HK1192161B - Pharmaceutical composition comprising linagliptin and optionally a sglt2 inhibitor, and uses thereof - Google Patents

Description

Pharmaceutical compositions comprising linagliptin and optionally an SGLT2 inhibitor and uses thereof

The present application is a divisional application of an invention patent application filed on February 11, 2010, with application number 201080007663.6 (international application number PCT/EP2010/051735), and with the invention name “Pharmaceutical composition comprising linagliptin and an optional SGLT2 inhibitor and its use”.

Technical Field

The present invention relates to a pharmaceutical composition comprising linagliptin as the first active pharmaceutical ingredient. Furthermore, the present invention relates to a pharmaceutical dosage form comprising the pharmaceutical composition. Furthermore, the present invention relates to a method for preparing the pharmaceutical dosage form. Furthermore, the present invention relates to the use of the pharmaceutical composition and the pharmaceutical dosage form for treating and/or preventing selected diseases and medical conditions, in particular one or more conditions selected from type I diabetes, type II diabetes, impaired glucose tolerance, impaired fasting blood glucose, and hyperglycemia. Furthermore, the present invention relates to a method for treating and/or preventing these diseases and medical conditions, wherein the pharmaceutical composition or pharmaceutical dosage form of the present invention is administered to a patient in need thereof.

Existing technology

The compound linagliptin is a DPP-IV inhibitor. The enzyme DPP-IV (Dipeptidyl Peptidase IV), also known as CD26, is a serine protease known to cleave dipeptides from the N-terminus of various proteins with proline or alanine residues at the N-terminus. Due to this property, DPP-IV inhibitors interfere with the plasma levels of bioactive peptides, including the peptide GLP-1, and are considered promising drugs for the treatment of diabetes, particularly type 2 diabetes.

In attempts to prepare pharmaceutical compositions of selected DPP-IV inhibitors (e.g., linagliptin), it has been observed that DPP-IV inhibitors with primary or secondary amino groups exhibit incompatibility, degradation problems, or extraction problems with a variety of conventional excipients (e.g., microcrystalline cellulose, sodium starch glycolate, croscarmellose sodium, tartaric acid, citric acid, glucose, fructose, sucrose, lactose, maltodextrin). Although the compounds themselves are very stable, they react with many excipients used in solid dosage forms and with excipient impurities, especially when providing intimate contact in tablets and at high excipient/drug ratios. The amino groups appear to react with reducing sugars, as well as other reactive carbonyl groups, and carboxylic acid functional groups formed, for example, on the surface of microcrystalline cellulose due to oxidation.

These unknown difficulties are primarily due to the low dosage range required due to the surprising efficacy of selected inhibitors (e.g., linagliptin). Therefore, a pharmaceutical composition is needed to address these technical issues associated with the unexpected efficacy of selected DPP-IV inhibitor compounds. WO 2007/128724 discloses a pharmaceutical composition comprising linagliptin as the sole active pharmaceutical ingredient.

Type 2 diabetes is an increasingly prevalent disease that significantly shortens life expectancy due to a high frequency of complications. Due to diabetes-related microvascular complications, type 2 diabetes is currently the most common cause of adult-onset blindness, renal failure, and amputations in the industrialized world. In addition, the presence of type 2 diabetes is associated with a 2- to 5-fold increased risk of cardiovascular disease.

After long-term persistence of the disease, most patients with type 2 diabetes eventually fail oral therapy and become insulin dependent, necessitating daily insulin injections and multiple daily glucose measurements.

Commonly used oral antidiabetic drugs in therapy (e.g., first-line or second-line therapy and/or monotherapy or (initial or add-on) combination therapy) include, but are not limited to, metformin, sulfonylureas, thiazolidinediones, glinides, and α-glucosidase inhibitors.

The high incidence of treatment failure is the main reason for the high rate of complications or chronic damage associated with long-term hyperglycemia in patients with type 2 diabetes, including microvascular and macrovascular complications, such as diabetic nephropathy, retinopathy or neuropathy, or cardiovascular complications.

Thus, there is an unmet need for methods, medicaments, and pharmaceutical compositions that have good efficacy with respect to glycemic control, with respect to disease-modifying properties, and with respect to reducing cardiovascular morbidity and mortality, while exhibiting an improved safety profile.

SGLT2 inhibitors represent a class of new drugs developed for treating or improving glycemic control in patients with type 2 diabetes. Glucopyranosyl-substituted benzene derivatives are disclosed in the prior art as SGLT2 inhibitors, for example in WO01/27128, WO03/099836, WO2005/092877, WO2006/034489, WO2006/064033, WO2006/117359, WO2006/117360, WO2007/025943, WO2007/028814, WO2007/031548, WO2007/093610, WO2007/128749, WO2008/049923, WO2008/055870, and WO2008/055940. Glucopyranose-substituted benzene derivatives are proposed as inducers of urinary sugar excretion and as drugs for treating diabetes.

Purpose of the Invention

It is an object of the present invention to provide a pharmaceutical composition comprising linagliptin which shows no or only minimal signs of degradation of linagliptin, thereby resulting in a good to excellent shelf life.

Another object of the present invention is to provide a pharmaceutical composition comprising linagliptin which has a high content uniformity and/or allows an efficient production in terms of time and cost of pharmaceutical dosage forms.

Another object of the present invention is to provide a pharmaceutical dosage form comprising linagliptin, which has a good shelf life, a short disintegration time, good dissolution properties and/or allows for high bioavailability of linagliptin in patients.

Another object of the present invention is to provide a pharmaceutical composition comprising a combination of a DPPIV inhibitor and an SGLT2 inhibitor.

Another object of the present invention is to provide a pharmaceutical composition comprising linagliptin in combination with an SGLT2 inhibitor, which pharmaceutical composition shows no or only minimal signs of degradation of linagliptin and thus has a good to excellent shelf life.

Another object of the present invention is to provide a pharmaceutical composition comprising linagliptin in combination with an SGLT2 inhibitor, which has a high content uniformity and/or allows for an efficient production in terms of time and cost of the pharmaceutical dosage form.

Another object of the present invention is to provide a pharmaceutical dosage form comprising linagliptin in combination with an SGLT2 inhibitor, which has a good shelf life, a short disintegration time, good dissolution properties and/or allows for high bioavailability of linagliptin in patients.

Another object of the present invention is to provide a pharmaceutical composition and a pharmaceutical dosage form comprising linagliptin in combination with an SGLT2 inhibitor, as well as a method for preventing metabolic disorders (especially type II diabetes), slowing the progression of the metabolic disorders, delaying or treating the metabolic disorders.

Another object of the present invention is to provide a pharmaceutical composition and a pharmaceutical dosage form comprising linagliptin in combination with an SGLT2 inhibitor, as well as a method for improving glycemic control in patients in need thereof (especially patients with type 2 diabetes).

Another object of the present invention is to provide pharmaceutical compositions and pharmaceutical dosage forms comprising linagliptin in combination with an SGLT2 inhibitor, as well as methods for improving glycemic control in patients whose glycemic control is insufficient despite monotherapy with an antidiabetic drug (e.g., metformin or an SGLT2 inhibitor or a DPPIV inhibitor).

Another object of the present invention is to provide a pharmaceutical composition and a pharmaceutical dosage form comprising linagliptin in combination with an SGLT2 inhibitor, as well as a method for preventing, slowing down or delaying the progression of impaired glucose tolerance (IGT), impaired fasting glucose (IFG), insulin resistance and/or metabolic syndrome to type 2 diabetes.

Another object of the present invention is to provide a pharmaceutical composition and a pharmaceutical dosage form comprising linagliptin in combination with an SGLT2 inhibitor, as well as a method for preventing, slowing the progression of, delaying or treating a condition or disorder selected from diabetic complications.

Another object of the present invention is to provide pharmaceutical compositions and pharmaceutical dosage forms comprising linagliptin in combination with an SGLT2 inhibitor, as well as methods for reducing body weight or preventing weight gain in patients in need thereof.

Another object of the present invention is to provide novel pharmaceutical compositions and pharmaceutical dosage forms, each comprising linagliptin in combination with an SGLT2 inhibitor, which have high efficacy in treating metabolic disorders, in particular diabetes, impaired glucose tolerance (IGT), impaired fasting glucose (IFG) and/or hyperglycemia, and which have good to excellent pharmacological and/or pharmacokinetic and/or physicochemical properties.

Another object of the present invention is to provide a method for preparing the pharmaceutical dosage form according to the invention which is highly efficient in terms of cost and/or time.

From the above description and the following embodiments, other objects of the present invention will be apparent to those skilled in the art.

SUMMARY OF THE INVENTION

In a first aspect, the present invention provides a pharmaceutical composition comprising linagliptin as a first active pharmaceutical ingredient and one or more excipients (particularly one or more diluents, one or more binders, and/or one or more disintegrants). The pharmaceutical composition of the present invention is preferably a solid pharmaceutical composition, for example, a solid pharmaceutical composition for oral administration.

Within the scope of the present invention, it has been found that pharmaceutical compositions comprising linagliptin as active pharmaceutical ingredient with a particle size distribution of X90 <200 μm show a favorable dissolution profile and/or good bioavailability, have a high content uniformity and allow for efficient production of pharmaceutical dosage forms in terms of time and cost.

Therefore, in another aspect, the present invention provides a pharmaceutical composition comprising linagliptin as a first active pharmaceutical ingredient and one or more excipients, wherein the first active ingredient has a particle size distribution of X90 < 200 μm, preferably determined by volume by laser diffraction.

Furthermore, within the scope of the present invention, it has been found that linagliptin in combination with certain excipients shows no or only minimal signs of linagliptin degradation and thus has a good to excellent shelf life. In particular, it has been found that the objects of the present invention can be achieved by a pharmaceutical composition as described above comprising only one diluent.

Furthermore, within the scope of the present invention, it has been discovered that pharmaceutical compositions comprising linagliptin as the first active pharmaceutical ingredient in combination with a glucopyranosyl-substituted benzene derivative of formula (I) as described below as an SGLT2 inhibitor show no or minimal signs of linagliptin degradation and thus have a good to excellent shelf life. This result could not have been predicted prior to the present invention, given the chemical properties of linagliptin and the functional groups of the glucopyranosyl-substituted benzene derivative (particularly the glucopyranosyl ring and the hydroxyl group therein).

Therefore, in another aspect, the present invention provides a pharmaceutical composition comprising linagliptin as an active pharmaceutical ingredient; a pyranosyl-substituted benzene derivative of formula (I)

wherein R ¹ represents chlorine or methyl; and R ³ represents ethyl, ethynyl, ethoxy, (R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy, or a prodrug thereof, as an active pharmaceutical ingredient; one or more diluents; one or more binders; and one or more disintegrants.

Within the scope of the present invention, it has been found that pharmaceutical compositions comprising as active pharmaceutical ingredients glucopyranosyl-substituted benzene derivatives having a particle size distribution of 1 μm < X90 < 200 μm exhibit favorable dissolution properties and/or good bioavailability, have high content uniformity and allow efficient production of pharmaceutical dosage forms in terms of time and cost.

Therefore, in another aspect, the present invention provides a pharmaceutical composition comprising linagliptin as a first active pharmaceutical ingredient and a glucopyranosyl-substituted benzene derivative of formula (I) as described below as a second active pharmaceutical ingredient, and one or more excipients, wherein the second active ingredient has a particle size distribution of 1 μm < X90 < 200 μm, preferably determined by volume by laser diffraction.

The pharmaceutical compositions of the present invention have high content uniformity and allow for time- and cost-effective production of pharmaceutical dosage forms (e.g., tablets and capsules). Furthermore, these pharmaceutical dosage forms (particularly tablets, e.g., monolayer tablets or bilayer tablets) show no or only minimal signs of linagliptin degradation and thus have a long shelf life.

Therefore, in another aspect, the present invention provides a pharmaceutical dosage form comprising the pharmaceutical composition of the present invention.The pharmaceutical dosage form of the present invention is preferably a solid pharmaceutical dosage form, even more preferably a solid pharmaceutical dosage form for oral administration.

In another aspect, the present invention provides a process for preparing a pharmaceutical dosage form according to the invention, the process comprising one or more granulation steps, wherein one or both active pharmaceutical ingredients are granulated together with one or more excipients.

Furthermore, it has been discovered that pharmaceutical compositions comprising linagliptin in combination with a glucopyranosyl-substituted benzene derivative of formula (I) described below can be advantageously used to prevent, slow the progression of, delay, or treat metabolic disorders in patients, particularly for improving glycemic control in patients whose glycemic control is inadequate on existing therapies containing oral antidiabetic drugs. This opens up new therapeutic possibilities for the treatment and prevention of type 2 diabetes, overweight, obesity, diabetic complications, and related conditions.

According to another aspect of the present invention, a method for preventing, slowing the progression of, delaying or treating a metabolic disorder in a patient in need thereof is provided, wherein the metabolic disorder is selected from the group consisting of: type I diabetes, type II diabetes, impaired glucose tolerance (IGT), impaired fasting glucose (IFG), hyperglycemia, postprandial hyperglycemia, overweight, obesity and metabolic syndrome, characterized in that the pharmaceutical composition or pharmaceutical dosage form defined above and below is administered to the patient.

According to another aspect of the present invention, there is provided a method for improving glycemic control and/or lowering fasting plasma glucose, postprandial plasma glucose and/or glycosylated hemoglobin HbA1c in a patient in need thereof, characterized in that the pharmaceutical composition or pharmaceutical dosage form as defined above and below is administered to the patient.

The pharmaceutical compositions and pharmaceutical dosage forms of the present invention may also have valuable disease-modifying properties with respect to diseases or conditions associated with impaired glucose tolerance (IGT), impaired fasting glucose (IFG), insulin resistance and/or metabolic syndrome.

According to another aspect of the present invention, there is provided a method for preventing, slowing, delaying or reversing the progression of impaired glucose tolerance (IGT), impaired fasting glucose (IFG), insulin resistance and/or metabolic syndrome to type 2 diabetes in a patient in need thereof, characterized in that the pharmaceutical composition or pharmaceutical dosage form defined above and below is administered to the patient.

By using the pharmaceutical composition and pharmaceutical dosage form of the present invention, blood sugar control in patients in need thereof can be improved, and conditions and/or diseases associated with or caused by increased blood sugar levels can be treated.

According to another aspect of the present invention, there is provided a method for preventing a condition or disorder, slowing the progression of the condition or disorder, delaying or treating the condition or disorder in a patient in need thereof, the condition or disorder being selected from the group consisting of: diabetic complications, such as cataracts and microvascular and macrovascular diseases, such as nephropathy, retinopathy, neuropathy, tissue ischemia, diabetic foot, arteriosclerosis, myocardial infarction, acute coronary syndrome, unstable angina, stable angina, stroke, peripheral arterial occlusive disease, cardiomyopathy, heart failure, arrhythmias and vascular restenosis, characterized in that the pharmaceutical composition or pharmaceutical dosage form defined above and below is administered to the patient. The term "tissue ischemia" particularly encompasses diabetic macrovascular disease, diabetic microangiopathy, wound healing abnormalities and diabetic ulcers. In particular, one or more aspects of diabetic nephropathy (e.g., hyperperfusion, proteinuria and albuminuria) can be treated, their progression slowed, or their onset delayed or prevented. The terms "microvascular and macrovascular disease" and "microvascular and macrovascular complications" are used interchangeably in this application.

By administering the pharmaceutical composition and dosage form of the present invention and due to the activity of the SGLT2 inhibitor, the excessive blood sugar content is not converted into insoluble storage forms (such as fat), but is excreted through the patient's urine. Therefore, the result is no weight gain or even weight loss.

According to another aspect of the present invention, there is provided a method for reducing body weight or preventing weight gain or promoting weight loss in a patient in need thereof, characterized in that the pharmaceutical composition or pharmaceutical dosage form as defined above and below is administered to the patient.

The pharmacological effects of the glucopyranosyl-substituted benzene derivatives used in the pharmaceutical compositions of the present invention as SGLT2 inhibitors are independent of insulin. Therefore, it is possible to improve glycemic control without causing additional damage to pancreatic beta cells. Administration of the pharmaceutical compositions or dosage forms of the present invention can delay or prevent beta cell degeneration and decreased beta cell function, such as apoptosis or necrosis of pancreatic beta cells. Furthermore, pancreatic cell function can be improved or restored, and the number and size of pancreatic beta cells can be increased. It has been shown that treatment with the pharmaceutical compositions or dosage forms of the present invention can normalize the differentiation and proliferation of pancreatic beta cells, which are disrupted by hyperglycemia.

According to another aspect of the present invention, there is provided a method for preventing, slowing, delaying or treating pancreatic β cell degeneration and/or decreased pancreatic β cell function, and/or improving and/or restoring pancreatic β cell function, and/or restoring pancreatic insulin secretion function in a patient in need thereof, characterized in that the pharmaceutical composition or pharmaceutical dosage form defined above and below is administered to the patient.

By administering the pharmaceutical composition and pharmaceutical dosage form of the present invention, the abnormal accumulation of fat in the liver can be reduced or inhibited. Therefore, according to another aspect of the present invention, a method for preventing, slowing down, delaying or treating a disease or condition caused by abnormal accumulation of fat in the liver in a patient in need is provided, characterized in that the pharmaceutical composition or pharmaceutical dosage form defined above and below is administered to the patient. The disease or condition caused by abnormal accumulation of fat in the liver is particularly selected from: general fatty liver, non-alcoholic fatty liver (NAFL), non-alcoholic steatohepatitis (NASH), fatty liver induced by overnutrition, diabetic fatty liver, alcohol-induced fatty liver or toxic fatty liver.

Thus, another aspect of the present invention provides a method for maintaining and/or improving insulin sensitivity and/or treating or preventing hyperinsulinemia and/or insulin resistance in a patient in need thereof, characterized in that a pharmaceutical composition or pharmaceutical dosage form as defined above and below is administered to the patient.

According to another aspect of the present invention, there is provided a use of the pharmaceutical composition of the present invention in the preparation of a medicament for achieving the following purposes in a patient in need:

- preventing, slowing the progression of, delaying or treating a metabolic disorder selected from the group consisting of type I diabetes, type II diabetes, impaired glucose tolerance (IGT), impaired fasting glucose (IFG), hyperglycemia, postprandial hyperglycemia, overweight, obesity and metabolic syndrome; or

- Improved glycemic control and/or reduction in fasting plasma glucose, postprandial plasma glucose and/or glycosylated haemoglobin HbA1c; or

- prevent, slow, delay or reverse the progression of impaired glucose tolerance (IGT), impaired fasting glucose (IFG), insulin resistance and/or metabolic syndrome to type 2 diabetes; or

- preventing, slowing the progression of, delaying or treating a condition or disorder selected from the group consisting of: diabetic complications, such as cataracts and microvascular and macrovascular diseases, such as nephropathy, retinopathy, neuropathy, tissue ischemia, diabetic foot, arteriosclerosis, myocardial infarction, acute coronary syndrome, unstable angina, stable angina, stroke, peripheral arterial occlusive disease, cardiomyopathy, heart failure, arrhythmia and vascular restenosis; or

- Reduce weight or prevent weight gain or promote weight loss; or

- preventing, slowing down, delaying or treating pancreatic beta cell degeneration and/or reduction of pancreatic beta cell function, and/or improving and/or restoring pancreatic beta cell function and/or restoring pancreatic insulin secretion function; or

-Prevent, slow, delay or treat a disease or condition caused by abnormal accumulation of fat in the liver; or

- Maintaining and/or improving insulin sensitivity and/or treating or preventing hyperinsulinemia and/or insulin resistance.

According to another aspect of the present invention, there is provided use of the pharmaceutical composition or pharmaceutical dosage form of the present invention in the preparation of a medicament for use in the therapeutic and prophylactic methods described above and below.

definition

The term "active ingredient" or "active pharmaceutical ingredient" of the pharmaceutical composition or dosage form of the present invention refers to linagliptin and optionally the glucopyranosyl-substituted benzene derivative of formula (I) of the present invention, in particular compound (I.3).

The term "body mass index" or "BMI" for a human patient is defined as the weight in kilograms divided by the square of the height in meters, such that the units of BMI are kg/ ^m2 .

The term "overweight" is defined as a condition in which an individual has a BMI greater than 25 kg/m ² and less than 30 kg/m ^2. The terms "overweight" and "pre-obesity" are used interchangeably.

The term "obesity" is defined as a condition in which an individual has a BMI equal to or greater than 30 kg/m ^2. According to the WHO definition, the term obesity can be classified as follows: the term "class I obesity" is a condition in which the BMI is equal to or greater than 30 kg/m ² but less than 35 kg/m ² ; the term "class II obesity" is a condition in which the BMI is equal to or greater than 35 kg/m ² but less than 40 kg/m ² ; and the term "class III obesity" is a condition in which the BMI is equal to or greater than 40 kg/m ² .

The term "visceral obesity" is defined as a condition where a waist-to-hip ratio is measured to be greater than or equal to 1.0 in men and greater than or equal to 0.8 in women. This defines the risk of developing insulin resistance and prediabetes.

The term "abdominal obesity" is generally defined as a condition in which a waist circumference is >40 inches or 102 cm in men and >35 inches or 94 cm in women. With respect to Japanese ethnicity or Japanese patients, abdominal obesity can be defined as a waist circumference ≥85 cm in men and ≥90 cm in women (e.g., see the investigating committee for the diagnosis of metabolic syndrome in Japan).

The term "euglycemia" is defined as a condition in which an individual's fasting blood glucose concentration is within the normal range, ie, greater than 70 mg/dL (3.89 mmol/L) and less than 100 mg/dL (5.6 mmol/L). The term "fasting" has the general meaning of medical terminology.

The term "hyperglycemia" is defined as a condition in which a subject's fasting blood glucose concentration is above the normal range, ie, greater than 100 mg/dL (5.6 mmol/L). The term "fasting" has its ordinary meaning as a medical term.

The term "hypoglycemia" is defined as a condition in which a subject's blood glucose concentration is below the normal range, particularly less than 70 mg/dL (3.89 mmol/L).

The term "postprandial hyperglycemia" is defined as a condition in which a subject's blood glucose or serum glucose concentration is greater than 200 mg/dL (11.11 mmol/L) two hours after a meal.

The term "improper fasting glucose" or "IFG" is defined as a condition in which a subject has a fasting blood glucose concentration, or fasting serum glucose concentration, in the range of 100 to 125 mg/dL (i.e., 5.6 to 6.9 mmol/L), particularly greater than 110 mg/dL and less than 126 mg/dL (7.00 mmol/L). "Normal fasting glucose" refers to a fasting glucose concentration of less than 100 mg/dL, i.e., less than 5.6 mmol/L.

The term "impaired glucose tolerance" or "IGT" is defined as a condition in which an individual's blood glucose or serum glucose concentration is greater than 140 mg/dL (7.78 mmol/L) and less than 200 mg/dL (11.11 mmol/L) two hours after a meal. Abnormal glucose tolerance (i.e., blood glucose or serum glucose concentration two hours after a meal) can be measured as the blood glucose level in milligrams of glucose per deciliter of plasma two hours after ingesting 75 g of glucose after a fasting period. Individuals with "normal glucose tolerance" have a blood glucose or serum glucose concentration of less than 140 mg/dL (7.78 mmol/L) two hours after a meal.

The term "hyperinsulinemia" is defined as a condition in which individuals with insulin resistance and normoglycemia or ectopic glucose have elevated fasting or postprandial serum or plasma insulin concentrations compared to normal lean individuals without insulin resistance and with waist-to-hip ratios <1.0 (males) or <0.8 (females).

The terms "insulin sensitivity," "improvement in insulin resistance," or "reduction in insulin resistance" are synonymous and used interchangeably.

The term "insulin resistance" is defined as a state in which circulating insulin levels exceed the normal response to glucose stimulation to maintain a normal blood sugar state (Ford ES et al., JAMA. (2002) 287: 356-9). The method for determining insulin resistance is the euglycemic-hyperinsulinaemic clamp test. The ratio of insulin to glucose is determined within the context of a combined insulin-glucose infusion technique. If glucose absorption is less than 25% of the background population studied, it is considered to be insulin resistant (WHO definition). Much simpler than the clamp test is the so-called minimal model, in which insulin and glucose concentrations in the blood are measured at fixed time intervals during an intravenous glucose tolerance test, and insulin resistance is calculated from this. It is not possible to distinguish between hepatic insulin resistance and peripheral insulin resistance with this method.

In addition, insulin resistance (i.e., the response of patients with insulin resistance to therapy), insulin sensitivity, and hyperinsulinemia can be quantified by assessing the "homeostasis model assessment of insulin resistance (HOMA-IR)" score (a reliable indicator of insulin resistance) (Katsuk IA et al., Diabetes Care 2001; 24: 362-5). Reference is also made to methods for determining the HOMA index of insulin sensitivity (Matthews et al., Diabetologia 1985, 28: 412-19), methods for determining the ratio of intact proinsulin to insulin (Forst et al., Diabetes 2003, 52 (Suppl 1): A459), and euglycemic clamp studies. In addition, plasma adiponectin levels can be monitored as a possible surrogate for insulin sensitivity. The homeostasis model assessment (HOMA)-IR score is used to estimate insulin resistance (Galvin P et al., Diabet Med 1992; 9: 921-8) using the following formula:

HOMA-IR = [fasting serum insulin (μU/mL)] × [fasting plasma glucose (mmol/L)/22.5]

Typically, other parameters are used in daily clinical practice to assess insulin resistance. Preferably, for example, the patient's triglyceride concentration is used, since an increase in triglyceride levels is significantly correlated with the presence of insulin resistance.

Patients with a tendency to develop IGT or IFG or type II diabetes are those with hyperinsulinemia and are defined as normal blood sugar individuals with insulin resistance. Typical patients with insulin resistance are generally overweight or obese. If insulin resistance can be detected, this is a strong indicator of the presence of pre-diabetes. Therefore, in order to maintain glucose homeostasis, the individual may require 2-3 times the amount of insulin as a healthy individual before any clinical symptoms occur.

Methods for studying pancreatic β-cell function are similar to those described above for insulin sensitivity, hyperinsulinemia, or insulin resistance: improvements in β-cell function can be measured, for example, by determining the HOMA index of β-cell function (Matthews et al., Diabetologia 1985, 28:412-19), the ratio of intact proinsulin to insulin (Forst et al., Diabetes 2003, 52(Suppl 1):A459), insulin/C-peptide secretion after an oral glucose tolerance test or a meal tolerance test, or by using a hyperglycemic clamp study and/or a mini-model after a frequently sampled intravenous glucose tolerance test (Stumvoll et al., Eur J Clin Invest 2001, 31:380-81).

The term "prediabetes" is a condition in which an individual is prone to developing type 2 diabetes. Prediabetes expands the definition of impaired glucose tolerance to include individuals with fasting blood glucose in the high normal range (≥100 mg/dL) (J.B. Meigs et al., Diabetes 2003; 52: 1475-1484) and fasting hyperinsulinemia (high plasma insulin concentration). The American Diabetes Association and the National Institute of Diabetes and Digestive and Kidney Diseases (National Institute of Diabetes and Digestive and Kidney Diseases) jointly published a status report entitled "The Prevention or Delay of Type 2 Diabetes" to describe the scientific and medical basis for identifying prediabetes as a serious health threat (Diabetes Care 2002; 25: 742-749).

The individuality that may have insulin resistance is the individuality with two or more following characteristics: 1) being overweight or obese, 2) hypertension, 3) hyperlipidemia, 4) one or more first degree relatives are diagnosed with IGT or IFG or type II diabetes.Can determine the insulin resistance of these individuals by calculating HOMA-IR score.For purposes of the present invention, insulin resistance is defined as the clinical condition that individuality has HOMA-IR score＞4.0 or HOMA-IR score is higher than the upper limit of normal that the laboratory carries out glucose and insulin analysis and defines.

The term "type 2 diabetes" is defined as a condition in which a person's fasting blood sugar or serum glucose concentration is greater than 125 mg/dL (6.94 mmol/L). The measurement of blood sugar levels is a standard procedure in routine medical analysis. If a glucose tolerance test is performed, the blood sugar level of a diabetic patient will exceed 200 mg of glucose (11.1 mmol/l) per deciliter of plasma 2 hours after taking 75 g of glucose on a fasting stomach. In a glucose tolerance test, 75 g of glucose is orally administered to the patient to be tested 10-12 hours after fasting, and blood sugar levels are recorded immediately before and 1 hour and 2 hours after taking the glucose. In healthy individuals, the blood sugar level before taking the glucose will be 60 mg to 110 mg per deciliter of plasma, 1 hour after taking the glucose, it will be less than 200 mg/dL, and 2 hours after taking it, it will be less than 140 mg/dL. If the value is 140 mg to 200 mg 2 hours after taking it, this is considered to be abnormal glucose tolerance.

The term "advanced type 2 diabetes" includes patients who have developed microvascular and macrovascular complications such as diabetic nephropathy or coronary heart disease (CHD) secondary to drug failure and are candidates for insulin therapy.

The term "HbA1c" refers to the product of non-enzymatic glycosylation of the hemoglobin B chain. Its determination is well known to those skilled in the art. HbA1c values are particularly important when monitoring the treatment of diabetes. Because HbA1c production is essentially dependent on blood glucose levels and the lifespan of red blood cells, HbA1c reflects the average blood glucose levels over the preceding 4-6 weeks in the sense of a "glycemic memory." Diabetic patients whose HbA1c values are consistently well-regulated by intensive diabetes treatment (i.e., less than 6.5% of the total hemoglobin in the sample) are significantly better protected from diabetic microangiopathy. For example, metformin alone achieves an average improvement of approximately 1.0-1.5% in HbA1c values in diabetic patients. In all diabetic patients, this reduction in HbA1c values is insufficient to reach the desired target range of HbA1c <6.5%, and preferably <6%.

In the context of the present invention, the term "inadequate glycemic control" or "insufficient glycemic control" refers to a situation in which a patient shows an HbA1c value above 6.5%, in particular above 7.0%, even higher than 7.5%, in particular above 8%.

"Metabolic syndrome", also known as "Syndrome X" (used in the context of metabolic disorders), also known as "dysmetabolic syndrome", is a syndrome whose main feature is insulin resistance (Laaksonen DE et al., Am J Epidemiol 2002; 156: 1070-7). According to the ATP III/NCEP guidelines (Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) JAMA: Journal of the American Medical Association (2001) 285: 2486-2497), metabolic syndrome is diagnosed when three or more of the following risk factors are present:

1. Abdominal obesity, defined as a waist circumference >40 inches or 102 cm for men and >35 inches or 94 cm for women; or for Japanese ethnicity or Japanese patients, a waist circumference ≥85 cm for men and ≥90 cm for women;

2. Triglycerides: ≥150 mg/dL

3. Male HDL-cholesterol <40 mg/dL

4. Blood pressure ≥130/85 mm Hg (SBP ≥130 or DBP ≥85)

5. Fasting blood glucose ≥100 mg/dL

The NCEP definition has been validated (Laaksonen DE et al., Am J Epidemiol. (2002) 156: 1070-7). Triglycerides and HDL cholesterol in blood can also be determined by standard methods in medical analysis and as described, for example, in Thomas L (ed.): "Labor und Diagnose", TH-Books Verlagsgesellschaft mbH, Frankfurt/Main, 2000.

According to the commonly used definition, hypertension is diagnosed when systolic blood pressure (SBP) exceeds 140 mm Hg and diastolic blood pressure (DBP) exceeds 90 mm Hg. If a patient has manifest diabetes, it is currently recommended to lower systolic blood pressure to less than 130 mm Hg and diastolic blood pressure to less than 80 mm Hg.

The term "treat" encompasses therapeutic treatment of a patient who has already developed the disorder, particularly the overt form of the disorder. Therapeutic treatment can be symptomatic treatment to alleviate the symptoms of a particular indication, or causal treatment to reverse or partially reverse the condition of the indication or to halt or slow disease progression. Thus, the compositions, dosage forms, and methods of the present invention can be used, for example, as therapeutic treatment over a period of time, as well as for long-term therapy.

The terms "prophylactic treatment" and "prevention" are used interchangeably and encompass treating a patient at risk of developing the conditions mentioned above so as to reduce that risk.

As used herein, the term "therapeutically effective amount" refers to the amount or dosage of the active pharmaceutical ingredient that achieves a desired therapeutic response (e.g., lowering blood glucose levels, lowering HbA1c, or reducing body weight) in a mammalian subject or patient, but preferably does not cause hypoglycemia in the subject or patient. Where a pharmaceutical composition or dosage form comprises two active pharmaceutical ingredients, the term "therapeutically effective amount" as used herein refers to the amount or dosage of each active pharmaceutical ingredient in combination with the other active pharmaceutical ingredient that achieves a desired therapeutic response (e.g., lowering blood glucose levels, lowering HbA1c, or reducing body weight) in a mammalian subject or patient, but preferably does not cause hypoglycemia in the subject or patient.

The term "tablet" includes uncoated tablets and tablets with one or more layers of coating. In addition, the term "tablet" includes tablets with one, two, three or even more layers and compressed coated tablets, wherein each of the above types of tablets can be uncoated or have one or more layers of coating. The term "tablet" also includes mini tablets, melt tablets, chewable tablets, effervescent tablets and orally disintegrating tablets.

The term "pharmacopoeia" refers to a standard pharmacopoeia, such as "USP31-NF26 through Second Supplement" (United States Pharmacopeial Convention) or "European Pharmacopoeia 6.3" (European Directorate for the Quality of Medicines and Health Care, 2000-2009).

BRIEF DESCRIPTION OF THE DRAWINGS

FIG1 shows an X-ray powder diffraction pattern of a crystalline form (I.3X) of compound (I.3).

FIG2 shows the thermal analysis of the crystalline form (I.3X) of compound (I.3) and the determination of the melting point by DSC.

Figure 3 shows glucose excursions quantified by calculating reactive glucose AUC after glucose stimulation in four different groups of ZDF rats that received control, linagliptin (Compound A), Compound (I.3) (Compound B), or the combination of linagliptin and Compound (I.3) (Combination A+B).

FIG4 shows the dissolution profiles of the tablets of Examples 4 and 6, wherein API 1 is compound (I.3) and API 2 is linagliptin.

Figure 5 shows the dissolution profile of the tablet of Example 8, wherein API 1 is compound (I.3) and API 2 is linagliptin.

Detailed Description of the Invention

Aspects of the present invention (particularly pharmaceutical compositions, pharmaceutical dosage forms, methods and uses) relate to linagliptin and glucopyranosyl-substituted benzene derivatives as defined above and below.

As used herein, the term "linagliptin" refers to linagliptin and its pharmaceutically acceptable salts, including hydrates and solvates thereof, and crystalline forms thereof. Crystalline forms are disclosed in WO 2007/128721. Preferred crystalline forms are polymorphs A and B described herein. Methods for preparing linagliptin are disclosed, for example, in patent applications WO 2004/018468 and WO 2006/048427. Linagliptin differs from structurally comparable DPP IV inhibitors in that, when used in combination with the glucopyranosyl-substituted benzene derivatives of the present invention, it combines exceptional potency and long-lasting action with favorable pharmacological properties, receptor selectivity, and a favorable side effect profile, resulting in unexpected therapeutic advantages or improvements.

The glucopyranosyl-substituted benzene derivatives are defined by formula (I),

wherein R ¹ represents chloro or methyl; and R ³ represents ethyl, ethynyl, ethoxy, (R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy; or a prodrug thereof.

The compound of formula (I) and its synthesis method are disclosed in, for example, the following patent applications: WO 2005/092877, WO 2006/117360, WO 2006/117359, WO 2006/120208, WO 2006/064033, WO 2007/028814, WO 2007/031548, WO 2008/049923.

In the above glucopyranosyl-substituted benzene derivatives of formula (I), the following definitions of substituents are preferred.

R ¹ preferably represents chlorine.

R ³ preferably represents ethynyl, (R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy.

Most preferably, R ³ represents (R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy.

Preferred glucopyranosyl-substituted benzene derivatives of the formula (I) are selected from compounds (I.1) to (I.5):

Even more preferred glucopyranosyl-substituted benzene derivatives of the formula (I) are selected from compounds (I.2) and (I.3).

According to the present invention, it should be understood that the definition of the glucopyranosyl-substituted benzene derivatives of formula (I) listed above also includes their hydrates, solvates, polymorphs thereof, and prodrugs thereof. With respect to the preferred compound (I.1), favorable crystalline forms are disclosed in International Patent Application WO 2007/028814, which is incorporated herein by reference in its entirety. With respect to the preferred compound (I.2), favorable crystalline forms are disclosed in International Patent Application WO 2006/117360, which is incorporated herein by reference in its entirety. With respect to the preferred compound (I.3), favorable crystalline forms are disclosed in International Patent Application WO 2006/117359, which is incorporated herein by reference in its entirety. With respect to the preferred compound (I.5), favorable crystalline forms are disclosed in International Patent Application WO 2008/049923, which is incorporated herein by reference in its entirety. These crystalline forms have good solubility properties, which impart good bioavailability to the glucopyranosyl-substituted benzene derivatives. In addition, the crystalline forms are physicochemically stable, thus providing good shelf-life stability for the pharmaceutical composition.

A preferred crystalline form (I.3X) of compound (I.3) is characterized by an X-ray powder diffraction pattern comprising peaks at 18.84, 20.36 and 25.21 degrees 2θ (±0.1 degrees 2θ), wherein the X-ray powder diffraction pattern (XRPD) is obtained using CuK _α1 radiation.

Specifically, the X-ray powder diffraction pattern includes peaks at 14.69, 18.84, 19.16, 19.50, 20.36, and 25.21 degrees 2θ (±0.1 degrees 2θ), wherein the X-ray powder diffraction pattern is obtained using CuK _α1 radiation.

Specifically, the X-ray powder diffraction pattern includes peaks at 14.69, 17.95, 18.43, 18.84, 19.16, 19.50, 20.36, 22.71, 23.44, 24.81, 25.21 and 25.65 degrees 2θ (±0.1 degrees 2θ), wherein the X-ray powder diffraction pattern is obtained using CuK _α1 radiation.

More specifically, form (I.3X) is characterized by an X-ray powder diffraction pattern obtained using CuK _α1 radiation, comprising peaks at degrees 2θ contained in Table 1 (±0.1 degrees 2θ).

Table 1: X-ray powder diffraction pattern of crystalline form (I.3X) (only peaks with 2θ up to 30° are listed):

Even more particularly, Form (I.3X) is characterized by an X-ray powder diffraction pattern obtained using CuK _α1 radiation comprising a peak at degrees 2Θ (±0.1 degrees 2Θ) as shown in FIG1 .

Furthermore, the crystalline form (I.3X) is characterized by a melting point of about 149° C.±3° C. (determined by DSC; evaluated as onset temperature; heating rate 10 K/min). The DSC curve obtained is shown in FIG. 2 .

Within the scope of the present invention, X-ray powder diffraction patterns were recorded using a STOE-STADI P diffractometer in transmission mode, equipped with a position-sensitive detector (OED) and a Cu anode as an X-ray source (Cu K _α1 radiation, 40 kV, 40 mA). In Table 1 above, the value "2θ [°]" represents the diffraction angle in degrees, and the value "d" represents the interplanar spacing in meters. The intensities shown in FIG1 are expressed in the unit cps (counts per second).

In order to allow for experimental error, the above 2θ values should be considered accurate to ±0.1 degrees 2θ, especially ±0.05 degrees 2θ. That is, when assessing whether a given crystalline sample of compound (I.3) is a crystalline form of the present invention, if the 2θ value of the sample observed experimentally is within ±0.1 degrees 2θ of the characteristic value described above, especially if it is within ±0.05 degrees 2θ of the characteristic value, it should be considered identical.

Melting points were determined by DSC (Differential Scanning Calorimetry) using a DSC821 (Mettler Toledo).

With regard to the active pharmaceutical ingredient, it has been found that the dissolution properties of pharmaceutical compositions and dosage forms and, therefore, the bioavailability of the active ingredient are particularly affected by the particle size and particle size distribution of the individual active pharmaceutical ingredients. In the pharmaceutical compositions and dosage forms of the present invention, the particle size distribution of the active pharmaceutical ingredient is preferably such that at least 90% of the individual active pharmaceutical ingredient particles have a particle size of less than 200 μm, i.e., X90 < 200 μm (based on volume distribution).

Specifically, in the pharmaceutical compositions and dosage forms of the present invention, the particle size distribution (by volume) of linagliptin (e.g., a crystalline form thereof) is preferably such that at least 90% of the individual active pharmaceutical ingredients have a particle size less than 200 μm, i.e., X90 < 200 μm, more preferably X90 ≤ 150 μm. The particle size distribution is more preferably such that X90 ≤ 100 μm, even more preferably X90 ≤ 75 μm. Furthermore, the particle size distribution is preferably such that X90 > 0.1 μm, more preferably X90 ≥ 1 μm, and most preferably X90 ≥ 5 μm. Thus, the particle size distribution is preferably such that 0.1 μm < X90 < 200 μm, particularly 0.1 μm < X90 ≤ 150 μm, more preferably 1 μm ≤ X90 ≤ 150 μm, and even more preferably 5 μm ≤ X90 ≤ 100 μm. Preferred examples of the particle size distribution of linagliptin are such that X90 ≤ 50 μm or 10 μm ≤ X90 ≤ 50 μm.

Furthermore, in the pharmaceutical compositions and dosage forms of the present invention, the particle size distribution (by volume) of linagliptin (e.g., a crystalline form thereof) is preferably such that X50 ≤ 90 μm, more preferably X50 ≤ 75 μm, even more preferably X50 ≤ 50 μm, and most preferably X50 ≤ 40 μm. Furthermore, the particle size distribution is preferably such that X50 ≥ 0.1 μm, more preferably X50 ≥ 0.5 μm, and even more preferably X50 ≥ 4 μm. Thus, the particle size distribution is preferably such that 0.1 μm ≤ X50 ≤ 90 μm, particularly 0.5 μm ≤ X50 ≤ 75 μm, more preferably 4 μm ≤ X50 ≤ 75 μm, and even more preferably 4 μm ≤ X50 ≤ 50 μm. A preferred example is 8 μm ≤ X50 ≤ 40 μm.

Furthermore, in the pharmaceutical composition and pharmaceutical dosage form of the present invention, the particle size distribution (by volume) of linagliptin (eg, a crystalline form thereof) is preferably such that X10 ≥ 0.05 μm, more preferably X10 ≥ 0.1 μm, even more preferably X10 ≥ 0.5 μm.

Specifically, with respect to the glucopyranosyl-substituted benzene derivatives of formula (I), particularly compound (I.3), it was surprisingly found that excessively small particle sizes can affect manufacturability, for example through adhesion or film formation. On the other hand, excessively large particle sizes can adversely affect the dissolution properties of pharmaceutical compositions and dosage forms, thereby negatively impacting bioavailability. Preferred ranges for particle size distribution are disclosed below.

In the pharmaceutical compositions and dosage forms of the present invention, the particle size distribution (by volume) of the glucopyranosyl-substituted benzene derivative of formula (I), in particular compound (I.3) (e.g., its crystalline form (I.3X)), is preferably such that at least 90% of the individual active pharmaceutical ingredients have a particle size of less than 200 μm, i.e., X90 < 200 μm, preferably X90 ≤ 150 μm. The particle size distribution is more preferably such that X90 ≤ 100 μm, even more preferably X90 ≤ 90 μm. Furthermore, the particle size distribution is preferably such that X90 ≥ 1 μm, more preferably X90 ≥ 5 μm, even more preferably X90 ≥ 10 μm. Thus, the particle size distribution is preferably such that 1 μm ≤ X90 < 200 μm, in particular 1 μm ≤ X90 ≤ 150 μm, more preferably 5 μm ≤ X90 ≤ 150 μm, even more preferably 5 μm ≤ X90 ≤ 100 μm, even more preferably 10 μm ≤ X90 ≤ 100 μm. A preferred example is X90≤75 μm, and another preferred example is 20 μm≤X90≤50 μm.

Furthermore, in the pharmaceutical compositions and dosage forms of the present invention, the particle size distribution (by volume) of the glucopyranosyl-substituted benzene derivative of formula (I), in particular compound (I.3) (e.g., its crystalline form (I.3X)), is preferably such that X50 ≤ 90 μm, more preferably X50 ≤ 75 μm, even more preferably X50 ≤ 50 μm, and most preferably X50 ≤ 40 μm. Furthermore, the particle size distribution is preferably such that X50 ≥ 1 μm, more preferably X50 ≥ 5 μm, and even more preferably X50 ≥ 8 μm. Thus, the particle size distribution is preferably such that 1 μm ≤ X50 ≤ 90 μm, in particular 1 μm ≤ X50 ≤ 75 μm, more preferably 5 μm ≤ X50 ≤ 75 μm, and even more preferably 5 μm ≤ X50 ≤ 50 μm. A preferred example is 8 μm ≤ X50 ≤ 40 μm.

In addition, in the pharmaceutical compositions and pharmaceutical dosage forms of the present invention, the particle size distribution (by volume) of the glucopyranose-substituted benzene derivative of formula (I), in particular compound (I.3) (e.g., its crystalline form (I.3X)) is preferably such that X10 ≥ 0.1 μm, more preferably X10 ≥ 0.5 μm, even more preferably X10 ≥ 1 μm.

Therefore, the pharmaceutical composition or pharmaceutical dosage form according to the invention is preferably characterized by the above-specified particle size distribution X90, X50 and/or X10 or by one of the following embodiments:

The value X90 refers to the 90% volume distribution value measured using a laser diffractometer. In other words, for the purposes of the present invention, the X90 value represents the particle size below which 90% of the particles are distributed according to volume. Similarly, the value X50 refers to the 50% volume distribution value (median value) measured using a laser diffractometer. In other words, for the purposes of the present invention, the X50 value represents the particle size below which 50% of the particles are distributed according to volume. Similarly, the value X10 refers to the 10% volume distribution value measured using a laser diffractometer. In other words, for the purposes of the present invention, the X10 value represents the particle size below which 10% of the particles are distributed according to volume.

Preferably, all X90, X50, and X10 values in this context are measured by volume and by laser diffraction (particularly small-angle laser scattering, i.e., Fraunhofer diffraction). Preferred tests are disclosed in the experimental section. Laser diffraction is sensitive to the volume of the particles and provides a volume-average particle size, which is equal to the weight-average particle size if the density is constant. It is known to those skilled in the art that the results of the particle size distribution measurement obtained by one technique can be correlated with the results obtained by another technique, for example, based on routine experiments. Alternatively, the particle size distribution in a pharmaceutical composition or dosage form can be determined by microscopy (particularly electron microscopy or scanning electron microscopy).

To provide a suitable starting material consisting of the active pharmaceutical ingredient, for example linagliptin or a glucopyranosyl-substituted benzene derivative (especially compound (I.3) and its crystalline form (I.3X)) is milled (eg jet-milled or pin-milled).

Hereinafter, preferred excipients and carriers in the pharmaceutical composition of the present invention are described in further detail. The excipient is preferably pharmaceutically acceptable.

Preferably, the excipients are selected to be compatible with linagliptin, i.e., such that there is no or only minimal degradation of linagliptin in the pharmaceutical composition. Degradation can be tested in standard tests, for example after 6 months of storage at 40°C and 75% relative humidity. In this context, the term "marginal degradation" shall mean that the chemical degradation of linagliptin is less than 5% by weight, preferably less than 3% by weight, and even more preferably less than 2% by weight of linagliptin. The content and corresponding degradation can be determined by known analytical methods, for example using HPLC or UV methods.

In the pharmaceutical compositions of the present invention, the excipients preferably comprise one or more diluents.

Furthermore, in the pharmaceutical composition of the present invention, the excipient preferably comprises one or more diluents and one or more binders.

Furthermore, in the pharmaceutical composition of the present invention, the excipient preferably comprises one or more diluents, one or more binders, one or more disintegrants, and optionally other ingredients.

Furthermore, in the pharmaceutical composition of the present invention, the excipient even more preferably comprises one or more diluents, one or more binders, one or more disintegrants, one or more lubricants, and optionally other ingredients.

Some excipients can have two or more functions simultaneously, for example, they can act as a diluent and a binder, or as a binder and a disintegrant, or as a diluent, a binder, and a disintegrant.

When the amount of active pharmaceutical ingredient is small, one or more diluents (also known as fillers) are added to achieve the minimum tablet weight according to the pharmacopoeia (e.g., 100 mg or more) and satisfactory content uniformity (e.g., standard deviation <3%). Common diluents such as lactose, sucrose, and microcrystalline cellulose have been observed to be incompatible with linagliptin.

One or more diluents suitable for the pharmaceutical composition of the present invention are preferably selected from the group consisting of cellulose (especially cellulose powder), calcium hydrogen phosphate (especially anhydrous calcium hydrogen phosphate or dihydrated calcium hydrogen phosphate), erythritol, mannitol, starch, pregelatinized starch, and xylitol, including derivatives and hydrates thereof. The diluent pregelatinized starch exhibits additional adhesive properties. Of the diluents listed above, mannitol and pregelatinized starch are particularly preferred.

In case the pharmaceutical composition of the present invention comprises a diluent, then the diluent is preferably mannitol or pregelatinized starch, most preferably mannitol.

In case the pharmaceutical composition of the present invention comprises two or more diluents, then the first diluent is preferably mannitol and the second diluent is selected from the diluents mentioned above, even more preferably pregelatinized starch showing additional adhesive properties.

Mannitol as described above and below is preferably a small particle size grade suitable for granulation. An example is Pearlitol ^™ 50C (Roquette).

The pregelatinized starch described above and below may be any commercially available grade. An example is Starch 1500 ^™ (Colorcon).

The pharmaceutical composition of the present invention preferably does not contain substances selected from the group consisting of glucose, fructose, sucrose, lactose and maltodextrin, in particular lactose. Preferably, the amount of such substances (in particular lactose) contained does not exceed 2% by weight of the total composition, and even more preferably does not exceed 0.5% by weight of the total composition.

One or more binders in the pharmaceutical composition provide cohesiveness to the pharmaceutical composition (e.g., during granulation) and to the compressed tablet. They increase the cohesive strength already present in the diluent. Common binders such as sucrose and microcrystalline cellulose have been observed to be incompatible with linagliptin.

One or more binders suitable for the pharmaceutical composition of the present invention are preferably selected from: copovidone, hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC) and polyvinyl pyrrolidone, pregelatinized starch and low-substituted hydroxypropyl cellulose (L-HPC), including derivatives and hydrates of the above-mentioned substances. Even more preferred binders are copovidone and/or pregelatinized starch.

The copovidones mentioned above and below are preferably copolymers of vinylpyrrolidone and vinyl acetate, preferably having a molecular weight of about 45 000 to about 70 000. An example is Kollidon ^™ VA64 (BASF).

The hydroxypropyl methylcellulose (also known as HPMC or hypromellose) described above and below is preferably hypromellose 2910. The viscosity of the hydroxypropyl methylcellulose is preferably in the range of about 4 cps to about 6 cps. An example is Methocel ^™ E5Prem LV (Dow Chemicals).

The viscosity of hydroxypropyl cellulose (also referred to as HPC) as described above and below is preferably in the range of about 300 mPa·s to about 600 mPa·s. The molecular weight of hydroxypropyl cellulose is preferably about 60,000 to about 100,000, for example about 80,000. An example is Klucel ^™ EF (Aqualon).

The molecular weight of polyvinylpyrrolidone (also known as PVP, polyvidone or povidone) as described above and below is preferably about 28000 to about 54000. The viscosity of polyvinylpyrrolidone is preferably in the range of about 3.5 mPa·s to about 8.5 mPa·s. Examples are Kollidon ^™ 25 or Kollidon ^™ 30 (BASF).

The hydroxypropyl content of the low-substituted hydroxypropyl cellulose (also referred to as L-HPC) described above and below is preferably in the range of about 5% to about 16% by weight.

The binders pregelatinized starch and L-HPC described above exhibit additional diluent and disintegrant properties and may also serve as a secondary diluent or disintegrant.

One or more disintegrants are used to aid in the breakup of pharmaceutical compositions and dosage forms after administration. Common disintegrants such as microcrystalline cellulose have been observed to be incompatible with linagliptin.

The one or more disintegrants suitable for the pharmaceutical composition of the present invention are preferably selected from: crospovidone, low-substituted hydroxypropyl cellulose (L-HPC) and starch (e.g., natural starch, especially corn starch and pregelatinized starch), including derivatives and hydrates of the above substances. Among the above disintegrants, corn starch, pregelatinized starch and crospovidone are even more preferred.

Surprisingly, it has been found that when linagliptin and a glucopyranosyl-substituted benzene derivative of formula (I) are combined in a pharmaceutical composition according to the present invention (especially in one dosage form, such as a tablet or capsule), at least two disintegrants are preferred. Preferred disintegrants are corn starch and crospovidone.

If linagliptin is combined with a glucopyranosyl-substituted benzene derivative inhibitor of formula (I) in a pharmaceutical composition of the present invention (especially in one dosage form, such as a tablet or capsule), a combination of at least three disintegrants is even more preferred. Preferred disintegrants are corn starch, pregelatinized starch, and crospovidone.

The crospovidones mentioned above and below are preferably insoluble povidones, ie cross-linked forms of PVP. Examples are Kollidon ^™ CL or Kollidon ^™ CL-SF (BASF).

The corn starch described above and below is preferably a natural starch. An example is maize starch (Roquette).

The above-mentioned disintegrant starches and pregelatinized starches exhibit additional diluent properties and can therefore also be used as, for example, a second diluent.

The lubricant(s) in the pharmaceutical composition reduce friction during tablet preparation (i.e., during the compression and demoulding cycles). In addition, they help prevent the tablet material from sticking to the die and punch.

The pharmaceutical composition of the present invention preferably further comprises one or more lubricants. The one or more lubricants suitable for the pharmaceutical composition of the present invention are preferably selected from the group consisting of talc (e.g. from Luzenac), polyethylene glycol (especially polyethylene glycol having a molecular weight in the range of about 4400 to about 9000), hydrogenated castor oil, fatty acids and fatty acid salts (especially their calcium, magnesium, sodium or potassium salts, such as calcium behenate, calcium stearate, sodium stearyl fumarate or magnesium stearate (e.g. Mallinckrodt or Peter Greven). More preferably, the lubricant is magnesium stearate and talc.

Surprisingly, it has been found that when linagliptin is combined with a glucopyranosyl-substituted benzene derivative of formula (I) in a pharmaceutical composition according to the present invention (particularly in a single dosage form, such as a tablet or capsule), at least two lubricants are preferred. Preferred lubricants are talc and magnesium stearate. Combinations of two or more lubricants provide low demoulding forces and, for example, prevent adhesion of the final mixture during tablet preparation.

One or more glidants are agents that improve the powder flow properties of a pharmaceutical composition.

The pharmaceutical composition of the present invention may further comprise one or more glidants. The one or more glidants suitable for the pharmaceutical composition of the present invention are preferably selected from the group consisting of talc and colloidal silicon dioxide (eg Aerosil ^™ 200 Pharma (Evonik)).

The particle size of the excipients (particularly one or more diluents, such as mannitol) is preferably in the range of 1 to 500 μm. The particle size during the granulation step is preferably 25 to 160 μm. The particle size during the direct compression process is preferably 180 to 500 μm. The particle size is preferably analyzed by sieve analysis. Preferably, at least 80% by weight, more preferably at least 90% by weight, and most preferably at least 95% by weight of the particles are within the specified range.

According to a first embodiment of the present invention, the pharmaceutical composition comprises only one active pharmaceutical ingredient, namely linagliptin.

A preferred composition according to the first embodiment of the present invention comprises a diluent, a binder, and a disintegrant. The composition preferably comprises only one diluent. Even more preferably, the composition comprises only one diluent and only one binder. Even more preferably, the composition comprises only one diluent, only one binder, and only one disintegrant. The composition may further comprise at least one lubricant. Furthermore, the composition may further comprise at least one glidant.

The pharmaceutical composition of the first embodiment preferably comprises

The percentages are by weight of the total composition.

The following ranges are even more preferred:

The percentages are by weight of the total composition.

Another pharmaceutical composition of the first embodiment preferably comprises

The percentages are by weight of the total composition.

The following ranges are even more preferred:

The percentages are by weight of the total composition.

In the pharmaceutical composition described above, the preferred diluent is mannitol. The preferred binder is copovidone. The preferred disintegrant is corn starch. The preferred lubricant is magnesium stearate. Where the pharmaceutical composition includes a secondary diluent, pregelatinized starch is preferred. This has additional binder properties.

Pharmaceutical dosage forms (e.g., tablets or capsules) prepared using the pharmaceutical composition of the first embodiment preferably contain a therapeutically effective amount of linagliptin as the active ingredient. The preferred dosage range is 0.1 to 100 mg, more preferably 0.5 to 20 mg, and even more preferably 1 to 10 mg. Preferred dosages include, for example, 0.5 mg, 1 mg, 2.5 mg, 5 mg, and 10 mg.

According to a second embodiment of the present invention, the pharmaceutical composition comprises two active pharmaceutical ingredients, namely linagliptin and a glucopyranosyl-substituted benzene derivative of formula (I) as defined above and below, in particular linagliptin and compound (I.3).

Surprisingly, it was observed that glucopyranosyl-substituted benzene derivatives of formula (I), in particular compound (I.3), despite having a glucopyranosyl moiety containing a free hydroxyl group, are compatible with linagliptin, i.e. linagliptin in combination with the glucopyranosyl-substituted benzene derivatives shows no or only minimal degradation.

Preferred pharmaceutical compositions according to the second embodiment comprise linagliptin and compound (I.3) as two active pharmaceutical ingredients. The pharmaceutical composition or dosage form preferably comprises linagliptin and compound (I.3), wherein at least 50% by weight of compound (I.3) is in the form of its crystalline form (I.3X) as defined above. More preferably, at least 80% by weight, even more preferably at least 90% by weight of compound (I.3) is in the form of its crystalline form (I.3X) as defined above in the pharmaceutical composition or dosage form. The pharmaceutical composition or dosage form preferably comprises linagliptin in one or more crystalline forms, particularly polymorphs A and B, as described in WO 2007/128721 (incorporated by reference in its entirety).

Preferred pharmaceutical compositions according to the second embodiment of the present invention comprise one or more diluents, one or more binders, and one or more disintegrants. Even more preferred pharmaceutical compositions according to the second embodiment of the present invention comprise one or more diluents, one or more binders, one or more disintegrants, and one or more lubricants. Such compositions preferably comprise one or two diluents. Even more preferably, such compositions comprise one or two diluents and a binder. Even more preferably, such compositions comprise one or two diluents, a binder, and a disintegrant. Even more preferably, such compositions comprise one or two diluents, a binder, and at least two disintegrants. Even more preferably, such compositions comprise one or two diluents, one or two binders, and at least two disintegrants. Even more preferably, such compositions comprise one or two diluents, one or two binders, at least two disintegrants, and a lubricant. Even more preferably, such compositions comprise one or two diluents, one or two binders, at least two disintegrants, and one or two lubricants. Even more preferably, such compositions comprise one or two diluents, one or two binders, at least two disintegrants, and two lubricants. Even more preferably, such compositions comprise one or two diluents, one or two binders, three disintegrants, and two lubricants. Furthermore, the composition may further comprise at least one glidant.Preferred diluents, binders, disintegrants, lubricants and glidants are disclosed above and below.

The pharmaceutical composition of the second embodiment preferably comprises

The percentages are by weight of the total composition.

The following ranges are even more preferred:

The percentages are by weight of the total composition.

Additionally, the pharmaceutical composition may comprise one or more lubricants in an amount ranging from 0.1 to 15% by weight of the total composition.

The pharmaceutical composition of the second embodiment preferably comprises

The percentages are by weight of the total composition.

In the above pharmaceutical composition, the preferred diluent is mannitol, the preferred binder is copovidone, and the preferred disintegrant is selected from corn starch and crospovidone. The preferred lubricant is selected from magnesium stearate and talc. In the case where the pharmaceutical composition includes a second diluent, pregelatinized starch is preferred. Pregelatinized starch has additional binder and disintegrant properties.

Therefore, the preferred pharmaceutical composition of the second embodiment is characterized by the following composition:

The percentages are by weight of the total composition.

Another preferred pharmaceutical composition of the second embodiment is characterized by the following composition:

The percentages are by weight of the total composition.

The pharmaceutical composition described above preferably further comprises a lubricant. The lubricant is preferably magnesium stearate in an amount of 0.5-2% by weight of the total composition.

The pharmaceutical composition preferably further comprises at least two lubricants. The first lubricant is preferably magnesium stearate in an amount of 0.5-2% by weight of the total composition. The second lubricant is preferably talc in an amount of 0.5-10% by weight of the total composition.

Therefore, the preferred pharmaceutical composition of the second embodiment is characterized by the following composition:

The percentages are by weight of the total composition.

Another preferred pharmaceutical composition of the second embodiment is characterized by the following composition:

The percentages are by weight of the total composition.

The pharmaceutical compositions of the present invention may further comprise one or more taste masking agents (eg, sweeteners or flavorings) and coloring agents.

The pharmaceutical composition of the present invention may further comprise one or more coatings, preferably non-functional coatings.

The pharmaceutical composition of the present invention is preferably a solid pharmaceutical composition, in particular for oral administration. The pharmaceutical dosage form of the present invention comprising the pharmaceutical composition of the present invention is preferably a solid pharmaceutical dosage form, in particular for oral administration. Examples are capsules, tablets (e.g., film-coated tablets), or granules.

The pharmaceutical dosage form (eg, capsule or tablet) of the first embodiment of the present invention contains only one active pharmaceutical ingredient, namely, linagliptin.

The pharmaceutical dosage form (e.g., capsule or tablet) according to the second embodiment of the present invention comprises two active pharmaceutical ingredients, namely, linagliptin and a glucopyranosyl-substituted benzene derivative of formula (I) as defined above and below, in particular, linagliptin and compound (I.3). The tablet may be a single-layer tablet, wherein both active pharmaceutical ingredients are present in the single layer. Alternatively, the tablet may be a bilayer tablet, wherein one of the two active pharmaceutical ingredients is present in the first layer and the other active pharmaceutical ingredient is present in the second layer. Alternatively, the formulation may be a film-coated tablet, wherein one of the two active pharmaceutical ingredients is present in the core and the other active pharmaceutical ingredient is present in the film-coating layer. Alternatively, the tablet may be a three-layer tablet, wherein two layers, each containing only one active pharmaceutical ingredient, are separated by a third layer that does not contain any active pharmaceutical ingredient. Alternatively, the tablet may be a press-coated tablet, i.e., a tablet in which one active pharmaceutical ingredient is contained in a small tablet, e.g., with a diameter of 2-6 mm, and the other active pharmaceutical ingredient is contained in a second granulate or mixture, which is compressed with the small tablet to form a larger press-coated tablet. All of the above-mentioned tablet types may be uncoated or may have one or more coatings, in particular a film coating. A non-functional coating is preferred.

It should be understood that the amount of one or more active pharmaceutical ingredients of the present invention to be administered to a patient and required for use in the treatment or prevention of the present invention will vary depending on the route of administration, the nature and severity of the condition to be treated or prevented, the patient's age, weight and physical condition, concomitant medications, and will ultimately be determined by the attending physician. However, the preferred amount is generally such that the administration of the pharmaceutical dosage form improves glycemic control in the patient to be treated.

Preferred ranges for the amounts of linagliptin and glucopyranosyl-substituted benzene derivatives to be used in the pharmaceutical dosage forms of the present invention are described below. These ranges refer to daily dosages for adult patients (particularly, for example, those weighing approximately 70 kg) and can be adjusted accordingly for administration two, three, four, or more times per day, other routes of administration, and the age of the patient. Doses and amount ranges are calculated for the respective active moieties.

Preferred pharmaceutical dosage forms of the second embodiment contain a therapeutically effective amount of linagliptin and a therapeutically effective amount of a glucopyranosyl-substituted benzene derivative (especially compound (I.3)). The preferred amount of linagliptin ranges from 0.1 to 30 mg, preferably from 0.5 to 20 mg, even more preferably from 1 to 10 mg, and most preferably from 2 to 5 mg. Preferred doses are, for example, 0.5 mg, 1 mg, 2.5 mg, 5 mg, and 10 mg. The preferred amount of the glucopyranosyl-substituted benzene derivative (especially compound (I.3)) ranges from 0.5 to 100 mg, preferably from 0.5 to 50 mg, even more preferably from 1 to 25 mg, even more preferably from 5 to 25 mg, and most preferably from 10 to 25 mg. Preferred doses of the glucopyranosyl-substituted benzene derivative are, for example, 1 mg, 2 mg, 2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg, 20 mg, 25 mg, and 50 mg. The pharmaceutical dosage form of the second embodiment contains, for example, a dosage combination selected from the embodiments described in the following table:

The tablets of the present invention may be film-coated tablets. The film coating typically accounts for 2-5% by weight of the total composition and preferably comprises a film former, a plasticizer, a glidant, and optionally one or more pigments. Exemplary coating compositions may comprise hydroxypropyl methylcellulose (HPMC), polyethylene glycol (PEG), talc, titanium dioxide, and optionally iron oxide, including red iron oxide and/or yellow iron oxide. Exemplary coating compositions may comprise hydroxypropyl methylcellulose (HPMC), polyethylene glycol (PEG), talc, titanium dioxide, mannitol, and optionally iron oxide, including red iron oxide and/or yellow iron oxide.

The dissolution properties of the pharmaceutical dosage form of the present invention are preferably such that after 45 minutes, at least 75% by weight, even more preferably at least 90% by weight of each of the one or two active pharmaceutical ingredients is dissolved. In a more preferred embodiment, after 30 minutes, at least 75% by weight, even more preferably at least 90% by weight of each of the one or two active pharmaceutical ingredients is dissolved. In a most preferred embodiment, after 15 minutes, at least 75% by weight, even more preferably at least 90% by weight of each of the one or two active pharmaceutical ingredients is dissolved. Dissolution properties can be determined in a standard dissolution test, such as described in the pharmacopoeia of USP31-NF26S2, Chapter 711 (Dissolution). Preferred tests are disclosed in the experimental section.

The disintegration properties of the pharmaceutical dosage form according to the invention are preferably such that the pharmaceutical dosage form disintegrates within 40 minutes, more preferably within 30 minutes, even more preferably within 20 minutes, and most preferably within 15 minutes. The disintegration properties can be determined in a standard disintegration test, such as that described in the pharmacopoeia USP 31-NF 26S2, Chapter 701 (Disintegration). A preferred test is disclosed in the experimental section.

The content uniformity of the pharmaceutical dosage forms of the present invention for each of one or two active pharmaceutical ingredients is preferably high, preferably in the range of 85 to 115 weight %, more preferably in the range of 90 to 110 weight %, even more preferably in the range of 95 to 105 weight %. Content uniformity can be determined in a standard test using, for example, 30 randomly selected pharmaceutical dosage forms, as described in the pharmacopoeia of USP 31-NF 26S2, Chapter 905 (Uniformity of Dosage Units).

The dosage forms of the present invention, such as tablets, capsules or film-coated tablets, can be prepared by methods well known to those skilled in the art.

A preferred method of preparing tablets is to compress the pharmaceutical composition in powder form (ie, direct compression) or in granular form, and if desired, with additional excipients.

The granules of the pharmaceutical composition of the present invention can be prepared by methods well known to those skilled in the art. Preferred methods for granulating one or more active ingredients with excipients include wet granulation (e.g., high shear wet granulation or fluidized bed wet granulation) and dry granulation (also known as roller compaction).

In a preferred wet granulation step, the granulation liquid is simply a solvent or a solvent mixture, or a preparation of one or more binders in a solvent or a solvent mixture. Suitable binders are disclosed above. An example is copovidone. Suitable solvents are, for example, water, ethanol, methanol, isopropanol, acetone, preferably purified water, including mixtures thereof. The solvent is a volatile component that does not remain in the final product. One or more active ingredients are premixed with other excipients (especially one or more diluents, optionally one or more binders, and optionally one or more disintegrants, usually excluding lubricants) and granulated together with the granulation liquid, for example using a high shear granulator. The wet granulation step is generally followed by one or more drying and sieving steps. Optionally, a wet sieving step is inserted, followed by drying the granules and dry sieving. For example, a fluidized bed dryer can then be used for drying.

The preparation method of the present invention is preferably characterized by a granulation step, wherein the first and second active pharmaceutical ingredients are granulated together with one or more diluents, one or more binders and one or more disintegrants.

The preparation method of the present invention is preferably characterized by at least two granulation steps: wherein in one granulation step, the first active pharmaceutical ingredient is granulated together with one or more diluents, one or more binders and one or more disintegrants, and in another granulation step, the second active pharmaceutical ingredient is granulated together with one or more diluents, one or more binders and one or more disintegrants.

Preferably, in the above-described process, the granules obtained from the one or more granulation steps are optionally mixed with one or more additional disintegrants and with one or more lubricants.

The dried granules are sieved through an appropriate sieve. After adding the other excipients (especially one or more disintegrants, and glidants, and optionally the lubricant talc, excluding lubricants especially magnesium stearate), the mixture is mixed in a suitable mixer, such as a free fall blender, followed by the addition of one or more lubricants (e.g. magnesium stearate) and final mixing in the mixer.

Thus, an exemplary wet granulation procedure for preparing granules comprising the pharmaceutical composition of the present invention comprises

a. optionally dissolving one or more binders in a solvent or solvent mixture such as purified water at ambient temperature to produce a granulating liquid;

b. mixing one or more active pharmaceutical ingredients, one or more diluents, optionally one or more binders and optionally one or more disintegrants in a suitable mixer to prepare a premix;

c. Wetting the premix with the granulating liquid, and then granulating the wetted premix in, for example, a high shear mixer;

d. optionally sieving the granulated premix through a sieve, wherein the mesh size of the sieve is at least 1.0 mm and preferably 3 mm;

e. drying the granules in, for example, a fluidized bed dryer at an inlet air temperature of about 40-75°C and preferably 55-65°C until the desired loss on drying value is obtained in the range of 1-5%;

f, for example by screening through a sieve having a mesh size of 0.6mm-1.6mm, preferably 1.0mm, the dried particles are deblocked; and

g. Preferably a sieved lubricant is added to the granules for final mixing in a cube mixer.

In another method, a portion of the excipients (e.g., a portion of one or more disintegrants such as corn starch) or additional disintegrants (e.g., crospovidone) and/or one or more diluents (e.g., pregelatinized starch) may be added as granules before the final mixing in step g.

In another embodiment of the process, the granules obtained in steps a to e are prepared in a single-pot high shear granulation step and subsequently dried in a single-pot granulator. Thus, one aspect of the present invention relates to granules comprising a pharmaceutical composition of the present invention.

An exemplary dry granulation procedure for preparing granules comprising the pharmaceutical composition of the present invention comprises

(1) Mixing one or two active pharmaceutical ingredients with all or part of the excipients in a mixer;

(2) compacting the mixture of step (1) in a suitable roller compactor;

(3) breaking the ribbons obtained during step (2) into small particles by a suitable grinding or sieving step;

(4) optionally mixing the granules of step (3) with the remaining excipients in a mixer to obtain a final mixture;

(5) tableting the granules of step (3) or the final mixture of step (4) by compacting them on a suitable tablet press to obtain tablet cores;

(6) Optionally, a non-functional coating is applied to the tablet cores obtained in step (5).

The granules of the first embodiment of the present invention contain only one active pharmaceutical ingredient (drug), namely linagliptin.

The granules according to the second embodiment of the present invention comprise two active pharmaceutical ingredients, namely linagliptin and a glucopyranosyl-substituted benzene derivative of formula (I) as defined above and below, in particular linagliptin and compound (I.3).

The preferred size of the particles is in the range of 25 to 800 μm, even more preferably in the range of 40 to 500 μm. The size is preferably measured by sieving (e.g., using a sonic sifter). Preferably, at least 80% by weight, more preferably at least 90% by weight, and most preferably at least 95% by weight of the particles are within the given range.

When preparing capsules, the granules or the final mixture as described in steps (f.) and (g.) above are further filled into the capsules.

When preparing the capsules according to the second embodiment of the present invention, the granules according to the second embodiment of the present invention, i.e., granules comprising two active pharmaceutical ingredients, can be used. Alternatively, the granules according to the first embodiment of the present invention, i.e., granules comprising linagliptin as an active pharmaceutical ingredient and granules comprising a glucopyranosyl-substituted benzene derivative of formula (I) as defined above and below, in particular compound (I.3), can be used.

When preparing tablets or tablet cores, the granules or final mixture of step (g.) above are further compressed into tablets having a target tablet core weight and appropriate size and compressive strength using a suitable tablet press. The final mixture comprises the granules of the present invention, one or more lubricants, and optionally one or more disintegrants, and optionally one or more glidants. The additional disintegrant is, for example, crospovidone.

When preparing the monolayer tablet according to the second embodiment of the present invention, the granules according to the second embodiment of the present invention, i.e., granules comprising two active pharmaceutical ingredients, can be used. Alternatively, the granules according to the first embodiment of the present invention, i.e., granules comprising linagliptin as an active pharmaceutical ingredient and granules comprising a glucopyranosyl-substituted benzene derivative of formula (I) as defined above and below, in particular compound (I.3), can be used.

When preparing the bilayer tablet according to the second embodiment of the present invention, the granules according to the first embodiment of the present invention, i.e., granules comprising linagliptin as an active pharmaceutical ingredient, can be used in the first layer, and granules comprising a glucopyranosyl-substituted benzene derivative of formula (I) as defined above and below, in particular compound (I.3), can be used in the second layer.

The tablet according to the second embodiment of the present invention (eg, a single-layer tablet) preferably comprises

The percentages are by weight of the total composition.

The following ranges are even more preferred:

The percentages are by weight of the total composition.

In addition, the following excipients and ranges are preferred:

The percentages are by weight of the total composition. In particular, in cases where a higher tablet weight is to be achieved, such as in the case of a single-layer tablet made from two granules (each layer having one active ingredient) or a bilayer tablet as described above, an additional disintegrant (e.g., crospovidone) may be used in an amount of 0 to 2% by weight of the total composition.

In addition, the following excipients and ranges are more preferred:

The percentages are by weight of the total composition.

To reduce the amount of lubricant required in the tablet, an external lubrication system may be used.

To prepare film-coated tablets, a coating suspension is prepared and compressed tablet cores are coated with the coating suspension using a standard film coater until the weight gain is approximately 2-5%, preferably approximately 3%. The film coating solvent is a volatile component that does not remain in the final product. In another embodiment, the film coating may contain one of two active pharmaceutical ingredients.

Alternatively, the tablets of the present invention may be prepared by direct compression. A suitable direct compression method comprises the following steps:

(1) Premixing one or two active ingredients with most of the excipients in a mixer to obtain a premix;

(2) optionally dry screening the premix through a sieve to separate agglomerated particles and improve content uniformity;

(3) mixing the premix of step (1) or (2) in a mixer, optionally adding the remaining excipients to the mixture and continuing mixing;

(4) tableting the final mixture of step (3) by compressing it on a suitable tablet press to prepare tablet cores;

(5) Optionally, a non-functional coating is applied to the tablet core obtained in step (4).

The pharmaceutical compositions and dosage forms (particularly tablets or capsules) of the present invention can be packaged using known packaging materials (e.g., PVC-blister, PVDC-blister, PVC/PVDC-blister) or moisture-proof packaging materials (e.g., aluminum foil blister packs, aluminum/aluminum blisters, transparent or opaque polymer blisters with pouches, polypropylene tubes, glass bottles, PP bottles, and HDPE bottles, which optionally contain child-resistant features (e.g., press-and-twist closures or tamper-evident seals). The inner packaging material may include a desiccant (e.g., molecular sieve or silica gel) to improve the chemical stability of the active pharmaceutical ingredient. Opaque packaging (e.g., colored blister material, tube, brown glass bottle, etc.) can be used to extend the shelf life of the active pharmaceutical ingredient by reducing photodegradation. The article for distribution may include a pharmaceutical composition or dosage form packaged in a packaging material as described above and a label or package insert, which refers to the instructions typically included in the commercial packaging of the therapeutic product (which may include relevant indications, usage, dosage, administration, contraindications and/or precautions for the use of the therapeutic product). In one embodiment, the label or package insert indicates that the composition can be used for any purpose described herein.

The pharmaceutical compositions and dosage forms of the present invention exhibit advantageous effects in treating and preventing the diseases and conditions described above relative to antidiabetic monotherapy. Advantageous effects can be found, for example, in terms of effectiveness, dosage strength, dosage frequency, pharmacodynamic properties, pharmacokinetic properties, fewer adverse reactions, convenience, compliance, etc.

Compared to monotherapy with a single SGLT2 inhibitor or DPP IV inhibitor or metformin monotherapy, the pharmaceutical compositions and dosage forms of the present invention significantly improve glycemic control, particularly in patients described below. Improved glycemic control is determined as an increase in blood glucose reduction and an increase in HbA1c reduction. For monotherapy in patients (particularly patients described below), administration of a drug above a specific maximum dose generally does not further significantly improve glycemic control. In addition, given the potential side effects, long-term treatment with the maximum dose may not be desirable. Therefore, satisfactory glycemic control cannot be achieved in all patients by monotherapy with a single SGLT2 inhibitor or DPP IV inhibitor or with another antidiabetic drug (e.g., metformin). In these patients, diabetes may continue to progress and complications related to diabetes, such as macrovascular complications, may occur. Compared to antidiabetic monotherapy, the pharmaceutical compositions and dosage forms of the present invention and the methods of the present invention reduce the HbA1c values of more patients to the desired target range, e.g., <7% and preferably <6.5%, and the therapeutic treatment time is longer.

The pharmaceutical compositions and pharmaceutical dosage forms of the present invention provide well-tolerated therapy to patients and improve patient compliance.

The monotherapy using DPP IV inhibitor is relevant with patient's insulin secretion capacity or insulin sensitivity.On the other hand, it is unrelated to patient's insulin secretion capacity or insulin sensitivity by giving SGLT2 inhibitor treatment.Therefore, any patient can benefit from the therapy using pharmaceutical composition of the present invention and pharmaceutical dosage form combination under the irrelevant situation with high insulin content or insulin resistance and/or hyperinsulinemia.Because combination or alternatively give SGLT2 inhibitor, these patients can still use pharmaceutical composition and pharmaceutical dosage form treatment under the irrelevant situation with high insulin content or insulin resistance or hyperinsulinemia.

By increasing the active GLP-1 content, the linagliptin of the present invention can reduce glucagon secretion in patients. This, in turn, limits hepatic glucose production. Furthermore, the high active GLP-1 levels produced by linagliptin can have beneficial effects on beta cell regeneration and neogenesis. All of these features make the pharmaceutical composition and dosage form highly suitable and therapeutically significant.

When the present invention refers to patients in need of treatment or prevention, this primarily refers to human treatment and prevention, but the pharmaceutical compositions may also be used in veterinary medicine in mammals. Within the scope of the present invention, adult patients are preferably those aged 18 or older. Also within the scope of the present invention, patients are adolescents, i.e., those aged 10 to 17, preferably 13 to 17. It is believed that in adolescents, administration of the pharmaceutical compositions of the present invention will result in excellent HbA1c reduction and excellent fasting plasma glucose reduction. Furthermore, it is believed that significant weight loss will be observed in adolescents, particularly in overweight and/or obese patients.

As described above, by administering the pharmaceutical compositions and pharmaceutical preparations of the present invention, and particularly due to the high SGLT2 inhibitory activity of the glucopyranosyl-substituted benzene derivatives therein, excess blood glucose is excreted through the patient's urine, making it possible for weight to not increase or even decrease. Therefore, the treatment or prevention of the present invention is advantageously suitable for patients in need of such treatment or prevention, who have been diagnosed with one or more conditions selected from the following: overweight and obesity, particularly class I obesity, class II obesity, class III obesity, visceral obesity, and abdominal obesity. In addition, the treatment or prevention of the present invention is advantageously suitable for patients for whom weight gain is contraindicated.

The pharmaceutical compositions and dosage forms of the present invention exhibit excellent glycemic control efficacy, particularly in reducing fasting plasma glucose, postprandial plasma glucose, and/or glycosylated hemoglobin (HbA1c). By administering the pharmaceutical compositions or dosage forms of the present invention, a reduction in HbA1c of preferably 1.0% or greater, more preferably 2.0% or greater, and even more preferably 3.0% or greater can be achieved, with the reduction particularly being within the range of 1.0% to 3.0%.

Furthermore, the methods and/or uses of the present invention are advantageously used in patients showing one, two or more of the following conditions:

(a) Fasting blood glucose or serum glucose concentration greater than 100 mg/dL, especially greater than 125 mg/dL;

(b) postprandial plasma glucose equal to or greater than 140 mg/dL;

(c) an HbA1c value equal to or greater than 6.5%, in particular equal to or greater than 7.0%, in particular equal to or greater than 7.5%, even more in particular equal to or greater than 8.0%.

The present invention also discloses the use of a pharmaceutical composition or dosage form for improving glycemic control in patients with type 2 diabetes or displaying the first signs of prediabetes. Thus, the present invention also encompasses diabetes prevention. Thus, if the pharmaceutical composition or dosage form of the present invention is used to improve glycemic control after the onset of one of the aforementioned prediabetes symptoms, the onset of overt type 2 diabetes can be delayed or prevented.

Furthermore, the pharmaceutical compositions and dosage forms of the present invention are particularly suitable for treating patients with insulin dependence, i.e., patients who are being treated with, will be treated with, or are in need of treatment with insulin or insulin derivatives or insulin substitutes or formulations comprising insulin or its derivatives or substitutes. These patients include patients with type II diabetes as well as patients with type I diabetes.

Therefore, according to a preferred embodiment of the present invention, a method for improving glycemic control and/or reducing fasting plasma glucose, postprandial plasma glucose and/or glycosylated hemoglobin HbA1c in a patient in need thereof, wherein the patient is diagnosed with impaired glucose tolerance (IGT), impaired fasting glucose (IFG), insulin resistance, metabolic syndrome and/or type II or type I diabetes, is provided, characterized in that the pharmaceutical composition or pharmaceutical dosage form as defined above and below is administered to the patient.

According to another preferred embodiment of the present invention, a method for improving blood sugar control in patients with type 2 diabetes, particularly adult patients, is provided as an adjunct to diet and exercise.

It can be found that by using the pharmaceutical composition or pharmaceutical dosage form of the present invention, an improvement in glycemic control can be achieved even in patients with inadequate glycemic control (especially patients with inadequate glycemic control despite treatment with antidiabetic drugs, for example, despite oral monotherapy with the maximum recommended or tolerated dose of metformin, SGLT2 inhibitors or DPPIV inhibitors). The maximum recommended dose of metformin is, for example, 2000 mg per day or 850 mg three times a day or any equivalent thereof. The maximum recommended dose of the SGLT2 inhibitor of the present invention, in particular compound (I.3), is, for example, 100 mg, preferably 50 mg or even 25 mg once a day or any equivalent thereof. The maximum recommended dose of linagliptin is, for example, 10 mg, preferably 5 mg, or any equivalent thereof once a day.

Therefore, the methods and/or uses of the present invention are advantageously used in patients showing one, two or more of the following conditions:

(a) Inadequate glycemic control using diet and exercise alone;

(b) Inadequate glycemic control despite oral metformin monotherapy, particularly despite the maximum recommended or tolerated dose of metformin;

(c) Inadequate glycemic control despite oral monotherapy with another antidiabetic agent, particularly despite oral monotherapy with the maximum recommended or tolerated dose of another antidiabetic agent;

(d) inadequate glycemic control despite oral monotherapy with an SGLT2 inhibitor, particularly despite the maximum recommended or tolerated dose of an SGLT2 inhibitor;

(e) Inadequate glycemic control despite oral monotherapy with a DPPIV inhibitor, particularly despite the maximum recommended or tolerated dose of a DPPIV inhibitor.

The reduction in blood sugar levels caused by administration of the glucopyranosyl-substituted benzene derivatives of the present invention is independent of insulin. Therefore, the pharmaceutical compositions of the present invention are particularly suitable for treating patients diagnosed with one or more of the following conditions:

- Insulin resistance,

- Hyperinsulinemia,

- Prediabetes,

-Type II diabetes, especially late-stage type II diabetes,

-Type 1 diabetes.

Furthermore, the pharmaceutical compositions and pharmaceutical dosage forms of the present invention are particularly suitable for treating patients diagnosed with one or more of the following conditions:

(a) obesity (including class I, II and/or III obesity), visceral obesity and/or abdominal obesity,

(b) triglyceride blood level ≥150 mg/dL,

(c) HDL-cholesterol blood level <40 mg/dL in female patients and <50 mg/dL in male patients,

(d) systolic blood pressure ≥130 mm Hg and diastolic blood pressure ≥85 mm Hg,

(e) Fasting blood glucose level ≥100 mg/dL.

Patients diagnosed with impaired glucose tolerance (IGT), impaired fasting glucose (IFG), insulin resistance and/or metabolic syndrome are believed to have an increased risk of developing cardiovascular disease (e.g., myocardial infarction, coronary heart disease, cardiac insufficiency, thromboembolic events). Glycemic control according to the present invention can result in a reduction in cardiovascular risk.

The pharmaceutical compositions and dosage forms of the present invention exhibit a favorable safety profile. Thus, the treatment or prevention of the present invention may be beneficial for patients for whom monotherapy with another antidiabetic agent (e.g., metformin) is contraindicated and/or who are intolerant to therapeutic doses of these drugs. The treatment or prevention of the present invention may be particularly beneficial for patients who exhibit or are at increased risk for one or more of the following conditions: renal insufficiency or renal disease, heart disease, heart failure, liver disease, lung disease, a catabolytic state and/or risk of lactic acidosis, or pregnant or lactating female patients.

Furthermore, it was found that administration of the pharmaceutical composition or pharmaceutical dosage form according to the invention results in no or a low risk of hypoglycemia. Thus, the treatment or prevention according to the invention may also be beneficial for patients who exhibit hypoglycemia or who are at increased risk of developing hypoglycemia.

The pharmaceutical composition or pharmaceutical dosage form according to the present invention is particularly suitable for the long-term treatment or prevention of the diseases and/or conditions mentioned above and below in patients with type 2 diabetes, in particular for their long-term glycemic control.

The term "long-term" as used above and below means that the treatment of a patient or the administration of the drug to a patient is longer than 12 weeks, preferably longer than 25 weeks, even more preferably longer than 1 year.

Therefore, a particularly preferred embodiment of the present invention provides a method of treating (preferably oral therapy) for improving (especially long-term improvement) glycemic control in patients with type 2 diabetes, especially patients with advanced type 2 diabetes, especially patients who are also diagnosed with overweight, obesity (including class I, class II and/or class III obesity), visceral obesity and/or abdominal obesity.

In all the methods and uses described above and below, in particular in methods of treatment, prevention, etc., the pharmaceutical composition or pharmaceutical dosage form of the present invention is preferably administered to the patient once a day.

Any of the above compositions and dosage forms within the scope of the present invention can be tested by animal models known in the art and in clinical studies. In the following, in vivo experiments suitable for evaluating the pharmacologically relevant properties of the pharmaceutical compositions and dosage forms of the present invention are described:

The pharmaceutical compositions, dosage forms, and methods of the present invention are tested in genetically hyperinsulinemic or diabetic animals such as db/db mice, ob/ob mice, Zucker Fatty (fa/fa) rats, or Zucker Diabetic Fatty (ZDF) rats. In addition, they can be tested in experimentally induced diabetic animals such as Han Wistar or Sprague Dawley rats pretreated with streptozotocin.

The effects of the pharmaceutical compositions and dosage forms of the present invention on glycemic control can be tested in an oral glucose tolerance test in the animal models described above. Following an oral glucose challenge in animals fasted overnight, blood glucose changes are tracked over time. A decrease in peak glucose concentration or glucose AUC, as measured, demonstrates that the compositions and dosage forms of the present invention significantly improve glucose excursion compared to the respective monotherapies. Furthermore, the effects on glycemic control can be determined by measuring HbA1c levels in the blood following multiple administrations of the active pharmaceutical ingredient alone and the pharmaceutical compositions or dosage forms in the animal models described above. The compositions and dosage forms of the present invention significantly reduce HbA1c compared to the respective monotherapies.

In the animal model described above, the treatment of the present invention has been shown to improve insulin dependence after a single dose in an oral glucose tolerance test. Plasma insulin changes over time following a glucose challenge in overnight fasted animals have been tracked. Compared to linagliptin alone, the compositions and dosage forms of the present invention demonstrate lower peak insulin concentrations or insulin AUCs with lower blood glucose excursions.

Increases in active GLP-1 levels following single or multiple doses of the treatments described herein can be determined by measuring these levels in the plasma of the animal models described above in the fasting or fed state. Similarly, decreases in glucagon levels in plasma can be measured under the same conditions. The compositions and dosage forms of the present invention will exhibit higher active GLP-1 concentrations and lower glucagon concentrations compared to the use of the glucopyranosyl-substituted benzene derivatives alone.

The excellent effects of the compositions and dosage forms of the present invention on β-cell regeneration and neogenesis can be determined by measuring the increase in insulin content after multiple administration in the animal models described above, or by measuring the increased β-cell mass by morphometric analysis after immunohistochemical staining of pancreatic sections, or by measuring the increase in glucose-stimulated insulin secretion in isolated pancreatic islets.

Pharmacological Examples

The following examples show the beneficial effects of the combination of the present invention on glycemic control.

Example 1:

According to the first embodiment, oral glucose tolerance test is carried out in 9-week-old male Zucker Diabetic Fatty (ZDF) rats (ZDF/Crl-Lepr ^fa ) that fast overnight. Blood sample before administration is obtained by taking blood from the tail. Blood glucose is measured with a glucometer, and animals are randomly divided into groups for blood glucose test (n=5 per group). Subsequently, each group receives a single oral administration of a single medium (0.5% hydroxyethyl cellulose aqueous solution containing 3mM HCl and 0.015% Polysorbat80) or a medium containing a combination of an SGLT2 inhibitor, or a DPP IV inhibitor, or an SGLT2 inhibitor plus a DPP IV inhibitor. 30 minutes after giving the compound, animals receive an oral glucose load (2g/kg). 30 minutes, 60 minutes, 90 minutes, 120 minutes and 180 minutes after glucose stimulation, the blood glucose in the tail blood is measured. Quantitative glucose fluctuation is carried out by calculating reactive glucose AUC. Data are represented by means ± SEM. Two-way unpaired Student's t test was used to statistically compare the control group with the active group.

The results are shown in Figure 3. "Compound A" is linagliptin at a dose of 1 mg/kg. Compound B is compound (I.3), i.e., 1-chloro-4-(β-D-pyranosylglucopyranos-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-benzene, at a dose of 3 mg/kg. Combination A+B is the combination of linagliptin and compound (I.3) at the same dose. The P value relative to the control group is indicated by the symbol above the bar graph. The P value of the combination relative to the monotherapy is indicated below the graph (*, p < 0.05; **, p < 0.01; ***, p < 0.001). Linagliptin reduced glucose excursion by 56%, and compound (I.3) reduced glucose excursion by 51%. In an oral glucose tolerance test, the combination reduced glucose excursion by 84%, and this reduction in glucose AUC was statistically significant relative to each monotherapy.

Example II:

According to a second embodiment, oral glucose tolerance test is carried out in male Sprague Dawley rats (Crl:CD (SD)) fasted overnight that body weight is about 200g. Blood sample before administration is obtained by blood sampling from tail. Blood glucose is measured with a glucometer, and animals are randomly divided into groups for blood glucose test (n=5 per group). Subsequently, each group receives a single oral administration of a single medium (0.5% hydroxyethylcellulose aqueous solution containing 0.015% Polysorbat80) or a medium containing a combination of SGLT2 inhibitor, or DPPIV inhibitor, or a third antidiabetic drug, or SGLT2 inhibitor plus DPP IV inhibitor plus a third antidiabetic drug. Alternatively, each group receives a single oral administration of a single medium or a medium containing a combination of SGLT2 inhibitor, or DPPIV inhibitor, or a third antidiabetic drug, or SGLT2 inhibitor plus DPP IV inhibitor plus a third antidiabetic drug. 30 minutes after administration of compound, animals receive oral glucose load (2g/kg). Blood glucose was measured in tail blood 30, 60, 90, and 120 minutes after glucose stimulation. Glucose fluctuations were quantified by calculating the reactive glucose AUC. Data are presented as mean ± S.E.M. Statistical comparisons were performed using the Student's t-test.

Example III: Treatment of prediabetes

Clinical studies can be used to test the efficacy of the pharmaceutical compositions or dosage forms of the present invention in treating prediabetes characterized by pathological fasting glucose and/or impaired glucose tolerance. In studies of shorter duration (e.g., 2-4 weeks), treatment success is tested by measuring fasting glucose values and/or glucose values after a meal or after a stress test (an oral glucose tolerance test or food tolerance test after a given meal) after the treatment period of the study, and comparing them to these values before the start of the study and/or to these values in the placebo group. In addition, fructosamine values can be measured before and after treatment and compared to initial values and/or placebo values. A significant decrease in fasting or non-fasting glucose levels confirms treatment efficacy. In studies of longer duration (12 weeks or more), treatment success is tested by measuring HbA1c values and comparing them to initial values and/or placebo group values. A significant change in HbA1c values compared to initial values and/or placebo values demonstrates the efficacy of the compositions or dosage forms of the present invention for treating prediabetes.

Example IV: Prevention of Overt Type II Diabetes

Treatment of patients with pathological fasting glucose and/or impaired glucose tolerance (prediabetes) also aims to prevent the transition to overt type 2 diabetes. The efficacy of treatment can be investigated in comparative clinical studies in which prediabetic patients are treated with a pharmaceutical composition of the present invention or a placebo or non-drug therapy or other drug for an extended period (e.g., 1-5 years). During and at the end of treatment, the number of patients who develop overt type 2 diabetes is determined by measuring fasting glucose and/or a stress test (e.g., oGTT), e.g., a fasting glucose level >125 mg/dl and/or a 2-hour value according to the oGTT >199 mg/dl. A significant reduction in the number of patients who develop overt type 2 diabetes when treated with the pharmaceutical composition or dosage form of the present invention, compared to one other form of treatment, demonstrates efficacy in preventing the transition from prediabetes to overt diabetes.

Example V: Treatment of Type II Diabetes

Treatment of patients with type 2 diabetes with the pharmaceutical composition or dosage form of the present invention not only produces a rapid improvement in glucose metabolism but also prevents worsening of the metabolic status over the long term. This result can be observed in patients treated with the pharmaceutical composition or dosage form of the present invention for a longer period of time (e.g., 3 months to 1 year or even 1 to 6 years) and compared to patients treated with placebo or other antidiabetic drugs. If no increase or only a slight increase in fasting glucose and/or HbA1c values is observed, then evidence indicates that the treatment was successful compared to patients treated with placebo or other antidiabetic drugs. Further evidence indicates that the treatment was successful is obtained if a significantly smaller percentage of patients treated with the pharmaceutical composition or dosage form of the present invention experience a worsening of their glucose metabolism (e.g., an increase in HbA1c values to >6.5% or >7%) to an extent indicating the need for treatment with additional oral antidiabetic drugs or insulin or insulin analogs compared to patients treated with other drugs.

Example VI: Treatment of Insulin Resistance

In clinical studies of varying lengths (e.g., 2 weeks to 12 months), hyperinsulinemic-euglycemic clamp studies were used to examine the success of treatment. A significant increase in glucose infusion rate at the end of the study compared to the initial value or placebo group, or a group given a different therapy, demonstrated the efficacy of the pharmaceutical composition or dosage form of the present invention in treating insulin resistance.

Example VII: Treatment of Hyperglycemia

In clinical studies of varying lengths (e.g., 1 day to 24 months), the success of treatment in hyperglycemic patients is examined by measuring fasting glucose or non-fasting glucose (e.g., after a meal or after an oGTT loading test or after a limited meal). Significant reductions in these glucose values during or at the end of the study compared to the initial values or the placebo group, or a group given a different therapy, demonstrate the efficacy of the pharmaceutical composition or dosage form of the present invention in treating hyperglycemia.

Example VIII: Prevention of Microvascular or Macrovascular Complications

Treatment of patients with type 2 diabetes or prediabetes with a pharmaceutical composition or dosage form of the present invention prevents or reduces microvascular complications (e.g., diabetic neuropathy, diabetic retinopathy, diabetic nephropathy, diabetic foot, diabetic ulcers) or macrovascular complications (e.g., myocardial infarction, acute coronary syndrome, unstable angina, stable angina, stroke, peripheral arterial occlusive disease, cardiomyopathy, heart failure, arrhythmias, vascular restenosis) or reduces the risk of developing these complications. Patients with type 2 diabetes or prediabetes are treated with a pharmaceutical composition or dosage form of the present invention or a combination of active ingredients of the present invention for a long period of time (e.g., 1-6 years) and compared to patients who have been treated with other antidiabetic drugs or placebos. A lower number of single or multiple complications compared to patients treated with other antidiabetic drugs or placebos indicates successful treatment. In the case of macrovascular events, diabetic foot, and/or diabetic ulcers, the number is calculated based on medical history and various test methods. In the case of diabetic retinopathy, treatment success is determined by computer-controlled illumination and assessment of the fundus or other ophthalmic methods. In the case of diabetic neuropathy, in addition to the medical history and clinical examination, nerve conduction velocity can be measured using, for example, a calibrated tuning fork. With regard to diabetic nephropathy, the following parameters can be studied before, during, and at the end of the study: albumin secretion, creatinine clearance, serum creatinine value, time to doubling of the serum creatinine value, and time until dialysis is necessary.

Example IX: Treatment of Metabolic Syndrome

The efficacy of the pharmaceutical composition or dosage form of the present invention can be tested in clinical studies of varying lengths of time (e.g., 12 weeks to 6 years) by measuring fasting glucose or non-fasting glucose (e.g., after a meal or after an oGTT stress test or after a limited meal) or HbA1c values. Significant reductions in these glucose or HbA1c values during or at the end of the study, compared to initial values or a placebo group, or a group given a different therapy, demonstrate the efficacy of the pharmaceutical composition or dosage form of the present invention in treating metabolic syndrome. Examples include decreased systolic and/or diastolic blood pressure, decreased plasma triglycerides, decreased total cholesterol or LDL cholesterol, increased HDL cholesterol, or decreased body weight, compared to initial values at the beginning of the study or a group of patients treated with a placebo or a different therapy.

Examples of pharmaceutical compositions and dosage forms

In the following, the term "API 1" denotes a glucopyranosyl-substituted benzene derivative of formula (I), in particular compound (I.3), preferably its crystalline form (I.3X), and the term "API 2" denotes linagliptin.

The active pharmaceutical ingredients, i.e., Linagliptin and compound (I.3), preferably crystalline form (I.3X), are ground using a suitable mill such as a pin-mill or jet-mill to obtain the desired particle size distribution prior to preparing pharmaceutical compositions or dosage forms.

The following table shows examples of typical particle size distribution values X90, X50 and X10 of preferred active pharmaceutical ingredients of the present invention.

Example 1: Single-layer tablet granulated once

Copovidone was dissolved in purified water at ambient temperature (approximately 20°C) to prepare a granulation liquid. API 2 and API 1, mannitol, pregelatinized starch, and corn starch were mixed in a suitable mixer to prepare a premix. The premix was moistened with the granulation liquid and then granulated. The moistened granules were sieved through a suitable screen. The granules were dried in a fluidized bed dryer at an inlet air temperature of approximately 60°C until the loss on drying value was 1-4%. The dried granules were sieved through a screen with a mesh size of 1.0 mm.

Magnesium stearate was passed through a screen to de-agglomerate and added to the granules.The final mixture was then prepared by final mixing in a suitable mixer for 3 minutes and compressed into 8 mm disc cores at a compression force of 15 kN.

Hydroxypropyl methylcellulose, polyethylene glycol, talc, titanium dioxide, and iron oxide are suspended in purified water in a suitable mixer at ambient temperature to prepare a coating suspension. The core tablets are coated with the coating suspension until the weight gain is approximately 3% to prepare film-coated tablets. The following formulations are available:

Element mg/tablet mg/tablet mg/tablet mg/tablet mg/tablet API1 2.5 5.0 10.0 25.0 50.0 API2 5.0 5.0 5.0 5.0 5.0 Mannitol 128.4 125.9 120.9 105.9 80.9 Pregelatinized starch 18.0 18.0 18.0 18.0 18.0 corn starch 18.0 18.0 18.0 18.0 18.0 Copolyvidone 5.4 5.4 5.4 5.4 5.4 magnesium stearate 2.7 2.7 2.7 2.7 2.7 film coating 5.0 5.0 5.0 5.0 5.0 total 185.0 185.0 185.0 185.0 185.0

The resulting tablets had a tablet hardness of approximately 85N and a friability of less than 0.5%. Content uniformity met USP requirements. The disintegration time was approximately 7 minutes, and the dissolution rates of both API 1 and API 2 after 15 minutes were greater than 85%, for example, 97% for API 1 and 101% for API 2.

Example 2: Single-layer tablets granulated once

Dissolve copovidone in purified water at ambient temperature to prepare a granulation liquid. Combine API1, API2, mannitol, pregelatinized starch, and corn starch in a suitable mixer to prepare a premix. Moisten the premix with the granulation liquid and then granulate. Sieve the moistened granules through a suitable sieve. Dry the granules in a fluidized bed dryer at an inlet air temperature of approximately 60°C to a loss on drying of 1-4%. Sieve the dried granules through a sieve with a mesh size of 1.0 mm.

Magnesium stearate was passed through a screen to de-lump and added to the granules.The final blend was then prepared by final mixing for 3 minutes in a suitable mixer and compressed into 8 mm disc cores at a compression force of 17 kN.

Prepare a coating suspension by suspending hydroxypropyl methylcellulose, polyethylene glycol, talc, titanium dioxide, and iron oxide in purified water in a suitable mixer at ambient temperature. Coat the core tablets with the coating suspension until the weight gain reaches approximately 3% to produce film-coated tablets. The following formulations are available:

Element mg/tablet mg/tablet mg/tablet mg/tablet mg/tablet API1 2.5 5.0 10.0 25.0 50.0 API2 5.0 5.0 5.0 5.0 5.0 Mannitol 127.5 125.0 120.0 105.0 80.0 Pregelatinized starch 18.0 18.0 18.0 18.0 18.0 corn starch 18.0 18.0 18.0 18.0 18.0 Copolyvidone 5.4 5.4 5.4 5.4 5.4 magnesium stearate 3.6 3.6 3.6 3.6 3.6 film coating 5.0 5.0 5.0 5.0 5.0 total 185.0 185.0 185.0 185.0 185.0

Tablet hardness, friability, content uniformity, disintegration time, and dissolution properties were determined as described above.

Example 3: Single-layer tablets granulated once

Copovidone is dissolved in purified water at ambient temperature to produce a granulation liquid. API1, API2, mannitol, pregelatinized starch, and corn starch are mixed in a suitable mixer to produce a premix. The premix is moistened with the granulation liquid and then granulated. The moistened granules are sieved through a suitable screen. The granules are dried in a fluidized bed dryer at an inlet air temperature of approximately 60°C until the loss on drying is 1-4%. The dried granules are sieved through a screen with a mesh size of 1.0 mm. Crospovidone is added to the dried granules and mixed for 5 minutes to produce the main mixture. Magnesium stearate is passed through a screen to de-block and added to the main mixture. Subsequently, the final mixture is obtained by final mixing for 3 minutes in a suitable mixer and compressed into 8 mm disc cores with a compression force of 16 kN.

Prepare a coating suspension by suspending hydroxypropyl methylcellulose, polyethylene glycol, talc, titanium dioxide, and iron oxide in purified water in a suitable mixer at ambient temperature. Coat the core tablets with the coating suspension until the weight gain reaches approximately 3% to produce film-coated tablets. The following formulations are available:

Element mg/tablet mg/tablet mg/tablet mg/tablet mg/tablet API1 2.5 5.0 10.0 25.0 50.0 API2 5.0 5.0 5.0 5.0 5.0 Mannitol 127.5 125.0 120.0 105.0 80.0 Pregelatinized starch 18.0 18.0 18.0 18.0 18.0 corn starch 18.0 18.0 18.0 18.0 18.0 Crospovidone 2.0 2.0 2.0 2.0 2.0 Copolyvidone 5.4 5.4 5.4 5.4 5.4 magnesium stearate 3.6 3.6 3.6 3.6 3.6 film coating 5.0 5.0 5.0 5.0 5.0 total 187.0 187.0 187.0 187.0 187.0

Tablet hardness, friability, content uniformity, disintegration time, and dissolution properties were determined as described above.

Example 4: Single-layer tablets granulated twice

Two separate granulations each containing only one active pharmaceutical ingredient were performed. In the two granulations, copovidone was dissolved in purified water at ambient temperature to prepare the granulation liquid.

Mix API2, mannitol, pregelatinized starch, and corn starch in a suitable mixer to prepare a premix. Moisten the premix with a granulation liquid and then granulate. Sieve the moistened granules through a suitable sieve. Dry the granules in a fluidized bed dryer at an inlet air temperature of approximately 60°C to a loss on drying of 1-4%. Sieve the dried granules through a sieve with a mesh size of 1.0 mm.

API1, mannitol, pregelatinized starch, corn starch, and optionally a pigment (e.g., red iron oxide) are mixed in a suitable mixer to prepare a premix. The premix is moistened with a granulation liquid and subsequently granulated. The moistened granules are sieved through a suitable screen. The granules are dried in a fluidized bed dryer at an inlet air temperature of approximately 60°C to a loss on drying of 1-4%. The dried granules are sieved through a screen with a mesh size of 1.0 mm.

Combine the two granules, add crospovidone and mix all the components in a suitable mixer for 5 minutes to prepare the main mixture. Magnesium stearate is passed through a screen to de-lump and added to the main mixture. Subsequently, the final mixture is prepared by final mixing in a suitable mixer for 3 minutes and compressed into 15×6 mm oval tablet cores at a compression force of 17 kN. The following formulations are obtained:

Element mg/tablet mg/tablet mg/tablet mg/tablet mg/tablet First granulation API1 2.5 5.0 10.0 25.0 50.0 Mannitol 123.5 121.0 116.0 101.0 76.0 Pregelatinized starch 18.0 18.0 18.0 18.0 18.0 corn starch 18.0 18.0 18.0 18.0 18.0 Iron oxide red 2.7 2.7 2.7 2.7 2.7 Copolyvidone 5.4 5.4 5.4 5.4 5.4 Second granulation API2 5.0 5.0 5.0 5.0 5.0 Mannitol 130.9 130.9 130.9 130.9 130.9 Pregelatinized starch 18.0 18.0 18.0 18.0 18.0 corn starch 18.0 18.0 18.0 18.0 18.0 Copolyvidone 5.4 5.4 5.4 5.4 5.4 Final Mix magnesium stearate 7.2 7.2 7.2 7.2 7.2 Crospovidone 5.4 5.4 5.4 5.4 5.4 total 360.0 360.0 360.0 360.0 360.0

The resulting tablets had a tablet hardness of approximately 10⁵ N. Content uniformity met USP requirements. Friability was less than 0.5%. Disintegration time was approximately 5 minutes, and dissolution of both APIs was greater than 85% after 15 minutes.

Example 5: Single-layer tablets granulated twice

Two separate granulations each containing only one active pharmaceutical ingredient were performed.

Dissolve copovidone in purified water at ambient temperature to prepare a granulation liquid. Combine API2, mannitol, pregelatinized starch, and corn starch in a suitable mixer to prepare a premix. Moisten the premix with the granulation liquid and then granulate. Sieve the moistened granules through a suitable sieve. Dry the granules in a fluidized bed dryer at an inlet air temperature of approximately 60°C to a loss on drying of 1-4%. Sieve the dried granules through a sieve with a mesh size of 1.0 mm.

API1, mannitol, microcrystalline cellulose, hydroxypropyl cellulose, and an optional pigment (such as red iron oxide) are mixed in a suitable mixer to prepare a premix. The premix is moistened with purified water and then granulated. The moistened granules are sieved through a suitable screen. The granules are dried in a fluidized bed dryer at an inlet air temperature of approximately 60°C to a loss on drying of 1-4%. The dried granules are sieved through a screen with a mesh size of 1.0 mm.

Combine the two granules, add crospovidone and mix all the components in a suitable mixer for 5 minutes to prepare the main mixture. Magnesium stearate is passed through a sieve to de-lump and added to the main mixture. Subsequently, the final mixture is prepared by final mixing in a suitable mixer for 3 minutes and compressed into 15×6 mm oval tablet cores at a compression force of 15 kN. The following formulations are obtained:

Element mg/tablet mg/tablet mg/tablet mg/tablet mg/tablet First granulation API1 2.5 5.0 10.0 25.0 50.0 Mannitol 123.5 121.0 116.0 101.0 76.0 microcrystalline cellulose 36.0 36.0 36.0 36.0 36.0 Iron oxide red 2.7 2.7 2.7 2.7 2.7 Hydroxypropyl cellulose 5.4 5.4 5.4 5.4 5.4 Second granulation API2 5.0 5.0 5.0 5.0 5.0 Mannitol 130.9 130.9 130.9 130.9 130.9 Pregelatinized starch 18.0 18.0 18.0 18.0 18.0 corn starch 18.0 18.0 18.0 18.0 18.0 Copolyvidone 5.4 5.4 5.4 5.4 5.4 Final Mix magnesium stearate 7.2 7.2 7.2 7.2 7.2 Crospovidone 5.4 5.4 5.4 5.4 5.4 total 360.0 360.0 360.0 360.0 360.0

Tablet hardness, friability, content uniformity, disintegration time, and dissolution properties were determined as described above.

Example 6: Double-layer tablets granulated twice

Two separate granulations each containing only one active pharmaceutical ingredient were performed. In the two granulations, copovidone was dissolved in purified water at ambient temperature to prepare the granulation liquid.

Mix API2, mannitol, pregelatinized starch, and corn starch in a suitable mixer to prepare a premix. Moisten the premix with a granulation liquid and then granulate. Sieve the moistened granules through a suitable sieve. Dry the granules in a fluidized bed dryer at an inlet air temperature of approximately 60°C to a loss on drying of 1-4%. Sieve the dried granules through a sieve with a mesh size of 1.0 mm.

API1, mannitol, pregelatinized starch, corn starch, and optional pigment (e.g., red iron oxide) are mixed in a suitable mixer to prepare a premix. The premix is moistened with a granulating liquid and subsequently granulated. The moistened granules are sieved through a suitable screen. The granules are dried in a fluidized bed dryer at an inlet air temperature of approximately 60°C until a loss on drying value of 1-4% is achieved. The dried granules are sieved through a screen with a mesh size of 1.0 mm, crospovidone is added, and the components are mixed in a suitable mixer for 5 minutes.

Magnesium stearate was passed through a screen to de-agglomerate and added to both granulations. Subsequently, two final blends were prepared by final blending in a suitable mixer for 3 minutes. The first layer of the bilayer tablets used the final blend containing API 1, and the second layer used the final blend containing API 2. The bilayer tablets were prepared on a suitable tablet press with a primary compression force of 2 kN for the first layer and a primary compression force of 12 kN for preparing 10 mm round cores. The following formulations were obtained:

Element mg/tablet mg/tablet mg/tablet mg/tablet mg/tablet First floor API1 2.5 5.0 10.0 25.0 50.0 Mannitol 123.5 121.0 116.0 101.0 76.0 Pregelatinized starch 18.0 18.0 18.0 18.0 18.0 corn starch 18.0 18.0 18.0 18.0 18.0 Iron oxide red 2.7 2.7 2.7 2.7 2.7 Copolyvidone 5.4 5.4 5.4 5.4 5.4 magnesium stearate 4.5 4.5 4.5 4.5 4.5 Crospovidone 5.4 5.4 5.4 5.4 5.4 Second floor API2 5.0 5.0 5.0 5.0 5.0 Mannitol 130.9 130.9 130.9 130.9 130.9 Pregelatinized starch 18.0 18.0 18.0 18.0 18.0 corn starch 18.0 18.0 18.0 18.0 18.0 Copolyvidone 5.4 5.4 5.4 5.4 5.4 magnesium stearate 2.7 2.7 2.7 2.7 2.7 total 360.0 360.0 360.0 360.0 360.0

The resulting tablets had a tablet hardness of approximately 120 N and a friability of less than 0.5%. Content uniformity met USP requirements. The disintegration time was approximately 6 minutes, and the dissolution rates of both APIs were greater than 85% after 15 minutes.

Example 7: Double-layer tablets granulated twice

Two separate granulations each containing only one active pharmaceutical ingredient were performed.

Dissolve copovidone in purified water at ambient temperature to prepare a granulation liquid. Combine API2, mannitol, pregelatinized starch, and corn starch in a suitable mixer to prepare a premix. Moisten the premix with the granulation liquid and then granulate. Sieve the moistened granules through a suitable sieve. Dry the granules in a fluidized bed dryer at an inlet air temperature of approximately 60°C to a loss on drying of 1-4%. Sieve the dried granules through a sieve with a mesh size of 1.0 mm.

API1, mannitol, microcrystalline cellulose, hydroxypropyl cellulose, and optional pigment (such as red iron oxide) are mixed in a suitable mixer to prepare a premix. The premix is moistened with purified water and then granulated. The moistened granules are sieved through a suitable screen. The granules are dried in a fluidized bed dryer at an inlet air temperature of approximately 60°C until the loss on drying is 1-4%. The dried granules are sieved through a screen with a mesh size of 1.0 mm, crospovidone is added, and the components are mixed in a suitable mixer for 5 minutes.

Magnesium stearate was passed through a screen to de-agglomerate and added to both granulations. Subsequently, two final blends were prepared by final blending in a suitable mixer for 3 minutes. The first layer of the bilayer tablets used the final blend containing API 1, and the second layer used the final blend containing API 2. The bilayer tablets were prepared on a suitable tablet press with a primary compression force of 2 kN for the first layer and a primary compression force of 12 kN for preparing 10 mm round cores. The following formulations were obtained:

Element mg/tablet mg/tablet mg/tablet mg/tablet mg/tablet First floor API1 2.5 5.0 10.0 25.0 50.0 Mannitol 123.5 121.0 116.0 101.0 76.0 microcrystalline cellulose 36.0 36.0 36.0 36.0 36.0 Iron oxide red 2.7 2.7 2.7 2.7 2.7 Hydroxypropyl cellulose 5.4 5.4 5.4 5.4 5.4 magnesium stearate 4.5 4.5 4.5 4.5 4.5 Crospovidone 5.4 5.4 5.4 5.4 5.4 Second floor API2 5.0 5.0 5.0 5.0 5.0 Mannitol 130.9 130.9 130.9 130.9 130.9 Pregelatinized starch 18.0 18.0 18.0 18.0 18.0 corn starch 18.0 18.0 18.0 18.0 18.0 Copolyvidone 5.4 5.4 5.4 5.4 5.4 magnesium stearate 2.7 2.7 2.7 2.7 2.7 total 360.0 360.0 360.0 360.0 360.0

Tablet hardness, friability, content uniformity, disintegration time, and dissolution properties were determined as described above.

Example 8: Single-layer tablets granulated once

Copovidone is dissolved in purified water at ambient temperature (about 20°C) to prepare a granulation liquid. API1, API2, mannitol, pregelatinized starch, and corn starch are mixed in a suitable mixer to prepare a premix. The premix is moistened with the granulation liquid and then granulated. The moistened granules are sieved through a suitable screen. The granules are dried in a fluidized bed dryer at an inlet air temperature of about 60°C until the loss on drying is 1-4%. The dried granules are sieved through a screen with a mesh size of 1.0 mm.

Crospovidone and talc were added to the dried granules and mixed for 5 minutes to prepare the main mixture. Magnesium stearate was passed through a screen to deblock and added to the main mixture. Subsequently, the final mixture was prepared by final mixing for 3 minutes in a suitable mixer and compressed into 8 mm round tablet cores with a compression force of 16 kN. When API1 and API2 were combined in a single granulation and subsequently combined in a tablet, the combination of two lubricants, talc and magnesium stearate, was found to be particularly suitable for imparting low ejection force and preventing the final mixture from adhering to the tablet punch.

Prepare a coating suspension by suspending hydroxypropyl methylcellulose, polyethylene glycol, talc, titanium dioxide, mannitol, and iron oxide in purified water in a suitable mixer at ambient temperature. Coat the core tablets with the coating suspension until the weight gain reaches approximately 3% to produce film-coated tablets. The following formulations are available:

Element mg/tablet mg/tablet mg/tablet mg/tablet mg/tablet API1 2.5 5.0 10.0 25.0 50.0 API2 5.0 5.0 5.0 5.0 5.0 Mannitol 114.0 111.5 106.5 91.5 66.5 Pregelatinized starch 18.0 18.0 18.0 18.0 18.0 corn starch 19.8 19.8 19.8 19.8 19.8 Crospovidone 3.6 3.6 3.6 3.6 3.6 Copolyvidone 5.4 5.4 5.4 5.4 5.4 talcum powder 9.0 9.0 9.0 9.0 9.0 magnesium stearate 2.7 2.7 2.7 2.7 2.7 Hydroxypropyl methylcellulose 1.7500 1.7500 1.7500 1.7500 1.7500 polyethylene glycol 0.6000 0.6000 0.6000 0.6000 0.6000 Iron oxide 0.0125 0.0125 0.0125 0.0125 0.0125 Titanium dioxide 0.7375 0.7375 0.7375 0.7375 0.7375 talcum powder 0.9000 0.9000 0.9000 0.9000 0.9000 Mannitol 1.0000 1.0000 1.0000 1.0000 1.0000 total 185.0 185.0 185.0 185.0 185.0

Tablet hardness, friability, content uniformity, disintegration time, and dissolution properties were determined as described above.

Examples of tests on properties of pharmaceutical compositions and pharmaceutical dosage forms

1. Disintegration test

Disintegration testing was performed as described in USP31-NF26S2, Chapter 701 (Disintegration).

2. Dissolution Testing

The standard dissolution test is disclosed in USP31-NF26S2, Chapter 711 (Dissolution). A paddle method (Apparatus 2) with a stirring speed of 50 rpm was used. The dissolution medium was 900 mL of 0.05 M potassium phosphate buffer (pH 6.8) at a temperature of 37°C. Samples were taken after 10, 15, 20, 30, and 45 minutes. The samples were analyzed by HPLC.

FIG4 depicts the dissolution profiles of the tablets of Examples 4 and 6, wherein API1 is compound (I.3) and API2 is linagliptin.

Figure 5 depicts the dissolution profile of the tablet of Example 8, wherein API1 is compound (I.3) and API2 is linagliptin.

3. Particle size distribution measurement by laser diffraction

Particle size distribution is measured, for example, by light scattering or laser diffraction techniques. To determine the particle size, the powder is fed into a laser diffraction spectrometer, for example, via a dispersion unit. The test method is described in detail below:

The instrument was set up according to the manufacturer's recommendations and using the manufacturer's software. The sample container was thoroughly mixed and tumbled before removing a portion of the sample to ensure a representative sample was tested. Duplicate samples were prepared by transferring approximately 100 mg of sample to an ASPIROS glass vial using a spatula and capping the vial. The capped vial was placed in the feeder.

4. Tablet hardness and friability

Tablet hardness and friability testing were performed as described in USP 31-NF 26S2, Chapter 1217 (Tablet Breaking Strength).

In summary, the present invention relates to the following technical solutions:

1. A pharmaceutical composition comprising linagliptin as the first active pharmaceutical ingredient and one or more excipients.

2. The pharmaceutical composition of technical solution 1, which further comprises a pyranose glucopyranose-substituted benzene derivative of formula (I)

wherein R ¹ represents chlorine or methyl; and R ³ represents ethyl, ethynyl, ethoxy, (R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy, or a prodrug thereof, as the second active pharmaceutical ingredient.

3. The pharmaceutical composition of technical solution 1, wherein the particle size distribution of the first active ingredient is X90<200 μm.

4. The pharmaceutical composition of technical solution 2 or 3, wherein the particle size distribution of the second active ingredient is 1 μm<X90<200 μm.

5. The pharmaceutical composition of any one of technical solutions 1, 2, 3 or 4, wherein the one or more excipients comprise one or more diluents.

6. The pharmaceutical composition of any one of technical solutions 1, 2, 3 or 4, wherein the one or more excipients comprise one or more diluents and one or more binders.

7. The pharmaceutical composition of any one of technical solutions 1, 2, 3 or 4, wherein the one or more excipients comprise one or more diluents, one or more binders and one or more disintegrants.

8. The pharmaceutical composition according to any one of the above technical solutions, comprising

0.5-25% one or two active ingredients,

40-88% one or more diluents,

0.5-20% of one or more binders, and

0.5-20% one or more disintegrants,

The percentages are by weight of the total composition.

9. The pharmaceutical composition of any one of technical solutions 1 to 8, which is in the form of granules, capsules, tablets or film-coated tablets.

10. A pharmaceutical dosage form comprising the pharmaceutical composition of any one of technical solutions 1 to 9.

11. The pharmaceutical dosage form of technical solution 10 is characterized in that it is a solid pharmaceutical dosage form, especially a capsule or tablet.

12. The pharmaceutical dosage form of technical solution 10 or 11, comprising linagliptin in an amount of 0.1 to 30 mg as the first active pharmaceutical ingredient.

13. The pharmaceutical dosage form of any one of technical solutions 10, 11 or 12, further comprising a pyranosyl-substituted benzene derivative of formula (I) as defined in technical solution 2 in an amount of 0.5 to 100 mg as a second active pharmaceutical ingredient.

14. The pharmaceutical dosage form of any one of technical solutions 10, 11, 12 or 13, characterized in that in a dissolution test, after 45 minutes, at least 75 weight % of the first active pharmaceutical ingredient or at least 75 weight % of the first active pharmaceutical ingredient and at least 75 weight % of the second active pharmaceutical ingredient are dissolved.

15. The pharmaceutical dosage form of any one of technical solutions 10, 11, 12, 13 or 14, characterized in that in a disintegration test, the pharmaceutical dosage form disintegrates within 30 minutes.

16. A method for preparing the pharmaceutical dosage form of any one of technical solutions 10-15, comprising one or more granulation steps, wherein the one or two active pharmaceutical ingredients are granulated together with one or more excipients.

17. A method for preventing, slowing the progression of, delaying or treating a metabolic disorder in a patient in need thereof, wherein the metabolic disorder is selected from: type I diabetes, type II diabetes, impaired glucose tolerance, impaired fasting blood glucose, hyperglycemia, postprandial hyperglycemia, overweight, obesity and metabolic syndrome, characterized in that the pharmaceutical composition of any one of technical solutions 1-9 or the pharmaceutical dosage form of any one of technical solutions 10-15 is administered to the patient.

18. A method for improving glycemic control and/or reducing fasting plasma glucose, postprandial plasma glucose and/or glycosylated hemoglobin HbA1c in a patient in need thereof, characterized in that the pharmaceutical composition of any one of technical solutions 1-9 or the pharmaceutical dosage form of any one of technical solutions 10-15 is administered to the patient.

19. A method for preventing, slowing, delaying or reversing the progression of impaired glucose tolerance, impaired fasting blood glucose, insulin resistance and/or metabolic syndrome to type 2 diabetes in a patient in need thereof, characterized in that the pharmaceutical composition of any one of technical solutions 1-9 or the pharmaceutical dosage form of any one of technical solutions 10-15 is administered to the patient.

20. A method for preventing, slowing the progression of, delaying or treating a condition or disorder selected from the following in a patient in need: diabetic complications, such as cataracts and microvascular and macrovascular diseases, such as nephropathy, retinopathy, neuropathy, tissue ischemia, diabetic foot, arteriosclerosis, myocardial infarction, acute coronary syndrome, unstable angina, stable angina, stroke, peripheral arterial occlusive disease, cardiomyopathy, heart failure, arrhythmia and vascular restenosis, characterized in that the pharmaceutical composition of any one of technical solutions 1-9 or the pharmaceutical dosage form of any one of technical solutions 10-15 is administered to the patient.

21. A method for reducing weight or preventing weight gain or promoting weight loss in a patient in need thereof, characterized in that the pharmaceutical composition of any one of technical solutions 1-9 or the pharmaceutical dosage form of any one of technical solutions 10-15 is administered to the patient.

22. Use of the pharmaceutical composition of any one of technical solutions 1 to 9 in the preparation of a medicament for achieving the following purposes in a patient in need:

- preventing, slowing the progression of, delaying or treating a metabolic disorder selected from the group consisting of type I diabetes, type II diabetes, impaired glucose tolerance, impaired fasting glucose, hyperglycemia, postprandial hyperglycemia, overweight, obesity and metabolic syndrome; or

- Improved glycemic control and/or reduction in fasting plasma glucose, postprandial plasma glucose and/or glycosylated haemoglobin HbA1c; or

- prevent, slow, delay or reverse the progression of impaired glucose tolerance, insulin resistance and/or metabolic syndrome to type 2 diabetes; or

- preventing, slowing the progression of, delaying or treating a condition or disorder selected from the group consisting of: diabetic complications, such as cataracts and microvascular and macrovascular diseases, such as nephropathy, retinopathy, neuropathy, tissue ischemia, arteriosclerosis, myocardial infarction, stroke and peripheral arterial occlusive disease; or

- Reduce weight or prevent weight gain or promote weight loss; or

- prevent, slow down, delay or treat pancreatic beta cell degeneration and/or decreased pancreatic beta cell function, and/or improve and/or restore pancreatic beta cell function and/or restore pancreatic insulin secretion function; or

-Prevent, slow, delay or treat a disease or condition caused by abnormal accumulation of fat in the liver; or

- Maintaining and/or improving insulin sensitivity and/or treating or preventing hyperinsulinemia and/or insulin resistance.

23. The method of any one of technical solutions 17-21 or the use of technical solution 22, wherein the patient is an individual diagnosed with one or more conditions selected from overweight, obesity, visceral obesity and abdominal obesity.

24. The method of any one of technical solutions 17-21 or the use of technical solution 22, wherein the patient is an individual showing one, two or more of the following symptoms:

(a) Fasting blood glucose or serum glucose concentration greater than 100 mg/dL, especially greater than 125 mg/dL;

(b) postprandial plasma glucose equal to or greater than 140 mg/dL;

(c) HbA1c value equal to or greater than 6.5%, especially equal to or greater than 7.0%.

25. The method of any one of technical solutions 17-21 or the use of technical solution 22, wherein the patient is an individual suffering from one, two, three or more of the following conditions:

(a) obesity, visceral obesity and/or abdominal obesity,

(b) triglyceride blood level ≥150 mg/dL,

(c) HDL-cholesterol blood level <40 mg/dL in female patients and <50 mg/dL in male patients,

(d) systolic blood pressure ≥130 mm Hg and diastolic blood pressure ≥85 mm Hg,

(e) Fasting blood glucose level ≥100 mg/dL.

26. The method of any one of technical solutions 17 to 21 or the use of technical solution 22, wherein the patient has inadequate glycemic control despite diet and exercise therapy or despite monotherapy with an antidiabetic drug.

Claims (6)

1. A solid dosage form comprising liraglitin in a concentration of 5 mg as the primary active pharmaceutical ingredient and 1-chloro-4-(β-D-glucopyrano-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-benzene in a concentration of 10 mg or 25 mg as the secondary active pharmaceutical ingredient. The solid drug dosage form includes 0.5-25% active pharmaceutical ingredient, 40-88% of one or more diluents, 0.5-20% of one or more adhesives, and 0.5-20% of one or more disintegrants, The percentages are weight percentages of the total composition. The one or more diluents mentioned above are selected from mannitol and pregelatinized starch. The one or more adhesives mentioned above are selected from copovidone and/or pregelatinized starch. The one or more disintegrants mentioned above are selected from corn starch, pregelatinized starch, and crospovidone. The solid drug dosage form is a single-layer tablet, in which two active pharmaceutical ingredients are present in the single layer. The particle size distribution of the second active ingredient is 1μm < x 90 < 200μm, and In the dissolution test, at least 75% by weight of the first active pharmaceutical ingredient and at least 75% by weight of the second active pharmaceutical ingredient dissolved after 45 minutes. The “liraglitin” mentioned therein refers to liraglitin and its pharmaceutically acceptable salts. 2. The solid pharmaceutical dosage form of claim 1, further comprising: 0.1-15% of one or more lubricants, The percentages are weight percentages of the total composition. 3. The solid pharmaceutical dosage form of claim 2, wherein the one or more lubricants are selected from: talc; polyethylene glycol, especially polyethylene glycol with a molecular weight in the range of about 4400 to about 9000; hydrogenated castor oil; fatty acids and fatty acid salts, especially their calcium, magnesium, sodium or potassium salts, such as calcium docosanoate, calcium stearate, sodium stearoyl fumarate or magnesium stearate. 4. The solid pharmaceutical dosage form of claim 3, wherein the one or more lubricants are selected from magnesium stearate and talc. 5. The solid pharmaceutical dosage form of any of the preceding claims, which is in the form of granules, capsules, tablets or film-coated tablets. 6. The solid drug dosage form of any of the preceding claims, characterized in that, in a disintegration test, the drug dosage form disintegrates within 30 minutes.