Pharmaceutical combination formulation comprising sitagliptin and empagliflozin and preparing method thereof

Abstract

The present invention discloses a pharmaceutical combination formulation comprising sitagliptin and empagliflozin and a preparation method thereof.

Description

PHARMACEUTICAL COMBINATION FORMULATION COMPRISING SITAGLIPTIN AND EMPAGLIFLOZIN AND PREPARING METHOD THEREOF

[0001] The present invention relates to a pharmaceutical combination formulation comprising sitagliptin and empagliflozin and a preparation method thereof, and more particularly, to a pharmaceutical combination formulation comprising sitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor that regulates insulin secretion, and empagliflozin, a sodium-glucose cotransporter-2 (SGLT-2) inhibitor that inhibits glucose reabsorption, as active ingredients.

[0002] Sitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor drug represented by Chemical Formula 1 below, controls blood sugar by inhibiting the decomposition of incretin, which is a gastrointestinal hormone, thereby enabling the function of incretin, which regulates insulin and glucagon, to be performed well in the body. It is known that when sitagliptin is orally administered to patients with type 2 diabetes, the HbA1c level significantly decreases, and the fasting blood sugar and postprandial blood sugar secretion decrease.

[0003] [Chemical Formula 1]

[0004]

[0005] Empagliflozin, a sodium-glucose cotransporter-2 (SGLT-2) inhibitor drug represented by Chemical Formula 2 below, reduces the reabsorption of glucose filtered in the tubular lumen and lowers the renal threshold for glucose (RTG).

[0006] [Chemical Formula 2]

[0007]

[0008] Diabetes is often treated with the administration of a combination of more than one antidiabetic drug for the purpose of controlling blood sugar levels, reducing side effects, and the like. In particular, sitagliptin and empagliflozin are effective in the treatment of diabetes, and their combination formulations have very high clinical usefulness.

[0009] However, considering the total mass of a typical tablet containing each of the active ingredients, sitagliptin and empagliflozin, when a combination formulation preparation containing each active ingredient is prepared, the total mass of the active ingredients and pharmaceutical excipients increases, and the size of the tablet increases accordingly, causing the problem of decreased patient compliance.

[0010] Therefore, it is necessary to develop a pharmaceutical combination formulation that allows to reduce the tablet size and ensure a drug pharmacokinetic (PK) profile equivalent to that of the reference sample.

[0011] [Prior Art Documents]

[0012] [Patent Documents]

[0013] (Patent Document 1) Korean Patent Application Publication No. 10-2016-0111237

[0014] (Patent Document 2) Korean Patent Application Publication No. 10-2023-0001000

[0015] An object of the present invention is to provide a pharmaceutical combination formulation comprising sitagliptin and empagliflozin, which are type 2 diabetes therapeutics, as active ingredients, and to achieve the technical task of increasing patient compliance. Specifically, when a pharmaceutical combination formulation is prepared in the form of a single-layer tablet (single tablet), the tablet weight is 600 mg or more, similar to Januvia tablet 100 mg (416.1 mg) and Jardiance tablet 25 mg (206 mg), but in the case of the pharmaceutical combination formulation according to the present invention, the content of pharmaceutical additives may be reduced to significantly reduce the tablet size, thereby increasing patient compliance.

[0016] Another object of the present invention is to provide a pharmaceutical combination formulation comprising sitagliptin and empagliflozin, which are type 2 diabetes therapeutics, as active ingredients, and to achieve the technical task of providing a single-layer tablet combination formulation that has been proven to be biologically equivalent to Januvia tablet (sitagliptin) and Jardiance tablet (empagliflozin), which are reference samples.

[0017] In order to achieve the above-described technical tasks, the present invention discloses the following means.

[0018] In one aspect, the present invention discloses a pharmaceutical combination formulation comprising sitagliptin or a pharmaceutically acceptable salt thereof, or a hydrate thereof, and empagliflozin or a pharmaceutically acceptable salt thereof, or a hydrate thereof, as active ingredients, wherein the active ingredients comprise 30% to 60% by weight based on the total weight of the entire pharmaceutical combination formulation.

[0019] In another aspect, the present invention discloses a preparation method of a pharmaceutical combination formulation, comprising: a step of preparing a binding solution by dissolving a binder in a solvent; a step of preparing a mixed portion by mixing sitagliptin or a pharmaceutically acceptable salt thereof, or a hydrate thereof, empagliflozin or a pharmaceutically acceptable salt thereof, or a hydrate thereof, an excipient, and a disintegrant; a step of preparing a wet granule by mixing the mixed portion and the binding solution and then wet screening after wetting; a step of drying the wet granule to prepare a dried granule; a step of dry screening the dried granule; and a step of uniformly mixing the sized granule, an excipient, a disintegrant, and a lubricant.

[0020] The pharmaceutical combination formulation according to the present invention can provide a pharmaceutical combination formulation that can increase patient compliance by reducing the size of the tablet.

[0021] The pharmaceutical combination formulation according to the present invention is characterized in that the deviation of drug release is reduced and can provide a single-layer combination formulation that is biologically equivalent to a reference sample.

[0022] The effects of the present invention are not limited to the above-mentioned effects, and various effects can be comprised within a range that is obvious to one of ordinary skill in the art from the descriptions below.

[0023] FIG. 1 shows the appearance, total tablet mass, major axis and minor axis, and thickness of uncoated tablets prepared according to comparative example 1, Example 1 to 2.

[0024] FIG. 2 shows the results according to Experimental Example 1.

[0025] FIG. 3 shows the results of drug release characteristics for the reference samples Januvia tablets and Jardiance tablets (combined use) and the coated tablet according to Example 4 as a test sample.

[0026] FIG. 4 shows the results of equivalent drug pharmacokinetic (PK) profiles in blood of the reference samples Januvia tablets and Jardiance tablets (combined use) and the coated tablet according to Example 4 as a test sample.

[0027] Hereinafter, the present specification will be described in more detail.

[0028] The present specification is specifically described below. The terms used herein are selected as general terms that are currently widely used as much as possible while considering the functions in the present invention, but they may vary depending on the intention or precedent of those of ordinary skill in the art, the emergence of new technology, or the like.　In addition, in certain cases, there are terms arbitrarily selected by the applicant, and in this case, the meaning will be described in the corresponding part of the detailed description of the invention.　Therefore, the terms used in the present invention should be defined based on the meaning of the terms and the overall content of the present invention, rather than simply the names of the terms.

[0029] Unless otherwise defined, all terms, comprising technical and scientific terms used herein, have the same meaning as generally understood by one of ordinary skill in the art to which the present invention pertains.　Terms, such as those defined in commonly used dictionaries, should be interpreted as having a meaning that is consistent with their meaning in the context of the relevant art and are not interpreted in an idealized or overly formal sense unless clearly so defined in the present invention.

[0030] Numerical ranges are inclusive of the values defined therein. Every maximum numerical limitation given throughout the present specification includes every lower numerical limitation, as if such lower numerical limitations were expressly written. Every minimum numerical limitation given throughout the present specification includes every higher numerical limitation, as if such higher numerical limitations were expressly written. Every numerical limitation given throughout the present specification will include every better numerical range within the broader numerical range, as if the narrower numerical limitations were expressly written.

[0031] Hereinafter, each description and embodiment disclosed in the present application may also be applied to other descriptions and embodiments for each.　In other words, all combinations of the various elements disclosed in the present application fall within the scope of the present invention.　In addition, the scope of the present invention is not limited by the specific description described below.

[0032] Expressions such as 'comprising' as used herein should be understood as open-ended terms implying the possibility of including other embodiments, unless specifically stated otherwise in the phrase or sentence in which the expression is included.

[0033] The present inventors conducted research and development to develop a pharmaceutical combination formulation containing antidiabetic drugs sitagliptin and empagliflozin, as active ingredients, and confirmed that two drugs (Januvia tablets 100 mg (416.1 mg) and Jardiance tablets 25 mg (206 mg)) may be prepared into a single-layer tablet to reduce the size of the tablet, so that patient compliance can be increased, and a single-layer tablet combination formulation that has proven to be biologically equivalent to the reference samples Januvia (sitagliptin) and Jardiance tablets (empagliflozin) can be provided to be used as an antidiabetic therapeutic, thereby completing the present invention.

[0034] Hereinafter, the present invention will be described in detail.

[0035] The term 'sitagliptin' as used herein may refer to sitagliptin or a pharmaceutically acceptable salt thereof, or a hydrate thereof. Therefore, the term 'pharmaceutical combination formulation comprising sitagliptin' may refer to a pharmaceutical combination formulation comprising sitagliptin or a pharmaceutically acceptable salt thereof, or a hydrate thereof.

[0036] The term 'empagliflozin' as used herein may refer to empagliflozin or a pharmaceutically acceptable salt thereof, or a hydrate thereof. Therefore, the term 'pharmaceutical combination formulation comprising empagliflozin' may refer to a pharmaceutical combination formulation comprising empagliflozin or a pharmaceutically acceptable salt thereof, or a hydrate thereof.

[0037] In addition, although the content (% by weight) for each component is described based on the total weight of the pharmaceutical combination formulation, the pharmaceutical combination formulation specifically refers to an uncoated tablet.

[0038] Pharmaceutical combination formulation

[0039] To achieve the above-described technical task, the present invention discloses a means described below.

[0040] In one aspect, the present invention provides a pharmaceutical combination formulation comprising sitagliptin or a pharmaceutically acceptable salt thereof, or a hydrate thereof, and empagliflozin or a pharmaceutically acceptable salt thereof, or a hydrate thereof, as active ingredients, wherein the active ingredients comprise 30% to 60% by weight based on the total weight of the entire pharmaceutical combination formulation.

[0041] In the present invention, the active ingredient, sitagliptin, is a dipeptidyl peptidase-4 (DPP-4) inhibitor, represented by Chemical Formula 1 below, and the compound name is (R)-3-Amino-1-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-4-(2,3,5-trifluorophenyl)butan-1-one.

[0042] [Chemical Formula 1]

[0043]

[0044] In the present invention, the active ingredient, empagliflozin, is a sodium-glucose cotransporter-2 (SGLT-2) inhibitor, represented by Chemical Formula 2 below, and the compound name is (2S,3R,4R,5S,6R)-2-[4-chloro-3-[[4-[(3S)-oxolan-3-yl]oxyphenyl]methyl]phenyl]-6-(hydroxymethyl)oxane-3,4,5-triol.

[0045] [Chemical Formula 2]

[0046]

[0047] In the present invention, the term 'pharmaceutically acceptable salt' includes a salt derived from a pharmaceutically acceptable inorganic acid, organic acid, or base. The term 'hydrate' refers to 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.

[0048] In the present invention, the pharmaceutically acceptable salt of sitagliptin, or a hydrate thereof, may be sitagliptin phosphate or sitagliptin phosphate hydrate.

[0049] In the present invention, the pharmaceutically acceptable salt of empagliflozin may be empagliflozin L-proline.

[0050] In the present invention, the pharmaceutical combination formulation may be a tablet formulation, and specifically, the tablet may be a single-layer tablet as a single-dosage form.

[0051] In the present invention, the tablet may be 290 to 450 mg based on an uncoated tablet, and specifically, the tablet may be 290 to 450 mg or 290 to 350 mg based on an uncoated tablet, but is not limited thereto.

[0052] Specifically, when the reference samples Januvia tablet 100 mg (416.1 mg) and Jardiance tablet 25 mg (206 mg) are implemented into a single tablet form, the tablet weight is 600 mg or more, whereas in the case of the pharmaceutical combination formulation according to the present invention, even when the two active ingredients are implemented into a single-layer form, the content of the pharmaceutical additive may be reduced to 290 to 450 mg based on an uncoated tablet, thereby significantly reducing the size of the tablet and increasing patient compliance.

[0053] In the present invention, the single-layer tablet may be a film-coated tablet coated with a film coating agent. At this time, any film coating agent may be applied without limitation as long as it may be used in the pharmaceutical field when preparing a coated tablet, and specifically, the film coating agent may be Opadry, but is not limited thereto.

[0054] In the present invention, the single-layer tablet may be prepared by a wet granulation method, and specifically, may comprise 35% to 56% by weight of the active ingredients, but is not limited thereto. Specifically, the fact that the content of the active ingredients comprised in the single-layer tablet is 35% to 56% by weight means that the content is calculated based on the total weight of the uncoated tablet. At this time, the pharmaceutical combination formulation may be a coated tablet, and when the calculation is based on the coated tablet, the content of the active ingredients may be 34% to 53% by weight based on the total weight of the entire coated tablet, but is not limited thereto.

[0055] In the present invention, the pharmaceutical combination formulation may comprise one or more pharmaceutical additives selected from the group consisting of an excipient, a disintegrant, a binder, and a lubricant, but is not limited thereto.

[0056] In the present invention, the excipient may comprise 25% to 55% by weight based on the total weight of the pharmaceutical combination formulation, specifically, 30% to 51% by weight, but is not limited thereto.

[0057] In the present invention, the excipient may be mannitol, microcrystalline cellulose, or a mixture thereof, but is not limited thereto.

[0058] In the present invention, the disintegrant may be comprised in an amount of 1% to 15% by weight based on the total weight of the pharmaceutical combination formulation, specifically, 5% to 10% by weight, but is not limited thereto.

[0059] In the present invention, the disintegrant may be croscarmellose sodium, but is not limited thereto.

[0060] In the present invention, the binder may be comprised in an amount of less than 10% by weight based on the total weight of the pharmaceutical combination formulation, specifically, 0% to 9.9% by weight, and more specifically, 0% to 7% by weight, but is not limited thereto.

[0061] Specifically, when the binder is comprised in an amount of 10% by weight or more based on the total weight of the pharmaceutical combination formulation, there is a problem that an dissolution deviation occurs, so it is preferable to use the binder by adjusting the content within the above-described range.

[0062] Here, the content of 0% by weight may mean that the binder is not comprised, and when it is not comprised, the lower limit of the content of each component may be expressed as 0% by weight. In other words, in the present invention, the content of 0% by weight means that the component may be used selectively as needed.

[0063] In addition, not only formally not comprising a binder at all in the pharmaceutical combination formulation, but also comprising the binder to an extent that the technical task of the present invention is equally implemented for the purpose of substantially avoiding the present invention may be regarded as not comprising the binder.

[0064] In the present invention, the binder may be hydroxypropyl cellulose, but is not limited thereto.

[0065] In the present invention, the lubricant may be comprised in an amount of 0.5% to 7% by weight based on the total weight of the pharmaceutical combination formulation, specifically 2% to 5% by weight, but is not limited thereto.

[0066] In the present invention, the lubricant may be colloidal silicon dioxide, sodium stearyl fumarate, magnesium stearate, or a mixture thereof, but is not limited thereto.

[0067] In the present invention, when the lubricant is a mixture of colloidal silicon dioxide and sodium stearyl fumarate, the colloidal silicon dioxide and sodium stearyl fumarate may be comprised in a weight ratio of 1:1 to 1.5 (w / w), and specifically, the colloidal silicon dioxide and sodium stearyl fumarate may be comprised in a weight ratio of 1:1 (w / w), but are not limited thereto.

[0068] Specifically, when the weight ratio (w / w) of colloidal silicon dioxide and sodium stearyl fumarate is 1:4 (w / w), there is a problem of capping (a phenomenon in which the upper part of a tablet is peeled off in the shape of a hat) and sticking (a phenomenon in which powder adheres to a punch surface, causing a flaw on a tablet surface) during tableting, and when the weight ratio (w / w) is 1:2 (w / w), there is a problem of capping.

[0069] Therefore, when the weight ratio (w / w) of colloidal silicon dioxide and sodium stearyl fumarate is adjusted to 1:1 to 1.5 (w / w), there is an advantage in that the mass of the uncoated tablets may be reduced without causing tableting problems during tableting, thereby increasing patient compliance.

[0070] In the present invention, the pharmaceutical combination formulation may contain 50 to 100 mg of sitagliptin or a pharmaceutically acceptable salt thereof, or a hydrate thereof as sitagliptin per unit dosage form, for example, 50 mg, 75 mg, 85 mg, or 100 mg of sitagliptin.

[0071] In the present invention, the pharmaceutical combination formulation may contain 10 to 25 mg of empagliflozin or a pharmaceutically acceptable salt thereof, or a hydrate thereof as empagliflozin per unit dosage form, for example, 10 mg, 15 mg, 20 mg, or 25 mg of empagliflozin per unit dosage form.

[0072] In the present invention, the pharmaceutical combination formulation may be a pharmaceutical combination formulation for treating or preventing diabetes, but is not limited thereto.

[0073] Preparation method of pharmaceutical combination formulation

[0074] In order to achieve the above-described technical task, the present invention discloses the means below.

[0075] In one aspect, the present invention provides a preparation method of a pharmaceutical combination formulation, comprising: a step of preparing a binding solution by dissolving a binder in a solvent; a step of preparing a mixed portion by mixing sitagliptin or a pharmaceutically acceptable salt thereof, or a hydrate thereof, empagliflozin or a pharmaceutically acceptable salt thereof, or a hydrate thereof, an excipient, and a disintegrant; a step of preparing a wet granule by mixing the mixed portion and the binding solution and then wet screening after wetting; a step of drying the wet granule to prepare a dried granule; a step of dry screening the dried granule; and a step of uniformly mixing the sized granule, an excipient, a disintegrant, and a lubricant.

[0076] In the present invention, after the step of uniformly mixing the sized granule, an excipient, a disintegrant, and a lubricant, a tableting and coating process may be further comprised, but is not limited thereto.

[0077] Specifically, the tableting process refers to a process of tableting a granulated product using a tableting machine widely known in the art.

[0078] Specifically, the coating process refers to a process of applying a coating solution prepared by dispersing a coating agent widely known in the art (e.g., Opadry coating agent) in a coating solvent, onto a tableted uncoated tablet. At this time, a coating method widely known in the art may be used, but is not limited thereto.

[0079] The above-described contents regarding the pharmaceutical combination formulation may all be applied to the preparation method of pharmaceutical combination formulation, unless they are contradictory.

[0080] Hereinafter, the present invention will be described in detail based on examples and experimental examples. However, the following examples and experimental examples are only for illustrating the present invention, and the scope of the present invention is not limited thereto.

[0081] Examples and Comparative Examples

[0082] Examples 1 and 2 and Comparative Example 1

[0083] Example 1

[0084] (1) Preparation of granules

[0085] After weighing each component according to Table 1 below, a binding solution was prepared with hydroxypropyl cellulose as a binder. The active ingredients, which were sitagliptin phosphate hydrate, empagliflozin L-proline, the excipients, which were mannitol and microcrystalline cellulose, croscarmellose sodium as a disintegrant, and the binding solution were placed in an automatic high-speed mixer, and mixing and wetting were performed for three minutes each. The wet granule was granulated with Comil, dried, and then sized. The sized granule, croscarmellose sodium as a disintegrant, colloidal silicon dioxide as a lubricant, and D-mannitol as an excipient were placed in a Bin mixer and mixed at 10 rpm for nine minutes. Then, the lubricants, sodium stearyl fumarate, and magnesium stearate, were sieved and placed in the Bin Mixer and mixed at 10 rpm for three minutes to prepare granules.

[0086] (2) Preparation of uncoated tablets

[0087] The granules obtained by the above-described process (1) were tableted to prepare uncoated tablets.

[0088] (3) Preparation of coated tablets

[0089] The uncoated tablets obtained by the above-described process (2) were coated with Opadry to prepare coated tablets.

[0090] Example 2

[0091] A coated tablet according to Example 2 was prepared in the same manner as Example 1 using each component and content according to Table 1 below.

[0092] Comparative Example 1

[0093] A coated tablet according to Comparative Example 1 was prepared in the same manner as Example 1 using each component and content according to Table 1 below.

[0094] ComponentComparative Example 1(Active ingredients: 27%)Example 1(Active ingredients: 36%)Example 2(Active ingredients: 46%)mg / T% by weightmg / T% by weightmg / T% by weightSitagliptin phosphate hydrate128.5021.4128.5028.5128.5036.7(as sitagliptin)100.00-100.00-100.00-Empagliflozin L-proline31.385.231.387.031.389.0(as empagliflozin)25.00-25.00-25.00-Mannitol318.9253.2199.2244.3119.3734.1microcrystalline cellulose34.205.725.505.720.005.7Croscarmellose sodium48.008.036.008.028.008.0Hydroxypropyl cellulose18.003.013.503.010.503.0Colloidal silicon dioxide3.000.52.400.51.750.5Sodium stearyl fumarate12.002.09.002.07.002.0Magnesium stearate6.001.04.501.03.501.0Total (uncoated tablet)600.00100.0450.00100.0350.00100.0Opadry AMB II (pink)18.0014.0011.00Coating solvent (purified water)90.00-70.00-55.00-Total (coated tablet)618.00100.0464.00100.0361.00100.0

[0095] Experimental Example 1. Confirmation of the tableting properties of Examples 1 and 2 and Comparative Example 1

[0096] While preparing tablets according to Examples 1 to 2 and Comparative Example 1, the occurrence of tableting problems (capping and sticking) was confirmed, and the results are shown in Table 2 and FIG. 2.

[0097] Referring to Table 2 and FIG. 2, in the case of the tablets according to Examples 1 and 2, the tablet size could be reduced compared to Comparative Example 1 by reducing the content of pharmaceutical additives, but it was confirmed that tableting problems (capping and sticking) occurred due to problems in the preparing process.

[0098] ComponentComparative Example 1(Active ingredients: about 27%)Example 1(Active ingredients: 36%)Example 2(Active ingredients: about 46%)Preparing process(Tableting)Occurrence of cappingOOOOccurrence of stickingOOO

[0099] Accordingly, in order to present a prescription that can increase patient compliance by reducing the size of the tablet compared to Comparative Example 1 while not causing tableting problems during preparing of the tablet, the following example prescriptions and experiments were further conducted.

[0100] Examples 3 to 6. Prescription for improving preparing process

[0101] Specifically, in the Examples 3 to 6 described below, tableting problems occurred due to the reduction of the tablet size (reduction of additives, Example 2), and the proportion of the lubricant was adjusted to overcome the problems. The specific details are as shown in Table 3 below.

[0102] Example 3

[0103] A coated tablet according to Example 3 was prepared in the same manner as Example 1 using each component and content according to Table 3 below.

[0104] Example 4

[0105] A coated tablet according to Example 4 was prepared in the same manner as Example 1 using each component and content according to Table 3 below.

[0106] Example 5

[0107] A coated tablet according to Example 5 was prepared in the same manner as Example 1 using each component and content according to Table 3 below.

[0108] Example 6

[0109] A coated tablet according to Example 6 was prepared in the same manner as Example 1 using each component and content according to Table 3 below.

[0110] ComponentExample 3(Active ingredients: 46%)Example 4(Active ingredients: 46%)Example 5(Active ingredients: 36%)Example 6(Active ingredients: 56%)mg / T%mg / T%mg / T%mg / T%Sitagliptin phosphate hydrate128.5036.7128.5036.7128.5028.5128.5044.3(as sitagliptin)100.00-100.00-100.00-100.00-Empagliflozin L-proline31.389.031.389.031.387.031.3810.8(as empagliflozin)25.00-25.00-25.00-25.00-Mannitol117.6233.6121.1234.6201.6244.873.0225.2Microcrystalline cellulose20.005.720.005.725.505.716.505.7Croscarmellose sodium28.008.028.008.036.008.023.208.0Hydroxypropyl cellulose10.503.010.503.013.503.08.703.0Colloidal silicon dioxide3.501.03.501.04.501.02.901.0Sodium stearyl fumarate7.002.03.501.04.501.02.901.0Magnesium stearate3.501.03.501.04.501.02.901.0Total (uncoated tablet)350.00100.0350.00100.0450.00100.0290.00100.0Opadry AMB II (pink)11.0011.0014.009.00Coating solvent (purified water)55.00-55.00-70.00-45.00-Total (coated tablet)361.00100.0361.00100.0464.00100.0299.00100.0

[0111] Experimental Example 2. Confirmation of tableting properties and dissolution properties in preparing coated tablets according to Comparative Example 1 and Examples 2 to 6

[0112] 1. Confirmation of tableting properties

[0113] While preparing tablets according to Examples 3 to 6, the occurrence of tableting problems (capping and sticking) was confirmed, and the results are shown in Table 4.

[0114] Referring to Table 4, it was confirmed that in the prescription of Example 2, where the weight ratio (w / w) of colloidal silicon dioxide and sodium stearyl fumarate was adopted as 1:4 (w / w), capping and sticking occurred. Accordingly, it was confirmed that in the prescription of Example 3, where the weight ratio (w / w) of colloidal silicon dioxide and sodium stearyl fumarate was adopted as 1:2 (w / w), sticking was improved during tableting, but capping occurred. Accordingly, the weight ratio (w / w) of colloidal silicon dioxide and sodium stearyl fumarate was finally set to 1:1 (w / w), and it was confirmed that no tableting problems occurred during tableting in Examples 4 to 6, which were prescription where the weight ratio (w / w) of colloidal silicon dioxide and sodium stearyl fumarate was 1:1 (w / w). It was confirmed that the mass of the uncoated tablet could be reduced down to 290 mg by adjusting the weight ratio (w / w) of colloidal silicon dioxide and sodium stearyl fumarate to 1:1 (w / w).

[0115] ComponentComparative Example 1(Active ingredients: 27%)Example 2(Active ingredients: 46%)Example 3(Active ingredients: 46%)Example 4(Active ingredients: 46%)Example 5(Active ingredients: 36%)Example 6(Active ingredients: 56%)Preparing process(Tableting)Occurrence of cappingOOOXXXOccurrence of stickingOOXXXX

[0116] 2. Confirmation of dissolution properties

[0117] A. Analytical method

[0118] In the case of the prescriptions of Examples 4 to 6, where the weight ratio (w / w) of colloidal silicon dioxide and sodium stearyl fumarate was adjusted to 1:1 (w / w), to determine whether there is a difference in the tablet size and whether there is a difference in the release pattern depending on the tablet size, the dissolution properties of the tablets according to the prescriptions of Comparative Example 1 and Examples 4 to 6 were confirmed, and the results are shown in Table 5.

[0119] The method for analysing the dissolution properties is described below.

[0120] <High-performance liquid chromatography (HPLC) analysis conditions>

[0121] ㆍ Column: C18, 250 X 4.6 mm, 5 μm

[0122] ㆍ Mobile phase: 50 mM ammonium acetate solution:MeOH = 40:60

[0123] ㆍ Flow rate: 1.0 mL / min

[0124] ㆍ Injection amount: 10 μL

[0125] ㆍ Temperature: 40 °C

[0126] ㆍ Wavelength: 210 nm (sitagliptin); and 220 nm (empagliflozin)

[0127] B. Analytical results

[0128] Referring to Table 5, it was confirmed that there was no difference in the release pattern according to the tablet size of the tablets according to Examples 4 to 6. In addition, it was confirmed that the tablets according to Examples 4 to 6 exhibited the same dissolution properties as the tablets according to Comparative Example 1.

[0129] Active ingredientSampleTablet mass(Active ingredient content)pH1.2Test methodPaddle method, 50 rpm5 minutes10 minutes15 minutes30 minutes45 minutes1 hour200rpmEmpaComparative Example 1618 MG(about 26%)45.1±4.886.3±5.292.9±2.296.5±0.897.1±1.097.7±1.398.7±0.9Example 4361 MG(about 46%)53.0±6.084.9±0.489.0±0.393.1±0.494.6±0.397.1±0.496.8±0.4Example 5464 MG(about 36%)46.0±10.487.5±2.494.4±1.397.8±0.798.7±0.798.6±0.698.4±0.4Example 6299 MG(about 56%)42.6±8.585.2±2.392.8±1.598.0±1.398.5±1.599.2±1.798.9±1.3SitaComparative Example 1618 MG(about 26%)47.2±6.496.6±7.1100.5±2.9101.4±0.4100.9±0.2100.5±0.4100.1±0.6Example 4361 MG(about 46%)74.1±8.199.8±0.399.2±0.398.6±0.298.1±0.297.5±0.296.9±0.3Example 5464 MG(about 36%)59.1±14.599.0±2.9100.2±1.5100.2±1.099.5±0.899.2±0.998.7±0.8Example 6299 MG(about 56%)57.3±11.698.7±2.1100.9±2.0100.8±1.699.7±1.7100.0±1.799.4±1.5

[0130] (In Table 5, 'Empa' refers to empagliflozin, and 'Sita' refers to sitagliptin. The tablet mass is for coated tablets, and the active ingredient content refers the content of the active ingredients based on the total weight of the uncoated tablet (unit: % by weight).)

[0131] Examples 7 to 11. Prescriptions with controlled binder content

[0132] Specifically, in Examples 7 to 11, the binder content ratio was controlled based on the prescription of Example 4, which was confirmed to be an excellent prescription through Experimental Example 2. The specific details are as shown in Table 6 below.

[0133] Example 7

[0134] A coated tablet according to Example 7 was prepared in the same manner as Example 1, except that the binder hydroxypropyl cellulose was not used, using the components and contents according to Table 6 below.

[0135] Example 8

[0136] A coated tablet according to Example 8 was prepared in the same manner as Example 1, using the components and contents according to Table 6 below.

[0137] Example 9

[0138] A coated tablet according to Example 9 was prepared in the same manner as Example 1, using the components and contents according to Table 6 below.

[0139] Example 10

[0140] A coated tablet according to Example 10 was prepared in the same manner as Example 1, using the components and contents according to Table 6 below.

[0141] Example 11

[0142] A coated tablet according to Example 11 was prepared in the same manner as Example 1, using the components and contents according to Table 6 below.

[0143] ComponentExample 7(Binder 0%)Example 8(Binder 1%)Example 4(Binder 3%)Example 9(Binder 5%)Example 10(Binder 7%)Example 11(Binder 10%)mg / Tmg / Tmg / Tmg / Tmg / Tmg / TSitagliptin phosphate hydrate128.50128.50128.50128.50128.50128.50(as sitagliptin)100.00100.00100.00100.00100.00100.00Empagliflozin L-proline31.3831.3831.3831.3831.3831.38(as empagliflozin)25.0025.0025.0025.0025.0025.00Mannitol131.62128.12121.12114.12107.1296.62Microcrystalline cellulose20.0020.0020.0020.0020.0020.00croscarmellose sodium28.0028.0028.0028.0028.0028.00Hydroxypropyl cellulose0.003.5010.5017.5024.5035.00Colloidal silicon dioxide3.503.503.503.503.503.50Sodium stearyl fumarate3.503.503.503.503.503.50Magnesium stearate3.503.503.503.503.503.50Total (uncoated tablet)350.00350.00350.00350.00350.00350.00Opadry AMB II (pink)11.0011.0011.0011.0011.0011.00Coating solvent (purified water)55.0055.0055.0055.0055.0055.00Total (coated tablet)361.00361.00361.00361.00361.00361.00

[0144] (In Table 6, the percentage (%) of binder refers to the content of binder in percentage by weight based on the total weight of the uncoated tablet.)

[0145] Experimental Example 3. Confirmation of dissolution properties for prescriptions of Examples 4 and 7 to 11

[0146] 1. Analytical method

[0147] The analytical method was the same as that described in Experimental Example 2, and the results are shown in Table 7.

[0148] 2. Analytical results

[0149] Referring to Table 7, it was confirmed that there was no significant difference in the drug release pattern when the binder was used in an amount of 0% to 10% by weight based on the total weight of the uncoated tablet. However, it was confirmed that in the case of the prescription (Example 11) containing 10% by weight or more, an dissolution deviation occurred for up to 15 minutes.

[0150] Active ingredientSample(Binder)pH1.2Test methodPaddle method, 50 rpm5 minutes10 minutes15 minutes30 minutes45 minutes1 hour200 rpmEmpaExample 7(0%)71.2±4.090.7±0.391.9±1.996.4±0.497.7±0.597.5±0.897.9±0.6Example 8(1%)68.3±3.991.9±1.192.9±1.093.9±0.995.4±0.498.6±0.698.5±0.5Example 4(3%)53.0±6.084.9±0.489.0±0.393.1±0.494.6±0.397.1±0.496.8±0.4Example 9(5%)56.6±3.582.2±1.385.7±0.689.6±0.793.6±0.796.4±0.697.6±0.7Example 10(7%)37.0±7.072.4±5.886.5±4.287.4±1.692.4±1.597.4±0.498.5±0.6Example 11(10%)19.9±5.157.4±10.382.5±8.290.0±4.593.6±2.597.2±0.597.4±0.9SitaExample 7(0%)81.8±5.395.7±4.597.5±0.596.7±0.596.3±0.495.6±0.495.1±0.4Example 8(1%)78.7±4.499.9±0.699.5±0.398.6±0.498.0±0.497.6±0.797.0±0.6Example 4(3%)74.1±8.199.8±0.399.2±0.398.6±0.298.1±0.297.5±0.296.9±0.3Example 9(5%)84.4±4.298.7±0.898.0±1.098.1±0.397.4±0.397.0±0.396.4±0.3Example 10(7%)58.8±9.299.3±1.199.0±1.298.5±1.097.7±1.097.2±1.196.7±1.0Example 11(10%)23.0±5.163.3±10.692.4±8.1100.5±2.4100.4±1.7100.7±0.8100.2±0.8

[0151] (In Table 7, 'Empa' refers to empagliflozin, and 'Sita' refers to sitagliptin.)

[0152] Experimental Example 4. Confirmation of drug release properties

[0153] 1. Analytical method

[0154] In order to determine thein vitro-in vivocorrelation and drug absorption correlation, the reference samples, which were Januvia tablet and Jardiance tablet (combined use), and the test sample, which was the coated tablets according to Example 4, were evaluated for dissolution using the Dissolution test (USP Apparatus 3), and the results are shown in FIG. 3.

[0155] The dissolution test conditions and the analytical method for the dissolution test are described below.

[0156] <Conditions of the Dissolution test (USP Apparatus 3) Method>

[0157] 1) Test solution: pH 1.2

[0158] 2) Flow rate: 4.0 mL / min

[0159] 3) Cell diameter: 22.6 mm

[0160] <HPLC analysis conditions>

[0161] 1) Detector: Ultraviolet spectrophotometer (Measurement wavelength: sitagliptin 210 nm; and empagliflozin 220 nm)

[0162] 2) Column: C18 (4.6 X 250 mm, 5 μm) or equivalent column

[0163] 3) Injection amount: 10 μL

[0164] 4) Flow rate: 1.0 mL / min

[0165] 5) Column temperature: Constant temperature around 40 °C

[0166] 6) Mobile phase: Mixture of 50 mM ammonium acetate aqueous solution and methanol (40:60)

[0167] 2. Analytical results

[0168] Referring to FIG. 3, it was confirmed that the coated tablet according to Example 4, which was the test sample, exhibited a release pattern similar to the reference samples, Januvia tablet and Jardiance tablet (combined use), according to the Dissolution test (USP Apparatus 3) Method.

[0169] Experimental Example 5. Bioequivalence test

[0170] 1. Analytical method

[0171] To evaluate whether the reference samples, which are Januvia tablet and Jardiance tablet (combined use), and the test sample, which is the coated tablet according to Example 4, exhibit equivalent drug PK profiles in blood, a clinical test was conducted on healthy adults.

[0172] The clinical test conditions are described below.

[0173] <Clinical test conditions>

[0174] Test type: Phase 1 clinical test

[0175] Test design: Open, randomized, 2X2 crossover test

[0176] Active ingredients and doses: Sitagliptin 100.00 mg (128.50 mg as sitagliptin phosphate hydrate) and empagliflozin 25.00 mg (31.38 mg as empagliflozin L-proline)

[0177] Test subjects: 32 healthy adult subjects

[0178] 2. Analytical results

[0179] Referring to FIG. 4 and Table 8, when the results of measuring sitagliptin and empagliflozin in the blood were log-transformed into comparative evaluation items (AUClastand Cmax) and statistically processed, the 90% confidence interval (CI) for Cmaxwas log0.8973 to log1.0665 (sitagliptin) and log1.0077 to log1.1872 (empagliflozin), and the intrasubject coefficient of variation (CV) was 19.62% (sitagliptin) and 18.62% (empagliflozin).

[0180] For AUClast, the 90% CI was log1.0016 to log1.0486 (sitagliptin) and log1.0397 to log1.1023 (empagliflozin), and the intrasubject CV was 5.22% (sitagliptin) and 6.64% (empagliflozin).

[0181] Since the 90% CI of the difference in the average of AUClastand Cmaxfor both active ingredients was within log0.8 to log1.25, it was proven that the reference samples, Januvia tablet and Jardiance tablet (combined use), and the test sample, the coated tablet according to Example 4, were biologically equivalent.

[0182] Active ingredientParameter90% confidence intervalIntra-subject CV (%)SitagliptinCmax0.8973-1.066519.62AUClast1.0016-1.04865.22EmpagliflozinCmax1.0077-1.187218.62AUClast1.0397-1.10236.64

[0183] While the specific parts of the present invention have been described in detail above, it is obvious to those skilled in the art that these specific descriptions are merely preferred embodiments and that the scope of the present invention is not limited thereto. Accordingly, the actual scope of the present invention will be defined by the appended claims and their equivalents.

Claims

1.A pharmaceutical combination formulation comprising:sitagliptin or a pharmaceutically acceptable salt thereof, or a hydrate thereof; andempagliflozin or a pharmaceutically acceptable salt thereof, or a hydrate thereof, as active ingredients,wherein the active ingredients comprise 30% to 60% by weight based on the total weight of the entire pharmaceutical combination formulation.2.The pharmaceutical combination formulation according to claim 1, wherein the pharmaceutical combination formulation is a single-layer tablet.3.The pharmaceutical combination formulation according to claim 2, wherein the single-layer tablet is prepared by a wet granulation method.4.The pharmaceutical combination formulation according to claim 1, further comprising one or more pharmaceutical additives selected from the group consisting of an excipient, a disintegrant, a binder, and a lubricant.5.The pharmaceutical combination formulation according to claim 4, wherein the lubricant is any one of colloidal silicon dioxide, sodium stearyl fumarate, magnesium stearate, or a mixture thereof.6.The pharmaceutical combination formulation according to claim 5, wherein, when the lubricant is a mixture of colloidal silicon dioxide and sodium stearyl fumarate, the colloidal silicon dioxide and sodium stearyl fumarate are comprised in a weight ratio of 1:1 to 1.5 (w / w).7.The pharmaceutical combination formulation according to claim 4, wherein the binder is comprised in an amount of less than 10% by weight based on the total weight of the entire pharmaceutical combination formulation.8.The pharmaceutical combination formulation according to claim 1, wherein the pharmaceutical combination formulation is a tablet.9.The pharmaceutical combination formulation according to claim 8, wherein the tablet is 290 to 450 mg based on an uncoated　tablet.10.A preparation method of a pharmaceutical combination formulation, comprising:a step of preparing a binding solution by dissolving a binder in a solvent;a step of preparing a mixed portion by mixing sitagliptin or a pharmaceutically acceptable salt thereof, or a hydrate thereof, empagliflozin or a pharmaceutically acceptable salt thereof, or a hydrate thereof, an excipient, and a disintegrant;a step of preparing a wet granule by mixing the mixed portion and the binding solution and then wet screening after wetting;a step of drying the wet granule to prepare a dried granule;a step of dry screening the dried granule; anda step of uniformly mixing the sized granule, an excipient, a disintegrant, and a lubricant.

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