WO2015189858A1

WO2015189858A1 - A synergistic herbal composition useful for the management of diabetes

Info

Publication number: WO2015189858A1
Application number: PCT/IN2015/000238
Authority: WO
Inventors: Chandra Shekhar Nautiyal; Chandana Venkateshwara Rao; Sanjeev Kumar Ojha; Ajay Kumar Singh Rawat; Dayanandan MANI; Anirban Pal; Dinesh Kumar
Original assignee: Council Of Scientific & Industrial Research
Priority date: 2014-06-12
Filing date: 2015-06-11
Publication date: 2015-12-17

Abstract

The present invention provides a synergistic herbal composition useful for lowering elevated levels of blood glucose, which comprises the plant extracts of Gymneme sylvestre (Gudmar), Tinospora cordifolia (Giloy), Pterocarpus marsupium (Vijaysar), Trigonella foenum graecum (Methi), Rubia cordifolia (Majeeth) and Berberis aristata (Daru Haridra) together with pharmaceutically acceptable additives. The process of the preparation of the composition comprises mixing of extracts of the above herbs optionally along with additives to form the oral dosage forms, which include capsules and tablets.

Description

A SYNERGISTIC HERBAL COMPOSITION USEFUL FOR THE MANAGEMENT

OF DIABETES

FIELD OF THE INVENTION [1] The present invention relates to a synergistic herbal composition useful for the management of diabetes, comprising the plant extracts of Gymneme sylvestre (Gudmar), Tinospora cordifolia (Giloy), Pterocarpus marsupium (Vijaysar), Trigonella foenum graec m (Methi), R bia cordifolia (Majeeth) and Berberis aristata (Daru Haridra). The composition serves as a remedy to relieve frequent urination, dryness of mouth, numbness debility, fatigue, excessive thirst associated with increased blood sugar. Different plant ingredients were mixed and formulated using suitable natural additives to prepare a pharmaceutically acceptable formulation useful in in treatment of diabetes.

BACKGROUND OF THE INVENTION AND DESCRIPTION OF PRIOR ART

[2] Diabetes is a chronic disorder of carbohydrate, fat and protein metabolism characterized by increased fasting and post prandial blood sugar levels. The global prevalence of diabetes is estimated to increase, from 4% in 1995 to 5.4% by the year 2025. WHO has predicted that the major burden will occur in developing countries. Studies conducted in India in the last decade have highlighted that not only is the prevalence of diabetes high but also that it is increasing rapidly in the urban population. (Ramachandran A., Snehalatha C, Viswanathan V. Burden of type 2 diabetes and its complications- the Indian scenario. Curr. Sci. 2002;83:1471-1476). Diabetes is usually a lifelong (chronic) disease in which there are high levels of sugar in the blood. There are two major types of diabetes. The causes and risk factors are different for each type:

[3] Type 1 diabetes can occur at any age, but it is most often diagnosed in children, teens, or young adults. In this disease, the body makes little or no insulin. Daily injections of insulin are needed. The exact cause is unknown. [4] Type 2 diabetes makes up most diabetes cases. It most often occurs in adulthood. However, because of high obesity rates, teens and young adults are now being diagnosed with it. Many people with type 2 diabetes do not know they have it.

[5] High blood sugar levels can cause several symptoms, including:

• Blurry vision

• Excess thirst

• Fatigue

• Hunger

• Frequent Urination

• Weight loss

[6] Because type 2 diabetes develops slowly, some people with high blood sugar have no symptoms.

[7] There are two major kinds of problem/drawbacks associated with modern antidiabetic therapy:

• Drug resistance

• Side effects of the drug.

[8] Drug resistance is the reduction in the effectiveness of a drug in curing a disease or condition. This often leads to either increase in dose or use of combination therapy. After prolonged use the combination therapy also fails, ultimately leading to dependence of the diabetic on injection of Insulin, which also shows resistance.

[9] A variety of different antidiabetic drugs are available, each performing a different function. Many people with diabetes have to take more than one type of pill, with some taking pills which combine two types of drug in one tablet.

[10] Some people experience a variety of side effects from different diabetes drugs. A side effect is an unwanted issue that is caused by a medicine. Some antidiabetic medications unfortunately include common side effects such as nausea or an upset stomach. The treating physician only will be able to advise about specific side effects and the best ways possible to avoid them.

[11] No diabetic patients should suffer the side effects of the antidiabetic drugs, and should contact the doctor immediately if side effects are causing pain. Often in the case of antidiabetic drugs such as Metformin, side effects will only be temporary.

Potential side effects of common diabetes drugs are:

Sulfonylureas: low blood sugar, upset stomach, skin rash or itching, weight gain.

Biguanides/Metformin: sickness with alcohol, kidney complications, upset stomach, tiredness or dizziness, metal taste. Alpha-glucosidase inhibitors: gas, bloating and diarrhea.

Thiazolidinediones: weight gain, risk of liver disease, anaemia risk, swelling of legs or ankles.

Meglitinides: weight gain, low blood sugar.

Advantages of herbal antidiabetics:

[12] In comparison to the allopathic drugs, the herbal antidiabetics are having less side effects with lesser incidences of drug resistance. They can be used as adjuvant to diabetes therapy and as preventive for prediabetics as well.

[13] Pterocarpus marsupium, also known as Vijayasar or the Indian Kino Tree, is a medium to large, deciduous tree that can grow up to 30 metres tall. The bark is grey, rough, longitudinally fissured and scaly. The older trees exude a blood red gum-resin. The leaves are imparip innate: the leaflets are oblong; the flowers occur in large panicles, they are yellowish and fragrant; the pods are orbicular, flat, winged. An aqueous infusion of the wood is said to be of use in diabetes. Tests on mice and rabbits with alcohol and aqueous extracts of the heartwood are said to have shown hypoglycemic action, probably by hindering the absorption of glucose in the intestine. It is effective in lowering blood sugar and total cholesterol levels in the body. The heartwood is used as an astringent and in the treatment of inflammation and diabetes, for which it has been shown to be effective due to its high pterostilbene content. In vitro studies into the plant's anti-diabetic properties have also been carried out. The gum resin of P. marsupium is the only herbal product ever found to regenerate beta cells that produce insulin in the pancreas.

[14] Gymneme sylvestre belongs to the family Asclepidaceae. Chewing the leaves suppresses the sensation of sweet. This effect is attributed to the eponymous gymnemic acids. G. sylvestre has been used in herbal medicine as a treatment for diabetes for nearly two millennia and though there is insufficient scientific evidence to draw definitive conclusions about its efficacy two small clinical trials have shown gymnema to reduce glycosylated hemoglobin levels.

[15] Tinospora Cordifolia (Amritha) is an Important Ayurvedic Plant commonly known as Guduchi. It is a large, glabrous, deciduous climbing shrub belonging to the family menispermaceae. The active principles of Tinospora cordifolia, a traditional Indian medicinal plant were found to posess anticomplementary and immunomodulatory activities. The stems are rather succulent with long filiform fleshy aerial roots from the branches. The bark is grey, brown and warty. The leaves are membranous and cordate, the flowers, small, yellow and seeds are curved.

[16] Fenugreek (Trigonella foenum-graecum): It is an annual plant of the family Fabaceae. Fenugreek is used as a herb, spice and vegetable. ESCOP and the WHO monographs indicate the use of the seeds as an adjuvant in therapies for diabetes mellitus, anorexia, and high cholesterol. The herb is helpful in lowering blood sugar and cholesterol levels. [17] Rubia cordifolia LINN.(Manjistha) is a perennial, herbaceous prickly climber which can grow to 1.5 m in height. The evergreen leaves are 5-10 cm long and 2-3 cm broad, produced in whorls of 4-7 starlike around the central stem. The flowers are small (3- 5 mm across), with five pale yellow petals, in dense racemes, and appear from June to August, followed by small (4-6 mm diameter) red to black berries. The roots can be over 1 m long, up to 12 mm thick. It prefers loamy soils with a constant level of moisture.

[18] Berberis aristata: The plant belongs to family Berberidaceae. The branches of these bushes are covered with sharp spines and are divided into 3 to 5 or even more. The leaves are bordered with spiny teeth and form the midst of the leaf cluster appears with yellow flowers in drooping racemes or fascicles. Berberis aristata has found an important place in ancient Ayurvedic systems of medicine for their efficacious medicinal properties.

[19] Thus, keeping in view the drawbacks of the hitherto reported herbal antidiabetic formulations, the inventors of the present invention realized that there exists a dire need to provide a synergistic herbal antidiabetic composition which serves as a remedy to relieve frequent urination, dryness of mouth, numbness debility, fatigue, excessive thirst associated with increased blood sugar.

OBJECTS OF THE INVENTION

[20] The main objective of the present invention is therefore to provide a herbal composition useful to overcome the symptoms of diabetes.

[21] Another objective of the invention is to provide a composition which affects the amount of insulin released by pancreas.

[22] Yet another objective of the invention is to provide a composition that increases the sensitivity of target organs to insulin.

[23] Still another objective of the invention is to provide a composition which decreases the rate at which glucose is absorbed from gastrointestinal tract with lipid lowering.

[24] A further objective of the invention is to provide a process for the preparation of the herbal composition. SUMMARY OF THE INVENTION

[25] The present invention relates to a synergistic herbal composition comprising the extracts of the plants Gymneme sylvestre (Gudmar), Tinospora cordifolia (Giloy), Pterocarpus marsupium (Vijaysar), Trigonella foenum graecum (Methi), Rubia cordifolia (Majeeth) and Berberis aristata (Daru Haridra) useful as a remedy to relieve frequent urination, dryness of mouth, numbness debility, fatigue, excessive thirst associated with increased blood sugar. Different plant ingredients were mixed and formulated using suitable natural additives to prepare a pharmaceutically acceptable formulation useful in the control of diabetes and to relieve symptoms associated therewith.

In an embodiment, the present invention provides a synergistic herbal composition comprising the extracts of the plants Gymneme sylvestre (Gudmar), Tinospora cordifolia (Giloy), Pterocarpus marsupium (Vijaysar), Trigonella foenum graecum (Methi), Rubia cordifolia (Majeeth) and Berberis aristata (Daru Haridra) in the ratio 1 :2: 1 :2:3:3. DETAILED DESCRIPTION OF THE INVENTION

[26] The words "composition" and "formulation" are used interchangeably in the present disclsoure.

[27] The present invention provides a synergistic herbal composition useful for the treatment of diabetes and lowering cholesterol, wherein the composition comprises of 50% aqueous ethanolic extracts of the plants selected from the group consisting of Gymneme sylvestre (2-5 wt%,. Gudmar), Tinospora cordifolia (1 to 3 wt%, Giloy), Pterocarpus marsupium (1-3.5 wt%, Vijaysar), Trigonella foenum graecum (1 -3.5 wt%, Methi), Rubia cordifolia (1 -3 wt%, Majeeth) and Berberis aristata (1-3 wt%, Daru Haridra) along with pharmaceutically acceptable additives and excipients. The composition can be administered in an oral dosage form such as tablets and capsules. [28] The plants used for the purposes of the present invention were procured as per the following details. Only Tinospora cordifolia [Giloy] was obtained from the Botanical Garden of CSIR-NBRI.

[29] The present invention further provides a process for the preparation of the synergistic herbal composition useful for managing diabetes, wherein the method comprising the steps of:

I. Obtaining the parts of medicinal plants namely Gymneme sylvestre (Gudmar), Tinospora cordifolia (Giloy), Pterocarpus marsupium (Vijaysar), Trigonella foenum graecum

(Methi), Rubia cordifolia (Majeeth) and Berberis aristata (Daru Haridra) such as leaves, and aerial parts.

II. Drying the plant material in shade.

IH.Powdering the dried plant material to a coarse powder.

IV.Extracting the powdered dried plant material with 50% aqueous ethanol at a temperature of 25 to 35 degree C.

V.Concentrating the obtained extract at reduced pressure at a temperature of 40 to 60 degree C.

VI.Lyophilizing the concentrated extract for complete removal of solvent.

[30] In an embodiment, the present invention provides a herbal composition wherein the composition was tested on Streptozotocin [STZ] induced diabetic rats and was found effective in treating diabetes.

[31] In another embodiment, the present invention provides a herbal composition comprising the extracts of plants selected from the group consisting of Gymneme sylvestre (2-5 wt%), Tinospora cordifolia (1-3 wt%), Pterocarpus marsupium (1-3.5 wt%), Trigonella foenum graecum (1-3.5 wt%), Rubia cordifolia (Majeeth) (1 -3 wt%) and Berberis aristata (1-3 wt%) along with pharmaceutically acceptable additives and excipients.

[32] In another embodiment, the present invention provides a herbal composition useful for the management of diabetes.

[33] In another embodiment, the present invention provides a herbal composition, wherein the plant extracts used are 50% aqueous ethanolic extracts. [34] In still another embodiment, the present invention provides a herbal composition, having the property of controlling stress and anti-diabetic property and used in treatment of both type II diabetes and type I diabetes.

[35] In yet another embodiment, the present invention provides a herbal composition useful as an anti- oxidant.

[36] In still another embodiment of the present invention, the herbal composition further comprises 80.6 - 90.7% proteins.

[37] In yet another embodiment of the present invention, the herbal composition further comprises 1.0 - 19.0% amino acids.

[38] In still another embodiment of the present invention, the herbal composition further comprises 2.845 - 6.27% fibre.

[39] In yet another embodiment of the present invention, the herbal composition further comprises 0.69% phosphorus.

[40] In still another embodiment of the present invention, the herbal composition further comprises 13.5 - 24.2% fat.

[41] In another embodiment of the present disclosure, the herbal composition reduces elevated blood sugar levels at dose levels of 50 to 200 mg/kg when administered in pharmaceutically effective dosage form.

[42] In another embodiment of the present invention, the herbal composition at a dose of 50 to 200 mg/kg did not show any abnormality of general condition during treatment of anti-diabetic activity.

[43] In still another embodiment of the present invention, the herbal composition exhibits anti- oxidant, cooling, oleaginous, astringent and nerves relaxant properties.

[44] In yet another embodiment of the present invention, the herbal composition is used to treat diabetic related diseases, serves as a blood purifier and is useful as an anti-periodic and can be externally applied on sprains and wounds. EXAMPLES

[45] The following examples are given by way of illustration and therefore should not be construed to limit the scope of the present invention. Example 1: Formulation 1 (Fl)

a. Gymneme sylvestre (Gudmar) 3wt. %

b. Starch 10wt.%

c. Calcium carbonate q.s. to make 100%

[46] Mixed the aforesaid plant constituents and filtered the solution followed by adding specified quantity of starch. Heating of the mixture was done until the starch dissolves followed by cooling and finally making up the volume to 100% with required amount of calcium carbonate. The composition was tested as to whether it is useful as an anti-diabetic or not.

Example 2: Formulation 2 (F2)

a. Gymneme sylvestre (Gudmar) 3wt. %

b. Tinospora cordifolia (Giloy) 1.5wt. %

c. Starch 10wt.%

d. Calcium carbonate q.s. to make 100%

[47] The dried plant materials were (lKg) powdered and extracted with water for 5 days. At the end of this, the solvent was decanted and filtered to remove the plant debris. The extract was then concentrated under vacuum at a temperature of less than 50 degree C.

Then the extract was lyophilized to obtain the extract in powder form. Mixed the plant extracts and dissolve them in water, filtered the solution and added specified quantity of starch and heated until the starch dissolved followed by cooling and making up the volume to 100% with required amount of Calcium carbonate. The composition was tested as to whether it is useful as an anti-diabetic or not.

Example 3: Formulation 3 (F3)

a. Gymneme sylvestre (Gudmar) 3wt. % b. Tinospora cordifolia (Giloy) 1.5wt. %

c. Pterocarpus marsupium (Vijaysar) 1.5wt%

d. Starch 10wt%

e. Calcium carbonate q.s. to make 100%

[48] The dried plant materials were (lKg) powdered and extracted with water for 5 days.

At the end of this, the solvent was decanted and filtered to remove the plant debris. The extract was then concentrated under vacuum at a temperature of less than 50 degree C.

Example 4: Formulation 4 (F4)

a. Gymneme sylvestre (Gudmar) 3wt. %

b. Tinospora cordifolia (Giloy) 1.5wt. %

c. Pterocarpus marsupium (Vijaysar) 1.5wt%

d. Rubia cordifolia 2wt.%

e. Berber is aristata 3wt. %

f. Starch 10wt.%

g. Calcium carbonate q.s. to make 100%

[49] The dried plant materials were ( 1 Kg) powdered and extracted with water for 5 days.

Then the extract was lyophilized to obtain the extract in powder form. Mixed the plant extracts and dissolve them in water, filtered the solution and added specified quantity of starch and heated until the starch dissolved followed by cooling and making up the volume to 100% with required amount of Calcium carbonate. The composition was tested as to whether it is useful as an anti-diabetic or not. Example 5: Formulation 5 (F5)

a. Gymneme sylvestre (Gudmar) 3wt. %

b. Tinospora cordifolia (Giloy) 1.5wt. %

c. Pterocarpus marsupium (Vijaysar) 1.5wt%

d. Rubia cordifolia 2wt.%

e. Berberis aristata 3wt. %

f. Trigonella foenum graecum 3wt. %

g. Starch 10wt.%

h. Calcium carbonate q.s. to make 100%

[50] The dried plant materials were (lKg) powdered and extracted with water for 5 days.

[51] Table 1: Effect of the compositions prepared in examples 1 to 5 on blood glucose levels in normal and STZ induced diabetic rats

rats 4.05 ± 14.9 ± 21.0 ± 8.31

Group III: 98.5 ± ¹⁵⁵¹ 351.5 [56] 288.0 [57] 167.3

F- 1 3.87 ± 10.6* ± 20.5 ± 7.35^*

Group IV: 101.2 345.1 ± 12.8 198.6 ± 18.4 123.5 ±

F- 2 ± 5.18 6.72

Group V: 93.8 ± 321.8 ± 12.76 169.3 ± 94.5 ±

F- 3 4.97 6.02"^* 9.24

Group VI: 103.3 327.3 ± 13.41 172.3 ± 80.16 ±

_{Λ Λ}„***

F- 4 ± 7.16 8.36 2.79^***

Group VII: F- 5 108.5 325.1 ± 12.01 170.7 ± 70.11 ±

± 8.13 g I ] *** 2 22***

Group VIII: 85.3 ± 350.6 ± 17.34 175.5 ± 71.5 ±

(Metformin) 2.67 2.83*** 4_]***

[58] The values are expressed as mean ± S.E.M., n = 6 rats per group.

[59] Significant difference of diabetic control from normal control on consecutive days:

#P < 0.001

[60] Significant difference of treated groups from diabetic control on the corresponding days: * P < 0.05, ** P < 0.01 , *** P < 0.001.

[61] The animals were grouped and treated for 21 days to monitor the effect of the prepared compositions on streptozotocin induced diabetic rats for 21 days. The details of the groups are presented below:

[62] Group 1: Vehicle control given distilled water only. [63] Group 2: Diabetic rats which served as negative control and given distilled water only.

[64] Group 3: Diabetic rats treated with 200mg/Kg body weight of formulation 1 (Fl).

[65] Group 4: Diabetic rats treated with 200mg/Kg body weight of formulation 2 (F2). [66] Group 5: Diabetic rats treated with 200mg/Kg body weight of formulation 2 (F3).

[67] Group 6: Diabetic rats treated with 200mg/Kg body weight of formulation 2 (F4).

[68] Group 7: Diabetic rats treated with 200mg/Kg body weight of formulation 2 (F5).

[69] Group 8: Diabetic rats treated with 200mg/Kg body weight of Metformin.

[70] Moreover, from table 1 it is observed that the results using F5 and commercial sample (metformin) are comparable. Thus, the advantages of F5 do not pull down the normal glucose levels in normal or fasting subjects.

[71] Formulation (F 1 ) consists of Gymneme sylvestre (Gudmar).

[72] Formulation (F2) consists of Gymneme sylvestre (Gudmar), Tinospora cordifolia (Giloy). [73] Formulation (F3) consists of Gymneme sylvestre (Gudmar), Tinospora cordifolia (Giloy), Pterocarpus marsupium (Vijaysar).

[74] Formulation (F4) consists of Gymneme sylvestre (Gudmar), Tinospora cordifolia (Giloy), Pterocarpus marsupium (Vijaysar), Rubia cordifolia (Majeeth) and Berberis aristata (Daru Haridra). [75] Formulation (F5) consists of Gymneme sylvestre (Gudmar), Tinospora cordifolia (Giloy), Pterocarpus marsupium (Vijaysar), Rubia cordifolia (Majeeth) and Berberis aristata (Daru Haridra), Trigonella foenum graecum (Methi). The results showed significant reduction of blood glucose levels in the group treated with a dose of 200 mg/kg/day (p<0.001) for 21 days and F5 shows maximum protection and significantly reduced the blood glucose levels. ADVANTAGES OF THE INVENTION

[76] The developed formulation does not have any side effects in saturation of beta cells of the pancreas and main advantage is that it does not lower the normal blood glucose levels and brings back the elevated levels of the biochemical glucose parameters in diabetes pateients.

Claims

We claim:

1. A synergistic herbal composition comprising the extracts of plants selected from the group consisting of Gymneme sylvestre (2 to 5 wt%), Tinospora cordifolia (1 to 3 wt%), Pterocarpus marsupium (1 to 3.5 wt%), Trigonella foenum graecum ( 1 to 3.5 wt%), Rubia cordifolia (1 to 3 wt%) and Berberis aristata ( 1 to 3 wt%) along with pharmaceutically acceptable additives and excipients.

2. A composition as claimed in claim 1 , useful for the management of diabetes.

3. A composition as claimed in claim 1 , wherein the plant extracts used are 50% aqueous ethanolic extracts.

4. A composition as claimed in claim 1 , wherein it exhibits the property of controlling stress and used in treatment of both type II and type I diabetes.

5. A composition as claimed in claim 1 , wherein it reduces elevated blood sugar levels at dose levels of 50 to 200 mg/kg when administered in pharmaceutically effective dosage form.

6. A process for the preparation of the synergistic herbal composition as claimed in claim 1, wherein the steps comprising:

[a] drying the leaves and aerial parts of the medicinal plants Gymneme sylvestre (Gudmar), Tinospora cordifolia (Giloy), Pterocarpus marsupium (Vijaysar), Trigonella foenum graecum (Methi), Rubia cordifolia (Majeeth) and Berberis aristata (Daru Haridra) in shade; [b] powdering the dried plant material as obtained in step [a] to a coarse powder;

[c] extracting the powdered plant material as obtained in step [b] with 50% aqueous ethanol at a temperature of 25 to 35 degree C;

[d] concentrating the extract as obtained in step [c] at a temperature of

40 to 60 degree C;

[e] lyophilizing the concentrated extract as obtained in step [d] for complete removal of solvent.