Pharmaceutical compositions comprising enavogliflozin and metformin

Abstract

The present invention relates to a pharmaceutical composition comprising enavogliflozin and metformin. The pharmaceutical composition according to the present invention embodies an excellent formulation that provides a level of efficacy equivalent to that of a combination therapy of metformin and enavogliflozin alone, despite the significantly different contents of metformin and enavogliflozin.

Description

[Technical Field]

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

[0002] Metformin, an oral biguanide hypoglycemic drug, is commonly used as the first-line drug for the treatment of diabetes. Metformin improves blood glucose levels, but one of its mechanisms of action is known to be that it activates AMP-activated protein kinase (AMPK) in the liver, preventing gluconeogenesis and promoting glucose absorption into cells, thereby suppressing metabolic syndrome.

[0003] Metformin has the advantage of being highly effective in enhancing hemoglobin A1c, with few side effects such as weight gain and hypoglycemia, and significantly reducing both diabetes-related and all-cause mortality. However, it may cause gastrointestinal side effects such as diarrhea, abdominal discomfort, nausea, and vomiting, so caution is required when administering it to patients with severe kidney or liver dysfunction.

[0004] Because metformin alone often fails to control blood sugar levels, sulfonylurea drugs have been commonly prescribed as second-line treatments for diabetes. However, insulin secretagogues such as sulfonylurea can cause a decrease in pancreatic beta cells when administered over the long term, ultimately resulting in decreased insulin secretion.

[0005] In addition, α-glucosidase inhibitors, DPP-4 inhibitors, and SGLT2 inhibitors are also used as oral diabetes treatment drugs in combination with metformin.

[0006] SGLT2 (sodium-glucose cotransporter 2) inhibitors are a new type of hypoglycemic agent. They reduce glucose reabsorption in the proximal nephron and promote glucose excretion through an insulin-independent mechanism. Numerous studies have confirmed the safety and efficacy of SGLT2 inhibitors for the treatment of type 2 diabetes.

[0007] The currently approved SGLT2 inhibitors include dapagliflozin, empagliflozin, ipragliflozin, ertugliflozin, and enavogliflozin.

[0008] Enavogliflozin (compound 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) is a drug disclosed in U.S. Patent Publication No. 2015 / 0152075, and has been reported to exhibit excellent blood glucose lowering effects at a dose of 0.3 mg, which is less than one-thirtieth of that of conventional SGLT2 inhibitors.

[0009] Metformin can be administered at a maximum dose of 2000 mg per day, and tablets with single doses of 500 mg, 750 mg, and 1000 mg have been developed.

[0010] As formulations for combination therapy of metformin and SGLT2 inhibitors, combination compositions of metformin and dapagliflozin, combination compositions of metformin and empagliflozin, etc. have been developed. Based on a metformin dose of 1000 mg, the dapagliflozin content is approximately 10 mg and the empagliflozin content is approximately 12.5 mg.

[0011] However, in the case of enavogliflozin, the single dose is 0.3 mg, which is less than one-thirtieth of that of existing SGLT2 inhibitors, and unlike combination preparations of metformin and existing SGLT2 inhibitors, there are aspects that make it difficult to realize into a combination preparation.

[0012] Metformin has a dosage of 500 mg to 1000 mg per tablet, while enavogliflozin has a dosage of 0.3 mg per tablet. These significant differences in active ingredient content make it extremely difficult to formulate these compounds into a single matrix tablet using conventional formulation methods. Furthermore, metformin is highly soluble in water. Formulation of a standard tablet formulation could result in a sudden release of the drug, potentially causing a sudden drop in blood sugar levels and gastrointestinal disorders. Therefore, a sustained-release formulation with gradual release is necessary. In this case, the highly viscous, swellable sustained-release base used to gradually release metformin is likely to delay the release of enavogliflozin, which should be released quickly, making it unlikely that metformin and enavogliflozin can be formulated into a single matrix tablet.

[0013] There is a case where Astrazeneca's Zigduo tablet, a combination drug of dapagliflozin and metformin, has been formulated into a bilayer tablet. However, compared with the maximum dose of Zigduo, dapagliflozin 10 mg and metformin 1000 mg, the doses of enavogliflozin 0.3 mg and metformin 1000 mg differ greatly in the content of the two ingredients, making it difficult to formulate these drugs into a bilayer tablet.

[0014] The total weight of the enavogliflozin mono-drug pharmaceutical composition disclosed in Korean Patent Application No. 10-2021-0130239 (Patent Document 1) is 75 mg. However, when the enavogliflozin portion of a combined composition is formed using the composition of this mono-drug, the total amount of the enavogliflozin portion is less than about 1 / 13 of the total amount of metformin portion containing 1,000 mg of metformin. Therefore, it is difficult to meet the ratio conditions between the first and second drugs required for a bilayer tablet press, and it is not even possible to attempt to manufacture a combined formulation with metformin into a bilayer tablet based on the composition of enavogliflozin mono-drug, even by tableting. [Prior art documents] [Patent documents]

[0015] [Patent Document 1] Korean Patent Application No. 10-2021-0130239 Summary of the Invention [Problem to be solved by the invention]

[0016] The present invention relates to a combination composition for combination therapy of metformin and enavogliflozin.

[0017] To provide a combination composition of metformin and enavogliflozin that can solve the above-mentioned problems, a new formulation is required that takes into account the different contents of the two drugs, and at the same time, such a combination composition needs to have the same efficacy as the control drug combination therapy of metformin and enavogliflozin alone. [Means for solving the problem]

[0018] As a result of extensive research into formulating a combination composition of metformin and enavogliflozin, the present inventors have found that the above problems can be solved when the pharmaceutical composition is formulated as follows.

[0019] Specifically, the present invention provides: A pharmaceutical composition in a single formulation comprising a zone containing enavogliflozin or a pharmaceutically acceptable salt thereof; and a zone containing metformin or a pharmaceutically acceptable salt thereof, wherein the zones are formulated in a manner separated from each other, The enavogliflozin zone is contained in an amount of 10 to 20 parts by weight based on 100 parts by weight of the total pharmaceutical composition, The pharmaceutical composition includes the enavogliflozin zone, wherein the enavogliflozin or a pharmaceutically acceptable salt thereof is contained in an amount of less than 0.3 parts by weight per 100 parts by weight of the total weight of the enavogliflozin zone.

[0020] As described above, since the content of enavogliflozin in the formulation is very low, it is difficult to realize a combined composition with metformin into a single matrix formulation. Therefore, a pharmaceutical composition is preferred in which a zone containing enavogliflozin or a pharmaceutically acceptable salt thereof (hereinafter also referred to as the "enavogliflozin zone" or "enavogliflozin portion") and a zone containing metformin or a pharmaceutically acceptable salt thereof (hereinafter also referred to as the "metformin zone" or "metformin portion") are formulated in a separated form.

[0021] Enavgliflozin used as an active ingredient in the present invention can be synthesized according to known prior art documents. In the present invention, enavogliflozin may be in a crystalline or amorphous form. For example, enavogliflozin may be enavogliflozin crystalline form A, crystalline form B, crystalline form C, crystalline form D, crystalline form E, or amorphous enavogliflozin, which are reported to have the following X-ray diffraction spectra in Korean Patent Publication No. 2017-0142904 or Korean Patent Application No. 2022-0123673.

[0022] Crystalline form A: A crystalline form having an X-ray diffraction (XRD) spectrum including 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°. Crystalline form B: A crystalline form having an X-ray diffraction (XRD) spectrum including 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°. Crystalline form C: A crystalline form having an X-ray diffraction (XRD) spectrum including 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°. Crystalline form D: A crystalline form having an X-ray diffraction (XRD) spectrum including 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°. Crystalline form E: A crystalline form having an X-ray diffraction (XRD) spectrum containing 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°.

[0023] The crystalline forms A, B, C, D and E can each be identified by an X-ray diffraction spectrum having four or more, e.g., four, five, six, seven, eight or more, peaks from the 2[θ] values ​​listed above.

[0024] In an embodiment of the present invention, the average particle size of enavogliflozin may be 15 μm or less, preferably 10 μm or less. If the average particle size of enavogliflozin exceeds 15 μm, it may be difficult to achieve a desired dissolution rate.

[0025] In the present invention, the enavogliflozin zone is contained in an amount of 10 to 20 parts by weight per 100 parts by weight of the total pharmaceutical composition. Generally, when preparing a combination formulation with separate zones, such as a bilayer tablet, the weight ratio of the first drug zone to the second drug zone is within 1:2 to 1:4. This is because if the total weight of the zone with the lower drug content is too small, it may cause problems with tableting.

[0026] When the enavogliflozin zone is contained in an amount of 10 to 20 parts by weight relative to 100 parts by weight of the total pharmaceutical composition, the metformin zone is contained in an amount of 90 to 80 parts by weight relative to 100 parts by weight of the total pharmaceutical composition. The weight ratio of the enavogliflozin zone to the metformin zone is 10 to 20:90 to 80, which is different from the composition of a typical separated zone formulation.

[0027] Furthermore, the enavogliflozin zone contains less than 0.3 parts by weight of enavogliflozin or a pharmaceutically acceptable salt thereof relative to 100 parts by weight of the total weight of the enavogliflozin zone, which differs from the composition of an enavogliflozin monotherapy agent containing only enavogliflozin or a pharmaceutically acceptable salt thereof as an active ingredient (see Patent Document 1, which contains 0.3 mg of enavogliflozin in a total tablet volume of 75 mg).

[0028] More specifically, in the pharmaceutical composition according to the present invention, the enavogliflozin zone includes enavogliflozin or a pharmaceutically acceptable salt thereof, an excipient, a disintegrant, and a lubricant, and the metformin zone includes metformin or a pharmaceutically acceptable salt thereof, a binder, a sustained-release formulation, and a lubricant.

[0029] In one embodiment, the enavogliflozin zone 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.

[0030] The following examples show how the dissolution rate of enavogliflozin changes depending on the excipient selected. In the following examples, it was found that the excipients used in the enavogliflozin zone, such as lactose hydrate alone, mannitol alone, a mixture of microcrystalline cellulose and lactose hydrate, or a mixture of microcrystalline cellulose, mannitol, and pregelatinized starch, exhibited the same dissolution rate as enavogliflozin alone, compared to enavogliflozin alone.

[0031] The excipient is included in an amount of 80 to 85 parts by weight based on 100 parts by weight of the total weight of the enavogliflozin zone, but is not limited thereto.

[0032] In one embodiment of the present invention, when the enavogliflozin zone contains lactose hydrate as an excipient, the lactose hydrate is contained in an amount of 40 to 100 parts by weight out of 100 parts by weight of all excipients in the enavogliflozin zone. When lactose hydrate is used as the sole excipient, it accounts for 100 parts by weight of all excipients. When lactose hydrate is used together with microcrystalline cellulose, it is used in an amount of 40 to 100 parts by weight out of 100 parts by weight of all excipients.

[0033] In one embodiment of the present invention, when the enavogliflozin zone contains mannitol as an excipient, the mannitol may be contained in an amount of 20 to 100 parts by weight out of 100 parts by weight of the total weight of all excipients in the enavogliflozin zone. When mannitol is used as the sole excipient, it accounts for 100 parts by weight of the total weight of all excipients. When mannitol is used together with microcrystalline cellulose and pregelatinized starch, it is used in an amount of 20 to 100 parts by weight out of 100 parts by weight of the total weight of all excipients.

[0034] In a specific example of the present invention, when the enavogliflozin zone contains microcrystalline cellulose as an excipient, if the content of microcrystalline cellulose is too high, dissolution of enavogliflozin decreases, so it is not preferable to use it as the sole excipient, and it is preferable to use it as a mixture of microcrystalline cellulose and lactose monohydrate, or a mixture of microcrystalline cellulose, mannitol, and pregelatinized starch. Without being limited thereto, microcrystalline cellulose may be contained in an amount of less than 65 parts by weight out of a total weight of 100 parts by weight of all excipients in the enavogliflozin zone.

[0035] In a specific example of the present invention, when the enavogliflozin zone contains pregelatinized starch as an excipient, the pregelatinized starch may be contained in an amount of 5 to 40 parts by weight relative to 100 parts by weight of the total weight of all excipients in the enavogliflozin zone.

[0036] In another specific example, when the enavogliflozin zone contains microcrystalline cellulose, mannitol, and pregelatinized starch as excipients, mannitol may be contained in an amount of 20 to 65 parts by weight relative to 100 parts by weight of the total weight of all excipients in the enavogliflozin zone.

[0037] In another specific example, when the enavogliflozin zone contains microcrystalline cellulose, mannitol, and pregelatinized starch as excipients, the microcrystalline cellulose, mannitol, and pregelatinized starch in the enavogliflozin zone are contained in a weight ratio of 1:1-1.5:0.15-1.5. According to the present invention, it has been found that when the content of microcrystalline cellulose in the enavogliflozin zone is high, it tends to be less soluble in water than other components, hindering the release of enavogliflozin and leading to reduced dissolution. Mannitol and pregelatinized starch can compensate for the shortcomings of microcrystalline cellulose and improve the dissolution rate of enavogliflozin.

[0038] In one embodiment of the present invention, the enavogliflozin zone may contain a disintegrant selected from the group consisting of croscarmellose sodium, sodium starch glycolate, crospovidone, and low-substituted hydroxypropyl cellulose, and the disintegrant may be included in an amount of 5 to 20 parts by weight per 100 parts by weight of the total weight of the enavogliflozin zone. According to the following examples, it was confirmed that when the content of the disintegrant in the enavogliflozin zone is 25 parts by weight or more, the dissolution rate within 10 minutes is not 80% or more and the final dissolution rate is not 85% or more, resulting in an unfavorable dissolution profile in terms of bioavailability. This is because excessive use of the disintegrant actually lengthens the disintegration time and reduces the dissolution rate.

[0039] In one embodiment of the present invention, the enavogliflozin zone contains one or more of hard anhydrous silicic acid and talc as a lubricant, and the lubricant may be contained in an amount of 1.5 to 3 parts by weight per 100 parts by weight of the total weight of the enavogliflozin zone.

[0040] Meanwhile, in one embodiment of the present invention, the metformin zone contains sodium carboxymethylcellulose, povidone, or a mixture thereof as a binder, and the binder may be contained in an amount of 2 to 5 parts by weight based on 100 parts by weight of the total weight of the metformin zone.

[0041] In another embodiment, the metformin zone contains one or more of hydroxypropylmethylcellulose and polyethylene oxide as a sustained-release preparation, and the sustained-release preparation may be contained in an amount of 15 to 40 parts by weight per 100 parts by weight of the total weight of the metformin zone.

[0042] 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 2,000,000-5,000,000. If the viscosity of hydroxypropyl cellulose and the molecular weight of polyethylene oxide are low, the formation of the polymer matrix for sustained release may be incomplete, which may affect the drug release rate.

[0043] In one embodiment of the present invention, the metformin zone may contain magnesium stearate as a lubricant in an amount of 0.5 to 1 part by weight based on 100 parts by weight of the total weight of the metformin zone.

[0044] As disclosed in Patent Document 1, enavogliflozin has a drug characteristic of having a Tmax of 1 to 2 hours, and is preferably formulated into an immediate-release form to achieve appropriate Cmax and AUC.

[0045] Preferably, in the pharmaceutical composition according to the present invention, the dissolution rate of the enavogliflozin or a pharmaceutically acceptable salt thereof in a dissolution medium of pH 1.2 after 10 minutes is 75% or more, preferably 80% or more, of the total content of the enavogliflozin or a pharmaceutically acceptable salt thereof.

[0046] Preferably, in the pharmaceutical composition according to the present invention, the dissolution rate of the enavogliflozin or a pharmaceutically acceptable salt thereof in a pH 1.2 dissolution medium after 45 minutes is 80% or more, preferably 85% or more, of the total content of the enavogliflozin or a pharmaceutically acceptable salt thereof.

[0047] The dissolution rate of an active ingredient in a pharmaceutical composition affects the maximum blood concentration (Cmax) and area under the blood concentration-time curve (AUC) upon drug administration. Conversely, adjusting the dissolution rate of a pharmaceutical composition is important to achieve an appropriate Cmax and AUC. Since enavogliflozin has a Tmax of 1-2 hours, the drug absorption rate in the stomach is considered important. The dissolution rate was measured under conditions of dissolution medium 1.2 according to Method 2 (paddle method) of the Korean Pharmacopoeia for dissolution testing. Specific conditions may be found in the following experimental examples.

[0048] When metformin is formulated into a general tablet, rapid drug release may cause excessive hypoglycemia or gastrointestinal disorders, so it is preferable to formulate it as a sustained-release tablet.

[0049] Preferably, in the pharmaceutical composition according to the present invention, the dissolution rate of the metformin or pharmaceutically acceptable salt thereof in a pH 6.8 dissolution medium after 1 hour is 15 to 35%, preferably 20% or more, of the total content of metformin or a pharmaceutically acceptable salt thereof.

[0050] Preferably, in the pharmaceutical composition according to the present invention, the dissolution rate of the metformin or pharmaceutically acceptable salt thereof in a pH 6.8 dissolution medium after 3 hours is 40 to 60%, preferably 45% or more, of the total content of metformin or a pharmaceutically acceptable salt thereof.

[0051] Preferably, in the pharmaceutical composition according to the present invention, the dissolution rate of the metformin or pharmaceutically acceptable salt thereof in a pH 6.8 dissolution medium after 12 hours is 80% or more, preferably 85% or more, of the total content of metformin or a pharmaceutically acceptable salt thereof.

[0052] Metformin has a Tmax of approximately 4 hours before meals and approximately 6 hours after meals, so the drug absorption rate in the intestine is considered important. The dissolution rate was measured according to Method 1 of the Korean Pharmacopoeia's Dissolution Test (rotating basket method) under conditions of a dissolution medium pH of 6.8. Specific conditions may be found in the following experimental examples.

[0053] The pharmaceutical composition according to the present invention may further contain pharmaceutically acceptable additives in addition to the ingredients listed above. Examples of such additives include lubricants, colorants, etc.

[0054] The lubricants include stearic acid, stearates (e.g., magnesium stearate), hard anhydrous silicic acid, talc, corn starch, canauba wax, magnesium silicate, synthetic aluminum silicate, hydrogenated oil, white lead, titanium oxide, microcrystalline cellulose, macrogol 4000 and 6000, isopropyl myristate, calcium hydrogen phosphate, and mixtures thereof.

[0055] In one embodiment of the present invention, the enavogliflozin zone comprises a granule obtained by mixing pre-blended granules containing enavogliflozin or a pharmaceutically acceptable salt thereof and a post-blended portion.

[0056] In the course of research into formulations of enavogliflozin, the present inventors have confirmed that producing granules and formulating them into tablets or the like is advantageous in terms of uniformity of the drug content and formulation uniformity.

[0057] The granules in the enavogliflozin zone are produced by mixing the pre-mixed granules with the post-mixing section.

[0058] The pre-blended granules may contain enavogliflozin or a pharmaceutically acceptable salt thereof, an excipient, and a lubricant, and the post-blending section may contain an excipient, a disintegrant, and a lubricant.

[0059] The explanations for the excipients, disintegrants, lubricants, etc. in the enavogliflozin zone are the same as those described above, so they will be omitted to avoid duplication.

[0060] In an embodiment of the present invention, the pre-blended granules in the enavogliflozin zone and the post-blended zone may each contain one or more excipients.

[0061] In one embodiment of the present invention, the pre-blended granules in the enavogliflozin zone may contain microcrystalline cellulose, and the post-blended zone may contain mannitol and pregelatinized starch.

[0062] The weight ratio of the excipient in the pre-blended granules to the excipient in the post-blended zone in the enavogliflozin zone may be 1:1 to 1:4.

[0063] It was found that the higher the proportion of microcrystalline cellulose in the pre-mixed granules in the enavogliflozin zone, the lower the dissolution rate may be, and therefore it is preferable to adjust the weight ratio within an appropriate range.

[0064] Without being limited thereto, the granules in the enavogliflozin zone of the pharmaceutical composition of the present invention may be dry granules. Dry granulation allows the formation of granules with a suitable particle size distribution and provides excellent flow and compression during the tableting process, minimizing weight variation among individual tablets. Dry granules play an important role in preparing bilayer tablets with a uniform enavogliflozin content. In another embodiment, the granules may be wet granules.

[0065] In one embodiment of the present invention, the metformin zone comprises a granule obtained by mixing pre-mixed granules containing metformin or a pharmaceutically acceptable salt thereof and a post-mixed portion.

[0066] In the case of metformin zone, the content of the main ingredient metformin is very high and the physical properties are poor, so it is preferable to manufacture it in the form of wet or dry granules to avoid various problems in the manufacturing process such as poor tableting and poor coating.

[0067] The granules in the metformin zone may be wet granules, but are not limited thereto. Alternatively, they may be dry granules.

[0068] The granules in the metformin zone are produced by mixing the pre-mixed granules with the post-mixing section.

[0069] The pre-blended granules may contain metformin or a pharmaceutically acceptable salt thereof and a binder, and the post-blended portion may contain a sustained-release formulation and a lubricant.

[0070] The explanations for the binder, sustained release formulation, lubricant, etc. in the metformin zone are the same as those described above, so they will be omitted to avoid duplication.

[0071] Meanwhile, in the present invention, the pharmaceutical composition may have a dosage form for oral administration, such as a tablet. In one embodiment of the present invention, the pharmaceutical composition may have a tablet dosage form. In a preferred embodiment, the pharmaceutical composition may have a bilayer tablet dosage form.

[0072] In one embodiment of the present invention, the pharmaceutical composition may contain enavogliflozin in a dose of 0.1 to 0.5 mg, preferably 0.15 mg or 0.3 mg.

[0073] In a preferred embodiment, the pharmaceutical composition may contain metformin in a dose of 500 mg to 1000 mg, preferably 500 mg, 750 mg, or 1000 mg.

[0074] The pharmaceutical composition according to the present invention is orally administered once a day, but is not limited thereto. [Effects of the Invention]

[0075] The pharmaceutical composition according to the present invention embodies an excellent formulation that provides the same level of efficacy as a combination therapy of metformin alone and enavogliflozin alone, despite the very different contents of metformin and enavogliflozin. [Brief explanation of the drawings]

[0076] [Figure 1]1 is a graph comparing the dissolution rates of enavogliflozin from the preparations of Examples 1 to 4 and Comparative Examples 1 and 2 with those of the control drug under a pH 1.2 condition. [Figure 2] 1 is a graph comparing the dissolution rates of enavogliflozin from the preparations of Example 1, Examples 5 and 6, and Comparative Example 3 with those of a control drug under a pH 1.2 condition. [Figure 3] 1 is a graph comparing the dissolution rates of enavogliflozin from the preparations of Example 1, Examples 7 to 10, and Comparative Example 4 with those of a control drug under a pH 1.2 condition. [Figure 4] 1 is a graph comparing the dissolution rates of metformin hydrochloride from the preparations of Examples 1 and 11 to 17 with those of a control drug under a pH 1.2 condition. DETAILED DESCRIPTION OF THE INVENTION

[0077] Although preferred examples are presented below to aid in understanding the present invention, the following examples are merely illustrative of the present invention and the scope of the present invention is not limited to the following examples. In addition, although preferred methods and samples are described in this specification, similar or equivalent methods and samples are also included in the scope of the present invention. [Example]

[0078] Example 1 Step 1: Preparation of granules containing enavogliflozin Granules containing enavogliflozin were prepared according to the composition of the enavogliflozin portion shown in Table 1 below. Enavoliflozin was mixed with microcrystalline cellulose, hard anhydrous silicic acid, and talc, and the resulting dry granules were compressed into plates and pulverized in a Comil to prepare dry granules. Mannitol, pregelatinized starch, croscarmellose sodium, talc, and a pigment blend were then added to and mixed with the dry granules to prepare enavogliflozin granules.

[0079] Step 2: Preparation of granules containing metformin hydrochloride Granules containing metformin hydrochloride were prepared according to the composition of the metformin portion in Table 1 below. Metformin hydrochloride and sodium carboxymethylcellulose were mixed and dried together using water as a binder. The dried product was sized to prepare wet granules, which were then mixed with hydroxypropylmethylcellulose (average viscosity 100,000 mPa.s) and magnesium stearate to prepare metformin hydrochloride granules.

[0080] Step 3: Manufacturing the combination tablet Using a bilayer tablet press, metformin hydrochloride granules were placed in the first layer and enavogliflozin granules in the second layer to form bilayer tablets, producing bilayer composite tablets containing 1000 mg of metformin hydrochloride and 0.3 mg of enavogliflozin.

[0081] [Table 1]

[0082] Comparative Examples 1-2 Step 1: Preparation of granules containing enavogliflozin Granules containing enavogliflozin were produced according to the composition of the enavogliflozin portion in Table 2 below. Enavogliflozin was mixed with microcrystalline cellulose, hard anhydrous silicic acid, and talc, and the resulting dry granules were compressed to prepare a plate-shaped compressed product. These were then pulverized using a Comil to prepare dry granules, and croscarmellose sodium, talc, and a pigment blend were mixed to prepare the enavogliflozin granules of Comparative Example 1. Enavogliflozin was mixed with pregelatinized starch, hard anhydrous silicic acid, and talc, and the resulting dry granules were compressed to produce a plate-like compressed product. These were then pulverized using a Comil to produce dry granules, and pregelatinized starch, croscarmellose sodium, talc, and a pigment blend were mixed to produce the enavogliflozin granules of Comparative Example 2.

[0083] Step 2: Preparation of granules containing metformin hydrochloride Granules containing metformin hydrochloride were prepared according to the composition of the metformin portion in Table 2 below. Metformin hydrochloride and sodium carboxymethylcellulose were mixed and dried together using water as a binder. The dried product was sized to prepare wet granules, which were then mixed with hydroxypropylmethylcellulose (average viscosity 100,000 mPa.s) and magnesium stearate to prepare metformin hydrochloride granules.

[0084] Step 3: Manufacturing the combination tablet Using the same method as in Example 1, a bilayer tablet was compressed using a bilayer tablet press with metformin hydrochloride granules as the first layer and enavogliflozin granules as the second layer to prepare a bilayer composite tablet containing 1000 mg of metformin hydrochloride and 0.3 mg of enavogliflozin.

[0085] [Table 2]

[0086] Examples 2 to 4 Step 1: Preparation of granules containing enavogliflozin Granules containing enavogliflozin were produced according to the composition of the enavogliflozin portion in Table 3 below. Enavogliflozin was mixed with microcrystalline cellulose, lactose hydrate, hard anhydrous silicic acid, and talc, and the resulting dry granules were compressed to produce a plate-shaped compressed product. These were then pulverized using a Comil to produce dry granules, and croscarmellose sodium, talc, and a pigment blend were mixed to produce the enavogliflozin granules of Example 2. Enavogliflozin was mixed with lactose hydrate, hard anhydrous silicic acid, and talc, and the resulting dry granules were compressed to produce a plate-shaped compressed product. These were then pulverized using a Comil to produce dry granules, and croscarmellose sodium, talc, and a pigment blend were mixed to produce the enavogliflozin granules of Example 3. Enavogliflozin was mixed with mannitol, hard anhydrous silicic acid, and talc, and the resulting dry granules were compressed to prepare a plate-shaped compressed product. These were then pulverized using a Comil to prepare dry granules, and mannitol, croscarmellose sodium, talc, and a pigment blend were mixed to prepare the enavogliflozin granules of Example 3.

[0087] Step 2: Preparation of granules containing metformin hydrochloride Granules containing metformin hydrochloride were prepared according to the composition of the metformin portion in Table 3 below. Metformin hydrochloride and sodium carboxymethylcellulose were mixed and dried together using water as a binder. The dried product was sized to prepare wet granules, which were then mixed with hydroxypropylmethylcellulose (average viscosity 100,000 mPa.s) and magnesium stearate to prepare metformin hydrochloride granules.

[0088] Step 3: Manufacturing the combination tablet Using the same method as in Example 1, a bilayer tablet was compressed using a bilayer tablet press with metformin hydrochloride granules as the first layer and enavogliflozin granules as the second layer to prepare a bilayer composite tablet containing 1000 mg of metformin hydrochloride and 0.3 mg of enavogliflozin.

[0089] [Table 3]

[0090] Comparative Example 3 Step 1: Preparation of granules containing enavogliflozin Granules containing enavogliflozin were produced according to the composition of the enavogliflozin portion in Table 4 below. Enavogliflozin was mixed with microcrystalline cellulose, hard anhydrous silicic acid, and talc, and the resulting dry granules were compressed to prepare a plate-shaped compressed product. These were then pulverized using a Comil to prepare dry granules, and mannitol, pregelatinized starch, croscarmellose sodium, talc, and a pigment blend were mixed to prepare the enavogliflozin granules of Comparative Example 3.

[0091] Step 2: Preparation of granules containing metformin hydrochloride Granules containing metformin hydrochloride were produced according to the composition of the metformin portion in Table 4 below. Metformin hydrochloride and sodium carboxymethylcellulose were mixed and dried using water as a binder. The dried mixture was sized to produce wet granules, which were then mixed with hydroxypropylmethylcellulose (average viscosity 100,000 mPa.s) and magnesium stearate to produce metformin hydrochloride granules.

[0092] Step 3: Manufacturing the combination tablet Using the same method as in Example 1, a bilayer tablet was compressed using a bilayer tablet press with metformin hydrochloride granules as the first layer and enavogliflozin granules as the second layer to prepare a bilayer composite tablet containing 1000 mg of metformin hydrochloride and 0.3 mg of enavogliflozin.

[0093] [Table 4]

[0094] Examples 5-6 Step 1: Preparation of granules containing enavogliflozin Granules containing enavogliflozin were produced according to the composition of the enavogliflozin portion in Table 5 below. Enavogliflozin was mixed with microcrystalline cellulose, hard anhydrous silicic acid, and talc, and the resulting dry granules were compressed to prepare a plate-shaped compressed product. These were then pulverized using a Comil to prepare dry granules, and mannitol, pregelatinized starch, croscarmellose sodium, talc, and a pigment blend were mixed to prepare the enavogliflozin granules of Examples 5 and 6.

[0095] Step 2: Preparation of granules containing metformin hydrochloride Granules containing metformin hydrochloride were produced according to the composition of the metformin portion in Table 5 below. Metformin hydrochloride and sodium carboxymethylcellulose were mixed and dried using water as a binder. The dried mixture was sized to produce wet granules, which were then mixed with hydroxypropylmethylcellulose (average viscosity 100,000 mPa.s) and magnesium stearate to produce metformin hydrochloride granules.

[0096] Step 3: Manufacturing the combination tablet Using the same method as in Example 1, a bilayer tablet was compressed using a bilayer tablet press with metformin hydrochloride granules as the first layer and enavogliflozin granules as the second layer to prepare a bilayer composite tablet containing 1000 mg of metformin hydrochloride and 0.3 mg of enavogliflozin.

[0097] [Table 5]

[0098] Comparative Example 4 Step 1: Preparation of granules containing enavogliflozin Granules containing enavogliflozin were produced according to the composition of the enavogliflozin portion in Table 6 below. Enavogliflozin was mixed with microcrystalline cellulose, hard anhydrous silicic acid, and talc, and the dry granules were compressed to prepare a plate-shaped compressed product. The product was then pulverized using a Comil to prepare dry granules, which were then mixed with mannitol, pregelatinized starch, croscarmellose sodium, talc, and a pigment blend to prepare the enavogliflozin granules of Comparative Example 4.

[0099] Step 2: Preparation of granules containing metformin hydrochloride Granules containing metformin hydrochloride were produced according to the composition of the metformin portion in Table 6 below. Metformin hydrochloride and sodium carboxymethylcellulose were mixed and dried using water as a binder. The dried mixture was sized to produce wet granules, which were then mixed with hydroxypropylmethylcellulose (average viscosity 100,000 mPa.s) and magnesium stearate to produce metformin hydrochloride granules.

[0100] Step 3: Manufacturing the combination tablet Using the same method as in Example 1, a bilayer tablet was compressed using a bilayer tablet press with metformin hydrochloride granules as the first layer and enavogliflozin granules as the second layer to prepare a bilayer composite tablet containing 1000 mg of metformin hydrochloride and 0.3 mg of enavogliflozin.

[0101] [Table 6]

[0102] Examples 7 to 10 Step 1: Preparation of granules containing enavogliflozin Granules containing enavogliflozin were produced according to the composition of the enavogliflozin portion in Table 7 below. Enavogliflozin was mixed with microcrystalline cellulose, hard anhydrous silicic acid, and talc, and the resulting dry granules were compressed to prepare a plate-shaped compressed product. These were then pulverized using a Comil to prepare dry granules, and mannitol, pregelatinized starch, croscarmellose sodium, talc, and a pigment blend were mixed to prepare the enavogliflozin granules of Example 7. The dry granules were mixed with mannitol, pregelatinized starch, sodium starch glycolate, talc, and a pigment blend to produce enavogliflozin granules of Example 8. The dry granules were mixed with mannitol, pregelatinized starch, crospovidone, talc, and a pigment blend to produce enavogliflozin granules of Example 9. The dry granules were mixed with mannitol, pregelatinized starch, and low-substituted hydroxypropyl cellulose to prepare enavogliflozin granules of Example 10.

[0103] Step 2: Preparation of granules containing metformin hydrochloride Granules containing metformin hydrochloride were produced according to the composition of the metformin portion in Table 7 below. Metformin hydrochloride and sodium carboxymethylcellulose were mixed and dried using water as a binder. The dried mixture was sized to produce wet granules, which were then mixed with hydroxypropylmethylcellulose (average viscosity 100,000 mPa.s) and magnesium stearate to produce metformin hydrochloride granules.

[0104] Step 3: Manufacturing the combination tablet Using the same method as in Example 1, a bilayer tablet was compressed using a bilayer tablet press with metformin hydrochloride granules as the first layer and enavogliflozin granules as the second layer to prepare a bilayer composite tablet containing 1000 mg of metformin hydrochloride and 0.3 mg of enavogliflozin.

[0105] [Table 7]

[0106] Examples 11 to 14 Step 1: Preparation of granules containing enavogliflozin Granules containing enavogliflozin were produced according to the composition of the enavogliflozin portion in Table 8 below. Enavogliflozin was mixed with microcrystalline cellulose, hard anhydrous silicic acid, and talc, and the dry granules were compressed to produce a plate-shaped compressed product, which was then pulverized using a Comil to produce dry granules. Mannitol, pregelatinized starch, croscarmellose sodium, talc, and a pigment blend were added and mixed to produce enavogliflozin granules.

[0107] Step 2: Preparation of granules containing metformin hydrochloride Granules containing metformin hydrochloride were produced according to the composition of the metformin portion in Table 8 below. Metformin hydrochloride and povidone were mixed and dried using water as a binder. The dried mixture was sized to prepare wet granules, which were then mixed with hydroxypropylmethylcellulose (average viscosity 100,000 mPa.s) and magnesium stearate to prepare metformin hydrochloride granules of Example 11. Hydroxypropylmethylcellulose (average viscosity 200,000 mPa·s) and magnesium stearate were added to the wet granules and mixed to prepare metformin hydrochloride granules of Example 12. The wet granules were mixed with polyethylene oxide (average molecular weight 2,000,000) and magnesium stearate to prepare metformin hydrochloride granules of Example 13. The wet granules were mixed with polyethylene oxide (average molecular weight 5,000,000) and magnesium stearate to prepare metformin hydrochloride granules of Example 14.

[0108] Step 3: Manufacturing the combination tablet Using the same method as in Example 1, a bilayer tablet was compressed using a bilayer tablet press with metformin hydrochloride granules as the first layer and enavogliflozin granules as the second layer to prepare a bilayer composite tablet containing 1000 mg of metformin hydrochloride and 0.3 mg of enavogliflozin.

[0109] [Table 8]

[0110] Examples 15 to 17 Step 1: Preparation of granules containing enavogliflozin Granules containing enavogliflozin were produced according to the composition of the enavogliflozin portion in Table 9 below. Enavogliflozin was mixed with microcrystalline cellulose, hard anhydrous silicic acid, and talc, and the dry granules were compressed to produce a plate-shaped compressed product, which was then pulverized using a Comil to produce dry granules. Mannitol, pregelatinized starch, croscarmellose sodium, talc, and a pigment blend were then added and mixed to produce enavogliflozin granules.

[0111] Step 2: Preparation of granules containing metformin hydrochloride Granules containing metformin hydrochloride were prepared according to the composition of the metformin portion in Table 9 below. Metformin hydrochloride and sodium carboxymethylcellulose were mixed and then dried together using water as a binder. The dried product was sized to prepare wet granules, which were then mixed with hydroxypropylmethylcellulose (average viscosity 200,000 mPa s) and magnesium stearate to prepare metformin hydrochloride granules of Example 15. The wet granules were mixed with polyethylene oxide (average molecular weight 2,000,000) and magnesium stearate to prepare metformin hydrochloride granules of Example 16. The wet granules were mixed with polyethylene oxide (average molecular weight 5,000,000) and magnesium stearate to prepare metformin hydrochloride granules of Example 17.

[0112] Step 3: Manufacturing the combination tablet Using the same method as in Example 1, a bilayer tablet was compressed using a bilayer tablet press with metformin hydrochloride granules as the first layer and enavogliflozin granules as the second layer to prepare a bilayer composite tablet containing 1000 mg of metformin hydrochloride and 0.3 mg of enavogliflozin.

[0113] [Table 9]

[0114] Experimental example 1: Hardness test The hardness test is a test to physically measure the degree of hardness of an oral dosage form (unit: kP). The test method involved placing a tablet on a hardness tester to measure the hardness, and the test was performed on tablets manufactured in each of the Examples and Comparative Examples. The tableting pressure applied to the tablets was set to 25 to 28 kN, and the results of the tablet hardness measurements are shown in Table 10 below.

[0115] [Table 10]

[0116] As a result of the hardness test, all the produced tablets showed a hardness of 15 kP or more, confirming that there were no problems in tablet production.

[0117] Experimental Example 2: Disintegration test According to the disintegration test method among the general testing methods in the Korean Pharmacopoeia, a disintegration test was carried out on the enavogliflozin layers of Comparative Examples 1 to 4 and Examples 1 to 10. The results are shown in Table 11 below.

[0118] [Table 11]

[0119] The disintegration test is a test method to check whether tablets, capsules, granules, pills, and suppositories disintegrate (crumble or disperse into a specified particle size or less) in a test solution within a specified time under specified conditions. It does not check whether the active ingredient of the formulation is completely dissolved, but it can predict to some extent the dissolution, which indicates the degree of dissolution in the solvent. As a result of the disintegration test, it was confirmed that the comparative example disintegrated relatively slowly compared to the examples.

[0120] Experimental Example 3: Stability evaluation The dosage forms of Example 1 were sealed in HDPE (High Density Polyethylene) bottles and stored under long-term test conditions (25°C, 60% RH), and the contents of enavogliflozin and metformin and the amounts of related substances were measured by liquid chromatography at 3, 6, 9, and 12 months after storage.The dosage forms of Example 1 were also stored under accelerated test conditions (40°C, 75% RH), and the contents of enavogliflozin and metformin and the amounts of related substances were measured by liquid chromatography at 1, 3, and 6 months after storage.The results are shown in Tables 12 and 13 below.

[0121] [Table 12]

[0122] [Table 13]

[0123] As shown in Tables 12 and 13, stability was confirmed under long-term and accelerated test conditions for 12 months through stability tests using the contents and related substances of Example 1. In addition, it was confirmed that the amount of NDMA (N-nitrosodimethylamine), a carcinogen, generated was below the maximum daily allowable amount (48 nanograms, 0.048 ppb), which is the provisional management standard, when taken at a maximum of 2,000 mg per day.

[0124] Experimental Example 4: Dissolution test Dissolution tests were carried out on the enavogliflozin and metformin prepared in Comparative Examples 1 to 4 and Examples 1 to 17 under the same conditions as those described in Tables 14 and 15 below in accordance with the dissolution test method of the Korean Pharmacopoeia. To compare the dissolution rate with that of the combination tablet of the present invention, Daewoong Pharmaceutical's "Embro Tablets," a single agent of enavogliflozin, and Merck's "Glucophage XR Sustained-Release Preparation 1000 mg," a single agent of metformin, were also tested under the same conditions as those of the combination tablet of the present invention.

[0125] [Table 14]

[0126] [Table 15]

[0127] The results of the dissolution test of enavogliflozin are shown in Tables 16 to 18 below and Figures 1 to 3.

[0128] [Table 16]

[0129] [Table 17]

[0130] [Table 18]

[0131] Since enavogliflozin is a component with a Tmax of approximately 1 hour, its dissolution in gastric juice is expected to have a significant effect on its bioavailability. Therefore, the dissolution rate at pH 1.2 is considered to be important, and Comparative Examples 1 to 4, which do not show a dissolution rate of 80% or more within 10 minutes and a final dissolution rate of 85% or more, are considered to be unfavorable in terms of bioavailability.

[0132] The results of the metformin dissolution test are shown in Table 19 below and Figure 4.

[0133] [Table 19]

[0134] In all examples, the metformin dissolution rate was confirmed to be equivalent when, as specified by the pharmaceutical equivalence test standards, i) the difference in average dissolution rate between the control drug and the test drug was within 15% at all dissolution rate comparison time points, and ii) the similarity factor (f2) was 50 or more at all dissolution rate measurement times as comparison time points.

[0135] Experimental Example 5: Clinical Trial A pharmacokinetic study (PK study) was conducted on the pharmaceutical composition of Example 1 to evaluate its bioequivalence with a control drug. According to the bioequivalence test standards for pharmaceutical equivalence tests in the Pharmacist Law-related Law Collection, the pharmaceutical equivalence test is deemed equivalent if the 90% confidence interval for the logarithmically transformed mean difference between the control drug and the test drug is within log0.8 to log1.25 for both items. The pharmaceutical composition of Example 1 was selected as the test drug, and a clinical trial was conducted to compare the blood concentrations of each drug using a control group consisting of a combination of Daegu Pharmaceutical's "Embro Tablets," a single agent of enavogliflozin, and Merck's "Glucophage XR sustained-release preparation 1000 mg," a single agent of metformin. The clinical trial was a randomized, two-arm, phase IV crossover study (before and after meals), and blood samples were taken at appropriate times after administration. Plasma concentrations of enavogliflozin and metformin were then measured, and pharmacokinetic parameters (AUC and Cmax) were calculated and evaluated.

[0136] [Table 20]

[0137] [Table 21]

[0138] As a result of the test, it was confirmed that the pharmaceutical composition of Example 1, both before and after meals, exhibited bioequivalence with the combined administration of the control drug.

Claims

1. A pharmaceutical composition in a single formulation, comprising: a zone containing metformin or a pharmaceutically acceptable salt thereof; and a zone containing enavogliflozin or a pharmaceutically acceptable salt thereof, wherein the zones are formulated in a manner separated from each other, The enavogliflozin zone is contained in an amount of 10 to 20 parts by weight per 100 parts by weight of the total pharmaceutical composition; A pharmaceutical composition, wherein the enavogliflozin zone contains enavogliflozin or a pharmaceutically acceptable salt thereof in an amount of less than 0.3 parts by weight per 100 parts by weight of the total weight of the enavogliflozin zone.

2. The enavogliflozin zone contains enavogliflozin or a pharmaceutically acceptable salt thereof, an excipient, a disintegrant, and a lubricant, 2. The pharmaceutical composition according to claim 1, wherein the metformin zone comprises metformin or a pharmaceutically acceptable salt thereof, a binder, a sustained-release formulation, and a lubricant.

3. 2. The pharmaceutical composition according to claim 1, wherein the enavogliflozin zone comprises an excipient selected from the group consisting of lactose hydrate; mannitol; a mixture of microcrystalline cellulose and lactose hydrate; and a mixture of microcrystalline cellulose, mannitol, and pregelatinized starch, and the excipient is included in an amount of 80 to 85 parts by weight per 100 parts by weight of the total weight of the enavogliflozin zone.

4. 2. The pharmaceutical composition according to claim 1, wherein when the enavogliflozin zone contains lactose hydrate as an excipient, the lactose hydrate is contained in an amount of 40 to 100 parts by weight, relative to 100 parts by weight of the total weight of all excipients in the enavogliflozin zone.

5. 2. The pharmaceutical composition according to claim 1, wherein, when the enavogliflozin zone contains mannitol as an excipient, the mannitol is contained in an amount of 20 to 100 parts by weight, relative to 100 parts by weight of the total weight of all excipients in the enavogliflozin zone.

6. 2. The pharmaceutical composition according to claim 1, wherein when the enavogliflozin zone contains microcrystalline cellulose as an excipient, the microcrystalline cellulose is contained in an amount of less than 65 parts by weight out of 100 parts by weight of the total weight of all excipients in the enavogliflozin zone.

7. 2. The pharmaceutical composition according to claim 1, wherein when the enavogliflozin zone contains pregelatinized starch as an excipient, the pregelatinized starch is contained in an amount of 5 to 40 parts by weight, relative to 100 parts by weight of the total weight of all excipients in the enavogliflozin zone.

8. 2. The pharmaceutical composition according to claim 1, wherein when the enavogliflozin zone contains microcrystalline cellulose, mannitol, and pregelatinized starch as excipients, the mannitol is contained in an amount of 20 to 65 parts by weight relative to 100 parts by weight of the total weight of all excipients in the enavogliflozin zone.

9. 2. The pharmaceutical composition according to claim 1, wherein when the enavogliflozin zone contains microcrystalline cellulose, mannitol, and pregelatinized starch as excipients, the microcrystalline cellulose, mannitol, and pregelatinized starch in the enavogliflozin zone are contained in a weight ratio of 1:0.5-2:0.15-1.

5.

10. 2. The pharmaceutical composition according to claim 1, wherein the enavogliflozin zone comprises a disintegrant selected from the group consisting of croscarmellose sodium, sodium starch glycolate, crospovidone, and low-substituted hydroxypropyl cellulose, and the disintegrant is contained in an amount of 5 to 20 parts by weight per 100 parts by weight of the total weight of the enavogliflozin zone.

11. 2. The pharmaceutical composition according to claim 1, wherein the enavogliflozin zone contains one or more of hard anhydrous silicic acid and talc as a lubricant, and the lubricant is contained in an amount of 1.5 to 3 parts by weight per 100 parts by weight of the total weight of the enavogliflozin zone.

12. The pharmaceutical composition according to claim 1, wherein the metformin zone contains sodium carboxymethylcellulose, povidone, or a mixture thereof as a binder, and the binder is contained in an amount of 2 to 5 parts by weight per 100 parts by weight of the total weight of the metformin zone.

13. 2. The pharmaceutical composition according to claim 1, wherein the metformin zone contains one or more of hydroxypropyl methylcellulose and polyethylene oxide as a sustained-release formulation, and the sustained-release formulation is contained in an amount of 15 to 40 parts by weight per 100 parts by weight of the total weight of the metformin zone.

14. 2. The pharmaceutical composition according to claim 1, wherein the metformin zone contains magnesium stearate as a lubricant in an amount of 0.5 to 1 part by weight per 100 parts by weight of the total weight of the metformin zone.

15. 2. The pharmaceutical composition according to claim 1, wherein the dissolution rate of the enavogliflozin or a pharmaceutically acceptable salt thereof in a pH 1.2 dissolution medium after 10 minutes is 80% or more of the total content of the enavogliflozin or a pharmaceutically acceptable salt thereof.

16. 2. The pharmaceutical composition according to claim 1, wherein the dissolution rate of the enavogliflozin or a pharmaceutically acceptable salt thereof in a pH 1.2 dissolution medium after 45 minutes is 85% or more of the total content of the enavogliflozin or a pharmaceutically acceptable salt thereof.

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

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

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

20. 2. The pharmaceutical composition according to claim 1, wherein the enavogliflozin zone comprises a granule obtained by mixing pre-mixed granules containing enavogliflozin or a pharmaceutically acceptable salt thereof and a post-mixed portion.

21. 21. The pharmaceutical composition according to claim 20, wherein the pre-blended granules comprise enavogliflozin or a pharmaceutically acceptable salt thereof, an excipient, and a lubricant.

22. 21. The pharmaceutical composition according to claim 20, wherein the post-mixing section comprises an excipient, a disintegrant, and a lubricant.

23. 21. The pharmaceutical composition according to claim 20, wherein the pre-blended granules and the post-blended portion each contain one or more excipients.

24. 21. The pharmaceutical composition according to claim 20, wherein the weight ratio of the excipients in the pre-blended granules to the excipients in the post-blended portion is 1:1 to 1:

4.

25. 21. The pharmaceutical composition of claim 20, wherein the granules are dry granules.

26. 2. The pharmaceutical composition according to claim 1, wherein the metformin zone comprises a granule obtained by mixing pre-mixed granules containing metformin or a pharmaceutically acceptable salt thereof and a post-mixed portion.

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

28. The pharmaceutical composition of 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. 10. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition comprises enavogliflozin in a dose of 0.1 mg to 0.5 mg.

31. 10. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition comprises metformin in a dose of 500 mg to 1000 mg.

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