WO2008041049A1 - Extraits végétaux de cinnamomum zeylanicum destinés au traitement du diabète et procédé d'extraction de celui-ci - Google Patents
Extraits végétaux de cinnamomum zeylanicum destinés au traitement du diabète et procédé d'extraction de celui-ci Download PDFInfo
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- WO2008041049A1 WO2008041049A1 PCT/IB2006/002906 IB2006002906W WO2008041049A1 WO 2008041049 A1 WO2008041049 A1 WO 2008041049A1 IB 2006002906 W IB2006002906 W IB 2006002906W WO 2008041049 A1 WO2008041049 A1 WO 2008041049A1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/54—Lauraceae (Laurel family), e.g. cinnamon or sassafras
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
- A23L33/105—Plant extracts, their artificial duplicates or their derivatives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
Definitions
- the present invention relates to herbal extracts from Cinnamomun zeylanicum plant species with hypoglycemic activity, which is characterized in delaying of onset and / or management of diabetes by inhibiting the glucose absorption in the intestine and by mimicking and potentiating the insulin activity and also to a method for producing the extract and the use of the extract in the treatment of diabetes.
- the invention relates to the extraction process of derivation of the extract from Cinnamomun zeylanicum, which is characterized in that the solvent used is 70% ethanol.
- the herbal extracts comprise active ingredients that delay saccharide digestion or absorption thereby suppressing a rise in postprandial and / or fasting blood glucose levels.
- IDDM insulin-dependent diabetes mellitus
- NIDDM non-insulin-dependent diabetes mellitus
- IDDM results from insulin deficiency caused by cell-mediated autoimmune destruction of pancreatic beta cells, and generally develops in the young (Bach J F., Insulin-dependent diabetes mellitus as a beta cell targeted disease of immunoregulation. J. Autoimm. 8:439-463,1995).
- IDDM accounts for approximately 10-15% of the diabetic population worldwide (World Health Organization Study Group. Diabetes mellitus. WHO Tech. Rep. Ser. 727:1-113,1985). In contrast, NIDDM results from a variable combination of insulin resistance and insulin deficiency and generally develops in adults (Jun H S, et al., Pathogenesis of non-insulin- dependent (Type II) diabetes mellitus (NIDDM) Genetic predisposition and metabolic abnormalities. Advanced Drug Delivery Reviews 35:157-177, 1999; DeFronzo R A., The triumvirate beta cell, muscle, liver: a collusion responsible for NIDDM. Diabetes 37:667- 687, 1988).
- NIDDM can also develop at a younger age, as seen in the maturity- onset diabetes of the young (Pirart J., Diabetes mellitus and its degenerative complications: a prospective study of 4400 patients observed between 1947 and 1973. Diabetes Care 1:168-188, 1978). NIDDM accounts for over 85% of the diabetic population worldwide.
- Factors responsible for causing diabetes are heredity and obesity.
- Heredity increases the susceptibility of beta cells to viral invasions or favor the development of autoimmune antibodies against the beta cells, thus leading to their destruction.
- Obesity decreases the number of insulin receptors in the insulin target cells throughout the body. Hence, the amount of insulin present is inadequate to induce its usual metabolic effects.
- blood glucose levels goes as high as 1200 mg/dl are known to occur which is 12 times higher than the normal. Levels of 300 mg/dl to 500 mg/dl are common in diabetic patients.
- Diabetic Symptoms which may arise due to pathological physiology of Insulin lack, are Polyuria, Polydipsia, Polyphagia, Asthenia and diminished utilization of carbohydrates for energy.
- Diabetic Neuropathy is the most common and affects patients at earlier stages.
- the usual methods for diagnosing diabetes are based on various chemical tests of urine and the blood viz, Urinary Sugar, Fasting Blood Glucose Level, Postprandial Blood Glucose Level (Glucose Tolerance Test) and Acetone breath.
- Reduction of carbohydrate absorption in the intestine of animals, especially humans is nutritionally and medically of great importance. Reduction of absorption can for example facilitate body weight management, e.g. as part of a method of treating obesity, and can be advantageous for subjects suffering form diabetes or hypoglycemic state.
- Herbal ingredients such Gurmar leaves ⁇ Gymnema sylvestre), Methi seeds (Trigonella foenumgrecum), Vijayasar heartwood (Pterocarpus marsuphim), Jamun seeds (Eugenia jambolana), Karela (Momordica charantid) etc are few examples in this category.
- the present invention relates to the extracts of Cinnamomun zeylanicum in the delaying the onset and / or management of diabetes and the related conditions thereof as the complications mentioned supra.
- the genus Cinnamomnm is comprised of over 250 species of trees and shrubs from east and Southeast Asia to Australia (Bailey et al., 1976, Riffle 1998, Wagner et al. 1999). Cinnamomum spp. originates from the island Sri Lanka. It is also native to South-west India and the Tenasserim Hills of Burma.
- Cinnamomum burmannii Indonesian Cinnamomun
- Cinnamomum cassia Cinnamomum cassia
- Cinnamomum lourerase Vietnamese Cinnamomun
- Cinnamomum zeylanicum Cinnamomum zeylanicum
- Cinnamomun 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.
- Cinnamomun is one of the oldest herbal medicines known, having been mentioned in Chinese texts as long as 4,000 years ago. The first medicinal use of Cinnamomun was in Egypt and parts of Europe as far back as 500 BC. Cinnamomun is often used for medicinal purposes due to its unique properties. These main properties of Cinnamomun are astringent, warming stimulant, carminative, antiseptic, antifungal, anti-viral, blood purifier, and digestive aid. All of these properties of Cinnamomun make it a good medicinal plant. Cinnamomun has many historical medicinal uses in different cultures. Some of these uses include treatment of diarrhea, arthritis, menstrual cramps, heavy menstruation, and yeast infections.
- Cinnamomun was taken as medicine for colds, flu, and digestive problems.
- Today Cinnamomun is used for many of these same traditional reasons. Often Cinnamomun is used as a nonessential addition to other remedies, than as a remedy by itself. Often this is because Cinnamomun is a stimulant to other herbs and the body, enabling herbal remedies to work faster.
- Cinnamomun is also known to be acting as an insulin substitute in type 2 diabetes. Cinnamomun contains bioactive components that scientists believed has the potential to either prevent or overcome diabetes.
- Cinnamomum cassia ranging from 1- 6 grams a day provided in divided daily doses all produced some significant reductions in blood sugar levels, total cholesterol levels, triglyceride levels and finally even lower levels of LDL lipoproteins. But this study was limited to the Chinese Cinnamomun herb.
- Cinnamomun has a positive effect on the glycemic control and the lipid profile in patients with diabetes mellitus type 2.
- the aim of this trial was to determine whether an aqueous Cinnamomun purified extract improves glycated hemoglobin AIc (HbAIc), fasting plasma glucose, total cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL) and triacylglycerol concentrations in patients with type 2 diabetes.
- HbAIc glycated hemoglobin AIc
- LDL low-density lipoprotein
- HDL high-density lipoprotein
- Cinnamomun bark and olive leaf has certain effects on streptozotocin-induced tissue injury.
- the effects on glycaemia were evaluated. Long-term administration of olive leaf caused significant improvement in tissue injury induced by streptozotocin treatment; the effect of Cinnamomun bark was less extent. No effects on blood glucose levels were detected. However, significant decreases in some increased biochemical and haematological parameters of streptozotocin-treated rats were observed. Aspartate aminotransferase, urea and cholesterol levels were significantly decreased by treatment with both plant materials, and alanine aminotransferase by treatment with olive leaf. Cinnamomun bark also caused a significant decrease in platelet counts.
- Cinnamomun extracts on blood glucose, triglyceride, total cholesterol, HDL cholesterol, and LDL cholesterol levels in people with type 2 diabetes by Khan et a L, in 2003.
- the Cinnamomun was consumed for 40 days followed by a 20-day washout period.
- Cinnamomun extract CE
- HFD high- fructose diet
- the decreased glucose infusion rate (GIR) in HFD-fed rats 60 % of controls, p ⁇ 0.01 was improved by CE administration to the same level of controls (normal chow diet) and the improving effect of CE on the GIR of HFD-fed rats was blocked by approximately 50 % by N-monometyl-L-arginine. The same tendency was found during the 30-mU/kg/min insulin infusions.
- IR skeletal muscle insulin receptor
- IRS IR substrate
- PI phosphatidylinositol
- the subject matter of the current invention describes extracts isolated from Cinnamomum zeylanicum and other related species of Cinnamomum such as C.burmannii which was the result of the planned experiments conducted to test the hypoglycemic potential of the said extracts, further analysis of their potential positive hypoglycemic properties which include its potent inhibitory effect on glucose absorption in the intestine.
- the present invention relates to methods and various compositions and / or formulations for treating and preventing diabetes and its associated symptoms and conditions. Specifically, the present invention relates to ethanol based extracts obtained from the Cinnamomun plant sp based on extraction methods and nutraceutical formulations comprising the foregoing extracts for treating Type II Diabetes and related conditions. Further, the present invention provides methods for inhibiting the onset or reducing the onset potential of future or additional diabetic developments. The present invention is suited for treatment and prevention of diabetes as commonly experienced in mammals, and particularly humans. Pharmaceuticals play a major role in the treatment of diabetes. Medications, such as Glycosidase inhibitors (Glucobai), Amylase, Glibenclamide, and Niacinamide are effective control drugs. Treatment of Type 1 diabetes functions to maintain blood glucose at near normal levels, and may require home blood glucose testing and multiple daily insulin injections. While the existing therapies have some efficacy, there remains a continuing need for alternative therapeutic preferably herbal remedies that can augment or replace the existing therapies.
- Type II diabetes patients suggested treatments start with diet and exercise. If the two measures fail to bring blood sugar levels under control, anti-diabetic drugs may be prescribed.
- the most commonly prescribed drugs categories for treatment of Type II diabetes are 1) drugs that stimulate insulin secretion; and 2) drugs that sensitize cells to insulin action.
- Side effects include hypoglycemia, upset stomach, skin rash or itching, weight gain, kidney problems, fatigue, dizzy spells, gloating and diarrhea. Beyond the unpleasant side effects associated with traditional oral medication, there are two problems with such drugs. One is the sudden surge of insulin in response to the blockage of the potassium channels. Ideally, insulin should be secreted after a meal when the glucose level is high.
- insulin release stimulated by drugs may not happen at the right time, or may be excessive causing a great fall in blood sugar level, or hypoglycemia, a dangerous condition with neurological side effects.
- the other problem is that long-term drug use may cause degeneration of insulin granules causing them to have to work harder.
- Herbal medications would be naturally available with minimal or no side effects, lower costs and of equal or greater efficacy than the existing therapies and medications. Nevertheless, it would be preferable instead of treating diabetes with drugs. Natural means are generally much more acceptable to patients, which results in an increased compliance.
- Figure 1 Shows the free radical scavenging ability of the Cinnamomum zeylanicum 70% ethanol based bark extract comparable to ascorbic acid standard.
- Figure 2 Shows the percent polyphenol content of the Cinnamomum zeylanicum 70% ethanol based bark extract comparable to gallic acid standard.
- Figure 3 Shows the IC50 ( ⁇ g/ml) value for a-glucosidase (0.2 EU) inhibition of the Cinnamomum zeylanicum 70% ethanol based bark extract compared to acarbose standard in a reaction mixture containing 3mM Para-nitro-phenyl-D-glucose.
- Figure 4 Shows Insulin mimetic activity of the 3.33 ⁇ g of Cinnamomum zeylanicum 70% ethanol based bark extract compared to that of 1OnM Insulin using tritiated glucose as an energy source in 3T3 L-I adipocyte cell lines.
- Figure 5 Shows Insulin sensitization activity of the 3.33 ⁇ g of Cinnamomum zeylanicum 70% ethanol based bark extract compared to that of 1 OnM Insulin using tritiated glucose as an energy source in 3T3 L-I adipocyte cell lines.
- Figure 6 Shows Insulin mimetic activity of the 3.33 ⁇ g of Cinnamomum zeylanicum 70% ethanol based bark extract compared to that of 1OnM Insulin using tritiated glucose as an energy source in C2C12 myocyte cell lines.
- Figure 7 Shows Insulin sensitization activity of the 3.33 ⁇ g Cinhamomum zeylanicum 70% ethanol based bark compared to that of 1OnM Insulin using tritiated glucose as an energy source in C2C12 myocyte cell lines.
- Figure 8 Shows the percent changes in postprandial blood glucose level of diabetic Sprague dawley rats at different levels of Cinnamomum zeylanicum 70% ethanol based bark extract intervention (50, 125 and 250 mpk) compared to that of baseline values over 5 weeks.
- Figure 9 Shows the percent changes in fasting blood glucose level of diabetic Sprague dawley rats at different levels of Cinnamomum zeylanicum 70% ethanol based bark extract intervention (50, 125 and 250 mpk) compared to that of baseline values over 5 weeks.
- the primary objective of the present invention is to identify, test, characterize and screen extracts isolated from the plant species of family Lauraceae, preferably of the genus Cinnamomum for their potent inhibitory effects on diabetes.
- Another object of the invention is to provide a method of treating diabetes comprising administering to a person in need thereof an anti- diabetic or hypoglycemic effective amount of a composition comprising the extracts of the plant Cinammonium (Cinnamon).
- a particular embodiment of the invention describes the method of a suitable aqueous or organic solvent-based extraction of a specific therapeutically important phytochemical extract.
- the therapeutic potential of the said extracts has been studied and confirmed through standard in vitro cell free and cell based assays.
- the present invention also features a nutraceutical formulation comprising the extracts isolated designed to treat diabetes and its associated or related conditions and symptoms, as well as to balance and normalize insulin output and subsequent glucose transfer and to help maintain these to be within proper ranges.
- 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, which results in the lowering of the blood glucose level of the patient. Administration of the composition to the patient both prevented and treated incidences of clinical diabetes.
- the potential plant is a member of the family Lauraceae.
- the potential plant 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 personal suffering from diabetes which results in the lowering of the blood glucose level of the patient.
- Cinnamomun 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.
- extract refers to a concentrated preparation of the essential constituents of the medicinal plant.
- an extract is prepared by drying and powderizing the plant.
- the plant, the dried plant or the powderized plant may be boiled in solution.
- the extract may be used in liquid form, or it may be mixed with other liquid or solid medicinal herbal extracts.
- the medicinal herbal extract may be obtained by further precipitating solid extracts from the liquid form.
- 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.
- 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.
- a process for obtaining a plant extract possessing hypoglycemic properties 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) analyzing the plant extracts for free radical scavenging potential, Intestinal alpha-glucosidase inhibition potential, in-vitro screening of Cinnamomum zeylanicum 70% ethanol bark extracts for glucose uptake and the in-vivo efficacy studies.
- 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 seed of the plant.
- the plant material can be treated prior to extraction, for example, by drying, freezing, lyophilizing, or some combination thereof.
- the plant material can be fragmented and/or homogenized by some means such that a greater surface area is presented to the solvent.
- 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 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.
- plant material is extracted with an aqueous solvent.
- suitable solvents include but are not limited to water, buffers, cell media, dilute acids or bases and the like.
- the plant material is extracted with an alcoholic solvent.
- suitable alcoholic solvents include, but are not limited to methanol, ethanol, n-propanol, iso-propanol, 2-butanol, ter-butanol, and combinations thereof. But preferably 70% ethanol water is used as solvent for extraction purposes.
- the coarse powder of herbal material is soaked in 70% ethanol water for a fixed duration at room temperature with constant stirring in pharmaceutical grade solvent extractor.
- the extract is passed though a continuous centrifuge rotating at 3000rpm to separate extract supernatant and material debris.
- the clear supernatant obtained is concentrated to 1/10 volume using concentrator and is treated with food grade organic solvents in a definite proportion to remove any unpleasant smell, taste and color.
- the concentrated and organoleptically optimized extract is dried completely using either spray drier or vacuum drier to get powdered extract.
- Thus prepared dried extract is stored in airtight food grade plastic bins and the same is taken through several in-vitro cells free and cell based bioassay to validate the extract efficacy.
- 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, which is the potential extract, and a solid fraction. Separation of the liquid and solid fractions can be achieved by one or more standard processes known to those skilled in art.
- the present invention contemplates the large-scale preparation of the selected plant extracts of the invention.
- Such extracts can be prepared on a commercial scale by repeating the extraction process that lead to the isolation of the extract of interest.
- the small-scale extraction procedure can simply be scaled up and additional steps of quality control can be included to ensure reproducible results for the resulting extracts.
- modifications to the small-scale procedure that may be required during the scale up for the industrial level production of the extract.
- modifications may include for example, alterations to the solvent being used or to the extraction procedure per se employed in order to compensate for variations that occur during the scale-up and render the overall procedure more amenable to industrial scale production, or more cost effective. Modifications of this type are standard in the industry and would be readily apparent to those skilled in the art.
- concentration of the purified extracts or partially purified extracts by solvent removal from the original extract and/or fractionated extract, and/or purified extract.
- solvent removal include, but are not limited to rotary evaporation, distillation (normal and reduced pressure), centrifugal vacuum evaporation (speed vac), and lyophilisation.
- the potential extracts obtained thereof are concentrated and solubilised in an appropriate solvent preferably ethyl acetate.
- an appropriate solvent preferably ethyl acetate.
- organic solvents include but are not limited to, di-ethyl ether, hexane, heptane, dichloromethane, ethyl acetate, butyl alcohol, ether, acetone and the combinations thereof.
- 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.
- the isolated extracts 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 Cinnamomun 70% ethanol extract isolated from the barks of the plant showed nearly 34% of free radical scavenging potency equivalent to that of ascorbic acid.
- apple polyphenols have a positive effect on diabetes and insulin resistance in animals and humans.
- European researchers announced that an apple-derived polyphenol, phlorizin, "completely normalized insulin response" in diabetic rats.
- 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.”
- the total polyphenol content of the Cinnamomun 70% ethanol extract was estimated relative to gallic acid using Calorimetric - Singleton method (Singleton, V.L. and Ropssi, J. A. Jr (1965). Calorimetry of total phenolics with phosphomolybdic - phosphotungstic acid reagent, Am. J. Enol. Vitig. 16: 144 - 158).
- the Cinnamomun 70% ethanol bark extract showed 16 ⁇ 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. Tests to confirm the Intestinal ⁇ -glucosidase inhibition potential
- oligosacharrides (carbohydrates having 2 to 10 glucose residues connected by 1-4 or 1-6 ⁇ -D-glycosidic linkage) into monosaccharides by alpha- glucohydrolase-catalyzed enzymatic reactions was tested for Cinnamomum zeylanicum 70% ethanol bark extract using Calorimetric - para-nitro-phenyl (pNP) release method using pNP-a-D-glucoside (Halvorson. H, 'Methods in enzymology' VoI 8, Academics Press, New York, 1966, p 559-562).
- Cinnamomun 70% ethanol bark extract showed greater ⁇ -glucosidase inhibition potential (IC50 value of 147.06 ⁇ g/ml) relative to the commercially available ⁇ - glucosidase inhibitor, acarbose (IC50 value of 146.55 ⁇ g/ml) for 0.2 ⁇ -glucosidase enzyme units at standard enzymatic reaction conditions.
- Insulin-stimulated 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 Cinnamomun 70% ethanol extract (0.034 ⁇ g to 33.4 ⁇ g) are tested for insulin mimetic and sensitization effects with / without insulin.
- 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 microliter 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.
- 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.
- 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.
- compositions comprising two or more plant extracts various ratios of the constituent plant extracts are contemplated.
- the ratio of extract A to extract B can vary anywhere between 1 :99 and 99:1.
- anywhere between 99:1 and 1 :99 it is meant that the ratio of the two extracts can be defined by any ratio within this ratio can be between 98:2 and about 1 :99 between about 98:2 and 2:98, between 97:3 and 1 :99, between 97:3 and 2:98, between 97:3 and 3:97, etc.
- the present invention contemplates the ratio of the two extracts is between about 90:10 and 10:90, 80:20 and 20:80, 70:30 and 30:70, 60:40 and 40:60 or 50: 50.Analogous ratios are contemplated for compositions comprising more than two or more plant extracts.
- 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.
- 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. Modes of administration:
- 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 earners, 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.
- 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.
- suitable non-toxic physiologically acceptable excipients including, for example,
- 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, phospliotidyl inositol, phospliotidyl serine, phosphotidyl choline, phosphotidyl ethanolamine as well as phosphatide acids, ceramide, cerebrosides, sphingomyelins and cardiolipins.
- compositions for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatine capsules wherein the active ingredient is mixed with water or an oil based medium such as peanut oil, liquid paraffin or olive oil.
- an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
- 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.
- a comestible that is to say, a foodstuff comprising at least an extract of the invention, typically in dried form, such as in a lyophilised form.
- cosmetibles 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.
- 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.
- 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.
- processed food such as confectionaries,
- the present ethanol based plant extracts can also be used for the management of other diabetic complications 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.
- the invention will now be exemplified with reference to the following Examples section. It is to be understood that the examples are not to be construed as limiting the scope of the invention in any way.
- the present invention relates to mixtures, which can be isolated from Cinnamomun bark (Lauraceae family) for the management of an important clinical problem like diabetes.
- Cinnamomun bark Lauraceae family
- the following examples set forth and present the effects of Cinnamomum species on both pre-existing diabetes conditions, as well as the preventative effects of Cinnamomum species against the onset of or contracting diabetes. These examples are not intended to be limiting in any way, but are merely illustrative of the beneficial, advantageous, and remedial effects of Cinnamomum species on diabetes. Other non-limiting examples of the present invention are described below.
- Cinnamomum zeylanicum bark is selected and tested for quality by pharmacognosy techniques.
- the authentic plant material is procured for bioactive extraction. Good quality bark is macerated into solvent extractable seed powder of preferable size of lOO ⁇ m.
- the bioactive extract is prepared from the bark. 70% ethanol water mixtures are used as solvent for the preparation of the bioactive extract.
- the extraction process is carried out in a solvent extraction vessel of 100-liter capacity. The extraction process is undertaken at a temperature of 25 0 C and for a duration of 240 minutes. The extraction is carried out with constant stirring at the rate of 200 rpm allowing the heavier particles in the extraction mixture to settle down and later the mixture is allowed to stand undisturbed for 120 minutes.
- the liquid phase of the extract is clarified by centrifugation.
- the centrifugation process is undertaken at 3000 rpm and at room temperature.
- the clarified extract was then concentrated to 1/10 of the total volume.
- the concentrated extract (two parts) is mixed well with a moderately non-polar solvent such as ethyl acetate (one part) in an extraction vessel for 60 minutes and left undisturbed for 120 minutes.
- the lower water phase is then separated and dried completely to powder using either spray drier or vacuum dried under reduced pressure.
- the powdered extract is then stored in an airtight plastic container. This extract is further used for all the biochemical, physiochemical, heavy metal, natural toxin and detailed efficacy study.
- Cinnamomun 70% ethanol bark extract isolated by the above mentioned method is tested 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 Cinnamomun 70% ethanol bark extract showed 34 ⁇ 2.5 % free radical scavenging potency equivalent to ascorbic acid upon comparison, which is depicted in figure 1.
- the total polyphenol content of the Cinnamomun 70% ethanol bark extract is estimated relative to gallic acid using Calorimetric - Singleton method (Singleton, V. L. and Ropssi, J. A. Jr (1965). Calorimetry of total phenolics with phosphomolybdic - phosphotungstic acid reagent, Am. J. Enol. Vitig. 16: 144 - 158).
- the Cinnamomun 70% ethanol bark extract showed 16 ⁇ 2.25 % total phenol content equivalent to gallic acid, which is shown in figure 2.
- oligosacharrides carbohydrates having 2 to 10 glucose residues connected by 1-4 or 1-6 alpha-D-glycosidic linkage
- pNP Calorimetric - para-nitro-phenyl
- Cinnamomum 70% ethanol bark extract showed greater ⁇ -glucosidase inhibition potential (IC50 value of 147.06 ⁇ g/ml) relative to the commercially available - ⁇ glucosidase inhibitor, acarbose (IC50 value of 146.55 ⁇ g/ml) for 0.2 ⁇ -glucosidase enzyme units at standard enzymatic reaction conditions.
- IC50 value 147.06 ⁇ g/ml
- acarbose IC50 value of 146.55 ⁇ g/ml
- Example 5 In- vitro screening of Cinnamomun 70% ethanol bark extract for glucose uptake
- Insulin-stimulated 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 Cinnamomun 70% ethanol extract (0.034 ⁇ g to 33.4 ⁇ g) are tested for insulin mimetic and sensitization effects with / without insulin.
- 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 microtiter 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.
- the amount that showed best insulin mimetic and sensitization activity in 3T3L-1 adipocyte cells and C2C12 myocyte cells for glucose uptake was around 0.334 ⁇ g.
- the method followed for screening is as follows:
- Preadipocytes (3T3L-1) and premyocytes (C2C12) are cultured in DMEM containing 10%FCS, 4mM Glutamine, 2 % NaHCC ⁇ and antimycotic, in an atmosphere of 5% CO2 at 370C, separately.
- Myoblasts are cultured up to 80% confluency 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 Shours.
- 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 (300 ⁇ g/well, 30 ⁇ g/well, 3 ⁇ g/well and 0.3 ⁇ g/well) in triplicates for 18 hours at 370 C and 5%CO2 lOO ⁇ l of DMEM. The medium is then removed and the cells are incubated with ICRH buffer (100 microliters) at 37 0 C and 5% CO2 for 10 minutes. Cells are incubated with insulin.
- ICRH buffer 100 microliters
- the cells are washed three times with ice-cold KRH buffer (lOO ⁇ l). KRH buffer is removed and 20 ⁇ l 1 % Triton X is added to each well to lyse the cells and incubate for 10 min at 37 0 C and 5%CO 2 . 200 ⁇ l 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 Cinnamomun 70% ethanol bark extract is depicted in figure 4 to figure 7 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 6 In-vivo efficacy screening using Sprague dawley rats
- hi- vivo efficacy screening of Cinnamomun 70% ethanol extract was done using Sprague dawley rats and the procedure undertaken is as follows: Sprague dawley rats weighing ⁇ 250g with a variation of + 20% of the mean weight are selected for In-vivo efficacy screening of Cinnamomun 70% ethanol extract.
- the identification is undertaken by the cage tag and the corresponding picric acid color body markings.
- the number of animals selected in a group is five and kept in a experimental room after veterinary examination.
- the route of administration is oral gavage.
- the rats are fed with 5 % glucose water for two days before STZ injection to avoid death due to hypoglycemic shock.
- Rats are fasted for 12 hours and injected intraperitoneally with 45mg/kg-body weight of streptozotocin. Blood collection is undertaken with CO2 anesthesia and FBG analysis before STZ injection is performed which serves as the normal baseline (60-120mg/dl) for the animals. Citrate buffer (Ph of 4.5) is used as the vehicle. STZ is a photo, temperature and Ph sensitive chemical; hence the animals are injected with in 45 minutes of the dose formulation. Animals initially become hypoglycemic for the first 3 days because of the insulin surge into the blood stream. Gradually from day 4 animals attain hyperglycemia.
- Example 7 Screening of Cinnamomun 70% bark extract at 50, 125 and 200 mg/kg- body weight.
- the dosing formulations are prepared freshly each day 0.5% CMC was used as the vehicle.
- the test article Cinnamomun 70% bark extract * is administered by oral gavage to each rat daily, for 35 consecutive days.
- the animals were dosed at approximately the same time each day where possible using a stainless steel intubation needle fitted onto a suitably graduated glass syringe.
- the dosage volume administered to individual rat was adjusted according to its most recently recorded body weights. Treatment in this manner continued once a day, seven days a week, for a total period of 35 days.
- Vehicle control group animals are treated with the vehicle only at the same dosage volume i.e. 10 ml/kg body weight.
- the Groups include: Gl -Vehicle control, G2-Diabetic control, G-3 Diabetic animals treated with Pioglitazone (Standard anti-diabetic drug) 20mg/kg-body weight.
- all cages were checked early on each working day and again in the afternoon and evening to look for dead or moribund animals to allow necropsy examination to be carried out during the working hours of that day.
- the postprandial blood glucose lowering potential of Cinnamomun 70% bark extract extracts at different concentrations are illustrated in figure 9.
- the diabetic control rat group showed 240% increase in their postprandial blood glucose levels compared to the baseline values of the same group at the start of the study. While the groups treated with pioglitazone, Cinnamomum zeylanicum 70% bark extract at 50, 125 and 200mpk (milligram per kg body weight) did not show any significant percent change from their baseline values.
- the results have been represented in Table No. 1
- the postprandial blood glucose lowering potential of Cinnamomum 70% ethanol bark extracts at different concentrations are illustrated in figure 8.
- the diabetic control rat group showed 240% increase in their postprandial blood glucose levels compared to the baseline values of the same group at the start of the study. While the groups treated with pioglitazone, Cinnamomum 70% ethanol bark extract at 50, 125 and 200mpk (milligram per kg body weight) did not show any significant percent change from their baseline values.
- the results have been represented in Table No. 1
- the fasting blood glucose lowering potential of the Cinnamomum 70% ethanol bark extracts at different concentrations are illustrated in figure 9.
- the diabetic control rat group showed 246% increase in their fasting blood glucose levels compared to the baseline values of the same group at the start of the study.
- the results have been represented in Table No. 2
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Abstract
La présente invention concerne des extraits végétaux provenant du végétal Cinnamomun zeylanicum qui présente une activité hypoglycémiante. Lesdits extraits se caractérisent en ce qu'ils retardent le déclenchement du diabète et/ou permettent de le gérer, en inhibant l'absorption du glucose dans l'intestin, et en imitant et potentialisant l'activité de l'insuline. L'invention concerne également un procédé de production dudit extrait, ainsi que l'utilisation de l'extrait dans le traitement du diabète. L'invention concerne le procédé d'extraction de dérivation de l'extrait à partir de Cinnamomun zeylanicum, qui se caractérise en ce que le solvant utilisé est de l'éthanol à 70 %. Les extraits végétaux comprennent des ingrédients actifs qui retardent la digestion du saccharide ou son absorption, réprimant ainsi une augmentation du taux de glycémie postprandial et/ou à jeun.
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WO2012085266A2 (fr) * | 2010-12-23 | 2012-06-28 | Dialpha | Composition comprenant de l'extrait de cannelle |
CN112869166A (zh) * | 2021-02-10 | 2021-06-01 | 中国林业科学研究院林产化学工业研究所 | 肉桂均一多糖及其抗氧化用途 |
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WO2001072316A1 (fr) * | 2000-03-30 | 2001-10-04 | Victor Hettigoda | Composition ayurvedique pour le traitement du diabete |
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WO2012085266A2 (fr) * | 2010-12-23 | 2012-06-28 | Dialpha | Composition comprenant de l'extrait de cannelle |
WO2012085266A3 (fr) * | 2010-12-23 | 2012-08-16 | Dialpha | Composition comprenant de l'extrait de cannelle |
US10076128B2 (en) | 2010-12-23 | 2018-09-18 | Naturex | Composition comprising cinnamon extract |
US11044930B2 (en) | 2010-12-23 | 2021-06-29 | Naturex | Composition comprising cinnamon extract |
CN112869166A (zh) * | 2021-02-10 | 2021-06-01 | 中国林业科学研究院林产化学工业研究所 | 肉桂均一多糖及其抗氧化用途 |
CN112869166B (zh) * | 2021-02-10 | 2023-04-11 | 中国林业科学研究院林产化学工业研究所 | 肉桂均一多糖及其抗氧化用途 |
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