WO2013040712A1 - Composition comprising ku ding cha and ginseng for managing blood glucose levels - Google Patents

Abstract

Compositions comprising Ku Ding Cha, or Ku Ding Cha in combination with ginseng, that have blood glucose lowering and/or regulating activity are provided. These compositions can be used in the preparation of medicaments, pharmaceutical compositions, foods, nutraceuticals or dietary supplements that may be used to manage blood-glucose levels in subjects or to treat conditions associated with higher than normal blood glucose levels such as Type 2 diabetes; metabolic syndrome; hyperglycemia; a thyroid disorder; Cushing's disease; polycystic ovary syndrome; or abnormal glucose levels induced by a medication.

Description

COMPOSITION COMPRISING KU DING CHA AND GINSENG FOR MANAGING BLOOD GLUCOSE LEVELS

FIELD OF THE INVENTION

[0001] The present invention relates to extracts of Ku Ding Cha and ginseng and, in particular, to compositions comprising Ku Ding Cha or combinations of Ku 5 Ding Cha and ginseng and their use in lowering and/or regulating of blood glucose levels.

BACKGROUND OF THE INVENTION

[0002] Type 2 diabetes (also referred to as non-insulin dependent diabetes or adult onset diabetes) is the most common form of diabetes, with a prevalence of about0 4% in the general population. Type 2 diabetes is marked by high levels of sugar in the blood and occurs when the body fails to correctly control blood glucose levels which can result from either an inadequate release of or a failure to respond correctly to insulin, a hormone released by the pancreas. In addition, the lack of correct blood- glucose control in Type 2 diabetes is often connected to many associated disorders and5 health complications such as cardiovascular disease, hypertension, obesity, hyperlipidemia, accelerated atherosclerosis and (diabetic) neuropathy. Diabetes is the 6^th leading cause of death accounting for approximately 3% of all deaths in the US.

[0003] When diet and exercise do not help maintain normal or near-normal blood glucose levels, oral medications may be prescribed. For example, oral0 sulfonylureas (for example, tolazamide, tolbutamide, chlorpropamide, glyburide, glipizide, and glimepiride) trigger the pancreas to release insulin. Alpha-glucosidase inhibitors (for example, acarbose and miglitol) decrease the absorption of carbohydrates from the digestive tract, thereby lowering the after-meal glucose levels. Biguanides (for example, metformin) instruct the liver to decrease its production of5 glucose, which decreases glucose levels in the blood stream. Meglitinides (for example, repaglinide and nateglinide) trigger the pancreas to release more insulin in response to how much glucose is in the blood. Thiazolidinediones (for example, rosiglitazone) increase the cell's sensitivity (responsiveness) to insulin, but may increase the risk of heart problems. These oral medications are associated with a number of adverse side-effects, for example, hypoglycemia, vomiting, diarrhea, and liver dysfunction.

[0004] In cases in which lifestyle changes and oral medications are unsuccessful, insulin is prescribed. Insulin must be injected under the skin, causing discomfort to the patient and requiring patient training and compliance to administer the injection as needed. As a result, often insulin is not taken as prescribed and the patient is at greater risk for diabetes related health complications. Cost for such medications and supplies (for example, syringes, blood glucose monitor including a lancing device, lancet, control solution, test strips and meter) may total from $1000 to $15,000 annually.

[0005] Herbal extracts tend to exhibit fewer deleterious side effects associated with traditional pharmaceuticals and tend to have relative low-costs associated with their manufacture. [0006] Ginsenosides, steroid glycosides found in the various species of Panax, may exhibit glycemic control activity.¹ For example, a Panax ginseng berry extract, and its major constituent ginsenoside Re were found to be effective in treating obese diabetic C57BL/6J ob/ob mice. After 12 days of treatment with either the extract or the isolated ginsenoside Re the ob/ob mice were found to be normoglycemic.¹ In addition, a number of small-scale clinical studies have noted glucose regulation upon administration of extracts derived from various species of ginseng.²

[0007] Ku Ding Cha (also referred to as Kudingcha, Kuding tea, bitter tea, ku cha), is widely consumed in China as a tea or functional drink. Species from the genus Ligustrum, Oleaceae, and Ilex (of the Aquifoliaceae family) including Ligustrum pedunciare, Ligustrum purpurascens, Ligustrum japonicum, Ligustrum robustrum, Ilex cornuta, Ilex kudingcha C. J. Tseng (Aquifoliaceae), Ilex latifolia, Cratoxylum prunifolium, Ehretia thyrsiflora, Photinia serruiata and Ilex paraguariensis (Yerba Mate) are commonly used to make this tea.³

[0008] Aqueous and alcoholic extracts of leaves of various Ilex species contain numerous terpenoids, triterpenes, and caffeoyl derivatives thereof.³'⁴ Triterpenoid saponins have been isolated from Ilex kudingcha including: ilekudinosides A-S, ilexoside XL VIII, cynarasaponin C, latifolosides A, C, G and H, and kudinoside G.⁴ Extracts of Ilex kudingcha have also been found to contain chlorogenic acid (CA)³ and triterpenes including ursolic acid and lupeol⁵. Ursolic acid ^-Hydroxy-12-ursen-28- ic acid), has been identified as an inhibitor of several enzymes, including adenosine deaminase, arachidonate lipoxygenase, aromatase, cyclooxygenase, DNA ligase I, elastase, protein kinases A and C, and RNA-directed DNA polymerase.⁶ In addition, ursolic acid has been shown to act as an effective insulin mimetic at doses above 50 ug/mL in vitro ¹ [0009] CA, and derivatives of CA, act as inhibitors of glucose-6-phosphate translocase (G6P Ti-translocase: a transporter of G6P across the endoplasmic reticulum) but have no effect on the function of the enzyme system glucose-6- phosphatase (G6Pase), which catalyzes hydrolysis of G6P in both gluconeogenesis and glycogenolysis.⁸ The use of CA for glycemic control in both normal and diabetic rats has been investigated by a number of research groups.⁹ Recently, Bassoli and coworkers reported that oral ingestion of CA reduced post-prandial serum glycemic peaks of male albino Wistar rats, whereas large dosages administered by IV injection had no effect on glycemia and CA directly infused into the liver did not affect hepatic glucose production.¹⁰ However, G6P Ti-translocase inhibitors, such as CA, have not been tested clinically since doses required for blood-glucose regulation induce hypoglycemia and hyperlactatemia in rodents.⁹ Such a condition in a human patient, particularly one afflicted with diabetes, could be catastrophic.

[00010] The direct effect of CA on glucose uptake is unclear. While Prabhakar et al. reported that 25 μΜ CA (8.85 μg/mL) increased glucose uptake in L6 myotubes by 3-fold, Tousch et al. found that CA alone had no effect on glucose uptake in myotubes at concentrations as high as 100 μg/mL¹¹'¹².

[00011] There exists a need for medicaments or supplements derived from plants or other natural sources for lowering, regulating, or lowering and regulating blood glucose in a subject in need of such lowering, regulating, or lowering and regulating. [00012] This background information is provided for the purpose of making known information believed by the applicant to be of possible relevance to the present invention. No admission is necessarily intended, nor should be construed, that any of the preceding information constitutes prior art against the present invention.

SUMMARY OF INVENTION

[00013] An object of the present invention is to provide compositions for managing blood glucose levels. In accordance with one aspect of the invention, there is provided a composition comprising a Ku Ding Cha (KDC) component and a ginseng component, wherein the KDC component comprises one or more parts of a KDC plant, a KDC extract, one or more compounds found in KDC, or a combination thereof, and the ginseng component comprises one or more parts of a ginseng plant, a ginseng extract, one or more compounds found in ginseng, or a combination thereof.

[00014] In accordance with another aspect of the present invention, there is provided a composition comprising a Ku Ding Cha (KDC) component and a ginseng component, wherein the KDC component comprises one or more parts of a KDC plant, a KDC extract, one or more compounds found in KDC, or a combination thereof, and the ginseng component comprises one or more parts of a ginseng plant, a ginseng extract, one or more compounds found in ginseng, or a combination thereof, for use to manage blood glucose levels in a subject in need thereof.

[00015] In accordance with another aspect of the present invention, there is provided a use of a composition comprising a Ku Ding Cha (KDC) component and a ginseng component, wherein the KDC component comprises one or more parts of a KDC plant, a KDC extract, one or more compounds found in KDC, or a combination thereof, and the ginseng component comprises one or more parts of a ginseng plant, a ginseng extract, one or more compounds found in ginseng, or a combination thereof, for managing blood glucose levels in a subject in need thereof. [00016] In accordance with another aspect of the present invention, there is provided a use of a composition comprising a Ku Ding Cha (KDC) component and a ginseng component, wherein the KDC component comprises one or more parts of a KDC plant, a KDC extract, one or more compounds found in KDC, or a combination thereof, and the ginseng component comprises one or more parts of a ginseng plant, a ginseng extract, one or more compounds found in ginseng, or a combination thereof, in the manufacture of a medicament, nutraceutical or supplement, for managing blood glucose levels in a subject.

[00017] In accordance with another aspect of the present invention, there is provided a composition comprising a Ku Ding Cha (KDC) component and a ginseng component, wherein the KDC component comprises one or more parts of a KDC plant, a KDC extract, one or more compounds found in KDC, or a combination thereof, and the ginseng component comprises one or more parts of a ginseng plant, a ginseng extract, one or more compounds found in ginseng, or a combination thereof, for use to treat a condition associated with higher than normal blood glucose levels in a subject in need thereof.

[00018] In accordance with another aspect of the present invention, there is provided a use of a composition comprising a Ku Ding Cha (KDC) component and a ginseng component, wherein the KDC component comprises one or more parts of a KDC plant, a KDC extract, one or more compounds found in KDC, or a combination thereof, and the ginseng component comprises one or more parts of a ginseng plant, a ginseng extract, one or more compounds found in ginseng, or a combination thereof, for treating a condition associated with higher than normal blood glucose levels in a subject in need thereof. [00019] In accordance with another aspect of the present invention, there is provided a use of a composition comprising a Ku Ding Cha (KDC) component and a ginseng component, wherein the KDC component comprises one or more parts of a KDC plant, a KDC extract, one or more compounds found in KDC, or a combination thereof, and the ginseng component comprises one or more parts of a ginseng plant, a ginseng extract, one or more compounds found in ginseng, or a combination thereof, in the manufacture of a medicament, nutraceutical or supplement, for treating a condition associated with higher than normal blood glucose levels.

[00020] In accordance with another aspect of the present invention, there is provided a method for managing blood glucose levels in a subject in need thereof comprising administering to the subject an effective amount of a composition comprising a Ku Ding Cha (KDC) component and a ginseng component, wherein the KDC component comprises one or more parts of a KDC plant, a KDC extract, one or more compounds found in KDC, or a combination thereof, and the ginseng component comprises one or more parts of a ginseng plant, a ginseng extract, one or more compounds found in ginseng, or a combination thereof. [00021] In accordance with another aspect of the present invention, there is provided a method for treating a condition associated with higher than normal blood glucose levels in a subject in need thereof, comprising administering to the subject an effective amount of a composition comprising a Ku Ding Cha (KDC) component and a ginseng component, wherein the KDC component comprises one or more parts of a KDC plant, a KDC extract, one or more compounds found in KDC, or a combination thereof, and the ginseng component comprises one or more parts of a ginseng plant, a ginseng extract, one or more compounds found in ginseng, or a combination thereof.

[00022] In accordance with another aspect of the present invention, there is provided a composition comprising a Ku Ding Cha (KDC) component for use to manage blood glucose levels in a subject in need thereof, wherein the KDC component comprises one or more parts of a KDC plant, a KDC extract, one or more compounds found in KDC, or a combination thereof.

[00023] In accordance with another aspect of the present invention, there is provided a composition comprising a Ku Ding Cha (KDC) component for use to treat a condition associated with higher than normal blood glucose levels in a subject in need thereof, wherein the KDC component comprises one or more parts of a KDC plant, a KDC extract, one or more compounds found in KDC, or a combination thereof.

[00024] In accordance with another aspect of the present invention, there is provided a use of a composition comprising a Ku Ding Cha (KDC) component for managing blood glucose levels in a subject in need thereof, wherein the KDC component comprises one or more parts of a KDC plant, a KDC extract, one or more compounds found in KDC, or a combination thereof.

[00025] In accordance with another aspect of the present invention, there is provided a use of a composition comprising a Ku Ding Cha (KDC) component for treating a condition associated with higher than normal blood glucose levels in a subject in need thereof, wherein the KDC component comprises one or more parts of a KDC plant, a KDC extract, one or more compounds found in KDC, or a combination thereof.

[00026] In accordance with another aspect of the present invention, there is provided a use of a composition comprising a Ku Ding Cha (KDC) component in the manufacture of a medicament, nutraceutical or supplement, for managing blood glucose levels in a subject in need thereof, wherein the KDC component comprises one or more parts of a KDC plant, a KDC extract, one or more compounds found in KDC, or a combination thereof. [00027] Use of a composition comprising a Ku Ding Cha (KDC) component in the manufacture of a medicament, nutraceutical or supplement, for treating a condition associated with higher than normal blood glucose levels in a subject, wherein the KDC component comprises one or more parts of a KDC plant, a KDC extract, one or more compounds found in KDC, or a combination thereof. [00028] In accordance with another aspect of the present invention, there is provided a method for managing blood glucose levels in a subject in need thereof comprising administering to the subject an effective amount of a composition comprising a Ku Ding Cha (KDC) component for treating a condition associated with higher than normal blood glucose levels in a subject in need thereof, wherein the KDC component comprises one or more parts of a KDC plant, a KDC extract, one or more compounds found in KDC, or a combination thereof.

[00029] In accordance with another aspect of the present invention, there is provided a method for managing blood glucose levels in a subject in need thereof comprising administering to the subject an effective amount of a composition comprising a Ku Ding Cha (KDC) component for treating a condition associated with higher than normal blood glucose levels in a subject in need thereof, wherein the KDC component comprises one or more parts of a KDC plant, a KDC extract, one or more compounds found in KDC, or a combination thereof.

[00030] In accordance with another aspect of the present invention, there is provided a method for treating a condition associated with higher than normal blood glucose levels in a subject in need thereof, comprising administering to the subject an effective amount of a composition comprising a Ku Ding Cha (KDC) component for treating a condition associated with higher than normal blood glucose levels in a subject in need thereof, wherein the KDC component comprises one or more parts of a KDC plant, a KDC extract, one or more compounds found in KDC, or a combination thereof.

[00031] One embodiment of the present invention provides a composition comprising from about 1 to about 8% (w/w) of Rgl+Re, from about 5 to about 10% (w/w) Rbl, from about 0.5 to about 8% (w/w) Rd, and from about 1 to about 8% (w/w) Rc, 1-50% (w/w) total saponins, 0.1-15% (w/w) ursolic acid and 0.1-10% (w/w), chlorogenic acid. The composition may be used to lower, regulate, or lower and regulate blood glucose levels in a subject.

[00032] In another embodiment, the present invention provides a method of lowering, regulating, or lowering and regulating blood glucose levels in a subject the method comprising administering to the subject a blood glucose lowering, regulating, or lowering and regulating effective amount of a composition comprising from about 1 to about 50% (w/w) total saponins, from about 0.1 to about 15% (w/w) ursolic acid, and about 0.1 to about 10% chlorogenic acid.

[00033] In another embodiment, the present invention provides a method of lowering, regulating, or lowering and regulating blood glucose levels in a subject the method comprising administering to the subject a blood glucose lowering, regulating, or lowering and regulating effective amount of a composition comprising about 1 to about 8% (w/w) of Rgl+Re, from about 5 to about 10% (w/w) Rbl, from about 0.5 to about 8% (w/w) Rd, from about 1 to about 8% (w/w) Rc, from about 1 to about 50% (w/w) total saponins, from about 0.1 to about 15% (w/w) ursolic acid and from about 0.1 to about 10% (w/w) chlorogenic acid. BRIEF DESCRIPTION OF THE DRAWINGS

[00034] These and other features of the invention will become more apparent from the following detailed description in which reference is made to the appended drawings. [00035] Figure 1 shows the modulation of glucose uptake in C2C12 cells, a model of skeletal cell glucose handling, upon treatment with an exemplary KDC extract, KDC-001. Data are shown as mean percentage of control (untreated) cell glucose content +/- SD. * p<0.05, ** p<0.01, *** p<0.001 when compared to control (One Way ANOVA). [00036] Figure 2 illustrates the results of the non-linear blending experiment and shows the experimental results and the predicted average additive response upon combining the exemplary KDC extract KDC-001 and the exemplary ginseng extract HT1001.

[00037] Figure 3A illustrates isobologram curves; the downward curve (A), or bow shape, indicates synergy, a linear curve (B) is indicative of additivity, and the upward curve (C) results from antagonistic interactions betwen the components, and Figure 3B shows the results of isobologram experiments using a combination of exemplary KDC extract KDC-001 and exemplary ginseng extract HT1001.

DETAILED DESCRIPTION OF THE INVENTION [00038] The present invention relates to extracts of Ku Ding Cha and ginseng, and compositions comprising Ku Ding Cha or Ku Ding Cha and ginseng suitable for managing blood glucose levels. The invention also relates to methods of managing blood-glucose levels (for example, by lowering, regulating, or lowering and regulating blood glucose levels) in a subject using compositions comprising Ku Ding Cha or Ku Ding Cha and ginseng.

[00039] The invention will now be described by way of the following exemplary embodiments. When describing the present invention, all terms not defined herein have their common art-recognized meanings. To facilitate understanding of the invention, the following definitions are provided.

[00040] As used herein, the term "about" refers to an approximately +/-10% variation from a given value. It is to be understood that such a variation is always included in any given value provided herein, whether or not it is specifically referred to.

[00041] "Biocompatible" means a compound or mixture of compounds that does not generate a significant undesirable host response for the intended utility. Biocompatible materials are typically non-toxic for the intended utility. For human utility, a biocompatible compound or mixture of compounds is most preferably nontoxic to humans or human tissues.

[00042] "Carrier" means a suitable vehicle which is in certain embodiments biocompatible and/or pharmaceutically acceptable, including for instance, one or more solid, semisolid or liquid diluents, excipients, adjuvants, flavours, or encapsulating substances which are suitable for administration.

[00043] An "extract" refers to a preparation obtained following extraction of a plant or plant part with a suitable solvent such as, for example, water, alcohol, a mixture thereof, oils or other suitable solvent well known in the state of the art of plant extraction. The extract can be used as such if it is pharmacologically acceptable (i.e., having pharmacological activity for the intended purpose), or the solvent of the resulting solutions may be removed and the residue used as such or after further work up, for example, after further purification, blending with other active ingredients, adding a carrier, or re-suspending or dissolving in a suitable solvent. The term "plant" is understood to mean the whole plant or a plant part or combination of plant parts, for example, the leaves, the stems, the fruits or roots, comprising one or more active ingredients. In certain embodiments, the plant or plant part may be dried and powdered before the extract is obtained.

[00044] "Ginseng" is meant to refer to any variety or type of plant from the

Panax genus comprising ginsenosides, for example the ginsenosides Rgl, Re, Rbl, Rd and Rc, for example a plant comprising from about 0.1 to about 8% (w/w) of Rgl+Re or any amount therebetween, for example 0.1, 0.2, 0.4, 0.6, 0.8, 1, 2, 3, 4, 5, 6, 7, 8% (w/w), or any amount therebetween, from about 1-10% (w/w) Rbl or any amount therebetween, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10%, or any amount therebetween, from about 0.1%-8% (w/w) Rd or any amount therebetween, for example, 0.1, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0% (w/w), or any amount therebetween, from about 0.1 to about 8% Rc or any amount therebetween, for example, 0.1, 0.2, 0.4, 0.6, 0.8, 1, 2, 3, 4, 5, 6, 7, 8% (w/w), or any amount therebetween. For example, ginseng may refer to plants including, but not limited to, those listed in Table 1. It will be understood by those skilled in the art that there are other species belonging in the Panax genus which may be used within the context of the present invention. The term "ginseng" also includes wild or processed ginseng. Wild ginseng is ginseng which has not been planted and cultivated domestically, but grows naturally and is harvested from wherever it is found to be growing. Processed ginseng includes, for example, fresh or green ginseng, white ginseng, and red ginseng. Fresh or green ginseng is raw ginseng harvested in the field. White ginseng is obtained by drying fresh ginseng, and red ginseng is obtained by steaming fresh ginseng followed by drying the steamed ginseng.

TABLE 1. Examples of Varieties and Types of Ginseng

¹ Also sometimes referred to as Panax quinquefolium.

[00045] A "ginseng extract" is meant to refer to an extract made from any variety and type of ginseng as listed in Table 1 or described above, and subfractions obtained from these ginseng extracts, which exhibit the activity of lowering, regulating, or lowering and regulating blood glucose levels and/or which synergistically enhance the blood glucose lowering, regulating or lowering and regulating activity of KDC, as verified by conducting one or more in vitro or in vivo pharmacological evaluations. In certain embodiments, the ginseng extract may be obtained from North American ginseng {Panax quinquefolius). A non-limiting example of a ginseng extract from Panax quinquefolius is the ginseng extract HT1001, described in U.S. Patent No. 6,083,932.

[00046] "Ku Ding Cha" (KDC) as used herein, refers to any variety or type of plant from the species Ilex kudingcha (also referred to as Ilex kudingcha C. J. Tseng or Ilex kudincha in the art). [00047] A "KDC extract" is meant to refer to an extract made from any variety, type or part of a KDC plant as defined above, and subfractions obtained from these extracts, which exhibit the activity of lowering, regulating, or lowering and regulating blood glucose levels, as verified by conducting one or more in vitro or in vivo pharmacological evaluations. For example, the KDC extract may comprise saponins, ursolic acid, or chlorogenic acid, or a combination thereof. For example, the KDC extract may comprise from about 1 to about 50% (w/w) total saponins, or any amount therebetween, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, 20, 25, 30, 35, 40, 45, 50, or any amount therebetween, from about 0.1 to about 15% (w/w) ursolic acid, or any amount therebetween, for example, 0.1, 0.2, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or any amount therebetween, and from about 0.1 to about 10% (w/w) chlorogenic acid, or any amount therebetween, for example, 0.1, 0.2, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 6, 7, 8, 9, 10, or any amount therebetween.

[00048] "Blood glucose lowering, regulating, or lowering and regulating activity" means an activity associated with a compound, mixture or extract that results in a lowering, regulating, or lowering and regulating of blood glucose levels.

[00049] "Lowering blood glucose levels" means a reduction in an amount or concentration of blood glucose in a subject when compared to the amount or concentration of blood glucose in the same subject in the absence of any treatment. "Regulating blood glucose levels" or "regulation of blood glucose levels" refers to improving blood glucose levels in a subject over the level of blood glucose that would be found in that subject without intervention including, for example, improvement of baseline levels (fasted or non-fasted) and post-prandial levels including rate of rise of glucose, peak glucose and rate of decrease of glucose. Where improving blood glucose levels means maintaining blood glucose levels in a subject closer to or within medically acceptable norms for any stage of blood glucose control including, for example, baseline (fasted and non-fasted) and post prandial glucose levels. A baseline or normal blood glucose level will be evident to those skilled in the art. For example, the American diabetes association defines normal fasting plasma glucose levels (FPG) as being less than lOOmg/dl (5.6 mmol/L) and 2-h postload plasma glucose levels (2hPG; 2-h following an oral glucose tolerance test) as being less that 140 mg/dl (7.8 mmol/L).¹³ Those skilled in the art will recognize that there are a number of factors that contribute to the normal or baseline blood glucose level of an individual. For example, in an individual with a condition such as diabetes for example, baseline fasting plasma glucose levels may be higher than baseline levels in a non-diabetic subject, for example target baseline FPG levels for a diabetic subject may be defined as being less than 130 mg/dl.

[00050] "Preventing" or "prevention," as used herein in the context of blood glucose levels, refers to reducing the risk in a subject of developing a condition associated with higher than normal blood glucose levels or delaying the onset or progression of such a condition. Conditions associated with higher than normal blood glucose include, for example, but not limited to: Type 2 diabetes; metabolic syndrome; hyperglycemia, such as a subject with high baseline (fasted or non-fasted) glucose levels, high post prandial glucose levels, or both; a thyroid disorder; Cushing's disease; polycystic ovary syndrome; or abnormal glucose levels induced by a medication.

[00051] "Treating" or "treatment," as used herein in the context of blood glucose levels, refers to managing (for example, lowering and/or regulating) blood glucose levels in a subject in need of such management. A subject in need of blood glucose management may be, for example, but not limited to, a subject with Type 2 diabetes; metabolic syndrome; hyperglycemia, such as a subject with high baseline (fasted or non-fasted) glucose levels, high post prandial glucose levels, or both; a thyroid disorder; Cushing's disease; polycystic ovary syndrome; or abnormal glucose levels induced by a medication.

[00052] "Managing" blood glucose means altering blood glucose levels, including lowering, regulating, and lowering and regulating, for the purpose of bringing glucose levels in a subject closer to or within medically acceptable norms. [00053] "Metabolic syndrome" means a combination of medical disorders, which increase the risk of developing Type 2 diabetes and cardiovascular diseases (as defined by Medical Subject Heading "MeSH" controlled by the United States National Library of Medicine which includes but is not limited to, heart disease, stroke and hypertension). [00054] "Patient" means a subject with a condition requiring treatment or at risk of developing a condition requiring treatment.

[00055] The present invention provides compositions comprising a KDC component alone or in combination with a ginseng component that are useful for managing blood glucose levels. The KDC component may be, for example, an extract of KDC (KDC extract), parts of the KDC plant and chemical components found in said extract obtained by isolation from the extract or by chemical synthesis.

[00056] The KDC component of the compositions according to the present invention is derived from a plant from the species Ilex kudingcha also known as Ilex kudingcha C. J. Tseng or Ilex kudincha). The component may comprise one or more parts of a KDC plant, an extract from one or more parts of a KDC plant, one or more chemicals found in a KDC plant, or a combination thereof.

[00057] In certain embodiments, the KDC component comprises a KDC extract.

KDC extracts may be prepared by various methods and processes known in the art using solvents such as water, organic solvents and oils. Examples of organic solvents suitable for preparing plant extracts are well-known in the art and include, but are not limited to, alcohols (such as ethanol and methanol), polyols and esters (such as ethyl acetate).

[00058] A non-limiting process of preparing a KDC extract is provided in International Patent Application No. PCT/IB2009/005461. For example, the KDC extract may be prepared from Ilex kudingcha C. J. Tseng. KDC leaves, or other parts of the KDC plant, may be ground or pulverized to a powder. The KDC powder may then be combined with a first solvent which may comprise an alcohol or an alcohol solution such as an aqueous solution of alcohol, for example, in a ratio of KDCfirst solvent of between 1 :20 and 1 :5, or a ratio of 1 :5, 1 :6, 1 :7, 1 :8, 1 :9, 1 : 10, 1 : 11, 1 : 12, 1 : 13, 1 : 14, 1 : 15, 1 : 16, 1 : 17, 1 : 18, 1 : 19, 1 :20, or any ratio therebetween, to produce a slurry. The solvent may be an aqueous alcohol solution with an alcohol content of between from about 50 - 99 % (v/v), between about 60-80% (v/v), between about 65- 75% (v/v), or 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 99% (v/v), or any amount therebetween. The alcohol may be, for example, a short chain alcohol (for example, a C1-C4 alcohol) or a polyol. In certain embodiments, the alcohol is ethanol or methanol, for example ethanol. The resulting slurry of the KDC powder and first solvent is heated, to a temperature between from about 40 to about 100 °C, between about 60 to about 100 °C, between about 70 to about 80 °C, about 78 °C, or 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100 °C, or any amount therebetween. The slurry is heated for a period of between about 0.1 to 24 h, about 1- 16 h, about 1-3 h, or 0.1, 0.5, 1.0, 2.0, 3.0, 5.0, 8.0, 10, 12, 14, 16, 18, 20, 22, 24, 25 hours, or any amount therebetween. After the heating period the slurry is filtered and the supernatant retained. The supernatant is then dried, suitable methods of drying are known to the skilled artisan and include, but are not limited to, air drying, vacuum drying, spray drying and freeze drying. A worker skilled in the art would appreciate that alterations to the extraction procedure described above can be made while still providing a KDC extract having blood glucose level managing activity. Such alterations can be readily determined by those skilled in the art. Example 1 describes the preparation of a non-limiting example of a KDC extract, KDC-001. In addition, Example 1 identifies the variance in components that may result from certain alterations to the described method of preparing KDC extracts. [00059] KDC extracts suitable for use in accordance with the present invention preferably comprise total saponins from between about 1 to about 50% (w/w), between about 4 to about 50% (w/w), between about 30 to about 50% (w/w) or 1, 2, 4, 6, 8, 10, 15, 20, 25, 30, 35, 40, 50% (w/w) total saponins, or any amount therebetween; ursolic acid from between about 0.1 to about 15% (w/w), between about 1 to about 10% (w/w), between about 1 to about 5% (w/w), or 0.1, 0.5, 1, 2.5, 5.0, 7.5, 10.0, 12.5, 15% (w/w) ursolic acid, or any amount therebetween; or chlorogenic acid from between about 0.1 to about 10% (w/w), between about 1 to about 5% (w/w), between about 1 to about 4% (w/w), or 0.1, 0.5, 1.0, 2.0, 3.0, 4.0, 5.0, 6.0, 7.0, 8.0, 9.0, 10.0% (w/w) chlorogenic acid, or any amount therebetween; or a combination thereof. [00060] In certain embodiments, the KDC extract is substantially identical to the exemplary extract KDC-001. By "substantially identical to KDC-001" it is meant that the KDC extract comprises total saponins between about 30 to about 50% (w/w), for example between about 40 and about 50% (w/w), or about 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 or 50% (w/w) total saponins; ursolic acid between about 1 to about 5% (w/w), for example between about 1 and about 3% (w/w), or about 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5 or 5.0% (w/w) ursolic acid; and chlorogenic acid between about 1 to about 4% (w/w), for example between about 1.5 to about 3.5% (w/w), or about 1.0, 1.2, 1.4, 1.6, 1.8, 2.0, 2.2, 2.4, 2.6, 2.8, 3.0, 3.2, 3.4, 3.6, 3.8 or 4.0% (w/w) chlorogenic acid. [00061] In certain embodiments, the KDC component has a chemical composition that includes saponins between about 30 to about 50% (w/w), for example between about 40 and about 50% (w/w), or about 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 or 50% (w/w) saponins; ursolic acid between about 1 to about 5% (w/w), for example between about 1 and about 3% (w/w), or about 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5 or 5.0% (w/w) ursolic acid; and chlorogenic acid between about 1 to about 4% (w/w), for example between about 1.5 to about 3.5% (w/w), or about 1.0, 1.2, 1.4, 1.6, 1.8, 2.0, 2.2, 2.4, 2.6, 2.8, 3.0, 3.2, 3.4, 3.6, 3.8 or 4.0% (w/w) chlorogenic acid, in which the saponins comprise saponins found in KDC. In accordance with these embodiments, the KDC component may be a KDC extract, a combination of chemicals that are either synthetic or isolated from natural sources, or a combination of a KDC extract and one or more chemicals. For example, in certain embodiments, the KDC component may include a KDC extract that comprises saponins within a suitable range as outlined above, but which has levels of ursolic acid and/or chlorogenic acid that fall below the ranges outlined above, in which case, isolated ursolic acid and/or chlorogenic acid may be included in order to bring the levels within a suitable range. Likewise a KDC extract that comprises acceptable levels of ursolic acid may be supplemented as necessary with synthetic or isolated saponins and/or chlorogenic acid; and a KDC extract that comprises acceptable levels of chlorogenic acid may be supplemented as necessary with synthetic or isolated saponins and/or ursolic acid. [00062] The KDC component may be evaluated to assess and confirm the activity of blood glucose lowering, regulating, or lowering and regulating by conducting one or more in vitro or in vivo pharmacological evaluations. Examples of in vitro assays include, but are not limited to, those which measure glucose uptake; insulin sensitivity; insulin secretion; modulation of GLP-1 secretion; the mechanisms of GLP-1 secretion such as dipeptidyl peptidase 4 inhibition; a-glucosidase inhibition; or the mechanisms of insulin secretion (for example, K_ATP ion channel activity or other potassium channels such as the voltage gated potassium channels; intracellular calcium levels; modulation of calcium channels; modulation of the sodium-calcium exchanger). Non-limiting examples of in vivo assays include measurement of blood glucose from a subject who has fasted; a two-hour postprandial test where blood glucose is measured two hours after eating; a glucose challenge test where blood glucose is measured at different time point between 0 and 2hours after oral administration of glucose; and a random blood glucose test where blood glucose is measured regardless of the time at which a subject last ate. Suitable assays for the above measurements would be known to those skilled in the art.

[00063] As shown herein, an exemplary KDC extract KDC-001 (prepared using

70% aqueous ethanol as described in Example 1) was found to enhance glucose uptake by C2C12 cells with dose dependency (see Example 2 and Figure 1). Statistically significant enhanced glucose uptake relative to control was observed with a KDC extract concentration as low as 100 μg/mL. KDC extracts may therefore facilitate management of blood glucose levels, for example by lowering, regulating, or lowering and regulating blood glucose levels.

[00064] Thus certain embodiments of the present invention provide a composition comprising a KDC component for managing (for example, lowering, regulating, or lowering and regulating) blood glucose levels in a subject. In some embodiments, the present invention provides a method of managing (for example, lowering, regulating, or lowering and regulating) blood glucose levels in a subject, the method comprising administering to the subject an effective amount of a KDC extract, or a composition comprising a KDC component.

[00065] In certain embodiments, the present invention provides a food, or supplement, having blood glucose managing activity comprising a KDC component, where the KDC component comprises from about 1 to about 50% (w/w) total saponins, or any amount therebetween, from about 0.1 to about 15% (w/w) ursolic acid, or any amount therebetween, and from about 0.1 to about 10% (w/w) chlorogenic acid, or any amount therebetween.

[00066] Also provided in some embodiments is a medicament for managing blood glucose levels, the medicament comprising a KDC component as described above. In certain embodiments, the KDC component included in the medicament is one or more parts of a KDC plant, or a KDC extract, where the KDC component comprises from about 1 to about 50% (w/w) total saponins, or any amount therebetween, from about 0.1 to about 15% (w/w) ursolic acid, or any amount therebetween, and from about 0.1 to about 10% (w/w) chlorogenic acid, or any amount therebetween. In some embodiments, the KDC component may be formulated as a pharmaceutical composition comprising a pharmaceutically acceptable carrier. Those skilled in the art are familiar with any pharmaceutically acceptable carrier that would be useful in this regard, and therefore the procedure for making pharmaceutical compositions in accordance with the invention will not be discussed in detail. Suitably, the pharmaceutical composition may be in the form of tablets, capsules, liquids, lozenges, lotions, aerosol, and solutions suitable for various routes of administrations including, but not limited to, orally, via injection or infusion, intraperitoneally, topically, nasally, ocularly, vaginally, or rectally, in solid, semi-solid or liquid dosage forms as appropriate and in unit dosage forms suitable for easy administration of fixed dosages.

[00067] in certain embodiments, the compositions provided by the present invention also comprise a ginseng component, for example, an extract of ginseng (ginseng extract), one or more parts of a ginseng plant, or compounds found in the ginseng plant or extract. Preferably the ginseng component is derived from the roots of North American ginseng (Panax quinquefolius).

[00068] In some embodiments, the ginseng component is a ginseng extract. The extract may be prepared by a number of extraction methods or processes known in the art using solvents well-known in the art for the purposes of preparing plant extracts as described above with respect to the KDC extract. A non-limiting process of preparing an exemplary ginseng extract HT1001 is provided in U.S. Patent No. 6,083,932. For example, a ginseng root may be dried and milled. The resulting dried ginseng powder may be contacted with a solvent to produce a slurry. The solvent may be an alcohol, or an aqueous alcohol solution, between about 10-99% (v/v) alcohol, about 30-95% (v/v) alcohol, between about 50-95% (v/v) alcohol, between about 70-95% (v/v) alcohol, or 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 99% (v/v) alcohol, or any amount therebetween. The alcohol may be, for example, a short chain alcohol (for example, a C1-C4 alcohol) or a polyol. In certain embodiments, the alcohol is ethanol or methanol, for example ethanol. A solid: solvent ratio between about 1 :5 to 1 : 14 is suitable, for example 1 :5, 1 :6, 1 :7, 1 :8, 1 :9, 1 : 10, 1 : 11, 1 : 12, 1 : 13, 1 : 14, 1 : 15, or any ratio therebetween. Extraction can proceed for about one to five hours, for example, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0 hours, or any amount therebetween. Longer extraction periods may also be used, for example, when the temperature used for the extraction is at the lower end of the following ranges. The slurry may be heated with stirring for a period of time to ensure sufficient extraction. The extraction temperature can be in a range of from 20-105°C, for example 90-95 °C, or 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105°C, or any amount therebetween. Stirring is recommended. The liquid and solid phases are then separated using any suitable method of separation, for example decanter centrifuge. The liquid phase is retained, the solvent removed, for example using vacuum, distillation, and dried for example using freeze drying, oven drying, spray dried to produce the ginseng extract. Using this method, the ginseng extract may comprise a total saponin (ginsenoside) fraction of about 20 to about 50% by weight of the ginseng extract. Chemical and biological fingerprinting such as that described in U.S. Patent No. 6,156,291 may be used to verify the chemical consistency of the ginseng extract if desired.

[00069] A pharmaceutically acceptable excipient may be added to the concentrated extract before drying. The excipient may be selected from rice starch, maltodextrin or other suitable excipients as are known in the art. If blended with an excipient, then the total saponins concentration of the final dried product (extract and excipient) is about 10-35% (w/w), or any amount therebetween. Thus the ginseng extract may comprise from about 10 to about 50% ginsenoside by weight, or any amount therebetween, for example, 10, 15, 20, 25, 30, 35, 40, 45, or 50% (w/w), or any amount therebetween.

[00070] The ginseng component for inclusion in the compositions typically comprises a total ginsenoside fraction of about 10 to about 50% (w/w), for example, between about 20 to about 50% (w/w). [00071] In certain embodiments, the total ginsenoside fraction of the ginseng component comprises the following concentrations of certain saponins: Rgl+Re: about 1-8% (w/w), or any amount therebetween, for example 1, 2, 3, 4, 5, 6, 7, 8% (w/w), or any amount therebetween, or about 4% (w/w); Rbl : about 5-10% (w/w), or any amount therebetween, for example, 5, 6, 7, 8, 9, 10%, or any amount therebetween, or about 4% (w/w); Rd: about 0.5%-8% (w/w), or any amount therebetween, for example, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0% (w/w), or any amount therebetween, or about 1%; Rc: from about 1 to about 8%, or any amount therebetween, for example, 1, 2, 3, 4, 5, 6, 7, 8% (w/w), or any amount therebetween, or about 2% (w/w). When the ginseng component comprises a ginseng extract, these saponins may be naturally present in the extract within the noted levels, or the ginseng component may comprise synthetic or isolated saponins in addition to the extract to ensure that each of the noted saponins is present within these ranges.

[00072] When an exemplary KDC extract and an exemplary ginseng extract are combined, the resulting composition synergistically enhances glucose uptake by C2C12 cells (see Example 4, Figures 2 and 3B). Thus, certain embodiments of the present invention provide a composition having blood glucose managing activity, wherein the composition is comprised of a KDC component, for example a KDC extract, or compounds found in KDC either isolated from a KDC extract or synthetically prepared, and a ginseng component, for example a ginseng extract, or compounds found in ginseng either isolated from an extract of same or synthetically prepared, wherein the KDC and ginseng components interact synergistically. The KDC component may comprise from about 1 to about 50% total saponins, or any amount therebetween, from about 0.1 to about 15% ursolic acid, or any amount therebetween, and from about 0.1 to about 10% chlorogenic acid, or any amount therebetween, for example. For example, the KDC extract may be the exemplary extract KDC-001 or other KDC extract comprising from about 1 to about 50% (w/w) saponins, from about 0.1 to about 2% (w/w) ursolic acid, from about 1 to about 5% (w/w) chlorogenic acid, and optionally from about 0.01 to about 0.1 % lupeol by weight. The ginseng extract may comprise from about 10 to about 50% (w/w) ginsenosides, or any amount therebetween, for example. For example, the ginseng extract may be the exemplary ginseng extract HT1001 or other ginseng extract that comprises about 20-50% ginsenosides by weight, or any amount therebetween, and may optionally be prepared by the method described above and in U.S. Patent No. 6,083,932. The ginseng extract may be blended during the drying process such that the final ginsenoside content is diluted; for example, the ginseng extract may be diluted such that the final product is comprised of about 10- 35% ginsenosides by weight, or any amount therebetween. In certain embodiments, the ginseng component comprises from about 1 to about 8% (w/w) Rgl+Re, or any amount therebetween, from about 5 to about 10% (w/w) Rbl, or any amount therebetween, from about 0.5 to about 8% (w/w) Rd, or any amount therebetween, and from about 1 to about 8% (w/w) Rc, or any amount therebetween

[00073] As shown herein, when a KDC extract and a ginseng extract are combined at between 25-75% (w/w) KDC extract, for example, at a 1 : 1 ratio (KDC extractginseng extract) by weight, the composition exhibits synergistic activity with respect to glucose uptake of C2C12 cells in vitro. Accordingly, in certain embodiments, the present invention provides a composition for managing (for example, lowering, regulating, or lowering and regulating) blood glucose levels in a subject, the composition comprising a KDC component and a ginseng component, as described in the preceding paragraphs, combined at between about 10-90% (w/w) of KDC extract, for example, between 25-75% (w/w) KDC extract, or 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95% (w/w) KDC extract, or any amount therebetween. In some embodiments, the KDC and ginseng components are combined at ratios of KDCginseng of between 1 :3 and 3: 1, for example, 0.5: 1, 1: 1, 1.5: 1, 2: 1, 2.5: 1, 3: 1, or any ratio therebetween. In some embodiments, the KDC extract may be the exemplary KDC extract KDC-001 or an extract substantially identical thereto, and/or the ginseng extract may be the exemplary ginseng extract HT1001 or an extract substantially identical thereto. The combination of KDC and ginseng components may exhibit additive, more than additive or synergistic activity with respect to glucose uptake of C2C12 cells in vitro. Thus in some embodiments, the compositions comprising the KDC and ginseng components exhibit synergistic activity with respect to glucose uptake of C2C12 cells in vitro. In certain embodiments, the compositions comprising the KDC and ginseng components exhibit additive or more than additive activity with respect to glucose uptake of C2C12 cells in vitro. Methods of assessing synergy and additive effects are well-known in the art and include those described in the Examples provided herein. Various pharmacological evaluations known in the art may be used to determine blood glucose managing activity (for example, blood glucose lowering, regulating, or lowering and regulating activity), and may be used to determine efficacy of the selected KDC component and ginseng component, for example, a batch of a KDC extract, a batch of a ginseng extract, or a combination of a KDC extract and a ginseng extract, or a sample of any of these extracts that may be produced during large scale manufacture. Batch-to-batch quality of a KDC extract, a ginseng extract, or a combination of a KDC extract and a ginseng extract may be verified for example by a Chemical and Biological fingerprinting method such as the method described in United States Patent No. 6,156,291. [00074] In addition, the present invention provides a composition comprising compounds found in KDC and ginseng extracts, for example, a composition comprising from about 1 to about 50% (w/w) total saponins, or any amount therebetween, from about 0.1 to about 15% (w/w) ursolic acid, or any amount therebetween, from about 0.1 to about 10% (w/w) chlorogenic acid, or any amount therebetween, from about 1 to about 8% (w/w) of Rgl+Re, or any amount therebetween, from about 5 to about 10% (w/w) Rbl, or any amount therebetween, from about 0.5 to about 8% (w/w) Rd, or any amount therebetween, and from about 1 to about 8% (w/w) Rc, or any amount therebetween. These compounds may be obtained from a KDC extract and from a ginseng extract as described herein, or purified and obtained from a KDC or ginseng plant or other plant sources, or obtained as synthetically prepared compounds, for example, they may be obtained from ChromaDex (Irvine, CA, USA) or Sigma Aldrich (St. Louis, MO, USA).

[00075] The present invention also provides a method of managing (for example, lowering, regulating, or lowering and regulating) blood glucose levels in a patient in need of such managing. The method comprising administering to the patient an effective dosage of a KDC component, for example, a KDC extract, or a composition comprising KDC and ginseng components, for example a KDC extract and a ginseng extract. The composition can be used where managing of blood glucose may be required, for example, but not limited to: Type 2 diabetes; metabolic syndrome; hyperglycemia, such as a subject with high baseline (fasted or non-fasted) glucose levels, high post prandial glucose levels, or both; a thyroid disorder; Cushing's disease; polycystic ovary syndrome; or abnormal glucose levels induced by a medication.

[00076] The present invention also provides a method of treating or preventing a condition associated with higher than normal blood glucose levels in a patient in need of such treatment or prevention by administering to the patient a composition comprising a KDC component, or a composition comprising a KDC component and a ginseng component as described above. Such conditions include, for example, but are not limited to: Type 2 diabetes; metabolic syndrome; hyperglycemia, such as a subject with high baseline (fasted or non-fasted) glucose levels, high post prandial glucose levels, or both; a thyroid disorder; Cushing's disease; polycystic ovary syndrome; or abnormal glucose levels induced by a medication. In certain embodiments, the method comprises administering to the patient an effective dosage of a KDC extract or a composition comprising a KDC extract and a ginseng extract.

[00077] The present invention is also directed in some embodiments to a composition for managing (for example, lowering, regulating, or lowering and regulating) blood glucose levels comprising a ginseng extract and a KDC extract. Some embodiments include the preparation of a medicament or a pharmaceutical composition comprising a composition comprising KDC and ginseng components, a pharmaceutically acceptable carrier, and optionally other pharmaceutically active agents. Those skilled in the art are familiar with pharmaceutically acceptable carriers that would be useful in this regard, and therefore the procedure for making pharmaceutical compositions in accordance with the invention will not be discussed in detail. Suitably, the pharmaceutical compositions may be in the form of tablets, capsules, liquids, lozenges, lotions, aerosol, and solutions suitable for various routes of administration including, but not limited to, orally, via injection or infusion, intraperitoneally, topically, nasally, ocularly, vaginally or rectally, in solid, semi-solid or liquid dosage forms as appropriate and in unit dosage forms suitable for easy administration of fixed dosages.

[00078] Also provided is a food, nutraceutical or supplement, having blood glucose managing activity, comprising KDC and ginseng components. The KDC component may be one or more parts of a KDC plant, a KDC extract, or both a part of the KDC plant and a KDC extract, or obtained as synthetically produced compounds, or compounds isolated and purified from a KDC plant or a KDC extract, for example, compounds commercially available from Sigma-Aldrich or ChromaDex, and the ginseng component may be one or more parts of a ginseng plant, a ginseng extract, or both a part of the ginseng plant and a ginseng extract, or obtained as synthetically produced compounds, or compounds isolated and purified from a ginseng plant or a ginseng extract, for example, but not limited to, compounds available from ChromaDex. In certain embodiments, the food, nutraceutical or supplement may be characterized as comprising a composition comprising from about 0.1 to about 15% ursolic acid, or any amount therebetween, from about 1 to about 50% total saponins, or any amount therebetween, from about 0.1 to about 10% (w/w) chlorogenic acid, or any amount therebetween, from about 1 to about 8% (w/w) of Rgl+Re, or any amount therebetween, from about 5 to about 10% (w/w) Rbl, or any amount therebetween, from about 0.5 to about 8% (w/w) Rd, or any amount therebetween, and from about 1 to about 8% (w/w) Rc, or any amount therebetween.

[00079] In certain embodiments, the composition comprising a KDC component or KDC and ginseng components may be formulated for oral administration. For the purpose of oral administration, the KDC component or extract, the ginseng component or extract, a composition comprising KDC and ginseng components, or a composition comprising KDC and ginseng extracts, can be incorporated with excipients and used in the form of tablets, troches, or capsules, e.g., gelatin capsules. The oral compositions can include an inert diluent or an edible carrier. Oral compositions can also be prepared using a fluid carrier. Pharmaceutically compatible binding agents or other carrier materials can be included as part of the composition. Such binding agents and carriers can be a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, or gelatinized starch; a lubricant such as magnesium stearate; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent. Other suitable agents, carriers and combinations are known in the art.

[00080] Systemic administration may be for example by transmucosal or transdermal means. For transmucosal or transdermal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art. Transmucosal administration can be accomplished through the use of nasal sprays, suppositories or retention enemas for rectal delivery. The suppositories can include conventional suppository bases such as cocoa butter and other glycerides. For transdermal administration, the active compounds are formulated into ointments, salves, gels, or creams as generally known in the art.

[00081] Diverse solid, semi-solid or liquid food items may be prepared to include the KDC component, the ginseng component, or the composition comprising KDC and ginseng components, as active ingredients. Non-limiting examples of such food items include cereal, pasta, confectionery products (for example, cookies, cakes, caramels, gum, hard candies), nutrition, snack or meal replacement bars, yogurt, gelatin, jam, puddings, soups, a base of fruits or vegetables, beverages (for example, juices, soft drinks, sports energy drinks, bottled water, milk, soy products), and child and infant foods (for example, infant formulas, modified milk powder, baby food). Further, the KDC component, the ginseng component, or the composition comprising KDC and ginseng component, may be used as active ingredients in functional foods, nutraceuticals, or dietary supplements.

[00082] Under some conditions, formulations comprising KDC components, ginseng components, or KDC and ginseng components may lose some activity with aging and are thus in some embodiments are either prepared in stable forms, or prepared fresh for administration, for example as a multicomponent kit and mixed prior to use so as to avoid aging and to maximize the effectiveness of the various components. Suitable kits or containers are well known for maintaining the phases of formulations separate until the time of use. For instance, a kit containing a KDC component, a ginseng component, or both a KDC component and a ginseng component, in powder or liquid form, may be packaged separately from a sterile carrier such as saline solution, alcohol or water, and possibly other ingredients in dosage specific amounts for mixing at the time of use. The KDC component, the ginseng component, or both the KDC and ginseng components may be provided in a "tea bag"- type infuser, pouch or sachet, for generating liquid formulations at the time of use. The tea bag-type infuser is advantageous in that the pouch may serve as a filter for small particulates of the powder that may be detrimental with certain types of administration (for example, via injection or infusion). Particulates may also be removed by for example, filtration. In addition, the components may be blended or combined with a preserving agent to retard any loss of activity.

[00083] Dosages of the compositions in accordance with the invention depend upon the particular condition to be treated, as well as the age, sex and general health condition of the patient. However, by way of example, suitable dosages for a KDC extract may be found in the range between about 100 mg and about 3000 mg per day for a patient of average body weight (70 kg), or any amount therebetween, for example 100, 125, 150, 175, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1200, 1500, 1750, 2000, 2250, 2500, 2750, 3000 mg per day, or any amount therebetween. Suitable dosages for a combination of KDC extract and ginseng extract may be found in the range between about 100 mg and about 3000 mg per day for a patient of average body weight (70 kg), or any amount therebetween, for example 100, 125, 150, 175, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1200, 1500, 1750, 2000, 2250, 2500, 2750, 3000 mg per day, or any amount therebetween. The KDC extract, the ginseng extract or the combination of KDC and ginseng extracts may be administered orally, via injection or infusion, topically, nasally, ocularly, vaginally or rectally.

[00084] To gain a better understanding of the invention described herein, the following examples are set forth. It will be understood that these examples are intended to describe illustrative embodiments of the invention and are not intended to limit the scope of the invention in any way.

EXAMPLES

Example 1 - Preparation and Compositional Analysis of KDC Extracts.

[00085] What follows is a description of an exemplary method of preparing the

KDC extract, KDC-001 (entry 4 in Table 5 below), alterations and modifications to the following procedure such as altering the temperature, solvent volume, ratio of alcohol, heating time, separation methods and drying methods can be made and would be apparent to those skilled in the art.

[00086] KDC leaves harvested from mature Ilex kudingcha trees grown in South China were dried and milled to yield a KDC powder. The KDC powder (10 g) is combined with 100 ml of a 70 % ethanol solution (aqueous) and heated to about 78 °C for about 2 h at which point the slurry is filtered to obtain a solid and a supernatant. The supernatant is concentrated by vacuum distillation then freeze-dried to yield a powdered KDC extract, KDC-001. HPLC analysis reveals that KDC-001 is comprised of about 1-50% saponins, 0.1-2% ursolic acid, 0.01-0.1 % lupeol and about 1-5% chlorogenic acid by weight.

[00087] Compositional analysis of a number of KDC extracts were conducted by standard HPLC methods that are well-known to those skilled in the art. Saponin content analysis can be conducted by HPLC-UV. Briefly, 250 mg of KDC extract is added to 25 mL of an aqueous methanol solution consisting of 70% methanol. The resulting slurry is shaken for 30 minutes. A 3 mL aliquot of the supernatant obtained from either extraction procedure was centrifuged for 5 min at 3000 rpm. From the clarified supernatant an aliquot of 0.9 mL is taken for analysis by the HPLC system consisting of an Agilent HP 1100 series HPLC coupled to an ultraviolet detector and equipped with an auto-injector. The column consists of a C₁₈ reverse phase column (250 mm x 4.6 mm). Separation is achieved using the gradient elution conditions given in Table 2. UV absorbance for detection is 208 nm.

TABLE 2. Gradient elution conditions for HPLC separation and quantification of KDC saponins

[00088] The content of chlorogenic acid was quantified by HPLC-UV chromatography and the use of calibration standards. Analysis samples are prepared by agitating 5 mg of the KDC extract with 1 mL of 70% v/v methanol in water. The resultant mixture is clarified by centrifugation and the supernatant is used for analysis. For HPLC, a Synergi Polar-RP column (4.6 x 150 mm), maintained at 25°C, is connected to an Agilent HP 1100 series or equivalent HPLC system, equipped with UV detector. The sample and calibration standards are eluted with the mobile phase gradient and flow rate as shown below, and detected with UV absorbance of 330 nm.

TABLE 3. Gradient elution conditions for HPLC separation and quantification of chlorogenic acid in KDC

Mobile phase A: 0.5% formic acid in water

Mobile phase B: 10:8:3 tetrahydrofuran- isopropyl alcohol- acetonitrile Time (minutes) Mobile phase composition Flow rate

0.0 95.0% A/5.0% B 1.0

30.0 87.0% A/13.0% B 1.0

[00089] The contents of betulin, betulinic acid, ursolic acid and lupeol were also analyzed by HPLC chromatography and calibration standards. Analysis samples are prepared by agitating 10 mg of KDC extract with 1 mL of methanol. For HPLC, a Cis reverse phase column, maintained at 30°C, is connected to an Agilent 1100 series or equivalent HPLC system, equipped with a UV detector. The sample and calibration standards are eluted with the mobile phase gradient and flow rate shown below (Table 4) and detected with UV absorbance of 210 nm.

TABLE 4. Gradient elution conditions for HPLC separation and quantification of betulin, betulinic acid, ursolic acid and lupeol in KDC

Mobile phase A: 10 mM ammonium formate in water

Mobile phase B: Methanol

[00090] The extracts were prepared by the above method as well as alternative methods based on this method in which the solvent was changed or modified. The results are given in Table 5 below. Entry 4 in Table 5 corresponds to the KDC extract, KDC-001, prepared by the method described above. TABLE 5. Chemical composition of KDC extracts prepared using different alcohol solution concentrations or neat alcohol.

Concentrations are given in as % by weight, error (in brackets) is provided as standard error. (ND = not detected)

Example 2 - Effect of a KDC Extract on Glucose Uptake in a Model of Skeletal Muscle Cell Glucose Handling

[00091] The ability of various doses of the KDC extract KDC-001 to modulate skeletal muscle glucose uptake was investigated. Glucose uptake was measured utilizing C2C12 murine skeletal myotubes derived from C2C12 myoblasts.

[00092] Without wishing to be bound by theory, skeletal muscles play an important role in the maintenance of whole body glucose homeostasis. Uptake of glucose in these cells takes place by facilitated diffusion and this process is stimulated by insulin and is mediated by specific glucose transporters, primarily GLUT4.¹⁴ C2C12 is a mouse myoblast cell line derived from thigh muscles of C3H mice. Upon treatment with horse serum, this cell line differentiates rapidly to produce myotubes. Differentiated C2C12 myotubes have been found to contain basic GLUT4 translocation machinery that can be activated by insulin. These cells are also responsive to insulin- induced expression of hexokinase 2. These properties make the C2C12 cell line a good model for studies pertaining to glucose uptake in skeletal muscles.

[00093] Myoblasts were maintained in DMEM supplemented with 10% fetal bovine serum and 1% antibiotic. At 80% confluency, cells were detached by trypsinization and then seeded at a density of lxl 0⁵ cells/ well with 1 ml of DMEM supplemented with 10% FBS in a 12-well plate. Following 24 hours incubation, the medium was changed to DMEM containing 2% horse serum to facilitate differentiation of myoblasts to myotubes. Differentiation occurred in approximately 6 days and during this period medium was changed every other day. The differentiated C2C12 myotubes were either treated with 10 uL aliquots of the test solutions of KDC-001 or metformin (used as a positive control) or untreated (used as negative control) for 20 hours. During the last 3 hours of treatment, the medium containing the test compound was replaced with serum-free DMEM. The cells were then washed with glucose-free Krebs- phosphate buffer (KPB) and then were treated with 0.5 μθί/ιηΐ of 2-deoxy-D-glucose- [³H] prepared in KPB for 10 minutes at 37°C. The plate was then placed on ice and cells were immediately washed twice with ice-cold KPB. Cells were then lysed with 1 ml of 0.1 M NaOH for 30 min at room temperature and were subsequently harvested by scraping. The cell lysate was transferred to a scintillation vial and was counted for ³H in a liquid scintillation counter. ³H count represents cellular glucose content. Glucose uptake was increased in a concentration dependent manner over control (untreated cells) (Figure 1). Data are shown as percentage of control with a small increase at 25 μg/ml KDC extract, a significant increase at all concentrations above 100 μg/ml, and maximal increase at 200 μg/ml. Concentrations of 100 μg/ml KDC extract and above demonstrated an increase in glucose uptake equivalent and possibly better than Metformin at 700μΜ.

Example 3 - Preparation of a Ginseng Extract

[00094] The method to prepare the exemplary ginseng extract HT1001, is provided in U.S. Patent No. 6,083,932. Briefly, 300 kg of dried ginseng root is used as a starting material. The dried ginseng may be grown in North America, for example the ginseng may be Panax quinquefolius, and may be over three years of age prior to harvest. The ginseng is placed into a Fitz mill and milled to about between 20 and 80 mesh and then subjected to an extraction process using an 85% aqueous ethanol solution using a solid: solvent ratio of 1 :8 (w/w). Extraction proceeds for three hours at a temperature of about between 90-95°C with stirring. The liquid and solid phases are separated by decanter centrifuge at a speed of about 4200 rpm using a 25 micron in-line cartridge filter in the output line (at back drive speed of about 30 rpm). If a number of extractions are done, the supernatants can be pooled. The supernatant (or pooled supernatants) is concentrated by vacuum distillation and the ethanol recovered. The target solution is characterized by a solid content of about 10-12° (Brix) and a solution density of about 1.15-1.25. The concentrated ethanol solution is spray dried at a feed temperature of about 40-60 °C and a feed rate of about 20 kg/h with an inlet temperature of about 150-175 °C, and the outlet temperature is about 70-90 °C to produce the ginseng extract. The extract may be milled using a Fitz mill fitted with a 0.065 inch screen and milled to about 80 mesh. The ginseng extract comprises a total saponins (ginsenoside) fraction of about 20-50% by weight of the ginseng extract. To aid in the spray drying process a pharmaceutically acceptable excipient is added to the concentrated extract before drying such that the final total saponins fraction is about 10-35% by weight of the ginseng extract and excipient. The excipient may be selected from rice starch, maltodextrin or other suitable excipients as are known in the art. If an excipient is added, the extract is blended to produce a yield of about 20% (w/w) ginseng extract.

[00095] The total ginsenoside fraction comprises the following concentrations of certain saponins: Rgl+Re: about 4%; Rbl : about 4%; Rd: about 1%; Rc: about 2%.

[00096] Chemical analyses are conducted by chromatographic separation by HPLC column, followed by detection using an UV absorbance detector and then electrospray mass spectrometry. Briefly, 1.0 g of ginseng extract was added to 50 ml of an aqueous methanol solution consisting of 70% methanol. The resulting slurry was shaken for 30 minutes. In an alternative method, 1.0 g of ginseng extract was added to 35 mL of methanol, shaken for 15 minutes, then an additional 15 mL of water was added, and the mixture was shaken for an additional 15 minutes. A 3 mL aliquot of the supernatant obtained from either extraction procedure was centrifuged for 5 min at 3000 rpm. From the clarified supernatant an aliquot of 0.5 mL was taken for analysis by the HPLC system consisting of an Agilent HP 1100 series HPLC coupled to an ultraviolet detector and equipped with an auto-injector. The column consisted of a C₁₈ reverse phase column (250 mm x 4.6 mm). Separation was achieved using the gradient elution conditions given in Table 6.

TABLE 6. Gradient elution conditions for HPLC separation and quantification of ginsenosides

[00097] A post time of 5 min was performed prior to each sample injection.

Ultraviolet detection was monitored at 208 nm with a bandwidth of 8 nm. Electrospray mass spectroscopy was performed using a Fisons Instruments VG Quatro instrument. Following elution from the ultraviolet absorbance detector, the flow from the HPLC equipment was split and 2% (30 μΐ/minute) was diverted into the mass spectrometer and ionization was achieved by electrospray. Chemicals eluting from the HPLC instrument were monitored in positive mode for mass between 200 and 1200 molecular weight. A number of chemicals provided mass spectra characteristic of the ginseng extract. A number of the chemicals provided mass spectra characteristics of the ginseng extract. Chemical and Biological fingerprinting (such as the method described in United States Patent No. 6,156,291, may be used to verify the chemical consistency of the ginseng extract.

Example 4 - Synergism of KDC and Ginseng in a Model of Skeletal Muscle Glucose Handling

Non-Linear Blending

[00098] Synergism between components may be quantified in a number of ways.

One such method is the establishment of a non-linear blending curve which can be applied to an empirical (or mechanistic) response curve to establish synergism. If synergism exists, the empirical (or mechanistic) response curve will be non-linear whereas the predicted additive response curve is linear. Non-linear blending profiles help to establish the most appropriate proportions to blend the various components of the complex composition to achieve the desired effect. Peterson and Novick have provided a complete description of non-linear blending for assessing combination drug synergy¹⁵ and thus non-linear blending is a method known to those skilled in the art and will not be extensively described.

[00099] The glucose uptake assays were performed as described in Example 2 using C2C12 myotubes derived from C2C12 myoblasts. Synergism between components of the two extracts was established by non-linear blending. Briefly, in a two component non-linear blending experiment the total amount of active component is kept constant while varying the proportions of the two components or extracts. The KDC and ginseng extracts were prepared as described in Examples 1 and 3, respectively. In this example, the concentration of active ingredients (KDC extract and ginseng extract) in the test sample was always made up to 100 μg/mL and the partial concentrations of the KDC extract and ginseng extract were varied between 0 - 100% such that:

[ginseng] + [KDC] = 100 ug/mL [000100] For example, for a sample containing 10% KDC extract the partial concentration of the KDC extract would be 10 μg/mL and the partial concentration of HT1001 would be 90 μg/mL. Compositions were prepared using varying proportions of the two extracts ranging from 100% KDC extract (using the KDC extract KDC-001 prepared by the method described in Example 1 above) to 100% ginseng extract (using the ginseng extract HT1001 prepared by the method described in Example 3). Figure 2 illustrates the glucose uptake response of the compositions and compares the experimental data to the expected linear additive response. At relative concentrations of about 25% to about 75% KDC extract (i.e. ratios of KDC extractginseng extract of 1 :3 to 3: 1), synergistic interactions were observed for the multi-component compositions, with maximal synergistic interactions for a composition comprised of equal amounts of the KDC extract and HT1001. The observation of a non-linear blending curve confirms the synergistic interaction between the KDC extract and the ginseng extract with respect to glucose uptake.

Isobologram

[000101] Another method of establishing the presence and degree of synergy between components of a bio-active composition is isobologram analysis.¹⁶ This methodology involves graphical presentation (see Figure 3A) of specific responses, usually based on the EC5₀ of various drug combinations. The EC5₀ is defined as the concentration of the drug (or extract, etc.) that produces a response halfway between baseline and the maximum response. If the isobologram produced from the experimental data bows downwards, it represents synergy; if it is a straight line it indicates additive interactions and if it bows upwards it represents antagonism (see Figure 3A).

[000102] The EC₅₀ values of KDC-001 and HTIOOI extracts, alone and in combination with regards to induction of glucose uptake by C2C12 myotubes are given in the Table 7 below.

TABLE 7. EC50 values obtained for various ratios of HTIOOI and KDC-001

[000103] The EC₅₀ values of the KDC-001 and HT 1001 extracts alone were found to be 131.2 and 274.6 ug/mL, respectively. To test the synergy of the combination, the concentration of KDC-001 was kept constant at 25, 50 or 75 ug/mL and the concentration of HT 1001 was varied to reach the EC50. Assuming an additive interaction between the two extracts, the predicted concentrations of HTIOOI required to reach the EC5₀ would be 222.7, 170.7, and 118.8 ug/mL, respectively. However, the actual concentrations of HT1001 required were 192.8., 114.1 and 109.9 ug/mL respectively. The corresponding EC5₀ values for the combined extracts are shown in Table 7. An isobologram of this experiment is illustrated in Figure 3B. Upon examination of Figure 3B it is clear that the isobologram curve bows downwards which indicates that KDC-001 and HT 1001 interact synergistically in enhancing glucose uptake by C2C12 cells.

Combination Index

[000104] A third method of establishing synergy is the calculation of the Combination Index (CI). Similar to isobologram analysis, CI provides quantitative information of the nature of drug interaction. It is calculated through the following equation:

CI = (CA,X / ICX,_A) + (CB,X / ICX,B) where, CA,X and CB,X, are the concentrations of drug A and drug B used in the combination to achieve x% drug effect. ICX_;A and ICX_;B are the concentrations for single agents to achieve the same effect. A CI of less than, equal to, or greater than 1 indicates synergy, additivity, and antagonism, respectively.

[000105] Based on the data presented in Table 7 above, for compositions containing KDC-001 concentrations of 25, 50 and 75 ug/mL, the CIs have been calculated to be 0.84, 0.81 and 0.97, respectively. The establishment of CI values of less than 1 once again supports the presence of synergistic interactions between the two extracts, KDC-001 and HTlOOl .

[000106] The disclosures of all patents, patent applications, publications and database entries referenced in this specification are hereby specifically incorporated by reference in their entirety to the same extent as if each such individual patent, patent application, publication and database entry were specifically and individually indicated to be incorporated by reference.

[000107] Although the invention has been described with reference to certain specific embodiments, various modifications thereof will be apparent to those skilled in the art without departing from the spirit and scope of the invention. All such modifications as would be apparent to one skilled in the art are intended to be included within the scope of the following claims.

References

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2. Jia, L.; Zhao, Y.; Liang, X. J. Current evaluation of the millennium phytomedi cine- ginseng (II): Collected chemical entities, modem pharmacology, and clinical applications emanated from traditional Chinese medicine. Curr Med Chem 2009, 16 (22), 2924-2942.

3. Negishi, O.; Negishi, Y.; Yamaguchi, F.; Sugahara, T. Deodorization with ku-ding- cha containing a large amount of caffeoyl quinic acid derivatives. J. Agric. Food Chem. 2004, 5^ (17), 5513-5518. 4. Nishimura, K.; Miyase, T.; Noguchi, H. Triterpenoid saponins from Ilex kudincha. J. Nat. Prod. 1999, 62 (8), 1128-1133.

5. Liu, S.; Qin, Y.; Du, F. L. [Studies on chemical constituents in leafs of Ilex kudingcha]. Zhongguo Zhong. Yao Za Zhi. 2003, 28(9), 834-836.

6. Zollner Handbook of Enzyme Inhibitors; Wiley -VCH: Weinheim, Germany, 1999. 7. Jung, S. H.; Ha, Y. J.; Shim, E. K.; Choi, S. Y.; Jin, J. L.; Yun-Choi, H. S.; Lee, J. R. Insulin-mimetic and insulin-sensitizing activities of a pentacyclic triterpenoid insulin receptor activator. Biochemical Journal 2001 , 403, 243-250.

8. Hemmerle, H.; Burger, H. J.; Below, P.; Schubert, G.; Rippel, R.; Schindler, P. W.; Paulus, E.; Herling, A. W. Chlorogenic acid and synthetic chlorogenic acid derivatives: Novel inhibitors of hepatic glucose-6-phosphate translocase. Journal of Medicinal Chemistry 1997, 40 (2), 137-145. 9. Kurukulasuriya, R.; Link, J. T.; Madar, D. J.; Pei, Z.; Richards, S. J.; Rohde, J. J.; Souers, A. J.; Szczepankiewicz, B. G. Potential drug targets and progress towards pharmacologic inhibition of hepatic glucose production. Current Medicinal Chemistry 2003, 10 (2), 123-153. 10. Bassoli, B. K.; Cassolla, P.; Borba-Murad, G. R.; Constantin, J.; Salgueiro- Pagadigorria, C. L.; Bazotte, R. B.; da Silva, R. S. D. F.; de Souza, H. M. Chlorogenic acid reduces the plasma glucose peak in the oral glucose tolerance test: effects on hepatic glucose release and glycaemia. Cell Biochemistry and Function 2008, 26 (3), 320-328. 11. Prabhakar, P. K.; Doble, M. Synergistic effect of phytochemicals in combination with hypoglycemic drugs on glucose uptake in myotubes. Phytomedicine. 2009, 16 (12), 1119-1126.

12. Tousch, D.; Lajoix, A. D.; Hosy, E.; Azay-Milhau, J.; Ferrare, K.; Jahannault, C; Cros, G; Petit, P. Chicoric acid, a new compound able to enhance insulin release and glucose uptake. Biochem. Biophys. Res. Commun. 2008, 577(1), 131-135.

13. American Diabetes Association . Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 29[suppl 1], s43-s48. 2006.

14. Nedachi, T.; Kanzaki, M. Regulation of glucose transporters by insulin and extracellular glucose in C2C12 myotubes. Am. J. Physiol Endocrinol. Metab 2006, 291 (4), E817-E828.

15. Peterson, J. J.; Novick, S. J. Nonlinear blending: a useful general concept for the assessment of combination drug synergy. J. Recept. Signal. TransducL Res. 2007 ^', 27 (2-3), 125-146.

16. Chou, T. C. Theoretical basis, experimental design, and computerized simulation of synergism and antagonism in drug combination studies. Pharmacological Reviews

2006, 58(3), 621-681.

Claims

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

A composition comprising a Ku Ding Cha (KDC) component and a ginseng component, wherein the KDC component comprises one or more parts of a KDC plant, a KDC extract, one or more compounds found in KDC, or a combination thereof, and the ginseng component comprises one or more parts of a ginseng plant, a ginseng extract, one or more compounds found in ginseng, or a combination thereof.

The composition according to claim 1, wherein the KDC component is a KDC extract.

The composition according to claim 2, wherein the KDC extract is an alcoholic or aqueous alcoholic extract.

The composition according to any one of claims 1-3, wherein the KDC component comprises a total saponin content of about 1% to about 50% (w/w).

The composition according to any one of claims 1-4, wherein the KDC component comprises ursolic acid in an amount from about 0.1% to about 15% (w/w).

The composition according to any one of claims 1-5, wherein the KDC component comprises chlorogenic acid in an amount from about 0.1% to about 10% (w/w).

The composition according to any one of claims 1-6, wherein the ginseng component is from Panax quinquefolius.

The composition according to any one of claims 1-7, wherein the ginseng component is a ginseng extract.

The composition according to claim 8, wherein the ginseng extract is an alcoholic or aqueous alcoholic extract.

10. The composition according to any one of claims 1-9, wherein the ginseng component comprises a total ginsenoside fraction of about 10% to about 50% (w/w).

11. The composition according to any one of claims 1-10, wherein the ginseng component comprises a total ginsenoside fraction of about 20% to about 50%

(w/w).

12. The composition according to any one of claims 1-11, wherein the ginseng component comprises Rgl+Re in an amount between about 1% and about 8% (w/w), Rbl in an amount between about 5% and about 10% (w/w), Rd in an amount between about 0.5% and about 8% (w/w), and Rc in an amount between about 1% and about 8%.

13. The composition according to any one of claims 1-12, wherein the KDC component and the ginseng component are present in a ratio of about 1 :3 to 3: 1.

14. The composition according to any one of claims 1-12, wherein the KDC component and the ginseng component are present in a ratio of about 1 : 1.

15. The composition according to any one of claims 1-14, wherein combination of the KDC component and the ginseng component exhibits additive, more than additive or synergistic activity with respect to glucose uptake of C2C12 cells in vitro.

16. A composition according to any one of claims 1-15 for use to manage blood glucose levels in a subject in need thereof.

17. Use of the composition according to any one of claims 1-15 for managing blood glucose levels in a subject in need thereof.

18. Use of the composition according to any one of claims 1-15 in the manufacture of a medicament, nutraceutical or supplement, for managing blood glucose levels in a subject.

19. A composition according to any one of claims 1-15 for use to treat a condition associated with higher than normal blood glucose levels in a subject in need thereof.

20. Use of the composition according to any one of claims 1-15 for treating condition associated with higher than normal blood glucose levels in a subject need thereof.

21. Use of the composition according to any one of claims 1-15 in the manufacture of a medicament, nutraceutical or supplement, for treating a condition associated with higher than normal blood glucose levels.

22. The composition according to claim 19, or the use according to claim 20 or 21, wherein the condition associated with higher than normal blood glucose levels is Type 2 diabetes, metabolic syndrome, hyperglycemia, a thyroid disorder, Cushing's disease, polycystic ovary syndrome, or abnormal glucose levels induced by a medication.

23. A method for managing blood glucose levels in a subject in need thereof comprising administering to the subject an effective amount of the composition according to any one of claims 1-15. 24. A method for treating a condition associated with higher than normal blood glucose levels in a subject in need thereof, comprising administering to the subject an effective amount of the composition according to any one of claims 1- 15.

25. The method according to claim 24, wherein the condition associated with higher than normal blood glucose levels is Type 2 diabetes, metabolic syndrome, hyperglycemia, a thyroid disorder, Cushing's disease, polycystic ovary syndrome, or abnormal glucose levels induced by a medication.

26. A composition comprising a Ku Ding Cha (KDC) component for use to manage blood glucose levels in a subject in need thereof, wherein the KDC component comprises one or more parts of a KDC plant, a KDC extract, one or more compounds found in KDC, or a combination thereof.

27. A composition comprising a Ku Ding Cha (KDC) component for use to treat a condition associated with higher than normal blood glucose levels in a subject in need thereof, wherein the KDC component comprises one or more parts of a KDC plant, a KDC extract, one or more compounds found in KDC, or a combination thereof.

28. Use of a composition comprising a Ku Ding Cha (KDC) component for managing blood glucose levels in a subject in need thereof, wherein the KDC component comprises one or more parts of a KDC plant, a KDC extract, one or more compounds found in KDC, or a combination thereof.

29. Use of a composition comprising a Ku Ding Cha (KDC) component for treating a condition associated with higher than normal blood glucose levels in a subject in need thereof, wherein the KDC component comprises one or more parts of a KDC plant, a KDC extract, one or more compounds found in KDC, or a combination thereof.

30. Use of a composition comprising a Ku Ding Cha (KDC) component in the manufacture of a medicament, nutraceutical or supplement, for managing blood glucose levels in a subject in need thereof, wherein the KDC component comprises one or more parts of a KDC plant, a KDC extract, one or more compounds found in KDC, or a combination thereof.

31. Use of a composition comprising a Ku Ding Cha (KDC) component in the manufacture of a medicament, nutraceutical or supplement, for treating a condition associated with higher than normal blood glucose levels in a subject, wherein the KDC component comprises one or more parts of a KDC plant, a

KDC extract, one or more compounds found in KDC, or a combination thereof.

32. The composition according to claim 27, or the use according to claim 29 or 31, wherein the condition associated with higher than normal blood glucose levels is Type 2 diabetes, metabolic syndrome, hyperglycemia, a thyroid disorder, Cushing's disease, polycystic ovary syndrome, or abnormal glucose levels induced by a medication.

33. The composition according to any one of claims 26, 27 and 32, or the use according to any one of claims 28-32, wherein the KDC component is a KDC extract.

34. The composition according to claim 33, or the use according to claim 33, wherein the KDC extract is an alcoholic or aqueous alcoholic extract.

35. The composition according to any one of claims 26, 27 and 32-34, or the use according to any one of claims 28-34, wherein the KDC component comprises a total saponin content of about 1% to about 50% (w/w).

36. The composition according to any one of claims 26, 27 and 32-35, or the use according to any one of claims 28-35, wherein the KDC component comprises ursolic acid in an amount from about 0.1% to about 15% (w/w).

37. The composition according to any one of claims 26, 27 and 32-36, or the use according to any one of claims 28-36, wherein the KDC component comprises chlorogenic acid in an amount from about 0.1% to about 10% (w/w).

38. A method for managing blood glucose levels in a subject in need thereof comprising administering to the subject an effective amount of a composition comprising a Ku Ding Cha (KDC) component for treating a condition associated with higher than normal blood glucose levels in a subject in need thereof, wherein the KDC component comprises one or more parts of a KDC plant, a KDC extract, one or more compounds found in KDC, or a combination thereof.

39. A method for treating a condition associated with higher than normal blood glucose levels in a subject in need thereof, comprising administering to the subject an effective amount of a composition comprising a Ku Ding Cha (KDC) component for treating a condition associated with higher than normal blood glucose levels in a subject in need thereof, wherein the KDC component comprises one or more parts of a KDC plant, a KDC extract, one or more compounds found in KDC, or a combination thereof. 40. The method according to claim 39, wherein the condition associated with higher than normal blood glucose levels is Type 2 diabetes, metabolic syndrome, hyperglycemia, a thyroid disorder, Cushing's disease, polycystic ovary syndrome, or abnormal glucose levels induced by a medication.

41. The method according to any one of claims 38-40, wherein the KDC component is a KDC extract.

42. The method according to claim 41, wherein the KDC extract is an alcoholic or aqueous alcoholic extract. 43. The method according to any one of claims 38-42, wherein the KDC component comprises a total saponin content of about 1% to about 50% (w/w).

44. The method according to any one of claims 38-43, wherein the KDC component comprises ursolic acid in an amount from about 0.1% to about 15% (w/w).

45. The method according to any one of claims 38-44, wherein the KDC component comprises chlorogenic acid in an amount from about 0.1% to about 10% (w/w).