Complex formulation for oral administration comprising SGLT-2 inhibitor and method for preparing same

Abstract

The present invention relates to a pharmaceutical composition for oral administration, the composition comprising an SGLT-2 inhibitor and metformin for treating type 2 diabetes mellitus as active ingredients. The present invention provides a novel formulation that solves problems associated with existing complexes of metformin and enavogliflozin in the form of bilayer tablets, and a method for preparing same. The pharmaceutical composition according to the present invention provides the effect of simultaneously achieving process and physical stability (suppression of layer separation and reduction of breakage) and pharmaceutical quality (content uniformity and dissolution reproducibility).

Description

Oral combination formulation containing an SGLT-2 inhibitor and method for manufacturing the same

[0001] The present invention relates to an orally administered pharmaceutical composition comprising an SGLT-2 inhibitor and metformin as active ingredients for the treatment of type 2 diabetes.

[0002] Type 2 diabetes mellitus is a major chronic metabolic disease with a high prevalence worldwide, and metformin, a biguanide, is widely used as a first-line treatment for its treatment.

[0003] Metformin is a drug that effectively lowers blood glucose by inhibiting gluconeogenesis through the AMP-activated protein kinase (AMPK) activation mechanism in the liver and improving insulin sensitivity in peripheral tissues. In particular, it is used as a standard drug in the treatment of diabetes because it has a low risk of hypoglycemia and exhibits weight neutrality or weight reduction effects.

[0004] However, there are many patients for whom it is difficult to achieve sufficient blood sugar control with metformin alone. Accordingly, as a second-line treatment strategy for diabetes, drugs with various mechanisms of action, including sulfonylurea drugs, α-glucosidase inhibitors, DPP-4 inhibitors, and SGLT-2 inhibitors, are being administered in combination.

[0005] Among these, SGLT2 inhibitor drugs are gaining increasing importance as they effectively improve blood glucose levels by selectively blocking glucose reabsorption in the renal tubules, and are reported to additionally provide benefits regarding weight loss and cardiovascular disease. Inabogliflozin, a recently launched SGLT2 inhibitor, is a drug that treats type 2 diabetes through the selective inhibition of SGLT2; it demonstrates equivalent or superior efficacy with only 0.3 mg, which is less than one-thirtieth the dosage of existing SGLT2 inhibitors. Inabogliflozin received marketing approval after demonstrating superior efficacy in lowering HbA1c and fasting blood glucose, as well as safety, compared to existing drugs through Phase 3 clinical trials conducted on patients with type 2 diabetes.

[0006] Metformin can be administered at doses ranging from 500 mg to 2000 mg per day; however, when prescribed a 1000 mg single-dose tablet, patients often find it difficult to swallow orally due to the large size of the tablet. In particular, problems regarding reduced medication convenience arise when metformin is used in combination with other drugs. To address these issues with medication adherence, various metformin-based combination drugs for the treatment of diabetes have been developed, and combination drugs of SGLT-2 inhibitors and metformin have also been commercialized.

[0007] Previously reported combination products of inabogliflozin and metformin were manufactured as bilayer tablets in a dual-release formulation. Specifically, the inabogliflozin layer was developed as an immediate-release type, and the metformin layer was developed as a sustained-release type containing a high-viscosity swelling sustained-release agent.

[0008] However, these bilayer tablets have the following limitations:

[0009] 1) In the bilayer tablet, the inabogliflozin layer accounts for 200 mg (0.3 mg inabogliflozin) and the metformin layer accounts for 1360 mg (1000 mg metformin), with a total mass of 1560 mg. Although the drug content of inabogliflozin contained in the inabogliflozin layer is only 0.3 mg, there is a limitation in that the total mass of the combination product inevitably increases because the weight of the inabogliflozin layer relative to the metformin layer must be sufficiently secured for the drug to be compressed into a bilayer tablet, making oral administration of the combination product difficult.

[0010] 2) In the tableting process of a bilayer tablet, the metformin layer is filled first, and then the inabogliflozin layer is filled and compressed. If the weight of the metformin layer filled first is not accurately controlled, there is a risk that the weight precision of the inabogliflozin layer, which has a relatively small weight (about 12.8% of the total weight), will be reduced.

[0011] 3) Conventional uncoated tablet bilayer tablets have a simple manufacturing process and are easy to control the drug release rate, but they may lower patient compliance due to the unpleasant taste of the drug when taken.

[0012] 4) Due to the structural characteristics of bilayer tablets, lamination (layer separation) can easily occur at interlayer boundaries due to uneven powder distribution or insufficient interlayer compressive force. Additionally, the tablet hardness is lower compared to coated tablets, resulting in a greater risk of breakage from impact.

[0013] The present invention aims to provide a novel formulation and a method for manufacturing the same that resolves the problems of existing combination products of metformin and inabogliflozin in the form of bilayer tablets. To achieve this objective, it is necessary to design a formulation that takes into account the difference in content scale and the heterogeneity of release characteristics between the two active ingredients.

[0014] Specifically, the present invention aims to provide a composite composition that processesively controls the interaction between the two components and the problem of physical separation, while designing the inabogliflozin compartment with immediate-release characteristics and the metformin compartment with immediate-release or sustained-release characteristics as needed. To this end, the composition is compartmentalized into an inabogliflozin compartment and a metformin compartment, and drug coating and film coating are applied to control the dissolution profile while ensuring the mechanical strength of the tablet.

[0015] Furthermore, the present invention aims for a composite composition designed in this manner to simultaneously satisfy process and physical stability (inhibition of layer separation, reduction of breakage) and pharmaceutical quality (uniformity of content, content of impurities, reproducibility of dissolution).

[0016] The inventors confirmed through various studies on formulating a combination composition of metformin and inabogliflozin that the above technical problem can be achieved when the composition of the pharmaceutical composition is configured as follows.

[0017] Specifically, the present invention

[0018] A pharmaceutical composition of a single formulation comprising a compartment containing inabogliflozin or a pharmaceutically acceptable salt thereof; and a compartment containing metformin or a pharmaceutically acceptable salt thereof, wherein said compartments are formulated in a form separated from each other,

[0019] A compartment containing metformin or a pharmaceutically acceptable salt thereof forms a core, and a compartment containing inabogliflozin or a pharmaceutically acceptable salt thereof forms a shell surrounding the core.

[0020] The above-mentioned inabogliflozin compartment is included in an amount of 1 to 15 parts by weight per 100 parts by weight of the total pharmaceutical composition, and

[0021] The present invention provides a pharmaceutical composition in which inabogliflozin or a pharmaceutically acceptable salt thereof is included in an amount of 1.5 parts by weight or less per 100 parts by weight of the total inabogliflozin compartment.

[0022] As explained above, since the content of inabogliflozin in the formulation is very low, it is difficult to implement a single matrix formulation when configuring a combination composition with metformin. Therefore, it is desirable to physically separate and compartmentalize the composition into a compartment containing inabogliflozin or a pharmaceutically acceptable salt thereof (hereinafter also referred to as the 'inabogliflozin compartment' or 'inabogliflozin part') and a compartment containing metformin or a pharmaceutically acceptable salt thereof (hereinafter also referred to as the 'metformin compartment' or 'metformin part').

[0023] The inventors intended to design the inabogliflozin compartment with immediate-release characteristics and the metformin compartment with immediate-release or sustained-release characteristics as needed. Accordingly, the present invention provides a pharmaceutical composition of a single formulation in which the metformin compartment forms an inner layer, i.e., a core, and the inabogliflozin compartment forms an outer layer, i.e., a shell.

[0024] Inabogliflozin used as an active ingredient in the present invention can be synthesized through known prior art. In the present invention, inabogliflozin may be in a crystalline or amorphous form. For example, inabogliflozin may be inabogliflozin crystalline form A, crystalline form B, crystalline form C, crystalline form D, crystalline form E, or inabogliflozin amorphous form, which are reported to have the following X-ray diffraction spectra through Korean Patent Publication No. 2017-0142904 or Korean Patent Application No. 2022-0123673.

[0025] Crystalline Form A: A crystalline form having an X-ray diffraction (XRD) spectrum including peaks at a 2[θ] value 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°.

[0026] Crystalline Form B: Crystalline form having an X-ray diffraction (XRD) spectrum including peaks at a 2[θ] value 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°.

[0027] Crystalline form C: Crystalline form having an X-ray diffraction (XRD) spectrum including peaks at a 2[θ] value 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°.

[0028] Crystalline form D: Crystalline form having an X-ray diffraction (XRD) spectrum including peaks at a 2[θ] value 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°.

[0029] Crystalline form E: Crystalline form having an X-ray diffraction (XRD) spectrum including peaks at a 2[θ] value 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°.

[0030] The above crystal forms A, B, C, D, and E can each be identified by an X-ray diffraction spectrum having four or more, for example, four, five, six, seven, eight or more peaks at the 2[θ] value presented above.

[0031] In a specific embodiment of the present invention, the average particle size of inabogliflozin may be 15 µm or less, preferably 10 µm or less.

[0032] In a specific embodiment of the present invention, the inabogliflozin compartment may be included in an amount of 1 to 15 parts by weight, for example, 1.5 to 15 parts by weight, 3 to 14 parts by weight, 4 to 13 parts by weight, or 5 to 12 parts by weight, based on 100 parts by weight of the total pharmaceutical composition. Unlike conventional bilayer tablets, where a large amount of additives had to be included in the inabogliflozin layer to properly perform the tablet compression process, the pharmaceutical composition of the present invention does not require tablet compression and uses a coating process, so a relatively small amount of additives is included in the inabogliflozin compartment. This allows for a reduction in the total weight of the pharmaceutical composition, thereby improving the convenience of patient administration.

[0033] In a specific embodiment of the present invention, in the inabogliflozin compartment, inabogliflozin or a pharmaceutically acceptable salt thereof may be included in an amount of 1.5 parts by weight or less, for example, 0.1 to 1.5 parts by weight, 0.1 to 1.2 parts by weight, 0.1 to 1 part by weight, 0.1 to 0.8 parts by weight, 0.1 to 0.6 parts by weight, 0.1 to 0.5 parts by weight, 0.1 to 0.4 parts by weight, 0.2 to 0.4 parts by weight, 0.15 to 0.35 parts by weight, 0.2 to 0.35 parts by weight, or 0.25 to 0.35 parts by weight, based on a total of 100 parts by weight of the inabogliflozin compartment.

[0034] More specifically, in the pharmaceutical composition according to the present invention, the inabogliflozin compartment may comprise inabogliflozin or a pharmaceutically acceptable salt thereof, an excipient, and a coating agent.

[0035] In a specific embodiment of the present invention, one or more sugar alcohols such as mannitol, sorbitol, maltitol, lactitol, isomalt, polyglycitol, erythritol, inositol, etc., may be selected as excipients usable in the inabogliflozin compartment. The excipients may be included in an amount of 20 to 80 parts by weight, for example, 25 to 75 parts by weight, 30 to 70 parts by weight, or 35 to 60 parts by weight, based on a total of 100 parts by weight of the inabogliflozin compartment. By adjusting the ratio of the excipients, the drug dissolution rate of inabogliflozin can be controlled, and the amount of the coating layer can be controlled, thereby improving the quality of the finished product.

[0036] In a specific embodiment of the present invention, the coating agent usable in the inabogliflozin compartment may be one or more selected from the group consisting of hydroxypropylmethylcellulose, methylcellulose, hydroxypropylcellulose, ethylcellulose, polyvinyl alcohol, and polyvinyl alcohol-polyethylene glycol copolymer. Preferably, the coating agent may be polyvinyl alcohol. In a specific embodiment of the present invention, the coating agent may be included in an amount of 15 to 70 parts by weight, for example, 20 to 70 parts by weight, 25 to 70 parts by weight, 30 to 65 parts by weight, or 35 to 60 parts by weight, based on a total of 100 parts by weight of the inabogliflozin compartment.

[0037] Although not limited thereto, the weight ratio of the coating agent and the excipient within the above-mentioned inabogliflozin compartment may be 4:1 to 1:6, for example, 3:1 to 1:5, 3:1 to 1:4, for example, 4:1, 3:1, 3:2, 2:1, 1:1, 2:3, 1:2, 1:3, 3:5, 1:4, 1:5, etc.

[0038] In a specific embodiment of the present invention, the inabogliflozin compartment may additionally include a plasticizer. Although not limited thereto, the plasticizer may be one or more of polyethylene glycol, hydroxypropylcellulose, polyvinylpyrillidone, glycerol, triacetin, triethylene citrate, and castor oil. The plasticizer may be included in an amount of 0.1 to 10 parts by weight, for example, 1 to 5 parts by weight, per 100 parts by weight of the total inabogliflozin compartment.

[0039] Meanwhile, in the pharmaceutical composition of the present invention, the metformin compartment may include metformin or a pharmaceutically acceptable salt thereof, a binder, a sustained-release agent, and a lubricant.

[0040] Although not limited thereto, in one embodiment of the present invention, the metformin compartment may include one or more selected from the group consisting of low-viscosity hydroxypropylmethylcellulose, carboxymethylcellulose, and povidone as a binder. Although not limited thereto, the binder may be included in an amount of 2 to 10 parts by weight, for example, 2 to 8 parts by weight, per 100 parts by weight of the total metformin compartment.

[0041] Unless otherwise noted, the viscosity of hydroxypropylmethylcellulose mentioned in this specification refers to the viscosity (mPa·s) measured at 20°C by dissolving hydroxypropylmethylcellulose in water to prepare a 2% by weight aqueous solution.

[0042] Low viscosity hydroxypropylmethylcellulose means, but is not limited to, hydroxypropylmethylcellulose having a viscosity of 3 to 1,000 mPa·s, for example, 3 to 500 mPa·s, 10 to 200 mPa·s, 20 to 100 mPa·s, or 30 to 80 mPa·s.

[0043] In addition, the metformin compartment may include high-viscosity hydroxypropylmethylcellulose as a sustained-release agent. Although not limited thereto, the sustained-release agent may be included in an amount of 5 to 40 parts by weight, for example, 10 to 40 parts by weight, 10 to 35 parts by weight, 10 to 30 parts by weight, or 10 to 25 parts by weight, based on a total of 100 parts by weight of the metformin compartment.

[0044] High-viscosity hydroxypropylmethylcellulose means, but is not limited to, hydroxypropylmethylcellulose having a viscosity of 10,000 to 300,000 mPa·s, for example, 20,000 to 300,000 mPa·s, 50,000 to 300,000 mPa·s, 50,000 to 250,000 mPa·s, 80,000 to 250,000 mPa·s, 100,000 to 300,000 mPa·s, or 100,000 to 250,000 mPa·s.

[0045] In a specific embodiment of the present invention, the metformin compartment comprises colloidal anhydrous silica and magnesium stearate as a lubricant, and the lubricant may be included in an amount of 0.5 to 1 weight part per 100 weight parts of the total metformin compartment.

[0046] Although not limited thereto, in one embodiment of the present invention, the metformin compartment may comprise granules prepared by mixing wet granules comprising metformin or a pharmaceutically acceptable salt thereof, a binder and a sustained-release agent with a post-mixture comprising a sustained-release agent and a lubricant.

[0047] The pharmaceutical composition according to the present invention may additionally include pharmaceutically acceptable additives in addition to the components presented above.

[0048] As previously explained, when the pharmaceutical composition is formulated such that the metformin compartment forms the inner layer, i.e., the core, and the inabogliflozin compartment forms the outer layer, i.e., the shell, the composition may have the form of a coated tablet, although this is not limited thereto.

[0049] When the inabogliflozin compartment contains inabogliflozin or its pharmaceutically acceptable salt, excipient, and coating agent, the inabogliflozin portion is prepared into a coating solution and can coat a metformin core tablet.

[0050] In one embodiment of the present invention, the coated tablet may be formed by first coating a core containing metformin or a pharmaceutically acceptable salt thereof with a film coating agent, and secondarily coating it with a coating solution containing inabogliflozin or a pharmaceutically acceptable salt thereof, an excipient, and a coating base.

[0051] The film coating agent used in the present invention refers to a component used to protect a tablet from the external environment and to improve the mechanical strength and appearance of the tablet by forming a thin polymer film on the surface of the tablet. Any commercial film coating agent used in conventional tablet film coating processes may be used as such a film coating agent. Examples of the film coating agent include, but are not limited to, compositions comprising film-forming polymers such as the following: a hypromellose (HPMC)-based film coating composition; a film coating composition comprising polyvinyl alcohol (PVA) or a copolymer thereof; a film coating composition comprising hydroxypropyl cellulose (HPC) or hydroxyethyl cellulose (HEC); a film coating composition comprising an acrylic copolymer (e.g., methacrylate-alkyl acrylate copolymer), etc.

[0052] In particular, in the present invention, the film coating agent inhibits moisture absorption and serves as a physical and chemical separation layer from the coating layer additionally formed on the tablet. The primary coating of a metformin core tablet using a film coating agent, for example, Opadry, prevents interference between the metformin compartment and the inabogliflozin compartment, thereby preventing delayed drug release of inabogliflozin, and prevents the deterioration of the coated tablet's properties by preventing hygroscopicity of the metformin core tablet by the coating solution containing inabogliflozin. The film coating agent may be, for example, a commercial film coating composition containing hypromellose as a film-forming polymer (e.g., an HPMC-based film coating system), but is not limited thereto; any film coating composition commonly used may be used without limitation as long as it can achieve prevention of hygroscopicity of the tablet and separation from the upper coating layer. In one embodiment of the present invention, additionally, the coating tablet obtained through the first and second coatings may be tertiarily coated with a coating solution comprising a coating agent and titanium dioxide. The tertiary coating may be optionally performed for laser printing using titanium dioxide.

[0053] Although not limited thereto, in the pharmaceutical composition of the present invention, the shell, for example, the coating layer, may have a thickness of 0.1 to 0.3 mm.

[0054] Due to the characteristics of the drug, the inabogliflozin compartment has a Tmax of 1 to 2 hours, and it is desirable to formulate it as an immediate-release type to achieve appropriate Cmax and AUC.

[0055] Preferably, in the pharmaceutical composition according to the present invention, the dissolution rate of the inabogliflozin or its pharmaceutically acceptable salt in the pH 1.2 eluent after 10 minutes is 75% or more, preferably 80% or more, of the total content of inabogliflozin or its pharmaceutically acceptable salt.

[0056] Preferably, in the pharmaceutical composition according to the present invention, the dissolution rate of the inabogliflozin or its pharmaceutically acceptable salt in the pH 1.2 eluent after 45 minutes is 80% or more, preferably 85% or more, of the total content of inabogliflozin or its pharmaceutically acceptable salt.

[0057] The dissolution rate of an active ingredient in a pharmaceutical composition is the peak blood concentration (C) at the time of drug administration. max Since it affects the blood concentration-time curve (AUC), conversely, it is important to adjust the dissolution rate of the pharmaceutical composition to achieve appropriate Cmax and AUC. As Inabogliflozin has a Tmax of 1 to 2 hours, the drug absorption rate in the stomach is considered important. The above dissolution rate was measured under conditions 1.2 of the dissolution solution by the Korean Pharmacopoeia Dissolution Test Method 2 (Paddle Method). Specific conditions can be referenced in the following experimental examples.

[0058] It is desirable for the metformin compartment to be formulated as a sustained-release formulation because rapid drug release can cause excessive hypoglycemia and gastrointestinal disorders when formulated as a standard tablet.

[0059] Preferably, in the pharmaceutical composition according to the present invention, the dissolution rate of the metformin or its pharmaceutically acceptable salt in a pH 6.8 dissolution solution (basket method 100 rpm) after 1 hour is 15 to 35%, preferably 20% or more, of the total content of the metformin or its pharmaceutically acceptable salt.

[0060] Preferably, in the pharmaceutical composition according to the present invention, the dissolution rate of the metformin or its pharmaceutically acceptable salt in a pH 6.8 eluent (basket method 100 rpm) after 3 hours is 40 to 60%, preferably 45% or more, of the total content of the metformin or its pharmaceutically acceptable salt.

[0061] Preferably, in the pharmaceutical composition according to the present invention, the dissolution rate of the metformin or its pharmaceutically acceptable salt in a pH 6.8 dissolution solution (basket method 100 rpm) after 12 hours is 80% or more, preferably 85% or more, of the total content of the metformin or its pharmaceutically acceptable salt.

[0062] Since metformin has a Tmax of approximately 4 hours before meals and 6 hours after meals, the drug absorption rate in the intestines is considered important. The above dissolution rate was measured under conditions of a dissolution solution pH of 6.8 by the Korean Pharmacopoeia Dissolution Test Method 1 (Rotating Specimen Method). Specific conditions may be referenced in the experimental examples below.

[0063] In one embodiment of the present invention, the pharmaceutical composition may contain inabogliflozin in a dose of 0.1 to 0.5 mg, preferably 0.15 mg or 0.3 mg.

[0064] In one embodiment of the present invention, the pharmaceutical composition may contain metformin in a dose of 500 mg to 1000 mg. Preferably, the pharmaceutical composition may contain metformin in a dose of 500 mg, 750 mg, or 1000 mg.

[0065] In one embodiment of the present invention, the pharmaceutical composition may contain inabogliflozin in a dose of 0.3 mg and metformin in a dose of 1,000 mg. In another embodiment of the present invention, the pharmaceutical composition may contain inabogliflozin in a dose of 0.15 mg and metformin in a dose of 750 mg. In yet another embodiment of the present invention, the pharmaceutical composition may contain inabogliflozin in a dose of 0.3 mg and metformin in a dose of 500 mg.

[0066] The pharmaceutical composition according to the present invention may be administered orally once a day, but is not limited thereto.

[0067] The pharmaceutical composition according to the present invention enables the realization of an excellent formulation that provides a level of pharmacological efficacy equivalent to that of combination therapy with metformin single tablet and inabogliflozin single tablet, despite the large difference in content between metformin and inabogliflozin.

[0068] The present invention provides a novel formulation and a method for manufacturing the same that resolves the problems of existing combination drugs of metformin and inabogliflozin in the form of bilayer tablets. The pharmaceutical composition according to the present invention provides the effect of simultaneously satisfying process and physical stability (inhibition of layer separation, reduction of breakage) and pharmaceutical quality (uniformity of content, reproducibility of dissolution).

[0069] Figure 1 is a graph comparing the dissolution rates of inabogliflozin of the combination formulations of Examples 13 to 15 under water conditions.

[0070] Figure 2 is a graph comparing the dissolution rates of inabogliflozin of the combination formulations of Examples 16 to 20 under water conditions.

[0071] Figure 3 is a graph comparing the dissolution rates of inabogliflozin of the combination formulations of Examples 27 to 28 under water conditions.

[0072] Figure 4 is a graph comparing the dissolution rates of inabogliflozin of Example 29 and Comparative Example 2 under water conditions.

[0073] Figure 5 is a graph comparing the dissolution rates of inabogliflozin of Example 29 and Comparative Example 2 under pH 1.2 conditions.

[0074] Figure 6 is a graph comparing the dissolution rates of inabogliflozin of Example 29 and Comparative Example 2 under pH 4.5 conditions.

[0075] Figure 7 is a graph comparing the dissolution rates of inabogliflozin of Example 29 and Comparative Example 2 under pH 6.8 conditions.

[0076] FIG. 8 is a graph comparing the dissolution rates of inabogliflozin of Examples 30 to 32 and Comparative Example 2 under water conditions.

[0077] Figure 9 is a graph comparing the dissolution rates of metformin of Example 29 and Comparative Example 2 under water (paddle, 50 rpm) conditions.

[0078] Figure 10 is a graph comparing the dissolution rates of metformin in Example 29 and Comparative Example 2 under pH 4.5 (paddle, 50 rpm) conditions.

[0079] Figure 11 is a graph comparing the dissolution rates of metformin in Example 29 and Comparative Example 2 under pH 6.8 (paddle, 50 rpm) conditions.

[0080] Figure 12 is a graph comparing the dissolution rates of metformin in Example 29 and Comparative Example 2 under pH 6.8 (basket 100 rpm) conditions.

[0081] Figure 13 is a graph comparing the dissolution rates of metformin in Examples 30 to 31 and Comparative Example 3 under pH 6.8 (paddle, 50 rpm) conditions.

[0082] Preferred embodiments of the present invention will be described in detail below.

[0083] To aid in understanding the present invention, the following examples are provided; however, the following examples are merely illustrative of the invention and the scope of the invention is not limited to the following examples. Furthermore, while preferred methods or samples are described herein, similar or equivalents are also included within the scope of the invention.

[0084] A combination formulation containing metformin and inabogliflozin according to the following examples was implemented in a form including a metformin core tablet and an inabogliflozin coating layer surrounding it, thereby resolving formulation uniformity issues and ensuring drug release and stability.

[0085]

[0086] [Example]

[0087] Comparative Example 1: Bilayer tablet containing metformin hydrochloride and inabogliflozin

[0088] Step 1. Preparation of granules containing metformin hydrochloride

[0089] Granules containing metformin hydrochloride were prepared according to the metformin composition of Table 1 below. Metformin hydrochloride and sodium carboxymethylcellulose were mixed, combined with water as a binder, and dried. The dried material was granulated to produce wet granules, and then hydroxypropylmethylcellulose (average viscosity 100,000 mPa·s) and magnesium stearate were added and mixed to produce metformin hydrochloride granules.

[0090] Step 2. Preparation of granules containing inabogliflozin

[0091] Granules containing inabogliflozin were prepared according to the composition of the inabogliflozin component in Table 1 below. Inabogliflozin, microcrystalline cellulose, hard anhydrous silica, and talc were mixed, and the mixture was compressed under high pressure using a roller compactor to form a ribbon or sheet, and then granulated to produce dry granules. Subsequently, pregelatinized starch, D-mannitol, sodium croscarmellose, talc, and pigment blend orange were mixed to produce inabogliflozin granules.

[0092] Step 3. Preparation of a bilayer tablet containing metformin hydrochloride and inabogliflozin

[0093] Each manufactured granule was used to perform a tablet compression process using a bilayer tablet press to produce a bilayer tablet containing 1000 mg of metformin hydrochloride and 0.3 mg of inabogliflozin.

[0094] Comparison of Ingredients Example 1 Metformin Hydrochloride Metformin Hydrochloride 1000.0 Sodium Carboxymethylcellulose 50.0 Hydroxypropylmethylcellulose 300.0 Magnesium Stearate 10.0 Inabogliflozin 0.3 Microcrystalline Cellulose 55.0 Hard Anhydrous Silicate 2.0 Pregelatinized Starch 40.0 D-Mannitol 70.0 Sodium Croscarmellose 30.0 Talc 2.5 Pigment Blend Orange 0.2

[0095]

[0096] Examples 1 to 6

[0097] Step 1. Preparation of granules containing metformin hydrochloride

[0098] Granules containing metformin hydrochloride were prepared according to the metformin composition of Table 2 below. Metformin hydrochloride, hydroxypropylmethylcellulose (average viscosity 50 mPa·s), and hydroxypropylmethylcellulose (average viscosity 200,000 mPa·s) were mixed, combined with water as a binder, and dried. The dried material was granulated to produce wet granules, and then hydroxypropylmethylcellulose (average viscosity 50 mPa·s), colloidal anhydrous silica, and magnesium stearate were added and mixed to produce metformin hydrochloride granules.

[0099] Step 2. Preparation of a core tablet containing metformin hydrochloride

[0100] A core tablet containing 1000 mg of metformin hydrochloride was manufactured by using the manufactured granules and performing a tablet compression process with a tablet press.

[0101] Step 3. Preparation of a primary coated tablet containing metformin hydrochloride

[0102] A coating solution was prepared by dispersing Opadry 20A680000 in purified water, and a coating process was carried out on a metformin hydrochloride core tablet using a tablet film coating machine to produce a primary coated tablet containing 1000 mg of metformin hydrochloride.

[0103] Step 4. Preparation of a complex secondary coated tablet containing metformin hydrochloride and inabogliflozin

[0104] A coating solution containing inabogliflozin was prepared according to the composition of the inabogliflozin portion in Table 2 below, and a composite coated tablet was manufactured by performing a coating process on a primary coated tablet using a tablet film coater. A composite coated tablet containing 1000 mg of metformin hydrochloride and 0.3 mg of inabogliflozin was manufactured by varying the main coating agent. The types of coating agents used included cellulose-based materials such as hydroxypropylmethylcellulose, methylcellulose, and hydroxypropylcellulose, as well as polyvinyl alcohol, polyvinylpyrrolidone, and polyvinyl alcohol-polyethylene glycol copolymer, and polyethylene glycol was used as a plasticizer.

[0105] Classification Components Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Metformin Hydrochloride Bumetformin Hydrochloride 1000.01000.01000.01000.01000.01000.01000.0 Hydroxypropylmethylcellulose (average viscosity 200,000 mPa·s) 200.0200.0200.0200.0200.0200.0 Hydroxypropylmethylcellulose (average viscosity 50 mPa·s) 70.070.070.070.070.070.0 Colloidal Anhydrous Silica 5.05.05.05.05.05.0 Magnesium Stearate 5.05.05.05.05.05.05.0 1st Coating Buofadry 20A68000040.040.040.040.040.040.040.0 Secondary coating section (Inabogliflozin section) Inabogliflozin 0.30.30.30.30.30.3 Hydroxypropylmethylcellulose (average viscosity 3 mPa) 100 Methylcellulose 100 Hydroxypropylcellulose 100 Polyvinyl alcohol 100 Polyvinylpyrrolidone 100 Polyvinyl alcohol-polyethylene glycol copolymer 100 Polyethylene glycol 101010101010

[0106]

[0107] Examples 7 to 12

[0108] Step 1. Preparation of granules containing metformin hydrochloride

[0109] Granules containing metformin hydrochloride were prepared according to the metformin composition of Table 3 below. Metformin hydrochloride, hydroxypropylmethylcellulose (average viscosity 50 mPa·s), and hydroxypropylmethylcellulose (average viscosity 200,000 mPa·s) were mixed, combined with water as a binder, and dried. The dried material was granulated to produce wet granules, and then hydroxypropylmethylcellulose (average viscosity 50 mPa·s), colloidal anhydrous silica, and magnesium stearate were added and mixed to produce metformin hydrochloride granules.

[0110] Step 2. Preparation of a core tablet containing metformin hydrochloride

[0111] A core tablet containing 1000 mg of metformin hydrochloride was manufactured by using the manufactured granules and performing a tablet compression process with a tablet press.

[0112] Step 3. Preparation of a primary coated tablet containing metformin hydrochloride

[0113] A coating solution was prepared by dispersing Opadry 20A680000 in purified water, and a coating process was carried out on a metformin hydrochloride core tablet using a tablet film coating machine to produce a primary coated tablet containing 1000 mg of metformin hydrochloride.

[0114] Step 4. Preparation of a complex secondary coated tablet containing metformin hydrochloride and inabogliflozin

[0115] According to the composition of the inabogliflozin portion in Table 3 below, a coating solution containing inabogliflozin was prepared using water and ethanol as coating solvents, and a composite coated tablet was manufactured by carrying out a coating process on a primary coated tablet using a tablet film coater. Polyvinyl alcohol was used as the coating base and D-mannitol was used as an excipient, but the weights of these were varied in each example to manufacture a composite coated tablet containing 1000 mg of metformin hydrochloride and 0.3 mg of inabogliflozin.

[0116] Classification Components Example 7 Example 8 Example 9 Example 10 Example 11 Example 12 Metformin Hydrochloride But Metformin Hydrochloride 1000 1000 1000 1000 1000 1000 Hydroxypropylmethylcellulose (average viscosity 200,000 mPa·s) 200 200 200 200 200 200 Hydroxypropylmethylcellulose (average viscosity 50 mPa·s) 70 70 70 70 70 70 Colloidal Anhydrous Silica 55 55 55 Magnesium Stearate 55 55 55 1st Coating Part Opadry 20A 68 0000 40 40 40 40 40 40 2nd Coating Part (Inabogliflozin part) Inabogliflozin 0.30.30.30.30.30.3 Polyvinyl alcohol 1030405075100D-Mannitol 1030405075100

[0117]

[0118] Examples 13 to 15

[0119] Step 1. Preparation of granules containing metformin hydrochloride

[0120] Granules containing metformin hydrochloride were prepared according to the metformin composition of Table 4 below. Metformin hydrochloride, hydroxypropylmethylcellulose (average viscosity 50 mPa·s), and hydroxypropylmethylcellulose (average viscosity 200,000 mPa·s) were mixed, combined with water as a binder, and dried. The dried material was granulated to produce wet granules, and then hydroxypropylmethylcellulose (average viscosity 50 mPa·s), colloidal anhydrous silica, and magnesium stearate were added and mixed to produce metformin hydrochloride granules.

[0121] Step 2. Preparation of a core tablet containing metformin hydrochloride

[0122] A core tablet containing 1000 mg of metformin hydrochloride was manufactured by using the manufactured granules and performing a tablet compression process with a tablet press.

[0123] Step 3. Preparation of a primary coated tablet containing metformin hydrochloride

[0124] A coating solution was prepared by dispersing Opadry 20A680000 in purified water, and a coating process was carried out on a metformin hydrochloride core tablet using a tablet film coating machine to produce a primary coated tablet containing 1000 mg of metformin hydrochloride.

[0125] Step 4. Preparation of a complex secondary coated tablet containing metformin hydrochloride and inabogliflozin

[0126] According to the composition of the inabogliflozin portion in Table 4 below, a coating solution containing inabogliflozin was prepared using water and ethanol as coating solvents, and a coating process was carried out on a primary coated tablet using a tablet film coating machine to produce a composite coated tablet. Hydroxypropylmethylcellulose was used as the coating base, D-mannitol was used as the excipient, and hydroxypropylcellulose was used as the plasticizer, but the weights of D-mannitol and hydroxypropylcellulose were varied for each example to produce a composite coated tablet containing 1000 mg of metformin hydrochloride and 0.3 mg of inabogliflozin.

[0127] Classification Components Example 13 Example 14 Example 15 Metformin Hydrochloride Part Metformin Hydrochloride 1000 1000 1000 Hydroxypropylmethylcellulose (average viscosity 200,000 mPa·s) 200 200 200 Hydroxypropylmethylcellulose (average viscosity 50 mPa·s) 70 70 70 Colloidal Anhydrous Silica 55 5 Magnesium Stearate 55 5 Primary Coating Part Opadry 20A 68 0000 40 40 40 Secondary Coating Part (Inabogliflozin Part) Inabogliflozin 0.3 0.3 0.3 Hydroxypropylmethylcellulose (average viscosity 3 mPa·s) 50 50 50 D-Mannitol 50 40 30 Hydroxypropylcellulose-10 20

[0128]

[0129] Examples 16 to 20

[0130] Step 1. Preparation of granules containing metformin hydrochloride

[0131] Granules containing metformin hydrochloride were prepared according to the metformin composition of Table 5 below. Metformin hydrochloride, hydroxypropylmethylcellulose (average viscosity 50 mPa·s), and hydroxypropylmethylcellulose (average viscosity 200,000 mPa·s) were mixed, combined with water as a binder, and dried. The dried material was granulated to produce wet granules, and then hydroxypropylmethylcellulose (average viscosity 50 mPa·s), colloidal anhydrous silica, and magnesium stearate were added and mixed to produce metformin hydrochloride granules.

[0132] Step 2. Preparation of a core tablet containing metformin hydrochloride

[0133] A core tablet containing 1000 mg of metformin hydrochloride was manufactured by using the manufactured granules and performing a tablet compression process with a tablet press.

[0134] Step 3. Preparation of a primary coated tablet containing metformin hydrochloride

[0135] A coating solution was prepared by dispersing Opadry 20A680000 in purified water, and a coating process was carried out on a metformin hydrochloride core tablet using a tablet film coating machine to produce a primary coated tablet containing 1000 mg of metformin hydrochloride.

[0136] Step 4. Preparation of a complex secondary coated tablet containing metformin hydrochloride and inabogliflozin

[0137] According to the composition of the inabogliflozin portion in Table 5 below, a coating solution containing inabogliflozin was prepared using water and ethanol as coating solvents, and a composite coated tablet was manufactured by carrying out a coating process on a primary coated tablet using a tablet film coater. Polyvinyl alcohol was used as the coating agent, D-mannitol as the excipient, and polyethylene glycol as the plasticizer, but the weights of these were varied in each example to manufacture a composite coated tablet containing 1000 mg of metformin hydrochloride and 0.3 mg of inabogliflozin.

[0138] Classification Components Example 16 Example 17 Example 18 Example 19 Example 20 Metformin Hydrochloride Metformin Hydrochloride 1000.01000.01000.01000.01000.0 Hydroxypropylmethylcellulose (average viscosity 200,000 mPa·s) 200.0200.0200.0200.0200.0 Hydroxypropylmethylcellulose (average viscosity 50 mPa·s) 70.070.070.070.070.0 Colloidal Anhydrous Silica 5.05.05.05.05.0 Magnesium Stearate 5.05.05.05.05.0 1st Coating Opadry 20A68000040.040.040.040.040.02nd coating part (Inabogliflozin part) Inabogliflozin 0.30.30.30.30.3 Polyvinyl alcohol 10080604020D-Mannitol 020406080 Polyethylene glycol 108642

[0139]

[0140] Examples 21 to 26

[0141] Step 1. Preparation of granules containing metformin hydrochloride

[0142] Granules containing metformin hydrochloride were prepared according to the metformin composition of Table 6 below. Metformin hydrochloride, hydroxypropylmethylcellulose (average viscosity 50 mPa·s), and hydroxypropylmethylcellulose (average viscosity 200,000 mPa·s) were mixed, combined with water as a binder, and dried. The dried material was granulated to produce wet granules, and then hydroxypropylmethylcellulose (average viscosity 50 mPa·s), colloidal anhydrous silica, and magnesium stearate were added and mixed to produce metformin hydrochloride granules.

[0143] Step 2. Preparation of a core tablet containing metformin hydrochloride

[0144] A core tablet containing 1000 mg of metformin hydrochloride was manufactured by using the manufactured granules and performing a tablet compression process with a tablet press.

[0145] Step 3. Preparation of a primary coated tablet containing metformin hydrochloride

[0146] A coating solution was prepared by dispersing Opadry 20A680000 in purified water, and a coating process was carried out on a metformin hydrochloride core tablet using a tablet film coating machine to produce a primary coated tablet containing 1000 mg of metformin hydrochloride.

[0147] Step 4. Preparation of a complex secondary coated tablet containing metformin hydrochloride and inabogliflozin

[0148] According to the composition of the inabogliflozin portion in Table 6 below, a coating solution containing inabogliflozin was prepared using water and ethanol as coating solvents, and a coating process was carried out on a primary coated tablet using a tablet film coating machine to produce a composite coated tablet. Polyvinyl alcohol was used as the coating base and D-mannitol as the excipient, but for each example, polyethylene glycol, hydroxypropylcellulose, polyvinylpyrrolidone, glycerol, triacetin, or triethyl citrate was used as the plasticizer to produce a composite coated tablet containing 1000 mg of metformin hydrochloride and 0.3 mg of inabogliflozin.

[0149] Classification Components Example 21 Example 22 Example 23 Example 24 Example 25 Example 26 Metformin Hydrochloride Bu Metformin Hydrochloride 1000.01000.01000.01000.01000.01000.01000.0 Hydroxypropylmethylcellulose (Average viscosity 200,000 mPa·s) 200.0200.0200.0200.0200.0200.0 Hydroxypropylmethylcellulose (Average viscosity 50 mPa·s) 70.070.070.070.070.070.0 Colloidal anhydrous silica 5.05.05.05.05.05.0 Magnesium stearate 5.05.05.05.05.05.05.0 Primary coating Bu Opadry 20A68000040.040.040.040.040.040.0 Secondary coating part (Inabogliflozin part) Inabogliflozin 0.30.30.30.30.30.3 Polyvinyl alcohol 404040404040 D-Mannitol 606060606060 Polyethylene glycol 4 Hydroxypropyl cellulose 4 Polyvinylpyrrolidone 4 Glycerol 4 Triacetin 4 Triethyl citrate 4

[0150]

[0151] Examples 27 to 28

[0152] Step 1. Preparation of granules containing metformin hydrochloride

[0153] Granules containing metformin hydrochloride were prepared according to the metformin composition of Table 7 below. Metformin hydrochloride, hydroxypropylmethylcellulose (average viscosity 50 mPa·s), and hydroxypropylmethylcellulose (average viscosity 200,000 mPa·s) were mixed, combined with water as a binder, and dried. The dried material was granulated to produce wet granules, and then hydroxypropylmethylcellulose (average viscosity 50 mPa·s), colloidal anhydrous silica, and magnesium stearate were added and mixed to produce metformin hydrochloride granules.

[0154] Step 2. Preparation of a core tablet containing metformin hydrochloride

[0155] A core tablet containing 1000 mg of metformin hydrochloride was manufactured by using the manufactured granules and performing a tablet compression process with a tablet press.

[0156] Step 3. Preparation of a primary coated tablet containing metformin hydrochloride

[0157] A coating solution was prepared by dispersing Opadry 20A680000 in purified water, and a coating process was carried out on a metformin hydrochloride core tablet using a tablet film coating machine to produce a primary coated tablet containing 1000 mg of metformin hydrochloride.

[0158] Step 4. Preparation of a complex secondary coated tablet containing metformin hydrochloride and inabogliflozin

[0159] According to the composition of the inabogliflozin portion in Table 7 below, a coating solution containing inabogliflozin was prepared using water and ethanol as coating solvents, and a composite coated tablet was manufactured by carrying out a coating process on a primary coated tablet using a tablet film coater. A composite coated tablet containing 1000 mg of metformin hydrochloride and 0.3 mg of inabogliflozin was manufactured using polyvinyl alcohol as a coating agent and D-mannitol or sorbitol as an excipient.

[0160] Classification Components Example 27 Example 28 Metformin Hydrochloride Metformin Hydrochloride 1000.0 1000.0 Hydroxypropylmethylcellulose (average viscosity 200,000 mPa·s) 200.0 200.0 Hydroxypropylmethylcellulose (average viscosity 50 mPa·s) 70.0 70.0 Colloidal Anhydrous Silica 5.0 5.0 Magnesium Stearate 5.0 5.0 Primary Coating Part Opadry 20A680000 40.0 40.0 Secondary Coating Part (Inabogliflozin Part) Inabogliflozin 0.3 0.3 Polyvinyl Alcohol 40 40 D-Mannitol 60 Sorbitol 60

[0161]

[0162] Comparative Example 2. Inabogliflozin monotherapy and metformin monotherapy

[0163] For the inabogliflozin monotherapy, Enblo 0.3 mg tablets marketed by Daewoong Pharmaceutical Co., Ltd. were used. For the metformin monotherapy, Glucophage XR 1000 mg extended-release tablets marketed by Merck & Co., Ltd. were used.

[0164]

[0165] Example 29

[0166] Step 1. Preparation of granules containing metformin hydrochloride

[0167] Granules containing metformin hydrochloride were prepared according to the metformin composition of Table 8 below. Metformin hydrochloride, hydroxypropylmethylcellulose (average viscosity 50 mPa·s), and hydroxypropylmethylcellulose (average viscosity 200,000 mPa·s) were mixed, combined with water as a binder, and dried. The dried material was granulated to produce wet granules, and then hydroxypropylmethylcellulose (average viscosity 50 mPa·s), colloidal anhydrous silica, and magnesium stearate were added and mixed to produce metformin hydrochloride granules.

[0168] Step 2. Preparation of a core tablet containing metformin hydrochloride

[0169] A core tablet containing 1000 mg of metformin hydrochloride was manufactured by using the manufactured granules and performing a tablet compression process with a tablet press.

[0170] Step 3. Preparation of a primary coated tablet containing metformin hydrochloride

[0171] A coating solution was prepared by dispersing Opadry 20A680000 in purified water, and a coating process was carried out on a metformin hydrochloride core tablet using a tablet film coating machine to produce a primary coated tablet containing 1000 mg of metformin hydrochloride.

[0172] Step 4. Preparation of a complex secondary coated tablet containing metformin hydrochloride and inabogliflozin

[0173] According to the composition of the inabogliflozin portion in Table 8 below, a coating solution containing inabogliflozin was prepared using water and ethanol as coating solvents, and a coating process was carried out on a primary coated tablet using a tablet film coater to produce a composite coated tablet containing 1000 mg of metformin hydrochloride and 0.3 mg of inabogliflozin.

[0174] Step 5. Preparation of a complex tertiary-coated tablet containing metformin hydrochloride and inabogliflozin

[0175] A complex tertiary coated tablet containing 1000 mg of metformin hydrochloride and 0.3 mg of inabogliflozin was prepared by performing a coating process on a complex secondary coated tablet containing metformin hydrochloride and inabogliflozin using a tablet film coating machine with a coating solution containing polyvinyl alcohol, D-mannitol, titanium dioxide, and water.

[0176] Classification Components Example 29 Metformin Hydrochloride Part Metformin Hydrochloride 1000.0 Hydroxypropylmethylcellulose (average viscosity 200,000 mPa·s) 200.0 Hydroxypropylmethylcellulose (average viscosity 50 mPa·s) 70.0 Colloidal Anhydrous Silica 5.0 Magnesium Stearate 5.0 1st Coating Part Opadry 20A680000 40.0 2nd Coating Part (Inabogliflozin Part) Polyvinyl Alcohol 40.0 D-Mannitol 60.0 Inabogliflozin 0.3 3rd Coating Part Polyvinyl Alcohol 5.0 D-Mannitol 5.0 Titanium Dioxide 5.0

[0177]

[0178] Comparative Example 3. Metformin monotherapy

[0179] For the metformin monotherapy, Glucophage XR 500 mg extended-release tablets marketed by Merck Inc. were used.

[0180]

[0181] Examples 30 to 32

[0182] Step 1. Preparation of granules containing metformin hydrochloride

[0183] Granules containing metformin hydrochloride were prepared according to the metformin composition of Table 9 below. Metformin hydrochloride, a binder, and a sustained-release agent were mixed, combined with water as the binder, and dried. The dried material was granulated to produce wet granules, and then a binder, a sustained-release agent, and a lubricant were added and mixed to produce metformin hydrochloride granules.

[0184] Step 2. Preparation of a core tablet containing metformin hydrochloride

[0185] A core tablet containing 500 mg of metformin hydrochloride was manufactured by using the manufactured granules and performing a tablet compression process with a tablet press.

[0186] Step 3. Preparation of a primary coated tablet containing metformin hydrochloride

[0187] A coating solution was prepared by dispersing Opadry 20A680000 in purified water, and a coating process was carried out on a metformin hydrochloride core tablet using a tablet film coating machine to produce a primary coated tablet containing 500 mg of metformin hydrochloride.

[0188] Step 4. Preparation of a complex secondary coated tablet containing metformin hydrochloride and inabogliflozin

[0189] According to the composition of the inabogliflozin portion in Table 9 below, a coating solution containing inabogliflozin was prepared using water and ethanol as coating solvents, and a coating process was carried out on a primary coated tablet using a tablet film coater to produce a composite coated tablet containing 500 mg of metformin hydrochloride and 0.3 mg of inabogliflozin.

[0190] Step 5. Preparation of a complex tertiary-coated tablet containing metformin hydrochloride and inabogliflozin

[0191] A complex tertiary coated tablet containing 500 mg of metformin hydrochloride and 0.3 mg of inabogliflozin was prepared by performing a coating process on a complex secondary coated tablet containing metformin hydrochloride and inabogliflozin using a tablet film coating machine with a coating solution containing polyvinyl alcohol, D-mannitol, titanium dioxide, and water.

[0192]

[0193] Classification Components Example 30 Example 31 Example 32 Metformin Hydrochloride Metformin Hydrochloride 500 500 500 Carboxymethylcellulose 25 25 Hydroxypropylmethylcellulose (average viscosity 100,000 mPa·s) 25 0 200 Hydroxypropylmethylcellulose (average viscosity 200,000 mPa·s) 100 Hydroxypropylmethylcellulose (average viscosity 50 mPa·s) 35 Colloidal Anhydrous Silica 2.5 Magnesium Stearate 55 2.5 1st Coating Part Opadry 20A 68 0000 40 40.0 40 2nd Coating Part (Inabogliflozin Part) Polyvinyl Alcohol 40 40.0 30 D-Mannitol 60 60.0 50 Inabogliflozin 0.3 0.3 0.3 3rd Coating part Polyvinyl alcohol 2.5 2.5 2.5 D-Mannitol 2.5 2.5 2.5 Titanium dioxide 2.5 2.5 2.5

[0194]

[0195] Test Example 1. Test of the appearance of a metformin and inabogliflozin combination preparation

[0196] This test is designed to verify whether the external characteristics of the manufactured formulation match the appearance described in the approval details. The appearance test for tablets consists of external identification elements regarding color, shape, formulation, and surface condition, and is one of the factors that can affect the sorting rate during formulation production.

[0197] The manufactured examples are described in Table 10 below.

[0198] Comparative Example of Appearance 1 Example 1 Example 2 Example 3 Example 4 Example 5 Two-layer crack occurrence Suitable Suitable Orange peel peeling Example 6 Example 7 Example 8 Example 9 Example 10 Example 11 Suitable Suitable Suitable Suitable Suitable Example 12 Example 13 Example 14 Example 15 Example 16 Example 17 Suitable Crack occurrence Suitable Suitable Orange peel Orange peel Example 18 Example 19 Example 20 Example 21 Example 22 Example 23 Suitable Suitable Suitable Suitable Suitable Example 24 Example 25 Example 26 Example 27 Example 28 Example 29 Suitable Suitable Suitable Suitable Suitable 30 Example 31 Example 32 Suitable Suitable Suitable

[0199] In the case of the combination formulations of Examples 4, 16, and 17, an orange peel phenomenon appeared on the surface of the formulation, confirming that the appearance becomes unsuitable if the proportion of the coating base in the drug coating amount is too high. On the other hand, the combination formulations of Examples 18 to 20 were confirmed to meet the appearance criteria, suggesting that the appropriate ratio of the coating base and excipients affects the appearance. In the case of the combination formulations of Examples 1 and 13, cracking occurred on the surface of the coating layer, but it was confirmed that this improved depending on the ratio of plasticizers or additives due to the impact caused during the coating process. Although cracking occurred in Example 1, which used hydroxypropylmethylcellulose as the coating base, Examples 14 and 15, which used the same coating base in different weight parts or used different coating bases (hydroxypropylcellulose) or excipients together, were confirmed to meet the appearance criteria.

[0200]

[0201] Test Example 2. Formulation uniformity test of Inabogliflozin according to Examples and Comparative Examples

[0202] This experiment is intended to verify the uniformity of the active ingredient content among manufactured formulation units and to evaluate whether the formulation uniformity criteria are met. Depending on the characteristics of the formulation, content uniformity or mass deviation tests are applied, and in the case of Inabogliflozin, the criteria are applied through the content uniformity test.

[0203] The results of the formulation uniformity test performed on the formulations of Comparative Example 1 and Examples 7 to 15 are listed in Table 11 below.

[0204] Formulation Uniformity (%) Comparative Example 1 Example 7 Example 8 Example 9 Example 10 Example 11 Example 12 Example 13 Example 14 Example 15 Content (%) 99.4 98.1 97.4 95.7 99.7 104.2 105.4 97.3 91.4 105.9 Standard Deviation (%) 4.7 3.5 1.8 2.6 5.6 2.8 2.5 3.3 2.7 4.1 Judgment Value (%) 10.3 8.5 5.3 9.1 13.4 9.6 10.4 8.8 13.1 4.9

[0205] If the judgment value is 15% or less, it is judged to be compliant with the finished product test standards, and Examples 7 to 15 according to the coating layer content are judged to be compliant with the standards as the judgment value is 15% or less.

[0206]

[0207] Test Example 3. Hardness test according to Example 29 and Comparative Example 1

[0208] The hardness test is a test that quantifies mechanical hardness by applying a load along the axial direction of a tablet and measuring the force required to break the tablet at the point where it breaks. The hardness of a tablet affects drug release, disintegration, and abrasion, and tablets with high hardness can minimize mechanical damage occurring during packaging and transportation of the finished product.

[0209] The composite formulations prepared in Comparative Example 1 and Example 29 were tested, and the hardness measurement results are shown in Table 12 below.

[0210] Hardness (kp) Comparative Example 1 Example 29 Tablet 1st Coated Tablet 2nd Coated Tablet 3rd Coated Tablet 20.6 23.6 37.2 55.7 61.3

[0211] Through a hardness test, it was confirmed that the coated tablet of Example 30 had a higher hardness value compared to the bilayer tablet of Comparative Example 1.

[0212]

[0213] Test Example 4. Test of Inabogliflozin Impurities in the Combination Preparations of Examples 21 to 26

[0214] This test is a quantitative and qualitative evaluation of organic impurities generated during the manufacture of complex formulations, classifying them into individual impurities and total impurities. The evaluation was performed using complex formulations manufactured according to each example.

[0215] Based on Flexible Substance (%): Other individual flexible substances ≤ 1.0%, Total flexible substances ≤ 2.0% Examples 21, 22, 23, 24, 25, 26 Other individual flexible substances (%) 0.17 0.23 0.22 0.20 0.19 0.21 Total flexible substances (%) 1.35 0.60 1.26 1.49 0.79 1.48

[0216] As a result of the impurity test, the combination formulations of Examples 21 to 26 are judged to meet the standards in the impurity test of inabogliflozin.

[0217]

[0218] Test Example 5. Comparative dissolution test of inabogliflozin for the combination formulations of Examples 13 to 20, 27, and 28

[0219] According to the dissolution test method standards of the Korean Pharmacopoeia, the combination preparations of Examples 13 to 20, 27, and 28 were compared by conducting dissolution tests under the following conditions.

[0220] [Elution Conditions]

[0221] Elutant: DW

[0222] Device: USP paddle method, 50 rpm

[0223] Temperature: 37 ℃

[0224] For combination formulations of metformin and inabogliflozin, the standard for the inabogliflozin dissolution test is evaluated as a dissolution rate of 80% or more in water over 1 hour.

[0225] Dissolution rate of Inabogliflozin in the case of an HPMC-based drug coating layer Time (min) 5 10 15 30 45 60 Example 1 3 37.5 6 3.1 7 3.4 8 2.4 8 58 6.1 Example 1 4 25.2 50 6 4.2 7 8.6 8 2.7 8 4.2 Example 1 5 25 53 7 2.1 9 4.4 10 0.3 10 2.7

[0226] Figure 1 is a graph comparing the dissolution rates of inabogliflozin in the combination preparations of Examples 13 to 15 under water conditions. The combination preparations of Examples 13 to 15 are hydroxypropylmethylcellulose-based drug-coated tablets, and although the amounts of the excipient mannitol and the plasticizer hydroxypropylcellulose were set differently, all of Examples 13 to 15 were confirmed to meet the standards for the dissolution test of the finished product.

[0227] Dissolution rate of Inabogliflozin according to the ratio of excipients and coating base of the drug coating layer Time (min) 5 10 15 30 45 60 Example 16 18.3 36.5 5 3.9 84.4 90.8 93.3 Example 17 16.7 39.2 5 8.4 89.2 91.6 92.4 Example 18 19.8 41.9 6 8.7 80.1 81.6 87.3 Example 19 73.4 85.9 90.3 91.7 92.8 94.9 Example 20 77.4 89.2 91.5 88.1 92.1 94.6

[0228] Figure 2 is a graph comparing the dissolution rates of inabogliflozin in the combination formulations of Examples 16 to 20 under water conditions. The combination formulations of Examples 16 to 20 are formulations in which the ratio of polyvinyl alcohol, a coating agent, and mannitol, an excipient, is set differently. As a result of the dissolution evaluation, the initial dissolution rate tended to be slow when the polyvinyl alcohol content was high, but all of Examples 16 to 20 met the standards for the finished product dissolution test during the dissolution evaluation.

[0229] Dissolution rate of Inabogliflozin according to excipients of the drug coating layer Time (min) 5 10 15 30 45 60 Example 27 42.8 7 7.18 7.6 9 2.9 9 49 4.3 Example 28 38.17 1.9 8 5.28 9.7 9 1.6 9 2.7

[0230] Figure 3 is a graph comparing the dissolution rates of inabogliflozin in the combination formulations of Examples 27 and 28 under water conditions. The combination formulations of Examples 27 and 28 were designed to evaluate the effect of the type of excipient (mannitol and sorbitol) on dissolution, and the dissolution test results showed that there was no significant change in the dissolution rate due to the change in excipient, and both combination formulations of Examples 27 and 28 met the standards for finished product dissolution testing.

[0231]

[0232] Test Example 6. Comparative dissolution test of inabogliflozin according to Example 29 and Comparative Example 2

[0233] According to the dissolution test method standards of the Korean Pharmacopoeia, the combination preparation of Example 29 was subjected to a dissolution test under the following conditions and compared with Comparative Example 2.

[0234] [Elution Conditions]

[0235] Eluent: DW, pH 1.2, 4.5, 6.8

[0236] Device: USP paddle method, 50 rpm

[0237] Temperature: 37 ℃

[0238] Comparative dissolution rate of Inabogliflozin in Example 29 and Comparative Example 2 Medium Time (min) 5 10 15 30 45 60 DW Comparative Example 2 (Enblo Tablet 0.3 mg) 5 1.6 9 1.8 9 8.5 10 0.4 10 1.5 10 1.5 Example 29 4 5.8 8 3.7 9 3.4 9 8.5 9 9.5 9 9.9 pH 1.2 Comparative Example 2 (Enblo Tablet 0.3 mg) 6 2.3 9 0.7 9 5.5 9 9.1 9 9.9 10 0.3 Example 29 4 2.7 8 1.3 9 2.8 9 8.5 9 9.4 10 0.1 pH 4.5 Comparative Example 2 (Enblo Tablet 0.3 mg) 6 8.2 9 4.5 9 8.1 10 0.9 10 1.7 10 2.2 Example 2944.482.393.499.7101.1101.8 pH 6.8 Comparative Example 2 (Enblo Tablet 0.3 mg) 72.791.997.4100.6101.6102.1 Example 2939.782.295.2101.4102.8103.6

[0239] Figure 4 is a graph comparing the dissolution rates of inabogliflozin of Example 29 and Comparative Example 2 under water conditions.

[0240] Figure 5 is a graph comparing the dissolution rates of inabogliflozin of Example 29 and Comparative Example 2 under pH 1.2 conditions.

[0241] Figure 6 is a graph comparing the dissolution rates of inabogliflozin of Example 29 and Comparative Example 2 under pH 4.5 conditions.

[0242] Figure 7 is a graph comparing the dissolution rates of inabogliflozin of Example 29 and Comparative Example 2 under pH 6.8 conditions.

[0243] Since the Tmax of inabogliflozin is approximately 1 hour, its dissolution in the gastrointestinal tract is expected to have a significant impact on bioavailability. Therefore, the dissolution rate at pH 1.2, which is a pH condition similar to gastric juice, is considered important. When compared to the reference drug, Comparative Example 2, the test drug can be judged to be equivalent as it exceeds 85% dissolution rate in the entire medium at the 15-minute mark.

[0244]

[0245] Test Example 7. Comparative dissolution test of inabogliflozin on the combination preparations of Examples 30 to 32

[0246] According to the dissolution test method standards of the Korean Pharmacopoeia, the combination preparations of Examples 30 to 32 were subjected to a dissolution test under the following conditions and compared with Comparative Example 2.

[0247] [Elution Conditions]

[0248] Elutant: DW

[0249] Device: USP paddle method, 50 rpm

[0250] Temperature: 37 ℃

[0251] Comparative dissolution rate of Inavogliflozin with Comparative Example 2 according to low dose of Metformin and content of Enavogliflozin coating layer Medium Time (min) 5 10 15 30 45 60 DW Comparative Example 2 (Enblo Tablet 0.3 mg) 7 1.0 9 2.7 9 6.5 9 9.5 10 0.3 10 0.6 Example 3 0 36.6 7 6.5 9 2.2 9 9.9 10 0.7 10 1.3 Example 3 1 38.0 7 3.7 8 7.9 9 5.0 9 5.9 6.3 Example 3 2 49.4 8 3.8 9 2.8 9 5.7 9 6.8 9 7.4

[0252] FIG. 8 is a graph comparing the dissolution rates of inabogliflozin in Examples 30 to 32 and Comparative Example 2 under water conditions. Although the composition of the metformin part in Examples 30 and 31 differs from that of Examples 1 to 29 and Example 32, it was confirmed that the dissolution rate of inabogliflozin in all combination preparations of Examples 30 to 32 was suitable for the finished product dissolution test standards regardless of the change in the composition of the metformin part.

[0253]

[0254] Test Example 8. Comparative dissolution test of metformin according to Example 29 and Comparative Example 2

[0255] According to the dissolution test method standards of the Korean Pharmacopoeia, the combination preparation of Example 29 was subjected to a dissolution test under the following conditions and compared with Comparative Example 2.

[0256] [Elution Conditions]

[0257] Eluent: DW, pH 4.5, 6.8

[0258] Device: USP Paddle method, 50 rpm / USP Basket method, 100 rpm

[0259] Temperature: 37 ℃

[0260] Comparison of metformin in Example 29 and Comparative Example 2 Dissolution Rate Medium Time (min) 15 30 60 90 120 180 300 480 60 0 720 Similarity Factor DW (paddle, 50 rpm) Comparative Example 2 (Glucophage XR Tablet 1000 mg) 10 15 23 30 35 46 61 78 87 91 81.8 Example 29 61 32 230 34 46 59 75 85 88 pH 4.5 (paddle, 50 rpm) Comparative Example 2 (Glucophage XR Tablet 1000 mg) 11 18 27 34 41 52 71 90 99 10 58 2.8 Example 29 71 52 634 41 52 69 91 9810 pH 6.8 (paddle, 50 rpm) Comparative Example 2 (Glucophage XR Tablet 1000 mg) 10 16 25 3 13 6 4 4 6 27 7 8 69 4 8 1.0 Example 2 9 6 14 23 30 36 4 6 6 28 09 197 pH 6.8 (Basket 100 rpm) Comparative Example 2 (Glucophage XR Tablet 1000 mg) 11 17 26 35 4 0 5 37 0 8 69 5 100 8 1.5 Example 2 9 7 16 27 36 4 25 5 7 38 69 697

[0261] Figure 9 is a graph comparing the dissolution rates of metformin of Example 29 and Comparative Example 2 under water (paddle, 50 rpm) conditions. Figure 10 is a graph comparing the dissolution rates of metformin of Example 29 and Comparative Example 2 under pH 4.5 (paddle, 50 rpm) conditions.

[0262] Figure 11 is a graph comparing the dissolution rates of metformin in Example 29 and Comparative Example 2 under pH 6.8 (paddle, 50 rpm) conditions.

[0263] Figure 12 is a graph comparing the dissolution rates of metformin in Example 29 and Comparative Example 2 under pH 6.8 (basket 100 rpm) conditions.

[0264] Since metformin is designed as a sustained-release tablet, it is desirable to ensure that the drug is released at multiple time points over a period of 12 hours. When conducting a comparative dissolution evaluation with Comparative Example 2, the difference in dissolution rates between the reference drug and the test drug is within 15% at all dissolution rate comparison time points, and they are judged to be equivalent with a similarity factor value of 50 or higher at all comparative dissolution time points.

[0265]

[0266] Test Example 9. Comparative dissolution test of metformin according to Examples 30 to 31

[0267] According to the dissolution test method standards of the Korean Pharmacopoeia, the combination preparations of Examples 30 to 31 were subjected to dissolution tests under the following conditions and compared.

[0268] [Elution Conditions]

[0269] Elution: pH 6.8

[0270] Device: USP paddle method, 50 rpm

[0271] Temperature: 37 ℃

[0272] Comparative dissolution rate of metformin in Examples 30 to 31 and Comparative Example 3 Medium Time (min) 15 30 60 90 120 18 0 30 0 36 0 48 0 60 0 720 Similarity factor pH 6.8 (paddle, 50 rpm) Comparative Example 31 11 72 73 44 15 16 87 587 93 98 Example 30 8 15 25 32 384 864 70 8 18 894 71 Example 31 9 16 263 44 15 16 87 587 93 97 95

[0273] Figure 13 is a graph comparing the dissolution rates of metformin in Examples 30 to 31 and Comparative Example 3 under pH 6.8 (paddle, 50 rpm) conditions.

[0274] Since metformin is designed as a sustained-release tablet, it is desirable to ensure that the drug is released at multiple time points over a period of 12 hours. When conducting a comparative dissolution evaluation with Comparative Example 3, the difference in dissolution rates between the reference drug and the test drug is within 15% at all dissolution rate comparison points, and they are judged to be equivalent with a similarity factor value of 50 or higher at all comparative dissolution points.

Claims

1. A pharmaceutical composition of a single formulation comprising a compartment containing inabogliflozin or a pharmaceutically acceptable salt thereof; and a compartment containing metformin or a pharmaceutically acceptable salt thereof, wherein said compartments are formulated in a form separated from each other, The compartment containing metformin or its pharmaceutically acceptable salt forms the core, and the compartment containing inabogliflozin or its pharmaceutically acceptable salt forms the shell, and The above-mentioned inabogliflozin compartment is included in an amount of 1 to 15 parts by weight per 100 parts by weight of the total pharmaceutical composition, and A pharmaceutical composition comprising 1.5 parts by weight or less of inabogliflozin or its pharmaceutically acceptable salt in the inabogliflozin compartment, based on 100 parts by weight of the total inabogliflozin compartment.

2. A pharmaceutical composition according to claim 1, wherein the inabogliflozin compartment comprises inabogliflozin or a pharmaceutically acceptable salt thereof, an excipient, and a coating base.

3. A pharmaceutical composition according to claim 2, wherein one or more sugar alcohols are included as excipients in an amount of 20 to 80 parts by weight per 100 parts by weight of the total inabogliflozin compartment.

4. A pharmaceutical composition according to claim 1, wherein the coating base is one or more selected from the group consisting of hydroxypropylmethylcellulose, methylcellulose, hydroxypropylcellulose, ethylcellulose, polyvinyl alcohol, and polyvinyl alcohol-polyethylene glycol copolymer, and is included in an amount of 15 to 70 parts by weight per 100 parts by weight of the total inabogliflozin compartment.

5. A pharmaceutical composition according to claim 1, wherein the inabogliflozin compartment further comprises a plasticizer, and the plasticizer is included in an amount of 0.1 to 10 parts by weight per 100 parts by weight of the total inabogliflozin compartment.

6. A pharmaceutical composition according to claim 1, wherein the metformin compartment comprises metformin or a pharmaceutically acceptable salt thereof, a binder, a sustaining agent, and a lubricant.

7. A pharmaceutical composition according to claim 6, wherein the metformin compartment comprises one or more selected from the group consisting of low-viscosity hydroxypropylmethylcellulose, carboxymethylcellulose, and povidone as a binder, and the binder is included in an amount of 2 to 10 parts by weight per 100 parts by weight of the total metformin compartment.

8. A pharmaceutical composition according to claim 6, wherein the metformin compartment comprises high-viscosity hydroxypropylmethylcellulose as a sustained-release agent, and the sustained-release agent is included in an amount of 5 to 40 parts by weight per 100 parts by weight of the total metformin compartment.

9. A pharmaceutical composition according to claim 6, wherein the metformin compartment comprises colloidal anhydrous silica and magnesium stearate as lubricants, and the lubricant is included in an amount of 0.5 to 1 weight part per 100 weight parts of the total metformin compartment.

10. A pharmaceutical composition according to claim 1, wherein the metformin compartment comprises granules prepared by mixing wet granules comprising metformin or a pharmaceutically acceptable salt thereof, a binder, and a sustained-release agent with a post-mixture comprising a sustained-release agent and a lubricant.

11. A pharmaceutical composition according to claim 1, wherein the pharmaceutical composition has the formulation of a coated tablet.

12. A pharmaceutical composition according to claim 11, wherein the coated tablet is formed by first coating a core containing metformin or a pharmaceutically acceptable salt thereof with a film coating agent, and secondarily coating it with a coating solution containing inabogliflozin or a pharmaceutically acceptable salt thereof, an excipient, and a coating base.

13. A pharmaceutical composition according to claim 12, wherein the coated tablet is further coated tertiarily with a coating solution comprising a coating agent and titanium dioxide.

14. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition comprises inabogliflozin in a dose of 0.1 mg to 0.5 mg.

15. 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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