WO2020130502A1 - Pharmaceutical composition comprising empagliflozin and sitagliptin - Google Patents

Abstract

The present invention relates to an oral composite preparation comprising empagliflozin and sitagliptin as effective ingredients. According to the present invention, the preparation is advantageous in pharmacological aspects not only because the drugs are contained in a monolayer to exhibit the effect of alleviating blood glucose level instantly and sustainably, but also because the storage stability and content uniformity of the active ingredients are improved.

Description

Pharmaceutical composition comprising empagliflozin and sitagliptin

The present invention relates to an oral combination preparation comprising empagliflozin and sitagliptin as active ingredients.

Diabetes is one of the leading causes of adult death worldwide, and the number of diabetic patients is rapidly increasing with the increase in the obese population, which is characterized by hyperglycemia due to excessive glucose production and peripheral insulin resistance. Plasma glucose is usually filtered in the kidney glomerulus and is actively reabsorbed in the proximal tubule. SGLT-2 is believed to be the major transporter involved in the reuptake of glucose at this site.

Therefore, selective inhibition of SGLT-2 (Sodium-Glucose linked transporter 2) in diabetic patients can normalize plasma glucose by increasing glucose excretion in the urine without significant gastrointestinal side effects, improving insulin sensitivity and delaying the onset of diabetes complications. . Accordingly, SGLT-2 inhibitors have attracted attention as a preventive or therapeutic agent for diabetes, diabetes-related diseases and diabetic complications.

Empagliflozin, one of the SGLT-2 inhibitors, is commercially available under the trade name Jardiance™, and the chemical name is 1-chloro-4-(β-D-glucopyranos-1-yl)- 2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-benzene, has the structure of Formula 1 below, and is disclosed in WO 2005/092877.

[Formula 1]

On the other hand, Sitagliptin (Sitagliptin) is a dipeptidyl peptidase-IV (DPP-4) inhibitor, a drug developed for the treatment of type 2 diabetes or improving blood sugar control, and cytagliptin in type 2 diabetes patients When orally administered, HbA1 c level is significantly decreased, and it is known that blood sugar and post-prandial blood sugar secretion decrease upon fasting.

[Formula 2]

The present inventors selected empagliflozin and sitagliptin as active ingredients of a diabetes complex agent having a synergistic therapeutic effect compared to administration of a single agent, and prepared a complex formulation therefrom, and showed that the stability and content uniformity of each active ingredient are excellent. Upon confirmation, the present invention was completed.

An object of the present invention is to provide an oral combination preparation of empagliflozin and sitagliptin, which is capable of obtaining an immediate and sustained release of empagliflozin and sitagliptin while having high stability and content uniformity of the active ingredient. Is doing.

Another object of the present invention is to provide a method for producing a combination preparation of empagliflozin and sitagliptin.

In order to solve the above problems, the present invention empagliflozin or a pharmaceutically acceptable salt thereof; And sitagliptin or a pharmaceutically acceptable salt thereof. At this time, the oral combination formulation is characterized in that it exhibits the following dissolution profile when measured in pH1.2, pH4.0, pH6.8 or water according to the second method (paddle method) of the Korean Pharmacopoeia (KP) dissolution test :　 The release rate of both drugs at a time point of 15 minutes or more is 75 to 100% (preferably, the release rate of empagliflozin or a pharmaceutically acceptable salt thereof is 90 to 100%, and sitagliptin or a pharmaceutically acceptable thereof The release rate of salt is 80 to 100%).

The oral composite agent may be in the form of a monolayer tablet.

The monolayer tablet is empagliflozin or a pharmaceutically acceptable salt thereof; And sitagliptin or a pharmaceutically acceptable salt thereof.

The pharmaceutically acceptable salt of empagliflozin or the pharmaceutically acceptable salt of sitagliptin includes an acid addition salt, for example, but is not limited to, hydrochloride, succinate, or fumarate. . In one embodiment, the pharmaceutically acceptable salt of sitagliptin is sitagliptin phosphate.

The combination preparation may contain 10 to 25 mg of empagliflozin per unit dosage form, for example, 10 mg, 15 mg, 20 mg or 25 mg per unit dosage form.

The combination preparation may also contain 50 to 100 mg of sitagliptin per unit dosage form, for example, 50 mg, 75 mg, 85 mg or 100 mg.

The monolayer tablet may be formed into tablets of granules of a mixture containing empagliflozin and sitagliptin or a pharmaceutically acceptable salt thereof, and the granules include dry granules and wet granules. In one embodiment of the present invention, the granules are preferably wet granules, and dry granules may exhibit a phenomenon in which elution decreases during tableting and a decrease in fluidity of the granules, and thus may adversely affect physical properties during tableting. .

The monolayer tablet may further contain, in addition to the active ingredient, any pharmaceutically acceptable additive known in the art for the preparation of the granules. The pharmaceutically acceptable additive can be selected from the group consisting of plasticizers, dispersants, diluents, disintegrants, lubricants, and any combinations thereof.

The diluent may be selected from the group consisting of microcrystalline cellulose, calcium hydrogen phosphate anhydrous, mannitol, sucrose, lactose hydrate, sorbitol, xylitol, glucose, and mixtures thereof, but is not limited thereto. The diluent is microcrystalline cellulose and lactose hydrate. The diluent may be contained in an amount of 1 to 10 parts by weight based on 100 parts by weight of empagliflozin and sitagliptin or a pharmaceutically acceptable salt thereof. The binder is low-substituted hydroxypropyl methyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, methyl cellulose, ethyl cellulose, polyethylene oxide, guar gum, locust bean gum, xanthan gum, glyceryl distearate , Sodium carboxymethylcellulose, polyvinylpyrrolidone and mixtures thereof, but is not limited thereto. The binder is a low-substituted hydroxypropyl cellulose. The diluent may be contained in an amount of 1 to 10 parts by weight based on 100 parts by weight of empagliflozin and sitagliptin or a pharmaceutically acceptable salt thereof.

The disintegrant may be selected from the group consisting of alginic acid, sodium alginate, sodium carboxymethylcellulose, microcrystalline cellulose, powdered cellulose, croscarmellose sodium, crospovidone, pregelatinized starch, sodium starch glycolate, starch and mixtures thereof. However, it is not limited thereto. The disintegrant is croscarmellose sodium. The binder may be contained in an amount of 3 to 10 parts by weight based on 100 parts by weight of empagliflozin and sitagliptin or a pharmaceutically acceptable salt thereof. The lubricant is calcium stearate, glyceryl monostearate, glyceryl palmitostearate, magnesium stearate, sodium lauryl sulfate, sodium stearyl fumarate, zinc stearate, stearic acid, cured vegetable oil, polyethylene glycol, benzoic acid Sodium, talc, silicon dioxide, and mixtures thereof. The lubricant is silicon dioxide and magnesium stearate. The lubricant may be contained in an amount of 1 to 5 parts by weight based on 100 parts by weight of empagliflozin and sitagliptin or a pharmaceutically acceptable salt thereof.

The coating agent may be selected from the group consisting of a mixture of HPC and HPMC, or a mixture of polyvinyl alcohol (PVA) and PEG (polyethylene glycol) and mixtures thereof, but is not limited thereto. The coating agent is a mixture of HPMC. The coating agent may be contained in an amount of 1 to 10 parts by weight based on 100 parts by weight of empagliflozin and sitagliptin or a pharmaceutically acceptable salt thereof.

The film-coated tablet may be formed by tableting in the form of a monolayer tablet with a mixture containing the empagliflozin or sitagliptin or a pharmaceutically acceptable salt thereof.

The film-coated tablets may contain empagliflozin and sitagliptin in one tablet, thereby exhibiting blood sugar improving effects of empagliflozin and sitagliptin.

According to one embodiment of the present invention, the single-layered tablet according to the present invention is a composite formulation, but can also secure the stability of empagliflozin and sitagliptin, but is a single-layered tablet, but forms a granular layer, respectively, to control the stability of the controlled release composite formulation. Excellent in terms of aspect.

Therefore, the combination agent of the present invention has both immediate release properties of empagliflozin and sitagliptin, but has excellent stability of the active ingredient compared to the conventional combination agent.

According to one embodiment of the present invention, the oral combination preparation is stored for 4 weeks at a long-term storage condition of 25±2℃/relative humidity of 60±5% and an accelerated condition of 40±2℃/relative humidity of 75±5%. It can be confirmed that the city content and related substances are suitable for the standard. Specifically, when the oral combination preparation is stored for 4 weeks under conditions of 25±2° C. and 60±5% relative humidity, the individual related substances of empagliflozin are 0.2% by weight or less (preferably, 0.1% by weight or less), Total related substances are 0.6% by weight or less (preferably, 0.2% by weight or less), and individual related substances of sitagliptin are 0.2% by weight or less (preferably, 0.1% by weight or less), and total related substances are 0.6% by weight or less ( Preferably, 0.2% by weight or less). In addition, when the oral combination preparation is stored for 4 weeks under conditions of 40±2° C. and 75±5% relative humidity, the individual related substances of empagliflozin are 0.2% by weight or less (preferably 0.1% by weight) or less. The related substance is 0.6% by weight or less (preferably, 0.3% by weight or less), the individual related substances of sitagliptin are 0.2% by weight or less (preferably, 0.1% by weight or less), and the total related substances are 0.6% by weight or less (preferably It can be maintained at 0.3% by weight or less).

The oral combination preparation may be administered as an adjunct to diet therapy and exercise therapy to improve blood sugar control in adult type 2 diabetes patients.

In another aspect, there is provided a method for preparing an oral composite preparation, including a wet granulation step.

Furthermore, the present invention provides a use for use in a pharmaceutical composition for preventing or treating diabetes, including the oral combination preparation.

In addition, the present invention provides a use for use in a health functional food composition for preventing or improving diabetes comprising the oral combination preparation.

In addition, the present invention provides a method for preventing or treating diabetes, comprising orally administering the oral combination preparation to an individual.

In the present invention, "individual" refers to a subject in need of treatment of a disease, and more specifically, a human or non-human primate, mouse, rat, dog, cat, horse, and cow, etc. Means mammal.

According to the present invention, as a combination preparation containing both empagliflozin and sitagliptin in one tablet, these drugs are included in a single layer to exhibit an immediate and sustained improvement of blood sugar, and storage stability of the active ingredient And the improved content uniformity has an advantage in terms of pharmaceuticals.

Figure 1 shows the dissolution rate of empagliflozin over time with 50 rpm dissolution test results, performance results, and time in 4 solutions of water, pH 1.2, 4.0, and 6.8 using the eluator for the formulations of Example 1 and Comparative Example 1. It is a graph showing the measured results.

Figure 2 shows the results of the dissolution test for 50 rpm in 4 solutions of water, pH 1.2, 4.0, 6.8 using the eluator for the formulations of Example 1 and Comparative Example 2, the results of the test, and the dissolution rate of cytagliptin over time It is a graph showing the results.

Hereinafter, the present invention will be described in more detail by examples. However, the following examples are only for illustrating the present invention, and the scope of the present invention is not limited thereby.

[Example 1]

Preparation of a composite monolayer tablet of empagliflozin and sitagliptin

A monolayer tablet of a mixture of empagliflozin and sitagliptin was prepared according to the composition of Table 1 below. Specifically, empagliflozin, sitagliptin, lactose hydrate, low-substituted hydroxypropylcellulose, microcrystalline cellulose, and croscarmellose sodium (half injection) are used as high-speed mixers (PKM-20, Pharmatech Korea) After wet granulation with ), dried with a plate or fluidized bed dryer, and then sized with a sizing machine. Then, croscarmellose sodium (the other half input) and silicon dioxide were added, followed by post-mixing with a high-speed mixer. Finally, magnesium stearate was added and mixed, followed by tableting with a tableting machine (TPR-1002, Yenchen).

Molded empagliflozin and sitagliptin phosphate tablets were coated with the composition of [Table 1] to prepare a film coated tablet. Specifically, a film coating tablet was prepared by dissolving an HPMC-based coating agent in ethanol with a coater.

Purpose of blending	Raw material name	Example 1 (mg)	Example 1 (%)
chief ingredient	Empagliflozin	25.00	7.23
chief ingredient	Sitagliptin	100.00	28.90
diluent	Lactose hydrate	150.00	43.35
diluent	Microcrystalline cellulose	25.00	7.23
Binder	Low substitution high profile cellulose	7.00	2.02
Disintegrant	Croscarmellose sodium	18.00	5.20
Lubricant	Silicon dioxide	5.00	1.45
Lubricant	Sodium stearate	5.00	1.45
Coating	Opadry (03B620011)	11.00	3.18
Sum		346.00	100.00

[Comparative example]

Jadiang tablets (Berlinger Ingelheim Korea) tablets containing 25 mg of empagliflozin and Januvia tablets (MSD Korea) tablets containing 100 mg of sitagliptin were purchased.

Comparative Example 1	Comparative Example 2
Jadiangjung 25mg (Empagliflozin)	Januvia Tablet 100mg (Citagliptin)
Boehringer Ingelheim Korea	MSD Korea

Experimental Example 1: Dissolution test

With the tablets of Comparative Examples 1 and 2 and Examples, the dissolution rate was measured at 50 rpm in the 4th solution according to the Paddle Method of the Dissolution Test Method 2 of the General Test Methods of the Korean Pharmacopoeia, and the results of measuring the dissolution rate were as follows [Table] 3].

1-1. Experiment method

Sitagliptin

1) Standard solution: Approximately 20 mg of the standard product of sitagliptin phosphate is precisely weighed and placed in a 50 mL volumetric flask and marked with the dissolution test solution. Take 9 mL of this solution, put it in a 50 mL volumetric flask, add the dissolution test solution, mark it, and use the standard filtrate as a solution filtered with a 0.45 μm membrane filter.

2) Test Solution: Test with 50 tablets per minute according to the Dissolution Test Method 2 (Paddle Method) of the General Test Methods of the Korean Pharmacopoeia using 1 tablet of dissolution and 900 mL of dissolution test solution. 30 minutes after the start of the dissolution test, 10 mL of the eluate is taken and filtered through a 0.45 μm membrane filter. Take 5 mL of this solution accurately, put it in a 10 mL volumetric flask, and use the solution selected as the dissolution test solution as the sample solution.

3) Operation: Test according to the device operating conditions of the content test method with the above standard solution, test solution, and system compatibility solution.

4) Calculation formula

The dissolution rate of cytagliptin (%) = AT/AS × WS/DS × DT/L × F × P

AT: the peak area of sitagliptin in the sample solution

AS: the peak area of sitagliptin in the standard solution

WS: Standard product intake (mg)

P: Standard product purity (%, as is)

DT: Dilution of test solution (900)

DS: Standard solution diluted multiple

F: Conversion factor from sitagliptin phosphate to inorganic salt = 0.7783

L: sitagliptin display amount (mg/T)

5) System suitability: The relative standard deviation of the peak area when the standard solution is repeated 6 times is 2.0% or less. When the standard solution is injected once, the tail peak has a tailing coefficient of 2.0 or less.

6) Dissolution test conditions: Korea Pharmacopoeia Dissolution Test Method 2 (Paddle Method)

Eluent: pH 1.2, pH4.0, pH6.8 or water, 900 mL

Elution temperature: 37±0.5℃

Speed: 50 rpm

Test time: 60 minutes

Empagliflozin

1) Standard solution: Accurately weigh about 14 mg of empagliflozin standard, put it in a 250 mL volumetric flask, add 3 mL of methanol to dissolve it, dissolve it, and align the mark with the dissolution test solution. Take 4 mL of this solution accurately, put it in a 20 mL volumetric flask, add the dissolution test solution, mark it, and use the solution filtered with a 0.45 μm membrane filter as a standard solution.

2) Test Solution: Take 900 tablets of dissolution test with 1 tablet of this drug and test at 50 revolutions per minute according to the Dissolution Test Method 2 (Paddle Method) of the General Test Methods of the Korean Pharmacopoeia. 30 minutes after the start of the dissolution test, 10 mL of the eluate is taken and filtered through a 0.45 μm membrane filter. Take 5 mL of this solution accurately, put it in a 10 mL volumetric flask, and use the solution selected as the dissolution test solution as the sample solution.

3) Operation: Test according to the device operating conditions of the content test method with the above standard solution, test solution, and system compatibility solution.

4) Calculation formula

Dissolution rate of empagliflozin (%) = AT/AS × WS/DS × DT/L × P

AT: Peak area of empagliflozin in the sample solution

AS: Peak area of empagliflozin in standard solution

WS: Standard product intake (mg)

P: Standard product purity (%, as is)

DT: Dilution of test solution (900)

DS: Standard solution diluted multiple

F: Conversion factor from empagliflozin monohydrate to inorganic salt = 0.7783

L: Empagliflozin display amount (mg/T)

5) System suitability: Relative standard deviation of the peak area when the standard solution is repeated 6 times is 2.0% or less. When the standard solution is injected once, the tail peak has a tailing coefficient of 2.0 or less. 6) Dissolution test conditions

Dissolution test method: Korean Pharmacopoeia dissolution test method 2 (paddle method)

Eluent: pH 1.2, pH4.0, pH6.8 or water, 900 mL

Elution temperature: 37±0.5℃

Speed: 50 rpm

Test time: 60 minutes

1-2. Experiment result

According to the Drug Equivalence Test Standard [2018-29], it is judged that it is equivalent if one of the following conditions is satisfied. As shown in Tables 3, 4 and 1 below, Example 1 proved to be equivalent to Comparative Examples 1 and 2 through the dissolution test.

1) When the dissolution rates of Comparative Examples 1 and 2 reach 85% within 15 minutes, the dissolution rates of Example 1 are equal if they reach 85% within 15 minutes.

2) When the dissolution rates of Comparative Examples 1 and 2 reached 85% between 15 and 30 minutes, the dissolution rates of Example 1 were comparative examples 1 at two time points, where the dissolution rates of Comparative Examples 1 and 2 were around 60% and 85%. , 2 within ±15% of the equivalent.

3) In other cases, the dissolution rates of Example 1 and 2 are equivalent to ±15% of Comparative Examples 1 and 2 at two time points in which the dissolution rates of Comparative Examples 1 and 2 are around 40% and 85%.

Dissolution rate of empagliflozin

(pH1.2)	Empagliflozin dissolution rate (%)
	5 minutes	10 minutes	15 minutes	30 minutes	45 minutes	60 minutes
Comparative Example 1	86.30	93.00	96.90	98.90	99.70	99.90
Example 1	87.50	91.20	97.00	99.50	100.40	100.90
Comparative Example 1-Example 1 (%)	-1.2	1.8	-0.1	-0.6	-0.7	-1.0
(pH 4.0)	Empagliflozin dissolution rate (%)
	5 minutes	10 minutes	15 minutes	30 minutes	45 minutes	60 minutes
Comparative Example 1	75.30	87.50	92.60	96.30	98.40	99.90
Example 1	74.10	86.90	96.20	99.50	100.10	100.70
Comparative Example 1-Example 1 (%)	1.2	0.6	-3.6	-3.2	-1.7	-0.8
(pH 6.8)	Empagliflozin dissolution rate (%)
	5 minutes	10 minutes	15 minutes	30 minutes	45 minutes	60 minutes
Comparative Example 1	64.50	85.10	91.90	95.40	96.80	98.40
Example 1	61.10	84.20	91.60	95.20	96.50	97.20
Comparative Example 1-Example 1 (%)	3.40	0.90	0.30	0.20	0.30	1.20
(water)	Empagliflozin dissolution rate (%)
	5 minutes	10 minutes	15 minutes	30 minutes	45 minutes	60 minutes
Comparative Example 1	81.70	95.00	97.60	98.80	99.60	100.00
Example 1	84.10	92.60	96.30	99.00	99.80	100.20
Comparative Example 1-Example 1 (%)	-2.40	2.40	1.30	-0.20	-0.20	-0.20

The dissolution rate of sitagliptin

(pH1.2)	Cytagliptin dissolution rate (%)
	5 minutes	10 minutes	15 minutes	30 minutes	45 minutes	60 minutes
Comparative Example 1	81.40	91.50	96.70	99.30	99.90	100.10
Example 1	80.80	93.00	100.00	100.50	100.60	100.70
Comparative Example 1-Example 1 (%)	0.6	-1.5	-3.3	-1.2	-0.7	-0.6
(pH 4.0)	Cytagliptin dissolution rate (%)
	5 minutes	10 minutes	15 minutes	30 minutes	45 minutes	60 minutes
Comparative Example 1	70.30	78.10	82.40	85.70	86.70	90.70
Example 1	68.30	79.60	84.80	88.20	89.40	93.60
Comparative Example 1-Example 1 (%)	2.0	-1.5	-2.4	-2.5	-2.7	-2.9
(pH 6.8)	Cytagliptin dissolution rate (%)
	5 minutes	10 minutes	15 minutes	30 minutes	45 minutes	60 minutes
Comparative Example 1	70.40	76.70	80.20	84.00	87.00	90.20
Example 1	68.00	78.10	85.30	88.30	89.30	92.70
Comparative Example 1-Example 1 (%)	2.4	-1.4	-5.1	-4.3	-2.3	-2.5
(water)	Cytagliptin dissolution rate (%)
	5 minutes	10 minutes	15 minutes	30 minutes	45 minutes	60 minutes
Comparative Example 1	64.80	80.80	88.50	92.50	93.60	95.90
Example 1	60.30	83.00	90.70	94.80	95.60	96.00
Comparative Example 1-Example 1 (%)	4.5	-2.2	-2.2	-2.3	-2.0	-0.1

Experimental Example 2: Stability test

With respect to the Comparative Example and Example 1, sealed in Alu-Alu and PVDC blister packaging, long-term storage conditions (25±2℃/relative humidity 60±5%), acceleration conditions (40±2℃/relative humidity 75± 5%), the contents were measured at 1, 2, 3, and 4 weeks to evaluate the stability of the formulation.

2-1. Experiment method

Citagliptin Phosphate

1) Standard solution: Precisely weigh approximately 10 mg of the standard product of sitagliptin phosphate monohydrate, put it in a 100 mL volumetric flask, dissolve the solution, sonicate it, dissolve it, and dissolve it, and align the mark with dilution solution Note 4). Should be 2) Test Solution: Take 10 tablets of this drug, put it in a 1 L volumetric flask, add diluent Note 4) and stir for 1 hour. Take 8 mL of this solution accurately, place it in a 100 mL volumetric flask, align the mark with diluent Note 4) and filter with a 0.45 μm membrane filter. This solution is used as the sample solution.

3) HPLC operating conditions

Detector: Ultraviolet absorption photometer (Measurement wavelength: 210 nm)

Column: Inno column C18 (4.6 × 150 mm, 5 μm) or equivalent column

Column temperature: 30℃

Injection volume: 10 μL

Flow rate: 1.0 mL/min

Analysis time: 10 minutes

Mobile phase: mixed solution of water, acetonitrile and phosphoric acid (65:35:1)

4) System suitability: The tailing coefficient of the main peak is 2.0 or less when the standard solution is repeatedly injected 6 times, and the relative standard deviation of the peak area is 2.0% or less.

5) Calculation formula

Content (%) for the amount of sitagliptin displayed = AT/AS × WS/DS × DT/L × F/L × P

AT: Peak area of sitagliptin in the test solution

AS: peak area of sitagliptin in the standard solution

WS: Standard amount taken (mg)

P: Standard product purity (%, as is)

DT: Dilution of test solution

DS: Standard solution dilution factor

N: number of tablets (10)

F: Conversion factor from cytagliptin phosphate monohydrate to inorganic salt (0.7783)

L: The amount of peri-sitagliptin (mg)

Empagliflozin

1) Standard solution: About 25 mg of empagliflozin standard is precisely weighed, placed in a 50 mL volumetric flask, and diluted 3) and sonicated to dissolve. Align the mark with diluent Note 3), and the solution filtered with a 0.45 μm membrane filter is used as the standard solution.

2) Test Solution: Take 10 tablets of this drug, place it in a 500 mL volumetric flask, add diluent Note 3) and dissolve by ultrasonic treatment. Align the mark with diluent Note 3) and use the solution filtered with a 0.45 μm membrane filter as the sample solution.

3) HPLC operating conditions

Detector: Ultraviolet absorption photometer (Measurement wavelength: 210 nm)

Column: Inno column C18 (4.6 × 150 mm, 5 μm) or equivalent column

Column temperature: 30℃

Injection volume: 10 μL

Flow rate: 1.0 mL/min

Analysis time: 10 minutes

Mobile phase: mixed solution of water, acetonitrile and phosphoric acid (65:35:1)

4) System suitability: The tailing coefficient of the main peak is 2.0 or less when the standard solution is repeatedly injected 6 times, and the relative standard deviation of the peak area is 2.0% or less.

5) Calculation formula

Content of empagliflozin display amount (%) = AT/AS × WS/DS × DT/L × P/L

AT: Peak area of empagliflozin in the sample solution

AS: Peak area of empagliflozin in the standard solution

WS: Standard amount taken (mg)

P: Standard product purity (%, as is)

DT: Dilution of test solution

DS: Standard solution dilution factor

N: number of tablets (10)

L: amount of 1 party empagliflozin (mg)

2-2. Experiment result

As shown in Tables 5 to 8, the tablets of Example 1 showed less change in content than the formulations of Comparative Examples 1 and 2, indicating that storage stability was better.

Content stability of empagliflozin under long-term storage conditions

		Example 1	Comparative Example 1
Content test (long-term storage condition: 25±2℃/relative humidity 60±5%)	Early	100.08%	98.37%
	1 week	99.97%	98.05%
	2 weeks	100.05%	97.59%
	3 weeks	100.31%	96.29%
	4 weeks	99.59%	95.84%

Content stability of sitagliptin under long-term storage conditions

		Example 1	Comparative Example 2
Content test (long-term storage condition: 25±2℃/relative humidity 60±5%)	Early	100.84%	97.21%
	1 week	100.51%	96.83%
	2 weeks	99.68%	96.81%
	3 weeks	100.19%	95.22%
	4 weeks	100.32%	95.18%

Content stability of empagliflozin under accelerated conditions

		Example 1	Comparative Example 1
Content test (acceleration condition: 40±2℃/relative humidity 75±5%)	Early	100.08%	97.38%
	1 week	100.78%	96.88%
	2 weeks	100.46%	96.35%
	3 weeks	100.64%	95.78%
	4 weeks	99.26%	95.46%

Content stability of cytagliptin under accelerated conditions

		Example 1	Comparative Example 2
Content test (acceleration condition: 40±2℃/relative humidity 75±5%)	Early	100.84%	97.10%
	1 week	100.42%	96.49%
	2 weeks	100.35%	96.11%
	3 weeks	100.94%	95.23%
	4 weeks	100.06%	94.73%

Experimental Example 3: Stability test related substances

For Comparative Example and Example 1, sealed in Alu-Alu and PVDC blister packaging, long-term storage conditions (25±2℃/relative humidity 60±5%) and acceleration conditions (40±2℃/relative humidity 75±5 %), and the amount of related substances produced by empagliflozin and sitagliptin was measured at 1, 2, 3, and 4 weeks.

3-1. Experiment method

Sitagliptin

1) Standard solution: About 10 mg of sitagliptin phosphate monohydrate standard is precisely weighed, placed in a 100 mL volumetric flask, diluted with ultrasonic solution, dissolved, filtered with a 0.45 μm membrane filter as a standard solution.

2) Test Solution: Take 2 tablets of this drug, put it in a 250 mL volumetric flask, add diluent Note 1) and stir for 1 hour. After marking with dilution solution Note 1), 10 mL of this solution is accurately taken, placed in a 100 mL volumetric flask, and the solution selected with Dilution Note 1) is filtered with a 0.45 μm membrane filter. This solution is used as the sample solution.

3) Equipment operating conditions

Detector: Ultraviolet absorption photometer (Measurement wavelength: 205 nm)

Column: Supelco Discovery Cyano Column (4.6 × 150 mm, 5 μm) or equivalent

Column temperature: 30℃

Injection volume: 20 μL

Flow rate: 1.0 mL/min

Analysis time: 60 minutes

Mobile phase: mixed solution of buffer and acetonitrile.(85:15)

4) System suitability

The relative standard deviation of the peak area when repeated injection of the standard solution 6 times is 2.0% or less.

5) Calculation formula

Amount of analog (%) = AT/AS × WS/DS × DT/L × F/RRF × P/N

AT: Peak area of related substances in the test solution

AS: peak area of sitagliptin in the standard solution

WS: Standard amount taken (mg)

P: Standard product purity (%, as is)

DT: Dilution of test solution

DS: Standard solution dilution factor

N: number of tablets (2)

F: Conversion factor of cytagliptin phosphate monohydrate to inorganic salt (0.7783)

L: The amount of peri-sitagliptin (mg)

RRF: Relative reaction coefficient

Total related substances: sum of individual flexible substances

6) Related material standards, RRT and RRF

Related substances	RRT	RRF	standard(%)
Sitagliptin acid 1)	0.55	0.65	0.2
Sitagliptin	One	-	-
Sitagliptin triazecine analog 2)	1.8	One	0.2
Sitagliptin styrylacetyl analog 3)	4.1	One	0.2
Sitagliptin phenylcrotonyl analog 4)	4.7	2.1	0.2
Other related substances	-	One	0.2
Total analogs	-	-	0.6

1) Sitagliptin acid: (R)-3-Amino-4-(2,4,5-trifluorophenyl)butanoic acid

2) Sitagliptin triazecine analog: 10-(2,4,5-Trifluorobenzyl)-3-(trifluoromethyl)-6,7,10,11-tetrahydro-[1,2,4]triazolo[3,4-c][ 1,4,7]triazecine-8,12(5H,9H)-dione

3) Sitagliptin styrylacetyl analog: (E)-1-(3-(Trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)- 4-(2,4,5-trifluorophenyl)but-3-en-1-one

4) Sitagliptin phenylcrotonyl analog: (E)-1-(3-(Trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)- 4-(2,4,5-trifluorophenyl)but-2-en-1-one

Empagliflozin

1) Standard solution: About 25 mg of empagliflozin standard is precisely weighed, placed in a 50 mL volumetric flask, diluted with a diluent and sonicated to dissolve, and the solution aligned with the diluent note 3) is filtered through a 0.45 μm membrane filter. Let this solution be the standard solution.

2) Test Solution: Take 10 tablets of this drug, put it in a 250 mL volumetric flask, add diluent solution 3), dissolve by ultrasonic treatment, and align the mark with diluent solution 3). Take 10 mL of this solution, put it in a 20 mL volumetric flask, and filter the lined solution with diluent Note 3) with a 0.45 μm membrane filter. This solution is used as the sample solution.

3) Equipment operating conditions

Detector: Ultraviolet absorption photometer (Measurement wavelength: 220 nm)

Column: YMC Pack Pro C18 (4.6 × 150 mm, 3.0 μm) or equivalent column

Column temperature: 35℃

Injection volume: 10 μL

Flow rate: 0.8 mL/min

Analysis time: 50 minutes

Phase: A-0.1% phosphoric acid aqueous solution

B-A mixture of phosphoric acid, acetonitrile and methanol (0.1: 80: 20)

Concentration gradient of mobile phase

Hour (minute)	Mobile phase A (%)	Mobile phase B (%)
0	60	40
5	60	40
30	20	80
40	20	80
45	60	40
50	60	40

4) System suitability: The tailing coefficient of the main peak is 2.0 or less when the standard solution is repeatedly injected 6 times, and the relative standard deviation of the peak area is 2.0% or less.

Substance name	Relative retention period
EGS	0.47
Empagliflozin	One
TMF	1.33
DGF	1.5
MAE impurity	1.71
EAP	2.6
CHA	3.12
DGF-IV	3.62

5) Calculation formula

Amount of analog (%) = AT/AS × WS/DS × DT/L × P/N × 1/RRF

AT: Peak area of related substances in the test solution

AS: Peak area of empagliflozin in the standard solution

WS: Standard amount taken (mg)

P: Standard product purity (%, as is)

DT: Dilution of test solution

DS: Standard solution dilution factor

N: number of tablets (10)

L: amount of 1 party empagliflozin (mg)

RRF: Relative reaction coefficient

3-2. Experiment result

As shown in Tables 12 to 17, it was found that the tablets of Example 1 showed less amount of the related substances than the formulations of Comparative Examples 1 and 2, and thus the storage stability was better.

The rate of production of analogs of sitagliptin under long-term storage conditions

Example 1
Related substances	RRT	RRF	standard(%)	1 week (%)	2 weeks(%)	3 weeks (%)	4 weeks (%)
Sitagliptin acid	0.55	0.65	0.2	0	0	0	0
Sitagliptin	One	-	-	0	0	0	0
Sitagliptin triazecine analog	1.8	One	0.2	0	0	0	0
Sitagliptin styrylacetyl analog	4.1	One	0.2	0	0	0	0
Sitagliptin phenylcrotonyl analog	4.7	2.1	0.2	0	0	0	0
Other related substances	-	One	0.2	0	0	0	0
Total analogs	-	-	0.6	0	0	0	0
Comparative Example 2
Related substances	RRT	RRF	standard(%)	1 week (%)	2 weeks(%)	3 weeks (%)	4 weeks (%)
Sitagliptin acid	0.55	0.65	0.20	0.02	0.05	0.08	0.09
Sitagliptin	One	-	-	0	0	0	0
Sitagliptin triazecine analog	1.8	One	0.20	0.04	0.06	0.09	0.11
Sitagliptin styrylacetyl analog	4.1	One	0.20	0.01	0.02	0.07	0.09
Sitagliptin phenylcrotonyl analog	4.7	2.1	0.20	0	0.01	0.05	0.08
Other related substances	-	One	0.20	0.01	0.03	0.05	0.07
Total analogs	-	-	0.60	0.05	0.10	0.20	0.30

Empagliflozin related material production rate of Example 1 under long-term storage conditions

Example 1
Substance name	Relative holding time (RRT)	1 week (%)	2 weeks(%)	3 weeks (%)	4 weeks (%)
EGS	0	0	0	0	0
TMF	One	0	0	0	0
DGF	2	0	0	0	0
MAE impurity	2	0	0	0	0
EAP	3	0	0	0	0
CHA	3	0	0	0	0
DGF-IV	4	0	0	0	0
Other flexible substances	-	0	0	0	0
Total analogs	-	0	0	0	0

Empagliflozin related material production rate in Comparative Example 1 under long-term storage conditions

Comparative Example 1
Substance name	standard(%)	2 weeks(%)	3 weeks (%)	4 weeks (%)
EPG8	0	0.02	0.03	0.03
TOS4	0	0.01	0.02	0.02
Beta furanose	0	0.03	0.04	0.05
5-Di THF impurity	0	0.02	0.02	0.04
6-Di THF impurity	0	0.03	0.06	0.07
Single maximun unspecified	0	0.05	0.06	0.08
Total impurities	0	0.52	0.64	0.71

The rate of formation of analogs of cytagliptin under accelerated conditions

Example 1
Related substances	RRT	RRF	standard(%)	1 week (%)	2 weeks(%)	3 weeks (%)	4 weeks (%)
Sitagliptin acid	0.55	0.65	0.2	0	0	0	0
Sitagliptin	One	-	-	0	0	0	0
Sitagliptin triazecine analog	1.8	One	0.2	0	0	0	0
Sitagliptin styrylacetyl analog	4.1	One	0.2	0	0	0	0
Sitagliptin phenylcrotonyl analog	4.7	2.1	0.2	0	0	0	0
Other related substances	-	One	0.2	0	0	0	0
Total analogs	-	-	0.6	0	0	0	0
Comparative Example 2
Related substances	RRT	RRF	standard(%)	1 week (%)	2 weeks(%)	3 weeks (%)	4 weeks (%)
Sitagliptin acid	0.55	0.65	0.20	0.03	0.06	0.09	0.10
Sitagliptin	One	-	-	0.00	0.00	0.00	0.00
Sitagliptin triazecine analog	1.8	One	0.20	0.06	0.08	0.10	0.12
Sitagliptin styrylacetyl analog	4.1	One	0.20	0.03	0.05	0.09	0.11
Sitagliptin phenylcrotonyl analog	4.7	2.1	0.20	0.00	0.02	0.06	0.09
Other related substances	-	One	0.20	0.03	0.05	0.07	0.08
Total analogs	-	-	0.60	0.08	0.17	0.28	0.36

Empagliflozin related material production rate of Example 1 under accelerated conditions

Example 1
Substance name	Relative holding time (RRT)	1 week (%)	2 weeks(%)	3 weeks (%)	4 weeks (%)
EGS	0	0	0	0	0
TMF	One	0	0	0	0
DGF	2	0	0	0	0
MAE impurity	2	0	0	0	0
EAP	3	0	0	0	0
CHA	3	0	0	0	0
DGF-IV	4	0	0	0	0
Other flexible substances	-	0	0	0	0
Total analogs	-	0	0	0	0

Comparative Example 1
Substance name	standard(%)	2 weeks(%)	3 weeks (%)	4 weeks (%)
EPG8	0	0.03	0.05	0.06
TOS4	0	0.02	0.03	0.03
Beta furanose	0	0.05	0.06	0.07
5-Di THF impurity	0	0.03	0.03	0.06
6-Di THF impurity	0	0.04	0.07	0.08
Single maximun unspecified	0	0.06	0.07	0.09
Total impurities	0	0.57	0.64	0.78

Claims (12)

1. Empagliflozin or a pharmaceutically acceptable salt thereof; And sitagliptin or a pharmaceutically acceptable salt thereof, wherein the oral combination preparation is pH 1.2, pH 4 according to the Korean Pharmacopoeia (KP) dissolution test method 2 (paddle method). Oral combination preparations characterized by exhibiting the following dissolution profiles when measured at 0, pH 6.8 or water:

   The release rate of the two drugs was 75 to 100% at the time of 15 minutes or longer.
2. According to claim 1,

   The oral combination preparation is empagliflozin or a pharmaceutically acceptable salt thereof; And a mixed portion containing sitagliptin or a pharmaceutically acceptable salt thereof, which is a monolayer tablet contained in the same layer.
3. According to claim 1,

   The empagliflozin and sitagliptin are formed by tableting of wet granules, an oral combination preparation.
4. According to claim 1,

   The oral combination preparation is an oral combination preparation further comprising a pharmaceutically acceptable additive selected from the group consisting of diluents, binders, disintegrants, lubricants, film coating agents and any combinations thereof.
5. According to claim 4,

   The diluent is an oral combination preparation selected from the group consisting of microcrystalline cellulose, calcium hydrogen phosphate anhydrous, mannitol, sucrose, lactose hydrate, sorbitol, xylitol, glucose, and any combination thereof.
6. According to claim 4,

   The binder is low-substituted hydroxypropyl methyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, methyl cellulose, ethyl cellulose, polyethylene oxide, guar gum, locust bean gum, xanthan gum, glyceryl distearate , Sodium carboxymethyl cellulose, polyvinylpyrrolidone, and oral combinations selected from the group consisting of mixtures thereof.
7. According to claim 4,

   The disintegrant is orally selected from the group consisting of alginic acid, sodium alginate, sodium carboxymethylcellulose, microcrystalline cellulose, powdered cellulose, croscarmellose sodium, crospovidone, pregelatinized starch, sodium starch glycolate, starch and mixtures thereof. Dragon compound preparation.
8. According to claim 4,

   The lubricant is calcium stearate, glyceryl monostearate, glyceryl palmitostearate, magnesium stearate, sodium lauryl sulfate, sodium stearyl fumarate, zinc stearate, stearic acid, cured vegetable oil, polyethylene glycol, benzoic acid Oral combination preparations selected from the group consisting of sodium, talc, silicon dioxide and mixtures thereof.
9. According to claim 4,

   The coating agent is an oral combination preparation selected from the group consisting of a mixture of HPC and HPMC, or a mixture of polyvinyl alcohol (PVA) and PEG (polyethylene glycol) and mixtures thereof.
10. According to claim 1,

    Empagliflozin is contained in an amount of 10 to 25mg, sitagliptin is contained in an amount of 50 to 100mg Oral combination formulation.
11. According to claim 1,

    When the oral combination preparation is stored for 4 weeks at 25±2° C. and 60±5% relative humidity, the individual related substances of empagliflozin are 0.2% by weight or less, the total related substances are 0.6% by weight or less, and An oral composite preparation wherein the individual related substances of liptin are kept at 0.2% by weight or less and the total related substances are kept at 0.6% by weight or less.
12. According to claim 1,

    When the oral combination preparation is stored for 4 weeks under conditions of 40±2℃ and 75±5% relative humidity, the individual related substances of empagliflozin are 0.2% by weight or less, the total related substances are 0.6% by weight or less, and sitag An oral composite preparation wherein the individual related substances of liptin are kept at 0.2% by weight or less and the total related substances are kept at 0.6% by weight or less.

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