WO2012148252A2

WO2012148252A2 - Metformin-based ionic co-crystals

Info

Publication number: WO2012148252A2
Application number: PCT/MX2012/000043
Authority: WO
Inventors: José Manuel Francisco LARA OCHOA
Original assignee: Instituto De Investigación En Química Aplicada, S.A. De C.V.
Priority date: 2011-04-29
Filing date: 2012-04-20
Publication date: 2012-11-01
Also published as: WO2012148252A3; MX339374B; MX2011004549A

Abstract

The invention relates to two novel metformin-based compounds obtained using the antidiabetic agent glimepiride as a contra-ion in one case and using the antidiabetic agent pioglitazone as a contra-ion in the other case. The resulting spectroscopy, as well as an evaluation of the physicochemical properties thereof, indicate that, in the solid state, both compounds correspond to ionic co-crystals attracted by ionic forces and interactions of the hydrogen bond type. The physicochemical properties of the ionic co-crystals have been shown to have better intrinsic dissolution rates and improved solubilities in relation to those of the precursor contra-ions; properties that can impact favourably on the bioavailability of the novel active principles. Said improved novel active principles are formulated in oral solid pharmaceutical compositions such as tablets or caplets that have advantages over existing commercial tablets. Consequently, tablets containing these novel active principles provide an improved treatment for controlling blood glucose levels in patients with type II diabetes.

Description

IONIC COCRYSTALS BASED ON METFORMIN

FIELD OF THE INVENTION

The active ingredient N, N dimethyldiguanide is an unstable compound, so it is not suitable for the preparation of pharmaceutical compositions making it necessary to deliver the compound as a salt. In the present invention, two new compounds have been developed, based on metformin, which show important advantages over existing salts, which have been proposed to control blood glucose of diabetic patients. The solid form of the new compounds obtained corresponds to ionic co-crystals, stabilized by ionic attractions and hydrogen type bridge interactions.

BACKGROUND OF THE INVENTION

N, N dimethyldiguanide, generically called metformin, is a potent antidiabetic agent used as a first level treatment in the treatment of patients with type II diabetes. Metformin works by reducing gluconeogenesis and reducing glucose absorption at the level of the gastrointestinal (TG) tract. This active ingredient also increases insulin sensitivity, which is manifested by increasing peripheral glucose utilization. This effect may be due to the fact that metformin improves the binding of insulin to its cellular receptor, which is explained by the increase in activity induced in the dessertceptor tyrosine kinase and the consequent increase in the number and activity of GLUT4 carriers.

Metformin oxidizes very quickly by exposure to air, especially if the air contains some moisture, which makes it difficult to make pharmaceutical forms, such as tablets or capsules. Currently the commercially used medicine to control blood glucose in diabetic patients is the hydrochloride salt. Notwithstanding both, metformin base and its hydrochloride salt, have low intestinal absorption in the colon and in the lower TG. In addition, the gastrointestinal adverse effects associated with metformin hydrochloride therapy, caused by the acid generated by salt ionization, often cause gastric disorders due to its prolonged use, all of these are inconveniences that can invalidate its use and have led to great number of studies and inventions having proposed new metformin salts, currently being an active field of development and innovation.

Among the salts that have been proposed in the literature, there is Belgian patent BE 568513 which discloses acid salts of metformin, including metformin hydrochloride; WO 03/068209 A1 patent application disclosing salts with lipophilic acids, such as laurate and palmitate; US patent application 2005/0158374, which describes the use of metformin associated with fatty acids which, it is argued, shows an improved absorption in the lower TG. In this patent application metformin is associated with fatty acids, such as laurate, succinate, caprate, oleate or palmitate, complexes that were created to increase the association in the lower TG, which facilitates greater absorption throughout the entire TG.

Another document that is relevant to the state of the art in this area is the European patent EP 1039890 of Bristol-Myers Squibb, which concerns several salts of dicarboxylic acids with metformin, alone or in combination with other antidiabetic agents such as glyburide. The patent protects the salts of fumarate, succinate, and maleate. Other documents concerning metformin salts include US Patent 3, 174, 901 which discloses phosphate, sulfate, hydrobromide and salicylate salts; US Patent 4,835, 184 which refers to the p-chlorophenoxyacetate salt of metformin; FR 2320735 and FR 2037002 patents which disclose the salt of metformin pamoate; US Patent 3,957,853 describing the acetylsalicylate salt of metformin; patents DE 2357864 and DE 1967138 that disclose the salt of nicotinic acid with metformin and the patent JO 64008237 that discloses salts of hydroxy acids, including salts of hydroxyl acids. dicarboxylic aliphatics, such as mesotartaric, tartaric, mesoxalic and oxidized maleates. It can be seen that all these patents concern metformin salts with organic acids. Several additional patents and other studies on metformin salts can be found in the literature and in the patent databases. Recently, the international application WO 20099144527 (A1) called A New Metformin Glycinate Salt for Blood Glucose Control, concerning the new salt: metformin glycinate was submitted.

In the present invention two new metformin-based compounds were synthesized. In one, metformin was bound to sulfonylurea 1 - [4- [2- (3-ethyl-4- methyl-2-oxo-3-pyrrolin-1-carboxamido) ethyl] -phenylsulfonyl] -3- (4-methylcyclohexyl ) urea or 3- ethyl-2,5-dihydro-4-methyl-N- [2- [4 - [[[[(trans-4-methylcyclohexyl) amino] carbonyl] -amino] sulfonyl] phenyl] ethyl] - 2-oxo-1 H-pyrrole-1-carboxamide, generically called glimepiride. In the other compound metformin is bound to thiazolidinedione 5- [[4- [2- (5-ethyl-2-pyridinyl) ethoxy] benzyl] -2, 4-thiazolidinedione, or 5- [p- [2- ( ethyl-2-pyridyl) ethoxy] benzyl] -2,4-thiazolidinedione generically called pioglitazone.

These two new compounds were designed and synthesized and their intrinsic dissolution rates and solubilities were determined. The physicochemical properties showed that these new salts dissolve faster and were more soluble in water than commercially available precursors. In addition, a pharmaceutical composition consisting of controlled release tablets was formulated and developed. These new compounds offer better alternatives for the treatment of type II diabetes mellitus by performing high absorption and lessening uncomfortable adverse effects that are associated with metformin hydrochloride therapy.

BRIEF DESCRIPTION OF THE FIGURES

The preceding aspects and many of the advantages related to this invention will be more readily appreciated, if they become better. 12 000043

4

understood by reference to the following detailed descriptions, when taken in conjunction with the accompanying figures.

FIGURE 1. SYNTHETIC DIAGRAM FOR THE REACTION OF METFORMIN AND GLIMEPIRIDE.

FIGURE 2. SYNTHETIC DIAGRAM FOR THE REACTION OF METFORMIN AND PIOGLITAZONE.

FIGURE 3. TF-INFRARED SPECTERS FOR A) METFORMIN, B) GLIMEPIRIDE, C) METFORMIN GLIMEPIRIDATE. THE ABSORPTION SIGNS FOR C) CORRESPOND TO THE EXPECTED STRUCTURE OF THE INVENTED COMPOUND REPRESENTED IN THE DIAGRAM OF FIGURE 1.

FIGURE 4. A) NUCLEAR MAGNETIC RESONANCE (NMR) SPECTRUMS OF HYDROGEN AND B) NMR SPECTERS OF C-13, OF THE NEW METFORMIN GLIMEPIRIDATE COMPOUND. THE ALLOCATION OF THE DISPLACEMENTS CORRESPONDS WITH THE EXPECTED STRUCTURE, WHICH IS REPRESENTED IN THE DIAGRAM OF FIGURE 1.

FIGURE 5. MASS SPECTERS FOR METHFORMINE GLIMEPIRIDATE (PM 619.79) OBTAINED BY TECHNIQUES A) FAB ^" AND B) FAB ⁺ , WHERE IT CAN BE APPRECIATED THAT THE MOLECULAR ION OF THE CATION (FAB ⁺ ) IS FOUND AT 130 (M + 1) / Z, AND WHERE THE MOLECULAR ION OF THE ANION (FAB) IS IN 489 (M-1) / Z.

FIGURE 6. ENDOTHERMES DETERMINED BY DIFFERENTIAL SWEEPING CALORIMETRY (CBD) FOR A) METFORMIN (START POINT OF THE FUSION 1 17.08 ° C), B) GLIMEPIRIDE (START POINT OF THE FUSION 208.65 ° C), AND C) METHYLMORMIRIDATE GLIMEPIRIDATE (START POINT OF THE FUSION 95.49 ° C).

FIGURE 7. COMPARISON OF THE NMR SPECTRUM OF CARBON POWDER-13 FOR A) METFORMIN, B) GLIMEPIRIDE AND C) METFORMIN GLIMEPIRIDATE. THIS LAST SPECTRUM INDICATES THAT EFFECTIVELY A NEW COMPOUND DIFFERENT FROM PRECURSOR COMPOUNDS.

FIGURE 8. COMPARISON OF THE X-RAY DIFRACTION SPECTRUM FOR A) METFORMIN, B) GLIMEPIRIDE AND C) METFORMIN GLIMEPIRIDATE, WHICH INDICATES THAT A NEW COMPOUND HAS BEEN FORMED DIFFERENTLY FROM RAW MATERIALS. FIGURE 9. MONOCRISTAL X-RAY DIFFACTION OF THE NEW METFORMIN GLIMEPIRIDATE COMPOUND.

FIGURE 10. ORTEP DRAWING OF THE MONOCRISTAL X-RAY DIFFACTION OF THE NEW METFORMIN GLIMEPIRIDATE COMPOSITE REPRESENTED IN ELIPSOIDS.

FIGURE 1 1. TF-IR SPECTERS FOR A) METFORMINE, B) PIOGLITAZONA, C) METFORMIN PIOGLITAZONATE. THE ABSORPTION SIGNS FOR C) CORRESPOND TO THE EXPECTED STRUCTURE OF THE NEW COMPOUND.

FIGURE 12. A) PROTON NMR AND B) ³ C NMR OF METFORMIN PIOGLITAZONATE. THE ALLOCATION OF THE DISPLACEMENTS CORRESPONDS WITH THE EXPECTED STRUCTURE.

FIGURE 13. MASS SPECTROS FOR METFORMIN PIOGLITAZONATE (PM 485.62) OBTAINED BY TECHNIQUES A) FAB ^" AND B) FAB ⁺ , WHERE IT CAN BE APPRECIATED THAT THE MOLECULAR ION OF THE CATION (FAB ⁺ ) IS FOUND AT 130 (M + 1) / Z, AND WHERE THE MOLECULAR ION OF THE ANION (FAB) IS IN 355 (M-1) / Z.

FIGURE 14. ENDOTHERMES DETERMINED BY CBD FOR A) METFORMIN (START POINT OF THE FUSION 1 17.08 ° C), B) PIOGLITAZONE (START POINT OF THE FUSION 180.33 ° C), and C) METFORMINE PIOGLITAZONATE (START POINT OF THE FUSION 183.53 ° C).

FIGURE 15. COMPARISON OF THE ¹³ C NMR SPECTRUM OF POWDER FOR A) METFORMIN, B) PIOGLITAZONE AND C) METFORMINE PIOGLITAZONATE, WHOSE DIFFERENCES INDICATE THAT C) CORRESPONDS WITH A DIFFERENT COMPOUND TO PRECURSORS.

FIGURE 16. COMPARISON OF THE X-RAY DIFRACTION SPECTRUM FOR A) METFORMIN, B) PIOGLITAZONE AND C) METFORMIN PIOGLITAZONATE, WHICH INDICATES THAT A NEW COMPOUND DIFFERENTLY RAWED FROM THE RAW MATERIALS.

FIGURE 17. MONOCRISTAL X-RAY DIFFACTION OF THE NEW METFORMIN PIOGLITAZONATE COMPOUND

FIGURE 18. UNIT CELL ORTEP SIGN OF THE MONOCRISTAL X-RAY DIFRACTION OF THE NEW METOFORMINE PIOGLITAZONATE COMPOSITE REPRESENTED IN ELIPSOIDS. FIGURE 19. INTRINSECA DISSOLUTION SPEED OF THE NEW METROFORMINE GLIMEPIRIDATE COMPOUND IN WATER USING TABLETS WITH DIFFERENT COMPRESSION FORCE. THE GLIMEPIRIDE PRECURSOR IS PRACTICALLY INSOLUBLE IN WATER.

FIGURE 20. INTRINSECA DISSOLUTION SPEED OF METFORMINE PIOGLITAZONATE, COMPARED TO THE PIOGLITAZONA CHLORIDE HYDROCHERED SALT. OF THESE DATA IT IS APPRECIATED THAT IN NEW WATER THE NEW SALT HAS A GREATER SPEED OF DISSOLUTION INSTRUMENTS THAT COMMERCIAL SALT, WHICH IS PRACTICALLY INSOLUBLE IN WATER. IN THE MIDDLE ACID 0.1 N THE PIOGLITAZONA CHLORIDEHYDRATE SALT IS 20 TIMES MORE SOLUBLE THAN THE NEW COMPOUND

FIGURE 21 FAR MACOC I ETI CAS IN HEALTHY VOLUNTEERS OF COMMERCIAL TABLETS OF IMMEDIATE RELEASE WITH 850 MG OF METHFORMINE CHLORIDEHYDRATE (GLUCOPHAGE, MARK OF MERCK) AND OF COMMERCIAL TABLETS OF CONTROLLED LIBERATION (DABEX XR, MARK OF LABORATORY MERCK. IN THE FIGURE IT CAN BE OBSERVED THAT FOR THE FIRST 6 HOURS THERE IS MUCH MORE ABSORPTION OF METFORMIN FROM THE IMMEDIATE RELEASE TABLETS AND THAT AFTER THAT TIME BOTH TYPES OF TABLETS MAINTAIN BIODISPONIBILITIES.

FIGURE 22. DISSOLUTION PROFILE OF A CONTROLLED RELEASE NUCLEUS, WITH 500 MG OF METFORMIN CLOHYDRATE DEVELOPED IN THE PRESENT INVENTION, COMPARED TO THE DISSOLUTION PROFILES OF PREDIAL PLUS TABLETS (REGISTERED TRADEMARK OF SILANEX LABORATORIES) REGISTERED MARK OF MERCK LABORATORIES).

FIGURE 23. DISSOLUTION PROFILE OF A CONTROLLED RELEASE NUCLEUS WITH 500 MG OF METHFORMINE CHLORHYDRATE DEVELOPED IN THE PRESENT INVENTION. THIS NUCLEO WAS COVERED WITH A LAYER OF THE NEW METFORMIN GLIMEPIRIDATE SALT. THE NUCLEUS DISSOLUTION PROFILE IS COMPARED TO THAT OF GLIMETAL LEX COMMERCIAL TABLETS (TRADEMARK OF SILANES LABORATORY) AND DABEX XR (MERCK LABORATORY TRADEMARK).

FIGURE 24. PHARMACOCINETICS IN HEALTHY VOLUNTEERS OF A NUCLEO WITH 850 MG OF METHFORMINE CHLORHYDRATE, MANUFACTURED ACCORDING TO THE PROCEDURE INDICATED IN EXAMPLES 3,4 AND 5, AND IN WHICH IT CAN BE OBSERVED THAT THE NEW FORMULATION ALLOWS THE RELEASE OF THE MEDICATION LESS 12 HOURS, WHAT REPRESENTS 4 HOURS MORE THAN THOSE ACHIEVED BY COMMERCIAL DRUGS AVAILABLE IN THE MARKET.

FIGURE 25. DISSOLUTION PROFILE OF THE IMMEDIATE RELEASE COVERING CONTAINING THE NEW METHFORMINE GLIMEPIRIDATE SALT (IN AN AMOUNT EQUIVALENT TO 2 MG OF GLIMEPIRIDE), AND WHICH COVERED TO A CONTROLLED RELEASE CORE AS IS AND DESCRIBED IN FIGURES 22 AND 23 THIS PROFILE IS COMPARED TO THE DISSOLVING PROFILES OF THE COATING OF PROLONGED LIBERATION TABLETS, GLIMETAL LEX WITH 2 MG AND GLIMETAL LEX WITH 4 MG (REGISTERED TRADEMARKS OF SILAN LABORATORIES), AND WHERE IT CAN BE APPRECIATED THAT OUR PERFORMANCE DISSOLUTION

FIGURE 26. DISSOLUTION PROFILE OF THE IMMEDIATE RELEASE COVERING CONTAINING THE NEW METFORMIN PIOGLITAZONATE SALT (IN AN AMOUNT EQUIVALENT TO 15 MG OF PIOGLITAZONE) AND COVERING A CONTROLLED RELEASE NUCLEUS AS DESCRIBED IN FIG. 22 AND 23. THIS PROFILE IS COMPARED TO THE DISPOSAL PROFILES OF COMMERCIAL TABLETS OF THE ZACTOS MEDICINAL PRODUCT CONTAINING PIOGLITAZONA CHLORIDE HYDROGATE (REGISTERED TRADEMARK OF ELI LILLY) AND WHERE IT CAN BE OBSERVED THAT THE SALT OF THE PRESENT INVENTION MAKES A SIMILAR TO BE DISSOLVED.

DESCRIPTION OF THE INVENTION

The purpose of the present invention is to develop two new metformin compounds, without the obvious disadvantages of existing commercial salts. According to the synthetic scheme shown in Figure 1, one of the new compounds was synthesized from metformin and glimepiride precursors. Spectroscopic and other physicochemical evidence on the structure of this new compound are shown in Figures 3 through 10. Particularly, Figure 9 shows the monocrystalline X-ray diffraction of the new metformin glymepiridate molecule and where It can be seen that the existence of ionic interactions and hydrogen bonds simultaneously stabilize the crystal. An interesting aspect of this Figure 9 is that nitrogen on glimepiride, which transfers its acid proton to the base Metformin interacts directly with a neutral molecule of water through a hydrogen bond. Quantum chemical calculations using the Spartan 9 package (Wavefunction Inc., Irvine, CA. 92612, USA) show that the negative charge on nitrogen is partially delocalized to adjacent carbonyl and sulfonyl, which increases the acidity of the proton and facilitates the transfer to the organic base (metformin). In addition, this delocalisation of the charge favors that these groups can establish hydrogen bond interactions with the metformin cation itself and with other water molecules in a solid medium. In the same way, the intramolecular hydrogen bond formed by metformin with its own amine makes it possible to establish hydrogen bridge interactions with atoms of glimepiride and other neighboring atoms of the same metformin. Such systems, which simultaneously involve ionic interactions and hydrogen bond interactions are known in the literature as ionic co-crystals (Kin-Shan Huang, et al., J. Mater. Chem. 7 (5), 713-720 (1977 )). Other references in the literature concerning the conditions for the formation of co-crystals can be found in Crystal Growth and Design, 9, 1344-1352 (2009), 2881-2899 (2009) and 10, 1435-1442 (2010).

The second compound, whose synthetic scheme is shown in Figure 2, has as precursors metformin and pioglitazone, the latter component being an important member of the thiazolidinediones family and also used as a first level treatment for patients with type 2 diabetes. Spectroscopic and physicochemical evidence of the structure of this new compound is shown in Figures 1 to 18. Particularly, Figure 17 shows the structure obtained by monocrystalline X-ray diffraction for this new compound. From this Figure 17 it can be seen that the molecule is stabilized by a combination of ionic attractions and hydrogen bridge interactions, the latter with carbonyl adjacent to the thiazolidinedionic ring nitrogen, which supports the charge of the acid proton transferred to metformin. Through quantum chemical calculations using the Spartan 9 package (Wavefunction, Inc., Irvine, CA. 92612, USA), it can be seen that the charge on nitrogen it delocals towards α-carbonyls, favoring the formation of hydrogen bonds with neighboring metformin molecules. In addition, as in the structure of the previously described compound, the positive charge on the metformin amine is partially neutralized by intramolecular hydrogen bonds established with neighboring amines (see Figure 17). Then, as in the case of the previous ionic co-crystal, the attraction between the molecules is further stabilized by hydrogen bonds allowing the formation of an ionic co-crystal (Kin-Shan Huang, et al., J. Mater. Chem. 7 (5) , 713-720 (1997)).

In the design of new drugs, a first strategy to increase the absorption of an active substance is to increase the rate of intrinsic dissolution and solubility, physicochemical characteristics that are essential for drugs to spread to the surface of the membrane, where they can be absorbed As the solubility increases, the concentration of a compound in solution in the membrane surface increases reaching better absorption (EH L. Kerns and D, Drug-Like Properties:.. Structure Design Concepts and Methods, Ed 1, Elsevier, 2008, page 9). This phenomenon can be explained by analyzing the cellular properties of the upper and lower TG, which are different. In addition, the polar characteristics of the active ingredients must be taken into account since, for example, polar molecules are easily dissolved in the upper Gl tract where a large surface for drug absorption exists, but not in the lower TG . In the inferior TG or colon, the microvello present in the superior TG is lacking. The presence of the microvello greatly increases the surface for the absorption of the active substance; for example, in the upper TG there is a surface 480 times the surface of the colon. Then, the form and place of absorption is important in deciding the polarity of the active substance and the characteristics of the pharmaceutical preparation. The individual epithelial cells form a cell barrier along the small and large intestines, which are separated from each other by water channels between the tight joints of the cells. Transport through the epithelium occurs through a path transcellular and a paracellular path (using either of them or both paths simultaneously). The transcellular path for transport involves movement of the compound through the wall and body of the epithelial cell by passive diffusion or by carrier-mediated transport. The paracellular path involves the movement of molecules through tight joints between individual cells. Paracellular transport is less specific but has a much greater total capacity because it takes place throughout the TG. However, tight joints vary along the TG, with the duodenum in the upper TG being more permeable than the jejunum and more permeable than the ileum; while the colon in the lower Gl tract is the least permeable (Knauf, H. et al., Klin. Wochenschr. 60 (19), 1 191-1200 (1982). Then, considering that the typical residence time of a medication in the upper TG is about four to six hours, after oral ingestion, medications that have poor absorption in the colon only have this time to be absorbed.In this case, any medication not absorbed during this time will be expelled. of the body.

Concerning the developments of the present invention, glimepiride is in itself practically insoluble in water (0.19 mg / 25 mL), but when bound to metformin its solubility increases to 0.3 mg / mL which can improve its bioavailability. In addition, the new metformin glimepiridate compound shows a higher intrinsic dissolution rate than commercially available glimepiride (Figure 19), a property that is usually associated with a faster therapeutic response. In the case of diabetes, this property is highly relevant, since the response time for the control of glucose peaks or sudden hyperglycemias caused by ingestion of food or metabolic imbalances is so crucial, that it can be the cause of life or death. in patients with advanced diabetes. The second metformin pioglitazonate compound also shows a higher intrinsic dissolution rate (Figure 20) and better water solubility (1.33 X 10 ^{~ 3} mg / mL) than pioglitazone, which is "practically insoluble" in water ( see Index Merck, 40 ^a Edition). Then it is expected that, as in the case of the previous compound, metformin pioglitazonate also shows a faster response to blood glucose imbalances and that, given its greater solubility, a greater absorption in the upper TG is achieved. Current therapy with metformin has proven to be less than optimal, since it is associated with a high incidence of gastrointestinal side effects. In addition, the active substance is commonly administered at high doses (as oral tablets) two or three times a day to achieve an effective treatment that lowers glucose. The side effects associated with these metformin levels are the occurrence of gastrointestinal reactions such as diarrhea, nausea, vomiting, abdominal inflammation, flatulence and anorexia. These reactions occur with approximately 30% of patients when compared to subjects treated with placebo, particularly at the initiation of metformin administration (US patent 6451808). In addition, the reactions are dose related and the method of controlling these reactions includes reducing the dose and gradually escalating the dose or taking the medication along with food. However, in severe cases dehydration and pre-renal azotemia can occur and many subjects undergoing metformin therapy are forced to discontinue the use of the drug (US Patent 6,451, 808). Based on the improved physicochemical properties of the new compounds synthesized in the present invention, greater bioavailability is expected allowing the dose to be reduced, which will decrease the adverse gastric effects. In addition, considering that the ionization of the components of our new compounds does not produce the hydrochloride ion, generated by the dissolution of commercial salts of metformin, this will be of great help to avoid gastric disorders. In the case of metformin glimepiridate, the dissociated counter-glymepiridate is a weak acid and in the case of metformin pioglitazonate, the ion released is the weak acid pioglitazonate. Furthermore, in commercial combinations containing, for example, the salts of pioglitazone hydrochloride and metformin hydrochloride (physical mixtures), each component releases ions hydrochloride causing strong gastrointestinal effects. So, in our case, having active ingredients with reduced side effects is undoubtedly a collateral benefit of the nature of our compounds.

A common medical practice, when blood glucose regulation is no longer possible with the use of a single active substance, is to prescribe the simultaneous use of two medications. In general, the medical strategy is to add an additional medication, such that by a complementary mechanism the regulation of blood glucose of the diabetic patient can be achieved. A frequent prescription is to prescribe the commercial salt metformin a) at the same time as a sulfonylurea such as glimepiride or the commercial salt metformin together with a commercial thiazolidinedione, such as pioglitazone hydrochloride. In our case, it is expected that a single active ingredient will act against diabetes through two complementary mechanisms. On the one hand there is the mechanism of action of metformin, which as mentioned above consists in its ability to prevent the desensitization of human pancreatic islets, which is usually induced by hyperglycemia. As a result of this action, both fasting glucose is decreased and after eating food, HbA-i _{c levels} and lipid profile are decreased. Metformin increases the sensitivity of both liver and peripheral tissue (primary muscle) to insulin. It does not increase lactate production beyond what other biguanides do, such as fenformin and so lactic acidosis associated with metformin use is rare (reported incidence of 0.03 / 1000 patient-years of exposure). Metformin reduces glucose levels by decreasing liver glucose output by inhibiting gluconeogenesis and glycogenolysis. To a lesser degree this medication increases the action of insulin in peripheral tissues and reduces the absorption of glucose in the intestine. On the other hand, sulfonylurea glimepiride primarily increases insulin secretion. This action is initiated by binding to and closing an ATP-sensitive pancreatic channel to K + β cells. When closing decreases the entry of K + leading to membrane depolarization and activation of a voltage dependent Ca ²⁺ channel. The resulting increase in Ca ²⁺ flow in β cells activates a cytoskeleton system that causes insulin translocation to the cell surface and its expulsion by exocytosis (US Patent 6,693094). These two complementary mechanisms are simultaneously operated by the components of the new compound reported in the present invention 1- [4- [2- (3-ethyl-4-methyl-2-oxo-3-pyrroline-1- carboxamido) ethyl ] - N, N-dimethyldiguanide or 3-ethyl-2,5-dihydro-4-methyl-N- [2- [4 - [[[[(trans-4] -phenylsulfonyl] -3- (4-methylcyclohexyl) ureate -methylcyclohexyl) amino] carbonyl] - amino] sulfonyl] phenyl] ethyl] -2-oxo-1 H -pyrrol-1-carboxamidate of N, N-dimethyldiguanide or generic name metformin glymepiridate and which was one of the purposes of the present invention

The first history of the simultaneous use of the glimepiride and metformin components in a fixed relationship are the reports of G. Charpentier using two different medications (see for example G. Charpentier, Improved Glycaemic Control by Addition of Glimepiride to metformin Monotherapy in Type 2 Diabetic Patients , Diabetic Medicine 18, 828-834 (2001)). The combined use of metformin and glimepiride has additional advantages over other combinations, such as metformin and glibenclamide, since scientific reports have shown that the first combination does not induce hypoglycemia that can trigger an irreversible decompensation in diabetic patients (M. Gonzalez-Ortiz et al. Diabetics and its Complications, 23, 376-379, (2009)). The first pharmaceutical laboratory to offer in a single tablet the combination (physical mixture) of metformin hydrochloride and glimepiride was the Mexican laboratory Silanes, who patented the combination and owns EP 1482919 patents in Europe, MX 248,617 in Mexico and 10 / 502,403 in the United States. The patents were granted because it was demonstrated with clinical studies that this combination triggered a synergistic effect, with important advantages compared to the separate use of both active ingredients. Now, with the present invention, a new active ingredient is developed further with the added properties of showing a better solubility and a faster intrinsic dissolution rate than commercial salts, properties that may have a favorable impact on the bioavailability and efficacy of the drug (Edgard H. Kems & Li Di, Drug-like properties, concepts, structure, design and methods. From ADME to Toxicity Optimization, Academia Press / Elsevier, 2008).

The second compound invented 5 - [[4- [2- (5-ethill-2-pyridinyl) ethoxy] benzyl] -2,4-thiazolidinedionate of Ν, Ν-dimethyldiguanide or 5- [p- [2- (ethyl- 2-Pyridyl) ethoxy] benzyl] -2,4-thiazolidinedioneate, Ν-dimethyldiguanide, generically called metformin pioglitazonate also has the advantage that being a monopharmaceutical, it can act through two simultaneous mechanisms. First through the mechanism of metformin, previously described and second, through the mechanism of pioglitazone itself. This counterion acts by increasing insulin sensitivity, which is why it is called insulin resistance blocker (WO 9857634). This unblocker acts by normalizing the damaged function of the insulin receptor and normalizing the uneven distribution of glucose transporters in cells, systems associated with glucometabolism. As a result, insulin resistance is unlocked by improving glucose tolerance and decreasing plasma concentrations of neutral lipids and free fatty acids (EP patent 17641 10 A1). In animal models, with type II diabetes, pioglitazone decreases hyperglycemia, hyperinsulinemia and hypertriglyceridemia, which are characteristic metabolic alterations of insulin resistance states similar to that observed in type II diabetes. It has been reported that in combination with metformin, pioglitazone provides a particular beneficial effect on glycemic control with no observed side effects. Therefore, such a combination is particularly useful for the treatment of type II diabetes mellitus and associated conditions (WO 9857634). The importance of the physical mixture of pioglitazone with metformin is highlighted in an international patent of the Takeda company of Japan (US Patent 5,952, 356). However, this combination does not show a synergistic effect as observed in the case of the combination of metformin with glimepiride. However, as described above, the importance of the combination is that for patients who do not respond to the use of only one of the medications (monotherapy), the combination allows adequate regulation of blood glucose. The new compounds of the present invention must show the combined effect of each of the components.

In the design of new drugs, a second strategy to increase the absorption in the TG of the new compounds may be by adjustment or development of the appropriate pharmaceutical composition (eg immediate release tablets, controlled release, etc.) that optimizes bioavailability. of the medication Metformin is an active substance with poor absorption in the colon (Marathe, P. et al., Br. J. Clin. Pharmacol., 50, 325-332 (2000)). Consequently, the commercial salt, metformin hydrochloride, has an intrinsic poor permeability and poor absorption in the lower TG or colon, leading to the absorption being almost exclusively in the upper part of the TG. Consequently, it was convenient for our compounds to design a rapid disintegration of the new oral solid medicine, to take advantage of the dissolution rates and improved solubilities of the invented active ingredients, to be absorbed in the upper TG. This pharmaceutical composition should facilitate a greater absorption of the active ingredient during the four to six hours that it will reside in the upper TG (WO 03/068209 A1). This strategy, in addition to the previously described strategy of improving the polarity of the active substance, should allow a greater amount of metformin glimepiridate or metformin piogiitazonate to be completely dissolved in the upper TG and greater absorption (EH Kerns and L . Di, drug-like Properties: Concepts, Structure, Design and Methods, Ed Elsevier 1, 2008)..

A pharmacokinetic curve of commercially released metformin hydrochloride of 850 mg is shown in Figure 21. (Glucophage, brand of Merck laboratories; data partially taken from US Patent 6,866, 866 of March 15, 2005). These data were determined in 12 healthy volunteers, and where it can be seen that effectively the absorption time of metformin is around 6 hours, which corresponds to the estimated residence time in the superior TG referred to above (US patent application 2005/0158374 A1). Figure 21 also shows a bioavailability curve of metformin hydrochloride, from a 850 mg commercial extended-release tablet (Dabex XR, brand of Merck laboratories), determined in healthy volunteers. With this prolonged-release tablet it is appreciated that plasma levels of 500 ng / ml metformin are reached approximately 30 minutes after those reached with the immediate-release caplet. The concentration of 1400 ng / ml is reached by the controlled release caplet about 2 hours after that reached with the immediate release caplet and the concentration of 1450 ng / ml is reached with the controlled release caplet about 3 hours later than with the capleta of immediate release. This concentration of 1450 ng / ml is the C _max of the controlled release caplet. That is, the C _max of the controlled release caplet is about 750 ng / ml lower than that achieved by the immediate release caplet. It can also be seen that the area under the curve is approximately 30% smaller than the immediate release caplet. In conclusion, this means that with the controlled release caplets smaller amounts of active substance are absorbed than with the immediate release caplets. After 6 hours, once the granules of the caplets are outside the upper TG, the released metformin is only metabolized and / or expelled from the body without any benefit to the patient. Consequently, probably all extended-release formulations of metformin hydrochloride, as shown for Dabex XR, does not provide a real benefit to patients, compared to that of immediate release caplets, which provide more active substance, to be absorbed during the six hours that the granules remain disintegrating in the upper Gl tract (see Figure 22). Metformin doses are commonly between 500 mg and 850 mg (although in many cases it is prescribed up to 3 grams). The usual doses of glimepiride are between 2 mg and 4 mg every 24 hours and the usual doses of pioglitazone are between 15 mg and 30 mg. The stoichiometric proportion of metformin with the glimepiride or pioglitazone counterions in the new salts is 1: 1, indicating that the required doses of metformin are much higher than the doses of glutamine or pioglitazone. Because of this, suitable pharmaceutical compositions were formulated to provide adequate doses of both components, designing a controlled release core or matrix with the usual dose of metformin hydrochloride (eg 500 mg) and an immediate release layer or coating containing the new active substance (where appropriate, the amount of metformin contained in the new active ingredients can be subtracted from this nucleus to adjust exactly to 500 mg the total amount of metformin in the caplet). In the case of the new metformin glymepiridate ionic co-crystal, the nucleus or matrix must contain 499,474 mg of metformin hydrochloride, which is coated with a layer of metformin glimepiridate containing an amount equivalent to 2 milligrams of glimepiride (see Table 2, in example 3, below). For the metformin pioglitazonate compound the tablet core should contain 494,565 mg of metformin hydrochloride coated with an immediate release layer containing metformin pioglitazonate in an amount equivalent to 15 mg of pioglitazone (see Table 3, in Example 4, then).

A pharmacokinetic study was carried out of the extended-release core developed in the present invention (examples 3,4 and 5), containing 850 mg of metformin hydrochloride, in a single dose in 15 healthy volunteers. This core was coated with an inert layer of polyvinyl acetate SR 30D and Opadry II (see examples 3,4 and 5). The average results obtained when healthy volunteers were subject to conditions of not eating food are shown in Figure 24. The average Cmax (+/- SD, n = 15) was 1,770 ng / mL and the area under the curve was 1 7450 ng-hrs / m L. From these data it is concluded that with the formulation developed in the present invention plasma concentrations of metformin are achieved that are maintained at concentrations greater than 750 ng / mL for a period of about 12, which is 4 hours more than with Dabex XR (brand of Merck, Inc.), which was the reference medicine).

The dissolution profile of a central core of metformin hydrochloride is shown in Figures 23 and 24, compared to the dissolution profiles of commercially available extended-release tablets. In Figure 23 it is compared with Dabex XR (brand of Merck Inc.) and Predial Plus (brand of Silanes laboratories). In Figure 24 it is compared with the commercial drug Glimetal-Lex (Silanes laboratory brand) which is constituted by a central core of metformin hydrochloride coated by a layer containing glimepiride in two doses 2 mg or 4 mg. In addition, the Dabex XR profile is maintained as a reference. The dissolution behavior of our core is very similar to that of commercial salts.

Figure 25 shows the dissolution profile of the immediate-release coating containing the new metformin glimepiridate ionic cochstal, in a concentration equivalent to 2 mg of glimepiride. This coating is the layer on the central core of controlled release of metformin chlorhydride. The profile is compared (see Fig. 25) with commercial tablets of Glimetal Lex (brand of Silanes laboratories) containing the doses of 2 mg and 4 mg of glimepiride. It can be seen that our ionic co-crystal dissolves faster and in greater quantities than that of the reference compounds.

Figure 26 shows the dissolution profile of the immediate release coating of the layer containing the new metformin pioglitazonate ionic co-crystal, in an amount equivalent to 1.5 mg of pioglitazone The profile is compared with commercial tablets of the drug Zactos (brand of Eli Lilly, Inc.).

The synthetic process of each of the invented compounds, outlined in Figures 1 and 2, is described below. In addition, the formulation and manufacturing techniques of the core or matrix of the controlled-release caplets, as well as those of the coatings, are provided immediate release containing the new ionic co-crystals

EXAMPLES

Example 1. Synthesis Process for the manufacture of the New Metformin Glimepiridate Salt.

In a 500 ml round bottom flask 64 ml of ethanol are added and cooled to -100 C under nitrogen atmosphere. Then, 16 g (296 mmol) of sodium methoxide (97% purity) are poured into the bottle and 46.6 g (281 mmol) of metformin hydrochloride are added. The resulting suspension is stirred for 40 minutes and the flask is allowed to reach room temperature. The resulting suspension is filtered and washed with 30 ml of methane! The solid filtrate, solid chloride, is separated and the methanolic solution is concentrated by evaporation in vacuo crystallizing a white solid, which corresponds to the crude base metformin.

Metformin base (23.16 g, 179 mmol) was dissolved in 82 ml of ethanol in an erlenmeyer flask. To this flask were added 80 g (163 mmol) of glimepiride in portions. The suspension was heated between 50 ° C and 55 ° C and stirred until the solids were completely dissolved. To this solution was added 1.4 L of ethyl acetate and the solution was stirred for 6 hours, producing a new suspension. This suspension was filtered and the powder was washed with 60 ml of ethyl acetate and dried under vacuum at 60 ° C. Raw metformin, 81 g, was obtained as a white powder with a very low density. The corresponding performance of this process was 79%.

The crude material was crystallized according to the following procedure: 81 g of crude metformin glimepiridate were dissolved in 60 ml of ethanol (96%) in a 3 L erlenmeyer flask. This suspension was heated to 70 ° C and stirred until the solids were completely dissolved. Then, 1.9 L of ethyl acetate were added slowly and the resulting solution was stirred for 16 hours, producing a white suspension. This suspension was filtered and the powder was washed with 100 ml of ethyl acetate and dried under vacuum at 60 ° C. The yield of this compound was 78% (60.8 g).

The product obtained was analyzed by different techniques. Figure 3 shows the spectrum of TF-infrared compared to that of the precursors metformin and glimepiride. The absorption bands observed correspond to that of the expected structure (See Figure 1), being the most characteristic, on the metformin cation those located at 3381 cm ^' , 3254 cm ^"1 , 3168 cm ^{" 1} corresponding to the "stretching" of the NH of the different amines and on the glimepiridate anion the absorption bands in 1703 cm ^"1 and 1655 cm ^{" 1} of the carbonyls and the band in 1275 cm ^"1 are assigned to the sulfonamide also of the glimepiridate. Figure 4 shows the respective spectra of nuclear magnetic resonance (NMR) of H ⁺ and C ³ , whose displacements could be assigned to the expected structure. Figure 5 shows the mass spectra obtained by the techniques FAB ⁺ and FAB ^" , and in which it can be observed that the molecular ion of FAB ⁺ is at 130 m / z, which corresponds to (M + 1) of the metformin cation and that the molecular ion of FAB ^' is at 489 m / z, which corresponds to (M-1) of the glimepiridate anion, results that confirm the assigned structure to. Figure 6 shows the endotherms determined by differential scanning calorimetry for A) metformin (melting start at 1 7.08 ° C), B) glimepiride (melting start at 208.65 ° C) and C) metformin glymepiridate (melting start at 95.49 ° C), very low value and which was identified by thermogravimetric analysis (TG / DTA) which corresponds to the loss of a water molecule. The fact that there is only one endotherm, with onset of the melting point ("onset") at 95.49 ° C, can be explained considering that once the crystallization water is released, which is essential to maintain the crystalline structure, the crystal loses stability and it is possible that then it adopts an amorphous form, which lacks a melting point and that therefore does not generate endotherms or, it may be possible that once the water is released, the ionic co-crystal assisted by hydrogen bonds is transformed into a common salt This would coincide with the results obtained by DSC / DTA where, after the loss of water around 96 ° C, another mass loss is seen at 139.9 ° C after which a decomposition occurs at 250 ° C. This decomposition can also observed in the DSC where an exotherm appears around 140 ° C. This decomposition could be attributed to anyone, either to the assumed amorphous form or to common salt. By melting a sample of this co-crystal in a Fisher-Jones apparatus it was observed that water is lost around 97 ° C, which is manifested by a liquefaction of the sample and in the temperature range of 145 ° C to 250 ° C a color change from pale brown to brown is observed.

Figure 7 compares the ¹³ C NMR spectrum of powders of the new compound with that of the precursors and where it can be seen that the spectrum of the co-crystal is clearly different from that of the raw materials, indicating that it is a new structure, different to that of raw materials or to a physical mixture. In Figure 8 the X-ray diffraction pattern of powders of the synthesized compound is compared with that of the precursors and where it can be seen that the spectrum is clearly different, indicating that it is a molecular structure different from that of the raw materials or of a physical mixture. Figure 9 shows the structure of the new compound obtained by monocrystalline X-ray diffraction and which shows that the structure is stabilized by ionic attractions and hydrogen bond interactions and where a neutral water molecule participates in the stabilization of the molecule. These types of compounds are referred to in the ionic co-crystals literature (Kin-Shan Huang et al. J. Mater. Chem. 7 (5), 713-720 (1997)). Figure 10 shows the unit cell of the ionic cocristal in ellipsoidal representation and Table 1 shows the crystalline data and structural parameters obtained in the monocrystalline X-ray diffraction. All these data corroborate that the expected structure of this new salt corresponds to that shown in Figure 1 and that the solid form of the new compound corresponds to the metformin glymepiridate ionic co-crystal.

Example 2 Synthesis Process for the Manufacture of the New Metformin Pioglitazonate Salt.

A 500 ml round bottom flask was loaded with 64 ml of ethanol and cooled to -1 00 C under nitrogen atmosphere. Then, 1 6 g (296 mmol) of sodium methoxide (97% purity) was poured into the bottle and 46.6 g (281 mmol) of metformin hydrochloride were added and the resulting suspension was stirred 40 minutes. During this time the flask was allowed to reach room temperature. The resulting suspension was filtered and washed with 30 ml of methanol. The solid filtrate, solid chloride, was separated. The methanolic solution was transferred to a 2L erlenmeyer flask, to which 80 g (224 mmol) of pioglitazone was added slowly, over a period of 1 hour, forming a viscous solution difficult to stir. To this, 1 06 μL of methanol was added dropwise, stirring the solution for 1-5 minutes. 600 ml of isopropanol was added to the resulting suspension. Then, the solution was cooled to 0 ^o C and left with stirring an additional 1 hour before it was filtered and the product washed with 50 ml of isopropanol. The white powder obtained was dried at 60 ° C for two hours and once dry it was weighed to obtain 89.6 g, which means 76% yield of crude product. The 89.6 g of crude product were dissolved in ethanol and left under reflux for 1 5 minutes, where 1.78 L of isopropanol were poured and cooled to 0 ^o C. Once small crystals are observed the suspension is left at rest for crystallization for 1.5 hours. Filter and the product is washed with 1 50 ml of isopropanol. It is dried under vacuum at 60 ° C for 2 hours and 68 g of a white powder are obtained which yields 76%. The total reaction yield is 62%.

The product obtained was analyzed by different spectroscopic and physicochemical techniques. Figure 1 1 shows the infrared TF-spectrum for the new compound, compared to that of metformin and pioglitazone precursors. The spectrum for the synthesized compound shows characteristic absorption bands for NH in the region between 3440 cm ^" and 3353 crrT ¹ , which would correspond to the amines of the metformin cation and the amine of the thiazolidinedinone ring of the pioglitazonate anion and the carbonyl of the ring amides thiazolidinedinone in 1691 cm ^"1 and 1675 cm ^{" 1} absorption bands corresponding to the structure shown in Figure 2. Figure 12 shows the NMR spectra of H ⁺ and C ³ and whose displacements could be assigned to the expected structure.

Figure 1 3 shows the mass spectrum for metformin pioglitazonate (PM = 485.62) obtained by the FAB ⁺ and FAB techniques. ^" From these spectra it can be seen that the molecular ion obtained by FAB ⁺ is at 130 m / z, which corresponds to the cation (M + 1) metformin and it can be seen that the molecular ion obtained by FAB ^" corresponds to the anion (M-1) pioglitazonate. In Figure 14 the endotherms determined by differential scanning calorimetry are compared for A) metformin (melting start at 1 17.8 ° C), B) pioglitazone (melting start at 180.33 ° C) and C) and metformin pioglitazonate (start melting at 183.53 ° C), which confirms that a new compound other than raw materials was obtained. Figure 1 5 compares the spectrum of ¹³ C NMR of powders of the compound synthesized with that of the precursors and where it can be seen that they are very different indicating that the new compound is a new structure, different from that of the raw materials or a physical mixture. In Figure 16, the X-ray powder diffraction pattern of the new compound is compared with that of the precursors, showing that the spectrum is clearly different, indicating that it is a different molecular structure from that of raw materials or a mixture physical. Figure 17 shows the structure of the new molecule obtained by the monocrystalline X-ray diffraction technique, which shows that the structure of the molecule is stabilized by ionic attractions and interacting by strong hydrogen bonds of the order of 7 kcal / mol. These energies were determined by quantum chemical calculations using the Spartan Package (Wavefunction, Inc. Irvine, CA. 92612, USA). In this case the structure is not stabilized by a neutral molecule, as in the case of water from the previous structure. These types of molecules stabilized by ionic attractions and hydrogen bridge type interactions are called ionic co-crystals (Kin-Shan Huang et al., J. Mater. Chem. 7 (5), 713-720 (1997). 18 shows the unit cell of the new co-crystal obtained by monocrystalline X-ray diffraction, in ellipsoidal representation, Table 1 shows the crystalline data and structural parameters obtained in the monocrystalline X-ray diffraction technique.

All these data corroborate that the expected structure of this new salt corresponds to that shown in Figure 2 and that in the solid form the new compound corresponds to the ionic co-crystalline metformin pioglitazonate.

Example 3 Formulation of Tablets Based on the New Metformin Glimepiridate Salt

Because the stoichiometric ratio of metformin and glimepiride in the new cocristal is 1: 1, the amount of metformin in the new The molecule is insufficient for the required doses, which are usually between 500 mg and 3 grams every 24 hours. Then, the tablet formulation was designed with a controlled release core or matrix with the required dose of metformin hydrochloride and with an immediate release coating layer, containing the new active ingredient in an amount equivalent to the required dose of glimepiride. .

The formulation of tablets, FORMULA 1, is described in Figure 28, consisting of a 500 mg controlled release core of metformin hydrochloride and an immediate release coating containing the new active substance metformin glimepiridate, in an amount equivalent to 2 mg of glimepiride Being rigorous, the amount of metformin contained in the new active ingredients can be subtracted from the amount contained in the extended release core or matrix, to adjust exactly to 500 mg the total amount of metformin in the tablet. However, the usual dose does not require a degree of accuracy of this nature, since it ranges from 500 mg to 3 grams, the dose being modified, depending on the patient's response to the medication).

Table 2. FORMULATION 1. Tablets Consisting of a Controlled Release Core, with 500 mg of Hydrochloride

Metformin and an Immediate Release Coating Containing Mimeformin Glimepiridate, in an Amount Equivalent to 2 mg of Glimepiride. WEIGHT/

FORMULA 1: COMPONENTS UNITS

(mg)

a) Metformin Hydrochloride Core 500.00

Microcrystalline Cellulose PH 301 30.00

Kollicoat SR 30 D ¹ 140.00

30% Dispersion 42.00

Hydroxypropyl methylcellulose 268.50

Colloidal Silicon Dioxide 3.00

Magnesium Stearate 6.50

SUBTOTAL WEIGHT 850.00

b) Core Coating

Kollicoat SR 30 D ¹ 15.00

30% Scatter 4.50

Purified Water 80.50

c) Coating with Hydrochloride 2.80

of Metformin ²

Opadry Blue 85F99160 41 .00

Purified Water 443.00

Polyethylene Glycol 6000 4.70

Purified Water 54.00

TOTAL WEIGHT 910.00

Kolliccoat SR 30 D. The dispersion consists of about 27 polyvinyl acetate, 2.7% povidone and 0.3% sodium laurel sulfate

10% excess glimepiride and 0.1 1% metformin hydrochloride are taken into account

Example 4. Formulation of Tablets Based on the New Metformin Pioglitazonate Salt As described in the previous example, the prescribed doses of metformin when used as a monopharmaceutical are between 500 mg and 3 grams, but in a combined dose it is usually recommended that you start with the minimum dose of metformin. However, this also depends on how advanced the disease is and the patient's response to treatment. The usual doses of pioglitazone are between 15 mg and 30 mg per day, in a combined regimen, but when pioglitazone is used as a single medication it is possible to use up to 45 mg every 24 hours.

Because in the new salt the stoichiometric ratio of metformin and pioglitazone is 1: 1, the amount of metformin is insufficient for the required doses. Then the tablet formulation consists of a controlled release core or matrix with the usual doses of metformin hydrochloride between 500 mg and 3 grams and with an immediate release coating containing 15 mg or 30 mg of pioglitazone.

Figure 29 describes the formulation of tablets, FORMULA 2, consisting of a controlled-release core of 500 mg of metformin hydrochloride and an immediate-release coating, containing the new active substance metformin pioglitazonate, in an amount equivalent to 15 Pioglitazone mg

Table 3. FORMULA 2, Tablets Consisting of a Core of

Controlled Release with 500 mg Metformin Hydrochloride and an Immediate Release Coating Containing

Metformin pioglitazonate, in an amount equivalent to 1.5 mg of Pioglitazone. WEIGHT/

FORMULA 2: UNIT COMPONENTS

(mg) a) Metformin Hydrochloride Core 500.00

Microcrystalline Cellulose PH 301 30.00

Kollicoat SR 30 D ¹ 140.00

30% Dispersion 42.00

Hydroxypropyl methylcellulose 268.50

Colloidal Silicon Dioxide 3.00

Magnesium Stearate 6.50

SUBTOTAL WEIGHT 850.00 b) Core Coating

Kollicoat SR 30 D ¹ 15.00

30% Scatter 4.50

Purified Water 35.00

Opadry Pink II 85F 14399 7.00

Purified Water 80.50

c) Coating with Pioglitazonate 22.50

of Metformin ²

Opadry Pink II 85F 14399 43.50

Purified Water 443.00

Polyethylene Glycol 6000 2.50

Purified Water 22.50

TOTAL WEIGHT 930.00

¹ KolliccoatSR 30 D. The dispersion consists of about 27% polyvinyl acetate, 2.7% povidone and 0.3% sodium laurel sulfate

² 10% excess glimepiride and 0.1 1% metformin hydrochloride are taken into account Example 5. Manufacturing Method of the Controlled Release Matrix of the Immediate Release Coating containing the New Salts a) Granulation Process to Form the Controlled Release Core of the Tablets.

First, all materials are passed through a mesh to make a homogeneous and suitable mixture. Subsequently metformin hydrochloride is mixed with microcrystalline cellulose! Ina PH 301 and passed through a 20 mesh. Then, this mixture is introduced into a "high cut" mixer to be homogenized for 2 minutes at 300 revolutions / minute (rpm) in the mixer and 1000 rpm in the blades. The mixture is granulated in a continuous manner by spraying the binding dispersion containing Kollicoat SR 30D at a spray rate of 24 grams / minute. After this operation the wet granulate is taken out of the high cut mixer and placed in a fluidized bed dryer with an inlet air temperature of 70 ° C to 90 ° C for 30 minutes or until the moisture of the granulated mixture is between 0.7% to 2.5%. The dried granules are milled with a Quadro Cornil mill, with a screen equivalent to a 20 mesh. The hydroxypropyl methylcellulose 2208 and the colloidal silicon dioxide are mixed with the granulate of metformin hydrochloride for 10 minutes, after which the stearate lubricant of Magnesium is added and mixed with the rest of the powders for 5 minutes. b) Compression Process of the Granulate For Formation of the Matrix or Tablet Core

The compression process was performed using a rotary tabletead with variable speed using concave punches. The feed rate and rotor speed were adjusted to obtain an appropriate weight for the tablet or caplet. c) Coating to Divide the Controlled Release Core of the Exterior Coating contained in the New Active Principle. Seal-coating 1

The core of the tablets are sealed-coated with the dispersion of Kollicoat SR 30D which is diluted with purified water and sprinkled on the tablet core using a "drum" coating under the following conditions: inlet air temperature 58 ° C at 65 ° C, outlet air temperature 40 ° C to 45 ° C, product temperature 38 ° C to 42 ° C, atomization pressure from 28 ° C to 30 lb / in ² and spray speed from 4 to 5 grams / minute

Seal-coating 2

A dispersion of opadry II was diluted with purified water and sprinkled on the tablet core using a coating “bass drum” under the following conditions: inlet air temperature 58 ° C to 65 ° C, outlet air temperature 40 ° C to 45 ° C, product temperature 38 ° C to 42 ° C, atomization pressure from 28 ° C to 30 lb / in ² and spray speed of 4 to 5 grams / minute. The tablet is coated with the sealing dispersion to reach a total of 1 1.5 mg / tablet. d) Immediate Release Coating Containing the New Active Principle In a dispersion of Opadry II in purified water, either of the two new active principles is poured. If the compound to be used is metformin glimepiridate, Opadry II is blue and if it is metformin pioglitazonate, Opadry II is pink. The dispersion is stirred for 10 minutes at 600 rpm until the dispersion appears homogeneous. An excess of 1.0% of the active compound is considered lost during the sprinkling step, so it is compensated. The conditions used for this step are the same operating conditions used for the previous spraying operations. Given the high solubility of the active ingredients, it is not necessary to use a surfactant compound to favor water solubility. In the last step an aqueous solution of polyethylene glycol 6000 is used to polish the tablets. This solution is sprayed on the tablet, under the same operating conditions used in the previous spray operations.

Claims

CLAIMS Having described the present invention it is considered that it meets the requirement of being an innovation, for which we claim the following.

1. The new chemical compound 1- [4- [2- (3-ethyl-4-methyl-2-oxo-3-pyrrolin-1- carboxamido) ethyl] -phenylsulfonyl] -3- (4-methylcyclohexyl) ureate N, N-dimethyldiguanide or 3-ethyl-2,5-dihydro-4-methyl-N- [2- [4 - [[[[(trans-4-methylcyclohexyl) amino] carbonyl] -amino] sulfonyl] phenyl] ethyl] -2-oxo-1 H-pyrrol-1-carboxamidate of Ν, Ν-dimethyldiguanide and which can generically be named metformin glymepiridate.

2. - In accordance with clause I, the metformin glimepiridate compound, characterized by the following physicochemical properties: a) An infrared TF spectrum with characteristic absorption bands at 3381 cm ^"1 , 3254 cm ^{" 1} , 3168 cm ^"1; in 1703 cm ^"1 ¡in 1655 cm ^{" 1} and in 1275 cm ^{~ 1.} B) A nuclear magnetic resonance spectrum of H ⁺ , with displacements in parts per million located at 0.81-0.83 with doublet; at 0.96-0 , 99 with triplet; in 1.59-1.61 with doublet; in 1.86-1.89 with doublet; in 2.01 with singlet; in 2.18-2.19 with quadruple!; In 2.49-2.51 with multiplet; in 2.80-2.87 with triplet; in 2.92 with singlet; with broadband singlet in 3.15; in 3.32 with singlet; in 3.46 with quadruplet; in 4.17 with singlet; with broadband singlet in 6.80; in 7.17-7.19 with doublet; in 7.61-7.63 doublet. c) A spectrum C ³ nuclear magnetic resonance imaging with displacements in parts per million located at 171.77; 159.06; 158.55; 151.9, 15 1.57; 145.62; 131.88; 126.28; 51.82; 37.30; 12.66; 12.75; 15.93, 22.19; 40.53; 31.54; 32.21; 33.87; 35.03. d) A mass spectrum obtained by the FAB technique ^" with a molecular ion at 489 m / z, and a mass spectrum obtained by the FAB ⁺ technique with a molecular ion obtained at 130 m / z. e) A thermogram obtained by differential scanning calorimetry, with an endotherm whose fusion start is located at 95.49 ⁰ C f) A ³ C nuclear magnetic resonance spectrum of powders with displacements in ppm at 172, 160, 152, 145, 140, 132.5, 130, 127.5, 53, 50, 42.5, 37, 33, 30, 22, 17, 15, 12. g) An X-ray powder diffraction pattern with major signals in degrees (2Θ) in 8.5, 10.2, 1 3.3, 1 5.9 and 16.2, 21 .8, 22.6, 25. h) A structure obtained by monocrystalline X-ray diffraction, in accordance with the following most relevant crystallographic data and structural parameters, monoclinic crystalline system, spatial group P 21 / c, unit cell dimensions: a = 30.964 A °, b = 8.9179 A °, c = 1 1.883 A °; α = 90.00 °, β = 98.851 °, γ = 90.00 ° , Volume 3,242.2 A ³ , Z = 4 i) Solubility in aqueous medium of 0.3 mg / mL

3. The new chemical compound 5 - [[4- [2- (5-ethill-2-pyridinyl) ethoxy] benzyl] -2,4-thiazolidinedionate of Ν, Ν-dimethyldiguanide or 5- [p- [2- ( Ethyl-2-pyridyl) ethoxy] benzyl] -2,4-thiazolidinedionate, Ν-dimethyldiguanide, and which can generically be named metformin pioglitazonate

4. In accordance with clause 3, the metformin pioglitazonate compound, characterized by the following physicochemical properties: a) A spectrum of TF-infrared with characteristic absorption bands at 3120 cm ^"1 , 3353 cm ^'1 , 3440 cm ^" , 2960 cm ^"1 , 2929 cm ^{' 1} , 2871 cm ^{" 1} , 1691 cm ^"1 , 1675 cm ^"

1 b) A spectrum of H ⁺ Nuclear Magnetic Resonance with displacements in parts per million located in 1 .16-1.19 with a triplet; in 2.49-2.51 multiplet; in 2.56-2.63 multiplet; in 2.92 with singlet; in 3.10-3.13 with triplet; in 3.30-3.35 with double doublet, in 4.09-4.12 with double doublet, in 4.26-4.29 triplet; in 6.66-6.69 with wide signal; in 6.79-6.81 multiplet; in 7.07-7.09 double; in 7.27-29 double; in 7.56-7.62 double double; at 8,364-8,368 double. c) A spectrum of Nuclear Magnetic Resonance of ¹³ C with displacements in parts per million located in 190.48; 181 .57; 136.53, 159.09, 131 .91; 135.58, 148.44, 129.68, 122.91; 58.76; 24.87, 36.73, 37.30, 66.59; 15.28; 158.41, and in 156.81. d) A mass spectrum by the FAB technique ^" with a molecular ion at 355 m / z and a mass spectrum by the FAB ⁺ technique with a molecular ion at 130 m / z. e) A thermogram obtained by differential scanning calorimetry with an endotherm whose onset of fusion is located at 183.53 ⁰ C. f) A spectrum of ¹³ C Nuclear Magnetic Resonance, with major displacements in parts per million located 195, 160, 150, several displacements in the range between 135 and 1 10, between 70 and 52.5, and two displacements around 40 and another in 25. g) An X-ray powder diffraction pattern with major signals in parts per million located in degrees (2Θ) in 14, 17.5, 18.2, 19 , 19.8, 20.8, 21.9, 22.7, 23.7 h) A structure obtained by monocrystalline X-ray diffraction, in accordance with the following most relevant crystallographic data and structural parameters, triclinic crystalline system, spatial group P-1, unit cell dimensions: a = 5.4973 A °, b = 10.634 A °, c = 22.152 A °; = 97,521 °, β = 96,248 ° γ = 96,160 °, Volume 1,266.5A ³ , Z = 2 i) a solubility in aqueous medium of 13.3 mg / ml.

5. In accordance with clause 1, a process for the manufacture of metformin glimepiridate that is characterized by dissolving metformin base in ethanol and adding glimepiride. The suspension is heated between 50 ° and 55 ° C, and stirred until completely dissolved. Ethyl acetate is then added and the mixture is stirred, until a homogeneous suspension is produced. This suspension is filtered and the powder is washed with ethyl acetate and dried under vacuum. A white powder is recovered, which corresponds to crude metformin glimepiridate. This crude is dissolved in ethanol and the suspension is heated and stirred until completely dissolved. Then, ethyl acetate is added slowly and the mixture is stirred to obtain a white suspension. This suspension is filtered and the powder is washed with ethyl acetate and dried under vacuum. The recovered crystals correspond to the metformin glimepiridate ionic cocristal.

6. In accordance with clause 3, a process for the manufacture of metformin pioglitazonate that is characterized by dissolving metformin base in methanol and adding pioglitazone in portions. A very viscous solution difficult to stir is formed. More methanol is added dropwise and the suspension is stirred. Isopropanol is then added and the solution is cooled while stirring, filtered and the separated product is washed with isopropanol. The white powder obtained corresponds to crude metformin pioglitazonate. This crude is dissolved in ethanol and left under reflux. The solution obtained is cooled and mixed with isopropanol. Once small crystals are observed, the suspension is allowed to crystallize and after one night the obtained crystals are filtered, which they are washed with isopropanol. The crystals obtained are dried under vacuum and the ionic cocristal metformin pioglitazonate is obtained.

7. In accordance with clauses 1 and 2, the pharmaceutical composition of an oral solid, such as tablets or caplets consisting of a combination of metformin hydrochloride with the appropriate amount of metformin glimepiridate.

8. In accordance with clauses 1 and 2, the pharmaceutical composition of an oral solid, such as tablets or caplets consisting of a matrix or core of controlled release metformin hydrochloride, coated with an immediate release layer containing the new ionic co-crystal metformin glimepiridate.

9. In accordance with clauses 7 and 8, the amount of metformin glimepiridate in tablets or caplets should preferably be in the range of 0.5 mg to 10 mg and the amount of metformin hydrochloride in the range of 125 mg to 2 gr.

10. In accordance with clauses 3 and 4, a pharmaceutical composition of an oral solid, such as tablets or caplets consisting of a combination of metformin hydrochloride with the appropriate amount of metformin pioglitazonate.

eleven . In accordance with clauses 3 and 4, a pharmaceutical composition of an oral solid, such as tablets or caplets consisting of a matrix or core of controlled release metformin hydrochloride, coated with an immediate release layer containing the new ionic co-crystal pioglitazonate metformin

1 2. In accordance with clauses 1 0 and 1 1 the amount of metformin pioglitazonate in the tablets or caplets should be in the range of 2.5 mg to 50 mg and the amount of metformin hydrochloride in the range of 1 25 mg to 2 gr.

1 3. In accordance with clauses 1 and 3, a pharmaceutical composition of an oral solid such as tablets or caplets consisting of a combination of metformin glimepiridate with metformin pioglitazonate.

14. In accordance with clause 1 3, the amount of metformin glimepiridate should preferably be in the range of 0.5 mg to 10 mg and the amount of metformin pioglitazonate preferably in the range of 2.5 mg to 50 mg.

1 5. In accordance with clauses 7 and 8, the use of the pharmaceutical composition in the form of tablets or in caplets for the treatment of diabetes mellitus disease in mammals.

16. In accordance with clauses 9 and 1 0, the use of the pharmaceutical composition in the form of tablets or caplets for the treatment of diabetes mellitus disease in mammals.

17. In accordance with clause 1 3 and 14, the use of the pharmaceutical composition in the form of tablets or caplets for the treatment of diabetes mellitus disease in mammals.