WO2012148252A2 - Co-cristaux ioniques à base de metformine - Google Patents
Co-cristaux ioniques à base de metformine Download PDFInfo
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- WO2012148252A2 WO2012148252A2 PCT/MX2012/000043 MX2012000043W WO2012148252A2 WO 2012148252 A2 WO2012148252 A2 WO 2012148252A2 MX 2012000043 W MX2012000043 W MX 2012000043W WO 2012148252 A2 WO2012148252 A2 WO 2012148252A2
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- metformin
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- pioglitazonate
- glimepiridate
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
- C07C279/20—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups containing any of the groups, X being a hetero atom, Y being any atom, e.g. acylguanidines
- C07C279/24—Y being a hetero atom
- C07C279/26—X and Y being nitrogen atoms, i.e. biguanides
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
- C07D207/263—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms
- C07D207/27—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
Definitions
- 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.
- 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.
- N, N dimethyldiguanide 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.
- TG gastrointestinal
- 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.
- the hydrochloride salt 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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 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.
- 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.
- 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.
- 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.
- the purpose of the present invention is to develop two new metformin compounds, without the obvious disadvantages of existing commercial salts.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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 .
- 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.
- 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. Weinschr. 60 (19), 1 191-1200 (1982).
- 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.
- 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.
- 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.
- 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).
- 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.
- 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).
- 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.
- 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.
- a single active ingredient will act against diabetes through two complementary mechanisms.
- metformin 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.
- sulfonylurea glimepiride primarily increases insulin secretion. This action is initiated by binding to and closing an ATP-sensitive pancreatic channel to K + ⁇ 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 ⁇ cells activates a cytoskeleton system that causes insulin translocation to the cell surface and its expulsion by exocytosis (US Patent 6,693094).
- 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)).
- G. Charpentier Improved Glycaemic Control by Addition of Glimepiride to metformin Monotherapy in Type 2 Diabetic Patients , Diabetic Medicine 18, 828-834 (2001)).
- 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.
- 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).
- insulin resistance blocker 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.
- insulin resistance is unlocked by improving glucose tolerance and decreasing plasma concentrations of neutral lipids and free fatty acids (EP patent 17641 10 A1).
- pioglitazone decreases hyperglycemia, hyperinsulinemia and hypertriglyceridemia, which are characteristic metabolic alterations of insulin resistance states similar to that observed in type II diabetes.
- 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.
- 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.
- 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.
- 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.
- FIG. 21 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.
- Dabex XR commercial extended-release tablet
- 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.
- 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).
- metformin hydrochloride eg 500 mg
- 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.
- 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).
- 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).
- 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.
- Figure 23 it is compared with Dabex XR (brand of Merck Inc.) and Predial Plus (brand of Silanes laboratories).
- 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.
- 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.).
- 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).
- 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.
- TG / DTA thermogravimetric analysis
- 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.
- 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.
- 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.
- 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 ⁇ L 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%.
- 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 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.
- 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.
- ionic co-crystals 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.
- 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
- 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.
- 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).
- the dispersion consists of about 27 polyvinyl acetate, 2.7% povidone and 0.3% sodium laurel sulfate
- Example 4 Formulation of Tablets Based on the New Metformin Pioglitazonate Salt
- 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.
- 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
- the dispersion consists of about 27% polyvinyl acetate, 2.7% povidone and 0.3% sodium laurel sulfate
- 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.
- 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
- 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.
- 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.
- 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.
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Abstract
On a découvert deux nouveaux composés à base de metformine utilisant comme contre-ions, dans un cas, l'antidiabétique glymépiride et dans l'autre cas, l'antidiabétique pioglytazone. La spectroscopie obtenue, ainsi que l'étude des propriétés physico-chimiques, montrent qu'à l'état solide les deux composés correspondent à des co-cristaux ioniques attirés par des forces ioniques et des interactions de type pont d'hydrogène. Les propriétés physico-chimiques des co-cristaux ioniques montrent qu'ils possèdent de plus grandes vitesses de dissolution intrinsèque et de meilleures solubilités que celle des contre-ions précurseurs, propriétés qui peuvent avoir un impact favorable sur la biodisponibilité des nouveaux principes actifs. Ces nouveaux principes actifs améliorés sont formulés dans des compositions pharmaceutiques de solides oraux comme des comprimés ou des comprimés-capsules qui présentent des avantages par rapport aux comprimés ou comprimés-capsules existants sur le marché. Ainsi, les comprimés contenant les nouveaux principes actifs représentent un traitement amélioré pour la régulation de la glycémie chez des patients atteints de diabète de type II.
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Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2003061643A1 (fr) * | 2002-01-25 | 2003-07-31 | Laboratorios Silanes, S.A. De C.V. | Composition pharmaceutique permettant de surveiller le glucose dans le sang de patients souffrant de diabete de type 2 |
WO2007073136A1 (fr) * | 2005-12-20 | 2007-06-28 | World-Trade Import-Export, Wtie, Ag. | Compositions pharmaceutiques comprenant des substances derivees de la thiazolidinedione combinees au biguanide utilisees contre le diabete sucre de type 2 |
US20070264331A1 (en) * | 2005-09-08 | 2007-11-15 | Laboratorios Silanes, S.A De C.V. | Stable pharmaceutical composition of immediate-release glimepiride and extended-release metformin |
CN101531657A (zh) * | 2009-04-23 | 2009-09-16 | 重庆医科大学 | 噻唑烷二酮类药物的二甲双胍盐及其制备方法和用途 |
WO2011128782A2 (fr) * | 2010-04-13 | 2011-10-20 | Jorge Luis Rosado | Compositions et procédés pour traiter le diabète de type ii et des troubles associés |
-
2011
- 2011-04-29 MX MX2011004549A patent/MX339374B/es active IP Right Grant
-
2012
- 2012-04-20 WO PCT/MX2012/000043 patent/WO2012148252A2/fr active Application Filing
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2003061643A1 (fr) * | 2002-01-25 | 2003-07-31 | Laboratorios Silanes, S.A. De C.V. | Composition pharmaceutique permettant de surveiller le glucose dans le sang de patients souffrant de diabete de type 2 |
US20070264331A1 (en) * | 2005-09-08 | 2007-11-15 | Laboratorios Silanes, S.A De C.V. | Stable pharmaceutical composition of immediate-release glimepiride and extended-release metformin |
WO2007073136A1 (fr) * | 2005-12-20 | 2007-06-28 | World-Trade Import-Export, Wtie, Ag. | Compositions pharmaceutiques comprenant des substances derivees de la thiazolidinedione combinees au biguanide utilisees contre le diabete sucre de type 2 |
CN101531657A (zh) * | 2009-04-23 | 2009-09-16 | 重庆医科大学 | 噻唑烷二酮类药物的二甲双胍盐及其制备方法和用途 |
WO2011128782A2 (fr) * | 2010-04-13 | 2011-10-20 | Jorge Luis Rosado | Compositions et procédés pour traiter le diabète de type ii et des troubles associés |
Non-Patent Citations (1)
Title |
---|
DATABASE WPI Derwent Publications Ltd., London, GB; AN 2009-P02744 & CN 101 531 657 A (CHONGQUING MEDICAL UNIV.) 16 September 2009 * |
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