Pharmaceutical composition, methods for treating and uses thereof

Abstract

The invention relates to a pharmaceutical composition according to the claim 1 comprising an SGLT2 inhibitor, a DPPIV inhibitor and a third antidiabetic agent which is suitable in the treatment or prevention of one or more conditions selected from type 1 diabetes mellitus, type 2 diabetes mellitus, impaired glucose tolerance and hyperglycemia. In addition the present invention relates to methods for preventing or treating of metabolic disorders and related conditions.

Description

[0001]This application claims benefit from U.S. Provisional Application No. 61 / 152,302, filed on Feb. 13, 2009, the content of which is incorporated herein in its entirety.TECHNICAL FIELD OF THE INVENTION[0002]The invention relates to a pharmaceutical composition comprising an SGLT2-inhibitor, a DPPIV inhibitor and a third antidiabetic agent selected from the group G3 as described hereinafter which is suitable in the treatment or prevention of one or more conditions selected from type 1 diabetes mellitus, type 2 diabetes mellitus, impaired glucose tolerance, impaired fasting blood glucose and hyperglycemia inter alia.[0003]Furthermore the invention relates to methods[0004]for preventing, slowing progression of, delaying, or treating a metabolic disorder;[0005]for improving glycemic control and / or for reducing of fasting plasma glucose, of postprandial plasma glucose and / or of glycosylated hemoglobin HbA1c;[0006]for preventing, slowing, delaying or reversing progression from impaired...

AI Technical Summary

Benefits of technology

[0327]The pharmaceutical compositions and methods according to this invention show advantageous effects in the treatment and prevention of those diseases and conditions as described hereinbefore compared with pharmaceutical compositions and methods which comprise only one or two of the three active ingredients. Advantageous effects may be seen for example with respect to efficacy, dosage strength, dosage frequency, pharmacodynamic properties, pharmacokinetic properties, fewer adverse effects, convenience, compliance, etc.

[0328]Methods for the manufacture of SGLT2 inhibitors according to this invention and of prodrugs thereof are known to the one skilled in the art. Advantageously, the compounds according to this invention can be prepared using synthetic methods as described in the literature, including patent applications as cited hereinbefore. Preferred methods of manufacture are described in the WO 2006 / 120208 and WO 2007 / 031548. With regard to the preferred compound (I.9) an advantageous crystalline form is described in the international patent application WO 2006 / 117359 which hereby is incorporated herein in its entirety.

[0329]With respect to linagliptin, the methods of synthesis are known to the skilled person and as described in the literature, in particular as described in WO 2002 / 068420, WO 2004 / 018468, or WO 2006 / 048427, the disclosures of which are incorporated herein. Polymorphous crystal modifications and formulations of particular DPP IV inhibitors are disclosed in WO 2007 / 128721 and WO 2007 / 128724, respectively, the disclosures of which are incorporated herein in their entireties.

[0330]The methods of synthesis for the further DPP IV inhibitors are described in the scientific literature and / or in published patent documents, particularly in those cited hereinbefore.

[0331]The active ingredients, in particular the DPP IV inhibitor and / or the third antidiabetic agent, may be present in the form of a pharmaceutically acceptable salt. Pharmaceutically acceptable salts include, without being restricted thereto, such as salts of inorganic acid like hydrochloric acid, sulfuric acid and phosphoric acid; salts of organic carboxylic acid like oxalic acid, acetic acid, citric acid, malic acid, benzoic acid, maleic acid, fumaric acid, tartaric acid, succinic acid and glutamic acid and salts of organic sulfonic acid like methanesulfonic acid and p-toluenesulfonic acid. The salts can be formed by combining the compound and an acid in the appropriate amount and ratio in a solvent and decomposer. They can be also obtained by the cation or anion exchange from the form of other salts.

[0332]The active ingredients or a pharmaceutically acceptable salt thereof may be present in the form of a solvate such as a hydrate or alcohol adduct.

Problems solved by technology

In addition, the presence of type 2 diabetes is associated with a two to five fold increase in cardiovascular disease risk.

In addition, even in patients within the intensive treatment arm glycemic control deteriorated significantly over time and this was attributed to deterioration of β-cell function.

Therefore many patients with type 2 diabetes remain inadequately treated, partly because of limitations in long term efficacy, tolerability and dosing inconvenience of existing antihyperglycemic therapies.

The high incidence of therapeutic failure is a major contributor to the high rate of long-term hyperglycemia-associated complications or chronic damages (including micro- and macrovascular complications such as e.g. diabetic nephrophathy, retinopathy or neuropathy, or cardiovascular complications) in patients with type 2 diabetes.

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