solid pharmaceutical composition comprising a sglt-2 inhibitor and its pharmaceutical dosage form

专利摘要:
"PHARMACEUTICAL COMPOSITION, PHARMACEUTICAL DOSAGE FORM, PROCESS FOR THEIR PREPARATION, METHODS OF TREATMENT AND ITS USE" The present invention relates to pharmaceutical compositions comprising fixed dose combinations of an SGLT-2 inhibitor and an associated drug, processes for its preparation, and its use to treat certain diseases.
公开号:BR112012009376B1
申请号:R112012009376-2
申请日:2010-10-01
公开日:2021-02-09
发明作者:Peter Schneider；Wolfram Eisenreich；Nantharat Pearnchob
申请人:Boehringer Ingelheim International Gmbh；
IPC主号:

专利说明:

Technical Field of the Invention
[0001] The present invention relates to pharmaceutical compositions comprising fixed dose combinations of an SGLT-2 inhibitor drug and an associated drug, processes for its preparation and its use for the treatment of certain diseases.
[0002] In a more detailed aspect, the present invention relates to solid oral dosage forms for the fixed dose combination (FDC) of a selected SGLT-2 inhibitor drug and a particular associated drug.
[0003] Furthermore, the invention relates to a process for the preparation of such a pharmaceutical dosage form. In addition, the 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, in particular of one or more selected type 1 diabetes mellitus, type 2 diabetes mellitus conditions impaired glucose tolerance, impaired fasting blood glucose and hyperglycemia inter alia. In addition, the present invention relates to methods of treating and / or preventing such diseases and medical conditions in which a pharmaceutical composition or pharmaceutical dosage form according to the invention is administered to a patient in need. Background of the Invention
[0004] Type 2 diabetes is an increasingly prevalent disease that, due to a high frequency of complications, leads to a significant reduction in life expectancy. Because of the microvascular complications associated with diabetes, type 2 diabetes is currently the most frequent cause of onset of vision loss in adulthood, kidney failure and amputations in the industrialized world. In addition, the presence of type 2 diabetes is associated with a 2- to 5-fold increase in the risk of cardiovascular disease.
[0005] After long-term illness, most patients with type 2 diabetes will eventually fail on oral therapy and become insulin-dependent with the need for daily injections and multiple daily glucose measurements.
[0006] The UKPDS (United Kingdom Prospective Diabetes Study) demonstrated that intensive treatment with metformin, sulfonylureas or insulin resulted in only a limited improvement in glycemic control (difference in HbA1c ~ 0.9%). In addition, even in patients within intensive care brachial glycemic control it has deteriorated significantly over time and this has been attributed to the deterioration of β cell function. Most importantly, intensive treatment was not associated with a significant reduction in macrovascular complications, that is, in cardiovascular events. Therefore, many patients with type 2 diabetes remain without adequate treatment, in part because of the limitations of long-term efficacy, tolerability and inconvenience of dosing existing anti-hyperglycemic therapies.
[0007] Oral antidiabetic drugs conventionally used in therapy (such as, for example, first or second line, and / or mono- or (initial or extra) combination therapy) include, but are not limited to, metformin, sulfonylureas , thiazolidinediones, glinides and α-glycosidase inhibitors.
[0008] The high incidence of therapeutic failure is a major contributor to the high rate of complications associated with long-term hyperglycemia or chronic damage (including micro- and macrovascular complications such as, for example, nephropathy, retinopathy or diabetic neuropathy, or cardiovascular complications) in patients with type 2 diabetes.
[0009] Therefore, there is an unmet medical need for methods, drugs and pharmaceutical compositions with good efficacy with regard to glycemic control, with reference to disease-modifying properties and with regard to the reduction of morbidity and mortality cardiovascular disease while at the same time showing an improved safety profile.
[00010] SGLT2 inhibitors represent a new class of agents that are being developed for the treatment or improvement in glycemic control in patients with type 2 diabetes. Benzene derivatives substituted by glycopyranosyl are described in the prior art as SGLT2 inhibitors, for example example, in WO 01/27128, WO 03/099836, WO 2005/092877, WO 2006/034489, WO 2006/064033, WO 2006/117359, WO 2006/117360, WO 2007/025943, WO 2007/028814, WO 2007 / 031548, WO 2007/093610, WO 2007/128749, WO 2008/049923, WO 2008/055870, WO 2008/055940. Benzene derivatives substituted by glycopyranosyl are proposed as inducers of sugar excretion in urine and as drugs in the treatment of diabetes.
[00011] Renal glucose filtration and reuptake contribute, among other mechanisms, to the constant concentration of glucose in plasma and can therefore serve as an anti-diabetic target. The uptake of filtered glucose through kidney epithelial cells proceeds through sodium-dependent glucose co-transporters (SGLTs) located on the brush-bordered membranes in the tubules along the sodium gradient. There are at least 3 isoforms of SGLT that differ from their expression pattern, as well as from their physicochemical properties. SGLT2 is additionally expressed in the kidney, while SGLT1 is additionally expressed in other tissues such as the intestine, colon, skeleton and heart muscle. SGLT3 was observed to be a glucose sensor in the interstitial cells of the intestine, without any transport function. Potentially, other related genes, but not yet characterized, can contribute even more to the renal glucose uptake. Under normoglycemia, glucose is completely reabsorbed by SGLTs in the kidney, while the kidney's re-uptake capacity is saturated at glucose concentrations higher than 10 mM, resulting in glycosuria ("diabetes mellitus"). This threshold concentration can be decreased by inhibiting SGLT2. It has been shown in experiments with the SGLT inhibitor florizine that inhibition of SGLT will partially inhibit glucose uptake from the glomerular filtrate into the blood which leads to a decrease in blood glucose concentrations and glycosuria. Purpose of the present invention
[00012] The purpose of the present invention is to provide a pharmaceutical composition comprising an SGLT2 inhibitor and an associated drug that has high content uniformity for the SGLT2 inhibitor and the associated drug.
[00013] Another objective of the present invention is to provide a pharmaceutical composition comprising an SGLT2 inhibitor and an associated drug that has a very high drug load for the associated drug and a very low drug load for the SGLT2 inhibitor.
[00014] Another objective of the invention is to provide a pharmaceutical composition comprising an SGLT2 inhibitor and an associated drug that allows for efficient production with respect to the time and costs of pharmaceutical dosage forms.
[00015] Another objective of the present invention is to provide a pharmaceutical composition comprising an SGLT-2 inhibitor and an associated drug that prevents or reduces the adhesion and displacement of the coating during the production process of the composition.
[00016] Another objective of the present invention is to provide a pharmaceutical composition comprising an SGLT-2 inhibitor and an associated drug that prevents or reduces the formation of a film during the production process of the composition.
[00017] Another objective of the present invention is to provide a pharmaceutical dosage form comprising an SGLT-2 inhibitor and an associated drug that has an acceptable size.
[00018] Another objective of the invention is to provide a pharmaceutical dosage form comprising an SGLT-2 inhibitor and an associated drug that has a short disintegration time, that has good dissolution properties and / or that allows a high bioavailability of the inhibitor of SGLT-2 in one patient.
[00019] Another objective of the invention is to provide a pharmaceutical composition and a pharmaceutical dosage form, each comprising an SGLT2 inhibitor and an associated drug, and a method for the prevention, retardation of the progression, delay or treatment of a metabolic disorder, particularly type 2 diabetes mellitus.
[00020] Another objective of the present invention is to provide a pharmaceutical composition and a pharmaceutical dosage form, each comprising an SGLT2 inhibitor and an associated drug, and a method for improving glycemic control in a patient in need, in particularly in patients with type 2 diabetes mellitus.
[00021] Another objective of the present invention is to provide a pharmaceutical composition and a pharmaceutical dosage form, each comprising an SGLT2 inhibitor and an associated drug, and a method for improving glycemic control in a patient with insufficient glycemic control.
[00022] Another objective of the present invention is to provide a pharmaceutical composition and a pharmaceutical dosage form, each comprising an SGLT2 inhibitor and an associated drug, and a method for preventing, delaying or delaying the progression of impaired glucose tolerance ( IGT), impaired fasting blood glucose (IFG) insulin resistance and / or metabolic syndrome for type 2 diabetes mellitus.
[00023] Another object of the present invention is to provide a pharmaceutical composition and a pharmaceutical dosage form, each comprising an SGLT2 inhibitor and an associated drug, and a method for preventing, delaying progression, delaying or treating a condition or group disorder consisting of complications of diabetes mellitus.
[00024] An object of the present additional invention is to provide a pharmaceutical composition and a pharmaceutical dosage form, each comprising an SGLT2 inhibitor and an associated drug, and a method for reducing weight or preventing weight gain in a patient with Your necessity.
[00025] Another objective of the present invention is to provide a pharmaceutical composition and a pharmaceutical dosage form, each comprising an SGLT2 inhibitor and an associated drug, with a high efficacy for the treatment of metabolic disorders, in particular diabetes mellitus, tolerance impaired glucose (IGT), impaired fasting blood glucose (IFG), and / or hyperglycemia, which has good to very good pharmacological and / or pharmacokinetic and / or physico-chemical properties.
[00026] Another objective of the present invention is to provide a process for the preparation of a pharmaceutical dosage form according to the invention that is cost-effective and / or time-consuming.
[00027] Other objectives of the invention become evident to a person skilled in the art from the description above and in the following and from the examples. Summary of the Invention
[00028] In one aspect the present invention provides a pharmaceutical composition comprising an SGLT-2 inhibitor and an associated drug as an active pharmaceutical ingredient and one or more excipients. In one aspect, a pharmaceutical composition according to the invention is a solid pharmaceutical composition, for example, a solid pharmaceutical composition for oral administration.
[00029] In one aspect, the drugs associated to be combined with the SGLT-2 inhibitor within the pharmaceutical compositions according to this invention are biguanides (for example, metformin such as metformin hydrochloride).
[00030] A preferred associated drug within the meaning of the present invention is metformin, particularly metformin hydrochloride (1,1-dimethylbiguanide hydrochloride or metformin HCl).
[00031] In general, pharmaceutical excipients that can be used can be selected from the group consisting of one or more fillers, one or more binders or diluents, one or more lubricants, one or more disintegrants, and one or more glidants, one or more more film coating agents, one or more plasticizers, one or more pigments, and the like.
[00032] The pharmaceutical compositions (tablets) of this invention generally comprise a binder.
[00033] In more detail, the pharmaceutical compositions (tablets) of this invention generally comprise one or more fillers (for example, D-mannitol, corn starch and / or pregelatinized starch and / or microcrystalline cellulose), a binder (e.g. example, copovidone), a lubricant (for example, magnesium stearate, sodium stearyl fumarate), and a glidant (for example, colloidal anhydrous silica).
[00034] Suitably the pharmaceutical excipients used within this invention are conventional materials such as D-mannitol, corn starch, microcrystalline cellulose, pregelatinized starch as a filler, copovidone as a binder, magnesium stearate, or sodium stearyl fumarate as a lubricant, colloidal anhydrous silica as a glidant, hypromellose as a film coating agent, propylene glycol as a plasticizer, titanium dioxide, red / yellow / black iron oxide or a mixture of these as a pigment, and talc, etc.
[00035] A typical composition according to the present invention comprises the copovidone binder (also known as copolividone or Kollidon VA64).
[00036] In addition, a typical composition according to the present invention comprises the corn starch filler, the copovidone binder, the magnesium stearate lubricant, and the colloidal anhydrous silica glidant.
[00037] In addition, a typical composition according to the present invention comprises the microcrystalline cellulose filler, the copovidone binder, the magnesium stearate or sodium stearyl fumarate lubricant, and the colloidal anhydrous silica glide and optionally the disintegrating crospovidone or croscarmellose sodium .
[00038] Thus, in particular, the present invention is directed to a pharmaceutical composition (especially a solid oral dosage form, in particular a tablet) comprising an SGLT-2 inhibitor, metformin hydrochloride and one or more pharmaceutical excipients, particularly one or more fillers, one or more binders, one or more glidants and / or one or more lubricants.
[00039] In particular, the present invention is directed to a pharmaceutical composition (especially a solid oral dosage form, in particular a tablet) comprising a SGLT-2 inhibitor, metformin hydrochloride, copovidone as a binder and one or more other pharmaceutical excipients.
[00040] The typical pharmaceutical compositions of this invention may comprise in the SGLT-2 inhibitor part (% by weight of the total SGLT-2 inhibitor part): from 0.1 to 10% SGLT-2 inhibitor, from 0 , 1 to 3% SGLT-2 inhibitor, 0.4 to 2.2% SGLT-2 inhibitor, or 0.1 to 2.11% SGLT-2 inhibitor
[00041] The typical pharmaceutical compositions of this invention may also comprise in the SGLT-2 inhibitor part (% by weight of the total SGLT-2 inhibitor part): from 0.1 to 10% SGLT-2 inhibitor, from 0.1 to 3% SGLT-2 inhibitor, from 0.4 to 2.2% SGLT-2 inhibitor, or from 0.1 to 2.12% SGLT-2 inhibitor.
[00042] The typical pharmaceutical compositions of this invention may comprise one or more of the following amounts (% by weight of the total coated tablet mass): from 0.1 to 2.11% SGLT-2 inhibitor, from 47 to 88% metformin HCl, 3.9 to 8.3% binder (eg copovidone), 2.3 to 8.0% filler 1 (eg corn starch), 0 to 4.4 % load 2 (eg, pregelatinized starch), 0 to 33% load 3 (eg, D-mannitol), 0.7 to 1.5% lubricant (eg, magnesium stearate) , from 0.05 to 0.5% of slider (for example, colloidal anhydrous silica), from 0.00 to 3.0% of disintegrant (for example, crospovidone or croscarmellose sodium).
[00043] The typical pharmaceutical compositions of this invention can comprise one or more of the following amounts (% by weight of total coated tablet mass): from 0.1 to 2.12% SGLT-2 inhibitor, from 47 to 88% metformin hydrochloride, 3.9 to 8.3% binder (eg copovidone), 2.3 to 8.0% filler 1 (eg corn starch), 0 to 4.4 % load 2 (eg, pregelatinized starch), 0 to 33% load 3 (eg, D-mannitol), 0.7 to 1.5% lubricant (eg, magnesium stearate) , from 0.05 to 0.5% of slider (for example, colloidal anhydrous silica), from 0.00 to 3.0% of disintegrant (for example, crospovidone or croscarmellose sodium).
[00044] In one embodiment, FDC formulations are chemically stable and a) show similarity in-vitro dissolution profiles and / or are bioequivalent to the free combination, or b) allow in-vitro and in vivo performance to be adjusted to levels desirable. In a preferred embodiment the invention relates to chemically stable FDC formulations maintaining the original dissolution profiles of corresponding mono-tablets from each individual entity, with a reasonable tablet size.
[00045] In one embodiment, a pharmaceutical composition of this invention is produced using fluid bed granulation.
[00046] Further details on the FDC formulations of this invention, for example, the ingredients, ratio of ingredients (such as, for example, ratio of SGLT-2 inhibitor, metformin hydrochloride, and / or excipients), particularly with respect the special dosage forms (tablets) used within this invention as well as their preparation, become apparent to the person skilled in the art from the above description and thereafter (including by way of example the following examples).
[00047] Preferably the SGLT2 inhibitor is selected from a benzene derivative substituted by glycopyranosyl of formula (I)
wherein R1 means Cl, methyl or cyano; R2 means H, methyl, methoxy or hydroxy and R3 means ethyl, cyclopropyl, ethynyl, ethoxy, (R) -tetrahydrofuran-3-yloxy or (S) -tetrahydrofuran-3-yloxy; or a prodrug from one of the aforementioned SGLT2 inhibitors.
[00048] In benzene derivatives substituted by glycopyranosyl above formula (I) the following definitions of the substituents are preferable.
[00049] Preferably R1 means chlorine or cyano; in particular chlorine.
[00050] Preferably R2 means H.
[00051] Preferably R3 means ethyl, cyclopropyl, ethynyl, (R) - tetrahydrofuran-3-yloxy or (S) -tetrahydrofuran-3-yloxy. Even more preferably R3 means cyclopropyl, ethynyl, (R) -tetrahydrofuran-3-yloxy or (S) -tetrahydrofuran-3-yloxy. More preferably R3 means ethynyl, (R) -tetrahydrofuran-3-yloxy or (S) -tetrahydrofuran-3-yloxy.
[00052] Preferred glucopyranosyl-substituted benzene derivatives of formula (I) are selected from the group of compounds from (I.1) to (I.11):



[00053] The even more preferred glycopyranosi-substituted benzene derivatives of formula (I) are selected from compounds (I.6), (I.7), (I.8), (I.9) and (I.11 ).
[00054] The most preferred glycopyranosyl substituted benzene derivatives of formula (I) are selected from compounds (I.8) and (I.9), or a crystalline form (I.9X) of the compound (I.9) .
[00055] The pharmaceutical compositions according to the invention allow for a high content uniformity and an efficient production with regard to the time and costs of the pharmaceutical dosage forms, such as tablets and capsules. In addition, in one embodiment, these pharmaceutical dosage forms are in particular tablets.
[00056] Therefore, in another aspect, the present invention provides a pharmaceutical dosage form comprising a pharmaceutical composition according to the invention. In one aspect, the pharmaceutical dosage form according to the invention is a solid pharmaceutical dosage form, for example, a solid pharmaceutical dosage form for oral administration.
[00057] In another aspect, the present invention provides a process for the preparation of a pharmaceutical dosage form according to the invention which comprises one or more granulation processes in which the active pharmaceutical ingredient together with one or more excipients is granulated.
[00058] It can be found that a pharmaceutical composition comprising an SGLT2 inhibitor and associated drug as defined below can be advantageously used for the prevention, retardation of progression, delay or treatment of a metabolic disorder, in particular to improve glycemic control in patients. This opens up new therapeutic possibilities in the treatment and prevention of type 2 diabetes mellitus, overweight, obesity, complications of diabetes mellitus and borderline sick states.
[00059] Therefore, in a first aspect the present invention provides a method for the prevention, progression delay, delay or treatment of a metabolic disorder selected from the group consisting of type 1 diabetes mellitus, type 2 diabetes mellitus, impaired glucose tolerance ( IGT), impaired fasting blood glucose (IFG), hyperglycemia, postprandial hyperglycemia, overweight, obesity and metabolic syndrome in a patient with his need characterized by the fact that a pharmaceutical composition or pharmaceutical dosage form of the present invention is administered to the patient.
[00060] In accordance with another aspect of the invention, a method is provided to improve glycemic control and / or to reduce fasting plasma glucose, postprandial plasma glucose and / or glycosylated hemoglobin HbA1c in a patient with their need characterized by the fact that the pharmaceutical composition or a pharmaceutical dosage form of the present invention is administered to the patient.
[00061] The pharmaceutical composition according to the present invention can also have valuable disease-modifying properties with respect to diseases or conditions related to impaired glucose tolerance (IGT), impaired fasting blood glucose (IFG), insulin resistance and / or metabolic syndrome.
[00062] In accordance with another aspect of the invention, a method is provided for preventing, delaying, delaying or reversing the progression of impaired glucose tolerance (IGT), impaired fasting blood glucose (IFG), insulin resistance and / or the metabolic syndrome for type 2 diabetes mellitus in a patient with his need characterized by the fact that a pharmaceutical composition or pharmaceutical dosage form of the present invention is administered to the patient.
[00063] As through the use of a pharmaceutical composition according to this invention, an improvement of glycemic control in patients with their need is obtainable, also these conditions and / or diseases related or caused by an increase in the level of glucose in the blood can be treated.
[00064] According to another aspect of the invention, a method is provided for the prevention, retardation of progression, delay or treatment of a condition or disorder selected from the group consisting of complications of diabetes mellitus, such as cataracts and micro and macrovascular diseases, such as nephropathy, retinopathy, neuropathy, tissue ischemia, diabetic foot, arteriosclerosis, myocardial infarction, acute coronary syndrome, unstable angina pectoris, stable angina pectoris, stroke, peripheral arterial occlusive disease, cardiomyopathy, heart failure, disorders of cardiac rhythm and vascular restenosis, in a patient with his need characterized by the fact that a pharmaceutical composition or a pharmaceutical dosage form of the present invention is administered to the patient. In particular, one or more aspects of diabetic nephropathy such as hyperperfusion, proteinuria and albuminuria can be treated, their progression slowed or their onset delayed or prevented. The term "tissue ischemia" particularly comprises diabetic macroangiopathy, diabetic microangiopathy, impaired wound healing and diabetic ulcer. The terms "micro- and macrovascular diseases" and "micro- and macrovascular complications" are used interchangeably in this application.
[00065] By administering a pharmaceutical composition according to this invention and due to the activity of SGLT2 inhibitors, excessive blood glucose levels are not converted into insoluble storage forms, such as fat, but excreted in the patient's urine. Therefore, no weight gain or even a reduction in body weight is the result.
[00066] According to another aspect of the invention, a method is provided for reducing body weight or preventing an increase in body weight or facilitating a reduction in body weight in a patient with his need characterized by the fact that a composition pharmaceutical or pharmaceutical dosage form of the present invention is administered to the patient.
[00067] The pharmacological effect of the SGLT2 inhibitor on the pharmaceutical composition according to this invention is independent of insulin. Therefore, an improvement in glycemic control is possible without additional effort on the beta cells of the pancreas. By administering a pharmaceutical composition according to this invention, a degeneration of beta cells and a decline in beta cell functionality such as, for example, apoptosis or necrosis of pancreatic beta cells, can be delayed or prevented. In addition, the functionality of pancreatic cells can be improved or restored, and the number and size of pancreatic beta cells increased. It can be shown that the state of differentiation and hyperplasia of pancreatic beta cells disturbed by hyperglycemia can be normalized by treatment with a pharmaceutical composition according to this invention.
[00068] According to another aspect of the invention, a method is provided for the prevention, delay, delay or treatment of pancreatic beta cell degeneration and / or the decline in the functionality of pancreatic beta cells and / or for the improvement and / or restoring the functionality of pancreatic beta cells and / or restoring the functionality of pancreatic insulin secretion in a patient with his need characterized by the fact that a pharmaceutical composition or pharmaceutical dosage form of the present invention is administered to the patient.
[00069] By administering a pharmaceutical composition according to the present invention, an abnormal accumulation of fat in the liver can be reduced or inhibited. Therefore, according to another aspect of the present invention, a method is provided for the prevention, delay, delay or treatment of diseases or conditions attributed to an abnormal accumulation of fat in the liver of a patient with his need characterized by the fact that an inhibitor SGLT2 as above and then defined is administered to the patient. The diseases or conditions that are attributed to an abnormal accumulation of fat in the liver are particularly selected from the group consisting of general fatty liver, non-alcoholic fatty liver (NAFL), non-alcoholic steatohepatitis (NASH), fatty-induced fatty liver, diabetic fatty liver , alcohol-induced fatty liver or toxic fatty liver.
[00070] As a result of this fact, another aspect of the invention provides a method for maintaining and / or improving insulin sensitivity and / or for the treatment or prevention of hyperinsulinemia and / or insulin resistance in a patient with his need characterized by the fact that a pharmaceutical composition or pharmaceutical dosage form of the present invention is administered to the patient.
[00071] According to another aspect of the invention there is provided the use of a pharmaceutical composition or pharmaceutical dosage form of the present invention for the manufacture of a drug to - prevent, slow the progression of, delay or treat a metabolic disorder selected from the group consisting of type 1 diabetes mellitus, type 2 diabetes mellitus, impaired glucose intolerance (IGT), impaired fasting blood glucose (IFG), hyperglycemia, postprandial hyperglycemia, overweight, obesity and metabolic syndrome; or - improve glycemic control and / or to reduce fasting plasma glucose, postprandial plasma glucose and / or glycosylated hemoglobin HbA1c; or - prevent, decrease, delay or reverse the progression of impaired glucose tolerance (IGT), impaired fasting blood glucose (IFG), insulin resistance and / or the metabolic syndrome for type 2 diabetes mellitus; or - prevent, delay progression, delay or treat a condition or disorder selected from the group consisting of complications of diabetes mellitus such as cataracts and micro- and macrovascular diseases, such as nephropathy, retinopathy, neuropathy, tissue ischemia, diabetic foot, arteriosclerosis , myocardial infarction, acute coronary syndrome, unstable angina pectoris, stable angina pectoris, stroke, peripheral arterial occlusive disease, cardiomyopathy, heart failure, heart rhythm disorders and vascular restenosis; or - reduce body weight or prevent an increase in body weight or facilitate a reduction in body weight; or - prevent, delay, delay or treat pancreatic beta cell degeneration and / or the decline in pancreatic beta cell functionality and / or to improve and / or restore pancreatic beta cell functionality and / or restore the secretion functionality of pancreatic insulin; or - prevent, delay, delay or treat diseases or conditions attributed to an abnormal accumulation of fat in the liver; or - maintain and / or improve insulin sensitivity and / or to treat or prevent hyperinsulinemia and / or insulin resistance; in a patient with his need characterized by the fact that the SGLT2 inhibitor is administered, as defined above and then.
[00072] According to another aspect of the invention, the use of a pharmaceutical composition or pharmaceutical dosage form of the present invention according to the present invention is provided for the manufacture of a drug for a therapeutic and preventive method as described above and then. Definitions
[00073] The term "active ingredient" of a pharmaceutical composition according to the present invention means the SGLT2 inhibitor according to the present invention. An "active ingredient is also sometimes referred to here as an" active substance ".
[00074] The term "body mass index" or "BMI" of a human patient is defined as the weight in kilograms divided by the square of the height in meters, such that the BMI has units of kg / m2.
[00075] The term "overweight" is defined as the condition in which the individual has a BMI greater than 25 kg / m2 and less than 30 kg / m2. The terms "overweight" and "pre-obesity" are used interchangeably.
[00076] The term "obesity" is defined as the condition in which the individual has a BMI equal to or greater than 30 kg / m2. According to a WHO definition the term obesity can be classified as follows: the term "class I obesity" is the condition in which the BMI is equal to or greater than 30 kg / m2, but lower than 35 kg / m2; the term "class II obesity" is the condition in which the BMI is equal to or greater than 35 kg / m2, but lower than 40 kg / m; the term "class III obesity" is the condition in which the BMI is equal to or greater than 40 kg / m2.
[00077] The term "visceral obesity" is defined as the condition in which a waist-to-hip ratio greater than or equal to 1.0 in men and 0.8 in women is measured. It defines the risk for insulin resistance and the development of pre-diabetes.
[00078] The term "abdominal obesity" is generally defined as the condition where the waist circumference is> 40 inches or 102 cm in men, and is> 35 inches or 94 cm in women. For Japanese ethnicity or Japanese patients, abdominal obesity can be defined as waist circumference> 85 cm in men and> 90 cm in women (see, for example, the research committee for the diagnosis of the syndrome in Japan).
[00079] The term "euglycemia" is defined as the condition in which an individual has a fasting blood glucose concentration within the normal range, greater than 70 mg / dL (3.89 mmols / L) and less than 110 mg / dL (6.11 mmol / L). The word "fasting" has the usual meaning as a medical term.
[00080] The term "hyperglycemia" is defined as the condition in which an individual has a fasting blood glucose concentration above the normal range, greater than 110 mg / dL (6.11 mmol / L). The word "fasting" has the usual meaning as a medical term.
[00081] The term "hypoglycemia" is defined as the condition in which an individual has a blood glucose concentration below the normal range of 60 to 115 mg / dL (3.3 to 6.3 mmols / L).
[00082] The term "postprandial hyperglycemia" is defined as the condition in which an individual has a two-hour postprandial blood glucose or serum glucose concentration greater than 200 mg / dL (11.11 mmols / L).
[00083] The term "impaired fasting blood glucose" or "IFG" is defined as the condition in which an individual has a fasting blood glucose concentration or fasting serum glucose concentration in a range of 100 to 125 mg / dl (i.e., from 5.6 to 6.9 mmols / l), in particular greater than 110 mg / dL and less than 126 mg / dL (7.00 mmols / L). An individual with "normal fasting glucose" has a fasting glucose concentration less than 100 mg / dl, that is, less than 5.6 mmol / l.
[00084] The term "impaired glucose tolerance" or "IGT" is defined as the condition in which an individual has a two-hour postprandial blood glucose or serum glucose concentration greater than 140 mg / dL (7 , 78 mmols / L) and less than 200 mg / dL (11.11 mmols / L). Abnormal glucose tolerance, that is, two-hour postprandial blood glucose or serum glucose concentration, can be measured as blood sugar level in mg of glucose per dL of plasma 2 hours after taking 75 g of glucose after a fast. An individual with "normal glucose tolerance" has a 2 hour postprandial blood glucose or serum glucose concentration less than 140 mg / dL (7.78 mmols / L).
[00085] The term "hyperinsulinemia" is defined as the condition in which an individual with insulin resistance, with or without euglycemia, has an elevated insulin concentration in the fasting or postprandial serum or plasma higher than that of normal lean individuals without resistance insulin, with a waist-to-hip ratio of <1.0 (for men) or <0.8 (for women).
[00086] The terms "insulin sensitization", "improved insulin resistance" or "decreased insulin resistance" are synonymous and used interchangeably.
[00087] The term "insulin resistance" is defined as a state in which circulating insulin levels in excess of the normal response to a glucose load are necessary to maintain the euglycemic state (Ford ES, et al. JAMA. ( 2002) 287: 356-9). One method of determining insulin resistance is the euglycemic-hyperinsulinemic fixation test. The insulin-to-glucose ratio is determined within the scope of a combined insulin-glucose infusion technique. It is observed to be insulin resistant if glucose absorption is below the 25th percentile of the investigated environment population (WHO definition). A little less laborious than the fixation test, the so-called minimal models in which, during an intravenous glucose tolerance test, the insulin and glucose concentrations in the blood are measured at fixed time intervals and, from these , insulin resistance is calculated. With this method, it is not possible to distinguish between hepatic and peripheral insulin resistance.
[00088] In addition, insulin resistance, the response of a patient with insulin resistance to therapy, insulin sensitivity and hyperinsulinemia can be quantified by calculating the "homeostasis model assessment score on insulin resistance" (HOMA-IR) ", a confidence indicator of insulin resistance (Katsuki A, et al. Diabetes Care 2001; 24: 362-5). Another reference is made to methods for determining the HOMA index with respect to insulin sensitivity (Matthews et al., Diabetologia 1985, 28: 412-19), from the ratio of intact proinsulin to insulin (Forst et al., Diabetes 2003 ,. 52 (Suppl. 1): A459) and for a study of euglycemic fixation. In addition, plasma adiponectin levels can be monitored as a potential substitute for insulin sensitivity. The estimate of insulin resistance by the score of the homeostasis assessment model (HOMA) -IR is calculated with the formula (Galvin P, et al. Diabet Med 1992; 9: 921-8.): HOMA IR [insulin in serum in fasting (μU / mL] x [fasting plasma glucose (mmol / L)] - "22.5
[00089] Generally, other parameters are used in daily clinical practice to assess insulin resistance. Preferably, the concentration of triglycerides in the patient is used, for example, as the increased triglyceride levels significantly correlated with the presence of insulin resistance.
[00090] Patients predisposed to the development of IGT or IFG or type 2 diabetes are those having euglycemia with hyperinsulinemia and are, by definition, resistant to insulin. A typical insulin-resistant patient is usually overweight or obese. If insulin resistance can be detected, this is a particularly strong indication of the presence of pre-diabetes. Thus, it may be that in order to maintain glucose homeostasis, a person needs 2 to 3 times more insulin than a healthy person, without this resulting in any clinical symptoms.
[00091] The methods for investigating pancreatic beta cell function are similar to the above methods in relation to insulin sensitivity, hyperinsulinemia, or insulin resistance: An improvement in beta cell function can be measured, for example, by determining a HOMA index with respect to cell function (Matthews et al., Diabetologia 1985, 28: 412-19), the ratio of intact 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 using a hyperglycemic fixation study and / or minimal modeling after a glucose tolerance test intravenously with sampling frequency (Stumvoll et al., Eur J Clin Invest 2001, 31: 380-81).
[00092] The term "pre-diabetes" is the condition in which an individual is predisposed to the development of type 2 diabetes. Pre-diabetes extends the definition of impaired glucose tolerance to include individuals with fasting blood glucose within high normal range> 100 mg / dL (JB Meigs, et al. Diabetes 2003; 52: 1475-1484) and fasting hyperinsulinemia (high plasma insulin concentration). The scientific and medical basis for identifying prediabetes as a serious health threat is defined in a Position Statement entitled "The Prevention or Delay of Type 2 Diabetes" issued jointly by the American Diabetes Association and the National Institute of Diabetes and Digestive and Kidney Diseases (Diabetes Care 2002; 25: 742-749).
[00093] Individuals likely to have insulin resistance are those who have two or more of the following attributes: 1) overweight or obese, 2) high blood pressure, 3) hyperlipidemia, 4) one or more 1st in connection with a diagnosis of IGT or IFG or type 2 diabetes. Insulin resistance can be confirmed in these individuals by calculating the HOMA-IR score. For the purpose of this invention, insulin resistance is defined as the clinical condition in which an individual has an HOMA-IR score> 4.0 or an HOMA-IR score above the upper limit of normal as defined for the laboratory that performs the glucose and insulin assays.
[00094] The term "type 2 diabetes" is defined as the condition in which an individual has a fasting blood glucose or serum glucose concentration greater than 125 mg / dL (6.94 mmols / L). Measuring blood glucose values is a standard procedure in routine medical analysis. If a glucose tolerance test is performed, the blood sugar level of a diabetic will be in excess of 200 mg of glucose per dL (11.1 mmols / l) of plasma 2 hours after 75 g of glucose has been taken with an empty stomach. In a glucose tolerance test, 75 g of glucose is administered orally to the patient being tested after 10 to 12 hours of fasting and the blood sugar level is recorded immediately before taking the glucose and 1 and 2 hours after ingesting it. In a healthy individual, the blood sugar level before taking glucose will be between 60 and 110 mg per dL of plasma, less than 200 mg per dL 1 hour after taking glucose and less than 140 mg per dL after 2 hours. If after 2 hours the value is between 140 and 200 mg, this is considered to be abnormal glucose tolerance.
[00095] The term "end-stage type 2 diabetes mellitus" includes patients with secondary drug failure with respect to insulin therapy and progression of micro and macrovascular complications, for example, diabetic nephropathy, or coronary heart disease (CHD).
[00096] The term "HbA1c" refers to the product of a non-enzymatic glycation of the hemoglobin B chain. Its determination is well known to a person skilled in the art. In monitoring the treatment of diabetes mellitus, the value of HbA1c is of exceptional importance. When their production essentially depends on the blood sugar level and the life of the erythrocytes, HbA1c in the sense of a "blood sugar memory" reflects the average blood sugar levels of the last 4 to 6 weeks. Diabetic patients whose HbA1c value is consistently well adjusted through intensive treatment of diabetes (ie, <6.5% of the total hemoglobin in the sample), are significantly better protected against diabetic microangiopathy. For example, metformin alone achieves an average improvement in the value of HbA1c in diabetics in the order of 1.0 to 1.5%. This reduction in the HbA1C value is not sufficient in all diabetics to reach the desired target range of <6.5% and preferably <6% HbA1c.
[00097] The term "insufficient glycemic control" or "inadequate glycemic control" within the scope of the present invention means a condition in which patients have HbA1c values above 6.5%, in particular above 7.0%, even more preferably above 7.5%, especially above 8%.
[00098] The "metabolic syndrome", also called "syndrome X" (when used in the context of a metabolic disorder), also called "dysmetabolic syndrome" is a syndrome complex with the cardinal characteristic being insulin resistance (Laaksonen DE, et al. Am J Epidemiol 2002; 156: 1070-7). According to the ATP III / NCEP (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) guidelines JAMA: Journal of the American Medical Association (2001) 285: 2486-2497), the diagnosis of metabolic syndrome is made when three or more of the following risk factors are present: 1. Abdominal obesity, defined as waist circumference> 40 inches or 102 cm in men and> 35 cm or 94 cm in women; or with respect to a Japanese ethnicity or Japanese patients defined as waist circumference> 85 cm in men and> 90 cm in women; 2. Triglycerides:> 150 mg / dL 3. HDL cholesterol <40 mg / dL in men 4. Blood pressure> 130/85 mmHg (SBP> 130 or DBP> 85) 5. Fasting blood glucose> 110 mg / dL
[00099] The NCEP definitions have been validated (Laaksonen DE, et al. Am J Epidemiol. (2002) 156: 1070-7). Triglycerides and HDL cholesterol in the blood can also be determined by standard methods in medical analysis and are described, for example, in Thomas L (Editor): "Labor und Diagnose", TH-Books Verlagsgesellschaft mbH, Frankfurt / Main, 2000.
[000100] According to a commonly used definition, hypertension is diagnosed if the systolic blood pressure (SBP) exceeds a value of 140 mm Hg and the diastolic blood pressure (DBP) exceeds a value of 90 mm Hg. If a patient is suffering from overt diabetes, it is currently recommended that systolic blood pressure be reduced to below 130 mm Hg and diastolic blood pressure to be reduced below 80 mm Hg.
[000101] The term "SGLT2 inhibitor" in the scope of the present invention refers to compounds, in particular glycopyranosyl derivatives, that is, compounds having a glycopyranosyl component, which have an inhibitory effect on the sodium-glucose transporter 2 (SGLT2), in particular human SGLT2. The inhibitory effect on hSGLT2 measured as IC 50 is preferably below 1000 nM, even more preferably below 100 nM, most preferably below 50 nM. The inhibitory effect on hSGLT2 can be determined by methods known in the literature, in particular as described in application WO 2005/092877 or WO 2007/093610 (pages 23/24), which are hereby incorporated by reference in their entirety. The term "SGLT2 inhibitor" also includes its pharmaceutically acceptable salts, its hydrates and solvates, including the respective crystalline forms.
[000102] The terms "treatment" and "treat" include the therapeutic treatment of patients who have already developed said condition, in particular in the manifest form. Therapeutic treatment can be symptomatic treatment in order to alleviate the symptoms of the specific indication or causal treatment in order to reverse or partially reverse the conditions of the indication or to stop or slow the progression of the disease. Thus, the compositions and methods of the present invention can be used, for example, as therapeutic treatment for a period of time as well as for chronic therapy.
[000103] The terms "prophylactically treat", "preventively treat" and "prevent", are used interchangeably and comprise a treatment of patients at risk of developing a condition mentioned above, thus reducing said risk.
[000104] The term "tablet" includes tablets without a coating and tablets with one or more coatings. In addition, the term "tablet" comprises tablets having one, two, three or more layers and press-coated tablets, each of the aforementioned types of tablets may be without or with one or more coatings. The term "tablet" also includes mini, fusion, chewable, effervescent and oral disintegrating tablets.
[000105] The terms "pharmacopoeia" and "pharmacopoeias" refer to standard pharmacopoeias such as "USP 31-NF 26 through Second Supplement" (United States Pharmacopeial Convention) or "European Pharmacopoeia 6.3" (European Directorate for the Quality of Medicines and Health Care, 2000-2009). Detailed Description
[000106] Aspects according to the present invention, in particular pharmaceutical compositions, methods and uses, refer to SGLT2 inhibitors as above and further defined.
[000107] Preferably, the SGLT2 inhibitor is selected from a benzene derivative substituted by glycopyranosyl of formula (I)
wherein R1 means Cl, methyl or cyano; R2 means H, methyl, methoxy or hydroxy and R3 means ethyl, cyclopropyl, ethynyl, ethoxy, (R) -tetrahydrofuran-3-yloxy or (S) -tetrahydrofuran-3-yloxy; or a prodrug from one of the aforementioned SGLT2 inhibitors.
[000108] The compounds of formula (I) and the methods of their synthesis are described, for example, in the following patent applications: WO 2005/092877, WO 2006/117360, WO 2006/117359, WO 2006/120208, WO 2006 / 064033, WO 2007/031548, WO 2007/093610, WO 2008/020011, WO 2008/055870.
[000109] In benzene derivatives substituted by glycopyranosyl above formula (I) the following definitions of the substituents are preferred.
[000110] Preferably R1 means chlorine or cyano; in particular chlorine.
[000111] Preferably R2 means H.
[000112] Preferably R3 means ethyl, cyclopropyl, ethynyl, (R) - tetrahydrofuran-3-yloxy or (S) -tetrahydrofuran-3-yloxy. Even more preferably R3 means cyclopropyl, ethynyl, (R) -tetrahydrofuran-3-yloxy or (S) -tetrahydrofuran-3-yloxy. Most preferably R3 means ethynyl, (R) -tetrahydrofuran-3-yloxy or (S) -tetrahydrofuran-3-yloxy.
[000113] Preferred glucopyranosyl-substituted benzene derivatives of formula (I) are selected from the group of compounds of



[000114] The even more preferred glycopyranosyl-substituted benzene derivatives of formula (I) are selected from compounds (I.6), (I.7), (I.8), (I.9) and (I.11 ).
[000115] The even more preferred glycopyranosyl-substituted benzene derivatives of formula (I) are selected from compounds (I.8) and (I.9).
[000116] According to this invention, it should be understood that the definitions of the glycopyranosyl-substituted benzene derivatives listed above of formula (I) also include their hydrates, solvates and their polymorphic forms, and prodrugs thereof. As regards the preferred compound (I.7), an advantageous crystalline form is described in international patent application WO 2007/028814 which is hereby incorporated in its entirety. As regards the preferred compound (I.8), an advantageous crystalline form is described in international patent application WO 2006/117360 which is hereby incorporated in its entirety. As regards the preferred compound (I.9), an advantageous crystalline form is described in international patent application WO 2006/117359, which hereby is incorporated in its entirety here. With regard to the preferred compound (I.11), an advantageous crystalline form is described in international patent application WO 2008/049923, which hereby is incorporated in its entirety here. These crystalline forms have good solubility properties that allow good bioavailability of the SGLT2 inhibitor. In addition, the crystalline forms are physically and chemically stable and thus provide good shelf life stability of the pharmaceutical composition.
[000117] For the avoidance of doubt, the description of each of the previous documents cited above in connection with the specified SGLT2 inhibitors is hereby specifically incorporated by reference in its entirety.
[000118] A preferred crystalline form (I.9X) of the compound (I.9) can be characterized by an X-ray powder diffraction pattern comprising peaks at 18.84, 20.36 and 25.21 degrees 20 ( ± 0.1 degrees 20), where said X-ray powder diffraction pattern (XRPD) is formed using CUKα1 radiation.
[000119] In particular, said X-ray powder diffraction pattern comprises peaks at 14.69, 18.84, 19.16, 19.50, 20.36 and 25.21 degrees 20 (± 0.1 degrees 20 ), in which said X-ray powder diffraction pattern is formed using Cukα1 radiation.
[000120] In particular, said X-ray powder diffraction pattern comprises 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 20 (± 0.1 degrees 20) in which said X-ray powder diffraction pattern is formed using Cukα1 radiation.
[000121] More specifically, the crystalline form (I.9X) is characterized by an X-ray powder diffraction pattern, formed using CuKαl radiation, which comprises peaks in degrees 20 (± 0.1 degree 20) as contained in Table 1. Table 1: X-ray powder diffraction pattern of crystalline form (I.9X) (only peaks up to 30o in 20 are listed):


[000122] Even more specifically, the crystalline form (I.9X) is characterized by an X-ray powder diffraction pattern, formed using CUKα1 radiation, which comprises peaks in degrees (± 0.1 degree 20) as shown in figure 1 of WO 2006/117359.
[000123] In addition, the crystalline form (I.9X) is characterized by a melting point of about 151 ° C ± 5 ° C (determined by DSC; assessed as the initial temperature; heating rate of 10 K / min ). The obtained DSC curve is shown in figure 2 of WO 2006/117359.
[000124] X-ray powder diffraction patterns are recorded, within the scope of the present invention, using a STOE - STADI P diffractometer in transmission mode adapted with a location sensitive detector (OED) and a Cu anode such as X-ray source radiation (CuKα radiation, À = 1.54056 Â, 40 kV, 40 mA). In Table 1 above the values of "20 [o]" mean the diffraction angle in degrees and the values of "d [A]" mean the distances specified in A between the planes of the truss. The intensity shown in figure 1 of WO 2006/117359 is given in units of cps (counts per second).
[000125] In order to take into account the experimental error, the values 20 described above must be considered accurate to ± 0.1 degree 20, in particular ± 0.05 degree 20. That is, when it is evaluated that a given sample of crystals of the compound (I.9) is the crystalline form according to the invention, a value 20 that is experimentally observed for the sample must be considered identical with a characteristic value described above if it falls within ± 0.1 degree 20 of the characteristic value, in particular if it falls within ± 0.05 degree 20 of the characteristic value.
[000126] The melting point is determined by DSC (Differential Scanning Calorimetry) using a DSC 821 (Mettler Toledo).
[000127] In one embodiment, a pharmaceutical composition or dosage form according to the present invention comprises the compound (I.9), wherein at least 50% by weight of the compound (I.9) is in the form of its form crystalline (I.9X) as defined above. Preferably, in said composition or dosage form at least 80% by weight, more preferably at least 90% by weight of the compound (I.9) is in the form of its crystalline form (I.9X) as defined above.
[000128] The preferred dosage range of the SGLT2 inhibitor is in the range of 0.5 mg to 200 mg, even more preferably from 1 to 100 mg, most preferably from 1 to 50 mg per day. Oral administration is preferred. Therefore, a pharmaceutical composition of the present invention can comprise the amounts mentioned above, in particular from 0.5 to 50 mg, preferably from 1 to 25 mg, even more preferably from 2.5 to 12.5 mg. The particular dosage intensities for use in the present invention (for example, per tablet or capsule) are, for example, 0.5, 1, 1.25, 2, 2.5, 5, 7.5, 10, 12, 5, 15, 20, 25 or 50 mg of the SGLT2 inhibitor, for example, a compound of the formula (I), in particular the compound (I.9) or its crystalline form (I.9X). Particularly preferred dosage intensities (for example, per tablet or capsule) are, for example, 0.5, 1, 1.25, 2.5, 5, 10 or 12.5, mg of the SGLT2 inhibitor, for example , a compound of the formula (I), in particular of the compound (I.9) or its crystalline form (I.9X).
[000129] In one aspect, the drugs associated with being combined with SGLT-2 within the pharmaceutical compositions according to this invention are biguanides (for example, metformin such as metformin hydrochloride).
[000130] A preferred associated drug within the meaning of this invention is metformin, particularly metformin hydrochloride (1,1-dimethylbiguanide hydrochloride or metformin HCl).
[000131] The anti-hyperglycemic agent of biguanide metformin is disclosed in US Patent No. 3,174,901. The preparation of metformin (dimethyldiguanide) and its hydrochloride salt is the state of the art and was first disclosed by Emil A. Werner and James Bell, J. Chem. Soc. 121, 1922, 1790-1794. Other pharmaceutically acceptable salts of metformin can be found in US application Serial No. 09 / 262,526 filed March 4, 1999 or US Patent No. 3,174,901. It is preferable that the metformin used here is the metformin hydrochloride salt.
[000132] Metformin is generally administered in doses ranging from about 250 mg to 3000 mg, particularly from 500 mg to 2000 mg to 2500 mg per day using the various dosing regimens.
[000133] A dosage range of the drug associated with metformin is generally from 100 mg to 500 mg or 200 mg to 850 mg (1 to 3 times a day), or from 300 mg to 1000 mg once or twice a day.
[000134] The unit dosage intensities of metformin hydrochloride for use in the present invention can be from 100 mg to 2000 mg or from 100 mg to 1500 mg, preferably from 250 mg to 1000 mg. Particular dosage intensities can be 250, 500, 625, 750, 850 and 1000 mg of metformin hydrochloride. These metformin hydrochloride unit dosing intensities represent the US approved dosing intensities for commercialization to treat type 2 diabetes. The most particular unit dosing intensities of metformin hydrochloride for incorporation into the fixed dose combination pharmaceutical compositions of the present invention are 500, 850 and 1000 mg of metformin hydrochloride.
[000135] In another aspect of the present invention, the present invention provides a pharmaceutical composition, formulation, mixture, or dosage form of this invention that is substantially free or only marginally comprises impurities and / or degradation products; which means, for example, that the composition, formulation, mixture, or dosage form includes about <5%, or about <4%, or about <3%, or less than about 2%, of preferably less than about 1%, more preferably less than about 0.5%, even more preferably less than about 0.2% of any individual or total impurity or total weight degradation product (s).
[000136] The dosage forms for the FDC formulations of this invention:
[000137] Another objective of this invention is to develop the FDC formulations of this invention with a reasonable tablet size, with good tablet properties (for example, stability, hardness, friability, disintegration, dissolution profile, content uniformity and more) .
[000138] Thus, it has been observed that the suitable dosage forms for the FDC formulations of this invention are film-coated tablets (film coating for drug loading, such as particularly SGLT-2 inhibitor drug loading per coating. film in tablet cores containing the associated drug), monolayer tablets, bilayer tablets, trilayer tablets and press coated tablets (for example, tablet tablet or bull's eye tablet with SGLT- inhibitor core) 2), whose dosage forms are good measures to achieve the objective under consideration of the desired pharmaceutical profiles and characteristics of an SGLT-2 inhibitor and an associated drug used.
[000139] Said dosage forms have been observed to be applicable in FDC formulations maintaining the original dissolution profiles of each mono tablet or adjusting the profiles to the desired levels, and a reasonable tablet size.
[000140] A typical monolayer tablet of this invention comprises an SGLT-2 inhibitor, metformin hydrochloride, one or more fillers (such as, for example, corn starch), one or more binders (such as, for example, copovidone ), one or more glidants (such as, for example, colloidal anhydrous silica) and one or more lubricants (such as, for example, magnesium stearate).
[000141] In one embodiment of the present invention, the present invention is directed to a solid oral pharmaceutical composition, preferably a tablet, particularly a monolayer tablet, in which one or more of the following applies: - the percentage of metformin hydrochloride is about 84% by weight of the core of the total tablet, - the percentage of SGLT-2 inhibitor is about 0.1% to 2.12%, for example from 0.1% to 2.11% in total tablet core weight, - the crushing strength of the tablet is greater than or equal to 100 N, - the friability of the tablet is less than or equal to 0.5%, - the core weight of the tablet is about 560 at about 1180 mg, and - the disintegration time of the tablets is less than or equal to 15 min.
[000142] In one embodiment, the SGLT-2 inhibitor of a compound of formula (I), in particular of the compound (I.9) or its crystalline form (I.9X).
[000143] In a preferred embodiment of the present invention, the present invention is directed to a solid oral pharmaceutical composition, preferably a tablet, particularly a monolayer tablet comprising or formed of a compound of formula (I), for example of formula ( I.9) or its crystalline form (I.9X), for example, in an amount of 0.5, 1, 1.25, 2.5, 5, 10 or 12.5 mg, metformin, particularly hydrochloride metformin, for example, in an amount of 500 mg, 850 mg or 1000 mg, and one or more pharmaceutical excipients, particularly one or more fillers (for example, corn starch), one or more binders (for example, copovidone), one or more glidants (for example, colloidal anhydrous silica) and / or one or more lubricants (for example, magnesium stearate), as well as, optionally, a film coating, for example, comprising one or more film coating agents (e.g., hypromellose), one or more plasticizers (e.g., propylene glycol, polyethylene glycol, or triethyl citrate), one or more pigments (eg titanium dioxide, red / yellow / black iron oxide or a mixture thereof) and / or one or more glidants (eg talc) .
[000144] In another aspect of the present invention, the present invention provides methods of manufacturing the compositions, formulations, mixtures or dosage forms of this invention, such as, for example, using methods known to a person skilled in the art and / or in a manner as described herein, for example, they can be obtained by processes that comprise the use (for example, mixing, combining, mixing and / or compositing) of the components and / or ingredients, or their premixes, mentioned above and thereafter, just as the present invention further provides compositions, formulations, mixtures or dosage forms that can be obtained by these methods or processes and / or obtainable from the components, ingredients and premixtures and / or mixtures mentioned above and then.
[000145] A method of making a tablet of this invention comprises forming tablets (e.g., compression) of one or more final mixtures in the form of granules. The granules of the (final) mixture according to the present invention can be prepared by methods well known to a person skilled in the art (for example, high shear wet granulation or fluid bed granulation). The granules according to this invention as well as the details of the granulation processes (including their separate steps) for the preparation of granules of this invention are described by way of example in the examples that follow.
[000146] An illustrative granulation process for the preparation of granules comprising the monolayer composition comprises i) the combination (e.g., dissolution or dispersion) of a binder (e.g., copovidone) and, optionally, the SGLT-2 inhibitor (for example, a compound of formula (I), for example, of formula (I.9) or its crystalline form (I.9X)) in a solvent or mixture of solvents such as purified water at room temperature to produce a liquid granulation; ii) mixing metformin HCl, a filler (e.g., corn starch) and, optionally, the SGLT-2 inhibitor in a suitable mixer (e.g., fluid bed granulator) to produce a premix; wherein the SGLT-2 inhibitor can be included in the granulation liquid obtained in i) or in the premix obtained in ii), preferably the SGLT-2 inhibitor is dispersed in the granulation liquid and is absent in the premix; iii) spraying the granulation liquid into the premix and granulating the mixture, for example, in a fluid bed granulator, preferably under a dry condition; iv) the drying of the granulate, for example, around the air inlet temperature of 70 ° C until the desired loss in the drying value in the range of 1 to 3%, for example, from 0.8 to 2%, is obtained; v) the fragmentation of the dry granulate, for example, by sifting through a sieve with a mesh size of 0.5 to 1.0 mm; vi) the combination of the sieved and preferably sieved sliding granules (for example, colloidal anhydrous silica) in a suitable mixer; vii) adding preferably the sieved lubricant (for example, magnesium stearate) in the granulate for the final mixture, for example, in the free-fall mixer.
[000147] Preferably, a monolayer tablet according to this invention comprises or is obtainable from a mixture comprising the SGLT-2 inhibitor and metformin.
[000148] A typical bilayer tablet of this invention comprises a SGLT-2 inhibitor part comprising an SGLT-2 inhibitor, one or more fillers (such as, for example, D-mannitol, pregelatinized starch and corn starch ), one or more binders (such as, for example, copovidone) and one or more lubricants (such as, for example, magnesium stearate), and a part of metformin HCl comprising metformin hydrochloride, one or more fillers (such such as, for example, corn starch), one or more binders (such as, for example, copovidone), one or more glidants (such as, for example, colloidal anhydrous silica) and one or more lubricants (such as, for example , magnesium stearate).
[000149] A typical press-coated tablet (tablet tablet or ox-eye tablet) of this invention comprises a SGLT-2 inhibitor core part comprising an SGLT-2 inhibitor, one or more fillers (such as, eg D-mannitol, pregelatinized starch and corn starch), one or more binders (such as, for example, copovidone) and one or more lubricants (such as, for example, magnesium stearate), and a part of metformin HCl comprising metformin hydrochloride, one or more fillers (such as, for example, corn starch), one or more binders (such as, for example, copovidone), one or more glidants (such as, for example, colloidal anhydrous silica) and one or more lubricants (such as, for example, magnesium stearate).
[000150] A typical film-coated tablet (SGLT-2 inhibitor coating on metformin hydrochloride tablet, i.e. drug layers per film coating for drug loading) of this invention comprises a HCl core portion of metformin comprising metformin hydrochloride, one or more glidants (such as, for example, corn starch), one or more binders (such as, for example, copovidone), one or more glidants (such as, for example, colloidal anhydrous silica ) and one or more lubricants (such as, for example, magnesium stearate), wherein said core part is coated by sealing with a film covering comprising one or more film coating agents (such as, for example, hypromellose ), one or more plasticizers (such as, for example, propylene glycol, Macrogol 400, Macrogol 6000, Macrogol 8000), one or more pigments (such as, for example, titanium dioxide, red / yellow / black iron oxide O a mixture of these) and one or more glidants (such as, for example, talc); and an SGLT-2 inhibitor layer comprising an SGLT-2 inhibitor, one or more film-coating agents (such as, for example, hypromellose) and one or more plasticizers (such as, for example, propylene glycol, Macrogol 400, Macrogol 6000, or Macrogol 8000, triethyl citrate).
[000151] Another typical film-coated tablet (the SGLT-2 inhibitor coating on a metformin HCl tablet, i.e. drug layers per film coating for drug loading) of this invention comprises a part of the HCl core metformin comprising metformin hydrochloride, one or more fillers (such as, for example, corn starch), one or more binders (such as, for example, copovidone), one or more glidants (such as, for example, anhydrous silica colloidal) and one or more lubricants (such as, for example, magnesium stearate), wherein said core part is coated by sealing with a film covering comprising one or more film coating agents (such as, for example, hypromellose), one or more plasticizers (such as, for example, propylene glycol Macrogol 400, Macrogol 6000, or Macrogol 8000, triethyl citrate), one or more pigments (such as, for example, titanium dioxide, red / yellow / black of iron oxide or mixtures thereof) and one or more glidants (such as, for example, talc); and an SGLT-2 inhibitor layer comprising an SGLT-2 inhibitor, one or more film-coating agents (such as, for example, hypromellose) and one or more plasticizers (such as, for example, propylene glycol, Macrogol 400, Macrogol 6000, or Macrogol 8000, triethyl citrate).
[000152] Preferably, these aforementioned tablets (mono-, bilayer, press-coated and drug-coated tablets) are further coated with a final film coating, which comprises a film coating agent (such as, for example , hypromellose), a plasticizer (such as, for example, propylene glycol, Macrogol 400, Macrogol 6000, or Macrogol 8000, triethyl citrate), pigments (such as, for example, titanium dioxide, red / yellow / black oxide iron or mixtures thereof) and a glidant (such as, for example, talc). Typically, this additional film coverage can represent 1 to 4%, preferably 1 to 2%, of the total mass of the composition.
[000153] A pharmaceutical composition or dosage form according to the present invention can be a pharmaceutical composition or immediate release dosage form, or a composition or dosage form with a release time.
[000154] The pharmaceutical immediate release dosage forms of this invention preferably have dissolving properties such that after 45 minutes for each of the active ingredients at least 75%, even more preferably at least 90% by weight of the respective active ingredient is dissolved. In a particular embodiment, after 30 minutes for each of the active ingredients, especially the monolayer tablet according to this invention (including tablet core and film-coated tablet) at least 70 to 75% (preferably at least 80% ) by weight of the respective active ingredient is dissolved. In another embodiment, after 15 minutes for each of the active ingredients, especially the monolayer tablet according to this invention (including tablet core and film-coated tablet), at least 55 to 60% by weight of the respective active ingredient is dissolved. The dissolution properties can be determined in standard dissolution tests, for example, according to standard pharmacopoeias (for example, using the paddle method with agitation speed of 50 or 75 or 100 rpm, pH of the dissolution medium 6, 8 at a temperature of 37 ° C).
[000155] A release time dosage form refers to a formula that is not an immediate release dosage form. In a release time dosage form, the release of the active ingredient is slow and occurs over time. Time release dosage forms are also known as sustained release (SR), sustained action (SA), prolonged release (ER, XR, or XL), timed release or timed release, controlled release (CR), modified release (MR), or continuous release (CR or Contin). In one aspect, a release time dosage form can be a bilayer tablet in which one or more of the active ingredients is released slowly. In one aspect, in a pharmaceutical composition and pharmaceutical dosage form according to the invention, the SGLT-2 inhibitor, for example, a compound of formula (I), for example, of formula (I.9) or its form crystalline (I.9X), or the associated drug, for example, a biguanide, for example, metformin such as metformin hydrochloride, is the release time.
[000156] In another aspect, in a pharmaceutical composition and pharmaceutical dosage form according to the invention, the SGLT-2 inhibitor, for example, a compound of formula (I), for example, of formula (I.9 ) or its crystalline form (I.9X), and the associated drug, for example a biguanide, for example, metformin such as metformin hydrochloride, are the release time.
[000157] In the pharmaceutical compositions and pharmaceutical dosage forms according to the invention, the SGLT-2 inhibitor, for example, a compound of formula (I), for example, of formula (I.9) or its crystalline form ( I.9X), preferably has a particle size distribution (preferably by volume) such that at least 90% of the respective pharmaceutical active ingredient has a particle size less than 200 μm, that is, X90 <200 μm, more preferably X90 <150 μm. More preferably the particle size distribution is such that X90 <100 μm, more preferably X90 <90 μm, even more preferably X90 <75 μm. In addition, the particle size distribution is preferably such that X90> 1 μm, more preferably X90> 5 μm, most preferably X90> 10 μm. Therefore, the preferred particle size distributions are such that 1 μm <X90 <200 μm, particularly 1 μm <X90 <150 μm, more preferably 5 μm <X90 <150 μm, even more preferably 5 μm <X90 <100 μm, even more preferably 10 μm <X90 <100 μm. A preferred example of a particle size distribution of the SGLT-2 inhibitor is 20 μm <X90 <50 μm. It can be seen that a pharmaceutical composition comprising the compound (I.9), or crystalline form (I.9X) of compound (I.9) with a particle size distribution as indicated above shows desired properties (for example, in the which refers to dissolution, uniformity of content, production, or more). The particle size properties indicated are determined by the laser diffraction method, in particular low-angle laser light scattering, ie Fraunhofer diffraction. Alternatively, particle size properties can also be determined by microscopy (for example, electron microscopy or scanning electron microscopy). The results of the particle size distribution determined by different techniques can be correlated with each other. Optimized formulation of the HCl part of metformin:
[000158] Another purpose of this invention is to provide improved formulations of the HCl part of metformin in the pharmaceutical compositions according to this invention.
[000159] For the HCl part of metformin a high drug load is advantageous to be achieved as a prerequisite for a reasonable small tablet size.
[000160] Thus, it has been observed that the metformin HCl drug load and the compaction capacity (compressive strength-crush strength profile) of the tablets of this invention can be improved by surface treatment of metformin HCl with a water-soluble polymer, particularly copolividone.
[000161] Various water-soluble polymers including polyvinyl alcohol (PVA), hypromellose (HPMC), hydroxypropyl cellulose (HPC), methyl cellulose (MC), povidone (PVP) and copolividone can be tested to improve compaction capacity (profile of compression force - crush resistance). Like the results, PVA shows the best effect in terms of compaction capacity, but the manufacturing capacity may be weak due to the problem of fixation during fluid bed granulation. Further, PVA may not be finally selected due to its negative impact on the stability of certain SGLT-2 inhibitors of this invention.
[000162] Formulation optimization studies have identified a composition with more than 83% metformin HCl drug loading and improved crush resistance by surface treatment of metformin HCl with the water-soluble polymer copolividone.
[000163] Therefore, finally, copolividone is selected and advantageously results in stable formulations and the viscosity of the granulation solution is low enough to prepare the aqueous solution and operate by spraying a fluid bed granulator.
[000164] When this invention relates to patients in need of treatment or prevention, it mainly relates to treatment and prevention in humans, but the pharmaceutical composition can also be used accordingly in veterinary medicine in mammals. Within the scope of this invention, adult patients are preferably human beings aged 18 years or older.
[000165] As described above by the administration of the pharmaceutical composition according to this invention and in particular in view of the high SGLT2 inhibitory activity of the SGLT2 inhibitors contained therein, excessive glucose in the blood is excreted in the patient's urine, so that no weight gain or even a reduction in body weight can result. Therefore, a treatment or prophylaxis according to this invention is advantageously suitable in those patients in need of such treatment or prophylaxis who are diagnosed with one or more of the conditions selected from the group consisting of overweight and obesity, in particular obesity class I, obesity class II , class III obesity, visceral obesity and abdominal obesity. In addition, a treatment or prophylaxis according to this invention is advantageously suitable in those patients in whom an increase in weight is contraindicated. The pharmaceutical composition as well as the methods according to the present invention allows a reduction of the HbA1c value to a desired target range, for example, <7% and preferably <6.5%, for a greater number of patients and for a longer therapeutic treatment time compared to a corresponding monotherapy or a therapy that uses only two of the combination pairs.
[000166] The pharmaceutical composition according to the present invention and in particular the SGLT2 inhibitor contained therein has a very good efficacy with respect to glycemic control, in particular in view of a reduction in fasting plasma glucose, glucose in post-plasma -prandial and / or glycosylated hemoglobin (HbA1c). Upon administration of a pharmaceutical composition according to this invention, a reduction in HbA1c equal to or greater than preferably 0.5%, even more preferably equal to or greater than 1.0%, can be achieved and the reduction is particularly in the range from 1.0% to 2.0%.
[000167] In addition, the method and / or use according to this invention is advantageously applicable in those patients who present one, two or more of the following conditions: (a) a fasting blood glucose concentration or serum glucose greater than than 110 mg / dL, in particular greater than 125 mg / dL; (b) a glucose in the postprandial plasma equal to or greater than 140 mg / dL; (c) an HbA1c value equal to or greater than 6.5%, in particular equal to or greater than 7.0%, especially equal to or greater than 7.5%, even more particularly equal to or greater than 8, 0%.
[000168] The present invention also discloses the use of the pharmaceutical composition to improve glycemic control in patients having type 2 diabetes or who have the first signs of pre-diabetes. Thus, the invention also includes the prevention of diabetes. If, therefore, a pharmaceutical composition according to this invention is used to improve glycemic control as soon as one of the aforementioned signs of pre-diabetes is present, the onset of overt type 2 diabetes mellitus can be delayed or prevented.
[000169] Furthermore, the pharmaceutical composition according to this invention is particularly suitable for the treatment of patients with insulin dependence, that is, in patients who are treated or would otherwise be treated or need treatment with an insulin or a derivative insulin or an insulin substitute or a formulation comprising an insulin or a derivative or substitute thereof. These patients include patients with type 2 diabetes and patients with type 1 diabetes.
[000170] Therefore, according to a preferred embodiment of the present invention, a method is provided to improve glycemic control and / or to reduce fasting plasma glucose, postprandial plasma glucose and / or glycosylated hemoglobin HbA1c in a patient who needs it who is diagnosed with impaired glucose tolerance (IGT), impaired fasting blood glucose (IFG) with insulin resistance, with metabolic syndrome and / or with type 2 or type 1 diabetes mellitus characterized by the fact that an SGLT2 inhibitor as defined above and then is administered to the patient.
[000171] According to another preferred embodiment of the present invention, a method is provided to improve glycemic control in patients, in particular in adult patients, with type 2 diabetes mellitus as an adjunct to diet and exercise.
[000172] Therefore, the method and / or use according to this invention is advantageously applicable to those patients who present one, two or more of the following conditions: (a) insufficient glycemic control with only diet and exercise; (b) insufficient glycemic control despite oral metformin monotherapy, in particular, despite oral monotherapy at a maximum tolerated dose of metformin; (c) insufficient glycemic control despite oral monotherapy with another antidiabetic agent, in particular despite oral monotherapy at a maximum tolerated dose of the other antidiabetic agent.
[000173] The reduction in the level of glucose in the blood by the administration of an SGLT2 inhibitor according to this invention is independent of insulin. Therefore, a pharmaceutical composition according to this invention is particularly suitable in the treatment of patients who are diagnosed having one or more of the following conditions - insulin resistance, - hyperinsulinemia, - pre-diabetes, - type 2 diabetes mellitus, in particular having a late stage type 2 diabetes mellitus, - type 1 diabetes mellitus.
[000174] In addition, a pharmaceutical composition according to this invention is particularly suitable for treating patients who are diagnosed having one or more of the following conditions (a) obesity (including obesity class I, II and / or III), obesity visceral and / or abdominal obesity, (b) blood triglyceride level> 150 mg / dL, (c) blood HDL cholesterol level <40 mg / dL in female patients and <50 mg / dL in sex patients male, (d) a systolic blood pressure> 130 mm Hg and a diastolic blood pressure> 85 mm Hg, (e) a fasting blood glucose level> 110 mg / dL.
[000175] Diagnostic patients with impaired glucose tolerance (IGT), impaired fasting blood glucose (IFG), insulin resistance and / or with metabolic syndrome are assumed to have an increased risk of developing cardiovascular disease, such as, for example, myocardial infarction, coronary heart disease, heart failure, thromboembolic events. A glycemic control according to this invention can result in a reduction in cardiovascular risks.
[000176] A pharmaceutical composition according to the present invention has a good safety profile. Therefore, a treatment or prophylaxis according to this invention is advantageously possible in those patients for whom monotherapy with another antidiabetic drug, such as, for example, metformin, is contraindicated and / or who have an intolerance against such drugs at therapeutic doses. In particular, a treatment or prophylaxis according to this invention may be advantageously possible in those patients who have or are at increased risk for one or more of the following disorders: kidney failure or disease, heart disease, heart failure, liver disease, lung diseases, catabolytic states and / or risk of lactic acidosis, or female patients, being pregnant or while breastfeeding.
[000177] Furthermore, it can be seen that the administration of a pharmaceutical composition according to this invention does not result in any risk or a low risk of hypoglycemia. Therefore, a treatment or prophylaxis according to this invention is also advantageously possible in those patients who have or are at increased risk for hypoglycemia.
[000178] A pharmaceutical composition according to this invention is particularly suitable for long-term treatment or prophylaxis of diseases and / or conditions as described above and thereafter, in particular for long-term glycemic control in patients with type 2 diabetes mellitus .
[000179] The term "long term" as used above and then indicates treatment or administration to a patient within a period of time longer than 12 weeks, preferably more than 25 weeks, even more preferably longer than 1 year.
[000180] Therefore, a particularly preferred embodiment of the present invention provides a method for therapy, preferably oral therapy, for the improvement, especially the long-term improvement, of glycemic control in patients with type 2 diabetes mellitus, especially in patients with late-stage type 2 diabetes mellitus, in particular in patients additionally diagnosed with overweight, obesity (including class I, class II and / or class III obesity), visceral obesity and / or abdominal obesity.
[000181] It will be appreciated that the amount of the pharmaceutical composition according to this invention to be administered to the patient and necessary for use in the treatment or prophylaxis according to the present invention will vary with the route of administration, the nature and severity of the condition for which treatment or prophylaxis is required, the age, weight and condition of the patient, concomitant medication and will be at the discretion of the attending physician. In general, however, the SGLT2 inhibitor and the associated drug according to this invention are included in the pharmaceutical composition or dosage form in an amount sufficient that, upon administration, glycemic control in the patient to be treated is improved.
[000182] In the following preferred ranges of the amount of the SGLT2 inhibitor and associated drug to be employed in the pharmaceutical composition and the methods and use according to this invention are described. These ranges refer to the amounts to be administered per day with respect to an adult patient, in particular to a human being, for example, of approximately 70 kg of body weight, and can be adapted accordingly with respect to an administration of 2, 3, 4 or more times daily and with respect to other routes of administration and with respect to the age of the patient.
[000183] Within the scope of the present invention, the pharmaceutical composition is preferably administered orally. Other forms of administration are possible and described below. Preferably, one or more dosage forms comprising the SGLT2 inhibitor and associated drug are oral or generally well known.
[000184] A pharmaceutical composition that is present as a separate or multiple dosage form, preferably as a kit of parts, is useful in combination therapy to flexibly adapt the patient's individual therapeutic needs.
[000185] According to a first embodiment a preferred kit of parts comprises a retention containing a dosage form comprising the SGLT2 inhibitor and associated drug and at least one pharmaceutically acceptable carrier.
[000186] An additional aspect of the present invention is a manufacture comprising the pharmaceutical composition which is present as separate dosage forms in accordance with the present invention and a label or packaging supplement comprising instructions that the separate dosage forms are to be administered in combination or alternation.
[000187] According to a first embodiment, a manufacture comprises (a) a pharmaceutical composition according to the present invention and (b) a label or packaging supplement comprising instructions that the drug is to be administered.
[000188] The desired dose of the pharmaceutical composition according to this invention can conveniently be presented in a single daily or divided dose administered at appropriate intervals, for example, as two, three or more doses per day.
[000189] The pharmaceutical composition can be formulated for oral, rectal, nasal, topical (including buccal and sublingual), transdermal, vaginal or parenteral (including intramuscular, subcutaneous and intravenous) administration in liquid or solid form or in a form suitable for administration by inhalation or insufflation. Oral administration is preferred. The formulations can, where appropriate, be conveniently presented in discrete dosage units and can be prepared by any of the methods well known in the pharmacy art. All methods include the step of bringing the active ingredient into association with one or more pharmaceutically acceptable carriers, such as liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired formulation.
[000190] The pharmaceutical composition can be formulated in the form of tablets, granules, fine granules, powders, capsules, capsules, soft capsules, pills, oral solutions, syrups, dry syrups, chewable tablets, troches, effervescent tablets, drops, suspension, quick dissolving tablets, orally dispersing tablets, etc.
[000191] The pharmaceutical composition and dosage forms preferably comprise one or more acceptable pharmaceutical carriers which must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not harmful to its recipient. Examples of pharmaceutically acceptable carriers are known to the person skilled in the art.
[000192] Pharmaceutical compositions suitable for oral administration can conveniently be presented as discrete units such as capsules, including soft gelatin capsules, capsules or tablets, each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution, a suspension or as an emulsion, for example, as syrups, elixirs or self-emulsifying delivery systems (SEDDS). The active ingredients can also be presented as a cake, eletuary or paste. Tablets and capsules for oral administration may contain conventional excipients such as binding agents, fillers, lubricants, disintegrants, or wetting agents. The tablets can be coated according to methods well known in the art. Liquid oral preparations can be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or they can be presented as a dry product for constitution with water or another suitable vehicle before use. Such liquid preparations can contain conventional additives such as suspending agents, emulsifying agents, non-aqueous vehicles (which may include edible oils), or preservatives.
[000193] The pharmaceutical composition according to the invention can also be formulated for parenteral administration (for example, by injection, for example, bolus injection or continuous infusion) and can be presented as a unit dose in ampoules, pre-filled syringes -fills, small volume infusion or in multiple dose containers with an added preservative. The compositions can take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and can contain formulation agents such as suspending, stabilizing and / or dispersing agents. Alternatively, the active ingredients can be in powder form, obtained by aseptic isolation of sterile solid or by lyophilization of the solution, for constitution with a suitable vehicle, for example, sterile pyrogen-free water, before use.
[000194] Pharmaceutical compositions suitable for rectal administration in which the carrier is a solid are most preferably presented as unit dose suppositories. Suitable carriers include cocoa butter and other materials commonly used in the art, and suppositories can be conveniently formed by mixing the active compound with the softened or molten carrier, followed by cooling and molding in molds.
[000195] The pharmaceutical compositions and methods according to the present invention show advantageous effects in the treatment and prevention of those diseases and conditions as described above. Advantageous effects can be seen, for example, in relation to efficacy, dosing intensity, dosing frequency, pharmacodynamic properties, pharmacokinetic properties, less adverse effects, convenience, compliance, etc.
[000196] The methods for making SGLT2 inhibitors according to this invention and its prodrugs are known to the person skilled in the art. Advantageously, the compounds according to this invention can be prepared using synthetic methods as described in the literature, including the aforementioned patent applications. Preferred methods of manufacture are described in WO 2006/120208 and WO 2007/031548. With regard to compound (I.9), an advantageous crystalline form is described in international patent application WO 2006/117359 which is hereby incorporated in its entirety.
[000197] The active ingredients can be present in the form of a pharmaceutically acceptable salt. Pharmaceutically acceptable salts include, but are not limited to, such as inorganic acid salts such as hydrochloric acid, sulfuric acid and phosphoric acid; salts of organic carboxylic acid 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 acid such as methanesulfonic acid and p-toluenesulfonic acid . Salts can be formed by combining the compound and an acid in the appropriate amount and ratio in a solvent and decomposition. They can also be obtained by cationic and anionic exchange or from the form of other salts.
[000198] The active ingredients or a pharmaceutically acceptable salt thereof can be present in the form of a solvate such as a hydrate or alcohol adduct.
[000199] Any of the aforementioned pharmaceutical compositions and methods within the scope of the invention can be tested on animal models known in the art. In what follows, in vivo experiments are described which are suitable for evaluating the pharmacologically relevant properties of pharmaceutical compositions and methods according to the present invention.
[000200] The pharmaceutical compositions and methods according to this invention can be tested on genetically hyperinsulinemic or diabetic animals such as db / db mice, ob / ob mice, Zucker Fatty (fa / fa) mice or Zucker Diabetic Fatty (ZDF) mice rats. In addition, they can be tested on animals with experimentally induced diabetes like HanWistar or Sprague Dawley rats pretreated with streptozotocin.
[000201] The effect on glycemic control according to the present invention can be tested after a single dose in an oral glucose tolerance test in the animal models described above. The blood glucose time course is followed after an oral glucose challenge in fasting animals overnight. The pharmaceutical compositions according to the present invention significantly improve glucose excursion, for example, compared to another monotherapy, as measured by the reduction of the maximum glucose concentrations or the reduction of glucose AUC. In addition, after multiple dosing in the animal models described above, the effect on glycemic control can be determined by measuring the blood HbA1c value. The pharmaceutical compositions according to this invention significantly reduce HbA1c, for example, in comparison with another monotherapy or in comparison with a dual combination therapy.
[000202] The improved insulin independence with the treatment according to this invention can be shown after single dosing in oral glucose tolerance tests in the animal models described above. The time course of plasma insulin is followed after a glucose challenge in fasting animals overnight.
[000203] The increase in the levels of active GLP-1 through treatment according to this invention after single or multiple dosing can be determined by measuring those levels in the plasma of animal models described above in the fasted or postprandial state. Likewise, a reduction in plasma glucagon levels can be measured under the same conditions.
[000204] The effect of an SGLT2 inhibitor and associated drug according to the present invention on beta cell regeneration and neogenesis, can be determined after multiple dosages in the animal models described above by measuring the increase in insulin content in pancreas, or by measuring the increase in beta cell mass by morphometric analysis after immunohistochemical staining of pancreatic sections, or by measuring insulin secretion stimulated by increased glucose in isolated pancreatic islets.
[000205] The present invention should not be limited in scope by the specific modalities described here. Various modifications of the invention in addition to those described herein may become apparent to those skilled in the art from the present description. Such modifications are intended to fall within the scope of the appended claims.
[000206] All patent applications cited herein are hereby incorporated by reference in their entirety.
[000207] Other modalities, aspects and advantages of the present invention may become evident from the examples that follow. The following examples serve to illustrate, by way of example, the principles of the invention without restricting it. Examples 1. Mono-layer tablet
[000208] Examples of the mono-layer tablet composition for a SGLT-2 inhibitor of this invention (compound (I.9), or a crystalline form (I.9X) of the compound (I.9)) + metformin HCl FDC (film-coated tablets) are shown in Tables 1.1 to 1.11. Table 1.1: Examples of composition of FDC Monolayer Tablets of SGLT-2 inhibitor + Metformin HCl

Table 1.2: Examples of composition of FGL Monolayer Tablets of SGLT-2 inhibitor + Metformin HCl

Table 1.3: Examples of composition of FDC Monolayer Tablets of SGLT-2 inhibitor + Metformin HCl

Table 1.4: Examples of composition of FDC Monolayer Tablets of SGLT-2 inhibitor + Metformin HCl

Table 1.5: Examples of composition of FGL Monolayer Tablets of SGLT-2 inhibitor + Metformin HCl

Table 1.6: Examples of composition of FDC Monolayer Tablets of SGLT-2 inhibitor + Metformin HCl

Table 1.7: Examples of the composition of FGL Monolayer Tablets of SGLT-2 inhibitor + Metformin HCl

Table 1.8: Examples of the composition of FDC Monolayer Tablets of SGLT-2 inhibitor + Metformin HCl

Table 1.9: Examples of the composition of FGL Monolayer Tablets of SGLT-2 inhibitor + Metformin HCl with MCC

Table 1.10: Examples of the composition of FDC Monolayer Tablets of SGLT-2 inhibitor + Metformin HCl with MCC

Table 1.11: Examples of composition of FDC Monolayer Tablets of SGLT-2 inhibitor + Metformin HCl







[000209] A wide range of SGLT-2 inhibitor, for example, 1.25, 5 or 12.5 mg, can be used, in which case the amount of corn starch binder or microcrystalline cellulose is adjusted. In place of corn starch, microcrystalline cellulose can be used. In the further description of the manufacturing procedure only corn starch is described.
[000210] Manufacturing procedure (monolayer tablets):
[000211] The SGLT-2 inhibitor of this invention (for example, compound (I.9), or crystalline form (I.9X) of compound (I.9)) + metformin HCl FDC monolayer tablets are produced by a fluid bed granulation process and a conventional tablet forming process with a rotary press. Metformin HCl and corn starch, whose SGLT-2 inhibitor is added as a powder and premixed before fluid bed granulation, are conducted by spraying "Granulation Liquid" composed of copolividone (Kollidon VA64) and purified water, or directly dispersed in the "granulation liquid". Alternatively, the SGLT-2 inhibitor is added as a powder together with metformin HCl and corn starch in the fluid bed granulator. After the completion of the fluid bed granulation, the granulate is sieved with a suitable screen. The sieved granulate is mixed with colloidal anhydrous silica (Aerosil 200) and magnesium stearate as a lubricant. The final blend is compressed into tablets using a conventional rotary tablet press.
[000212] The tablet cores can be coated with film by an aqueous suspension of film coating, containing hypromellose as a film-forming agent, propylene glycol as a plasticizer, talc as a glidant and black, red, yellow and iron oxide pigments mixture of red / yellow / black and titanium dioxide. More specific narrative description of the preferred manufacturing process for monolayer tablets: a) Metformin HCl and corn starch are sieved using a 0.5 to 1 mm mesh size screen prior to distribution. b) Compound (I.9), or crystalline form (I.9X) of compound (I.9)) and finally copolividone are dissolved, respectively dispersed in purified water at room temperature with a propeller mixer to produce the "Liquid of Granulation". c) Metformin HCl and corn starch are aspirated into a chamber of a suitable fluid bed granulator and preheated to a target product temperature of approx. 36 ° C. Preheating is optional. Alternatively, the compound (I.9), or the crystalline form (I.9X) of the compound (I.9)) and HCl of metformin and corn starch are aspirated into a suitable fluid bed granulator chamber. d) Immediately after the temperature of the target product has been reached, the "Granulation Liquid" is sprayed into the mixture for fluid bed granulation under dry condition to avoid blocking during granulation. e) At the end of the spraying, the resulting granulate is dried in approx. 70 ° C inlet air temperature until the desired LOD value (i.e., 1 to 3%, for example, 0.8 to 2%) is reached. f) The granulate is sieved using a screen with a mesh size of 0.5 to 1.0 mm. g) The sieved granules and colloidal anhydrous silica (Aerosil 200) are mixed with a suitable mixer. Aerosil 200 must be pre-sieved with a small portion of the sieved granules through a 0.8 mm screen before use. h) Magnesium stearate is passed through a 0.8 mm sieve and added to the granules. Subsequently, the "Final Mix" is produced by the final mix in the free-fall mixer. i) The "Final Mixture" is compressed into tablets with a rotary press. j) Titanium dioxide, polyethylene glycol or propylene glycol and iron oxide (yellow, red, black or a mixture of these) are dispersed in purified water with a high-shear homo-mixer. Then, hypromellose and talc are added and dispersed with a homo-mixer and a propeller mixer at room temperature to produce the "Coating Suspension". k) The tablet cores are coated with the "Coating Suspension" for the target weight gain to produce the "Film coated tablets". The "Coating Suspension" must be stirred again before use and kept under slow stirring during the coating (spraying) process. More specific narrative description of an alternative manufacturing process for monolayer tablets: a) Metformin HCl is sieved using a screen with a mesh size of 0.5 to 1 mm before weighing. b) copolividone is dissolved in purified water at room temperature with a propeller mixer to produce the "Granulation Liquid" c) is added to the container, then mixed with metformin HCl and corn starch in the fluid bed granulator. d) "Granulation Liquid" is sprayed into the mixture for fluid bed granulation under dry condition to prevent blockage during granulation. e) At the end of the spraying, the resulting granulate is dried in approx. 70 to 80 ° C up to the desired LOD value (ie, 1 to 3%, for example, 0.8 to 2%), in this case the LOD is more than 2%. f) The granulate is sieved using a screen with a mesh size of 0.5 to 1.0 mm. g) The sieved granules and colloidal anhydrous silica (Aerosil 200) are mixed with a suitable mixer. Aerosil 200 must be sieved with a 0.5 mm screen before use. h) Magnesium stearate is passed through a 0.5 mm sieve and added to the granules. Subsequently, the "Final Mix" is produced by the final mix in the mixer. i) The "Final Mixture" is compressed into tablets with a rotary press. j) Hypromellose and polyethylene glycol or propylene glycol are dissolved in purified water with a propeller mixer. Talc, titanium dioxide, and iron oxide (yellow, red and / or black and their mixtures) are dispersed in purified water with a homomixer. The suspension is added to the hypromellose solution, then mixed with a propeller mixer at room temperature to produce the "Coating Suspension". k) The tablet cores are coated with the "Coating Suspension" for the target weight gain to produce the "Film coated tablets". The "Coating Suspension" must be stirred again before use and kept under slow stirring during the coating (spraying) process. 2. Bilayer tablet
[000213] Examples of the bilayer tablet composition for a SGLT-2 inhibitor of this invention (compound (I.9), or a crystalline form (I.9X) of compound (I.9)) + metformin HCl FDC (Film-coated tablets) are shown in Table 2. Table 2: Examples of the composition of SGLT-2 inhibitor Bi-layer Tablets + Metformin HCl


[000214] A wide dose range of SGLT-2 inhibitor, for example, 1.25, 5 or 12.5 mg, can be used, in which case the amount of corn starch binder or microcrystalline cellulose is adjusted. In place of corn starch, microcrystalline cellulose can be used. In the further description of the manufacturing procedure only corn starch is described. Manufacturing procedure (Bi-layer tablets):
[000215] The SGLT-2 inhibitor of this invention (for example, the compound (I.9), or crystalline form (I.9X) of compound (I.9)) + metformin HCl FDC bi-layer tablets are produced by a high shear wet granulation process (for the SGLT-2 inhibitor granulate), a fluid bed granulation process (for the metformin HCL granulate), and a bi-tablet formation process layer with a multi-layer rotary press. SGLT-2 inhibitor granulate: Using a high shear granulator for the active SGLT-2 inhibitor. The general manufacturing process consisted of the following steps: 1) Sieve the hydroxypropyl cellulose (HPC) 2) Add the portion of intragranular microcrystalline cellulose, SGLT-2 inhibitor, lactose, HPC and croscarmellose sodium in the granulator 3) Granulate the mixture with water . 4) Dry the granulate in the fluid bed dryer: less than 1.5% LOD 5) Grind the granulation inside the mixer container • Quadro mill • Quadro mill screen - mesh 18. 6) Sieve what follows in the crushed granulation in the container of an overturning mixer • Pre-mixing the colloidal silicon dioxide with a portion of the extragranular microcrystalline cellulose sifted through a 20 to 25 mesh. 7) Pre-mixing of magnesium stearate with a part of the mixed granulation, mesh (mesh 18) in the rest of the granulation in the mixer.
[000216] Subsequently, "Final Mixture A" is produced by the final mixture in a suitable mixer. Granules of metformin HCl: metformin HCl and corn starch, fluid bed granulation is conducted by spraying "Granulation Liquid" composed of copolividone (Kollidon VA64) and purified water. Alternatively, the SGLT-2 inhibitor is added as a powder together with metformin HCl and corn starch in the fluid bed granulator. After the completion of the fluid bed granulation, the granulate is sieved with a suitable screen. The sieved granulate is mixed with colloidal anhydrous silica (Aerosil 200) and magnesium stearate as a lubricant. More specific narrative description of the manufacturing process for the metformin HCl granules: a) Metformin HCl is sieved using a screen with a mesh size of 0.5 to 1 mm before weighing. b) Copolividone is dissolved with purified water at room temperature with a propeller mixer to produce the "Granulation Liquid". c) "Granulation Liquid" is sprayed into the mixture for fluid bed granulation under dry condition to prevent blockage during granulation. d) At the end of the spraying, the resulting granulate is dried at 70 to 80 ° C until the desired LOD value (that is, from 0.8 to 2%, for example, 1 to 2%), in which case the LOD is more than 2%. e) The granulate is sieved using a screen with a mesh size of 0.5 to 1.0 mm. f) The sieved granules and colloidal anhydrous silica (Aerosil 200) are mixed with a suitable mixer. Aerosil 200 must be sieved with a 0.5 mm screen before use. g) Magnesium stearate passed through a 0.5 mm sieve and was added to the granulate. Subsequently, "Final Mix B" is produced by the final mix in the mixer.
[000217] The "Final Mixture A" and "Final Mixture B" are compressed into bilayer tablets using a multi-layer rotary press. The tablet cores can be coated with film by an aqueous suspension of film coating, containing hypromellose as a film-forming agent, polyethylene glycol or propylene glycol as a plasticizer, talc as a glidant and yellow, red, black and iron oxide pigments mixtures and titanium dioxide. More specific narrative description of the manufacturing process for the film coating: a) hypromellose and polyethylene glycol or propylene glycol are dissolved in purified water with a propeller mixer. Talc, titanium dioxide, and iron oxide (yellow, red, or yellow and red) are dispersed in purified water with a homomixer. The suspension is added to the hypromellose solution, then mixed with a propeller mixer at room temperature to produce the "Coating Suspension". b) The tablet cores are coated with the "Coating Suspension" for the target weight gain to produce the "Film Coated Tablets". The "Coating Suspension" must be stirred again before use and kept under slow stirring during the coating (spraying) process. 3. Tablets or Bull's Eye Tablets
[000218] Examples of the composition of Tablets in Tablets or Ox-Eye Tablets for a SGLT-2 inhibitor of the present invention (compound (I.9), or crystalline form (I.9X) of the compound (I.9)) + Metformin HCl FDC (Film-Coated Tablets) are shown in Table 3. Table 3: Examples of the composition of Tablet in Tablets or Bull's Eye FDC tablets of compound (I.9), or crystalline form (I.9X) of compound (I.9) + metformin hydrochloride HCl.


[000219] A wide dose range of SGLT-2 inhibitor, for example, 1.25, 5 or 12.5 mg, can be used, in which case the amount of corn starch binder or microcrystalline cellulose is adjusted. In place of corn starch, microcrystalline cellulose can be used. In the further description of the manufacturing procedure only corn starch is described. Manufacturing procedure (Tablets in tablets or Ox eye tablets):
[000220] The SGLT-2 inhibitor of this invention (for example, the compound (I.9), or crystalline form (I.9X) di compound (I.9)) + Tablets in Tablets or Ox-eye tablets FDC of Metformin HCl are produced by a high shear wet granulation process (for the SGLT-2 inhibitor granulate), a rotary press (for the SGLT-2 inhibitor core tablet), a fluid bed granulation process (for metformin HCl granules), and press coating process with a press applicator. SGLT-2 inhibitor granulate: Using a high shear granulator for the active SGLT-2 inhibitor.
[000221] The general manufacturing process consisted of the following steps: 1) Sieve hydroxypropyl cellulose (HPC) 2) Add the portion of intragranular microcrystalline cellulose, SGLT-2 inhibitor, lactose, HPC and croscarmellose sodium in the granulator 3) Granulate the mixture with water. 4) Dry the granulate in a fluid bed dryer: less than 1.5% LOD 5) Grind the granulation in the mixer container • Mill frame with mesh - mesh 18. 6) Sieve what follows in the crushed granulation in the container of a tumbling mixer • Pre-mixing colloidal silicon dioxide with a portion of extragranular microcrystalline cellulose sieved through a 20-25 mesh. • The rest of the extragranular microcrystalline cellulose and mix. 7) Pre-mix the magnesium stearate with a portion of the mixed granulation, mesh (mesh 18) in the rest of the granulation in the mixer.
[000222] Subsequently, the "Final Mix" is produced by the final mix in the free-fall mixer. 8) The "Final Mixture" of the SGLT-2 inhibitor is compressed into tablets with a rotary press.
[000223] Metformin HCl granules: Metformin HCl and corn starch, fluid bed granulation is conducted by spraying "Granulation Liquid" composed of copolividone (Kollidon VA64) and purified water. Alternatively, the SGLT-2 inhibitor is added as a powder together with metformin HCl and corn starch in the fluid bed granulator. After the completion of the fluid bed granulation, the granulate is sieved with a suitable screen. The sieved granulate is mixed with colloidal anhydrous silica (Aerosil 200) and magnesium stearate as a lubricant.
[000224] More specific narrative description of the manufacturing process for the metformin HCl granules: a) Metformin HCl is sieved using a screen with a mesh size of 0.5 to 1 mm before weighing. b) Copolividone is dissolved with purified water at room temperature with a propeller mixer to produce the "Granulation Liquid". c) "Granulation Liquid" is sprayed into the mixture for fluid bed granulation under dry condition to prevent blockage during granulation. d) At the end of the spraying, the resulting granulate is dried at 70 to 80 ° C until the desired LOD value (that is, from 0.8 to 2%, for example, 1 to 2%), in which case the LOD is more than 2%. e) The granulate is sieved using a screen with a mesh size of 0.5 to 1.0 mm. f) The sieved granules and colloidal anhydrous silica (Aerosil 200) are mixed with a suitable mixer. Aerosil 200 must be sieved with a 0.5 mm screen before use. g) Magnesium stearate passed through a 0.5 mm sieve and was added to the granulate. Subsequently, the "Metformin HCl Granules" is produced by the final mixture in the mixer.
[000225] "SGLT-2 inhibitor core tablets" and "Metformin HCl granules" are tablets in Tablet Tablets or porthole tablets using a press applicator. The difference between the Tablet in Tablets and the bull's eye tablet is the position of the tablet in the core. More specific narrative description of the manufacturing process for the Tablet in Tablets: a) Load a half of metformin HCl granules in a mold. b) Place a compound core tablet (I.9), or crystalline form (I.9X) of compound (I.9) on the surface of metformin HCl granules. c) Cover the core tablet with the second half of metformin HCl granules, then compressed into the tablet (Tablet in Tablets). More specific narrative description of the manufacturing process for porthole pills: a) Load the metformin HCl granules into a mold. b) Place the compound core tablet (I.9), or crystalline form (I.9X) of compound (I.9) on the metformin HCl granule in the mold, then compressed into the tablet (bull's eye tablet) .
[000226] The tablets can be film-coated by an aqueous suspension of film-coating, containing hypromellose as a film-forming agent, polyethylene glycol or propylene glycol as a plasticizer, talc as a glidant and yellow, red, black and iron oxide pigments mixture of these and titanium dioxide. More specific narrative description of the manufacturing process for the film coating: a) Hypromellose and polyethylene glycol or propylene glycol are dissolved in purified water with a propeller mixer. Talc, titanium dioxide, and iron oxide (yellow, red, black or mixtures thereof) are dispersed in purified water with a homomixer. The suspension is added to the hypromellose solution, then mixed with a propeller mixer at room temperature to produce the "Coating Suspension". b) The tablet cores are coated with the "Coating Suspension" for the target weight gain to produce the "Film Coated Tablets". The "Coating Suspension" must be stirred again before use and kept under slow stirring during the coating (spraying) process. 4. SGLT-2 Inhibitor - Layered drug on Metformin HCl Tablet (film coating for drug load)
[000227] Examples of the composition of a SGLT-2 inhibitor of this invention (Compound (I.9), or crystalline form (I.9X) of compound (I.9)) + metformin HCl FDC (Film-coated tablets) which are prepared by loading the drug by film coating on the metformin HCl Tablet are shown in Table 4. Table 4: Examples of the SGLT-2 FDC Compound (I.9) inhibitor coating composition, or form crystalline (I.9X) of compound (I.9) + metformin HCl on the metformin HCl Tablet


[000228] A wide dose range of SGLT-2 inhibitor, for example, 1.25, 5 or 12.5 mg, can be used, in which case the amount of corn starch binder or microcrystalline cellulose is adjusted. In place of corn starch, microcrystalline cellulose can be used. In the further description of the manufacturing procedure only corn starch is described. Manufacturing procedure (SGLT-2 inhibitor layered by film coating on the Metformin HCL Tablet):
[000229] The SGLT-2 inhibitor (for example, the compound (I.9), or crystalline form (I.9X) di compound (I.9)) + drug-coated metformin HCl FDC are produced by a fluid bed granulation process, a conventional tablet forming process, and a three-stage film coating process: sealing coating, drug loading and finishing. The finish may be able to be omitted by combining with the drug load, if stability is acceptable.
[000230] Metformin HCl tablets: Metformin HCl and corn starch, fluid bed granulation is conducted by spraying "Granulation Liquid" composed of copolividone (Kollidon VA64) and purified water. Alternatively, the SGLT-2 inhibitor is added as a powder together with metformin HCl and corn starch in the fluid bed granulator. After the completion of the fluid bed granulation, the granulate is sieved with a suitable screen. The sieved granulate is mixed with colloidal anhydrous silica (Aerosil 200) and magnesium stearate as a lubricant. The final mixture is compressed into tablets using a conventional rotary press. More specific narrative description of the manufacturing process for the metformin HCl granules: a) Metformin HCl is sieved using a screen with a mesh size of 0.5 to 1 mm before weighing. b) Copolividone is dissolved with purified water at room temperature with a propeller mixer to produce the "Granulation Liquid". c) "Granulation Liquid" is sprayed into the mixture for fluid bed granulation under dry condition to prevent blockage during granulation. d) At the end of the spraying, the resulting granulate is dried at 70 to 80 ° C until the desired LOD value (that is, from 0.8 to 2%, for example, 1 to 2%), in which case the LOD is more than 2%. e) The granulate is sieved using a screen with a mesh size of 0.5 to 1.0 mm. f) The sieved granules and colloidal anhydrous silica (Aerosil 200) are mixed with a suitable mixer. Aerosil 200 must be sieved with a 0.5 mm screen before use. g) Magnesium stearate passed through a 0.5 mm sieve and added to the granules. Subsequently, the "Final Mix" is produced by the final mix in the mixer. h) The "Final Mixture" is compressed into the tablets with a conventional rotary press. Film coating:
[000231] The tablets are coated with film by (1) sealing coating: by an aqueous suspension of film coating, containing hypromellose as a film-forming agent, polyethylene glycol (Macrogol, especially Macrogol 400, 6000 or 8000) as a plasticizer, propylene glycol as an alternative plasticizer, talc as a glidant and pigments of yellow iron oxide and / or red iron oxide or mixtures with black iron oxide and titanium dioxide, (2) drug loading: by an aqueous suspension of film, containing hypromellose as the film-forming agent, polyethylene glycol or propylene glycol as a plasticizer, the compound (I.9), or crystalline form (I.9X) of compound (I.9) as a drug substance and (3) finish : by an aqueous suspension of a film coating, containing hypromellose as a film-forming agent, polyethylene glycol or propylene glycol as a plasticizer, talc as a glidant and oxide pigments yellow iron oxide and / or red and / or black iron oxide and titanium dioxide.
[000232] More specific narrative description of the manufacturing process for coating film with a coating machine: a) Hypromellose and polyethylene glycol or propylene glycol are dissolved in purified water with a propeller mixer. Talc, titanium dioxide, and iron oxide (yellow, red, black or yellow and red and black and their mixtures) are dispersed in purified water with a homomixer. The suspension is added to the hypromellose solution, then mixed with a propeller mixer at room temperature to produce the "Coating Suspension" for the "sealing coating and" finish. B) Hypromellose, polyethylene glycol or propylene glycol are dissolved in Purified water with a propeller mixer The compound (I.9), or crystalline form (I.9X) of compound (I.9) (active drug) is added to the hypromellose solution, then dispersed with a propeller mixer in the room temperature to produce the "Drug Suspension" for the "drug load." c) Metformin HCl tablets are coated with the "Coating Suspension" for the target weight gain to form the "sealing cover". The "Coating Suspension" must be stirred again before use and kept under slow stirring during the coating (spraying) process. D) Following the sealing coating, the "Drug Suspension" is applied to the surface of the HCl tablets. metformin to form the "drug layer" (drug load). The "Drug Suspension" must be stirred again before use and kept under slow stirring during the coating (spraying) process. The coating end point can be determined by the available PAT (Process Analysis Technology). e) After drug loading, "Coating Suspension" is applied to compound drug loading tablets (I.9), or crystalline form (I.9X) of compound (I.9) to form the "final coating" "and to produce the" Film Coated Tablets ". The "Coating Suspension" must be stirred again before use and kept under slow stirring during the coating (spraying) process. Product Description:
[000233] Product description of FDC mono-layer tablets of Compound (I.9), or crystalline form (I.9X) of compound (I.9) + metformin HCl (tablet core and film-coated tablets) ) is shown in Table 8 and Table 9, respectively. Table 8a: Product Description of Compound FDC Monolayer Tablets (I.9), or crystalline form (I.9X) of compound (I.9) + Metformin HCl (Tablet core)
Table 8b: Product Description of FDC Mono-layer Tablets of Compound (I.9), or crystalline form (I.9X) of compound (I.9) + Metformin HCl (Tablet core)
Table 9a: Product Description of FDC Mono-layer Tablets of Compound (I.9), or crystalline form (I.9X) of compound (I.9) + Metformin HCl (coated)
Table 9b: Product Description of FDC Mono-layer Tablets of Compound (I.9), or crystalline form (I.9X) of compound (I.9) + Metformin HCl (coated)
Stability Data:
[000234] The stability data of Compound (I.9) FDC monolayer tablets, or crystalline form (I.9X) of compound (I.9) + Metformin HCl (Tables 1.1 and 1.7 ) are shown in the following tables. 12.5 + 500 mg tablets
12.5 + 500 mg tablets
12.5 + 500 mg tablets
12.5 + 500 mg tablets
1.25 + 500 mg tablets
1.25 + 500 mg tablets
1.25 + 500 mg tablets
1.25 + 500 mg tablets
Stability Data:
[000235] The stability data of FDC mono-layer tablets of Compound (I.9), or crystalline form (I.9X) of compound (I.9) + Metformin HCl (Table 1.9 and 1.10 ) are shown in the following tables. 12.5 + 500 mg tablets
12.5 + 500 mg tablets
12.5 + 500 mg tablets
12.5 + 500 mg tablets
1.25 + 500 mg tablets
1.25 + 500 mg tablets

1.25 + 500 mg tablets
1.25 + 500 mg tablets

权利要求:
Claims (6)
[0001]
1. Solid pharmaceutical composition, characterized by the fact that it comprises the SGLT-2 inhibitor 1-chloro-4- (β-D-glucopyran-1-yl) -2- [4 - ((S) -tetrahydrofuran-3- iloxy) -benzyl] -benzene, metformin hydrochloride, and pharmaceutical excipients, where the SGLT-2 inhibitor is present at a dosage intensity of 5 mg or 12.5 mg, and where metformin hydrochloride is present in a dosage intensity of 500 mg, 850 mg or 1000 mg, and wherein the pharmaceutical composition comprises copovidone as a binder, and the pharmaceutical excipients are selected from the group consisting of microcrystalline cellulose; D-mannitol, corn starch, pregelatinized starch.
[0002]
Solid pharmaceutical composition according to claim 1, characterized in that it further comprises the lubricant of magnesium stearate or sodium stearyl fumarate.
[0003]
Solid pharmaceutical composition according to claim 1 or 2, characterized by the fact that it also comprises the colloidal anhydrous silica glider.
[0004]
Solid pharmaceutical composition according to any one of claims 1 to 3, characterized by the fact that it comprises the following amounts (% by weight of the total mass of coated tablet): 0.1-2.11% the SGLT-2 inhibitor , 47-88% metformin HCl, 3.9- 8.3% copovidone as a binder, 3.10-, 0% corn starch as a filler, 0-4.4% pregelatinized starch as a filler, 0-33% D -manitol as a filler, 0.7-1.5% magnesium stearate as a lubricant, 0.05-0.5% colloidal anhydrous silica as a glidant, 0.00-3.0% crospovidone or croscarmellose sodium as a disintegrating.
[0005]
Solid pharmaceutical composition according to any one of claims 1 to 4, characterized in that it is in the dosage form of a tablet.
[0006]
6. Pharmaceutical dosage form, characterized by the fact that it comprises a pharmaceutical composition, as defined in any one of claims 1 to 5, characterized by the fact that it is a solid pharmaceutical dosage form and is a capsule or a tablet.

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引用文献:

---

公开号 | 申请日 | 公开日 | 申请人 | 专利标题

---

---

US3174901A|1963-01-31|1965-03-23|Jan Marcel Didier Aron Samuel|Process for the oral treatment of diabetes|

---

NL167151C|1971-04-09|1981-11-16|Acf Chemiefarma Nv|PROCESS FOR THE PREPARATION OF MEDICINAL PRODUCTS WITH ANTI-PARASITARY ACTION ON THE BASIS OF HALOGEN CONTAINING THE 2,2'-METHYLENE DIFENOL DERIVATIVES, AND METHOD FOR PREPARING THESE MEDICINAL COMPOUNDS.|

---

NO154918C|1977-08-27|1987-01-14|Bayer Ag|ANALOGUE PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE DERIVATIVES OF 3,4,5-TRIHYDROXYPIPERIDINE.|

---

DE2758025A1|1977-12-24|1979-07-12|Bayer Ag|Tri:hydroxy-piperidine derivs. - useful as glucosidase inhibitors for treating diabetes etc. and as animal feed additives|

---

DE2951135A1|1979-12-19|1981-06-25|Hoechst Ag, 6230 Frankfurt|SULFONYL UREAS, METHOD FOR THE PRODUCTION THEREOF, PHARMACEUTICAL PREPARATIONS BASED ON THESE COMPOUNDS AND THEIR USE|

---

JPS5748146B2|1980-07-16|1982-10-14|

---

JPH0153642B2|1982-03-26|1989-11-15|Chugai Pharmaceutical Co Ltd|

---

US4786755A|1985-06-03|1988-11-22|Warner-Lambert Company|Diphenic acid monoamides|

---

US4602023A|1985-06-03|1986-07-22|Warner-Lambert Company|Diphenic acid monoamides|

---

US4786023A|1987-08-19|1988-11-22|Harris Leverett D|Drafting implement holder|

---

US5145684A|1991-01-25|1992-09-08|Sterling Drug Inc.|Surface modified drug nanoparticles|

---

JPH1085502A|1996-09-19|1998-04-07|Konica Corp|Crystallization|

---

US5807580A|1996-10-30|1998-09-15|Mcneil-Ppc, Inc.|Film coated tablet compositions having enhanced disintegration characteristics|

---

WO1998031697A1|1997-01-15|1998-07-23|Sankyo Company, Limited|Aryl c-glycoside compounds and sulfated esters thereof|

---

JPH11124392A|1997-10-21|1999-05-11|Sankyo Co Ltd|C-glycosylated aryltin compound|

---

US6613806B1|1999-01-29|2003-09-02|Basf Corporation|Enhancement of the efficacy of benzoylbenzenes|

---

AU782330B2|1999-08-31|2005-07-21|Kissei Pharmaceutical Co. Ltd.|Glucopyranosyloxypyrazole derivatives, medicinal compositions containing the same and intermediates in the production thereof|

---

PH12000002657B1|1999-10-12|2006-02-21|Squibb Bristol Myers Co|C-aryl glucoside SGLT2 inhibitors|

---

US6515117B2|1999-10-12|2003-02-04|Bristol-Myers Squibb Company|C-aryl glucoside SGLT2 inhibitors and method|

---

US6498193B2|1999-12-22|2002-12-24|Trustees Of Dartmouth College|Treatment for complications of type 2 diabetes|

---

US6627611B2|2000-02-02|2003-09-30|Kotobuki Pharmaceutical Co Ltd|C-glycosides and preparation of thereof as antidiabetic agents|

---

JP4456768B2|2000-02-02|2010-04-28|壽製薬株式会社|Drug containing C-glycoside|

---

US6683056B2|2000-03-30|2004-01-27|Bristol-Myers Squibb Company|O-aryl glucoside SGLT2 inhibitors and method|

---

US6627634B2|2000-04-08|2003-09-30|Boehringer Ingelheim Pharma Kg|Bicyclic heterocycles, pharmaceutical compositions containing them, their use, and processes for preparing them|

---

DE60122193T2|2000-09-29|2007-07-05|Kissei Pharmaceutical Co., Ltd., Matsumoto|GLUCOPYRANOSYLOXYBENZYLBENZEN DERIVATIVES AND MEDICAL COMPOSITIONS CONTAINING THESE COMPOUNDS|

---

CA2429833A1|2000-11-30|2002-06-06|Kissei Pharmaceutical Co., Ltd.|Glucopyranosyloxybenzylbenzene derivatives, medicinal compositions containing the same and intermediates in the production thereof|

---

US7019012B2|2000-12-20|2006-03-28|Boehringer Ingelheim International Pharma Gmbh & Co. Kg|Quinazoline derivatives and pharmaceutical compositions containing them|

---

TWI255817B|2001-02-14|2006-06-01|Kissei Pharmaceutical|Glucopyranosyloxybenzylbenzene derivatives and medicinal use thereof|

---

EP1364958B1|2001-02-27|2010-09-08|Kissei Pharmaceutical Co., Ltd.|Glycopyranosyloxypyrazole derivatives and medicinal use thereof|

---

US6936590B2|2001-03-13|2005-08-30|Bristol Myers Squibb Company|C-aryl glucoside SGLT2 inhibitors and method|

---

JP3698067B2|2001-03-30|2005-09-21|Ｊｓｒ株式会社|Monomer having electron-withdrawing group and electron-donating group, copolymer using the same, and proton conducting membrane|

---

CA2444481A1|2001-04-11|2002-10-24|Bristol-Myers Squibb Company|Amino acid complexes of c-aryl glucosides for treatment of diabetes and method|

---

JP2002338471A|2001-05-23|2002-11-27|Asahi Kasei Corp|Therapeutic agent for erectile incompetence|

---

US20030087843A1|2001-09-05|2003-05-08|Washburn William N.|O-pyrazole glucoside SGLT2 inhibitors and method of use|

---

WO2003031458A1|2001-10-12|2003-04-17|Dana-Farber Cancer Institute|Methods for synthesis of diarylmethanes|

---

GB0206215D0|2002-03-15|2002-05-01|Novartis Ag|Organic compounds|

---

DE10231370B4|2002-07-11|2006-04-06|Sanofi-Aventis Deutschland Gmbh|Thiophene glycoside derivatives, medicaments containing these compounds and methods of making these medicaments|

---

TWI254635B|2002-08-05|2006-05-11|Yamanouchi Pharma Co Ltd|Azulene derivative and salt thereof|

---

KR100985502B1|2002-08-08|2010-10-05|깃세이 야쿠힌 고교 가부시키가이샤|Pyrazole derivative, medicinal composition containing the same, medicinal use thereof, and intermediate for production thereof|

---

US7407955B2|2002-08-21|2008-08-05|Boehringer Ingelheim Pharma Gmbh & Co., Kg|8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and their use as pharmaceutical compositions|

---

KR101111101B1|2002-08-21|2012-06-13|베링거 잉겔하임 파르마 게엠베하 운트 코 카게|A pharmaceutical composition and a combination comprising 8-[3-amino-piperidin-1-yl]-xanthines, and the production of the pharmaceutical composition|

---

JP3567162B1|2002-11-20|2004-09-22|日本たばこ産業株式会社|4-oxoquinoline compounds and their use as HIV integrase inhibitors|

---

EP2161258A3|2002-11-20|2010-04-07|Japan Tabacco Inc.|4-oxoquinoline compound and use thereof as hiv integrase inhibitor|

---

JP4651934B2|2002-12-04|2011-03-16|キッセイ薬品工業株式会社|Benzylphenol derivative, pharmaceutical composition containing it, and pharmaceutical use thereof|

---

DE10258007B4|2002-12-12|2006-02-09|Sanofi-Aventis Deutschland Gmbh|Aromatic fluoroglycoside derivatives, medicaments containing these compounds and methods for the preparation of these medicaments|

---

DE10258008B4|2002-12-12|2006-02-02|Sanofi-Aventis Deutschland Gmbh|Heterocyclic fluoroglycoside derivatives, medicaments containing these compounds and methods of making these medicaments|

---

EP1581543A4|2003-01-03|2008-03-19|Squibb Bristol Myers Co|Methods of producing c-aryl glucoside sglt2 inhibitors|

---

US7164015B2|2003-02-27|2007-01-16|Bristol-Myers Squibb Company|Non-cryogenic process for forming glycosides|

---

ZA200507754B|2003-03-14|2007-01-31|Astellas Pharma Inc|C-glycoside derivatives and salts thereof|

---

US7674486B2|2003-05-14|2010-03-09|Indus Biotech Pvt. Ltd.|Synergistic composition for the treatment of diabetes mellitus|

---

CA2528152A1|2003-06-03|2005-01-06|The Regents Of The University Of California|Compositions and methods for treatment of disease with acetylated disaccharides|

---

JP2004359630A|2003-06-06|2004-12-24|Yamanouchi Pharmaceut Co Ltd|Difluorodiphenylmethane derivative and its salt|

---

FR2855756B1|2003-06-06|2005-08-26|Ethypharm Sa|MULTILAYER ORODISPERSIBLE TABLET|

---

US20050027236A1|2003-07-30|2005-02-03|Medtronic Ave, Inc.|Aspiration catheter having a variable over-the-wire length and methods of use|

---

US7094763B2|2003-08-01|2006-08-22|Janssen Pharaceutica, N.V.|Substituted fused heterocyclic C-glycosides|

---

ES2402098T5|2003-08-01|2021-06-09|Mitsubishi Tanabe Pharma Corp|Novel compounds that have inhibitory activity against the sodium-dependent transporter|

---

US6995183B2|2003-08-01|2006-02-07|Bristol Myers Squibb Company|Adamantylglycine-based inhibitors of dipeptidyl peptidase IV and methods|

---

JP4131216B2|2003-08-20|2008-08-13|Ｊｓｒ株式会社|Polyarylene, production method thereof, solid polymer electrolyte and proton conducting membrane|

---

US7375090B2|2003-08-26|2008-05-20|Boehringer Ingelheim International Gmbh|Glucopyranosyloxy-pyrazoles, pharmaceutical compositions containing these compounds, the use thereof and processed for the preparation thereof|

---

DE502004008951D1|2003-08-26|2009-03-19|Boehringer Ingelheim Pharma|GLUCOPYRANOSYLOXY-PYRAZOLE, MEDICAMENT CONTAINING THESE COMPOUNDS, THEIR USE AND METHOD FOR THE PRODUCTION THEREOF|

---

US20050085680A1|2003-10-21|2005-04-21|Joseph Auerbach|Method for industrial decontamination|

---

WO2005049022A2|2003-11-17|2005-06-02|Novartis Ag|Use of dipeptidyl peptidase iv inhibitors|

---

US7371732B2|2003-12-22|2008-05-13|Boehringer Ingelheim International Gmbh|Glucopyranosyloxy-substituted aromatic compounds, medicaments containing such compounds, their use and process for their manufacture|

---

DE10361133A1|2003-12-22|2005-07-21|Boehringer Ingelheim Pharma Gmbh & Co. Kg|Glucopyranosyloxy-substituted aromatics, medicaments containing these compounds, their use and processes for their preparation|

---

EP1715893B8|2004-01-20|2009-12-16|Novartis Ag|Direct compression formulation and process|

---

ZA200608028B|2004-03-04|2009-03-25|Kissei Pharmaceutical|Fused heterocycle derivative, medicinal composition containing the same, and medicinal use thereof|

---

JP5078350B2|2004-03-04|2012-11-21|キッセイ薬品工業株式会社|Fused heterocyclic derivative, pharmaceutical composition containing the same, and pharmaceutical use thereof|

---

PL1730131T3|2004-03-16|2012-10-31|Boehringer Ingelheim Int|Glucopyranosyl-substituted benzol derivatives, drugs containing said compounds, the use thereof and method for the production thereof|

---

US7935723B2|2004-06-04|2011-05-03|Novartis Pharma Ag|Use of organic compounds|

---

US7393836B2|2004-07-06|2008-07-01|Boehringer Ingelheim International Gmbh|D-xylopyranosyl-substituted phenyl derivatives, medicaments containing such compounds, their use and process for their manufacture|

---

JPWO2006006496A1|2004-07-08|2008-04-24|アステラス製薬株式会社|Method for producing azulene derivatives and synthetic intermediates thereof|

---

DE102004034690A1|2004-07-17|2006-02-02|Boehringer Ingelheim Pharma Gmbh & Co. Kg|Methylidene-D-xylopyranosyl and oxo-D-xylopyranosyl-substituted phenyls, medicaments containing these compounds, their use and processes for their preparation|

---

TW200606129A|2004-07-26|2006-02-16|Chugai Pharmaceutical Co Ltd|Novel cyclohexane derivative, its prodrug, its salt and diabetic therapeutic agent containing the same|

---

EP1773800A1|2004-07-27|2007-04-18|Boehringer Ingelheim International GmbH|D-glucopyranosyl phenyl-substituted cyclene, medicaments containing these compounds, their use, and method for the production thereof|

---

WO2006018150A1|2004-08-11|2006-02-23|Boehringer Ingelheim International Gmbh|D-xylopyranosyl-phenyl-substituited cyclene, medicaments containing said compounds, use thereof and method for the production thereof|

---

AR051446A1|2004-09-23|2007-01-17|Squibb Bristol Myers Co|C-ARYL GLUCOSIDS AS SELECTIVE INHIBITORS OF GLUCOSE CONVEYORS |

---

DE102004048388A1|2004-10-01|2006-04-06|Boehringer Ingelheim Pharma Gmbh & Co. Kg|D-pyranosyl-substituted phenyls, pharmaceutical compositions containing them, their use and processes for their preparation|

---

EP1828216B1|2004-12-16|2008-09-10|Boehringer Ingelheim International GmbH|Glucopyranosyl-substituted benzene derivatives, medicaments containing such compounds, their use and process for their manufacture|

---

GB0428180D0|2004-12-23|2005-01-26|Biopartners Ltd|Combination therapy|

---

GT200600008A|2005-01-18|2006-08-09|FORMULATION OF DIRECT COMPRESSION AND PROCESS|

---

CA2595257A1|2005-02-23|2006-08-31|Boehringer Ingelheim International Gmbh|Glucopyranosyl-substituted arylethynyl-benzyl)-benzene derivatives and use thereof as sodium-dependent glucose cotransporter 2 inhibitors|

---

CA2605245A1|2005-04-15|2006-10-19|Boehringer Ingelheim International Gmbh|Glucopyranosyl-substituted -benzene derivatives as sglt inhibitors|

---

US7723309B2|2005-05-03|2010-05-25|Boehringer Ingelheim International Gmbh|Crystalline forms of 1-chloro-4--2-[4--tetrahydrofuran-3-yloxy)-benzyl]-benzene, a method for its preparation and the use thereof for preparing medicaments|

---

US7713938B2|2005-05-03|2010-05-11|Boehringer Ingelheim International Gmbh|Crystalline form of 1-chloro-4--2-[4--tetrahydrofuran-3-yloxy)-benzyl]-benzene, a method for its preparation and the use thereof for preparing medicaments|

---

US7772191B2|2005-05-10|2010-08-10|Boehringer Ingelheim International Gmbh|Processes for preparing of glucopyranosyl-substituted benzyl-benzene derivatives and intermediates therein|

---

WO2007000445A1|2005-06-29|2007-01-04|Boehringer Ingelheim International Gmbh|Glucopyranosyl-substituted benzyl-benzene derivatives, medicaments containing such compounds, their use and process for their manufacture|

---

WO2007014894A2|2005-07-27|2007-02-08|Boehringer Ingelheim International Gmbh|Glucopyranosyl-substituted cycloalyklethynyl-benzyl) -benzene derivatives and use thereof as sodium-dependent glucose cotransporter inhibitors|

---

KR100780553B1|2005-08-18|2007-11-29|한올제약주식회사|Pharmaceutical compositions and formulations of Metformin extended release tablets and its preparing method|

---

US7452872B2|2005-08-24|2008-11-18|Salix Pharmaceuticals, Inc.|Formulations and uses of 2-hydroxy-5-phenylazobenzoic acid derivatives|

---

WO2007025943A2|2005-08-30|2007-03-08|Boehringer Ingelheim International Gmbh|Glucopyranosyl-substituted benzyl-benzene derivatives, medicaments containing such compounds, their use and process for their manufacture|

---

US8507450B2|2005-09-08|2013-08-13|Boehringer Ingelheim International Gmbh|Crystalline forms of 1-chloro-4--2-[4-ethynyl-benzyl)-benzene, methods for its preparation and the use thereof for preparing medicaments|

---

AR056195A1|2005-09-15|2007-09-26|Boehringer Ingelheim Int|PROCEDURES TO PREPARE DERIVATIVES OF -BENZENE REPLACED GLUCOPYRANOSIL AND INTERMEDIATE COMPOUNDS OF THE SAME|

---

JOP20180109A1|2005-09-29|2019-01-30|Novartis Ag|New Formulation|

---

BRPI0617208A2|2005-09-30|2011-07-19|Boehringer Ingelheim Vetmed|pharmaceutical preparation containing meloxicam|

---

PE20080697A1|2006-05-03|2008-08-05|Boehringer Ingelheim Int|BENZONITRILE DERIVATIVES SUBSTITUTED WITH GLUCOPYRANOSIL, PHARMACEUTICAL COMPOSITIONS CONTAINING COMPOUNDS OF THIS TYPE, THEIR USE AND PROCEDURE FOR THEIR MANUFACTURE|

---

TW200801029A|2006-02-15|2008-01-01|Boehringer Ingelheim Int|Glucopyranosyl-substituted benzonitrile derivatives, pharmaceutical compositions containing such compounds, their use and process for their manufacture|

---

EP1852108A1|2006-05-04|2007-11-07|Boehringer Ingelheim Pharma GmbH & Co.KG|DPP IV inhibitor formulations|

---

PE20080251A1|2006-05-04|2008-04-25|Boehringer Ingelheim Int|USES OF DPP IV INHIBITORS|

---

AU2007252432B2|2006-05-19|2011-11-17|Taisho Pharmaceutical Co., Ltd.|C-phenyl glycitol compound|

---

DE602007012692D1|2006-06-16|2011-04-07|Lek Pharmaceuticals|PHARMACEUTICAL COMPOSITION WITH HYDROCHLOROTHIAZIDE AND TELMISARTAN|

---

PE20120542A1|2006-06-27|2012-05-14|Novartis Ag|SOLID DOSAGE FORMS OF VALSARTAN, AMLODIPINE AND HYDROCHLOROTHIAZIDE AND METHOD OF PREPARING THEM|

---

TW200817424A|2006-08-04|2008-04-16|Daiichi Sankyo Co Ltd|Benzylphenyl glucopyranoside derivatives|

---

CA2656847A1|2006-08-15|2008-02-21|Boehringer Ingelheim International Gmbh|Glucopyranosyl-substituted cyclopropylbenzene derivatives, pharmaceutical compositions containing such compounds, their use as sglt inhibitors and process for their manufacture|

---

EP2056673A4|2006-08-17|2010-06-16|Wellstat Therapeutics Corp|Combination treatment for metabolic disorders|

---

CA2664095A1|2006-09-21|2008-03-27|Boehringer Ingelheim International Gmbh|Glucopyranosyl-substituted difluorobenzyl-benzene derivatives, medicaments containing such compounds, their use and process for their manufacture|

---

US8283326B2|2006-10-27|2012-10-09|Boehringer Ingelheim International Gmbh|Crystalline form of 4--1-methyl-2-[4--tetrahydrofuran-3-yloxy)-benzyl]-benzene, a method for its preparation and the use thereof for preparing medicaments|

---

WO2008101938A1|2007-02-21|2008-08-28|Boehringer Ingelheim International Gmbh|Glucopyranosyl-substituted benzyl-benzonitrile derivatives, medicaments containing such compounds, their use and process for their manufacture|

---

EP2079753A1|2006-11-06|2009-07-22|Boehringer Ingelheim International GmbH|Glucopyranosyl-substituted benzyl-benzonitrile derivatives, medicaments containing such compounds, their use and process for their manufacture|

---

CN101534815A|2006-11-09|2009-09-16|贝林格尔.英格海姆国际有限公司|Combination therapy with SGLT-2 inhibitors and their pharmaceutical compositions|

---

WO2008062273A2|2006-11-20|2008-05-29|Cadila Pharmaceuticals Limited|Solid oral dosage form having antidiabetic drug combination|

---

AT514692T|2007-01-26|2011-07-15|Sanofi Aventis|PHENOTHIAZIN DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS MEDICAMENTS|

---

TW200838549A|2007-01-26|2008-10-01|Boehringer Ingelheim Int|Methods for preventing and treating neurodegenerative disorders|

---

WO2008101939A1|2007-02-21|2008-08-28|Boehringer Ingelheim International Gmbh|Tetrasubstituted glucopyranosylated benzene derivatives, medicaments containing such compounds, their use and process for their manufacture|

---

ITFI20070042A1|2007-02-21|2008-08-22|Laboratori Guidotti Spa|PHARMACEUTICAL FORMULATION AND COMPRESSED INCLUDING THIS FORMULATION.|

---

US8551524B2|2008-03-14|2013-10-08|Iycus, Llc|Anti-diabetic combinations|

---

AR065809A1|2007-03-22|2009-07-01|Squibb Bristol Myers Co|PHARMACEUTICAL FORMULATIONS CONTAINING AN SGLT2 INHIBITOR|

---

TW200904454A|2007-03-22|2009-02-01|Squibb Bristol Myers Co|Methods for treating obesity employing an SGLT2 inhibitor and compositions thereof|

---

PE20090696A1|2007-04-20|2009-06-20|Squibb Bristol Myers Co|CRYSTALLINE FORMS OF SAXAGLIPTIN AND PROCESSES FOR PREPARING THEM|

---

JP2010528023A|2007-05-18|2010-08-19|ブリストル−マイヤーズスクイブカンパニー|Crystal structure of SGLT2 inhibitor and method for producing the same|

---

PE20090938A1|2007-08-16|2009-08-08|Boehringer Ingelheim Int|PHARMACEUTICAL COMPOSITION INCLUDING A BENZENE DERIVATIVE SUBSTITUTED WITH GLUCOPYRANOSIL|

---

PE20090603A1|2007-08-16|2009-06-11|Boehringer Ingelheim Int|PHARMACEUTICAL COMPOSITION INCLUDING A SGLT2 INHIBITOR AND A DPP IV INHIBITOR|

---

DK2200606T3|2007-09-10|2017-12-04|Janssen Pharmaceutica Nv|PROCEDURE FOR THE PREPARATION OF RELATIONSHIP USED AS INHIBITORS OF SGLT|

---

CL2008003653A1|2008-01-17|2010-03-05|Mitsubishi Tanabe Pharma Corp|Use of a glucopyranosyl-derived sglt inhibitor and a selected dppiv inhibitor to treat diabetes; and pharmaceutical composition.|

---

CN101503399B|2008-02-04|2012-06-27|白鹭医药技术（上海）有限公司|C-aryl glucoside SGLT2 inhibitor|

---

CA2713361A1|2008-02-05|2009-08-13|Merck Sharp & Dohme Corp.|Pharmaceutical compositions of a combination of metformin and a dipeptidyl peptidase-iv inhibitor|

---

PE20091730A1|2008-04-03|2009-12-10|Boehringer Ingelheim Int|FORMULATIONS INVOLVING A DPP4 INHIBITOR|

---

WO2010045656A2|2008-10-17|2010-04-22|Nectid, Inc.|Novel sglt2 inhibitor dosage forms|

---

HUE050287T2|2009-02-13|2020-11-30|Boehringer Ingelheim Int|Pharmaceutical composition comprisng a sglt2 inhibitor, a dpp-iv inhibitor and optionally a further antidiabetic agent and uses thereof|

---

CN102387783A|2009-02-13|2012-03-21|贝林格尔.英格海姆国际有限公司|Pharmaceutical composition comprising glucopyranosyl diphenylmethane derivatives, pharmaceutical dosage form thereof, process for their preparation and uses thereof for improved glycemic control in a patient|

---

UY32427A|2009-02-13|2010-09-30|Boheringer Ingelheim Internat Gmbh|PHARMACEUTICAL COMPOSITION, PHARMACEUTICAL FORM, PROCEDURE FOR PREPARATION, METHODS OF TREATMENT AND USES OF THE SAME|

---

EP2395988A2|2009-02-13|2011-12-21|Boehringer Ingelheim International GmbH|Antidiabetic medications comprising a dpp-4 inhibitor optionally in combination with other antidiabetics|

---

SG10201600204YA|2009-02-13|2016-02-26|Boehringer Ingelheim Int|SGLT-2 Inhibitor For Treating Type 1 Diabetes Mellitus, Type 2 Diabetes Mellitus, Impaired Glucose Tolerance Or Hyperglycemia|

---

EP2829271A3|2009-04-16|2015-05-27|Taisho Pharmaceutical Co., Ltd.|Pharmaceutical compositions with -1,5-anhydro-1-[5--2-methoxy-4-methylphenyl]-1-thio-D-glucitol and a further antidiabetic agent|

---

CN102639125A|2009-05-27|2012-08-15|百时美施贵宝公司|Methods for treating type 2 diabetes in patients resistant to previous treatment with other anti-diabetic drugs employing an SGLT2 inhibitor and compositions thereof|

---

US20110077212A1|2009-09-25|2011-03-31|Theracos, Inc.|Therapeutic uses of sglt2 inhibitors|

---

BR112012007085B8|2009-09-30|2021-05-25|Boehringer Ingelheim Int|processes for the preparation of glycopyranosyl substituted benzyl-benzene derivatives|

---

HUE029381T2|2009-09-30|2017-02-28|Boehringer Ingelheim Int|Method for the preparation of a crystalline form of 1-chloro-4--2--tetrahydrofuran-3-yloxy)benzyl)benzene|

---

UY32919A|2009-10-02|2011-04-29|Boehringer Ingelheim Int|Pharmaceutical composition, pharmaceutical dosage form, procedure for its preparation, methods for its treatment and its uses|

---

SI2498759T1|2009-11-13|2018-12-31|Astrazeneca Ab|Immediate release tablet formulations|

---

WO2011120923A1|2010-03-30|2011-10-06|Boehringer Ingelheim International Gmbh|Pharmaceutical composition comprising an sglt2 inhibitor and a ppar- gamma agonist and uses thereof|

---

MX2013002146A|2010-09-03|2013-04-03|Astrazeneca Uk Ltd|Drug formulations using water soluble antioxidants.|

---

US20120283169A1|2010-11-08|2012-11-08|Boehringer Ingelheim International Gmbh|Pharmaceutical composition, methods for treating and uses thereof|

---

AU2012212448B9|2011-02-01|2015-06-25|Astrazeneca Uk Limited|Pharmaceutical formulations including an amine compound|

---

US20130035281A1|2011-02-09|2013-02-07|Boehringer Ingelheim International Gmbh|Pharmaceutical composition, methods for treating and uses thereof|

---

UY33937A|2011-03-07|2012-09-28|Boehringer Ingelheim Int|PHARMACEUTICAL COMPOSITIONS CONTAINING DPP-4 AND / OR SGLT-2 AND METFORMIN INHIBITORS|

---

CN103596574A|2011-06-03|2014-02-19|勃林格殷格翰国际有限公司|SGLT-2 inhibitors for treating metabolic disorders in patients treated with neuroleptic agents|

---

US20130035298A1|2011-07-08|2013-02-07|Boehringer Ingelheim International Gmbh|Pharmaceutical composition, methods for treating and uses thereof|

---

US20150119399A1|2012-01-10|2015-04-30|President And Fellows Of Harvard College|Beta-cell replication promoting compounds and methods of their use|

---

US9555001B2|2012-03-07|2017-01-31|Boehringer Ingelheim International Gmbh|Pharmaceutical composition and uses thereof|

---

US9192617B2|2012-03-20|2015-11-24|Boehringer Ingelheim International Gmbh|Pharmaceutical composition, methods for treating and uses thereof|

---

US20160000816A1|2013-04-05|2016-01-07|Boehringer Ingelheim International Gmbh|Pharmaceutical composition, methods for treating and uses thereof|

---

US20140303097A1|2013-04-05|2014-10-09|Boehringer Ingelheim International Gmbh|Pharmaceutical composition, methods for treating and uses thereof|

---

TR201901110T4|2013-04-05|2019-02-21|Boehringer Ingelheim Int|Therapeutic uses of empagliflozin.|

---

CA2909728A1|2013-04-18|2014-10-23|Boehringer Ingelheim International Gmbh|Therapeutic uses of empagliflozin|

---

JP6561136B2|2015-04-30|2019-08-14|ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング|Method for treating or ameliorating erectile dysfunction and pharmaceutical composition comprising SGLT2 inhibitor|

---

WO2017064193A1|2015-10-15|2017-04-20|Boehringer Ingelheim International Gmbh|Sglt-2 inhibitor for use in the treatment of a metabolic myopathy|

---

US20180344647A1|2015-12-04|2018-12-06|Boehringer Ingelheim International Gmbh|Pharmaceutical composition, methods for treating and uses thereof|

---

US20170266152A1|2016-03-16|2017-09-21|Boehringer Ingelheim International Gmbh|Pharmaceutical composition, methods for treating and uses thereof|

---

EP3526229B1|2016-10-13|2021-04-28|Boehringer Ingelheim International GmbH|Process for preparing glucopyranosyl-substituted benzyl-benzene derivatives|

---

US20180125813A1|2016-11-10|2018-05-10|Boehringer Ingelheim International Gmbh|Pharmaceutical composition, methods for treating and uses thereof|US7407955B2|2002-08-21|2008-08-05|Boehringer Ingelheim Pharma Gmbh & Co., Kg|8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and their use as pharmaceutical compositions|

---

DE102004054054A1|2004-11-05|2006-05-11|Boehringer Ingelheim Pharma Gmbh & Co. Kg|Process for preparing chiral 8--xanthines|

---

US7713938B2|2005-05-03|2010-05-11|Boehringer Ingelheim International Gmbh|Crystalline form of 1-chloro-4--2-[4--tetrahydrofuran-3-yloxy)-benzyl]-benzene, a method for its preparation and the use thereof for preparing medicaments|

---

US7772191B2|2005-05-10|2010-08-10|Boehringer Ingelheim International Gmbh|Processes for preparing of glucopyranosyl-substituted benzyl-benzene derivatives and intermediates therein|

---

US8507450B2|2005-09-08|2013-08-13|Boehringer Ingelheim International Gmbh|Crystalline forms of 1-chloro-4--2-[4-ethynyl-benzyl)-benzene, methods for its preparation and the use thereof for preparing medicaments|

---

PE20080697A1|2006-05-03|2008-08-05|Boehringer Ingelheim Int|BENZONITRILE DERIVATIVES SUBSTITUTED WITH GLUCOPYRANOSIL, PHARMACEUTICAL COMPOSITIONS CONTAINING COMPOUNDS OF THIS TYPE, THEIR USE AND PROCEDURE FOR THEIR MANUFACTURE|

---

PE20080251A1|2006-05-04|2008-04-25|Boehringer Ingelheim Int|USES OF DPP IV INHIBITORS|

---

EP1852108A1|2006-05-04|2007-11-07|Boehringer Ingelheim Pharma GmbH & Co.KG|DPP IV inhibitor formulations|

---

KR101452915B1|2006-05-04|2014-10-21|베링거 인겔하임 인터내셔날 게엠베하|Polymorphs|

---

US8283326B2|2006-10-27|2012-10-09|Boehringer Ingelheim International Gmbh|Crystalline form of 4--1-methyl-2-[4--tetrahydrofuran-3-yloxy)-benzyl]-benzene, a method for its preparation and the use thereof for preparing medicaments|

---

PE20090938A1|2007-08-16|2009-08-08|Boehringer Ingelheim Int|PHARMACEUTICAL COMPOSITION INCLUDING A BENZENE DERIVATIVE SUBSTITUTED WITH GLUCOPYRANOSIL|

---

CA2706018C|2007-11-30|2015-11-24|Boehringer Ingelheim International Gmbh|1, 5-dihydro-pyrazolo [3,4-d]pyrimidin-4-one derivatives and their use as pde9a modulators for the treatment of cns disorders|

---

AU2010230290B2|2009-03-31|2013-03-14|Boehringer Ingelheim International Gmbh|1-heterocyclyl-1, 5-dihydro-pyrazolo [3, 4-d] pyrimidin-4-one derivatives and their use as PDE9A modulators|

---

AR071577A1|2008-04-02|2010-06-30|Boehringer Ingelheim Int|PIRAZOLO-PYRIMIDINONE FOR THE TREATMENT OF DISORDERS OF THE CENTRAL NERVOUS SYSTEM|

---

PE20091730A1|2008-04-03|2009-12-10|Boehringer Ingelheim Int|FORMULATIONS INVOLVING A DPP4 INHIBITOR|

---

UY32030A|2008-08-06|2010-03-26|Boehringer Ingelheim Int|"TREATMENT FOR DIABETES IN INAPPROPRIATE PATIENTS FOR THERAPY WITH METFORMIN"|

---

BRPI0916997A2|2008-08-06|2020-12-15|Boehringer Ingelheim International Gmbh|DPP-4 INHIBITOR AND ITS USE|

---

BRPI0918527A2|2008-09-08|2015-12-01|Boehring Ingelheim Internat Gmbh|compounds for the treatment of cns disorders|

---

KR20110103968A|2008-12-23|2011-09-21|베링거 인겔하임 인터내셔날 게엠베하|Salt forms of organic compound|

---

AR074990A1|2009-01-07|2011-03-02|Boehringer Ingelheim Int|TREATMENT OF DIABETES IN PATIENTS WITH AN INAPPROPRIATE GLUCEMIC CONTROL THROUGH METFORMIN THERAPY|

---

HUE050287T2|2009-02-13|2020-11-30|Boehringer Ingelheim Int|Pharmaceutical composition comprisng a sglt2 inhibitor, a dpp-iv inhibitor and optionally a further antidiabetic agent and uses thereof|

---

HUE029381T2|2009-09-30|2017-02-28|Boehringer Ingelheim Int|Method for the preparation of a crystalline form of 1-chloro-4--2--tetrahydrofuran-3-yloxy)benzyl)benzene|

---

BR112012007085B8|2009-09-30|2021-05-25|Boehringer Ingelheim Int|processes for the preparation of glycopyranosyl substituted benzyl-benzene derivatives|

---

UY32919A|2009-10-02|2011-04-29|Boehringer Ingelheim Int|Pharmaceutical composition, pharmaceutical dosage form, procedure for its preparation, methods for its treatment and its uses|

---

SI2498759T1|2009-11-13|2018-12-31|Astrazeneca Ab|Immediate release tablet formulations|

---

ES2689107T3|2009-11-13|2018-11-08|Astrazeneca Ab|Bilayer tablet formulations|

---

EP3646859A1|2009-11-27|2020-05-06|Boehringer Ingelheim International GmbH|Treatment of genotyped diabetic patients with dpp-iv inhibitors such as linagliptin|

---

EP2566469A1|2010-05-05|2013-03-13|Boehringer Ingelheim International GmbH|Combination therapy|

---

KR20200028498A|2010-06-24|2020-03-16|베링거 인겔하임 인터내셔날 게엠베하|Diabetes therapy|

---

UA110347C2|2010-08-12|2015-12-25|Бьорінгер Інгельхайм Інтернаціональ Гмбх|Derivative 6-cycloalkanes 1.5 dyhidropirazol [3,4-d] pyrimidine-4-one and their use as inhibitors pde9a|

---

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---

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---

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---

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---

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---

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---

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---

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---

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---

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---

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---

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---

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---

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---

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---

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---

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---

WO2015101916A1|2013-12-30|2015-07-09|Mylan Laboratories Ltd.|Process for the preparation of empagliflozin|

---

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---

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---

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---

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---

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---

US9949964B2|2016-09-07|2018-04-24|Saniona A/S|Tesofensine compositions|

---

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---

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法律状态:
2018-01-23| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|

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2018-04-10| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|

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2019-01-29| B07E| Notice of approval relating to section 229 industrial property law [chapter 7.5 patent gazette]|Free format text: NOTIFICACAO DE ANUENCIA RELACIONADA COM O ART 229 DA LPI |

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2019-04-16| B06T| Formal requirements before examination [chapter 6.20 patent gazette]|

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2020-08-04| B07A| Technical examination (opinion): publication of technical examination (opinion) [chapter 7.1 patent gazette]|

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2020-11-24| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|

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2021-02-09| B16A| Patent or certificate of addition of invention granted|Free format text: PRAZO DE VALIDADE: 10 (DEZ) ANOS CONTADOS A PARTIR DE 09/02/2021, OBSERVADAS AS CONDICOES LEGAIS. |

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2021-05-25| B16C| Correction of notification of the grant|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 01/10/2010 OBSERVADAS AS CONDICOES LEGAIS. PATENTE CONCEDIDA CONFORME ADI 5.529/DF |

优先权:

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申请号 | 申请日 | 专利标题

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EP09172081|2009-10-02|

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EP09172081.3|2009-10-02|

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PCT/EP2010/064619|WO2011039337A1|2009-10-02|2010-10-01|Pharmaceutical composition, pharmaceutical dosage form, process for their preparation, methods for treating and uses thereof|

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