WO2008142702A1

WO2008142702A1 - A synergistic ayurvedic / functional food bioactive composition [cincata]

Info

Publication number: WO2008142702A1
Application number: PCT/IN2007/000264
Authority: WO
Inventors: Villoo Morawala-Patell; Rajesh Ullanat; Ashok Mundrigi; Jagadeesh Badamaranahalli Henjarappa; Chandramohan Bangalore Siddaiah
Original assignee: Avesthagen Limited
Priority date: 2007-05-23
Filing date: 2007-06-29
Publication date: 2008-11-27
Also published as: EP2152284A4; EP2152284A1

Abstract

The present invention relates to a synergistic ayurvedic / functional food bioactive composition for managing diabetes and related disorders, said composition comprising extracts of atleast two plants selected from a group comprising Eugenia, Cinnamomum and Salacia optionally alongwith pharmaceutically acceptable excipients; a process for preparation of a synergistic ayurvedic / functional food bioactive composition for treating diabetes and related disorders, and a method of treating diabetes and/or related disorders in a subject in need thereof by administering the composition comprising extracts of atleast two plants selected from a group comprising Eugenia, Cinnamomum and Salacia optionally alongwith pharmaceutically acceptable excipients to the subject.

Description

A SYNERGISTIC AYURVEDIC / FUNCTIONAL FOOD BIOACTIVE

COMPOSITION (CINCATA)

FIELD OF THE INVENTION The invention relates to clinically safe and non-toxic plant extract mixtures useful for the treatment of diabetes and related disorders. The invention also relates to plant extract mixtures containing a synergistic mix of plant extracts useful in the treatment of diabetes and related disorders. In particular, the invention relates to an easily administrable synergistic mixture of extracts obtained from plant parts of Eugenia sp., Cinnamon sp. and Salacia sp. with an improved efficacy for the treatment of diabetes and related disorders. The invention further discloses mixtures of plant extracts with improved organoleptic properties. The invention thereafter discloses easily administrable mixture of plant extracts, which can be safely administered both to children and adults. Also, the invention discloses a process for the preparation of the instant mixture of plant extracts wherein each of the particular plant extract is added in a predetermined and justified ratio.

BACKGROUND OF THE INVENTION Diabetes mellitus, commonly referred to as diabetes, is a medical condition associated with abnormally high levels of glucose (or sugar) in the blood (hyperglycemia). Normally, blood glucose levels are tightly controlled by insulin, a chemical signalling substance (hormone) that is produced by a gland near the stomach called the pancreas. Insulin helps lower the blood glucose level and stimulates the body to make use of glucose. When the amount of glucose in the blood increases, for example, after eating food, insulin is released from the pancreas to normalise the glucose level. However, in patients with diabetes mellitus, the elevated glucose levels cannot be normalised. This causes abnormally high levels of blood glucose, which ultimately leads to the presence of glucose in the urine (glucosuria). The disease can be divided into two major subclasses: insulin-dependent diabetes mellitus (IDDM), also known as type I diabetes, and non-insulin-dependent diabetes mellitus (NIDDM), also known as type II diabetes. IDDM results from insulin deficiency caused by cell-mediated autoimmune destruction of pancreatic beta cells, and generally develops in the young. IDDM accounts for approximately 10-15% of the diabetic population worldwide. In contrast, NIDDM results from a variable combination of insulin resistance and insulin deficiency and generally develops in adults. However, NIDDM can also develop at a younger age. NIDDM accounts for over 85% of the diabetic population worldwide. Complications of disease diabetes mellitus involves many organ systems of the human body leading to many systemic complications like Diabetic Neuropathy, Diabetic Diarrhea, Urinary retention, Gustatory Swelling, Papillary Reflexes, Cardiac Autonomic Disturbances, Collagen Disturbances, thickening of capillary basement membrane, increase in vessel wall matrix and cellular proliferation resulting in vascular complications like lumen narrowing, early atherosclerosis, sclerosis of glomerular capillaries, retinopathy, neuropathy and peripheral vascular insufficiency. Of these disorders Diabetic Neuropathy is the most common and affects patients at earlier stages. As such, there is no drug available for the treatment of these diabetic complications. Diabetes is a life style disease. It can be controlled though not completely cured.

There are very many known therapies for the management of diabetes. Firstly, diabetes may be managed with a carbohydrate-based, low-fat diet. The carbohydrates in such a diet inevitably put large amounts of glucose in the bloodstream. The patients therefore need to be administered insulin daily. The drawback associated with this therapy is that the right dosage of insulin needs to be administered every time. A greater than required insulin dosage can reduce the glucose level too much such that it may become risky for the patient. A skilled administrator is therefore a must in following such a therapy. The complications attached to such a form of therapy, makes it tedious and less patient compliant. The second method of controlling diabetes is chemotherapy. Based upon the kinds of diabetes prevalent, the drugs available for treatment can be grouped under the following heads: i. Pancreatic stimulators: - This class of drugs helps to stimulate the pancreas, leading to increased secretion of insulin. This addresses the diabetes caused by inadequate insulin secretion. Common examples of this category are sulphonylureas and meglitinides. ii. Insulin sensitizers: -This category of drugs improves the cell's sensitivity to the presence of insulin, thereby improving the uptake of glucose into the cells, leading to better blood sugar control. The common examples for this category are the biguanides, thiazolidinediones. iii. Alpha-glucosidase inhibitors: - Acarbose and meglitol are the commonly known alpha-glucosidase inhibitors. These drugs help the body to lower blood glucose levels by blocking the breakdown of starches in the intestine. They also slow the breakdown of some sugars. Their action slows the rise in blood glucose levels after a meal. They should be taken with the first bite of a meal. iv. Insulin: -As explained earlier, insulin is exogenously supplemented in the case of people suffering from both type I and type II diabetes.

The available synthetic drugs however suffer from concomitant side effects caused due to long duration of usage. It is indicated that cardiovascular mortality is higher in patients with oral hypoglycemic than in those who are treated without them.

Sulphonylureas cause hypoglycemia as a side effect. Biguanides cause lactic acidosis. Oral hypoglycemic drugs also cause GIT irritation, weight gain, hypertension, etc. On continuous and constant exertion, the diabetic person is also liable for pancreatic fatigue. In addition, many of these available drugs lead to drug resistance in patients with long durations of use. Acarbose and meglitol are known to cause gas and diarrhea.

Added to these are the long-term complications of diabetes, which are still more damaging. Spikes in blood sugar in patients cause these complications during the day.

Increased blood sugar even for short periods leads to glycosylation of hemoglobin.

Glycosylated hemoglobin causes long-term irreversible damages to eyes, kidneys, nerves and blood vessels.

The drugs listed above have different mechanisms of action to lower blood glucose levels. They are therefore often prescribed in the form of a combination therapy. More over combination therapy suits best, when one single drug docs not seem to show the desired effects. Many combinations are known and used. For example, a biguanide and a sulfonylurea may be used together. Adding a drug from a different category of diabetes therapy is definitely more effective than switching from one single pill to another. Yet the disadvantages associated, with combinatorial effect of taking more than one drug each of which has individual side effect attached to it, cannot be avoided. Besides, taking more than one drug at a time makes the therapy more costly and less patient compliant The ayurvedic and ancient Indian literature refers to the usefulness of many plant extracts in the treatment of diabetes mellitus. The use of traditional medicines, mainly derived from plant sources, has been a major part in the management of many chronic ailments including diabetes. Physicians in India who practice Ayurveda, Unani, and Sidha have long used extracts of leaves, flowers, fruits, seeds, wood, bark, roots, or even whole plants of more than a hundred Indian medicinal plants for the treatment of diabetes.

Eugenia, Cinnamon and Salacia species have been actively used in Ayurveda for the treatment of diabetes. Salacia Oblonga, commonly called "Ponkoranti", is a large, straggling, woody shrub found in southern India and Sri Lanka. It can also be traced in the evergreen forests of Western Ghats. Salacia belongs to the family Celastraceae. The roots and stems of this plant are used for the treatment of diabetes. Salacia has also proven effective against increasing problem of other life stage diseases like hypertension. It has also been found effective in lowering triglyceride and LDL cholesterol levels. Salacia oblonga is known to exhibit alpha glucosidase activity. It contains two potent α-Glucosidase inhibitors: Salicinol and Kotalanol. Methanol extracts from the roots of Salacia oblonga exhibit an inhibitory effect on the increase of serum glucose levels in sucrose- and maltose-loaded rats. Salacia oblonga has also been found to show inhibitory activity on Aldose reductase, which is related to such chronic diabetic complications as peripheral neuropathy, retinopathy, and cataracts.

Cinnamomum is a tropical evergreen tree growing up to 7m (56 ft) in its wild state. It has deeply-veined ovate leaves that are dark green on top, lighter green underneath. The bark is smooth and yellowish. Both the bark and leaves are aromatic. It has small yellowish-white flowers with a disagreeable odour that bear dark purple berries. It prefers a humid tropical climate at a low altitude. In cultivated plantations grow as small bushes, no taller than 3 m (10 ft), as the stems are continually cut back to produce new stems for bark. The outer bark, cork and the pithy inner lining are scraped off and the remaining bark is left to dry completely, when it curls and rolls into quills. Many of these are rolled together to produce a compact final product, which is then cut into uniform lengths and graded according to thickness, aroma and appearance.

Eugenia jambolana or Syzygium cumini L belongs to the myrtaceae plant family. Common names are Java plum, black plum, jambul and Indian blackberry. It grows naturally in clayey loam soil in tropical as well as sub-tropical zones. It is widely cultivated in Haryana as well as the rest of the Indo-gangetic plains on a large scale. Its habitat starts from Myanmar and extends up to Afghanistan. It is generally cultivated as a roadside avenue tree as well. Yet it is well known that in Ayurveda, each herb has properties of curbing many disorders and this property is attributed to the composite nature of the herbal preparation. Therefore, any single component of the extract of herb has failed in offering clinically significant results for a particular disorder. Comprehensive studies on the components of the herb that are responsible for certain indications need to be undertaken to obtain effective medications from this therapy. Also, not necessarily all the ayurvedic extracts are non-toxic.

Earlier, the Applicant has carried studies for screening a majority of the plant extracts for their efficiency against degenerative diseases which is disclosed in the PCT Application PCT/IB2004/002531. It relates to the function of multiple plant extracts that have been validated for specific anti-diabetic usage using multiple etiology based cell assays. These multiple plant extracts have shown to have insulin-mimetic and insulin-sensitizalion activity. Currently, studies were carried to obtain a mixture of plant extracts which shows enhanced insulin-mimetic and insulin-sensitzation activity along with alpha-glucosidase inhibition. Further, the present invention provides for a synergistic ayurvedic / functional food bioactive composition named as "Cincata" comprising the mixture of plant extracts which can be used for management of diabetes and related disorders.

Salacia extracts are known to have alpha glucosidase inhibition activity. Yet the insulin mimetic activity and insulin sensitization activity have never been expressed or stated in any salacia extract till date.

Cinnamon extract is known for insulin potentiating activity. Yet an extract, which potentiates alpha glucosidase activity and brings out its insulin mimetic activity, is not known in the art.

In the instant invention, the plant extract mixtures so prepared laid down hereunder have been very surprisingly found to display three different modes of action.

These extract mixtures not just show optimized alpha glucosidase activity and work equivalent to well-known insulin sensitizer drugs. Furthermore, the extract mixtures as disclosed in the instant invention exhibit insulin mimetic activity, insulin sensitization activity and free radical scavenging abilities. The invention relates to plant extracts, which are capable of managing blood sugar in diabetes mellitus patients and also lend themselves for long-term use without any side effects and without developing resistance. It is therefore the main objective of the invention to provide a safe and efficacious plant extract mixture, which acts upon diabetes by at least three different mechanisms.

PRIOR ART US Patent 6,200,569 states a cinnamon extract with an insulin potentiating activity. No mimetic activity with respect to insulin or alpha glucosidase inhibition activity is however stated.

US 6,194,412 relates to mixtures derived from grains of Eugenia Jambolana

Lamarck preparation and use of said mixtures and some of their constituents as medicaments. The mixture however does not relate to improved organoleptic properties

US Patent application 6,376,682 relates to compound extracted from salacia oblonga having the characteristic of specifically inhibiting the activity of alpha.- glucosidase (an enzyme that breaks down disaccharides, etc.) at the intestinal level. It does not reflect on the additional, insulin mimetic and insulin sensitization activities of found in a well-extracted salacia extract.

US Patent 5,691,386 relates to a compound extracted from a woody climbing plant belonging to the Celastaceae family and inhibits the activity of alpha.- glucosidase, and further to an antidiabetic and dieting agent containing the compound and a method for producing such a compound. It does not mention any insulin mimetic activity attached to salacia extract. Similarly no insulin sensitization activity of salacia is shown by treatment disclosed in the patent.

US Patent Application 20020041904 states a compound which is extracted from

Salacia oblonga or Salacia prinoides and contains a compound having an alpha.- glucosidasc inhibiting effect. It however does not state any extract showing insulin mimetic and insulin sensitization activities in salacia. The invention therefore discloses an extract, which acts with a single mode of action.

Plant extract mixtures of these three particular plant extracts with synergistic qualities that potentiate each other's activity are not known in the art. The need of the hour therefore is a naturo-therapy, which even though exhibits the combinatorial effect of two or more different categories of anti-diabetes drugs, is necessarily devoid of any side effects associated with them. The plant extract mixtures so prepared by making use of the ^■ instant invention laid down hereunder have been very surprisingly found to display three different modes of action. These extract mixtures not just show optimized alpha glucosidase activity and work equivalent to well-known insulin sensitizer drugs. Furthermore, the extract mixtures as disclosed in the instant invention exhibit insulin mimetic activity, insulin sensitization activity and free radical scavenging abilities. The invention relates to plant extracts, which are capable of managing blood sugar in diabetes mellitus patients and also lend themselves for long-term use without any side effects and without developing resistance. It is therefore the main objective of the invention to provide a safe and efficacious plant extract mixture, which acts upon diabetes by at least three different mechanisms.

OBJECTS QF THE INVENTION

The main object of the present invention is to obtain a synergistic ayurvedic / functional food bioactive composition (Cinacata) for managing diabetes and related disorder.

Another main object of the present invention is to obtain a synergistic ayurvedic / functional food bioactive composition (Cincata) comprising extracts of atleast two plants selected from a group comprising Eugenia, Cirmamomum and Salacia.

Yet another object of the present invention is to develop a process for preparation of a synergistic ayurvedic / functional food bioactive composition (Cincata). '

Yet another object of the present invention is to obtain a method of treating diabetes and/or related disorders by administering the said composition (Cincata).

STATEMENT OF THE INVENTION The present invention relates to a synergistic ayurvedic / functional food bioactive composition (Cincata) for managing diabetes and related disorders, said composition comprising extracts of atleast two plants selected from a group comprising Eugenia, Cirmamomum and Salacia optionally alongwith pharmaceutically acceptable excipients; a process for preparation of a synergistic ayurvedic / functional food bioactive composition for treating diabetes and related disorders, wherein the process comprising steps of: a) obtaining extracts of Eugenia, Cinnamomiim and Salacia separately through steps comprising: 1. contacting powdered plant material with organic or aqueous solvent to obtain solution; 2. heating the solution close to boiling point of the solvent followed by its cooling; 3. size-fractionating the cooled solution to . obtain liquid fraction; 4. concentrating and drying the liquid fraction to obtain the extracts of Eugenia, Cinnamomiim and Salacia separately; and b) mixing the extracts of atleast two plants optionally alongwith pharmaceutically acceptable excipients to arrive at the synergistic composition; and a method of treating diabetes and/or related disorders in a subject in need thereof by administering the composition comprising extracts of atleast two plants selected from a group comprising Eugenia, Cinnamomum and Salacia optionally alongwith pharmaceutically acceptable excipients to the subject.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a synergistic ayurvedic / functional food bioactive composition for managing diabetes and related disorders, said composition comprising extracts of atleast two plants selected from a group comprising Eugenia, Cinnamomum and Salacia optionally alongwith pharmaceutically acceptable excipients.

In another embodiment of the present invention, the extract is obtained from plant parts selected from a group comprising root, shoot, leaf, seed, and fruit; or the whole plant.

In still another embodiment of the present invention, the extract is either an aqueous or organic extract.

In still another embodiment of the present invention, the concentration of Eugenia extract ranges between 0-50%.

In still another embodiment of the present invention, the concentration of Cinnamomum extract ranges between 5-50%.

In still another embodiment of the present invention, the concentration of Salacia extract ranges between 0-40%. In still another embodiment of the present invention, the excipients are selected from a group comprising additives, gums, sweeteners, coatings, binders, d is integrants, lubricants, disintegration agents, .suspending agents, granulating agents, solvents, colorants, glidants, anti-adherents, anti-static agents, surfactants, plasticizers, emulsifying agents, flavoring agents, viscocity enhancers and antioxidants.

In still another embodiment of the present invention, the composition is formulated into dosage forms selected from a group comprising liquid, troches, lozenges, powder, granule, capsule, tablet, patch, , gel, emulsion, cream, lotion, dentrifice, spray, drop, suspension, syrups, elixirs, phyotceuticals and neutraceuticals.

In still another embodiment of the present invention, the composition is free of side effects.

The present invention also relates to a process for preparation of a synergistic ayurvedic

/ functional food bioactive composition for treating diabetes and related disorders, wherein the process comprising steps of: a) obtaining extracts of Eugenia, Cinnamomum and Salacia separately through steps comprising:

> contacting powdered plant material with organic or aqueous solvent to obtain solution; y heating the solution close to boiling point of the solvent followed by its cooling; > size-fractionating the cooled solution to obtain liquid fraction;

> concentrating and drying the liquid fraction to obtain the extracts of Eugenia, Cinnamomum and Salacia separately; and b) mixing the extracts of atleast two plants optionally alongwith pharmaceutically acceptable excipients to arrive at the synergistic composition,

In still another embodiment of the present invention, the plant material is selected from a group comprising root, shoot, leaf, seed and fruit; or the whole plant. In stilt another embodiment of the present invention, the organic solvents are selected from a group comprising heterocyclic aromatic compounds, aliphatic compounds, ketones, cyanides, alcohols, nitriles, esters, ether and mixtures of one or more thereof.

In still another embodiment of the present invention, the organic solvent is ethanol.

In still another embodiment of the present invention, the concentrated Eugenia extract is treated with hexane followed by collection of lower aqueous layer for preparing the synergistic composition.

In still another embodiment of the present invention, the concentrated extracts are treated with organoleptic agents selected from a group comprising decolorizing agents, deodorizing agents and debitterizing agents.

In still another embodiment of the present invention, the decolorizing agents are selected from a group comprising peroxides, carbon, metals and organic solvents.

In still another embodiment of the present invention, the decolorizing agent is preferably hydrogen peroxide.

In still another embodiment of the present invention, the deodorizing agents arc selected from a group comprising peroxides, carbon and organic solvents.

In still another embodiment of the present invention, the deodorizing agent is preferably ketone.

In still another embodiment of the present invention, the composition is formulated into dosage forms like liquid, troches, lozenges, powder, granule, capsule, tablet, patch, gel, emulsion, cream, lotion, dentrifice, drop, suspension, syrups, elixirs, phyotceuticals and neutraceuticals.

The present invention also relates to a method of treating diabetes and/or related disorders in a subject in need thereof by administering the composition comprising extracts of atleast two plants selected from a group comprising Eugenia, Cinnamonnim and Salacia optionally alongwith pharmaceutically acceptable excipients to the subject.

In still another embodiment of the present invention, the related disorders comprise diabetic acidosis, diabetic xanthoma, diabetic myatrophy, diabetic ketosis, diabetic coma, diabetic stomach disorders, diabetic gangrene, diabetic ulcer, diabetic diarrhea, diabetic microangiopathy, diabetic uterosclerosis, diabetic cardiomyopathy, diabetic neuropathy, diabetic nephropathy, diabetic blister, diabetic cataract, diabetic dermatitis, diabetic scleredema, diabetic retinopathy, diabetic necrobiosis lipoidica, diabetic and blood flow obstructions.

In still another embodiment of the present invention, the concentration of Cinnamomiim extract ranges between 5-50%.

In still another embodiment of the present invention, the concentration of Salacia extract ranges between 0-40%.

In still another embodiment of the present invention, the excipients are selected from a group comprising additives, gums, sweeteners, coatings, binders, disintegrants, lubricants, disintegration agents, suspending agents, granulating agents, solvents, colorants, glidants, anti -adherents, anti-static agents, surfactants, plasticizers, emulsifying agents, flavoring agents, viscocity enhancers and antioxidants.

In still another embodiment of the present invention, the composition is formulated into dosage forms selected from a group comprising liquid, troches, lozenges, powder, granule, capsule, tablet, patch, gel, emulsion, cream, lotion, dentrifice, drop, suspension, syrups, elixirs, phyotceuticals and neutraceuticals. The composition of the present invention is synergistic in nature in that it exhibits surprising result even when atleast two plant extracts selected from a group comprising Eugenia, Cinnamomu^' m and Salacia are used.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1: Bar graph showing percentage insulin mimetic activities shown by the plant extract mixtures as determined in adipocytes.

Figure 2: Bar graph showing percentage insulin mimetic activities shown by the plant extract mixtures, as compared to individual plant extracts, determined in myocytes.

Figure 3: Bar graph showing percent insulin sensitization activity of different plant extract mixtures as compared to individual plant extract, shown in adipocytes.

Figure 4: Bar graph showing percent insulin sensitization activity of different plant extract mixtures as compared to individual plant extract, shown in myocytes.

Figure 5: Bar graph showing the 1C50 value of the plant extract mixtures as compared to individual plant extracts. Exp A herein shows IC50 value of an arbitrary, disproportionate mix of plant extracts.

Figure 6: Free radical scavenging ability of an exemplary plant mixture named alpha SM8

Figure 7: Total Polyphenol estimation of an exemplary plant mixture named alpha SM8

It will be readily understood that the components of the present invention, as generally described herein, could be arranged and designed in a wide variety of different configurations. Thus, the following more detailed description of the embodiments of the system and method of the present invention is not intended to limit the scope of the invention, as claimed, but is merely ^• representative of the presently preferred embodiments of the invention. As used herein, "extract" refers to a concentrated preparation of the essential constituents of the medicinal plant. Typically, an extract is prepared by drying and powderizing the plant. Optionally, the plant, the dried plant or the powderized plant may be boiled in solution. The extract as used herein may be used in liquid form, or it may be mixed with other liquid or solid medicinal herbal extracts. Alternatively, this medicinal herbal extract may be obtained by further precipitating solid extracts from the liquid form.

As used herein, "anti-diabetic" or "hypoglycemic" compound or composition generally refers to an agent that lowers blood glucose levels. If blood glucose level is decreased by at least about 100 mg/dl, then the compound is considered to be a hypoglycemic agent. The hypoglycemic or anti-diabetic effect can be measured by a variety of methods including, but not limited to, measuring the blood glucose levels, the rate of insulin binding to its receptor, the level of insulin secretion from pancreatic beta cells, and inhibition of glucohydrolase activity. As used herein the term, "related disorders" means disorders related to diabetes mellitus, which include but are not limited to Diabetic Neuropathy, Diabetic Diarrhea, Urinary retention, Gustatory Swelling, Papillary Reflexes, Cardiac Autonomic Disturbances, Collagen Disturbances, thickening of capillary basement membrane, increase in vessel wall matrix and cellular proliferation resulting in vascular complications like lumen narrowing, early atherosclerosis, sclerosis of glomerular capillaries, retinopathy, neuropathy and peripheral vascular insufficiency.

As used herein the term, "potential plants" includes plants from which antidiabetic extracts can be extracted out. The term comprises of plants like Momordica sp., Salacia, Eugenia, Coccimia, Chviamonmm sp, Gymnema sp, Pterocarpus sp. Azadiricla sp., Trigoriella sp. Cymopsis sp.

As used herein the term, "treated extract" refers to the dried, extract produced after treatment of the concentrated extract with deodourizing /decolorizing/ debitterizing agents. Such reagents include but are not restricted to peroxides, carbon, metals and organic solvents.

As used herein the term "composition" means any administrable form of the herbal extract given alone or in combination with other herbal, ayurvedic or pharmaceutical composition. The term includes but is not restricted to tablets, capsules, lozenges, creams, lotions, suspensions, oils and the like.

In one of its embodiments, the present invention details the composition of a plant extract mix, with improved therapeutic and organoleptic properties, for administration to diabetic patients.

In another embodiment the -present invention details, an extraction procedure for the improvement of basic therapeutic activity of any given plant extract and its organoleptic appeal. It discloses unique procedures for preparation of improved plant extracts with increased efficacy. The plant extracts so produced by making use of the procedures laid down hereunder act in unprecedented modes of action towards the treatment of diabetes. Plant material suitable for preparation of the plant extract for inclusion of the therapeutic composition of the invention is derived from a potential plant administered to a person suffering from diabetes. Administration of plant extracts from such potential plants results in the lowering of the blood glucose level of the patient.

In accordance with a further embodiment of the present invention, the potential plant is a member of the family Celastraceae. In another embodiment of the invention, the potential plant is a member of the genus Salacia. It will be readily apparent to one skilled in art that other extracts capable of potential positive anti-diabetic properties could be isolated using similar techniques from well known Salacia species and also from a wide range of plants i.e., potential plants. The potential plants include all species of the genus salacia, including terrestrial, aquatic or other plants that can be subjected to standard extraction procedures such as those described herein in order to generate an extract that can be tested for its therapeutic abilities, including but not limited to Salacia oblonga, S. zeylanica, S. chimensis, S. prinoides. The present invention is directed to a herbal medicinal composition comprising the foregoing plant extracts that can be administered to a person suffering from diabetes which results in the lowering of the blood glucose level of the patient.

In accordance with a further embodiment of the present invention, the potential plant is a member of the family Lauraceae. The potential plant, in particular, is a member of the genus Cinammomum. It will be readily apparent to one skilled in art that other extracts capable of potential positive anti-diabetic properties could be isolated using similar techniques from a wide range of plants i.e., potential plants. The potential plants include all species of the family Lauraceae, including terrestrial, aquatic or other plants that can be subjected to standard extraction procedures such as those described herein in order to generate an extract that can be tested for its therapeutic abilities. The present invention is directed to a herbal medicinal composition comprising the foregoing plant extracts that can be administered to a person suffering from diabetes which results in the lowering of the blood glucose level of the patient.

In accordance with a further embodiment of the present invention, the potential plant is a member of the family Myrtaceae. In another embodiment of the invention, the potential plant is a member of the genus Eugenia. It will be readily apparent to one skilled in art that other extracts capable of potential positive anti-diabetic properties could be isolated using similar techniques from a wide range of plants i.e., potential plants. The potential plants include all species of the family Myrtaceae, including terrestrial, aquatic or other plants that can be subjected to standard extraction procedures such as those described herein in order to generate an extract that can be tested for its therapeutic abilities. The present invention is directed to a herbal medicinal composition comprising the foregoing plant extracts that can be administered to a person suffering from diabetes which results in the lowering of the blood glucose level of the patient.

In another embodiment of the invention, there is provided a process for obtaining a plant extracts possessing improved hypoglycemic properties, the processes comprising (a) obtaining plant material from one or more plants (b) obtaining an extract from the plant material by contacting the plant material with an aqueous, an ethanolic or an organic solvent, or a combination thereof, thereby providing one or more plant extracts (c) treating the extract with reagents/ decolorizing, deodorizing, debitterizing agents to obtain an organoleptically improved product (d) analyzing the plant extracts for free radical scavenging potential, Intestinal alpha-glucosidase inhibition potential, insulin mimetic activity and insulin sensitizing activity, in-vitro screening of plant extracts for glucose uptake and the in-vivo efficacy studies (e) mixing the plant extracts in predetermined ratios. The extracted plant extracts do however differ in the degree of anti-diabetic activity shown. For example, Eugenia extract shows the best of alpha glucosidase inhibitory activity amongst the three plant extracts i.e. salacia plant extract, cinnamon plant extract and Eugenia plant extract. The insulin sensitization activity, on the other hand, is best shown amongst all in Cinnamon extract. Also, it is seen that the extraction solvent used makes a difference in the activities shown. Therefore, a need remains for a desired synergistic plant extracts mixture, which shows the optimum anti-diabetic activity through all possible modes of action. Thus none of the three extracts, when considered individually, treats diabetes through all three different modes in the optimum desired levels.

In one embodiment of the invention, there is provided a process for selecting the composition of the plant extract mixture of the instant invention. It is noteworthy that the various plant extracts used for the preparation of the instant mixture are those, which have been obtained by the extraction procedure laid down in the instant invention. When formulated as a mixture, these plant extracts show unprecedented insulin sensitization activities and insulin mimetic activities in various cells and tissues. Additionally, the alpha glucosidase inhibitory activity, shown by these extracts is invariably enhanced. This is evident in the figure 5 which compares the individual activities of the plant extracts to those of the formulated mixtures. Invariably it is shown that the activities are potentiated.

It has been found by intense experimentation, that not all mixtures obtained by adm ixing known plant extracts in an arbitrary ratio display the optimum anti-diabetic ^•qualities required. Thus in case of an arbitrary mix of two or more plant extracts, the insulin mimetic activity exhibited by the mixture might be more pronounced as compared to that shown by the individual extract yet at the same time its insulin sensitization activity might be compromised. As an example, it is shown that a mixture prepared by adding Eugenia ethanol extract, Eugenia water extract, Cinnamon water extract, cinnamon water extract and salacia water extract in a particular ratio shows an enhanced alpha glucosidase inhibition activity, however, the insulin mimetic activity shown herein is much below the desired level.

A technique as disclosed in the instant invention must therefore be applied to formulate a mixture of plant extracts which synergies each individual anti diabetic effect of a plant extract to produce a multi dimensional, combinatorial anti diabetic effect. It has been found that the various extract must be added in particular determined ratio only. It is seen that the anti diabetic effects in a plant mixture containing Eugenia ethanol extract, Eugenia water extract, Cinnamon water extract, cinnamon water extract and salacia water extract in a ratio 20:30:20:20: 10 are far less achieved as compared to a composition wherein the same plant extracts are added in a ratio 0: 15:35: 15:35 grams. Thus it is from imminent hard toil and intense experimentation that the scientists have derived such peculiar concentration combinations, which when formulated into a composition mixture show the optimum synergistic effect of the desired plant extracts. Moreover such mixtures must be selected which shows desired effect on desired cell sites and tissues only. Such a mixture then has an optimized quantity of each plant extract mixed to obtain insulin mimetic and sensitization activity at the desired sites.

The invention is further elaborated with the following examples. However, these examples should not be construed to limit the scope of the invention.

Examples:

Extraction of the plant material by solvent extraction process:

The plant material employed in the extraction process can be the entire potential plant, or it can be one or more distinct tissues from the plant for example, leaves, seeds, roots, stems, flowers, or various combinations thereof but preferably the root of the plant. The plant material may also be treated prior to extraction, for example, by drying, freezing, lyophilizing, or some combination thereof. If desired, the plant material can be fragmented and/or homogenized by some means such that a greater surface area is presented to the solvent. For example, the plant material can be crushed or sliced mechanically, using a grinder or other device to fragment the plant parts into small pieces or particles, or the plant material can be frozen in liquid nitrogen and then crushed or fragmented into smaller pieces.

The solvent used for the extraction process can be aqueous, alcoholic or organic, or a combination thereof. In one embodiment of the present invention, plant material is extracted with an aqueous solvent. Examples of suitable solvents include but are not limited to water, buffers, cell media, dilute acids or bases and the like. In an alternate embodiment of the invention, the plant material is extracted with an alcoholic solvent. Examples of suitable alcoholic solvents include, but are not limited to methanol, ethanol, n-propanol₅ iso-propanol, 2-butanol, tert-butanol, and combinations thereof.

Various extraction processes are known in the art and can be employed in the methods of the present invention. The extract is generally produced by contacting the solid plant material with a solvent with adequate mixing and for a period of time sufficient to ensure adequate exposure of the solid plant material to the solvent such that inhibitory activity present in the plant material can be taken up by the solvent.

The solvent extraction process may be selected from direct and successive extraction types such as extraction from plant parts in soxhlet apparatus or in flasks at room temperature or at higher temperature with polar and/or non-polar solvent (s). Regardless of the number of extraction processes, each extraction process typically is conducted over a period of time between about 6 hours to 24 hours at room temperature. Adequate contact of the solvent with the plant material can be encouraged by shaking the suspension.

The liquid fraction is then separated from the solid (insoluble) matter resulting in the generation of two fractions: a liquid fraction and a solid fraction, which is the potential extract. Separation of the liquid and solid fractions can be achieved by one or more standard processes known to those skilled in art.

The potential extracts obtained thereof may be concentrated and solubilised in an appropriate solvent preferably ethyl acetate. Examples of various other organic solvents include but are not limited to, di-ethyl ether, hexane, heptane, dichloromethane, ethyl acetate, butyl alcohol, ether, acetone and the combinations thereof.

The purified extracts or partially purified extracts are concentrated by solvent removal from the original extract and/or fractionated extract, and/or purified extract. The techniques of solvent removal are known to those skilled in the art and include, but are not limited to rotary evaporation, distillation (normal and reduced pressure), centrifugal vacuum evaporation, and lyophilisation.

The extract referred to herein can be produced by any of the two procedures stated hereunder. The procedures laid down herewith are general procedures alterable with variations known to one skilled in the art. These may not in any way be treated as restrictive to the instant invention.

Extraction procedure:

1. Powder the plant material and contact it with the solvent.

2. Heat the solution at a temperature close to the boiling point of the solvent. 3. Continue the extraction for at least 3 hours.

4. After cooling, size fractionate the plant material and collect the heavier fraction.

5. The extract collected after the extraction is concentrated by known procedures such as soxhelation.

6. Dry the extract so obtained by known procedures such as vacuum drying or lyophilization.

The above concentrated extract may thereafter be treated with a decolorizing agent such as hydrogen peroxide to produce an extract with improved organoleptic properties. After treatment the mixture is stored for approximately 10 — 20 hours and dried. The above-obtained extract is much lighter in color when compared with the normal extract.

The solvents used in the process may be aqueous, alcoholic or organic solvents well known in the art and include but are not restricted to heterocyclic aromatic compounds, aliphatic compounds, ketones, cyanides, alcohols, nitriles, esters, ether and mixtures of one or more thereof.

Plant extracts like those of Eugenia are known to be black and hygroscopic in nature hence a slightly modi fied protocol is used to obtain Eugenia extracts of lighter shade, which are additionally non- hygroscopic.

1. Powder the plant material and contact it with the solvent.

4. After cooling, size-fractionate the plant material and collect the heavier fraction. 5. The extract collected after the extraction is concentrated by known procedures such as soxhelation.

6. Dry the extract so obtained by known procedures such as vacuum drying or lyophilization. 7. The concentrate obtained in step 6 is cooled. Hexane is added and solvent partitioning is performed on the concentrate.

8. The lower aqueous layer is collected and treated with decolorizing agent such as Hydrogen peroxide. The treated concentrate is dried and later stored.

The above-obtained extract is much lighter in color and comparatively non hygroscopic when compared with the normal extract.

Modifications of the type, which are required to scale up the procedures and such as are standard in the industry, are included, with in the realm and scope of the invention laid down. Similarly, modifications as would be readily apparent to those skilled in the art fall within the scope of the invention.

By making use of the processes stated above with variations known to a person skilled in the art, plant extracts of Eugenia, cinnamon and salacia water extract were prepared using varied solvents, solubilizers and concentration procedures. Thereafter the extracts were mixed in a ratio as given hereunder, in table A, to form the desired mixture.

Table A: Plant mixture compositions

Various synergistic mixtures were prepared by taking the plant extracts in varying concentrations. The same are stated herewith as examples. It may be noted that the examples stated herewith are merely illustrative and should not in any way be treated restrictive to the invention.

Example 1

Table 1: Mixture composition for Experiment No. 1.

Example 2

Table 2: Mixture composition for Experiment No. 2

Example 3

Table 3: Mixture composition for Experiment No. 3

Example 4

Table 4: Mixture composition for Experiment No. 4

Example 5

Table 5: Mixture composition for Experiment No. 5

Example 6

Table 6: Mixture composition for Experiment No. 6

Example 7

Table 7: Mixture composition for Experiment No. 7

Example 8

Table 8: Mixture composition for Experiment No. 8

Example 9

Table 9: Mixture composition for Experiment No. 9

Example 10

Table 10: Mixture composition for Experiment No. 10

Addition of a particular plant extract at a concentration below or above the cited concentrations produces plant extract mixtures which are devoid of the desirable synergistic activities for counteracting diabetes. An example of the said effect is depicted herewith to prove that the addition of the plant extracts prepared by the same extraction processes when added in a different concentration produces plant extract mixtures devoid of the desirable characteristics.

Experiment A

Example 11:

Tests to determine the anti-diabetic efficacy of plant extract mixture

ϊn-vitro screening of plant extract mixture for glucose uptake

Insulin-slimulaled glucose uptake in adipose tissue and striated muscle is critical for reducing postprandial blood glucose concentration and the dysregulation of this process is one of the hallmarks of Type -II Diabetes mellitus (Non Insulin dependent). Oral therapies for Diabetes mellitus have emerged out of this interest and are widely used still today. But rather than acting by mimicking insulin, these drugs acts either by stimulating insulin release [Sulphonylurease], potentiating insulin action (thiazolidinedione) or lowering hepatic glucose production (biguanides). Various amounts of plant extract mixtures (0,034Dg to 33.4Dg) are tested for insulin mimetic and sensitization effects with / without insulin.

Example 12:

Insulin mimetic activity shown by plant extract mixture

Radio labeled glucose is used to measure the changes in the level of glucose uptake activity of the adipocyte cells in response to treatment with samples in the presence or absence of insulin. The assay is performed in a 96-well microtitre plate format and the counts per minute are measured using a radioactive counter. The count per minute can be measured on a microtitre plate by radioactive counter.

Insulin mimetic activity was tested in both 3T3-1 adipocyte cells and C2C12 myocyte cells. Three different concentrations of plant extract mixture were used. The extracts showed insulin mimetic activity in varying concentration. The results obtained are stated in tables 1 1- 20 and shown in figures 1,2. Figure 2 is clearly indicative of the enhanced insulin mimetic activity seen in the plant extract mixtures over and above the individual plant extracts. Herein the bar for Exp A shows the insulin mimetic activity shown by the Eugenia ethanol extract. The bar for Exp. B shows the insulin mimetic activity shown by an individual extract of cinnamon in water base. Table 11

S.No. Concentration in μg Insulin Mimetic Activity Insulin Sensitization Activity

1

3.33ug/well 52.26 101.51

2

0.33ug/well 76.32 143.94

Table 1 1 : Insulin Mimetic and Insulin sensitization activities shown by the extract of example 1 , at different concentrations.

Table 12

1

3.33ug/well 3.28 1 13.45

2

0.33ug/well -17.87 158.78

Table 12: Insulin Mimetic and Insulin sensitization activities shown by the extract of example 2, at different concentrations.

Table 13

Table 13: Insulin Mimetic and Insulin sensitization activities shown by the extract of example 3, at different concentrations.

Table 14

Table 14: Insulin Mimetic and Insulin sensitization activities shown by the extract of example 4, at different concentrations.

Tabic 15

Table 15: Insulin Mimetic and Insulin sensitization activities shown by the extract obtained from example 5, at different concentrations.

Table 16

1

3.33ug/well 35.71 104.19

2

0.33ug/well 47.72 189.99

Table 16: Insulin Mimetic and Insulin sensitization activities shown by the extract obtained from example 6, at different concentrations.

Table 17

Table 1 7: Insulin Mimetic and Insulin sensitization activities shown by the extract obtained from example 7, at different concentrations.

Table 18

1

3.33ug/well -2.75 62.05

?

0.33ug/well 108.30 109.47 Table 18: Insulin Mimetic and Insulin sensitization activities shown by the extract obtained from example 8, at different concentrations.

Table 19

S .No. Concentration in μg Insulin Mimetic Activity Insulin Sensitization Activity

1

3.33ug/well -0.32 66.54

2

0.33ug/well 39.95 59.06

Table 19: Insulin Mimetic and Insulin sensitization activities shown by the extract obtained from example 9, at different concentrations.

Table 20

obtained from example 10, at different concentrations

Example 13:

Insulin sensitization activity shown by Plant extract mixtures

Insulin sensitization activity was tested in both 3T3-1 adipocyte cells and C2C12 myoblast cells. Different concentrations of extract mixtures were used and tested. The extract mixtures showed insulin-sensitizing activity in all concentrations. The results obtained are stated in tables 11 to 20 and shown in figures 3 and 4. Figure 3 depicts the enhanced insulin sensitization activity shown by the plant extract mixtures in comparison to an individual plant extract. Herein the bar for Exp A shows the insulin sensitization activity shown by Eugenia water extract in adipocyte cells. Exp B shows the insulin sensitization activity shown by cinnamon water extract. Exp C shows the insulin sensitization activity seen in salacia water extract.

Figure 4 shows a comparative bar graph wherein the insulin sensitization activity of the plant extract mixtures is compared with the individual plant extract insulin sensitization activities of Eugenia, cinnamon and salacia. Herein the Exp A depicts insulin sensitization obtained in Eugenia ethanol extract. Exp B depicts the insulin sensitization activity obtained in an individual extract of cinnamon in ethanol. Exp. C depicts the insulin sensitization activity of salacia water extract. The graph in itself is indicative of an enhanced insulin sensitization activity produced in all plant extract mixtures over and above each individual plant extract used to prepare the mixture composition.

The general method was Followed for screening. .

Preadipocytes (3T3L-1) and premyocytes (C2C12) are cultured in DMEM containing 10%FCS, 4mM Glutamine, 2 % NaHCO3 and antimycotic, in an atmosphere of 5% CO2 at 370C, separately. Myoblasts are cultured up to 80% confiuency and the cells are sub-cultured at three-day intervals. 20,000 of preadipocytes and myocytes are seeded separately in each well of a 96 well plate and differentiated for 48 hours in DMEM:F12(1 : 1 ), 0.5mMIBMX,^' 0.25mM Dexmethasone and lug Insulin for 48hrs followed by incubation with lug of Insulin for 8hours. The ability of the plant extract to induce glucose uptake is tested in two different ways 1) glucose uptake in presence of insulin (extract + insulin) and 2) glucose uptake in absence of insulin (extract alone). Therefore incubate in duplicate (one set to evaluate glucose uptake in presence of insulin i.e. extract + insulin and other set without insulin i.e. extract alone) with different concentration of extracts (300μg/well, 30 Dg/well, 3 Dg/well and 0.3 []g/well) in triplicates for 18 hours at 370 C and 5%CO2 100Dl of DMEM. The medium is then removed and the cells are incubated with KRH buffer (100 microliters) at 370C and 5% CO2 for 10 minutes. Cells are incubated with insulin. For standard insulin response incubate cells with 5nM, 1OnM, 25nM, 5OnM and 10OnM in KRH buffer in triplicate. To one set of wells to be treated with extract +insulin, 5nM of insulin in KRFI buffer is added and in other set of well treated with extract alone, 100D l of KRH buffer is added for 15 minutes al 370 C and 5%CO2. Glucose uptake reaction is initiated by adding 0.1 mM 2-dcoxy glucose containing 2-deoxy [3H] glucose (final concentration 12.2 kBq/ml) and incubated for 1 hour at 37°C and 5%CO2. assay is terminated by adding 40 μM Cytochalasin B. The cells are washed three times with ice-cold KRH buffer (100 Dl). KRH buffer is removed and 20 μl 1% Triton X is added to each well to lyse the cells and incubate for 10 min at 37°C and 5%CO2. 20OHl of Aqualite is added per well and the supernatant is transferred back to the plates and counted on a micro-titer plate radioactive counter. The results obtained for insulin mimetic and sensitization potential of Salacia 70% ethanol root extract and water extracts are depicted in figure 1 to figure 6 using differentiated adipocyte and myocytes. All the observed values of glucose uptake activity are blank corrected using the control (cells alone background . value). These values are normalized with MTT cell viability assay values for the corresponding extracts. The degree of insulin mimetic/sensitization activity of each sample concentration is calculated as a percentage of that observed using 1OnM insulin alone.

Example 14:

Tests to confirm the Intestinal α-glucosidase inhibition potential of Plant Extract Mixture

The inhibition of degradation of oligosacharrides (carbohydrates having 2 to 10 glucose residues connected by 1-4 or 1-6 α-D-glycosidic linkage) into monosaccharides by alpha-glucohydrolase-catalyzed enzymatic reactions was tested for plant extract mixtures using Calorimetric — para-nitro-phenyl (pNP) release method using pNP-a-D- glucoside. The plant extract mixtures showed greater α-glucosidase inhibition potential (IC50 value of 51.45 μg/ml) relative to the commercially available α-glucosidase inhibitor, acarbose (IC50 value of 146.55 μg/ml) for 0.2 α -glucosidase enzyme units at standard enzymatic reaction conditions. The same has been depicted in figure 5. Herein Exp A is an arbitrary mix of the individual plant extracts. The graph clearly shows that the desired anti diabetic activities are not obtained by mixing the plant extracts arbitrarily. Thus the extracts must be mixed in the determined ratio and proportions disclosed in the instant invention only.

Example 15:

Free radical scavenging potential of the Plant extract mixture

There are several intriguing human studies show that administration of antioxidants plays a role in the reduced metabolic effects of insulin. In humans, the diabetogenic process appears to be caused by immune destruction of the beta cells; part of this process is apparently mediated by white cell production of active oxygen species. It has been shown that scavengers of oxygen radicals are effective in preventing diabetes in these animal models. Not only are oxygen radicals involved in the cause of diabetes, they also appear to play a role in some of the complications seen in long-term treatment of diabetes. Oberley et.al Free radicals and diabetes, Free Radic Biol Med. 1988; 5(2): 113-24. Free radical reactions and non-enzymatic glycosylation may play important roles not only in the development of diabetes but also in its complications. Hayakawa et al, Free radicals and diabetes mellitus, Nippon Ronen Igakkai Zasshi. 1990 Mar; 27(2): 149-54.

In the present invention the isolated plant extract mixtures were used to estimate its free radical scavenging potency relative to ascorbic acid by using Calorimetric-DPPH method (Polterait O. (1997) Anti Oxidants and free-radical Scavengers of Natural origin Current Org. Chem. 1. 415-440). The Plant extract mixtures showed nearly 16% of free radical scavenging potency equivalent to that of ascorbic acid. The result is represented as a bar graph in figure 6. Herein the bar alpha SM8 shows the additional free radical scavenging activity shown by one of the extract mixtures.

Example 16:

Estimation of total polyphenols and its hypoglycemic effects.

Several studies show that apple polyphenols have a positive effect on diabetes and insulin resistance in animals and humans. In 2004, scientists at the National Institutes of Health in the U.S. gave this same apple polyphenol to mice. Two weeks of treatment

"significantly decreased blood glucose levels" in diabetic mice. Whole body fat mass was also "significantly reduced." An Asian study in diabetic human volunteers showed that even weak polyphenols in apple juice produced "avoidance of sharp peaks" in blood glucose levels.. The polyphenolic polymers have anti-oxidant effects, which provides synergistic benefits to persons with various forms of diabetes.

In the current invention, the total polyphenol content of the plant extract mixtures was estimated relative to gallic acid using Calorimetric - Singleton method (Singleton, V. L. and Ropssi, J.A. Jr (1965). The plant extract mixtures showed 21 ± 2.25 % total phenol content equivalent to gallic acid clearly indicative of the potential beneficial effects the extracts possess with respect to the management of diabetes and its medicative properties. The results are represented in the form of bar graph in figure 7. Herein the bar alpha SM8 shows the additional polyphenol activity shown by one of the extract mixtures.

Example 17:

Use of the extract as a therapeutic composition:

The present invention envisages the method of treating diabetes and other related diseases thereof by administering an effective amount of the therapeutic composition comprising the single plant extract or the screened plant extracts purified there from in combination. The therapeutic compositions of the invention can be administered alone or in combination with one or more standard anti-diabetic therapeutics. The present invention also contemplates the administration of sub-optimal doses of the therapeutic composition, for example, chemotherapeutic drug(s), in combination with the therapeutic composition of the instant invention. Thus, in one embodiment of the present invention, in order to prepare a therapeutic combination, one or more plant extracts is first selected and then the efficacy of the extract(s) in controlling diabetes and maintaining glucose homeostasis is determined using standard techniques as one of

• those outlined above. The efficacy of the one or more plant extract alone is then compared to the efficacy of the one or more plant extract in combination with varying amounts of another component i.e., another plant extract. The invention also contemplates the combination the plant extract with another synthetic inhibitor. A combination that demonstrates therapeutic index in comparison to the individual properties is considered to be an effective combination.

The formulations of the present invention contain at least an effective amount of the therapeutic composition. The effective amount is considered to be that amount of the composition, in weight percent of the overall formulation, which must be present in order to produce the desired therapeutic effect. As would be apparent to one skilled in art, the effective amount may vary, depending upon, for example the disease to be treated and the form of administration. In general the therapeutic composition will be present in an amount ranging from about 1% to 100% by weight of the formulation, 10% to about 90% by weight of the formulation, 20% to about 80% by weight of the formulation, 30% to 70% by weight of the formulation, from about 40% to 60% by weight of the formulation and about 50% by weight of the formulation.

The present invention contemplates the use of the therapeutic compositions at various stages in the disease development and progression, including in the treatment of early stage, or advanced and/or aggressive stage of hyperglycemia, diabetes or related disorders. The administration of the therapeutic composition comprising the isolated and screened extracts to mammal having an early stage of the disorder can help to attenuate the progression of the disease.

The dosage of the therapeutic composition to be administered is not subject to defined limits, but will usually be an effective amount. However it will be understood that the actual amount of the composition to be administered will be determined by a physician, in the light of the relevant circumstances, including the exact condition to be treated, the chosen route of administration, the actual composition administered, the age, the weight, and the response of the individual, patient and the severity of the patient's symptoms. The dosage ranges are not intended to limit the scope of the invention in any way.

The therapeutic compositions comprising the plant extract are not limited to only those for humans but also include those for various animals, in particular, other mammals. Therefore, the food compositions include foods for animals such as cats, dogs, and the like pets, and the medical compositions include those for animals other than humans.

Example 18:

Modes of administration:

For administration to a mammal, the therapeutic composition can be formulated as a pharmaceutical or naturopathic formulation such as phytoceuticals or nutraceuticals, for oral, topical, rectal or parenteral administration or for administration by inhalation or spray. The phytoceutical or naturopathic formulation may comprise the one or more plant extracts in dosage unit formulations containing the conventional non-toxic physiologically acceptable carriers, adjuvants and vehicles. The pharmaceutical or naturopathic formulations may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion hard or soft capsules, or syrups or elixirs. The therapeutic compositions of the invention may be formulated as phytoceuticals, or nutraceuticals. Phytoceuticals may optionally comprise other plant-derived components and can therefore be delivered by such non-limiting vehicles as teas, tonics, juices or syrups. Nutraceuticals contemplated by the present invention may provide nutritional and/or supplemental benefits and therefore be delivered, for example as foods, dietary supplements, extracts, beverages or the like. Phytoceutical and nutraceuticals can be administered in accordance with conventional treatment programs and/or may be a part of the dietary or supplemental program.

Formulations intended for oral use may be prepared according to methods known in art for the manufacture of pharmaceutical compositions and may contain one or more agents selected from the group of flavoring agents, coloring agents and preserving agents in order to provide palatable preparations.

Tablets contain the active ingredient in admixture with suitable non-toxic physiologically acceptable excipients including, for example, inert diluents, such as calcium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, such as corn starch, or alginic acid, binding agents, such as starch, gelatine or acacia, and lubricating agents, such as magnesium stearate, stearic acid or talc. The tablets can be uncoated, or they may be coated by known techniques in order to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.

Various additives or carriers can be incorporated into the orally delivered pharmaceutical naturopathic formulations or the invention. Optional additives of the present composition include, without limitation, phospholipids, such as phosphatidyl glycerol, phosphatidyl inositol, phosphotidyl serine, phosphotidyl choline, phosphotidyl ethanolamine as well as phosphatide acids, ceramide, cerebrosides, sphingomyelins and cardiolipins. Pharmaceutical or naturopathic formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil based medium such as peanut oil, liquid paraffin or olive oil.

Oily suspensions may be formulated by suspending the plant extract(s) in a vegetable oil, for example, arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Flavoring agents may be added to provide palatable oral preparations. These formulations can be preserved by the addition of an anti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation suitable for an aqueous suspension by the addition of water provide the active ingredient in admixture with dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents, sweetening, flavoring and coloring agents may also be present.

In another aspect of the invention, the extract produced by the invention can be used in combination with other known extracts from different plant sources. Also, the instant invention can be prepared and used in combination with other therapeutic agents such as well known drugs selected from the groups consisting of sulfonylurea, a biguanide, a thiazolidinedione, a P3-adrenergic receptor agonist, an alpha.-glycosidase inhibitor, insulin and mixtures thereof. The common yet delimiting examples of such drugs are biguanide such as metformin or buformin; a sulfonylurea such as acetohexamide, chlorpropamide, tolazamide, tolbutamide, glyburide, glypizide or glyclazide; a thiazolidinedione such as troglitazone; an a-glycosidase inhibitor such as acarbose or miglatol; or a P3-adrenergic receptor agonist such as CL-316, 243, etc; or mixtures thereof. In a further aspect of the invention there is provided a comestible, that is to say, a foodstuff comprising at least an extract of the invention, typically in dried form, such as in a lyophilized form. The skilled addressee will appreciate that such comestibles may contain more than one extract of the invention and may be used. Such foodstuffs may be used in a prophylactic manner and may contain further extracts having a similar function to the first added extract or further added extracts may be added that have a different prophylactic function. Thus a foodstuff could either comprise extracts that provide for a comestible having a single functional aspect, or a comestible may have a multi-functional prophylactic effect against two or more disease types. It is thought that a multi-functional role could be assigned to pharmaceutical formulations comprising two or more extracts possessing dissimilar therapeutic or prophylactic properties designed either for prophylaxis or for the treatment of more than one disease(s) in a mammal, particularly in a human.

The type of foodstuff or comestible to which at least an extract of the invention may be added includes any processed food such as confectionaries, baked products including breads such as loafs, and flat breads such as pitta bread, naan bread and the like, cakes, snack foods such as museli bars, compressed dried fruit bars, biscuits, dairy products such as yoghurts, milk and milk-based products such as custards, cream, cheese, butter and creme fraiche, simulated dairy food product such as Elmlea products, fruits and vegetable juices, aerated drinks, such as carbonated soft drinks and non-aerated drinks such as squashes, soya milk, rice milk and coconut milk and the like, pastas, noodles, vegetables, seed and nut oils, fruited oils such as sunflower oil, rapeseed oil, olive oil, walnut, hazelnut, and sesame seed oil and the like, and frozen confectionaries such as ice cream, iced yoghurts and the like.

The present water and ethanol based plant extracts can also be used for the management of diabetic related disorders, which are general, or local diseases directly or indirectly caused by diabetes. Specific examples thereof are diabetic acidosis, diabetic xanthoma, diabetic myatrophy, diabetic ketosis, diabetic coma, diabetic stomach disorders, diabetic gangrene, diabetic ulcer, diabetic diarrhea,' diabetic microangiopathy, diabetic uterosclerosis, diabetic cardiomyopathy, diabetic neuropathy, diabetic nephropathy, diabetic blister, diabetic cataract, diabetic dermatitis, diabetic scleredema, diabetic retinopathy, diabetic necrobiosis lipoidica, diabetic blood flow obstructions, etc

While the invention has been described in connection with specific and preferred. embodiments thereof, it is capable of further modifications without departing from the spirit and scope of the invention. This application is intended to cover all variations, uses, or adaptations of the invention, following, in general, the principles of the invention and including such departures from the present disclosure as come within known or customary practice within the art to which the invention pertains, or as are obvious to persons skilled in the art, at the time the departure is made. It should be appreciated that the scope of this invention is not limited to the detailed description of the invention hereinabove, which is intended merely to be illustrative, but rather comprehends the subject matter defined by the claims. Although the present invention has been described in considerable detail with reference to certain preferred versions thereof, other versions are possible. Therefore, the spirit and scope of the appended claims should not be limited to the description of the preferred versions contained herein.

Example 19:

Non-toxicitv data:

Acute oral toxicity study of Antidiabetic Extract Mixture — αSM8 in Sprague Dawley rats was performed in compliance with the OECD Guidelines for Testing of Chemicals, Section 4, No. 423 - Acute Oral Toxicity - Acute Toxic Class Method, adopted 17 December, 2001. The method uses pre-defined doses and the results allow a substance to be ranked and classified according to the Globally Harmonised System (GHS) for classification of chemicals which cause acute toxicity.

In the present study, single oral administration of Antidiabetic Extract Mixture — α SM8, suspended in aqueous solution of 0.5% solution of carboxy methyl cellulose (CMC), wasmade to groups of three female Sprague Dawley rats in step-wise manner to assess its acute toxicity. Following the starting dose of 2000 mg/kg, which was also repeated in the second step of the test, Antidiabetic Extract Mixture - α SM8 did not cause death of any of the treated females. Also, no abnormal clinical signs were observed in the six female rats.

In next step of the study Antidiabetic Extract Mixture - α SM8 was further tested at the dose of 5000 mg/kg, on three female rats in stepwise manner. The test article did not cause death of any of the female rats treated at 5000 mg/kg after dosing and also did not induce any signs of evident toxicity. Antidiabetic Extract Mixture - α SM8, at the dose levels of 2000 mg/lcg and 5000 mg/kg body weight, did not adversely affect body weight gain by treated rats during the 14 day observation period, post-treatment. The test article did not induce any gross pathological alterations in the tissues / organs of the treated rats as was evident during the terminal necropsy.

Based on these results, and according to the "Globally Harmonised System (GHS) for classification of chemicals which cause acute toxicity, OECD series on testing and assessment, Number 33 ; Harmonised Integrated Classification System for Human Health and Environmental Hazards of Chemical Substances and Mixtures [ENVZJMZMONO(IOO I )O]", the test article Antidiabetic Extract Mixture - α SM8 has to be classified as GHS Category 5 or Unclassified for the obligatory labeling requirement For oral toxicity. This category indicates that following acute oral exposure to Antidiabetic Extract Mixture - α SM8 in female rats, the LD50 value is expected to exceed 5000 mg/kg.

Example 20: Table 21 below shows the relative ingredient ratios of the individual extract constituents used to derive putative extract-mixtures that were subject to enzymatic and

cell-based assays.

Note:

AU formulation ingredient depicted in the table are in percentages

SMl- SM3- formulation have insulin mimetic and insulin sensitization activity α 1- formulation having α- glucosidase activity Table: The extract -mixtures with discrete bioaclivity tested.

Note: The total score of each extract is indicative of the cumulative anti-diabetic potential of the extract as inferred from the performance of individual extracts-mixtures in each of the bioactivity assays.

Claims

We claim:

1. A synergistic ayurvedic / functional food bioactive composition for managing diabetes and related disorders, said composition comprising extracts of atleast two plants selected from a group comprising Eugenia, Cinnamomum and

Salacia optionally alongwith pharmaceutically acceptable excipients.

2. The synergistic ayurvedic / functional food bioactive composition as claimed in claim 1 , wherein the extract is obtained from plant parts selected from a group comprising root, shoot, leaf, seed, and fruit; or the whole plant.

3. The synergistic ayurvedic / functional food bioactive composition as claimed in claim 1, wherein the extract is either an aqueous or organic extract.

4. The synergistic ayurvedic / functional food bioactive composition as claimed in claim 1, wherein the concentration of Eugenia extract ranges between 0-50%.

5. The synergistic ayurvedic / functional food bioactive composition as claimed in claim 1, wherein the concentration of Cinnamomum extract ranges between 5- 50%.

6. The synergistic ayurvedic / functional food bioactive composition as claimed in claim 1 , wherein the concentration of Salacia extract ranges between 0-40%.

7. The synergistic ayurvedic / functional food bioactive composition as claimed in claim 1, wherein the excipients are selected from a group comprising additives, gums, sweeteners, coatings, binders, d is integrants, lubricants, disintegration agents, suspending agents, granulating agents, solvents, colorants, glidants, anti- adherents, anti-static agents, surfactants, plasticizers, emulsifying agents, flavoring agents, viscocity enhancers and antioxidants.

8. The synergistic ayurvedic / functional food bioactive composition as claimed in claim 1, wherein the composition is formulated into dosage forms selected from a group comprising liquid, troches, lozenges, powder, granule, capsule, tablet, patch, , gel, emulsion, cream, lotion, dentrifice, spray, drop, suspension, syrups, elixirs, phyotceuticals and neutraceuticals.

9. The synergistic ayurvedic / functional food bioactive composition as claimed in claim 1, wherein the composition is free of side effects.

10. A method of treating diabetes and/or related disorders in a subject in need thereof by administering the composition comprising extracts of atleast two plants selected from a group comprising Eugenia, Cirmamomum and Salacia optionally alongwith pharmaceutically acceptable excipients to the subject.

11. The method as claimed in claim 10, wherein the related disorders comprise diabetic acidosis, diabetic xanthoma, diabetic myatrophy, diabetic ketosis, diabetic coma, diabetic stomach disorders, diabetic gangrene, diabetic ulcer, diabetic diarrhea, diabetic microangiopathy, diabetic uterosclerosis, diabetic cardiomyopathy, diabetic neuropathy, diabetic nephropathy, diabetic blister, diabetic cataract, diabetic dermatitis, diabetic scleredema, diabetic retinopathy, diabetic necrobiosis lipoidica, diabetic and blood flow obstructions.

12. The method as claimed in claim 10, wherein, the concentration of Eugenia extract ranges between 0-50%.

13. The method as claimed in claim 10, wherein the concentration of Cirmamomum extract ranges between 5-50%.

14. The method as claimed in claim 10, wherein the concentration of Salacia extract ranges between 0-40%.

15. The method as claimed in claim 10, wherein the excipients are selected from a group comprising additives, gums, sweeteners, coatings, binders, disintegrants, lubricants, disintegration agents, suspending agents, granulating agents, solvents, colorants, glidants, anti-adherents, anti-static agents, surfactants, plasticizers, emulsifying agents, flavoring agents, viscocity enhancers and antioxidants.

16. The method as claimed in claim 10, wherein the composition is free of side effects.

17. The method as claimed in claim 10, wherein the composition is formulated into dosage forms selected from a group comprising liquid, troches, lozenges, powder, granule, capsule, tablet, patch, gel, emulsion, cream, lotion, dentrifice,

5 drop, suspension, syrups, elixirs, phyotceuticals and neutraceuticals.

18. A process for preparation of a synergistic ayurvedic / functional food bioactive composition for treating diabetes and related disorders, wherein the process comprising steps of:

10 A) obtaining extracts of Eugenia, Cinnamomum and Salacia separately through steps comprising: a) contacting powdered plant material with organic or aqueous solvent to obtain solution; b) heating the solution close to boiling point of the solvent ,15 followed by its cooling; c) size-fractionating the cooled solution to obtain liquid fraction; d) concentrating and drying the liquid fraction to obtain the extracts of Eugenia, Cinnamomum and Salacia separately; and

B) mixing the extracts of atleast two plants optionally alongwith 20 pharmaceutically acceptable excipients to arrive at the synergistic composition.

19. The process as claimed in claim 18, wherein the plant material is selected from a group comprising root, shoot, leaf, seed and fruit; or the whole plant.

25 .

20. The process .as claimed in claim 18, wherein the organic solvents are selected from a group comprising heterocyclic aromatic compounds, aliphatic compounds, ketones, cyanides, alcohols, nitriles, esters, ether and mixtures of one or more thereof.

30 21. The process as claimed in claim 18, wherein the organic solvent is ethanol.

22. The process as claimed in claim 18, wherein the concentrated Eugenia extract is treated with hexane followed by collection of lower aqueous layer for preparing the synergistic composition.

23. The process as claimed in claim 18, wherein the concentrated extracts are treated with organoleptic agents selected from a group comprising decolorizing agents, deodorizing agents and debitterizing agents.

24. The process as claimed in claim 23, wherein the decolorizing agents are selected from a group comprising peroxides, carbon, metals and organic solvents.

25. The process as claimed in claim 23, wherein the decolorizing agent is preferably hydrogen peroxide.

26. The process as claimed in claim 23, wherein the deodorizing agents are selected from a group comprising peroxides, carbon and organic solvents.

27. The process as claimed in claim 23, wherein the deodorizing agent is preferably ketone.

28. The process as claimed in claim 18, wherein the composition is formulated into dosage forms like liquid, troches, lozenges, powder, granule, capsule, tablet, patch, gel, emulsion, cream, lotion, dentrifice, drop, suspension, syrups, elixirs, phyotceuticals and neutraceuticals.