COMBINATION MEDICATION FOR THE CONTROL AND MANAGEMENT OF TYPE 2 DIABETES MELLITUS

Abstract

The present invention relates to an innovative, stable, immediate-release drug for the treatment, control, and improved management of type 2 diabetes mellitus, containing a sulfonylurea such as glimepiride, a dipeptidyl peptidase-4 (DPP4) inhibitor such as vildagliptin, and a biguanide such as metformin. Furthermore, the present invention addresses several significant technological challenges in the manufacture of this drug due to the physicochemical properties and dosage differences of the synergistic combination of the drugs.

Description

COMBINATION MEDICATION FOR THE CONTROL AND MANAGEMENT OF TYPE 2 DIABETES MELLITUS FIELD OF INVENTION The present invention belongs to the field of health, in particular it refers to the pharmaceutical field in the manufacture of medicines for the control and management of type 2 diabetes mellitus. BACKGROUND OF THE INVENTION Diabetes mellitus, commonly called diabetes, is a chronic disease associated with abnormally high blood glucose levels. Diabetes occurs because the pancreas does not produce enough insulin and / or the body's cells do not respond properly to insulin. According to the World Health Organization, diabetes affects approximately 347 million people, and this number is likely to more than double by 2030. The global increase in diabetes will be due to aging, population growth, the rise in obesity, unhealthy diets, and sedentary lifestyles (Danaei G, Finucane MM, Lu Y, Singh GM, Cowan MJ, Paciorek CJ et al. National, regional, and global trends in fasting plasma glucose and diabetes prevalence since 1980: systematic analysis of health examination surveys and epidemiological studies with 370 country-years and 2030).7 million participants, Lancet, 2011, 378(9785): 31-40.) http: / / www.who.int / mediacentre / factsheets / fs312 / es / ). Type 1 diabetes is characterized by the pancreas ceasing to produce insulin, while type 2 diabetes is characterized by the body's inability to effectively use insulin, often as a result of excess weight or physical inactivity. Both types of diabetes lead to high blood glucose levels (hyperglycemia). Treatments for diabetes include monotherapy and combination therapies. Medical practice indicates that the best treatment for managing type 2 diabetes is calorie restriction and increased physical activity; however, these are difficult to adhere to, and medication is often necessary for control. Current diabetes therapies focus on achieving and maintaining blood glucose levels as close to normal as possible to prevent microvascular complications (eye damage, kidney damage, nerve damage, and diabetic foot) and macrovascular complications (cardiovascular diseases such as heart attacks, strokes, and poor circulation in the lower extremities) of the disease. Several drugs are available for the treatment of type 2 diabetes; to date, biguanides, sulfonylureas, glucosidase inhibitors, and insulin sensitizing agents have been used. These drugs are indicated as monotherapies; however, 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 (W02006073197). For example, glimepiride is a drug indicated for the treatment of type 2 diabetes in adults as an adjunct to diet and exercise to improve glycemic control as monotherapy. It may also be indicated for use in combination with metformin or insulin to lower blood glucose in patients with type 2 diabetes whose high blood sugar levels cannot be controlled by diet and exercise alone. rere ίη / ζζηζ / Ε / γίΛΐ According to its biopharmaceutical classification, glimepiride is a type II drug with low solubility and high permeability. Vildagliptin belongs to a class of orally active antidiabetic drugs known as DPP-IV proteolytic enzyme inhibitors, which have multiple functional benefits beyond simply controlling blood glucose. One of these is a possible protective effect on pancreatic beta cells, which deteriorate in diabetes. Vildagliptin appears to be safe, very well tolerated, and effective. After a meal, intestinal incretin hormones are released. 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 rising glucose levels. Unlike agents that promote insulin secretion through glucose-independent mechanisms, GLP-1's dependence on glucose concentration is considered beneficial due to a lower risk of hypoglycemia.GLP-1 also inhibits glucagon secretion and increases beta-cell mass by stimulating proliferation and neogenesis. 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, DPP-IV inhibition is emerging as a novel therapeutic approach in the treatment of diabetes. Vildagliptin administration increases GLP-1's ability to produce insulin in response to elevated blood glucose levels, inhibits glucagon release after meals, decreases the rate of nutrient absorption into the bloodstream, slows gastric emptying, and reduces food intake. rere ίη / ζζηζ / Ε / γίΛΐ According to its biopharmaceutical classification, vildagliptin is a type III drug with high solubility and low permeability.Metformin is a biguanide used as an antidiabetic; its chemical name is 1(diaminomethylen)-3,3-dimethylguanidine. It is frequently used in the treatment of type 2 diabetes, especially when there is insulin resistance. A maximum dose of 3000 mg / day of metformin is generally recommended for an adult, and 500 mg and 850 mg tablets are available. (US2012021049A). Metformin reduces glucose production in the liver, increases insulin sensitivity in hepatic and peripheral tissue, mainly in muscle tissue, and has also been shown to induce weight loss in subjects with type 2 diabetes. (Stumvoll M, Nurjihan N and Perriello G, et al. Metabolic Effects of Metformin in Non-insulin-dependent diabetes mellitus. A / . Engl J Med 1995; 333:550-554) and (Gerich JE: The genetic basis of type 2 diabetes mellitus: Impaired insulin secretion versus impaired insulin sensitivity. Endocr Rev 19:491-503,1998).Medications marketed as metformin contain metformin hydrochloride. Side effects of metformin hydrochloride include gastrointestinal intolerance (e.g., diarrhea, nausea / vomiting). Metformin hydrochloride is contraindicated in patients with kidney disease or renal dysfunction, or acute or chronic metabolic acidosis. rere ίη / ζζηζ / Ε / γίΛΐ CH H NH NH nh2• HCl According to its biopharmaceutical classification, metformin is a type III drug with high solubility and low permeability. In the treatment of type 2 diabetes, the prolonged use of a single drug, the high doses administered for some of them, and the side effects hinder good control. Therefore, it is necessary to find new antidiabetic drugs that offer improved glycemic control or combinations of drugs that act through different or complementary mechanisms of action to achieve good glycemic control and management with fewer side effects. On the other hand, there is little evidence on the feasibility of combining multiple drugs such as a sulfonylurea, a dipeptidyl peptidase-4 (DPP4) inhibitor and a biguanidine into a single dosage unit that is stable and allows the management of chronic diseases such as type 2 diabetes mellitus. Patent MX 339374 relates to a metformin glimepiridate co-crystal characterized by its physicochemical properties, including a powder X-ray diffraction pattern. Chinese patent application CN201910577018 from WEIHAI DISU PHARMACEUTICAL CO LTD seeks to claim a method for preparing crystalline form I of glimepiride. Patent MX 301408 from Novartis AG protects the use of vildagliptin or a salt thereof in combination with insulin, in the preparation of a medicament to reduce severe hypoglycemic events in a patient suffering from diabetes mellitus. Subsequently, patent application CN201910562736 describes a metformin hydrochloride crystalline compound characterized by a powder X-ray diffraction pattern. They are found in the range of 1-4 mg, 50 mg and 500-1000 mg respectively, in combination with pharmaceutically acceptable excipients and / or vehicles. The drug of the invention is in solid form and is adapted to be for immediate release. In one embodiment, the sulfonylurea is present in a pharmaceutically acceptable amount preferably of 1 mg, more preferably 2 mg, and more preferably 4 mg. In another form, the biguanide is found in a pharmaceutically acceptable amount preferably of 500 mg, more preferably 1000 mg. In another embodiment, the combination drug of the present invention is preferably in pharmaceutically acceptable amounts of 1 / 50 / 500 mg respectively, in combination with pharmaceutically acceptable excipients and / or vehicles. In another embodiment, the combination drug of the present invention is preferably in pharmaceutically acceptable amounts of 2 / 50 / 1000 mg respectively, in combination with pharmaceutically acceptable excipients and / or vehicles. In another embodiment, the combination drug of the present invention is preferably in pharmaceutically acceptable amounts of 4 / 50 / 1000 mg respectively, in combination with pharmaceutically acceptable excipients and / or vehicles. The pharmaceutically acceptable excipients and / or vehicles used for the manufacture of the drug of the present invention are, for example, binders, diluents, disintegrants, lubricants, solvents and / or solubilizers, adsorbents and coatings. A further object of the present invention also relates to the use of (a) a sulfonylurea, (b) a dipeptidyl peptidase-4 (DPP4) inhibitor, and (c) a biguanide, or a pharmaceutical salt of any of the same, in pharmaceutically acceptable amounts in the range of 1-4 mg, 50 mg, and 500-1000 mg, respectively, in combination with pharmaceutically acceptable excipients and / or vehicles for the manufacture of a medicament useful for the treatment, control, and management of type 2 diabetes mellitus in individuals requiring triple oral therapy, wherein the sulfonylurea, the dipeptidyl peptidase-4 (DPP4) inhibitor, and the biguanide are preferably glimepiride, vildagliptin, and metformin, or a pharmaceutically acceptable salt of any of the same. Preferably, the metformin is in its hydrochloride salt form. The manufacturing process lies in the selection of unit operations, the order and execution time to control the different physicochemical properties of the drugs, so the critical operations of the manufacturing process are described in the following detailed description. In one embodiment, the drug is in a single solid dosage unit selected from the group comprising a tablet, caplet, granules, pills, or lozenges; preferably in tablet form. Another object of the present invention is a stable, immediate-release innovative drug for the treatment, control, and improved management of type 2 diabetes mellitus containing a sulfonylurea such as glimepiride, a dipeptidyl peptidase-4 (DPP4) inhibitor such as vildagliptin, and a biguanidine such as metformin in its hydrochloride form. In one embodiment of the invention, the pharmacokinetic parameters of Cmax and area under the plasma concentration curve with respect to time (ABCo-t) are determined, which allow the bioavailability of the drug of the present invention to be characterized from its pharmaceutical form, in terms of the respective rate and degree of absorption. BRIEF DESCRIPTION OF THE FIGURES Figure 1. Dissolution profile of vildagliptin from the combination drug comprising glimepiride 4 mg / vildagliptin 50 mg / metformin hydrochloride 1000 mg. Figure 2. Dissolution profile of vildagliptin from the combination drug comprising glimepiride 2 mg / vildagliptin 50 mg / metformin hydrochloride 1000 mg. rere ίη / ζζηζ / Ε / γίΛΐ Figure 3. Dissolution profile of glimepiride from the combination drug comprising glimepiride 4 mg / vildagliptin 50 mg / metformin hydrochloride 1000 mg. Figure 4. Dissolution profile of glimepiride from the combination drug comprising glimepiride 2 mg / vildagliptin 50 mg / metformin hydrochloride 1000 mg. Figure 5. Dissolution profile of metformin from the combination drug comprising glimepiride 4 mg / vildagliptin 50 mg / metformin hydrochloride 1000 mg. Figure 6. Dissolution profile of metformin from the combination drug comprising glimepiride 2 mg / vildagliptin 50 mg / metformin hydrochloride 1000 mg. Figure 7. Dissolution profile of vildagliptin in the combination drug comprising glimepiride, vildagliptin, metformin hydrochloride. Figure 8. Dissolution profile of glimepiride in the combination drug comprising glimepiride, vildagliptin, metformin hydrochloride. Figure 9. Dissolution profile of metformin hydrochloride in the combination drug comprising glimepiride, vildagliptin, metformin hydrochloride. Figure 10. Graph of average plasma concentration versus time. Average pharmacokinetic profile of glimepiride ± standard error on an arithmetic scale (A: reference drug; B: test drug). Figure 11. Graph of average plasma concentration versus time. Average pharmacokinetic profile of glimepiride ± standard error on a semi-logarithmic scale (A: reference drug; B: test drug). Figure 12. Graph of average plasma concentration versus time. Average pharmacokinetic profile of metformin ± standard error on an arithmetic scale (A: reference drug; B: test drug). rere Ln / zznz / E / YiAi Figure 13. Graph of average plasma concentration versus time. Average pharmacokinetic profile of metformin ± standard error on a semi-logarithmic scale (A: reference drug; B: test drug). Figure 14. Graph of average plasma concentration versus time. Average pharmacokinetic profile of vildagliptin ± standard error on an arithmetic scale (A: reference drug; B: test drug). Figure 15. Graph of average plasma concentration versus time. Average pharmacokinetic profile of vildagliptin ± standard error on a semi-logarithmic scale (A: reference drug; B: test drug). DETAILED DESCRIPTION OF THE INVENTION Definitions Pharmaceutically acceptable salt. In the present invention, a pharmaceutically acceptable salt is understood to be a compound that retains the biological efficacy and properties of the 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), Welley-VCH; 2nd Revised Edition (May 16, 2011)). Pharmaceutically acceptable base addition salts can be prepared from inorganic or organic bases. Salts derived from inorganic bases include, by way of example only, salts of sodium, potassium, lithium, ammonium, calcium, and magnesium. 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, hydrabamine, choline, betaine, ethylenediamine, glucosamine, N-alkylglucamines, theobromine, purines, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like. 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, phosphoric acid, and the like. Salts derived from organic acids include acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. rere Ln / zznz / E / YiAi Excipient. In the present invention, the term “excipient” shall be understood as the ingredient that forms part of the present pharmaceutical composition, including diluents, disintegrants, lubricants, coatings, absorbents, among others. Stability. It is the ability of a pharmaceutical product to maintain its chemical, physical, microbiological, and biopharmaceutical properties within specified limits throughout its shelf life. The present invention relates to an innovative, stable drug adapted for immediate release in a single dosage unit for use in the treatment, improved control, and management of type 2 diabetes mellitus. It also addresses several significant technological challenges in the manufacture of this drug due to the physicochemical properties and varying dosages of the drug combination it comprises, in order to guarantee a stable product for these purposes. Thus, a combination drug is described, characterized in that it comprises: (a) a sulfonylurea, (b) a dipeptidyl peptidase-4 (DPP4) inhibitor, and (c) a biguanide, or a pharmaceutical salt of any of these, in pharmaceutically acceptable amounts ranging from 1-4 mg, 50 mg, and 500-1000 mg, respectively, in combination with pharmaceutically acceptable excipients and / or vehicles. In one embodiment of the invention, the sulfonylurea is present in a preferably pharmaceutically acceptable amount of 1 mg. In another embodiment of the invention, the sulfonylurea is present in a preferably pharmaceutically acceptable amount of 2 mg. In another preferred embodiment of the invention, the sulfonylurea is present in a pharmaceutically acceptable amount of 4 mg. In another embodiment of the invention, the biguanide is present in a preferably pharmaceutically acceptable amount of 500 mg. In another embodiment of the invention, the biguanide is present in a preferably pharmaceutically acceptable amount of 1000 mg. In a more preferred embodiment of the invention, the drug combines in a single dosage unit: (a) a sulfonylurea, (b) a dipeptidyl peptidase-4 (DPP4) inhibitor and (c) a biguanide, or a pharmaceutical salt of any of the same, in pharmaceutically acceptable amounts of 1 / 50 / 500 mg respectively. rere ίη / ζζηζ / Ε / γίΛΐ In a more preferable embodiment of the invention, the drug combines in a single dosage unit: (a) a sulfonylurea, (b) a dipeptidyl peptidase-4 (DPP4) inhibitor and (c) a biguanide, or a pharmaceutical salt of any of the same, in pharmaceutically acceptable amounts of 2 / 50 / 1000 mg respectively. In a still more preferable embodiment of the invention, the drug combines in a single dosage unit: (a) a sulfonylurea, (b) a dipeptidyl peptidase-4 (DPP4) inhibitor and (c) a biguanide, or a pharmaceutical salt of any of the same, in pharmaceutically acceptable amounts of 4 / 50 / 1000 mg respectively. Furthermore, the fixed-dose combination of a sulfonylurea, a dipeptidyl peptidase-4 (DPP-4) inhibitor, and a biguanide in a single unit is preferably glimepiride, vildagliptin, and metformin, or a pharmaceutically acceptable salt of any of these. Preferably, metformin is in its hydrochloride salt form. The combination drug of the present invention is also provided in a single solid dosage form, adapted for immediate release. The solid dosage form of the combination drug is selected from the group comprising tablets, caplets, granules, lozenges, and pills. In one embodiment of the invention, the preferred solid dosage form is the tablet due to its dosage accuracy and because it is the most widely accepted dosage form due to its ease of administration. Capsules are an alternative; however, it is not possible to dose such a high concentration of drugs due to the limited size of the capsules. In the case of tablets, it is possible to reduce the volume of the powder, thereby facilitating handling and administration. Tablets designed in a caplet shape are also easier to swallow and are the smallest possible size for their quantity and weight. One version also features a groove in its design. In this regard, the present invention also relates to the use of (a) a sulfonylurea, (b) a dipeptidyl peptidase-4 (DPP4) inhibitor and (c) a biguanide, or a pharmaceutical salt of any of the same, in pharmaceutically acceptable amounts in the range of 1-4 mg, 50 mg and 500-1000 mg respectively, in combination with pharmaceutically acceptable excipients and / or vehicles for the manufacture of a medicament useful for the treatment, control and management of type 2 diabetes mellitus in individuals requiring triple oral therapy, and wherein the sulfonylurea, the dipeptidyl peptidase-4 (DPP4) inhibitor and the biguanide are preferably glimepiride, vildagliptin and metformin, or a pharmaceutically acceptable salt of any of the same. Metformin is preferably found in its hydrochloride salt form.The method allows the medication to be obtained in a single dosage unit for easy administration. In one embodiment of the invention, the sulfonylurea, the dipeptidyl peptidase-4 (DPP4) inhibitor, and the biguanide, or a pharmaceutical salt of any of the same, are preferably in pharmaceutically acceptable amounts of 1 / 50 / 500 mg, more preferably 2 / 50 / 1000 mg, and even more preferably 4 / 50 / 1000 mg respectively, in combination with pharmaceutically acceptable excipients and / or vehicles. The combination of (a) a sulfonylurea, (b) a dipeptidyl peptidase-4 (DPP-4) inhibitor, and (c) a biguanide, or a pharmaceutical salt of any of these, in pharmaceutically acceptable quantities presents a set of significant technological challenges due to the physicochemical properties of the drugs. The technological complexity lies in the fact that, with these three drugs present, one of them is sensitive to humidity and light, requiring a dispensing medium that does not affect their absorption, with a light-protective coating that does not impair drug release. Furthermore, the appropriate selection of excipients and manufacturing conditions, as well as the dosage variations necessary to ensure a stable product during drug formulation development, play a crucial role in drug release and absorption rate in the body. The process relies on the selection of unit operations, their sequence, and execution time to control the various physicochemical properties of the drugs. The critical operations in the manufacturing process are described below: Mixing 1 is necessary to improve the technological properties of the drugs with the granulation materials; while Mixing 2 is necessary to protect the drug with the adsorbent. Sieving is essential to homogenize the particle size of the drugs and materials used in these steps, ensuring uniformity. Coating is necessary and should be carried out at a temperature range of 40-55°C to prevent prolonged contact between water and the active ingredients, thus creating a barrier against light and moisture. Preferably, the temperature range is 45-50°C, more specifically 45-47°C. A series of tests were carried out in which the components of the formulation were selected based on their function and their concentration was established in relation to the behavior of the product ensuring the proper functioning of the drug, where the absence or modification of one of them does not meet the established quality characteristics. The pharmaceutical composition of the present invention comprises acceptable pharmaceutical excipients and / or vehicles, including but not limited to: binders, diluents, disintegrants, lubricants, solvents and / or solubilizers, adsorbents and coatings. Examples of pharmaceutically acceptable diluents, whose known function in the prior art includes adjusting and maintaining constant tablet weight, compaction, and flow, include, but are not limited to, cellulose derivatives such as microcrystalline cellulose, phosphate derivatives such as dibasic calcium phosphate, starch derivatives such as pregelatinized starch and corn starch, as well as mannitol, xylitol, maltitol, lactitol, sorbitol, sucrose, or combinations thereof. In one embodiment, the diluent is preferably microcrystalline cellulose, preferably microcrystalline cellulose PH 101, in a pharmaceutically acceptable amount in the range of 5–90%, preferably at a concentration of 5–10%, and more preferably at an amount of 6–8%. Pharmaceutically acceptable disintegrants include, but are not limited to, croscarmellose; cellulose derivatives such as hydroxypropylcellulose, carboxymethylcellulose, and microcrystalline cellulose; povidone derivatives such as crospovidone; and starch derivatives such as pregelatinized starch, sodium starch glycolate, and corn starch. In one embodiment, the disintegrant is preferably crospovidone, which is selected in the present invention for its high capacity to rapidly absorb water and increase its volume, thus providing a shorter disintegration time compared to other materials, in a pharmaceutically acceptable amount in the range of 0.5–15%, preferably 0.5–5%, and more preferably 4–5%. rere ίη / ζζηζ / Ε / γίΛΐ Pharmaceutically acceptable adsorbents include, but are not limited to, aluminum derivatives (aluminum hydroxide, aluminum oxide, aluminum phosphate), clays or earths (atalpugite, 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 onto the solid pharmaceutical form or water captured from the environment to improve drug stability. In one embodiment, the adsorbent is preferably aluminum magnesium metasilicate present in a pharmaceutically acceptable amount in the range of 0.5 to 90%, preferably 0.5–1%. Examples of pharmaceutically acceptable binders include, but are not limited to, cellulose derivatives (hydroxypropylcellulose, carboxymethylcellulose), hydrogenated vegetable oil derivatives, ethylene glycol derivatives (PEG-300, PEG-3000), gum derivatives (acacia gum), agar, alginate derivatives (alginic acid), calcium derivatives (calcium carbonate, calcium phosphate), carbomers, chitosan, and povidone derivatives (copovidone, copovidone). In one embodiment, the binder is preferably povidone K90, which is selected in the present invention because it is a binding agent that, due to its characteristics, generates, upon contact with water and other materials, an optimal granule for the compression stage, improving flow and increasing the density of the materials. It is present in a pharmaceutically acceptable amount in the range of 0.5 to 5%, more preferably 2-4%. Examples of pharmaceutically acceptable solubilizers include, but are not limited to, polyethylene glycol derivatives and derivatives (polyoxethyl alkyl ether, hydrogenated castor oil), sodium lauryl sulfate, sorbitan esters, and benzalkonium chloride. In one embodiment, the binder is preferably poloxamer 188, which is selected in the present invention due to the low solubility of glimepiride, thus slowing the solvation rate of the three drugs, and which is present in a pharmaceutically acceptable amount in the range of 0.01 to 5%, more preferably in the range of 0.01 to 2%. rere ίη / ζζηζ / Ε / γίΛΐ Examples of pharmaceutically acceptable lubricants include, but are not limited to, magnesium stearate, zinc stearate, calcium stearate, stearic acid monostearate, stearyl fumarate, talc, and sulfate derivatives such as magnesium lauryl sulfate. The lubricant prevents sticking between the different tools during the compression process of the solid dosage form. In one embodiment, the lubricant is preferably magnesium stearate in a pharmaceutically acceptable amount in the range of 0.25 to 10%, more preferably 0.25–1%. On the other hand, the composition of the present invention may contain coatings, which may be, but are not limited to, selected from cellulose derivatives such as hydroxypropyl methylcellulose, hydroxypropyl cellulose, and carboxymethylcellulose; polyvinyl derivatives such as polyvinyl alcohol; polyethylene glycol; povidones in all grades K and their derivatives; and moisture barrier coatings. In one embodiment, the moisture and light barrier coating is preferably Opadry, such as Opadry AMB II, in a pharmaceutically acceptable amount in the range of 0.5 to 6%, more preferably in the range of 1 to 4%, and more preferably from 3 to 4%. The composition of the present invention also comprises a solvent, such as and preferably water in a pharmaceutically acceptable amount or as much as is sufficient for (q.s.). Once the drug formulation and process were evaluated and defined as described above, the drug formula comprises the following components according to Table 1: rere Ln / zznz / E / YiAi Table 1. Components in the drug formulation Components Function Glimepiride Drug 1 Vildagliptin Drug 2 Metformin Hydrochloride Drug 3 Microcrystalline Cellulose PH 101 Diluent Povidone K90 Binder Poloxamer 188 Solubilizer Aluminum Magnesium Metasilicate Adsorbent Crospovidone Disintegrant Magnesium Stearate Lubricant Opadry AMB II Moisture Barrier Purified Water (mL) Solvent Thanks to innovations in the drug's manufacturing process and formulation, it was possible to obtain a product with proven stability, demonstrated through studies conducted in accordance with current regulations. These studies ensured that the product met all quality attributes throughout the evaluation period. Stability testing provides a means to compare different 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 product's stability and determine its shelf life and storage conditions. The initial results for determining the stability of the drug formulation under the 40sC / 75%RH condition are shown below (Table 2), where the drug formulations are presented in doses of 1 / 50 / 500mg, 2 / 50 / 1000mg and 4 / 50 / 1000mg for the sulfonylurea, the dipeptidyl peptidase-4 (DPP4) inhibitor and the biguanide respectively: rere ίη / ζζηζ / Ε / γίΛΐ Table 2. Initial stability data (time zero) Determination Specification Initial Result Batch 1 (dose 1 / 50 / 500mg) Batch 2 (dose 2 / 50 / 1000mg) Batch 3 (dose 4 / 50 / 1000mg) Glimepiride Content 90-110% 98.30 98.40 95.60 Vildagliptin Content 90-110% 98.80 97.70 94.00 Metformin HCI Content 90-110% 99.50 99.50 99.00 Glimepiride Dissolution Q=70% in 60 minutes 96.70 94.90 98.30 Vildagliptin Dissolution Q=70% in 30 minutes 97.70 97.90 99.52 Metformin HCI Dissolution Q=70% in 60 minutes 100.54 100.20 100.88 The results at 6 months under the 40sC / 75%HR condition are shown below (Table 3), where the drug formulations are presented in doses of 1 / 50 / 500mg, 2 / 50 / 1 OOOmg and 4 / 50 / 1 OOOmg for sulfonylurea, dipeptidyl peptidase-4 (DPP4) inhibitor and biguanide respectively. rere Ln / zznz / E / YiAi Table 3. Stability data at 6 months Determination Specification Result Batch 1 (dose 1 / 50 / 500mg) Batch 2 (dose 2 / 50 / 1000mg) Batch 3 (dose 4 / 50 / 1000mg) Glimepiride Content 90-110% 94.2 94.1 96.7 Vildagliptin Content 90-110% 98.2 99.3 98.3 Metformin HCI Content 90-110% 99.7 100.5 100.27 Glimepiride Dissolution Q=70% in 60 min 95.4 91.6 102.66 Vildagliptin Dissolution Q=70% in 30 min 101.1 97.9 96.35 Metformin HCI Dissolution Q=70% in 60 min 98.9 102.3 100.63 In another embodiment of the invention, bioavailability tests are performed for the purpose of determining whether there are differences in the magnitude and rate of absorption between the test product of the present invention (fixed combination) and the co-administration of reference drugs that impact the bioavailability of the drugs when administered. After administering the reference drug A: Glimetal® tablets with 4 mg glimepiride / 1000 mg metformin hydrochloride, lot 19C105V2 made by Laboratorios Silanes SA de CV and the reference drug vildagliptin indicated by COFEPRIS, the results of the study show no statistically significant differences for the Cmax and ABCo-t parameters of metformin and vildagliptin; however, with the intention of reducing the risk of acute hypoglycemia, the comparative analysis of glimepiride shows no differences in the amount absorbed (ABCo-t) but does show differences in the absorption rate (Cmax) taking into account the 80-125% intervals (see Example 6). The expert in the art will find that multiple variations and modalities are possible in the realization of the present invention without departing from its spirit and scope to ensure the proper functioning of the product and to meet the required quality characteristics. Examples Example 1. Manufacturing process for the production of the combination drug in tablet form 1. Sieve 35% of diluent, Drug 1, Drug 3, solubilizer, binder and 60% of disintegrant and mix (mixing 1) for 1.6 minutes (Sieving 1). 2. Sieve Drug 2, 40% disintegrant, 65% diluent and adsorbent and mix (mixing 2) for 3 minutes (Sieving 2). 3. Moisten and granulate sieving 1 for 1.6 minutes with 44% of the purified water. 4. Dry the granules until a moisture content of 1.5-2.5% w / w is obtained (Granule 1). 5. Sieve the granule 1 (Sieving 3). 6. Mix sieving 2 and sieving 3 for 3 minutes (Mixing 3). 7. Sift the lubricant and mix with the powder from mixture 3 for 5 minutes. 8. Compress according to specifications. 9. Mix the solvent and the moisture barrier for 45 minutes 10. Coat with a temperature range of not less than 40°C and not greater than 55°C, preferably in the range of 45°-50°C, more preferably between 45-47°C, using the above system in accordance with specifications. rere ίη / ζζηζ / Ε / γίΛΐ Example 2. Qualitative and quantitative formula of the combination drug rere ίη / ζζηζ / Ε / γίΛΐ Table 4. Components in the drug formulation Components mg / Tab Function Glimepiride 1.00 Drug 1 Vildagliptin 50.00 Drug 2 Metformin Hydrochloride 500.00 Drug 3 Microcrystalline Cellulose PH 101 44.90 Diluent Povidone K90 19.30 Binder Poloxamer 188 0.60 Solubilizer Aluminum Magnesium Metasilicate 5.00 Adsorbent Crospovidone 30.00 Disintegrant Magnesium Stearate 3.20 Lubricant Opadry AMB II white 88A180021 21.00 Moisture Barrier Purified Water (mL) q.s. Solvent Example 3. Qualitative and quantitative formula of the combination drug Table 5. Components in the drug formulation Components mg / Tab Function Glimepiride 2.00 Drug 1 Vildagliptin 50.00 Drug 2 Metformin Hydrochloride 1000.00 Drug 3 Microcrystalline Cellulose PH 101 103.0 Diluent Povidone K90 43.0 Binder Poloxamer 188 1.00 Solubilizer Aluminum Magnesium Metasilicate 5.00 Adsorbent Crospovidone 60.00 Disintegrant Magnesium Stearate 6.00 Lubricant Opadry AMB II white 88A180021 40.00 Moisture Barrier Purified Water (mL) q.s. Solvent Example 4. Qualitative and quantitative formula of the combination drug rere ίη / ζζηζ / Ε / γίΛΐ Table 6. Components in the drug formulation Components mg / Tab Function Glimepiride 4.00 Drug 1 Vildagliptin 50.00 Drug 2 Metformin Hydrochloride 1000.00 Drug 3 Microcrystalline Cellulose PH 101 100.0 Diluent Povidone K90 43.0 Binder Poloxamer 188 2.00 Solubilizer Aluminum Magnesium Metasilicate 5.00 Adsorbent Crospovidone 60.00 Disintegrant Magnesium Stearate 6.00 Lubricant Opadry AMB II white 88A180021 40.00 Moisture Barrier Purified Water (mL) qpb Solvent Example 5. Test content and dissolution The expert in the field will be able to see that various methodologies for content testing exist in the state of the art, such as in Pharmacopoeias: the FEUM, USP, British Pharmacopoeia, pharmaceutical norms and standards, so it will be evident for a technician in the field to follow or combine the cited existing pharmaceutical reference documents to solve and carry out this methodology, where multiple variations are possible in carrying out this test without departing from the spirit and scope of the same to ensure the proper functioning of the product and meet the required quality characteristics. The expert in the field will also be able to notice that various methodologies for the dissolution test exist in the state of the art, such as in Pharmacopoeias: the FEUM, USP, British Pharmacopoeia, pharmaceutical norms and standards, so it will be evident for a technician in the field to follow or combine the cited existing pharmaceutical reference documents to solve and carry out this methodology, where multiple variations are possible in carrying out this test without deviating from the spirit and scope of it to ensure the proper functioning of the product and meet the required quality characteristics. On the other hand, the dissolution test (in vitro test) serves to determine the rate (quantity / time) and extent (total amount) at which a drug is released from the dosage form; in the case of the dissolution profile, it corresponds to the quantification of the dissolved drug at different times under standardized conditions. The importance of the dissolution test lies in the following: a) It is a guide for the development of new formulations during product development: it allows the evaluation of possible interference from excipients or the manufacturing process on drug release. b) Process control and quality assurance: helps to ensure continuous product quality and its optimization after a change in manufacturing, formulation, manufacturing site and process scale-up. c) In vivo development indicator: it is an indicator of bioavailability, it allows establishing the correlation between in vitro parameters with bioavailability results. Thus, the dissolution tests of the present invention were implemented in accordance with the description in the FEUM 12th edition (2018) and internationally recognized scientific literature and subsequently validated; one method to quantify glimepiride, another to quantify vildagliptin, and a third method to quantify metformin hydrochloride. The results demonstrated that the methods are precise, accurate, linear, and selective. The dissolution profile of the combination drugs comprising: • glimepiride 2 mg / vildagliptin 50 mg / metformin hydrochloride 1000 mg (tablets), lot DFF1901-24. This drug has an assay for glimepiride of 95.7% (3.8 mg / tablet); for vildagliptin of 96.5% (48.3 mg / tablet); and for metformin of 97.9% (979.0 mg / tablet). • glimepiride 4 mg / vildagliptin 50 mg / metformin hydrochloride 1000 mg (tablets), lot 19F081G1. This medicine has an assay for glimepiride of 97.1% (1.9 mg / tablet); for vildagliptin of 99.9% (50.0 mg / tablet); and for metformin of 98.6% (986.0 mg / tablet). Dissolution profile of vildagliptin, glimepiride, metformin The dissolution profile test was performed in duplicate for a total of 12 dose units of each drug composition: 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 apparatus was used, with a dissolution medium temperature of 37°C ± 0.5°C and a dissolution medium volume of 900 mL ± 1% (9 mL) (except for metformin). Manual sampling was used for a sample volume of 10 mL. A calibration curve was constructed for the results using a linear least squares regression model (excluding zero) y = mx + b, where: “y” is the analytical response (area of ​​Vildagliptin, Glimepiride or Metformin hydrochloride) “x” is the added concentration of Vildagliptin, Glimepiride or Metformin hydrochloride, b = Y-intercept of the calibration curve obtained from the regression. m = Slope of the calibration curve obtained from the regression. Vildagliptin dissolution conditions Dissolving Apparatus 2 (paddles) Dissolution Medium: Water Stirring Speed ​​75 rpm ± 2 rpm Sampling times 5, 10, 15, 20, 30 min. ± 2% Chromatographic conditions vildagliptin HPLC AGILENT 1200 UV Wavelength 210 nm ZORBAX SB-C18 Analytical Column 2.1 x 100 3.5 pm Mobile phase Potassium monobasic phosphate 0.02 M / Acetonitrile (90:10) Flow rate 0.3 mL / min Column temperature 45 oC Running time 4 minutes Injection Volume 40 pL rere ίη / ζζηζ / Ε / γίΛΐ Glimepiride dissolution conditions Dissolving Apparatus 2 (paddles) Dissolution Medium: Phosphate Buffer pH 7.8 Stirring Speed ​​75 rpm ± 3 rpm Sampling times 5, 10, 15, 20, 30 and 45 min ± 2% Chromatographic conditions glimepiride HPLC AGILENT 1200 UV Wavelength 228 nm KINETEX C18 analytical column 2.1 x 100 5.0 pm Mobile phase Formic Acid 0.2% / Acetonitrile: MEOH (40:30:30) Flow rate 0.5 mL / min Column temperature 40 oC Running time 4 minutes Injection Volume 50 pL Metformin dissolution conditions Dissolving Apparatus Apparatus 1 (baskets). Dissolution Medium: Monobasic potassium phosphate 0.68% w / v pH: 6.8 ± 0.1 Volume of Dissolution Medium 1000 mL ± 1% (10 mL) Stirring Speed ​​100 rpm ± 3 rpm Sampling times 5, 10, 15, 20 and 30 min ± 2% Chromatographic conditions metformin HPLC AGILENT 1200 UV Wavelength 233 nm ZORBAX SB-C18 column 2.1 x 100 mm and 3.5 pm particles Mobile phase Potassium monobasic phosphate 0.02 M / (Methanol-Acetonitrile 50:50) 80:20 Flow rate 0.3 mL / min Column temperature 45 oC Running time: 3 minutes Injection Volume 5 pL rere ίη / ζζηζ / Ε / γίΛΐ The individual results obtained from the dissolution profile test for the combination drugs are shown below. Tables 7-12 show the percentages dissolved in each beaker at the sampling times performed and the graph of the average percentages dissolved as a function of sampling times. Table 7. Vildagliptin % dissolved - combination drug comprising glimepiride 4 mg / vildagliptin 50 mg / metformin hydrochloride 1000 mg rere Ln / zznz / E / YiAi GLASS Time (minutes) 5 10 15 20 30 10 1 38 22 67.28 88.46 90 86 88.49 2 31.86 65.30 84.69 88.45 90.57 3 34 31 70.09 90.30 91.61 91.90 4 29 45 62.91 84.23 92.1 1 91.35 5 32 71 62.97 85.61 89.1 1 87.70 6 32 69 63.79 85.17 88.96 88.17 7 41 32 75.04 87.56 86.85 87.37 8 40 05 69.03 92.17 91.64 90.10 1 R 9 33 37 70.47 90.47 90 94 91.17 ID 10 35 97 71.41 90.48 91.57 89.59 1 1 34 05 70.44 82.95 82.65 80.42 12 38 13 69.18 86.88 88.91 88.04 Average 35.18 68.16 87.41 89.47 88.74 Minimum 29.45 62.91 82.95 82.65 80.42 Maximum 41.32 75.04 92.17 92.11 91.90 CV% 10.19 5.53 3.39 3.01 3.43 Table 8. Vildagliptin % dissolved - combination drug comprising glimepiride 2 mg / vildagliptin 50 mg / metformin hydrochloride 1000 mg BOWL 1 Time (minutes) 5 65 33 10 86.34 15 88.78 20 87.6 l 30 84.63 25 2 72 30 88.22 91.24 87.93 87.18 3 64 25 89.19 9 1.96 89.51 87 21 4 60 83 86.04 87.31 90 02 86.65 73 73 88.28 89.18 86.14 86.52 6 71 45 88.19 89.38 85.53 87.56 7 65 71 87.34 88.99 87.56 84.86 8 76 80 87.60 90.25 88.06 89.03 9 77 15 88.66 89.04 87.47 89.10 30 10 55 75 85.57 89.07 91.37 89.93 11 80 33 88.39 87.49 87.27 87.25 12 64.28 89.29 90.71 89.46 89.69 Average 68.99 87.76 89.45 88.16 87.47 Minimum 55.75 85.57 87.31 85.53 84.63 Maximum 80.33 89.29 91.96 91.37 89.93 CV% 10.76 1.38 1.55 1.88 1.97 Table 9. Glimepiride % dissolved - combination drug comprising glimepiride 4 mg / vildagliptin 50 mg / metformin hydrochloride 1000 mg Time (minutes) GLASS 5 5 10 15 20 30 45 l 32.98 7161 90 04 92 22 90 91 91 55 2 33.48 68 85 91 36 91 75 91 92 92 66 3 35 56 72 37 90 47 93 05 92 70 93 35 4 32.56 68 07 94 58 94 93 93 95 93 80 5 37.52 66 93 94 08 95 94 96 27 94 91 5 29.08 59 86 88 60 95 40 95 04 95 32 7 38.73 73 91 91 46 92 71 92 04 92 64 8 27 80 62 30 91 24 94 40 93 80 92 63 10 9 29.09 69.54 88 13 93.00 94 63 93 85 10 33.40 72 81 92 83 94 02 92 83 92 64 1 1 35.75 71 37 91 48 91 73 92 08 95 71 12 33.15 65 35 90.20 94 74 95 96 93 55 Average 33.26 68.58 91.21 93.66 93.51 93.55 Minimum 27.80 59.86 88.13 91.73 90.91 91.55 Maximum 38.73 73.91 94.58 95.94 96.27 95.71 CV% 10.13 6.33 2.13 1.54 1.83 1.33 Table 10. Glimepiride % dissolved - combination drug comprising glimepiride 2 mg / vildagliptin 50 mg / metformin hydrochloride 1000 mg Time (minutes) GLASS 5 10 15 20 30 45 1 51.89 89 60 101.61 101 59 99 45 99 09 2 72 82 99 00 98 44 97 88 97 81 97 48 3 60.75 95 55 99.29 99 18 99 75 98 49 4 62.08 100.52 101.72 100 85 100 33 99.96 5 66.48 96 99 100.36 100 88 99 38 98 85 6 74.94 95 39 97 81 99 37 97 54 96 60 25 7 56.90 96 01 99 79 98 78 98 60 98.65 8 54.49 97 47 101.28 99 11 98 64 97 74 9 56.12 96 12 100.84 98 53 97 18 97 40 10 51.49 93 39 99 61 98.17 98 45 96 16 1 1 80.93 103.70 99.20 97 69 97 69 98 53 12 76.89 93.12 95 20 94.03 96 38 92 79 Average 63.82 96.40 99.60 98.84 98.43 97.65 Min 51.49 89.60 95.20 94.03 96.38 92.79 30 Max 80.93 103.70 101.72 101.59 100.33 99.96 CV% 16.20 3.78 1.86 1.98 1.18 1.91 rere ίη / ζζηζ / Ε / γίΛΐ Table 11. Metformin % dissolved - combination medication comprising glimepiride 4 mg / vildagliptin 50 mg / metformin hydrochloride 1000 mg rere ίη / ζζηζ / Ε / γίΛΐ GLASS Time (minutes) 5 5 10 15 20 30 1 25 36 60.01 83.83 100.60 101 29 2 33 86 64.17 99.26 101.68 98 89 3 34 05 70 99 97.66 104.64 100 73 4 30 55 72 92 99.89 96.96 103 02 n 34 01 67.65 100.95 100.62 105 51 6 34 31 65.26 91.77 103.18 104.22 7 21 89 54.87 81.34 95.98 98 44 8 24 53 60.93 84.40 93 76 93 66 10 9 29 16 64.15 89.87 95.16 96 05 10 25 64 59.60 91.44 94.31 98 31 11 17 96 48.34 66.43 88.79 94 28 12 26 63 66.46 81.71 89.84 92 42 Average 28.16 62.94 89.05 97.13 98.90 Minimum 17.96 48.34 66.43 88.79 92.42 Maximum 34.31 72.92 100.95 104.64 105.51 cv% 19.13 10.81 11.36 5.24 4.29 Table 12. Metformin % dissolved - combination drug comprising glimepiride 2 mg / vildagliptin 50 mg / metformin hydrochloride 1000 mg 20 GLASS Time (minutes) 5 10 15 20 30 1 66 01 100 39 100.95 100.95 98.99 2 77 13 101 08 103.31 99.64 99 60 49 98 89.86 107.40 105.70 102 79 4 62.26 99.21 103.64 102.09 100 74 60 00 98.61 101.75 101.29 101 08 6 67.96 100 68 100.86 103.13 100 20 25 7 60 64 98.94 103.63 101.68 101 45 8 66 99 100 77 100.65 103.89 100.95 9 52 10 95.29 100.39 101.25 100 91 10 53 81 100 97 103.46 102.22 99 27 11 62 93 103 24 98.35 101.24 101 49 12 71 81 100 15 104.31 96.56 98 95 Average 62.63 99.10 102.39 101.64 100.53 Minimum 49.98 89.86 98.35 96.56 98.95 30 Maximum 77.13 103.24 107.40 105.70 102.79 CV% 12.86 3.51 2.32 2.20 1.16 Comparison of dissolution profiles The average percentages of each drug dissolved at the sampling times performed are shown below in the form of a comparative table (Tables 13-15) and a graph (Figures 7-9) (the notation used “drug (A)” and “drug (B)” is different from that used in example 6 of bioavailability tests). rere ίη / ζζηζ / Ε / γίΛΐ Table 13. Dissolved percentage of vildagliptin Time (min) Combination drug (A) comprising glimepiride 4 mg / vildagliptin 50 mg / metformin hydrochloride 1000 mg Combination drug (B) comprising glimepiride 2 mg / vildagliptin 50 mg / metformin hydrochloride 1000 mg 0 0.00 0.00 5 35.18 68.99 10 68.16 87.76 14 87.41 89.45 20 89.47 88.16 30 88.74 84.47 Table 14. Percentage of glimepiride dissolved Time (min) Combination drug (A) comprising glimepiride 4 mg / vildagliptin 50 mg / metformin hydrochloride 1000 mg Combination drug (B) comprising glimepiride 2 mg / vildagliptin 50 mg / metformin hydrochloride 1000 mg 0 0.00 0.00 5 33.26 63.82 10 68.58 96.40 15 91.21 99.60 20 93.66 98.84 30 93.51 98.43 45 93.55 94.65 Table 15. Dissolved percentage of metformin hydrochloride rere ίη / ζζηζ / Ε / γίΛΐ Time (min) Combination drug (A) comprising glimepiride 4 mg / vildagliptin 50 mg / metformin hydrochloride 1000 mg Combination drug (B) comprising glimepiride 2 mg / vildagliptin 50 mg / metformin hydrochloride 1000 mg 0 0.00 0.00 5 28.16 62.63 10 62.94 99.10 15 89.05 102.39 20 97.13 101.64 30 98.90 100.53 In the graphical results, we can see that the drugs under study show some similarity in their dissolution profiles, since the combination drug comprising glimepiride 2 mg / vildagliptin 50 mg / metformin hydrochloride 1000 mg has a more pronounced ascending phase than the combination drug comprising glimepiride 4 mg / vildagliptin 50 mg / metformin hydrochloride 1000 mg in the three drugs evaluated (Vildagliptin, Glimepiride and Metformin hydrochloride), which is confirmed by reviewing the percentages dissolved at the sampling times in the results tables.Low variability of the dissolved percentages was also observed in both medications. In the three drugs evaluated (Vildagliptin, Glimepiride and Metformin hydrochloride), the CV% of the dissolved percentage was less than 20% at the first sampling time and less than 10% at subsequent sampling times (except for Metformin hydrochloride for the drug comprising glimepiride 4 mg / vildagliptin 50 mg / metformin hydrochloride 1000 mg). The results of the dissolution profiles in both drugs showed rapid dissolution of the three drugs evaluated Vildagliptin, Glimepiride and Metformin hydrochloride with dissolution percentages greater than 85% at 15 minutes; therefore, the dissolution profiles are considered similar and the products can be classified as very fast dissolving. Example 6. Bioavailability tests Algorithm 1, “Treatment Regimens in Type 2 Diabetes Mellitus (T2DM),” included in the Clinical Practice Guideline for the Treatment of Type 2 Diabetes Mellitus at the Primary Care Level, published by CENETEC, indicates that in cases of inadequate glycemic control (HbA1c > 7% and FPG > 130), dual oral therapy plus a sulfonylurea should be initiated as one of the options. Additionally, the ADA (American Diabetes Association: Standards of Medical Care in Diabetes - 2019) indicates that with inadequate glycemic control using metformin as first-line treatment, a DPP-4 inhibitor can be added, and if control is not achieved despite the dual regimen, a sulfonylurea can be added. Furthermore, when cost is a factor, treatment should begin with metformin; if control is not achieved, a sulfonylurea should be added; and if the therapeutic goal is not reached, then a DPP-4 inhibitor can be included. On the other hand, determining the pharmacokinetic parameters of Cmax and area under the plasma concentration-time curve (AUC-t) allows for characterizing the bioavailability of the active ingredients of this drug from its pharmaceutical form, in terms of the rate and extent of absorption. Therefore, the purpose of the bioavailability tests is to determine if there are differences in the magnitude and rate of absorption between the test product of the present invention (fixed-dose combination) and the co-administration of reference drugs that impact the bioavailability of the drugs when administered under fasting conditions. This is based on the approach established by the QMS for new fixed-dose combinations, in compliance with scenario 2 (World Health Organization. WHO Technical Report Series, No. 929, 2005).According to this scenario, it is necessary to demonstrate that the individual drugs have been administered together at the same doses and regimen as the fixed-dose combination is intended to be administered, in addition to documenting that the safety and efficacy profile for this combination has been well characterized. Thus, a single-center, open-label, two-period, two-treatment, two-sequence (AB and BA), crossover, randomized, single-dose comparative bioavailability study was conducted of an oral tablet preparation with the fixed combination of 4 mg glimepiride, 50 mg vildagliptin, and 1000 mg metformin hydrochloride (treatment B, test drug, test product of Laboratorios Silanes SA de CV) against the co-administration of the reference drugs (reference drugs (A)): Glimetal® (treatment A1, reference drug containing 4 mg glimepiride / 1000 mg metformin hydrochloride, lot 19C105V2, product of Laboratorios Silanes SA de CV) and the vildagliptin reference drug (treatment A2) indicated by the COFEPRIS, in healthy fasting volunteers to determine bioequivalence in terms of absorption rate and magnitude. A total of 44 healthy volunteers (27 men and 17 women) were randomized to the study, of whom 42 completed their participation, and 2 withdrew their informed consent. The sampling period was 48 hours, chosen based on the reported elimination half-life of glimepiride, which is the longest (7.5 ± 4 hours in the Mexican population). In this regard, after four half-lives, more than 90% of the administered dose of each drug would have been eliminated. The minimum washout period of four days was established according to the elimination half-life of glimepiride. After seven half-lives, the carryover pharmacokinetic effect can be completely ruled out. Each volunteer received the treatments under study, according to the randomization. Blood samples were collected and processed to obtain plasma before each administration (pre-dose 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 of each drug. Samples from volunteers were analyzed to quantify the three drugs using a high-performance liquid chromatography method, with protein precipitation as the extraction method, following a separation process on a reversed-phase column chromatographic display with detection by mass spectrometry (HPLC-MS / MS) and as internal standards metformin HCl-d6, vildagliptin-d3 and glibenclamide, in plasma. The analytical method was previously validated under the parameters established in the Mexican Official Standard NOM-177-SSA1-2013 and was applied in this study for the characterization of pharmacokinetic profiles. rere Ln / zznz / E / YiAi (The notation used “reference drug (A)”, “treatment (A2) reference drug”, “treatment (B) test drug” and “treatment (A1) reference drug” is different from that used in example 5 of test and dissolution profile). Table 16. Descriptive statistics for plasma concentrations of vildagliptin with respect to time for treatment B (test drug) rere Ln / zznz / E / YiAi Time (h) N Media (ng / mL) Desv. Est (ng / mL) Error Est (ng / mL) Min (ng / mL) Median (ng / mL) Max (ng / mL) cv% 0.00 42 0.000 0.000 0.000 0.00 0.00 0.00 - 0.25 42 10.044 8.973 1.384 0.00 8.19 39.52 89.3 0.50 42 42.955 25.538 3.941 8.92 36.53 111.06 59.5 1.00 42 77.464 29.964 4.624 14.17 83.64 169.53 38.7 1.25 42 81.921 30.813 4.755 13.99 77.41 171.80 37.6 1.50 42 88.105 38.446 5.932 17.65 82.51 235.89 43.6 1.75 42 98.006 44.339 6.842 19.38 88.18 240.24 45.2 2.00 42 104.238 46.793 7.220 25.28 98.15 218.38 44.9 2.50 42 124.320 52.205 8.055 40.47 108.63 247.27 42.0 3.00 42 139.930 45.299 6.990 42.83 134.95 254.70 32.4 3.50 42 135.471 45.695 7.051 27.95 133.64 258.96 33.7 4.00 42 120.051 47.874 7.387 31.47 108.54 263.43 39.9 4.50 42 95.227 39.721 6.129 43.95 87.18 264.86 41.7 5.00 42 78.568 28.136 4.342 34.73 67.83 174.04 35.8 6.00 42 57.597 23.886 3.686 24.91 50.48 131.90 41.5 8.00 42 33.184 11.123 1.716 15.76 30.79 65.76 33.5 10.00 42 17.750 6.446 0.995 7.00 17.61 33.13 36.3 12.00 42 9.162 4.091 0.631 0.00 9.03 18.75 44.7 18.00 42 0.406 1.494 0.231 0.00 0.00 6.62 367.7 24.00 42 0.000 0.000 0.000 0.00 0.00 0.00 36.00 41 0.000 0.000 0.000 0.00 0.00 0.00 - 48.00 42 0.000 0.000 0.000 0.00 0.00 0.00 -. Table 17. Descriptive statistics for plasma concentrations of glimepiride with respect to time for treatment B (test drug) PFCC ίη / ΖΖΠΖ / Ε / ΥΙΛΙ Time (h) N Media (ng / mL) Desv. Est (ng / mL) Error Est (ng / mL) Min (ng / mL) Median (ng / mL) Max (ng / mL) CV% 0.00 42 0.000 0.000 0.000 0.00 0.00 - 0.25 42 6.763 13.420 2.071 0.00 0.00 61.20 198.4 0.50 42 41.037 51.737 7.983 0.00 22.19 202.10 126.1 1.00 42 88.913 74.516 11.498 5.92 69.84 319.80 83.8 1.25 42 97.221 74.375 11.476 6.60 79.31 310.71 76.5 1.50 42 99.154 71.758 11.073 8.68 82.98 322.70 72.4 1.75 42 105.110 76.704 11.830 10.17 82.00 370.40 73.0 2.00 42 106.944 73.223 11.299 16.24 86.27 344.80 68.5 2.50 42 115.604 67.249 10.377 33.70 98.60 331.77 58.2 3.00 42 124.261 66.828 10.312 37.09 117.06 317.55 53.8 3.50 42 127.945 61.896 9.551 40.06 130.70 285.60 48.4 4.00 42 132.327 61.718 9.523 45.51 132.30 282.10 46.6 4.50 42 137.172 50.283 7.759 50.55 130.26 244.12 36.7 5.00 42 104.295 36.731 5.668 36.83 103.27 194.00 35.2 6.00 42 71.554 24.766 3.821 29.35 70.40 122.12 34.6 8.00 42 57.017 22.170 3.421 19.76 57.80 117.77 38.9 10.00 42 43.984 15.458 2.385 16.19 41.95 84.32 35.1 12.00 42 33.495 11.240 1.734 14.99 32.87 65.30 33.6 18.00 42 13.263 4.496 0.694 7.47 12.25 24.90 33.9 24.00 42 12.265 6.663 1.028 0.00 11.35 27.39 54.3 36.00 41 4.680 6.081 0.950 0.00 0.00 19.24 129.9 48.00 42 1.601 3.761 0.580 0.00 0.00 17.55 234.9. Table 18. Descriptive statistics for plasma concentrations of metformin with respect to time for treatment B (test drug) rere ίη / ζζηζ / E / γίΛΐ Time (h) N Media (ng / mL) Desv. Est (ng / mL) Error Est (ng / mL) Min (ng / mL) Median (ng / mL) Max (ng / mL) CV% 0.00 42 0.000 0.000 0.00 0.00 0.00 0.00 - 0.25 42 427.205 215.518 33.255 36.77 390.66 953.56 50.4 0.50 42 1051.936 434.373 67.025 431.93 1031.46 2007.10 41.3 1.00 42 1588.913 563.927 87.016 586.59 1557.20 3071.61 35.5 1.25 42 1567.651 528.249 81.511 698.92 1538.51 2925.03 33.7 1.50 42 1558.951 465.147 71.774 724.78 1592.87 2812.11 29.8 1.75 42 1593.480 434.867 67.101 750.26 1579.39 2623.74 27.3 2.00 42 1600.398 417.239 64.381 810.47 1551.41 2537.79 26.1 2.50 42 1625.901 364.246 56.204 841.81 1555.14 2251.74 22.4 3.00 42 1663.037 402.349 62.084 816.56 1577.14 2566.13 24.2 3.50 42 1599.506 415.446 64.105 629.19 1561.56 2656.73 26.0 4.00 42 1551.503 424.092 65.439 682.09 1474.78 2599.53 27.3 4.50 42 1417.422 418.178 64.526 775.57 1328.03 2625.00 29.5 5.00 42 1263.759 360.643 55.648 736.06 1180.62 2239.04 28.5 6.00 42 956.532 266.147 41.067 563.13 909.30 1763.75 27.8 8.00 42 595.614 173.414 26.758 355.73 595.07 1202.16 29.1 10.00 42 334.341 102.274 15.781 175.05 336.70 656.09 30.6 12.00 42 209.386 60.269 9.300 123.13 201.43 354.41 28.8 18.00 42 75.118 18.193 2.807 43.16 71.22 127.38 24.2 24.00 42 36.933 9.062 1.398 20.01 36.27 58.78 24.5 36.00 41 11.254 13.120 2.049 0.00 0.00 34.70 116.6 48.00 42 1.162 5.331 0.823 0.00 0.00 28.34 458.8. In order to visualize the possible differences between the formulations and / or treatments, the plasma concentration profiles (± standard error) with respect to time, obtained in the participating volunteers (Figures 10-15) were plotted on an arithmetic and semi-logarithmic scale. Descriptive statistics of pharmacokinetic parameters Pharmacokinetic parameters were determined using independent model methods. Descriptive statistics are presented below in Tables 19-21. ω Ν μ -> j οι o 01 o σι o > ai\ cl\ l\ c c G Table 19. Descriptive statistics of the pharmacokinetic parameters of glimepiride by treatment (A: reference drug; or B: trial drug) Variable Trat N Geometric Mean Mean Desv. Est. Error Est Min Median Max CV% Tmax (h) A 42 3.423 3.662 1.294 0.200 1.50 4.00 8.00 35.3 B 42 3.239 3.548 1.241 0.192 1.00 4.00 5.00 35.0 Cmax (ng / mL) A 42 216.385 230.193 80.520 12.424 82.96 225.81 441.78 35.0 B 42 164.222 174.353 64.297 9.921 93.06 158.36 370.49 36.9 ABCo-t (h*ng / mL) A 42 1232.834 1273.681 333.485 51.458 574.33 1201.44 2222.49 26.2 B 42 1155.852 1207.939 358.671 55.344 685.95 1216.01 1867.16 29.7 ABCo-inf (h*ng / mL) A 42 1323.282 1362.257 341.812 52.743 711.12 1295.90 2358.23 25.1 B 42 1273,565 1330,705 394,351 60,850 776.42 1337.79 2157.02 29.6 ABC%extrap (%) A 42 5,750 6,732 4,301 0.664 1.52 5.55 21.91 63.9 B 42 7.807 9.103 5.019 0.775 2.07 7.48 21.55 55.1 K(1 / h) A 42 0.103 0.115 0.053 0.008 0.03 0.11 0.25 45.6 B 42 0.089 0.101 0.046 0.007 0.02 0.10 0.23 46.0 Ti / 2(h) A 42 6.704 7.654 4.638 0.716 2.78 6.33 26.38 60.6 B 42 7.787 9.129 6.097 0.941 3.07 7.09 32.44 66.8 Ν Ü1 Μ -> ο σι > α ι\ C ι\ Ι\ C CG Table 20. Descriptive statistics of the pharmacokinetic parameters of metformin by treatment (A: reference drug; or B: trial drug) Variable Trat N Geometric Mean Mean Desv. Est. Error Est Min Median Max cv% Tmax (h) A 42 2.293 2.513 1.023 0.158 1.00 2.50 4.00 40.7 B 42 2.208 2.476 1.149 0.177 1.00 2.50 6.00 46.4 Cmax (ng / mL) A 42 1955.279 2034.569 590.612 91.133 1184.30 1933.55 3529.75 29.0 B 42 1893.058 1958.858 502.007 77.461 848.66 1905.01 3071.61 25.6 ABCos (h*ng / mL) A 42 12602.401 12962.823 3144.641 485.229 6966.76 12111.49 20295.08 24.3 B 42 12321.994 12607.936 2719.863 419.684 7638.77 12271.24 18508.01 21.6 ABCo-inf (h*ng / mL) A 42 12833.583 13185.175 3133.841 483,562 7345.32 12402.47 20540.69 23.8 B 42 12587.307 12873.205 2764.212 426.527 7857.69 12454.55 18792.97 21.5 ABC%extrap (%) A 42 1.627 1.797 0.897 0.138 0.66 1.67 5.15 49.9 B 42 1.748 2.090 1.841 0.284 0.90 1.54 10.74 88.1 Foot(1 / h) A 42 0.140 0.146 0.037 0.006 0.07 0.15 0.23 25.4 B 42 0.132 0.146 0.048 0.007 0.02 0.16 0.22 33.0 Tv2(h) A 42 4.936 5.153 1.682 0.260 3.06 4.58 10.35 32.6 B 42 5.245 6.570 7.249 1.119 3.19 4.43 38.44 110.3 ω μ i\) -k -> ο ϋ) ο σ> ο Table 21. Descriptive statistic of vildagliptin pharmacokinetic parameters by treatment (A: reference drug; B: test drug) > ai\ cl\ l\ cccoc Variable Trat N Geometric Mean Mean Desv. Est. Error Est Min Median Max cv% Tmax (h) A 42 2.630 2.929 1.213 0.187 0.50 3.00 6.00 41.4 B 42 3.010 3.185 1.014 0.156 1.00 3.00 6.00 31.8 Cmax (ng / mL) A 42 168,931 180,158 67,513 10,417 85.18 154.35 326.53 37.5 B 42 160,107 167,616 50,399 7,777 78.24 166.87 264.86 30.1 ABCo-t (h*ng / mL) A 42,718,085 736,562 177,932 27,455 483.82 699.51 1331.00 24.2 B 42 703,987 722,076 167,251 25,807 454.71 704.19 1166.48 23.2 ABCo-inf (h*ng / mL) A 42 753.116 771.915 182.266 28.124 498.85 734.76 1386.84 23.6 B 42 735.860 752,532 164,280 25,349 486.47 735.99 1197.32 21.8 ABC%extrap (%) A 42 4,143 4,623 2,343 0.362 1.30 4.14 12.80 50.7 B 42 3,843 4.308 2.113 0.326 1.19 3.62 8.99 49.0 Feet(1 / h) A 42 0.298 0.305 0.062 0.010 0.17 0.31 0.42 20.4 B 42 0.303 0.310 0.067 0.010 0.21 0.30 0.50 21.5 Ti / 2(h) A 42 2.323 2.379 0.552 0.085 1.64 2.22 4.14 23.2 B 42 2.285 2.336 0.500 0.077 1.38 2.27 3.23 21.4 ω ι\) ι\) -χ of U1 o 01 o Confidence intervals and boundary tests for pharmacokinetic parameters > ai\ cl\ l\ cccoc Table 22. Confidence intervals and boundary tests for the logarithmically transformed pharmacokinetic parameters of glimepiride (Treatment A vs Treatment B) Pharmacokinetic Parameter Average Reference (A)' Average Test (B)' Ratio of Averages [B / A] (%) Classical Confidence Interval Schuirmann's One-Sided T-Test Anderson-Hauck Test Power Lower Upper P < 80 P > 125 Ln (Cmax) 216.707 164.067 75.71 68.38 83.82 0.8163 0.0000 0.8163 0.9742 Ln(ABCo-t) 1230.492 1156.671 94.00 88.80 99.51 0.0000 0.0000 0.0000 1.0000 Criterion >80 <125 <0.05 <0.05 <0.05 >0.8 * Geometric mean Table 23. Within-subject variability and coefficients of variation for the pharmacokinetic parameters of glimepiride Pharmacokinetic parameter Coefficient of Intrasubject Variability (%) Ln (Cmax) 28.21 Ln(ABCo-t) 15.58 > α ι\ ω Ν Ν -k -i Üi C ο σι ο (η οΙ\ ι\ C Table 24. Confidence intervals and boundary tests for logarithmically transformed pharmacokinetic parameters of metformin (Treatment A vs Treatment B) Pharmacokinetic Parameter Average Reference (A)* Average Test (B)' Ratio of Averages [B / A] (%) Classical Confidence Interval Schuirmann's One-Sided T-Test Anderson-Hauck Test Power Lower Upper P < 80 P > 125 Ln (Cmax) 1959.488 1897.582 96.84 90.56 103.55 0.0000 0.0000 0.0000 0.9998 Ln(ABCo-t) 12622.141 12368.848 97.99 93.08 103.16 0.0000 0.0000 0.0000 1.0000 Criterion >80 <125 <0.05 <0.05 <0.05 >0.8 * Geometric mean ω Table 25. Within-subject variability and coefficients of variation for the pharmacokinetic parameters of metformin® Pharmacokinetic parameter Coefficient of Intrasubject Variability (%) Ln (Cmax) 18.37 Ln(ABCo-t) 14.05 > α ι\ ω Μ N 01C O 0) O 0) oh ι\ C Table 26. Confidence intervals and boundary tests for logarithmically transformed pharmacokinetic parameters of vildagliptin (Treatment A vs Treatment B) Pharmacokinetic Parameter Average Reference (A)' Average Test (B)' Ratio of Averages [B / A] (%) Classical Confidence Interval Schuirmann's One-Sided T-Test Anderson-Hauck Test Power Lower Upper P < 80 P > 125 Ln (Cmax) 169.256 160.703 94.95 88.55 101.80 0.0001 0.0000 0.0001 0.9997 Ln (ABCo-t) 718.554 705.309 98.16 94.92 101.51 0.0000 0.0000 0.0000 1.0000 Criterion >80 <125 <0.05 <0.05 <0.05 >0.8 * Geometric mean Table 27. Within-subject variability and coefficients of variation for the pharmacokinetic parameters of vildagliptin ω (O Pharmacokinetic parameter Coefficient of Intrasubject Variability (%) Ln (Cmax) 19.12 Ln (ABCo-t) 9.14 Application and advantages of the invention The invention relates to an innovative, more effective fixed-combination drug comprising a sulfonylurea, a dipeptidyl peptidase-4 (DPP4) inhibitor, and a biguanidine for improved management of type 2 diabetes mellitus. The sulfonylurea, dipeptidyl peptidase-4 (DPP4) inhibitor and biguanidine used to manufacture this drug, which is adapted to be immediate release, are glimepiride, vildagliptin and metformin in its hydrochloride form. At the same time, the present invention allows for the resolution of a set of significant technological challenges in the manufacture of said drug due to the physicochemical properties and the dosage differences of the synergistic combination of the sulfonylurea, dipeptidyl peptidase-4 (DPP4) inhibitor, and biguanide it comprises, in order to guarantee the production of a stable product for such purposes. The drug comprises: (a) a sulfonylurea, (b) a dipeptidyl peptidase-4 (DPP4) inhibitor, and (c) a biguanide, or a pharmaceutical salt of any of the same, in pharmaceutically acceptable amounts ranging from 1-4 mg, 50 mg, and 500-1000 mg, respectively, in combination with pharmaceutically acceptable excipients and / or vehicles.

Claims

1. A combination drug characterized in that it comprises: (a) a sulfonylurea, (b) a dipeptidyl peptidase-4 (DPP4) inhibitor and (c) a biguanide, or a pharmaceutical salt of any of the same, in pharmaceutically acceptable amounts in the range of 1-4 mg, 50 mg and 500-1000 mg respectively, in combination with pharmaceutically acceptable excipients and / or vehicles; and wherein said drug is in solid form and is adapted for immediate release.

2. The combination drug according to claim 1, characterized in that the sulfonylurea is present in a preferably pharmaceutically acceptable amount of 1 mg.

3. The combination drug according to claim 1, characterized in that the sulfonylurea is present in a preferably pharmaceutically acceptable amount of 2 mg.

4. The combination drug according to claim 1, characterized in that the sulfonylurea is present in a preferably pharmaceutically acceptable amount of 4 mg.

5. The combination drug according to claim 1, characterized in that the biguanide is present in a preferably pharmaceutically acceptable amount of 500 mg.

6. The combination drug according to claim 1, characterized in that the biguanide is present in a preferably pharmaceutically acceptable amount of 1000 mg.

7. The combination medicinal product according to any one of claims 1-6, characterized in that (a) the sulfonylurea, (b) the dipeptidyl peptidase-4 (DPP4) inhibitor, and (c) the biguanide, or a pharmaceutical salt thereof, are preferably in pharmaceutically acceptable amounts of 1 / 50 / 500 mg respectively, in combination with pharmaceutically acceptable excipients and / or vehicles.

8. The combination drug according to any of claims 1-6, characterized in that (a) the sulfonylurea, (b) the dipeptidyl peptidase-4 (DPP4) inhibitor and (c) the biguanide, or a pharmaceutical salt of any of the same, are preferably in pharmaceutically acceptable amounts of 2 / 50 / 1000 mg respectively, in combination with pharmaceutically acceptable excipients and / or vehicles.

9. The combination medicinal product according to any of claims 1-6, characterized in that (a) the sulfonylurea, (b) the dipeptidyl peptidase-4 (DPP4) inhibitor and (c) the biguanide, or a pharmaceutical salt of any of the same, are preferably in pharmaceutically acceptable amounts of 4 / 50 / 1000 mg respectively, in combination with pharmaceutically acceptable excipients and / or vehicles.

10. The combination drug according to any of claims 1-4 and 7-9, characterized in that the sulfonylurea is glimepiride.

11. The combination drug according to claim 1 and 7-9, characterized in that the dipeptidyl peptidase-4 (DPP4) inhibitor is vildagliptin.

12. The combination drug according to any of claims 1 and 5-9, characterized in that the biguanide is metformin.

13. The combination drug according to claim 12, characterized in that the metformin is preferably metformin hydrochloride.

14. The combination medicament according to claims 1-13, characterized in that the pharmaceutically acceptable excipients and / or vehicles comprise binders, diluents, disintegrants, lubricants, solvents and / or solubilizers, adsorbents and coatings.

15. The combination drug according to claim 14, characterized in that the diluent is preferably microcrystalline cellulose PH 101 in a pharmaceutically acceptable amount in the range of 5 to 90%.

16. The combination drug according to claim 14, characterized in that the disintegrant is preferably crospovidone in a pharmaceutically acceptable amount in the range of 0.5-15%.

17. The combination drug according to claim 14, characterized in that the adsorbent is preferably aluminum magnesium metasilicate in a pharmaceutically acceptable amount in the range of 0.5 to 90%.

18. The combination drug according to claim 14, characterized in that the binder is preferably povidone K90 in a pharmaceutically acceptable amount in the range of 0.5 to 5%.

19. The combination drug according to claim 14, characterized in that the solubilizer is preferably poloxamer 188 in a pharmaceutically acceptable amount in the range of 0.01 to 5%.

20. The combination medicament according to claim 14, characterized in that the lubricant is preferably magnesium stearate in a pharmaceutically acceptable amount in the range of 0.25 to 10%.

21. The combination drug according to claim 14, characterized in that the coating is a moisture and light barrier coating.

22. The combination drug according to claim 21, characterized in that the moisture and light barrier coating is preferably Opadry AMB II in a pharmaceutically acceptable amount in the range of 0.5 to 6%.

23. The combination drug according to claim 14, characterized in that the solvent is preferably water in a pharmaceutically acceptable amount.

24. The combination medicament according to any one of claims 1-2-3, characterized in that it is contained in a single solid dosage unit selected from the group comprising a tablet, caplet, granule, lozenge, pill, or pill.

25. The combination drug according to claim 24, characterized in that it is preferably in tablet form.

26. The combination drug of any of claims 1-25 for use in the control and management of type 2 diabetes mellitus in individuals requiring triple oral therapy.

27. Use of (a) a sulfonylurea, (b) a dipeptidyl peptidase-4 (DPP4) inhibitor and (c) a biguanide, or a pharmaceutical salt of any of the same, in pharmaceutically acceptable amounts in the range of 1-4 mg, 50 mg and 500-1000 mg respectively, in combination with pharmaceutically acceptable excipients and / or vehicles for the manufacture of a drug useful for the control and management of type 2 diabetes mellitus in individuals requiring triple oral therapy.

28. Use in accordance with claim 27, wherein said drug is in solid form and is adapted to be for immediate release.

29. Use according to claims 27-28, wherein the pharmaceutically acceptable amounts of the sulfonylurea, the dipeptidyl peptidase-4 (DPP4) inhibitor and the biguanide, or a pharmaceutical salt of any of the same, are preferably in pharmaceutically acceptable amounts of 1 / 50 / 500 mg respectively, in combination with pharmaceutically acceptable excipients and / or vehicles.

30. Use according to claims 27-28, wherein the pharmaceutically acceptable amounts of the sulfonylurea, the dipeptidyl peptidase-4 (DPP4) inhibitor and the biguanide, or a pharmaceutical salt of any of the same, are preferably in pharmaceutically acceptable amounts of 2 / 50 / 1000 mg respectively, in combination with pharmaceutically acceptable excipients and / or vehicles.

31. Use according to claims 27-28, wherein the pharmaceutically acceptable amounts of the sulfonylurea, the dipeptidyl peptidase-4 (DPP4) inhibitor, and the biguanide, or a pharmaceutical salt of any of the same, are preferably in pharmaceutically acceptable amounts of 4 / 50 / 1000 mg respectively, in combination with pharmaceutically acceptable excipients and / or vehicles.

32. Use in accordance with any of claims 27-31, wherein the sulfonylurea is glimepiride.

33. Use in accordance with any of claims 27-31, wherein the dipeptidyl peptidase-4 (DPP4) inhibitor is vildagliptin.

34. Use in accordance with any of claims 27-31, wherein the biguanide is metformin.

35. Use in accordance with claim 34, wherein the metformin is preferably metformin hydrochloride.