The present invention relates to herbal medicines which are useful in the treatment of but not limited to ageing, cancer, diabetes, Alzheimers, arthrosclerosis, arteriosclerosis, diabetes and cardiac ailments.

BACKGROUND OF THE INVENTION

There is a considerable amount of epidemiological evidence indicating association between diet rich in fruits and vegetables and a decreased risk of cardiovascular disease and certain forms of cancer. It is generally assumed that the active principles contributing to these protective effects are nothing but primarily, the antioxidant phytochemicals. Research in the past decades have accumulated enough evidence to show the beneficial effect of free-radical scavengers/antioxidants as antimutagenic, antiinflammatory, antiatherosclerotic, antidiabetic, in constipation, in kidney diseases, in insulin resistance, antihepatotoxic, antiageing and in a variety of neurological disorders.

The search for new antioxidant principles is becoming therefore, essential to improve the pharmacological treatment of pathological conditions related either due to free radical/oxidative damage or due to imbalance between antioxidant/oxidant homeostasis. The medicinal importance of plants bearing rich proportion of antioxidant principles is therefore becoming a popular item.

The prophylactic and therapeutic activities of resveratrol are widely known. Resveratrol formulations have been reported to be potentially effective in the prevention and treatment of cancer, in the suppression of angiogenesis, in anti-ageing therapy, in the treatment of chronic obstructive pulmonary disease and as a selective COX inhibitor. Further, resveratrol is unique in its ability to modulate multiple cellular targets and is, therefore, suitable for the prevention and treatment of wide variety of diseases. Drakshasava, 5000 year old Ayurvedic formulation which contains phytophenols like resveratrol pterostilbenes is known in India as an antioxidant and cancer chemo preventive agent. It is also known to reduce mortality from coronary heart diseases by increasing high density lipoproteins like cholesterol and inhibiting platelet aggregation (Soleas et ah, Clinical Biochem, 30 (2), 19-1 13).

Extensive research in the last few years has revealed that most of the diseases are caused by the deregulation of multiple genes. Thus drugs targeting to a single gene are not likely to cure a disease even when the gene's association with that particular disease is well established. As an alternative, certain foods and food-derived phytochemicals, such as resveratrol, have been used as treatment. Resveratrol is present in the red grapes, peanuts, berries, and several other food plants. Resveratrol's ability to modulate multiple cellular targets, makes it suitable for the prevention and treatment of a wide variety of diseases. Among a large number of resveratrol's targets, cyclooxygenase-2 is ideal one. Further, it presumably lacks the toxicity which is now a days found in most of the COX -2 inhibitors such Rofecoxib(Vioxx), Celecoxib (Celebrex) and Valadocoxib (Bextra).

In 1916 resveratrol was detected in the leaf epidermis and the skin of grape berries but not in the flesh. Fresh grape skins contain 50 to 100 mg resveratrol per gram and the concentration in wine may range from 0.2 to 7.7 mg per liter. Resveratrol was first identified in 1940 as a constituent of the roots of white hellebore (Veratrum grandiflorum O. Loes) and later in the dried roots of Polygollwn cuspidalum in traditional Chinese and Japanese medicine to treat supportive dermatitis, like gonorrhea favus, athlete's foot (tinea pedis) and hyperlipidemia [Takaoka MJ, J Faculty Sci Hokkaido Imperial Univ 3, 1-16, 1940; Vastano BC et al., Isolation and identification of stilbenes in two varieties of Polygonum cuspidatum, J Agric Food Chem 48, 253-256, 2000.; Lee SK et al., Evaluation of the antioxidant potential of natural products, Comb. Chem. High Throughput Screen I, 35-46, 1998.; Cichewicz RH etal., Resveratrol oligomers: structure, chemistry, and biological activity, J Nal. Prod. Chem 26, 507-579, 2002.]

Resveratrol is now recognized as a naturally occurring phytoalexin produced by a wide variety of plants other than grapes such as peanuts and mulberries in response to stress, injury, ultraviolet (UV) irradiation, and fungal (Botrytis cinerea) infection as part of their defense mechanism.

Table 1: Molecular Targets of Resveratrol

Target Effect

Cytokines

Transforming growth factor β2 (TGFp 2) Upregulated

Transforming growth factor (TGF)-a Downregulated

Epidermal growth factor (EGF) Downregulated

Tumor necrosis factor (TNF) Downregulated

FasL Upregulated

Interleukin (IL)-lp Downregulated

Interleukin (IL)-6 Downregulated

Vascular epithelial growth factor (VEGF) Downregulated

Insulin-like growth factor 1 receptor (IGF-IR) Downregulated

Transcription Factors Downregulated

Activator protein-1 (AP-1) Downregulated Nuclear factor-kappa B (NF-KB) Downregulated

Beta catenin (β-catenin) Downregulated

Early growth response(egr)-l Upregulated

Androgen receptor (AR) Downregulated

Cell Cycle Proteins

Cyclin Dl Downregulated

Retinoblastoma (Rb) Downregulated

Cyclin A Downregulated

Cyclin-dependent kinase (cdk)-2 Upregulated

Cyclin Bl Downregulated

p21~HWAFI Upregulated

p27"'l Upregulated

Cyclooxygenase(COX)-2 Downregulated

5-Lipoxygenase(5-LOX) Downregulated

Inducible nitric oxide synthase(iNOS) Downregulated

Vascular cell adhesion molecule (VCAM-1) Downregulated

Intracellular adhesion molecule (ICAM-1) Downregulated

Tissue Factor Downregulated

NADPH:quinone oxidoreductase(NQO)- 1 Upregulated

Apaptosis

Bax Upregulated

Bcl-2 Downregulated

Survivin Downregulated

P 53 Upregulated

Kinases

Protein kinase C(PKC) Downregulated

Syk Downregulated

Protein kinase D(PKD) Downregulated

Caesin kinase II(CKII) Downregulated

Extracellular signal-reguated kinase (ERK) ½ Downregulated Others

Ribonucleotide reductase Downregulated

DNA polymerase Downregulated

CYPIA 1 Downregulated

Nonsteroidal antiinflammatory drug-activated gene (NAG-1) Upregulated

Bioavalibility of resveratrol

Resveratrol may have a chemo preventive effect against cardiovascular disease and a variety of cancers in model systems however; it is not clear whether the drug reaches the proposed sites of action in vivo after oral ingestion, especially in humans. Walle et al. examined the absorption, bioavailability, and metabolism of C-resveratrol after oral doses in six human volunteers [High absorption but very low bioavailability of oral resveratrol in humans, Drug Metab Dispos. 2004 Dec;32(12): 1377-82]. The absorption of a dietarily relevant 25 mg oral dose was at least 70%, with peak plasma levels of resveratrol and metabolites reaching 491 ± 90 ng/ml (about 2uM) and a plasma half-life of 9.2 ± 0.6 hours. However, only trace amounts of unchanged resveratrol (<5 ng/ml) could be detected in plasma. Most of the oral dose was recovered in urine, and liquid chromatography/mass spectrometry analysis identified three metabolic pathways, i.e., sulfate and glucuronic acid conjugation of the phenolic groups and, interestingly, hydrogenation of the aliphatic double bond, the latter likely produced by intestinal microflora. Extremely rapid sulfate conjugation by the intestine/liver appeared to be the rate-limiting step in resveratrol's bioavailability. Although the systemic bioavailability of resveratrol is very low, accumulation of resveratrol in epithelial cells along the aero digestive tract and potentially active resveratrol metabolites may still produce cancer- preventive and other effects.

Following documents disclose various activities of resveratrol

Wu et al., investigated the ability of resveratrol to enhance the sensitivity to chemotherapeutic agents in vivo. The transplantable murine hepatoma22 model was used to evaluate the antitumor activity of resveratrol alone or in combination with 5-fluorouracil (5-FU) in vivo. It was found that 10 mg/kg or 15 mg/kg resveratrol for ten days inhibited the growth of murine bcpatoma22 by 36.3% (n = 10) and 49.3% (n = 9) respectively, which increased obviously compared with that in the control group (85 ± 22 VS. 68 ± 17, PO.OI). The enhanced inhibition of tumor growth by 5-FU was also observed in hepatoma22-bearing mice when 5-FU was administered in combination with 10 mg/kg resveratrol. The results suggested that resveratrol, as a biochemical modulator of the therapeutic effects of 5-FU may be useful in cancer chemotherapy. [Effect resveratrol and in combination with 5-FU on murine liver cancer, World J Gastroenterol 10, 3048-3052, 2004]

While enhancing the toxicity against tumor cells, resveratrol seems to protect normal cells from chemotherapeutic agents. Olas et al., found that resveratrol protects hematopoietic cells from chemotherapy-induced toxicity. [Resveratrol protects against peroxynitrite-induced thiol oxidation in blood platelets, Cell Mol Biol Lett 9, 577-587,2004]

Baatout et al., described that resveratrol can act as a potential radiation sensitizer at high concentrations, because prostaglandin has been implicated in the cytotoxic and cytoprotective responses of tumor cells to ionizing radiation. [Enhanced radiation-induced apoptosis of cancer cell lines after treatment with resveratrol, Ins JMol Med 13, 895-902, 2004.]

Zoberi et al., hypothesized that tumor cells may exhibit changes in the cellular response to ionizing radiation following exposure to resveratrol [Radiosensitizing and anti-prolife -rative effects of resveratrol in two human cervical tumor cell lines, Cancer Lett 175, 65-173, 2002.]

Docherty et al., found that resveratrol inhibits herpes simplex virus types 1 and 2 (HSV-1 and HSV- 2) replication. The results found in this study suggest that a critical early event in the viral replication cycle that has a compensatory cellular counterpart is being adversely affected. [Resveratrol inhibition of herpes simplex virus replication, Antiviral Res 43. 145-155,1999] In a later study, the same investigators determined the effect of resveratrol on HSV-1 in vivo. These studies demonstrate that topically applied resveratrol inhibits HSV lesion formation in the skin of mice. [Effect o topically applied resveratrol on cutaneous herpes simplex virus infections in hairless mice. Antiviral Res 61, 19-26, 2O04.J

Murias et al., found that resveratrol is a nonselective inhibitor of COX-I and COX-2 .To produce more selective COX-2 inhibitors, they synthesized a series of methoxylated and hydroxylated derivatives and evaluated their activity against COX-I and COX-2 using in vitro PGE2 assays. Hydroxylated but not methoxylated resveratrol derivatives showed a high rate of inhibition. The most potent resveratrol compounds were trans-SJ'^'.S-telrahydroxystilbene (COX-1 : IC(50) = 4.713 μΜ, COX-2: IC(50) = 0.0113 μΜ, selectivity index = 417.08) and ti s^. AA'.S - hexahydroxystilbene (COX.I: IC{50) = 0.748 μΜ, COX-2: IC(50) = 0.00104 μΜ. [Resveratrol analogues as selective cyclooxygenase-2 inhibitors: synthesis and structure—activity relationship, Bioorg Med ChemU, 5571-5578, 2004]

Walle T. et al., examined the absorption, bioavailability, and metabolism of 14C-resveratrol after oral and i.v. doses in six human volunteers. It was found that although the systemic bioavailability of resveratrol is very low, accumulation of resveratrol in epithelial cells along the aero digestive tract and potentially active resveratrol metabolites may still produce cancer-preventive and other effects. [High absorption but very low bioavailability of oral resveratrol in humans, Drug Metab Dispos. 2004 Dec;32(l 2): 1377-82] Ebba Brakenhielm et al., demonstrated that resveratrol acts as inhibitor of endothelial cell growth and also act as an oral angiogenesis inhibitor. The antiangiogenic property of resveratrol was examined in several in vivo models including the mouse corneal model, the chick chorioallantoic membrane assay, a wound-healing model, and a tumor model. [Suppression of angiogenesis, tumor growth and wound healing by resveratrol, a natural compound in red wine and grapes, The FASEB Journal, 2001 ; 15 : 1798- 1800]

Xia Wen et al., found that the higher hepatic metabolic stability and intestinal absorption of the methylated polyphenols make them more favorable than the unmethylated polyphenols developed as potential cancer chemopreventive agents. [Drug metabolism and disposition, October 2006 vol. 34 no. 10 1786-1792]

S. Garvin et al., observed significantly lower tumor growth, decreased angiogenesis, and increased apoptotic index in Era-ER-β + MDA-Mb-231 tumors in resveratrol-treated nude mice compared with controls. In vitro he found a significant increase in apoptosis in resveratrol-treated MDA-MB-231 cells in addition to significantly reduced extra cellular levels of VEGF. [Cancer Letters, Volume 231, Issue 1, Pages 113-122]

John Lacey, Harvard Medical School, found the risk of death cut by 31 percent for obese mice treated with the compound and treated mice seen living as long as lean mice. In obese mice, molecule reversed nearly all pathways activated in mice by high calorie diets. Findings suggest broad implications for the treatment of age related diseases, including diabetes and heart diseases. [Harvard Medical School Office of Public Affairs 617-432-0442.]

According to Aruna Kode et al resveratrol induces glutathione synthesis by activation of Nrf2 and protects against cigarette smoke-mediated oxidative stress in human lung epithelial cells. [Am J Physiol Lung Cell Mol Physiol 294: L478-L488, 2008.]

J Alex Parker et al., found that resveratrol rescued mutant polyglutamine specific cell death in neuronal cells derived from HdhQl 1 knock in mice. He concluded that SIR2 activation may protect against mutant polyglutamines. [Nature genetics 37, 349-350, 2005]

J. Leiro et al., found that resveratrol has a significant modulatory effect on the NF-kB signaling pathway and consequently, an important antioxidant role that may partially explain the cardioprotective effects attributed to long term moderate red wine consumption. [International Immunopharmacology, Volume 5, Issue 2, February 2005, Pages 393-406]

Schreiber et al., found that resveratrol is an effective counter measure to exercise induced oxidative stress and immune system activation. [Medicine & Science in

Sports & Exercise: May 2008 - Volume 40 - Issue 5 - p S246.]

Following Patents/ Patent applications disclose use of resveratrol and composition comprising the same.

WO 9904747 describes the use of resveratrol to improve the appearance of human skin and to enhance differentiation and inhibit proliferation of keratonocytes. Resveratrol in pure form is given as a topical formulation in doses of 0.00002 to 10% resveratrol by weight.

WO 9903816 discloses a composition of resveratrol esters end their oligomers for use as anti- tumour and vasoprotective agents in animals and humans. The resveratrol derivates are monomer or oligomers having at least one ester group with the formula -O-CO-A.

WO 9901148 describes a composition containing resveratrol and other polyphenols for the treatment of metabolic disorders such as anoxia. The polyphenols are extracts from grapes and grape products or wine with yeast extracts combined.

Japanese Patent No. 9328410 discloses the use of an extract of the Yucca plant which contains saponin, flavone and resveratrol as a cosmetic for prevention of rough skin and cutaneous aging. The extract was shown to have antimicrobial activity as well as UV absorbing ability.

Another Japanese Patent 61171427 describes use of an extract of Polygonaceae as an anti thrombosis agent. The extract contains a pterestilbene compound comprising resveratrol as well as other components.

Chinese Patent 1127070 discloses the use of resveratrol in combination with a variety of other compounds as additives for a nutritional milk powder. The powder was developed for use in the elderly for immunostimulation and prevention of heart disease, as well as milk powder for pregnant women and children and a health drink for athletes. U.S. Patent No. 5,747,536 discloses use of trithydroxy or terrahydroxystilbene, such as resveratrol, in combination with L-carnitine and alkanoy L-carnitine to prevent or treat cardiovascular diseases, peripheral cardiopathies and diabetic peripheral neuropathies.

U.S. Patent No. 7026518 discloses antioxidant Resveratrol analogs such as 5-[(lE)-2-(3,4- dihydroxyphenyl)vinyl]-benzenel,2,3-triol and 5-[(lE)-2-(5-bromo-3,4-dihydroxy phenyl) vinyl]- benzene 1,2,3-triol.

WO 2008092221 disclose a process for obtaining trans-resveratrol and/or emodin characterized by comprising the selective solid-liquid solvent extraction of Polygonum Cuspidatum and/or Rumex acetosa materials, said process comprising the following steps: a) extraction with aromatic solvent for obtaining emodin; b) extraction with open-chain hydrocarbon and/or ether, both with six atoms of carbon, for eliminating impurities; and c) extraction with polar solvent for obtaining trans- resveratrol.

US 20090175803 discloses a composition for administering at least one compound selected from the group consisting of resveratrol and pterostilbene comprising adding the at least one compound to a carrier that requires chewing or retention in the mouth for from about 20 seconds to about twenty minutes.

US Patent No. 6270780 discloses topical application of resveratrol for improving the appearance of wrinkled, lined, dry, flaky, aged, or photo-damaged skin and improving skin thickness, elasticity, flexibility, radiance, glow and plumpness.

US Patent 6358517 discloses a cosmetic skin care composition comprising: (i) resveratrol in an amount of from 0.00001 to 10 wt. %; (ii) a retinoid selected from the group consisting of retinoic acid, retinol, and retinyl acetate; and (iii) a cosmetically acceptable vehicle.

Numerous studies have indicated that resveratrol has great potential for the treatment of a wide variety of diseases. However, a number of problems associated with the use of resveratrol still exist. Resveratrol exhibits maximum activity in its free, un-reacted form. Although resveratrol has been demonstrated to be quite significantly effective in vitro in anti-aging, anti-tumor, anti-inflammatory, anti-oxidant, anti-estrogenic and antimmunomodulatory therapies, its effectiveness in vivo has been limited by its low bio-availability in the free unreacted form. Various factors such as low concentration of the free resveratrol in the administered natural formulations, low intestinal absorption of the free resveratrol, low stability of the free resveratrol leading to its conversion into less active forms and sulfation and glucuronidation of resveratrol in the liver and in the intestines limit the bioavailability of resveratrol in the free unreacted form. Synthetic resveratrol having more than 99% purity is known to be effective and bio-active, but is extremely unstable. Further, resveratrol conventionally used have been reported to cause chelation of trace mineral, copper resulting in inhibition of its absorption and consequent cardiac problems. Resveratrol formulations capable of delivering resveratrol in free, unreacted form and of retaining it in the bloodstream for a prolonged period of time, is therefore, very much desired.

OBJECTS OF THE INVENTION

It is an object of the invention to provide an herbal formulation.

It is another object of the present invention to provide an anti-ageing herbal formulation.

It is still another object of the present invention to provide an herbal formulation for the treatment of cancer, diabetes, Alzheimers, arthrosclerosis, arteriosclerosis, diabetes, metabolic diseases, viral diseases, inflammation and cardiac ailments.

It is another object of the present invention to provide an herbal formulation for improving overall symptoms & quality of life, increasing energy level, HDL level, ejection fraction of heart, hair growth, bone & tissue mineral level, muscle mass, quality of sleep, improving bowel movement, mitochondrial function, rejuvenation of skin, detoxification, gene repairing and immunomodulation for cancer patients

It is yet another object of the present invention to provide a formulation which is capable of delivering the active ingredient in the blood stream for a prolonged period of time.

It is a further object of the present invention to provide a formulation which is capable of retaining the active ingredient in free, un-reacted form.

It is still further object of the present invention to provide a formulation with improved efficacy and bioavailability. It is another object of the present invention to provide a formulation that improves patient compliance and reduces the chances of discontinuation of the treatment.

It is another object of the invention to provide a formulation that avoids the chances of development of resistance.

SUMMARY OF THE INVENTION

In accordance with the present invention there is provided a bio-stabilized resveratrol formulation comprising 50 to 80% virtus resveratrol, 2 to 6% lotus seed powder, 0.8 to 6% grape seed extract, 0.6 to 7% sesame seed, 1.4 to 10% sunflower seed, 0.4 to 5% pumpkin seed, 1.8 to 15% Kelp, 1.2 to 5% carrot seed powder, 1 to 5 % onion seed, 2 to 6 % Medicago sativa, 2 to 12 % Amaranthus spinosus, 1 to 5 % mulberry and pharmaceutically acceptable carrier; the proportions of the active ingredients being based on the total mass of the formulation.

Typically, the formulation is capable of stabilizing resveratrol for prolonged time and of delivering resveratrol in the free, unreacted form to enable a concentration in the range of 35 nmols/liter to 40000 nmols/liter in the blood stream.

Preferably, the formulation is capable of delivering resveratrol in the bloodstream in free, unreacted form at a concentration in the range of 10000 nmols/liter to 40000 nmols/liter.

Typically, the formulation is capable of retaining free/unreacted resveratrol in the blood stream for upto 6 hours.

Typically, the formulation is capable of being delivered orally, buccally or transdermally.

Typically, the carrier is selected from the group consisting of cream, gel, ointment, liquid, oil, suspension, paste, aerosol spray, gauge, fibrous wad, membrane, film, tape, plaster, tablet, capsule, granules, powder and emulsion. In accordance with another embodiment of the present invention the formulation further comprises at least one oil selected from the group consisting of jojoba, lemon, rosemary, lavender, tea tree, mandarin, pomegranate seed, avocado, almond, pumpkin seed, mustard, coconut, fenugreek, Chironji and Alangium lamarckii Thwaites.

Typically, the amount of jojoba oil is in the range of about 6 to about 24 % of the mass of the formulation.

Typically, the amount of lemon oil is in the range of about 1.5 to 20 % of the mass of the formulation.

Typically, the amount of rosemary oil is in the range of about 1.5 to 17 % of the mass of the formulation.

Typically, the amount of lavender oil is in the range of about 1.5 to 58 % of the mass of the formulation.

Typically, the amount of tea tree oil is in the range of about 1.5 to 30 % of the mass of the formulation.

Typically, the amount of mandarin oil is in the range of about 1.5 to 24 % of the mass of the formulation.

Typically, the amount of pomegranate seed oil is in the range of about 2.5 to 14 % of the mass of the formulation.

Typically, the amount of avocado oil is in the range of about 2 to 10 % of the mass of the formulation.

Typically, the amount of almond oil is in the range of about 1.25 to 8 % of the mass of the formulation.

Typically, the amount of pumpkin seed oil is in the range of about 10 to 40 % of the mass of the formulation. Typically, the amount of mustard oil is in the range of about 66 to 95 % of the mass of the formulation.

Typically, the amount of coconut oil is in the range of about 4.5 to 25 % of the mass of the formulation.

Typically, the amount of fenugreek oil is in the range of about 2 to 28 % of the mass of the formulation.

Typically, the amount of Chironji oil is in the range of about 4 to 24 % of the mass of the formulation.

Typically, the amount of Alangium lamarckii Thwaites(ALA) oil is in the range of about 2 to 30 % of the mass of the formulation.

In accordance with another embodiment of the present invention the formulation further comprises at least one ingredient selected from the group consisting of magnesium chloride and choline chloride.

Typically, the amount of magnesium chloride is in the range of about 4.5 to 30 % of the mass of the formulation.

Typically, the amount of choline chloride is in the range of about 4 to 25 % of the mass of the formulation.

In accordance with another aspect of the present invention there is provided a process for the preparation of a formulation; said process comprising:

a. homogenously blending at least one plant tissue selected from a group of plant tissues which include leaves, roots, stems, flowers and fruits of the following plants Peanuts (Arachis hypogea ), Lotus Seed Powder(Se/Men Nelumbinis), Grape Seed Extract (Vitis Vinifera), Sesame Seeds(Dalbergia Sissoo), Sunflower Seeds(Helianthus annuus), Pumpkin Seeds(Lagenaria Vulgaris), Kelp (Barilla), Carrot seed powder (Daucus carota), A\fa\fa(Medicago sativa), ?wnpkin(Cucurbita pepo.Cucurbitamaxima), Amaranth {Amaranthus spinosus), Onion Seeds {Allium cepa) and Mulberry to form a blend;

b. optionally subjecting the blend to cryogenic treatment

c. soaking the blend in water for a period of about 2 to about 14 days.

d. wrapping the blend followed by keeping it in dark under vacuum

e. keeping the blend at a temperature of about 20 to 40°C, at about 75 to 95 % humidity to allow the growth of fungi

f. optionally subjecting the blend to cryogenic treatment

g. boiling the blend under pressure for a period of about 10 to 40 minutes

h. crushing the blend

i. drying the blend in a lyophilizer to obtain a formulation in the form of powder.

In accordance with another embodiment of the present invention there is provided a medicament used for the treatment of diseases and conditions selected from the group consisting of cancer, Alzheimer's disease, obesity, metabolic diseases, cardiac diseases, viral diseases, inflammation, impaired mitochondrial function, ageing, diabetes and insulin related disorders comprising administering to a subject in need thereof an effective amount of a bio-stabilized resveratrol formulation.

In accordance with still another embodiment of the present invention there is provided a medicament used for improving overall symptoms & quality of life, increasing energy level, HDL level, ejection fraction of heart, hair growth, bone & tissue mineral level, muscle mass, quality of sleep, improving bowel movement, mitochondrial function, rejuvenation of skin, detoxification, gene repairing and immunomodulation for cancer patients, comprising administering an effective amount of a bio-stabilized resveratrol formulation.

DETAILED DESCRIPTION OF THE INVENTION

In accordance with the present invention there is provided a bio-stabilized resveratrol formulation comprising 50 to 80% virtus resveratrol, 2 to 6% lotus seed powder, 0.8 to 6% grape seed extract, 0.6 to 7% sesame seed, 1.4 to 10% sunflower seed, 0.4 to 5% pumpkin seed, 1.8 to 15% Kelp, 1.2 to 5% carrot seed powder, 1 to 5 % onion seed, 2 to 6 % Medicago sativa, 2 to 12 % Amaranthus spinosus, 1 to 5 % mulberry and pharmaceutically acceptable carrier; the proportions of the active ingredients being based on the total mass of the formulation. The formulation prepared in accordance with the present invention is capable of stabilizing resveratrol for prolonged time and of delivering resveratrol in the free, unreacted form to enable a concentration in the range of 35 nmols/liter to 40000 nmols/liter in the blood stream.

Preferably, the formulation is capable of delivering resveratrol in the bloodstream in free, unreacted form at a concentration in the range of 10000 nmols/liter to 40000 nmols/liter.

The formulation of the present invention is capable of retaining free/unreacted resveratrol in the blood stream for upto 6 hours.

The formulation of the present invention is capable of being delivered orally, buccally or transdermally.

The carrier used for the preparation of the present formulation is selected from the group consisting of cream, gel, ointment, liquid, oil, suspension, paste, aerosol spray, gauge, fibrous wad, membrane, film, tape, plaster, tablet, capsule, granules, powder and emulsion.

In accordance with another embodiment of the present invention the formulation further comprises at least one oil selected from the group consisting of jojoba, lemon, rosemary, lavender, tea tree, mandarin, pomegranate seed, avocado, almond, pumpkin seed, mustard, coconut, fenugreek , Chironji and Alangium lamarckii Thwaites.

Typically, the amount of jojoba oil is in the range of about 6 to about 24 % of the mass of the formulation.

Typically, the amount of lemon oil is in the range of about 1.5 to 20 % of the mass of the formulation.

Typically, the amount of rosemary oil is in the range of about 1.5 to 17 % of the mass of the formulation.

Typically, the amount of lavender oil is in the range of about 1.5 to 58 % of the mass of the formulation. Typically, the amount of tea tree oil is in the range of about 1.5 to 30 % of the mass of the formulation.

Typically, the amount of mandarin oil is in the range of about 1.5 to 24 % of the mass of the formulation.

Typically, the amount of pomegranate seed oil is in the range of about 2.5 to 14 % of the mass of the formulation.

Typically, the amount of avocado oil is in the range of about 2 to 10 % of the mass of the formulation.

Typically, the amount of almond oil is in the range of about 1.25 to 8 % of the mass of the formulation.

Typically, the amount of pumpkin seed oil is in the range of about 10 to 40 % of the mass of the formulation.

Typically, the amount of mustard oil is in the range of about 66 to 95 % of the mass of the formulation.

Typically, the amount of coconut oil is in the range of about 4.5 to 25 % of the mass of the formulation.

Typically, the amount of fenugreek oil is in the range of about 2 to 28 % of the mass of the formulation.

Typically, the amount of Chironji oil is in the range of about 4 to 24 % of the mass of the formulation.

Typically, the amount of Alangium lamarckii Thwaites(ALA) oil is in the range of about 2 to 30 % of the mass of the formulation. In accordance with another embodiment of the present invention the formulation further comprises at least one ingredient selected from the group consisting of magnesium chloride and choline chloride.

Typically, the amount of magnesium chloride is in the range of about 4.5 to 30 % of the mass of the formulation.

Typically, the amount of choline chloride is in the range of about 4 to 25 % of the mass of the formulation.

In another embodiment of the present invention there is also provided formulation comprising 5 to 50 % of bio-stabilized vitrus resveratrol, 2 to 20 % Fenugreek , 6 to 20 % Jojoba oil, 1.5 to 20 % lemon oil, 1.5 to 15 % Rosemary oil, 1.5 to 30 % Mandarin oil, 1.5 to 11 % of Lavender oil, 1.5 to 25 % of tea tree oil and alangium Lamer (ki) thwaites, the proportions of the active ingredients being based on the total mass of the formulation and a carrier.

In still another embodiment of the present invention there is also provided formulation comprising 50 to 85 % of bio-stabilized vitrus resveratrol, 10 to 30 % Fenugreek, 10 to 25 % Jojoba oil, 2 to 15 % lemon oil, 2 to 20 % Rosemary oil, 4 to 25 % Mandarin oil, 4 to 60 % of Lavender oil and 5 to 30 % of tea tree oil, the proportions of the active ingredients being based on the total mass of the formulation and a carrier.

In yet another embodiment of the present invention there is also provided formulation comprising 40 to 60 % of bio-stabilized vitrus resveratrol, 2 to 15 % Pomegranate seed oil, 2 to 10 % Avocado oil, 4 to 25 % of Chironji oil, 1 to 8 % Almond oil, 10 to 40 % Pumkin seed oil, 4 to 30 % of Magnessium chloride and 4 to 25 % of Choline chloride, the proportions of the active ingredients being based on the total mass of the formulation and a carrier.

In further embodiment of the present invention there is also provided formulation comprising 15 to 30 % of bio-stabilized vitrus resveratrol, 60 to 95 % Mustard oil and 4 to 25 % coconut oil, the proportions of the active ingredients being based on the total mass of the formulation and a carrier.

In accordance with another aspect of the present invention there is provided a process for the preparation of a formulation; said process comprising: a. homogenously blending at least one plant tissue selected from a group of plant tissues which include leaves, roots, stems, flowers and fruits of the following plants Peanuts (Arachis hypogea ), Lotus Seed Pov/der(Semen Nelumbinis), Grape Seed Extract (Vitis Vinifera), Sesame Seeds(Dalbergia Sissoo), Sunflower Seeds(Helianthus annuus), Pumpkin Seeds(Lagenaria Vulgaris), Kelp (Barilla), Carrot seed powder (Daucus carotd), Alfalfa(Medicago sativa), Pumpkin(Cwcwr6zY pepo,Cucurbitamaxima), Amaranth {Amaranthus spinosus), Onion Seeds {Allium cepa) and Mulberry to form a blend;

b. optionally subjecting the blend to cryogenic treatment

c. soaking the blend in water for a period of about 2 to about 14 days.

d. wrapping the blend followed by keeping it in dark under vacuum

e. keeping the blend at a temperature of about 20 to 40°C, at about 75 to 95 % humidity to allow the growth of fungi

f. optionally subjecting the blend to cryogenic treatment

g. boiling the blend under pressure for a period of about 10 to 40 minutes

h. crushing the blend

i. drying the blend in a lyophilizer to obtain a formulation in the form of powder.

In accordance with another embodiment of the present invention there is provided a medicament used for the treatment of diseases and conditions selected from the group consisting of cancer, Alzheimer's disease, obesity, metabolic diseases, cardiac diseases, viral diseases, inflammation, impaired mitochondrial function, ageing, diabetes and insulin related disorders comprising administering to a subject in need thereof an effective amount of a bio-stabilized resveratrol formulation.

In accordance with still another embodiment of the present invention there is provided a medicament used for improving overall symptoms & quality of life, increasing energy level,

HDL level, ejection fraction of heart, hair growth, bone & tissue mineral level, muscle mass, quality of sleep, improving bowel movement, mitochondrial function, rejuvenation of skin, detoxification, gene repairing and immunomodulation for cancer patients, comprising administering an effective amount of a bio-stabilized resveratrol formulation. Following examples illustrate the invention, but are not intended to limit the scope of the present invention.

Example 1:

Each 500 gm of powder contains:

Example 2:

Each 100 ml oil contains:

Example 3:

Each 150 ml oil contains:

Example 4:

Each 150 ml oil contains:

Example 5:

Each 150 ml oil contains:

Bioavailability study:

Method of analysis: LC-MS/MS

Trial I]

Table 2:

ND- Not detectable

Trial II]

Table 3:

The formulation of the invention enables stabilization of resveratrol and prevents formation of conjugates. Sulfation and glucuronidation in the liver and intestines are prevented when resveratrol is administered as an ingredient in the formulation of the invention. Further, when administered as an ingredient in the formulation of the invention, resveratrol is delivered in the free, unreacted form to enable a concentration of upto 40000 nmoles/liter in the bloodstream. Advantageously, resveratrol is delivered in the free, unreacted form at a concentration in the range of 10000 nmoles/liter to 40000 nmoles/liter. Furthermore, the formulation of the invention is capable of retaining free/unreacted resveratrol in the blood stream for upto 6 hours. Clinical Trials:

Clinical studies for the efficacy of the formulation prepared in accordance with the present invention were carried out by administering the formulation to non cancer and cancer patients.

I. Non- Cancer Patients

a. Table 2 displays changes in various parameters of physical and mental health in a middle aged (46 years old) volunteer before and after administration of the formulation prepared in accordance with the present invention.

Table 4 : Changes in various parameters of physical and mental health in a middle aged (46 years old) volunteer

From table 4 it was found that, upon administration of the formulation of the invention, there was improvement in the quality of sleep, energy levels and complexion and reduction in constipation, depression, cramps and irritability in a middle aged volunteer.

Table 5 : Change in various parameters of physical and mental health of a senior (Age: 61 years) volunteer before and after administration of the formulation

Energy 30% 70% 80%

Fatigue 80% 50% 10%

Table 5 shows that, upon administration of the formulation of the invention, there was improvement in appetite, complexion, hair growth and reduction in fatigue and recovery time in a senior volunteer.

Table 6 : Change in various parameters of physical and mental health of a senior (Age: 58 years) volunteer before and after administration of the formulation

From table 6 it was found that, upon administration of the formulation of the invention for one month there is improvement in appetite, complexion, hair growth and reduction in fatigue and recovery time in a senior volunteer.

Table 7: Change in various parameters of physical and mental health of a young (Age: 18 years) volunteer before and after administration of the formulation

Table 7 shows that upon administration of the formulation of the invention for two months, there was improvement in concentration and energy levels and reduction in squint in eyes, oedema, depression, frequency of seizures and hair fall in a young healthy volunteer.

II. Cancer Patients

The patients were observed for one month while on chemotherapy. The symptoms were graded as 0=absent, l=mild, 2=moderate, 3=severe.

Case 1:

A 60 years old female patient having history of tobacco addiction for past 46 years, presented with the complaints of weight loss, Indigestion, Insomnia, pain in abdomen and bloated abdomen since last 4 months.

The patient had no history of hypertension, diabetes mellitus, Ischemic heart disease, osteoarthritis or, thyroid disorder. Her hysterectomy was done 10 years back without removal of ovaries. CT scan-of abdomen and pelvis revealed bilateral adnexal lesions showing heterogeneous contrast enhancement. A biopsy was performed under local anesthesia and histopathology confirmed the growth of adenocarcinoma of right ovary and anaplastic undifferentiated carcinoma of left ovary. Her CEA -125 was positive with a value of 15.0. Her electrocardiogram and X-ray were normal.

Patient took three cycles of chemo therapy. She was prescribed the medicines which include Inj Granisteron 3mg in 100 ml normal saline, Inj Flurourocil 127.5 mg in 1 lit normal saline over 12-16 hours, inj cisplastin 35 mg in 500 ml normal saline and inj Taxim.

After first chemotherapy, she suffered from unwanted effects of chemotherapy as vertigo, vomiting, weakness and cramps, headache. Patient was then operated and bilateral oopherectomy was done after second chemotherapy. Bilateral ovarian masses measuring 4x3 cm and 5x4 cm were removed. Bilateral pelvic lymph nodes were also removed.

The formulation in accordance with the present invention was then started after second chemo therapy. The formulation in accordance with the present invention was continued during third cycle of chemotherapy and she was able to tolerate the third chemotherapy. Table 8: Relief in physical and mental discomforts of cancer patient, after administration of the formulation

Table 8 shows significant improvement in patient's health with respect to symptoms such as vomiting, nausea, fatigue and constipation. Furthermore, a relief from cachexia was also reported. Still further after the treatment with present formulation she was able to sleep for at least 5 hours. Apart from this her mood and work output get elevated with reduction in irritability.

Case 2;

A 65 years old male patient having a history of alcohol & smoking addiction for last 45 years presented with the complaints of submandibular swelling, difficulty in swallowing, hoarseness of voice, pain and bleeding since past 3 months. His pre and post auricular and submandibular lymph nodes were palpable. Cervical lymph node too was also palpable. The patient had no history of hypertension, diabetes mellitus, ischemic heart disease, osteoarthritis or, thyroid disorder. His CEA was - 4.7 ng/nl

CT scan of neck revealed that heterogeneously enhancing soft tissue density lesion arising from epiglottis and right ary-epiglottic fold with extension into pre- epiglottis and right Para laryngeal spaces. CT findings were clearly suggestive of malignant neoplasm. There was involvement of false as well as true vocal cords. CT scan also confirmed bilateral cervical metastasis lymphadenopathy (level I and III). Histopathology report confirmed severe degree dysphasia Report of cytology suggested secondary deposits of well differentiated squamous cell carcinoma in left cervical lymph node.

The patient was operated for the same and left level II, III, IV lymph node dissection was done on September 2008. The formulation in accordance with present invention was continued before and after the surgery. His first cycle of chemotherapy was given in July 2008 followed by chemotherapy cycle every month. Fifth cycle was given in October 2008. He was taking the medicines which include Inj Granisteron 3mg with inj Dexona 8mg 2 cc intravenously in 100ml normal saline, Inj Flurourocil 275 mg in 1 lit normal saline over 12 hrs, Inj Cisplastin 35 mg in 500 ml normal saline.

Table 9: Relief in physical and mental discomforts of cancer patient, after administration of the formulation

Form table 9, it clear that, upon administration of the formulation of the invention, there was moderate reduction in his severe indigestion, headache, pain and nausea. Further, depression and pain were reduced to some extent. The hoarseness of voice also got reduced. Still further there was improvement in cachexia, work out put, quality of sleep and quality of life. There was also no change in hair fall.

Case 3:

A 47 yrs old female patient, known case of carcinoma of left breast presented with complaints of constipation, weight gain, fatigue body ache hair fall, cachexia, and post chemotherapy headache. Further, she was not able to tolerate chemotherapy at all. Her lumpectomy done was done in November 2005 followed by hysterectomy in 2006. She completed 6 cycles of chemotherapy. In November 2007, she developed metastasis of mammary gland carcinoma in right cervical lymph node. The patient had history of hypertension since last 13 years and migraine since last 10 years.

It is found that she is able to tolerate chemotherapy well after the treatment with present formulation. Further, she is able to evacuate bowel properly. Her difficulty in reading a newspaper, watching TV etc. is relieved. Further her energy level also gets improved.

Table 10: Relief in physical and mental discomforts of cancer patient, after administration of the formulation

Table 10 shows that, upon administration of the formulation of the invention, the constipation and fatigue were completely relieved but there was no much improvement in pain. Further, there was improvement in her cachexia to a great extent.

Case 4:

A 45 years old male patient presented with complaints of breathlessness, difficulty to climb, acute dyspnoea and tachycardia. He was admitted in hospital in Mumbai on 1 ^st Nov 2008. Pleural tapping was done immediately but it was not able to decrease dyspnoea. The patient was non alcoholic and non smoker. Patient had no history of hypertension, diabetes mellitus, and cardiovascular disease. Patient had strong family history of carcinoma as below:

His father died due to bone and prostate carcinoma. His mother died of ovarian cancer. Maternal grandmother died due to breast cancer. His sister has breast cancer. His both niece 15 years old and 23 years old died of blood cancer. The cytology examination revealed pleural effusion with Aden carcinoma of left lung. The biopsy confirmed the same. He was shifted to Mohintara hospital, Pune on 22 Nov 2008. He was not able to talk or do movements. His respiratory rate was 35-40 cycle/min considering respiratory failure; he was put on ventilator on 23 Nov 2008. He was seen by the oncologist and was put on chemotherapy on 24 Nov 2008. ( Inj Avartin 600 mg, Inj Paclitax 280 mg, Inj carboplatin 600 mg, capsule apricap and Tab. practin 4 mg). His dyspnoea was gradually reduced to 50 %. His clinical symptoms were reduced to 80 %.but there was no change in his energy levels. He still was not able to walk or talk for five minutes.

After first chemotherapy he had cramps in legs, and cachexia. He was given total 5 cycles of chemotherapy. Ten days after the first chemotherapy the patient was given formulation in accordance with the present invention. After 10 days of the treatment patient was able to get up on his own. His will power was increased. He felt more energetic and was even able to climb up to three staircases. Further he was able to tolerate all the chemotherapies very well after the treatment with formulation of present invention. Furthermore, his energy level and attitude towards life were improved.

Table 11: Relief in physical and mental discomforts of cancer patient, after administration of the formulation

From table 11 , it is clear that, upon administration of the formulation of the invention, there was no change in hair fall. Furthermore, his constipation, Hoarseness of voice and severe fatigue problems were relieved.

Case 5:

A 57 years old female presented with complaints of enlarged abdomen, loss of appetite, fatigue, reduced energy levels and hair fall. The patient had history of hypertension since last 2 years and her both sisters died due to cancer. Her X-ray showed mild cardiomegaly, with left sided pleural effusion. Ultra sonography revealed mass in pelvis highly suggestive of neo-plastic mass, most likely of ovarian origin. Multiple hepatic and peritoneal metastases, paraaortic, periportal and mesenteric lymphadenopathy left sided plural effusion and moderate ascites. CT scan revealed bilateral adnexal ovarian neoplastic masses with peritoneal spread. Her CA 125 was 13639.72.

The patient was given three cycles of chemotherapy along with formulation in accordance with the present invention. The patient had complaints like cramps, nausea during first cycle and she could tolerate other two cycles of chemotherapy well.

Table 12: Relief in physical and mental discomforts of cancer patient, after administration of the formulation

Table 12 shows that, upon administration of the formulation of the invention, there was reduction in symptoms like headache, fatigue, constipation and indigestion. Furthermore, there was improvement in Cachexia, work ability, quality and quantity of sleep. There was also no change in the hair fall. Table 13: Summary of relief in physical and mental discomforts ¹ of cancer patients, after administration of the present formulation

^† The numbers in various fields indicate the number of patients for whom improvement is observed of a particular symptom

From table 13, it is clear that majority of cancer patients have found significant improvement in various physical and mental discomforts after administration of the formulation of the invention. There was remarkable overall improvement in the quality of life in cancer patients, after administration of the formulation of the invention.

Table 14 : Hamilton Scores of depression and anxiety observed for different patients, after administration of the formulation prepared according to Example 1

The Hamilton scores displayed in table 14 for different cancer patients indicate reduction in anxiety in patients, upon administration of the formulation of the invention. Table 15: Detection of Calcium, Magnesium, High-density lipoprotein (HDL), dehydroepiandrosterone DHlT/l,), Low-density lipoprotein(LDL) and Triglyceride levels

[All volunteers have sedentary life style except R B.; R. B. is professional competitive international sportsman]

The results as shown in table 15 clearly indicate that the DHEA levels in volunteers involved in independent pilot studies are between 27 to 220 % after the treatment. Anecdotal Studies:

1. A 28 year old sport person was prescribed a formulation prepared in accordance with the present invention for a period of 36 days. The performance of sportsman in international competition was improved by 20%. Furthermore, other benefits such as higher sustained energy, better quality sleep, more concentration and improved bowel movement were reported.

2. A 28 year old male was prescribed a formulation prepared in accordance with the present invention for a period of 7 days. After 7 days of consumption of the product of this invention, the volunteer felt 15% slimmer, fitter and trimmed. Furthermore, the calmness, focus, reflexes and concentration were improved by about 40%.

3. A 38 year old female was presented with chronic Candida yeast infection. The patient was prescribed a formulation prepared in accordance with the present invention for a period of 180 days. After 30 days of treatment, the infection was cured by 90 %.

4. A 54 year old female was presented with hair fall & ageing problems. She was prescribed a formulation prepared in accordance with the present invention for a period of 7days. After 7 days of treatment she noticed that her hair fall was stopped by 100%. Also there was a 20% increase in hair volume and considerable hair growth. After 3 months of the treatment, it was found that her white hairs (50 %) were changed to 30% grey hair. Further, her skin texture was improved with reduction in wrinkles. Apart from this she felt a 75% improvement in energy & stamina levels. Still further, she noted a 70% increase in her calmness and tranquility of mind

5. A 65 year old male with sedentary life styles was prescribed a formulation prepared in accordance with the present invention. It was found that there was increase in minerals levels in the tissues by 4% and in bones by 0.22% in less than six months. Further, the muscle mass also increased correspondingly by about 4%.

6. A 72 year old male was presented with diabetes history for 22 years who also had undergone heart bypass surgery and with an ejection fraction of 46 after heart bypass surgery. He was prescribed a formulation prepared in accordance with the present invention. After the treatment he showed gradual molecular improvement. After three years of the treatment he achieved an ejection fraction of 68, his insulin resistance was improved from 6.8 to 0.84 and his A/C value was changed from 8.5 to 6.5. Furthermore, his HDL level was up from 33 to 56, LDL level was improved from 135 to 61.2 and DHEA hormone level was improved from 531 ng/ml to 850 ng/ml.

7. A 71 year old male was presented with arthrosclerosis. His anterior tibial artery and dorsals pedis artery were 75% blocked. After using the product of the invention, it was found that artery had become patent.

8. A 65. year old female was presented with ageing problems. She was prescribed a formulation prepared in accordance with the present invention for a period of 45 days. After the treatment it was found that the skin ageing was reversed by up to 20 years, as was measured by moisture globules per square inch of their skin.

TECHNICAL ADVANCEMENT

The invention provides a significantly effective formulation of resveratrol having efficacy in terms of increased stability of resveratrol and retention thereof in the blood stream in concentration hitherto not attainable using any conventional formulations of resveratrol. The clinical studies have demonstrated that the formulation of the invention is highly effective in reducing the discomforts in patients suffering from cancer as well as in improving the health and quality of life of healthy individuals. Further, the formulation of the invention having all-natural ingredients allows treatment of cancer and other ailments without side effects and advantageously increasing the serum mineral levels.

While considerable emphasis has been placed herein on the specific ingredients of the formulation of the preferred embodiment, it will be appreciated that many alterations can be made and that many modifications can be made in the preferred embodiment without departing from the principles of the inventions. These and other changes in the preferred embodiments as well as other embodiments of the invention will be apparent to those skilled in the art from the disclosure herein, whereby it is to be distinctly understood that the foregoing descriptive matter is to be interpreted merely as illustrative of the invention and not as a limitation.