Pharmaceutical composite formulation comprising metformin and empagliflozin with improved dissolution rate and productivity

Abstract

The present invention relates to: a pharmaceutical composite formulation comprising metformin and empagliflozin, the composite formulation having excellent stability and exhibiting a dissolution profile similar to that when a single drug is administered; and a method for preparing the composite formulation with high productivity.

Description

Pharmaceutical combination formulation comprising metformin and empagliflozin with improved dissolution rate and productivity

[0001] Cross-citation with related application(s)

[0002] This application claims the benefit of priority to Korean Patent Application No. 10-2024-0100858, filed July 30, 2024, the entire contents of which are incorporated herein by reference.

[0003] The present invention relates to a pharmaceutical composition comprising metformin and empagliflozin, which has improved productivity and a sustained-release dissolution rate.

[0004] Diabetes is a chronic metabolic disease, categorized as type 1 and type 2. Type 2 diabetes is caused by insulin resistance, which occurs when the insulin that lowers blood sugar levels declines. SGLTs are glucose transporters found in the small intestinal mucosa and the proximal tubules of the kidney. They primarily include SGLT-1 and SGLT-2, and diabetes treatments targeting SGLT-2 are being widely developed. One drug developed as an SGLT-2 inhibitor is empagliflozin, currently marketed under the brand name Jardiance.

[0005] Metformin is a widely used first-line drug for treating hyperglycemia. Its blood sugar control mechanism is independent of insulin secretion and is known to involve the activation of glucose transporters in the liver. Metformin promotes weight loss in diabetic patients, reduces blood triglycerides and low-density lipoproteins, and increases high-density lipoproteins. Therefore, it is used as a first-line drug for patients with insulin-resistant, non-insulin-dependent diabetes.

[0006] Type 2 diabetes is a chronic disease that is known to cause secondary chronic diseases such as hypertension, hyperlipidemia, myocardial infarction, and stroke, as well as metabolic syndrome. Combination therapy is actively recommended for treatment. In particular, the combination of metformin, a biguanide, and empagliflozin, a sodium-glucose cotransporter 2 (SGLT-2) inhibitor, has recently been proven to be effective and efficacious in the treatment of diabetes. However, when manufacturing combination formulations that combine two or more drugs, various factors must be considered, such as drug interactions, storage stability, and the dissolution rates of individual drugs. Therefore, manufacturing combination formulations is not easy.

[0007] The development of a combination drug of metformin and empagliflozin may contribute to improving medication compliance in diabetic patients who require multiple medications. However, the development of such a combination drug may cause problems in the productivity of tablets due to differences in the physical properties of each active ingredient (API). In particular, in the case of a bilayer tablet formulation, compared to a general single-layer tablet formulation, there is a possibility that the dissolution pattern may not be appropriate, such as the dissolution rate becoming faster or slower due to the difference in the disintegration patterns between the upper and lower layers. In addition, when producing a bilayer tablet formulation, if the hardness is low, the tablet may break or the upper and lower tablets may separate, and conversely, if the hardness is high, various problems may occur, such as showing a delayed dissolution pattern.

[0008] As a result of extensive efforts, the inventors of the present invention have developed a formulation with improved productivity by controlling the dissolution pattern of metformin and empagliflozin and suppressing breakage and separation of tablets, thereby completing the present invention.

[0009] [Prior Art Literature]

[0010] (Patent Document 1) KR Publication No. 10-2023-0001000

[0011] (Patent Document 2) KR Publication No. 10-2021-0084053

[0012] One object of the present invention is to provide a combination preparation containing metformin and empagliflozin, which has an excellent dissolution pattern equivalent to that when the active ingredients are administered as a single drug.

[0013] Another object of the present invention is to provide a process capable of manufacturing the above-mentioned metformin and empagliflozin-containing tablets with high productivity.

[0014] However, the technical problems to be solved by the present invention are not limited to the problems mentioned above, and other problems not mentioned can be clearly understood by those skilled in the art from the description below.

[0015] According to one embodiment of the present invention, the pharmaceutical combination formulation may comprise (1) a first layer comprising metformin or a pharmaceutically acceptable salt thereof; and (2) a second layer comprising empagliflozin or a pharmaceutically acceptable salt thereof.

[0016] The second layer may include 7 to 45 wt% of low-substituted hydroxypropyl cellulose, 0.1 to 13 wt% of croscarmellose sodium, and 0.1 to 6.5 wt% of hydroxypropyl cellulose based on the total weight of the second layer.

[0017] The above low-substituted hydroxypropyl cellulose and croscarmellose sodium may be included in a weight ratio of 1:0.01 to 0.5.

[0018] The above low-substituted hydroxypropyl cellulose and hydroxypropyl cellulose may be included in a weight ratio of 1:0.01 to 0.2.

[0019] The second layer may further include one or more pharmaceutically acceptable additives selected from the group consisting of excipients, disintegrants, binders, and lubricants.

[0020] The first layer may further include one or more pharmaceutically acceptable additives selected from the group consisting of a fluidizing agent, a stabilizer, a release agent, and a lubricant.

[0021] The first layer may contain metformin or a pharmaceutically acceptable salt thereof in an amount of 500 mg to 1,000 mg.

[0022] The second layer may comprise empagliflozin or a pharmaceutically acceptable salt in an amount of 5 mg to 25 mg.

[0023] The above pharmaceutical combination preparation may be a tablet for oral administration.

[0024] The above pharmaceutical combination preparation may be a bilayer tablet or a multilayer tablet.

[0025] The above pharmaceutical combination formulation may have a hardness of 30 to 55 kp.

[0026] When the above pharmaceutical compound preparation is tested under the conditions of 900 mL of a pH 6.8 dissolution test solution, a rotation speed of 100 rpm, and a temperature of 37±5℃ according to the Korean Pharmacopoeia dissolution test method (rotary sample container method), the 5-minute dissolution rate of empagliflozin may be 61 to 84%, the 10-minute dissolution rate may be 79 to 97%, or the 15-minute dissolution rate may be 89 to 99%.

[0027] According to another embodiment of the present invention, a method for preparing a pharmaceutical combination formulation comprises the steps of: (a) preparing a first mixture comprising metformin or a pharmaceutically acceptable salt thereof; (b) preparing a second mixture comprising empagliflozin or a pharmaceutically acceptable salt; and (c) compressing the first mixture as a first layer and the second mixture as a second layer to prepare a tablet.

[0028] The second mixture may contain 7 to 45 wt% of low-substituted hydroxypropyl cellulose, 0.1 to 13 wt% of croscarmellose sodium, and 0.1 to 6.5 wt% of hydroxypropyl cellulose based on the total weight of the second mixture.

[0029] The tableting of the above (c) can be performed by filling the first mixture into the container of the tableting machine, applying pre-pressure to form a first layer, filling the second mixture on top of the first layer, and then applying main pressure.

[0030] The tableting process of the above (c) can be performed so that the hardness of the tablet becomes 30 to 55 kp.

[0031] The combination formulation of the present invention contains both metformin and empagliflozin, but shows a dissolution pattern with a drug dissolution rate equivalent to that of the reference drug.

[0032] In addition, the composite formulation of the present invention has excellent hardness, so it not only shows a stable dissolution pattern of active ingredients, but also has excellent productivity because no tableting problems occur during the manufacturing process.

[0033] Figure 1 shows the results of a comparative experiment on the change in the dissolution rate of empagliflozin over time under the conditions of a pH 6.8 solution for tablets and control drugs manufactured in Examples 1 to 3 and Comparative Examples 1 to 6 in Experimental Example 1.

[0034] Figure 2 shows the results of a comparative experiment on the change in the dissolution rate of empagliflozin over time under the conditions of a pH 6.8 solution for tablets and control drugs manufactured in Examples 1, 4, and 5 and Comparative Examples 7 to 10 in Experimental Example 2.

[0035] Figure 3 shows the results of a comparative experiment on the change in the dissolution rate of empagliflozin over time under the conditions of a pH 6.8 solution for tablets and control drugs manufactured in Examples 1, 6 to 8 and Comparative Examples 11 to 13 in Experimental Example 3.

[0036] Figure 4 shows the results of a comparative experiment on the change in the dissolution rate of empagliflozin over time under the conditions of a pH 6.8 solution for tablets and control drugs manufactured in Examples 1A to 1C and Comparative Examples 14A to 14C in Experimental Example 4.

[0037] According to one embodiment of the present invention, the pharmaceutical combination formulation may comprise (1) a first layer comprising metformin or a pharmaceutically acceptable salt thereof; and (2) a second layer comprising empagliflozin or a pharmaceutically acceptable salt thereof.

[0038] The second layer may include 7 to 45 wt% of low-substituted hydroxypropyl cellulose, 0.1 to 13 wt% of croscarmellose sodium, and 0.1 to 6.5 wt% of hydroxypropyl cellulose based on the total weight of the second layer.

[0039] According to another embodiment of the present invention, a method for preparing a pharmaceutical combination formulation comprises the steps of: (a) preparing a first mixture comprising metformin or a pharmaceutically acceptable salt thereof; (b) preparing a second mixture comprising empagliflozin or a pharmaceutically acceptable salt; and (c) compressing the first mixture as a first layer and the second mixture as a second layer to prepare a tablet.

[0040] The second mixture may contain 7 to 45 wt% of low-substituted hydroxypropyl cellulose, 0.1 to 13 wt% of croscarmellose sodium, and 0.1 to 6.5 wt% of hydroxypropyl cellulose based on the total weight of the second mixture.

[0041] According to one embodiment of the present invention, there is provided a pharmaceutical combination formulation comprising a first layer comprising metformin or a pharmaceutically acceptable salt thereof; and a second layer comprising empagliflozin or a pharmaceutically acceptable salt thereof.

[0042] "Pharmaceutical combination preparations" are formulations that improve the convenience of taking two or more ingredients by putting them into a single dosage form. However, these combination preparations have the advantage of increasing the convenience of taking, and the dissolution of each ingredient is reduced due to mutual interference between the active ingredients. In particular, the dissolution pattern of a bilayer tablet formulation may not be appropriate, such as the dissolution rate being faster or slower due to the difference in the disintegration pattern between the upper and lower layers compared to a single-layer tablet formulation. In addition, when producing a bilayer tablet formulation, if the hardness is low, the tablet may break or the upper and lower layers may separate, and conversely, if the hardness is high, the dissolution pattern may be delayed.

[0043] However, the pharmaceutical combination formulation of the present invention adjusts the composition of the first layer containing metformin and the second layer containing empagliflozin so that the first layer has a sustained-release dissolution profile and the second layer has an immediate-release dissolution profile, so that both ingredients can have a dissolution profile equivalent to that of the reference drug despite the physical difference between the two active ingredients. In addition, the combination formulation can increase the stability of the dissolution rate of the active ingredient and also increase productivity by making the hardness of the formulation approximately 30 to 55 kp.

[0044] In the composite formulation of the present invention, the first layer and the second layer exist in a physically separated state, and the composite formulation of the present invention may be in the form of a bilayer tablet or a multilayer tablet. Here, the bilayer tablet or multilayer tablet refers to a composite formulation in which the compartments are separated so that each component is not mixed and exists independently in each layer.

[0045] In the present invention, the descriptions of "first layer" and "second layer" are used to distinguish different layers (i.e., the first layer refers to any one layer of the two-layer tablet, and the second layer refers to a layer other than the layer mentioned above). The first layer may be located above (upper layer), but may also be located below (lower layer), and the second layer may be located below (lower layer), but may also be located above (upper layer). This means that in such a two-layer tablet, metformin and empagliflozin are each included in a different layer.

[0046] In the present invention, metformin is an oral antidiabetic agent of the biguanide family, with the IUPAC name N,N-dimethylimidodicarbonimidic diamide. While it is effective in improving blood sugar levels, evidence for its effectiveness in preventing cardiovascular disease is still limited. Its mechanism of action is known to be to inhibit gluconeogenesis by activating AMP-activated protein kinase (AMPK) in the liver, thereby promoting glucose uptake into cells and suppressing metabolic syndrome.

[0047] In the present invention, the empagliflozin is a compound whose IUPAC name is (2S,3R,4R,5S,6R)-2-[4-chloro-3-[[4-[(3S)-oxolan-3-yl]oxyphenyl]methyl]phenyl]-6-(hydroxymethyl)oxane-3,4,5-triol, and belongs to the SGLT-2 ((Sodium-Glucose linked Transporter 2)) inhibitor. Empagliflozin is an antidiabetic drug used to improve glucose control in patients with type 2 diabetes.

[0048] In the present invention, the term "pharmaceutically acceptable salt" refers to a salt commonly used in the relevant technical field, and includes not only salts prepared with inorganic ions, inorganic acids or organic acids, but also hydrates or solvates of the salts. In the present invention, pharmaceutically acceptable salts of metformin or empagliflozin include acetate, adipate, L-ascorbate, L-aspartate, caprate, carbonate, citrate, fumarate, mucosal salt, D-glucoheptone, D-gluconate, D-glucuronate, glutamate, glutarate, glycerophosphate, glycolate, hippurate, hydrochloride, DL-lactate, laurate, maleate, (-)-L-malic acid, palmitate, phosphate, sebacate, stearate, succinate, sulfate, (+)-L-tartrate, thiocyanate, alginic acid, benzenesulfonate, benzoate, (+)-camphorate, caprylate, cyclamate, dodecylsulfate, ethane-1,2-disulfonate, 2-hydroxyethanesulfonate, Examples thereof include, but are not limited to, ethanesulfonate, gentisate, 2-oxo-glutarate, isobutyrate, lactobionic acid salt, malonate, methanesulfonate, naphthalene-1,5-disulfonate, naphthalene-2-sulfonate, 1-hydroxy-2-naphthoate, nicotinate, oleate, orotate, oxalate, pamoate, propionate, (-)-L-pyroglutamate, and p-toluenesulfonate.

[0049] In the present invention, the pharmaceutically acceptable salt of metformin or empagliflozin may be selected from the group consisting of hydrochloride, succinate, fumarate, methanesulfonate, benzenesulfonate, and toluenesulfonate, but is not limited thereto. As an example, the pharmaceutically acceptable salt of metformin may be metformin hydrochloride, but is not limited thereto.

[0050] In the present invention, one or more amino acids may be included together with the empagliflozin. Wherein the amino acids include: glycine, alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan, serine, cysteine, threonine, tyrosine, asparagine, glutamine, aspartic acid, glutamic acid, arginine, histidine, and lysine. In addition, in the present invention, the empagliflozin and the amino acid may be in the form of a co-crystal. In one example, the active ingredient may include, but is not limited to, empagliflozin and proline (e.g., L-proline or D-proline).

[0051] In the compound formulation of the present invention, the pharmaceutically acceptable salt of the active ingredient may also include a hydrate or solvate of the active ingredient. The hydrate or solvate may be formed by dissolving the active ingredient in a water-miscible solvent, such as methanol, ethanol, acetone, or 1,4-dioxane, and then crystallizing or recrystallizing the active ingredient after adding a free acid or free base, but is not limited thereto.

[0052] In the present invention, the metformin or a pharmaceutically acceptable salt thereof may be included in an amount of 70 to 90 wt%, 70 to 85 wt%, 75 to 90 wt%, or 75 to 85 wt% based on the total weight of the pharmaceutical combination preparation of the present invention.

[0053] In the present invention, the metformin may be included in the pharmaceutical combination preparation of the present invention in an amount of 250 mg to 1,000 mg, preferably 500 mg to 1,000 mg, more preferably 500 mg or 1,000 mg. As an example, the pharmaceutical combination preparation of the present invention may include metformin as an active ingredient in an amount of, but not limited to, 500 mg, 850 mg, or 1,000 mg, but not limited to, this. As another example, the pharmaceutical combination preparation of the present invention may include metformin as an active ingredient in an amount of, but not limited to, 500 mg, 850 mg, or 1,000 mg per unit dosage form. Here, the content refers to the amount contained as metformin in a free state, that is, not in the form of an inorganic or organic salt, ester, hydrate, or solvate.

[0054] In the present invention, the empagliflozin or a pharmaceutically acceptable salt thereof may be included in an amount of 0.1 to 5 wt%, and preferably 0.3 to 3 wt%, based on the total weight of the pharmaceutical combination preparation of the present invention.

[0055] In the present invention, the empagliflozin may be included in the pharmaceutical combination formulation of the present invention in an amount of 5 mg to 25 mg. For example, the pharmaceutical combination formulation of the present invention may include empagliflozin as an active ingredient in an amount of 5 mg, 10 mg, 12.5 mg, 15 mg, 20 mg, or 25 mg per unit dosage form, but is not limited thereto. Here, the content refers to the amount contained as empagliflozin in a free state, i.e., not in the form of an inorganic or organic salt, ester, hydrate, or solvate.

[0056] As an example, the combination formulation of the present invention may contain, but is not limited to, 500 mg to 1000 mg of metformin and 5 mg to 25 mg of empagliflozin per unit dosage form.

[0057] The composite formulation of the present invention comprises low-substituted hydroxypropyl cellulose, and preferably comprises at least one of croscarmellose sodium and general hydroxypropyl cellulose together with the low-substituted hydroxypropyl cellulose, thereby securing a dissolution profile equivalent to that when metformin and empagliflozin are administered as a single drug as active ingredients, and producing a formulation with high hardness.

[0058] The above "low-substituted hydroxypropyl cellulose (L-HPC)" is a form in which the hydroxypropoxy group is less substituted in the general hydroxypropyl cellulose structure. While the hydroxypropoxy group content of general hydroxypropyl cellulose is approximately 53.4 to 77.5 wt%, that of L-HPC is 5 to 16 wt%. This value is measured by the method listed in the Japanese Pharmacopoeia, and the range is clearly specified in the monograph of "Low-substituted Hydroxypropyl Cellulose" of the Japanese Pharmacopoeia.

[0059] The low-substituted hydroxypropyl cellulose may be included in an amount of 1.5 to 11 wt%, 1.5 to 10.5 wt%, 1.5 to 10 wt%, 2 to 11 wt%, 2 to 10.5 wt%, or 2 to 10 wt% based on the total weight of the composite formulation. If the low-substituted hydroxypropyl cellulose is included in an amount less than 1.5 wt%, the disintegration of the formulation may be slowed, thereby reducing the dissolution rate of the active ingredient, particularly empagliflozin. If the low-substituted hydroxypropyl cellulose is included in an amount exceeding 11 wt%, a rapid dissolution pattern may be observed, but the degree of attrition of the formulation may increase, thereby reducing the productivity of the product.

[0060] The combination formulation of the present invention can increase the dissolution rate of active ingredients, particularly empagliflozin, by including croscarmellose sodium together with low-substituted hydroxypropyl cellulose. The croscarmellose sodium may be included in an amount of 0.1 to 3 wt%, 0.1 to 2.7 wt%, 0.1 to 2.5 wt%, 0.2 to 3 wt%, 0.2 to 2.7 wt%, or 0.2 to 2.5 wt% based on the total weight of the combination formulation. When the croscarmellose sodium is included in an amount less than 0.1 wt%, the dissolution rate of the active ingredients may decrease. When the croscarmellose sodium is included in an amount exceeding 3 wt%, the degree of friability may increase, which may lower productivity and also lower the dissolution stability of the active ingredients.

[0061] The above low-substituted hydroxypropyl cellulose and croscarmellose sodium may be included in a weight ratio of 1:0.01 to 0.5, or a weight ratio of 1:0.05 to 0.5. If the weight ratio of the above low-substituted hydroxypropyl cellulose and croscarmellose sodium is outside the above range, the dissolution rate of the active ingredient may decrease.

[0062] The composite formulation of the present invention is preferable because it can have a dissolution pattern similar to that when the active ingredients are administered as a single drug by including common hydroxypropyl cellulose together with low-substituted hydroxypropyl cellulose, and can reduce the degree of wear of the formulation.

[0063] The above hydroxypropyl cellulose may be included in an amount of 0.1 to 6 wt%, 0.1 to 5.5 wt%, 0.1 to 5.0 wt%, 0.3 to 6 wt%, 0.3 to 5.5 wt%, or 0.3 to 5.0 wt% based on the total weight of the composite formulation. If the hydroxypropyl cellulose is included in an amount less than 0.1 wt%, the dissolution rate of empagliflozin may excessively increase or the friability may decrease. If the hydroxypropyl cellulose is included in an amount exceeding 6 wt%, the dissolution rate of empagliflozin may decrease.

[0064] The above low-substituted hydroxypropyl cellulose and hydroxypropyl cellulose may be included in a weight ratio of 1:0.01 to 0.2. If the weight ratio of the above low-substituted hydroxypropyl cellulose and hydroxypropyl cellulose exceeds the above range, the dissolution rate of the active ingredient may decrease.

[0065] Preferably, the above low-substituted hydroxypropyl cellulose, and at least one of croscarmellose sodium and common hydroxypropyl cellulose may be included in the second layer containing empagliflozin in the combination formulation of the present invention.

[0066] As described above, in the composite formulation of the present invention, the first layer comprises metformin or a pharmaceutically acceptable salt thereof as an active ingredient. In addition, the first layer may be a layer comprising a sustained-release compartment of metformin.

[0067] Metformin, which is included as an active ingredient in the first layer, may be included in an amount of 10 to 95 wt%, 20 to 90 wt%, or 30 to 90 wt% based on the total weight of the first layer, but is not limited thereto.

[0068] The first layer may further include one or more pharmaceutically acceptable additives selected from the group consisting of a fluidizing agent, a stabilizer, a release agent, and a lubricant.

[0069] The fluidizing agent included in the first layer may be included in an amount of 0.01 to 10 wt%, 0.05 to 5 wt%, 0.05 to 3 wt%, 0.05 to 1 wt%, 0.1 to 5 wt%, 0.1 to 3 wt%, or 0.1 to 1 wt% based on the total weight of the first layer, but is not limited thereto.

[0070] The fluidizing agent may be, but is not limited to, light anhydrous silicic acid, synthetic aluminum silicate, calcium silicate, magnesium metasilicate aluminate (magnesium aluminum silicate), ammonium alginate, calcium alginate, carrageenan, or mixtures thereof.

[0071] The stabilizer included in the first layer may be included in an amount of 0.01 to 10 wt%, 0.01 to 5 wt%, 0.01 to 3 wt%, 0.01 to 1 wt%, 0.05 to 5 wt%, 0.05 to 3 wt%, or 0.05 to 1 wt% based on the total weight of the first layer, but is not limited thereto.

[0072] The stabilizer included in the first layer may include an acidic stabilizer, a basic stabilizer, or a combination thereof.

[0073] The acid stabilizer may be at least one selected from the group consisting of citric acid, fumaric acid, malic acid, lactic acid, tartaric acid, and succinic acid, and preferably may include citric acid.

[0074] The above basic stabilizer may be at least one selected from the group consisting of meglumine, precipitated calcium carbonate, L-arginine, sodium bicarbonate (NaHCO3), magnesium carbonate (MgCO3), and magnesium oxide, and preferably may include meglumine.

[0075] The release-controlling agent included in the first layer may be included in an amount of 1 to 50 wt%, 3 to 50 wt%, 3 to 45 wt%, 5 to 45 wt%, 5 to 40 wt%, 5 to 35 wt%, or 5 to 30 wt% based on the total weight of the first layer, but is not limited thereto. Within the above range, sufficient release-controlling effect and dissolution of the active ingredient are controlled.

[0076] The preservative included in the first layer may include a non-swelling polymer such as an ammoniomethacrylate copolymer, a fatty acid alcohol, a fatty acid ester, or a mixture thereof.

[0077] As the above ammoniomethacrylate copolymer, Eudragit® RS polymer, which is a 1:2:0.1 copolymer of ethyl acrylate-methyl methacrylate-trimethylammonioethyl methacrylate chloride, can be used. In this case, Eudragit® RS can be Eudragit® RS 100 or RS PO, but is not limited thereto.

[0078] As the above fatty acid alcohol, at least one selected from the group consisting of lauryl alcohol, oleyl alcohol, pelargonic alcohol, ceryl alcohol, linoleyl alcohol, capryl alcohol, cetyl alcohol, palmistyl alcohol, stearyl alcohol, cetostearyl alcohol, and myristyl alcohol can be used.

[0079] In addition, the fatty acid ester may be at least one selected from the group consisting of glyceryl monooleate, glyceryl monostearate, glyceryl distearate, glyceryl palmitostearate, stearic acid, oleic acid, palmitic acid, lauric acid, sebacic acid, and glyceryl behenate. Preferably, the sustained-release agent in the present invention may include a fatty acid ester, and more preferably, glyceryl behenate, but is not limited thereto. In the present invention, the glyceryl behenate may also function as a lubricant.

[0080] The lubricant included in the first layer may be included in an amount of 0.1 to 20 wt%, 0.1 to 10 wt%, 0.1 to 5 wt%, or 0.1 to 3 wt% based on the total weight of the first layer, but is not limited thereto.

[0081] The above lubricant may be, for example, at least one selected from the group consisting of stearic acid, stearic acid metal salts such as calcium stearate or magnesium stearate, talc, colloidal silica, sucrose fatty acid ester, hydrogenated vegetable oil, high-melting-point wax, glyceryl fatty acid ester, and glyceryl behenate, but is not limited thereto, and any substance used as a lubricant in the art or any substance capable of functioning as a lubricant may be included without limitation.

[0082] The first layer may be a tablet comprising granules containing metformin or a pharmaceutically acceptable salt thereof, and a post-mixing portion, to control the release rate of metformin.

[0083] In the first layer, the granules may include a fluidizing agent, a stabilizer, and a release-promoting agent, and the post-mixing section may include a lubricant and further include a release-promoting agent.

[0084] In the first layer, the non-swelling sustained-release agent, ammoniomethacrylate copolymer, may be present within the granules, but may be uniformly coated on the surface of the granules to enhance the sustained-release effect of metformin, the active ingredient.

[0085] In the combination formulation of the present invention, the second layer comprises empagliflozin or a pharmaceutically acceptable salt thereof as an active ingredient. In addition, the second layer may be a layer formed of an immediate-release compartment of empagliflozin.

[0086] In the present invention, empagliflozin included as an active ingredient in the second layer may be included in an amount of 0.5 to 50 wt%, 1 to 40 wt%, or 10 to 20 wt% based on the total weight of the second layer, but is not limited thereto.

[0087] The second layer includes low-substituted hydroxypropyl cellulose as a pharmaceutically acceptable additive together with empagliflozin, and further includes at least one of croscarmellose sodium and hydroxypropyl cellulose.

[0088] In the present invention, the low-substituted hydroxypropyl cellulose included in the second layer may be included in an amount of 7 to 45 wt%, 7 to 42 wt%, 10 to 45 wt%, 10 to 42 wt%, or 10 to 40 wt% based on the total weight of the second layer, but is not limited thereto. In the present invention, if the content of the low-substituted hydroxypropyl cellulose is included in an amount less than 7 wt% based on the total weight of the second layer, the disintegration of the tablet is slow, resulting in a slow release pattern of empagliflozin, and if it is included in an amount exceeding 45 wt%, a fast dissolution pattern is shown compared to the control drug, and the fragility of the tablet increases, which may lower the productivity of the product.

[0089] In the present invention, by using low-substituted hydroxypropyl cellulose together with the active ingredient of empagliflozin in the second layer, an excellent dissolution pattern of the active ingredient and reduced friability of the composite formulation (particularly, tablets) can be achieved simultaneously. These effects are significantly superior to those achieved when using other excipients, such as microcrystalline cellulose or pregelatinized starch.

[0090] Croscarmellose sodium included in the second layer may be included in an amount of 0.1 to 13 wt%, 0.1 to 12 wt%, 0.1 to 11 wt%, 0.1 to 10 wt%, 0.5 to 13 wt%, 0.5 to 12 wt%, 0.5 to 11 wt%, 0.5 to 10 wt%, or 1 to 10 wt% based on the total weight of the second layer, but is not limited thereto.

[0091] In the present invention, if the content of the croscarmellose sodium is included in an amount less than 0.1 wt% based on the total weight of the second layer, the disintegration of the tablet is slow, resulting in a slow release pattern of empagliflozin, and if it is included in an amount exceeding 13 wt%, a fast dissolution pattern is shown compared to the control drug, and the fragility of the tablet increases, which may lower the productivity of the product.

[0092] By including croscarmellose sodium together with the active ingredient of empagliflozin and low-substituted hydroxypropyl cellulose in the second layer, an excellent and stable dissolution pattern of the active ingredients can be secured, and the degree of attrition of the manufactured composite preparation can be reduced, which is preferable.

[0093] The low-substituted hydroxypropyl cellulose and croscarmellose sodium included in the second layer may be included in a weight ratio of 1:0.01 to 0.5, or a weight ratio of 1:0.05 to 0.5. If the weight ratio of the low-substituted hydroxypropyl cellulose and croscarmellose sodium is outside the above range, the dissolution pattern of the active ingredient may be different from that of the reference drug.

[0094] In addition, the second layer may also include general hydroxypropyl cellulose together with low-substituted hydroxypropyl cellulose. The hydroxypropyl cellulose may be included in an amount of 0.1 to 6.5 wt%, 0.1 to 6 wt%, 0.3 to 6 wt%, 0.3 to 5 wt%, 0.4 to 5 wt% or 0.5 to 5 wt% based on the total weight of the second layer, but is not limited thereto. When the content of the hydroxypropyl cellulose is less than 0.1 wt% based on the total weight of the second layer, the degree of friability increases rapidly, and when it exceeds 6.5 wt%, the initial dissolution rate of empagliflozin may be greatly reduced.

[0095] The low-substituted hydroxypropyl cellulose and hydroxypropyl cellulose included in the second layer may be included in a weight ratio of 1:0.01 to 0.2. If the weight ratio of the low-substituted hydroxypropyl cellulose and hydroxypropyl cellulose is outside the above range, the dissolution pattern of the active ingredient may be different from that of the control drug.

[0096] In addition to the above-mentioned components, the second layer may further include one or more pharmaceutically acceptable additives selected from the group consisting of excipients, disintegrants, binders, and lubricants.

[0097] The low-substituted hydroxypropyl cellulose included in the second layer above can function as an excipient, but additional excipients may be included in addition to it.

[0098] The excipient included in the second layer may be at least one selected from the group consisting of microcrystalline cellulose, silicified microcrystalline cellulose, magnesium aluminometasilicate, magnesium aluminosilicate, aluminum silicate, sodium silicate, potassium silicate, magnesium silicate, calcium silicate, lactose, lactose hydrate, lactose anhydrous, calcium hydrogen phosphate, hydroxypropylmethylcellulose, dextrin, mannitol, sorbitol, starch, calcium phosphate hydrate, calcium carbonate, and sugars, and may be, for example, mannitol, but is not limited thereto. Any substance used as an excipient in the art may be included without limitation.

[0099] The excipients that may be additionally included in the second layer may be included in an amount of 1 to 80 wt%, 5 to 80 wt%, 10 to 80 wt%, 20 to 80 wt%, 30 to 80 wt%, or 40 to 80 wt% based on the total weight of the second layer, but are not limited thereto.

[0100] Croscarmellose sodium, as a component included in the second layer, can function as a disintegrant; however, if necessary, other disintegrants may be additionally included in the second layer in addition to croscarmellose sodium.

[0101] Additional disintegrants may be selected from the group consisting of, but not limited to, crospovidone, sodium starch glycolate, calcium carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, starch, pregelatinized starch, corn starch, potato starch, alginic acid or its sodium salt, and any combination thereof, and any material used as a disintegrant in the art may be included without limitation.

[0102] The disintegrant that may be additionally included in the second layer may be included in an amount of 1 to 50 wt%, 1 to 30 wt%, or 1 to 10 wt% based on the total weight of the second layer, but is not limited thereto.

[0103] In the present invention, the hydroxypropyl cellulose additionally included in the second layer can function as a binder, but if necessary, the second layer may additionally include a binder of another type other than hydroxypropyl cellulose.

[0104] The binder that may be additionally included in the second layer may be selected from the group consisting of povidone, hypromellose, copovidone, and any combination thereof, but is not limited thereto, and any material used as a binder in the art may be included without limitation.

[0105] The binder that may be additionally included in the second layer may be included in an amount of 1 to 50 wt%, 1 to 30 wt%, or 1 to 10 wt% based on the total weight of the second layer, but is not limited thereto.

[0106] The second layer may further include a fluidizing agent. The fluidizing agent may be included in an amount of 0.1 to 5 wt% or 0.1 to 3 wt% based on the total weight of the second layer, but is not limited thereto.

[0107] In the present invention, the fluidizing agent may be, for example, light anhydrous silicic acid (SiO2, Aerosil), synthetic aluminum silicate, calcium silicate, magnesium metasilicate aluminate (magnesium aluminum silicate), ammonium alginate, calcium alginate, carrageenan, or a mixture thereof, but is not limited thereto.

[0108] The second layer may further include a lubricant. The lubricant may be included in an amount of 0.1 to 10 wt%, 0.1 to 5 wt%, 0.5 to 5 wt%, 0.5 to 3 wt%, 1 to 5 wt%, or 1 to 3 wt% based on the total weight of the second layer, but is not limited thereto.

[0109] In the present invention, the lubricant may be selected from the group consisting of calcium stearate, glyceryl monostearate, glyceryl palmitostearate, magnesium stearate, sodium lauryl sulfate, sodium stearyl fumarate, zinc stearate, stearic acid, hardened vegetable oil, polyethylene glycol, sodium benzoate, talc, and any combination thereof, but is not limited thereto, and any substance used as a lubricant in the art may be included without limitation.

[0110] The above second layer may contain the above components in a mixed powder form.

[0111] In the present invention, various additives may be additionally mixed into the first layer and / or the second layer to improve the physical properties, manufacturability, compressibility, appearance, preference, and / or drug stability of the final composite formulation. In this case, the additives may be included in at least one of the first layer and the second layer. In addition, such additives may include, but are not limited to, stabilizers, solubilizers, sweeteners, maturing agents, pigments, humectants, fillers, stabilizers, surfactants, lubricants, solubilizers, buffers, sweeteners, adsorbents, maturing agents, binders, suspending agents, curing agents, antioxidants, brighteners, flavoring agents, flavoring agents, pigments, coating agents, humectants, moisture regulators, fillers, antifoaming agents, refreshing agents, chewing agents, antistatic agents, coloring agents, sugar coating agents, isotonic agents, softeners, emulsifiers, adhesives, thickeners, foaming agents, pH regulators, excipients, dispersants, disintegrants, waterproofing agents, preservatives, preservatives, solubilizing agents, solvents, and fluidizing agents, as long as they are pharmaceutically acceptable.

[0112] The pharmaceutical combination formulation of the present invention may be a film-coated tablet. Any coating agent commonly used in the art may be used without limitation, but examples thereof include polyvinylpyrrolidone, copovidone, the Opadry series, and the Eudragit series.

[0113] The total weight of the above complex formulation may be, but is not limited to, 600 to 2,000 mg, 700 to 1,800 mg, or 800 to 1,600 mg.

[0114] The combination formulation according to the present invention, which contains two pharmacologically active ingredients, metformin and empagliflozin, in a single formulation, may be useful for the treatment or prevention of diabetes, alleviating the inconvenience of having to take two formulations separately and significantly improving patient convenience in taking the medication. The combination formulation may be administered once daily, twice daily, three times daily, or four times daily, depending on the content of the main ingredients contained.

[0115] The above compound preparation may be a preparation for oral administration.

[0116] The above pharmaceutical preparation may be a tablet for oral administration. The tablet may be, but is not limited to, a single-layer tablet, a multi-layer tablet, a cored tablet, or a drug-coated tablet.

[0117] The composite formulation of the present invention, particularly the tablet, preferably has a hardness of 30 to 55 kp. If the hardness is less than 30 kp, the low hardness may result in tablet breakage or separation of the upper and lower layers. Conversely, if the hardness exceeds 55 kp, the dissolution of the active ingredients may be delayed.

[0118] The pharmaceutical combination formulation of the present invention can exhibit a dissolution profile of metformin equivalent to that of Glucophage XR sustained-release tablet 1,000 mg (Merck, Inc.), which is commercially available as a control drug.

[0119] The pharmaceutical combination preparation according to the present invention, when tested under the conditions of 900 mL of a pH 6.8 dissolution test solution, a rotation speed of 100 rpm, and a temperature of 37±5℃ according to the dissolution test method of the Korean Pharmacopoeia (rotary sample container method), may have a 2-hour dissolution rate of the main ingredient, metformin, or a pharmaceutically acceptable salt thereof, of 35 to 52% or 40 to 50%, and / or a 4-hour dissolution rate of 50 to 70% or 53 to 68%, and / or a 6-hour dissolution rate of 62 to 85% or 64 to 82%, but is not limited thereto.

[0120] The pharmaceutical combination formulation of the present invention can exhibit an empagliflozin dissolution profile equivalent to that of Jardiance (Boehringer Ingelheim), a commercially available control drug.

[0121] When the pharmaceutical combination preparation according to the present invention is tested under the conditions of 900 mL of a pH 6.8 dissolution test solution, a rotation speed of 100 rpm, and a temperature of 37±5℃ according to the dissolution test method of the Korean Pharmacopoeia (rotary sample container method), the 5-minute dissolution rate of empagliflozin may be 61 to 84%, 65 to 81%, or 66 to 78%, the 10-minute dissolution rate may be 79 to 97%, or 85 to 96%, or the 15-minute dissolution rate may be 89 to 99%, or 92 to 99%, but is not limited thereto.

[0122]

[0123] According to another embodiment of the present invention, there is provided a method for preparing the above-described pharmaceutical combination preparation.

[0124] When producing a two-layer tablet formulation, various problems may arise, such as tablet breakage or separation of the upper and lower layers due to low hardness, and delayed dissolution patterns due to high hardness. In the present invention, the composition of the second layer is limited, and the tableting pressure during the first and second tableting processes is controlled.

[0125] The manufacturing method of the present invention comprises the steps of (a) preparing a first mixture comprising metformin or a pharmaceutically acceptable salt thereof; (b) preparing a second mixture comprising empagliflozin or a pharmaceutically acceptable salt; and (c) compressing the first mixture and the second mixture into tablets. In this case, the first layer comprising the first mixture is a sustained-release layer, and the second layer comprising the second mixture is a rapid-release layer.

[0126] In the present invention, steps (a) and (b) do not necessarily have to be performed sequentially, and step (b) may be performed after step (a), or step (a) may be performed after step (b), or steps (a) and (b) may be performed simultaneously.

[0127] In the present invention, the step of preparing the first mixture (a) may include a step of mixing metformin or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable additive. In the present invention, the pharmaceutically acceptable additive may be at least one selected from a fluidizing agent, a stabilizer, a release-promoting agent, a fatty alcohol, a fatty acid ester, or a mixture thereof, and a lubricant.

[0128] In the present invention, the content of each component mixed during the preparation of the first mixture overlaps with that described in the first layer of the composite preparation according to the present invention, and thus, in order to avoid excessive complexity of the specification, a detailed description thereof is omitted below.

[0129] In the present invention, the step of preparing the first mixture (a) may include the step of preparing a composition for forming granules by mixing metformin or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable additive; (a-2) the step of preparing a coating solution for a sustained-release agent; (a-3) the step of preparing granules coated with the sustained-release agent; and (a-4) the step of mixing with a post-mixing unit.

[0130] In the present invention, the step of preparing a composition for forming granules (a-1) in the preparation of the first mixture may further include a step of sieving a mixture of metformin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive.

[0131] In the present invention, the pharmaceutically acceptable additives of (a-1) may be a fluidizing agent and a stabilizer.

[0132] In the present invention, when preparing the first mixture, in step (a-2), the curing agent can prepare a coating solution containing an ammoniomethacrylate copolymer.

[0133] In the present invention, the solvent may be one selected from alcohol (methanol, ethanol, isopropyl alcohol, etc.), acetone, acetonitrile, methylene chloride, hexane, ethyl acetate, or a mixture of two or more thereof.

[0134] In the present invention, the solvent may be a mixed solvent of isopropyl alcohol and acetone, and more preferably, a solvent in which isopropyl alcohol and acetone are mixed in a volume ratio of 1:5 to 5:1 or a volume ratio of 1:3 to 3:1 is preferable because it can significantly improve the solubility of the water-insoluble ammoniomethacrylate copolymer.

[0135] In the present invention, the amount of the solvent is in the range of 60 to 150% by weight relative to the total weight of metformin or a pharmaceutically acceptable salt thereof.

[0136] Additionally, in the present invention, the coating solution containing the ammoniomethacrylate copolymer may have a viscosity of 1 to 7.5 mPA·s.

[0137] In the present invention, when preparing the first mixture, (a-3) the step of preparing granules coated with the release agent may be performed by preparing a coating solution containing a composition for forming granules and an ammoniomethacrylate copolymer as described above, and then preparing metformin granules coated with the ammoniomethacrylate copolymer.

[0138] In the present invention, the step of manufacturing metformin granules coated with the ammoniomethacrylate copolymer of (a-3) can be performed using a fluid bed granulator.

[0139] In the present invention, the fluidized bed granulator can be divided into a top spray or a bottom spray according to the spray injection method, and preferably, the bottom spray method is used to coat the ammoniomethacrylate copolymer more uniformly on the granules.

[0140] In addition, in the present invention, the step of manufacturing granules using the fluidized bed granulator can be performed by suspending the granule-forming composition in the fluidized bed granulator, spraying a binding coating solution containing an ammoniomethacrylate copolymer as a binding agent, manufacturing wet granules, and drying, if necessary.

[0141] In the present invention, the conditions of the fluidized bed granulation process are not particularly limited, but the supply air temperature may be 40 to 60°C, preferably 40 to 45°C, the spray pressure of the coating solution may be 1.2 to 3.0 bar, and the product temperature during drying may be 30 to 40°C, preferably 30 to 35°C. In the present invention, the spray speed of the coating solution (the amount of coating solution sprayed per hour) may be 300 mg / min or less, and in particular, 250 mg / min or less is preferable because a sufficient sustained-release effect can be obtained while increasing the productivity of the formulation. At this time, the lower limit of the spray speed is not particularly limited, but may be 100 mg / min or more in consideration of productivity.

[0142] The manufacturing method of the present invention may further include a granulating or sieving step of passing the granules coated with the ammoniomethacrylate copolymer through a sieve having pores of a predetermined size in multiple stages during or after the manufacturing process of the granules, if necessary, in order to control the particle size range of the coated granules. In the present invention, the step of passing the granules through the sieve as described above may be performed once or twice or more times in multiple stages. At this time, the sieve is not particularly limited, but, for example, a sieve having a mesh size of 20 may be used.

[0143] The manufacturing method of the present invention may further include, if necessary, a step of drying the granules coated with the ammoniomethacrylate copolymer. The drying process of the granules may be performed by any method generally used for drying formulations, such as vacuum drying or fluidized bed drying.

[0144] The manufacturing method of the present invention may include a step of mixing metformin granules coated with the obtained ammoniomethacrylate copolymer with a post-mixing unit containing a fatty acid alcohol, fatty acid ester, or a mixture thereof, and a lubricant to produce a final mixed powder. In the present invention, by adding a lubricant or additional fatty alcohol, fatty acid ester, or a mixture thereof to the post-mixing unit, the fluidity of the particles can be improved, and friction between particles or with a compression device can be reduced during a subsequent tableting process, thereby facilitating a compression operation.

[0145] In the present invention, the step of preparing the first mixture (a) may include the step of (a-1) preparing a composition for forming granules by mixing metformin or a pharmaceutically acceptable salt thereof with a fluidizing agent and a stabilizer; (a-2) preparing a coating solution containing an ammoniomethacrylate copolymer as a sustained-release agent; (a-3) preparing granules coated with the sustained-release agent; and (a-4) mixing with a post-mixing portion containing a lubricant.

[0146] In the present invention, (b) a step of preparing a second mixture by mixing empagliflozin or a pharmaceutically acceptable salt with low-substituted hydroxypropyl cellulose, croscarmellose sodium, and hydroxypropyl cellulose may be included.

[0147] In the present invention, a second mixture can be prepared by additionally adding an excipient and a lubricant to (b).

[0148] In the present invention, the second mixture obtained in (b) above may be a mixed powder.

[0149] In the present invention, the step of preparing the second mixture (b) may further include a step of sieving a mixture of empagliflozin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive, and the specific process follows that mentioned in the process of the first mixture.

[0150] In the present invention, the content of each component mixed during the preparation of the second mixture overlaps with that described in the second layer of the composite preparation according to the present invention, and thus, in order to avoid excessive complexity of the specification, a detailed description thereof is omitted below.

[0151] When the first mixture and the second mixture are prepared as described above, (c) a step of compressing the first mixture and the second mixture to produce a composite formulation in tablet form can be performed.

[0152] In the present invention, the tableting step (c) can be performed using a tableting machine commonly used for tableting granules, for example, a rotary tableting machine.

[0153] In order to manufacture a two-layer tablet form using the above-described composite formulation in the present invention, the first mixture obtained in the above-described step (a-3) and the second mixture obtained in the above-described step (b) may be used as the lower layer mixture and the upper layer mixture of the two-layer tablet, respectively, or conversely, as the upper layer mixture and the lower layer mixture, during the tableting process in the above-described step (c), and pressure may be applied using a tableting machine to manufacture a two-layer tablet.

[0154] In general, a composite tablet in the form of a two-layer tablet may experience layer separation due to external impact, etc., so in the present invention, the first mixture and the second mixture can be simultaneously compressed in step (c).

[0155] In the present invention, the tableting of (c) is performed by filling the first mixture into a container of a tableting machine, applying pre-pressure to form a first layer, filling the second mixture on top of the first mixture, and then applying main pressure to perform tableting, thereby manufacturing a two-layer tablet including an upper layer and a lower layer, thereby preventing layer separation and also suppressing interference between the active ingredients in the upper and lower layers.

[0156] In the present invention, the preload is preferably in the range of more than 0.1 kN and less than 4 kN, and more preferably may be 0.5 kN to 2 kN. When the preload is 0.1 kN or less, a high dissolution deviation of the active ingredient may occur due to interference between the upper and lower layers, and when the preload is 4 kN or more, the interlayer bonding force between the upper and lower layers may decrease, resulting in interlayer cracking or layer separation.

[0157] In the present invention, the level of the main pressure is not particularly limited, and can be adjusted to an appropriate level to obtain the desired tablet hardness, but may be, for example, 10 kN to 20 kN, or 12 kN to 14 kN.

[0158] In the present invention, the appropriate hardness of the tablets manufactured by the above-described compression method before forming the film coating layer may be, for example, 30 to 55 kp. The compression pressure may be adjusted to an appropriate level to obtain the desired tablet hardness, and is preferably in the range of 30 kp or more and less than 55 kp. When the compression pressure is 30 kp or less, a high dissolution deviation of the active ingredient may occur due to interference between the first and second layers, and when the compression pressure is 55 kp or more, the interlayer bonding force between the first and second layers may decrease, resulting in interlayer cracking or layer separation.

[0159] In the present invention, the tablet obtained after the step (c) of pressing can be manufactured in various shapes, for example, oval, rectangular, egg-shaped, triangular, almond-shaped, peanut-shaped, parallelogram-shaped, circular, pentagonal, hexagonal or trapezoidal, preferably circular, egg-shaped or parallelogram-shaped.

[0160] The manufacturing method of the present invention may further include a step of coating the obtained composite formulation, particularly in the form of a bilayer tablet, with a pharmaceutical rapid-release film coating agent commonly used in the art according to a conventional method. At this time, conventional coating agents may be, for example, hydroxypropylmethyl cellulose, Opadry series, Eudragit series, etc., but are not limited thereto. As an example, based on the total weight of the uncoated tablet of the bilayer tablet, a moisture-proof film coating may be performed at about 3% with an Opadry II coating solution, but are not limited thereto.

[0161]

[0162] Hereinafter, the present invention will be described in more detail through examples. These examples are intended solely to illustrate the present invention more specifically, and it will be apparent to those skilled in the art that the scope of the present invention is not limited by these examples, in accordance with the gist of the present invention.

[0163]

[0164] Example

[0165] [Dissolution pattern analysis method]

[0166] <Dissolution test conditions>

[0167] Dissolution solution: pH 6.8 buffer 900mL

[0168] Dissolution device: Basket

[0169] Rotation speed: 100rpm

[0170] Temperature: 37℃

[0171] Preparation of test solution: After adding 1 tablet of this drug to the corresponding solution, take 5 mL of the test solution at the corresponding time points of 5, 10, 15, 30, and 45 minutes, filter it through a 0.45 μm membrane filter, and sample 1 mL.

[0172] Preparation of standard solution: Take 11.1 mg of empagliflozin standard and place it in a 200 mL flask. Add 10 mL of acetonitrile and dissolve it. Then, adjust to the marked line with the dissolution test solution. Take 10 mL of this solution and place it in a 20 mL flask, and then adjust to the marked line with the dissolution test solution.

[0173]

[0174] [Manufacturing Example 1] Manufacturing of a combination formulation of metformin and empagliflozin

[0175] (1) Preparation of the first mixture containing metformin

[0176] A primary mixture for granule formation was prepared by mixing metformin hydrochloride and light anhydrous silicic acid according to the composition shown in Table 1 below. In addition, a coating binder was prepared by mixing ammoniomethacrylate copolymer (Eudragit® RS PO or RS 100) in a solvent containing isopropyl alcohol and acetone in a weight ratio of 2:1. The primary mixture was placed in a fluidized bed granule coater, and the mixed coating binder was sprayed to prepare granules coated with ammoniomethacrylate copolymer. However, in the case of the fluidized bed granulator process, granules were produced in a batch size of 50,000T per production, the supply air temperature was 42℃, the product temperature was 34-35℃, the coating binder spray amount per hour was 250g / min, and the spray pressure was set to 3 bar, and the process was performed for 3 hours and 30 minutes. The coating granules thus obtained were sieved and refined, and then magnesium stearate was mixed in to prepare the final mixture (first mixture).

[0177] Process composition Manufacturing example 1, content (mg / T) Fluid bed granules Mixed powder for granule manufacturing Metformin hydrochloride 1000 Light anhydrous silicic acid 2.00 Citric acid 1.00 Sustained release agent Ammonio methacrylate copolymer 150.00 Post-mixed glyceryl behenate 5.00 Magnesium stearate 5.00 Total tablet weight 1163.00

[0178] (2) Preparation of a combination formulation of metformin and empagliflozin

[0179] Each component included in the second layer (upper layer) per unit dosage form was designed to manufacture a mixture of the second mixture containing empagliflozin propanediol.

[0180] The final mixed powder of metformin manufactured in the above Manufacturing Example 1 was placed in the container of a double-layer tablet press (Autotab-200TR, Ichihashi Seiki), a pre-pressure of 1 kN was applied to compress the lower layer (first layer), and then the mixed powder of the second mixture was filled as the upper layer (second layer), and then the main pressure was applied so that the hardness of the double-layer tablet to be manufactured was approximately 30 kP, thereby manufacturing a composite double-layer tablet.

[0181]

[0182] [Experimental Example 1] Evaluation of composite bilayer tablets according to excipients

[0183] A metoprin-empagliflozin composite bilayer tablet was manufactured using the method described in Manufacturing Example 1. The following experiment was conducted to determine how the excipients used in the second layer affect the dissolution pattern of empagliflozin (second layer) and the friability of the tablet. In Table 3 below, low-substituted hydroxypropyl cellulose (L-HPC), microcrystalline cellulose (MCC), and pregelatinized starch (Pre. Starch) were used as excipients.

[0184] Content (mg / T) Example 1 Example 2 Example 3 Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 Comparative Example 5 Comparative Example 6 Second layer (upper layer) Empagliflozin 25.00 25.00 25.00 25.00 25.00 25.00 25.00 25.00 25.00 25.00 D-Mannitol 210 273.5 164.5 291.7 129.3 273.5 164.5 273.5 164.5 Low-substituted Hydroxypropylcellulose 100.00 36.50 145.50 18.30 180.70 ----Microcrystalline cellulose----- 36.50 145.50 ----Pregelatinized starch------- 36.50 145.50 Croscarmellose sodium 16.70 16.70 16.70 16.70 16.70 16.70 16.70 16.70 16.70 16.70 16.70 16.70 Hydroxypropylcellulose 6.00 6.00 6.00 6.00 6.00 6.00 6.00 6.00 6.00 6.00 Colloidal silicon dioxide 2.00 2.00 2.00 2.00 2.00 2.00 2.00 2.00 2.00 2.00 Stearic acid Magnesium 4.204.204.204.204.204.204.204.204.20 Upper layer mass 363.90 363.90 363.90 363.90 363.90 363.90 363.90 363.90 1st layer (lower layer) Metformin sustained-release tablet 1163.001163.001163.001163.001163.001163.001163.001163.001163.001163.001163.001163.001163.001163.001163.001163.001163.001163.001163.001163.00 Total uncoated tablets Weight 1526.90 1526.90 1526.90 1526.90 1526.90 1526.90 1526.90 1526.90 1526.90

[0185] Dissolution and friability evaluations were performed on the tablets manufactured in the examples and comparative examples, and the results are shown in Table 3 and Figure 1 below. As a control drug, commercially available Jardiance 25 mg (Boehringer Ingelheim) was used.

[0186] Classification Example 1 Example 2 Example 3 Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 Comparative Example 5 Comparative Example 6 Control Example Type of excipient L-HPCL-HPCL-HPCL-HPCL-HPCMCCMCCPre. Starch Pre. Starch - Content (wt%) 27.50 10.00 40.00 5.00 50.00 10.00 40.00 10.00 40.00 Dissolution rate (%) 0 min 0000000000 5 min 70.36 6.97 7.84 4.89 0.54 1.43 4.23 9.25 0.47 2.310 min 88.9 86.99 3.47 0.59 7.864 344.25 5.86 7.49 0.71 5 min 9 5.493.298.182.199.577.355.870.672.796.830min99.899.4100.193.699.987.970.682.790.699.945min100.1101.5100.298.9100.290.275.395.397.9100.2Wearability(%)0.20.10.40.10.80.20.30.20.2-

[0187] Referring to Table 3 and Figure 1 above, the tablets of Examples 1 to 3 had a dissolution rate of approximately 67 to 78% after 5 minutes, a pattern comparable to that of the control, Jardiance, at approximately 72.3%. In addition, the tablets of Examples 1 to 3 showed a dissolution rate of over 99% after 30 minutes, dissolving empagliflozin at a level comparable to that of the control. In addition, the tablet friability was also very low, at 0.1 to 0.4%.

[0188] The tablet of Comparative Example 1 had a relatively low content of low-substituted hydroxypropyl cellulose, and the dissolution rate after 5 minutes was approximately 45%, which was very low compared to the control example, and the dissolution pattern also showed a slow release pattern.

[0189] The tablet of Comparative Example 2 had a relatively high content of low-substituted hydroxypropyl cellulose, and thus the dissolution rate after 5 minutes was approximately 91%, which was a significant increase compared to the control example, and the friability of the tablet was 0.8%. The standard for the friability test method of the Korean Pharmacopoeia is 1.0% or less, but considering the production and distribution process of the product, 0.5% or less is considered to be an appropriate friability, and the composite bilayer tablet of Comparative Example 2 did not meet this standard.

[0190] The tablets of Comparative Examples 3 and 4 were manufactured using microcrystalline cellulose and adjusting its content. Looking at Comparative Examples 3 and 4, when microcrystalline cellulose was used, the dissolution pattern showed a different tendency from that of Comparative Examples 1 and 2, which used low-substituted hydroxypropyl cellulose. The tablets of Comparative Examples 3 and 4 showed a very low dissolution rate of about 34-41% after 5 minutes, and showed a lower dissolution rate than the control drug even after 45 minutes. In addition, looking at the dissolution pattern of Fig. 1, it was confirmed that a slow dissolution pattern was shown.

[0191] The tablets of Comparative Examples 5 and 6 were manufactured using pregelatinized starch and adjusting its content. The tablets of Comparative Examples 5 and 6 exhibited low dissolution rates and slow dissolution patterns, similar to those manufactured using microcrystalline cellulose in Comparative Examples 3 and 4.

[0192] Therefore, based on the above results, the upper layer containing empagliflozin had a similar dissolution pattern to the control drug when it contained low-substituted hydroxypropyl cellulose in a content of more than 5 wt% and less than 50 wt%, preferably 7 to 45 wt%, and more preferably 10 to 40 wt%, and secured a tablet friability of 0.5% or less.

[0193]

[0194] [Experimental Example 2] Evaluation of composite bilayer tablets according to disintegrant

[0195] A bilayer tablet containing metoprin-empagliflozin was manufactured using the method described in Manufacturing Example 1. The following experiment was conducted to determine how the disintegrant used in the second layer affects the dissolution pattern of empagliflozin (second layer) and the friability of the tablet. In Table 4 below, croscarmellose sodium (Cros CMC Na), crospovidone (CrosPVP), and sodium starch glycolate (SSG) were used as disintegrants.

[0196] Content (mg / T) Example 1 Example 4 Example 5 Comparative Example 7 Comparative Example 8 Comparative Example 9 Comparative Example 10 Second layer (upper layer) Empagliflozin 25.00 25.00 25.00 25.00 25.00 25.00 25.00 25.00 D-Mannitol 210.00 223.00 190.35 226.70 172.20 210.00 210.00 Low-substituted hydroxypropyl cellulose 100.00 100.00 100.00 100.00 100.00 100.00 100.00 100.00 Croscarmellose sodium 16.70 3.70 36.35-54.50--Crospovidone----- 16.70-Starch glycolic acid Sodium------16.70 Hydroxypropyl cellulose 6.006.006.006.006.006.006.006.00 Colloidal silicon dioxide 2.002.002.002.002.002.002.00 Magnesium stearate 4.204.204.204.204.204.204.20 Mass of upper layer 363.90 363.90 363.90 363.90 363.90 363.90 363.90 1st layer (lower layer) Metformin sustained-release tablet 1163.001163.001163.001163.001163.001163.001163.001163.00 Lower layer Mass 1163.001163.001163.001163.001163.001163.001163.001163.00 Total weight 1526.901526.901526.901526.901526.901526.90

[0197] Dissolution and friability evaluations were performed on the tablets manufactured in the examples and comparative examples, and the results are shown in Table 5 and Figure 2 below. As a control drug, commercially available Jardiance 25 mg (Boehringer Ingelheim) was used.

[0198] ClassificationExample 1Example 4Example 5Comparative Example 7Comparative Example 8Comparative Example 9Comparative Example 10Control ExampleType of excipientCros CMC NaCros CMC NaCros CMC NaNo-addedCros CMC NaCrosPVPSSG-Content (weight%)4.601.0010.00-15.004.604.60Dissolution rate (%)0min000000005min70.369.37428.974.221.375.872.310min88.985.795.442.397.834.291.290 .715min95.493.2985598.846.994.496.830min99.899.2100.182.310057.997.999.945min100.110199.595.5101.469.898100.2Wear and tear rate(%)0.20.10.40.110.21.2

[0199] Referring to Table 5 and Figure 2 above, the tablets of Examples 1, 4, and 5 have a dissolution rate of approximately 69-74% after 5 minutes, which is equivalent to the dissolution rate of approximately 72.3% of the control example, Jardiance. In addition, it can be seen that the tablets of Examples 1, 4, and 5 have a dissolution rate of over 99% after 30 minutes, dissolving empagliflozin at a level equivalent to that of the control example. In addition, the tablet friability was also very low at 0.1-0.4%.

[0200] The tablet of Comparative Example 7 did not use croscarmellose sodium and exhibited a slower dissolution pattern compared to the control drug, and the dissolution rate was particularly low for the first 15 minutes. This was also observed in the tablet of Comparative Example 9 using crospovidone.

[0201] The tablet of Comparative Example 8 used an excessive amount of croscarmellose sodium, and the dissolution rate after 10 minutes was about 98%, which was higher than that of the control example, and the tablet friability tended to be high at 1.0% or more.

[0202] The tablet of Comparative Example 10 used sodium starch glycolate and showed a similar dissolution pattern to the control example, Jardiance, but the tablet friability was 1.2%, showing an unsuitable result in terms of tablet productivity.

[0203] Therefore, based on the above results, the upper layer containing empagliflozin contained croscarmellose sodium, but when the content was adjusted to 0.1 to 14.9 wt%, preferably 0.1 to 13 wt%, and more preferably 1 to 10 wt%, it was possible to have a dissolution pattern similar to that of the control drug and secure a tablet friability of 0.5% or less.

[0204]

[0205] [Experimental Example 3] Evaluation of composite bilayer tablets according to binder

[0206] The following experiments were conducted to determine the effect of the binder used in the second layer on the dissolution pattern of empagliflozin (second layer) and the friability of the tablets. In Table 6, hydroxypropyl cellulose was used as the binder, and composite bilayer tablets were prepared with varying amounts of hydroxypropyl cellulose.

[0207] Content (mg / T) Example 1 Example 6 Example 7 Example 8 Comparative Example 11 Comparative Example 12 Comparative Example 13 Second layer (upper layer) Empagliflozin 25.00 25.00 25.00 25.00 25.00 25.00 25.00 25.00 D-Mannitol 210.00 214.00 205.00 197.8 00 216.00 190.50 179.50 Low-substituted hydroxypropyl cellulose 100.00 100.00 100.00 100.00 100.00 100.00 100.00 100.00 Croscarmellose sodium 16.70 16.70 16.70 16.70 16.70 16.70 16.70 Hydroxypropyl Cellulose 6.002.0011.0018.200.0025.5036.50Colloidal silicon dioxide 2.002.002.002.002.002.002.00Magnesium stearate 4.204.204.204.204.204.204.20Upper layer mass 363.90363.90363.90363.90363.90363.90First layer (lower layer)Metformin sustained-release tablet 1163.001163.001163.001163.001163.001163.001163.00Lower layer Mass 1163.001163.001163.001163.001163.001163.001163.001163.00 Total weight 1526.901526.901526.901526.901526.901526.90

[0208] Dissolution and friability evaluations were performed on the tablets manufactured in the examples and comparative examples, and the results are shown in Table 7 and Figure 3 below. As a control drug, commercially available Jardiance 25 mg (Boehringer Ingelheim) was used.

[0209] In addition, considering the subsequent outer coating of the composite two-layer tablet, 100 tablets of each tablet were placed in the coating machine, rotated at 10 rpm for 10 minutes without spraying the coating solution, and then the tablets were taken out to check for damage.

[0210] ClassificationExample 1Example 6Example 7Example 8Comparative Example 11Comparative Example 12Comparative Example 13Control ExampleBinder TypeHPCHPCHPCHPCHPCHPCHPC-Content (weight%)1.600.503.005.0007.0010.00Dissolution Rate(%)0min000000005min70.373.269.167.780.560.243.272.310min88.990.687. 986.192.878.464.990.715 minutes95.497.293.492.398.288.480.496.830 minutes99.899.997.996.7100.496.295.599.945 minutes100.1101.2100.499.7100.5100.197.9100.2 Wear rate(%)0.20.30.10.11.100-Damage in coating machine0 / 100T0 / 100T0 / 100T0 / 100T12 / 100T0 / 100T0 / 100T-

[0211] Referring to Table 7 and Figure 3 above, the tablets of Examples 1, 6 to 8 had a dissolution rate of approximately 68 to 73% after 5 minutes, which was equivalent to approximately 72.3% of the control example, Jardiance, and it was found that empagliflozin was dissolved at a dissolution rate equivalent to that of the control example after 30 minutes. In addition, the tablet friability was very low at 0.1 to 0.3%, and no tablets were broken in the coating machine.

[0212] In Comparative Example 11, when hydroxypropyl cellulose was not included, the tablet friability was as high as 1.1%, and it was confirmed that the tablet was broken inside the coating machine.

[0213] The tablets of Comparative Examples 12 and 13 had a higher content of hydroxypropyl cellulose, and the higher the content, the lower the initial dissolution rate and the slower the dissolution pattern.

[0214] Therefore, based on the above results, it can be seen that when the upper layer containing empagliflozin includes hydroxypropyl cellulose and the content thereof is adjusted to 0.1 to 7 wt%, preferably 0.1 to 6.5 wt%, and more preferably 0.5 to 5 wt%, it has a dissolution pattern similar to that of the control drug, and there is no attrition of tablets of 0.5% or less and no breakage of tablets in the coating machine.

[0215]

[0216] [Experimental Example 4] Evaluation by Refining Hardness

[0217] The following experiment was conducted to determine how the hardness of a composite bilayer tablet affects the dissolution pattern of empagliflozin (second layer) and the friability of the tablet in the same formulation. The content of the composite bilayer tablet was as in Example 1, as shown in Table 8 below.

[0218] Content (mg / T) Second layer (upper layer) Empagliflozin 25.00 D-mannitol 210.00 Low-substituted hydroxypropyl cellulose 100.00 Croscarmellose sodium 16.70 Hydroxypropyl cellulose 6.00 Colloidal silicon dioxide 2.00 Magnesium stearate 4.20 Upper layer mass 363.90 First layer (lower layer) Metformin sustained-release tablet 1163.00 Lower layer mass 1163.00 Total tablet weight 1526.90

[0219] The same formulation of the composite bilayer tablet was used to evaluate dissolution and friability by hardness. Friability evaluations excluded the control drug. Furthermore, considering the future outer coating of the composite bilayer tablet, 100 tablets of each tablet were placed in a coating machine, rotated at 10 rpm for 10 minutes without spraying the coating solution, and then the tablets were removed and checked for damage.

[0220] Each example and comparative example was performed with the same content but with different hardness during tableting, and the results obtained are as shown in the table below.

[0221] Classification Example 1A Example 1B Example 1C Comparative Example 14A Comparative Example 14B Comparative Example 14C Control Example Hardness (kp) 30 4 5 5 1 0 2 0 6 0 - Dissolution Rate (%) 0 min 0 ... 390.715 minutes 97.295.492.998.29884.896.830 minutes 99.799.897.899.3100.596.799.945 minutes 101.3100.199.599.5100.9100.8100.2 Wear rate (%) 0.20.101.30.70 - Damaged tablets in coating machine 0 / 100T 0 / 100T 0 / 100T 13 / 100T 2 / 100T 0 / 100T -

[0222] As shown in Table 9 and Figure 4 above, the tablets of Examples 1A to 1C had a hardness in the range of 30 to 55 kp, and within this hardness range, they exhibited similar dissolution patterns to the control drug. In addition, the friability was good, and no tablets were broken within the coating machine.

[0223] In comparison, the tablet of Comparative Example 14A with a hardness of 10 kp had a faster dissolution rate after 5 minutes compared to the control drug, and the degree of wear was very high at 1.3%, and it was confirmed that the degree of breakage of the tablet occurred very high within the coating machine.

[0224] It was confirmed that the tablet of Comparative Example 14B, which had a hardness of 20 kp, had a wear rate exceeding 0.5% and that the tablet was broken within the coating machine.

[0225] In addition, it was confirmed that the tablet of Comparative Example 14C with a hardness of 60 kp had good tablet friability and breakage in the coating machine, but the initial disintegration time was significantly delayed compared to the tablet with a hardness of 30 to 55 kp, and the dissolution pattern was slow.

[0226] Therefore, based on the above results, when the hardness range is set to 30 to 55 kp during the production of a composite two-layer tablet, it can be seen that it has a similar dissolution pattern to the control drug, has a tablet wear rate of less than 0.5%, and has no breakage of tablets in the coating machine.

[0227]

[0228] [Experimental Example 5] Evaluation of a low-dose composite bilayer tablet

[0229] A composite bilayer tablet was manufactured to contain a low dose of metformin in the first layer (lower layer) and empagliflozin in the second layer (upper layer) per unit dosage form. The specific manufacturing method was the same as in Example 1.

[0230] Content (mg / T) Example 9 Example 10 Example 11 Prescription dose 10 / 1000 5 / 1000 5 / 500 Second layer (upper layer) Empagliflozin 10.00 5.00 5.00 D-mannitol 145.00 150.00 150.00 Low-substituted hydroxypropyl cellulose 80.00 80.00 80.00 Croscarmellose sodium 5.00 5.00 5.00 Hydroxypropyl cellulose 3.00 3.00 3.00 Colloidal silicon dioxide 1.00 1.00 1.00 Magnesium stearate 3.00 3.00 3.00 Second layer total Weight 247.00 247.00 247.00 1st layer (lower layer) Metformin 1000.00 1000.00 500.00 Light anhydrous silicic acid 2.00 2.00 1.00 Citric acid 1.00 1.00 0.50 Ammonio methacrylate copolymer 120.00 120.00 200.00 Glyceryl behenate 5.00 5.00 2.50 Magnesium stearate 5.00 5.00 2.50 Total weight of the 1st layer 1133.00 1133.00 70 6.50 Total weight of uncoated tablets 1380.00 1380.00 95 3.50

[0231] As a result of conducting a dissolution evaluation on the tablets manufactured in Examples 9 to 11, it was confirmed that they had a dissolution pattern similar to that of the control drug.

[0232]

[0233] While specific aspects of the present invention have been described in detail above, it should be apparent to those skilled in the art that these specific descriptions are merely preferred implementation examples and do not limit the scope of the present invention. Therefore, the substantial scope of the present invention is defined by the appended claims and their equivalents.

[0234] The present invention is applicable to a pharmaceutical combination preparation comprising metformin and empagliflozin.

Claims

1. (1) A first layer comprising metformin or a pharmaceutically acceptable salt thereof; (2) a second layer comprising empagliflozin or a pharmaceutically acceptable salt; A pharmaceutical composite formulation comprising, in the second layer, 7 to 45 wt% of low-substituted hydroxypropyl cellulose, 0.1 to 13 wt% of croscarmellose sodium, and 0.1 to 6.5 wt% of hydroxypropyl cellulose based on the total weight of the second layer.

2. In paragraph 1, A pharmaceutical combination preparation comprising the above low-substituted hydroxypropyl cellulose and croscarmellose sodium in a weight ratio of 1:0.01 to 0.

5.

3. In paragraph 1, A pharmaceutical combination preparation comprising the above-mentioned low-substituted hydroxypropyl cellulose and hydroxypropyl cellulose in a weight ratio of 1:0.01 to 0.

2.

4. In paragraph 1, A pharmaceutical composite formulation, wherein the second layer further comprises at least one pharmaceutically acceptable additive selected from the group consisting of excipients, fluidizing agents, disintegrants, binders, and glidants.

5. In paragraph 1, A pharmaceutical composite formulation, wherein the first layer further comprises at least one pharmaceutically acceptable additive selected from the group consisting of a fluidizing agent, a stabilizer, a release agent, and a lubricant.

6. In paragraph 1, The first layer comprises granules containing metformin or a pharmaceutically acceptable salt thereof in an amount of 500 mg to 1,000 mg, A pharmaceutical combination formulation comprising the second layer comprising empagliflozin or a pharmaceutically acceptable salt thereof in an amount of 5 mg to 25 mg.

7. In paragraph 1, The above pharmaceutical combination preparation is a tablet for oral administration.

8. In paragraph 7, The above pharmaceutical combination preparation is a bilayer tablet or multilayer tablet.

9. In paragraph 7, The above pharmaceutical combination preparation is a pharmaceutical combination preparation having a hardness of 30 to 55 kp.

10. In paragraph 1, The above pharmaceutical combination preparation is a pharmaceutical combination preparation in which, when tested under the conditions of 900 mL of a pH 6.8 dissolution test solution, a rotation speed of 100 rpm, and a temperature of 37±5℃ according to the dissolution test method of the Korean Pharmacopoeia (rotary sample container method), the 5-minute dissolution rate of empagliflozin is 61 to 84%, the 10-minute dissolution rate is 79 to 97%, or the 15-minute dissolution rate is 89 to 99%. 11.(a) A step of preparing a first mixture comprising metformin or a pharmaceutically acceptable salt thereof; (b) preparing a second mixture comprising empagliflozin or a pharmaceutically acceptable salt; and (c) a step of manufacturing a tablet by forming the first mixture as the first layer and the second mixture as the second layer; A method for producing a pharmaceutical combination formulation, wherein the second mixture comprises 7 to 45 wt% of low-substituted hydroxypropyl cellulose, 0.1 to 13 wt% of croscarmellose sodium, and 0.1 to 6.5 wt% of hydroxypropyl cellulose based on the total weight of the second mixture.

12. In paragraph 11, The method for producing a pharmaceutical composite formulation of the above (c) is to form a first layer by filling the first mixture into a container of a tablet press, applying pre-pressure, and then filling the second mixture on top of the first layer and applying main pressure to form a tablet.

13. In paragraph 11, A method for manufacturing a pharmaceutical composite preparation, wherein the tableting of the above (c) is performed so that the hardness of the tablet is 30 to 55 kp.

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