Solid pharmaceutical dosage form comprising linagliptin and 1-chloro-4-(α-d-glucpiranos-1-yl)-2-[4-((s)-tetrahydrofuran-3-yloxy)-benzyl]-benzene

Abstract

The present invention relates to pharmaceutical compositions of linagliptin, pharmaceutical dosage forms, their preparation, their use and methods for treating metabolic disorders. This invention relates to solid pharmaceutical dosage forms comprising linagliptin and 1-chloro-4-(bd-glucopyranosom1-yl)-2-[4-((s)-tetrahydrofuran-3-yloxy)-benzyl]-benzene.

Description

1 / 96 Descriptive Report of the Invention Patent for SOLID PHARMACEUTICAL DOSAGE FORM COMPRISING LINAGLIPTIN AND 1-CHLORO-4-(BD-GLUCPIRANOS-1-YL)-2-[4-((S)TETRA-HYDROFURAN-3-YLOXY)-BENZYL]-BENZENE. Technical Field of the Invention

[001] The present invention relates to pharmaceutical compositions comprising linagliptin as a first active pharmaceutical ingredient. Furthermore, the present invention relates to a pharmaceutical dosage form. The invention also relates to a process for preparing such a pharmaceutical dosage form. Moreover, the invention relates to the use of the pharmaceutical composition and the pharmaceutical dosage form in the treatment and / or prevention of selected diseases and medical conditions, in particular one or more conditions selected from among others type 1 diabetes mellitus, type 2 diabetes mellitus, impaired glucose tolerance, impaired fasting blood glucose, and hyperglycemia. Furthermore, the present invention relates to methods for treating and / or preventing such diseases and medical conditions, wherein a pharmaceutical composition or pharmaceutical dosage form, according to the invention, is administered to a patient in need thereof. Background of the Invention

[002] 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 a dipeptide from the N-terminal end of various proteins having a proline or alanine residue at their N-terminal end. Due to this property, DPP-IV inhibitors interfere with the plasma levels of bioactive peptides, including the GLP-1 peptide, and are considered promising drugs for the treatment of diabetes mellitus, particularly type 2 diabetes mellitus. Petition 870210017171, dated 22 / 02 / 2021, page 6 / 112 2 / 96

[003] In attempts to prepare pharmaceutical compositions of selected DPP-IV inhibitors, such as linagliptin, it has been observed that DPP-IV inhibitors with a primary or secondary amino group exhibit incompatibilities, degradation problems, or extraction problems with various routine excipients such as microcrystalline cellulose, sodium amide glycolate, croscarmellose sodium, tartaric acid, citric acid, fructose, sucrose, lactose, and maltodextrins. Although the compounds themselves are quite stable, they react with various excipients used in solid dosage forms and with excipient impurities, especially in evenly proportioned contact in tablets and at high excipient / drug ratios. The amino group appears to react with reducing sugars and with other reactive carbonyl groups and with carboxylic acid functional groups formed, for example, on the surface of microcrystalline cellulose by oxidation.

[004] These unforeseen difficulties are mainly observed in low dosage ranges, which are required due to the surprising potency of selected inhibitors, such as linagliptin. Thus, pharmaceutical compositions are required to solve these technical problems associated with the technical potency of selected DPP-IV inhibitor compounds. Pharmaceutical compositions comprising linagliptin as the pharmaceutical ingredient are described in WO2007 / 128724.

[005] Type 2 diabetes is a prevalent and increasing disease that, due to the high frequency of complications, leads to a significant reduction in life expectancy. Due to the microvascular complications associated with diabetes, type 2 diabetes is currently the most frequent cause of early vision loss in adults, kidney failure, and amputations in the industrialized world. Furthermore, the presence of type 2 diabetes is associated with a two- to five-fold increase in risk. Petition 870210017171, dated 22 / 02 / 2021, p. 7 / 112 3 / 96 of cardiovascular disease.

[006] After a long course of the disease, most patients with type 2 diabetes will eventually fail oral therapy and become insulin-dependent, requiring daily injections and multiple daily glucose measurements.

[007] Oral antidiabetic drugs used in therapy (such as, for example, first- or second-line combination therapy or (initial or add-on)) include, without limitation, metformin, sulfonylureas, thiazolidinediones, glinides and aglycosidase inhibitors.

[008] The high incidence of treatment failure is the major contributor to the high rate of complications associated with long-term hyperglycemia or chronic lesions (including micro- and macrovascular complications such as, for example, diabetic nephropathy, retinopathy or neuropathy, or cardiovascular complications) in patients with type 2 diabetes.

[009] Therefore, there is an unmet medical need for methods, drugs and pharmaceutical compositions with good efficacy with respect to glycemic control, with respect to disease-modifying properties and with respect to the reduction of vascular morbidity and mortality, while showing, at the same time, an improved safety profile.

[0010] SGLT2 inhibitors represent a new class of agents being developed for the treatment or improvement of glycemic control in patients with type 2 diabetes. Glycopyranosyl-substituted benzene derivatives are described in the prior art as SGLT2 inhibitors, for example, in WO 01 / 27128, WO 03 / 099836, WO 2005 / 092877, WO 2006 / 034489, WO 2006 / 064033, WO 2006 / 117359, WO 2006 / 117360, WO 2007 / 025943, WO 2007 / 028814, WO 2007 / 031548, WO 2007 / 093610, WO Petition 870210017171, dated 22 / 02 / 2021, page 8 / 112 4 / 96 2007 / 128749, WO 2008 / 049923, WO 2008 / 055870, WO 2008 / 055940. Glycopyranosyl-substituted benzene derivatives are proposed as inducers of urinary sugar excretion and as medications in the treatment of diabetes. Purpose of the Present Invention

[0011] The objective of the present invention is to provide a pharmaceutical composition comprising linagliptin that shows no signs or only marginal signs of linagliptin and thus allows a good to very good shelf life.

[0012] Another objective of the invention is to provide a pharmaceutical composition comprising linagliptin, which has a high uniformity, enabling efficient production with respect to time and costs of pharmaceutical dosage forms.

[0013] Another objective of the invention is to provide a pharmaceutical dosage form comprising linagliptin, with a good shelf life, which has a short disintegration time, with good dissolution properties and / or which allows high bioavailability of linagliptin in a patient.

[0014] Yet another objective of the present invention is to provide a pharmaceutical composition comprising a combination of a DPP-IV inhibitor and a DSGLT2 inhibitor.

[0015] Another objective of the present invention is to provide a pharmaceutical composition comprising linagliptin with an SGLT2 inhibitor, which shows no signs or only marginal signs of linagliptin degradation and thus allows for a good to very good shelf life.

[0016] Another objective of the invention is to provide a pharmaceutical composition comprising linagliptin in combination with an SGLT2 inhibitor, which has high content uniformity and / or allows for efficient production with respect to time and cost of dosage forms. Petition 870210017171, dated 22 / 02 / 2021, page 9 / 112 5 / 96 of pharmaceutical dosages.

[0017] Another objective of the 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 high bioavailability of linagliptin in the patient.

[0018] Another objective of the invention is to provide a pharmaceutical composition and a pharmaceutical dosage form, each comprising linagliptin in combination with an SGLT2 inhibitor, and a method for preventing, slowing the progression, delaying or treating metabolic disorders, in particular, type 2 diabetes mellitus.

[0019] Yet another objective of the present invention is to provide a pharmaceutical composition and a pharmaceutical dosage form, each comprising linagliptin in combination with an SGLT2 inhibitor, and a method for improving glycemic control in patients requiring it, particularly in patients with type 2 diabetes mellitus.

[0020] Another objective of the present invention is to provide a pharmaceutical composition and a pharmaceutical dosage form, each comprising linagliptin in combination with an SGLT2 inhibitor, and a method for improving glycemic control in a patient with insufficient glycemic control despite monotherapy with an antidiabetic drug, for example, metformin or an SGLT2 inhibitor or a DPP-IV inhibitor.

[0021] Another objective of the present invention is to provide a pharmaceutical composition and a pharmaceutical dosage form, each comprising linagliptin in combination with an SGLT2 inhibitor, and a method for preventing, slowing, and delaying the progression of impaired glucose tolerance (IGT), impaired fasting blood glucose (IFG), insulin resistance, and / or meta-syndrome. Petition 870210017171, dated 22 / 02 / 2021, page 10 / 112 6 / 96 bolic to type 2 diabetes mellitus.

[0022] Yet another objective of the present invention is to provide a pharmaceutical composition and a pharmaceutical dosage form, each comprising linagliptin in combination with an SGLT2 inhibitor, and a method for preventing, slowing the progression, delaying or treating a condition or disorder of the group consisting of complications of diabetes mellitus.

[0023] Also, another objective of the present invention is to provide a pharmaceutical composition and a pharmaceutical dosage form, each comprising linagliptin in combination with an SGLT2 inhibitor, and a method for reducing weight or preventing weight gain in patients who need this.

[0024] Another objective of the present invention is to provide a new pharmaceutical composition and a pharmaceutical dosage form, each comprising linagliptin in combination with an SGLT2 inhibitor, with high efficacy for the treatment of metabolic disorders, in particular diabetes mellitus, impaired glucose tolerance (IGT), impaired fasting blood glucose (IFG), and / or hyperglycemia, which have good to very good pharmacological and / or pharmacokinetic and / or physicochemical properties.

[0025] Another objective of the present invention is to provide a process for the preparation of a pharmaceutical dosage form, according to the invention, which is highly cost-effective and / or time-effective.

[0026] Other objectives of the present invention will become apparent to those skilled in the art from the description above and below, and from the examples. Summary of the Invention

[0027] In a first aspect, the present invention provides a pharmaceutical composition comprising linagliptin as a first active pharmaceutical ingredient and one or more excipients, in Petition 870210017171, dated 22 / 02 / 2021, page 11 / 112 7 / 96 in particular one or more diluents, one or more binders and / or one or more disintegrants. The pharmaceutical composition according to the invention is preferably a solid pharmaceutical composition, for example, a pharmaceutical composition for oral administration.

[0028] Within the scope of the present invention, it has been found that a pharmaceutical composition comprising linagliptin as an active pharmaceutical ingredient with a particle size distribution of X90 < 200 µm exhibits an advantageous dissolution profile and / or good availability and allows for high content uniformity and efficient production with respect to time and costs of pharmaceutical dosage forms.

[0029] 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 method.

[0030] Furthermore, within the scope of the present invention, it has been found that linagliptin combined with certain excipients shows no signs or only marginal signs of linagliptin degradation and thus allows for a shelf life ranging from good to very good. In particular, it has been found that the objectives of the present invention can be achieved with a pharmaceutical composition as described above, comprising only a diluent.

[0031] Furthermore, within the scope of the present invention, it has been found that a pharmaceutical composition comprising linagliptin as the first active pharmaceutical ingredient in combination with a glycopyranosyl-substituted benzene derivative of formula (I) as described below as an SGLT2 inhibitor shows no signs or only marginal signs of linagliptin degradation and Petition 870210017171, dated 22 / 02 / 2021, page 12 / 112 8 / 96 allows for a shelf life of good to very good. This result may not have been predicted given the chemical nature of linagliptin and the functional groups of the glycopyranosyl-substituted benzene derivative, in particular the glycopyranosyl ring and the hydroxyl groups on it.

[0032] Therefore, in another aspect, the present invention provides a pharmaceutical composition comprising linagliptin as an active pharmaceutical ingredient, a glycopyranosyl-substituted benzene derivative of formula (I):

[0033] wherein R1 represents chlorine or methyl; and R3 represents ethyl, ethinyl, ethoxy, (R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy, or a prodrug thereof, as the active ingredient, one or more diluents, one or more binders and one or more disintegrants.

[0034] Within the scope of the present invention, it has been found that the pharmaceutical composition comprising the glycopyranosyl-substituted benzene derivative as the active pharmaceutical ingredient with a particle size distribution of 1 μm < X90 < 200 μm exhibits an advantageous dissolution profile and / or good bioavailability and allows for high content uniformity and efficient production with respect to the time and costs of pharmaceutical dosage forms.

[0035] Therefore, in another aspect, the present invention provides a pharmaceutical composition comprising linagliptin as the first active pharmaceutical ingredient and a glycopyranosyl-substituted benzene derivative of formula (I) as described below as the second active pharmaceutical ingredient and one or more excipients, wherein the second active ingredient has a particle size distribution of Petition 870210017171, dated 22 / 02 / 2021, page 13 / 112 9 / 96 la of 1 um < X90 < 200 um, preferably determined by volume by laser diffraction method.

[0036] The pharmaceutical compositions according to the invention allow for high content uniformity and efficient production with respect to time and cost of pharmaceutical dosage forms, such as tablets and capsules. Furthermore, these pharmaceutical dosage forms, in particular tablets, such as single-layer tablets or double-layer tablets, according to the invention, show no signs or only marginal signs of linagliptin degradation and thus allow for a long shelf life.

[0037] Therefore, in another aspect, the present invention provides a pharmaceutical dosage form comprising a pharmaceutical composition according to the invention. The pharmaceutical dosage forms according to the invention are preferably solid pharmaceutical dosage forms, even more preferably solid pharmaceutical dosage forms for oral administration.

[0038] In another aspect, the present invention provides a process for preparing a pharmaceutical dosage form, according to the invention, comprising one or more granulation processes, wherein one or more active pharmaceutical ingredients, together with one or more excipients, are granulated.

[0039] Furthermore, it can be noted that the pharmaceutical composition comprising linagliptin in combination with a glycopyranosyl-substituted benzene derivative of formula (I), as described below, can be used advantageously to prevent, slow the progression of, delay or treat a metabolic disorder, in particular to improve glycemic control in patients, for example, in patients with inadequate glycemic control with existing oral antidiabetic therapy. This opens up a range of new therapeutic possibilities in the treatment and prevention of diabetes. Petition 870210017171, dated 22 / 02 / 2021, page 14 / 112 10 / 96 type 2 diabetes mellitus, overweight, obesity, complications of diabetes mellitus and related disease states.

[0040] According to another aspect of the invention, a method is provided for preventing, slowing the progression of, delaying or treating a selected metabolic disorder from the group consisting of type 1 diabetes mellitus, type 2 diabetes mellitus, impaired glucose tolerance (IGT), impaired fasting blood glucose (IFG), hyperglycemia, postprandial hyperglycemia, overweight, obesity and metabolic syndrome in a patient in need thereof, characterized in that a pharmaceutical composition or pharmaceutical dosage form as defined above and below is administered to the patient.

[0041] According to another aspect of the invention, a method is provided for improving glycemic control and / or for reducing fasting plasma glucose, postprandial plasma glucose and / or glycosylated hemoglobin (HbA1c) in a patient who needs this, characterized in that a pharmaceutical composition or pharmaceutical dosage form as defined above or below is administered to the patient.

[0042] The pharmaceutical composition and pharmaceutical dosage form, according to this invention, may also have valuable disease-modifying properties with respect to diseases or conditions related to impaired glucose tolerance (IGT), impaired fasting blood glucose (IFG), insulin resistance and / or metabolic syndrome.

[0043] According to another aspect of the invention, a method is provided for preventing, slowing, delaying or reversing the progression of impaired glucose tolerance (IGT), impaired fasting blood glucose (IFG), insulin resistance and / or metabolic syndrome to type 2 diabetes mellitus in a patient who requires Petition 870210017171, dated 22 / 02 / 2021, page 15 / 112 11 / 96 of this, characterized by the fact that a pharmaceutical composition or pharmaceutical dosage form, as defined above or below, is administered to the patient.

[0044] When using a pharmaceutical composition and dosage form according to this invention, an improvement in glycemic control is obtained in patients who need it, and also those conditions and / or diseases related to or caused by increased blood glucose levels can be treated.

[0045] According to another aspect of the invention, a method is provided for preventing, slowing the progression of, delaying or treating a selected condition or disorder from the group consisting of complications of diabetes mellitus such as cataracts and micro- and macrovascular diseases such as neuropathy, retinopathy, neuropathy, tissue ischemia, diabetic foot, arteriosclerosis, myocardial infarction, acute coronary syndrome, unstable angina pectoris, stable angina pectoris, stroke, peripheral arterial occlusive disease, cardiomyopathy, heart failure, cardiac rhythm disorders and vascular restenosis, in a patient in need thereof, characterized in that a pharmaceutical composition or pharmaceutical dosage form as defined above or below is administered to the patient. The term tissue ischemia particularly includes diabetic macroangiopathy, diabetic microangiopathy, impaired wound healing and diabetic ulcer.In particular, one or more aspects of diabetic nephropathy, such as hyperperfusion, proteinuria, and albuminuria, can be treated, their progression slowed, or their onset delayed or prevented. The terms microvascular and macrovascular diseases and microvascular and macrovascular complications are used interchangeably in this descriptive report.

[0046] By administering a pharmaceutical composition and pharmaceutical dosage form, according to this invention, and Petition 870210017171, dated 22 / 02 / 2021, page 16 / 112 Due to the activity of the SGLT2 inhibitor, excess blood glucose levels are not converted into insoluble storage forms, such as fat, but are excreted through the patient's urine. Therefore, it does not result in any weight gain or even reduction in body weight.

[0047] According to another aspect of the invention, a method is provided for reducing body weight or preventing an increase in body weight or facilitating the reduction of body weight in a patient who needs it, characterized in that a pharmaceutical composition or pharmaceutical dosage form as defined above or below is administered to the patient.

[0048] The pharmacological effect of the glycopyranosyl-substituted benzene derivative as an SGLT2 inhibitor in the pharmaceutical composition according to this invention is insulin-independent. Therefore, improved glycemic control is possible without additional stress on pancreatic beta cells. By administering a pharmaceutical composition or dosage form according to this invention, beta cell degeneration and decline in beta cell functionality, such as, for example, apoptosis or necrosis of pancreatic beta cells, can be delayed or prevented. Furthermore, pancreatic cell functionality can be improved or regenerated, and the number and size of pancreatic cells increased.It can be shown that the state of differentiation and hyperplasia of pancreatic beta cells, disrupted by hyperglycemia, can be normalized by treatment with a pharmaceutical composition or dosage form according to this invention.

[0049] According to another aspect of the invention, a method is provided for preventing, slowing down, delaying or treating the degeneration of pancreatic beta cells and / or the decline in functionality. Petition 870210017171, dated 22 / 02 / 2021, page 17 / 112 13 / 96 of pancreatic beta cells and / or to improve and / or regenerate the functionality of pancreatic beta cells and / or regenerate the functionality of pancreatic insulin secretion in a patient who needs it, characterized in that a pharmaceutical composition or pharmaceutical dosage form as defined above and below is administered to the patient.

[0050] By administering the pharmaceutical composition and dosage form according to the present invention, abnormal fat accumulation in the liver can be reduced or inhibited. Therefore, according to another aspect of the present invention, a method is provided for preventing, slowing down, delaying, or treating diseases or conditions attributed to abnormal fat accumulation in the liver in a patient in need thereof, characterized in that a pharmaceutical composition or dosage form as defined above or below is administered to the patient. Diseases or conditions that are attributed to abnormal fat accumulation in the liver are particularly selected from the group that generally consists of fatty liver, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), alcohol-induced fatty liver disease, or toxic fatty liver disease.

[0051] As a consequence of these, another aspect of the invention provides a method for maintaining and / or improving insulin sensitivity and / or for treating or preventing hyperinsulinemia and / or insulin resistance in a patient who needs it, characterized in that a pharmaceutical composition or pharmaceutical dosage form as defined above and below is administered to the patient.

[0052] According to another aspect of the invention, the use of a pharmaceutical composition according to the invention is provided in the manufacture of a medicament for: - to prevent, slow the progression of, delay or treat Petition 870210017171, dated 22 / 02 / 2021, page 18 / 112 14 / 96 a metabolic disorder selected from the group consisting of type 1 diabetes mellitus, type 2 diabetes mellitus, impaired glucose tolerance (IGT), impaired fasting blood glucose (IFG), hyperglycemia, postprandial hyperglycemia, overweight, obesity, and metabolic syndrome; or - to improve glycemic control and / or reduce fasting plasma glucose, postprandial plasma glucose and / or glycosylated hemoglobin (HbA1c); or - to prevent, slow down, delay or reverse the progression of impaired glucose tolerance (IGT), impaired fasting blood glucose (IFG), insulin resistance and / or metabolic syndrome of type 2 diabetes mellitus; or - to prevent, slow the progression of, delay, or treat a selected condition or disorder from the group consisting of complications of diabetes mellitus such as cataracts and micro- and macrovascular diseases, such as nephropathy, retinopathy, neuropathy, tissue ischemia, diabetic foot, arteriosclerosis, myocardial infarction, acute coronary syndrome, unstable angina pectoris, stable angina pectoris, stroke, peripheral arterial occlusive disease, cardiomyopathy, heart failure, cardiac rhythm disorders, and vascular restenosis; or - to reduce body weight or prevent weight gain or facilitate weight loss; or - to prevent, slow down, delay or treat pancreatic beta cells and / or the decline in pancreatic beta cell function and / or to improve and / or regenerate pancreatic beta cell function and / or regenerate pancreatic insulin secretion function; or - to prevent, slow down, delay, or treat diseases or conditions attributed to the abnormal accumulation of fat in the liver; or Petition 870210017171, dated 22 / 02 / 2021, page 19 / 112 15 / 96 - To maintain and / or improve insulin sensitivity and / or treat or prevent hyperinsulinemia and / or insulin resistance;

[0053] in a patient who needs this.

[0054] According to another aspect of the invention, the use of a pharmaceutical composition or a pharmaceutical dosage form according to the present invention is provided in the manufacture of a medicament for therapeutic or preventive purposes as described above or below. Definitions

[0055] The term active ingredient or active pharmaceutical ingredient of a pharmaceutical composition or pharmaceutical dosage form, according to the present invention, means linagliptin and optionally a glucopyranosyl-substituted benzene derivative of formula (I), according to the present invention, in particular compound (I.3).

[0056] The term body mass index or BMI of a human patient is defined as weight in kilograms divided by the square of the height in meters, so the unit of BMI is kg / m2.

[0057] The term overweight is defined as the condition in which an individual has a BMI greater than 25 kg / m2 and less than 30 kg / m2. The terms overweight and pre-obese are used interchangeably.

[0058] The term obesity is defined as the condition in which an individual has a BMI equal to or greater than 30 kg / m2. According to the WHO definition, the term obesity can be categorized as follows: the term class I obesity is the condition in which the BMI is equal to or greater than 30 kg / m2, but less than 35 kg / m2; the term class II obesity is the condition in which the BMI is equal to or greater than 35 kg / m2, but less than 40 kg / m2; the term class III obesity is the condition in which the BMI is equal to or greater than 40 kg / m2.

[0059] The term visceral obesity is defined as the condition Petition 870210017171, dated 22 / 02 / 2021, p. 20 / 112 16 / 96, where the waist-to-hip ratio is greater than 1.0 in men and 0.8 in women. It defines the risk of insulin resistance and the development of prediabetes.

[0060] The term abdominal obesity is usually defined as the condition in which the 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 may be defined as a waist circumference > 85 cm in men and > 90 cm in women (see, for example, the investigating committee for the diagnosis of metabolic syndrome in Japan).

[0061] The term euglycemia is defined as the condition in which a patient has a fasting blood glucose concentration within the normal range of 70 mg / dL (3.89 mmol / L) and less than 100 mg / dL (5.6 mmol / L). The word fasting has its usual meaning as a medical term.

[0062] The term hyperglycemia is defined as the condition in which a patient has a fasting blood glucose concentration above the normal range, greater than 100 mg / dL (5.6 mmol / L). The word fasting has its usual meaning in the medical term.

[0063] The term hypoglycemia is defined as the condition in which a patient has a glucose concentration below the normal range, in particular below 70 mg / dL (3.89 mmol / L).

[0064] The term postprandial hyperglycemia is defined as the condition in which the patient has a blood glucose or serum glucose concentration, 2 hours postprandial, greater than 200 mg / dL (11.11 mmol / L).

[0065] The term impaired fasting blood glucose or IFG is defined as the condition in which a patient 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), in part. Petition 870210017171, dated 22 / 02 / 2021, page 21 / 112 17 / 96 particular greater than 110 mg / dL and less than 126 mg / dL (7.00 mmol / dL). A patient with normal fasting glucose has a fasting glucose concentration less than 100 mg / dL, that is, less than 5.6 mmol / L.

[0066] The term impaired glucose tolerance or IGT is defined as the condition in which a patient has a blood glucose or serum glucose concentration 2 hours postprandial greater than 140 mg / dL (7.78 mmol / L) and less than 200 mg / dL (11.11 mmol / L). Normal glucose tolerance, that is, the blood or serum glucose concentration 2 hours postprandial, can be measured as the blood sugar level in mg of glucose per dL of plasma 2 hours after ingesting 75 g of glucose after fasting. A patient with normal glucose tolerance has a blood glucose concentration or serum glucose 2 hours postprandial of less than 140 mg / dL (7.78 mmol / L).

[0067] The term hyperinsulinemia is defined as the condition in which a patient with insulin resistance, with or without euglycemia, has a postprandial serum or plasma insulin concentration elevated above that of lean, normal individuals without insulin resistance, with a waist-to-hip ratio < 1.0 (for men) or < 0.8 (for women).

[0068] The terms insulin sensitization, improving insulin resistance, or reducing insulin resistance are synonymous and used interchangeably.

[0069] The term insulin resistance is defined as a state in which circulating insulin levels in excess of the normal response to a glucose load are required to maintain a euglycemic state (Ford ES, et al. JAMA. (2002) 287:356-9). One method for determining insulin resistance is the euglycemic-hyperinsulinemic clamp test. The insulin-to-glucose ratio is determined within the scope of a combined insulin-glucose infusion technique. Insulin resistance is diagnosed if absorption Petition 870210017171, dated 22 / 02 / 2021, page 22 / 112 18 / 96 glucose is below the 25th percentile of the secondary population investigated (WHO definition). Much less laborious than the clamp test are the so-called minimal models, in which, during an intravenous glucose tolerance test, blood glucose and insulin concentrations are measured at fixed time intervals and insulin resistance is calculated from them. With this method, it is not possible to distinguish between hepatic and peripheral insulin resistance.

[0070] Furthermore, insulin resistance, a patient's response to therapy, insulin sensitivity, and hyperinsulinemia can be quantified by determining the Homeostasis Model Assessment Index (HOMA-IR) score, a reliable indicator of insulin resistance (Katsuki A, et al. Diabetes Care 2001; 24: 362-5). Reference is also made to methods for determining the HOMA index for insulin sensitivity (Matthews et al., Diabetologia 1985, 28: 412-19), the proinsulin-to-insulin ratio (Forst et al., Diabetes 2003, 52(Suppl.1): A459), and a euglycemic clamp study. Additionally, plasma adiponectin levels can be monitored as a potential surrogate for insulin sensitivity. The estimation of insulin resistance by the Homeostasis Model Assessment-Insulin Resistance (HOMA-IR) classification is calculated using the formula (Galvin P, et al. Diabet Med 1992;9:921-8): HOMA-IR = [fasting serum insulin (U / mL)] x [fasting plasma glucose (mmol / L) / 22.5]

[0071] As a rule, other parameters are used in daily clinical practice to assess insulin resistance. Preferably, the patient's triglyceride concentration is used, for example, as elevated triglyceride levels correlate significantly with the presence of insulin resistance.

[0072] Patients with a predisposition to developing IGT Petition 870210017171, dated 22 / 02 / 2021, page 23 / 112 19 / 96 or IFG or type 2 diabetes are those who have euglycemia with hyperinsulinemia and are, by definition, insulin resistant. A typical patient with insulin resistance is usually overweight or obese. If insulin resistance can be detected, this is a particularly strong indication of the presence of prediabetes. Thus, it may be that to maintain glucose homeostasis, a person needs as much as 2 to 3 times the amount of insulin as a healthy person, without this resulting in any clinical symptoms.

[0073] The methods for investigating pancreatic beta cell function are similar to the methods above with respect to insulin sensitivity, hyperinsulinemia, or insulin resistance: An improvement in beta cell function can be measured, for example, by determining the HOMA index for beta cell function (Matthews et al., Diabetologia 1985, 28: 412-19), the intact proinsulin ratio (Forst et al., Diabetes 2003, 52(Suppl.1): A459), insulin / C-peptide secretion after an oral glucose tolerance test, or a food tolerance test, or by employing a hyperglycemic clamp study and / or minimal models after an intravenous glucose test, often with samples (Stumvoll et al., Eur J Clin Invest 2001, 31:380-81).

[0074] The term prediabetes refers to the condition in which an individual is predisposed to developing type 2 diabetes. Prediabetes broadens the definition of glucose tolerance to include individuals with fasting blood glucose in the high normal range > 100 mg / dL (JB Meigs, et al. Diabetes 2003; 52:1475-1484) and fasting hyperinsulinemia (elevated plasma insulin concentration). The scientific and medical basis for identifying prediabetes as a serious health threat is a Position Statement entitled The Prevention or Delay of Type 2 Diabetes, jointly issued by the American Diabetes Association and the National Institute of Diabetes and Digestive and Kidney Diseases. Petition 870210017171, dated 22 / 02 / 2021, p. 24 / 112 20 / 96 Diseases (Diabetes Care 2002; 25:742-749).

[0075] Individuals likely to have insulin resistance are those who have two or more of the following attributes: 1) overweight or obese, 2) high blood pressure, 3) hyperlipidemia, 4) one or more of the categories related to the diagnosis of IGT or IFG or type 2 diabetes. Insulin resistance can be confirmed in these individuals by calculating the HOMA-IR score. For the purposes of this invention, insulin resistance is defined as the clinical condition in which an individual has a HOMA-IR score > 4.0 or a HOMA-IR score above the upper limit of normal as defined by the laboratory performing glucose and insulin assays.

[0076] The term type 2 diabetes is defined as the condition in which a patient has a fasting blood or serum glucose concentration greater than 125 mg / dL (6.94 mmol / L). Measuring blood glucose levels is a standard procedure in routine medical analysis. If a glucose tolerance test is performed, a diabetic's blood sugar level will be in excess of 200 mg of glucose per dL (11.1 mmol / L) of plasma 2 hours after 75 g of glucose have been ingested on an empty stomach. In a glucose tolerance test, 75 g of glucose are administered orally to the test patient after 1-12 hours of fasting, and the blood sugar level is recorded immediately before glucose ingestion and 1 and 2 hours after ingestion. In a healthy person, the blood sugar level before ingesting glucose will be between 60 and 110 mg per dL of plasma, less than 200 mg per dL 1 hour after ingesting glucose, and less than 140 mg per dL after 2 hours.If after 2 hours the value is between 140 and 200 mg, this is considered abnormal glucose tolerance.

[0077] The term type 2 diabetes mellitus in the early stage includes Petition 870210017171, dated 22 / 02 / 2021, p. 25 / 112 21 / 96 patients with failure to secondary drugs, indication for insulin therapy and progression to micro- and macrovascular complications, for example, diabetic nephropathy or coronary heart disease (CHD).

[0078] The term HbA1c refers to the non-enzymatic glycation end product of the hemoglobin B chain. Its determination is well known to those skilled in the art. In monitoring the treatment of diabetes mellitus, the HbA1c value is of exceptional importance. As its production depends essentially on the blood sugar level and the lifespan of erythrocytes, HbA1c in the sense of blood sugar memory reflects the medical blood sugar levels of the preceding 4-6 weeks. Diabetic patients whose HbA1c value is consistently well adjusted by intensive diabetes treatment (i.e., < 6.5% of total hemoglobin in the sample) are significantly better protected against diabetic microangiopathy. For example, metformin alone achieves a measured improvement in HbA1c value in diabetics of the order of 1.0-1.5%. This reduction in HbA1c levels is not sufficient in all diabetics to achieve the desired target range of < 6.5% and, preferably, < 6% HbA1c.

[0079] The term insufficient glycemic control or inadequate glycemic control within the scope of the present invention means a condition in which patients show HbA1c values ​​above 6.5%, in particular above 7.0%, even more preferably above 7.5%, especially above 8%. Metabolic syndrome, also called syndrome X (when used in the context of a metabolic disorder), also known as dysmetabolic syndrome, is a complex of syndromes with insulin resistance as its cardinal characteristic (Laaksonen DE, et al. Am J Epidemiol 2002;156:1070-7). According to the Petition 870210017171, dated 22 / 02 / 2021, page 26 / 112 According to the 22 / 96 guidelines of the ATP III / NCEP (Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) JAMA: Journal of the American Medical Association (2001) 285:2486-2497), the diagnosis of metabolic syndrome is made when three or more of the following risk factors are present: 1. Abdominal obesity, defined as a waist circumference > (40 inches) or 102 cm in men, and (> 35 inches) or 94 cm in women; or with respect to Japanese ethnicity or Japanese patients, defined as a waist circumference > 85 cm in men and > 90 cm in women; 2. Triglycerides: > 150 mg / L; 3. HDL cholesterol < 40 mg / L in men; 4. Blood pressure > 130 / 85 mmHg (SBP > 130 or PSD > 85) 5. Fasting blood glucose > 100 mg / dL.

[0080] The NCEP definitions have been validated (Laaksonen DE, et al. Am J Epidemiol 2002;156:1070-7). Triglycerides and HDL cholesterol in the blood can also be determined by standard methods of medical analysis and are described, for example, by Thomas L (Editor): Labor und Diagnose, TH-Books Verlagsgesellschaft mbH, Frankfurt / Main, 2000.

[0081] According to the commonly used definition, hypertension is diagnosed if systolic blood pressure (SBP) exceeds 140 mmHg and diastolic blood pressure exceeds 90 mmHg. If the patient is suffering from overt diabetes, it is currently recommended that systolic blood pressure be reduced to a level below 130 mmHg and diastolic blood pressure be reduced to less than 80 mmHg. Petition 870210017171, dated 22 / 02 / 2021, page 27 / 112 23 / 96

[0082] The terms treatment and treat encompass therapeutic treatment of patients who have developed said condition, in particular the manifest form. Therapeutic treatment may be symptomatic to alleviate the symptoms of the specific indication or causal treatment to partially reverse or alleviate the conditions of the indication or to halt or slow the progression of the disease. Thus, the compositions and dosage forms and methods of the present invention may be used, for example, as therapeutic treatment for a period of time as well as for chronic therapy.

[0083] The terms treat prophylactically, treat preventively and prevent are used interchangeably and encompass the treatment of patients who are at risk of developing a condition mentioned above and thus reducing that risk.

[0084] The term therapeutically effective amount, as used herein, refers to an amount or dose of the active pharmaceutical ingredient that achieves the desired therapeutic response, for example, reduction of blood glucose levels, reduction of HbA1c or weight reduction, in a mammalian individual or patient, but preferably does not cause hypoglycemia in the individual or patient. In the case of a pharmaceutical composition or dosage form comprising two active pharmaceutical ingredients, the term therapeutically effective amount, as used herein, refers to an amount or dose of the respective active pharmaceutical ingredient that, in combination with or with other active pharmaceutical ingredients, achieves the desired therapeutic response, for example, reduction of blood glucose levels, reduction of HbA1c or weight reduction, in a mammalian individual or patient, but preferably does not cause hypoglycemia in the individual or patient.

[0085] The term tablet includes coated tablets and tablets with one or more coatings. In addition, Petition 870210017171, dated 22 / 02 / 2021, p. 28 / 112 24 / 96 the term tablet includes tablets with one, two, three or more layers and press-coated tablets, wherein each of the types of tablets mentioned above may be without or with one or more coatings. The term tablet also includes mini, meltable, chewable, effervescent and orally disintegrable tablets.

[0086] The term pharmacopoeias refers to standard pharmacopoeias such as USP 31-NF 26 through Second Supplement (United States Pharmacopeial Convention) or the European Pharmacopoeia 6.3 (European Directorate for the Quality of Medicines and Health Care, 2000-2009). Brief description of the figures

[0087] Figure 1 shows an X-ray powder diffractogram of the crystalline form (I. 3X) of compound (I. 3).

[0088] Figure 2 shows the thermoanalysis and DSC melting point determination of the crystalline form (I3.X) of compound (I.3).

[0089] Figure 3 shows the glucose excursion as quantified by the AUC of reactive glucose after glucose challenge in four different ZDF beam groups, which received control, linagliptin (Comp. A), compound (I.3) (Comp. B) or a combination of linagliptin and compound (I.3) (Combination A + B).

[0090] Figure 4 shows tablet dissolution profiles according to Example 4 and Example 6, where API 1 is compound (I.3) and API 2 is linagliptin.

[0091] Figure 5 shows tablet dissolution profiles according to Example 8, where API 1 is compound (I.3) and API 2 is linagliptin. Detailed Description

[0092] Aspects according to the present invention, in particular pharmaceutical compositions, pharmaceutical dosage forms Petition 870210017171, dated 22 / 02 / 2021, page 29 / 112 25 / 96 CAS, methods and uses, refer to linagliptin and glycopyranosyl-substituted benzene derivatives as defined above and below.

[0093] The term linagliptin, as used herein, refers to linagliptin and pharmaceutically acceptable salts thereof, including hydrates and solvates thereof, and crystalline forms thereof. The crystalline forms thereof are described in WO 2007 / 128721. The preferred crystalline forms are the A and B polymorphs described therein. Methods for manufacturing linagliptin are described in patent applications WO 2004 / 018468 and WO 2006 / 048427, for example. Linagliptin is distinguished from structurally comparable DPPP IV inhibitors in that it combines exceptional potency and a long-lasting effect with favorable pharmacological properties, receptor selectivity, and a favorable side effect profile, or produces unexpected therapeutic advantages and improvements, when used with a glycopyranosyl-substituted benzene derivative according to this invention.

[0094] The glycopyranosyl-substituted benzene derivative is defined by formula (I)

[0095] where R1 is chlorine or methyl; and R3 is ethyl, ethinyl, ethoxy, (R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy; or a prodrug thereof.

[0096] The compounds of formula (I) and methods of their synthesis are described, for example, in the following patent applications WO 2005 / 092877, WO 2006 / 117360, WO 2006 / 117359, WO 2006 / 120208, WO 2006 / 064033, WO 2007 / 028814, WO 2007 / 031548, WO 2008 / 049923. Petition 870210017171, dated 22 / 02 / 2021, p. 30 / 112 26 / 96

[0097] In glycopyranosyl-substituted benzene derivatives of formula (I), the following definitions of the substituents are preferred.

[0098] Preferably, R1 is chlorine.

[0099] Preferably, R3 is ethinyl, (R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy.

[00100] More preferably, R3 is (R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy.

[00101] Preferred glycopyranosyl-substituted benzene derivatives of formula (I) are selected from the group of compounds (I.1) Petition 870210017171, dated 22 / 02 / 2021, p. 31 / 112 27 / 96

[00102] Furthermore, the most preferred glycopyranosyl-substituted benzene derivative compounds of formula (I) are selected from compounds (I. 2) and (I. 3).

[00103] According to the invention, it should be understood that the definitions of the glycopyranosyl-substituted benzene derivatives of formula (I) listed above also include their hydrates, solvates and polymorphic forms, and their prodrugs. With respect to the preferred compound (I. 1), an advantageous crystalline form is described in international patent application WO 2007 / 028814, which is incorporated herein by reference in its entirety. With respect to the preferred compound (I. 2), a preferred advantageous crystalline form is described in international patent application WO 2006 / 117360, which is incorporated herein by reference in its entirety. With respect to the preferred compound (I. 3), an advantageous crystalline form is described in international patent application WO 2006 / 117359, which is incorporated herein by reference in its entirety. With respect to the preferred compound (1.5), an advantageous crystalline form is described in international patent application WO 2008 / 049923, which is incorporated herein by reference in its entirety. These. Petition 870210017171, dated 22 / 02 / 2021, page 32 / 112 28 / 96 crystalline forms possess good solubility properties, which allow for good bioavailability of the glycopyranosyl-substituted benzene derivative. Furthermore, the crystalline forms are physicochemically stable and thus provide good shelf-life stability for the pharmaceutical composition.

[00104] A preferred crystalline form (I.3X) of compound (I.3) can be characterized by a powder X-ray pattern comprising peaks at 18.84, 20.36 and 25.21 degrees 2© (±0.1 degree 2©), wherein the powder X-ray diffraction pattern (XRPD) is made using CuK«1 radiation.

[00105] In particular, the powder X-ray diffraction pattern comprises peaks at 14.69, 18.84, 19.16, 19.50, 20.36 and 25.21 degrees 2© (±0.1 degree 2©), wherein the powder X-ray diffraction pattern (XRPD) is made using CuK«1 radiation.

[00106] In particular, said powder X-ray diffraction pattern comprises peaks at 14.69, 17.95, 18.43, 19.16, 19.50, 20.36, 22.71, 23.44, 24.81 and 25.65 degrees 2© (±0.1 degree 2©), wherein the powder X-ray diffraction pattern (XRPD) is made using CuK«1 radiation.

[00107] More specifically, the crystalline form (I.3X) is characterized by a powder X-ray diffraction pattern, made using CuK«1 radiation, comprising peaks at degrees 2© (±0.1 degree 2©), as shown in Table 1. Table 1: X-ray diffraction pattern of crystalline powder (I.3X) (only peaks for 30 oem 2Θ are listed): 2 Q [°] Value d [A] Intensity I / I0 [%] 4.46 19.80 8 9.83 8.99 4 11.68 7.57 4 13.35 6.63 14 14.69 6.03 42 Petition 870210017171, dated 22 / 02 / 2021, page 33 / 112 29 / 96 15.73 5.63 16 16.20 5.47 8 17.95 4.94 30 18.31 4.84 22 18.43 4.81 23 18.84 4.71 100 19.16 4.63 42 19.50 4.55 31 20.36 4.36 74 20.55 4.32 13 21.18 4.19 11 21.46 4.14 13 22.09 4.02 19 22.22 4.00 4 22.71 3.91 28 23.44 3.79 27 23.72 3.75 3 24.09 3.69 3 24.33 3.66 7 24.81 3.59 24 25.21 3.53 46 25.65 3.47 23 26.40 3.37 2 26.85 3.32 8 27.26 3.27 17 27.89 3.20 2 28.24 3.16 3 29.01 3.08 4 29.41 3.03 18 Petition 870210017171, dated 22 / 02 / 2021, page 34 / 112 30 / 96

[00108] More specifically, the crystalline form (I.3X) is characterized by a powder X-ray diffraction pattern, made using CuK«1 radiation, comprising peaks at degrees 2© (±0.1 degree 2©), as shown in figure 1.

[00109] Furthermore, the crystalline form (i.3) is characterized by a melting point of approximately 149°C ± 3°C (determined via DSC; assessed as initial temperature; healing rate of 10 k / min). The DSC curve obtained is shown in Figure 2.

[00110] X-ray powder diffraction patterns are recorded, within the scope of the present invention, using a STOE-STADI P diffractometer in transmission mode coupled to a location-sensitive detector (OED) and a Cu anode as the X-ray source (CuK₂ radiation, λ = 1.54056 A, 40 kV, 40 mA). In Table 1 above, the values ​​of 2© [o] represent the diffraction angle in degrees and the values ​​of d[A] represent the distances specified in A between the planes of the crystal lattice. The intensity shown in Figure 1 is given in units of cps (counts per second).

[00111] To allow for experimental error, the 2© values ​​described above should be considered accurate to ±0.1 degree 2©, in particular ± 0.05 degree 2©. This means that when assessing whether a given sample of crystals of compound (I.3) is the crystalline form according to the invention, a 2© value that is experimentally observed for the sample should be considered identical to a characteristic value described above if it falls within ± 0.1 degree 2© of the characteristic value, in particular if it falls within ± 0.05 degree 2© of the characteristic value.

[00112] The melting point is determined by DSC (differential scanning calorimetry), using a DSC 821 (Mettler Toledo).

[00113] With respect to pharmaceutical ingredients, it can be noted that the dissolving properties of the pharmaceutical composition Petition 870210017171, dated 22 / 02 / 2021, page 35 / 112 31 / 96 The pharmaceutical composition and dosage form, and thus the bioavailability of the active ingredients, are affected, among other things, by the particle size and particle size distribution of the respective active pharmaceutical ingredient. In the pharmaceutical composition and dosage form according to the invention, the active pharmaceutical ingredients preferably have a particle size distribution such that at least 90% of the respective active pharmaceutical ingredient particles, with respect to the volume distribution, have a particle size smaller than 200 μm, that is, X90 < 200 μm, or in other words, X90 < 200 μτ.

[00114] In particular, in the pharmaceutical composition and dosage form according to the invention, linagliptin, for example, a crystalline form thereof, preferably has a particle size distribution (by volume) such that at least 90% of the respective active pharmaceutical ingredient has a particle size less than 200 μm, i.e., X90 < 200 μm, more preferably X90 < 150 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, most preferably X90 > 5 μm. Therefore, preferred particle size distributions are such that 0.1 μτ < X90 < 200 μm, particularly 0.1 μm < X90 < 150 μm, more preferably 1 μm < X90 < 100 μm. A preferred example of a linagliptin particle size distribution is such that X90 < 50 uT or 10 uT < X90 < 50 uT.

[00115] Furthermore, in the pharmaceutical composition and dosage form according to the invention, linagliptin, for example, a crystalline form thereof, preferably has a particle size distribution (by volume) such that X50 < 90 μτ, more preferably X50 < 75 μτ, even more preferably X50 < 50 μτ, most preferably X50 < 40 μτ. In addition, the particle size distribution is preferably such that X50 > 0.1 μm, more preferably X50 > 0.5 μm, even more preferably X50 > 4 μm. Therefore, the preferred particle size distributions are such that 0.1 pm < X50 < 90 pm, particularly 0.5 pm < X50 < 75 pm, more preferably 4 pm < X50 < 75 pm, even more preferably 4 pm < X50 < 50 pm. A preferred example is 8 pm < X50 < 40 pm.

[00116] Furthermore, in the pharmaceutical composition and dosage form according to the invention, linagliptin, for example, a crystalline form thereof, preferably has a particle size distribution (by volume) such that X10 > 0.05 pm, more preferably X10 > 0.1 pm, even more preferably X10 > 0.5 pm.

[00117] In particular, with respect to the glycopyranosyl-substituted benzene derivative of formula (I), in particular compound (I.3), it was surprisingly found that very small particle sizes influence the manufacturing capability, for example, by forming sticks or films. On the other hand, very large particles negatively affect the dissolution properties of the pharmaceutical composition and the dosage form and thus the bioavailability. The preferred ranges of particle size distribution are described below.

[00118] In the pharmaceutical composition and dosage range according to the invention, the glycopyranosyl-substituted benzene derivative of formula (I), in particular compound (I.3), for example, its crystalline form (13X), preferably has a particle size distribution (by volume) such that at least 90% of the respective active pharmaceutical ingredient has a particle size smaller than 200 µm, i.e. X90 < 200 µm, preferably X90 < 150 µm. More preferably, the particle size distribution is such Petition 870210017171, dated 22 / 02 / 2021, page 37 / 112 33 / 96 that X90 < 100 pm, even more preferably X90 < 90 pm. Furthermore, the particle size distribution is such that X90 > 1 pm, more preferably X90 > 5 pm, even more preferably X90 > 10 pm. Therefore, the preferred particle size distributions are such that 1 pm < X90 < 200 pm, particularly 1 pm < X90 < 150 pm, more preferably 5 pm < X90 < 150 pm, even more preferably 5 pm < X90 < 100 pm, even more preferably 10 pm < X90 < 100 pm. A preferred example is X90 < 75 pm. Another preferred example is 20 pm < X90 < 50 pm.

[00119] Furthermore, in the pharmaceutical composition and dosage form according to the invention, the glycopyranosyl-substituted benzene derivative of formula (I), in particular compound (I.3), for example, its crystalline form (13.X), preferably has a particle size distribution (by volume) such that X50 < 90 pm, more preferably X50 < 75 pm, even more preferably X50 < 50 pm, most preferably X50 < 40 pm. In addition, the particle size distribution is preferably such that X50 > 1 pm, more preferably X50 > 5 pm, even more preferably X50 > 8 pm. Therefore, the preferred particle size distributions are such that 1 pm < X50 < 90 pm, particularly 1 pm < X50 < 75 pm, more preferably 5 pm < X50 < 75 pm, and even more preferably 5 pm < X50 < 50 pm. A preferred example is 8 pm < X50 < 40 pm.

[00120] Furthermore, in the pharmaceutical composition and pharmaceutical dosage form according to the invention, the glycopyranosyl-substituted benzene derivative of formula (I), in particular compound (I.3), for example, its crystalline form (I3.X), preferably has a particle size distribution (by volume) such that X10 > 0.1 μm, more preferably X10 > 0.5 μm, even more preferably X10 > 1 μm.

[00121] Therefore, a pharmaceutical composition or dosage form Petition 870210017171, dated 22 / 02 / 2021, page 38 / 112 34 / 96 pharmaceutical gem, according to this invention, can preferably be characterized by the particle size distributions specified above X90, X50 and / or X10 or one of the following embodiments: Linagliptin Modality Benzene derivative substituted with glycopyranosyl, in particular compound (I.3) E.1 X90 < 200 pm X90 < 200 pm E.2 0.1 pm < X90 < 150 pm 1 pm < X90 < 150 pm E.3 0.1 pm < X90 < 150 pm 5 pm < X90 < 150 pm E.4 0.1 pm < X90 < 150 pm 10 pm < X90 < 100 pm E.5 0.1 pm < X90 < 150 pm X90 < 150 pm 1 pm < X50 < 75 pm E.6 0.1 pm < X90 < 150 pm X90 < 150 pm 5 pm < X50 < 50 pm E.7 0.1 pm < X90 < 150 pm X90 < 150 pm 1 pm < X50 < 75 pm X10 > 0.1 pm E.8 0.1 pm < X90 < 150 pm X90 < 150 pm 5 pm < X50 < 50 pm X10 > 0.5 pm E.9 0.1 pm < X90 < 150 pm X90 < 100 pm 5 pm < X50 < 50 pm X10 > 0.5 pm E.10 5 pm < X90 < 100 pm X90 < 100 pm 5 pm < X50 < 50 pm Petition 870210017171, dated 22 / 02 / 2021, page. 39 / 112 35 / 96 X10 > 0.5 pm E.11 X90 <150 pm 4 pm < X50 < 75 pm 100 pm 5 pm < X50 < 50 pm

[00122] The X90 value refers to the 90% value of the distribution measured using a laser diffractometer. In other words, for the purposes of the present invention, the X90 value represents the particle size at which 90% of the particle quantity is found based on the volume distribution. Similarly, the X50 value refers to the 50% (average) value of the volume distribution 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 particle quantity is found based on the volume distribution. Similarly, the X10 value refers to the 10% value of the volume distribution 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 particle quantity is found based on the volume distribution.

[00123] Preferably, all X90, X50 and X10 values ​​above and below are in volume and determined by laser diffraction method, in particular small-angle laser light scattering, i.e. Fraunhofer diffraction. A preferred test is described in the experimental section. Petition 870210017171, dated 22 / 02 / 2021, page 40 / 112 36 / 96 mental. The laser diffraction method is sensitive to the volume of a particle and provides a volume-averaged particle size, which is equivalent to the weight-averaged particle size if the density is constant. Those skilled in the art know that the results of particle size determination by one technique can be correlated to those of another technique, for example, on an empirical basis by routine experimentation. Alternatively, the particle size distribution in the pharmaceutical composition or pharmaceutical dosage form can be determined by microscopy, in particular electron microscopy or scanning electron microscopy.

[00124] In order to provide suitable starting material consisting of the active pharmaceutical ingredient, such as linagliptin or the glycopyranosyl-substituted benzene derivative, in particular compound (I.3) and its crystalline form (I.3X) is ground, for example, jet ground or pin ground.

[00125] The preferred excipients and carriers of the pharmaceutical compositions according to the invention are described in more detail below. Preferably, the excipients are pharmaceutically stable.

[00126] Preferably, excipients are chosen so that they are compatible with linagliptin, i.e., so that there is no degradation or only marginal degradation 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 will mean a chemical degradation of linagliptin of less than 5%, preferably less than 3%, even more preferably less than 2% by weight of linagliptin. The content and thus the degradation can be determined by well-known analytical methods, for example, using HPLC or UV methods. Petition 870210017171, dated 22 / 02 / 2021, page 41 / 112 37 / 96

[00127] In the pharmaceutical composition according to the invention, the excipients preferably comprise one or more diluents.

[00128] Furthermore, in the pharmaceutical composition according to the invention, the excipients preferably comprise one or more diluents and one or more binders.

[00129] Furthermore, in the pharmaceutical composition according to the invention, the excipients preferably comprise one or more binders and one or more disintegrants and other optional ingredients.

[00130] Also, in the pharmaceutical composition according to the invention, the excipients more preferably comprise one or more diluents and one or more binders and one or more disintegrants and one or more lubricants and other optional ingredients.

[00131] Some of the excipients may have two or more functions at the same time, for example, they may act as a diluent or as a binder or as a binder and as a disintegrant or as a diluent, as a binder and as a disintegrant.

[00132] One or more diluents, another term is filler, are added when the amount of the active ingredient(s) is small in order to obtain a minimum tablet weight (e.g., 100 mg or more) and satisfactory content uniformity (e.g., < 3% standard deviation) according to pharmacopoeias. It has been observed that common diluents, such as lactose, sucrose, and microcrystalline cellulose, are not compatible with linagliptin.

[00133] Preferably, one or more suitable diluents for a pharmaceutical composition according to the invention are selected from the group consisting of cellulose, in particular cellulose powder, dibasic calcium phosphate, in particular anhydrous or dihydrated dibasic calcium phosphate, erythritol, mannitol, starch, pregelatinized starch, and xylitol, including derivatives and hydrates of the aforementioned substances. Petition 870210017171, dated 22 / 02 / 2021, page 42 / 112 38 / 96 above. Pregelatinized starch diluent shows additional binding properties. Among the diluents listed above, mannitol and pregelatinized starch are particularly preferred.

[00134] In the case of the pharmaceutical composition, according to the invention, comprising a diluent, then the diluent is preferably mannitol or pregelatinized starch, more preferably mannitol.

[00135] In the case of the pharmaceutical composition, according to the invention, comprising one or more diluents, then the first diluent is preferably mannitol and the second diluent is selected from the group of diluents as described above, even more preferably pregelatinized starch which shows additional binding properties.

[00136] Mannitol, as mentioned above and below, is preferably a small particle size grade suitable for granulation. An example is Pearlitol®50C (Roquette).

[00137] Pregelatinized starch, as mentioned above and below, can be any of the commercially available grades. An example is Starch 1500® (Colorcon).

[00138] The pharmaceutical composition according to the present invention preferably does not comprise a substance selected from the group of glucose, fructose, sucrose, lactose and maltodextrins, in particular lactose. Preferably, it does not comprise a substance from the aforementioned group, in particular lactose, above an amount of 2% by weight of the total composition, even more preferably above an amount of 0.5% by weight of the total composition.

[00139] One or more binders in the pharmaceutical composition provide adhesion to the pharmaceutical composition, for example, during granulation and to the pressed tablet. They add cohesive strength already available in the diluent. Common binders are, for example, Petition 870210017171, dated 22 / 02 / 2021, page 43 / 112 39 / 96 sucrose and microcrystalline cellulose, which were shown to be incompatible with linagliptin.

[00140] Preferably, one or more suitable binders for a pharmaceutical composition according to the invention are selected from the group consisting of copovidone, hydroxypropyl methylcellulose (HPMC), hydroxypropylcellulose (HPC) and polyvinylpyrrolidone, pregelatinized starch, and low-substituted hydroxypropylcellulose (LHPC), including derivatives and hydrates of the substances mentioned above. An even more preferred binder is copovidone and / or pregelatinized starch.

[00141] Copovidone as mentioned above and below is preferably a copolymerized vinylpyrrolidone with vinyl acetate, preferably with a molecular weight of about 45,000 to about 70,000. An example is Kollidon® VA 64 (BASF).

[00142] Hydroxypropyl methylcellulose (also called HPMC or hypromellose) as mentioned above and below is preferably hypromellose 2910. Hydroxypropyl methylcellulose preferably has a viscosity in the range of about 4 to about 6 cps. An example is 'Methocel® E5 Prem LV (Dow Chemicals).

[00143] Hydroxypropyl cellulose (also called HPC), as mentioned above and below, preferably has a viscosity range in the range of about 300 to about 600 mPa*s. Hydroxypropyl cellulose preferably has a molecular weight of about 60,000 to about 100,000, for example, around 80,000. An example is Klucel®EF (Aqualon).

[00144] Polyvinylpyrrolidone (also called PVP, povidone or polyvinylpyrrolidone), as mentioned above and below, preferably has a molecular weight of about 28,000 to about 54,000. Polyvinylpyrrolidone preferably has a viscosity in the range of about 3.5 to about 8.5 mPa*s. An example is Kollidon® 25 or Kollidon® 30 Petition 870210017171, dated 22 / 02 / 2021, page 44 / 112 40 / 96 (BASF).

[00145] Low-substituted hydroxypropylcellulose (also called L-HPC) as mentioned above and below preferably has a hydroxypropoxy content in the range of about 5 to about 16% by weight.

[00146] The binders mentioned above, pregelatinized starch and L-HPC, show additional diluent and disintegrant properties and can also be used as the second diluent or disintegrant.

[00147] One or more disintegrating agents serve to aid in the fragmentation of the pharmaceutical composition and dosage form after administration. A common disintegrant is, for example, microcrystalline cellulose, which has been found to be incompatible with linagliptin.

[00148] Preferably, one or more disintegrants suitable for a pharmaceutical composition according to the present invention are selected from the group consisting of crospovidone, low-substituted hydroxypropylcellulose (L-HPC), and starches, such as native starches, in particular corn starch and pregelatinized starch, including derivatives and hydrates of the substances mentioned above. Among the disintegrants mentioned above, corn starch, pregelatinized starch, and crospovidone are even more preferred.

[00149] Surprisingly, it was found that at least two disintegrants are preferred if linagliptin and a glycopyranosyl-substituted benzene derivative of formula (I) are combined in a pharmaceutical composition according to the invention, in particular in a dosage form, for example, a tablet or capsule. Preferred disintegrants are corn starch and crospovidone.

[00150] Even more preferable is a combination of at least Petition 870210017171, dated 22 / 02 / 2021, page 45 / 112 41 / 96 three ingredients, if the inhibitor linagliptin and a glycopyranosyl-substituted benzene derivative of formula (I) are combined in a pharmaceutical composition according to the invention, in particular in a dosage form, for example, tablet or capsule. Preferred disintegrants are corn starch, pregelatinized starch and crospovidone.

[00151] Copovidone as mentioned above and below is preferably an insoluble povidone, i.e., a cross-linked form of PVP. An example is Kollidon® CL or Kollidon® CL-SF (BASF).

[00152] The corn starch mentioned above and below is preferably native starch. An example is Maize (extra white) corn starch (Roquette).

[00153] The disintegrants mentioned above, starch and pregelatinized starch, show additional diluent properties, and thus can also be used, for example, as the second diluent.

[00154] One or more lubricants in the pharmaceutical composition reduce friction in tablet preparation, that is, during the compression and ejection cycle. In addition, they help eliminate sticking of the tablet material to the dies and punches.

[00155] Preferably, the pharmaceutical composition according to the invention further comprises one or more lubricants. Preferably, the one or more lubricants suitable for a pharmaceutical composition according to the invention are selected from the group consisting of talc (e.g., from Luzenac), polyethylene glycol, in particular polyethylene glycol with a molecular weight in the range of about 4,400 to about 9,000, hydrogenated castor oil, fatty acid and fatty acid salts, in particular their calcium, magnesium, sodium or potassium salts, for example, calcium behenate, calcium stearate, sodium stearyl fumarate or magnesium stearate (e.g., HyQaul®, Mallinckrodt or Ligamed®, Peter Greven). The lubricants Petition 870210017171, dated 22 / 02 / 2021, page 46 / 112 42 / 96 The most preferred adhesives are magnesium stearate and talc.

[00156] It has been surprisingly found that at least two lubricants are preferred if linagliptin and a glycopyranosyl-substituted benzene derivative of formula (I) are combined in a pharmaceutical composition according to the invention, in particular in a dosage form, for example, tablet or capsule. Preferred lubricants are talc and magnesium stearate. The combination of the two or more lubricants allows for low ejection forces and allows for the binding of the final mixture in tablet manufacturing, for example.

[00157] One or more glidants are agents that improve the flowability of powder in the pharmaceutical composition.

[00158] The pharmaceutical composition according to the present invention may further comprise one or more glide agents. Preferably, the one or more glide agents suitable for a pharmaceutical composition according to the invention are selected from the group consisting of talc and colloidal silicon dioxide (for example, Aerosil®200 Pharma (Evonik)).

[00159] It is preferred that the excipients, in particular one or more diluents, such as mannitol, have a particle size of 1 to 500 µm. A particle size of 25 to 160 µm is preferred in granulation processes. A particle size of 180 to 500 µm is preferred in direct tablet forming processes. The particle size is preferably analyzed by sieving. Preferably, at least 80%, more preferably at least 90%, most preferably at least 95% by weight of the particles are within the given range.

[00160] According to a first embodiment of the present invention, the pharmaceutical composition comprises only one active ingredient, which is linagliptin.

[00161] A preferred composition, according to the first mo Petition 870210017171, dated 22 / 02 / 2021, page 47 / 112 43 / 96 The purpose of the present invention comprises a diluent, a binder, and a disintegrant. Preferably, said composition comprises only a diluent. Even more preferably, said composition comprises only a diluent and only a binder. Even more preferably, said composition comprises only a diluent, only a binder, and only a disintegrant. The composition may further comprise at least one lubricant. In addition, the composition may further comprise at least one slip agent.

[00162] A pharmaceutical composition, according to the first embodiment, preferably comprises 0.5-20% active pharmaceutical ingredient, 40-88% one or more diluents, preferably 0.5-20% one or more binders, 0.5-20% one or more disintegrants.

[00163] where the percentages are by weight of the total composition.

[00164] The following tracks are even more preferred 0.5-10% active pharmaceutical ingredient, 50-75% one or more, preferably a diluent; 1-15% one or more binders, 1-15% one or more disintegrants.

[00165] where the percentages are by weight of the total composition.

[00166] Another pharmaceutical composition according to the first embodiment preferably comprises 0.5-20% active pharmaceutical ingredient, 40-88% one or more, preferably a diluent; 0.5-20% one or more binders, 0.5-20% one or more disintegrants, and Petition 870210017171, dated 22 / 02 / 2021, page 48 / 112 44 / 96 0.1-4% one or more lubricants

[00167] where percentages are given by weight of the total composition.

[00168] The following tracks are even more preferred: 0.5-10% active pharmaceutical ingredient, 50-75% one or more, preferably a diluent; 1-15% one or more binders, 1-15% one or more disintegrants, and 0.5-3% one or more lubricants.

[00169] where percentages are given by weight of the total composition.

[00170] In pharmaceutical compositions, the preferred diluent is mannitol. The preferred binder is copovidone. The preferred disintegrant is corn starch. A preferred lubricant is magnesium stearate. In the case where the pharmaceutical composition comprises a second diluent, pregelatinized starch would be preferred. It has additional binding properties.

[00171] A pharmaceutical dosage form, for example, a tablet or capsule, prepared with a pharmaceutical composition according to the first embodiment, contains linagliptin as the active ingredient, preferably in a therapeutically effective amount. A preferred dosage range is 0.1 to 100 mg, more preferably 0.5 to 20 mg, even more preferably 1 to 10 mg. Preferred dosages are, for example, 0.5 mg, 1 mg, 2.5 mg, 5 mg, and 10 mg.

[00172] According to a second embodiment of the present invention, the pharmaceutical composition comprises two active pharmaceutical ingredients, which are linagliptin and a glycopyranosyl-substituted benzene derivative of formula (I) as defined above and below, in particular La linagliptin and compound (I.3). Petition 870210017171, dated 22 / 02 / 2021, page 49 / 112 45 / 96

[00173] Surprisingly, it can be observed that a glycopyranosyl-substituted benzene derivative of formula (I), in particular compound (I.3), although it has a glycopyranosyl moiety with free hydroxyl groups, is compatible with linagliptin, i.e., linagliptin combined with the glycopyranosyl-substituted benzene derivative shows no or only marginal degradation.

[00174] A preferred pharmaceutical composition, according to the second embodiment, comprises linagliptin and compound (I.3) as the two active pharmaceutical ingredients. Preferably, the pharmaceutical composition or dosage form 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, in said pharmaceutical composition or dosage form, 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.3) as defined above. Preferably, the pharmaceutical composition or dosage form comprises linagliptin in one or more of the crystalline forms, in particular polymorphs A and B, as described in WO 2007 / 128721, incorporated herein in its entirety.

[00175] A pharmaceutical composition, according to the second embodiment of the present invention, comprises one or more diluents, one or more binders, and one or more disintegrants. An even more preferred pharmaceutical composition, according to the second embodiment of the present invention, comprises one or more diluents, one or more binders, one or more disintegrants, and one or more lubricants. Preferably, said composition comprises one or two diluents. Even more preferably, said composition also comprises one or two diluents and a binder. Even more preferably, said composition also comprises one or two diluents. Petition 870210017171, dated 22 / 02 / 2021, page 50 / 112 46 / 96 tes, a binder and a disintegrant. Even more preferably, said composition comprises one or two diluents, a binder and at least two disintegrants. Even more preferably, said composition comprises one or two diluents, one or two binders and at least two disintegrants.

[00176] Even more preferably, said composition comprises one or two diluents, one or two binders, at least two disintegrants and a lubricant. Even more preferably, said composition comprises one or two diluents, one or two binders, at least two disintegrants and one or two lubricants. Even more preferably, said composition comprises one or two diluents, one or two binders, at least two disintegrants and two lubricants. Even more preferably, said composition preferably comprises one or two diluents, one or two binders, three disintegrants and two lubricants. In addition, the composition may further comprise at least one slip agent. Preferred diluents, binders, disintegrants, lubricants and slip agents are described above and below.

[00177] A pharmaceutical composition, according to the second embodiment, preferably comprises 0.5-25% active pharmaceutical ingredient(s), 40-78% one or more diluents, 0.5-20% one or more binders, 0.5-20% one or more disintegrants,

[00178] where the percentages are by weight of the total composition.

[00179] The following tracks are even more preferred: 1-20% active pharmaceutical ingredient(s), 50-75% one or more diluents, 1-15% one or more binders, Petition 870210017171, dated 22 / 02 / 2021, page 51 / 112 47 / 96 1-15% one or more disintegrants,

[00180] where the percentages are by weight of the total composition.

[00181] Additionally, said pharmaceutical composition may comprise one or more lubricants in a range of 0.1-15% by weight of the total composition.

[00182] A pharmaceutical composition, according to the second embodiment, preferably comprises 0.5-25% active pharmaceutical ingredient(s), 40-88% one or more diluents, 0.5-20% one or more binders, 0.5-20% one or more disintegrants, 0.1-15% one or more lubricants,

[00183] where the percentages are by weight of the total composition.

[00184] In the pharmaceutical compositions above, the preferred diluent is mannitol, the preferred binder is copovidone, and the preferred disintegrants are selected from corn starch and crospovidone. Preferred lubricants are selected from magnesium stearate and talc. In the case where the pharmaceutical composition comprises a second diluent, pregelatinized starch is preferred. Pregelatinized starch has additional binding and disintegrating properties.

[00185] Therefore, the preferred pharmaceutical compositions, according to the second embodiment, are characterized by the following composition: 1-20% active pharmaceutical ingredients, 50-75% mannitol, 2-4% copovidone, 8-12% corn starch,

[00186] where the percentages are by weight of the composition Petition 870210017171, dated 22 / 02 / 2021, page 52 / 112 48 / 96 total.

[00187] Other preferred pharmaceutical compositions, according to the second embodiment, are characterized by the following composition: 1-20% active pharmaceutical ingredients, 50-75% mannitol, 0-15% pregelatinized starch, 2-4% copovidone, 8-12% corn starch, 0-2% crospovidone,

[00188] where the percentages are by weight of the total composition.

[00189] Preferably, the pharmaceutical compositions described above additionally comprise a lubricant. The lubricant is preferably magnesium stearate in an amount of 0.5-2% by weight of the total composition.

[00190] Preferably, the pharmaceutical compositions described above additionally comprise 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.

[00191] Therefore, the preferred pharmaceutical compositions, according to the second embodiment, are characterized by the following composition: 1-20% active pharmaceutical ingredients, 50-75% mannitol, 0-15% pregelatinized starch, 2-4% copovidone, 8-12% corn starch, Petition 870210017171, dated 22 / 02 / 2021, page 53 / 112 49 / 96 0-2% crospovidone, 0.5-2% magnesium stearate,

[00192] where the percentages are by weight of the total composition.

[00193] Other preferred pharmaceutical compositions, according to the second embodiment, are characterized by the following composition: 1-20% active pharmaceutical ingredients, 50-75% mannitol, 0-15% pregelatinized starch, 2-4% copovidone, 8-12% corn starch, 0-2% crospovidone, 0.5-2% magnesium stearate, 0.0-10% talc,

[00194] where the percentages are by weight of the total composition.

[00195] The pharmaceutical composition, according to the invention, may additionally comprise one or more flavor-masking agents, for example, sweeteners or flavorings, and pigments.

[00196] The pharmaceutical composition, according to the invention, may additionally comprise one or more coatings. Non-functional coatings are preferred.

[00197] The pharmaceutical compositions according to the invention are preferably solid pharmaceutical compositions, in particular intended for oral administration. A pharmaceutical dosage form according to the present invention, comprising a pharmaceutical composition according to the present invention, is preferably a pharmaceutical dosage form, in particular for oral administration. Examples include capsules, tablets, for example, Petition 870210017171, dated 22 / 02 / 2021, page 54 / 112 50 / 96 film-coated tablet, or granules.

[00198] A pharmaceutical dosage form, according to the first embodiment of the invention, for example, a capsule or tablet, comprises only one active pharmaceutical ingredient, which is linagliptin.

[00199] A pharmaceutical dosage form, according to the second embodiment of the invention, for example, a capsule or tablet, comprises two active pharmaceutical ingredients which are linagliptin and a glycopyranosyl-substituted benzene derivative of formula (I) as defined above or below, in particular linagliptin and compound (I.3). The tablet may be a single-layer tablet, in which the two active pharmaceutical ingredients are present in a single layer. Alternatively, the tablet may be a two-layer tablet, in which one of the two active pharmaceutical ingredients is present in a first layer and the other active pharmaceutical ingredient is present in the second layer. Alternatively, the formulation may be a film-coated tablet, in which one of the two active pharmaceutical ingredients is present in the tablet core and the other active pharmaceutical ingredient is present in the film coating layer.Alternatively, the tablet may be a three-layer tablet, in which the two layers containing only one active pharmaceutical ingredient are each separated by a third layer, which does not contain any active pharmaceutical ingredient. Alternatively, the tablet may be a press-coated tablet, that is, a tablet in which one active pharmaceutical ingredient is contained in small tablets, for example, with a diameter of 2-6 mm, and the other active pharmaceutical ingredient is contained in a second granulation and tablets joined together with a small tablet to make a large, press-coated tablet. All types of tablets. Petition 870210017171, dated 22 / 02 / 2021, page 55 / 112 51 / 96 mentioned above may be uncoated or may have one or more coatings, particularly film coatings. Non-functional coatings are preferred.

[00200] It will be appreciated that the amount of one or more active pharmaceutical ingredients, according to this invention, to be administered to the patient and required for use in treatment or prophylaxis according to the present invention will vary according to the route of administration, the nature and severity of the condition for which treatment or prophylaxis is required, the age, weight and condition of the patient, concomitant medication and will ultimately be varied according to the criteria of the attending physician. However, in general, a preferred amount is such that by administering the pharmaceutical dosage form glycemic control in the patient to be treated is improved.

[00201] The following describes the preferred ranges of the amount of linagliptin and the glycopyranosyl-substituted benzene derivative to be used in the pharmaceutical dosage form according to the invention. These ranges refer to the amounts to be administered per day with respect to an adult patient, in particular a human being, for example, weighing approximately 70 kg, and therefore can be adapted with respect to administration 2, 3, 4 or more times daily and with respect to other routes of administration and with respect to the patient's age. The dosage ranges and amounts are calculated for the individual active fraction.

[00202] A preferred pharmaceutical dosage form, according to the second embodiment, contains linagliptin in a therapeutically effective amount and the glycopyranosyl-substituted benzene derivative, in particular compound (I.3)) in a therapeutically effective amount. A preferred amount of linagliptin is in Petition 870210017171, dated 22 / 02 / 2021, page 56 / 112 52 / 96 range of 0.1 to 30 mg, preferably 0.5 to 20 mg, even more preferably 1 to 10 mg, most preferably 2 to 5 mg. Preferred dosages are, for example, 0.5 mg, 1 mg, 2.5 mg, 5 mg and 10 mg. A preferred amount of the glycopyranosyl-substituted benzene derivative (in particular compound (I.3)) is in the range of 0.5 to 100 mg, preferably 0.5 to 50 mg, even more preferably 1 to 25 mg, even more preferably 5 to 25 mg, most preferably 10 to 25 mg. Preferred dosages of the glycopyranosyl-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. A pharmaceutical dosage, according to the second embodiment, contains, for example, a combination of dosages selected from the embodiments as illustrated in the following table: Modality | Amount of linagliptin | Amount of benzene derivative substituted with glucopyranosyl, in particular compound (I.3) | 1. 2 mg to 5 mg | 1 mg to 25 mg | 2. 2 mg to 5 mg | 5 mg to 25 mg | 3. 2 mg to 5 mg | 10 mg to 25 mg | 4. 5 mg | 5 mg to 25 mg | 5. 2 mg to 5 mg | 5 mg | 6. 2 mg to 5 mg | 7.5 mg | 7. 2 mg to 5 mg | 10 mg | 8. 2 mg to 5 mg | 12.5 mg | 9. 2 mg to 5 mg | 15 mg | 10. 2 mg to 5 mg | 20 mg | 11. 2 mg to 5 mg | 25 mg | 12. 5 mg | 2.5 mg | 13. 5 mg | 5 mg Petition 870210017171, dated 22 / 02 / 2021, page 57 / 112 53 / 96 Ϊ.14 5 mg 7.5 mg !.15 5 mg 10 mg !.16 5 mg 12.5 mg !.17 5 mg 15 mg Ϊ.18 5 mg 20 mg !.19 5 mg 25 mg !.20 5 mg 30 mg !.21 5 mg 50 mg

[00203] The tablet according to the invention may be coated with a film. Typically, a film coating represents 2-5% by weight of the total composition and preferably comprises a film-forming agent, a plasticizer, a glidant and, optionally, one or more pigments. A coating composition may comprise hydroxypropylmethylcellulose (HPMC), polyethylene glycol (PEG), talc, titanium dioxide and, optionally, red and / or yellow iron oxide. An exemplary coating composition may comprise hydroxypropylmethylcellulose (HPMC), polyethylene glycol (PEG), talc, titanium dioxide, mannitol and, optionally, iron oxide, including red and / or yellow iron oxide.

[00204] The pharmaceutical dosage form, according to the invention, has dissolving properties such that after 45 minutes for each of the one or two active pharmaceutical ingredients, at least 75%, even more preferably at least 90% by weight of the respective active pharmaceutical ingredients are dissolved. In a more preferred embodiment, after 30 minutes for each of the one or two active pharmaceutical ingredients, at least 75%, even more preferably at least 90% by weight of the respective active pharmaceutical ingredients are dissolved. In the most preferred embodiment, after 15 minutes for each of the one or two active pharmaceutical ingredients, at least 75%, even more Petition 870210017171, dated 22 / 02 / 2021, p. 58 / 112 54 / 96 preferably at least 90% by weight of the respective active pharmaceutical ingredients are dissolved. Dissolution properties can be determined in a standard dissolution test, for example, as described in pharmacopoeias such as USP31NF26 S2, chapter 711 (dissolution). A preferred test is described in the experimental section.

[00205] The pharmaceutical dosage form according to the invention preferably has disintegration properties such that within 40 minutes, but preferably within 30 minutes, even more preferably within 20 minutes, most preferably within 15 minutes, the pharmaceutical dosage form is disintegrated. The disintegration process can be determined in a standard disintegration test, for example, as described in pharmacopoeias such as USP31-NF26 S2, chapter 905 (uniformity of dosage units).

[00206] The pharmaceutical dosage form according to the invention preferably has high content uniformity, preferably in the range of 85 to 115%, more preferably 90 to 110%, even more preferably 95 to 105% by weight with respect to each of the one or two active pharmaceutical ingredients. Content uniformity can be determined in a standard test using, for example, randomly selected pharmaceutical dosage forms, for example, as described in pharmacopoeias such as USP31-NF26 S2, chapter 905 (uniformity of dosage units).

[00207] A dosage form according to this invention, such as a tablet, capsule or film-coated tablet, can be prepared by methods well known to those skilled in the art.

[00208] Preferred methods for manufacturing a tablet Petition 870210017171, dated 22 / 02 / 2021, page 59 / 112 55 / 96 refers to compression of the pharmaceutical composition in powder form, i.e., direct compression, or compression of the pharmaceutical composition in granule form, and if necessary with additional excipients.

[00209] The granules of the pharmaceutical composition, according to the invention, can be prepared by methods well known to those skilled in the art. Preferred methods for granulating one or more active ingredients together with excipients include wet granulation, for example, high-shear wet granulation or fluidized bed wet granulation, and dry granulation, also called laminator compaction.

[00210] In a preferred wet granulation process, the granulation liquid is the solvent or mixture of solvents or a preparation of one or more binders in a solvent or mixture of solvents. Suitable binders are described above. An example is copovidone. Suitable solvents are, for example, water, ethanol, methanol, isopropanol, acetone, preferably purified water, including mixtures thereof. One or more active ingredients and other excipients, in particular one or more diluents, optionally one or more binders and, optionally, one or more disintegrants, usually excluding the lubricant, are premixed and granulated with the granulation liquid, for example, using a high-shear granulator. The wet granulation step is usually followed by one or more drying and sieving steps. Optionally, a wet sieving step is included, followed by drying and wet sieving of the granules.For example, a fluidized bed dryer can then be used for drying.

[00211] The preparation process according to this invention is preferably characterized by a granulation process in which the first and second active pharmaceutical ingredients together with one or more diluents, one or more binders and one or more Petition 870210017171, dated 22 / 02 / 2021, pp. 60 / 112 56 / 96 disintegrants are granulated.

[00212] The preparation process according to this invention is preferably characterized by at least two granulation processes, wherein in one granulation process the first active pharmaceutical ingredient together with one or more diluents, one or more binders and one or more disintegrants is granulated and in another granulation process the second active pharmaceutical ingredient together with one or more diluents, one or more binders and one or more disintegrants is granulated.

[00213] Preferably, in the above processes, the granulate obtained by one or more granulation processes is optionally mixed with one or more additional disintegrants and is mixed with one or more lubricants.

[00214] The dry granules are sieved through a suitable sieve. After the addition of the other excipients, in particular one or more disintegrants and the glide and, optionally, the talc lubricant, with the exception of the lubricant, in particular magnesium stearate, the mixture is mixed in a suitable mixer, for example, a dropless mixer, followed by the addition of one or more lubricants, for example, magnesium stearate, and final mixing in the mixer.

[00215] Thus, an example of a wet granulation process for the preparation of granules comprising the pharmaceutical composition according to the present invention comprises a. optionally dissolve one or more binders in a solvent or mixture of solvents, such as purified water, at room temperature, to produce a granulation liquid; b. Mix 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. Petition 870210017171, dated 22 / 02 / 2021, pp. 61 / 112 57 / 96 quado, to produce a premix; c. moisten the premix with the granulation liquid and subsequently granulate the moistened premix, for example, in a high-shear mixer; d. optionally sift the granulated premix through a sieve with a mesh size of at least 1.0 mm and preferably 3 mm; e. dry the granules at approximately 40-75°C and, preferably, 55-65°C inlet air temperature, for example, in a fluidized bed dryer until the desired drying loss in the range of 1-5% is achieved; f. to break up the clumps of dry granules, for example, by sieving through a sieve with a mesh size of 0.6 mm to 1.6 mm, preferably 1.0 mm; and g. preferably add lubricant(s) to the granules for final mixing, for example, in a bowl mixer.

[00216] In an alternative process, some of the excipients, such as some of one or more disintegrants, for example, corn starch or an additional disintegrant, for example, crospovidone, and / or one or more diluents, for example, pregelatinized starch, may be added extra granularly before the final mixing of step g.

[00217] In another alternative version of the process, the granulate produced in steps (a) to (e) is produced in a high shear pot granulation process and subsequent drying in a pot granulator. Therefore, one aspect of the present invention relates to granules comprising the pharmaceutical composition of the same invention.

[00218] An example of a dry granulation process for the preparation of granules comprising the pharmaceutical composition, according to the invention, comprises: Petition 870210017171, dated 22 / 02 / 2021, pp. 62 / 112 58 / 96 (1) mix one or two active pharmaceutical ingredients or with all or a portion of the excipients in a mixer. (2) compact the mixture from step (1) in a compactor with a suitable laminator; (3) reduce the ribbons obtained during step (2) to small granules by grinding or sieving steps; (4) optionally mix the granules from step (3) with the remaining excipients in a mixer to obtain the final mixture; (5) form tablets with the granules from the final mixture of step (4) by compressing it in a suitable tablet press to produce the tablet cores; (6) optionally coat the tablet cores from step (5) with film.

[00219] The granules, according to the first embodiment of the same invention, comprise only one active pharmaceutical ingredient (drug), which is lingliptin.

[00220] The granules, according to the second embodiment of the same invention, comprise two active pharmaceutical ingredients, which are linagliptin and a benzene derivative substituted with glucopyranosyl of formula (i), as defined above and below, in particular linagliptin and compound (I.3).

[00221] A preferred granule size is in the range of 25 to 800 μm, even more preferably from 40 μm to 500 μm. Preferably, the size is measured via sieve analysis, for example, with a conical sieve. Preferably at least 80%, more preferably at least 90%, most preferably at least 95% by weight of the granules are in the given range.

[00222] For the preparation of capsules, granules or a mixture Petition 870210017171, dated 22 / 02 / 2021, pp. 63 / 112 59 / 96 final, for example, as described above in steps (f.) and (g.) are still filled into capsules.

[00223] For the preparation of capsules according to the second embodiment of the invention, granules according to the second embodiment of the invention, i.e., granules comprising the two active pharmaceutical ingredients, may be used. Alternatively, granules according to the first embodiment of the invention, i.e., granules comprising linagliptin as the active pharmaceutical ingredient, and granules comprising glucopyranosyl-substituted benzene derivative of formula (I), as defined above and below, in particular compound (I.3), may be used.

[00224] For the preparation of tablets or tablet cores, the granules or fine mixture, for example, from step (g.) above, are further compressed to form tablets of the target tablet core weight with appropriate size and resistance to crushing, using a suitable tablet press. The final mixture comprises granules according to the invention and one or more lubricants and, optionally, one or more disintegrants and one or more optional glidants. For example, such an additional disintegrant is crospovidone.

[00225] For the preparation of single-layer tablets, according to the second embodiment of the invention, granules, according to the second embodiment of the invention, i.e., granules comprising the two active pharmaceutical ingredients, may be used. Alternatively, according to the first embodiment of the invention, i.e., granules comprising linagliptin as the active pharmaceutical ingredient, and granules comprising a glycopyranosyl-substituted benzene derivative of formula (I) as defined above and below, in particular compound (I.3) may be used.

[00226] For the preparation of two-layer tablets, of Petition 870210017171, dated 22 / 02 / 2021, pp. 64 / 112 60 / 96 according to the second embodiment of the invention, the granules according to the first embodiment of the invention, i.e., granules comprising linagliptin as an active pharmaceutical ingredient, may be used in a first layer and granules comprising benzene derivative substituted with glucopyranosyl of formula (I) as defined above and below, in particular compound (I.3) may be used in the second layer.

[00227] A tablet, for example, a single-layer tablet, according to the second embodiment of the invention, preferably comprises, 0.5-25% active pharmaceutical ingredient(s), 40-88% one or more diluents, 0.5-20% one or more binders, 0.5-20% one or more disintegrants, 0.1-15% one or more lubricants,

[00228] where the percentages are by weight of the total composition.

[00229] The following tracks are even more preferred: 0.5-20% active pharmaceutical ingredient(s), 50-75% one or more diluents, 1-15% one or more binders, 1-15% one or more disintegrants, 0.5-10% one or more lubricants,

[00230] where percentages are by weight of the total composition.

[00231] In addition, the following excipients and ranges are preferred: 0.5-20% active pharmaceutical ingredients, 50-75% mannitol (e.g., Pearlitol 50C, Roquette), 0-15% pregelatinized starch (e.g., Maize Starch 1500 INT (Colorcon)), 2-4% copovidone (e.g., Polividone VA 64 INT (Colorcon)). Petition 870210017171, dated 22 / 02 / 2021, pp. 65 / 112 61 / 96 (con)), 8-12% corn starch (e.g., Undried Maize Starch (Roquette)), 0.5-2% magnesium stearate (e.g., HyQual, (Mallinckrodt)),

[00232] where the percentages are by weight of the total composition. An additional disintegrant, for example crospovidone, in an amount of 0 to 2% by weight of the total composition may be used, particularly in cases where a higher tablet weight is obtained, such as in single-layer tablets, which are made of two types of granules (one for each of the active ingredients) or in two-layer tablets as described above.

[00233] In addition, the following excipients and ranges are preferred; 0.5-20% active pharmaceutical ingredients, 50-75% mannitol (e.g., Pearlitol 50C, Roquette), 0-15% pregelatinized starch (e.g., Maize Starch 1500 INT (Colorcon)), 2-4% copovidone (e.g., Polividone VA 64 INT (Colorcon)), 8-12% corn starch (e.g., undried Maize Starch (Roquette)), 0.5-2% magnesium stearate (e.g., HyQual (Mallinckrodt)), 0-10% talc (Talc (Luzenac))

[00234] where the percentages are by weight of the total composition.

[00235] To reduce the amount of lubricant required in the tablets, the use of an external lubrication system is optional.

[00236] For the preparation of film-coated tablets, a coating suspension is prepared and the tablet cores Petition 870210017171, dated 22 / 02 / 2021, pp. 66 / 112 62 / 96 pressed molds are coated with the coating suspension for a weight gain of about 2-5%, preferably about 3%, using a standard film coater. The film coating solvent is a volatile component that does not remain in the final product. In an alternative embodiment, the film coating may comprise one of two active pharmaceutical ingredients.

[00237] Alternatively, the tablets according to the invention can be prepared by direct compression. A suitable direct compression process comprises the following steps: (1) pre-mix one or two active ingredients and the main portion of the excipients in a mixer to obtain a premix; (2) optionally dry sift the premix through a sieve to separate cohesive particles and to improve the uniformity of the contents; (3) Mix the premix from step (1) or (2) in a mixer, optionally adding the remaining excipients to the mixture and continue mixing; (4) form the tablets from the final mixture of step (3) by compressing it in a tablet press suitable for producing tablet cores; (5) optionally coat the cores of step (4) with a non-functional coating.

[00238] The pharmaceutical compositions and dosage forms, in particular tablets or capsules, according to this invention, can be packaged using known packaging materials, such as PVC blisters, PVDC blisters, PVC / PVDC blisters or a moisture-proof packaging material, such as aluminum foil packaging, alu / alu blister, transparent or opaque polymer blister with pouch, polypropylene tubes, Petition 870210017171, dated 22 / 02 / 2021, p. 67 / 112 63 / 96 glass bottles, PP bottles and HDPE bottles, optionally containing a child-resistant feature (e.g., with a push-and-turn cap) or may be tamper-evident. The primary packaging material may comprise a desiccant, such as molecular sieve or silica gel, to enhance the chemical stability of the active pharmaceutical ingredient(s). Opaque packaging, such as colored blister materials, tubes, brown glass bottles or similar, may be used to extend the shelf life of the active ingredient(s) by reducing photodegradation.An article for distribution may comprise the pharmaceutical composition or dosage form packaged in packaging material as described above and a label or package insert, which refers to instructions commonly included on commercial packaging of therapeutic products, which may contain information on the indications, use, dosage, administration, contraindications and / or warnings with respect to the use of such therapeutic products. In one embodiment, the label or package insert indicates that the composition may be used for any of the purposes described herein.

[00239] The pharmaceutical compositions and dosage forms according to this invention show effects in the treatment and prevention of those diseases and conditions as described above in comparison with antidiabetic monotherapies. Advantageous effects can be seen, for example, with respect to efficacy, dosage resistance, dosage frequency, pharmacodynamic properties, pharmacokinetic properties, fewer adverse effects, convenience, compliance, etc.

[00240] The pharmaceutical composition and dosage form according to the invention significantly improve glycemic control, particularly in patients as described below, compared to monotherapy using either an inhibitor Petition 870210017171, dated 22 / 02 / 2021, pp. 68 / 112 64 / 96 SGLT2 inhibitor or a DPP-IV inhibitor alone or metformin monotherapy. Improved glycemic control is defined as a decrease in blood glucose and an increased reduction in HbA1c. With monotherapy in a patient, particularly in patients as described below, glycemic control usually cannot be significantly improved by administering the drug above a certain already higher dose. Furthermore, long-term treatment using a higher dose may be undesirable due to potential side effects. Therefore, satisfactory glycemic control cannot be achieved in all patients via monotherapy using an SGLT2 inhibitor or a DPP-IV inhibitor alone or another antidiabetic drug, such as metformin. In such patients, the progression of diabetes mellitus may continue and complications associated with diabetes mellitus may occur, such as macrovascular complications.The pharmaceutical composition and dosage form, as well as the methods according to the present invention, enable a reduction in HbA1c value to a desired target range, for example, < 7% and preferably < 6.5%, for a higher number and longer duration of therapeutic treatment compared to antidiabetic monotherapy.

[00241] The pharmaceutical composition and therapeutic dosage form, according to the present invention, enable a well-tolerated therapy for the patient and an improvement in patient compliance.

[00242] Monotherapy using a DPP-IV inhibitor is not independent of a patient's insulin secretory capacity or drug sensitivity. On the other hand, treatment with an SGLT2 inhibitor does not depend on the patient's insulin secretory capacity or insulin sensitivity. Therefore, any patient, regardless of prevalent or recurrent insulin levels... Petition 870210017171, dated 22 / 02 / 2021, pp. 69 / 112 65 / 96 Insulin resistance and / or hyperinsulinemia may benefit from a therapy using the pharmaceutical composition and a pharmaceutical dosage combination according to this invention. Regardless of their prevalent insulin levels or their insulin resistance or hyperinsulinemia, these patients can still be treated with a pharmaceutical composition and a pharmaceutical dosage due to the combined or alternating administration of the SGLT2 inhibitor.

[00243] Linagliptin, according to the present invention, is able – via increases in levels of active GLP-1 – to reduce glucagon secretion in the patient. Therefore, this limits hepatic glucose production. Furthermore, the elevated levels of active GLP-1 produced by linagliptin will have beneficial effects on beta cell regeneration and neogenesis. All these characteristics make the pharmaceutical composition and dosage quite useful and therapeutically relevant.

[00244] When this invention refers to patients requiring treatment or prevention, it refers primarily to treatment and prevention in humans, but the pharmaceutical composition can therefore also be used in veterinary medicine, in mammals. Within the scope of the same invention, adult patients are preferably humans aged 18 years or older. Also within the scope of the same invention, patients are adolescent humans, i.e., persons aged 10 to 17 years, preferably 13 to 17 years. It is assumed that in the adolescent population, particularly in overweight and / or obese patients, a marked weight loss may be observed.

[00245] As described above, through the administration of a pharmaceutical composition and a pharmaceutical dosage and, in particular, in view of the high SGLT2 inhibitory activity of the glucopyranosyl-substituted benzene derivative therein, blood glucose Petition 870210017171, dated 22 / 02 / 2021, pp. 70 / 112 Excess 66 / 96 is excreted through the patient's urine so that weight gain or even reduction in body weight cannot occur. Therefore, the treatment or prophylaxis according to this invention is advantageously suitable in those patients who need such treatment or prophylaxis, who have been diagnosed with one or more of the selected conditions from the group consisting of overweight and obesity, in particular class I obesity, class II obesity, class III obesity, visceral obesity and abdominal obesity. Furthermore, the treatment or prophylaxis according to this invention is advantageously suitable in those patients in whom weight gain is contraindicated.

[00246] The pharmaceutical composition and dosage form according to this invention exhibit very good efficacy with respect to glycemic control, particularly with regard to the reduction of fasting blood glucose, postprandial plasma glucose and / or glycosylated hemoglobin (HbA1c). By administering a pharmaceutical composition or dosage form according to this invention, a reduction in HbA1c equal to or greater than preferably 1.0%, more preferably equal to or greater than 2.0%, even more preferably equal to or greater than 3.0% can be obtained, and the reduction is particularly in the range of 1.0% to 3.0%.

[00247] Furthermore, the method and / or use, according to this invention, is advantageously applicable in those patients who exhibit one, two, or more of the following conditions: (a) a fasting serum glucose concentration or serum glucose greater than 100 mg / dL, in particular greater than 125 mg / dL; (b) a postprandial plasma glucose level equal to or greater than 140 mg / dL; (c) an HbA1c value equal to or greater than 6.5%, in particular equal to or greater than 7.0%, especially equal to or greater than Petition 870210017171, dated 22 / 02 / 2021, pp. 71 / 112 67 / 96 7.5%, or more preferably equal to or greater than 8.0%.

[00248] The present invention also describes the use of the pharmaceutical composition or dosage form to improve glycemic control in those with type 2 diabetes or showing the first signs of prediabetes. Thus, the invention also includes the prevention of diabetes. If, therefore, a pharmaceutical composition or dosage form according to this invention is used to improve glycemic control as soon as one of the aforementioned signs of prediabetes appears, the onset of manifest type 2 diabetes mellitus can be delayed or prevented.

[00249] Furthermore, the pharmaceutical composition and dosage form according to this invention are particularly suitable for the treatment of insulin-dependent patients, that is, patients who are treated or would otherwise be treated or would require treatment with insulin or an insulin derivative or an insulin substitute or a formulation comprising insulin or a derivative or substitute thereof. These patients include patients with type 2 diabetes and patients with type 2 diabetes.

[00250] Therefore, according to a preferred embodiment of the present invention, a method is provided for improving glycemic control and / or for reducing fasting plasma glucose, postprandial plasma glucose and / or glycosylated hemoglobin HbA1c, in a patient in need thereof, who is diagnosed with impaired glucose tolerance (IGT) with insulin resistance, with metabolic syndrome and / or with type 2 or type 1 diabetes mellitus, characterized in that a pharmaceutical composition or a pharmaceutical dosage form as defined above or below is administered to the patient.

[00251] According to another preferred embodiment of the present in Petition 870210017171, dated 22 / 02 / 2021, pp. 72 / 112 68 / 96 invention provides a method to improve glycemic control in patients, particularly adult patients, with type 2 diabetes mellitus as an adjunct to diet and exercise.

[00252] It can be observed that by using the pharmaceutical composition or dosage form according to this invention, an improvement in glycemic control can be achieved even in those patients who have insufficient glycemic control, in particular, despite treatment with antidiabetic drugs, for example, despite the maximum recommended or tolerated dose of oral monotherapy with metformin, an SGLT2 inhibitor or a DPP-IV inhibitor. The maximum recommended dose with respect to metformin is, for example, 2,000 mg per day or 850 mg three times a day or any equivalent thereof. The maximum recommended dose with respect to an SGLT2 inhibitor according to this invention, in particular with respect to 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 with respect to linagliptin is, for example, 10 mg, preferably 5 mg once a day or any equivalent thereof.

[00253] Therefore, the method and / or use, according to this invention, is advantageously applicable in those patients who exhibit one, two, or more of the following conditions: (a) Insufficient glycemic control with diet and exercise alone; (b) Insufficient glycemic control despite oral metformin monotherapy, in particular despite oral monotherapy at a maximum recommended or tolerated dose of metformin; (c) Insufficient glycemic control despite oral monotherapy with another antidiabetic agent, in particular despite oral monotherapy at a maximum recommended or tolerated dose of the other Petition 870210017171, dated 22 / 02 / 2021, pp. 73 / 112 69 / 96 antidiabetic agent; (d) Insufficient glycemic control despite SGLT2 inhibitor monotherapy, in particular despite oral monotherapy at a maximum recommended or tolerated dose of the SGLT2 inhibitor; (e) Insufficient glycemic control despite oral monotherapy with a DPP-IV inhibitor, in particular oral monotherapy at a maximum recommended or tolerated dose of the DPP-IV inhibitor.

[00254] The reduction of blood glucose levels by administering a benzene derivative substituted with glucopyranosyl, according to this invention, is insulin-independent. Therefore, the pharmaceutical composition, according to this invention, is particularly suitable in the treatment of patients who are diagnosed with one or more of the following conditions: - insulin resistance, - hyperinsulinemia, - pre-diabetes, - Type 2 diabetes mellitus, particularly being in an early stage of type 2 diabetes mellitus, Type 1 diabetes mellitus.

[00255] Furthermore, a pharmaceutical composition and a pharmaceutical dosage form, according to this invention, is particularly suitable for the treatment of patients who are diagnosed as having one or more of the following conditions: (a) obesity (including type I, II and / or III obesity), visceral obesity and / or abdominal obesity, (b) blood triglyceride level > 150 mg / dL, (c) blood HDL-cholesterol level < 40 mg / dL in female patients and < 50 mg / dL in male patients; (d) systolic blood pressure > 130 mmHg and diastolic blood pressure > 85 mmHg, Petition 870210017171, dated 22 / 02 / 2021, pp. 74 / 112 70 / 96 (e) fasting blood glucose level > 100 mg / dL.

[00256] It is assumed that patients diagnosed with impaired glucose tolerance (IGT), impaired fasting blood glucose (IFG), insulin resistance and / or metabolic syndrome suffer from an increased risk of developing cardiovascular disease such as, for example, myocardial infarction, coronary heart disease, heart failure, thromboembolic events. Glycemic control, according to this invention, can result in a reduction of cardiovascular risks.

[00257] The pharmaceutical composition and dosage form according to this invention exhibit a good safety profile. Therefore, treatment or prophylaxis according to this invention is advantageously possible in those patients for whom monotherapy with another antidiabetic drug, such as, for example, is contraindicated and / or who have an intolerance to such drugs at therapeutic doses. In particular, treatment or prophylaxis according to this invention may be advantageously possible in those patients who exhibit or have an increased risk for one or more of the following disorders: renal insufficiency or kidney disease, heart disease, heart failure, liver disease, lung disease, catabolic states and / or risk of lactate acidosis, or female patients who are pregnant or breastfeeding.

[00258] Furthermore, it can be observed that the administration of a pharmaceutical composition or pharmaceutical dosage form, according to this invention, results in no risk or a low risk of hypoglycemia. Therefore, treatment or prophylaxis, according to this invention, is also advantageously possible in those patients who exhibit or have an increased risk of hyperglycemia.

[00259] The pharmaceutical composition or pharmaceutical dosage, according to this invention, is particularly suitable for the treatment Petition 870210017171, dated 22 / 02 / 2021, pp. 75 / 112 71 / 96 to long-term or prophylactic use of diseases and / or conditions, as described above and below, particularly in long-term glycemic control in patients with type 2 diabetes mellitus.

[00260] The term long-term, as used above and below, indicates treatment or administration in a patient over a period of time greater than 12 weeks, preferably greater than 25 weeks, and even more preferably greater than 1 year.

[00261] Therefore, a particularly preferred embodiment of the present invention provides a method for therapy, preferably oral therapy, for improving, especially long-term improvement, glycemic control in patients with type 2 diabetes mellitus, particularly in patients with early-stage type 2 diabetes mellitus, in particular, in patients also diagnosed with overweight, obesity (including class I, class II and / or class III obesity), visceral obesity and / or abdominal obesity.

[00262] In all the methods and uses described above and below, in particular the methods for treating, preventing, etc., the pharmaceutical composition or pharmaceutical dosage form, according to this invention, is administered to the patient, preferably, once a day.

[00263] Any of the compositions and dosage forms mentioned above within the scope of the invention can be tested in animal models known to the art, as well as in clinical studies. The following describes in vivo experiments that are suitable for evaluating the pharmacologically relevant properties of pharmaceutical compositions and dosage forms according to this invention:

[00264] the pharmaceutical compositions, dosage forms and methods, according to this invention, can be tested in genetically hyperinsulinemic or diabetic animals such as db / db mice, ob / ob mice, Gordos Zucker (fa / fa) rats or Gordos rats. Petition 870210017171, dated 22 / 02 / 2021, page 76 / 112 72 / 96 of the Zucker Diabetic Diet (ZDF). Furthermore, they can be tested in animals with experimentally induced diabetes, such as HanWistar or Sprague Dawley rats, pre-treated with streptozotocin.

[00265] The effect on glycemic control of the pharmaceutical compositions and dosage forms according to this invention can be tested in an oral glucose tolerance test in the animal models described above. The time course of blood glucose is followed after an oral glucose challenge in animals fasted overnight. The compositions and dosage forms according to the present invention significantly improve the glucose excursion compared to each monotherapy as measured by reduction in peak glucose concentrations or reduction in glucose AUC. Furthermore, after multiple dosing of the active pharmaceutical ingredients and the pharmaceutical compositions or dosage forms in the animal models described above, the glycemic control effect can be determined by measuring the blood HbA1c value. The compositions and dosage forms according to this invention significantly reduce HbA1c compared to each monotherapy.

[00266] The improved insulin independence of treatment according to this invention can be shown after single dosing in glucose tolerance tests in the animal models described above. The time course of plasma insulin is followed after glucose challenge in overnight fasted animals. The compositions and dosage forms according to this invention will exhibit lower peak insulin concentrations or lower insulin AUC at a lower blood glucose excursion than linagliptin alone.

[00267] The increase in levels of active GLP-1 by treatment, according to this invention, after single or multiple dosing, can be determined by measuring those levels in the plasma of models. Petition 870210017171, dated 22 / 02 / 2021, pp. 77 / 112 73 / 96 animals described above in both the fasting and postprandial states. Likewise, the reduction in plasma glucagon levels can be measured under the same conditions. The compositions and dosage forms according to this invention will exhibit higher concentrations of active GLP-1 and lower concentrations of glucagon than the glucopyranosyl-substituted benzene derivative.

[00268] The superior effect of the compositions and dosage forms, according to the present invention, on the regeneration and neogenesis of beta cells, can be determined after multiple dosing in the animal models described above, by measuring the increase in pancreatic insulin content, or by measuring the mass of increased beta cells by morphometric analysis after immunohistochemical staining of pancreatic sections, or by measuring glucose-stimulated insulin secretion in isolated pancreatic islets. Pharmacological Examples

[00269] The following examples show the beneficial effect on glycemic control of the combination according to the present invention. Example I:

[00270] According to the first example, an oral glucose tolerance test is performed on 9-week-old, fasted overnight, male Zucker Diabetic Fatty (ZDF) (ZDF / Crl-Leprfa) mice. A pre-dose blood sample is obtained by tail bleeding. Blood glucose is measured with a glucometer, and animals are randomized to blood glucose (n = 5 / group). Subsequently, groups received a single oral administration of either the vehicle alone (0.5% aqueous hydroxyethylcellulose containing 3mM HCl and 0.015% Polysorbate 80) or the vehicle containing either the SGLT2 inhibitor or the DPPIV inhibitor, or the combination of the SGLT2 inhibitor plus the DPPIV inhibitor. Animals receive an oral glucose load (2 g / kg) 30 minutes after administration of the Petition 870210017171, dated 22 / 02 / 2021, pp. 78 / 112 74 / 96 compound. Blood glucose is measured in tail blood 30 minutes, 60 minutes, 90 minutes, 120 minutes, and 180 minutes after glucose challenge. The glucose excursion is quantified by calculating the AUC of reactive glucose. Data are presented as mean ± SEM. Student's t-test is used for statistical comparison of the control group and the active groups.

[00271] The result is shown in Figure 3. Comp. A is linagliptin at a dose of 1 mg / kg. Comp. B is compound (I.3), i.e., 1-chloro-4-(pD-glucopyran-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 doses. P-values ​​versus control are indicated by the symbols above the bars. P-values ​​for the combination versus monotherapy are indicated below the figure (*, p < 0.05; **, p < 0.01; ***, p < 0.001). Linagliptin reduces the glucose excursion by 56%, compound (I.3) reduces the glucose excursion by 51%. The combination decreased the glucose excursion in the oral glucose tolerance test by 84%, and this reduction in glucose AUC is statistically significant versus each monotherapy. Example II:

[00272] According to a second example, an oral glucose tolerance test is performed on male Sprague Dawley (Crl:CD(SD)) rats, fasted overnight and weighing approximately 200 g. A pre-dose blood sample is obtained by tail tapping. Blood glucose is measured with a glucometer, and animals are randomized to blood glucose (n = 5 / group). Subsequently, groups receive a single oral administration of either the vehicle alone (0.5% aqueous hydroxyethylcellulose containing 0.015% Polysorbate 80) or the vehicle containing the SGLT2 inhibitor or the DPPIV inhibitor or the third antidiabetic agent or the combination of the SGLT2 inhibitor plus the DPPPIV inhibitor plus the third agent. Petition 870210017171, dated 22 / 02 / 2021, pp. 79 / 112 75 / 96 antidiabetic agents. Alternatively, groups receive a single oral administration of either the vehicle alone or the vehicle containing either the SGLT2 inhibitor or the DPP-IV inhibitor plus the third antidiabetic agent, or the third antidiabetic agent, or the combination of the SGLT2 inhibitor plus the DPP-IV inhibitor plus the third antidiabetic agent. Animals receive an oral glucose load (2 g / kg) 30 minutes after administration of the compound. Blood glucose is measured in tail blood 30 minutes, 60 minutes, 90 minutes, and 120 minutes after the glucose challenge. The glucose excursion is quantified by calculating the AUC of reactive glucose. Data are presented as mean ± SEM. Statistical comparisons are conducted using Student's t-test. Example III: Treatment of prediabetes

[00273] The efficacy of the pharmaceutical composition or dosage form according to the invention in the treatment of prediabetes characterized by pathological fasting glucose intolerance and / or impaired glucose tolerance can be tested using clinical studies. In studies over a shorter period (e.g., 2 to 4 weeks), treatment success is examined by determining fasting glucose values ​​and / or glucose values ​​after a meal or after a loading test (oral glucose tolerance test or food tolerance test after a defined meal) after the end of the therapy period for the study and comparing these with values ​​before the start of the study and / or with those of a placebo group. In addition, the fructosamine value can be determined before and after therapy and compared with the baseline value and / or the placebo value.A significant drop in fasting or non-fasting glucose levels demonstrates the effectiveness of treatment over a longer period (12 weeks or more); treatment success is tested by determining the HbA1c value for comparison. Petition 870210017171, dated 22 / 02 / 2021, pages 80 / 112 76 / 96 with the baseline value and / or with the value of the placebo group. A significant change in HbA1c value compared to the baseline value and / or the placebo value demonstrates the efficacy of the composition or dosage form according to the invention for the treatment of prediabetes. Example IV: Prevention of manifested type 2 diabetes

[00274] The treatment of patients with impaired fasting glucose and / or glucose tolerance (prediabetes) is aimed at preventing the transition to the manifestation of type 2 diabetes. The efficacy of a treatment can be investigated in a comparative clinical study in which patients with prediabetes are treated for a period of time (e.g., 1-5 years) either with a pharmaceutical composition according to the invention or with placebo or with drug-free therapy or other modalities. During and at the end of therapy, fasting glucose and / or a glucose tolerance test (e.g., oGTT) are determined to assess how many patients exhibit the manifestation of type 2 diabetes, for example, a fasting glucose level of > 125 mg / dL and / or a 2-hour oGTT value of > 199 mg / dL.A significant reduction in the number of patients exhibiting overt type 2 diabetes when treated with a pharmaceutical composition or dosage form according to this invention, compared with one of the other forms of treatment, demonstrates the effectiveness in preventing the transition from prediabetes to overt diabetes. Example V: Treatment of type 2 diabetes

[00275] Treatment of patients with type 2 diabetes with the pharmaceutical composition or dosage form according to the invention, in addition to producing a significant improvement in the metabolic glucose status, prevents long-term deterioration in the metabolic status. This can be observed in patients who are treated Petition 870210017171, dated 22 / 02 / 2021, pages 81 / 112 77 / 96 for a longer period, for example, 3 months to 1 year or 1 to 6 years, with the pharmaceutical composition or dosage form according to the invention, or are compared with patients who were treated with placebo or other antidiabetic medications. There is evidence of therapeutic success compared with patients treated with placebo or other antidiabetic medications if no or only a slight increase in fasting glucose and / or HbA1c value is observed. Furthermore, evidence of therapeutic success is obtained if a significantly smaller percentage of patients treated with a pharmaceutical composition or dosage form according to the invention, compared with patients who were treated with other medications, experience a deterioration in glucose metabolic status (for example, an increase in HbA1c value to > 6.5% or > 7%) to the point where treatment with an oral antidiabetic medication such as insulin or an insulin analogue is indicated.Example VI: Treatment of insulin resistance.

[00276] In clinical studies conducted for different time periods (e.g., 2 weeks to 12 months), treatment success is checked using a hyperinsulinemic euglycemic glucose clamp study. A significant increase in the glucose infusion rate at the end of the study, compared to the baseline value or compared to a placebo group, or a group that received a different therapy, proves the efficacy of a pharmaceutical composition or dosage form according to the invention in the treatment of insulin resistance. Example VII: Treatment of hyperglycemia

[00277] In clinical studies conducted over different time periods (e.g., 1 day to 24 months), the success of treatment in patients with hyperglycemia is checked by determining fasting glucose or non-fasting glucose (e.g., after a meal or a Petition 870210017171, dated 22 / 02 / 2021, pp. 82 / 112 78 / 96 load test with the oGTT or a defined meal). A significant drop in these glucose values ​​during or at the end of the study, compared to the baseline value or compared to a placebo group, or a group that was given a different therapy, proves the efficacy of a pharmaceutical composition or dosage form, according to the invention, in the treatment of hyperglycemia. Example VIII. Prevention of micro- or macrovascular complications

[00278] Treatment of patients with type 2 diabetes or prediabetes with a pharmaceutical composition or dosage form, according to the invention, prevents or reduces the risk of developing microvascular complications (e.g., diabetic neuropathy, diabetic retinopathy, diabetic nephropathy, diabetic foot, diabetic ulcer) or macrovascular complications (e.g., myocardial infarction, acute coronary syndrome, unstable angina pectoris, stable angina pectoris, peripheral arterial occlusive disease, cardiomyopathy, heart failure, cardiac rhythm disorders, vascular restenosis).Patients with type 2 diabetes or prediabetes are treated long-term, for example, for 1 to 6 years, with a pharmaceutical composition or dosage form according to the invention, or a combination of active ingredients according to the invention, and compared with patients who were treated with other antidiabetic drugs or with a placebo. Evidence of therapeutic success compared with patients who were treated with other antidiabetic drugs or with a placebo can be seen by the lower number of simple or multiple complications. In the case of macromolecular events, diabetic foot and / or diabetic ulcer, the numbers are counted by anamnesis and various testing methods. In the case of diabetic retinopathy, treatment success is determined by computer-controlled illumination and fundus examination or other ophthalmic methods, in the case of diabetic neuropathy. In addition to anamnesis and... Petition 870210017171, dated 22 / 02 / 2021, pp. 83 / 112 79 / 96 clinical examination, nerve conduction rate can be measured using a calibrated tuning fork, for example. With respect to diabetic nephropathy, the following parameters can be investigated before the start, during and at the end of the study: albumin secretion, creatinine clearance, serum creatinine values, time taken to double serum creatinine values, time it takes until dialysis becomes necessary. Example IX; Treatment of Metabolic Syndrome

[00279] The efficacy of a pharmaceutical composition or dosage form, according to the invention, can be tested in clinical studies with varying running times (e.g., 12 weeks to 6 years) by determining fasting glucose or non-fasting glucose (e.g., after a meal or loading test with oGTT or a defined meal) or the HbA1c value. A significant decrease in these glucose or HbA1c values ​​during or at the end of the study, compared to the baseline value or compared to a placebo group, or a group that was administered a different therapy, proves the efficacy of a pharmaceutical composition or dosage form, according to the invention, in the treatment of Metabolic Syndrome.Examples of these include a reduction in systolic and / or diastolic blood pressure, a reduction in plasma triglycerides, a reduction in total cholesterol or LDL cholesterol, an increase in HDL cholesterol, or a reduction in weight, either compared to a baseline value at the start of the study or compared to a group of patients treated with placebo or with a different therapy. Examples of Pharmaceutical Compositions and Pharmaceutical Dosage Forms

[00280] Hereinafter, the term API 1 means a glycopyranosyl-substituted benzene derivative (I), in particular compound (I.3), preferably in its crystalline form (I3.X), and the term API 2 means Petition 870210017171, dated 22 / 02 / 2021, pp. 84 / 112 80 / 96 linagliptin.

[00281] The active pharmaceutical ingredients, i.e., linagliptin and compound (I.3), preferably in crystalline form (I3.X), are ground with a suitable grinder such as a pin grinder or jet grinder to obtain the desired particle size distribution before manufacturing the pharmaceutical composition or dosage form.

[00282] Examples of typical particle size distribution values ​​X90, X50 and X10, for the pharmaceutical ingredients according to the invention, are shown in the table below. API 1 Batch 1 API 1 Batch 2 API 2 Batch 1 API 2 Batch 2 X10 1.8 pm 1.7 pm 2.1 pm 2.0 pm X50 18.9 pm 12.1 pm 13.5 pm 17.3 pm X90 45.3 pm 25.9 pm 31.8 pm 36.8 pm Example 1: Monolayer tablet, with one granulation.

[00283] Copovidone is dissolved in purified water at room temperature (approximately 20°C) to produce a granulation liquid. API 2 and API 1, 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 subsequently granulated. The moistened granulate is sieved through a suitable sieve. The granulate is dried at an inlet air temperature of approximately 60°C in a fluidized bed dryer until a drying loss of 1 to 4% is obtained. The dried granulate is sieved through a sieve with a 1.0 mm mesh size.

[00284] Magnesium stearate is passed through a sieve to remove lumps and added to the granules. Subsequently, the final mixture is produced by final mixing in a suitable mixer. Petition 870210017171, dated 22 / 02 / 2021, pp. 85 / 112 81 / 96 for three minutes and compressed to form 8 mm round tablet cores with a compression force of 15 kN.

[00285] Hydroxypropyl methylcellulose, polyethylene glycol, talc, titanium dioxide, and iron oxide are suspended in purified water in a suitable mixer at room temperature to produce a coating suspension. Tablet cores are coated with the coating suspension to gain approximately 3% weight, producing film-coated tablets. The following formulation variants are obtained: Ingredient mg / tablet mg / tablet mg / tablet mg / tablet mg / tablet API 1 2.5 5.0 10.0 25.0 50.0 API 2 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 Maize 18.0 18.0 18.0 18.0 18.0 Copovidone 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

[00286] The resulting tablets have a tablet hardness of- Of that which is approximately 85N, the friability is below 0.5%. The uniformity of the contents meets the requirement according to the USP. The time of Petition 870210017171, dated 22 / 02 / 2021, pp. 86 / 112 82 / 96 disintegration takes about 7 minutes, and the dissolution of both API 1 and API 2 is > 85% after 15 minutes, for example, 95% for API 1 and 101% for API 2. Example 2: Monolayer tablet, single granulation

[00287] Copovidone is dissolved in purified water at room temperature to produce a granulation liquid. API 1, API 2, 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 subsequently granulated. The moistened granulate is sieved through a suitable sieve. The granulate is dried at an inlet air temperature of approximately 60°C in a fluidized bed dryer until a drying loss of 1 to 4% is obtained. The dried granulate is sieved through a sieve with a 1.0 mm mesh size.

[00288] Magnesium stearate is passed through a de-lumping sieve and added to the granules. Subsequently, the final mixture is produced by final mixing in a suitable mixer for three minutes and compressed to form 8 mm round tablet cores with a compression force of 17 kN.

[00289] Hydroxypropyl methylcellulose, polyethylene glycol, talc, titanium dioxide, and iron oxide are suspended in purified water in a suitable mixer at room temperature to produce a coating suspension. Tablet cores are coated with the coating suspension to gain approximately 3% weight, producing film-coated tablets. The following formulation variants can be obtained: Ingredient mg ​​ / tablet mg / tablet mg / tablet mg / tablet mg / tablet API 1 2.5 5.0 10.0 25.0 50.0 API 2 5.0 5.0 5.0 5.0 5.0 Petition 870210017171, dated 22 / 02 / 2021, page 87 / 112 83 / 96 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 Maize 18.0 18.0 18.0 18.0 18.0 Copovidone 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

[00290] Tablet hardness, friability, content uniformity, disintegration time and dissolution properties are determined as described above. Example 3: Monolayer tablet, single granulation

[00291] Crospovidone is dissolved in purified water at room temperature to produce a granulation liquid. API 1, API 2, mannitol, pregelatinized starch, and corn starch are mixed in a suitable mixer to produce a premix. The premix is ​​mixed with the granulation liquid and subsequently granulated. The wet granules are sieved through a suitable sieve. The granules are dried at an inlet air temperature of approximately 60°C in a fluidized bed dryer until a drying loss of 1 to 4% is obtained. The dried granules are sieved through a sieve with a 1.0 mm mesh size. Crospovidone is added to the dried granules and mixed for 5 minutes to produce the main mixture. Magnesium stearate is passed Petition 870210017171, dated 22 / 02 / 2021, pages 88 / 112 84 / 96 of the material is passed through a de-lumping sieve and added to the granules. Subsequently, the final mixture is produced by final mixing in a suitable mixer for three minutes and compressed to form 8 mm round tablet cores with a compression force of 16 kN.

[00292] Hydroxypropyl methylcellulose, polyethylene glycol, talc, titanium dioxide, and iron oxide are suspended in purified water in a suitable mixer at room temperature to produce a coating suspension. Tablet cores are coated with the coating suspension to gain approximately 3% weight, producing film-coated tablets. The following formulation variants are obtained: Ingredient mg ​​ / tablet mg / tablet mg / tablet mg / tablet mg / tablet API 1 2.5 5.0 10.0 25.0 50.0 API 2 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 Maize starch 18.0 18.0 18.0 18.0 18.0 Crospovidone 2.0 2.0 2.0 2.0 2.0 Copovidone 5.4 5.4 5.4 5.4 5.4 Magnesium stearate 3.6 3.6 3.6 3.6 3.6 Coating 5.0 5.0 5.0 5.0 5.0 Petition 870210017171, dated 22 / 02 / 2021, pp. 89 / 112 85 / 96 Total movie 187.0 187.0 187.0 187.0 187.0

[00293] Tablet hardness, friability, content uniformity, disintegration time and dissolution properties are determined as described above. Example 4: Monolayer tablet, two granulations

[00294] Two separate granules, each containing only one active pharmaceutical ingredient, are prepared. For both granules, copivodone is dissolved in purified water at room temperature to produce a granulation liquid.

[00295] API 2, 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 subsequently granulated. The moistened granulate is sieved through a suitable sieve. The granulate is dried at an inlet air temperature of approximately 60°C in a fluidized bed dryer until a drying loss of 1 to 4% is obtained. The dried granulate is sieved through a sieve with a 1.0 mm mesh size.

[00296] API 1, mannitol, pregelatinized starch, corn starch and, optionally, pigments such as iron oxides are mixed in a suitable mixer to produce a premix. The premix is ​​moistened with the granulation liquid and subsequently granulated. The moistened granules are sieved through a suitable sieve. The granules are dried at an inlet air temperature of about 60°C in a fluidized bed dryer until a drying loss of 1 to 4% is obtained. The dried granules are sieved through a sieve with a 1.0 mm mesh size.

[00297] The two granules are combined, crospovidone is added, and all components are mixed for 5 minutes in a mixer. Petition 870210017171, dated 22 / 02 / 2021, pages 90 / 112 86 / 96 suitable mixer to produce the main mixture. Magnesium stearate is passed through a sieve to de-lump and added to the main mixture. Subsequently, the final mixture is produced by final mixing in a suitable mixer for three minutes and compressed into oval-shaped tablet cores of 15x6 mm with a compression force of 17 kN. The following formulation variants can be obtained: Ingredient mg / tablet mg / tablet mg / tablet mg / tablet Mg / tablet 1a API 1 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 Maize starch 18.0 18.0 18.0 18.0 18.0 Iron oxide red 2.7 2.7 2.7 2.7 2.7 Copovidone 5.4 5.4 5.4 5.4 5.4 2a granulation API 2 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 Maize 18.0 18.0 18.0 18.0 18.0 Copovidone 5.4 5.4 5.4 5.4 5.4 Final mixture 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

[00298] The resulting tablets have a tablet hardness of around 105 N. Content uniformity satisfies the requirement according to the USP. Friability is below 0.5%. The time of Petition 870210017171, dated 22 / 02 / 2021, pp. 91 / 112 87 / 96 disintegration takes about 5 minutes, and the dissolution of both APIs is > 85% after 15 minutes. Example 5: Monolayer tablet, two granulations

[00299] Two separate granules, each containing only one active pharmaceutical ingredient, are prepared.

[00300] Copovidone is dissolved in purified water at room temperature to produce a granulation liquid. API 2, 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 subsequently granulated. The moistened granules are sieved through a suitable sieve. The granules are dried at an inlet air temperature of approximately 60°C in a fluidized bed dryer until a drying loss of 1 to 4% is obtained. The dried granules are sieved through a sieve with a 1.0 mm mesh size.

[00301] API 1, mannitol, microcrystalline cellulose, pregelatinized starch, corn starch, hydroxypropyl cellulose, and optionally pigments such as red iron oxide are mixed in a suitable mixer to produce a premix. The premix is ​​moistened with the granulation liquid and subsequently granulated. The moistened granules are sieved through a suitable sieve. The granules are dried at an inlet air temperature of about 60°C in a fluidized bed dryer until a drying loss of 1 to 4% is obtained. The dried granules are sieved through a sieve with a 1.0 mm mesh size.

[00302] The two granules are combined, crospovidone is added, and all components are mixed for 5 minutes in a suitable mixer to produce the main mixture. Magnesium stearate is passed through a sieve to break up lumps and added to the main mixture. Subsequently, the final mixture is processed. Petition 870210017171, dated 22 / 02 / 2021, pages 92 / 112 88 / 96 produced by final mixing in a suitable mixer for three minutes and compressed into oval-shaped tablet cores of 15x6 mm with a compression force of 15 kN. The following formulation variants can be obtained: Ingredient mg / tablet mg / tablet mg / tablet mg / tablet mg / tablet 1st granulation API 1 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 Red iron oxide 2.7 2.7 2.7 2.7 2.7 Hydroxypropyl cellulose 5.4 5.4 5.4 5.4 5.4 2nd granulation API 2 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 Maize 18.0 18.0 18.0 18.0 18.0 Copovidone 5.4 5.4 5.4 5.4 5.4 Final mixture 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

[00303] The tablet hardness, friability, content uniformity, disintegration time and dissolution properties are determined as described above. Example 6: Bilayer tablet, two granules

[00304] The two separate granules, each containing only one active pharmaceutical ingredient, are prepared. For both granules, copovidone is dissolved in purified water at the temperature Petition 870210017171, dated 22 / 02 / 2021, pp. 93 / 112 89 / 96 ambient temperature to produce a liquid granule.

[00305] API 2, 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 subsequently granulated. The moistened granulate is sieved through a suitable sieve. The granulate is dried at an inlet air temperature of approximately 60°C in a fluidized bed dryer until a drying loss of 1 to 4% is achieved. The dried granulate is sieved through a sieve with a 1.0 mm mesh size.

[00306] API 1, mannitol, pregelatinized starch, corn starch, and optionally pigments such as iron oxides are mixed in a suitable mixer to produce a premix. The premix is ​​moistened with the granulation liquid and subsequently granulated. The moistened granules are sieved through a suitable sieve. The granules are dried at an inlet air temperature of approximately 60°C in a fluidized bed dryer until a drying loss of 1 to 4% is obtained. The dried granules are sieved through a sieve with a 1.0 mm mesh size, crospovidone is added, and the components are mixed in a suitable mixer for 5 minutes.

[00307] Magnesium stearate is passed through a sieve to de-lump and added to the two granules separately. Subsequently, two final mixtures are produced by final mixing in a suitable mixer for three minutes. The final mixture containing API 1 is used for the first layer and the final mixture containing API 2 is used for the second layer of the bilayer tablet. The bilayer tablets are produced in a suitable tablet press with a first compression force of 2 kN for the first layer and a main compression force. Petition 870210017171, dated 22 / 02 / 2021, pp. 94 / 112 90 / 96 of 12 kN to produce 10 mm round tablet cores. The following formulation variants can be obtained: Ingredient mg / tablet mg / tablet mg / tablet mg / tablet mg / tablet 1st layer API 1 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 Maize 18.0 18.0 18.0 18.0 18.0 Red iron oxide 2.7 2.7 2.7 2.7 2.7 Copovidone 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 2nd layer API 2 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 Maize 18.0 18.0 18.0 18.0 18.0 Copovidone 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

[00308] The resulting tablets have a tablet hardness of around 120 N, and friability is below 0.5%. Content uniformity meets the requirements according to USP. Disintegration time is around 6 minutes, and dissolution of both APIs is > 85% after 15 minutes. Example 7: Bilayer tablet, two granules

[00309] Two separate granules, each containing only one active pharmaceutical ingredient, are prepared. Petition 870210017171, dated 22 / 02 / 2021, pages 95 / 112 91 / 96

[00310] Copovidone is dissolved in purified water at room temperature to produce a granulation liquid. API 2, 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 subsequently granulated. The moistened granules are sieved through a suitable sieve. The granules are dried at an inlet air temperature of approximately 60°C in a fluidized bed dryer until a drying loss of 1 to 4% is obtained. The dried granules are sieved through a sieve with a 1.0 mm mesh size.

[00311] API 1, mannitol, microcrystalline cellulose, hydroxypropyl cellulose and, optionally, pigments such as red iron oxide are mixed in a suitable mixer to produce a premix. The premix is ​​moistened with purified water and subsequently granulated. The moistened granules are sieved through a suitable sieve. The granules are dried at an inlet air temperature of approximately 60°C in a fluidized bed dryer until a drying loss of 1 to 4% is obtained. The dried granules are sieved through a sieve with a 1.0 mm mesh size, crospovidone is added and the components are mixed in a suitable mixer for 5 minutes.

[00312] Magnesium stearate is passed through a sieve to de-lump and added to the two granules separately. Subsequently, two final mixtures are produced by final mixing in a suitable mixer for three minutes. The final mixture containing API 1 is used for the first layer and the final mixture containing API 2 is used for the second layer of the bilayer tablet. The bilayer tablets are produced in a suitable tablet press with a first compression force of 2 kN for the first layer and a main compression force. Petition 870210017171, dated 22 / 02 / 2021, pp. 96 / 112 92 / 96 of 12 kN to produce 10 mm round tablet cores. The following formulation variants can be obtained: Ingredient mg / tablet mg / tablet mg / tablet mg / tablet mg / tablet 1st layer API 1 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 Red iron oxide 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 2nd layer API 2 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 Maize 18.0 18.0 18.0 18.0 18.0 Copovidone 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

[00313] The tablet hardness, friability, content uniformity, disintegration time, and dissolution properties are determined as described above. Example 8: Monolayer tablet, single granulation

[00314] Copovidone is dissolved in purified water at room temperature (approximately 20°C) to produce a granulation liquid. API 1, API 2, mannitol, pregelatinized starch, and corn starch are mixed in a suitable mixer to produce a pre Petition 870210017171, dated 22 / 02 / 2021, pp. 97 / 112 93 / 96 Mixture: The premix is ​​moistened with the granulation liquid and subsequently granulated. The moistened granules are sieved through a suitable sieve. The granules are dried at an inlet air temperature of approximately 60°C in a fluidized bed dryer until a drying loss of 1 to 4% is achieved. The dried granules are sieved through a sieve with a 1.0 mm mesh size.

[00315] Crospovidone and talc are added to the dry granules and mixed for 5 minutes to produce the master mix. Magnesium stearate is passed through a sieve to de-lump and added to the master mix. Subsequently, the master mix is ​​produced by final mixing in a suitable mixer for three minutes and compressed to form 8 mm round tablet cores with a compression force of 16 kN. The combination of the two lubricants, talc and magnesium stearate, was found to be especially useful when API 1 and API 2 were combined in a granulation and subsequently in a tablet to allow low ejection forces and prevent the master mix from sticking to the tablet perforations.

[00316] Hydroxypropyl methylcellulose, polyethylene glycol, talc, titanium oxide, mannitol, and iron oxide are suspended in purified water in a suitable mixer at room temperature to produce a coating suspension. Tablet cores are coated with the coating suspension to a weight gain of approximately 3% to produce film-coated tablets. The following formulation variants can be obtained: Ingredient mg / tablet mg / tablet mg / tablet mg / tablet mg / tablet API 1 2.5 5.0 10.0 25.0 50.0 API 2 5.0 5.0 5.0 5.0 5.0 Petition 870210017171, dated 22 / 02 / 2021, pages 98 / 112 94 / 96 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 Maize 19.8 19.8 19.8 19.8 19.8 Crospovidone 3.6 3.6 3.6 3.6 3.6 Copovidone 5.4 5.4 5.4 5.4 5.4 Talc 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 oxides 0.0125 0.0125 0.0125 0.0125 0.0125 Titanium dioxide 0.7375 0.7375 0.7375 0.7375 0.7375 Talc 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

[00317] The tablet hardness, friability, content uniformity, disintegration time, and dissolution properties are determined as described above. Examples of Tests Regarding the Properties of Pharmaceutical Compositions and Pharmaceutical Dosage Forms 1. Disintegration Test

[00318] Disintegration test was performed as described in USP31-NF26 S2, chapter 701 (disintegration). 2. Dissolution Test

[00319] The standard dissolution test is described in USP31NF26S2, chapter 711 (dissolution). The paddle method (Apparatus 2) was used with a stirring speed of 50 rpm. The dissolution medium Petition 870210017171, dated 22 / 02 / 2021, pp. 99 / 112 95 / 96 contains 900 mL of 0.05M 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 are analyzed via HPLC.

[00320] A dissolution profile of the tablets, according to example 4 and example 6, where API 1 is compound (I.3) and API 2 is linagliptin, is shown in figure 4.

[00321] A dissolution profile of the tablets, according to example 8, where API 1 is compound (I.3) and API 2 is linagliptin, is shown in figure 5. 3. Particle Size Distribution Measurement by Laser Diffraction

[00322] Particle size distribution measurement was performed, for example, via light scattering or laser diffraction techniques. To determine the particle size, powder is fed into a laser diffraction spectrophotometer, for example, via a scattering unit. The test method is described in detail below: Equipment: Sympatec HELOS Particle Sizer Laser Diffraction Spectrometer. Lens: R31(0.5 / 0.9 pm - 175 pm) Sample Dispersion Unit: RODOS / M Dry Disperser Vacuum: Nilfisk Feeder: ASPIROS Feed Rate: 60.00 mm / s Primary pressure: 200 kPa (2.00 bar) Injector depression: maximize (mbar)2 Reference Measurement: 10 seconds Cycle Time: 100 milliseconds Triggering Conditions: Initiate 0.0 seconds after optical concentration > 1% always validate Interrupt after 5.0 seconds concentration Petition 870210017171, dated 22 / 02 / 2021, pages 100 / 112 96 / 96 optical resolution < 1% or after 30 seconds of real-time Optical concentration: Range of approximately 3 - 12% Evaluation: HRLD Sample size: Approximately 100 mg Number of measurements: 2 (duplicate)

[00323] The instrument is adjusted according to the manufacturer's recommendation and the software provided by the manufacturer is used. The sample container is thoroughly mixed and placed in a drum before removing a portion of the sample to ensure that a representative sample is tested. Duplicate samples are prepared using a spatula to transfer approximately 100 mg of a sample into ASPIROS glass ampoules and cap the ampoules. The glass ampoules are placed in the feeder. 4. Hardness and friability of tablets

[00324] The tablet hardness and friability tests were performed as described in USP31-NF26 S2, chapter 1217 (tablet breaking strength). Petition 870210017171, dated 22 / 02 / 2021, pages 101 / 112

Claims

1 / 2 CLAIMS 1. A solid pharmaceutical dosage form, characterized in that it comprises linagliptin as a first active pharmaceutical ingredient in an amount of 5 mg and 1-chloro-4-(ε-D-glucopyranosom-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxy)benzyl]benzene as a second pharmaceutical ingredient in an amount of 10 mg or 25 mg and excipients, wherein the excipients comprise one or more diluents and one or more binders and a disintegrant and two lubricants, and wherein one or more diluents are selected from the group consisting of cellulose, mannitol, starch and pregelatinized starch, and wherein one or more binders are selected from the group consisting of copovidone, hydroxypropyl methylcellulose (HPMC), hydroxypropylcellulose (HPC), polyvinylpyrrolidone, starch pregelatinized, low-substituted hydroxypropylcellulose (L-HPC), and in which the disintegrant is crospovidone,and wherein the two lubricants are selected from the group consisting of talc and magnesium stearate, and wherein the relative amounts are 0.5-25% of the first and second active pharmaceutical ingredients, 40-88% of one or more diluents, 0.5-20% of one or more binders, 0.5-20% of the disintegrant, 0.1-15% of the lubricant, wherein the percentages are by weight of the total composition, and wherein the solid pharmaceutical dosage form is a single-layer tablet, in which the two active pharmaceutical ingredients are present in one layer. Petition 870220005952, dated 24 / 01 / 2022, page 10 / 18 2 / 2, 2. Solid pharmaceutical dosage form according to claim 1, characterized in that it comprises linagliptin as a first active pharmaceutical ingredient in an amount of 5 mg and 1-chloro-4-(εD-glucopyrans-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-benzene as a second pharmaceutical ingredient in an amount of 10 mg.

3. Solid pharmaceutical dosage form according to claim 1, characterized in that it comprises linagliptin as a first active pharmaceutical ingredient in an amount of 5 mg and 1-chloro-4-(εD-glucopyrans-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-benzene as a second pharmaceutical ingredient in an amount of 25 mg.

4. Solid pharmaceutical dosage form according to claim 1, characterized in that one or more diluents are selected from mannitol and pregelatinized starch.

5. Solid pharmaceutical dosage form according to claim 1, characterized in that one or more binders are selected from copovidone and / or pregelatinized starch.

6. Solid pharmaceutical dosage form according to any one of claims 1 to 5, characterized in that the single-layer tablet is film-coated. Petition 870220005952, dated 24 / 01 / 2022, page 11 / 18

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