Combination drugs for the control and management of type 2 diabetes mellitus.

Abstract

The present invention relates to an innovative stable immediate-release pharmaceutical preparation for the treatment, control and better management of type 2 diabetes mellitus, which contains a sulfonylurea such as glimepiride, a dipeptidyl peptidase 4 (DPP4) inhibitor such as vildagliptin and a biguanide such as metformin. At the same time, the present invention makes it possible to solve a series of important technical problems in the production of the above-mentioned pharmaceutical preparations, which are caused by the differences in physicochemical properties and dosage of the synergistic combination of the drugs.

Description

[Technical Field]

[0001] This invention belongs to the field of health. In particular, the field of health refers to the pharmaceutical field of manufacturing drugs for the control and management of type 2 diabetes mellitus. [Background technology]

[0002] Diabetes mellitus, commonly known as diabetes, is a chronic disease associated with abnormally high levels of glucose in the blood. Diabetes is caused by the spleen not producing enough insulin and / or cells in the body not responding properly to insulin. According to the World Health Organization, diabetes affects approximately 347 million people, and this number is expected to more than double by 2030. The global increase in diabetes is attributed to aging, population growth, increasing obesity rates, unhealthy diets, and sedentary lifestyles (Non-Patent Literature 1).

[0003] Type 1 diabetes is characterized by a spleen that no longer produces insulin, while type 2 diabetes is characterized by the body's inability to effectively use insulin, often resulting from being overweight or lacking physical activity. Both types of diabetes result in elevated blood glucose levels (hyperglycemia). Treatment for diabetes includes monotherapy and combination therapy.

[0004] Medical practices indicate that the best way to control type 2 diabetes is through calorie restriction and increased physical activity, but maintaining these is often difficult, and medication is frequently required for control. Current therapies for diabetes focus on achieving and maintaining blood glucose levels as close to normal as possible to avoid the disease's microvascular complications (eye damage, kidney damage, nerve damage, and diabetic foot complications) and macrovascular complications (cardiovascular diseases such as heart attacks, strokes, and poor circulation in the lower extremities).

[0005] Several drugs are available for the treatment of type 2 diabetes, and to date, biguanides, sulfonylureas, glucosidase inhibitors, and insulin resistance improvers have been used. These drugs are indicated as monotherapy, but adverse reactions or side effects such as lactic acidosis with biguanides, hypoglycemia with sulfonylureas, and diarrhea and severe liver dysfunction with glucosidase inhibitors have been reported (Patent Document 1).

[0006] For example, glimepiride is a drug indicated for the treatment of type 2 diabetes in adults, both as monotherapy and as a complement to diet and exercise to improve blood glucose control. It has also been shown in combination with metformin or insulin to lower blood glucose in patients with type 2 diabetes whose high blood glucose levels are not controllable by diet and exercise. [ka]

[0007] According to its biopharmaceutical classification, glimepiride is a type II drug characterized by low solubility and high permeability.

[0008] Vildagliptin belongs to a class of orally active antidiabetic drugs known as DPP-IV protease inhibitors, which offer several functional benefits beyond simple blood glucose control. One of these is the potential protective effect on splenic beta cells, which worsen in diabetes. Vildagliptin appears to be safe, highly tolerable, and effective. Incretin hormones are released from the intestines after meals. The most important incretin hormones are GLP-1 and glucose-dependent insulinotropic polypeptide (GIP). These hormones, secreted in the human small intestine, are responsible for insulin release in response to increased glucose levels. The dependence of GLP-1 on glucose concentration is considered beneficial because it carries a lower risk of hypoglycemia compared to drugs that promote insulin secretion via glucose-independent mechanisms. GLP-1 also increases beta cell mass by inhibiting glucagon secretion and stimulating proliferation and regeneration. However, the clinical utility of GLP-1 is limited by its short half-life (2 minutes). GLP-1 is rapidly degraded by the proteolytic enzyme DPP-IV. To enhance GLP-1 activity, inhibition of the DPP-IV enzyme is attracting attention as a novel therapeutic approach in the treatment of diabetes. Vildagliptin administration increases the ability of GLP-1 to produce insulin in response to rising blood glucose levels, inhibits postprandial glucagon release, slows the rate of nutrient absorption into the bloodstream, reduces gastric emptying rate, and decreases food intake. [ka]

[0009] According to its biopharmaceutical classification, vildagliptin is a type III drug with high solubility and low permeability.

[0010] Metformin is a biguanide used as an antidiabetic drug. Its chemical name is 1-(diaminomethidene)-3,3-dimethylguanidine. It is frequently used in the treatment of type 2 diabetes, especially when insulin resistance is present. Generally, a maximum dose of 3000 mg / day is recommended for adults, and 500 mg and 850 mg tablets are available (Patent Document 2). Metformin reduces glucose production in the liver and increases insulin sensitivity in liver and peripheral tissues, mainly in muscle tissue. It has also been shown to induce weight loss in subjects with type 2 diabetes (Non-Patent Documents 2 and 3). Commercially available metformin medications contain metformin hydrochloride. Side effects of metformin hydrochloride include gastrointestinal intolerance (e.g., diarrhea, nausea / vomiting). Metformin hydrochloride is contraindicated in patients with renal disease or renal failure, or acute or chronic metabolic acidosis. [ka]

[0011] According to its biopharmaceutical classification, metformin is a type III drug with high solubility and low permeability.

[0012] In the treatment of type 2 diabetes, long-term use of a single drug, sometimes high doses, and side effects make good control difficult. This is why it is necessary to find combinations of novel antidiabetic drugs that provide improved glycemic control or drugs that act through different or complementary mechanisms of action to improve glycemic control and management while minimizing side effects.

[0013] On the other hand, there is little evidence regarding the feasibility of combining multiple drugs, such as sulfonylurea, dipeptidyl peptidase 4 (DPP4) inhibitors, and biguanidine, into a stable single-dose formulation that can manage chronic diseases such as type 2 diabetes mellitus.

[0014] Patent document 3 relates to a cocrystal of metformin glimepiride characterized by physicochemical properties including powder X-ray diffraction patterns. Patent document 4 by WEIHAI DISU PHARMACEUTICAL Co., Ltd. claims a method for preparing crystalline form I of glimepiride. Patent document 5 by Novartis protects the use of vildagliptin or its salts in combination with insulin in the preparation of a drug to reduce severe hypoglycemic events in patients with diabetes mellitus. Subsequently, patent document 6 describes a metformin hydrochloride crystalline compound characterized by powder X-ray diffraction patterns.

[0015] Novartis's Patent Document 7 protects pharmaceutical compression tablets or direct compression tablets containing vildagliptin in free form or acidic salt form, wherein at least 60% of the particle size distribution in the tablets is less than 250 microns.

[0016] Patent document 8 from NOVARTIS describes a composition comprising 1.5-20% vildagliptin or a pharmaceutically acceptable salt thereof, 80-98.5% metformin or a pharmaceutically acceptable salt thereof as active ingredients, and further comprising an additional active ingredient such as sulfonylurea or glitazone, such as pioglitazone or rosiglitazone. The process of preparing the above pharmaceutical composition in layers of a tablet, such as two or three layers, is also within the scope of protection.

[0017] On the other hand, none of these documents disclose or suggest any dosage units or drug products in a stable solid pharmaceutically acceptable form containing drugs such as glimepiride, vildagliptin, and metformin that are useful for the treatment and control of type 2 diabetes mellitus. Furthermore, no method is described or suggested for manufacturing a fixed combination of these drugs in a stable, single-dose form that can be administered over time.

[0018] For new treatments and at the same time, in a study to solve a series of important technical problems caused by the physicochemical properties and dosage differences of the synergistic combination of drugs and to reliably obtain a stable drug in the control and management of diabetes, the present invention provides a treatment for type 2 diabetes (triple therapy) including sulfonylurea, dipeptidyl peptidase 4 (DPP4) inhibitor and biguanide, and presents various drug combinations for the manufacture of an innovative, fixed combination, stable immediate-release drug for better control and management.

Prior Art Documents

Patent Documents

[0019]

Patent Document 1

Patent Document 2

Patent Document 3

Patent Document 4

Patent Document 5

Patent Document 6

Patent Document 7

Patent Document 8

Non-Patent Documents

[0020]

Non-Patent Document 1

[0021] The present invention relates to a combination drug comprising (a) sulfonylurea, (b) dipeptidyl peptidase 4 (DPP4) inhibitor, and (c) a pharmaceutically acceptable salt thereof, in pharmaceutically acceptable amounts ranging from 1 to 4 mg, 50 mg, and 500 to 1000 mg, respectively, in combination with a pharmaceutically acceptable excipient and / or vehicle.

[0022] The agent of the present invention is in solid form and is adapted to be immediate-release.

[0023] In one embodiment, the amount of sulfonylurea is pharmaceutically acceptable, preferably 1 mg, more preferably 2 mg, and more preferably 4 mg.

[0024] In other embodiments, the biguanide is in a pharmaceutically acceptable amount, preferably 500 mg, more preferably 1000 mg.

[0025] In other embodiments, the formulation of the present invention is preferably formulated with pharmaceutically acceptable excipients and / or vehicles in pharmaceutically acceptable amounts of 1 / 50 / 500 mg each.

[0026] In other embodiments, the formulation of the present invention is preferably formulated with pharmaceutically acceptable excipients and / or vehicles in pharmaceutically acceptable amounts of 2 / 50 / 1000 mg each.

[0027] In other embodiments, the formulation of the present invention is preferably formulated with pharmaceutically acceptable excipients and / or vehicles in pharmaceutically acceptable amounts of 4 / 50 / 1000 mg each.

[0028] pharmaceutically acceptable excipients and / or vehicles employed for the manufacture of the pharmaceutical products of the present invention include, for example, binders, diluents, disintegrants, lubricants, solvents and / or solubilizers, adsorbents, and coatings.

[0029] An additional object of the present invention is the use of (a) sulfonylurea, (b) dipeptidyl peptidase 4 (DPP4) inhibitor, and (c) a pharmaceutically acceptable salt thereof, in combination with pharmaceutically acceptable excipients and / or vehicles in pharmaceutically acceptable amounts ranging from 1 to 4 mg, 50 mg, and 500 to 1000 mg, respectively, for the manufacture of a product of drugs useful for the treatment, control, and management of type 2 diabetes mellitus in individuals requiring tripartite oral therapy, wherein the sulfonylurea, dipeptidyl peptidase 4 (DPP4) inhibitor, and biguanide are preferably glimepiride, vildagliptin, and metformin, or a pharmaceutically acceptable salt thereof. Preferably, metformin is in the form of its hydrochloride salt.

[0030] The manufacturing process involves selecting unit operations, sequences, and execution times to control the different physicochemical properties of the drug, and the key operations of the manufacturing process are described in the detailed explanation below.

[0031] In one embodiment, the drug is a single-dose solid dosage form selected from the group including tablets, caplets, granules, lozenges, and pills, and is preferably in tablet form.

[0032] Another objective of the present invention is to provide innovative, stable, and immediately-release drug products for the treatment, control, and better management of type 2 diabetes mellitus, containing sulfonylureas such as glimepiride, dipeptidyl peptidase 4 (DPP4) inhibitors such as vildagliptin, and biguanides such as metformin in its hydrochloride form.

[0033] In one embodiment of the present invention, C max and area under the plasma concentration curve as time (ABC 0-t The pharmacokinetic parameters of the drug are determined, making it possible to characterize the bioavailability of the drug of the present invention according to its administration form in terms of the rate and degree of absorption of each drug. [Brief explanation of the drawing]

[0034] [Figure 1]This is the vildagliptin dissolution profile of a combination drug containing glimepiride 4 mg / vildagliptin 50 mg / metformin hydrochloride 1000 mg. [Figure 2] This is the vildagliptin dissolution profile of a combination drug containing glimepiride 2 mg / vildagliptin 50 mg / metformin hydrochloride 1000 mg. [Figure 3] This is the glimepiride dissolution profile of a combination drug containing glimepiride 4 mg, vildagliptin 50 mg, and metformin hydrochloride 1000 mg. [Figure 4] This is the glimepiride dissolution profile of a combination drug containing glimepiride 2 mg, vildagliptin 50 mg, and metformin hydrochloride 1000 mg. [Figure 5] This is the metformin dissolution profile of a combination drug containing glimepiride 4 mg, vildagliptin 50 mg, and metformin hydrochloride 1000 mg. [Figure 6] This is the metformin dissolution profile of a combination drug containing glimepiride 2 mg / vildagliptin 50 mg / metformin hydrochloride 1000 mg. [Figure 7] This is the vildagliptin dissolution profile of a combination drug containing glimepiride, vildagliptin, and metformin hydrochloride. [Figure 8] This is the glimepiride dissolution profile of a combination drug containing glimepiride, vildagliptin, and metformin hydrochloride. [Figure 9] This is the metformin dissolution profile of a combination drug containing glimepiride, vildagliptin, and metformin hydrochloride. [Figure 10] This shows the mean plasma concentration over time. It represents the mean pharmacokinetic profile of glimepiride on an arithmetic scale ± standard error (A: control drug, B: test drug). [Figure 11] This shows the mean plasma concentration over time. It represents the mean pharmacokinetic profile ± standard error of glimepiride on a semi-logarithmic scale (A: control drug, B: test drug). [Figure 12]This shows the mean plasma concentration over time. It represents the mean pharmacokinetic profile of metformin on an arithmetic scale ± standard error (A: control drug, B: test drug). [Figure 13] This shows the mean plasma concentration over time. It represents the mean pharmacokinetic profile ± standard error of metformin on a semi-logarithmic scale (A: control drug, B: test drug). [Figure 14] This shows the mean plasma concentration over time. It represents the mean pharmacokinetic profile of metformin on an arithmetic scale ± standard error (A: control drug, B: test drug). [Figure 15] This shows the mean plasma concentration over time. It represents the mean pharmacokinetic profile ± standard error of vildagliptin on a semi-logarithmic scale (A: control drug, B: test drug). [Modes for carrying out the invention]

[0035] definition Pharmaceutically acceptable salts In this invention, a pharmaceutically acceptable salt should be understood as a compound that retains the biological efficacy and properties of a given compound and is not biologically or otherwise undesirable (P. Heinrich Stahl and Camille G. Wermuth (Eds.) Pharmaceutical Salts Properties, Selection, and Use (International Union of Pure and Applied Chemistry), Wiley-VCH;2 aRevised edition (May 16, 2011). Pharmaceutically acceptable base addition salts can be prepared from inorganic or organic bases. Salts derived from inorganic bases include, for illustrative purposes only, sodium, potassium, lithium, ammonium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines. Specific examples of suitable amines include isopropylamine, trimethylamine, diethylamine, tri(isopropyl)amine, tri(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, tromethamine, lysine, arginine, histidine, caffeine, procaine, hydravamine, choline, betaine, ethylenediamine, glucosamine, N-alkylglucamine, theobromine, purine, piperazine, piperidine, morpholine, and N-ethylpiperidine.

[0036] Pharmaceutically acceptable acid addition salts can be prepared from inorganic or organic acids. Salts derived from inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid. Salts derived from organic acids include acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid.

[0037] Excipients In this invention, the term excipient should be understood as a raw material that is part of the pharmaceutical composition. Excipients may, among other things, be diluents, disintegrants, lubricants, coatings, or absorbents.

[0038] stability It is the ability of a pharmaceutical product to maintain its chemical, physical, microbiological, and biopharmaceutical properties within certain limits throughout its entire shelf life.

[0039] The present invention is an innovative novel drug adapted to be immediate-release in a single-dose form for use in the treatment, better control, and management of type 2 diabetes mellitus, and at the same time adapted to resolve a series of important technical challenges in the manufacture of the drug, resulting from differences in the physicochemical properties and dosages of the formulation of the drugs it contains, in order to ensure a stable product for its intended purpose. Accordingly, the present invention describes a combination drug product characterized by containing (a) sulfonylurea, (b) dipeptidyl peptidase 4 (DPP4) inhibitor, and (c) biguanide, or a pharmaceutically acceptable salt thereof, in pharmaceutically acceptable amounts ranging from 1 to 4 mg, 50 mg, and 500 to 1000 mg, respectively, in combination with pharmaceutically acceptable excipients and / or vehicles.

[0040] In one embodiment of the present invention, sulfonylurea is preferably included in a pharmaceutically acceptable amount of 1 mg. In another embodiment of the present invention, sulfonylurea is preferably included in a pharmaceutically acceptable amount of 2 mg. In another preferred embodiment of the present invention, sulfonylurea is preferably included in a pharmaceutically acceptable amount of 4 mg. In another embodiment of the present invention, biguanide is preferably included in a pharmaceutically acceptable amount of 500 mg. In another embodiment of the present invention, biguanide is preferably included in a pharmaceutically acceptable amount of 1000 mg.

[0041] In the most preferred embodiment of the present invention, the pharmaceutical product comprises a single-dose formulation of pharmaceutically acceptable amounts of (a) sulfonylurea, (b) dipeptidyl peptidase 4 (DPP4) inhibitor, and (c) biguanide, or a pharmaceutically acceptable salt thereof, in amounts of 1 / 50 / 500 mg each.

[0042] In a more preferred embodiment of the present invention, the pharmaceutical product comprises a single-dose formulation of 2 / 50 / 1000 mg each of pharmaceutically acceptable amounts of (a) sulfonylurea, (b) dipeptidyl peptidase 4 (DPP4) inhibitor, and (c) biguanide, or a pharmaceutically acceptable salt thereof.

[0043] In the most preferred embodiment of the present invention, the pharmaceutical product comprises a single-dose formulation of 4 / 50 / 1000 mg each of pharmaceutically acceptable amounts of (a) sulfonylurea, (b) dipeptidyl peptidase 4 (DPP4) inhibitor, and (c) biguanide, or a pharmaceutically acceptable salt thereof.

[0044] Similarly, the fixed formulation of a single-dose sulfonylurea, dipeptidyl peptidase 4 (DPP4) inhibitor, and biguanide is preferably glimepiride, vildagliptin, and metformin, or a pharmaceutically acceptable salt thereof. Metformin is preferably in the form of its hydrochloride salt.

[0045] Furthermore, the compounded drug of the present invention is in a single-dose solid dosage form and is adapted to be immediate-release. The solid pharmaceutically acceptable form of the compounded drug is selected from the group including tablets, caplets, granules, lozenges, and pills. In one embodiment of the present invention, the preferred solid dosage form is a tablet for its dosage accuracy and is also the most acceptable dosage form for its ease of administration. An alternative is a capsule, but the size limitations of the capsule prevent the administration of such high concentrations of the drug. In the case of tablets, it is possible to reduce the volume of powder, thereby facilitating their handling and administration.

[0046] Tablets designed in caplet form are also easy to swallow and offer the smallest possible size in terms of tablet volume and weight. In one embodiment, the design features grooves.

[0047] In this regard, the present invention also relates to the use of (a) sulfonylurea, (b) dipeptidyl peptidase 4 (DPP4) inhibitor, and (c) a pharmaceutically acceptable amount of any of these, in combination with a pharmaceutically acceptable excipient and / or vehicle, in amounts ranging from 1 to 4 mg, 50 mg, and 500 to 1000 mg, respectively, for the manufacture of a product of drugs useful for the treatment, control, and management of type 2 diabetes mellitus in individuals requiring tripartite oral therapy, wherein the sulfonylurea, dipeptidyl peptidase 4 (DPP4) inhibitor, and biguanide are preferably glimepiride, vildagliptin, and metformin, or a pharmaceutically acceptable salt of any of these. Metformin is preferably in the form of its hydrochloride salt. This method makes it possible to obtain a product of drugs that is easy to administer in a single dose.

[0048] In one embodiment of the present invention, a sulfonylurea, a dipeptidyl peptidase 4 (DPP4) inhibitor, and a biguanide, or a pharmaceutically acceptable salt thereof, is preferably formulated with a pharmaceutically acceptable excipient and / or vehicle in a pharmaceutically acceptable amount of 1 / 50 / 500 mg, more preferably 2 / 50 / 1000 mg, and most preferably 4 / 50 / 1000 mg, respectively.

[0049] The formulation of (a) sulfonylurea, (b) dipeptidyl peptidase 4 (DPP4) inhibitors and (c) biguanides, or their pharmaceutically acceptable salts, in pharmaceutically acceptable amounts presents a series of significant technical challenges stemming from the physicochemical properties of the drugs. The technical complexity lies in the fact that, when these three drugs are present, one of them is sensitive to humidity and light in a compounding medium where the absorption of these drugs is unaffected, and has a photoprotective coating without affecting drug release. Meanwhile, in the development of drug formulations, the appropriate selection of excipients and manufacturing conditions, as well as dosage differences, play a crucial role in ensuring a stable product in relation to the rate of drug release and absorption in the body.

[0050] The process involves selecting unit operations, sequences, and execution times to control the different physicochemical properties of the drug, and therefore the key operations of the manufacturing process are described below. Mix 1 is necessary to improve the technical properties of the drug with granulating material, while Mix 2 is necessary to protect the drug with an adsorbent. Sieving is essential because it is necessary to homogenize the particle size of the drug and material used in these steps, as they need to be uniform. Coating is necessary to prevent water from coming into contact with the active ingredients for too long and thus to obtain a shield against light and humidity, and should be carried out in a temperature range of 40-55°C. Preferably, the temperature interval is 45-50°C, specifically 45-47°C.

[0051] A series of tests were conducted. In these tests, the components of the formulation were selected based on their functions, their concentrations were established in relation to the product's behavior, and the proper functioning of the pharmaceutical product was ensured. The omission or modification of any one of the components of the formulation would result in a failure to achieve compliance with the established quality characteristics.

[0052] The pharmaceutical compositions of the present invention include, but are not limited to, binders, diluents, disintegrants, lubricants, solvents and / or solubilizers, adsorbents, and coatings, as well as pharmaceutically acceptable excipients and vehicles.

[0053] Examples of pharmaceutically acceptable diluents, whose functions are well known in the prior art and which include adjusting and maintaining a certain tablet weight, compression, and flow, include, but are not limited to, cellulose derivatives such as microcrystalline cellulose, phosphate derivatives such as dicalcium phosphate, starch derivatives such as pregelatinized starch and corn starch, and mannitol, xylitol, maltitol, lactitol, sorbitol, sucrose, or combinations thereof. In one embodiment, the diluent is preferably microcrystalline cellulose, preferably a pharmaceutically acceptable amount of microcrystalline cellulose PH101 in the range of 5 to 90%, preferably 5 to 10%, and more preferably 6 to 8%.

[0054] Pharmaceutically acceptable disintegrants include, but are not limited to, cellulose derivatives such as croscarmellose, hydroxypropyl cellulose, carboxymethyl cellulose, and microcrystalline cellulose; povidone derivatives such as crospovidone; and starch derivatives such as pregelatinized starch, sodium glycolate starch, and corn starch. In one embodiment, the disintegrant is preferably 0.5 to 15%, preferably 0.5 to 5%, more preferably 4 to 5%, of crospovidone in a pharmaceutically acceptable amount, which is selected in the present invention due to its high performance in rapidly absorbing water and increasing its volume, giving it a shorter disintegration time compared to other materials.

[0055] Pharmacoherent adsorbents include, but are not limited to, aluminum derivatives (aluminum hydroxide, aluminum oxide, aluminum phosphate), clay or soil (atapulgite, bentonite, hectorite, kaolin, pectin), silica derivatives (calcium silicate, colloidal silicon dioxide, aluminum magnesium silicate), cellulose derivatives (microcrystalline cellulose, cellulose), magnesium derivatives (magnesium carbonate, magnesium silicate), and aluminum magnesium metasilicate, due to their ability to adsorb residual water in solid pharmaceutical form or incorporated through the environment and improve the stability of the drug. In one embodiment, the adsorbent is preferably a pharmaceutically acceptable amount of aluminum magnesium metasilicate ranging from 0.5 to 90%, preferably 0.5 to 1%.

[0056] Examples of pharmaceutically acceptable binders, but not limited to these, include cellulose derivatives (hydroxypropylcellulose, carboxymethylcellulose), hydrogenated vegetable oil derivatives, ethylene glycol derivatives (PEG-300, PEG-3000), gum derivatives (acacia gum), agar, alginate derivatives (alginate), calcium derivatives (calcium carbonate, calcium phosphate), carbomer, chitosan, and povidone derivatives (copovidone, crospovidone). In one embodiment, the binder is preferably polyvidone K90, which is selected in the present invention because it generates granules that are optimal for the compression stage in contact with water and other materials, improves flowability, and increases the density of the material. The amount is a pharmaceutically acceptable amount in the range of 0.5 to 5%, more preferably 0.5 to 5%, and most preferably 2 to 4%.

[0057] Examples of pharmaceutically acceptable solubilizers, but not limited to these, include polyethylene glycol derivatives (polyoxyethyl alkyl ethers, hydrogenated castor oil), sodium lauryl sulfate, sorbitan esters, and benzalkonium chloride. In one embodiment, the binder is preferably poloxamer 188. Poloxamer 188 is selected in the present invention due to the low solubility of glimepiride, which stalls the solvation rate of the three agents, and its amount is in the range of 0.01 to 5%, more preferably 0.01 to 2%, which is a pharmaceutically acceptable amount.

[0058] Examples of pharmaceutically acceptable lubricants include, but are not limited to, magnesium stearate, zinc stearate, calcium stearate, stearic acid, monostearate, stearyl fumarate, talc, and sulfated derivatives such as magnesium lauryl sulfate. The lubricant enables the prevention of sticking between various tools during the compression process in solid dosage form. In one embodiment, the lubricant is preferably a pharmaceutically acceptable amount of magnesium stearate in the range of 0.25 to 10%, more preferably 0.25 to 1%.

[0059] On the other hand, the compositions of the present invention may contain cellulose derivatives such as hydroxypropyl methylcellulose, hydroxypropylcellulose, and carboxymethylcellulose, polyvinyl derivatives such as polyvinyl alcohol, polyethylene glycol, povidone of all grades K and their derivatives, and coatings which may be in definitive and non-limiting forms selected from water-blocking coatings. In one embodiment, the water-blocking and light-blocking coating is preferably an opadry such as opadryAMB II in a pharmaceutically acceptable amount in the range of 0.5 to 6%, more preferably 1 to 4%, and most preferably 3 to 4%.

[0060] The compositions of the present invention also contain a solvent, such as, and preferably water, a pharmaceutically acceptable or sufficient amount (qs) of water.

[0061] Based on the evaluation and definition of the drug formulation and process as described above, the drug formulation includes the following components as shown in Table 1. [Table 1]

[0062] Innovations in the drug's manufacturing process and formulation have made it possible to obtain products with proven stability through research under current regulations, and quality attributes have been met during the evaluation period. Stability testing is a means of comparing various formulations, packaging materials, or manufacturing processes in short-term experiments. As soon as the final formulation and manufacturing process are established, the manufacturer conducts a series of stability tests to predict the stability of the product or drug in this case, and to determine its shelf life and storage conditions.

[0063] The initial (zero-hour) results for assessing the stability of drug prescriptions under 40°C / 75%RH conditions are shown below (Table 2). Drug prescriptions are presented for sulfonylurea, dipeptidyl peptidase-4 (DPP4) inhibitors, and biguanides in doses of 1 / 50 / 500 mg, 2 / 50 / 1000 mg, and 4 / 50 / 1000 mg, respectively. [Table 2]

[0064] The results at 6 months under conditions of 40°C / 75%RH are shown below (Table 3). Drug prescriptions are presented for sulfonylurea, dipeptidyl peptidase-4 (DPP4) inhibitors, and biguanides in doses of 1 / 50 / 500 mg, 2 / 50 / 1000 mg, and 4 / 50 / 1000 mg, respectively. [Table 3]

[0065] In another embodiment of the present invention, a bioavailability test is performed to determine whether there is a difference in the magnitude and rate of absorption that affects the bioavailability of the drug during administration between the test product of the present invention (a fixed-dose formulation) and a control drug co-administered.

[0066] After co-administration of control drug A: Glimetal® tablets containing 4 mg glimepiride / 1000 mg metformin hydrochloride from Laboratorios Silanes, lot 19C105V2, and vildagliptin as indicated by COFEPRIS, the results of the study showed that metformin and vildagliptin were C max and ABC 0-t This indicates that there are no statistically significant differences in the parameters. On the other hand, with the intention of reducing the risk of acute hypoglycemia, a comparative analysis of glimepiride shows that absorption (ABC) 0-t Although it does not show the difference between ), considering the interval of 80-125%, the absorption rate (C max This shows the difference (see Example 6).

[0067] Those skilled in the art will see that multiple modifications and forms of implementing the present invention are possible without departing from the spirit and scope of the invention, in order to ensure the proper functioning of the product and to satisfy the required quality characteristics. [Examples]

[0068] Example 1: Manufacturing process for compounded drugs in tablet form Sift together 1.35% diluent, Drug1, Drug3, solubilizer, binder, and 60% disintegrant, and mix for 1.6 minutes (Mix1) (Sieve1). 2. Sift Drug2, 40% disintegrant, 65% diluent, and adsorbent together and mix for 3 minutes (Mix2) (Sieve2). 3. Wet Sieve1 with 44% purified water and granulate for 1.6 minutes. 4. Dry the granules to a moisture content of 1.5-2.5% w / w (Granulate 1). 5. Sieve through Granulate1 (Sieve3). 6. Mix Sieve2 and Sieve3 for 3 minutes (Mix3). 7. Sift the lubricant and mix it with the Mix3 powder for 5 minutes. 8. Compress according to the specifications. 9. Mix the solvent and moisture barrier for 45 minutes. The coating is recoated using the above system according to the specifications, within a temperature range of 10.40°C or higher and 55°C or lower, preferably in the range of 45°C to 50°C, and more preferably in the range of 45°C to 47°C.

[0069] Example 2. Qualitative and quantitative formulations of compound drugs [Table 4]

[0070] Example 3. Qualitative and quantitative formulations of compound drugs [Table 5]

[0071] Example 4. Qualitative and quantitative formulations of compound drugs [Table 6]

[0072] Example 5. Content and dissolution test Those skilled in the art will recognize that several methodologies for content testing exist in the current state of the art, such as the Pharmacopoeia:FEUM, USP, British Pharmacopoeia, and pharmaceutical standards and regulations. Therefore, it is obvious to those skilled in the art that this methodology can be solved and implemented by following or combining the existing pharmaceutical references cited. When conducting this test, several modifications are possible without deviating from its intent and scope, in order to ensure the proper function of the product and to meet the required quality characteristics.

[0073] Those skilled in the art will recognize that several methodologies for dissolution testing exist in the current state of the art, such as in pharmacopoeias (FEUM), USP, the British Pharmacopoeia, pharmaceutical standards and regulations. Therefore, it is obvious to those skilled in the art that this methodology can be solved and implemented by following or combining the cited existing pharmaceutical references. In conducting this test, several modifications are possible without deviating from its intent and scope, in order to ensure the proper functioning of the product and to meet the required quality characteristics.

[0074] On the other hand, dissolution tests (in vitro tests) measure the rate (amount / time) and range (total amount) of drug release from the administration form. In the case of dissolution profiles, this corresponds to the quantification of the drug dissolved under standardized conditions at various time points. The importance of dissolution tests lies in the following: a) This serves as a guideline for developing new formulations during product development, and it allows for the evaluation of potential interference from excipients or manufacturing processes on drug release. b) Process control and quality assurance: This helps ensure the continuous quality and optimization of products after changes in manufacturing, formulation, production site, and process scaling. c) In vivo development indicators: These are indicators of bioavailability, which allow for the establishment of a correlation between in vitro parameters and bioavailability results.

[0075] Therefore, the dissolution tests of the present invention were carried out and validated as described in FEUM 12th edition (2018) and available internationally recognized scientific literature, quantifying glimepiride by one method, vildagliptin by another method, and metformin hydrochloride by a third method. The results demonstrated that the methods were accurate, precise, linear, and selective.

[0076] Dissolution profiling was performed on combination drugs including the following: The formulation is glimepiride 2 mg / vildagliptin 50 mg / metformin hydrochloride (tablets) 1000 mg, lot DFF1901-24. This drug has a potency of 95.7% (3.8 mg / tablet) for glimepiride, 96.5% (48.3 mg / tablet) for vildagliptin, and 97.9% (979.0 mg / tablet) for metformin. This medication is formulated as follows: glimepiride 4 mg / vildagliptin 50 mg / metformin hydrochloride (tablets) 1000 mg, lot 19F081G1. This drug contains 97.1% (1.9 mg / tablet) of glimepiride, 99.9% (50.0 mg / tablet) of vildagliptin, and 98.6% (986.0 mg / tablet) of metformin.

[0077] Dissolution profiles of vildagliptin, glimepiride, and metformin Dissolution profile tests were performed on duplicates of 12 different drug compositions: glimepiride 2 mg / vildagliptin 50 mg / metformin hydrochloride 1000 mg and glimepiride 4 mg / vildagliptin 50 mg / metformin hydrochloride 1000 mg. An Agilent Technologies dissolution tester was used, with a dissolution medium volume of 900 mL ± 1% (9 mL) at a dissolution medium temperature of 37 °C ± 0.5 °C (except for metformin), and a manual sampling type was used for a sampling volume of 10 mL. For the results, a calibration curve was created using a zero-excluded least-squares linear regression model, y = mx + b. "y" is the analytical response (area of ​​vildagliptin, glimepiride, or metformin hydrochloride), "x" represents the concentration of vildagliptin, glimepiride, or metformin hydrochloride added. b is the vertical coordinate of the calibration curve obtained from the regression, relative to the origin. m is the slope of the calibration curve obtained from the regression.

[0078] Conditions for elution of vildagliptin Dissolution device 2 (paddle) Elution medium water Stirring speed: 75 rpm ± 2 rpm Sampling time: 5, 10, 15, 20, 30 minutes ± 2%

[0079] Chromatographic conditions for vildagliptin HPLC AGILENT 1200 UV wavelength 210nm Analytical column ZORBAX SB-C18 2.1×100 3.5μm Mobile phase: 0.02 M monobasic potassium phosphate / acetonitrile (90:10) Flow rate 0.3mL / min Column temperature 45℃ Analysis time 4 minutes Injection volume 40μL

[0080] Glimepiride elution conditions Dissolution device 2 (paddle) Elution medium: Phosphate buffer, pH 7.8 Stirring speed: 75 rpm ± 3 rpm Sampling times: 5, 10, 15, 20, 30, and 45 minutes ± 2%

[0081] Chromatography conditions for glimepiride HPLC AGILENT 1200 UV wavelength 228nm Analytical column: KINETEX C18 2.1×100 5.0μm Mobile phase: 0.2% formic acid / acetonitrile:MEOH (40:30:30) Flow rate 0.5mL / min Column temperature: 40°C Analysis time 4 minutes Injection volume 50μL

[0082] Metformin elution conditions Dissolution device 1 (basket) Elution medium: 0.68% m / v monobasic potassium phosphate, pH 6.8 ± 0.1 Volume of elution medium: 1000 mL ± 1% (10 mL) Stirring speed: 100 rpm ± 3 rpm Sampling time: 5, 10, 15, 20, and 30 minutes ± 2%

[0083] Chromatographic conditions for metformin HPLC AGILENT 1200 UV wavelength 233nm ZORBAX SB-C18 column for 2.1 × 100 nm and 3.5 μm particles Mobile phase: 0.02 M monobasic potassium phosphate / (50:50 methanol-acetonitrile) 80:20 Flow rate 0.3mL / min Column temperature 45℃ Analysis time 3 minutes Injection volume 5μL

[0084] The individual results obtained from dissolution profile tests for the compounded drugs are shown below. Tables 7-12 show plots of the dissolution rate in each beaker at the sampling time and the average dissolution rate as a function of sampling time. [Table 7]

[0085] [Table 8]

[0086] [Table 9]

[0087] [Table 10]

[0088] [Table 11]

[0089] [Table 12]

[0090] Comparison of dissolution profiles The average dissolution rates of each drug during the sampling time are shown below in comparison tables (Tables 13-15) and graphs (Figures 7-9) (the notations "Drug (A)" and "Drug (B)" used are different from those used in Example 6 for the bioavailability test).

[0091] [Table 13]

[0092] [Table 14]

[0093] [Table 15]

[0094] The graph results show that, among the three drugs evaluated (vildagliptin, glimepiride, and metformin hydrochloride), the combination drug containing glimepiride 2 mg / vildagliptin 50 mg / metformin hydrochloride 1000 mg exhibited a more pronounced upward phase than the combination drug containing glimepiride 4 mg / vildagliptin 50 mg / metformin hydrochloride 1000 mg. Therefore, the analyzed drugs showed a predetermined similarity in their dissolution profiles, which can be confirmed by reviewing the dissolution rates at the sampling times performed in the results table. Low variability in dissolution rates was also observed for both drugs; for the three drugs evaluated (vildagliptin, glimepiride, and metformin hydrochloride), the CV% of the dissolution rate was less than 20% at the first sampling time and less than 10% at subsequent sampling times (excluding metformin hydrochloride for the combination drug containing glimepiride 4 mg / vildagliptin 50 mg / metformin hydrochloride 1000 mg).

[0095] The dissolution profiles for both drugs showed rapid dissolution with dissolution rates exceeding 85% in 15 minutes for all three drugs evaluated: vildagliptin, glimepiride, and metformin hydrochloride. Therefore, the dissolution profiles are considered similar, and the products can be classified as very fast-dissolving.

[0096] Example 6. Bioavailability Test The algorithm 1 "Treatment Schemes in Diabetes Mellitus Type2 (DM2)" included in the Clinical Practice Guideline Treatment of Diabetes Mellitus Type2 in first level of care published by CENETEC states that in the event of insufficient glycemic control (HbA1c > 7% and ABG > 130), it is necessary to start with dual oral therapy + sulfonylurea as one of the options. Furthermore, the ADA (American Diabetes Association: Standards of medical care in Diabetes - 2019) indicates that under insufficient glycemic control with metformin as the first-choice treatment, iDPP4 may be added, and if it is not controlled despite the dual scheme, sulfonylurea may be added. Similarly, if cost is a matter to be considered, metformin should be initiated, sulfonylurea may be added if it is not controlled, and iDDP4 may be included if the treatment goal is not achieved.

[0097] On the other hand, C max and the area under the plasma concentration curve with respect to time (ABC 0-tThe results of the measurement of pharmacokinetic parameters are determined, thereby making it possible to characterize the bioavailability of the drug of the present invention in terms of its administration form in terms of the rate and degree of absorption of each. Therefore, the purpose of the bioavailability test is to determine whether there is a difference in the magnitude and rate of absorption that affects the bioavailability of the drug when administered under fasting conditions between the co-administration of the test product of the present invention (fixed formulation) and the control drug. This is based on the approach established by the WHO for novel fixed-dose formulations, in accordance with Scenario 2 (World Health Organization WHO Technical Report Series, No. 929, 2005). According to this scenario, in addition to documenting that the safety and efficacy profile of this formulation is well characterized, it is necessary to demonstrate that the individual drugs are administered together at the same dose and regimen as the fixed-dose formulation is intended to be administered.

[0098] Therefore, a single-center, open-label, two-period, two-treatment, two-system (AB and BA), crossover, randomized, single-dose comparative bioavailability study was conducted in fasted healthy volunteers to compare a fixed-combination oral tablet preparation (Treatment B, study drug, study product of Laboratorios Silanes) containing glimepiride 4 mg, vildagliptin 50 mg, and metformin hydrochloride 1000 mg with a control drug (Control Drug (A)): Glimetal® (Treatment A1 control drug containing glimepiride 4 mg / methogliptin hydrochloride 1000 mg, lot 19C105V2, product of Laboratorios Silanes) and a control drug vildagliptin (Treatment A2) as indicated by COFEPRIS. Bioequivalence was determined in terms of absorption rate and degree.

[0099] In this study, a total of 44 healthy volunteers (27 men and 17 women) were randomized. 42 volunteers decided to participate in the study, and 2 withdrew their informed consent. The sampling period was 48 hours, chosen considering the longest reported elimination half-life of glimepiride (7.5 ± 4 hours in the Mexican population). In this sense, more than 90% of the administered dose of each drug was eliminated after four half-lives. Based on the elimination half-life of glimepiride, a minimum drug-free period of 4 days was established. After seven half-lives, the pharmacokinetic effect of drug-free periods was completely negligible. Each volunteer was treated according to the study by randomization. Blood samples were collected and processed to obtain plasma at each administration time (pre-administration sample) and at 0.25, 0.50, 1.00, 1.25, 1.50, 1.75, 2.00, 2.50, 3.00, 3.50, 4.00, 4.50, 5.00, 6.00, 8.00, 10.00, 12.00, 18.00, 24.00, 36.00, and 48 hours after administration. Samples from volunteers were analyzed, and the three drugs were quantified using a reverse-phase chromatography column (HPLC-MS / MS) separation step with protein precipitation followed by mass spectrometry detection, and high-performance liquid chromatography using metformin HCl-d6, vildagliptin-d3, and glibenclamide as internal standards in the plasma. The analytical methods were validated according to parameters previously established in the Mexican official standard NOM-177-SSA1-2013 and applied to characterizing the pharmacokinetic profiles in this study.

[0100] (The notations used, "Control Agent (A)", "Treatment (A2) Control Agent", "Treatment (B) Test Agent", and "Treatment (A1) Control Agent", differ from those used in Example 5 of the test and dissolution profile.) [Table 16]

[0101] [Table 17]

[0102] [Table 18]

[0103] To visualize the possible differences between prescriptions and / or treatments, plasma concentration profiles (± standard error) obtained in volunteers were plotted against time on arithmetic and semi-logarithmic scales (Figures 10-15).

[0104] Descriptive statistics of pharmacokinetic parameters Pharmacokinetic parameters were determined using an independent model method. Descriptive statistics are presented in Tables 19-21 below. [Table 19]

[0105] [Table 20]

[0106] [Table 21]

[0107] Confidence interval and boundary test for pharmacokinetic parameters [Table 22]

[0108] [Table 23]

[0109] [Table 24]

[0110] [Table 25]

[0111] [Table 26]

[0112] [Table 27]

[0113] Advantageous effects and uses of the present invention The present invention relates to an innovative, fixed-formulation agent with increased efficacy for the improved management of type 2 diabetes mellitus, comprising a sulfonylurea, a dipeptidyl peptidase-4 (DPP4) inhibitor, and a biguanidine.

[0114] The sulfonylurea, dipeptidyl peptidase-4 (DPP4) inhibitor, and biguanidine used in the manufacture of the above-mentioned drug products and adapted to be immediate-release are glimepiride, vildagliptin, and metformin in its hydrochloride form.

[0115] At the same time, the present invention solves a series of important technical challenges in the manufacture of products of the above-mentioned drugs, arising from differences in the physicochemical properties and dosages of synergistic formulations of drugs containing sulfonylurea, dipeptidyl peptidase-4 (DPP4) inhibitors and biguanidine, thereby enabling the reliable acquisition of stable products for such purposes. The drug products comprise (a) sulfonylurea, (b) dipeptidyl peptidase-4 (DPP4) inhibitors and (c) biguanides, or pharmaceutically acceptable amounts of any of them, in the range of 1 to 4 mg, 50 mg and 500 to 1000 mg, respectively, in combination with pharmaceutically acceptable excipients and / or vehicles.

Claims

1. A combination drug comprising (a) 1 to 4 mg of sulfonylurea or a pharmaceutically acceptable salt thereof, (b) 50 mg of a dipeptidyl peptidase 4 (DPP4) inhibitor or a pharmaceutically acceptable salt thereof, and (c) 500 to 1000 mg of a biguanide or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable excipient and / or vehicle, The aforementioned dipeptidyl peptidase 4 (DPP4) inhibitor is vildagliptin. The drug product is a single-dose solid form selected from the group consisting of tablets, caplets, granules, lozenges, and pills, and is adapted to be immediate-release. The aforementioned sulfonylurea is glimepiride, The aforementioned biguanide is metformin, The pharmaceutically acceptable excipients and / or vehicles include binders, diluents, disintegrants, lubricants, solvents and / or solubilizers, adsorbents, and coatings. The diluent is microcrystalline cellulose PH101. The aforementioned disintegrant is crospovidone, The adsorbent is magnesium aluminum metasilicate. The aforementioned binder is polyvidone K90. The aforementioned solubilizing agent is poloxamer 188. The aforementioned lubricant is magnesium stearate. The aforementioned coating is a water-blocking and light-blocking coating. Compound drugs.

2. The formulation according to claim 1, comprising 1 mg of a pharmaceutically acceptable amount of sulfonylurea.

3. The formulation according to claim 1, comprising 2 mg of a pharmaceutically acceptable amount of sulfonylurea.

4. The formulation according to claim 1, comprising 4 mg of a pharmaceutically acceptable amount of sulfonylurea.

5. The combination drug according to claim 1, comprising 500 mg of a pharmaceutically acceptable amount of biguanide.

6. The compound according to claim 1, comprising 1000 mg of a pharmaceutically acceptable amount of biguanide.

7. A combination drug according to any one of claims 1 to 6, comprising (a) 1 mg of the sulfonylurea or a pharmaceutically acceptable salt thereof, (b) 50 mg of the dipeptidyl peptidase 4 (DPP4) inhibitor or a pharmaceutically acceptable salt thereof, and (c) 500 mg of the biguanide or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable excipient and / or vehicle.

8. A combination agent according to any one of claims 1 to 6, comprising (a) 2 mg of the sulfonylurea or a pharmaceutically acceptable salt thereof, (b) 50 mg of the dipeptidyl peptidase 4 (DPP4) inhibitor or a pharmaceutically acceptable salt thereof, and (c) 1,000 mg of the biguanide or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable excipient and / or vehicle.

9. A combination agent according to any one of claims 1 to 6, comprising (a) 4 mg of the sulfonylurea or a pharmaceutically acceptable salt thereof, (b) 50 mg of the dipeptidyl peptidase 4 (DPP4) inhibitor or a pharmaceutically acceptable salt thereof, and (c) 1,000 mg of the biguanide or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable excipient and / or vehicle.

10. The combination drug according to claim 1, wherein the metformin is metformin hydrochloride.

11. The compounded drug according to claim 1, wherein the diluent, which is microcrystalline cellulose PH101, is in a pharmaceutically acceptable amount in the range of 5 to 90%.

12. The compounded agent according to claim 1, wherein the disintegrant, crospovidone, is in a pharmaceutically acceptable amount in the range of 0.5 to 15%.

13. The compounded agent according to claim 1, wherein the adsorbent, which is magnesium aluminum metasilicate, is present in a pharmaceutically acceptable amount in the range of 0.5 to 90%.

14. The compound drug according to claim 1, wherein the binder, which is polyvidone K90, is in a pharmaceutically acceptable amount in the range of 0.5 to 5%.

15. The compounded agent according to claim 1, wherein the solubilizing agent, poloxamer 188, is present in a pharmaceutically acceptable amount in the range of 0.01 to 5%.

16. The compound according to claim 1, wherein the lubricant, magnesium stearate, is present in a pharmaceutically acceptable amount in the range of 0.25 to 10%.

17. The formulation according to claim 1, wherein the water-blocking and light-blocking coating is a pharmaceutically acceptable amount of Opadry AMB II in the range of 0.5 to 6%.

18. The compounded drug according to claim 1, wherein the solvent is a pharmaceutically acceptable amount of water.

19. The compound drug according to claim 1, which is in tablet form.

20. A combination drug according to any one of claims 1 to 19, for use in the control and management of type 2 diabetes mellitus in individuals requiring tripol oral therapy.

21. (a) a sulfonylurea or a pharmaceutically acceptable salt thereof in the range of 1 to 4 mg, (b) a dipeptidyl peptidase 4 (DPP4) inhibitor or a pharmaceutically acceptable salt thereof in the range of 500 to 1000 mg, in combination with a pharmaceutically acceptable excipient and / or vehicle, for use in the manufacture of a product useful for the control and management of type 2 diabetes mellitus in individuals requiring tripartite oral therapy, wherein the dipeptidyl peptidase 4 (DPP4) inhibitor is vildagliptin. The product of the aforementioned drug is a single-dose solid form selected from the group consisting of tablets, caplets, granules, lozenges, and pills, and is adapted to be immediate-release. The aforementioned sulfonylurea is glimepiride, The aforementioned biguanide is metformin, The pharmaceutically acceptable excipients and / or vehicles include binders, diluents, disintegrants, lubricants, solvents and / or solubilizers, adsorbents, and coatings. The diluent is microcrystalline cellulose PH101. The aforementioned disintegrant is crospovidone, The adsorbent is magnesium aluminum metasilicate. The aforementioned binder is polyvidone K90. The aforementioned solubilizing agent is poloxamer 188. The aforementioned lubricant is magnesium stearate. The aforementioned coating is a water-blocking and light-blocking coating. use.

22. The use according to claim 21, wherein a pharmaceutically acceptable amount of the sulfonylurea or a pharmaceutically acceptable salt thereof is 1 mg, the dipeptidyl peptidase 4 (DPP4) inhibitor or a pharmaceutically acceptable salt thereof is 50 mg, and the biguanide or a pharmaceutically acceptable salt thereof is 500 mg, each compounded with a pharmaceutically acceptable excipient and / or vehicle.

23. The use according to claim 21 or 22, wherein a pharmaceutically acceptable amount of the sulfonylurea or a pharmaceutically acceptable salt thereof is 2 mg, the dipeptidyl peptidase 4 (DPP4) inhibitor or a pharmaceutically acceptable salt thereof is 50 mg, and the biguanide or a pharmaceutically acceptable salt thereof is 1000 mg, each compounded with a pharmaceutically acceptable excipient and / or vehicle.

24. The use according to any one of claims 21 to 23, wherein a pharmaceutically acceptable amount of the sulfonylurea or a pharmaceutically acceptable salt thereof is 4 mg, the dipeptidyl peptidase 4 (DPP4) inhibitor or a pharmaceutically acceptable salt thereof is 50 mg, and the biguanide or a pharmaceutically acceptable salt thereof is 1000 mg, each compounded with a pharmaceutically acceptable excipient and / or vehicle.

25. The use according to claim 21, wherein the metformin is metformin hydrochloride.

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