Pharmaceutical compositions containing glucopyranosyldiphenylmethane derivatives, their pharmaceutical dosage forms, methods for preparing them, and their use to improve blood glucose control in patients.

Abstract

The present invention relates to pharmaceutical compositions comprising a SGLT-2 inhibitor, pharmaceutical dosage forms, their preparation, their use and methods for treating metabolic disorders.

Description

[Technical Field]

[0001] (Technical field of invention) The present invention relates to a pharmaceutical composition comprising an SGLT-2 inhibitor as an active pharmaceutical ingredient. Furthermore, the present invention relates to a pharmaceutical dosage form comprising the pharmaceutical composition. In addition, the present invention relates to a method for preparing the pharmaceutical dosage form. Furthermore, the present invention relates to the use of the pharmaceutical composition and pharmaceutical dosage form in the treatment and / or prevention of selected diseases and medical conditions, particularly one or more conditions selected from type 1 diabetes mellitus, type 2 diabetes mellitus, impaired glucose tolerance, fasting blood glucose abnormalities, and hyperglycemia. Furthermore, the present invention relates to a method for the treatment and / or prevention of said diseases and medical conditions, comprising administering the pharmaceutical composition or pharmaceutical dosage form of the present invention to a patient in need of treatment and / or prevention. [Background technology]

[0002] (Background of the invention) Type 2 diabetes is an increasingly prevalent disease that significantly reduces life expectancy due to its high incidence of complications. Due to diabetes-related microvascular complications, type 2 diabetes is currently the leading cause of adult-onset blindness, renal failure, and amputation in developed industrial countries. In addition, the presence of type 2 diabetes is associated with a 2- to 5-fold increased risk of cardiovascular disease. After a long period of illness, many patients with type 2 diabetes will eventually fail to manage oral therapy and become insulin-dependent, requiring daily injections and multiple glucose monitoring sessions. The UKPDS (United Kingdom Prospective Diabetes Study) demonstrated that intensive treatment with metformin, sulfonylurea, or insulin resulted in only limited improvement in glycemic control (HbA1c difference of approximately 0.9%). Furthermore, even in patients within the intensive treatment group, glycemic control significantly declined over time, attributable to decreased β-cell function. Importantly, intensive treatment was not associated with a significant reduction in macrovascular complications, i.e., cardiovascular events. Therefore, many patients with type 2 diabetes remain undertreated, partly due to the limitations of the long-term efficacy, tolerability, and inconvenience of existing antiglycemic therapies. Oral antidiabetic drugs commonly used in therapy (e.g., first-line or second-line, and / or monotherapy or (initial or additional) combination therapy) include, but are not limited to, metformin, sulfonylurea, thiazolidinediones, glinides, and alpha-glucosidase inhibitors. The high incidence of therapy failure is primarily due to the high rate of long-term hyperglycemia-related complications or chronic disorders in patients with type 2 diabetes (including microvascular and macrovascular complications such as diabetic nephropathy, retinopathy, or neuropathy, or cardiovascular complications). Therefore, there is an unaddressed medical need for methods, drugs, and pharmaceutical compositions that exhibit good efficacy in terms of blood glucose control, disease-modifying properties, and reduction of cardiovascular morbidity and mortality, while simultaneously demonstrating an improved safety profile. SGLT2 inhibitors represent a new class of drugs being developed to treat or improve blood glucose control in patients with type 2 diabetes. Glucopyranosyl-substituted benzene derivatives are described as SGLT2 inhibitors in the prior art, for example, WO01 / 27128, WO03 / 099836, WO2005 / 092877, WO2006 / 034489, WO2006 / 064033, WO2006 / 117359, WO2006 / 117360, WO2007 / 025943, WO2007 / 028814, WO2007 / 031548, WO2007 / 093610, WO2007 / 128749, WO2008 / 049923, WO2008 / 055870, and WO2008 / 055940. Glucopyranosyl-substituted benzene derivatives have been proposed as substances that induce urinary glucose excretion and as therapeutic agents for diabetes.

[0003] Renal filtration and reuptake of glucose, among several mechanisms, contribute particularly to steady-state plasma glucose concentration and therefore may be useful as an anti-diabetic target. Reuptake of filtered glucose across renal epithelial cells proceeds according to a sodium gradient via sodium-dependent glucose cotransporters (SGLTs) located in the brush border membrane within the tubules. There are at least three SGLT isotypes, which differ not only in expression patterns but also in physicochemical properties. SGLT2 is exclusively expressed in the kidney, while SGLT1 is further expressed in other tissues such as the intestine, colon, skeletal muscle, and cardiac muscle. SGLT3 has no transport function and is known to be a glucose sensor in intestinal interstitial cells. Other related but still uncharacterized genes may further contribute to renal glucose reuptake. Under euglycemic conditions, glucose is completely reabsorbed in the kidney by SGLTs, but the renal reuptake capacity becomes saturated at glucose concentrations above 10 mM, leading to glucosuria ("diabetes"). SGLT2 inhibition can lower this threshold concentration. Experiments using the SGLT inhibitor phlorizin have shown that SGLT inhibition partially inhibits glucose reuptake from glomerular filtrate into the bloodstream, leading to a reduction in blood glucose concentration and glucosuria. [Overview of the Initiative] [Problems that the invention aims to solve]

[0004] (Purpose of the present invention) The object of the present invention is to provide a pharmaceutical composition containing an SGLT-2 inhibitor that avoids or reduces sticking during the manufacturing process of the composition. Another object of the present invention is to provide a pharmaceutical composition comprising an SGLT-2 inhibitor that avoids or reduces filming during the manufacturing process of the composition. Another object of the present invention is to provide a pharmaceutical dosage form comprising an SGLT-2 inhibitor that has a short decay time, good solubility, and / or enables high bioavailability of the SGLT-2 inhibitor in patients. Another object of the present invention is to provide a pharmaceutical composition comprising an SGLT-2 inhibitor that has high content uniformity and / or can be manufactured efficiently in terms of time and cost in terms of pharmaceutical dosage forms. Another object of the present invention is to provide pharmaceutical compositions and dosage forms, as well as methods, each comprising an SGLT2 inhibitor, for the prevention, slowing, delaying, or treatment of metabolic disorders, particularly type 2 diabetes. A further object of the present invention is to provide pharmaceutical compositions, pharmaceutical dosage forms, and methods, each containing an SGLT2 inhibitor, for improving blood glucose control in patients who require improved blood glucose control, particularly in patients with type 2 diabetes. Another object of the present invention is to provide pharmaceutical compositions, pharmaceutical dosage forms, and methods, each containing an SGLT2 inhibitor, for improving glycemic control in patients with inadequate glycemic control. Another object of the present invention is to provide pharmaceutical compositions and dosage forms, as well as methods, each comprising an SGLT2 inhibitor, for the prevention, slowing, or delaying of the progression from impaired glucose tolerance (IGT), abnormal fasting blood glucose (IFG), insulin resistance, and / or metabolic syndromes to type 2 diabetes. A further object of the present invention is to provide pharmaceutical compositions and dosage forms, as well as methods, each comprising an SGLT2 inhibitor, for the prevention, slowing, delaying, or treatment of conditions or disorders selected from the group consisting of complications of diabetes. A further object of the present invention is to provide pharmaceutical compositions, pharmaceutical dosage forms, and methods comprising SGLT2 inhibitors, respectively, for weight loss or prevention of weight gain in patients who require such reduction or prevention. Another object of the present invention is to provide a pharmaceutical composition and a pharmaceutical dosage form having high efficacy for the treatment of metabolic disorders, particularly diabetes, impaired glucose tolerance (IGT), impaired fasting glucose (IFG), and / or hyperglycemia, and having good to very good pharmacological and / or pharmacokinetic and / or physicochemical properties, each containing an SGLT2 inhibitor. Another object of the present invention is to provide a method for preparing the pharmaceutical dosage form of the present invention, which is cost and / or time efficient. Those skilled in the art will be able to clarify further objects of the present invention from the above and the following descriptions and examples. [Means for Solving the Problems]

[0005] (Summary of the Invention) In a first aspect, the present invention provides a pharmaceutical composition comprising an SGLT-2 inhibitor as an active pharmaceutical ingredient and one or more excipients, particularly one or more diluents, and / or one or more disintegrants. In a further aspect, the pharmaceutical composition further comprises one or more binders. In one aspect, the pharmaceutical composition of the present invention is a solid pharmaceutical composition, for example, a solid pharmaceutical composition for oral administration. In one embodiment, the active ingredient corresponds to 25% or less of the mass of the pharmaceutical composition. Preferably, the active ingredient corresponds to 0.5% to 25% of the mass of the pharmaceutical composition. More preferably, the active ingredient corresponds to 1.0% to 20% of the mass of the pharmaceutical composition. Even more preferably, the active ingredient corresponds to 2.0% to 15% of the mass of the pharmaceutical composition. Within the scope of the present invention, a pharmaceutical composition containing an SGLT-2 inhibitor having a particle size distribution of X90 < 200 μm, particularly 1 μm < X90 < 200 μm, as an active pharmaceutical ingredient has been found to exhibit a beneficial dissolution profile and / or good bioavailability, provide high content uniformity, and enable efficient production of the pharmaceutical dosage form in terms of time and cost. Thus, in another aspect, the present invention provides a pharmaceutical composition comprising an SGLT-2 inhibitor as an active pharmaceutical ingredient and one or more excipients, wherein the active ingredient preferably has a particle size distribution with X90 < 200 μm determined by volume by laser diffraction method, particularly a particle size distribution with 1 μm < X90 < 200 μm. In one embodiment, the ratio of the disintegrant to the binder in the composition of the present invention is 1.5:3.5 to 1:1. In one embodiment, the disintegrant in the pharmaceutical composition is croscarmellose sodium. In one embodiment, the binder in the pharmaceutical composition is hydroxypropyl cellulose. In one embodiment, the diluent in the pharmaceutical composition is lactose monohydrate or microcrystalline cellulose. In one embodiment, the pharmaceutical composition contains lactose monohydrate and microcrystalline cellulose. In one embodiment, the pharmaceutical composition further contains a flow promoter, such as colloidal silicon dioxide or talc. In one embodiment, the pharmaceutical composition further contains a lubricant. In one embodiment, the binder in the composition of the present invention is a binder with a fine particle size. In one embodiment, at least 99% (by mass) of the particles of the binder are 250 μm or less. In one embodiment, at least 99.5% (by mass) of the particles of the binder are 250 μm or less. In one embodiment, at least 99.9% (by mass) of the particles of the binder pass through a sieve with a screen size of 60 mesh. That is, 250 μm or less. In another embodiment, the present invention provides a dosage form, such as a tablet, comprising the pharmaceutical composition of the present invention. In one embodiment, a dosage form, such as a tablet, contains the following components.

[0006] TIFF0005600328000001.tif41127

[0007] In another embodiment, a dosage form, such as a tablet, contains the following components.

[0008] TIFF0005600328000002.tif41127

[0009] In one embodiment, a dosage form, such as a tablet, contains the following components per 1 mg of the dosage form.

[0010] TIFF0005600328000003.tif46127

[0011] In one embodiment, a dosage form, such as a tablet, contains the following components per 1 mg of the dosage form.

[0012] TIFF0005600328000004.tif46127

[0013] In one embodiment, the dosage form, for example, a tablet, further contains a lubricant, for example, magnesium stearate, at a concentration of, for example, 0.25 to 2%. In one embodiment, the dosage form, for example, a tablet, further contains a flow enhancer, for example, colloidal silicon dioxide, at a concentration of, for example, 0.25 to 2%. The dosage form of the present invention, for example, tablets, may be film-coated. Typically, the film coating constitutes 2 to 5% by mass of the total composition and preferably includes a film-forming agent, a plasticizer, a flow promoter, and optionally one or more dyes. A typical coating composition may include hydroxypropyl methylcellulose (HPMC), polyethylene glycol (PEG), talc, titanium dioxide, and optionally iron oxides (including iron red and / or yellow). In another aspect, the present invention relates to a wet granulation method for producing a pharmaceutical composition, comprising the following steps: (1) A step of pre-mixing the active ingredient and the main portion of the excipients, including the binder, in a mixer to obtain a pre-mixture; (2) A step of granulating the pre-mixture from step (1) by adding a granulation liquid, preferably purified water; (3) A step of drying the granules from step (2) in a fluidized bed dryer or drying oven; (4) A step in which the dried granules from step (3) are sieved dry as needed; (5) A step in which the dried granules from step (4) are mixed in a mixer with the remaining excipients such as a flow promoter and a lubricant to obtain the final mixture; (6) A step of forming tablets by compressing the final mixture from step (5) in a suitable tablet press to produce tablet cores; (7) A step in which the tablet core from step (6) is film-coated with a non-functional coating agent as needed. This provides a method that includes this. In another aspect, the present invention provides a pharmaceutical composition obtained by the method described above.

[0014] In another aspect, the present invention relates to a direct compression method for producing a pharmaceutical composition, comprising the following steps: (1) A step of pre-mixing the active ingredient and the main part of the excipient in a mixer to obtain a pre-mixture; (2) A step of dry sieving the premixture through a sieve as necessary in order to separate agglomerating particles and to improve the uniformity of content; (3) Adding the remaining excipients to the mixture as needed and continuing to mix, thereby mixing the pre-mixture from step (1) or (2) in a mixer; (4) A step of forming tablets by compressing the final mixture from step (3) in a suitable tablet press to produce tablet cores; (5) A step in which the tablet core from step (4) is film-coated with a non-functional coating agent as needed. This provides a method that includes this. In another aspect, the present invention provides a pharmaceutical composition obtained by the method described above.

[0015] In another aspect, the present invention relates to a dry granulation method for producing a pharmaceutical composition, comprising the following steps: (1) A step of mixing all or some of the active ingredients with the excipients in a mixer; (2) The process of compressing the mixture from step (1) using a suitable roller compressor; (3) A step of converting the ribbon obtained in step (2) into granules, preferably small granules, by an appropriate milling or sieving process; (4) The granules from step (3) are mixed with the remaining excipients in a mixer as needed to obtain the final mixture; (5) A step of forming tablets by compressing the granules from step (3) or the final mixture from step (4) in a suitable tablet press to produce tablet cores; (6) A step in which the tablet core from step (5) is film-coated with a non-functional coating agent as needed. This provides a method that includes this. In another aspect, the present invention provides a pharmaceutical composition obtained by the method described above. In one embodiment, the pharmaceutical composition of the present invention is obtained by high-shear wet granulation. Preferably, the SGLT2 inhibitor is given by the following formula (I)

[0016] [ka]

[0017] (In the formula, R 1 represents Cl, methyl, or cyano; R 2 is a combination of H, methyl, methoxy, or hydroxy, and R 3 (This represents (R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy) A glucopyranosyl-substituted benzene derivative; or selected from one of the SGLT2 inhibitor prodrugs.

[0018] In the glucopyranosyl-substituted benzene derivative of formula (I) described above, the following definitions of substituents are preferred. Preferably R 1 This represents chloro or cyano, especially chloro. Preferably R 2 This represents H. Preferably R 3 This represents (R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy. Preferred glucopyranosyl-substituted benzene derivatives of formula (I) are selected from the group of compounds (I.8) to (I.11) listed below.

[0019] [ka]

[0020] A more preferred glucopyranosyl-substituted benzene derivative of formula (I) is selected from compounds (I.8), (I.9), and (I.11). Preferred glucopyranosyl-substituted benzene derivatives of formula (I) are selected from compounds (I.8) and (I.9), or the crystalline form (I.9X) of compound (I.9). The pharmaceutical composition of the present invention provides high content uniformity and enables efficient production of pharmaceutical dosage forms such as tablets and capsules in terms of time and cost. Furthermore, in one embodiment, these pharmaceutical dosage forms are particularly tablets. Accordingly, in another embodiment, the present invention provides a pharmaceutical dosage form comprising the pharmaceutical composition of the present invention. In one embodiment, the pharmaceutical dosage form of the present invention is a solid pharmaceutical dosage form, for example, a solid pharmaceutical dosage form for oral administration. In another aspect, the present invention provides a method for preparing a pharmaceutical dosage form of the present invention, comprising one or more granulation methods for granulating an active pharmaceutical ingredient together with one or more excipients. In another aspect, the pharmaceutical composition or dosage form of the present invention exhibits a characteristic pharmacokinetic profile after administration to a subject, particularly after administration to humans, as described later herein. It is evident that pharmaceutical compositions containing SGLT2 inhibitors as defined below can be advantageously used for the prevention, slowing, delaying, or treatment of metabolic disorders, particularly for improving patients' blood glucose control. This opens up the possibility of new therapies for the treatment and prevention of type 2 diabetes, overweight, obesity, diabetic complications, and related disease conditions.

[0021] Accordingly, in a first aspect, the present invention provides a method for preventing, slowing down, delaying, or treating a metabolic disorder selected from the group consisting of type 1 diabetes, type 2 diabetes, impaired glucose tolerance (IGT), abnormal fasting blood glucose (IFG), hyperglycemia, postprandial hyperglycemia, overweight, obesity, and metabolic syndromes, characterized by administering a pharmaceutical composition or pharmaceutical dosage form of the present invention to the patient. Another aspect of the present invention provides a method for improving and / or reducing blood glucose control in patients who require improvement of fasting plasma glucose, postprandial plasma glucose, and / or reduction of glycosylated hemoglobin HbA1c, characterized by administering the pharmaceutical composition or pharmaceutical dosage form of the present invention to the patient. The pharmaceutical compositions of the present invention may also possess beneficial disease-modifying properties with respect to diseases or conditions associated with impaired glucose tolerance (IGT), abnormal fasting blood glucose (IFG), insulin resistance, and / or metabolic syndromes. Another aspect of the present invention provides a method for preventing, slowing, delaying, or reversing the progression from impaired glucose tolerance (IGT), abnormal fasting blood glucose (IFG), insulin resistance, and / or metabolic syndrome to type 2 diabetes, characterized by administering a pharmaceutical composition or pharmaceutical dosage form of the present invention to the patient. The use of the pharmaceutical composition of this invention can improve blood glucose control in patients who require improved blood glucose control, and thus can also treat conditions and / or diseases associated with or caused by elevated blood glucose levels.

[0022] In another aspect of the present invention, a method is provided for the prevention, slowing, delaying, or treatment of a patient who needs to prevent, slow the progression of, delay, or treat a condition or disorder selected from the group consisting of diabetic complications, such as cataracts, and microvascular and macrovascular diseases, such as nephropathy, retinopathy, neuropathy, tissue ischemia, diabetic foot lesions, arteriosclerosis, myocardial infarction, acute coronary syndrome, unstable angina, stable angina, stroke, peripheral artery occlusive disease, cardiomyopathy, heart failure, heart rate disorders, and vascular restenosis, characterized by administering a pharmaceutical composition or pharmaceutical dosage form of the present invention to the patient. In particular, it is possible to treat one or more aspects of diabetic nephropathy, such as hyperperfusion, proteinuria, and albuminuria, slowing their progression or delaying or preventing their onset. The term "tissue ischemia" particularly includes diabetic macrovascular complications, diabetic microvascular complications, impaired wound healing, and diabetic ulcers. In this application, the terms "microvascular and macrovascular diseases" and "microvascular and macrovascular complications" are used interchangeably.

[0023] Upon administration of the pharmaceutical composition of this invention, and due to the activity of the SGLT2 inhibitor, excess blood glucose is excreted through the patient's urine rather than being converted into insoluble storage forms such as fat. Consequently, there is no weight gain, and even weight loss. Another aspect of the present invention provides a method for reducing, preventing, or promoting weight loss in patients who require weight loss or prevention of weight gain, or promotion of weight loss, characterized by administering the pharmaceutical composition or pharmaceutical dosage form of the present invention to the patient. The pharmacological action of the SGLT2 inhibitor in the pharmaceutical composition of this invention is independent of insulin. Therefore, it is possible to improve blood glucose control without further burdening pancreatic β-cells. Administration of the pharmaceutical composition of this invention can delay or prevent β-cell degeneration and decreased β-cell function, such as apoptosis or necrosis of pancreatic β-cells. Furthermore, it can improve or restore the function of pancreatic cells and increase the number and size of pancreatic β-cells. It can be shown that the differentiation state and hyperplasia of pancreatic β-cells disrupted by hyperglycemia can be normalized by treatment with the pharmaceutical composition of this invention.

[0024] Another aspect of the present invention provides a method for preventing, slowing, delaying, or treating pancreatic β-cell degeneration and / or functional decline of pancreatic β-cells, and / or improving and / or restoring the function of pancreatic β-cells and / or pancreatic insulin secretion, in which the pharmaceutical composition or pharmaceutical dosage form of the present invention is administered to the patient. The administration of the pharmaceutical composition of the present invention can reduce or inhibit the abnormal accumulation of fat in the liver. Accordingly, another aspect of the present invention provides a method for preventing, slowing, delaying, or treating a disease or condition caused by abnormal accumulation of liver fat in a patient, characterized by administering an SGLT2 inhibitor as defined above and below to the patient. The disease or condition caused by abnormal accumulation of liver fat is selected from the group consisting of general fatty liver, non-alcoholic fatty liver (NAFL), non-alcoholic steatohepatitis (NASH), overnutrition-induced fatty liver, diabetic fatty liver, alcohol-induced fatty liver, or toxic fatty liver. As a result, another aspect of the present invention provides a method for maintaining and / or improving insulin sensitivity and / or treating or preventing hyperinsulinemia and / or insulin resistance in patients who require such maintenance and / or improvement and / or treatment or prevention, characterized by administering a pharmaceutical composition or pharmaceutical dosage form of the present invention to the patient.

[0025] In another aspect of the present invention, - Prevention, slowing, delaying, or treatment of metabolic disorders selected from the group consisting of type 1 diabetes, type 2 diabetes, impaired glucose tolerance (IGT), abnormal fasting blood glucose (IFG), hyperglycemia, postprandial hyperglycemia, overweight, obesity, and metabolic syndromes; or -Improvement of blood glucose control and / or reduction of fasting plasma glucose, postprandial plasma glucose and / or glycosylated hemoglobin HbA1c; or - Prevention, slowing, delaying, or reversing the progression from impaired glucose tolerance (IGT), abnormal fasting blood glucose (IFG), insulin resistance and / or metabolic syndromes to type 2 diabetes; or - Prevention, slowing, delaying, or treating conditions or impairments selected from the group consisting of diabetic complications, such as cataracts, and microvascular and macrovascular diseases, such as nephropathy, retinopathy, neuropathy, tissue ischemia, diabetic foot lesions, arteriosclerosis, myocardial infarction, acute coronary syndrome, unstable angina, stable angina, stroke, peripheral artery occlusive disease, cardiomyopathy, heart failure, heart rate disorders, and restenosis; or - Weight loss, or prevention of weight gain or promotion of weight loss; or - Prevention, deceleration, delay or treatment of pancreatic β-cell degeneration and / or functional decline of pancreatic β-cells and / or improvement and / or restoration of the functionality of pancreatic β-cells and / or restoration of the functionality of pancreatic insulin secretion; or - Prevention, deceleration, delay or treatment of diseases or conditions resulting from abnormal accumulation of liver fat; or - Maintenance and / or improvement of insulin sensitivity and / or treatment or prevention of hyperinsulinemia and / or insulin resistance In the use of the pharmaceutical composition or pharmaceutical dosage form of the present invention for the manufacture of a drug for such patients who require the above, administration of an SGLT2 inhibitor as defined above and below is provided, characterized by the use.

[0026] According to another aspect of the present invention, there is provided the use of the pharmaceutical composition or pharmaceutical dosage form of the present invention for the manufacture of a drug for the above and below treatment and prevention methods.

[0027] Therefore, the present invention When administered to fasting humans, a. At a dose of 2.5 mg i. C of 40.3 - 96.3 nmol / L max ; and ii. AUC of 283 - 677 nmol * h / L is shown; and / or b. At a dose of 5.0 mg i. C of 123 - 230 nmol / L max ; and ii. AUC of 1,000 - 1,310 nmol * h / L is shown; and / or c. At a dose of 10.0 mg i. C of 143 - 796 nmol / L max ; and ii. AUC of 1,170 - 3,190 nmol * h / L is shown; and / or d. At a dose of 25.0 mg i. C of 334 - 1,030 nmol / L max ; and ii. 2,660~7,640 nmol * h / L AUC This indicates; and / or e. A dose of 50.0 mg i. 722~2,020 nmol / L of C max and ii. 6,450~14,100 nmol * h / L AUC To show, The following formula (I.9)

[0028] [ka] (I.9)

[0029] The present invention provides a pharmaceutical composition containing the compound. When administered to a person on an empty stomach, a. At a dose of 2.5 mg i. Geometric mean C for 52.9~66.6 nmol / L max and ii. 394~468 nmol * Geometric mean AUC of h / L This indicates; and / or b. At a dose of 10.0 mg i. Geometric mean C for 221-372 nmol / L max and ii. 1,690~2,660 nmol * Geometric mean AUC of h / L This indicates; and / or c. At a dose of 25.0 mg i. Geometric mean C for 490-709 nmol / L max and ii. 3,750~6,130 nmol * Geometric mean AUC of h / L This indicates; and / or d. A dose of 50.0 mg i. Geometric mean C for concentrations of 1,080 to 1,140 nmol / L max and ii. 8,310~8,460 nmol* Geometric mean AUC of h / L To show, The following formula (I.9)

[0030] [ka] (I.9)

[0031] The present invention provides a pharmaceutical composition containing the compound. For people who are hungry a. When administered as a single dose of 2.5 mg, i. C42.8~81.2 nmol / L max and ii. 326~631 nmol * h / L AUC 0-inf This indicates; and / or b. When administered as a single dose of 5.0 mg, i. 123-230 nmol / L C max and ii. 1,000~1,310 nmol * h / L AUC 0-inf This indicates; and / or c. When administered as a single dose of 10.0 mg, i. C143~796 nmol / L max and ii. 1,170~3,190 nmol * h / L AUC 0-inf This indicates; and / or d. When administered as a single dose of 25.0 mg, i. C34~1,030 nmol / L max and ii. 2,660~7,170 nmol * h / L AUC 0-inf This indicates; and / or e. When administered as a single dose of 50.0 mg, i. 722~2,020 nmol / L of C maxand ii. 6,450~14,100 nmol * h / L AUC 0-inf The present invention provides a pharmaceutical composition containing a compound of formula (I.9) that exhibits the following characteristics.

[0032] For people who are hungry a. When administered as a single dose of 2.5 mg, i. Geometric mean C for 52.9~61.3 nmol / L max and ii. 394~468 nmol * Geometric mean AUC of h / L 0-inf This indicates; and / or b. When administered as a single dose of 10.0 mg, i. Geometric mean C for 221-372 nmol / L max and ii. 1,690~2,660 nmol * Geometric mean AUC of h / L 0-inf This indicates; and / or c. When administered as a single dose of 25.0 mg, i. Geometric mean C for 490-709 nmol / L max and ii. 3,750~6,130 nmol * Geometric mean AUC of h / L 0-inf This indicates; and / or d. When administered as a single dose of 50.0 mg, i. Geometric mean C for concentrations of 1,080 to 1,140 nmol / L max and ii. 8,310~8,460 nmol * Geometric mean AUC of h / L 0-inf The present invention provides a pharmaceutical composition containing a compound of formula (I.9) that exhibits the following characteristics.

[0033] When administered to a person on an empty stomach, a. Multiple doses of 2.5 mg i. C40.3~96.3 nmol / L max,ss and ii. 283~677 nmol * h / L AUC τ,ss This indicates; and / or b. Multiple doses of 10.0 mg i. 166~479 nmol / L C max,ss and ii. 1,350~2,600 nmol * h / L AUC τ,ss This indicates; and / or c. Multiple doses of 25.0 mg i. 443~907 nmol / L C max,ss and ii. 2,790~7,640 nmol * h / L AUC τ,ss The present invention provides a pharmaceutical composition containing a compound of formula (I.9) that exhibits the following characteristics.

[0034] When administered to a person on an empty stomach, a. Multiple doses of 10.0 mg i. Geometric mean C for 252-272 nmol / L max,ss and ii. 1,850~2,000 nmol * Geometric mean AUC of h / L τ,ss This indicates; and / or b. Multiple doses of 25.0 mg i. Geometric mean C for 622~676 nmol / L max,ss and ii. 4,640~4,890 nmol * Geometric mean AUC of h / L τ,ss The present invention provides a pharmaceutical composition containing a compound of formula (I.9) that exhibits the following characteristics. When administered to fasting humans, the dose-normalized C is 13-80 nmol / L / mg. max,norm ; and 10⁶ to 30⁶ nmol * Dose-normalized AUC of h / L / mg0-inf,norm The following equation (I.9) shows this:

[0035] [ka] (I.9)

[0036] The present invention provides a pharmaceutical composition containing the compound of formula (I.9) over a dose range of 2.5 mg to 50 mg. max,norm and the dose-normalized AUC 0-inf,norm This indicates. When administered to a person in a fasted state, the following formula (I.9)

[0037] [ka] (I.9)

[0038] The compound was dose-normalized to 13-80 nmol / L / mg over a dose range of 5 mg to 25 mg. max,norm ; and 10⁶ to 30⁶ nmol * Dose-normalized AUC of h / L / mg 0-inf,norm The present invention provides a pharmaceutical composition containing the compound that exhibits the above characteristics. When administered to a fasted human, the dose-normalized geometric mean C is 20-37 nmol / L / mg. max,norm ; and 150-266 nmol * Dose-normalized geometric mean AUC for h / L / mg 0-inf,norm The following equation (I.9) shows this:

[0039] [ka] (I.9)

[0040] The present invention provides a pharmaceutical composition comprising the compound of formula (I.9) over a dose range of 2.5 mg to 50 mg. max,norm and the dose normalized geometric mean AUC 0-inf,norm This indicates. When administered to a person in a fasted state, the following formula (I.9)

[0041] [ka] (I.9)

[0042] The compound has a dose-normalized geometric mean of 20-37 nmol / L / mg over a dose range of 5 mg to 25 mg. max,norm ; and 150-266 nmol * Dose-normalized geometric mean AUC for h / L / mg 0-inf,norm The present invention provides a pharmaceutical composition containing the compound that exhibits the above characteristics. When administered as a single dose to a fasted human, the dose-normalized C is 13-80 nmol / L / mg. max,norm ; and 10⁶ to 287 nmol * Dose-normalized AUC of h / L / mg 0-inf,norm The following equation (I.9) shows this:

[0043] [ka] (I.9)

[0044] The present invention provides a pharmaceutical composition containing the compound of formula (I.9). In one embodiment, when the pharmaceutical composition is administered as a single dose to a fasted human, the dose-normalized C over a dose range of 2.5 mg to 50 mg of the compound of formula (I.9) is provided. max,norm and the dose-normalized AUC 0-inf,norm This indicates. When administered as a single dose to a fasted human, the following formula (I.9)

[0045] [ka] (I.9)

[0046] The compound was dose-normalized to 13-80 nmol / L / mg over a dose range of 5 mg to 25 mg. max,norm ; and 10⁶ to 287 nmol * Dose-normalized AUC of h / L / mg0-inf,norm To provide a pharmaceutical composition comprising the compound, which exhibits When administered to a fasting human as a single dose, the dose-normalized geometric mean C is 20 - 37 nmol / L / mg max,norm ; and 150 - 266 nmol * The dose-normalized geometric mean AUC is 150 - 266 nmol 0-inf,norm To provide a pharmaceutical composition comprising a compound of the following formula (I.9), which exhibits

[0047]

Chemical formula

[0048] To provide a pharmaceutical composition comprising a compound of formula (I.9). In one embodiment, when the pharmaceutical composition is administered as a single dose, the dose-normalized geometric mean C and the dose-normalized geometric mean AUC of the compound of formula (I.9) are shown over a dose range of 2.5 mg to 50 mg of the compound of formula (I.9). max,norm And the dose-normalized geometric mean AUC 0-inf,norm Are shown. When administered to a fasting human as a single dose, the dose-normalized geometric mean C is 20 - 37 nmol / L / mg over a dose range of 5 mg to 25 mg of a compound of the following formula (I.9):

[0049]

Chemical formula

[0052] The present invention provides a pharmaceutical composition containing the compound of formula (I.9). In one embodiment, when the pharmaceutical composition is administered to a fasted human in multiple doses, the dose-normalized C over a dose range of 2.5 mg to 25 mg of the compound of formula (I.9) is provided. max,ss,norm and the dose-normalized AUC τ,ss,norm This indicates. When administered multiple times to a fasted human, the dose-normalized geometric mean C is 25-27 nmol / L / mg. max,ss,norm ; and 184-200 nmol * Dose-normalized geometric mean AUC for h / L / mg τ,ss,norm The following equation (I.9) shows this:

[0053] [ka] (I.9)

[0054] The present invention provides a pharmaceutical composition containing the compound. In one embodiment, when the pharmaceutical composition is administered to a fasted human in multiple doses, the dose-normalized geometric mean C over a dose range of 2.5 mg to 25 mg of the compound of formula (I.9) is obtained. max,ss,norm and the dose normalized geometric mean AUC τ,ss,norm This indicates. The present invention provides a pharmaceutical composition as specified above, wherein the particle size distribution of the composition is X90 < 200 μm. The present invention provides a pharmaceutical composition as specified above, wherein the compound of formula (I.9) constitutes 25% or less of the mass of the composition. The following formula (I.9)

[0055] [ka] (I.9)

[0056] The present invention provides a pharmaceutical composition comprising the compound, wherein the particle size distribution of the composition is X90 < 200 μm, and the compound of formula (I.9) constitutes 25% or less of the mass of the composition. The present invention provides a pharmaceutical composition as specified above, wherein the composition comprises the crystalline form (I.9X) of the compound of formula (I.9). The present invention provides a pharmaceutical composition as specified above, wherein the particle size distribution of the composition is X90 ≤ 150 μm, X90 ≤ 100 μm, or X90 ≤ 90 μm. The present invention provides a pharmaceutical composition as specified above, wherein the compound of formula (I.9) constitutes 20% or less of the mass of the composition, or 15% or less of the mass of the composition. The present invention provides a pharmaceutical composition as specified above, wherein the particle size distribution of the composition is X90 < 100 μm, and the compound of formula (I.9) constitutes 20% or less of the composition. The present invention provides a pharmaceutical composition as specified above, wherein the particle size distribution of the composition is X90 < 90 μm, and the compound of formula (I.9) constitutes 15% or less of the composition. The present invention provides a pharmaceutical composition as specified above, wherein the composition comprises a disintegrant and a binder, and the ratio of the disintegrant to the binder is 1.5:3.5 to 1:1 (mass / mass). The present invention provides a pharmaceutical composition as specified above, wherein at least 99% (by mass) of the particles of the binder are 250 μm or smaller. The present invention provides a pharmaceutical composition as specified above, wherein the binder is hydroxypropylcellulose. The present invention provides a pharmaceutical composition as specified above, wherein the composition is obtained by high-shear wet granulation, the composition further comprises a diluent, and 5-20% (by mass) of the diluent is added to the composition as a drying additive after the wet granulation. The present invention provides a pharmaceutical composition as specified above, wherein the diluent is microcrystalline cellulose. A pharmaceutical composition as specified above, wherein the high-shear wet granulation process is as follows: (1) A step of pre-mixing the compound of formula (I.9) and the main part of the excipient, including the binder, in a mixer to obtain a pre-mixture; (2) A step of granulating the pre-mixture from step (1) by adding a granulation liquid, preferably water; (3) A step of drying the granules from step (2) in a fluidized bed dryer or drying oven; (4) A step in which the dried granules from step (3) are sieved dry as needed; (5) A step in which the dried granules from step (4) are mixed in a mixer with the remaining excipients such as a flow promoter and a lubricant to obtain the final mixture; (6) A step of forming tablets by compressing the final mixture from step (5) in a suitable tablet press to produce tablet cores; (7) A step in which the tablet core from step (6) is film-coated with a film coating agent as needed. The present invention provides a pharmaceutical composition containing [a specific compound / substance]. The present invention provides a pharmaceutical composition as specified above, wherein the composition contains the following components.

[0057] TIFF0005600328000020.tif41130

[0058] The present invention provides a pharmaceutical composition as specified above, wherein the composition contains the following components.

[0059] TIFF0005600328000021.tif46130

[0060] The present invention provides a pharmaceutical composition that conforms to the above regulations and further comprises one or more lubricants. The present invention provides a pharmaceutical composition as specified above, wherein the lubricant is magnesium stearate. The present invention provides a pharmaceutical composition that conforms to the above regulations and further comprises one or more flow promoters. The present invention provides a pharmaceutical composition as specified above, wherein the flow promoter is colloidal silicon dioxide. The present invention provides a pharmaceutical composition that conforms to the above regulations and further comprises one or more film coating agents. The present invention provides a pharmaceutical composition as specified above, wherein the film coating agent is applied at a concentration of 1 to 5%, and the composition comprises hypromellose, polyethylene glycol, talc, titanium dioxide, iron oxide, and optionally a dye.

[0061] The present invention provides a pharmaceutical dosage form containing one of the pharmaceutical compositions specified above. For example, the pharmaceutical dosage form is a tablet. This specification provides a method for treating a disease described herein, comprising the step of administering to a patient any one of the pharmaceutical compositions or pharmaceutical dosage forms specified above. A wet granulation method for producing a pharmaceutical dosage form comprising a compound of formula (I.9) and one or more excipients, comprising the following steps: (1) A step of premixing the compound of formula (I.9) and the main portion of the excipient, including the binder, in a mixer to obtain a premixture; (2) A step of granulating the pre-mixture from step (1) by adding a granulation liquid, preferably water; (3) A step of drying the granules from step (2) in a fluidized bed dryer or drying oven; (4) A step in which the dried granules from step (3) are sieved dry as needed; (5) A step in which the dried granules from step (4) are mixed with the remaining excipients in a mixer to obtain the final mixture; (6) A step of forming tablets by compressing the final mixture from step (5) in a suitable tablet press to produce tablet cores; (7) A step in which the tablet core from step (6) is film-coated with a film coating agent as needed. The present invention provides a wet granulation method that includes [a specific component]. In one embodiment, at least 99% (by mass) of the particles of the binder are 250 μm or smaller. In one embodiment, the excipient in step (1) also includes a diluent, 80-95% (by mass) of the diluent is pre-mixed with the compound of formula (I.9) in step (1), and 5-20% (by mass) of the diluent is added to the composition as a dry additive in step (5). The present invention provides a pharmaceutical composition obtained by the method specified above.

[0062] A direct compression method for producing a pharmaceutical composition comprising a compound of formula (I.9) and one or more excipients, comprising the following steps: (1) A step of pre-mixing the compound of formula (I.9) and the main portion of the excipient in a mixer to obtain a premixture; (2) A step of dry sieving the premixture through a sieve as necessary in order to separate agglomerating particles and to improve the uniformity of content; (3) Mixing the pre-mixture from step (1) or (2) in a mixer, and continuing to mix by adding any remaining excipients to the mixture as needed; (4) A step of forming tablets by compressing the final mixture from step (3) in a suitable tablet press to produce tablet cores; (5) A step in which the tablet core from step (4) is film-coated with a film coating agent as needed. This provides a method that includes this. The present invention provides a pharmaceutical composition obtained by the method specified above.

[0063] A dry granulation method for producing a pharmaceutical composition comprising a compound of formula (I.9) and one or more excipients, comprising the following steps: (1) A step of mixing all or part of the compound of formula (I.9) with the excipient in a mixer; (2) The process of compressing the mixture from step (1) using a suitable roller compressor; (3) A process of turning the ribbon obtained in process (2) into granules by an appropriate milling or sieving process; (4) The granules from step (3) are mixed with the remaining excipients in a mixer as needed to obtain the final mixture; (5) A step of forming tablets by compressing the granules from step (3) or the final mixture from step (4) in a suitable tablet press to produce tablet cores; (6) A step in which the tablet core from step (5) is film-coated with a film coating agent as needed. This provides a method that includes this. The present invention provides a pharmaceutical composition obtained by the method specified above.

[0064] (definition) In this specification, the term "active ingredient" in the pharmaceutical composition of the present invention means the SGLT2 inhibitor of the present invention. In this specification, the "active ingredient" may also be referred to as the "active substance." In human patients, the "body mass index" or "BMI" is defined as weight (in kilograms) divided by the square of height (in meters), so BMI is kg / m 2 It has units of . The term "overweight" refers to an individual weighing 25 kg / m² or more. 2 More than 30kg / m 2 It is defined as having a BMI below a certain level. The terms "overweight" and "pre-obese" are used interchangeably. The term "obese" refers to an individual weighing 30 kg / m² or more. 2 It is defined as having a BMI of 30 kg / m² or higher. According to the WHO definition, the term "obesity" is classified as follows: The term "Class I obesity" is defined as having a BMI of 30 kg / m² or higher. 2 More than 35kg / m 2 This refers to a state below; the term "Class II obesity" is defined as a BMI of 35 kg / m². 2 More than 40kg / m 2 This refers to a state below; the term "Class III obesity" is defined as a BMI of 40 kg / m². 2 The above is the current situation. The term "visceral obesity" is defined as a waist-to-hip ratio of 1.0 or higher for men and 0.8 or higher for women. It is associated with an increased risk of insulin resistance and the development of prediabetes. The term "abdominal obesity" is usually defined as a waist circumference of >40 inches or 102 cm for men and >35 inches or 94 cm for women. For Japanese ethnicity or Japanese patients, abdominal obesity is defined as a waist circumference of ≥85 cm for men and ≥90 cm for women (see, for example, the Japanese Committee for the Diagnosis and Research of Metabolic Syndromes). The term "normal blood glucose" is defined as a state in which the subject has a fasting blood glucose concentration that is higher than 70 mg / dL (3.89 mmol / L) but lower than 100 mg / dL (5.6 mmol / L), which is within the normal range. The term "fasting" has its usual meaning as a medical term. The term "hyperglycemia" is defined as a condition in which a subject has a fasting blood glucose concentration higher than 100 mg / dL (5.6 mmO1 / L), exceeding the normal range. The term "fasting" has its usual meaning as a medical term. The term "hypoglycemia" is defined as a condition in which the subject has a blood glucose concentration below the normal range of 60-115 mg / dL (3.3-6.3 mmol / L). The term "postprandial hyperglycemia" is defined as a condition in which the subject has a blood glucose or serum glucose concentration higher than 200 mg / dL (11.11 mmol / L) two hours after a meal. The term "abnormal fasting blood glucose" or "IFG" is defined as a condition in which the subject has a fasting blood glucose concentration or fasting serum glucose concentration in the range of 100-125 mg / dl (i.e., 5.6-6.9 mmol / l), particularly higher than 110 mg / dL and less than 126 mg / dL (7.00 mmol / L). "Normal fasting glucose" refers to a fasting glucose concentration of less than 100 mg / dl, i.e., less than 5.6 mmol / l.

[0065] The term "impaired glucose tolerance" or "IGT" is defined as a condition in which a subject has a 2-hour postprandial blood glucose or serum glucose concentration higher than 140 mg / dL (7.78 mmol / L) and less than 200 mg / dL (11.11 mmol / L). Abnormal glucose tolerance, i.e., 2-hour postprandial blood glucose or serum glucose concentration, can be measured as blood glucose levels in mg of glucose per dL of plasma 2 hours after ingesting 75 g of glucose after fasting. Subjects with "normal glucose tolerance" have a 2-hour postprandial blood glucose or serum glucose concentration of less than 140 mg / dL (7.78 mmol / L). The term "hyperinsulinemia" is defined as a condition in which individuals with insulin resistance (whether or not they have normal blood glucose levels) have higher fasting or postprandial serum or plasma insulin concentrations than normal, lean individuals without insulin resistance who have a waist-to-hip ratio of <1.0 (males) or <0.8 (females). The terms "insulin sensitization," "improvement of insulin resistance," and "reduction of insulin resistance" are synonymous and can be used interchangeably. The term "insulin resistance" is defined as a condition in which circulating insulin levels exceeding the normal response to glucose loading are required to maintain normal blood glucose levels (Ford ES, et al. JAMA. (2002) 287:356-9). The method for determining insulin resistance is the euglycemic-hyperinsulinemia clamp test. The insulin-to-glucose ratio is determined within the range of the combined insulin-glucose infusion method. Insulin resistance is indicated when glucose absorption is below the 25th percentile of the background population being investigated (WHO definition). A so-called minimal model, which involves measuring the concentrations of insulin and glucose in the blood at regular time intervals during an intravenous glucose tolerance test and calculating insulin resistance from these values, is less cumbersome than the clamp test. However, this method cannot distinguish between hepatic insulin resistance and peripheral insulin resistance. Furthermore, insulin resistance, the response to treatment in insulin-resistant patients, insulin sensitivity, and hyperinsulinemia can be quantified by evaluating the "Homeostasis Model Assessment to Insulin Resistance (HOMA-IR)" score, a reliable indicator of insulin resistance (Katsuki A, et al. Diabetes Care 2001; 24: 362-5). See also the method for determining the HOMA-IR for insulin sensitivity (Matthews et al., Diabetologia 1985, 28: 412-19), the method for determining the unchanged proinsulin to insulin ratio (Forst et al., Diabetes 2003, 52(Suppl.1): A459), and the euglycemic clamp test. In addition, plasma adiponectin levels can be monitored as a promising surrogate for insulin sensitivity. The formula is as follows: HOMA-IR = [Fasting serum insulin (μU / mL)] × [Fasting plasma glucose (mmol / L) / 22.5] The insulin resistance is estimated using the insulin resistance index (HOMA)-IR score (Galvin P, et al. Diabet Med 1992;9:921-8). As a general rule, other parameters are used in daily clinical practice to assess insulin resistance. For example, since elevated triglyceride levels are significantly correlated with the presence of insulin resistance, the patient's triglyceride concentration is preferably used.

[0066] Patients with a predisposition to developing IGT, IFG, or type 2 diabetes are those who have normal blood glucose and hyperinsulinemia and, by definition, are insulin resistant. Typical patients with insulin resistance are usually overweight or obese. If insulin resistance can be detected, this is a particularly strong sign of the presence of prediabetes. Therefore, such individuals require 2 to 3 times more insulin than healthy individuals to maintain glucose homeostasis, otherwise they may develop some clinical symptoms. Methods for investigating pancreatic β-cell function are similar to those for insulin sensitivity, hyperinsulinemia, or insulin resistance: for example, improvements in β-cell function can be measured by determining the HOMA index (Matthews et al., Diabetologia 1985, 28: 412-19), the ratio of unchanged proinsulin to insulin (Forst et al., Diabetes 2003, 52(Suppl.1): A459), insulin / C-peptide secretion after an oral glucose tolerance test or a meal tolerance test, or by utilizing minimal modeling after a hyperglycemic clamp test and / or a high-frequency sampling intravenous glucose tolerance test (Stumvoll et al., Eur J Clin Invest 2001, 31: 380-81). The term "prediabetes" refers to a condition in which an individual is predisposed to developing type 2 diabetes. Prediabetes expands the definition of impaired glucose tolerance to include individuals with high fasting blood glucose levels within the normal range (≧100 mg / dL) (JB Meigs, et al. Diabetes 2003; 52:1475-1484) and fasting hyperinsulinemia (elevated plasma insulin concentration). The scientific and medical basis for identifying prediabetes as a significant health threat is described in the Position Statement titled "The Prevention or Delay of Type 2 Diabetes," jointly published by the American Diabetes Association and the National Institute of Diabetes and Digestive and Kidney Diseases (Diabetes Care 2002; 25:742-749).

[0067] Individuals who may have insulin resistance are those who have two or more of the following characteristics: 1) overweight or obesity, 2) hypertension, 3) hyperlipidemia, and 4) one or more first-degree relatives diagnosed with IGT, IFG, or type 2 diabetes. In these individuals, insulin resistance can be confirmed by calculating the HOMA-IR score. For the purposes of this invention, insulin resistance is defined as a clinical condition in which an individual has a HOMA-IR score > 4.0 or a HOMA-IR score that exceeds the upper limit of normal as defined for laboratories performing glucose and insulin assays. The term "type 2 diabetes" is defined as a condition in which a subject has a fasting blood glucose or serum glucose concentration higher than 125 mg / dL (6.94 mmol / L). Blood glucose measurement is a standard procedure in routine medical analysis. In an oral glucose tolerance test, the blood glucose level of a diabetic patient will exceed 200 mg of glucose per dL of plasma (11.1 mmol / L) two hours after ingesting 75 g of glucose into an empty stomach. In an oral glucose tolerance test, 75 g of glucose is orally administered to the subject after 10-12 hours of fasting, and blood glucose levels are recorded immediately before glucose intake and one and two hours after glucose intake. In healthy subjects, the blood glucose level before glucose intake is 60-110 mg per dL of plasma, less than 200 mg / dL one hour after glucose intake, and less than 140 mg / dL two hours after glucose intake. If the blood glucose level is 140-200 mg / dL two hours after glucose intake, this is considered impaired glucose tolerance. The term "late-stage type 2 diabetes" includes patients who have failed with secondary medications, those who require insulin therapy, and those who have progressed to microvascular and macrovascular complications, such as diabetic nephropathy or coronary heart disease (CHD).

[0068] The term "HbA1c" refers to the non-enzymatic glycation product of the hemoglobin B chain. Its quantitative method is well known to those skilled in the art. HbA1c levels are extremely important when monitoring the treatment of diabetes. Since its production is essentially dependent on blood glucose levels and the life of red blood cells, HbA1c, meaning "blood glucose memory," reflects the average blood glucose level over the preceding 4-6 weeks. Diabetic patients whose HbA1c levels are consistently well-regulated by intensive diabetes treatment (i.e., total hemoglobin in the sample <6.5%) are significantly better protected against diabetic microangiopathy. For example, metformin alone achieves an average improvement of the order of 1.0-1.5% in HbA1c levels in diabetic patients. This reduction in HbA1c levels is not sufficient for all diabetic patients to achieve the desired target range of HbA1c levels <6.5%, preferably <6%. Within the scope of this invention, "insufficient blood glucose control" or "inappropriate blood glucose control" means a state in which a patient has an HbA1c value of more than 6.5%, particularly more than 7.0%, more preferably more than 7.5%, and particularly more than 8%. Also known as "Syndrome X" (when used in the context of metabolic disorders) and "metabolic disorder syndrome," metabolic syndrome is a complex syndrome characterized by insulin resistance (Laaksonen DE, et al. Am J Epidemiol 2002;156:1070-7). According to the ATP III / NCEP guidelines (Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) JAMA: Journal of the American Medical Association (2001) 285:2486-2497), metabolic syndrome is diagnosed when three or more of the following risk factors are present. 1. Abdominal obesity defined as a waist circumference of >40 inches or 102 cm for men and >35 inches or 94 cm for women; or, in the case of Japanese ethnicity or Japanese patients, a waist circumference of ≥85 cm for men and ≥90 cm for women; 2. Triglycerides: ≥150 mg / dL 3. In men, HDL cholesterol <40 mg / dL 4. Blood pressure ≥ 130 / 85 mmHg (SBP ≥ 130 or DBP ≥ 85) 5. Fasting blood glucose ≥100mg / dL. The NCEP definition has been validated (Laaksonen DE, et al. Am J Epidemiol. (2002) 156:1070-7). Triglycerides and HDL cholesterol in the blood can also be determined using standard medical analytical methods, for example, as described in Thomas L (Editor): “Labor und Diagnose”, TH-Books Verlagsgesellschaft mbH, Frankfurt / Main, 2000. According to the commonly used definition, hypertension is diagnosed when systolic blood pressure (SBP) exceeds 140 mmHg and diastolic blood pressure (DBP) exceeds 90 mmHg. If the patient has overt diabetes, it is currently recommended to reduce systolic blood pressure to below 130 mmHg and diastolic blood pressure to below 80 mmHg.

[0069] Within the scope of this invention, the term "SGLT2 inhibitor" relates to compounds, particularly glucopyranosyl derivatives, i.e., compounds having a glucopyranosyl component that exhibits inhibitory activity against sodium glucose transporter 2 (SGLT2), particularly human SGLT2. The inhibitory activity against hSGLT2, as measured as IC50, is preferably less than 1000 nM, more preferably less than 100 nM, and most preferably less than 50 nM. The inhibitory activity against hSGLT2 can be determined by methods known in the literature, particularly as described in applications WO2005 / 092877 or WO2007 / 093610 (pages 23 / 24) (the entirety of which is incorporated herein by reference). The term "SGLT2 inhibitor" includes any pharmaceutically acceptable salt thereof, its hydrate and solvate, and also encompasses their respective crystalline forms.

[0070] The terms “treatment” and “to treat” include treatments for patients who have already developed the manifest form of the aforementioned condition. Treatments may be symptomatic treatments to alleviate the symptoms of a specific indication, or causal treatments to reverse or partially reverse the state of the indication, or to halt or slow the progression of the disease. Accordingly, the compositions and methods of the present invention can be used, for example, as long-term treatments and for chronic treatments. The terms “treat preventively,” “preventive treatment,” and “prevention” are used interchangeably and include treating patients at risk of developing the aforementioned conditions, thereby reducing such risk. The term "tablet" includes uncoated tablets and tablets with one or more coatings. Furthermore, the term "tablet" includes tablets having one, two, three, or four or more layers and pre-coated tablets, each of which may or may not contain one or more coatings. The term "tablet" also includes mini, melt, chewable, effervescent, and orally disintegrating tablets. The terms "pharmacopoe" and "pharmacopoeia" refer to standard pharmacopoeias, such as "USP 31-NF 26 with Supplement 2" (United States Pharmacopeial Convention) or "European Pharmacopoeia 6.3" (European Directorate for the Quality of Medicines and Health Care, 2000-2009).

Brief Description of the Drawings

[0071] [Figure 1] The X-ray powder diffractogram of the crystalline form (I.9X) of compound (I.9) is shown. [Figure 2] The thermal analysis by DSC and determination of the melting point of the crystalline form (I.9X) of compound (I.9) are shown. [Figure 3A] The results of blood glucose values upon administration of the compounds of the present invention to ZDF rats are shown. [Figure 3B] The results of blood glucose AUC upon administration of the compounds of the present invention to ZDF rats are shown.

Modes for Carrying Out the Invention

[0072] (Detailed Description) Aspects of the present invention, particularly pharmaceutical compositions, methods and uses, relate to SGLT2 inhibitors as defined above and below. Preferably the SGLT2 inhibitor is of the following formula (I)

[0073]

Chemical Formula

[0074] (wherein R 1 represents Cl, methyl or cyano; R 2 represents H, methyl, methoxy or hydroxy, and R 3 represents (R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy) A glucopyranosyl-substituted benzene derivative; or selected from one of the SGLT2 inhibitor prodrugs. Compounds of formula (I) and methods for synthesizing them are described, for example, in the following patent applications: WO2005 / 092877, WO2006 / 117360, WO2006 / 117359, WO2006 / 120208, WO2006 / 064033, WO2007 / 031548, WO2007 / 093610, WO2008 / 020011, WO2008 / 055870. In the glucopyranosyl-substituted benzene derivative of formula (I) above, the following definitions of substituents are preferred. Preferably R 1 This represents chloro or cyano, especially chloro. Preferably R 2 This represents H. Preferably R 3 This represents (R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy. Preferred glucopyranosyl-substituted benzene derivatives of formula (I) are selected from the group of compounds (I.8) to (I.11) listed below.

[0075] [ka]

[0076] A more preferred glucopyranosyl-substituted benzene derivative of formula (I) is selected from compounds (I.8), (I.9), and (I.11). A more preferred glucopyranosyl-substituted benzene derivative of formula (I) is selected from compounds (I.8) and (I.9). With this invention, the definition of the glucopyranosyl-substituted benzene derivatives of formula (I) above should be interpreted to include their hydrates, solvates, and polymorphs, as well as their prodrugs. A preferred crystalline form of preferred compound (I.8) is described in international patent application WO2006 / 117360 (which is incorporated herein by reference in its entirety). A preferred crystalline form of preferred compound (I.9) is described in international patent application WO2006 / 117359 (which is incorporated herein by reference in its entirety). A preferred crystalline form of preferred compound (I.11) is described in international patent application WO2008 / 049923 (which is incorporated herein by reference in its entirety). These crystalline forms have good solubility properties that enable good bioavailability of SGLT2 inhibitors. Furthermore, because these crystalline forms are physicochemically stable, they result in good shelf-life stability of the pharmaceutical composition. To avoid any doubt, each of the disclosures of the aforementioned references cited above in relation to the identified SGLT2 inhibitors is incorporated herein by reference in their entirety. The preferred crystalline form (I.9X) of compound (I.9) is characterized by an X-ray powder diffraction pattern containing peaks at 18.84, 20.36, and 25.21 degrees 2Θ (±0.1 degrees 2Θ). Here, the X-ray powder diffraction pattern (XRPD) is characterized by CuK α1 It is made using lines. In particular, the X-ray powder diffraction pattern includes peaks at 14.69, 18.84, 19.16, 19.50, 20.36 and 25.21 degrees 2Θ (±0.1 degrees 2Θ). Here, the X-ray powder diffraction pattern (XRPD) is CuK α1 It is made using lines. In particular, the X-ray powder diffraction pattern includes peaks at 14.69, 17.95, 18.43, 18.84, 19.16, 19.50, 20.36, 22.71, 23.44, 24.81, 25.21 and 25.65 degrees 2Θ (±0.1 degrees 2Θ). Here, the X-ray powder diffraction pattern (XRPD) is CuK α1 It is made using lines. More specifically, the crystal form (I.9X) contains a peak at degree 2Θ (±0.1 degrees 2Θ) as shown in Table 1, CuK α1 It is characterized by the X-ray powder diffraction pattern created using a line.

[0077] Table 1: X-ray powder diffraction pattern of crystal form (I.9X) (only peaks up to 30°2Θ are shown): TIFF0005600328000024.tif196143

[0078] More specifically, the crystal form (I.9X) contains a peak at degree 2Θ (±0.1 degrees 2Θ) as shown in Figure 1, and is CuK α1 It is characterized by the X-ray powder diffraction pattern created using a line. Furthermore, the crystalline form (I.9X) is characterized by a melting point of approximately 149°C ± 3°C (determined by DSC; evaluated as the starting temperature; heating rate 10 K / min). The obtained DSC curve is shown in Figure 2. Within the scope of the present invention, position-sensitive detectors (OEDs) and X-ray sources (CuK α1 The X-ray powder diffraction pattern was recorded using a transmission-mode STOE-STADI P-diffractometer equipped with a Cu anode (linear, λ=1,54056 Å, 40 kV, 40 mA). In Table 1 above, the value "2Θ[°]" represents the diffraction angle in degrees, and the value "d[Å]" represents the specific distance in Å between lattice planes. The intensity shown in Figure 1 is given in units of cps (counts per second). To account for experimental errors, the above 2Θ values ​​should be considered to be precisely ±0.1 degrees 2Θ, and especially ±0.05 degrees 2Θ. That is, when evaluating whether a given sample of the crystal of compound (I.9) is the crystal form of the present invention, if the experimentally observed 2Θ value for the sample falls within the range of ±0.1 degrees 2Θ of the above characteristic value, and especially within the range of ±0.05 degrees 2Θ of the above characteristic value, then the sample should be considered identical to the above characteristic value. The melting point is determined by differential scanning calorimetry (DSC) using a DSC 821 (Mettler Toledo) machine.

[0079] In one embodiment, the pharmaceutical composition or dosage form of the present invention comprises compound (I.9), wherein at least 50% by mass of compound (I.9) is in the form of its crystalline form (I.9X) as defined above. Preferably, in the composition or dosage form, at least 80% by mass, and more preferably at least 90% by mass, of compound (I.9) is in the form of its crystalline form (I.9X) as defined above. With respect to active pharmaceutical ingredients, it is understood that the solubility properties of the pharmaceutical composition and dosage form are particularly influenced by the particle size and particle size distribution of each active pharmaceutical ingredient. In the pharmaceutical composition and dosage form of the present invention, the active pharmaceutical ingredients preferably have a particle size distribution such that, with respect to volume distribution, at least 90% of each active pharmaceutical ingredient particle has a particle size of less than 200 μm, i.e., X90 < 200 μm. In particular, with respect to glucopyranosyl-substituted benzene derivatives of formula (I), especially compound (I.9) or its crystalline form (I.9X), particle size, particularly particle size and particle size distribution, affects manufacturability. It has been found that particles that are too small, especially many particles that are too small (e.g., so-called "fine particles," i.e., particles smaller than 63 μm), affect manufacturability due to sticking or filming during tablet formation. On the other hand, particles that are too large adversely affect the solubility of the pharmaceutical composition and dosage form, and consequently, its bioavailability. The preferred range of particle size distribution is described below. Accordingly, in one embodiment, the pharmaceutical composition and pharmaceutical dosage form of the present invention preferably has a particle size distribution (by volume) such that at least 90% of each active pharmaceutical component has a particle size of less than 200 μm, i.e., X90 < 200 μm, preferably X90 ≤ 150 μm. More preferably, the particle size distribution is X90 ≤ 100 μm, and even more preferably X90 ≤ 90 μm. In addition, a particle size distribution of X90 ≥ 1 μm, more preferably X90 ≥ 5 μm, and even more preferably X90 ≥ 10 μm is preferred. Therefore, a particle size distribution such that 1μm≦X90<200μm, particularly 1μm≦X90≦150μm, more preferably 5μm≦X90≦150μm, even more preferably 5μm≦X90≦100μm, and even more preferably 10μm≦X90≦100μm is preferred. A preferred example is X90≦75μm. Another preferred example is 20μm≦X90≦50μm. Another particle size of the present invention is 10μm≦X90≦75μm. Another particle size of the present invention is 60μm≦X90≦150μm. Furthermore, in the pharmaceutical compositions and dosage forms of the present invention, the glucopyranosyl-substituted benzene derivative of formula (I), particularly compound (I.9), preferably its crystalline form (I9.X), has a particle size distribution (by volume) such that X50 ≤ 90 μm, more preferably X50 ≤ 75 μm, even more preferably X50 ≤ 50 μm, and most preferably X50 ≤ 40 μm. In addition, a particle size distribution such that X50 ≥ 1 μm, more preferably X50 ≥ 5 μm, and even more preferably X50 ≥ 8 μm is preferred. Therefore, a preferred particle size distribution is 1 μm ≤ X50 ≤ 90 μm, particularly 1 μm ≤ X50 ≤ 75 μm, more preferably 5 μm ≤ X50 ≤ 75 μm, and even more preferably 5 μm ≤ X50 ≤ 50 μm. A preferred example is 8 μm ≤ X50 ≤ 40 μm. Furthermore, in the pharmaceutical composition and pharmaceutical dosage form of the present invention, the glucopyranosyl-substituted benzene derivative of formula (I), particularly compound (I.9), preferably its crystalline form (I9.X), has a particle size distribution (by volume) such that X10 ≥ 0.1 μm, more preferably X10 ≥ 0.5 μm, even more preferably X10 ≥ 1 μm, and particularly X10 ≥ 2 μm. In addition, a particle size distribution such that X10 ≤ 10 μm, and more preferably X10 ≤ 5 μm, is preferred. Therefore, a preferred particle size distribution is 0.5 μm ≤ X10 ≤ 10 μm, and particularly 1 μm ≤ X10 ≤ 5 μm. Accordingly, the pharmaceutical composition or pharmaceutical dosage form of this invention is preferably characterized by the above particle size distribution X90, X50 and / or X10 or one of the embodiments described below.

[0080] TIFF0005600328000025.tif87110

[0081] The value X90 represents the 90th percentile of the volume distribution measured using a laser diffractometer. In other words, for the purposes of this invention, the X90 value represents the particle size at which 90% of the particle amount is less than its particle size based on the volume distribution. Similarly, the X50 value represents the 50th percentile (median) of the volume distribution measured using a laser diffractometer. In other words, for the purposes of this invention, the X50 value represents the particle size at which 50% of the particle amount is less than its particle size based on the volume distribution. Similarly, the X10 value represents the 10th percentile of the volume distribution measured using a laser diffractometer. In other words, for the purposes of this invention, the X10 value represents the particle size at which 10% of the particle amount is less than its particle size based on the volume distribution. Preferably, all X90, X50, and X10 values ​​described above and below are volume-dependent and determined by laser diffraction, particularly low-angle laser scattering, i.e., Fraunhofer diffraction. Preferred tests are described in the experimental section. Laser diffraction is sensitive to particle volume and gives volume-average particle size. This is equivalent to mass-average particle size when density is constant. Those skilled in the art know that the results of determining particle size distribution by one technique may correlate with the results of another technique based, for example, on empirical evidence from routine experiments. Alternatively, the particle size distribution of a pharmaceutical composition or dosage form can be determined by microscopy, particularly by electron microscopy or scanning electron microscopy.

[0082] The following describes in more detail the excipients and carriers suitable for the pharmaceutical composition of the present invention. The pharmaceutical composition of the present invention typically comprises one or more diluents, one or more disintegrants, and optionally one or more binders. Some excipients have two or more functions simultaneously, for example, acting as both a filler and a binder. Suitable diluents (also called fillers) of the present invention include, for example, lactose, especially lactose monohydrate; cellulose and derivatives, such as powdered cellulose, microcrystalline cellulose or silicified microcrystalline cellulose; cellulose acetate; starch and derivatives, such as pregelatinized starch, corn starch, wheat starch, rice starch, potato starch, sterilized corn; sodium chloride; calcium carbonate; calcium phosphate, especially dibasic calcium phosphate; calcium sulfate, dicalcium phosphate or tricalcium phosphate; magnesium carbonate; magnesium oxide; sugars and derivatives, such as powdered sugar; fructose; sucrose; dextrate; dextrin; D-sorbitol sulfobutyl ether β-cyclodextrin; dextrose; polydextrose; trehalose; maltose; maltitol; mannitol; maltodextrin; sorbitol; inulin; xylitol; erythritol; isomalt; kaolin; and lactitol. Preferred diluents are lactose monohydrate and microcrystalline cellulose. Suitable disintegrants of the present invention include, for example, powdered cellulose, crospovidone, croscarmellose sodium, doxate sodium, low-substituted hydroxypropyl cellulose, aluminum magnesium silicate, microcrystalline cellulose, polacrilin potassium, sodium starch glycolate, starch, especially pregelatinized starch and corn starch. A preferred disintegrant is croscarmellose sodium. Any binder commonly used in pharmaceutical compositions may be used in the context of this invention. Binders include, for example, naturally occurring or partially or entirely synthetic polymers such as acacia, agar, alginic acid, carbomer, carmellose sodium, carrageenan, cellulose acetate phthalate, ceratonia, chitosan, powdered sugar, copovidone, povidone, cottonseed oil, dextrate, dextrin, dextrose, polydextrose, maltodextrin, maltose, cellulose and its derivatives, such as microcrystalline cellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxyethylmethylcellulose, hydroxypropylcellulose, and carboxymethylcellulose. The following are selected from rose, hypromellose (cellulose hydroxypropyl methyl ether), starch and its derivatives, such as pregelatinized starch, hydroxypropyl starch, corn starch, gelatin, glyceryl behenate, tragacanth, guar gum, hydrogenated vegetable oil, inulin, poloxamer, polycarbophil, polyethylene oxide, polyvinylpyrrolidone, copolymer of N-vinylpyrrolidone and vinyl acetate, polymethacrylate, polyethylene glycol, alginates, such as sodium alginate, gelatin, sucrose, sunflower oil, zein, and their derivatives and mixtures. Preferred binders are microcrystalline cellulose and hydroxypropyl cellulose.

[0083] In one aspect, a fine particle size binder for the preparation of a pharmaceutical composition or dosage form is used to reduce the amount of small particles. Thus, in one embodiment, the binder in the composition of the present invention is a fine particle size binder, and the present invention provides a pharmaceutical composition comprising a glucopyranosyl-substituted benzene derivative of formula (I), particularly compound (I.9) or its crystalline form (I.9X), and a fine particle size binder. In one embodiment, at least 99% (by mass) of the particles of the binder are 250 μm or less. In one embodiment, at least 99.5% of the particles of the binder are 250 μm or less. For example, the binder in the composition of the present invention is hydroxypropylcellulose Klucel EXF. Another example of a fine particle size binder is Copovidone Kollidon VA 64 Fine. In one aspect, the present invention uses low viscosity hydroxypropylcellulose. Several grades of hydroxypropylcellulose with different molecular weight values, such as 80,000, 95,000, 140,000, 370,000, 850,000 and 1,150,000, are available. Low molecular weight hydroxypropylcellulose has low viscosity, and high molecular weight hydroxypropylcellulose becomes highly viscous. In the pharmaceutical composition or dosage form of the present invention, low viscosity of hydroxypropylcellulose is preferred. Thus, in one embodiment, a hydroxypropylcellulose grade with a molecular weight of 370,000 or less is used in the pharmaceutical composition or dosage form of the present invention. In another embodiment, a hydroxypropylcellulose grade with a molecular weight of 140,000 or less is used in the pharmaceutical composition or dosage form of the present invention. In another embodiment, a hydroxypropylcellulose grade with a molecular weight value of 80,000 or 95,000 is used in the pharmaceutical composition or dosage form of the present invention.

[0084] The pharmaceutical composition of the present invention may contain one or more lubricants. Suitable lubricants of the present invention include stearic acid and its salts, talc, sodium stearate, calcium stearate, zinc stearate, magnesium stearate, sodium stearyl fumarate, glyceryl monostearate, especially magnesium stearate, polyethylene glycol, especially polyethylene glycol with a molecular weight in the range of about 4400 to about 9000, hydrogenated castor oil, fatty acids, such as fumaric acid, and salts of fatty acids, especially calcium, magnesium, sodium or potassium salts of fatty acids, such as calcium behenate, calcium stearate, sodium stearyl fumarate or magnesium stearate (e.g., HyQual®, Mallinckrodt), glycerides, such as glyceryl behenate (Compritol® 888), Dynasan® 118 or Boeson® VP. The pharmaceutical composition of the present invention may contain one or more flow promoters. Suitable flow promoters of the present invention include silicon dioxide, particularly colloidal silicon dioxide (e.g., Aerosil®, Cab-O-Sil®), stearic acid, and salts thereof, including sodium stearate, calcium stearate, zinc stearate, magnesium stearate, magnesium silicate, calcium silicate, magnesium trisilicate, and talc. Preferred flow promoters are colloidal silicon dioxide and talc. In another embodiment, the pharmaceutical composition of the present invention comprises the following components.

[0085] TIFF0005600328000026.tif41127

[0086] In one embodiment, the active ingredient is a compound of formula (I), for example, formula (I.9), or its crystalline form (I.9X). In another embodiment, the pharmaceutical composition of the present invention comprises the following components.

[0087] TIFF0005600328000027.tif41127

[0088] In one embodiment, the active ingredient is a compound of formula (I), for example, formula (I.9), or its crystalline form (I.9X). In another embodiment, the pharmaceutical composition of the present invention comprises the following components.

[0089] TIFF0005600328000028.tif41127

[0090] The active ingredient is a compound of formula (I), for example, formula (I.9), or its crystalline form (I.9X). In another embodiment, the pharmaceutical composition of the present invention comprises the following components.

[0091] TIFF0005600328000029.tif41127

[0092] In one embodiment, the active ingredient is a compound of formula (I), for example, formula (I.9), or its crystalline form (I.9X). In another embodiment, the pharmaceutical composition of the present invention comprises the following components.

[0093] TIFF0005600328000030.tif46127

[0094] In one embodiment, the active ingredient is a compound of formula (I), for example, formula (I.9), or its crystalline form (I.9X). In another embodiment, the pharmaceutical composition of the present invention comprises the following components.

[0095] TIFF0005600328000031.tif46127

[0096] In one embodiment, the active ingredient is a compound of formula (I), for example, formula (I.9), or its crystalline form (I.9X). In another embodiment, the pharmaceutical composition of the present invention comprises the following components.

[0097] TIFF0005600328000032.tif46127

[0098] In one embodiment, the active ingredient is a compound of formula (I), for example, formula (I.9), or its crystalline form (I.9X). In another embodiment, the pharmaceutical composition of the present invention comprises the following components.

[0099] TIFF0005600328000033.tif46127

[0100] In one embodiment, the active ingredient is a compound of formula (I), for example, formula (I.9), or its crystalline form (I.9X). In another embodiment, the pharmaceutical composition of the present invention comprises the following components.

[0101] TIFF0005600328000034.tif46127

[0102] In one embodiment, the active ingredient is a compound of formula (I), for example, formula (I.9), or its crystalline form (I.9X). In one embodiment, the ratio of the disintegrant to the binder in the pharmaceutical composition of the present invention is 1.5:3.5 to 1:1. In one embodiment, it was found that with respect to glucopyranosyl-substituted benzene derivatives of formula (I), particularly compound (I.9) or its crystalline form (I.9X), the amount of the active ingredient affects the manufacturability of the pharmaceutical composition or dosage form, and that particularly high concentrations of the active ingredient affect manufacturability due to adhesion or filming during tablet formation. Therefore, in one embodiment, the active ingredient corresponds to 25% or less of the mass of the pharmaceutical composition. In another embodiment, the active ingredient corresponds to 20% or less of the mass of the pharmaceutical composition, preferably 15% or less. Preferably, the active ingredient corresponds to 0.5% to 25% of the mass of the pharmaceutical composition. More preferably, the active ingredient corresponds to 1.0% to 20% of the mass of the pharmaceutical composition. Even more preferably, the active ingredient corresponds to 2.0% to 15% of the mass of the pharmaceutical composition. The following indicates preferred ranges for the amount of glucopyranosyl-substituted benzene derivative used in the pharmaceutical dosage forms of this invention. These ranges represent the amount to be administered daily to an adult patient, particularly a person weighing approximately 70 kg, and can be adapted accordingly to administration frequency of 2, 3, 4 or more times per day, as well as to other routes of administration and the patient's age. The drug dose and amount range are calculated in accordance with the active ingredient. The preferred amount of glucopyranosyl-substituted benzene derivative, particularly compound (I.9) or its crystalline form (I.9X), is in the range of 0.5 to 100 mg, preferably 0.5 to 50 mg, more preferably 1 to 25 mg, and even more preferably 5 to 25 mg. Preferred drug doses of glucopyranosyl-substituted benzene derivative are, for example, 1 mg, 2 mg, 2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg, 20 mg, 25 mg, and 50 mg. The pharmaceutical composition of the present invention may be included in tablets, capsules, or film-coated tablets. In one embodiment, a tablet containing the pharmaceutical composition of the present invention contains a lubricant such as magnesium stearate. The lubricant may be present in the tablet at a concentration of 0.25 to 2%. In one embodiment, a tablet containing the pharmaceutical composition of the present invention contains a flow promoter such as colloidal silicon dioxide. The flow promoter may be present in the tablet at a concentration of 0.25 to 2%. The tablets of the present invention may be film-coated. Typically, the film coating accounts for 2 to 5% by mass of the total composition and preferably includes a film-forming agent, a plasticizer, an anti-tackifying agent, and optionally one or more dyes. A typical coating composition may include hydroxypropyl methylcellulose (HPMC), polyethylene glycol (PEG), talc, titanium dioxide, and optionally iron oxides (including iron red and / or yellow). For example, the film coating of the present invention contains 50% hypromellose, 5% macrogol, 24.75% titanium dioxide, 20% talc, and 0.25% iron oxide yellow (Opadry yellow 02B38190). In one embodiment, the film coating of the present invention comprises the following components.

[0103] TIFF0005600328000035.tif41127

[0104] In one embodiment, the pharmaceutical dosage form of the present invention has solubility properties such that at least 75% by mass, preferably at least 90% by mass, of the pharmaceutically active ingredient dissolves after 45 minutes. In another embodiment, at least 75% by mass, preferably at least 90% by mass, of the pharmaceutically active ingredient dissolves after 30 minutes. In yet another embodiment, at least 65% by mass, preferably at least 75% by mass, preferably at least 80% by mass, of the pharmaceutically active ingredient dissolves after 15 minutes. Solubility properties can be determined by standard solubility tests, such as those described in pharmacopoeias, for example, USP31-NF26 S2, Chapter 711 (Solubility). In one embodiment, the pharmaceutical dosage form of the present invention has disintegration properties such that the pharmaceutical dosage form disintegrates within 40 minutes, or within 30 minutes, preferably within 20 minutes, more preferably within 15 minutes, and even more preferably within 10 minutes. Disintegration properties can be determined by a standard disintegration test, for example, as described in pharmacopoeias such as USP31-NF26 S2, Chapter 701 (Disintegration). In one embodiment, the pharmaceutical dosage form of the present invention has high content uniformity of the pharmaceutical component, preferably within the range of 85-115%, more preferably 90-110%, and even more preferably 95-105% by mass. For example, as described in the pharmacopoeia, the content uniformity can be determined using, for example, 10 randomly selected pharmaceutical dosage forms.

[0105] The dosage forms of this invention, such as tablets, capsules, or film-coated tablets, are prepared by methods well known to those skilled in the art. Appropriate methods for manufacturing tablets include compression of a pharmaceutical composition in powder form, i.e., direct compression, or compression of a pharmaceutical composition in granular form with additional excipients if necessary. The granules of the pharmaceutical composition of the present invention are prepared by methods well known to those skilled in the art. Preferred methods for granulating the active ingredient together with excipients include wet granulation, such as high-shear wet granulation and fluidized bed wet granulation, and dry granulation, also known as roller compaction. In the wet granulation method, the granulation liquid is either a solvent alone or a preparation of one or more binders in a solvent or solvent mixture. Suitable binders are described above. Examples include hypromellose, hydroxypropylcellulose, povidone, and copovidone. Suitable solvents include, for example, purified water, ethanol, methanol, isopropanol, acetone, preferably purified water, and mixtures thereof. The solvent is a volatile component and does not remain in the final product. One or more active ingredients and other excipients, usually excluding lubricants, particularly one or more diluents and one or more disintegrants are pre-mixed, and granulation is carried out with the granulation liquid, for example, using a high-shear granulator. After the wet granulation process, there is usually one or more drying and sieving steps. For example, a fluidized bed dryer can be used for drying. The dried granules are sieved through a suitable sieve. If necessary, other excipients other than lubricants, especially disintegrants, binders, fillers and / or flow enhancers, are added. The mixture is then blended in a suitable blender, such as a free-fall blender, and one or more lubricants, such as magnesium stearate, are added. Final blending is then performed in the blender.

[0106] A typical wet granulation method for producing the pharmaceutical composition of the present invention includes the following steps: (1) A step of pre-mixing the active ingredient and the main portion of the excipients, including the binder, in a mixer to obtain a pre-mixture; (2) A step of granulating the pre-mixture from step (1) by adding a granulation liquid, preferably purified water; (3) A step of drying the granules from step (2) in a fluidized bed dryer or drying oven; (4) A step in which the dried granules from step (3) are sieved dry as needed; (5) A step of mixing the dried granules from step (4) in a mixer with the remaining excipients such as fillers (also called diluents), binders, disintegrants and / or flow enhancers to obtain the main mixture; (6) The main mixture from step (5) is mixed with a lubricant in a mixer to obtain the final mixture; (7) A step of forming a tablet core by compressing the final mixture from step (6) in a suitable tablet press; (8) A step of film coating the tablet core from step (7) with a non-functional coating agent as needed. In one embodiment, it has been found that supplying a portion of the diluent as a dry additive after wet granulation reduces adhesion and / or filming during the manufacture of the pharmaceutical composition or dosage form. Adding additional diluent after wet granulation can also improve the physical stability (tablet hardness) of the dosage form. Therefore, in one embodiment, in the wet granulation method of the present invention, the diluent is added as a dry additive after wet granulation, for example in step (5) above. In one embodiment, the amount of diluent added as a dry additive after wet granulation, for example in step (5) above, is 1% to 20% of the mass of the tablet (without film coating), preferably 2.5% to 10% of the mass of the tablet (without film coating). The diluent is, for example, microcrystalline cellulose. The diluent may be added in steps (1) and (5) above. In one embodiment, the pharmaceutical composition of the present invention is produced by high-shear wet granulation. The present invention also provides a pharmaceutical composition obtained by the above method.

[0107] A typical direct compression method of the present invention for producing a pharmaceutical composition includes the following steps: (1) A step of pre-mixing the active ingredient and the main portion of the excipient in a mixer to obtain a pre-mixture; (2) A step of dry sieving the premixture through a sieve, if necessary, in order to separate agglomerating particles and to improve the uniformity of content; (3) Mixing the pre-mixture from step (1) or (2) in a mixer, and continuing to mix by adding any remaining excipients to the mixture as needed; (4) A step of forming tablets by compressing the final mixture from step (3) in a suitable tablet press to produce tablet cores; (5) A step in which the tablet core from step (4) is film-coated with a non-functional coating agent as needed. The present invention also provides a pharmaceutical composition obtained by the above method.

[0108] A typical dry granulation method of the present invention for producing pharmaceutical compositions includes the following steps: (1) A step of mixing the active ingredient with all or part of the excipients in a mixer; (2) The process of compressing the mixture from step (1) using a suitable roller compressor; (3) A step of converting the ribbon obtained in step (2) into granules, preferably small granules, by an appropriate milling or sieving process; (4) The granules from step (3) are mixed with the remaining excipients in a mixer as needed to obtain the final mixture; (5) A step of forming tablets by compressing the granules from step (3) or the final mixture from step (4) in a suitable tablet press to produce tablet cores; (6) A step in which the tablet core from step (5) is film-coated with a non-functional coating agent as needed.

[0109] In one embodiment, the size of the granules of the present invention is in the range of 25 to 800 μm, for example, 40 μm to 500 μm. The size of the granules can be measured by sieve analysis, for example, using an ultrasonic sieve. In one embodiment, at least 80% by mass, at least 90% by mass, or at least 95% by mass of granules are within the predetermined range. In one embodiment, the pharmaceutical composition or dosage form of the present invention exhibits a characteristic pharmacokinetic profile after administration to a subject, particularly after administration to humans, as described later. Therefore, in one embodiment, when the pharmaceutical composition of the present invention is administered to a fasted human at a dose of 2.5 mg, it contains 40.3 to 96.3 nmol / L of C. max ; and 677 nmol * This shows the AUC for h / L. In one embodiment, when the pharmaceutical composition of the present invention is administered to a fasted human at a dose of 2.5 mg, it produces a geometric mean C of 52.9 to 66.6 nmol / L. max ; and 394-468 ​​nmol* The geometric mean AUC for h / L is shown. In one embodiment, when the pharmaceutical composition of the present invention is administered to a fasted human at a dose of 5.0 mg, it produces a C content of 123-230 nmol / L. max ; and 1,000~1,310 nmol * h / L AUC 0-inf This indicates. In one embodiment, when the pharmaceutical composition of the present invention is administered to a fasted human at a dose of 10.0 mg, it produces a concentration of 143-796 nmol / L of C. max ; and 1,170~3,190 nmol * This shows the AUC for h / L. In one embodiment, when the pharmaceutical composition of the present invention is administered to a fasted human at a dose of 10.0 mg, it produces a geometric mean C of 221-372 nmol / L. max ; and 1,690~2,660 nmol * The geometric mean AUC for h / L is shown. In one embodiment, when the pharmaceutical composition of the present invention is administered to a fasted human at a dose of 25.0 mg, it produces a concentration of 334-1,030 nmol / L of C. max ; and 2,660~7,640 nmol * This shows the AUC for h / L. In one embodiment, when the pharmaceutical composition of the present invention is administered to a fasted human at a dose of 25.0 mg, it produces a geometric mean C of 490-709 nmol / L. max ; and 3,750~6,130 nmol * The geometric mean AUC for h / L is shown. In one embodiment, when the pharmaceutical composition of the present invention is administered to a fasted human at a dose of 50.0 mg, it results in a concentration of 722-2,020 nmol / L of C. max ; and 6,450~14,100 nmol * This shows the AUC for h / L. In one embodiment, when the pharmaceutical composition of the present invention is administered to a fasted human at a dose of 50.0 mg, a geometric mean C of 1,080 to 1,140 nmol / L is obtained. max ; and 8,310~8,460 nmol * Geometric mean AUC of h / L 0-inf This indicates.

[0110] In one embodiment, when the pharmaceutical composition of the present invention is administered to a person in a fasted state, a) At a dose of 2.5 mg i. C40.3~96.3 nmol / L max and ii. 283~677 nmol * h / L AUC This indicates; and / or b) At a dose of 5.0 mg i. 123-230 nmol / L C max and ii. 1,000~1,310 nmol * h / L AUC This indicates; and / or c) At a dose of 10.0 mg i. C143~796 nmol / L max and ii. 1,170~3,190 nmol * h / L AUC This indicates; and / or d) At a dose of 25.0 mg i. C34~1,030 nmol / L max and ii. 2,660~7,640 nmol * h / L AUC This indicates; and / or e) At a dose of 50.0 mg i. 722~2,020 nmol / L of C max and ii. 6,450~14,100 nmol * h / L AUC This indicates.

[0111] In one embodiment, when the pharmaceutical composition of the present invention is administered to a person in a fasted state, a. At a dose of 2.5 mg iii. Geometric mean C for 52.9~66.6 nmol / L max and iv. 394~468 nmol * Geometric mean AUC of h / L This indicates; and / or b. At a dose of 10.0 mg i. Geometric mean C for 221-372 nmol / L max and ii. 1,690~2,660 nmol * Geometric mean AUC of h / L This indicates; and / or c. At a dose of 25.0 mg i. Geometric mean C for 490-709 nmol / L max and ii. 3,750~6,130 nmol * h / L AUC This indicates; and / or d. A dose of 50.0 mg i. Geometric mean C for concentrations of 1,080 to 1,140 nmol / L ma and ii. 8,310~8,460 nmol * Geometric mean AUC of h / L This indicates.

[0112] In one embodiment, when the pharmaceutical composition of the present invention is administered to a fasted human as a single dose of 2.5 mg, it contains 42.8 to 81.2 nmol / L of C. max ; and 326~631 nmol * h / L AUC 0-inf This indicates. In one embodiment, when the pharmaceutical composition of the present invention is administered as a single dose of 2.5 mg to a fasted human, it produces a geometric mean C of 52.9 to 61.3 nmol / L. max ; and of 394~468 nmol * Geometric mean AUC of h / L 0-inf This indicates. In one embodiment, when the pharmaceutical composition of the present invention is administered to a fasted human as a single dose of 5.0 mg, it produces a C content of 123-230 nmol / L. max ; and 1,000~1,310 nmol * h / L AUC 0-inf This indicates. In one embodiment, when the pharmaceutical composition of the present invention is administered to a fasted human as a single dose of 10.0 mg, it produces a concentration of 143-796 nmol / L of C. max; and 1,170~3,190 nmol * h / L AUC 0-inf This indicates. In one embodiment, when the pharmaceutical composition of the present invention is administered to a fasted human as a single dose of 10.0 mg, it produces a geometric mean C of 221-372 nmol / L. max ; and 1,690~2,660 nmol * Geometric mean AUC of h / L 0-inf This indicates. In one embodiment, when the pharmaceutical composition of the present invention is administered to a fasted human as a single dose of 25.0 mg, it contains 334 to 1,030 nmol / L of C. max ; and 2,660~7,170 nmol * h / L AUC 0-inf This indicates. In one embodiment, when the pharmaceutical composition of the present invention is administered to a fasted human as a single dose of 25.0 mg, it produces a geometric mean C of 490-709 nmol / L. max ; and 3,750~6,130 nmol * Geometric mean AUC of h / L 0-inf This indicates. In one embodiment, when the pharmaceutical composition of the present invention is administered to a fasted human as a single dose of 50.0 mg, it contains 722 to 2,020 nmol / L of C. max ; and 6,450~14,100 nmol * h / L AUC 0-inf This indicates. In one embodiment, when the pharmaceutical composition of the present invention is administered to a fasted human as a single dose of 50.0 mg, it produces a geometric mean C of 1,080 to 1,140 nmol / L. max ; and 8,310~8,460 nmol * Geometric mean AUC of h / L 0-inf This indicates.

[0113] In one embodiment, the pharmaceutical composition of the present invention is used in humans in a fasted state. a. When administered as a single dose of 2.5 mg, i. C42.8~81.2 nmol / L max and ii. 326~631 nmol * h / L AUC0-inf This indicates; and / or b. When administered as a single dose of 5.0 mg, i. 123-230 nmol / L C max and ii. 1,000~1,310 nmol * h / L AUC 0-inf This indicates; and / or c. When administered as a single dose of 10.0 mg, i. C143~796 nmol / L max and ii. 1,170~3,190 nmol * h / L AUC 0-inf This indicates; and / or d. When administered as a single dose of 25.0 mg, i. C34~1,030 nmol / L max and ii. 2,660~7,170 nmol * h / L AUC 0-inf This indicates; and / or e. When administered as a single dose of 50.0 mg, i. 722~2,020 nmol / L of C max and ii. 6,450~14,100 nmol * h / L AUC 0-inf This indicates.

[0114] In one embodiment, the pharmaceutical composition of the present invention is used in humans in a fasted state. a. When administered as a single dose of 2.5 mg, i. Geometric mean C for 52.9~61.3 nmol / L max and ii. 394~468 nmol * Geometric mean AUC of h / L 0-inf This indicates; and / or b. When administered as a single dose of 10.0 mg, i. Geometric mean C for 221-372 nmol / L max and ii. 1,690~2,660 nmol * Geometric mean AUC of h / L 0-inf This indicates; and / or c. When administered as a single dose of 25.0 mg, i. Geometric mean C for 490-709 nmol / L max and ii. 3,750~6,130 nmol * Geometric mean AUC of h / L 0-inf This indicates; and / or d. When administered as a single dose of 50.0 mg, i. Geometric mean C for concentrations of 1,080 to 1,140 nmol / L max and ii. 8,310~8,460 nmol * Geometric mean AUC of h / L 0-inf This indicates.

[0115] In one embodiment, when the pharmaceutical composition of the present invention is administered to a fasted human, multiple doses of 2.5 mg result in a concentration of 40.3 to 96.3 nmol / L of C. max,ss ; and 283-677 nmol * h / L AUC τ,ss This indicates. In one embodiment, when the pharmaceutical composition of the present invention is administered to a fasted human, multiple doses of 10.0 mg result in a concentration of 166-479 nmol / L of C. max,ss ; and 1,350~2,600 nmol * h / L AUC τ,ss This indicates. In one embodiment, when the pharmaceutical composition of the present invention is administered to a fasted human, multiple doses of 10.0 mg result in a geometric mean C concentration of 252-272 nmol / L. max,ss ; and 1,850~2,000 nmol * Geometric mean AUC of h / L τ,ss This indicates. In one embodiment, when the pharmaceutical composition of the present invention is administered to a fasted human, multiple doses of 25.0 mg result in a concentration of 443-907 nmol / L of C. max,ss ; and 2,790~7,640 nmol * h / L AUC τ,ss This indicates. In one embodiment, when the pharmaceutical composition of the present invention is administered to a fasted human, multiple doses of 25.0 mg result in a geometric mean C concentration of 622-676 nmol / L. max,ss ; and 4,640~4,890 nmol * Geometric mean AUC of h / L τ,ss This indicates.

[0116] In one embodiment, when the pharmaceutical composition of the present invention is administered to a person in a fasted state, a. Multiple doses of 2.5 mg i. C40.3~96.3 nmol / L max,ss and ii. 283~677 nmol * h / L AUC τ,ss This indicates; and / or b. Multiple doses of 10.0 mg i. 166~479 nmol / L C max,ss and ii. 1,350~2,600 nmol * h / L AUC τ,ss This indicates; and / or c. Multiple doses of 25.0 mg i. 443~907 nmol / L C max,ss and ii. 2,790~7,640 nmol * h / L AUC τ,ss This indicates.

[0117] In one embodiment, when the pharmaceutical composition of the present invention is administered to a person in a fasted state, a. Multiple doses of 10.0 mg i. Geometric mean C for 252-272 nmol / L max,ss and ii. 1,850~2,000 nmol * Geometric mean AUC of h / L τ,ss This indicates; and / or b. Multiple doses of 25.0 mg i. Geometric mean C for 622~676 nmol / L max,ss and ii. 4,640~4,890 nmol * Geometric mean AUC of h / L τ,ss This indicates.

[0118] In another embodiment, when administered to a fasted human, the pharmaceutical composition of the present invention produces a dose-normalized C of 13-80 nmol / L / mg. max,norm ; and 10⁶ to 30⁶ nmol * Dose-normalized AUC of h / L / mg 0-inf,norm This shows that in one embodiment, the pharmaceutical composition is dose-normalized C over a dose range of 2.5 mg to 50 mg of the active ingredient. max,norm ; and the dose-normalized AUC 0-inf,norm This indicates. In one embodiment, when administered to a fasted human, the pharmaceutical composition of the present invention exhibits a dose-normalized C of 13 to 80 nmol / L / mg over a dose range of 5 mg to 25 mg of the active ingredient. max,norm ; and 10⁶ to 30⁶ nmol * Dose-normalized AUC of h / L / mg 0-inf,norm This indicates. In one embodiment, when the pharmaceutical composition of the present invention is administered to a fasted human, it produces a dose-normalized geometric mean C of 20-37 nmol / L / mg. max,norm ; and 150-266 nmol * Dose-normalized geometric mean AUC for h / L / mg 0-inf,norm This shows that in one embodiment, the pharmaceutical composition has a dose-normalized geometric mean C over a dose range of 2.5 mg to 50 mg of the active ingredient. max,norm and the dose normalized geometric mean AUC 0-inf,norm This indicates. In one embodiment, when the pharmaceutical composition of the present invention is administered to a fasted human, it exhibits a dose-normalized geometric mean C of 20 to 37 nmol / L / mg over a dose range of 5 mg to 25 mg of the active ingredient. max,norm ; and 150-266 nmol * Dose-normalized geometric mean AUC for h / L / mg 0-inf,norm This indicates. In one embodiment, when the pharmaceutical composition of the present invention is administered as a single dose to a fasted human, it produces a dose-normalized C of 13-80 nmol / L / mg. max,norm ; and 10⁶ to 287 nmol * Dose-normalized AUC of h / L / mg 0-inf,norm This shows that, in one embodiment, when the pharmaceutical composition is administered as a single dose to a fasted human, the dose-normalized C is observed over a dose range of 2.5 mg to 50 mg of the active ingredient. max,norm and the dose-normalized AUC 0-inf,norm This indicates. In one embodiment, when the pharmaceutical composition of the present invention is administered as a single dose to a fasted human, it exhibits a dose-normalized C of 13 to 80 nmol / L / mg over a dose range of 5 mg to 25 mg of the active ingredient. max,norm ; and 10⁶ to 287 nmol * Dose-normalized AUC of h / L / mg 0-inf,norm This indicates. In one embodiment, when the pharmaceutical composition of the present invention is administered as a single dose to a fasted human, it produces a dose-normalized geometric mean C of 20-37 nmol / L / mg. max,norm ; and 150-266 nmol * Dose-normalized geometric mean AUC for h / L / mg 0-inf,norm This shows that, in one embodiment, when the pharmaceutical composition is administered as a single dose to a fasted human, the dose-normalized geometric mean C over the dose range of 2.5 mg to 50 mg of the active ingredient is max,norm and the dose normalized geometric mean AUC 0-inf,norm This indicates. In one embodiment, when the pharmaceutical composition of the present invention is administered as a single dose to a fasted human, it exhibits a dose-normalized geometric mean C of 20 to 37 nmol / L / mg over a dose range of 5 mg to 25 mg of the active ingredient. max, norm; and 150-266 nmol * Dose-normalized geometric mean AUC for h / L / mg 0-inf, norm This indicates.

[0119] In one embodiment, when the pharmaceutical composition of the present invention is administered to a fasted human in multiple doses, it produces a dose-normalized C of 16-48 nmol / L / mg. max,ss,norm ; and 112-306 nmol * Dose-normalized AUC of h / L / mg τ,ss,norm This shows that, in one embodiment, when the pharmaceutical composition is administered to a fasted human in multiple doses, the dose-normalized C is observed over a dose range of 2.5 mg to 25 mg of the active ingredient. max,ss,norm and the dose-normalized AUC τ,ss,norm This indicates. In one embodiment, when the pharmaceutical composition of the present invention is administered to a fasted human in multiple doses, it produces a dose-normalized geometric mean C of 25-27 nmol / L / mg. max,ss,norm ; and 184-200 nmol * Dose-normalized geometric mean AUC for h / L / mg τ,ss,norm This shows that, in one embodiment, when the pharmaceutical composition is administered to a fasted human in multiple doses, the dose-normalized geometric mean C over the dose range of 2.5 mg to 25 mg of the active ingredient max,ss,norm and the dose normalized geometric mean AUC τ,ss,norm This indicates.

[0120] When this invention refers to patients requiring treatment or prevention, it primarily concerns the treatment and prevention of humans, but the pharmaceutical composition can also be used appropriately in veterinary medicines for mammals. Within the scope of this invention, adult patients are preferably humans aged 18 years or older. As described above, administration of the pharmaceutical composition of this invention, particularly considering the high SGLT2 inhibitory activity of the SGLT2 inhibitor contained therein, results in the excretion of excess blood glucose through the patient's urine, thus preventing weight gain and potentially even leading to weight loss. Therefore, the treatment or prevention of this invention is advantageously suited to patients who require such treatment or prevention and are diagnosed with one or more conditions selected from the group consisting of overweight and obesity, particularly class I obesity, class II obesity, class III obesity, visceral obesity, and abdominal obesity. Furthermore, the treatment or prevention of this invention is advantageously suited to patients for whom weight gain is contraindicated. The pharmaceutical composition and method of this invention can reduce HbA1c levels to a desired target range, for example, <7%, preferably <6.5%, for a larger number of patients and for a longer treatment period compared to therapies using only the corresponding monotherapy or combination therapy of two agents. The pharmaceutical composition of this invention, and in particular the SGLT2 inhibitor contained therein, exhibits very good efficacy with respect to blood glucose control, especially in terms of reducing fasting plasma glucose, postprandial plasma glucose, and / or glycosylated hemoglobin (HbA1c). By administering the pharmaceutical composition of this invention, it is possible to achieve a reduction in HbA1c of preferably 0.5% or more, and more preferably 1.0% or more, and this reduction is particularly in the range of 1.0% to 2.0%.

[0121] Furthermore, the method and / or use of this invention is subject to the following conditions: (a) Fasting blood glucose or serum glucose concentration higher than 100 mg / dL, especially higher than 125 mg / dL; (b) Postprandial plasma glucose of 140 mg / dL or higher; (c) HbA1c values ​​of 6.5% or higher, especially 7.0% or higher, especially 7.5% or higher, and even more especially 8.0% or higher. This can be advantageously applied to patients who exhibit one or more of the following conditions. The present invention also discloses the use of a pharmaceutical composition for improving blood glucose control in patients who have type 2 diabetes or who are showing the first signs of prediabetes. Thus, the present invention also encompasses diabetes prevention. Therefore, if blood glucose control is improved using the pharmaceutical composition of this invention as soon as one of the above signs of prediabetes appears, the onset of overt type 2 diabetes can be delayed or prevented. Furthermore, the pharmaceutical compositions of this invention are particularly suitable for the treatment of insulin-dependent patients, i.e., patients who are being treated with, or would be being treated with, insulin or insulin derivatives or insulin substitutes or formulations containing insulin or its derivatives or substitutes, or who require such treatment. These patients include patients with type 2 diabetes and type 1 diabetes. Accordingly, according to a preferred embodiment of the present invention, a method is provided for improving and / or reducing conditions in patients diagnosed with impaired glucose tolerance (IGT), abnormal fasting blood glucose (IFG), insulin resistance, metabolic syndromes, and / or type 2 or type 1 diabetes, for whom improvement of blood glucose control and / or reduction of fasting plasma glucose, postprandial plasma glucose, and / or glycosylated hemoglobin HbA1c is necessary, characterized by administering an SGLT2 inhibitor as defined above and below to the patient. According to another embodiment of the present invention, a method is provided for improving blood glucose control in patients with type 2 diabetes, particularly in adult patients, as an adjunct to dietary restrictions and exercise.

[0122] It has been found that by using the pharmaceutical composition of this invention, improvement in blood glucose control can be achieved even in patients whose blood glucose control is insufficient despite treatment with antidiabetic drugs, for example, despite oral monotherapy with metformin at the maximum recommended dose or tolerable dose. The maximum recommended dose of metformin is, for example, 2000 mg per day or 850 mg three times a day or an equivalent dose thereof. Therefore, the method and / or use of this invention is subject to the following conditions: (a) Blood sugar control that is insufficient with diet and exercise alone; (b) Inadequate glycemic control despite oral monotherapy with metformin, particularly with the maximum tolerated dose of metformin; (c) Inadequate glycemic control despite oral monotherapy with another antidiabetic drug, particularly despite oral monotherapy with another antidiabetic drug at the maximum tolerated dose. This can be applied favorably to patients who exhibit one, two, or three or more of the following conditions.

[0123] The reduction in blood glucose levels achieved by administering the SGLT2 inhibitor of this invention is insulin-independent. Therefore, the pharmaceutical composition of this invention exhibits the following conditions: - Insulin resistance, - Hyperinsulinemia, - prediabetes, - Type 2 diabetes, especially late type 2 diabetes -Type 1 diabetes It is particularly suitable for treating patients diagnosed with one or more of the following conditions. Furthermore, the pharmaceutical composition of this invention is in the following state: (a) Obesity (including Class I, II and / or III obesity), visceral obesity and / or abdominal obesity, (b) Triglyceride blood level ≥ 150 mg / dL, (c) HDL cholesterol blood levels <40 mg / dL (female patients) and <50 mg / dL (male patients), (d) Systolic blood pressure ≥ 130 mmHg and diastolic blood pressure ≥ 85 mmHg, (e) Fasting blood glucose level ≥ 100 mg / dL It is particularly suitable for treating patients diagnosed with one or more of the following conditions. Patients diagnosed with impaired glucose tolerance (IGT), abnormal fasting blood glucose (IFG), insulin resistance, and / or metabolic syndromes are assumed to suffer from a high risk of developing cardiovascular diseases such as myocardial infarction, coronary heart disease, cardiac failure, and thromboembolism. The blood glucose control of this invention may result in a reduction of the risk of cardiovascular disease.

[0124] The pharmaceutical composition of this invention exhibits a good safety profile. Therefore, the treatment or prevention of this invention is advantageously possible in patients for whom monotherapy with another antidiabetic drug, such as metformin, is contraindicated and / or who are intolerant to therapeutic doses of the drug. In particular, the treatment or prevention of this invention is advantageously possible in patients who are at high risk of one or more of the following disorders: renal insufficiency or kidney disease, heart disease, heart failure, liver disease, lung disease, catabolic state, and / or lactic acidosis, or in pregnant or lactating female patients. Furthermore, administration of the pharmaceutical composition of this invention does not pose a risk of hypoglycemia or poses a low risk of it. Therefore, the treatment or prevention of hypoglycemia of this invention is advantageously possible even in patients who show or have a high risk of hypoglycemia. The pharmaceutical compositions of this invention are particularly suitable for the long-term treatment or prevention of the diseases and / or conditions described herein and later, especially for the long-term blood glucose control of patients with type 2 diabetes. In this specification, the term “long term” as used above and below refers to the treatment or administration of a patient for a period longer than 12 weeks, preferably longer than 25 weeks, and more preferably longer than 1 year. Accordingly, a particularly preferred embodiment of the present invention provides a treatment method, preferably an oral therapy, for improving, especially long-term improvement, blood glucose control in patients with type 2 diabetes, particularly in patients with late-stage type 2 diabetes, and especially in patients further diagnosed with overweight, obesity (including class I, class II and / or class III obesity), visceral obesity and / or abdominal obesity.

[0125] Naturally, the amount administered to and required by a patient for use in the treatment or prevention of the present invention will vary depending on the route of administration, the nature and severity of the condition requiring treatment or prevention, the patient's age, weight and condition, and concomitant medications, and ultimately will be at the discretion of the attending physician. However, generally speaking, the SGLT2 inhibitor of this invention is included in a pharmaceutical composition or dosage form in an amount sufficient to improve blood glucose control in the patient to be treated. The following describes preferred ranges for the amount of SGLT2 inhibitor to be used in the pharmaceutical composition, method, and use of this invention. These ranges represent the amount to be administered daily to an adult patient, particularly a person weighing approximately 70 kg, and can be adapted accordingly to two, three, four or more doses per day, as well as to other routes of administration and the patient's age. Within the scope of this invention, the pharmaceutical composition is preferably administered orally. Other forms of administration are possible and will be described later. Preferably, one or more dosage forms containing the SGLT2 inhibitor are oral or commonly known. Generally, the amount of SGLT2 inhibitor in the pharmaceutical composition and method of this invention is preferably the amount generally recommended for monotherapy using the SGLT2 inhibitor. The preferred dosage range for SGLT2 inhibitors is 0.5 mg to 200 mg per day, more preferably 1 to 100 mg, and most preferably 1 to 50 mg. Oral administration is preferred. Accordingly, the pharmaceutical composition may contain the aforementioned amounts, particularly 1 to 50 mg or 1 to 25 mg, and more preferably 5 to 25 mg. Specific active ingredient content (dosage strength) (for example, per tablet or capsule) is, for example, 1, 2.5, 5, 7.5, 10, 12.5, 15, 20, 25, or 50 mg of an SGLT2 inhibitor, such as a compound of formula (I), particularly compound (I.9) or its crystalline form (I.9X). The active ingredient may be applied up to three times a day, preferably once or twice a day, and most preferably once a day. Pharmaceutical compositions, existing as separate or multiple dosage forms, preferably as a kit of elements, are useful for combination therapy to flexibly adapt to the individual treatment needs of patients. According to the first embodiment, a preferred kit of elements includes a container for housing a dosage form comprising an SGLT2 inhibitor and at least one pharmaceutically acceptable carrier. A further aspect of the present invention is a product comprising a pharmaceutical composition existing as separate dosage forms of the present invention, and a label or accompanying document containing instructions that the separate dosage forms should be administered in combination or alternately. According to the first embodiment, the product comprises (a) a pharmaceutical composition comprising the SGLT2 inhibitor of the present invention, and (b) a label or accompanying information sheet containing instructions for administering the drug. For convenience, the desired dose of the pharmaceutical composition of this invention may be indicated as once a day, or as a divided dose administered at appropriate intervals, for example, twice, three times, or four or more times a day.

[0126] Pharmaceutical compositions can be formulated in liquid or solid form for oral, rectal, nasal, topical (such as buccal and sublingual), transdermal, vaginal, or parenteral (such as intramuscular, subcutaneous, and intravenous) administration, or in a form suitable for administration by inhalation or gas injection. Oral administration is preferred. Where appropriate, formulations may be provided in individual dosage units for convenience, and formulations can be prepared by any method well known in pharmaceutical art. All methods include the steps of associating the active ingredient with one or more pharmaceutically acceptable carriers, such as a liquid carrier or a micronized solid carrier or both, and then, if necessary, forming the product into a desired formulation. This pharmaceutical composition can be formulated in the form of tablets, granules, fine granules, powders, capsules, caplets, soft capsules, pills, oral solutions, syrups, dry syrups, chewable tablets, lozenges, effervescent tablets, drops, suspensions, rapidly dissolving tablets, orally rapidly dispersible tablets, and the like. The pharmaceutical compositions and dosage forms of this invention are packaged using PVC blisters, PVDC blisters, PVC / PVDC blisters, or moisture-proof packaging materials, such as aluminum foil blister packs, alu / alu blisters, transparent or opaque polymer blisters with pouches, polypropylene tubes, glass bottles, PP bottles, and HDPE bottles, and may include features that prevent children from handling them or that make signs of tampering immediately apparent, as necessary. The main packaging material may include a desiccant such as a molecular sieve or silica gel to improve the chemical stability of the active pharmaceutical ingredient. Opaque packaging, such as colored blister materials, tubes, or brown glass bottles, can extend the shelf life of the active pharmaceutical ingredient by reducing photodegradation. The pharmaceutical composition and dosage form preferably contain one or more pharmaceutically acceptable carriers, which must be "acceptable" in the sense that they are compatible with other components of the formulation and are not harmful to the recipient. Examples of pharmaceutically acceptable carriers are well known to those skilled in the art. Pharmaceutical compositions suitable for oral administration may be provided for convenience as individual units, such as capsules including soft gelatin capsules, cachets, or tablets, each containing a predetermined amount of the active ingredient as a powder or granules; or as a solution, suspension, or emulsion, such as a syrup, elixir, or self-emulsifying delivery system (SEDDS). The active ingredient may also be provided as a bolus, lick, or paste. Tablets and capsules for oral administration may contain common excipients, such as binders, fillers, lubricants, disintegrants, or wetting agents. Tablets may be coated according to technically well-known methods. Oral liquid formulations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs, or may be provided as dry products to be prepared with water or other suitable vehicles before use. The liquid formulation may contain common additives, such as suspending agents, emulsifiers, non-aqueous vehicles (which may include edible oils), or preservatives.

[0127] The pharmaceutical composition of the present invention may be formulated for parenteral administration (e.g., by injection, e.g., bolus injection or continuous infusion) and may be provided in ampoules, pre-filled syringes, unit dose forms for small infusions, or multi-dose containers with preservatives. The composition may take the form of a suspension, solution, or emulsion in an oily or aqueous vehicle and may contain a formulation agent such as a suspending agent, stabilizer, and / or dispersant. Alternatively, the active ingredient may be in powder form obtained by sterile isolation of a sterile solid or by freeze-drying from a solution, so that it is contained in a suitable vehicle before use, e.g., sterile water without a heat source. Pharmaceutical compositions suitable for rectal administration, in which the carrier is solid, are most preferably provided as unit-dose suppositories. Suitable carriers include cocoa butter and other materials commonly used in this art, and the suppositories can be conveniently formed by mixing the active compound with a softened or molten carrier, followed by cooling and molding in a mold.

[0128] The pharmaceutical compositions and methods of this invention exhibit advantageous effects in the treatment and prevention of the aforementioned diseases and conditions. For example, advantageous effects can be observed with respect to efficacy, active ingredient content, dosage frequency, pharmacodynamic properties, pharmacokinetic properties, low side effects, convenience, and compliance. Methods for producing the SGLT2 inhibitors and their prodrugs of this invention are well known to those skilled in the art. Advantageously, the compounds of the present invention can be prepared using synthetic methods described in the literature, including the patent applications previously cited herein. Preferred production methods are described in WO2006 / 120208 and WO2007 / 031548. For compound (I.9), an advantageous crystalline form is described in international patent application WO2006 / 117359, which is thereby incorporated herein by reference in its entirety. The active ingredient may exist in the form of a pharmaceutically acceptable salt. Examples of pharmaceutically acceptable salts, but not limited to, include salts of inorganic acids such as hydrochloric acid, sulfuric acid, and phosphoric acid; salts of organic carboxylic acids such as oxalic acid, acetic acid, citric acid, malic acid, benzoic acid, maleic acid, fumaric acid, tartaric acid, succinic acid, and glutamic acid; and salts of organic sulfonic acids such as methanesulfonic acid and p-toluenesulfonic acid. Salts can be formed by mixing the compound and the acid in appropriate amounts and ratios in a solvent or decomposer. Salts can also be obtained by cation or anion exchange from other salt forms. The active ingredient or a pharmaceutically acceptable salt thereof may exist in the form of a solvate, such as a hydrate or an alcohol adduct.

[0129] Any of the above-mentioned pharmaceutical compositions and methods within the scope of this invention can be tested in technically known animal models. Below, we describe in vivo experiments suitable for evaluating the pharmacologically relevant properties of the pharmaceutical compositions and methods of this invention. The pharmaceutical compositions and methods of this invention can be tested in genetically hyperinsulinic or diabetic animals such as db / db mice, ob / ob mice, Zucker Fatty (fa / fa) rats, or Zucker Diabetic Fatty (ZDF) rats. Furthermore, the compositions and methods of this invention can be tested in experimentally induced diabetic animals such as HanWistar or Sprague Dawley rats pretreated with streptozotocin. The effect of this invention on blood glucose control can be tested after monotherapy with an SGLT2 inhibitor in the aforementioned animal model oral glucose tolerance test. Blood glucose levels are tracked over time after oral glucose administration in animals fasted overnight. The pharmaceutical composition of this invention significantly improves glucose deviation compared to, for example, another monotherapy, as measured by a reduction in peak glucose concentration or a decrease in glucose AUC. Furthermore, the effect on blood glucose control can be determined by measuring blood HbA1c levels after multiple administrations of the SGLT2 inhibitor to the aforementioned animal model. The pharmaceutical composition of this invention significantly reduces HbA1c compared to, for example, another monotherapy or dual combination therapy.

[0130] The improved insulin-independent treatment of this invention can be demonstrated after a single dose in the oral glucose tolerance test of the animal model described above. The time course of plasma insulin was tracked after glucose administration in animals that had been fasted overnight. The increase in active GLP-1 levels after a single or multiple administrations of the treatment of this invention can be determined by measuring the level in the plasma of the animal model under fasting or postprandial conditions. Similarly, a decrease in plasma glucagon levels can be measured under the same conditions. The effects of the SGLT2 inhibitor of the present invention on β-cell regeneration and neogenesis can be determined by measuring the increase in pancreatic insulin content after multiple administrations to the aforementioned animal model, by measuring the increase in β-cell mass by morphometric analysis after immunohistochemical staining of pancreatic sections, or by measuring the increase in glucose-stimulated insulin secretion in isolated pancreatic islets. [Examples]

[0131] (Pharmacological examples) The following examples demonstrate the advantageous effects of the pharmaceutical composition of the present invention on blood glucose control. Example 1: In the first example, 9-week-old male Zucker Diabetic Fatty (ZDF) rats (ZDF / Crl-Lepr) were fasted overnight. fa An oral glucose tolerance test is performed. A pre-administration blood sample is obtained by tail bleeding. Blood glucose is measured using a glucometer, and animals are randomized based on blood glucose levels (n=5 / group). Subsequently, each group receives either a vehicle alone (0.5% hydroxyethylcellulose aqueous solution containing 3 mM HCl and 0.015% Polysorbat 80) or a vehicle containing an SGLT2 inhibitor as a single oral administration. Thirty minutes after compound administration, animals receive an oral glucose load (2 g / kg). Blood glucose is measured by tail bleeding at 30, 60, 90, 120, and 180 minutes after glucose administration. Glucose deviation is quantified by calculating reactive glucose AUC. Data are expressed as mean ± SEM. A two-sided unpaired Student t-test is used for statistical comparison between the control and active groups. Representative experiments are shown in Figures 3A and 3B. Compound (I.9) (1-chloro-4-(β-D-glucopyranose-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-benzene) was orally administered to ZDF rats at doses of 0.3 mg / kg, 3 mg / kg, or 30 mg / kg (body weight). The animals then received an oral glucose bolus. The resulting glucose-time profiles are shown in Figure 3A. The baseline corrected area under the glucose-time curve is shown in Figure 3B. Compound (I.9) reduced glucose deviation by 15% (not significant) at 0.3 mg / kg, 62% (p<0.001) at 3 mg / kg, and 89% (p<0.001) at 30 mg / kg.

[0132] Example 2: In the second example, an oral glucose tolerance test was performed on male Sprague Dawley rats (Crl:CD(SD)) weighing approximately 200g that had been fasted overnight. Pre-administration blood samples were obtained by tail bleeding. Blood glucose was measured using a glucometer, and the animals were randomized for blood glucose (n=5 / group). Subsequently, the groups received either vehicle alone (0.5% aqueous hydroxyethylcellulose solution containing 0.015% Polysorbat 80) or a vehicle containing an SGLT2 inhibitor as a single oral dose. Thirty minutes after compound administration, the animals received an oral glucose load (2g / kg). Blood glucose was measured by tail bleeding at 30, 60, 90, and 120 minutes after glucose administration. Glucose deviation was quantified by calculating reactive glucose AUC. Data were expressed as mean ± SEM. Statistical comparisons were performed using Student's t-test.

[0133] Example 3: Treatment of prediabetes The efficacy of the pharmaceutical compositions of the present invention in the treatment of prediabetes characterized by pathological fasting blood glucose and / or impaired glucose tolerance can be tested using clinical studies. In short-term studies (e.g., 2-4 weeks), fasting blood glucose levels and / or postprandial or post-load test (oral glucose tolerance test or prescribed postprandial food tolerance test) blood glucose levels are measured at the end of the study's treatment period and compared to the values ​​before the start of the study and / or the values ​​of the placebo group to assess the success of the treatment. Furthermore, fructosamine levels can be measured before and after treatment and compared to initial values ​​and / or placebo values. A significant decrease in fasting or non-fasting blood glucose levels demonstrates the efficacy of the treatment. In longer-term studies (12 weeks or more), the success of the treatment is assessed by determining HbA1c levels and comparing them to initial values ​​and / or placebo values. A significant change in HbA1c levels compared to initial values ​​and / or placebo values ​​demonstrates the efficacy of the pharmaceutical compositions of the present invention for the treatment of prediabetes.

[0134] Example 4: Prevention of overt type 2 diabetes Treating patients with pathological fasting blood glucose and / or impaired glucose tolerance (prediabetes) also aims to prevent progression to overt type 2 diabetes. The efficacy of treatment can be investigated in comparative clinical studies in which prediabetic patients are treated with the pharmaceutical composition of this invention or with placebo, non-pharmacological therapy, or other drugs over a long period (e.g., 1 to 5 years). During or at the end of therapy, fasting blood glucose levels are quantified and / or a glucose tolerance test (e.g., oGTT) is performed to determine how many patients develop overt type 2 diabetes, i.e., fasting blood glucose levels >125 mg / dl and / or oGTT 2h values ​​>199 mg / dl. A significant reduction in the number of patients developing overt type 2 diabetes when treated with the pharmaceutical composition of this invention compared to the number of patients with other forms of treatment demonstrates the efficacy in preventing progression from prediabetes to overt diabetes.

[0135] Example 5: Treatment of Type 2 Diabetes Treating patients with type 2 diabetes with the pharmaceutical composition of the present invention not only results in a rapid improvement in glucose metabolism but also prevents long-term deterioration of metabolic status. This can be observed when patients are treated with the pharmaceutical composition of the present invention for an extended period, for example, 3 months to 1 year or even 1 to 6 years, and compared to patients treated with other antidiabetic drugs. If no or only slight increase in fasting blood glucose and / or HbA1c levels is observed, it is evidence of successful treatment compared to patients treated with other antidiabetic drugs. Further evidence of successful treatment is obtained if a significantly lower proportion of patients treated with the pharmaceutical composition of the present invention experience deterioration in glucose metabolism to the point where additional oral antidiabetic drugs or insulin or insulin analogs are required (e.g., an increase in HbA1c levels to >6.5% or >7%) compared to patients treated with other drugs.

[0136] Example 6: Treatment of insulin resistance Clinical studies conducted over varying time periods (e.g., 2 weeks to 12 months) utilize hyperinsulinaemic euglycemic glucose clamp studies to assess treatment success. At the end of the study, a significant increase in glucose infusion rate compared to baseline, or compared to a placebo group or a group receiving a different therapy, demonstrates the efficacy of the pharmaceutical composition of the present invention in the treatment of insulin resistance.

[0137] Case 7: Treatment of hyperglycemia Clinical studies conducted over varying time periods (e.g., 1 day to 24 months) will examine the success of treating hyperglycemia patients by quantifying fasting blood glucose or non-fasting blood glucose (e.g., after meals or after an oGTT or prescribed food challenge). A significant reduction in these blood glucose levels during or at the end of the study, compared to initial values ​​or compared to a placebo group or a group receiving a different therapy, demonstrates the efficacy of the pharmaceutical composition of the present invention in the treatment of hyperglycemia.

[0138] Example 8: Prevention of microvascular or macrovascular complications Treatment of patients with type 2 diabetes or prediabetes with the pharmaceutical composition of the present invention prevents, reduces, or decreases the risk of developing microvascular complications (e.g., diabetic neuropathy, diabetic retinopathy, diabetic nephropathy, diabetic foot lesions, diabetic ulcers) or macrovascular complications (e.g., myocardial infarction, acute coronary syndrome, unstable angina, stable angina, stroke, peripheral artery occlusive disease, cardiomyopathy, heart failure, heart rate disorders, vascular restenosis). Patients with type 2 diabetes or prediabetes are treated with the pharmaceutical composition of the present invention for a long period, e.g., 1 to 6 years, and compared to patients treated with other antidiabetic drugs or placebo. Evidence of treatment success compared to patients treated with other antidiabetic drugs or placebo can be seen in a small number of single or multiple complications. In the case of macrovascular events, diabetic foot lesions, and / or diabetic ulcers, the number is counted by medical history and various testing methods. In the case of diabetic retinopathy, treatment success is determined by computer-controlled illumination and evaluation of the background to the eye or other ophthalmic methods. In cases of diabetic neuropathy, in addition to medical history and clinical tests, nerve conduction velocity can be measured, for example, using a calibrated tuning fork. For diabetic nephropathy, the following parameters may be investigated before the start of the study, during the study, and at the end of the study: albumin secretion, creatinine clearance, serum creatinine level, time to doubling of serum creatinine level, and time to the need for dialysis.

[0139] Example 9: Treatment of metabolic syndromes The efficacy of the pharmaceutical compositions of the present invention can be tested by measuring fasting blood glucose or non-fasting blood glucose (e.g., after meals or after an oGTT or prescribed dietary load test) or HbA1c levels in clinical studies with varying execution times (e.g., 12 weeks to 6 years). A significant decrease in these blood glucose or HbA1c levels during or at the end of the study, compared to initial values ​​or compared to a placebo group or a group given a different therapy, demonstrates the efficacy of the active substance in the treatment of metabolic syndromes. Examples include reductions in systolic and / or diastolic blood pressure, reductions in plasma triglycerides, decreases in total cholesterol or LDL cholesterol, increases in HDL cholesterol, or weight loss, compared to starting values ​​at the beginning of the study or compared to a group of patients treated with placebo or a different therapy.

[0140] (Example of formulation) The following examples of formulations obtained in a manner similar to that known in the art are helpful in further illustrating the present invention without limiting the present invention to the contents of these examples. The term “active substance” means the SGLT-2 inhibitor of this invention, in particular the compound of formula (I), for example the compound of formula (I.9), or its crystalline form (I.9X). Before manufacturing a pharmaceutical composition or dosage form, the active pharmaceutical ingredient or active substance, i.e., compound (I.9) preferably in crystalline form (I.9), is ground in a suitable mill such as a pin mill or jet mill to obtain a desired particle size distribution. Typical particle size distribution values ​​X90, X50, and X10 for preferred active pharmaceutical ingredients of the present invention are shown in the table below.

[0141] Typical particle size distribution results TIFF0005600328000036.tif3198

[0142] Example 1: Dry ampoule containing 50 mg of active substance per 10 ml composition: Active substance 50.0mg Mannitol 50.0 mg Add 10.0 ml of sterile water for injection. Manufacturing method: Dissolve the active ingredient and mannitol in water. After packaging, freeze-dry the solution. Dissolve the product in sterile water for injection to prepare a ready-to-use solution. Example 2: Dry ampoule containing 25 mg of active substance per 2 ml composition: Active substance 25.0mg Mannitol 100.0 mg Add 2.0 ml of sterile water for injection. Manufacturing method: Dissolve the active ingredient and mannitol in water. After packaging, freeze-dry the solution. To prepare a ready-to-use solution, dissolve the product in water for injection. Example 3: Tablets containing 50 mg of the active substance composition: (1)Active substance 50.0mg (2) Mannitol 98.0 mg (3) Corn starch 50.0 mg (4) Polyvinylpyrrolidone 15.0 mg (5) Magnesium stearate 2.0 mg 215.0 mg Manufacturing method: (1), (2), and (3) are mixed together and granulated using an aqueous solution of (4). (5) is added to the dried granular material. From this mixture, tablets are pressed into shape, each having two planes, facets on both sides, and a split notch on one side. Tablet diameter: 9mm. Example 4: Capsule containing 50 mg of the active substance composition: (1)Active substance 50.0mg (2) Dried corn starch 58.0 mg (3) Mannitol 50.0 mg (4) Magnesium stearate 2.0 mg 160.0 mg Manufacturing method: Grind (1) with (3). Add this ground mixture to the mixture of (2) and (4) while stirring vigorously. Fill this powder mixture into size 3 hard gelatin capsules using a capsule filling machine.

[0143] TIFF0005600328000037.tif156147

[0144] Example 6: (a) Method for producing tablets The tablets of Example 5 described above can be manufactured, for example, as follows. TIFF0005600328000038.tif234147

[0145] Example 6: (b) Method for producing tablets The tablets of Example 5 described above can be manufactured, for example, as follows. TIFF0005600328000039.tif233149

[0146] (Granulation of active substances) The active substances, such as the compound (I.9) preferably in crystalline form (I.9X), lactose monohydrate, croscarmellose sodium, hydroxypropyl cellulose, and microcrystalline cellulose, are sieved and subsequently pre-mixed in a suitable high-shear mixer. This premix is ​​moistened with purified water and granulated using a suitable high-shear mixer. The granules are then dried in a fluidized bed dryer. Subsequently, the granules are sieved through a suitable sieve. (Final blend) The pre-sieved colloidal anhydrous silica and microcrystalline cellulose are added to the granules and blended in a suitable free-fall blender. Add the pre-sieved magnesium stearate to the blend and continue with final blending in a suitable free-fall blender. (Pill core) The final blend is compressed into a tablet core using a standard rotary tablet press. (Film coating suspension) Disperse the aqueous suspension (dye suspension) of Opadry Yellow 02B38190 in purified water. (Film-coated tablets) A tablet core is coated with a film coating suspension in a drum coater to produce a film-coated tablet.

[0147] (Manufacturing method) 1. Granules 1.1. Wet granulation After compounding, pre-sieve the following ingredients using an appropriate sieving machine into an appropriate high-shear mixer / granulator or diffusion blender and pre-mix until homogeneous: -Lactose making up approximately 20-80% of the total amount (for example, 50%) -Active substances - 50-90% of the total amount (for example, 80%) -hydroxypropylcellulose - Croscarmellose sodium - Remaining lactose in total amount - Microcrystalline cellulose. Alternatively, the above excipients may be transferred to a suitable high-shear mixer / granulator or diffusion blender without prior sieving. Alternatively, the excipients may be individually transferred to a suitable high-shear mixer / granulator or diffusion blender without prior sieving, or they may be individually transferred to a suitable high-shear mixer / granulator or diffusion blender after prior sieving. When blending in a diffusion blender, transfer the pre-blended product to a high-shear mixer / granulator before wet granulation. To pre-screen the excipients, a sieving mill with a sieve size of 0.5 mm to 1.5 mm (e.g., 0.8 mm) can be used at 50 rpm to 2500 rpm (e.g., 970 rpm). Alternatively, use a manual sieve with a mesh size of 0.5 mm to 1.5 mm (for example, 0.8 mm).

[0148] Next, moisten the mixture with purified water in the range of 26-35% (w / w) of the total weight of the pre-mixed excipients (for example, 28% (w / w) purified water). The following process parameters can be applied for pre-mixing in a high-shear mixer / granulator. Duration: 3-12.5 minutes (for example, 5 minutes) Rotor speed setting: 100-600 rpm (e.g., 114 rpm) Chopper speed setting: 0-3000 rpm (e.g., 1450 rpm) Alternatively, the following process parameters can be applied for pre-mixing within a diffusion blender. Duration: 5-30 minutes Rotation speed: 5-30 rpm The following process parameters can be applied to moisten the material in a high-shear mixer / granulator. Moisture: Duration: 2-5 minutes (e.g., 2.5 minutes) Rotor speed setting: 50-600 rpm (e.g., 114 rpm) Chopper speed setting: 1500~3000rpm (e.g., 2900rpm) Granulation: Duration: 2-5 minutes (e.g., 2.5 minutes) Rotor speed setting: 100-600 rpm (e.g., 114 rpm) Chopper speed setting: 1500~3000rpm (e.g., 2900rpm) Purified water is sprayed into the high-shear mixer / granulator or poured into the high-shear mixer / granulator using a nozzle with a spray angle of 45-90° (e.g., 60°).

[0149] 1.2. Drying Dry the moist granules in a suitable fluidized bed dryer. Preheat the fluidized bed dryer or perform the drying without preheating. The following process parameters can be applied for drying in a fluidized bed dryer. Air volume: 100-5000 m³ 3 / time Inflow air temperature: 50-75°C (e.g., 70°C) Process endpoint: When the product temperature is in the range of 40-50°C The endpoint is monitored through in-process control of drying loss. An appropriate value for loss on drying is 0.5–5.0% (e.g., ≤1.5%).

[0150] 1.3. Dry sieving The dry granules are sieved using a suitable sieving mill with a mesh size of 0.5 mm to 2.0 mm (e.g., 1.0 mm) at 50 rpm to 2500 rpm (e.g., 970 rpm), or a manual sieve with a mesh size of 0.5 mm to 1.5 mm (e.g., 0.8 mm).

[0151] 2. Preparation of the final mixture 2.1. Main mixing process The sieved dry granules are mixed in a suitable diffusion blender with colloidal anhydrous silica (pre-sieved using a sieving mill or manual sieving machine) and microcrystalline cellulose (remaining amount) (pre-sieved using a sieving mill or manual sieving machine). A sieving mill with a mesh size of 0.5 mm to 1.5 mm (e.g., 0.8 mm) can be used at 50 rpm to 2500 rpm (e.g., 970 rpm) to sieve colloidal anhydrous silica and microcrystalline cellulose. Alternatively, a manual sieve with a mesh size of 0.5 mm to 1.5 mm (e.g., 0.8 mm) can be used. For blending, a diffusion blender can be used with the following process parameters. Duration: 5-30 minutes (e.g., 15 minutes) Rotation speed: 5-30 rpm (e.g., 10 rpm) Alternatively, the following process parameters can be applied to blend with a high-shear mixer / granulator. Duration: 3-30 minutes Rotor speed setting: 50-600 rpm Chopper speed setting: 0-3000rpm 2.2. Final mixing process Place the main blend into a suitable diffusion blender. Add the magnesium stearate (either pre-sieved through a 0.5mm manual sieve or not pre-sieved) to the main blend. For final blending, a diffusion blender is available with the following process parameters. Duration: 5-30 minutes (for example, 10 minutes) Rotation speed: 5-30 rpm (e.g., 10 rpm)

[0152] 3. Tablet core The final blend is compressed into tablet cores using a suitable rotary tablet press. The following process parameters can be applied for tablet formation. Tabletization rate: 20,000 to 300,000 tablets per hour, depending on the output of the tableting machine. Stripper blade speed: 10-50 rpm (e.g., 40 rpm) Compression force: 5-26 kN (depending on tablet size, e.g., 8-20 kN). 4. Film coating suspension Pour purified water into a suitable mixing container, add OPADRY YELLOW 02B38190, and stir with a propeller starter until completely dissolved. 5. Film coating Coat the tablet core with a film coating suspension in a suitable pan coater. Use a pan coater of a size appropriate for film coating the core tablets. The coating process is carried out in four steps: preheating the tablets, film coating, drying, and cooling. For film coating, the following process parameters can be applied depending on the size of the equipment. Drum speed: 6-18 rpm Inflow air velocity: 50-2000 m / s 3 / time Exhaust temperature: 40~54℃ Spraying speed: 3~500g / min

[0153] Example 7: Pharmaceutical composition containing other fillers Copovidone is dissolved in purified water at ambient temperature to produce a granulation solution. The glucopyranosyl-substituted benzene derivative of the present invention, mannitol, pregelatinized starch, and corn starch are blended in a suitable mixer to produce a premix. The premix is ​​moistened with the granulation solution and granulation is carried out. The moistened granules are sieved through a suitable sieve. The granules are dried in a fluidized bed dryer at an inflow air temperature of approximately 60°C until a drying loss of 1-4% is obtained. The dried granules are sieved through a sieve with a mesh size of 1.0 mm. Magnesium stearate is sifted to remove any clumps and added to the granules. The final blend is then produced by final blending for 3 minutes in a suitable blender and compressed into tablet cores. A coating suspension is prepared by suspending hydroxypropyl methylcellulose, polyethylene glycol, talc, titanium dioxide, and iron oxide in purified water at ambient temperature in a suitable mixer. A tablet core is coated with the coating suspension until its volume is increased by approximately 3% to produce a film-coated tablet. The following formulation variations can be obtained.

[0154] TIFF0005600328000040.tif61151

[0155] Example 8: Pharmaceutical composition containing other disintegrants Copovidone is dissolved in purified water at ambient temperature to produce a granulation solution. The glucopyranosyl-substituted benzene derivative of the present invention, mannitol, pregelatinized starch, and corn starch are blended in a suitable mixer to produce a premix. The premix is ​​moistened with the granulation solution and granulation is carried out. The moistened granules are sieved through a suitable sieve. The granules are dried in a fluidized bed dryer at an inflow air temperature of approximately 60°C until a drying loss of 1-4% is obtained. The dried granules are sieved through a 1.0 mm mesh sieve. Add crospovidone to the dry granules and mix for 5 minutes to produce the main blend. Sift in magnesium stearate to remove any clumps and add it to the main blend. Continue blending in a suitable blender for 3 minutes to produce the final blend, and compress into 8 mm round tablet cores with a compression force of 16 kN. A coating suspension is prepared by suspending hydroxypropyl methylcellulose, polyethylene glycol, talc, titanium dioxide, and iron oxide in purified water at ambient temperature in a suitable mixer. A tablet core is coated with the coating suspension until its volume is increased by approximately 3% to produce a film-coated tablet. The following formulation variations can be obtained.

[0156] TIFF0005600328000041.tif61153

[0157] As mentioned above, the tablet hardness, ease of crushing, content uniformity, disintegration time, and dissolution characteristics are determined. Example 9: Direct Compression Formulation 1. The active ingredient, microcrystalline cellulose, croscarmellose sodium, and either hydroxypropyl cellulose or polyethylene glycol powder are sieved through a 20-mesh hand screen. 2. Add the above items to a high-shear mixer and mix for 2 minutes. 3. Prepare a premix (approximately 1 / 1) of lactose and colloidal silicon dioxide. 4. Sift the premix through a 20-mesh hand screen and add it to the blender. 5. Sift the remaining lactose through a 20-mesh hand screen and add it to the blender. 6. Mix the ingredients in the blender for 2 minutes. 7. Sift the magnesium stearate through a 30-mesh hand screen and add it to the blender. 8. Mix for 1 minute and 30 seconds to obtain the final blend. 9. Form the final blend into tablets using an appropriate tableting machine. 10. If necessary, film-coat the tablet core.

[0158] TIFF0005600328000042.tif88151

[0159] Example 10: Tablets containing 0.5 mg, 5 mg, 25 mg, and 100 mg of the active substance. TIFF0005600328000043.tif93150

[0160] The active substance, preferably a crystalline (I.9X) compound (I.9), hydroxypropyl cellulose, and croscarmellose sodium are mixed in a blender. This premix is ​​mixed with lactose monohydrate and a portion of microcrystalline cellulose. The resulting blend is granulated using purified water. Depending on the batch size and equipment used, multiple granulation subparts may be produced as needed to suit individual tablet batches. The granules are released onto a drying tray and dried. The granules are then milled. The remaining microcrystalline cellulose is added to the milled granules (as a premix with colloidal silicon dioxide for all strengths except 0.5 mg) and mixed. Magnesium stearate is premixed with a portion of the blend and then sieved into the remaining granules and mixed. The final tablet blend is compressed into tablets using a tablet press. The finished tablets are packaged using an appropriate container sealing system.

[0161] Example 11: Tablets containing 1 mg, 5 mg, and 25 mg of the active substance TIFF0005600328000044.tif93129

[0162] The active substance, preferably a compound (I.9) in crystalline form (I.9X), is sieved and added to a blender or high-shear granulator. Hydroxypropyl cellulose and croscarmellose sodium are sieved and added to the drug and mixed. The inner granule portion of the microcrystalline cellulose is sieved into the high-shear granulator and mixed with the drug premix. Lactose is then added by sieving into the granulator and mixed. The resulting blend is granulated using purified water. For larger batches, depending on the batch size and equipment used, multiple granulation subparts may be produced as needed to match individual tablet batches. The granules are released onto a drying tray and dried. Next, the granules are passed through a mill and put into a blender. Colloidal silicon dioxide is pre-mixed with a portion of the microcrystalline cellulose of the outer granules. After this premix is ​​passed through a mill and put into the blender, the remaining microcrystalline cellulose of the outer granules is added and mixed with the ground granules. Magnesium stearate is pre-mixed with a portion of the blend and then passed through a mill and mixed with the rest of the granules. The final tablet blend is compressed into tablets using a suitable tablet press. The finished tablets are packaged using a suitable container sealing system.

[0163] (Examples of tests concerning the properties of pharmaceutical compositions and pharmaceutical dosage forms) 1. Disintegration Test Disintegration tests were conducted as described in USP31-NF26 S2, Chapter 701 (Disintegration). The table below shows the average disintegration times (in minutes) of tablets produced at the beginning, middle, and end of the tablet manufacturing process. The active substance in the tablets is preferably a compound (I.9) in crystalline form (I.9X).

[0164] 1.1. Disintegration of the tablets in Example 10 (Formulation Examples section) TIFF0005600328000045.tif93154

[0165] 1.2. Disintegration of the tablets in Example 11 (Formulation Examples section) TIFF0005600328000046.tif165154 TIFF0005600328000047.tif83124

[0166] 2. Dissolution Test The standard dissolution test is described in USP31-NF26 S2, Chapter 711 (Dissolution). The paddle method (Apparatus 2) was used with a stirring speed of 50 rpm. The dissolution medium was 900 mL of 0.05 M potassium phosphate or sodium phosphate buffer, pH 6.8, at 37°C. Samples were collected after 45 minutes. The samples were analyzed by HPLC. The active substance in the tablets is preferably the crystalline (I.9X) compound (I.9). The embodiments in Section 2.3 employed the same method, except that the stirring speed was 75 rpm.

[0167] 2.1. Dissolution of the tablets of Example 10 (Formulation Examples section) TIFF0005600328000048.tif36154 TIFF0005600328000049.tif72139

[0168] 2.2. Dissolution of the tablets of Example 11 (Formulation Examples section) TIFF0005600328000050.tif234154

[0169] 2.3. Dissolution of the tablets in Example 5 (Formulation Examples section) TIFF0005600328000051.tif114154

[0170] 3. Measurement of particle size distribution by laser diffraction For example, particle size distribution is measured using light scattering or laser diffraction techniques. To determine the particle size, for example, powder is supplied to a laser diffraction spectrometer using a dispersion device. The test method is described in detail below: Equipment: Laser Diffraction Spectrometer Sympatec HELOS Particle Sizer. Lens: R31 (0.5 / 0.9μm~175μm) Sample dispersion equipment: Drying disperser RODOS / M Vacuum: Nilfisk Feeding device: ASPIROS Feeding speed: 60.00mm / sec Primary pressure: 2.00 bar Syringe pressure: Maximum (mbar) 2 Standard measurement: 10 seconds Cycle time: 100 milliseconds Induction condition: Optical density ≥ 1% at 0.0 seconds after start is always effective. The process stops 5.0 seconds after the optical density becomes ≤1% or 30 seconds in real time. Optical density: Approximately 3-12% Rating: HRLD Sample size: Approximately 100 mg Number of measurements: 2 (pair)

[0171] Set up the instrument according to the manufacturer's recommendations and using the manufacturer's software. Before taking any sample, thoroughly mix and invert the sample container to ensure that a representative sample is tested. Prepare a pair of samples by transferring approximately 100 mg of sample to an ASPIROS glass vial using a spatula and capping the vial. Place the capped vial into the dispensing device. 4. Hardness and crushability of the tablets The hardness and brittleness of the tablets were tested as described in USP31-NF26 S2, Chapter 1217 (Tablet Breaking Power).

[0172] 5. Pharmacokinetic parameters The pharmacokinetic parameters of pharmaceutical compositions and dosage forms are evaluated in healthy volunteer and patient populations. In the studies described below, participants fasted on the day of sampling unless otherwise specified (see, for example, Study 3). The active substance in the studies below is preferably the crystalline (I.9X) compound (I.9), and the dose of the active ingredient is expressed in mg. To quantify the plasma concentration of the active ingredient, 2.7 mL of blood was collected and transferred to an EDTA (ethylenediaminetetraacetic acid) anticoagulant blood collection tube. The EDTA anticoagulant blood sample was centrifuged immediately after collection. Centrifugation was continued at 4-8°C for approximately 10 minutes (approximately 2,000 × gf to 4,000 × gf) or stored on ice for no more than 30 minutes. The concentration of the active substance in the EDTA human plasma sample was quantified using HPLC / MS / MS. The assay method included solid-phase supported liquid-liquid extraction of human plasma, followed by HPLC / MS / MS measurement of the extracted sample. The HPLC / MS / MS assay was effective for the range of 1.11 to 1110 nM in human plasma.

[0173] Study 1: A single-dose study in a healthy volunteer population of N=72. Healthy volunteers were administered the tablets described in Example 10 (Formulation Examples section). Study 2: A multi-dose escalation study in a group of 48 diabetic patients, administered once daily for 8 days. Patients were given the tablets described in Example 10 (Formulation Examples section). Study 3: A cross-effect study of single-dose food effects in a healthy volunteer population of N=14. Healthy volunteers were administered the tablets described in Example 10 (Formulation Examples section). Study 4: Treatment of a 78-person diabetic patient population over 4 weeks, administered once daily for 4 weeks. Patients were given the tablets described in Example 10 (Formulation Examples section). Study 5: A single-dose study in a healthy volunteer population (Japanese volunteers) of N=48. Healthy volunteers were administered the tablets described in Example 11 (Formulation Examples section).

[0174] AUC 0-inf : Area under the concentration-time curve of the analyte in plasma over a time interval extrapolated from 0 to infinity. C max : The maximum concentration of the analyte in plasma. T max : The time it takes for the concentration to reach its maximum after administration. AUC τ,ss : Area under the concentration-time curve of the analyte in plasma over a time interval of 0 to 24 hours under steady state. C max,ss : The maximum concentration of the analyte in plasma at a steady state over uniform dosing intervals. t max,ss : The time it takes from administration to reaching the maximum concentration in a steady state.

[0175] 5.1. Pharmacokinetic parameters, single dose

[0176] Table: Pharmacokinetic parameters: Area under the plasma concentration-time curve (AUC) from 0 hours to infinity 0-inf ) TIFF0005600328000052.tif88160

[0177] Table: Pharmacokinetic parameters: Maximum plasma concentration (C) max ) TIFF0005600328000053.tif88160

[0178] Table: Pharmacokinetic parameters: Time to reach maximum plasma concentration (t max ) TIFF0005600328000054.tif85159

[0179] 5.2. Pharmacokinetic parameters, steady state

[0180] Table: Pharmacokinetic parameters: Area under the plasma concentration-time curve (AUC) over the dosing interval at steady state. τ,ss ) TIFF0005600328000055.tif41158

[0181] Table: Pharmacokinetic parameters: Maximum plasma concentration (C) at steady state max,ss ) TIFF0005600328000056.tif41160

[0182] Table: Pharmacokinetic parameters: Time to reach maximum plasma concentration in steady state (t max,ss ) TIFF0005600328000057.tif41160

[0183] 5.3. Pharmacokinetic parameters, single dose, dose normalization

[0184] Table: Pharmacokinetic parameters: Area under the dose-normalized plasma concentration-time curve (AUC) from 0 hours to infinity 0-inf,norm ) and dose-normalized maximum plasma concentration (C max,norm ) TIFF0005600328000058.tif84159

[0185] 5.4. Pharmacokinetic parameters, steady state

[0186] Table: Pharmacokinetic parameters: Area under the dose-normalized plasma concentration-time curve (AUC) over the dosing interval at steady state. τ,ss, norm ) and dose-normalized maximum plasma concentration (C) at steady state max,ss,norm ) TIFF0005600328000059.tif41158

Claims

1. The following formula (I.9) 【Chemistry 1】 (I.9) A pharmaceutical composition comprising the compound, A pharmaceutical composition wherein the particle size distribution in the composition is 1 μm ≤ X90 < 200 μm, and the compound of formula (I.9) corresponds to 25% or less of the mass of the composition.

2. The pharmaceutical composition according to claim 1, wherein the particle size distribution of the compound of formula (I.9) in the composition is 5 μm ≤ X90 ≤ 150 μm.

3. The pharmaceutical composition according to claim 1, wherein the particle size distribution of the compound of formula (I.9) in the composition is X90 ≤ 150 μm, 5 μm ≤ X50 ≤ 50 μm, and X10 ≥ 0.5 μm.

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein the compound of formula (I.9) corresponds to 1.0 to 20% or less of the mass of the composition.

5. The pharmaceutical composition according to claim 4, wherein the compound of formula (I.9) is in an amount of 2.0 to 15% or less of the mass of the composition.

6. The pharmaceutical composition according to any one of claims 1 to 5, wherein the composition comprises the crystalline form (I.9X) of the compound of formula (I.9).

7. The pharmaceutical composition according to any one of claims 1 to 6, wherein the composition comprises a disintegrant and a binder, and the ratio of the disintegrant to the binder is 1.5:3.5 to 1:1 (mass / mass).

8. The pharmaceutical composition according to any one of claims 1 to 7, wherein at least 99% (by mass) of the particles of the binder are 250 μm or less.

9. The pharmaceutical composition according to any one of claims 1 to 8, wherein the composition is obtained by high-shear wet granulation, the composition further comprises a diluent, and 5 to 20% (by mass) of the diluent is added to the composition as a drying additive after the wet granulation.

10. The composition comprises the following components A pharmaceutical composition according to any one of claims 1 to 9, comprising:

11. The pharmaceutical composition according to any one of claims 1 to 10, wherein the diluent is lactose monohydrate and / or microcrystalline cellulose.

12. The pharmaceutical composition according to any one of claims 1 to 10, wherein the binder is hydroxypropyl cellulose and / or microcrystalline cellulose.

13. The pharmaceutical composition according to any one of claims 1 to 12, wherein the disintegrant is croscarmellose sodium.

14. The pharmaceutical composition according to any one of claims 1 to 13, further comprising one or more lubricants.

15. The pharmaceutical composition according to claim 14, wherein the lubricant is magnesium stearate.

16. The pharmaceutical composition according to any one of claims 1 to 15, further comprising one or more flow promoters.

17. The pharmaceutical composition according to claim 16, wherein the flow promoter is colloidal silicon dioxide or talc.

18. The pharmaceutical composition according to any one of claims 1 to 17, further comprising one or more film coating agents.

19. The composition comprises the following components A pharmaceutical composition according to any one of claims 1 to 18, comprising:

20. A pharmaceutical dosage form comprising the pharmaceutical composition according to any one of claims 1 to 19.

21. The pharmaceutical dosage form according to claim 20, wherein the dosage form is a tablet.

22. A pharmaceutical dosage form according to claim 20 or 21, comprising 5 to 25 mg of the compound of formula (I.9) described in claim 1.

23. The pharmaceutical dosage form according to claim 20 or 21, comprising 10 or 25 mg of the compound of formula (I.9) described in claim 1.

24. Use of a pharmaceutical composition or pharmaceutical dosage form according to any one of claims 1 to 23 for the manufacture of a pharmaceutical for the treatment of a metabolic disorder selected from the group consisting of type 1 diabetes, type 2 diabetes, impaired glucose tolerance (IGT), abnormal fasting blood glucose (IFG), hyperglycemia, postprandial hyperglycemia, overweight, obesity, and metabolic syndromes.

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