WO2007091151A2 - Composition synergique pharmaceutique et/ou nutraceutique de flavanoides pour le traitement du diabete sucre - Google Patents

Composition synergique pharmaceutique et/ou nutraceutique de flavanoides pour le traitement du diabete sucre Download PDF

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Publication number
WO2007091151A2
WO2007091151A2 PCT/IB2007/000290 IB2007000290W WO2007091151A2 WO 2007091151 A2 WO2007091151 A2 WO 2007091151A2 IB 2007000290 W IB2007000290 W IB 2007000290W WO 2007091151 A2 WO2007091151 A2 WO 2007091151A2
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agents
composition
management
diabetes mellitus
ranging
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PCT/IB2007/000290
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English (en)
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WO2007091151A3 (fr
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Sunil Bhaskaran
Mohan Vishwaraman
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Indus Biotech Private Limited
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
    • 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)
    • 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

Definitions

  • the present invention relates to a purified flavanoid composition derived from plant matter specifically from Theobroma Cocoa intended for a kinder and gentler management of blood glucose in subjects affected by Diabetes Mellitus.
  • This composition can be used as a pharmaceutical, nutraceutical or as functional food ingredient for this purpose.
  • Diabetes Mellitus is the most common endocrine disease. This disease is characterized by poor regulation of blood glucose levels in human beings. Blood glucose is the source of energy for basic cell functions. This glucose is driven to the cell by insulin, which is secreted by pancreas. Diabetes Mellitus is caused by inadequate insulin secretion by the pancreas or the resistance generated by cells to the insulin. Therefore, this disease is characterized by a metabolic abnormality. Diabetes is a major metabolic disorder in which the body does not produce or properly use insulin that is characterized by hyperglycemia, glycosuria, hyperlipidemia, negative nitrogen balance and sometimes ketonemia. Diabetes is one of the most common diseases affecting human population today.
  • Diabetes Mellitus is not curable.
  • this disorder can be managed by taking popular drugs available in the market place. These drugs fall into the following categories: - 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.
  • Insulin sensitisors - This category of drugs improves the cell's sensitivity to the presence of insulin, thereby improving uptake of glucose into the cells, leading to better blood sugar control, iii. Insulin: - This is exogenously supplemented in the case of people suffering from both type I and type II diabetes.
  • diabetes is a lifestyle disease and cannot be cured.
  • the current therapies available therefore only offer a blood sugar management mechanism.
  • these drugs need to be taken on a sustained basis.
  • available synthetic drugs suffer from concomitant side effects caused due to long duration of usage.
  • Literature survey indicates that cardio vascular mortality was higher in patients with oral hypoglycemics than in those treated with diet and exercise alone or with insulin.
  • Sulphonylureas cause hypoglycemia as a side effect. Biguanides cause lactic acidosis.
  • Oral hypoglycemic drugs cause GIT irritation, weight gain, hypertension, etc. On continuous and constant exertion, the diabetic person is liable for pancreatic fatigue.
  • HbAIc glycosylated hemoglobin
  • Cocoa derived from the seeds of Theobroma Cacao
  • Cocoa can be a rich source of flavanoids, especially the flavan-3-ols and their related oligomers.
  • flavanoids have been reported to have significant antioxidant and potential anti-carcinogenic activities.
  • Cocoa (Theobroma Cocoa) is well known for its application in confectionery.
  • Cocoa butter is the most commonly used ingredient of the fruit of Theobroma Cocoa, the fruit, particularly its Kernel, contains other ingredients, which are very interesting.
  • One such ingredient is Theobromine.
  • flavanoids Another significant ingredient of the Cocoa kernel is flavanoids. These flavanoids are not lipid soluble and hence do not come along with Cocoa butter. They are left behind in the kernel powder, when the butter is extracted. These flavanoids are very powerful anti-oxidants and have interesting properties in free radical scavenging, leading to increased cardiovascular health.
  • Flavanoid compounds are present in all aerial parts of plants with high concentrations found in the skin, bark and seeds. Such compounds are also found in beverage of botanical substances such as tea, wine, coffee and cocoa.
  • the flavanoids are member of a larger family of compounds called polyphenols. These compounds contain more than one phenolic -OH group on the respective benzene ring.
  • Procyanidins are particular class of colorless flavanoid compounds with a general structure as follows:
  • Proanthocyanidins yield anthocyanin upon hydrolysis with inorganic acids, and anthocyanins are responsible for the reddish color of grapes, flowers and other plant materials.
  • Catechin is the building unit of dimmers, trimmers and oligomers.
  • FLO familial alcohol
  • Cocoa monomer through decamer
  • PHA phytohemagglutinin
  • PBMC peripheral blood mononuclear cells
  • FLO fractions were unstimulatory for IL-5 secretion in resting cells
  • PHA - induced IL-5 release from PBMC was markedly affected by certain FLO fractions.
  • the monomeric and small oligomeric (dimer and trimer) fractions enhanced PHA stimulation by 50%, 54% and 43% respectively.
  • Chocolate Procyanidins decrease the leukotriene - prostacyclin ratio in humans and human aortic endothelial cells.
  • Derek D. Schramm Janice F. Wang et al. University of California, Davis.
  • Flavanoidic phytochemicals inhibit vascular and inflammatory processes that contribute to disease. These effects are hypothesized to result from flavanoid - mediated alterations in cellular eicosanoid synthesis.
  • the objective was to determine and compare the ability of Cocoa procyanidins to alter eicosanoid synthesis in human subjects and cultured human aortic endothelial cells. Data from this short-term investigation support the concept that certain food - derived flavanoids can favorably alter eicosanoid synthesis in humans, providing a plausible hypothesis for a mechanism by which they can decrease platelet activation in humans.
  • Flavanol concentrations can be moderately high in a number of foods that have been associated with a reduction in cardiovascular risk, including red wine as well as black and green tea.
  • Cocoa and chocolate products are extraordinarily rich in flavanols but, as with other flavanol- containing foods, certain post-harvesting and processing procedures can have a striking influence on the flavanol content of chocolate and Cocoa.
  • Endothelial dysfunction with a consequent reduction in nitric oxide production, has achieved a central conceptual role in the pathogenesis of atherosciorosis and coronary artery disease, diabetes mellitus and hypertension.
  • flavanol-rich cocoa activates vascular nitric oxide synthesis in endothelia, raises an interesting possibility of therapeutic potential. Effects of Cocoa Extracts on Endothelium - Dependent Relaxation. - J. Nutr.
  • the crude alcohol extract contains the alkaloid Theobromine at least at 8 - 10% level. This means that there is a Theobromine dosing of 66 mg/kg body weight for 660 mg/kg administration of the crude drug.
  • Theobromine is cardiac stimulant and cannot be given regularly at this dose due to adverse side effects.
  • Theobromine is having reproductive toxicity as per published studies. There have been various studies which confirm that higher level of flavanoid dosing leads to inhibition of iron absorption leading to reduction in RBC count and Hemoglobin. This is a very serious adverse reaction.
  • the main object of the present invention is to develop a synergistic pharmaceutical and/or neutraceutical flavanoid composition for management of Diabetes Mellitus.
  • Another main object of the present invention is to develop a method for sustained management of Diabetes Mellitus in a subject in need thereof.
  • Yet another object of the present invention is to develop a method for management of type II diabetes.
  • Still another object of the present invention is to develop a process for preparing a synergistic pharmaceutical and/or neutraceutical flavanoid composition for management of Diabetes Mellitus.
  • a synergistic pharmaceutical and/or neutraceutical flavanoid composition for management of Diabetes Mellitus comprising polyphenols of concentration ranging between 85 to 95% (w/w), theobromine of concentration ranging between 1 to 5 % (w/w), optionally along with pharmaceutically acceptable additives, a method for sustained management of Diabetes Mellitus in a subject in need thereof, said method comprising administering pharmaceutically effective amount of a synergistic pharmaceutical and/or neutraceutical flavanoid composition comprising polyphenols of concentration ranging between 85 to 95% (w/w); theobromine of concentration ranging between 1 to 5% (w/w), optionally along with pharmaceutically acceptable additives to the subject, and a process for preparing a synergistic pharmaceutical and/or neutraceutical flavanoid composition for management of Diabetes Mellitus, said composition comprising polyphenol of concentration ranging between 85 to 95% (w/w) and theobromine of concentration ranging between 1 to 5 % (w/w), optionally along with pharmaceutically
  • a synergistic pharmaceutical and/or neutraceutical flavanoid composition for management of Diabetes Mellitus comprising polyphenols of concentration ranging between 85 to 95% (w/w), theobromine of concentration ranging between 1 to 5 % (w/w), optionally along with pharmaceutically acceptable additives.
  • the concentration of polyphenol is about 90% w/w.
  • the concentration of theobromine is about 4% w/w.
  • the additives are selected from a group comprising granulating agents, binding agents, lubricating agents, disintegrating agents, coloring agents, flavoring agents, coating agents, plasticizers, preservatives, suspending agents, emulsifying agents and spheronization agents.
  • the composition has moisture content ranging between 0.5 to 10 % (v/w), preferably about 3% v/w.
  • composition comprises two major polyphenols at Rf 0.87 and 0.77; a minor polyphenol at Rf 0.71; and theobromine at Rf 0.14.
  • a method for sustained management of Diabetes Mellitus in a subject in need thereof comprising administering pharmaceutically effective amount of a synergistic pharmaceutical and/or neutraceutical flavanoid composition comprising polyphenols of concentration ranging between 85 to 95% (w/w); theobromine of concentration ranging between 1 to 5%
  • the concentration of polyphenol is preferably about 90% w/w. In yet another embodiment of the present invention, wherein the concentration of theobromine is preferably about 4% w/w.
  • composition has moisture content ranging between 0.5 to 10 % (v/w), preferably about 3% v/w.
  • the additives are selected from a group comprising granulating agents, binding agents, lubricating agents, disintegrating agents, coloring agents, flavoring agents, coating agents, plasticizers, preservatives, suspending agents, emulsifying agents and spheronization agents.
  • the subject is an animal including humans.
  • the subject is administered said composition at daily dosage of 1 mg/kg to 25mg/kg body weight.
  • composition is safe for administration.
  • diabetes is type II diabetes.
  • composition is administered orally.
  • a process for preparing a synergistic pharmaceutical and/or neutraceutical flavanoid composition for management of Diabetes Mellitus comprising polyphenol of concentration ranging between 85 to 95% (w/w) and theobromine of concentration ranging between 1 to 5 %
  • process comprising steps of: a) extracting cocoa beans using alkyl ester to obtain extract, b) drying the extract to obtain solvent free mass, c) extracting the dried mass with an aqueous alcoholic solvent to obtain extract, d) filtering and concentrating the extract to obtain pasty mass, e) dissolving the pasty mass in water and filtered to obtain clear solution, f) passing the clear solution through an adsorbent column, followed by washing the column with water, g) eluting the column with an pure alcohol to obtain elluent, and h) reducing the alcohol content of elluent to obtain the composition as pure flavanoid powder.
  • cocoa beans are obtained from Theobroma cocoa.
  • alkyl ester is selected from a group comprising methyl acetate, ethyl acetate, propyl acetate and butyl acetate.
  • the alcohol of aqueous alcoholic solvent is selected from a group comprising methyl alcohol, ethyl alcohol, isopropyl alcohol, and butanol.
  • aqueous alcoholic solvent is a mixture of ethyl alcohol and water in the ratio ranging between 4:3 to 19:1.
  • the water is de- mineralized water.
  • the extract is filtered with filter paper.
  • the adsorbent column is a non-ionic polymeric adsorbent column.
  • pure alcohol is selected from a group selected from methyl alcohol, ethyl alcohol, isopropyl alcohol, and butanol.
  • reducing the alcohol content of elluent with vacuum evaporation is selected from a group selected from methyl alcohol, ethyl alcohol, isopropyl alcohol, and butanol.
  • the additives are selected from a group comprising granulating agents, binding agents, lubricating agents, disintegrating agents, coloring agents, flavoring agents, coating agents, plasticizers, preservatives, suspending agents, emulsifying agents and spheronization agents.
  • the composition has moisture content ranging between 0.5 to 10 % (v/w), preferably about 3% v/w.
  • the solvent used for extraction is an aqueous alcoholic solvent preferably a mixture of ethyl alcohol and water in the ratio of 70: 30 to a maximum ratio of 95:5 over a period ranging from 8 hrs to 12 hrs, preferably 8 hrs, at temperature ranging from 2O 0 C to 4O 0 C, preferably at 35°C.
  • the alcohol chosen can be from any of the following; Methyl Alcohol,
  • Theobromine content is less than 5 %.
  • the composition thus obtained is having approximately 93 % polyphenol content, 4 % Theobromine content, 3 % Moisture ..
  • the packed mass is extracted with 5 liters of a solvent mixture comprising of 70: 30 mixture of ethyl alcohol and D.M water and the extract is recycled over the bed for about 8 hrs at 35 0 C to achieve efficient extraction.
  • the extract is filtered though filter paper and concentrated at 40 0 C under vacuum to get 50 grams of pasty material.
  • the isolated material is re dissolved in 3 liters of D.M water and passed through a column consisting of 100 ml of the adsorbent resin Amberlite XAD- 16 after the completion of the feed. The column was thoroughly washed with D.M. water free of adhering substances and the elluent is neutral.
  • the column is further eluted with pure Ethyl alcohol.
  • the elluent is concentrated and diluted with water and spray dried to get a free flowing powder.
  • the final weight is 10 gramsand the Folin C value of this is 92.3%.
  • Experiment No 2 lOOOgms of pulverized coco beans with an average size ranging from 16 mesh Passing. Is soaked in ethyl acetate and poured in to an extractor having a perforated Bottom sieve of the 200mesh sieve. The bottom elluent is recycled again and again over the packed mass to achieve effective extraction for a period of 8 hrs. The elluent is discarded and the mass is removed out of the extractor and dried in a forced draft Oven at 3O 0 C. After removal of solvent by evaporation, the mass was again packed in the extractor. The packed mass is extracted with 5 liters of a solvent mixture comprising of 60: 40 mixture of ethyl alcohol and D.M water.
  • the extract is recycled over the bed for about 8 hrs at 35°C to achieve efficient extraction.
  • the extract is filtered though filter paper and concentrated at 4O 0 C under vacuum to get 70 Gms of pasty material.
  • the isolated material is redissolved in 3 liters of D.M water and passed through a column consisting of 100 ml of the adsorbent resin Amberlite XAD- 16 after the Completion of the feed.
  • the column was thoroughly washed with D.M.water free of adhering substances and the elluent is neutral.
  • the column is further eluted with pure Ethyl alcohol & the collected elluent is concentrated and diluted with water and spray dried to get a free flowing powder.
  • the final weight is 9.5 Gms and the Folin C value is 94.7%.
  • Experiment No 3 lOOOgms of pulverized coco beans with an average size ranging from 16 mesh Passing. is soaked in ethyl acetate and poured in to an extractor having a perforated Bottom sieve of the 200mesh sieve. The bottom elluent is recycled again and again over the packed mass to achieve effective extraction for a period of 8 hrs. The elluent is discarded and the mass is removed out of the extractor and dried in a forced draft Oven at 3O 0 C. After removal of solvent by evaporation, the mass was again packed in the extractor. The packed mass is extracted with 5 liters of a solvent mixture comprising of 80: 20 mixture of Isopropyl alcohol and D.M water.
  • the extract is recycled over the bed for about 8 hrs at 35 0 C to achieve efficient extraction.
  • the extract is filtered though filter paper and concentrated at 4O 0 C under vacuum to get 46 Gms of pasty material.
  • the isolated material is redissolved in 3 liters of D. M water and passed through a column consisting of 100 ml of the adsorbent resin Amberlite XAD- 16 after the completion of the feed. The column was thoroughly washed with D.M.water free of adhering substances and the elluent is neutral. The column is further eluted with pure Ethyl alcohol & the collected elluent is concentrated and diluted with water and Spray dried to get a free flowing powder. The yield is 8gmsand the Folin C value is 91.9%.
  • Experiment No 4 lOOOgms of pulverized coco beans with an average size ranging from 16 mesh Passing. is soaked in ethyl acetate and poured in to an extractor having a perforated Bottom sieve of the 200mesh sieve. The bottom elluent is recycled again and again over the packed mass to achieve effective extraction for a period of 8 hrs. The elluent is discarded and the mass is removed out of the extractor and dried in a forced draft Oven at 3O 0 C. After removal of solvent by evaporation, the mass was again packed in the extractor. The packed mass is extracted with 5 liters of a solvent mixture comprising of 90 : 10 mixture of Isopropyl alcohol.
  • D.M water the extract is recycled over the bed for about 8 hrs at 35°C to achieve efficient extraction.
  • the extract is filtered though filter paper and concentrated at 4O 0 C under vacuum to get 60 Gms of pasty material.
  • the isolated material is redissolved in 3 liters of D.M water and passed through a column consisting of 100 ml of the adsorbent resin Amberlite XAD- 16 after the completion of the feed. The column was thoroughly washed with D. M. Water free of adhering substances and the elluent is neutral.
  • the column is further eluted with pure isopropyl alcohol & the collected elluent is concentrated and diluted with water and spray dried to get a free flowing powder.
  • the final dry weight is 8gmsand the Folin C value is 91.6%.
  • mice Male in the weight range 25 to 30 grams were studied for acute affect. They were made diabetic by the admnistration of Alloxan (with admnistration of 70 mg/kg Alloxan and in 48 hours the animals develop diabetes). As the mice became diabetic and the blood sugar was above 250 mg/kg, they were grouped into four groups of six each. Each group was administered by the test drug at 25 mg/kg, 50mg/kg 100 mg/kg and 250 mg /kg body weight. One group was administered a positive control drug glyburide at 10 mg/kg of body weight. Blood samples were drawn at 2 hour, 4 hour, 6 hour and 24 hour intervals for all mice. The blood sugar pattern is studied.
  • mice in the weight range of 25 to 30 gram were studied for sub acute effect for 28 days.
  • the mice were made diabetic by admnistration of Alloxan. As the mice became diabetic and the blood sugar was above 250 mg/kg they were chosen for the study. 4 groups were made. One group was given 50 mg /kg, 2 nd group 100 mg/kg, 3 rd group 250 mg/kg and the 4 th group positive control glyburide at 10 mg/kg.
  • Treatment was given for 28 days . A very interesting observation was made that the best effect was produced by the dose of 100 mg /kg body weight. The effect started by 7 th day and increased up to 28 th day.
  • Cocoa Flavanoids from Theobroma Cocoa is based on the following reference.
  • Detection limit fot UV is 10 ppm& Detection limit for folin-c spray is 50ppm
  • HPLC of the polyphenol confirmed 3 polyphenol peaks and one Theobromine peak.
  • test drug at a dose of 300 mg /kg was orally given in a hard gelatin capsule form to 6 treatment naive newly diagnosed diabetic subjects in the weight range of 60 to 72 kg of body weight. These subjects have elevated fasting and postprandial blood sugar after diet and exercise. These are candidates who may have to start with oral hypoglycemic agents soon.
  • the study was done for a period of 3 months with visits at each month. Prior to the study, fasting blood sugar, postprandial blood sugar, kidney function test, liver function test and blood hematology were tested. At the end of the study all the tests were repeated. During visit 1 and visit 2, only blood tests for fasting and postprandial sugar were taken.
  • Dosage of 300 mg per day was orally given to 6-treatment na ⁇ ve newly diagnosed diabetic patients (3 men and 3 women).
  • the composition of instant invention is synergistic in nature.
  • the composition shows extraordinary activity in the management of Diabetes Mellitus.
  • the activity of the composition is well beyond the expectations of the inventors and is also significantly more than the additive effect of the individual components of the composition.
  • the activity is surprising in nature and is thus both novel and inventive in nature.
  • the Industrial Application of the composition is well-established as the problem of Diabetes Mellitus is widespread and is affecting children also in a big way. Therefore, the instant composition is a leap forward towards the management of this menace.

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Abstract

La présente invention concerne une composition synergique pharmaceutique et/ou nutraceutique de flavanoïdes pour le traitement du diabète sucré, ladite composition comprenant un polyphénol à une concentration comprise entre 85 et 95 % (poids/poids), de la GAE théobromine à une concentration comprise entre 1 et 5 % (poids/poids) et une humidité comprise entre 0,5 et 10 % (volume/poids).
PCT/IB2007/000290 2006-02-06 2007-02-02 Composition synergique pharmaceutique et/ou nutraceutique de flavanoides pour le traitement du diabete sucre WO2007091151A2 (fr)

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Cited By (3)

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WO2014090512A1 (fr) 2012-12-13 2014-06-19 Unilever N.V. Composition comestible
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RU2532357C2 (ru) * 2010-07-28 2014-11-10 Индус Биотек Прайвит Лимитед Способ терапии бронхо-констриктивных состояний
WO2014090512A1 (fr) 2012-12-13 2014-06-19 Unilever N.V. Composition comestible
US9393276B2 (en) 2012-12-13 2016-07-19 Conopco, Inc. Edible composition
CN110621329A (zh) * 2017-04-03 2019-12-27 大江生医股份有限公司 植物萃取物在制备调控pdgfc、fgf2、igf1r、ptgis、nos3、edn1、plat、proc、vwf、f3、serpine1、il-8、icam1、vcam1及casp8基因的组合物中的用途

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