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EP-3713561-B1 - COMBINATION OF BUTEIN, ISOLIQUIRITIGENIN AND SULFURETIN, AND ITS USE FOR THE TREATMENT OF DIABETES AND ASSOCIATED DISORDERS

EP3713561B1EP 3713561 B1EP3713561 B1EP 3713561B1EP-3713561-B1

Inventors

  • Heyward, Philip Myers
  • Tups, Alexander

Dates

Publication Date
20260506
Application Date
20181126

Claims (8)

  1. A pharmaceutical composition comprising: • butein or a pharmaceutically acceptable salt, tautomer or solvate thereof (BTN); and • isoliquiritigenin or a pharmaceutically acceptable salt, tautomer or solvate thereof (ILQ); and • sulfuretin or a pharmaceutically acceptable salt, tautomer or solvate thereof (SLF).
  2. The pharmaceutical composition of claim 1, wherein the ratio of ILQ:BTN is from about 0.4:1 to about 3:1 by weight.
  3. The pharmaceutical composition of claim 1 or claim 2, wherein the ratio of SLF:BTN is from about 0.4:1 to about 5:1 by weight.
  4. The pharmaceutical composition of any one of claims 1 to 3, wherein the BTN, SLF and ILQ are provided as an extract of a Dahlia plant, optionally wherein the extract is of at least a petal of the Dahlia plant.
  5. The pharmaceutical composition of claim 4, wherein the Dahlia plant is extracted with an extractant comprising ethanol.
  6. A pharmaceutical composition for use in treating diabetes, the pharmaceutical composition comprising: butein or a pharmaceutically acceptable salt, tautomer or solvate thereof (BTN); and sulfuretin or a pharmaceutically acceptable salt, tautomer or solvate thereof (SLF); and isoliquiritigenin or a pharmaceutically acceptable salt, tautomer or solvate thereof (ILQ).
  7. The pharmaceutical composition for use according to claim 6, wherein the pharmaceutical composition is a pharmaceutical composition according to any one of claims 1 to 5.
  8. A pharmaceutical composition for use in treating type 2 diabetes and/or diet-induced impairment of glucose regulation, wherein the pharmaceutical composition is a pharmaceutical composition according to any one of claims 1 to 5.

Description

Field The invention relates to combinations of flavonoids that may be used to treat diabetes and/or diet-induced impairments in glucose regulation. Background Glucose metabolism involves the various biological processes that store, release, produce and process glucose in the body. A key feature of normal glucose metabolism is a highly regulated concentration of glucose in the blood. The main hormones involved in glucose homeostasis are glucagon and insulin. Glucagon is secreted by α-cells, and β-cells secret pro-insulin, which is later converted into insulin. Insulin production is increased in response to higher concentrations of blood glucose, and triggers multiple pathways to lower blood glucose levels. Glucagon has the opposite activity to insulin. Other hormones involved in glucose metabolism include amylin and incretin hormones, such as glucagon-like peptide-1 (GLP-1). Diabetes is a disease that results when the normal biological processes involved in glucose metabolism are impaired. The classic causes of the disease are either insufficient insulin production or the body failing to adequately respond to the insulin produced. There are many forms of the disease, with the three main types being: type 1, type 2 and gestational diabetes. Type 1 diabetes is characterised by the patient being unable to produce enough insulin in the pancreas. The onset of type 1 diabetes is usually in childhood. Type 2 diabetes begins by a period of insulin resistance, where the function of insulin is reduced in response to blood sugar. As the disease progresses, the amount of insulin produced may also diminish. Prediabetes is a term used to describe a state of abnormally elevated glucose levels between normal glucose metabolism and type 2 diabetes. Over 750 million people worldwide have prediabetes and, for example, it is estimated that 25% of the adult population of New Zealand are prediabetic. The rate of progression from prediabetes to type 2 diabetes is approximately 10% per year and 70% over a lifetime. In patients susceptible to the disease, type 2 diabetes is associated with lifestyle factors, such as excessive sugar consumption and lack of exercise. Gestational diabetes is a form of the disease that presents in women during pregnancy. Since 1980, the number of people suffering from type 2 diabetes worldwide has increased fourfold and is predicted to rise further to an estimated number of 552 million people in 2030. The IDF Diabetes Model projects that the total number of people with diabetes will increase from 415 million (2015) to 642 million (2040) resulting in a total annual cost of $802 billion worldwide. Twelve percent of global health expenditure is spent on diabetes treatment and it is predicted that by 2040 one in 10 adults will suffer from this disease. In addition to this enormous economic burden, poorly managed diabetes leads to serious complications and shorter life expectancy. WO2008150074 discloses the use of botanical flavonoids for the prevention and treatment of diabetic complications. Currently, there are several drugs available for the treatment of type 2 diabetes and most of them are effective in lowering blood glucose levels; however, they partially possess side effects such as hypoglycaemia, weight gain and increased risk of heart failure. There is therefore a continuing need to develop new therapies for diabetes and associated diseases, conditions and/or disorders, including prediabetes and/or diet-induced impairments in glucose regulation. Summary The inventors have found that treatment with a combination of butein or a pharmaceutically acceptable salt, tautomer or solvate thereof (BTN), and both of sulfuretin or a pharmaceutically acceptable salt, tautomer or solvate thereof (SLF) and isoliquiritigenin or a pharmaceutically acceptable salt, tautomer or solvate thereof (ILQ) may reverse the effects of impairments in glucose regulation, including impairment that is diet-induced. Treatment with these combinations may therefore be useful in the treatment of diabetes and associated diseases, conditions and/or disorders. In a first aspect, the invention provides a pharmaceutical composition comprising BTN and SLF and ILQ. In some embodiments, the combination of BTN and SLF and ILQ is provided as an extract of a Dahlia plant. Disclosed herein is a method of treating diabetes or an associated disease, condition and/or disorder, comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising BTN and SLF and/or ILQ. Disclosed herein is the use of BTN and SLF and/or ILQ in the preparation of a medicament for treating diabetes or an associated disease, condition and/or disorder. In a second aspect, the invention provides a pharmaceutical composition for use in treating diabetes, the pharmaceutical composition comprising BTN and SLF and ILQ. The pharmaceutical composition may be an antidiabetic agent comprising BTN and SLF and ILQ. Disclosed herein is a