WO2012140666A2 - Extraits végétaux et compositions préparées à partir de ceux-ci - Google Patents

Extraits végétaux et compositions préparées à partir de ceux-ci Download PDF

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WO2012140666A2
WO2012140666A2 PCT/IN2012/000220 IN2012000220W WO2012140666A2 WO 2012140666 A2 WO2012140666 A2 WO 2012140666A2 IN 2012000220 W IN2012000220 W IN 2012000220W WO 2012140666 A2 WO2012140666 A2 WO 2012140666A2
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group
extract
extraction
plant material
cassia auriculata
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PCT/IN2012/000220
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WO2012140666A3 (fr
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Amrutesh PURANIK
Bhushan Patwardhan
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Puranik Amrutesh
Bhushan Patwardhan
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Publication of WO2012140666A2 publication Critical patent/WO2012140666A2/fr
Publication of WO2012140666A3 publication Critical patent/WO2012140666A3/fr

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    • 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)
    • A61K36/48—Fabaceae or Leguminosae (Pea or Legume family); Caesalpiniaceae; Mimosaceae; Papilionaceae
    • A61K36/482—Cassia, e.g. golden shower tree
    • 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
    • A61K31/352—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 condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
    • C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms

Definitions

  • the present invention relates to processes for the preparation of extracts of Cassia auriculata (CA) and compositions comprising an extract of the same.
  • CA Cassia auriculata
  • the present invention also relates to pharmaceutically active compounds isolated from Cassia auriculata which are useful for the treatment of disorders which include diseases arising because of insulin resistance such as Type 2 Diabetes, obesity, cardiovascular diseases and associated increase in homocysteine.
  • Type 2 Diabetes Mellitus is a progressive disease in which the risks cf myocardial infarction, stroke, microvascular events and mortality are all strongly associated with hyperglycemia.
  • the disease course is characterized by a decline in the pancreatic beta cell function and worsening of insulin resistance.
  • T2DM is a global epidemic and has rapidly growing incidence rate, both in developing and developed nations.
  • the incidence of T2DM in the US in 2007 was about 24%.
  • An Increase in globalization led to the spread of this epidemic in Asia.
  • the incidence of T2DM in Asian populations has increased rapidly in recent decades.
  • more than 1 10 million individuals in Asia were living with T2DM, with a disproportionate burden among the young and the middle aged.
  • Therapeutic strategy for glucose control includes drugs which include insulin (long, intermediate and short acting), metformin (bi-guanide), pioglitazone (thiazolidinedione), exenatide (glucagon like peptide analogues), repaglinide, glipizide (insulin secretogogues), sitagliptin (dipeptidyl peptidase inhibitors), SIRT1 activators , and sodium-glucose co-transporter 2 (SGLT) inhibitors.
  • drugs include insulin (long, intermediate and short acting), metformin (bi-guanide), pioglitazone (thiazolidinedione), exenatide (glucagon like peptide analogues), repaglinide, glipizide (insulin secretogogues), sitagliptin (dipeptidyl peptidase inhibitors), SIRT1 activators , and sodium-glucose co-transporter 2 (SGLT) inhibitors.
  • Herbal(s) [also referred as herbal formulations or herbal drugs or herbal medicine or herbal extracts or dietary supplements in this thesis] can be considered important in multi-modal therapeutics. Herbals often administered as powders or extracts are mixtures of interacting compounds that can modulate multiple pharmacological targets and provide clinical efficacy beyond the reach of a single compound-based drugs.
  • Herbals have been used for glucose homeostasis inflammation, and to arrest diabetic complications.
  • the present invention envisages the extraction of the active phytochemical constituents particularly polyphenols from the Cassia auriculata and their subsequent use for the treatment of pathological conditions which include but are not limited to T2DM, obesity, hypertension, hypertriglyceridemia and CVDs.
  • R2 and R4 is selected from the group consisting of -H, nitro, halogens, hydroxyl, amines, aromatic amines, aliphatic alcohols, aromatic alcohols, aliphatic carboxylic acids, aromatic carboxylic acids, phenols, aliphatic or aromatic ethers, halogenated or non- halogenated aliphatic or aromatic compounds, alkanes, alkenes, alkynes and substituted aromatic rings containing electron withdrawing and electron releasing groups; and
  • R2 and R4 is hydrogen
  • a process for the preparation of cassia auriculata extract comprising the following steps: obtaining plant material from cassia auriculata;
  • the plant material is selected from the group consisting of roots, leaves, bark, flowers and seeds of cassia auriculata.
  • the plant material is seeds of cassia auriculata.
  • the extraction is carried out by at least one technique selected from the group consisting of maceration, quath preparation, solvent extraction and supercritical fluid extraction performed in any order.
  • the extraction is carried out by hydro-alcoholic maceration (cold extraction).
  • the solvent is at least one selected from the group consisting of water, methanol, ethanol, butanol, hexane, acetone, chloroform, petroleum ether and acetonitrile.
  • the extraction is carried out by boiling the plant material, preferably seeds, of cassia auriculata in water for a period of 2 hrs.
  • the extraction is carried out at a temperature in the range of -30 °C to 200 °C for a period of 1 to 6 hours.
  • the ratio of the dried plant material to the solvent ranges between 1 : 1 to 1 :20 (w/v).
  • a medicinal composition comprising therapeutically effective amount of cassia auriculata extract or a polyphenolic compound of formula I isolated from cassia auriculata extract for the treatment of cardiovascular diseases, diabetes and inflammation.
  • the composition further comprises at least one pharmaceutically acceptable excipient.
  • the composition is in a dosage form selected from the group consisting of a tablet, a capsule, powder, granules, a suspension, an emulsion, a liquid and an injection.
  • composition further comprises at least drug selected from the group consisting of anticoagulants, anti- hypertensives, antihyperlipidemics, anti-diabetics, anti-ischemics, antioxidants and antiinflammatory agents.
  • a method of treatment of at least one disease selected from the group consisting of cardiovascular diseases, diabetes and inflammation comprising administrating therapeutically effective amount of cassia auriculata extract or compound of formula I to mammals.
  • Fig. 1 illustrates regulation of secondary mediators of inflammatory & non-inflammatory origins in hyperglycemia
  • Fig. 2 illustrates HPLC standardization of hydro-alcoholic extract of Cassia auriculata for polyphenols
  • Fig. 3 illustrates HPLC standardization of supercritical extract of Cassia auriculata for polyphenols
  • Figure 4 illustrates comparison of HPLC fingerprint profile of hydroalcoholic extracts of seeds obtained from three different sources
  • Figure 5 illustrates LC-MS-MS studies which indicate presence of delphidin 3-0- rutinoside and procyanidin B2 in hydro-alcoholic extract of Cassia auriculata Linn;
  • Figure 6 illustrates identification of Peak at Rt 25 as quercetin glucosyl-rutinoside (MS 771 ; MS2 609, 463 and 301 );
  • Figure 7 illustrates HPLC fingerprint of supercritical extract of CA seed
  • Figure 8a illustrates scan from Mass 1000 - 2800 which shows that the molecular mass of peak 53 is 1 164
  • Figure 8b illustrates scan from Mass 100 - 1000 which shows that fragmentation of 1 164 is 878, 572 & 285;
  • Figure 8c illustrates mass spectroscopy (MS2) of 1 164 which is 879, 593 & 307;
  • Figure 9 illustrates breaking pattern of Cassia peak with molecular mass 1 164; MS2 877,287; MS2 593,308;
  • Figure 10 illustrates chromatogram at 366 nm using linear gradient of A (chloroform): B(ethanol) (100 to 40 %) which shows that cassia peak is retained at 9.4 min.;
  • Fig. 1 1 illustrates comparative HPLC chromatogram overlay of Ca-quath and CA-SFE
  • Fig. 12a- 12b illustrates blood lowering or anti-hyperglycemic activity of CA extracts in comparison to metformin
  • Fig. 12c illustrates insulin secretion potential of CA extracts in comparison to glibenclamide and metformin
  • Fig. 13a illustrates progress of nSTZ rat to T2DM
  • Fig. 13b illustrates prevention of progress of IGT to T2DM in rats treated with metformin & CA alone and in combination;
  • Fig. 14a illustrates glycemic control by 15 week treatments with metformin, CA & combination thereof.
  • Fig. 14b illustrates reduction in HbA lc by 15 week treatments with metformin, CA & combination thereof.
  • Botanical Species Cassia auriculata Linn.FamiSy : Caesalpiniaceae. Parts Used: Bark, Leaves, Flowers, Seeds.
  • CA is a perineal shrub indigenous to Maharashtra, Tamil, Bengal, Ceylon and South India, Rajputana Desert, Central provinces and Western Peninsula . In dry stony hills and black cotton soil.
  • Cultivation, Harvesting, and Post harvesting techniques Light porous soil is preferred. Cheapest method is sowing in furrows 2-5 in. apart and 4-6 in. deep. The tannins increase with age. More than the height of the plant the thickness of the bark is taken in to account. Usual product contains 18% tannins and 10% soluble non-tans.
  • Tanner's Cassia is a tall much branched shrub, bark smooth, reddish brown; branchlets finely- pubescent leaves 7.5 - 10 cm long; rachis densely fulvous.
  • Leaflets are 8 - 12 pairs, 2 - 2.5 x 1 - 1.3 cm, slightly overlapping, oblong- obovate and conspicuously mucronate. This shrub is famous for its yellow flowers, reaching 5 cm across, in terminal and axillary corymbose racemes; pedicels 2 - 2.5 cm long. Seeds 10 - 20 per pod obovate dark brown with hard shiny seed coat. Fruit Pod, 20 - 25 cm long.
  • the present invention envisages a process for preparation of an extract with enhanced phytochemical constituents.
  • the process for preparation of an extract in accordance with the present invention involves the use of solvent selected from the group that includes but is not limited to water, methanol, ethanol, butanol, hexane, acetone, chloroform, petroleum ether, acetonitrile and the like.
  • the extraction process may employ any part of the CA as a raw material either in wet or dry form which is selected from the group which includes but is not limited to roots, leaves, bark, flowers, seeds and the like.
  • the process involves pre-treatment of the plant material which include but is not limited to sorting, cleaning, sizing and the like.
  • seeds are used for preparing the extract of CA with enhanced phytochemical yield.
  • the process for extraction envisaged in accordance with the present invention employs a series of extraction techniques carried out in any sequence which are selected from the group which includes but is not limited to maceration, quath preparation, solvent extraction, supercritical fluid extraction and the like.
  • the extraction is carried out at a temperature of about in the range of -30 to 200°C for a period of 1 to 6 hours.
  • the ratio of the dried plant material to the solvent ranges between 1 : 1 to 1 :20.
  • seeds are isolated from the fruits and subjected to hydro-alcoholic maceration (cold extraction) for preparation of the extract.
  • the CA extract is in the form a Quath which is prepared by boiling CA seeds in water for ⁇ 2 hrs.
  • the CA extract is prepared by Supercritical Fluid Extraction (SFE) using carbon dioxide (C0 2 ). Carbon dioxide in the supercritical
  • a cassia auriculata extract enriched with polyphenolic compounds selected from the group consisting of procynidins and proanthocyanidins obtained by the process of the present invention.
  • Mobile Phase used for HPLC - A - watenmethanol: formic acid (79.5:20:0.5) and B acetonitrile : formic acid (99.7 : 0.3), at a flow rate of 0.4ml to 1 ml and ramp (gradient) from B - 5% to B - 95% for 60 min.
  • CA-HA was subjected to LC-MS-MS studies. This confirmed peak 32 as delphinidin-3- O-rutinoside as given below ( Figure 5) with mobile phase and column as mentioned above. This compound was not observed in hydro-alcoholic extract of CA flower and leaves. Inventors also observed that delphinidin-3-O-rutinoside ( Figure 6) was present in marginally higher quantity in the fruit skin than the seed.
  • the inventors of the present invention identified Procyanidin B2 and delphinidin-3-O- rutinoside in the CA-HA extracts by LC-MS-MS.
  • HPLC-PDA spectra and mass spectroscopy fingerprint was used to identify the procyanidin B2 and delphinidin in CA- HA extracts. These fingerprints were matched with the PubChem database and reports from Drynan et al (Nat Prod Rep 2010; 27:417-62), Crozier et al (Nat Prod Rep 2009;26: 1001 -43.) and Mullen et al (J Agric Food Chem 2007;55:3148-57.).
  • Inventors of the present invention identified various polyphenols in CA, however these compounds are generalized and available in many other herbals such as grape seeds, Red wine etc.
  • a unique phytomarker for CA is required that can be easily identified using HPLC or HPTLC.
  • HPLC or HPTLC For this a mobile phase that would cover both polar and non-polar compounds was developed.
  • inventors identified a peak at retention time 53 min. This mid-polar peak was present in water as well as supercritical extract. Peak 53 also referred as Cassia peak is around 87% in CA- SFE as compared to 45% in the water extract (quatha).
  • CA-SFE demonstrated a higher amount of non-polar peaks than CA-HA.
  • the HPLC fingerprint was different than CA-HA.
  • a non-polar peak 53.4 (PDA spectra 336, 342, 385) was present in very high amounts ( ⁇ 87% in CA-SFE) and can be the marker specific to CA seed.
  • the peak was isolated by FLASH chromatography. This peak is not found in fruit skin, flowers and leaves. However, this compound is extracted in Quath, chloroform and hydro-alcoholic extracts of CA seeds. Thus this compound is to be considered a phytomarker specific to CA seeds. From LC-MS-MS breaking pattern ( Figure 9), inventors have narrowed to a structure which suggest that this molecule is delphinidin rutinoside trimer with a molecular weight of 1 164.
  • the present invention envisages various polyphenolic compounds isolated from the extract of CA which are useful for treatment of diseases which include but are not limited diseases arising because of insulin resistance such as obesity, type 2 diabetes, cardiovascular and metabolic diseases.
  • the polyphenolic compounds isolated from the extract of CA in accordance with the present invention include but are not limited to polyphenolic compounds which include but are not limited to dimers, trimers, tetramers, pentamers, hexamers, heptamers, octamers, nonamers, decamers of (.+-.)-catechin and (.+-.)-epicatechin. (+)-Catechin, (-)- epicatechin units. More particularly, the polyphenolic compounds in accordance with the present invention include procynidins and proanthocyanidins
  • polyphenolic entity identified in accordance with the present invention is represented by the following Formula.
  • R2 and R4 may be;
  • inorganic groups like nitro, halogens, hydroxyl, organic compounds including aromatic substituents or aliphatic substituents which may include amines, aromatic amines, aliphatic alcohols, aromatic alcohols, aliphatic carboxylic acids, aromatic carboxylic acids, phenols, aliphatic or aromatic ethers, haiogenated or non- halogenated aliphatic or aromatic compounds, alkanes, alkenes, alkynes, substituted aromatic rings containing electron withdrawing and electron releasing groups and others.
  • aromatic substituents or aliphatic substituents which may include amines, aromatic amines, aliphatic alcohols, aromatic alcohols, aliphatic carboxylic acids, aromatic carboxylic acids, phenols, aliphatic or aromatic ethers, haiogenated or non- halogenated aliphatic or aromatic compounds, alkanes, alkenes, alkynes, substituted aromatic rings containing electron withdrawing and electron releasing groups and others.
  • substituent groups at R5 include but are not limited to the following :
  • R2 and R4 is hydrogen
  • a medicinal composition that comprises therapeutically effective amount of cassia auriculata extract or a polyphenolic compound of formula I isolated from cassia auriculata extract for the treatment of cardiovascular diseases, diabetes and inflammation.
  • the composition further comprises at least one pharmaceutically acceptable excipient.
  • the medicinal composition further comprises at least one other pharmaceutically active entity(drug) of natural or synthetic or semi-synthetic origin belonging to therapeutic classes selected from the groups which include but are not limited to anticoagulants, antihypertensives, antihyperlipidemics, anti-diabetics, anti-ischemics, antioxidants, antiinflammatory and the like.
  • the medicinal composition of the present invention can be formulated in at least one dosage form selected from the group consisting of a tablet, a capsule, powder, granules, a suspension, an emulsion, a liquid and an injection.
  • the composition is in the form of tablet.
  • the excipient used in the preparation of tablet is at least one selected from the group consisting of diluents, disintegrants, lubricants, glidents, binders, surfactants, solvents, matrix forming agents, coating polymers, effervescent agents, flavoring agents, colorants and preservatives.
  • the diluent is at least one selected from the group consisting of microcrystalline cellulose, starches, lactose, mannitol, calcium phosphate, dibasic calcium phosphate and mixture thereof.
  • the disintegrant is at least one selected from the group consisting of starches, clays, cellulose derivatives, gums, aligns including alginic acid, combinations of hydrocarbonates with weak acids, crospovidone, sodium starch glycolate, agar, veegum HV, cross-linked polyvinylpyrrolidone, carboxymethyl starch, natural starch, microcrystalline cellulose, carboxymethylcellulose calcium, carboxymethylcellulose sodium, colloidal silicon dioxide, croscarmellose sodium, guar gum, polacrilin potassium, pregelatinized starch, sodium alginate and sodium starch glycollate.
  • the lubricant is at least one selected from the group consisting of magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl paimitostearate, stearic acid, talc, and zinc stearate, magnesium lauryl sulfate, and colloidal silicon dioxide.
  • the binder is at least one selected from the group consisting of acacia, sodium alginate, starch, gelatin, pregelatinized starch, partly pregelatinized starch, saccharides, glucose, sucrose, dextrose, molasses, panwar gum, guar gum, ghatti gum, carboxy methylcellulose, methylcellulose, veegum, ethylcellulose, polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, gum arabic and dextrin.
  • the surfactant is at least one selected from the group consisting of alkyl poly(ethylene oxide), alkylphenol poly(ethylene oxide), alkyl alcohol, sodium lauryl sulfate, polyoxyethylene/polyoxypropylene block polymers (poloxamers), glycerols, polyglycerols, fatty acids, polyethylene glycol hydroxystearate, polyalkyi glucosides, ceramides, polyethylene glycol/alkyl glycol copolymers, and polyethylene glycol/polyalkylene glycol ether di-block or tri-block copolymers, diacetylated monoglycerides, diethylene glycol monostearate, ethylene glycol monostearate, glyceryl monooleate, propylene glycol monostearate, macrogol esters, macrogol stearate, polyoxyethylene 50 stearate, macrogol ethers, cetomacrogol 1000, lauromacrogols, nonoxinols,
  • the glidant is at least one selected from the group consisting of colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc, tribasic calcium phosphate, lactose, stearate, dibasic calcium phosphate, magnesium carbonate, magnesium oxide, calcium silicate and silicon dioxide.
  • the matrix forming agent is at least one selected from the group consisting of cellulose derivatives, acrylates, methacrylic acid derivatives, alginates, chitosan, eudragit and xanthan gum.
  • the coating polymer is at least one selected from the group consisting of polymethacrylate, polymethamethacrylate, ethyl cellulose, hydroxymethyl cellulose, hydroxymethylpropylcellulose, cellulose acetate phthalate, arabinogalactan, carboxymethylcellulose, gelatin, gum arabic, methylcellulose; polyvinyl alcohol, polyamide, silicones, polyvinyl acetate, hydroxypropyl methylcellulose acetate, rosin, partially hydrogenated rosin, glycerol esters of rosin and ready to use coating material.
  • the plasticizer is at least one selected from the group consisting of glycerol, polyethylene glycol, propylene glycol, sorbitol, diethyl butyl pthalate, diethyl phthalate, silicone, oil and mixtures thereof.
  • the effervescent agent is at least one selected from the group consisting of citric acid, tartaric acid, sodium bicarbonate, potassium bicarbonate and calcium carbonate.
  • the flavoring agent is at least one selected from the group consisting of anise oil, peppermint oil, lemon oil, mint, strawberry, banana, pineapple, orange, raspberry and vanilla.
  • the composition is in the form of capsule.
  • the excipient used in the preparation of capsule that includes but not limited to microcrystalline cellulose, lactose, starch, dicalcium phosphate, colloidal silica, magnesium stearate, talc, sodium starch glycollate, crospovidone, croscarmellose sodium, methyl paraben, propyl paraben, povidone, and pregelatinised starch.
  • the composition is in the form of powder.
  • the composition is in the form of granules/pills.
  • the composition is in the form of suspension.
  • the excipient used in the preparation of suspension that includes but not limited to wetting agents, thickening agents, suspending agents, preservatives, flavouring agents and colors.
  • the wetting agent is at least one selected from the group consisting of benzalkonium chloride, benzethonium chloride, cetylpyridinium chloride, dioctyl sodium sulfosuccinate, nonoxynol 9, nonoxynol 10, octoxynol 9, polyoxyethylene 8 caprylic/capric mono- and diglycerides, polyoxyethylene 35 castor oil, polyoxyethylene 20 cetostearyl ether, polyoxyethylene 40 hydrogenated castor oil, polyoxyethylene 10 oleyl ether, polyoxyethylene 40 stearate, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, propylene glycol laurate, sodium lauryl sulfate, sorbitan monolaurate, sorbitan monooleate, sorbitan monopalmitate, sorbitan monostearate, tyloxapol and combinations thereof.
  • the thickening agent is at least one selected from the group consisting of methylcellulose, ethyl cellulose, carboxy methyl cellulose, microcrystalline cellulose, hydroxyl propyl cellulose, hydroxyl ethyl cellulose, hydroxypropyl methylcellulose, polyvinyl pyrrolidone, polyvinyl alcohol, carbomers, xanthan gum, guar gum, acacia gum and tragacanth gum.
  • the suspending agent is at least one selected from the group consisting of colloidal silicon dioxide, bentonite and kaolin.
  • the preservative is at least one selected from the group consisting sodium benzoate, methyl paraben, propyl paraben, potassium sorbate, potassium sorbate and combination thereof.
  • the method of treatment comprises administration of therapeutically effective amount of cassia auriculata extract or compound of formula I to mammals.
  • CA treatment increased GLUT4 and SIRT1 (P ⁇ 0.05) than metformin. This indicates CA improves glucose homeostasis than metformin. There was no significant difference in expression of AMPK, IRS-1 and PPARy. Thus CA continues to prevent cardiac damage even after the treatment is stopped.
  • Multi-generational CR also induces increase in homocysteine.
  • Homocysteine can increase risk of CVD.
  • One of the mechanisms by which homocysteine can bring cardiac-dysfunction is through up- regulation of matrixmetalloproteinases (MMP) in the cytoplasma and decrease in concentration of endothelial nitric oxide.
  • MMP matrixmetalloproteinases
  • NF-kB also inhibits the triad of AMPK-SIRTl -PGC-l a that is vital in mitochondrial energetics and maintaining insulin sensitivity.
  • Sirtl has been implicated in the molecular control of aging and cell proliferation. Both, AMPK and SIRT1 are up-regulated with caloric restriction and exercise which in turn can trigger glucose transporters (GLUT) and insulin receptor substrates (IRS-1) to stimulate glucose uptake in the cell
  • GLUT glucose transporters
  • IRS-1 insulin receptor substrates
  • NF-kB and the AMPK-SIRT l -PGC- l a triad are well regulated.
  • NF-kB expression exceeds and down-regulates the triad (blue circle). Therefore, efforts are on to find small molecules that stimulate this triad or independent elements in triad.
  • targeting the inflammatory mediators in congruence with the AMPK-SIRTl-PGC- la triad can achieve modulation of multiple downstream events that can bring insulin sensitivity.
  • CA treatment inhibited the increase of homocysteine and systemic inflammatory mediators.
  • CA as anti-inflammatory was demonstrated through Western blot studies. CA inhibited both NF-kB and MMP-9 significantly. Moreover, the effect continued even after the treatment was withdrawn. This suggests that the CA might be bringing insulin sensitization and anti-hyperglycemic effect by virtue of its antiinflammatory effects. This can hold true because of the presence of polyphenols in CA.
  • the inventors of the present invention have identified some of these polyphenols which can be represented by Formula I. It was observed that CA was capable of inhibiting the rise in homocysteine. CA demonstrated this effect both in vivo and in vitro. However, there was no effect in plasma concentrations of vitamin B 12 and B6. Secondary mechanism to homocysteine inhibition is also mediated through NF-kB.
  • Hyperglycemia induced homocysteine increase was inhibited by CA.
  • hyperglycemia induced NF-kB expression was also inhibited by CA. Therefore, it is assumed that CA brings about insulin sensitization by its anti-inflammatory effect.
  • the AMPK-SIRT l and PPAR- ⁇ were positively, but mildly, modulated by CA. This modulation might be indirect in nature, because of NF-kB inhibition.
  • CA adipose tissue of insulin resistant rats were treated with CA.
  • PPAR- ⁇ adipose tissue of insulin resistant rats were treated with CA.
  • AMPK was significantly up-regulated.
  • Expression of inflammatory mediator viz, TNF-a, IL-6, MCP- 1 , HIF and PECAM was significantly decreased. Similar effects were observed from the protein expression study.
  • AMPK polyphenols as positive modulators of AMPK and SIRT- 1 .
  • High fat diet inactivates AMPK in liver thus increasing hyperlipidemia and atherogenesis.
  • Modulating AMPK by polyphenols inhibited the progress of atherosclerosis type 1 diabetic LDL receptor-deficient mice (DMLDLR(-/-)).
  • DMLDLR(-/-) atherosclerosis type 1 diabetic LDL receptor-deficient mice
  • Activated AMPK stimulates the production of ATP by regulating glucose and fatty acid metabolism. It has an inhibitory effect on cardiac protein synthesis.
  • AMPK may protect the heart from ischaemic injury and limit the development of cardiac myocyte hypertrophy to various stimuli.
  • CA promises targeting AMPK to preventing myocardial ischaemia or cardiac hypertrophy.
  • cardioprotective activity persisted even after the withdrawal of the CA treatment.
  • Adiponectin has a direct correlation with insulin sensitivity and CVDs.
  • High molecular weight adiponectin is a predictor of insulin resistance, T2DM and MS.
  • Adiponectin acts as a positive indicator of left ventricular diastolic dysfunction in patients with hypertrophic cardiomyopathy.
  • Adiponectin exerts its effect through modulation of AMPK. This suggested that effect of CA on AMPK might be regulated through increase of adiponectin.
  • Metformin is neutral to adiponectin.
  • CA demonstrated a significant insulin sensitizing activity. It is believed that this activity might be an indirect result of its anti-inflammatory and adiponectin increasing potential. In in-vitro studies, neither CA increased glucose uptake (Metformin effect) nor it stimulated adipogenesis (Pioglitazone effect). Moreover, the insulin sensitizing and cardioprotective effect of CA remained extended even after the treatment was withdrawn.
  • Inventors of the present invention evaluated anti-hyperglycemic potential of CA extracts at a single dose on streptozotocin induced diabetic rats for seven hours.
  • CA-HA at dose of 1000 mg kg demonstrated a significant (P ⁇ 0.05) increase than metformin.
  • both CA-SFE and CA-HA failed to show insulin secretion equivalent to glibenclamide.
  • CA extracts have a mild insulin secreting ability.
  • decrease BG appears to be because of its anti-hyperglycemic effect.
  • Anti-diabetic activity (neonatal model of streptozotocin induced T2DM & cataract)
  • nSTZ neonatal streptozotocin
  • This animal model has characteristics of impaired glucose induced insulin secretion and hyperinsulinemia.
  • the aim of the experiment was comparative evaluation of CA and metformin in isolation and combination. Briefly, the neonatal rats at day 2 were injected with STZ and were left with their mothers for weaning. At 15 weeks, intraperitoneal glucose tolerance test (i.p.GTT) of was carried in nSTZ rats. The ⁇ -cell function was analyzed by GTT.
  • i.p.GTT intraperitoneal glucose tolerance test
  • HbA lc glycosylated hemoglobin
  • CA does not have insulin secreting potential. However, it demonstrates good glycemic control.
  • CA's anti-diabetic activity extends to lowering the advanced glycated end-products (AGE) like glycosylated hemoglobin and preventing occurrence of cataract.
  • AGE advanced glycated end-products
  • CA is a good anti-diabetic.
  • the mechanistic aspect is still unknown. It is hypothesized that blood glucose lowering activity of CA is mediated by its insulin sensitizing potential.

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Abstract

L'invention concerne des procédés de préparation d'extraits de Cassia auriculata (CA) et des compositions comprenant un extrait de ceux-ci. Elle concerne également des composés pharmaceutiquement actifs isolés de Cassia auriculata, qui sont utiles pour le traitement de troubles, dont des maladies dues à la résistance à l'insuline, notamment le diabète non insulinodépendant, l'obésité, les maladies cardio-vasculaires et l'augmentation de l'homocystéine qui leur est associée.
PCT/IN2012/000220 2011-04-12 2012-03-29 Extraits végétaux et compositions préparées à partir de ceux-ci WO2012140666A2 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017203540A1 (fr) * 2016-05-21 2017-11-30 Laila Impex Compléments alimentaires et compositions permettant d'améliorer les performances physiques et les niveaux d'énergie

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
A.S. PURANIKL ET AL.: 'Effect of cassia auriculata seed extracts on blood glucose and lipids in wistar rats.' INTERNATIONAL JOURNAL OF DRUG DEVELOPMENT&RESEARCH vol. 2, no. 4, 2010, pages 790 - 798 *
RAJAGOPAL SENTHIL KUMAR MSC ET AL.: 'Effect of Cassia auriculata leaf extract on lipids in rats with alcoholic liver injury.' ASIA PACIFIC J CLIN NUTR vol. 11, no. 2, 2002, pages 157 - 163 *
S.MANEEMEGALAI ET AL.: 'Evaluation of Antibacterial Activity of Flower Extracts of Cassia auriculata L.' ETHNOBOTANICAL LEAFLETS vol. 14, 01 February 2010, pages 182 - 192 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017203540A1 (fr) * 2016-05-21 2017-11-30 Laila Impex Compléments alimentaires et compositions permettant d'améliorer les performances physiques et les niveaux d'énergie
US11122829B2 (en) 2016-05-21 2021-09-21 Laila Impex Dietary supplements and compositions for enhancing physical performance and energy levels

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