Pharmaceutical composition comprising enagliflozin and metformin

Abstract

The present invention relates to a pharmaceutical composition comprising enagliflozin and metformin. The pharmaceutical composition according to the present invention makes it possible to realize an excellent formulation that provides the same level of pharmaceutical efficacy as a combination therapy of a metformin single tablet and an enagliflozin single tablet, although the content difference between metformin and enagliflozin is large.

Description

Technical Field

[0001] The present invention relates to a pharmaceutical composition comprising empagliflozin and metformin. Background Art

[0002] Metformin is a biguanide oral hypoglycemic agent and is widely used as a first-line treatment for diabetes. Metformin has an effect of improving blood glucose and exerts one of the known mechanisms of action by activating AMP-activated protein kinase (AMPK) in the liver, thereby inhibiting gluconeogenesis, enhancing glucose uptake in cells, and suppressing metabolic syndrome.

[0003] Metformin has an excellent effect of reducing glycated hemoglobin, has fewer side effects (such as weight gain or hypoglycemia), and significantly reduces diabetes-related death and total mortality. However, metformin may cause gastrointestinal side effects (such as diarrhea, abdominal discomfort, nausea, and vomiting), and caution is required when administering the drug to patients with severe renal impairment or severe liver impairment.

[0004] Since the situation where blood glucose cannot be controlled by metformin alone often occurs, sulfonylurea drugs are usually used as a second-line treatment for diabetes. However, insulin secretagogues such as sulfonylureas cause a decrease in pancreatic β cells, ultimately leading to a decrease in insulin secretion.

[0005] In addition, oral antidiabetic drugs such as α-glucosidase inhibitors, DPP-4 inhibitors, and SGLT-2 inhibitors are also used in combination therapies with metformin.

[0006] Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a new type of antihyperglycemic agent. SGLT-2 inhibitors increase glucose excretion through a non-insulin-dependent mechanism by reducing glucose reabsorption in the proximal renal tubule. The safety and efficacy of SGLT2 inhibitors in the treatment of type 2 diabetes have been confirmed in a large number of studies.

[0007] Drugs that have currently been approved as SGLT-2 inhibitors include dapagliflozin, empagliflozin, ipragliflozin, ertugliflozin, and enavogliflozin.

[0008] It is reported that the drug empagliflozin (chemical name: (2S,3R,4R,5S,6R)-2-(7-chloro-6-(4-cyclopropylbenzyl)-2,3-dihydrobenzofuran-4-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol) disclosed in US Patent Application Publication No. 2015 / 0152075 exhibits excellent hypoglycemic effects at a dose of only 0.3 mg, which is less than one-thirtieth of the dose of conventional SGLT2 inhibitors.

[0009] The maximum daily dosage of metformin is 2,000 mg, and tablets with single-dose strengths of 500 mg, 750 mg, and 1,000 mg have been developed.

[0010] As a preparation for the combination therapy of metformin and SGLT2 inhibitors, a combined composition of metformin and dapagliflozin, and a combined composition of metformin and empagliflozin have been developed. Based on 1,000 mg of metformin, the content of dapagliflozin is approximately 10 mg, and the content of empagliflozin is approximately 12.5 mg.

[0011] However, the single dose of empagliflozin is 0.3 mg, which is only less than about one-thirtieth of the dose of conventional SGLT2 inhibitors, and different from the combined preparations containing metformin and conventional SGLT2 inhibitors, it is difficult to implement empagliflozin in combined preparations.

[0012] The content of each tablet of metformin is 500 to 1,000 mg, but the content of each tablet of empagliflozin is 0.3 mg. The difference in the content of the active ingredients is so large that it is difficult to uniformly mix them when formulating them into a single matrix tablet using conventional preparation methods. In addition, metformin is a highly water-soluble drug, and if formulated into ordinary tablets, it may cause excessive reduction of blood sugar and gastrointestinal disorders due to rapid drug release. Therefore, it is necessary to develop a sustained-release dosage form that allows gradual dissolution. In this case, due to the high-viscosity swelling sustained-release agent used for the sustained release of metformin, the main problem is that the release of empagliflozin that should be immediately released may be delayed, so it is difficult to expect metformin and empagliflozin to be formulated into a single matrix tablet.

[0013] Although it is possible to consider making AstraZeneca’Xigduo (which is a combined preparation containing dapagliflozin and metformin) into a bilayer tablet, compared with the highest dose of Xigduo (10 mg of dapagliflozin and 1,000 mg of metformin), the dose difference between 0.3 mg of empagliflozin and 1,000 mg of metformin is too large, and it is difficult to make these drugs into a bilayer tablet.

[0014] The total weight of the pharmaceutical composition of single - tablet empagliflozin disclosed in Korean Patent Application No. 10 - 2021 - 0130239 (Patent Document 1) is 75 mg. However, when the empagliflozin part of the composite composition consists of the composition of a single tablet, the total amount of the empagliflozin part is less than about 1 / 13 of the total amount of the metformin part including 1,000 mg of metformin. Therefore, it is difficult to satisfy the ratio condition between the first and second drugs required in a double - layer tablet press, and thus it is even impossible to attempt to prepare a double - layer tablet of a combined preparation containing metformin based on the composition of a single tablet of empagliflozin. Summary of the Invention

[0015] [Technical Problem]

[0016] The present invention relates to a composite composition for the combined therapy of metformin and empagliflozin.

[0017] In order to provide a composite composition of metformin and empagliflozin that can solve the above - mentioned problems, a new preparation composition taking into account the content difference between the two drugs is required. At the same time, the composite composition can achieve the same therapeutic efficacy as the combined therapy of a single - tablet of metformin and a single - tablet of empagliflozin used as a control drug.

[0018] [Technical Solution]

[0019] As a result of various studies on formulating a composite composition of metformin and empagliflozin, the present inventors have confirmed that the above - mentioned problems can be solved when the composition of the pharmaceutical composition is as follows.

[0020] Specifically, the present invention provides

[0021] A pharmaceutical composition in a single dosage form, which comprises a compartment containing empagliflozin or a pharmaceutically acceptable salt thereof and a compartment containing metformin or a pharmaceutically acceptable salt thereof, and the compartments are formulated in a separated form from each other,

[0022] wherein, relative to 100 parts by weight of the total pharmaceutical composition, the empagliflozin compartment comprises 10 to 20 parts by weight, and

[0023] in the empagliflozin compartment, relative to a total of 100 parts by weight of the empagliflozin compartment, it comprises less than 0.3 parts by weight of empagliflozin or a pharmaceutically acceptable salt thereof.

[0024] As described above, since the content of empagliflozin in the formulation is very low, it is difficult to implement in a single matrix dosage form when formulating a combined composition containing metformin. Therefore, it is preferred to formulate a single-type pharmaceutical composition by separating a compartment containing empagliflozin or a pharmaceutically acceptable salt thereof (hereinafter also referred to as "empagliflozin compartment" or "empagliflozin part") and a compartment containing metformin or a pharmaceutically acceptable salt thereof (hereinafter also referred to as "metformin compartment" or "metformin part").

[0025] Empagliflozin used as an active ingredient in the present invention can be synthesized with reference to known relevant literature. In the present invention, empagliflozin can be crystalline or amorphous. For example, according to Korean Unexamined Patent Application Publication No. 2017-0142904 or Korean Patent Application No. 2022-0123673, empagliflozin can be crystalline form A, crystalline form B, crystalline form C, crystalline form D or crystalline form E of empagliflozin, or amorphous empagliflozin, which are reported to have the following X-ray diffraction spectra.

[0026] Crystalline form A: A crystalline form having an X-ray diffraction (XRD) spectrum with peaks at 2[θ] values selected from 6.2° ± 0.2°, 7.2° ± 0.2°, 8.8° ± 0.2°, 17.6° ± 0.2°, 19.0° ± 0.2°, 22.5° ± 0.2° and 25.1° ± 0.2°

[0027] Crystalline form B: A crystalline form having an X-ray diffraction (XRD) spectrum with peaks at 2[θ] values selected from 7.0° ± 0.2°, 14.9° ± 0.2°, 17.7° ± 0.2°, 18.8° ± 0.2°, 20.6° ± 0.2°, 21.8° ± 0.2° and 23.5° ± 0.2°

[0028] Crystalline form C: A crystalline form having an X-ray diffraction (XRD) spectrum with peaks at 2[θ] values selected from 5.6° ± 0.2°, 7.3° ± 0.2°, 15.7° ± 0.2°, 17.2° ± 0.2°, 18.9° ± 0.2°, 21.2° ± 0.2° and 21.9° ± 0.2°

[0029] Crystalline form D: A crystalline form having an X-ray diffraction (XRD) spectrum with peaks at 2[θ] values selected from 5.5° ± 0.2°, 7.2° ± 0.2°, 15.3° ± 0.2°, 17.2° ± 0.2°, 17.6° ± 0.2°, 18.9° ± 0.2° and 21.1° ± 0.2°

[0030] Polymorph E: A polymorph having an X-ray diffraction (XRD) spectrum with peaks at 2[θ] values selected from 4.93° ± 0.2°, 6.12° ± 0.2°, 7.43° ± 0.2°, 8.89° ± 0.2°, 9.74° ± 0.2°, 14.79° ± 0.2°, 15.79° ± 0.2°, 16.11° ± 0.2°, 19.79° ± 0.2° and 22.83° ± 0.2°

[0031] Each of polymorphs A, B, C, D and E can be determined by an X-ray diffraction spectrum having four or more, such as 4, 5, 6, 7, 8 or more peaks at the given 2[θ] values.

[0032] In one embodiment of the present invention, the average particle size of empagliflozin can be 15 μm or less, preferably 10 μm or less. When the average particle size of empagliflozin is greater than 15 μm, it may be difficult to achieve the required solubility.

[0033] In the present invention, relative to 100 parts by weight of the total pharmaceutical composition, the empagliflozin compartment comprises 10 to 20 parts by weight. When generally preparing a combined preparation with separate compartments such as a bilayer tablet, the weight ratio of the first drug compartment to the second drug compartment is 1:2 to 1:4. The above ranges are because when the total weight of the compartment with a smaller content of the drug is too small, the tablet may not be properly compressed.

[0034] When, relative to 100 parts by weight of the total pharmaceutical composition, the empagliflozin compartment comprises 10 to 20 parts by weight, relative to 100 parts by weight of the total pharmaceutical composition, the metformin compartment comprises 90 to 80 parts by weight. The weight ratio of the empagliflozin compartment to the metformin compartment is 10 to 20:90 to 80, which is different from the composition of a conventional separate compartment preparation.

[0035] Furthermore, in the empagliflozin compartment, relative to a total of 100 parts by weight of the empagliflozin compartment, it comprises less than 0.3 parts by weight of empagliflozin or a pharmaceutically acceptable salt thereof. The above content is different from the composition content of a single empagliflozin tablet (see Patent Document 1, containing 0.3 mg of empagliflozin, and the total content of the tablet is 75 mg), and the single empagliflozin tablet only comprises empagliflozin or a pharmaceutically acceptable salt thereof as the active ingredient.

[0036] More specifically, in the pharmaceutical composition according to the present invention, the empagliflozin compartment comprises empagliflozin or a pharmaceutically acceptable salt thereof, an excipient, a disintegrant and a glidant, and the metformin compartment comprises metformin or a pharmaceutically acceptable salt thereof, a binder, a sustained release agent and a glidant.

[0037] In one embodiment, the empagliflozin compartment comprises an excipient selected from the group consisting of lactose monohydrate; mannitol; a mixture of microcrystalline cellulose and lactose monohydrate; and a mixture of microcrystalline cellulose, mannitol, and pregelatinized starch.

[0038] The following examples show the variation in the solubility of empagliflozin depending on the choice of excipient. In the examples below, lactose monohydrate alone; mannitol alone; a mixture of microcrystalline cellulose and lactose monohydrate; or a mixture of microcrystalline cellulose, mannitol, and pregelatinized starch is used as an excipient in the empagliflozin compartment, providing equal empagliflozin solubility compared to an empagliflozin single tablet.

[0039] Relative to a total of 100 parts by weight of the empagliflozin compartment, it includes 80 to 85 parts by weight of excipient, but the present invention is not limited thereto.

[0040] In one embodiment of the present invention, when the empagliflozin compartment comprises lactose monohydrate as an excipient, it may include 40 to 100 parts by weight of lactose monohydrate relative to a total of 100 parts by weight of all excipients in the empagliflozin compartment. When lactose monohydrate is used alone as an excipient, it totals 100 parts by weight of all excipients. When lactose monohydrate is used together with microcrystalline cellulose, its amount may be 40 parts by weight or more and less than 100 parts by weight relative to a total of 100 parts by weight of all excipients.

[0041] In one embodiment of the present invention, when the empagliflozin compartment contains mannitol as an excipient, it may include 20 to 100 parts by weight of mannitol relative to a total of 100 parts by weight of all excipients in the empagliflozin compartment. When mannitol is used alone as an excipient, it totals 100 parts by weight of all excipients. When mannitol is used together with microcrystalline cellulose and pregelatinized starch, its amount may be 20 parts by weight or more and less than 100 parts by weight relative to a total of 100 parts by weight of all excipients.

[0042] In one embodiment of the present invention, when the empagliflozin compartment includes microcrystalline cellulose as an excipient, too high a content of microcrystalline cellulose will reduce the solubility of empagliflozin. Therefore, it is not preferred to use it alone as an excipient. It is preferably used in the form of a mixture of microcrystalline cellulose and lactose monohydrate; or a mixture of microcrystalline cellulose, mannitol, and pregelatinized starch. It may include less than 65 parts by weight of microcrystalline cellulose relative to a total of 100 parts by weight of all excipients in the empagliflozin compartment, but the present invention is not limited thereto.

[0043] In one embodiment of the present invention, when the empagliflozin compartment includes pregelatinized starch as an excipient, 5 to 40 parts by weight of pregelatinized starch may be included relative to a total of 100 parts by weight of all excipients in the empagliflozin compartment.

[0044] In another embodiment, when the empagliflozin compartment includes microcrystalline cellulose, mannitol, and pregelatinized starch as excipients, 20 to 65 parts by weight of mannitol may be included relative to a total of 100 parts by weight of all excipients in the empagliflozin compartment.

[0045] In another embodiment, when the empagliflozin compartment includes microcrystalline cellulose, mannitol, and pregelatinized starch as excipients, microcrystalline cellulose, mannitol, and pregelatinized starch may be included in a weight ratio of 1:1 to 1.5:0.15 to 1.5 in the empagliflozin compartment. According to the present invention, it has been clarified that when included in a high content in the empagliflozin compartment, microcrystalline cellulose tends to hinder the dissolution of empagliflozin and reduce dissolution because it is not easily soluble in water compared to other components. Mannitol and pregelatinized starch can compensate for the deficiency of microcrystalline cellulose and improve the solubility of empagliflozin.

[0046] In one embodiment of the present invention, the empagliflozin compartment may include a disintegrant selected from the group consisting of sodium croscarmellose, sodium starch glycolate, crospovidone, and low-substituted hydroxypropyl cellulose. 5 to 20 parts by weight of the disintegrant may be included relative to a total of 100 parts by weight of the empagliflozin compartment. According to the following examples, when the content of the disintegrant in the empagliflozin compartment is 25 parts by weight or more, empagliflozin does not reach a solubility of 80% or more within 10 minutes and does not reach a final solubility of 85% or more, indicating a dissolution profile that is unfavorable in terms of bioavailability. This is because excessive use of the disintegrant actually slows down the disintegration time and reduces solubility.

[0047] In one embodiment of the present invention, the empagliflozin compartment includes one or more of light anhydrous silicic acid and talc as glidants, and 1.5 to 3 parts by weight of the glidant may be included relative to a total of 100 parts by weight of the empagliflozin compartment.

[0048] Meanwhile, in one embodiment of the present invention, the metformin compartment includes sodium carboxymethyl cellulose, polyvinylpyrrolidone, or a mixture thereof as a binder, and 2 to 5 parts by weight of the binder may be included relative to a total of 100 parts by weight of the metformin compartment.

[0049] In another embodiment, the metformin compartment includes one or more of hydroxypropyl methylcellulose and polyethylene oxide as a sustained-release agent, and 15 to 40 parts by weight of the sustained-release agent may be included relative to a total of 100 parts by weight of the metformin compartment.

[0050] Hydroxypropyl methylcellulose preferably has an average viscosity of 100,000 mPa·s (75,000 - 140,000 mPa·s) to 200,000 mPa·s (150,000 - 280,000 mPa·s) in a 2% w / w solution, and polyethylene oxide preferably has an average molecular weight of 2,000,000 to 5,000,000. When the viscosity of hydroxypropyl cellulose and the molecular weight of polyethylene oxide are low, incomplete formation of the polymer matrix for sustained release affects the drug release rate.

[0051] In one embodiment of the present invention, relative to a total of 100 parts by weight of the metformin compartment, the metformin compartment may include 0.5 to 1 part by weight of magnesium stearate as a glidant.

[0052] As disclosed in Patent Document 1, due to the drug properties, the empagliflozin compartment has a T max of 1 to 2 hours, and in order to obtain a suitable C max and AUC, the drug is preferably formulated into an immediate-release type.

[0053] Preferably, in the pharmaceutical composition according to the present invention, the solubility of empagliflozin or a pharmaceutically acceptable salt thereof after 10 minutes in a pH 1.2 dissolution solution may be 75% or more, preferably 80% or more, of the total content of empagliflozin or a pharmaceutically acceptable salt thereof.

[0054] Preferably, in the pharmaceutical composition according to the present invention, the solubility of empagliflozin or a pharmaceutically acceptable salt thereof after 45 minutes in a pH 1.2 dissolution solution may be 80% or more, preferably 85% or more, of the total content of empagliflozin or a pharmaceutically acceptable salt thereof.

[0055] On the other hand, since the solubility of the active ingredient in the pharmaceutical composition affects the peak blood drug concentration (C max ) and the area under the blood drug concentration-time curve (AUC) during drug administration, in order to obtain a suitable C max and AUC, it is important to regulate the solubility of the pharmaceutical composition. Since the T max of empagliflozin is 1 to 2 hours, the above drug absorption rate is very important. The solubility is measured under the conditions of a pH 1.2 dissolution solution according to Dissolution Test Method 2 (Paddle method). Specific conditions can be referred to the following experimental examples.

[0056] When formulated into a conventional tablet, the metformin compartment may cause excessive hypoglycemia and gastrointestinal disorders due to rapid drug release, so it is preferably formulated into a sustained-release type.

[0057] Preferably, in the pharmaceutical composition according to the present invention, the solubility of metformin or its pharmaceutically acceptable salt after 1 hour in a dissolution solution at pH 6.8 can be 15 to 35% of the total content of metformin or its pharmaceutically acceptable salt, preferably 20% or more.

[0058] Preferably, in the pharmaceutical composition according to the present invention, the solubility of metformin or its pharmaceutically acceptable salt after 3 hours in a dissolution solution at pH 6.8 can be 40 to 60% of the total content of metformin or its pharmaceutically acceptable salt, preferably 45% or more.

[0059] Preferably, in the pharmaceutical composition according to the present invention, the solubility of metformin or its pharmaceutically acceptable salt after 12 hours in a dissolution solution at pH 6.8 can be 80% or more of the total content of metformin or its pharmaceutically acceptable salt, preferably 85% or more.

[0060] The Tmax of metformin is about 4 hours when administered before meals and about 6 hours when administered after meals; therefore, the intestinal drug absorption rate is considered crucial. The solubility is measured under the conditions of a dissolution solution at pH 6.8 according to the dissolution test method 1 (Rotating Basket Method) of the Korean Pharmacopoeia. The specific conditions are listed in the following experimental examples.

[0061] The pharmaceutical composition according to the present invention may further comprise a pharmaceutically acceptable additive other than the above components. Examples of the additive include a glidant and a colorant.

[0062] Glidants include stearic acid, stearates (such as magnesium stearate), light anhydrous silicic acid, talc, corn starch, carnauba wax, magnesium silicate, synthetic aluminum silicate, hydrogenated oil, white wax, titanium oxide, microcrystalline cellulose, polyethylene glycol 4000 and 6000, isopropyl myristate, calcium hydrogen phosphate, and mixtures thereof.

[0063] In one embodiment of the present invention, the empagliflozin compartment comprises granules, wherein pre-mixed granules comprising empagliflozin or its pharmaceutically acceptable salt are mixed with a post-mixed portion.

[0064] The present inventors confirmed that during the study of empagliflozin formulations, it was confirmed that preparing granules and formulating them into tablets is advantageous in terms of drug content uniformity and formulation uniformity.

[0065] The granules in the empagliflozin compartment are prepared by mixing the pre-mixed granules with the post-mixed portion.

[0066] The pre-mixed granules may include empagliflozin or its pharmaceutically acceptable salt, an excipient, and a glidant. In addition, the post-mixed portion may include an excipient, a disintegrant, and a glidant.

[0067] The excipients, disintegrants, and glidants in the empagliflozin compartment are the same as those described above, and the description will be omitted to avoid repetition.

[0068] In one embodiment of the present invention, the premixed granules and the post-mixed portion in the empagliflozin compartment may each contain one or more excipients.

[0069] In one embodiment of the present invention, in the empagliflozin compartment, the premixed granules may include microcrystalline cellulose, and the post-mixed portion may include mannitol and pregelatinized starch.

[0070] In the empagliflozin compartment, the weight ratio of the excipients in the premixed granules to the excipients in the post-mixed portion may be in the range of 1:1 to 1:4.

[0071] As the proportion of microcrystalline cellulose in the premixed granules in the empagliflozin compartment increases, the solubility may decrease; therefore, it is confirmed that it is preferable to adjust the weight ratio within an appropriate range.

[0072] The granules in the empagliflozin compartment of the pharmaceutical composition of the present invention may be dry granules, but the present invention is not limited thereto. Dry granules can form granules with a suitable particle size distribution, which results in excellent fluidity and compression moldability during the tableting process, minimizing the weight difference between individual tablets. Dry granules play an important role in the preparation of bilayer tablets with a uniform content of empagliflozin. In another embodiment, the granules may be wet granules.

[0073] In one embodiment of the present invention, the metformin compartment includes granules, in which premixed granules containing metformin or a pharmaceutically acceptable salt thereof are mixed with a post-mixed portion.

[0074] The metformin compartment is preferably formed as wet granules or dry granules to avoid various problems during the formation process, such as tableting defects and coating defects due to the very high content of metformin as the main component and its poor physical properties.

[0075] The granules in the metformin compartment may be wet granules, but the present invention is not limited thereto. Alternatively, the granules may be dry granules.

[0076] The granules in the metformin compartment are prepared by mixing the premixed granules with the post-mixed portion.

[0077] The premixed granules may include metformin or a pharmaceutically acceptable salt thereof and a binder. In addition, the post-mixed portion may include a sustained-release agent and a glidant.

[0078] The binder, sustained-release agent, and glidant in the metformin compartment are the same as those described above, and thus the description will be omitted to avoid repetition.

[0079] Meanwhile, in the present invention, the pharmaceutical composition may have a dosage form for oral administration, such as tablets. In one embodiment of the present invention, the pharmaceutical composition may be formulated into tablets. In a preferred embodiment, the pharmaceutical composition may be formulated into bilayer tablets.

[0080] In one embodiment of the present invention, the pharmaceutical composition may include empagliflozin in a dose of 0.1 to 0.5 mg, preferably 0.15 to 0.3 mg.

[0081] In a preferred embodiment, the pharmaceutical composition may include metformin in a dose of 500 to 1,000 mg. Preferably, the pharmaceutical composition may include metformin in a dose of 500, 750, or 1,000 mg.

[0082] The pharmaceutical composition according to the present invention may be administered once a day, but the present invention is not limited thereto.

[0083] [Beneficial effects]

[0084] The pharmaceutical composition according to the present invention can achieve an excellent formulation, which provides an efficacy level equivalent to the combination therapy of metformin single tablets and empagliflozin single tablets, despite the significant difference in the content between metformin and empagliflozin. Description of the drawings

[0085] Figure 1 It is a graph comparing the solubility of empagliflozin in the formulations of Examples 1 to 4 and Comparative Examples 1 and 2 with the solubility of the control drug under the condition of pH 1.2.

[0086] Figure 2 It is a graph comparing the solubility of empagliflozin in the formulations of Examples 1, 5, and 6 and Comparative Example 3 with the solubility of the control drug under the condition of pH 1.2.

[0087] Figure 3 It is a graph comparing the solubility of empagliflozin in the formulations of Examples 1 and 7 - 10 and Comparative Example 4 with the solubility of the control drug under the condition of pH 1.2.

[0088] Figure 4 It is a graph comparing the solubility of metformin hydrochloride in the formulations of Examples 1 and 11 - 17 with the solubility of the control drug under the condition of pH 1.2. Detailed description

[0089] [Mode of the invention]

[0090] In the following text, preferred embodiments are given to assist in understanding the present invention. However, the following embodiments are only intended to illustrate the present invention, and the scope of the present invention is not limited to the following embodiments. In addition, although the specification describes preferred methods and samples, similar or equivalent methods are also included within the scope of the present invention.

[0091] [Examples]

[0092] Example 1

[0093] Step 1: Preparation of granules containing empagliflozin

[0094] Prepare granules comprising empagliflozin according to the composition of the empagliflozin part in Table 1 below. Mix empagliflozin with microcrystalline cellulose, light anhydrous silicic acid, and talc, prepare plate-shaped billets using dry granulation, and then grind using a Comil to produce dry granules. Thereafter, mix the dry granules with mannitol, pregelatinized starch, croscarmellose sodium, talc, and a pigment mixture to prepare empagliflozin granules.

[0095] Step 2: Preparation of granules containing metformin hydrochloride

[0096] Prepare granules comprising metformin hydrochloride according to the composition of the metformin part in Table 1 below. Mix metformin hydrochloride and sodium carboxymethylcellulose, combine with water as a binding solution, and dry. Screen the resulting dried material to prepare wet granules, and then add hydroxypropyl methylcellulose (average viscosity: 100,000 mPa·s) and magnesium stearate and mix with the wet granules to prepare metformin hydrochloride granules.

[0097] Step 3: Preparation of combined tablets

[0098] Prepare a bilayer combination tablet comprising the above components by using a bilayer tablet press to compress 1,000 mg of metformin hydrochloride and 0.3 mg of empagliflozin into a bilayer tablet comprising metformin hydrochloride granules as the first layer and empagliflozin granules as the second layer.

[0099] [Table 1]

[0100]

[0101] Comparative Examples 1 and 2

[0102] Step 1: Preparation of granules containing empagliflozin

[0103] Prepare granules comprising empagliflozin according to the composition of the empagliflozin part in Table 2 below.

[0104] Empagliflozin was mixed with microcrystalline cellulose, light anhydrous silicic acid and talc, and plate-shaped billets were prepared by dry granulation, and then ground using a Comil to produce dry granules. The dry granules were mixed with croscarmellose sodium, talc and a pigment mixture to prepare empagliflozin granules of Comparative Example 1.

[0105] Empagliflozin was mixed with pregelatinized starch, light anhydrous silicic acid and talc, and plate-shaped billets were prepared by dry granulation, and then ground using a Comil to produce dry granules. The dry granules were mixed with pregelatinized starch, croscarmellose sodium, talc and a pigment mixture to prepare empagliflozin granules of Comparative Example 2.

[0106] Step 2: Preparation of granules containing metformin hydrochloride

[0107] Granules containing metformin hydrochloride were prepared according to the composition of the metformin part in Table 2 below. Metformin hydrochloride and sodium carboxymethylcellulose were mixed, combined with water as a binding solution, and dried. The resulting dried material was sieved to prepare wet granules, and then hydroxypropyl methylcellulose (average viscosity: 100,000 mPa·s) and magnesium stearate were added and mixed with the wet granules to prepare metformin hydrochloride granules.

[0108] Step 3: Preparation of combined tablets

[0109] In the same manner as in Example 1, a bilayer combination tablet containing the above components was prepared by using a bilayer tablet press to compress 1,000 mg of metformin hydrochloride and 0.3 mg of empagliflozin into a bilayer tablet including metformin hydrochloride granules as the first layer and empagliflozin granules as the second layer.

[0110] [Table 2]

[0111]

[0112]

[0113] Examples 2 to 4

[0114] Step 1: Preparation of granules containing empagliflozin

[0115] Granules including empagliflozin were prepared according to the composition of the empagliflozin part in Table 3 below.

[0116] Empagliflozin was mixed with microcrystalline cellulose, lactose monohydrate, light anhydrous silicic acid and talc, and plate-shaped billets were prepared by dry granulation, and then ground using a Comil to produce dry granules. The dry granules were mixed with croscarmellose sodium, talc and a pigment mixture to prepare empagliflozin granules of Example 2.

[0117] Empagliflozin was mixed with lactose monohydrate, light anhydrous silicic acid, and talc, and tablet-shaped billets were prepared using dry granulation, and then ground using a Comil to produce dry granules. The dry granules were mixed with pregelatinized starch, croscarmellose sodium, talc, and a pigment mixture to prepare empagliflozin granules of Example 3.

[0118] Empagliflozin was mixed with mannitol, light anhydrous silicic acid, and talc, and tablet-shaped billets were prepared using dry granulation, and then ground using a Comil to produce dry granules. The dry granules were mixed with mannitol, croscarmellose sodium, talc, and a pigment mixture to prepare empagliflozin granules of Example 3.

[0119] Step 2: Preparation of granules containing metformin hydrochloride

[0120] Granules containing metformin hydrochloride were prepared according to the composition of the metformin part in Table 3 below. Metformin hydrochloride and sodium carboxymethylcellulose were mixed, combined with water as a binding solution, and dried. The resulting dried material was sieved to prepare wet granules, and then hydroxypropyl methylcellulose (average viscosity: 100,000 mPa·s) and magnesium stearate were added and mixed with the wet granules to prepare metformin hydrochloride granules.

[0121] Step 3: Preparation of combined tablets

[0122] In the same manner as in Example 1, a bilayer combination tablet containing the above components was prepared by using a bilayer tablet press to compress 1,000 mg of metformin hydrochloride and 0.3 mg of empagliflozin into a bilayer tablet comprising metformin hydrochloride granules as the first layer and empagliflozin granules as the second layer.

[0123] [Table 3]

[0124]

[0125] Comparative Example 3

[0126] Step 1: Preparation of granules containing empagliflozin

[0127] Granules containing empagliflozin were prepared according to the composition of the empagliflozin part in Table 4 below.

[0128] Empagliflozin was mixed with microcrystalline cellulose, light anhydrous silicic acid, and talc, and tablet-shaped billets were prepared using dry granulation, and then ground using a Comil to produce dry granules. The dry granules were mixed with mannitol, pregelatinized starch, croscarmellose sodium, talc, and a pigment mixture to prepare empagliflozin granules of Comparative Example 3.

[0129] Step 2: Preparation of granules containing metformin hydrochloride

[0130] Prepare granules containing metformin hydrochloride according to the composition of the metformin part in Table 4 below.

[0131] Mix metformin hydrochloride with sodium carboxymethylcellulose, combine with water as a binding solution, and then dry. Sieve the dried material to prepare wet granules, add hydroxypropyl methylcellulose (average viscosity: 100,000 mPa·s) and magnesium stearate and mix with the wet granules to prepare metformin hydrochloride granules.

[0132] Step 3: Preparation of combined tablets

[0133] In the same manner as in Example 1, prepare a bilayer combination tablet containing the above components by using a bilayer tablet press to compress 1,000 mg of metformin hydrochloride and 0.3 mg of empagliflozin into a bilayer tablet comprising metformin hydrochloride granules as the first layer and empagliflozin granules as the second layer.

[0134] [Table 4]

[0135] [[ID=,16]]

[0136] Examples 5 and 6

[0137] Step 1: Preparation of granules containing empagliflozin

[0138] Prepare granules containing empagliflozin according to the composition of the empagliflozin part in Table 5 below.

[0139] Mix empagliflozin with microcrystalline cellulose, light anhydrous silicic acid and talc, prepare plate-shaped billets by dry granulation, and then grind using a Comil to produce dry granules. Mix the dry granules with mannitol, pregelatinized starch, cross-linked sodium carboxymethylcellulose, talc and a pigment mixture to prepare empagliflozin granules for Examples 5 and 6.

[0140] Step 2: Preparation of granules containing metformin hydrochloride

[0141] Prepare granules containing metformin hydrochloride according to the composition of the metformin part in Table 5 below.

[0142] Mix metformin hydrochloride with sodium carboxymethylcellulose, combine with water as a binding solution, and then dry. Sieve the dried material to prepare wet granules, add hydroxypropyl methylcellulose (average viscosity: 100,000 mPa·s) and magnesium stearate and mix with the wet granules to prepare metformin hydrochloride granules.

[0143] Step 3: Preparation of combined tablets

[0144] In the same manner as in Example 1, a bilayer combined tablet comprising the above ingredients was prepared by using a bilayer tablet press to compress 1,000 mg of metformin hydrochloride and 0.3 mg of empagliflozin into a bilayer tablet comprising metformin hydrochloride granules as the first layer and empagliflozin granules as the second layer.

[0145] [Table 5]

[0146]

[0147]

[0148] Comparative Example 4

[0149] Step 1: Preparation of granules containing empagliflozin

[0150] Granules comprising empagliflozin were prepared according to the composition of the empagliflozin part in Table 6 below.

[0151] Empagliflozin was mixed with microcrystalline cellulose, light anhydrous silicic acid, and talc, and plate-like compacts were prepared using dry granulation and then ground using a Comil to produce dry granules. The dry granules were mixed with mannitol, pregelatinized starch, croscarmellose sodium, talc, and a pigment mixture to prepare the empagliflozin granules of Comparative Example 4.

[0152] Step 2: Preparation of granules containing metformin hydrochloride

[0153] Granules comprising metformin hydrochloride were prepared according to the composition of the metformin part in Table 6 below.

[0154] Metformin hydrochloride was mixed with sodium carboxymethylcellulose, combined with water as a binding solution, and then dried. The dried material was sieved to prepare wet granules, and hydroxypropyl methylcellulose (average viscosity: 100,000 mPa·s) and magnesium stearate were added and mixed with the wet granules to prepare metformin hydrochloride granules.

[0155] Step 3: Preparation of combined tablets

[0156] In the same manner as in Example 1, a bilayer combined tablet comprising the above ingredients was prepared by using a bilayer tablet press to compress 1,000 mg of metformin hydrochloride and 0.3 mg of empagliflozin into a bilayer tablet comprising metformin hydrochloride granules as the first layer and empagliflozin granules as the second layer.

[0157] [Table 6]

[0158]

[0159]

[0160] Examples 7 to 10

[0161] Step 1: Preparation of granules containing empagliflozin

[0162] Prepare granules comprising empagliflozin according to the composition of the empagliflozin part in Table 7 below.

[0163] Mix empagliflozin with microcrystalline cellulose, light anhydrous silicic acid, and talc, prepare plate-shaped billets using dry granulation, and then grind using a Comil to produce dry granules. Mix the dry granules with mannitol, pregelatinized starch, croscarmellose sodium, talc, and a pigment mixture to prepare the empagliflozin granules of Example 7.

[0164] Prepare the empagliflozin granules of Example 8 by mixing the dry granules with mannitol, pregelatinized starch, sodium starch glycolate, talc, and a pigment mixture.

[0165] Prepare the empagliflozin granules of Example 9 by mixing the dry granules with mannitol, pregelatinized starch, crospovidone, talc, and a pigment mixture.

[0166] Prepare the empagliflozin granules of Example 10 by mixing the dry granules with mannitol, pregelatinized starch, and low-substituted hydroxypropyl cellulose.

[0167] Step 2: Preparation of granules containing metformin hydrochloride

[0168] Prepare granules comprising metformin hydrochloride according to the composition of the metformin part in Table 7 below.

[0169] Mix metformin hydrochloride with sodium carboxymethyl cellulose, combine with water as a binding solution, and then dry. Screen the dried material to prepare wet granules, add hydroxypropyl methylcellulose (average viscosity: 100,000 mPa·s) and magnesium stearate and mix with the wet granules to prepare metformin hydrochloride granules.

[0170] Step 3: Preparation of combined tablets

[0171] In the same manner as in Example 1, prepare a bilayer combination tablet comprising the above components by using a bilayer tablet press to compress 1,000 mg of metformin hydrochloride and 0.3 mg of empagliflozin into a bilayer tablet comprising metformin hydrochloride granules as the first layer and empagliflozin granules as the second layer.

[0172] [Table 7]

[0173]

[0174] Examples 11 to 14

[0175] Step 1: Preparation of granules containing empagliflozin

[0176] Prepare granules containing empagliflozin according to the composition of the empagliflozin part in Table 8 below.

[0177] Mix empagliflozin with microcrystalline cellulose, light anhydrous silicic acid, and talc, prepare plate-shaped compacts using dry granulation, and then grind using a Comil to produce dry granules. Mix the dry granules with mannitol, pregelatinized starch, croscarmellose sodium, talc, and a pigment mixture to prepare empagliflozin granules.

[0178] Step 2: Preparation of granules containing metformin hydrochloride

[0179] Prepare granules containing metformin hydrochloride according to the composition of the metformin part in Table 8 below.

[0180] Mix metformin hydrochloride with povidone, combine with water as a binding solution, and then dry. Screen the dried material to prepare wet granules, add hydroxypropyl methylcellulose (average viscosity: 100,000 mPa·s) and magnesium stearate and mix with the wet granules to prepare the metformin hydrochloride granules of Example 11.

[0181] Prepare the metformin hydrochloride granules of Example 12 by adding hydroxypropyl methylcellulose (average viscosity: 200,000 mPa·s) and magnesium stearate to the wet granules and mixing them.

[0182] Prepare the metformin hydrochloride granules of Example 13 by adding polyethylene oxide (average molecular weight: 2,000,000) and magnesium stearate to the wet granules and mixing them.

[0183] Prepare the metformin hydrochloride granules of Example 14 by adding polyethylene oxide (average molecular weight: 5,000,000) and magnesium stearate to the wet granules and mixing them.

[0184] Step 3: Preparation of combined tablets

[0185] In the same manner as in Example 1, prepare a bilayer combination tablet containing the above components by using a bilayer tablet press to compress 1,000 mg of metformin hydrochloride and 0.3 mg of empagliflozin into a bilayer tablet comprising metformin hydrochloride granules as the first layer and empagliflozin granules as the second layer.

[0186] [Table 8]

[0187]

[0188]

[0189] Examples 15 to 17

[0190] Step 1: Preparation of granules containing empagliflozin

[0191] Prepare granules containing empagliflozin according to the composition of the empagliflozin part in Table 9 below.

[0192] Mix empagliflozin with microcrystalline cellulose, light anhydrous silicic acid, and talc, prepare plate-shaped billets using dry granulation, and then grind using a Comil to produce dry granules. Mix the dry granules with mannitol, pregelatinized starch, croscarmellose sodium, talc, and a pigment mixture to prepare empagliflozin granules.

[0193] Step 2: Preparation of granules containing metformin hydrochloride

[0194] Prepare granules containing metformin hydrochloride according to the composition of the metformin part in Table 9 below. Mix metformin hydrochloride with sodium carboxymethylcellulose, combine with water as a binding solution, and then dry. Screen the dried material to prepare wet granules, add hydroxypropyl methylcellulose (average viscosity: 200,000 mPa·s) and magnesium stearate and mix with the wet granules to prepare the metformin hydrochloride granules of Example 15.

[0195] Prepare the metformin hydrochloride granules of Example 16 by adding polyethylene oxide (average molecular weight: 2,000,000) and magnesium stearate to the wet granules and mixing them.

[0196] Prepare the metformin hydrochloride granules of Example 17 by adding polyethylene oxide (average molecular weight: 5,000,000) and magnesium stearate to the wet granules and mixing them.

[0197] Step 3: Preparation of combined tablets

[0198] In the same manner as in Example 1, prepare a bilayer combination tablet containing the above components by using a bilayer tablet press to compress 1,000 mg of metformin hydrochloride and 0.3 mg of empagliflozin into a bilayer tablet containing metformin hydrochloride granules as the first layer and empagliflozin granules as the second layer.

[0199] [Table 9]

[0200]

[0201] Experimental Example 1: Hardness test

[0202] The hardness test is a test for physically measuring the hardness (unit: kP) of an oral dosage form. The test is carried out by placing the tablet on a hardness measuring device and measuring the hardness, and for the test, the tablets prepared in the examples and comparative examples are used. The main compression pressure of each tablet is set to 25 - 28 kN, and the measurement results of the tablet hardness are shown in Table 10 below.

[0203] [Table 10]

[0204]

[0205]

[0206] In the results of the hardness test, all the prepared tablets showed a hardness of 15 kP or higher, confirming that there was no problem in the preparation of the tablets.

[0207] Experimental Example 2: Disintegration test

[0208] According to the disintegration test in the conventional test methods of the Korean Pharmacopoeia, the disintegration test was carried out on the empagliflozin layers of Comparative Examples 1 to 4 and Examples 1 to 10. The results are shown in Table 11 below.

[0209] [Table 11]

[0210]

[0211] The disintegration test is a test method for determining whether tablets, capsules, granules, pills, and suppositories disintegrate (disappear or disperse into a specific particle state) in a test solution under predetermined conditions and within a specific time. It allows to predict to a certain extent the degree of dissolution in a solvent, but cannot determine whether the active ingredient in the preparation is completely dissolved. In the results of the disintegration test, it was confirmed that the comparative examples disintegrated relatively slower than the examples.

[0212] Experimental Example 3: Stability assessment

[0213] After storing the dosage form of Example 1 in a sealed high-density polyethylene (HDPE) bottle, under long-term test conditions (25 °C, 60% RH), at 3, 6, 9, and 12 months, the contents of empagliflozin and metformin and the amount of related substances were measured by liquid chromatography analysis. After storing the dosage form of Example 1 under accelerated test conditions (40 °C, 75% RH), at 1, 3, and 6 months, the contents of empagliflozin and metformin and the amount of related substances were measured by liquid chromatography analysis. The results are shown in Tables 12 and 13 below.

[0214] [Table 12]

[0215] Long-term test results (unit: %)

[0216]

[0217] [Table 13]

[0218] Accelerated test results (unit: %)

[0219]

[0220]

[0221] As shown in Tables 12 and 13, through the use of the content of Example 1 and the stability test of related substances, the stability within 12 months was confirmed under long-term and accelerated test conditions. In addition, it was confirmed that when taking up to 2000 mg of N-nitrosodimethylamine (NDMA), a possible carcinogen, per day, its content was lower than the maximum allowable daily dose (48 ng, 0.048 ppb), and the maximum allowable daily dose is a temporary regulatory standard.

[0222] Experimental Example 4: Dissolution test

[0223] According to the dissolution test method of the Korean Pharmacopoeia, the dissolution tests of empagliflozin and metformin prepared in Comparative Examples 1 to 4 and Examples 1 to 17 were carried out under the same conditions as shown in Tables 14 and 15 below. In order to compare with the solubility of the combined tablets of the present invention, 'Envlo Tablet' (a single-drug preparation of empagliflozin) of Daewoong Pharmaceutical and 'Glucophage XR, extended-release tablet, 1,000 mg' (a single-drug preparation of metformin) of Merck were used to carry out this test under the same conditions as the combined tablets of the present invention.

[0224] [Table 14]

[0225] Dissolution test conditions for empagliflozin

[0226]

[0227] [Table 15]

[0228] Dissolution test conditions for metformin

[0229]

[0230] The results of the empagliflozin dissolution test are shown in Tables 16 to 18 below and Figures 1 to 3 .

[0231] [Table 16]

[0232] The solubility of empagliflozin depends on the type of filler

[0233] Time (h) 0 5 10 15 30 45 Control drug 0 79.9 91 92.8 94 94 Comparative Example 1 0 57.3 64.6 67.4 72.8 76.9 Comparative Example 2 0 26 64 72.1 76.2 78.4 Example 1 0 77.7 87.7 89.9 92.7 93.8 Example 2 0 70 79.8 83.4 88.1 90.1 Example 3 0 62.3 80 84.2 87.8 89.4 Example 4 0 79.9 88.2 89.8 91 91.1

[0234] [Table 17]

[0235] The solubility of empagliflozin depends on the proportion of filler

[0236]

[0237]

[0238] [Table 18]

[0239] The solubility of enagliflozin depends on the type of disintegrant

[0240] Time (h) 0 5 10 15 30 45 Control drug 0 79.9 91 92.8 94 94 Comparative Example 4 0 69.4 76.8 77.7 81 83.1 Example 1 0 77.7 87.7 89.9 92.7 93.8 Example 7 0 81.5 86.7 87.6 90.3 91.6 Example 8 0 73.7 83.4 83.5 85 86.8 Example 9 0 88.1 88.3 89.4 90.5 91.7 Example 10 0 85.7 91.2 90.6 92.7 93.8

[0241] Since enagliflozin is a T max For a component that takes about 1 hour to dissolve in gastric fluid, its dissolution is expected to have a significant impact on bioavailability. Therefore, solubility at pH 1.2 is considered critical, and Comparative Examples 1 to 4, which did not show a solubility of 80% or more within 10 minutes and a final solubility of 85% or more, are considered to be unsatisfactory in terms of bioavailability.

[0242] The results of the metformin dissolution test are shown in Tables 19 and Figure 4 .

[0243] [Table 19]

[0244]

[0245]

[0246] With respect to metformin solubility, for all examples, i) the average solubility difference between the control drug and the test drug was approximately 15% at all solubility comparison points specified in the pharmaceutical equivalence testing criteria, and ii) the similarity coefficient (f2) was 50 or greater at all solubility comparison points, indicating equivalence.

[0247] Experimental Example 5: Clinical trial

[0248] The pharmaceutical composition of Example 1 was subjected to a pharmacokinetic test (PK test) to evaluate its bioequivalence with a control drug.

[0249] According to bioequivalence testing based on the pharmaceutical equivalence testing standards under the Pharmaceutical Equivalence Act of the Pharmaceutical Affairs-related Law Collection, the control and test drugs are considered equivalent when they both meet the 90% confidence interval of their log-transformed mean difference within the range of log 0.8 to log 1.25.

[0250] A clinical trial was conducted to compare the blood drug concentrations after selecting the pharmaceutical composition of Example 1 as the test drug and a combination therapy as the control. The combination therapy was 'Envlo Tablet' (a single drug preparation of empagliflozin) of Daewoong Pharmaceutical and 'Glucophage XR, Extended Release Tablet, 1,000 mg' (a single drug preparation of metformin) of Merck.

[0251] The clinical trial was conducted in a randomized, two-group, and four-period (before and after meals) crossover study, and blood samples were collected at appropriate times after administration. Then, pharmacokinetic parameters (AUC and C max ) were calculated and evaluated by measuring the concentrations of empagliflozin and metformin in the plasma.

[0252] [Table 20]

[0253] Administration before meals

[0254]

[0255]

[0256] [Table 21]

[0257] Administration after meals

[0258]

[0259] This test demonstrated that the pharmaceutical composition of Example 1 exhibited bioequivalence to the combination therapy of the control drug both before and after meals.

Claims

1. A pharmaceutical composition, comprising: A single-type pharmaceutical composition, comprising a compartment including empagliflozin or a pharmaceutically acceptable salt thereof and a compartment including metformin or a pharmaceutically acceptable salt thereof, wherein the compartments are formulated in a separated form from each other. Wherein, relative to 100 parts by weight of the total pharmaceutical composition, 10 to 20 parts by weight of the empagliflozin compartment are included, and wherein, relative to a total of 100 parts by weight of the empagliflozin compartment, less than 0.3 part by weight of empagliflozin or a pharmaceutically acceptable salt thereof is included in the empagliflozin compartment.

2. The pharmaceutical composition according to claim 1, wherein the empagliflozin compartment comprises empagliflozin or a pharmaceutically acceptable salt thereof, an excipient, a disintegrant, and a glidant, and the metformin compartment comprises metformin or a pharmaceutically acceptable salt thereof, a binder, a sustained-release agent, and a glidant.

3. The pharmaceutical composition according to claim 1, wherein the empagliflozin compartment comprises an excipient selected from the group consisting of lactose monohydrate; mannitol; a mixture of microcrystalline cellulose and lactose monohydrate; and a mixture of microcrystalline cellulose, mannitol, and pregelatinized starch, and 80 to 85 parts by weight of the excipient are included relative to a total of 100 parts by weight of the empagliflozin compartment.

4. The pharmaceutical composition according to claim 1, wherein when the empagliflozin compartment comprises lactose monohydrate as an excipient, 40 to 100 parts by weight of the lactose monohydrate are included relative to a total of 100 parts by weight of all excipients in the empagliflozin compartment.

5. The pharmaceutical composition according to claim 1, wherein when the empagliflozin compartment comprises mannitol as an excipient, 20 to 100 parts by weight of the mannitol are included relative to a total of 100 parts by weight of all excipients in the empagliflozin compartment.

6. The pharmaceutical composition according to claim 1, wherein when the empagliflozin compartment comprises microcrystalline cellulose as an excipient, less than 65 parts by weight of the microcrystalline cellulose are included relative to a total of 100 parts by weight of all excipients in the empagliflozin compartment.

7. The pharmaceutical composition according to claim 1, wherein when the empagliflozin compartment comprises pregelatinized starch as an excipient, 5 to 40 parts by weight of the pregelatinized starch are included relative to a total of 100 parts by weight of all excipients in the empagliflozin compartment.

8. The pharmaceutical composition according to claim 1, wherein when the empagliflozin compartment comprises microcrystalline cellulose, mannitol, and pregelatinized starch as excipients, 20 to 65 parts by weight of the mannitol are included relative to a total of 100 parts by weight of all excipients in the empagliflozin compartment.

9. The pharmaceutical composition according to claim 1, wherein when the empagliflozin compartment comprises microcrystalline cellulose, mannitol, and pregelatinized starch as excipients, the microcrystalline cellulose, mannitol, and pregelatinized starch are included in the empagliflozin compartment at a weight ratio of 1:0.5 to 2:0.15 to 1.

5.

10. The pharmaceutical composition according to claim 1, wherein the empagliflozin compartment contains a disintegrant selected from the group consisting of sodium croscarmellose, sodium starch glycolate, crospovidone, and low-substituted hydroxypropyl cellulose, and includes 5 to 20 parts by weight of the disintegrant relative to a total of 100 parts by weight of the empagliflozin compartment.

11. The pharmaceutical composition according to claim 1, wherein the empagliflozin compartment contains one or more of light anhydrous silicic acid and talc as glidants, and includes 1.5 to 3 parts by weight of the glidant relative to a total of 100 parts by weight of the empagliflozin compartment.

12. The pharmaceutical composition according to claim 1, wherein the metformin compartment contains sodium carboxymethyl cellulose, povidone, or a mixture thereof as a binder, and includes 2 to 5 parts by weight of the binder relative to a total of 100 parts by weight of the metformin compartment.

13. The pharmaceutical composition according to claim 1, wherein the metformin compartment contains one or more of hydroxypropyl methylcellulose and polyethylene oxide as a sustained-release agent, and includes 15 to 40 parts by weight of the sustained-release agent relative to a total of 100 parts by weight of the metformin compartment.

14. The pharmaceutical composition according to claim 1, wherein the metformin compartment contains 0.5 to 1 part by weight of magnesium stearate as a glidant relative to a total of 100 parts by weight of the metformin compartment.

15. The pharmaceutical composition according to claim 1, wherein the solubility of the empagliflozin or a pharmaceutically acceptable salt thereof is 80% or more after 10 minutes in a dissolution solution at pH 1.2 relative to the total content of the empagliflozin or a pharmaceutically acceptable salt thereof.

16. The pharmaceutical composition according to claim 1, wherein the solubility of the empagliflozin or a pharmaceutically acceptable salt thereof is 85% or more after 45 minutes in a dissolution solution at pH 1.2 relative to the total content of the empagliflozin or a pharmaceutically acceptable salt thereof.

17. The pharmaceutical composition according to claim 1, wherein the solubility of the metformin or a pharmaceutically acceptable salt thereof is 20% or more after 1 hour in a dissolution solution at pH 6.8 relative to the total content of the metformin or a pharmaceutically acceptable salt thereof.

18. The pharmaceutical composition according to claim 1, wherein the solubility of the metformin or a pharmaceutically acceptable salt thereof is 45% or more after 3 hours in a dissolution solution at pH 6.8 relative to the total content of the metformin or a pharmaceutically acceptable salt thereof.

19. The pharmaceutical composition according to claim 1, wherein the solubility of the metformin or a pharmaceutically acceptable salt thereof is 85% or more after 12 hours in a dissolution solution at pH 6.8 relative to the total content of the metformin or a pharmaceutically acceptable salt thereof.

20. The pharmaceutical composition according to claim 1, wherein the empagliflozin compartment contains granules, wherein premixed granules comprising empagliflozin or a pharmaceutically acceptable salt thereof are mixed with a post-mixed portion.

21. The pharmaceutical composition according to claim 20, wherein the premixed granules comprise empagliflozin or a pharmaceutically acceptable salt thereof, an excipient, and a glidant.

22. The pharmaceutical composition according to claim 20, wherein the post - mixed portion comprises an excipient, a disintegrant, and a glidant.

23. The pharmaceutical composition according to claim 20, wherein the premixed granules and the post - mixed portion each comprise one or more excipients.

24. The pharmaceutical composition according to claim 20, wherein the weight ratio of the excipient in the premixed granules to the excipient in the post - mixed portion is 1:1 to 1:

4.

25. The pharmaceutical composition according to claim 20, wherein the granules are dry granules.

26. The pharmaceutical composition according to claim 1, wherein the metformin compartment comprises granules, wherein premixed granules comprising metformin or a pharmaceutically acceptable salt thereof are mixed with a post - mixed portion.

27. The pharmaceutical composition according to claim 26, wherein the granules are wet granules.

28. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is in the form of a tablet.

29. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is in the form of a bilayer tablet.

30. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition comprises empagliflozin in a dose of 0.1 to 0.5 mg.

31. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition comprises metformin in a dose of 500 to 1,000 mg.

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