EA044961B1 - TREATMENT OF DIABETES - Google Patents

Description

The present invention provides the use of a DPP-4 inhibitor, which is linagliptin, in a method of improving glycemic control in an elderly patient with type 2 diabetes, the method comprising adding a DPP-4 inhibitor to a long-acting insulin, which is basal insulin, alone or in combination with one or more other antidiabetic drugs selected from metformin, pioglitazone and a sulfonylurea, where the patient is inadequately controlled when treated with insulin alone or in combination with one or more other antidiabetic drugs selected from metformin, pioglitazone and a sulfonylurea.

In addition, the present invention provides the use of a DPP-4 inhibitor for a patient with impaired or declining renal function.

In addition, the present invention provides the use of a DPP-4 inhibitor for an elderly patient of 60-65 years of age or older.

In addition, the present invention provides the use of a DPP-4 inhibitor in a method that is further designed to reduce the dose of insulin required to achieve an adequate therapeutic effect.

In addition, the present invention provides the use of a DPP-4 inhibitor in a method that is further intended to reduce hypoglycemia and/or weight gain associated with insulin treatment.

In addition, the present invention provides the use of a DPP-4 inhibitor, which is linagliptin, which is administered in a daily oral amount of 5 mg.

Type 2 diabetes mellitus is a common, chronic and progressive disease caused by a complex pathophysiology, including the dual endocrine effects of insulin resistance and impaired insulin secretion, resulting in a lack of ability to maintain plasma glucose levels within the normal range. This leads to chronic hyperglycemia and associated micro- and macrovascular complications or chronic damage, such as, for example, diabetic nephropathy, retinopathy or neuropathy, or macrovascular (for example, cardiovascular or cerebrovascular) complications. The vascular disease component plays an important role, but is not the only factor in the spectrum of diabetes-related disorders. The high incidence of complications leads to a significant reduction in average life expectancy. Diabetes is now the most common cause of adult vision loss, kidney failure, and amputations in industrialized countries because diabetes causes complications and is associated with a 2- to 5-fold increase in the risk of cardiovascular disease.

Treatment of type 2 diabetes usually begins with diet and exercise followed by oral antidiabetic treatment as monotherapy, and although standard monotherapy treatment can initially control blood glucose in some patients, such treatment is associated with high rates of failure. secondary course of treatment. Limiting treatment to a single drug to achieve glycemic control can be avoided, at least in some patients and for a limited period of time, when combining several drugs to lower blood glucose levels, which cannot be achieved with long-term treatment with a single drug. Current evidence supports the conclusion that for the majority of patients suffering from type 2 diabetes, monotherapy is ineffective and treatment with multiple drugs is required.

But because type 2 diabetes is a progressive disease, even patients who initially respond well to standard combination treatment will need dose increases or additional insulin treatment over time because it is extremely difficult to maintain stable blood glucose levels over a long period of time. Thus, although current combination treatments improve glycemic control, such treatments are also limited (primarily in terms of effectiveness over the long term). In addition, the risk of side effects such as hypoglycemia or weight gain may increase with traditional treatments, resulting in reduced effectiveness and tolerability.

Thus, in many patients, these current drug treatments result in progressive deterioration of metabolic control despite treatment and poor metabolic control, primarily over long periods of time, and therefore do not provide or maintain glycemic control in advanced or late stage diabetes. type 2, including diabetes with inadequate glycemic control despite treatment with standard oral or non-oral antidiabetic drugs.

Therefore, although chronic damage can be reduced with intensive treatment of hyperglycemia, treatment for many patients suffering from type 2 diabetes remains ineffective due in part to limitations associated with decreased treatment effectiveness over the long term, tolerability and discomfort after administration of standard hypoglycemic drugs.

- 1 044961

This high rate of treatment failure is a major factor in the frequent development of long-term hyperglycemia-associated complications or chronic disorders (including micro- and macrovascular complications, such as diabetic nephropathy, retinopathy or neuropathy, or cerebrovascular or cardiovascular complications, such as heart attack myocardial injury, stroke, or death) in patients with type 2 diabetes.

Oral antidiabetic drugs commonly used for treatment (eg, first- or second-line agents and/or agents for mono- or combination therapy (primary or adjunctive therapy)) include, but are not limited to, metformin, sulfonylureas, thiazolidinediones , glinides and α-glucosidase inhibitors.

Non-oral (usually injectable) antidiabetic drugs commonly used for treatment (eg, first- or second-line agents and/or agents for mono- or combination therapy (primary or adjunctive therapy)) include, but are not limited to , GLP-1 or GLP-1 analogs, and insulin or insulin analogs.

However, the use of such standard antidiabetic or hypoglycemic agents may lead to various negative effects. For example, metformin can cause lactic acidosis or gastrointestinal side effects, sulfonylureas, glinides and insulin or insulin analogues can lead to hypoglycemia and weight gain, thiazolidinediones can cause edema, bone fractures, weight gain and lead to heart failure. cardiac effects, α-glucosidase and GLP-1 blockers or GLP-1 analogues may cause adverse gastrointestinal effects (eg, dyspepsia, flatulence or diarrhea, nausea or vomiting).

Therefore, there is still a need to develop an effective, safe and tolerable antidiabetic treatment.

Additionally, in the treatment of type 2 diabetes, there is a need for an effective way to treat the condition while eliminating complications associated with the condition and slowing the progression of the disease.

In addition, in the treatment of type 2 diabetes, there is a need for long-term improvement of the diabetic phenotype, glycemic and/or metabolic control, and/or blood glucose profile (preferably over time and/or over long-term treatment).

In addition, there is a need for antidiabetic treatment not only to prevent long-term complications often observed in the advanced stages of diabetes, but also a need to be able to provide antidiabetic treatment to diabetic patients who develop such complications or who are at risk of developing complications such as renal disorders.

Additionally, there is a need for methods to prevent or reduce the risk of adverse effects associated with standard diabetes treatments.

The enzyme DPP-4 (dipeptidyl peptidase-4), so-called CD26, is a serine protease that is known to cleave the dipeptide at the N-terminal fragment of a number of proteins containing a proline or alanine residue at the N-terminal fragment. Due to this property, DPP-4 inhibitors affect the level of bioactive peptides in the blood plasma, including the GLP-1 peptide, and are considered promising drugs for the treatment of diabetes mellitus.

For example, DPP-4 inhibitors and their use are described in WO 2002/068420, WO 2004/018467, WO 2004/018468, WO 2004/018469, WO 2004/041820, WO 2004/046148, WO 2005/051950, WO 2005/082906 , WO 2005/063750, WO 2005/085246, WO 2006/027204, WO 2006/029769, WO 2007/014886, WO 2004/050658, WO 2004/111051, WO 2005/058901, WO 2005/097798, WO 2006/068163 , WO 2007/071738, WO 2008/017670, WO 2007/128721, WO 2007/128724, WO 2007/128761 or WO 2009/121945.

Long-acting insulin, as described herein, refers to a formulation of insulin or insulin analog that typically begins to act within about 1 to 6 hours and is typically effective for up to 24 hours or more (eg, up to 36 hours). Long-acting insulin typically provides a continuous level of insulin activity (up to 24-36 hours) and usually works at peak effectiveness (flat action profile) after approximately 8-12 hours, sometimes over a longer period. Long-acting insulin is usually given in the morning or before bed. Examples of long-acting insulin may include, but are not limited to, insulin glargine, insulin detemir or insulin degludec, which are insulin analogues, and insulin ultralente, which is human insulin formulated for slow absorption. Long-acting insulin is intended to provide basal insulin, as opposed to prandial insulin, (eg, to control hyperglycemia). Long-acting insulin can usually be administered from once or twice a day to three times a week, or up to once a week (ultra-long-acting insulin). The method of administering insulin may include, but is not limited to, invasive delivery (such as, for example, parenteral administration, preferably subcutaneous injection) or non-invasive

- 2 044961 delivery (eg, such as oral, buccal/sublingual, pulmonary, intranasal or transdermal (eg, iontophoresis, sonophoresis or vesicular vehicles)), long-acting insulin for subcutaneous injection is preferred.

In one embodiment, the long-acting insulin of the present invention is any known basal insulin, preferably having a basal release profile. The basal release profile refers to the kinetics, amount, and rate of release of insulin or an insulin analogue from a formulation into the patient's systemic circulation. In a graph of a patient's plasma insulin level versus time, the basal release profile typically includes a minimal number of peaks (called a peakless or flat profile), with insulin released slowly and continuously over an extended period of time.

In another embodiment, the long-acting insulin is an acylated derivative of human insulin. In acylated insulin derivatives, the lipophilic group is attached to the lysine residue at position B29. The commercial product Levemir® includes Lys ^B29 (N ^ε tetradecanoyl) des(B30) human insulin (see insulin detemir). Another example includes No. ²⁹ -(N-(scarboxypentadecanoyl)-b-y-glutamyl)des(B30) human insulin (see insulin degludec).

In yet another embodiment, the long-acting insulin includes positively charged amino acids, such as Arg, attached to the C-terminal portion of the B chain. Commercial product Lantus® includes GlyA ²¹ , Arg ^B31 , Arg ^B32 human insulin (see insulin glargine).

Insulin glargine (brand name LANTUS® from Sanofi-Aventis) is approved for use and is available for subcutaneous administration once daily. Insulin glargine provides relatively constant glucose-lowering activity over 24 hours and can be administered at any time during the day as long as it is administered at the same time each day.

Insulin detemir (brand name LEVEMIR® from Novo Nordisk) is approved and available for subcutaneous administration twice daily or once daily, preferably at dinner or before bedtime.

Insulin degludec (NN1250) is a neutral, soluble ultra-long-acting insulin with a duration of action of more than 24 hours. Degludec has a very flat, expected and smoothed action profile. It is intended for subcutaneous administration once daily or less (eg, three times a week).

Additionally, additional examples of long-acting insulin may include, but are not limited to:

insulin lispro pegylated with high molecular weight polyethylene glycol derivatives, especially as described in WO 2009/152128 (incorporated herein by reference), such as, for example, pegylated insulin lispro of the formula P-[(A)-(B)], or a pharmaceutically acceptable formulation thereof salt wherein A is the A chain of insulin lispro, B is the B chain of insulin lispro, and P is a PEG with a molecular weight ranging from about 17.5 kDa to about 40 kDa, and where A and B are respectively attached and P is attached with a urethane a covalent bond to the s-amino group of lysine at position B28;

amidated insulin glargine, primarily in the form of Gly ^A21 , Arg ^B31 , Arg ^B32 -NH ₂ human insulin (insulin glargine amide, that is, the C-terminal fragment B of the insulin glargine chain is amidated), as described in WO 2008/006496 or WO 2008/ 006496 (incorporated herein by reference);

Lys ^B29 ( ^Nε -lithocholyl-γ-Glu)des(B30)human insulin or ^NεB29 -ω-carboxypentadecanoyl-γaminobutanoyldes(B30)human insulin, or amidated insulin analogues as described in WO 2009/087082 (incorporated herein as references), especially the analogue selected from claim 14 of the claims, or in WO 2009/087081 (incorporated here by reference), especially the analogue selected from claim 16 of the claims.

Long-acting insulin analogues are commonly prescribed for the basic antidiabetic treatment of type 2 diabetes, type 1 diabetes, or latent immunodiabetes of adults (LADA) in patients to control blood sugar levels during fasting periods. As stated above, this type of insulin provides a continuous level of insulin activity for up to 36 hours. Long-acting insulin exhibits maximum effectiveness after approximately 8-12 hours. Due to their advantages, it is believed that treatment with these insulin analogues may lead to beneficial effects, for example, a decrease in the severity of hypoglycemia, a decrease in the rate of weight gain, or improved metabolic control, which may presumably reduce the incidence of late diabetic complications such as eye, kidney, or foot problems, as well as myocardial infarction, stroke, or death. DPP-4 inhibitors are a diverse group of antidiabetic agents, but they also act by mechanisms that enhance insulin activity and are restricted to still functional β-cells to induce endogenous insulin secretion. DPP-4 inhibitors reduce glucagon levels and reduce postprandial glucose peaks during meals by increasing GLP-1 and downstream mechanisms. Due to

- 3 044961 This combination of these two principles is a promising approach for controlling effective fasting and postprandial glucose levels. In addition, as a result of the combined modes of action, glucose tolerance, improved metabolic (glycemic) status and/or prolonged efficacy can be achieved and/or maintained over an extended period of time.

Linagliptin is the only DPP-4 inhibitor that exhibits an excellent pharmacokinetic profile (e.g., half-life of up to 72 hours, stoichiometric irreversible binding to the DPP-4 protein) when administered once daily, every other day, or even over longer periods of time. . In addition, various DPP-4 substrates (eg, SDF-1, BNP) have been found to have increased half-lives and periods of action following DPP-4 inhibition and thus may provide additional beneficial effects on cardiovascular disease outcomes. Thus, the combination of linagliptin with insulin according to the present invention can be considered as an additional opportunity to reduce the intensity of late macrovascular complications.

When monitoring the treatment of diabetes mellitus, the level of glycosylated hemoglobin (HbA1c), a product of non-enzymatic glycosylation of the hemoglobin B chain, is of exceptional importance. Because the formation of HbA1c is highly dependent on blood sugar levels and the lifespan of red blood cells, the HbA1c level as a blood sugar memory reflects the average blood sugar level over the previous 4-12 weeks. Patients diagnosed with diabetes whose HbA1c levels are effectively (ie, <6.5% total hemoglobin in the sample) controlled over a long period of time through more intensive diabetes treatment are significantly more protected from diabetic microangiopathy. Known methods of treating diabetes reduce the HbA1c level in diabetics to an average of about 1.0-1.5%. This reduction in HbA1c is not sufficient for all diabetics to provide the required level of <7.0%, preferably <6.5%, and more preferably <6% HbA1c.

The term inadequate or insufficient glycemic control as used herein refers primarily to a condition in which patients have an HbA1c level of greater than 6.5%, preferably greater than 7.0%, more preferably greater than 7.5%, especially greater than 8%. In one embodiment, patients with inadequate or insufficient glycemic control include, but are not limited to, patients whose HbA1c level is from 7.5 to 10% (or in another embodiment from 7.5 to 11%). In a specific sub-option, patients with inadequate glycemic control refers to patients with poor glycemic control, including, but not limited to, patients whose HbA1c level is >9%.

For glycemic control, in addition to lowering HbA1c levels, other recommended treatment outcomes for patients diagnosed with type 2 diabetes include reducing fasting plasma glucose (FPG) and postprandial plasma glucose (PPG) levels to normal levels or, if possible, to normal levels . The recommended FPG target ranges are 70-130 mg/dL (or 90-130 mg/dL), or <110 mg/dL, and the recommended 2-hour postprandial PPG target ranges are <180 mg/dL, or <140 mg/dL. dl.

In one embodiment, patients suffering from diabetes according to the present invention may include patients who have not previously been treated with an antidiabetic drug (naïve patients). Thus, in this embodiment, the treatment described here can be used for naive patients. In another embodiment, diabetic patients of the present invention may include patients with advanced or late stage type 2 diabetes mellitus (including patients following failure of treatment with a standard antidiabetic agent), such as, for example, patients with inadequate glycemic control despite treatment with one, two or more three standard oral and/or non-oral antidiabetic drugs as described here, such as, for example, patients with inadequate glycemic control despite treatment with monotherapy with metformin, thiazolidinedione (primarily pioglitazone), sulfonylurea, glinide, GLP-1 or GLP-1 analog, insulin or insulin analog, or α-glucosidase inhibitor, or despite dual combination therapy with metformin/sulfonylurea, metformin/thiazolidinedione (primarily pioglitazone), sulfonylurea/α-glucosidase inhibitor, pioglitazone/sulfonylurea, metformin/insulin , pioglitazone/insulin or sulfonylurea/insulin. Thus, in one embodiment, the therapy described herein can be used for patients already treated with, for example, a standard oral and/or non-oral antidiabetic drug, in a monotherapy regimen or dual or triple combination therapy as described herein.

In another embodiment, patients of the present invention suffering from diabetes include patients unsuitable for treatment with metformin, including:

patients for whom treatment with metformin is contraindicated, for example, patients with one or more contraindications for treatment with metformin in accordance with the label directions for use, such as, for example, patients for whom at least one contraindication is selected from the following diseases:

kidney disease, renal failure or renal dysfunction (eg, as specified in the prescribing information for metformin approved by local health authorities), hypohydration, unstable or acute congestive heart failure, acute or chronic metabolic acidosis and hereditary galactose intolerance, and patients who suffer from one or more intolerable side effects associated with metformin, especially gastrointestinal side effects, such as, for example, patients suffering from at least one gastrointestinal side effect selected from the following symptoms:

nausea, vomiting, diarrhea, flatulence and severe abdominal discomfort.

In yet another embodiment, patients with diabetes who may be amenable to treatment according to the present invention may include, but are not limited to, patients suffering from diabetes for whom standard treatment with metformin is unacceptable, such as, for example, patients suffering from diabetes and who require reduced doses of metformin due to reduced tolerability, intolerance and contraindications to the use of metformin or due to mild renal impairment/reduced renal function (including elderly patients, for example, over 60-65 years).

In one embodiment, patients suffering from diabetes of the present invention include patients with kidney disease, renal dysfunction or renal failure or impaired renal function (including mild, moderate and severe renal impairment), for example, as evidenced by elevated creatinine levels serum creatinine levels (eg, serum creatinine levels exceed the upper limit of the normal range for a given age, e.g. >130-150 µmol/L, or >1.5 mg/dL (>136 µmol/L) in men and > 1.4 mg/dL (>124 µmol/L in women), or as indicated by abnormal creatinine clearance (eg, glomerular filtration rate (GFR) <30-60 mL/min.

Here, as a more specific example, mild renal impairment can be established, for example, by a creatinine clearance of 50-80 ml/min (approximately corresponding to serum creatinine levels <1.7 mg/dL in men and <1.5 mg/dL in women), moderate renal impairment can be determined, for example, by a creatinine clearance of 30-50 ml/min (approximately corresponding to serum creatinine levels from >1.7 to <3.0 mg/dl in men and from >1 .5 to <2.5 mg/dL in women), and severe renal impairment can be determined, for example, by creatinine clearance <30 ml/min (approximately equivalent to serum creatinine levels >3.0 mg/dL in men and >2.5 mg/dL in women). Patients with end-stage kidney disease require dialysis (eg, hemodialysis or peritoneal dialysis).

In a more detailed example, patients with kidney disease, renal dysfunction, or impaired renal function include patients with chronic renal failure or chronic renal impairment, which is classified according to glomerular filtration rate (GFR, ml/min/1.73 m ² ) into 5 grades: grade 1 is characterized by a normal GFR level (GFR >90) plus either persistent albuminuria or known structural or hereditary kidney disease; grade 2 is characterized by a slight decrease in GFR (GFR 60-89), and corresponds to mild renal dysfunction; grade 3 is characterized by a moderate decrease in GFR (GFR 30-59), and corresponds to moderate renal dysfunction; grade 4 is characterized by a significant decrease in GFR (GFR 15-29), and corresponds to severe renal impairment, and grade 5 is characterized by the need for dialysis or GFR <15, and corresponds to a stable form of renal failure (end-stage renal disease, ESRD).

In another embodiment, patients with diabetes, as described in the present invention, include patients with type 2 diabetes or at risk of developing renal complications such as diabetic nephropathy (including chronic and progressive renal failure, albuminuria, proteinuria, fluid retention (edema) ) and/or hypertension).

In yet another embodiment, patients with diabetes as described in the present invention include patients with type 1 diabetes, LADA or type 2 diabetes patients, obese or overweight patients, or non-obese or overweight patients.

The inventors of the present invention have surprisingly found that certain DPP-4 inhibitors

- 5 044961 as described in the present invention, as well as the pharmaceutical combinations, compositions or joint use of the present invention of said DPP-4 inhibitors and long-acting insulin (such as, for example, insulin glargine, insulin detemir or insulin degludec) exhibit properties that allow their use in the present invention and/or which meet one or more of the above needs.

Thus, a combination is provided containing a specific DPP-4 inhibitor (primarily BI 1356) and a long-acting insulin (such as, for example, insulin glargine, insulin detemir or insulin degludec), each of which is intended, as defined here, primarily for simultaneous , separately or sequentially used in treatment as defined herein.

Additionally, a specific DPP-4 inhibitor (primarily BI 1356) is provided in combination with a long-acting insulin (such as, for example, insulin glargine, insulin detemir or insulin degludec), each of which is described herein, for use in treatment as described herein.

The present invention provides the use of a DPP-4 inhibitor, which is linagliptin, in a method of improving glycemic control in an elderly patient with type 2 diabetes, the method comprising adding a DPP-4 inhibitor to a long-acting insulin, which is basal insulin, alone or in combination with one or more other antidiabetic drugs selected from metformin, pioglitazone and a sulfonylurea, where the patient is inadequately controlled when treated with insulin alone or in combination with one or more other antidiabetic drugs selected from metformin, pioglitazone and a sulfonylurea.

The combination described above can be used in a method of treating and/or preventing metabolic diseases, primarily type 2 diabetes mellitus and/or related conditions (for example, diabetic complications), wherein said method consists of the joint (simultaneous, separate or sequential) administration of an effective an amount of a long-acting insulin (such as, for example, insulin glargine, insulin detemir, or insulin degludec) as defined herein, and an effective amount of a DPP-4 inhibitor, as defined herein, to a patient (primarily a human) who requires said treatment, such such as the patient described here.

The combination described above can be used in at least one of the following ways:

prevention, slowing the progression, slowing the development or treatment of a metabolic disorder or disease, such as, for example, type 1 diabetes mellitus, type 2 diabetes mellitus, impaired glucose tolerance (IGT), impaired fasting blood glucose (IFG), hyperglycemia, hyperglycemia after food intake, post-absorption hyperglycemia, overweight, obesity, dyslipidemia, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, hypertension, atherosclerosis, endothelial dysfunction, osteoporosis, chronic systemic inflammation, non-alcoholic fatty liver disease (NAFLD), retinopathy, neuropathy; nephropathy, polycystic ovary syndrome and/or metabolic syndrome;

improving and/or maintaining glycemic control and/or reducing fasting plasma glucose, postprandial glucose, postabsorptive glucose and/or glycosylated hemoglobin HbA1c;

preventing, slowing, arresting or reversing the progression of prediabetes, impaired glucose tolerance (IGT), impaired fasting plasma glucose (IFG), insulin resistance and/or metabolic syndrome to type 2 diabetes mellitus;

prevention, risk reduction, slow progression, slow development or treatment of complications of diabetes mellitus such as micro- and macrovascular diseases such as nephropathy, micro- and macroalbuminuria, proteinuria, retinopathy, cataracts, neuropathy, learning or memory impairment, neurodegenerative or cognitive disorders , cardiac or cerebrovascular disease, tissue ischemia, diabetic foot or ulcer, atherosclerosis, hypertension, endothelial dysfunction, myocardial infarction, acute coronary syndrome, unstable angina, stable angina, peripheral arterial occlusive disease, cardiomyopathy, heart failure, cardiac arrhythmias, vascular restenosis and/or stroke;

reduction of body weight and/or body fat and/or liver fat and/or intramyocellular fat or prevention of increase in body weight and/or body fat and/or liver fat and/or intramyocellular fat or acceleration of weight loss and/or body fat and/or liver fat and/or intramyocellular fat;

preventing, slowing, arresting or treating degeneration of pancreatic β-cells and/or decreased functioning of pancreatic β-cells and/or improving, maintaining and/or restoring the functioning of pancreatic β-cells and/or stimulating and/or restoring or protecting function secretion of insulin by the pancreas;

preventing, slowing, stopping or treating non-alcoholic fatty liver disease

- 6 044961 (NAFLD), including hepatic steatosis, non-alcoholic steatohepatitis (NASH) and/or liver fibrosis (e.g. prevention, slow progression, arrest, symptomatic relief, treatment or reversal of hepatic steatosis, (hepatic) inflammation and/or abnormal accumulation fat in the liver);

prevention, slowdown of progression, suspension or treatment of type 2 diabetes after ineffective treatment with standard antidiabetic drugs in mono- or combination therapy;

reducing the dose of the standard antidiabetic drug required to achieve an adequate therapeutic effect;

reducing the risk of adverse effects associated with standard antidiabetic medications (eg, hyperglycemia or weight gain); and/or maintaining and/or improving insulin sensitivity and/or treating or preventing hyperinsulinemia and/or insulin resistance, in a patient in need of such treatment (such as, for example, a patient as described herein), and said method consists in combined (eg, simultaneously, separately or sequentially) administration of a DPP-4 inhibitor, as described here, and long-acting insulin, as described here.

A specific DPP-4 inhibitor (primarily BI 1356) as defined herein is provided for subcutaneous or transdermal use in the treatment described herein.

The combination described above can be used in a method of treating and/or preventing metabolic diseases, primarily type 2 diabetes mellitus and/or related conditions (eg, diabetic complications), which optionally includes administering an effective amount of a DPP-4 inhibitor, as defined herein in combination with one or more other therapeutic agents, as defined herein, to a patient (primarily a human) in need of said treatment (such as, for example, the patient described herein), wherein administration of a DPP-4 inhibitor and optionally one or more other therapeutic agents are administered parenterally, for example, subcutaneously or transdermally.

A DPP-4 inhibitor, as defined herein, is used for the preparation of a pharmaceutical composition intended for subcutaneous use in the treatment and/or prevention of metabolic diseases, disorders or conditions, such as, for example, as defined herein, primarily type 2 diabetes mellitus and/or related conditions with it (for example, diabetic complications).

The combination described above can be used in at least one of the following ways:

prevention, slow progression, arrest or treatment of a metabolic disorder or disease such as, for example, type 1 diabetes mellitus, type 2 diabetes mellitus, impaired glucose tolerance (IGT), impaired fasting blood glucose (IFG), hyperglycemia, hyperglycemia after post-absorption hyperglycemia, overweight, obesity, dyslipidemia, hyperlipidemia, hypercholesterolemia, hypertension, atherosclerosis, endothelial dysfunction, osteoporosis, chronic systemic inflammation, non-alcoholic fatty liver disease (NAFLD), retinopathy, neuropathy, nephropathy, polycystic ovary syndrome and /or metabolic syndrome;

improving and/or maintaining glycemic control and/or reducing fasting plasma glucose, postprandial plasma glucose, postabsorption and/or glycosylated hemoglobin HbA1c;

preventing, slowing, arresting or reversing the progression of a condition from a prediabetic state, impaired glucose tolerance (IGT), impaired fasting blood glucose (IFG), insulin resistance and/or metabolic syndrome to type 2 diabetes mellitus;

prevention, risk reduction, slow progression, arrest or treatment of complications of diabetes mellitus such as micro- and macrovascular diseases such as nephropathy, micro- or macroalbuminuria, proteinuria, retinopathy, cataracts, neuropathy, learning or memory impairment, neurodegenerative or cognitive impairment , cardiovascular or cerebrovascular disease, tissue ischemia, diabetic foot or ulcer, atherosclerosis, hypertension, endothelial dysfunction, myocardial infarction, acute coronary syndrome, unstable angina, stable angina, peripheral arterial occlusive disease, cardiomyopathy, heart failure, cardiac arrhythmias , vascular restenosis and/or stroke;

reduction of body weight and/or body fat and/or liver fat and/or intramyocellular fat or prevention of increase in body weight and/or body fat and/or liver fat and/or intramyocellular fat or acceleration of weight loss and/or body fat and/or liver fat and/or intramyocellular fat;

prevention, slowing, suspension or treatment of degeneration of pancreatic β-cells and/or decrease in the functioning of pancreatic β-cells and/or improvement and/or restoration of the functioning of pancreatic β-cells and/or stimulation and/or restoration or protecting the functioning of insulin secretion by the pancreas;

preventing, slowing, reversing, or treating non-alcoholic fatty liver disease (NAFLD), including hepatic steatosis, non-alcoholic steatohepatitis (NASH), and/or liver fibrosis (e.g., preventing, slowing the progression, stopping, reducing symptoms, treating, or reversing hepatic steatosis, ( hepatic) inflammation and/or abnormal accumulation of fat in the liver);

prevention, slowdown of progression, suspension or treatment of type 2 diabetes after ineffective treatment with standard antidiabetic drugs in mono- or combination therapy;

reducing the dose of the standard antidiabetic drug required to achieve an adequate therapeutic effect;

reducing the risk of adverse effects associated with a standard antidiabetic drug (eg, hypoglycemia or weight gain; and/or maintaining and/or improving insulin sensitivity and/or treating or preventing hyperinsulinemia and/or insulin resistance, in a patient requiring specified treatment (such as, for example, the patient described herein), said method involves parenteral, preferably subcutaneous or transdermal administration of a DPP-4 inhibitor as defined herein, optionally in combination with one or more other therapeutic agents as defined herein.

A combination comprising a DPP-4 inhibitor, as defined herein, and long-acting insulin, as defined herein, can be used for parenteral, especially subcutaneous or transdermal administration, of one or both active components to a patient in need of said treatment.

A composition comprising a DPP-4 inhibitor as defined herein, a long-acting insulin as defined herein, and optionally one or more pharmaceutically acceptable carriers and/or diluents can be used for subcutaneous administration to a patient in need of said treatment, for example by injection.

A combination comprising a DPP-4 inhibitor, as defined herein, and long-acting insulin, as defined herein, can be used for use in the treatment and/or prevention (including slowing the progression or delaying the development) of metabolic diseases, as defined herein, primarily diabetes ( primarily type 2 diabetes or related conditions, including complications of diabetes), optionally in combination with one or more other therapeutic agents as described herein.

It is also possible to use a combination comprising a DPP-4 inhibitor, as defined herein, and long-acting insulin, as defined herein, to produce a medicament for use in a method of treatment, as defined herein.

A combination comprising a DPP-4 inhibitor, as defined herein, and long-acting insulin, as defined herein, can be used for use in a method of treatment, as defined herein.

The combination described above can be used in a method of treating and/or preventing (including slowing the progression or delaying the development) of metabolic diseases, especially diabetes (especially type 2 diabetes) or related conditions, including complications of diabetes, which method includes administering to a patient in need of said treatment (such as, for example, the patient described herein), a combination of the present invention comprising a DPP-4 inhibitor, as defined herein, and long-acting insulin, as defined herein.

A DPP-4 inhibitor, as defined herein, can be used for use in a method as described herein, which method comprises administering to a patient a DPP-4 inhibitor, optionally in conjunction with one or more other active compounds (e.g., selected from those herein, such as as metformin or pioglitazone), in combination (eg, separately, simultaneously or sequentially) with a long-acting insulin, as defined herein.

In addition, long-acting insulin, as defined herein, can be used for use in a method as described herein, which method includes administering long-acting insulin to a patient, optionally in conjunction with one or more other active compounds (e.g., selected from those specified herein, such as eg, metformin or pioglitazone) in combination (eg, separately, simultaneously or sequentially) with a DPP-4 inhibitor as defined herein.

A DPP-4 inhibitor, as defined herein, can be used to prepare a medicament for use in combination with a long-acting insulin, as defined herein, for the treatment and/or prevention (including slowing the progression or slowing the development) of metabolic diseases , especially diabetes (especially type 2 diabetes) and related conditions, including complications of diabetes.

In addition, the use of long-acting insulin, as defined herein, can be used to prepare a medicament for use in combination with a DPP-4 inhibitor, as defined herein, for the treatment and/or prevention (including slowing the progression or delaying the development) of metabolic diseases, primarily diabetes (especially type 2 diabetes) and related conditions, including complications of diabetes.

A DPP-4 inhibitor, as defined herein, optionally in combination with one or more other active compounds (such as, for example, metformin or pioglitazone), can be used to prepare a medicament for use in combination with a long-acting insulin, as defined herein , for the treatment and/or prevention (including slowing the progression or delaying the development) of metabolic diseases, primarily diabetes (especially type 2 diabetes) and related conditions, including complications of diabetes.

The present invention further provides a DPP-4 inhibitor, as defined herein, for use in the combination treatment of the present invention for a patient in need of said treatment (eg, such a patient as described herein).

The present invention also provides long-acting insulin, as defined herein, for use in the combination treatment of the present invention for a patient in need of said treatment (eg, such a patient as described herein).

In addition, the present invention provides a DPP-4 inhibitor, as defined herein, optionally in combination with one or more other active compounds (such as, for example, metformin or pioglitazone), for use in the combination treatment of the present invention, a patient in need of the specified treatment.

The present invention also provides a DPP-4 inhibitor, as defined herein, for use in a method as described herein, which method comprises administering to a patient a DPP-4 inhibitor, as defined herein, optionally in combination with one or more other active compounds (eg , selected from those listed here, such as metformin or pioglitazone).

A DPP-4 inhibitor, as defined herein, can be used for use in a method of preventing, reducing the risk of, slowing the progression or delaying the development of, or treating weight gain associated with long-acting insulin treatment, as defined herein, and preferably, said method includes administering a DPP inhibitor -4 and long-acting insulin to a patient (eg, a patient with type 1 diabetes, LADA, or especially a patient with type 2 diabetes, with or without obesity or overweight).

A DPP-4 inhibitor, as defined herein, can be used for use in a method of preventing, reducing the risk of, slowing the progression or delaying the development of, or treating increases in body weight and/or body fat and/or liver fat and/or intramyocellular fat associated with long-acting insulin treatment as defined herein, and preferably said method comprises administering a DPP-4 inhibitor and long-acting insulin to a patient (for example, a patient with type 1 diabetes, LADA, or especially a patient with type 2 diabetes who is obese or overweight or without them).

A DPP-4 inhibitor, as defined herein, can be used for use in a method of improving body fat composition and/or obesity parameters associated with treatment with long-acting insulin, as defined herein, and preferably, said method includes administering a DPP-4 inhibitor and long-acting insulin actions to the patient (for example, with type 1 diabetes, LADA, or especially a patient with type 2 diabetes, with or without obesity or overweight).

The DPP-4 inhibitor and long-acting insulin, each as defined herein, can be used for use in a method of improving the diabetic phenotype, improving glycemic and/or metabolic control, improving the (blood) glucose profile (e.g., improving control of fasting glucose levels and/or postprandial blood) and/or improving glucagon suppression (eg, long-term and/or long-term treatment), and preferably said method includes administering a DPP-4 inhibitor and long-acting insulin to a patient (eg, a patient with type 1 diabetes, LADA or especially a patient with type 2 diabetes, with or without obesity or overweight).

A DPP-4 inhibitor, as defined herein, can be used for use in a method of providing an effective dose reduction or reduction in the amount of long-acting insulin, as defined herein, required for effective and/or safe treatment, the method comprising administering a DPP-4 inhibitor and insulin long-acting patient (eg, a patient with type 1 diabetes, LADA, or especially a patient with type 2 diabetes, with or without obesity or overweight).

A DPP-4 inhibitor, as defined herein, can be used for use in a method of treatment or prevention as described herein, said use including the addition of an inhibitor

- 9 044961

DPP-4 to long-acting insulin, as defined herein, alone or in combination with one or more other antidiabetic drugs (eg, selected from metformin, pioglitazone and sulfonylurea), for example, to improve glycemic control in a patient (eg, a patient with type 2 diabetes 1, LADA or especially with type 2 diabetes, with or without obesity or overweight) who may experience inadequate control when treated with insulin alone or in combination with one or more other antidiabetic drugs (for example, those selected from metformin, pioglitazone and sulfonylurea).

A DPP-4 inhibitor and long-acting insulin, as defined herein, can be used for use in a method of treatment or prevention as described herein, which use includes adding a DPP-4 inhibitor and long-acting insulin to one or more other antidiabetic drugs (eg , selected from metformin, pioglitazone and sulfonylurea), for example to improve glycemic control in a patient (for example, with type 1 diabetes, LADA or especially with type 2 diabetes, with or without obesity or overweight) who may have inadequate control during treatment with one or more other antidiabetic drugs (eg, those selected from metformin, pioglitazone and sulfonylureas).

A long-acting insulin, as defined herein, can be used for use in a method of treatment or prevention as described herein, wherein said use comprises adding the long-acting insulin to a DPP-4 inhibitor, as defined herein, alone or in combination with one or more other antidiabetic agents. drugs (eg, selected from metformin, pioglitazone and sulfonylureas), for example to improve glycemic control in a patient (eg, with type 1 diabetes, LADA or especially type 2 diabetes, with or without obesity or overweight), in which may be inadequately controlled when treated with a DPP-4 inhibitor alone or in combination with one or more other antidiabetic drugs (eg, those selected from metformin, pioglitazone and sulfonylureas).

The present invention also provides a combination or composition comprising a DPP-4 inhibitor and a long-acting insulin, each as defined herein, for use in treatment and/or prophylaxis as described herein, optionally in combination with one or more other therapeutic agents.

The present invention further provides a DPP-4 inhibitor, as defined herein, with or without metformin and/or pioglitazone, in combination with a long-acting insulin, as defined herein, for use in treatment or prophylaxis, as described herein.

The present invention also provides a DPP-4 inhibitor, as defined herein, in combination with a long-acting insulin, as defined herein, with or without metformin, for use in a method of treatment or prophylaxis as described herein.

Other aspects of the present invention will be apparent to one skilled in the art in view of the notes presented herein (including examples and claims).

The objects of the present invention, primarily pharmaceutical compounds, combinations, compositions, methods and uses relate to DPP-4 inhibitors and/or long-acting insulins, as defined herein.

A DPP-4 inhibitor as defined herein includes, but is not limited to, any of the DPP-4 inhibitors defined herein, preferably the orally and/or subcutaneously active DPP-4 inhibitors.

In one embodiment, the present invention provides a DPP-4 inhibitor for use in the treatment and/or prevention of metabolic diseases (primarily type 2 diabetes mellitus) in patients with type 2 diabetes, wherein said patients also suffer from renal disease, renal dysfunction or renal failure and said use is primarily characterized in that said DPP-4 inhibitor is administered to said patients at the same doses as those administered to patients with normal renal function, and thus does not require dose reduction optimization of the DPP-4 inhibitor for the treatment of patients with impaired renal function kidney

For example, a DPP-4 inhibitor of the present invention (primarily useful for the treatment of patients with impaired renal function) is an oral DPP-4 inhibitor that itself and the active metabolites of which are preferably characterized by a relatively broad spectrum (eg, approximately >100- multiple) therapeutic window and/or, primarily, which are eliminated mainly through hepatic metabolism or biliary excretion (preferably without additional load on the kidneys).

More specifically, the DPP-4 inhibitor of the present invention (primarily for patients with impaired renal function) is an orally administered DPP-4 inhibitor that has a relatively wide (eg, >100-fold) therapeutic window (preferably a safety profile comparable to placebo) and/or which is characterized by one or more of the following pharmacokinetic properties (preferably when administered its therapeutic

- 10 044961 oral doses):

the DPP-4 inhibitor is substantially or predominantly eliminated via the liver (e.g., >80% or even >90% of an administered oral dose), and/or renal excretion of the inhibitor represents little or only a minor route of elimination (e.g., <10%, preferably <7% of the administered oral dose, as determined, for example, by the elimination assay of a radiocarbon ( ¹⁴ C) labeled compound (after oral dosing), the DPP-4 inhibitor is eliminated largely unchanged as the parent drug (after an oral dose of a compound labeled with radiocarbon ( ¹⁴ C) is excreted in urine and feces, for example, on average >70%, or >80%, or preferably 90% of the radioactivity), and/or which has little or less substantially eliminated by metabolism (e.g. <30%, or <20%, or preferably 10%), the (major) metabolite(s) of the DPP-4 inhibitor is/are pharmacologically inactive, namely e.g. , the major metabolite does not bind to the DPP-4 enzyme target and is not necessarily rapidly cleared relative to the parent compound (eg, the terminal half-life of the metabolite is <20 hours, or preferably approximately <16 hours, e.g., 15.9 hours).

In one embodiment, the plasma (major) metabolite (which may not have pharmacological activity) of a DPP-4 inhibitor that contains 3-aminopiperidin-1-yl as a substituent is a derivative in which the amino group of 3-aminopiperidin-1-yl is substituted to the hydroxyl group, thereby forming a 3-hydroxypiperidin-1-yl residue (for example, a 3-(S)-hydroxypiperidin-1-yl residue, which is formed by inverting the configuration of the chiral center).

Other properties of the DPP-4 inhibitor of the present invention include one or more of the following: rapid achievement of steady state (e.g., achievement of steady state plasma concentrations (>90% of steady state plasma concentrations from day 2 to day 5 treatment at therapeutic oral doses), low levels of accumulation (e.g., mean accumulation coefficient RA,A _UC <1.4 at therapeutic oral doses), and/or maintenance of a long-lasting effect of DPP-4 inhibition, preferably when administered once daily (e.g. with almost complete (>90%) inhibition of DPP-4 at therapeutic oral doses, >80% inhibition within 24 hours of once daily therapeutic oral dosing), significant reduction (>80%) in the degree of change in glucose fluctuations in the blood within 2 hours after a meal (as early as day 1 of treatment) at therapeutic doses, as well as an excretion of a total amount of unchanged parent compound in urine on day 1 that is less than 1% of the administered dose, and an increase in glucose levels of no more than approximately 3-6% in a stable state.

Thus, for example, a DPP-4 inhibitor of the present invention is characterized in that said DPP-4 inhibitor is substantially excreted via the kidneys to a minor or less significant extent (e.g., <10%, preferably <7% of an administered oral dose, as defined , for example, according to the analysis of the elimination of a radioactive carbon ( ¹⁴ C) labeled compound (after administration of an oral dose)).

In addition, the DPP-4 inhibitor of the present invention is characterized in that said DPP-4 inhibitor is eliminated to a large extent or mainly through the liver or feces (as determined, for example, by an excretion assay of a radioactive carbon ( ¹⁴ C) compound ( after administration of an oral dose).

In addition, the DPP-4 inhibitor of the present invention is characterized in that said DPP-4 inhibitor is excreted substantially unchanged as the parent drug (for example, after an oral dose of a radiocarbon ( ¹⁴ C)-labeled compound in the urine and excreted in feces at an average level of >70%, or >80%, or preferably 90% of the radioactivity), with said DPP-4 inhibitor being excreted to a minor or only a lesser extent by metabolism, and/or the major metabolite of said DPP-4 inhibitor 4 is pharmacologically inactive or has a relatively wide therapeutic window.

In addition, the DPP-4 inhibitor of the present invention may be characterized in that the DPP-4 inhibitor does not significantly impair glomerular and/or tubular function in patients with type 2 diabetes with chronic renal failure (for example, with mild, moderate or severe renal impairment or end-stage renal disease), and/or plasma trough levels of the specified DPP-4 inhibitor in patients with type 2 diabetes with mild or moderate renal impairment are comparable to levels in patients with normal renal function, and/or in patients with type 2 diabetes with impaired renal function (eg, moderate to severe renal impairment or end-stage renal disease, preferably

- 11 044961 regardless of the stage of renal dysfunction) do not require optimization of the dose of the specified inhibitor

DPP-4.

In addition, the DPP-4 inhibitor of the present invention is characterized in that the DPP-4 inhibitor at the minimum effective dose inhibits >50% of DPP-4 activity (24 hours after the last dose) in >80% of patients, and/or in A full therapeutic dose of the indicated DPP-4 inhibitor inhibits >80% of DPP-4 activity at least (24 hours after the last dose) in >80% of patients.

In addition, the DPP-4 inhibitor of the present invention may be characterized in that it may be used to treat patients with type 2 diabetes who have been diagnosed with impaired renal function and/or who are at risk of developing renal complications, e.g. diabetic nephropathy (including chronic and progressive renal failure, albumiruria, proteinuria, fluid retention (edema) and/or hypertension).

The DPP-4 inhibitor (Option A), as described herein, is any DPP-4 inhibitor of formula (I)

ST N

About N\

I CN or formula (II) or formula (III) or formula (IV) where R1 is ([1,5]naphthyridin-2-yl)methyl, (quinazolin-2-yl)methyl, (quinoxalin-6-yl) methyl, (4-methylquinazolin-2-yl)methyl, 2-cyanobenzyl, (3-cyanoquinolin-2-yl)methyl, (3-cyanopyridin-2-yl)methyl, (4-methylpyrimidin-2-yl)methyl or (4 ,6-dimethylpyrimidin-2-yl)methyl, and R2 is 3(R)-aminopiperidin-1-yl, (2-amino-2-methylpropyl)methylamino group or (2-(S)-aminopropyl)methylamino group, or their pharmaceutical acceptable salt.

The DPP-4 inhibitor (Option B) as described herein is selected from the group consisting of sitagliptin, vildagliptin, saxagliptin, alogliptin, gemigliptin, (2S)-1-{[2-(5-methyl-2-phenyloxazol-4yl)ethylamino ]acetyl}pyrrolidine-2-carbonitrile, (2S)-1-{[1,1-dimethyl-3-(4-pyridin-3-ylimidazol-1yl)propylamino]acetyl}pyrrolidine-2-carbonitrile, (S) -1 -((2S,3S,11bS)-2-amino-9,10-dimethoxy-1,3,4,6,7,11 b-hexahydro-2H-pyrido[2,1-a]isoquinolin3-yl )-4-fluoromethylpyrrolidin-2-one, (3,3-difluoropyrrolidin-1-yl)-((2S,4S)-4-(4-(pyrimidin-2-yl)piperazin-1-yl)pyrrolidin-2 -yl)methanone, (1 -((3 S,4S)-4-amino-1 -(4-(3,3-difluoropyrrolidin-1 -yl)-1,3,5-triazin-2-yl)pyrrolidine -3 -yl)-5,5difluoropiperidin-2-one, (2S,4S)-1-{2-[(3S,1R)-3-(1H-1,2,4-triazol-1-ylmethyl)cyclopentylamino ]-acetyl}-4-fluoropyrrolidine-2-carbonitrile, (R)-2-[6-(3-aminopiperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H- pyrimidin-1-ylmethyl]-4fluorobenzonitrile, bis-dimethylamide 5-{(S)-2-[2-((S)-2-cyanopyrrolidin-1-yl)-2-oxoethylamino]propyl}-5-(1H -tetrazol-5-yl)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene-2,8-dicarboxylic acid,

3-{(2S,4S)-4-[4-(3-methyl-1-phenyl-1 H-pyrazol-5-yl)piperazin-1 -yl]pyrrolidin-2-ylcarbonyl}thiazolidine,

[(2R)-1-{[(3R)-pyrrolidin-3-ylamino]acetyl}pyrrolidin-2-yl]boronic acid, (2S,4S)-1-[2-[(4-ethoxycarbonylbicyclo[2.2.2 ]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile,

2-({6-[(3R)-3-amino-3-methylpiperidin-1-yl]-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydro-5H-pyr- 12 044961 rolo[3,2-b]pyrimidin-5-yl}methyl)-4-fluorobenzonitrile,

6-[(3 R)-3-aminopiperidin-1 -yl]-5 -(2-chloro-5-fluorobenzyl)-1,3-dimethyl-1, 5-dihydropyrrolo[3,2b]pyrimidine-2,4 -dione and {2-[(2-cyanopyrrolidin-1 -yl)-2-oxoethylamino]-2-methylpropyl}amide (S)-2-methylpyrazolo[1,5a]pyrimidine-6-carboxylic acid, or a pharmaceutically acceptable compound thereof salt.

According to the first option (Option A), preferred DPP-4 inhibitors are any or all of the following compounds and their pharmaceutically acceptable salts:

1-[(4-methylquinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-aminopiperidin-1-yl)xanthine (see for example, WO 2004/018468, example 2(142)):

1-[([1,5]naphthyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-aminopiperidin-1-yl)xanthine (see for example WO 2004/018468, example 2(252)):

1-[(quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-aminopiperidin-1-yl)xanthine (see e.g. , WO 2004/018468, example 2(80)):

2-((R)-3-aminopiperidin-1-yl)-3-(but-2-ynyl)-5-(4-methylquinazolin-2-ylmethyl)-3,5-dihydroimidazo[4,5-b] pyridazin-4-one (see, for example, WO 2004/050658, example 136):

1-[(4-methylquinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(2-amino-2-methylpropyl)methylamino]xanthine (see, for example WO 2006/029769, example 2(1)):

-[(3 -cyanoquinolin-2-yl)methyl]-3 -methyl-7-(2-butyn-1 -yl)-8-((R)-3 -aminopiperidin-1 -yl)xanthine (see, for example WO 2005/085246, example 1(30)):

1-(2-cyanobenzyl)-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-aminopiperidin-1-yl)xanthine (see, for example, WO 2005/085246 , example 1(39)):

1-[(4-methylquinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(S)-(2-aminopropyl)methylami- 13 044961 no]xanthine (see for example WO 2006/029769 example 2(4)):

-[(3-cyanopyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-((R)-3-aminopiperidin-1 -yl)xanthine (see, for example WO 2005/085246, example 1(52)):

-[(4-methylpyrimidin-2-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-((R)-3-aminopiperidin-1 -yl)xanthine (see, for example WO 2005/085246, example 1(81)):

1-[(4,6-dimethylpyrimidin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-aminopiperidin-1 yl)xanthine (cm ., for example, WO 2005/085246, example 1(82)):

1-[(quinoxalin-6-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((K)-3-aminopiperidin-1-yl)xanthine (see, for example , WO 2005/085246, example 1(83)):

These DPP-4 inhibitors differ from structurally related DPP-4 inhibitors in that they are both extremely potent and long lasting, as well as favorable pharmaceutical properties, receptor selectivity and a favorable side effect profile, or exhibit unexpected benefits or improvements in treatment in combinations with other pharmaceutically active compounds. These publications describe the preparation of such inhibitors.

A more preferred DPP-4 inhibitor among the above-mentioned DPP-4 inhibitors in Embodiment A of the present invention is 1-[(4-methylquinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1yl)-8- (3-(R)-aminopiperidin-1-yl)xanthine, primarily in the free base form (also known as linagliptin or BI 1356).

The following DPP-4 inhibitors may be mentioned:

sitagliptin (MK-0431) of structural formula A below is (3R)-3amino-1-[3-(trifluoromethyl)-5,6,7,8-tetrahydro-5H-[1,2,4]triazolo [4,3-a]pyrazin-7-yl]-4-(2,4,5-trifluorophenyl)butan-1-one, another name is (2R)-4-oxo-4-[3-(trifluoromethyl)- 5,6-dihydro[1,2,4]triazolo[4,3a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine,

In one embodiment, sitagliptin is in the form of dihydrogen phosphate, i.e. sitagliptin phosphate. In another embodiment, sitagliptin phosphate is in anhydrous crystalline or monohydrate form. In one embodiment, sitagliptin phosphate monohydrate is provided. Sitagliptin in free base form and its pharmaceutically acceptable salts are described in US 6699871 and WO 03/004498, Example 7. Crystalline sitagliptin phosphate monohydrate is described in WO 2005/003135 and WO

- 14 044961

2007/050485.

Detailed information, for example, a description of the method of obtaining, processing or using the specified compound or its salt is given in the specified documents.

Tablet formulations containing sitagliptin are commercially available under the trade name Januvia®. Tablets containing the sitagliptin/metformin combination are commercially available under the trade name Janumet®.

Vildagliptin (LAF-237) of structural formula B below is (2S){[(3-hydroxyadamantan-1-yl)amino]acetyl}-pyrrolidine-2-carbonitrile, also known as (S)-1-[( 3hydroxy-1-adamantyl)amino]acetyl-2-cyanopyrrolidine,

X o

^0H (V)

Vildagliptin is described in detail in US 6166063 and WO 00/34241, example 1. Some salts of vildagliptin are described in WO 2007/019255. The crystalline form of vildagliptin, as well as vildagliptin in tablet form, are described in WO 2006/078593. Methods for processing vildagliptin are described in WO 00/34241 or WO 2005/067976. The modified release formulation of vildagliptin is described in WO 2006/135723.

Detailed information, for example, a description of the method of preparation, processing and use of the specified compound or its salt is given in the specified documents.

It is planned to release a tablet formulation of vildagliptin as a commercial product under the trade name Galvus®. The vildagliptin/metformin combination tablet formulation is available commercially under the trade name Eucreas®.

Saxagliptin (BMS-477118) of structural formula C below is (1 S,3S,5S)-2-{(2S)-2-amino-2-(3-hydroxyadamantan-1-yl)acetyl}-2 -azabicyclo[3.1.0]hexane-3-carbonitrile, another name is (S)-3-hydroxyadamantylglycine-L-cis-4,5-methanoprolinenitrile,

N d N y_X/ ^νη _2γ τ^ iii ⁰ but N (C)

Saxagliptin is described in detail in US 6395767 and in WO 01/68603, example 60.

In one embodiment, saxagliptin in hydrochloride or monobenzoate form is described in WO 2004/052850. In another embodiment, saxagliptin is in free base form. In yet another embodiment, saxagliptin in the form of a free base monohydrate is described in WO 2004/052850. Crystalline forms of saxaliptin hydrochloride and free base are described in WO 2008/131149. The method for producing saxagliptin is also described in WO 2005/106011 and WO 2005/115982. The preparation of saxagliptin in tablet form is described in WO 2005/117841.

Detailed information, for example, a description of the method of obtaining, processing or using the specified compound or its salt is given in the specified documents.

Alogliptin (SYR-322) of structural formula E below is 2-({6[(3R)-3-aminopiperidin-1-yl]-3-methyl-2,4-dioxo-3,4-dihydro- 2H-pyrimidin-1-yl}methyl)benzonitrile

(E) .

Alogliptin is described in detail in US 2005/261271, EP 1586571 and WO 2005/095381.

In one embodiment, alogliptin in the form of a benzoate, hydrochloride or tosylate is described in WO 2007/035629. In one embodiment of the present invention, alogliptin benzoate is provided. Polymorphic forms of alogliptin benzoate are described in WO 2007/035372. The method for producing alogliptin is described in WO 2007/112368 and in more detail in WO 2007/035629. Alogliptin in tablet form (namely benzoate form) can be formulated into tablets and administered as described in WO 2007/033266. Solid composition

- 15 044961 alogliptin/pioglitazone and its preparation and use are described in WO 2008/093882. The solid composition of alogliptin/metformin and its preparation and use are described in WO 2009/011451.

Detailed information, for example, a description of the method of obtaining, processing or using the specified compound or its salt is given in the specified documents.

(2S)-1-{[2-(5-Methyl-2-phenyloxazol-4-yl)ethylamino]acetyl}pyrrolidine-2-carbonitrile or a pharmaceutically acceptable salt thereof, preferably mesylate, or (2S)-1-{[ 1,1-dimethyl-3-(4-pyridin-3-ylimidazol-1-yl)propylamino]-acetyl}pyrrolidine-2-carbonitrile or a pharmaceutically acceptable salt thereof.

These compounds and methods for their preparation are described in WO 03/037327.

The mesylate of the first compound mentioned above, as well as its crystalline polymorphs, are described in WO 2006/100181. The fumarate of the second of the above compounds, as well as its crystalline polymorphs, are described in WO 2007/071576. These compounds can be processed into pharmaceutical compositions as described in WO 2007/017423.

Detailed information, for example, a description of the method of obtaining, processing or using the specified compound or its salt is given in the specified documents.

(S)-1-((2S,3S,11bS)-2-Amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline3 -yl)-4-fluoromethylpyrrolidin-2-one (also known as carmegliptin) or a pharmaceutically acceptable salt thereof:

This compound and methods for its preparation are described in WO 2005/000848. The method for obtaining the said compound (primarily its dihydrochloride) is also described in WO 2008/031749, WO 2008/031750 and WO 2008/055814. Said compound can be processed into a pharmaceutical composition as described in WO 2007/017423.

Detailed information, for example, a description of the method of obtaining, processing or using the specified compound or its salt is given in the specified documents.

(3,3-Difluoropyrrolidin-1-yl)-((2S,4S)-4-(4-(pyrimidin-2-yl)piperazin-1-yl)pyrrolidin-2-yl)methanone (also known as gosogliptin) or its pharmaceutically acceptable salt.

This compound and methods for its preparation are described in WO 2005/116014 and US 7291618.

Detailed information, for example, a description of the method of obtaining, processing or using the specified compound or its salt is given in the specified documents.

(1-((3S,4S)-4-Amino-1-(4-(3,3-difluoropyrrolidin-1-yl)-1,3,5-triazin-2-yl)pyrrolidin-3-yl)- 5,5difluoropiperidin-2-one or a pharmaceutically acceptable salt thereof.

The specified compound and methods for its preparation are described in WO 2007/148185 and US 20070299076. Detailed information, for example, a description of the method of preparation, processing or use of the specified compound or its salt is given in these documents.

(2S,4S)-1 - {2-[(3S,1 R)-3 -(1H-1,2,4-Triazol-1-ylmethyl)cyclopentylamino]-acetyl}-4-fluoropyrrolidine-2-carbonitrile ( also known as melogliptin) or a pharmaceutically acceptable salt thereof.

This compound and methods for its preparation are described in WO 2006/040625 and WO 2008/001195. Primarily, the salts described include methanesulfonate and p-toluenesulfonate. Detailed information, for example, a description of the method of obtaining, processing or using the specified compound or its salt is given in the specified documents.

(R)-2-[6-(3-Aminopiperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl]-4fluorobenzonitrile or a pharmaceutically acceptable salt thereof .

- 16 044961

The specified compound, methods for its preparation and use are described in WO 2005/095381, US

2007060530, WO 2007/033350, WO 2007/035629, WO 2007/074884, WO 2007/112368, WO 2008/033851,

WO 2008/114800 and WO 2008/114807. Primarily the salts described include succinate (WO

2008/067465), benzoate, benzenesulfonate, p-toluenesulfonate, (R)-mandelate and hydrochloride. Detailed information, for example, a description of the method of obtaining, processing or using the specified compound

nia or its salts are given in the specified documents.

bis-Dimethylamide 5-{(S)-2-[2-((S)-2-cyanopyrrolidin-1-yl)-2-oxoethylamino]propyl}-5-(1H-tetrazol-5-yl)-10, 11-dihydro-5H-dibenzo[a,d]cycloheptene-2,8-dicarboxylic acid or a pharmaceutically acceptable salt thereof.

This compound and methods for its preparation are described in WO 2006/116157 and US 2006/270701. Detailed information, such as a description of the method of preparation, processing and use of the specified compound or its salt, is given in the specified documents.

3-{(2S,4S)-4-[4-(3-Methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl]pyrrolidin-2-ulcarbonyl}thiazolidine (also known as teneligliptin) or its pharmaceutically acceptable salt.

This compound and methods for its preparation are described in WO 02/14271. Certain salts are described in WO 2006/088129 and WO 2006/118127 (including hydrochloride, hydrobromide, among others). Combination therapy using the specified compound is described in WO 2006/129785. Detailed information, such as a description of the method of preparation, processing or use of the specified compound or its salt, is given in the specified documents.

[(2R)-1-{[(3R)-Pyrrolidin-3-ylamino]acetyl}pyrrolidin-2-yl]boronic acid (otherwise known as dutogliptin) or a pharmaceutically acceptable salt thereof.

This compound and methods for its preparation are described in WO 2005/047297, WO 2008/109681 and WO 2009/009751. Some salts are described in WO 2008/027273 (including citrate, tartrate). The composition of said compound is described in WO 2008/144730. A composition containing dutogliptin (as its tartrate) and metformin is described in WO 2009/091663. Detailed information, for example, a description of the method of obtaining, processing or using the specified compound or its salt is given in the specified documents.

(2S,4S)-1-[2-[(4-Ethoxycarbonylbicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (otherwise known as bisegliptin) or a pharmaceutically acceptable salt thereof.

This compound and methods for its preparation are described in WO 2005/075421, US 2008/146818 and WO 2008/114857. Detailed information, for example, a description of the method of obtaining, processing or using the specified compound or its salt is given in the specified documents.

2-({6-[(3K)-3-Amino-3-methylpiperidin-1-yl]-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydro-5H-pyrrolo[ 3,2-b]pyrimidin-5-yl}methyl)-4-fluorobenzonitrile or a pharmaceutically acceptable salt thereof, or 6-[(3R)-3-aminopiperidin-1-yl]-5-(2-chloro-5- fluorobenzyl)-1,3-dimethyl-1,5-dihydropyrrolo[3,2-d]pyrimidine-2,4-dione or a pharmaceutically acceptable salt thereof.

These compounds and methods for their preparation are described in WO 2009/084497 and WO 2006/068163, respectively. Combination therapy using the second of the above two compounds is described in WO 2009/128360. Detailed information, for example, a description of the method of obtaining the processing or use of the specified compound or its salt is given in the specified documents.

{2-[(2-Cyanopyrrolidin-1-yl)-2-oxoethylamino]-2-methylpropyl}amide (8)-2-methylpyrazolo[1,5a]pyrimidine-6-carboxylic acid (also called anagliptin) or its pharmaceutical acceptable salt.

This compound and methods for its preparation are described in WO 2004/067509. Combination therapy using the specified compound is described in WO 2009/139362. Detailed information, for example, a description of the method of obtaining, processing or using the specified compound or its salt is given in the specified documents.

- 17 044961

Preferably, the DPP-4 inhibitor is selected from the group (Group G1) consisting of linagliptin, sitagliptin, vidagliptin, alogliptin, saxagliptin, teneligliptin, anagliptin, gemigliptin and dutogliptin, or a pharmaceutically acceptable salt of one of these DPP-4 inhibitors or a prodrug thereof.

The most preferred DPP-4 inhibitor of the present invention is linagliptin. The term linagliptin as used herein includes linagliptin or a pharmaceutically acceptable salt thereof, including hydrates and solvates thereof and crystalline forms thereof, preferably the term linagliptin means 1-[(4-methylquinazolin-2-yl)methyl]-3-methyl-7-( 2-butyn-1-yl)-8-(3-(R)aminopiperidin-1-yl)xanthine. Crystal forms are described in WO 2007/128721. Methods for the production of linagliptin are described, for example, in WO 2004/018468 and WO 2006/048427. Linagliptin differs from structurally related DPP-4 inhibitors in that it is both exceptionally potent and long-acting with favorable pharmacological properties, receptor selectivity, and a favorable side effect profile, or provides unexpected therapeutic benefits or improved efficacy over the course of treatment in the regimen. monotherapy or double or triple combination therapy.

To avoid any uncertainty, the documents cited herein that describe the above DPP-4 inhibitors are incorporated herein by reference in their entirety.

Long-acting insulin as described herein includes, but is not limited to, any long-acting insulin as described herein, preferably long-acting insulin that is active when administered subcutaneously.

Examples of long-acting insulins may include (G2): insulin glargine, insulin detemir, insulin degludec, insulin lispro derivatives pegylated with high molecular weight polyethylene glycol as described in WO 2009/152128, amidated insulin glargine in the form of Gly ^A21 , Arg ^B31 , Arg ^B32 - NH ₂ of human insulin, Lys ^B29 (N ^ε -lithocholyl-γ-Glu) des(B30) of human insulin, Nω ^B29 -ω-carboxypentadecanoyl-γ-aminobutanoyl des(B30) of human insulin, amidated insulin analogs as described in WO 2009/ 087082 (primarily the analogue selected from claim 14), or amidated insulin analogs as described in WO 2009/087081 (primarily the analogue selected from claim 16).

Preferable examples of the long-acting insulin of the present invention include insulin glargine, insulin detemir and insulin degludec.

Unless otherwise indicated, it should be understood that the definitions of active agents (including DPP-4 inhibitors and long-acting insulin analogs) set forth herein may also include their pharmaceutically acceptable salts and prodrugs, hydrates, solvates, and polymorphs thereof. Primarily, the terms therapeutic agents as used herein refer to the corresponding active drugs. Reference to salts, hydrates and polymorphs primarily refers to the active agents described herein.

Option combinations, compositions, methods and uses refer to combinations in which the DPP-4 inhibitor and long-acting insulin are preferably selected from the following list (Table 1).

- 18 044961

Table 1

DPP-4 inhibitor Long acting insulin selected from option A selected from group G2 selected from option A insulin glargine selected from option A insulin detemir selected from option A insulin degludec selected from option B selected from group G2 selected from option B insulin glargine selected from option B insulin detemir selected from option B insulin degludec selected from group G1 selected from group G2 selected from group G1 insulin glargine selected from group G1 insulin detemir selected from group G1 insulin degludec selected from group G1 plus metformin selected from group G2 selected from group G1 plus metformin insulin glargine selected from group G1 plus metformin insulin detemir selected from group G1 plus metformin insulin degludec selected from group G1 plus pioglitazone selected from group G2 selected from group G1 plus pioglitazone insulin glargine selected from group G1 plus pioglitazone insulin detemir selected from group G1 plus pioglitazone insulin degludec linagliptin selected from group G2 linagliptin insulin glargine linagliptin insulin detemir linagliptin insulin degludec linagliptin plus metformin selected from group G2 linagliptin plus metformin insulin glargine linagliptin plus metformin insulin detemir linagliptin plus metformin insulin degludec linagliptin plus pioglitazone selected from group G2 linagliptin plus pioglitazone insulin glargine linagliptin plus pioglitazone insulin detemir linagliptin plus pioglitazone insulin degludec

A particular embodiment (Option E) of the combinations, compositions, methods and uses of the present invention relates to combinations wherein the DPP-4 inhibitor is linagliptin. According to this particular embodiment (Option E), the long-acting insulin is preferably selected from Options E1-E3 (Table 2).

table 2

Option Long acting insulin E1 insulin glargine E2 insulin detemir EZ insulin degludec

In the context of the present invention, it should be understood that the combinations, compositions or combined uses of the present invention may include simultaneous, sequential or separate administration of active components or ingredients.

The terms combination or combined as used herein may include, but are not limited to, fixed and non-fixed (eg, free) forms (including sets) and methods of application, such as, for example, simultaneous, sequential or separate use of components or ingredients.

The present invention also provides kits of components or a combination drug product comprising:

a) a pharmaceutical composition comprising a DPP-4 inhibitor as described herein, optionally in admixture with one or more pharmaceutically acceptable carriers and/or diluents, and

b) a pharmaceutical composition comprising long-acting insulin as described herein.

In addition, the present invention provides a kit comprising:

a) a DPP-4 inhibitor as described here, and

b) long-acting insulin, as described herein, and optionally instructions for use of a DPP-4 inhibitor and long-acting insulin in combination (e.g., simultaneous, separate, sequential, or alternating administration), for example, for purposes of the present invention, for example, for the treatment of type 1 diabetes 2 in patient 19044961 (human).

The present invention also provides a pharmaceutical composition or fixed combination containing:

a) a DPP-4 inhibitor as described herein, and

b) long-acting insulin, as described herein, and optionally one or more pharmaceutically acceptable carriers and/or diluents.

In addition, the present invention provides a pharmaceutical composition for transdermal or subcutaneous administration (injection), system or delivery device for systemic use, comprising:

a) a DPP-4 inhibitor as described herein, and

b) long-acting insulin, as described herein, and optionally one or more pharmaceutically acceptable carriers and/or diluents.

Co-administration of the present invention can be accomplished by administering the active components in mixtures, for example, by administering them simultaneously as a single formulation or two separate formulations or dosage forms. In another embodiment, administration can be accomplished by administering the active components or ingredients sequentially, for example, two separate formulations or two dosage forms one after the other.

For the combination therapy of the present invention, the active components or ingredients may be administered separately (i.e., they are meant to be presented as separate formulations) or as a single formulation (i.e., they are meant to be formulated into a single formulation or dosage form). form). Therefore, the administration of one combination element of the present invention can be carried out before or after the administration of, or simultaneously with, the administration of another combination element. In one embodiment of the combination therapy of the present invention, the DPP-4 inhibitor and long-acting insulin are administered in different formulations or different dosage forms. In another embodiment, the DPP-4 inhibitor and long-acting insulin are administered as a single formulation or dosage form.

Unless otherwise specified, the term combination therapy may refer to first-, second- or third-line therapy, or primary or additional combination therapy or replacement therapy.

Methods for preparing DPP-4 inhibitors according to option A are known to one skilled in the art. Preferably, DPP-4 inhibitors according to option A can be obtained according to synthesis methods described in the literature. For example, purine derivatives of formula (I) can be prepared as described in WO 2002/068420, WO 2004/018468, WO 2005/085246, WO 2006/029769 or WO 2006/048427, the contents of which are incorporated herein by reference. Purine derivatives of formula (II) can be prepared as described, for example, in WO 2004/050658 or WO 2005/110999, the contents of which are incorporated herein by reference. Purine derivatives of formula (III) and (IV) can be prepared as described, for example, in WO 2006/068163, WO 2007/071738 or WO 2008/017670, the contents of which are incorporated herein by reference. The preparation of the DPP-4 inhibitors, which are detailed above, is described in the publications mentioned in connection therewith. Polymorph crystal modifications and formulations of specific DPP-4 inhibitors are described in WO 2007/128721 and WO 2007/128724, respectively, the contents of which are incorporated herein by reference in their entirety. Formulations of specific DPP-4 inhibitors in admixture with metformin or other combination components are described in WO 2009/121945, the contents of which are incorporated herein by reference in their entirety.

Typical doses (active substance content of the dosage form) in the dual fixed combination (tablet) linagliptin/metformin IR (immediate release (IR)) are 2.5 mg/500 mg, 2.5 mg/850 mg and 2.5 mg /1000 mg, which can be administered 1-3 times a day, primarily twice a day.

Typical doses (active substance content of the dosage form) in a double fixed-dose combination (tablet) of linagliptin/metformin extended release (XR) are 5/500 mg, 5/10θΟ mg and 5/1500 mg (in each single tablet), or 2 .5/500 mg, 2.5/750 mg and 2.5/1θ0θ mg (in every two tablets, which can be administered 1-2 times a day, primarily once a day, preferably taken in the evening with meals.

The present invention further provides a DPP-4 inhibitor, as described herein, for use in (additional or primary) combination therapy with metformin (e.g., a total daily dose of 500 to 2000 mg metformin hydrochloride, e.g., 500 mg, 850 mg, or 1000 mg once or twice daily).

In embodiment B, methods for preparing DPP-4 inhibitors are described in the scientific literature and/or in publications, most notably in the publications cited herein.

The combination elements of the present invention can be administered by various routes, for example, oral, buccal, sublingual, enteral, parenteral (e.g., transdermal, intramuscular, or subcutaneous), inhalation (e.g., liquid or powder,

- 20 044961 aerosol), pulmonary, intranasal (for example, in the form of a spray), intraperitoneal, vaginal, rectal or local route of administration and can be processed, separately or together, into suitable dosage formulations containing standard non-toxic pharmaceutically acceptable carriers, adjuvants and excipients, suitable for each route of administration.

In a preferred embodiment, the DPP-4 inhibitor in the combination of the present invention is preferably administered orally. In another preferred embodiment, the long-acting insulin in the combination is preferably administered by injection (preferably subcutaneously). In yet another embodiment, the long-acting insulin in the combination is administered using a transdermal delivery system.

Suitable doses and dosage forms of DPP-4 inhibitors can be determined by one skilled in the art and may include those described herein or in the relevant references.

For pharmaceutical use in warm-blooded vertebrates, especially humans, the compounds of the present invention are typically administered at a dose of 0.001 to 100 mg/kg body weight, preferably at a dose of 0.01 to 15 mg/kg or 0.1 to 15 mg/kg , in each case from 1 to 4 times a day. For this purpose, the compounds, optionally in combination with other active compounds, can be included in mixtures with one or more inert standard carriers and/or diluents, such as corn starch, lactose, glucose, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water/ethanol mixture, water/glycerol mixture, water/sorbitol mixture, water/polyethylene glycol mixture, propylene glycol, cetyl stearyl alcohol, carboxymethylcellulose or fatty compounds such as tallow, or suitable mixtures thereof, in standard herbal preparations, such as flat or coated tablets, capsules, powders, suspensions or suppositories.

Thus, the pharmaceutical compositions of the present invention, including DPP-4 inhibitors as defined herein, can be prepared by methods known to one skilled in the art using pharmaceutically acceptable excipients described in the art for each route of administration. Examples of these excipients include, but are not limited to, diluents, binders, carriers, fillers, lubricants, flow agents, crystallization retardants, disintegrants, solubilizing agents, colorants, pH adjusting agents, surfactants, and emulsifiers.

The preparations or dosage forms for oral administration of the DPP-4 inhibitor of the present invention can be prepared by standard techniques.

Examples of suitable diluents for the compounds of Embodiment A of the present invention include powdered cellulose, calcium hydrogen phosphate, erythritol, low-substituted hydroxypropylcellulose, mannitol, pregelatinized starch or xylitol.

Examples of suitable lubricants for the compounds of embodiment A include talc, polyethylene glycol, calcium behenate, calcium stearate, hydrogenated castor oil or magnesium stearate.

Examples of suitable binders for the compounds of option A include copovidone (copolymers of vinylpyrrolidone with other vinyl derivatives), hydroxypropyl methylcellulose (HPMC), hydroxypropylcellulose (HPC), polyvinylpyrrolidone (povidone), pregelatinized starch, or low-substituted hydroxypropylcellulose (H3-HPC).

Examples of suitable disintegrating agents for the compounds of embodiment A include corn starch or crospovidone.

Suitable methods for preparing pharmaceutical formulations of DPP-4 inhibitors according to option A include:

direct tableting of the active compound in the form of powder mixtures with suitable tableting excipients, granulation in a mixture with suitable excipients, subsequent mixing with suitable excipients and subsequent tableting, as well as film coating or packaging of powder mixtures or granules into capsules. Suitable granulation methods include the following methods:

wet granulation in a high speed mixer followed by fluidized bed drying, single reactor granulation, fluidized bed granulation, or dry granulation (eg, rotary compaction) mixed with suitable excipients and subsequent tableting or capsule packaging.

A typical composition (e.g., tablet core) of a DPP-4 inhibitor of Option A includes a first diluent of mannitol, pregelatinized starch as a second diluent with additional binder properties, a binder of copovidone, a disintegrating agent of corn starch, and magnesium stearate as a lubricant. however, copovidone and/or corn starch are optional.

The DPP-4 inhibitor tablet of Embodiment A of the present invention can be coated with a film

- 21 044961 coating, preferably a film coating comprising hydroxypropyl methylcellulose (HPMC), polyethylene glycol (PEG), talc, titanium dioxide and iron oxide (eg red and/or yellow).

In one embodiment, the DPP-4 inhibitor in the combination of the present invention is administered by injection (preferably subcutaneously). In another embodiment, the long-acting insulin in the combination is preferably administered by injection (preferably subcutaneously). In yet another embodiment, the long-acting insulin in the combination is administered using a transdermal delivery system.

The long-acting insulin and/or DPP-4 inhibitor injection formulations of the present invention (primarily for subcutaneous use) can be prepared by known techniques, for example, using suitable liquid carriers for the preparation of injection solutions or suspensions, and which typically include sterile water and optionally, additional additives such as, for example, preservatives, pH adjusting agents, buffering agents, isotonic agents, solubility enhancing agents, and/or surfactants or the like. In addition, injection formulations may contain other additives, such as salts, solubility-modifying agents, or precipitating agents, which retard the release of the drug(s).

In addition, insulin injection formulations may contain insulin stabilizing agents such as zinc compounds.

In one embodiment, the DPP-4 inhibitor in the combination of the present invention is administered using a transdermal delivery system. In another embodiment, the long-acting insulin in the combination is also administered using a transdermal delivery system. In yet another embodiment, the long-acting insulin in the combination is preferably administered by injection (preferably subcutaneously). In another embodiment, the long-acting insulin in the combination is administered in the form of pellets (implanted under the skin).

Compositions for transdermal administration (eg, transdermal patches or gels) of long-acting insulin and/or DPP-4 inhibitor of the present invention can be prepared by known techniques, for example, using suitable carriers and, optionally, additional additives. To accelerate percutaneous permeability, various techniques and systems can be used, such as, for example, methods involving the formation of microchannels or micropores in the skin, such as, for example, iontophoresis (based on low-level electrical current), sonophoresis (based on low-frequency ultrasound) or mesotherapy, or the use of drug carrier agents (eg, elastic or lipid vesicles such as transferosomes) or permeation enhancers.

More detailed descriptions of the dosage forms, formulations and administration of the DPP-4 inhibitors of the present invention and/or the long-acting insulin of the present invention are provided in the scientific literature and/or published patent documents, primarily incorporated herein by reference.

Pharmaceutical compositions (or formulations) can be packaged in a variety of ways. Generally, a distribution article includes one or more containers that contain one or more pharmaceutical compositions in an appropriate form. Tablets are usually packaged in appropriate primary packaging to facilitate handling, distribution and storage and to ensure adequate stability of the composition during prolonged exposure to the environment during storage. Primary containers for tablets may be vials or blister packs.

A suitable bottle, for example, for a pharmaceutical composition or combination (tablet) comprising the DPP-4 inhibitor of Embodiment A of the present invention may be made of glass or a polymer (preferably polypropylene (PP) or high-density polyethylene (HDPE)), and is closed with a screw cap. lid. The screw cap may be a child-resistant cap (eg, push-and-turn) to prevent or impede children's access to the contents of the bottle. If necessary (eg, in areas of high humidity), an additional desiccant (such as bentonite clay, molecular sieves, or preferably silica gel) is used to extend the shelf life of the packaged composition.

A suitable blister pack, for example for a pharmaceutical composition or combination comprising the DPP-4 inhibitor of Embodiment A of the present invention, consists of or is formed from a top foil (which can be pierced by a tablet) and a bottom part (which contains tablet wells). The top foil may comprise metal foil, especially aluminum or aluminum alloy foil (for example, with a thickness of 20 to 45 µm, preferably 20 to 25 µm, which is coated with a layer of heat-sensitive polymer on the inside (insulating side). The bottom part may comprise a multilayer polymer film (such as, for example, polyvinyl chloride (PVC) coated with polyvinylidene chloride (PVDC), or a PVC film laminated with polychlorotrifluoroethylene (PCTFE)) or a polymer-metal-polymer multilayer film (such as, for example, a cold-formed laminated composition PVC/aluminum/polyamide).

To ensure long-term storage, especially in hot and humid climates, for

- 22 044961 blister packaging, you can use an additional outer wrapper or bag made of a multilayer film of the polymer-metal-polymer type (for example, a laminated composition of the polyethylene/aluminum/polyester type). An additional desiccant (eg, bentonite clay, molecular sieves, or preferably silica gel) in said packaging can further extend shelf life under such harsh conditions.

Injectable solutions may be provided in standard, suitable dosage forms such as vials, cartridges or pre-filled (disposable) pens, which may be further packaged.

The product may further include a label or package insert that refers to instructions commonly used in commercial packaging of therapeutic products and which may contain information regarding the indications, uses, dosages, routes of administration, contraindications and/or warnings regarding the use of said therapeutic products. In one embodiment, the label or package insert states that the composition can be used for any of the purposes described herein.

In the first embodiment of the present invention (Option A), the dosages typically required for the DPP-4 inhibitors mentioned herein in Option A are from 0.1 to 10 mg, preferably from 0.25 to 5 mg, when administered intravenously, and when administered intravenously oral administration is from 0.5 to 100 mg, preferably from 2.5 to 50 mg or from 0.5 to 10 mg, more preferably from 2.5 to 10 mg or from 1 to 5 mg, in each case the doses are administered from 1 to 4 times a day. Thus, for example, the dose of 1-[(4methylquinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-(3-(R)-aminopiperidin-1 -yl)xanthine when administered orally, it is from 0.5 to 10 mg per patient per day, preferably from 2.5 to 10 mg or from 1 mg to 5 mg per patient per day.

The dosage form obtained from the pharmaceutical composition comprising the DPP-4 inhibitor mentioned herein in Embodiment A of the present invention contains the active ingredient in a dose of 0.1-100 mg. Thus, for example, specific doses of 1-[(4-methylquinazolin-2-yl)methyl]-3-methyl7-(2-butyn-1-yl)-8-(3-(R)-aminopiperidin-1-yl )xanthine are 0.5, 1, 2.5, 5 and 10 mg.

In the second embodiment of the present invention (embodiment B), the doses of the DPP-4 inhibitors mentioned herein in embodiment B that are administered to a mammal, for example, a human weighing, for example, about 70 kg, are generally from about 0.5 mg to about 350 mg, for example, from about 10 mg to about 250 mg, preferably 20-200 mg, more preferably 20-100 mg of active agent per subject per day, or from about 0.5 mg to about 20 mg, preferably 2.5- 10 mg per subject per day, divided preferably into 1-4 single doses, which, for example, are the same. Single doses include, for example, 10, 25, 40, 50, 75, 100, 150 and 200 mg of the DPP-4 inhibitor active agent.

The oral dose of the DPP-4 inhibitor, sitagliptin, is usually 25 to 200 mg of active agent. The recommended dose of sitagliptin based on the active agent (anhydrous free base) is 100 mg once daily. Standard doses of sitagliptin anhydrous free base (active agent) are 25, 50, 75, 100, 150 and 200 mg. Specific unit doses of sitagliptin (eg, per tablet) are 25, 50, and 100 mg. In the pharmaceutical compositions, amounts of sitagliptin phosphate monohydrate equivalent to anhydrous sitagliptin free base are used, namely 32.13, 64.25, 96.38, 128.5, 192.75 and 257 mg, respectively. For patients with renal failure, optimized doses of sitagliptin are used, 25 and 50 mg. Typical doses of the sitagliptin/metformin dual combination are 50 mg/500 mg and 50 mg/1000 mg.

The oral dosage range of the DPP-4 inhibitor, vildagliptin, is typically 10 to 150 mg per day, most notably 25 to 150 mg, 25 to 100 mg, or 25 to 50 mg or 50 to 100 mg per day. Specific examples of daily oral doses are 25, 30, 35, 45, 50, 55, 60, 80, 100 or 150 mg. In a more specific setting, the daily dose of vildagliptin is 25 to 150 mg or 50 to 100 mg. In another more specific setting, the daily dose of vildagliptin is 50 or 100 mg. The active ingredient can be administered up to three times daily, preferably once or twice daily. Specific doses are 50 or 100 mg of vildagliptin. Typical doses of the vildagliptin/metformin double combination are 50 mg/850 mg and 50 mg/1000 mg.

Alogliptin may be administered to a patient at a daily dose of 5 mg/day to 250 mg/day, optionally 10 to 200 mg, optionally 10 to 150 mg, and optionally 10 to 100 mg of alogliptin (in each case based on molecular weight alogliptin in free base form). Thus, specific oral doses that may be used include, but are not limited to, 10, 12.5, 20, 25, 50, 75, and 100 mg of alogliptin per day. Alogliptin can be administered in free base form or as a pharmaceutically acceptable salt.

Saxagliptin can be administered to a patient at a daily oral dose of 2.5 mg/day to 100 mg/day, optionally 2.5 to 50 mg. Specific oral dosages that may be used include, but are not limited to, 2.5, 5, 10, 15, 20, 30, 40, 50, and 100 mg of saxagliptin per day. Typical doses of the saxagliptin/metformin dual combination are 2.5 mg/500 mg and 2.5 mg/1000 mg.

A specific embodiment of the DPP-4 inhibitors of the present invention relates to

- 23 044961 such orally administered DPP-4 inhibitors which are therapeutically effective at low dose levels, for example at an oral dose of <100 mg or <70 mg per patient per day, preferably <50 mg, more preferably <30 mg or <20 mg, even more preferably 1 to 10 mg, especially 1 to 5 mg (more preferably 5 mg) per patient per day (if necessary divided into 1-4 single doses, especially 1 or 2 single doses, which are the same), preferably administered orally once or twice daily (more preferably once daily), more preferably administered at any time of the day, with or without meals. Thus, for example, a daily oral dose of 5 mg B1 1356 can be administered once daily (i.e., 5 mg B1 1356 once daily) or twice daily (i.e., 2.5 mg B1 1356 twice daily) per day) at any time of the day during meals or regardless of meals.

Long-acting insulin is usually administered by subcutaneous injection, for example, ranging from twice daily, once daily to once weekly. Suitable doses and dosage forms of long-acting insulin can be determined by one skilled in the art. For all patients undergoing insulin treatment, monitoring blood glucose levels is essential.

For example, insulin glargine (Lantus) is administered subcutaneously once daily. Lantus can be given at any time of the day, as long as it is given at the same time every day. The dose of Lantus depends on the individual and their clinical response. The recommended starting dose of Lantus for patients with type 2 diabetes who are not currently receiving insulin treatment is 10 units (or 0.2 units/kg) once daily and is optimized based on the patient's needs.

Insulin detemir (Levemir) is administered subcutaneously once or twice a day. For patients treated with Levemir once daily, the dose is preferably administered in the evening with a meal or at bedtime. For patients requiring twice daily dosing, the evening dose may be administered with meals, at bedtime, or 12 hours after the morning dose. The dose of Levemir depends on the individual and his clinical response. For naïve patients with type 2 diabetes who have inadequate control after treatment with oral antidiabetic drugs, Levemir is started at a starting dose of 0.1 to 0.2 units/kg once daily in the evening or 10 units once or twice daily. day, and the dose is optimized to achieve glycemic targets.

The dosages of the active ingredients in the combinations and compositions of the present invention can be varied, although the amount of active ingredients must provide a suitable dosage form. Therefore, the selected dose and the selected dosage form depend on the desired therapeutic effect, route of administration and duration of treatment. Suitable dosage ranges for the combination range from the maximum tolerated dose for one agent to lower doses, for example, up to one tenth of the maximum tolerated dose.

First of all, the preferred DPP-4 inhibitor of the present invention is 1-[(4methylquinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-aminopiperidine -1-yl)xanthine (other name BI 1356 or linagliptin). BI 1356 is characterized by high efficiency, duration of action over 24 hours and a wide therapeutic window. In patients diagnosed with type 2 diabetes receiving multiple oral doses of 1, 2.5, 5 or 10 mg of compound BI 1356 once daily for 12 days, favorable pharmacokinetic and pharmacodynamic profiles of BI 1356 are observed (see, for example, Table 3 below) and rapid achievement of steady state (e.g., on day 2 to day 5 of treatment, all dose groups achieved steady state plasma concentrations (on day 13, >90% of predose plasma concentrations were achieved) drug)), low accumulation (e.g., average accumulation coefficient is RA,A _UC ^1.4 when administered at a dose of more than 1 mg) and maintenance of a long-lasting inhibitory effect on DPP-4 (e.g., almost complete (>90% ) inhibition of DPP-4 when administered at a dose of 5 and 10 mg, i.e., 92.3 and 97.3% inhibition is achieved at steady state, respectively, and >80% inhibition within 24 hours after drug administration), and also a significant reduction (>80%) in the degree of change in blood glucose levels 2 hours after ingestion (as early as day 1) when administered at a dose of >2.5 mg, while the total amount of unchanged parent compound excreted in urine per day 1 is less than 1% of the administered dose and increases by no more than 3-6% on day 12 (renal creatinine clearance CL _R , _ss ranges from approximately 14 ml/min to approximately 70 ml/min for administered oral doses, e.g. 5 mg renal creatinine clearance is approximately 70 ml/min). In patients diagnosed with type 2 diabetes, administration of BI 1356 resulted in safety and tolerability similar to that observed with placebo. At low doses of approximately >5 mg, BI 1356 exhibits the efficacy of a true once-daily oral drug that exhibits DPP-4 inhibition over a full 24-hour period. At therapeutic oral doses, BI 1356 is primarily excreted through the liver and only to a small extent (approximately <7% of the administered oral dose) via the kidneys. Basically, BI 1356 is excreted unchanged in the bile.

- 24 044961

The proportion of BI 1356 that is excreted through the kidneys increases only extremely slightly over time and with increasing dose, and therefore there is no need to change the dose of BI 1356 depending on the patient's renal function. The non-renal elimination of BI 1356, along with its low accumulation rate and wide range of safe doses, represents a significant advantage in a patient population characterized by a high incidence of renal failure and diabetic nephropathy.

Table 3

Geometric mean value (avg. geom.) and geometric coefficient of variation (geom. CV) of pharmacokinetic parameters of BI 1356 in a stable state (day 12)

Parameter 1 mg Wed geom. (geom. HF) 2.5 mg Wed geom. (geom. HF) 5 mg Wed geom. (geom. HF) 10 mg Wed geom. (geom. HF) AUCo-24 (nmol-h/l) 40.2 (39.7) 85.3 (22.7) 118 (16.0) 161 (15.7) AUC _T , _SS (nmol-h/l) 81.7 (28.3) 117 (16.3) 158 (10.1) 190 (17.4) Stach (nmol/l) 3.13 (43.2) 5.25 (24.5) 8.32 (42.4) 9.69 (29.8) Cmax,ss (nmol/l) 4.53 (29.0) 6.58 (23.0) P,1 (21.7) 13.6 (29.6) tmax* ( ^h ) 1.50 (1.00-3.00) 2.00 (1.00-3.00) 1.75 (0.92-6.02) 2.00 (1.50-6.00) tmax,ss* (h) 1.48 (1.00-3.00) 1.42 (1.00-3.00) 1.53 (1.00-3.00) 1.34 (0.50-3.00) T/ ₂ ,ss (h) 121 (21.3) 113 (10.2) 131 (17.4) 130 (11.7) Accumulation 1½. 23.9 (44.0) 12.5 (18.2) 11.4 (37.4) 8.59 (81.2) Parameter 1 mg Wed geom. (geom. HF) 2.5 mg Wed geom. (geom. HF) 5 mg Wed geom. (geom. HF) 10 mg Wed geom. (geom. HF) (h) Ra, C check 1.44 (25.6) 1.25 (10.6) 1.33 (30.0) 1.40 (47.7) ^r a,auc 2.03 (30.7) 1.37 (8.2) 1.33 (15.0) 1.18 (23.4) feo-24 (%) But 0.139 (51.2) 0.453 (125) 0.919 (115) fe _T ,ss (%) 3.34 (38.3) 3.06 (45.1) 6.27 (42.2) 3.22 (34.2) KHr ss (ml/min) 14.0 (24.2) 23.1 (39.3) 70 (35.0) 59.5 (22.5) * average value and range of values (minimum value - maximum value) n/a - not determined, because most values are below the lower limit of quantitation

Due to the fact that various metabolic functional disorders in most cases develop simultaneously, it is often recommended to combine several active agents with different mechanisms of action. Thus, depending on the functional disorders diagnosed, an improved treatment outcome may be observed if a DPP-4 inhibitor is combined with active compounds that are commonly used to treat the corresponding disorders, such as, for example, one or more active compounds selected from other antidiabetic compounds previously total active compounds that lower blood sugar or blood lipid levels, increase high-density lipoprotein (HDL) levels in the blood, lower blood pressure, or that are prescribed to treat atherosclerosis or obesity.

The DPP-4 inhibitors mentioned above, in addition to their use for treatment in monotherapy, can also be used in combination with other active compounds that can improve treatment results. This combination treatment can be used as a free combination of compounds or in the form of a fixed combination, for example, a tablet or capsule. The pharmaceutical compositions of the combination component required for this purpose can be used as commercial products or can be prepared by one skilled in the art using standard techniques. Active compounds that are commercial pharmaceutical compositions are described in the prior art, for example, in the annual drug list, the Rote Liste® of the Federal Association of the Pharmaceutical Industry, or in the annual directory of information from manufacturers of prescription drug products Physicians' Desk Reference.

Examples of antidiabetic combination components include metformin, sulfonylureas such as glibenclamide, tolbutamide, glimepiride, glipizide, gliquidone, glibornuride and gliclazide,

- 25 044961 nateglinide, repaglinide, mitiglinide, thiazolidinediones such as rosiglitazone and pioglitazone, PPAR-γ modulators such as metaglidases, PPAR-γ agonists such as rivoglitazone, mitoglitazone, INT-131 and balaglitazone, PPAR-γ antagonists, PPAR modulators -γ/α, such as tezaglitazar, muraglitazar, aleglitazar, indeglitazar and KRP297, PPAR-γ/α/δ modulators, such as, for example, lobeglitazone, AMPK activators, such as AICAR, acetyl-CoA carboxylase inhibitors (ACC1 and ACC2 ), diacylglycerol acetyltransferase (DGAT) inhibitors, pancreatic β-cell GCRP agonists such as SMT3 and GPR119 receptor agonists such as GPR119 agonists, 5-ethyl-2-{4-[4-(4-tetrazol-1ylphenoxymethyl)thiazol- 2-yl]piperidin-1-yl}pyrimidine or 5-[1-(3-isopropyl[1,2,4]oxadiazol-5yl)piperidin-4-ylmethoxy]-2-(4-methanesulfonylphenyl)pyridine, Πβ inhibitors -HSD, FGF19 agonists or analogs, α-glucosidase blockers such as acarbose, voglibose and miglitol, α2-antagonists, insulin and insulin analogs such as human insulin, insulin lispro, insulin glusilin, rDNAinsulinaspart, insulin NPH, insulin detemir, insulin degludec, insulin tregopil, zinc insulin suspension and insulin glargine, gastric inhibitory peptide (GIP), amylin and amylin analogs (eg pramlintide or dalintide), GLP-1 and GLP-1 analogs such as exendin-4, eg exenatide, exenatide LAR, liraglutide, taspoglutide, lixisenatide (AVE-0010), LY-2428757 (PEGylated variant of GLP-1), dulaglutide (LY-2189265), semaglutide or albiglutide, SGLT2 inhibitors such as dapagliflozin, sergliflozin (KGT-1251), atigliflozin, canagliflozin, ipragliflozin, tofogliflozin, luseogliflozin, protein tyrosine phosphatase inhibitors (eg, trodusquemin), glucose-6-phosphatase inhibitors, fructose 1,6-bisphosphatase modulators, glycogen phosphorylase modulators, glucagon receptor antagonists, phosphoenolpyruvate carboxykinase (PEPCK) inhibitors s pyruvate dehydrogenase- kinases (PDK), tyrosine kinase inhibitors (50 to 600 mg), such as PDGF receptor kinase (see. EP-A-564409, WO 98/35958, US 5093330, WO 2004/005281 and WO 2006/041976) or serine/threonine kinases, glucokinase/regulatory protein modulators, including glucokinase activators, glycogen synthase kinase inhibitors, inositol 5-phosphatase inhibitors SH2 domain containing type 2 (SHIP2), IKK inhibitors such as high dose salicylate, JNK1 inhibitors, protein kinase C-θ inhibitors, β3 agonists such as Ritobegron, YM 178, Solabegron, Talibegron, N5984, GRC-1087 , Rafabegron, FMP825, aldose reductase inhibitors such as AS 3201, zenarestat, fidarestat, epalrestat, ranirestat, NZ-314, CP-744809, as well as CT-112, SGLT-1 or SGLT2 inhibitors, KV 1.3 channel inhibitors, GPR40 modulators, such as for example [(3S)-6-({2',6'-dimethyl-4'-[3(methylsulfonyl)propoxy]biphenyl-3-yl}methoxy)-2,3-dihydro-1-benzofuran- 3-yl]acetic acid, SCD-1 inhibitors, CCR-2 antagonists, dopamine receptor agonists (bromocriptine mesylate (Cycloset)), 4-(3-(2,6-dimethylbenzyloxy)phenyl)-4-oxobutanoic acid, sirtuin stimulants and other DPP-4 inhibitors.

Metformin is typically administered in doses of about 500 to 2000 mg or up to 2500 mg per day, using various courses of treatment from about 100 to 500 mg or 200 to 850 mg (1-3 times daily), or about 300 to 1000 mg once or twice daily, or sustained release metformin in doses of about 100 to 1000 mg, or preferably 500 to 1000 mg once or twice daily, or about 500 to 2000 mg once daily. Specific doses may contain 250, 500, 625, 750, 850, and 1000 mg of metformin hydrochloride.

For children aged 10 to 16 years, the recommended starting dose of metformin is 500 mg once daily. If this dose is not sufficient to obtain adequate results, it can be increased to 500 mg twice daily. Further increases can be made by sequential additions of 500 mg per week to a maximum daily dose of 2000 mg, administered in divided doses (eg, 2 or 3 doses). Metformin can be given with food to reduce nausea.

The dose of pioglitazone is usually approximately 1-10, 15, 30 or 45 mg once daily.

Rosiglitazone is usually administered in doses of 4 to 8 mg once (or twice in divided doses) per day (typical doses are 2, 4, and 8 mg).

Glibenclamide (glyburide) is usually administered in doses of 2.5-5 to 20 mg once (or twice in divided doses) per day (usually the dose is 1.25, 2.5 and 5 mg), or micronized glibenclamide is administered in doses 0.75-3 to 12 mg once (or twice in divided doses) per day (usually the dose is 1.5, 3, 4.5 and 6 mg).

Glipizide is usually administered in doses of 2.5 to 10 to 20 mg once (or up to 40 mg twice in divided doses) per day (usually 5 and 10 mg doses), or extended-release glibenclamide in doses of 5 to 10 mg (up to 20 mg) once a day (usually the dose is 2.5, 5, and 10 mg).

Glimepiride is usually administered in doses of 1-2 to 4 mg (or up to 8 mg) once daily (usually the dose is 1, 2 and 4 mg).

The glibenclamide/metformin dual combination is usually administered in doses ranging from 1.25/250 once daily to 10/1000 twice daily (typical doses are 1.25/250, 2.5/500 and 5/500 mg).

The glipizide/metformin dual combination is usually administered in doses ranging from 2.5/250 to 10/1000 twice daily (typical doses are 2.5/250, 2.5/500 and 5/500 mg).

The glimepiride/metformin dual combination is usually administered in doses of 1/250 to 4/1000 twice

- 26 044961 per day.

The rosiglitazone/glimepiride dual combination is usually administered in doses ranging from 4/1 once or twice daily to 4/2 twice daily (typical doses are 4/1, 4/2, 4/4, 8/2 and 8/4 mg ).

The pioglitazone/glimepiride dual combination is usually administered in doses of 30/2 to 30/4 once daily (usually 30/4 and 45/4 mg).

The rosiglitazone/metformin dual combination is usually taken in doses of 1/500 to 4/1000 twice daily (typical doses are 1/500, 2/500, 4/500, 2/1000 and 4/1000 mg).

The pioglitazone/metformin dual combination is usually administered in doses ranging from 15/500 once or twice daily to 15/850 mg three times daily (typical doses are 15/500 and 15/850 mg).

Nateglinide, a non-sulfonylurea insulin secretagogue, is usually given at a dose of 60 mg to 120 mg with food (up to 360 mg/day, typical doses are 60 mg and 120 mg), repaglinide is usually given at a dose of 0 .5 to 4 mg with food (up to 16 mg/day; typical doses are 0.5, 1, and 2 mg). The double combination repaglinide/metformin is usually prescribed at a dose of 1 mg/500 mg and 2 mg/850 mg.

Acarbose is usually prescribed at a dose of 25 to 100 mg with food. Miglitol is usually prescribed at a dose of 25 to 100 mg with food.

Examples of components of combinations that lower blood lipid levels include hydroxymethylglutaryl-coenzyme A reductase (HMG-CoA reductase) inhibitors such as simvastatin, atorvastatin, lovastatin, fluvastatin, pravastatin, pitavastatin and rosuvastatin, fibrates such as bezafibrate, fenofibrate , clofibrate, gemfibrozil, etofibrate and etophylline clofibrate, nicotinic acid and its derivatives such as acipimox, PPAR-α agonists, PPAR-δ agonists such as, for example, {4-[(R)-2-ethoxy-3-(4 -trifluoromethylphenoxy)propylsulfanyl]-2-methylphenoxy}acetic acid, acyl-coenzyme A/cholesterol acyltransferase (ACAT, EC 2.3.1.26) inhibitors such as avasimibe, cholesterol resorption inhibitors such as ezetimibe, compounds that bind bile acid such as cholestyramine , colestipol and colesevelam, bile acid transport inhibitors, HDL modulating active compounds such as D4F, reverse D4F, LXR modulating active compounds as well as FXR modulating active compounds, CETP inhibitors such as torcetrapib, JTT-705 (dalcetrapib) or compound 12 described in WO 2007/005572 (anacetrapib), LDL receptor modulators, MTP inhibitors (eg lomitapide) and ApoB100 antisense RNA.

The dose of atorvastatin is usually 1 to 40 mg or 10 to 80 mg once daily.

Examples of components of combinations that lower blood pressure include β-blockers such as atenolol, bisoprolol, celiprolol, metoprolol and carvedilol, diuretics such as hydrochlorothiazide, chlorthalidone, xipamide, furosemide, pyretanide, torsemide, spironolactone, eplerenone, amiloride and triamterene, calcium channel blockers such as amlodipine, nifedipine, nitrendipine, nisoldipine, nicardipine, felodipine, lacidipine, lercanipidine, manidipine, isradipine, nilvadipine, verapamil, gallopamil and diltiazem ACE inhibitors such as ramipril, lisinopril, cilazapril, quinapril, captopril, enalapri l , benazepril, perindopril, fosinopril and trandolapril, as well as angiotensin II receptor blockers (ARBs) such as telmisartan, candesartan, valsartan, losartan, irbesartan, olmesartan, azilsartan and eprosartan.

The dose of telmisartan is usually from 20 to 320 mg or from 40 to 160 mg per day.

Examples of combination components that increase blood HDL levels include cholesteryl ester transfer protein (CETP) inhibitors, endothelial lipase inhibitors, ABC1 regulators, LXRa antagonists, LXRe agonists, PPAR-δ agonists, LXRa/β regulators, and compounds that increase expression and/or plasma concentration of apolipoprotein A-I.

Examples of components of combinations intended for the treatment of obesity include sibutramine, tetrahydrolipstatin (orlistat), alyzyme (cetilistat), dexfenfluramine, axokine, cannabinoid receptor 1 antagonists such as the CB1 antagonist rimonobant, MCH-1 receptor antagonists, MC4 receptor agonists, NPY5 antagonists and NPY2 (eg, wellneperit), e3-AR agonists such as SB-418790 and AD-9677, 5HT2c receptor agonists such as APD 356 (lorcaserin), myostatin, Acrp30 and adiponectin inhibitors, steroyl-coenzyme A desaturase inhibitors ( SCD1), fatty acid synthase inhibitors, CCK receptor agonists, ghrelin receptor modulators, Py 3-36, orexin receptor antagonists and tesofensine, as well as dual combinations of bupropion/naltrexone, bupropion/zonisamide, topiramate/phentermine and pramlintide/metreleptin.

Examples of components of combinations intended for the treatment of atherosclerosis include phospholipase A2 inhibitors, tyrosine kinase inhibitors (50 to 600 mg), such as PDGF receptor kinase (see EP-A-564409, WO 98/35958, US 5093330, WO 2004/005281 and WO 2006/041976), anti-oxLDL antibodies and vaccines against oxLDL, apoA-1 Milano, ASA, and VCAM-1 inhibitors.

The scope of the present invention is not limited to the specific embodiments described herein. Based on the present description, various modifications of the present invention will be apparent to those skilled in the art in addition to the modifications described herein. These modifications are included within the scope of the present invention and the accompanying

- 27 044961 claims.

All patent applications cited herein are incorporated herein by reference in their entirety.

Other embodiments, features and advantages of the present invention will be apparent from the following examples. The following examples are intended to illustrate the essence of the present invention and do not limit its scope.

Examples

Subcutaneous administration of linagliptin and inhibition of plasma DPP-4.

Subcutaneous administration of linagliptin and inhibition of plasma DPP-4 may be comparable in efficacy and duration of action to oral administration, allowing the use of linagliptin in a fixed combination with subcutaneous insulin.

Male ZDF rats (n=5) were administered subcutaneously (s.c.) BI 1356 according to the schedule of 0.001 mg/kg, 0.01 mg/kg, 0.1 mg/kg and 1 mg/kg in a NaCl solution in a volume of 0.5 ml/kg) and for comparison, 3 mg/kg was administered orally (po), in a volume of 5 ml/kg (in 0.5% natrosol).

DPP-4 activity in EDTA plasma was determined 1, 3, 5, 7, 24, 31, 48, 72 hours after drug administration (blood was collected by venipuncture after anesthesia with isoflurane from the sublingual vein).

When administered doses of BI 1356 starting from 0.01 mg/kg (s.c.), significant inhibition of DPP-4 activity was observed compared to control. When a dose of 0.1 mg/kg and 1 mg/kg (s.c.) is administered, sustained inhibition of DPP-4 is observed at a level of more than 64% for 7 hours. When a dose of 1 mg/kg is administered s.c., comparable results in effectiveness are observed and duration of action compared to a dose of 3 mg/kg po.

Drawing. DPP-4 activity in plasma after subcutaneous (SC) administration of linagliptin.

Effect of linagliptin on body weight, total body fat, liver fat and intramyocellular fat.

The following example examined the effectiveness of chronic treatment with linagliptin on body weight, total body fat, intramyocellular fat and liver fat in a non-diabetic diet-induced obesity (DIO) model, compared with the appetite suppressant sibutramine.

Rats were fed the high-fat diet for 3 months and were treated with either vehicle or linagliptin (10 mg/kg) or sibutramine (5 mg/kg) for 6 additional weeks, while the rats continued to receive the high-fat diet. Magnetic resonance spectroscopy (MRS) was used to determine total body fat, muscle fat, and liver fat before treatment and after testing.

Sibutramine causes a significant reduction in body weight (-12%) compared to control, while linagliptin has no significant effect (-3%). Sibutramine also markedly reduced total body fat (-12%), whereas animals treated with linagliptin showed no significant reduction (-5%). However, linagliptin and sibutramine caused a significant reduction in intramyocellular fat (-24 and -34%, respectively). In addition, treatment with linagliptin causes a significant reduction in liver fat content (-39%), whereas the effect of sibutramine (-30%) is not as great (see Table 4). Thus, linagliptin has no effect on body weight, but improves the accumulation of intramyocellular and hepatic lipids.

Table 4

Effect of linagliptin on body weight, total body fat, liver fat and intramyocellular fat

Body mass Total body fat content Liver fat content Intramyocellular fat content % counter. % bases lines % counter. % bases lines % counter. % bases lines % counter. % bases lines Control - + 15% p=0.016 - + 11% p=0.001 - +27% p=0.09 - +23% p=0.49 Linagliptin -3% p=0.56 + 12% p=0.001 -5% p=0.27 +5% p=0.06 -39% p=0.022 -30% p=0.05 -36% p=0.14 -24% p=0.039 Sibutramine -12% p=0.018 + 1% p=0.64 -12% p=0.008 -0.4% p=0.86 -thirty% p=0.13 -29% p=0.12 -55% p=0.037 -34% p=0.007

In conclusion, treatment with linagliptin causes significant reductions in intramyocellular lipids and liver fat, both of which are independent of weight loss. The effect of sibutramine on muscle and liver fat content is mainly due to the known weight loss that this compound causes.

Slowing the onset of diabetes and preserving β cell function in a model of type 1 diabetes without

-

Claims (6)

obesity. Although decreased T cell migration and altered cytokine production are considered important factors in the development of insulinitis, the exact mechanism and effect on the pancreatic cell pool is still not fully understood. To evaluate the effect of linagliptin on pancreatic inflammation and β cell mass, diabetes progression was studied in a non-obese diabetic (NOD) mouse model over 60 days, along with stereological assessment of pancreatic cell changes. The test used 60 female NOD mice (10 weeks old) and fed them normal chow or chow containing linagliptin (0.083 g linagliptin/kg chow, corresponding to 3-10 mg/kg p.o.). Plasma samples were obtained twice weekly to determine the onset of diabetes (blood glucose >11 mmol/L). At the completion of testing, the pancreas was removed and a final blood sample was obtained to assess active GLP-1 levels. After the end of the testing period, the incidence of diabetes was reduced in mice treated with linagliptin (9 of 30 mice) compared with controls (18 of 30 mice, p=0.021). Based on subsequent stereological assessment of B cell mass (identified by insulin immunoreactivity), a significant increase in β cell mass was observed in the group of linagliptin-treated mice (vehicle 0.18±0.03 mg, linagliptin 0.48±0.09 mg, p<0 .01) and the total mass of pancreatic islets (vehicle 0.40±0.04 mg, linagliptin 0.70±0.09 mg, p<0.01). At the same time, for linagliptin there is a tendency to reduce the perislet infiltration of lymphocytes (1.06 ± 0.15, linagliptin 0.79 ± 0.12 mg, p = 0.17). As expected, there was an increase in active GLP-1 levels in linagliptin-treated mice at the end of the trial. In conclusion, these data indicate the ability of linagliptin to delay the onset of diabetes in a mouse model of type 1 diabetes (NOD). The significant β cell-sparing effect that can be observed in this animal model indicates that this inhibition of DPP-4 not only protects β cells by increasing levels of active GLP-1, but may also have direct or indirect anti-inflammatory effects. action. CLAIM 1. Use of a DPP-4 inhibitor, which is linagliptin, in a method of improving glycemic control in an elderly patient with type 2 diabetes, the method comprising adding a DPP-4 inhibitor to a long-acting insulin, which is basal insulin, alone or in combination with one or more other antidiabetic drugs selected from metformin, pioglitazone and a sulfonylurea, where the patient has inadequate control when treated with insulin alone or in combination with one or more other antidiabetic drugs selected from metformin, pioglitazone and a sulfonylurea. 2. Use according to claim 1, where the patient has impaired or reduced renal function. 3. Use according to any of the preceding paragraphs, where the elderly patient is 60-65 years of age or older. 4. Use according to any of the preceding claims, wherein the method is further intended to reduce the dose of insulin required to achieve an adequate therapeutic effect. 5. Use according to any of the preceding claims, wherein the method is further intended to reduce hypoglycemia and/or weight gain associated with insulin treatment. 6. Use according to any of the previous paragraphs, where linagliptin is administered in a daily oral amount of 5 mg. -