutical combination may comprise a binder in an amount of 1% to 5% by weight based on the total weight of the pharmaceutical combination, but is not limited thereto.

In the present invention, the pharmaceutical combination may comprise a lubricant in an amount of 1% to 5% by weight based on the total weight of the pharmaceutical combination, but is not limited thereto.

In the present invention, the excipient may be at least one selected from the group consisting of anhydrous lactose, microcrystalline cellulose, anhydrous calcium hydrogen phosphate and siliconized microcrystalline cellulose, but is not limited thereto.

In the present invention, the disintegrant may be at least one selected from the group consisting of crospovidone, sodium croscarmellose and sodium starch glycolate, but is not limited thereto.

In the present invention, the binder may be at least one selected from the group consisting of copovidone and hydroxypropyl cellulose, but is not limited thereto.

In the present invention, the lubricant may be at least one selected from the group consisting of magnesium stearate, sodium stearyl fumarate and light silicic anhydride, but is not limited thereto.

In the present invention, the pharmaceutical combination according to the present invention may be one in which dapagliflozin or a pharmaceutically acceptable salt thereof, or a hydrate thereof and sitagliptin or a pharmaceutically acceptable salt thereof, or a hydrate thereof show a dissolution rate of 80% (Q) or higher within 30 minutes, when a dissolution test is conducted in a dissolution test solution at pH 6.8 according to Method 2 of the dissolution test according to the Korean Pharmacopoeia, but is not limited thereto.

Specifically, the pharmaceutical combination according to the present invention, when rotated for 30 minutes at a rotation speed of 50 rpm in 900 mL of a dissolution test solution at pH 6.8 according to Method 2 of the dissolution test according to the Korean Pharmacopoeia, may show within 30 minutes a dissolution rate of 80% to 85% (Q) for dapagliflozin or a pharmaceutically acceptable salt thereof, or a hydrate thereof, a main ingredient, or may show within 30 minutes a dissolution rate of 80% to 98% (Q) for sitagliptin or a pharmaceutically acceptable salt thereof, or a hydrate thereof, a main ingredient.

In the present invention, the pharmaceutical combination may be a pharmaceutical combination for the treatment or prevention of diabetes, but is not limited thereto.

Preparation method of pharmaceutical combination

According to an aspect of the present invention, there is provided a preparation method of the pharmaceutical combination, the preparation method comprising: preparing a binding solution by dissolving a binder in a solvent; preparing a mixing part by mixing dapagliflozin or a pharmaceutically acceptable salt thereof, or a hydrate thereof, sitagliptin or a pharmaceutically acceptable salt thereof, or a hydrate thereof, an excipient, and a disintegrant; preparing granulated product by mixing the mixing part and the binding solution, and kneading and granulating the resulting mixture; preparing a dry product by drying the granulated product; and deagglomerating the dry product; and homogeneously mixing the deagglomerated product, an excipient, and a disintegrant, and a lubricant.

Specifically, the inventors of the present invention confirmed that when the wet granulation method is applied, the weight can be reduced by about 45% by weight of the pharmaceutical combination of Forxiga ^TMtablet and Januvia^TM tablet prepared by the dry granulation method to increase the patient's convenience for internal use and to improve the release of dapagliflozin and sitagliptin, and at the same time, decrease the release difference.

In the present invention, the solvent may be ethanol or purified water, preferably purified water, but is not limited thereto.

The contents about the pharmaceutical combination formulation described above may be applied to the preparation method of the pharmaceutical combination formulation unless they contradict each other.

Hereinafter, the present invention will be described in details based on Examples and Experimental Examples. However, the Examples and Experimental Examples described below are only for illustrating the present invention, and the scope of the present invention is not limited thereto.

Examples

Example 1. Dry prescription of bilayer tablet for increasing convenience for internal use

(1) Preparation of granules of dapagliflozin layer

After weighing the individual ingredients according to Table 1 below, dapagliflozin, which is the main ingredient; anhydrous lactose, which is an excipient; microcrystalline cellulose, which is an excipient; crospovidone, which is a disintegrant; and copovidone, which is a binder were sieved and put into a bin mixer to mix for 15 minutes. Magnesium stearate, which is a lubricant, was sieved and put into a bin mixer to mix for 5 minutes. The mixture was compressed by using a roller compactor to form a flake, which was then deagglomerated by using an oscillator.

Crospovidone, which is a disintegrant; and colloidal silicon dioxide, which is a fluidizing agent, were sieved and were added to the deagglomerated product and mixed for 15 minutes. After that, magnesium stearate, which is a lubricant, was sieved and then put into a bin mixer to mix for 5 minutes and to prepare the granules for dapagliflozin layer.

(2) Preparation of granules of sitagliptin layer

After weighing the individual ingredients according to Table 1 below, siliconized microcrystalline cellulose, which is an excipient; sodium croscarmellose, which is a disintegrant; sodium starch glycolate, which is a disintegrant; and colloidal silicon dioxide, which is a fluidizing agent, were sieved and put into a bin mixer to mix for 15 minutes. sitagliptin phosphate hydrate, which is a main ingredient; and anhydrous calcium hydrogen phosphate, which is an excipient, were sieved and then put into a bin mixer to mix for 15 minutes. Magnesium stearate, which is a lubricant; and sodium stearyl fumarate, which is a lubricant, were put into a bin mixer to mix for 5 minutes to prepare the granules for sitagliptin layer.

(3) Preparation of bilayer tablet

The granules for dapagliflozin layer and the granules for sitagliptin layer were tableted into a bilayer tablet (naked tablet), which was then coated with Opadry Beige to prepare a bilayer tablet (coated tablet).

(4) Comparison of weight

Forxiga ^TMtablet, which is a control drug of dapagliflozin, is also a dry granule prescription, and the weight of the tablet is 260 mg (including 10 mg as dapagliflozin). Januvia^TM tablet, which is a control drug of sitagliptin, is a dry granule prescription, and the weight of the tablet is 416.1 mg (including 100 mg as sitagliptin). The bilayer tablet prepared according to Example 1 has a weight that is similar to the sum of the weight of Forxiga ^TMtablet and Januvia^TM tablet (676.1 mg) (The weight of the bilayer tablet according to Example 1 is 622 mg.).

Prescription according to Example 1
Item	Purpose of mixing	Name of ingredient	Used amount
Item	Purpose of mixing	Name of ingredient	mg/T	wt%
Dapagliflozin layer	Main ingredient	dapagliflozin	10.00	5.00
	Excipient	anhydrous lactose	110.00	55.00
	Excipient	microcrystalline cellulose	55.00	27.50
	Disintegrant	crospovidone	10.00	5.00
	Binder	copovidone	10.00	5.00
	Fluidizing agent	colloidal silicon dioxide	2.50	1.25
	Lubricant	magnesium stearate	2.50	1.25
Sub-total			200.00	100.00
Sitagliptin layer	Main ingredient	sitagliptin phosphate hydrate (as sitagliptin)	128.50 (100.00)	31.81
	Excipient	anhydrous calcium hydrogen phosphate	138.50	34.28
	Excipient	siliconized microcrystalline cellulose	93.00	23.02
	Disintegrant	sodium croscarmellose	15.00	3.71
	Disintegrant	sodium starch glycolate	15.00	3.71
	Fluidizing agent	colloidal silicon dioxide	4.00	0.99
	Lubricant	magnesium stearate	4.00	0.99
	Lubricant	sodium stearyl fumarate	6.00	1.49
Sub-total			404.00	100.00
Total (tablet)			604.00	-
Coating layer	Coating agent	Opadry Beige	18.00	-
Total (Coating)			622.00	-

(The bilayer tablet according to Example 1 comprises the main ingredients, dapagliflozin and sitagliptin, in an amount of 22.9% by weight based on the total weight of the bilayer tablet (naked tablet).)

Example 2. Wet granule prescription for reducing tablet size

After weighing the individual ingredients according to Table 2 below, hydroxypropyl cellulose, which is a binder, was dissolved in purified water to prepare a binding solution. Dapagliflozin and a sitagliptin phosphate hydrate, which are the main ingredients; microcrystalline cellulose, which is an excipient; and sodium croscarmellose, which is a disintegrant, were mixed by using a high-speed mixer for 2 minutes, and then the binding solution was put into the high-speed mixer. The resulting mixture was kneaded for 1 minute and the granulated by using Co-mil. Then, the granulated product prepared above was dried by using a flat forced-convention dying oven at 60℃ until the Loss of Drying (LOD) became 2.0% to 4.0%. The dried product was deagglomerated by using Co-mil. Then, the resulting deagglomerated product, microcrystalline cellulose, which is an excipient; and sodium croscarmellose, which is a disintegrant, were sieved and the mixed for 30 minutes by using a bin mixer. Additionally, light silicic anhydride and magnesium stearate, which are lubricants, were sieved and put into a bin mixer to mix for 5 minutes. The final mixture was tableted (naked tablet), and the resulting tablet was coated with Opadry Beige to prepare a single-layer tablet (coated tablet).

The single-layer tablet prepared according to Example 2 above was prepared by reducing the size of the tablet by about 45% in comparison with the weight of the bilayer tablet according to Example 1, and thus has the advantage of increasing the patient's convenience for internal use.

Specifically, Forxiga ^TMtablet (Forxiga ^TMtablet 10 mg including 10 mg as dapagliflozin), which is a control drug of dapagliflozin, is a dry granule prescription, and the weight of the tablet is 260 mg. Januvia^TM tablet (Januvia^TM tablet 100 mg including 100 mg as sitagliptin), which is a control drug of sitagliptin, is also a dry granule prescription, and the weight of the tablet is 416.1 mg. The tablet weight of the bilayer tablet prepared by the dry granule prescription according to Example 1 is 622 mg, which is similar to the sum of the total weight of the two pharmaceuticals. However, according to Example 2 of the present invention, two pharmaceuticals, each of which is a tablet (Forxiga ^TMtablet and Januvia^TM tablet), can be prepared as a single-layer tablet having the form of a single formulation, and the weight is 345 mg, confirming that the size of the tablet can be reduced (reduced by about 45% compared with the weight of the bilayer tablet according to Example 1).

Prescription according to Example 2
Item	Purpose of mixing	Name of ingredient	Used amount
Item	Purpose of mixing	Name of ingredient	mg/T	wt%
Kneading	Main ingredient	dapagliflozin	10.00	3.00
	Main ingredient	sitagliptin phosphate hydrate (as sitagliptin)	128.50 (100.00)	38.70
	Excipient	microcrystalline cellulose	91.50	27.60
	Disintegrant	sodium croscarmellose	5.00	1.50
	Binder	hydroxypropyl cellulose	13.00	3.90
	Solvent	purified water	70.00	-
Final mixing	Excipient	microcrystalline cellulose	64.00	19.3
	Disintegrant	sodium croscarmellose	5.00	1.50
	Lubricant	light silicic anhydride	4.00	1.20
	Lubricant	magnesium stearate	11.00	3.30
Total (tablet)			332.00	100.00
Coating	Coating agent	Opadry Beige	13.00	-
Total (Coating)			345.00

(The single-layer tablet according to Example 2 comprises the main ingredients, dapagliflozin and sitagliptin, in an amount of 41.7% by weight based on the total weight of the single-layer tablet (naked tablet).)

Control drugs

Control drug 1: Forxiga ^TMtablet (Forxiga ^TMtablet 10 mg including 10 mg as dapagliflozin, AstraZeneca Korea)

Control drug 2: Januvia^TM tablet (Januvia^TM tablet 100 mg including 100 mg as sitagliptin, MSD Korea)

Testing methods

1. Flowability analysis method

A. Measurement of bulk density (B/D) and tap density (T/D)

The USP <616> method using a tap density tester (PT-TD4, ERWEKA) was used to measure the bulk density (B/D) and tap density (T/D) together. The bulk density (B/D) was measured from the volume of the known mass of the powder sample in a graduated cylinder. The graduated cylinder was mechanically tapped until the volume was changed no more, to measure the tap density (T/D).

B. Calculation of Carr's index and Husner ratio

Carr's index was calculated by using Equation 1 below.

[Equation 1]

Carr's index = (tap density (T/D) - bulk density (B/D))/ tap density (T/D) x 100%

Hausner ratio was calculated by using Equation 2 below.

[Equation 2]

Hausner ratio = tap density (T/D)/ bulk density (B/D)

(The unit of tap density (T/D) and bulk density (B/D) is g/mL.)

2. Dissolution test method

A. Dissolution test conditions

1) Dissolution test method: Method 2 of the dissolution test according to the Korean Pharmacopoeia (Paddle method)

2) Dissolution solution: pH 6.8 liquid, 900 mL

3) Temperature: 37±0.5℃

4) Rotation speed: 50 rpm

5) Analysis time: 5 min, 10 min, 15 min, 30 min, 45 min and 60 min

B. Instrument operation conditions

1) Detector: UV absorbance spectrometer (measurement wavelength: 225 nm for dapagliflozin and 250 nm for sitagliptin)

2) Column: YMC ODS-A (4.6 X 150 mm, 5 μm) or an equivalent column

3) Injection volume: 50 μL

4) Flow rate: 1.0 mL/min

5) Column temperature: constant temperature around 40℃

6) Sample temperature: constant temperature around 20℃

7) Analysis time: 65 minutes

8) Mobile phase: A - a mixed solution of 50 mM ammonium acetate aqueous solution and methanol (80:20)

Mobile phase: B - a mixed solution of 50 mM ammonium acetate aqueous solution and methanol (10:90)

3. Content test method

1) Detector: UV absorbance spectrometer (measurement wavelength: 210 nm)

2) Column: YMC ODS-A (4.6 X 150 mm, 5 μm)

3) Injection volume: 20 μL

4) Flow rate: 1.0 mL/min

5) Column temperature: constant temperature around 40℃

6) Sample temperature: constant temperature around 20℃

7) Analysis time: 4 minutes

8) Mobile phase: 50 mM ammonium acetate aqueous solution : methanol = 25:75

4. Method for analyzing impurities

1) Detector: UV absorbance spectrometer (measurement wavelength: 205 nm)

2) Column: 4.6×150 mm, 5 μm (Packing L10) or an equivalent column

3) Injection volume: 20 μL

4) Flow rate: 1.0 mL/min

5) Column temperature: constant temperature around 30℃

6) Sample temperature: constant temperature around 25℃

7) Analysis time: 30 minutes

8) Mobile phase: ACN : pH 2.0 butter = 15:85

5. Stable storage conditions

1) Sever conditions: 60±2℃

2) Accelerated open conditions: 40±2℃, RH 75±5%

Experimental Examples

Experimental Example 1: Flowability evaluation

The flowability of dapagliflozin and sitagliptin included in the bilayer tablet of Example 1 prepared by the dry granulation method and the single-layer tablet of Example 2 prepared by the wet granulation method was evaluated, and the results are shown in Tables 3 and 4.

The flowability of granules, related with the layer separation between particles, the packability in the tableting process and the mass deviation, is an important index that can affect the content and the content uniformity. The flowability can be evaluated with two parameters, Carr's index and Hausner ratio, which are based on the bulk density (B/D) and tap density (T/D).

The flowability of the final mixture of Example 1 prepared by the dry granulation method was confirmed, and the results showed that the flowability of the sitagliptin layer was lower than that of the dapagliflozin layer.

However, the flowability of the final mixture of Example 2 prepared by the wet granulation method was confirmed, and the results showed that the flowability was improved despite the combination of two ingredients.

Example 1 IPC Data
Item		Dapagliflozin layer	Sitagliptin layer
Specific volume	B/D (g/mL)	0.59	0.39
	T/D (g/mL)	0.77	0.60
	Carr's index	23.5	34.5
	Hausner's ratio	1.31	1.53

Example 2 IPC Data
Item		Dapagliflozin + Sitagliptin
Specific volume	B/D (g/mL)	0.45
	T/D (g/mL)	0.57
	Carr's index	20.9
	Hausner's ratio	1.26

Experimental Example 2: Results of dissolution test with dapagliflozin and sitagliptin.

A dissolution test was performed with the bilayer tablet according to Example 1, the single-layer tablet according to Example 2, and control drugs 1 and 2, and the results are shown in Tables 5 and 6.

According to Tables 5 and 6, the bilayer tablet of Example 1 prepared by the dry granulation method showed drug release behavior that was similar to the control drugs (Control drug 1: Forxiga ^TMtablet 10 mg; and Control drug 2: Januvia^TM tablet 100 mg), but the single-layer table of Example 2 prepared by the wet granulation method showed the effects of improving the drug release and decreasing the drug release difference.

Dapagliflozin	Dissolution rate (%)
Prescription No.	5 min	10 min	15 min	30 min	45 min	60 min
Control drug 1[combined administration]	52.8±25.5	77.7±20.3	78.8±20.4	80.8±19.0	82.4±17.9	82.5±17.1
Example 1	44.1±26.9	61.5±31.0	63.4±30.5	65.9±28.3	67.3±26.4	68.6±25.4
Example 2	71.3±2.3	81.7±1.5	85.4±1.1	88.9±1.6	89.3±1.6	89.4±1.8

Sitagliptin	Dissolution rate (%)
Prescription No.	5 min	10 min	15 min	30 min	45 min	60 min
Control drug 2 [combined administration]	63.3±5.5	62.3±10.0	64.8±10.4	69.4±10.2	72.2±9.4	73.8±8.7
Example 1	64.9±13.9	68.4±13.0	70.4±12.5	74.6±11.7	76.8±10.9	78.5±10.2
Example 2	94.3±3.0	97.7±1.9	97.7±1.4	97.4±1.4	97.1±1.2	96.8±1.3

Experimental Example 3: Results of stability test

The impurities and the content of pharmaceutical combination were tested with the single-layer tablet according to Example 2 and the control drugs 1 and 2. The storage conditions included severe (60±2℃) conditions and accelerated open (40±2℃, 75±5%) conditions, and the results are shown in Tables 7 and 8.

According to Tables 7 and 8, the single-layer tablet according to Example 2 showed the content and the impurities concentrations that were similar to those of the control drugs 1 and 2, confirming that the prescription secures stability (Content evaluation criteria: 90.0% to 110.0%; impurities evaluation criteria: 0.2% or less for the individual impurities and 1.0% or less for the total amount of the impurities).

Storage conditions

Sever conditions (60±2℃)

Ingredient

Dapagliflozin / packing material: Alu-Alu

Sitagliptin / packing material: PVDC

Item

Control drug 1

Example 2

Control drug 2

Example 2

Storage period

Initial

Week 2

Week 4

Initial

Week 2

Week 4

Initial

Week 2

Week 4

Initial

Week 2

Week 4

Impurities (%)

Individual impurities

N.D

0.00

N.D

0.00

0.01

N.D

0.00

N.D

Total impurities

N.D

0.00

N.D

0.00

0.01

N.D

0.00

N.D

Content (%)

103.7

104.3

100.3

97.9

101.7

98.7

98.0

99.4

98.1

96.7

102.1

96.6

Storage conditions

Accelerated open conditions (40±2℃, 75±5%)

Ingredient

Dapagliflozin / packing material: Alu-Alu

Sitagliptin / packing material: PVDC

Item

Control drug 1

Example 2

Control drug 2

Example 2

Storage period

Initial

Week 2

Week 4

Initial

Week 2

Week 4

Initial

Week 2

Week 4

Initial

Week 2

Week 4

Impurities (%)

Individual impurities

N.D

0.00

0.01

N.D

Total impurities

N.D

0.00

0.01

N.D

Content (%)

103.7

105.4

101.5

97.9

102.3

97.5

98.0

99.2

98.0

96.7

103.8

97.1

As described above, a specific part of the present invention was described in details. The specific description is only a preferred embodiment for those of ordinary skill in the related art, and it is clear that the scope of the present invention is not limited thereto. Therefore, the substantial scope of the invention will be defined by the attached claims and their equivalents.

Claims

A pharmaceutical combination comprising dapagliflozin or a pharmaceutically acceptable salt thereof, or a hydrate thereof; and

sitagliptin or a pharmaceutically acceptable salt thereof, or a hydrate thereof, as main ingredients,

wherein the main ingredients are included 35% to 50% by weight based on the total weight of the whole pharmaceutical combination.
The pharmaceutical combination according to claim 1, wherein the pharmaceutical combination is a single-layer tablet.
The pharmaceutical combination of claim 1, wherein the pharmaceutical combination is prepared by wet granulation method.
The pharmaceutical combination of claim 1, wherein the pharmaceutical combination comprises at least one pharmaceutical additive consisting of an excipient, disintegrant, binder and lubricant.
The pharmaceutical combination of claim 1, wherein dapagliflozin or a pharmaceutically acceptable salt thereof, or a hydrate thereof and sitagliptin or a pharmaceutically acceptable salt thereof, or a hydrate thereof show a dissolution rate of 80% (Q) or higher within 30 minutes, when a dissolution test is conducted in a dissolution test solution at pH 6.8 according to Method 2 of the dissolution test according to the Korean Pharmacopoeia.
A preparation method of the pharmaceutical combination, the preparation method comprising:

Preparing a binding solution by dissolving a binder in a solvent;

Preparing a mixing part by mixing dapagliflozin or a pharmaceutically acceptable salt thereof, or a hydrate thereof, sitagliptin or a pharmaceutically acceptable salt thereof, or a hydrate thereof, an excipient, and a disintegrant;

Preparing granulated product by mixing the mixing part and the binding solution, and kneading and granulating the resulting mixture;

Preparing a dry product by drying the granulated product;

Deagglomerating the dry product; and

Homogeneously mixing the deagglomerated product, an excipient, and a disintegrant, and a lubricant.
The preparation method of the pharmaceutical combination of claim 6, wherein the solvent is any one of ethanol and purified water.