WO2014093313A1 - Compositions and methods for integrated metabolic interventions - Google Patents
Compositions and methods for integrated metabolic interventions Download PDFInfo
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- WO2014093313A1 WO2014093313A1 PCT/US2013/074071 US2013074071W WO2014093313A1 WO 2014093313 A1 WO2014093313 A1 WO 2014093313A1 US 2013074071 W US2013074071 W US 2013074071W WO 2014093313 A1 WO2014093313 A1 WO 2014093313A1
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- the invention generally relates to a method for preventing or alleviating a cancer, metabolic disease, or an inflammatory disease or condition, including:
- the composition includes one or more of Omega-3 fatty acid; a curcuminoid; and one of epigallocatechin-3-gallate (EGCG) and Vitamin D.
- EGCG epigallocatechin-3-gallate
- EGCG Epigallocatechin-3-gallate
- epigallocatechin-3-gallate EGCG
- Vitamin D epigallocatechin-3-gallate
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Abstract
The invention provides compositions and methods for improving health. More particularly, the invention relates to compositions and methods for integrated metabolic interventions to benefit patients suffering from various conditions including cancer, metabolic disease, inflammatory disorders, and other health conditions.
Description
COMPOSITIONS AND METHODS FOR INTEGRATED METABOLIC INTERVENTIONS
Priority Claims and Related Patent Applications
[0001] This application claims the benefit of priority from U.S. Provisional Application Serial No. 61/735,097, filed on December 10, 2012, the entire content of which is incorporated herein by reference in its entirety.
Technical Field of the Invention
[0002] The invention generally relates to compositions and methods for improving health. More particularly, the invention relates to compositions and methods for integrated metabolic interventions to benefit patients suffering from various conditions including cancer, metabolic disease,
inflammatory disorders, and other health conditions.
Background of the Invention
[0003] The concept of "oncogene addiction" has provided the pharmaceutical industry with a compelling rationale for targeted therapeutics. The idea that the growth and survival of cancer cells could be impaired by the inactivation of a single oncogene has been well aligned with the "one drug, one disease" model that both the industry and the FDA have relied upon for decades. Mounting evidence suggest now that narrowly targeted therapies are often met with adaptive resistance because most cancers contain a multitude of subpopulations of mutated cells which gain their immortality in slightly different ways. Combination chemotherapy is one way that clinicians have tried to overcome adaptive resistance, but toxicity and multiple drug resistance are complicating factors that place highly restrictive limitations on this approach. The current reality of chemotherapy is that the efficacy rate is quite low (25%), side effects are often severe, and the financial costs to the patient are extremely high. (See FIG. l)(Spear BB, Heath-Chiozzi M, Huff J. Trends Mol Med 2001 ; 7(5):201- 204.)
[0004] In Massachusetts alone, 345,000 people are living with cancer today. (Gotbaum R.
Survivors face a major gap in post-cancer care. CommonHealth WBUR (Boston, MA). November 12, 2012.) With earlier diagnosis and more effective treatments, the American Cancer Society expects the number of cancer survivors to climb nearly 40 percent over the next decade. But cancer patients are often living with side effects including chronic pain, fatigue and other disabilities. Usually,
oncologists and physicians can only prescribe drugs, and provide little support for patients' quality of life during and after treatment.
[0005] An enormous body of cancer research has emerged in the past decade that demonstrates that many naturally occurring chemicals (e.g., phytochemicals) are every bit as promising for the purpose of molecular targeting. Furthermore, these chemicals can typically be combined with far less danger of toxicity and much lower risk of encountering multiple drug resistance, which makes the concept of broad-spectrum targeting using complex combinations of chemicals a real possibility.
[0006] Recent research has also recognized that dysregulated energy metabolism, tumor- promoting inflammation, and the tumor microenvironment are emerging hallmarks of cancer.
(Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell 201 1 ; 144(5):646-74.) These pathways are linked to nutrient metabolism and can be significantly affected by the composition of nutrients in the diet. However, there still exist no clinically effective nutritional interventions for targeting these pathways.
[0007] Thus, there remains a major gap in the care for people who survive cancer. The
development of an optimized broad-spectrum intervention (i.e., one that can reach many molecular targets simultaneously) is urgently needed.
Summary of the Invention
[0008] The invention generally relates to a novel therapeutic formula that is suitable and beneficial for cancer patients.
[0009] In one aspect, the invention generally relates to a composition including therapeutically beneficial amount of one or more of Omega-3 fatty acid; and one of curcuminoid, epigallocatechin-3 - gallate (EGCG) and Vitamin D.
[0010] In another aspect, the invention generally relates to a nutritional supplement composition, including one or more of Omega-3 fatty acid; and one of curcuminoid, epigallocatechin-3 -gallate (EGCG) and Vitamin D, according to daily serving as provided in the table below
Omega-3 EPA & DHA 4 - 15 g
Curcumin 0.3 - 8 g
Epigallocatechin-3 -gallate (EGCG) 0.1 - i g
Vitamin D 1000 - 5000 IU
[001 1] In yet another aspect, the invention generally relates to a ready -to-eat food or ready-to- drink beverage product, including therapeutically beneficial amounts of one or more Omega-3 fatty acids; and one of a curcuminoid; epigallocatechin-3 -gallate (EGCG); and Vitamin D.
[0012] In yet another aspect, the invention generally relates to a food or beverage composition suitable for preventing or alleviating cancer, including Omega-3 EPA & DHA; Curcumin;
epigallocatechin-3-gallate (EGCG); and Vitamin D according to the following per daily serving:
Omega-3 EPA & DHA 4 - 15 g
Curcumin 0.3 - 8 g
Epigallocatechin-3-gallate (EGCG) 0.1 - i g
Vitamin D 1000 - 5000 IU
[0013] In yet another aspect, the invention generally relates to a food or beverage composition suitable for preventing or alleviating diabetes, including Omega-3 EPA & DHA; Curcumin;
epigallocatechin-3-gallate (EGCG); and Vitamin D according to the following per daily serving:
Omega-3 EPA & DHA 4 - 15 g
Curcumin 0.3 - 8 g
Epigallocatechin-3-gallate (EGCG) 0.1 - i g
Vitamin D 1000 - 5000 IU
[0014] In yet another aspect, the invention generally relates to a food or beverage composition suitable for preventing or alleviating cardiovascular diseases or conditions, including Omega-3 EPA & DHA; Curcumin; epigallocatechin-3-gallate (EGCG); and Vitamin D according to the following per daily serving:
Omega-3 EPA & DHA 4 - 15 g
Curcumin 0.3 - 8 g
Epigallocatechin-3-gallate (EGCG) 0.1 - i g
Vitamin D 1000 - 5000 IU
[0015] In yet another aspect, the invention generally relates to a ready-to-drink beverage product including Omega-3 EPA & DHA; Curcumin; epigallocatechin-3-gallate (EGCG); and Vitamin D according to the following per daily serving:
Omega-3 EPA & DHA 4 - 15 g
Curcumin 0.3 - 8 g
Epigallocatechin-3-gallate (EGCG) 0.1 - i g
Vitamin D 1000 - 5000 IU
[0016] In yet another aspect, the invention generally relates to a composition including therapeutically beneficial amount of one or more Omega-3 fatty acids; and one or more of a curcuminoid, epigallocatechin-3 -gallate (EGCG), and Vitamin D, wherein the composition provides one or more of complementary and synergistic effects, improved bioavailability, improved solubility, and improved stability.
[0017] In yet another aspect, the invention generally relates to a method for preventing or alleviating a cancer, metabolic disease, or an inflammatory disease or condition, including:
administering to a subject in need thereof a composition including therapeutically beneficial amount of one or more Omega-3 fatty acids, and one or more of a curcuminoid, epigallocatechin-3 -gallate (EGCG) and Vitamin D; and monitoring one or more biomarkers to monitor the status of the subject's disease or condition to determine the need for and dose of further administration of the composition.
Detailed Description of the Invention
[0018] The invention provides unique compositions and methods for integrated metabolic interventions to benefit patients suffering from various conditions including cancer, metabolic, inflammatory, and other diseases and conditions.
[0019] In one aspect, the invention generally relates to a composition including therapeutically beneficial amount of one or more of Omega-3 fatty acid; and one of curcuminoid, epigallocatechin-3 - gallate (EGCG) and Vitamin D.
[0020] In certain preferred embodiments, the composition includes therapeutically beneficial amount of one or more of Omega-3 fatty acid; a curcuminoid; and one of epigallocatechin-3 -gallate (EGCG) and Vitamin D.
[0021] In certain preferred embodiments, the composition includes therapeutically beneficial amount of one or more of Omega-3 fatty acid; epigallocatechin-3 -gallate (EGCG) and Vitamin D.
[0022] In certain preferred embodiments, the composition includes therapeutically beneficial amount of one or more Omega-3 fatty acids; a curcuminoid; epigallocatechin-3 -gallate (EGCG); and Vitamin D.
[0023] In another aspect, the invention generally relates to a nutritional supplement composition, including one or more of Omega-3 fatty acid; and one of curcuminoid, epigallocatechin-3 -gallate (EGCG) and Vitamin D, according to daily serving as provided in the table below
Omega-3 EPA & DHA 4 - 15 g
Curcumin 0.3 - 8 g
Epigallocatechin-3-gallate (EGCG) 0.1 - 1 g
Vitamin D 1000 - 5000 IU
[0024] In certain preferred embodiments, the nutritional supplement includes one or more of Omega-3 fatty acid; a curcuminoid; and one of epigallocatechin-3-gallate (EGCG) and Vitamin D.
[0025] In certain preferred embodiments, the nutritional supplement includes one or more of Omega-3 fatty acid; epigallocatechin-3-gallate (EGCG); and Vitamin D.
[0026] In certain preferred embodiments, the nutritional supplement includes one or more Omega- 3 fatty acids; a curcuminoid; epigallocatechin-3-gallate (EGCG); and Vitamin D.
[0027] In yet another aspect, the invention generally relates to a ready-to-eat food or ready-to- drink beverage product, including therapeutically beneficial amounts of one or more Omega-3 fatty acids; and one of a curcuminoid; epigallocatechin-3-gallate (EGCG); and Vitamin D.
[0028] In certain preferred embodiments, the ready-to-eat food or ready-to-drink beverage product includes one or more of Omega-3 fatty acid; a curcuminoid; and one of epigallocatechin-3-gallate (EGCG) and Vitamin D.
[0029] In certain preferred embodiments, the ready-to-eat food or ready-to-drink beverage product includes one or more of Omega-3 fatty acid; epigallocatechin-3-gallate (EGCG); and Vitamin D.
[0030] In certain preferred embodiments, the ready-to-eat food or ready-to-drink beverage product includes one or more Omega-3 fatty acids; a curcuminoid; epigallocatechin-3-gallate (EGCG); and Vitamin D.
[0031 ] In yet another aspect, the invention generally relates to a food or beverage composition suitable for preventing or alleviating cancer, including Omega-3 EPA & DHA; Curcumin;
epigallocatechin-3-gallate (EGCG); and Vitamin D according to the following per daily serving:
Omega-3 EPA & DHA 4 - 15 g
Curcumin 0.3 - 8 g
Epigallocatechin-3-gallate (EGCG) 0.1 - i g
Vitamin D 1000 - 5000 IU
[0032] In yet another aspect, the invention generally relates to a food or beverage composition suitable for preventing or alleviating diabetes, including Omega-3 EPA & DHA; Curcumin;
epigallocatechin-3-gallate (EGCG); and Vitamin D according to the following per daily serving:
Omega-3 EPA & DHA 4 - 15 g
Curcumin 0.3 - 8 g
Epigallocatechin-3-gallate (EGCG) 0.1 - 1 g
Vitamin D 1000 - 5000 IU
[0033] In yet another aspect, the invention generally relates to a food or beverage composition suitable for preventing or alleviating cardiovascular diseases or conditions, including Omega-3 EPA & DHA; Curcumin; epigallocatechin-3-gallate (EGCG); and Vitamin D according to the following per daily serving:
Omega-3 EPA & DHA 4 - 15 g
Curcumin 0.3 - 8 g
Epigallocatechin-3-gallate (EGCG) 0.1 - i g
Vitamin D 1000 - 5000 IU
[0034] In yet another aspect, the invention generally relates to a ready-to-drink beverage product including Omega-3 EPA & DHA; Curcumin; epigallocatechin-3-gallate (EGCG); and Vitamin D according to the following per daily serving:
Omega-3 EPA & DHA 4 - 15 g
Curcumin 0.3 - 8 g
Epigallocatechin-3-gallate (EGCG) 0.1 - i g
Vitamin D 1000 - 5000 IU
[0035] In yet another aspect, the invention generally relates to a composition including
therapeutically beneficial amount of one or more Omega-3 fatty acids; and one or more of a curcuminoid, epigallocatechin-3-gallate (EGCG), and Vitamin D, wherein the composition provides one or more of complementary and synergistic effects, improved bioavailability, improved solubility, and improved stability.
[0036] In certain preferred embodiments, the composition includes one or more Omega-3 fatty acids; a curcuminoid; and one of epigallocatechin-3-gallate (EGCG) and Vitamin D, wherein the composition provides one or more of complementary and synergistic effects, improved
bioavailability, improved solubility, and improved stability.
[0037] In certain preferred embodiments, the composition includes one or more Omega-3 fatty acids; epigallocatechin-3-gallate (EGCG); and Vitamin D, wherein the composition provides one or more of complementary and synergistic effects, improved bioavailability, improved solubility, and improved stability.
[0038] In certain preferred embodiments, the composition includes one or more Omega-3 fatty acids; a curcuminoid; epigallocatechin-3-gallate (EGCG); and Vitamin D, wherein the composition provides one or more of complementary and synergistic effects, improved bioavailability, improved solubility, and improved stability.
[0039] In yet another aspect, the invention generally relates to a method for preventing or alleviating a cancer, metabolic disease, or an inflammatory disease or condition, including:
administering to a subject in need thereof a composition including therapeutically beneficial amount of one or more Omega-3 fatty acids, and one or more of a curcuminoid, epigallocatechin-3-gallate (EGCG) and Vitamin D; and monitoring one or more biomarkers to monitor the status of the subject's disease or condition to determine the need for and dose of further administration of the composition.
[0040] In certain preferred embodiments of the method, the composition includes one or more of Omega-3 fatty acid; a curcuminoid; and one of epigallocatechin-3-gallate (EGCG) and Vitamin D.
[0041 ] In certain preferred embodiments of the method, the composition includes one or more of Omega-3 fatty acid; epigallocatechin-3-gallate (EGCG); and Vitamin D.
[0042] In certain preferred embodiments of the method, the composition includes one or more of Omega-3 fatty acids; a curcuminoid; epigallocatechin-3-gallate (EGCG); and Vitamin D.
[0043] In certain preferred embodiments of the method, the anti-cancer cocktail formula of the invention is composed of natural nutraceuticals with potent health benefits supported by scientific evidence, targeting multiple mechanisms for comprehensive metabolic intervention with minimal side effects, the efficacy of which can be evaluated and monitored by accessible biomarkers.
Table 1 Anti-cancer cocktail formula
Key Ingredients Daily Dose
Omega-3 EPA & DHA 4 - 15 g
Curcumin 0.3 - 8 g
Epigallocatechin-3-gallate (EGCG) 0.1 - 1 g
Vitamin D 1000 - 5000 IU
Supporting ingredients & natural
flavoring
[0044] There is a great deal of scientific evidence supporting the anti-cancer effects and benefits of these ingredients individually. However, a number of obstacles have arisen in translating these compounds into therapeutic treatments, including problems with bioavailability, stability, solubility,
and compatibility. The anti-cancer cocktail formula of the invention is developed to overcome these obstacles and provide a clinically effective treatment or adjunct treatment.
[0045] The formula is especially potent because the ingredients are selected so that their combined effects are complementary as well as synergistic. As each nutraceutical targets a distinct set of mechanisms, their combination allows for a comprehensive, well-rounded approach to inhibiting cancer-promoting pathways that would not be possible if using each nutraceutical alone. The compounds also interact to increase their bioavailability, solubility, and stability within the formula, and provide enhanced or additional anti-cancer effects. The formula is designed to be capable of simultaneously targeting multiple pathways of cancer, particularly those involved in inflammation, angiogenesis, cell proliferation, and metastasis. (See, FIG. 2)
[0046] The novel formula disclosed herein presents a number of advantages including:
complementary and synergistic benefits; easily evaluated by biomarker testing; improved
bioavailability; improved solubility; improved stability; and improved convenience, taste, and acceptability.
Synergistic effects
[0047] Thus, in addition to their individual and complementary effects, the combination of these nutraceuticals has synergistic effects that extend the novelty and efficacy of this formula for cancer prevention and treatment. While the literature for these effects is limited as research has only just begun to focus on these nutraceuticals and their possible combinations, and our particular combination is unique, the existing evidence is supportive of the synergistic effects that the formula of the invention can provide for anti-cancer treatment.
[0048] Omega-3 EPA/DHA and curcumin have been studied for their combined anti-inflammatory and anti-oxidative stress effects in several laboratory studies. In an in vitro study [48], RAW 264.7 cells were treated with combinations of omega-3 DHA or EPA with curcumin, and the results showed both additive and synergistic suppression of NO and PGE2 accumulation, inhibition of iNOS, COX-2, and 5-LOX expression, and induction of HO-1 expression. For example, pretreatment of the cells with curcumin or DHA alone did not inhibit iNOS protein expression, while EPA alone exhibited some degree of suppression of iNOS, but all the combination treatments with curcumin and DHA or EPA were able to suppress iNOS protein expression compared to the non-treated cells. Furthermore, very low doses of curcumin, DHA and EPA were tested in this study to mimic the low dietary consumption and bioavailability levels in the context of potential cancer chemoprevention,
providing convincing evidence for the translation of the observed synergistic effects into our more potent formula.
[0049] Another in vitro study tested the combination of omega-3 DHA and curcumin on breast cancer cell proliferation and observed potent synergistic effects in SK-BR-3 cells that trigger cell signaling events not associated to the activity of either compound alone. (Altenburg JD, Bieberich AA, Terry C, Harvey KA, Vanhorn JF, Xu Z, Jo Davisson V, Siddiqui RA.A synergistic
antiproliferation effect of curcumin and docosahexaenoic acid in SK-BR-3 breast cancer cells:
unique signaling not explained by the effects of either compound alone. BMC Cancer 201 1; 1 1 : 149.) The combination induced transcript-level responses that were largely non-overlapping with changes caused by curcumin or DHA individually; genes involved in cell cycle arrest, apoptosis, inhibition of metastasis, and cell adhesion were upregulated, whereas genes involved in cancer development and progression, metastasis, and cell cycle progression were downregulated. In addition to the synergistic responses, it was also found that DHA directly enhanced cellular uptake of curcumin (see section on improved bioavailability).
[0050] An in vivo study examined the synergistic efficacy of curcumin in an omega-3 FA-enriched diet on pancreatic cancer growth. (Swamy MV, Citineni B, Patlolla JM, Mohammed A, Zhang Y, Rao CV. Prevention and treatment of pancreatic cancer by curcumin in combination with omega-3 fatty acids. Nutr Cancer 2008; 60 Suppl 1 :81-9.) The combination of DHA and curcumin was first tested on pancreatic cancer BxPC-3 cells and showed a dose-dependent suppression of cell growth and stimulation of apoptosis. Then, in a mouse model, animals fed with the combined diet showed further delay in tumor latency compared to either an omega-3 FA-rich diet or curcumin alone. Mice fed the combined diet also showed enhanced suppression of COX-2, iNOS, and 5-LOX expression in tumors compared to the other experimental groups, as well as increased p21 activation.
[0051] The combination of curcumin and EGCG has also been examined for their enhanced effects on cancer cell growth and apoptosis. One in vitro study treated lung cancer PC-9 and A549 cells with the combination of curcumin and EGCG, and observed greater cell growth inhibition and apoptosis than with either compound alone. (Saha A, Kuzuhara T, Echigo N, Suganuma M, Fujiki H.New role of (-)-epicatechin in enhancing the induction of growth inhibition and apoptosis in human lung cancer cells by curcumin. Cancer Prev Res 2010; 3(8):953-62.) It was also found that the
combination upregulated the expression of GADD 153, GADD45, and p21, which are thought to promote apoptosis. Another in vitro study tested the combination of EGCG and curcumin on uterine leiomyosarcoma cells, a cancer that normally does not respond well to standard chemotherapeutic
regimens, and showed that the combination treatment reduced cell viability more than treatment with either drug alone. (Kondo A, Takeda T, Li B, Tsuiji K, Kitamura M, Wong TF, Yaegashi N.
Epigallocatechin-3 -gallate potentiates curcumin's ability to suppress uterine leiomyosarcoma cell growth and induce apoptosis. Int J Clin Oncol 2012.) A recent in vitro study found similar results on the suppression of esophageal cancer cell growth, while also observing that the combination reduced the expression of Ki67, phosphorylated Erkl/2 and COX-2. Another in vitro study also studied the combination of curcumin and EGCG on chronic lymphocytic leukemia (CLL) B, which is incurable with current chemotherapy treatments. (Ye F, Zhang GH, Guan BX, Xu XC. Suppression of esophageal cancer cell growth using curcumin, (-)-epigallocatechin-3 -gallate and lovastatin. World J Gastroenterol 2012; 18(2): 126-35; Ghosh AK, Kay NE, Secreto CR, Shanafelt TD. Curcumin inhibits prosurvival pathways in chronic lymphocytic leukemia B cells and may overcome their stromal protection in combination with EGCG. Clin Cancer Res 2009; 15(4): 1250-8.) This study found that in addition to increasing apoptotic cell death, the combination of EGCG and curcumin is also able to overcome the stromal mediated protection of CLL B cells at lower doses of curcumin, which could imply greater clinical efficacy at lower doses and reduced side effects or risk of toxicity. (See FIG. 11)
[0052] An in vivo study convincingly demonstrated the effects of the combination of EGCG and curcumin on the suppression of ERa- breast cancer cell growth. (Somers-Edgar TJ, Scandlyn MJ, Stuart EC, Le Nedelec MJ, Valentine SP, Rosengren RJ. The combination of epigallocatechin gallate and curcumin suppresses ER alpha-breast cancer cell growth in vitro and in vivo. Int J Cancer 2008; 122(9): 1966-71.) Tumor volume in the combination-treated mice decreased 49% compared to vehicle control mice (p < 0.05), which correlated with decreases in the protein expression of key growth factors, with a notable 78.6% reduction in VEGFR-1 levels. This study also demonstrated that an ineffective dose of curcumin could elicit significant tumor suppression when combined with EGCG, and that tumor suppression occurred at doses of curcumin that were 2.5- to 5-fold lower than required for other animal models of cancer. (See FIG. 12)
[0053] The synergistic potential of omega- 3 and EGCG has only been recently investigated, as these two ingredients are normally incompatible - omega-3 is only fat-soluble (hydrophobic), while EGCG is only water-soluble (hydrophilic). A recent study combined EGCG with the omega-3 DPA and showed greater anti-inflammatory functions in LPS-stimulated macrophages in vitro. (Zhong Y, Chiou YS, Pan MH, Shahidi F. Anti-inflammatory activity of lipophilic epigallocatechin gallate (EGCG) derivatives in LPS-stimulated murine macrophages. Food Chem 2012; 134(2):742-8.)
Specifically, the production of the pro-inflammatory mediators NO and PGE2 were significantly inhibited by treatment with EGCG-DPA esters, likely due to the observed downregulation of iNOS and COX-2 gene expression. The generation and application of lipophilic EGCG derivatives is an alternative technology that we are also capable of utilizing for our formulations. (See FIG. 13)
Bioavailability
[0054] The unique combination of ingredients disclosed herein is tailored to improve the absorption and bioavailability of each compound in order to provide maximum efficacy.
[0055] While curcumin and EGCG each have a strong body of laboratory evidence supporting their anti-cancer effects, a significant number of clinical trials have not shown outcomes that reflect the promising in vitro and in vivo studies, partially due to the poor availability of these compounds after oral ingestion by humans. Thus, a formula combining one or both of these compounds with omega-3 FA has yet to be established. Our formulation is designed to significantly enhance the bioavailability of these compounds.
[0056] The results from several preclinical and clinical trials showed that curcumin is remarkably well tolerated. Even at high doses, curcumin appears nontoxic to animals or humans. (Goel A, Kunnumakkara AB, Aggarwal BB. Curcumin as "Curecumin": from kitchen to clinic. Biochem Pharmacol 2008; 75(4):787-809.) When curcumin was administered as a single daily oral dose ranging from 500 to 8000 mg/day for 3 months, the treatment was well tolerated. (Cheng AL, Hsu CH, Lin JK, Hsu MM, Ho YF, et al. Phase I clinical trial of curcumin, a chemopreventive agent, in patients with high-risk or pre-malignant lesions. Anticancer Res 2001 ; 21(4B):2895-900.) However, the in vivo bioavailability of curcumin is poor, which may be an important obstacle to its utility as a therapeutic agent. It was suggested that the low systematic bioavailability of curcumin may be due to the hydrophobic nature of the molecule, poor absorption and the metabolic biotransformation in intestine and liver. (Zhou H, Beevers CS, Huang S. The targets of curcumin. Curr Drug Targets 201 1 ; 12(3):332-47.)
[0057] There are a number of possible approaches to improve the bioavailability of curcumin. One well-tested approach is the formation of curcumin-lipid complexes, such as phospholipid liposomes or nanoparticles. (Goel A, Kunnumakkara AB, Aggarwal BB. Curcumin as "Curecumin": from kitchen to clinic. Biochem Pharmacol 2008; 75(4):787-809; Marczylo TH, Verschoyle RD, Cooke DN, Morazzoni P, Steward WP, Gescher AJ. Comparison of systemic availability of curcumin with that of curcumin formulated with phosphatidylcholine. Cancer Chemother Pharmacol 2007;
60(2): 171-7.) Furthermore, the joint administration of DHA with curcumin and EGCG with
curcumin has been shown to increase the cellular uptake of curcumin. (Altenburg JD, Bieberich AA, Terry C, Harvey KA, Vanhorn JF, Xu Z, Jo Davisson V, Siddiqui RA.A synergistic antiproliferation effect of curcumin and docosahexaenoic acid in SK-BR-3 breast cancer cells: unique signaling not explained by the effects of either compound alone. BMC Cancer 201 1 ; 1 1 : 149; Kondo A, Takeda T, Li B, Tsuiji K, Kitamura M, Wong TF, Yaegashi N. Epigallocatechin-3-gallate potentiates curcumin's ability to suppress uterine leiomyosarcoma cell growth and induce apoptosis. Int J Clin Oncol 2012.) Based on this knowledge, our innovative formula combines these technologies together by providing omega-3 fish oil as a medium for curcumin, phospholipids to form lipid complexes, and EGCG to further enhance cellular uptake, creating a novel integrated approach compared to previous methods for ensuring curcumin bioavailability. (See FIG. 14)
[0058] EGCG is found abundantly in green tea as a major polyphenol with a variety of health benefits. However, the molecule is hydrophilic with poor solubility in lipid systems, which, at least partially, accounts for its low absorption by the cells and limited efficacy in the cellular environment. Moreover, cell line studies have suggested that EGCG and other tea catechins are subject to active efflux by multidrug resistance-related proteins, leading to restricted bioefficiency in vivo. (Zhong Y, Chiou YS, Pan MH, Shahidi F. Anti-inflammatory activity of lipophilic epigallocatechin gallate (EGCG) derivatives in LPS-stimulated murine macrophages. Food Chem 2012; 134(2):742-8.) The esterification of EGCG with omega-3 FAs, such as has been demonstrated with DPA, will allow for greater bioavailability as well as compatibility of EGCG in this formula.
[0059] Although omega-3 FAs present adequate bioavailability following oral administration, there remain bioavailability issues with current omega-3 FA supplements due to encapsulation, oil quality, and method of intake. Current clinical studies using omega-3 FA capsule supplements may not be seeing significant outcomes due to poor oil quality as well as the difficulty in administering enough capsules to patients, especially those who have a hard time swallowing. Our formula uses high quality oil in liquid form that allows patients to easily intake large quantities of omega-3 FA while also increasing omega-3 FA absorption, due to the lack of encapsulation.
Solubility
[0060] In selecting the main ingredients of this formula, we took advantage of their chemical properties. For example, the use of omega-3 fish oil would allow for the incorporation of fat-soluble curcumin and vitamin D, while also increasing their absorption. However, only EGCG is water- soluble. In order to overcome this obstacle of incompatibility, we utilized several methods in the preparation, including emulsion of EGCG in minimal amounts of water with phospholipids followed
by sonication and the dispersion of EGCG powder in coconut oil (MCFA). Another alternative method is the covalent linkage of EGCG with an omega-3 FA. These strategies allow us to create a compatible solution.
Stability
[0061] Under normal conditions, omega-3 FAs are highly susceptible to oxidation, and EGCG shows poor long-term stability in water. The formula of the invention overcomes these problems with the presence of vitamins D and E, curcumin, and EGCG as antioxidants to prevent the oxidation of omega-3 FA, while the mixture of omega-3 FA and coconut oil MCFA with EGCG preserves its stability in the solution. (See FIG. 15)
[0062] In developing this formula, we took into consideration several key aspects. To ensure the greatest efficacy, we selected scientifically proven nutraceuticals that target distinct mechanisms in key pathways of cancer such that their combination further provides complementary and synergistic effects. To optimize the formulation, we adapted their chemical properties and interactions to improve the overall bioavailability, stability, and solubility of the formula. From a manufacturing perspective, each of the possible formulations is relatively cost-effective and simple to produce. From a clinical perspective, the formulations are convenient, palatable, and easy to ingest, and can be tailored to suit individual patients' needs. In sum, this formula is a novel strategy for integrated metabolic interventions.
[0063] Ingredients of the compositions disclosed herein are selected based on the strength of the scientific evidence showing their benefits against cancer. The efficacy of this formula can be measured via established biomarkers that reflect the effects of these nutrients against cancer- promoting conditions. All biomarker measurements can be taken from blood or urine samples and only require standard equipment, so that they can be performed at any adequate medical facility. The four main categories for biomarker-based measurement are inflammation, oxidative stress, angiogenesis, and metabolism.
Inflammation
[0064] Chronic inflammation is now linked to all major metabolic and degenerative diseases, including cardiovascular disease, diabetes, Alzheimer's, stroke, and cancer. In the tumor
microenvironment, inflammation is a key contributor to cancer cell proliferation, survival and migration.
[0065] Omega-3 fatty (FA) acids, particularly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), can inhibit inflammation in several ways. For example, they can 1) displace
inflammatory omega-6 fatty acids, such as arachidonic acid (AA), and prevent them from making pro-inflammatory eicosanoids; 2) they downregulate gene transcription of the enzymes (e.g., COX-2) that catalyze the synthesis of lipid mediators; 3) they decrease the generation of inflammatory cytokines (e.g., TNF-2, IL-6, IL-Ι β) and 4) they generate novel anti-inflammatory compounds, including the resolvins and protectin. (Kang JX, Weylandt KH. Modulation of inflammatory cytokines by omega-3 fatty acids. Subcell Biochem 2008; 49133-43; Weylandt KH, Kang JX.
Rethinking lipid mediators. Lancet 2005; 366(9486):618-20.) In fact, low omega-3 FA levels in the Western diet are associated with chronic inflammatory disorders, and supplementation with omega-3 may decrease these diseases.
[0066] Dietary supplementation with omega-3 FA shows potential for mitigating cancer risks. In a landmark intervention study from 1989, dietary supplementation with fish oil concentrate was administered to healthy subjects, and after 20 weeks, IL-Ι β, IL-la, and TNF- a levels were significantly decreased and associated with a lower ratio of AA:EPA in membrane phospholipids. (Endres S, Ghorbani R, Kelley VE, Georgilis K, Lonnemann G, van der Meer JW, Cannon JG, Rogers TS, Klempner MS, Weber PC, et al. The effect of dietary supplementation with n-3 polyunsaturated fatty acids on the synthesis of interleukin- 1 and tumor necrosis factor by
mononuclear cells. N Engl J Med 1090; 320(5):265-71.) These findings suggest that the beneficial effects of omega-3 FA could be further improved by also lowering omega-6 FA intake, either through diet or drugs, and consequently also reducing the omega-6:omega-3 FA ratio. There have been numerous studies since then showing the beneficial effects of omega-3 FA supplementation in healthy individuals as well as clinical patients. One recent double-blind, placebo-controlled study from 2012 administered EPA/DHA supplementation to patients with advanced lung cancer, and after 66 days, significant differences were observed in plasma CRP, IL-6, PGE2 and TNF-a levels, showing the robust anti-inflammatory and anti-oxidative action of omega-3 FA supplementation. (Finocchiaro C, Segre O, Fadda M, Monge T, Scigliano M, Schena M, Tinivella M, Tiozzo E, Catalano MG, Pugliese M, Fortunati N, Aragno M, Muzio G, Maggiora M, Oraldi M, Canuto RA. Effect of n-3 fatty acids on patients with advanced lung cancer: a double-blind, placebo-controlled study. Br J Nutr 2012; 108(2):327-33.) Omega-3 FA supplementation has also been known to enhance the efficacy of chemotherapeutic drugs and reduce side effects, improve the quality of life of patients, and suppress cachexia. (See FIG. 3)
[0067] AA and EPA are important precursors for lipid mediators of the inflammatory response, and have distinct and opposing physiological effects. (Kang JX, Weylandt KH. Modulation of inflammatory cytokines by omega-3 fatty acids. Subcell Biochem 2008; 49133-43; Weylandt KH, Kang JX. Rethinking lipid mediators. Lancet 2005; 366(9486):618-20.) In general, AA and its metabolites promote inflammation, while EPA and its metabolites are anti-inflammatory. Thus, the tissue ratio of AA:EPA is a reflection of the body's inflammatory state, and can be directly modified by supplementation of omega-3 EPA. The AA:EPA ratio from RBC or WBC phospholipid samples can be used as a novel and reliable biomarker for monitoring the efficiency of omega-3 intake and tissue inflammatory state.
[0068] The anti-inflammatory function of curcumin has also been well demonstrated in numerous studies, as curcumin has been found to modulate the activation of various transcription factors and regulate the expression of inflammatory enzymes, cytokines, adhesion molecules, and cell survival proteins, including LOX, COX-2, LTs, PGs, NO, MCP-1, TNF, and IL-12. (Jurenka JS. Antiinflammatory properties of curcumin, a major constituent of Curcuma longa: a review of preclinical and clinical research. Altern Med Rev 2009; 14(2): 141 -53.) Curcumin has also been proven safe (up to an intake of 12 g / day) in human safety trials and has demonstrated anti-inflammatory effects in clinical trials from dosages as low as 450 mg / day. (Goel A, Kunnumakkara AB, Aggarwal BB. Curcumin as "Curecumin": from kitchen to clinic. Biochem Pharmacol 2008; 75(4):787-809.) However, the limited clinical outcomes of curcumin trials have not reflected the strong molecular evidence, largely due to its low solubility and poor bioavailability (rapid plasma clearance and conjugation) in humans. The formula of the invention allows for increased bioavailability of curcumin with oral administration.
[0069] Similarly, the anti-inflammatory effects of EGCG have been documented, as they modulate key pathways in inflammation such as NF-kB, MAPK, and COX-2, in addition to inhibiting the secretion of pro-inflammatory factors such as TNF-a, IL-Ι β, IL-6, and TGF-β. (Singh R, Akhtar N, Haqqi TM. Green tea polyphenol epigallocatechin-3-gallate: inflammation and arthritis, [corrected]. Life Sci 2010; 86(25-26):907-18.) Yet bioavailability issues have also arisen in clinical trials with EGCG, as plasma levels of these catechins in humans are mostly in the sub-μΜ or nM concentration range, which is much lower than the effective concentrations determined in most in vitro studies. Even so, several chemoprevention trials with EGCG have been conducted to date and have observed potential preventive activity for oral, prostate, and colorectal cancer. (Chow HH, Hakim IA.
Pharmacokinetic and chemoprevention studies on tea in humans. Pharmacol Res 201 1 ; 64(2): 105-12.) The formula of the invention allows for increased bioavailability of EGCG with oral administration.
Oxidative stress
[0070] Enhanced oxidative stress, which is characterized by excessive production of reactive oxygen species (ROS) and reduction of antioxidant defense mechanisms, is known to underlie tumor progression. Studies have clearly established that oxidative stress factors are abnormally expressed in cancer and promote cancer initiation and progression by acting on cell proliferation and anchorage independent cell growth, causing insensitivity to apoptosis, sustaining de novo angiogenesis, and modulating metastasis through metabolic and epigenetic mechanisms.
[0071] One method to quantify oxidative injury is to measure lipid peroxidation. F2-isoprostanes, a group of prostaglandin F2-like compounds derived from the non-enzymatic free radical
peroxidation of omega-6 arachidonic acid, provide the most reliable index of in vivo oxidative stress when compared to other biomarkers. (Milne GL, Yin H, Brooks JD, Sanchez S, Jackson Roberts L 2nd, Morrow JD. Quantification of F2-isoprostanes in biological fluids and tissues as a measure of oxidant stress. Methods Enzymol 2007; 433 : 1 13-26.) The antioxidant effects of omega-3
supplementation have been demonstrated in several clinical studies. One double-blind four-month trial included 106 healthy sedentary overweight middle-aged and older adults who received either omega-3 capsules (1.25 - 2.5 g /day) or placebo capsules that mirrored the proportions of fatty acids in the typical American diet. (Kiecolt-Glaser JK, Epel ES, Belury MA, Andridge R, Lin J, Glaser R, Malarkey WB, Hwang BS, Blackburn E. Omega-3 fatty acids, oxidative stress, and leukocyte telomere length: A randomized controlled trial. Brain Behav Immun 2012.) Omega-3
supplementation significantly lowered oxidative stress (-15%) compared to the placebo group as measured by F2-isoprostanes, and were correlated with changes in the n-6:n-3 PUFA plasma ratios. Another double-blind, placebo controlled trial of 59 type 2 diabetic subjects, randomized to 4 g daily of purified EPA, DHA, or olive oil for 6 weeks, showed a similar reduction in F2-isoprostanes. (See FIG. 4)( Mori TA, Woodman RJ, Burke V, Puddey IB, Croft KD, Beilin LJ. Effect of
eicosapentaenoic acid and docosahexaenoic acid on oxidative stress and inflammatory markers in treated-hypertensive type 2 diabetic subjects. Free Radic Biol Med. 2003; 35(7):772-81.)
[0072] A number of laboratory studies have reported the antioxidant properties of curcumin: it has been shown to inhibit ROS generation, scavenge free radicals, inhibit iNOS activity, induce HO-1 expression, and trigger Nrf2 signaling. (Zhou H, Beevers CS, Huang S. The targets of curcumin. Curr Drug Targets 201 1 ; 12(3):332-47; Balogun E, Hoque M, Gong P, Killeen E, Green CJ, Foresti R,
Alam J, Motterlini R. Curcumin activates the haem oxygenase- 1 gene via regulation of Nrf2 and the antioxidant-responsive element. Biochem J 2003; 371(3):887-95; Pan MH, Lin-Shiau SY, Lin JK. Comparative studies on the suppression of nitric oxide synthase by curcumin and its hydrogenated metabolites through down regulation of I kappa B kinase and NF kappa B activation in macrophages. Biochem Pharmacol 2000; 60: 1665-76.)
[0073] Lipid peroxidation can also be measured by levels of malonyldialdehyde (MDA) in red blood cells. In a pilot study, 20 patients with tropical pancreatitis were randomized to receive 500mg of curcumin with 5mg of piperine (to increase bioavailability), or placebo for 6 wk, and after treatment, there was a significant reduction in the erythrocyte MDA level (P< 0.01) in the curcumin group compared to the placebo, showing reversed lipid peroxidation in the treated patients.
(Durgaprasad S, Pai CG, Vasanthkumar, Alvres JF, Namitha S. A pilot study of the antioxidant effect of curcumin in tropical pancreatitis. Indian J Med Res. 2005; 122(4):315-8.) Interestingly, there was also a corresponding increase in levels of glutathione (GSH), although it was not statistically significant. GSH reflects the free radical scavenging capacity of the body, and its depletion leads to tissue damage due to lipid peroxidation. (See FIG. 5)
[0074] EGCG has been well-established as a potent antioxidant in laboratory studies and has also demonstrated its antioxidative effects in a number of clinical studies. (Yang CS, Lambert JD, Sang S. Antioxidative and anti-carcinogenic activities of tea polyphenols. Arch Toxicol 2009; 83(1): 1 1 -21 ; Rietveld A, Wiseman S. Antioxidant effects of tea: evidence from human clinical trials. J Nutr 2003; 133(10):3285S-3292S; Ellinger S, Miiller N, Stehle P, Ulrich-Merzenich G. Consumption of green tea or green tea products: is there an evidence for antioxidant effects from controlled interventional studies? Phytomedicine 201 1 ; 18(1 1):903-15.) Furthermore, it is thought that the observed anti- carcinogenic effect of EGCG is due to its ability to capture and detoxify ROS produced in the process of carcinogen metabolism, inflammation, aerobic respiration and exposure to background radiations. (Ahmad N, Feyes DK, Nieminen AL, Agarwal R, Mukhtar H. Green tea constituent epigallocatechin-3-gallate and induction of apoptosis and cell cycle arrest in human carcinoma cells. J Natl Cancer Inst 1997; 89: 1881-1886.)
[0075] Urinary 8-OHdG is considered a reliable biomarker of generalized, cellular oxidative stress as well as a risk factor for cancer, atherosclerosis and diabetes that is stable in urine and can therefore be non-invasively sampled. (Pilger A, Germadnik D, Riedel K, Meger-Kossien I, Scherer G, Rudiger HW. Longitudinal study of urinary 8-hydroxy-2'-deoxyguanosine excretion in healthy adults. Free Radic Res 2001 ; 35(3):273-80.) In a randomized, double-blinded and placebo-controlled phase II
chemoprevention trial, the 124 participants were at high-risk for liver cancer due to high oxidative burden from environmental exposure, as confirmed by the baseline data showing significant 8-OHdG levels for all participants. (Luo H, Tang L, Tang M, Billam M, Huang T, Yu J, Wei Z, Liang Y, Wang K, Zhang ZQ, Zhang L, Wang JS. Phase Ila chemoprevention trial of green tea polyphenols in high-risk individuals of liver cancer: modulation of urinary excretion of green tea polyphenols and 8- hydroxydeoxyguanosine. Carcinogenesis 2006; 27(2):262-8.) Three groups of participants took green tea polyphenol (GTP) capsules daily at doses of 500 mg, 1000 mg or a placebo for 3 months. The results showed that urinary excretion of 8-OHdG was significantly diminished by intervention (P = 0.007), demonstrating a reduction in oxidative DNA damage. (See FIG. 6)
[0076] Vitamin D deficiency is extremely common in patients with all types of cancer. (The Bone and Cancer Foundation (New York, NY). Vitamin D Deficiency: Information for Cancer Patients. 201 1. http://www.boneandcancerfoundation.org/pdfsA^itD_201 l .pdf) Vitamin D regulates the production of proteins that are responsible for cell division and growth, and its deficiency can cause abnormal production of these proteins. Cancer patients who are vitamin D deficient may experience muscle and bone discomfort and fatigue, in addition to those by radiation therapy, chemotherapy, or the cancer itself. Optimum vitamin D (serum 25(OH)D) levels for cancer patients are from 30 to 60 ng/niL, and daily supplements of between 1,000 and 2,000 IU of vitamin D should be taken
(although a dosage of up to 50,000 IU has been recommended for patients who are extremely deficient). Vitamins D and E are also known antioxidants, and will contribute to the anti-oxidative properties of this formula.
Angiogenesis
[0077] Angiogenesis, defined as the formation of new blood vessels, is controlled by a balance of pro-angiogenic growth factors and anti-angiogenic growth inhibitors. Abnormal angiogenesis underlies many chronic diseases. Excessive angiogenesis is associated with obesity, cancer, arthritis, and diabetic retinopathy.
[0078] Various molecules are responsible for promoting and sustaining angiogenesis. Common growth factors and their functions include vascular endothelial growth factor (VEGF), which causes dilation of blood vessels and endothelial cell proliferation/migration, platelet-derived growth factor (PDGF), which recruits smooth muscle cells to stabilize new vessels, basic fibroblast growth factor (bFGF) and fibroblast growth factor (FGF), which speed wound healing, matrix metalloproteinase (MMP), which causes breakdown of the basement membrane, and angiopoietin, which mediates vascular remodeling and maintains vascular integrity. In addition, some pro-angiogenic molecules
regulate the production of angiogenic growth factors. The inflammatory cytokine TNF-a increases expression of VEGF and MMP production, while another macrophage-derived chemokine, IL-8, upregulates MMP-2 and MMP-9. Therefore, molecules that regulate growth factor expression, production, or downstream effects will likewise impact angiogenesis.
[0079] Omega-3 FA modulate angiogenesis by suppressing downstream metabolites of omega-6 AA. (Kang JX, Liu A. The role of the tissue omega-6/omega-3 fatty acid ratio in regulating tumor angiogenesis. Cancer Metastasis Rev 2012.) Two critical elements of AA metabolism are the availabilities of substrate and enzyme. Omega-3 FA target both factors related to AA metabolism, displacing omega-6 FA from the cell membrane and successfully competing for COX, LOX, desaturases, and elongases. (Hyde CA, Missailidis S. Inhibition of arachidonic acid metabolism and its implication on cell proliferation and tumour-angiogenesis. Int Immunopharmacol 2009; 9(6):701- 15.) Supplementation with fish oil lowers production of the pro-angiogenic, AA-derived metabolites PGE2 and LTB4. (James MJ, Gibson RA, Cleland LG. Dietary polyunsaturated fatty acids and inflammatory mediator production. Am J Clin Nutr 2000; 71(1 Suppl):343S-8S.) Omega-3 FA work as natural inhibitors of n-6 eicosanoids and have the added benefit of anti-tumor properties, which include increased cancer cell apoptosis, altered estrogen metabolism, and decreased production of free radicals or reactive oxygen species. (Larsson SC, Kumlin M, Ingelman-Sundberg M, Wolk A. Dietary long-chain n-3 fatty acids for the prevention of cancer: A review of potential mechanisms. Am J Clin Nutr 2004; 79(6):935-45.) Population studies have demonstrated the anti-angiogenic effect of n-3 FA; one study observed that individuals with lower serum n-6 FA: n-3 FA ratios show lower circulating blood levels of VEGF. (Ambring A, Johansson M, Axelsen M, Gan L, Strandvik B, Friberg P. Mediterranean-inspired diet lowers the ratio of serum phospholipid n-6 to n-3 fatty acids, the number of leukocytes and platelets, and vascular endothelial growth factor in healthy subjects. Am J Clin Nutr 2006; 83(3):575-81.) In vitro, in vivo, and human experiments further show that EPA and DHA inhibit angiogenesis growth factors including VEGF, PDGF, COX2 and PGE 2 and MMP 2. (Spencer L, Mann C, Metcalfe M, Webb M, Pollard C, Spencer D, Berry D, Steward W, Dennison A. The effect of omega-3 FAs on tumour angiogenesis and their therapeutic potential. Eur J Cancer 2009; 45(12):2077-86.) For example, one study administered fish oil concentrate (7 g / day) to healthy volunteers, collected blood samples at 1 week and at 6 weeks, and observed significantly lowered levels of PDGF mRNA. (See FIG. 7)( Kaminski WE, Jendraschak E, Kiefl R, von Schacky C. Dietary omega-3 fatty acids lower levels of platelet-derived growth factor mRNA in human mononuclear cells. Blood 1993; 81(7): 1871-9.)
[0080] In addition to interfering with NFkB pathway activity, curcumin also modulates other angiogenic factors such as cyclin D l, COX-2, MMP-9, VEGF and CXCR4, and inhibits cytokine signaling receptors, such as EGF-R and IGF-IR, in in vitro and in vivo models. (Soung YH, Chung J. Curcumin inhibition of the functional interaction between integrin α6β4 and the epidermal growth factor receptor. Mol Cancer Ther 201 1 ; 10(5):883-91 ; Lin SS, Lai KC, Hsu SC, et al. Curcumin inhibits the migration and invasion of human A549 lung cancer cells through the inhibition of matrix metalloproteinase-2 and -9 and vascular endothelial growth factor (VEGF). Cancer Lett 2009;
285: 127-133; Patel BB, Gupta D, Elliott AA, et al. Curcumin targets FOLFOX-surviving colon cancer cells via inhibition of EGFRs and IGF-IR. Anticancer Res 2010; 30:319-325; Kunnumakkara AB, Diagaradjane P, Anand P, Harikumar KB, Deorukhkar A, Gelovani J, et al. Curcumin sensitizes human colorectal cancer to capecitabine by modulation of cyclin D l, COX-2, MMP-9, VEGF and CXCR4 expression in an orthotopic mouse model. Int J Cancer 2009; 125:2187-2197.) However, low bioavailability via oral administration has limited the data for the effects of curcumin on these factors in human patients.
[0081] EGCG has also been reported to have anti-angiogenic functions, such as inhibiting the growth and activation of the VEGF/VEGFR axis. (Yang CS, Wang H, Li GX, Yang Z, Guan F, Jin H. Cancer prevention by tea: Evidence from laboratory studies. Pharmacol Res 201 1 ; 64(2): 1 13-22; Singh BN, Shankar S, Srivastava RK. Green tea catechin, epigallocatechin-3-gallate (EGCG):
mechanisms, perspectives and clinical applications. Biochem Pharmacol 201 1 ; 82(12): 1807-21.) These effects were further demonstrated in a phase II clinical trial in which 26 men with prostate cancer were given daily doses of 800 mg of EGCG over an average of six weeks. (McLarty J, Bigelow RL, Smith M, Elmajian D, Ankem M, Cardelli JA. Tea polyphenols decrease serum levels of prostate-specific antigen, hepatocyte growth factor, and vascular endothelial growth factor in prostate cancer patients and inhibit production of hepatocyte growth factor and vascular endothelial growth factor in vitro. Cancer Prev Res 2009; 2(7):673-82.) A significant decrease was observed in serum levels of HGF, VEGF, PSA, IGF -I, and IGFBP-3 (p < 0.03), as well as a significant change in the IGF-I/IGFBP-3 ratio, without any adverse effects on liver function (which has been linked with high doses of EGCG previously). The potent inhibition of EGCG on HGF and VEGF production was then confirmed in vitro. (See FIG. 8)
Metabolism
[0082] Only recently have links been established between cancer progression and the altered mechanisms of tumor cell metabolism. These metabolic changes not only promote tumorigenesis, but also contribute to the development of other health complications, including obesity and diabetes.
[0083] One of the metabolic characteristics of cancer is the reliance on glucose metabolism in the tumor microenvironment. (Seyfried TN, Shelton LM. Cancer as a metabolic disease. Nutr Metab 2010; 7:7.) Many cancer patients also present high blood glucose and insulin levels. Thus, metabolism-based anti-cancer strategies include controlling blood glucose and insulin levels in order to suppress cancer metabolism, and inhibiting gluconeogenesis in the liver to reduce glucose synthesis. Omega-3 FA and EGCG have been suggested to inhibit gluconeogenesis while also increasing insulin sensitivity. (Carpentier YA, Portois L, Malaisse WJ. n-3 fatty acids and the metabolic syndrome. Am J Clin Nutr 2006; 83(6 Suppl): 1499S-1504S; Mohammadi E, Rafraf M, Farzadi L, Asghari-Jafarabadi M, Sabour S. Effects of omega-3 fatty acids supplementation on serum adiponectin levels and some metabolic risk factors in women with polycystic ovary syndrome. Asia Pac J Clin Nutr 2012; 21(4):51 1-8; Waltner-Law ME, Wang XL, Law BK, Hall RK, Nawano M, Granner DK. Epigallocatechin gallate, a constituent of green tea, represses hepatic glucose production. J Biol Chem 2002; 277(38):34933-40; Collins QF, Liu HY, Pi J, Liu Z, Quon MJ, Cao W. Epigallocatechin-3 -gallate (EGCG), a green tea polyphenol, suppresses hepatic gluconeogenesis through 5'-AMP-activated protein kinase. J Biol Chem 2007; 282(41):30143-9; Thielecke F,
Boschmann M.The potential role of green tea catechins in the prevention of the metabolic syndrome - a review. Phytochemistry 2009; 70(1): 1 1-24.) Adiponectin, a hormone secreted by adipocytes, is also known to play a role in mediating inflammation, as well as having anti-obesity and insulin sensitizing effects. A number of clinical studies and animal models have shown that consumption of either fish or fish oil supplements rich in omega-3 FA can upregulate adiponectin levels.
(Mohammadi E, Rafraf M, Farzadi L, Asghari-Jafarabadi M, Sabour S. Effects of omega-3 fatty acids supplementation on serum adiponectin levels and some metabolic risk factors in women with polycystic ovary syndrome. Asia Pac J Clin Nutr 2012; 21(4):51 1-8; Guebre-Egziabher F, Rabasa- Lhoret R, Bonnet B, et al. Nutritional intervention to reduce the n-6/n-3 fatty acid ratio increases adiponectin concentration and fatty acid oxidation in healthy subjects. Eur J Clin Nutr 2008;
62(1 1): 1287-1293; Krebs J, Browning L, McLean N, et al. Additive benefits of long-chain n-3 polyunsaturated fatty acids and weight-loss in the management of cardiovascular disease risk in overweight hyperinsulinaemic women. Int J Obes 2006; 30: 1535-154.) Glucose, insulin, and adiponectin levels can all be detected in via blood sampling.
[0084] Thus, each of the compounds in this formula is selected for their capability to affect the pathways of inflammation, oxidative stress, angiogenesis, and metabolism, but their individual use may not be effective enough on their own. By combining these complementary compounds to generate a comprehensive approach targeting multiple mechanisms of action, the formula of the invention can ensure an effective outcome.
[0085] Thus, in certain preferred embodiments, the invention provides a composition including therapeutically beneficial amount of two Omega-3 fatty acids; a curcuminoid; epigallocatechin-3 - gallate (EGCG); and Vitamin D.
[0086] In certain preferred embodiments, the invention provides a nutritional supplement composition, including per daily serving of
[0087] In certain preferred embodiments, the invention provides a ready-to-eat food or ready-to- drink beverage product, including therapeutically beneficial amounts of two Omega-3 fatty acids; a curcuminoid; epigallocatechin-3 -gallate (EGCG); and Vitamin D.
[0088] In certain preferred embodiments, the invention provides a ready-to-eat food or ready-to- drink beverage product suitable for preventing or alleviating inflammatory diseases or conditions, including: per daily dosing of
[0089] In certain preferred embodiments, the invention provides a food or beverage composition suitable for preventing or alleviating cancer, including Omega-3 EPA & DHA; Curcumin;
epigallocatechin-3-gallate (EGCG); and Vitamin D according to the following per daily serving:
[0090] In certain preferred embodiments, the invention provides a food or beverage composition suitable for preventing or alleviating diabetes, including Omega-3 EPA & DHA; Curcumin;
epigallocatechin-3 -gallate (EGCG); and Vitamin D according to the following per daily serving:
[0091] In certain preferred embodiments, the invention provides a food or beverage composition suitable for preventing or alleviating cardiovascular diseases or conditions, including Omega-3 EPA & DHA; Curcumin; epigallocatechin-3 -gallate (EGCG); and Vitamin D according to the following per daily serving:
(e.g., about 1000, 2000, 3000, 4000, 5000 IU)
[0092] In certain preferred embodiments, the invention provides a composition that includes therapeutically beneficial amount of one or more Omega-3 fatty acids; a curcuminoid;
epigallocatechin-3-gallate (EGCG); and Vitamin D, wherein the composition provides one or more of complementary and synergistic effects, improved bioavailability, improved solubility, and improved stability.
[0093] In certain preferred embodiments, the invention provides a method for preventing or alleviating a cancer, metabolic disease, or an inflammatory disease or condition. The method includes: administering to a subject in need thereof a composition including therapeutically beneficial amount of one or more Omega-3 fatty acids, a curcuminoid, epigallocatechin-3-gallate (EGCG), and Vitamin D; and monitoring one or more biomarkers to monitor the status of the subject's disease or condition to determine the need for and dose of further administration of the composition.
EXAMPLES
Formulations
[0094] The formula can be utilized in several forms of oral administration, depending on the patient's needs. Examples include: beverage, oral solution and biscuit bar.
Table 2 Formulation 1; A 20 mL Oral Solution
Main ingredients:
Omega-3 EPA / DHA 2 g
Curcumin 200 mg
EGCG 100 mg
Vitamin D 300 IU
Usage: 3 - 5 times a day
Preparation methods
1. Lipid nanoemulsions
[0095] Lipid nanoemulsions were prepared by a thin-film hydration method at room temperature (24°C). Briefly, the emulsions consisted of omega-3 fish oil, EGCG, curcumin, vitamin D, plant phospholipid, monoglyceride laurate, and water. The oil, vitamin D, and plant phospholipid (200 mg)
were dissolved in 5 mL of alcohol. Curcumin was dissolved in 2 mL of alcohol. Monoglyceride laurate (100 mg) was dissolved in 2 mL of alcohol. The mixture of the 3 solutions was dried by rotary evaporation and subjected to subsequent vacuum desiccation to generate the dried thin film. The dried thin film was hydrated with 18 mL of water containing 100 mg of EGCG warmed at 55- 60°C in a bath-type sonicator, followed by vigorous mixing and sonicating for 5 min to create coarse lipid emulsions. The fine lipid emulsions were prepared by 30-60 min sonication under
N2 atmosphere with a bath-type sonicator, which was thermostated at 55-60°C. The sonication was performed as follows: 3 min sonication and subsequent 2 min cooling, which were repeated for 30- 60 min. Natural flavoring, such as lemon or orange oil, can also be added to the solution.
2. Coconut oil-based liquid
[0096] Curcumin powder (200 mg) and vitamin D was mixed with 2.5 mL of 85% omega-3 fish oil. The solution was vigorously vortexed until the solution was homogenous. 100 mg of EGCG powder was suspended within coconut oil (8 g) warmed at 55-60°C, or the EGCG powder was dissolved in a minimal amount of water and then mixed with the coconut oil. The two solutions were mixed together.
Table 3 Formulation 2; A 200 mL Beverage
Main ingredients:
High quality omega-3 fish oil (70-85%, 2 g
EPA>DHA)
Curcumin 200 mg
Egg white powder 20 g
EGCG 100 mg
Fresh ginger juice 2 mL
Phospholipids-lecithin from plants or algae 2 g
Vitamin D 300 IU
Natural flavoring (e.g., lemon or orange oil) 0.1-1 mL
Usage: 3-5 times a day (600-1000 mL)
Preparation method
[0097] The egg white powder and EGCG were dissolved in water and mixed with ginger juice. Curcumin powder, phospholipids, and vitamin D were first dissolved in the omega-3 fish oil, 20 mL water was added, and the solution was sonicated to create coarse lipid emulsions. The two solutions were then mixed together. The composition can be adjusted as needed for different patient conditions.
[0098] The combination of the above ingredients will result in a stable and highly beneficial formula for cancer patients at all stages. Omega-3 fatty acids are normally difficult to dissolve in water and are prone to oxidation. Here, we solve these issues by using egg whites to provide albumin, a protein that binds to omega-3 fatty acids and enables their suspension in aqueous solution. Egg whites also serve as a good source of protein. The majority of the liquid solution is freshly brewed green tea, which provides antioxidants and protects omega-3 fatty acids from oxidation. Ginger juice has dual benefits in mitigating the common gastrointestinal symptoms of cancer patients and reducing the side effects of chemotherapy. Ginger juice also works to eliminate the fishy smell of the omega-3 fish oil, improve the taste of the formula, and supply more antioxidants.
Table 4 Formulation 3; Biscuit Bar (50 g)
Main ingredients:
Omega-3 EPA / DHA 2 g
Curcumin 200 mg
EGCG 100 mg
Vitamin D 300 IU
Egg white powder 5-10 g
Grounded nuts (flaxseed, walnuts, 35-40 g
etc.) and coconut
Usage: 3-5 bars a day
Preparation methods
[0099] Curcumin and vitamin D were dissolved in the omega-3 fish oil and then mixed with EGCG and egg white powder. The resulting solution was then mixed with the grounded nuts and coconut and shaped to form a biscuit bar.
[00100] In this specification and the appended claims, the singular forms "a," "an," and "the" include plural reference, unless the context clearly dictates otherwise.
[00101] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present disclosure, the preferred methods and materials are now described. Methods recited herein may be carried out in any order that is logically possible, in addition to a particular order disclosed.
Incorporation by Reference
[00102] References and citations to other documents, such as patents, patent applications, patent publications, journals, books, papers, web contents, have been made in this disclosure. All such documents are hereby incorporated herein by reference in their entirety for all purposes. Any material, or portion thereof, that is said to be incorporated by reference herein, but which conflicts with existing definitions, statements, or other disclosure material explicitly set forth herein is only incorporated to the extent that no conflict arises between that incorporated material and the present disclosure material. In the event of a conflict, the conflict is to be resolved in favor of the present disclosure as the preferred disclosure.
Equivalents
[00103] The representative examples are intended to help illustrate the invention, and are not intended to, nor should they be construed to, limit the scope of the invention. Indeed, various modifications of the invention and many further embodiments thereof, in addition to those shown and described herein, will become apparent to those skilled in the art from the full contents of this document, including the examples and the references to the scientific and patent literature included herein. The examples contain important additional information, exemplification and guidance that can be adapted to the practice of this invention in its various embodiments and equivalents thereof. What is claimed is:
Claims
A composition comprising therapeutically beneficial amount of
one or more of Omega-3 fatty acid; and
one of curcuminoid, epigallocatechin-3-gallate (EGCG) and Vitamin D. The composition of Claim 1, comprising therapeutically beneficial amount of one or more of Omega-3 fatty acid;
a curcuminoid; and
one of epigallocatechin-3-gallate (EGCG) and Vitamin D.
The composition of Claim 1, comprising therapeutically beneficial amount of one or more of Omega-3 fatty acid;
epigallocatechin-3-gallate (EGCG) and
Vitamin D.
The composition of Claim 2, comprising therapeutically beneficial amount of one or more Omega-3 fatty acids;
a curcuminoid;
epigallocatechin-3-gallate (EGCG); and
Vitamin D.
A nutritional supplement composition, comprising
one or more of Omega-3 fatty acid; and
one of curcuminoid, epigallocatechin-3-gallate (EGCG) and Vitamin D, according to daily serving as provided in the table below
Omega-3 EPA & DHA 4 - 15 g
Curcumin 0.3 - 8 g
Epigallocatechin-3-gallate (EGCG) 0.1 - i g
Vitamin D 1000 - 5000 IU
The nutritional supplement of Claim 5, comprising
one or more of Omega-3 fatty acid;
a curcuminoid; and
one of epigallocatechin-3-gallate (EGCG) and Vitamin D.
The nutritional supplement of Claim 5, comprising
one or more of Omega-3 fatty acid;
epigallocatechin-3-gallate (EGCG); and
Vitamin D.
The nutritional supplement of Claim 6, comprising
one or more Omega-3 fatty acids;
a curcuminoid;
epigallocatechin-3-gallate (EGCG); and
Vitamin D.
A ready-to-eat food or ready-to-drink beverage product, comprising therapeutically beneficial amounts of
one or more Omega-3 fatty acids; and
one of a curcuminoid; epigallocatechin-3-gallate (EGCG); and Vitamin D.
The ready-to-eat food or ready-to-drink beverage product of Claim 9, comprising
one or more of Omega-3 fatty acid;
a curcuminoid; and
one of epigallocatechin-3-gallate (EGCG) and Vitamin D.
The ready-to-eat food or ready-to-drink beverage product of Claim 9, comprising
one or more of Omega-3 fatty acid;
epigallocatechin-3-gallate (EGCG); and
Vitamin D.
The ready-to-eat food or ready-to-drink beverage product of Claim 10, comprising
one or more Omega-3 fatty acids;
a curcuminoid;
epigallocatechin-3-gallate (EGCG); and
Vitamin D.
A ready-to-eat food or ready-to-drink beverage product suitable for preventing or alleviating inflammatory diseases or conditions, comprising: per daily dosing of
Omega-3 EPA & DHA 4 - 15 g
Curcumin 0.3 - 8 g
Epigallocatechin-3-gallate (EGCG) 0.1 - i g
Vitamin D 1000 - 5000 IU
A food or beverage composition suitable for preventing or alleviating cancer, comprising Omega-3 EPA & DHA; Curcumin; epigallocatechin-3-gallate (EGCG); and Vitamin D according to the following per daily serving:
Omega-3 EPA & DHA 4 - 15 g
Curcumin 0.3 - 8 g
Epigallocatechin-3-gallate (EGCG) 0.1 - i g
Vitamin D 1000 - 5000 IU
A food or beverage composition suitable for preventing or alleviating diabetes, comprisin Omega-3 EPA & DHA; Curcumin; epigallocatechin-3-gallate (EGCG); and Vitamin D according to the following per daily serving:
Omega-3 EPA & DHA 4 - 15 g
Curcumin 0.3 - 8 g
Epigallocatechin-3-gallate (EGCG) 0.1 - i g
Vitamin D 1000 - 5000 IU
A food or beverage composition suitable for preventing or alleviating cardiovascular diseases or conditions, comprising Omega-3 EPA & DHA; Curcumin; epigallocatechin-3-gallate (EGCG); and Vitamin D according to the following per daily serving:
Omega-3 EPA & DHA 4 - 15 g
Curcumin 0.3 - 8 g
Epigallocatechin-3-gallate (EGCG) 0.1 - i g
Vitamin D 1000 - 5000 IU
A ready-to-drink beverage product comprising Omega-3 EPA & DHA; Curcumin;
epigallocatechin-3-gallate (EGCG); and Vitamin D according to the following per daily serving:
Omega-3 EPA & DHA 4 - 15 g
Curcumin 0.3 - 8 g
Epigallocatechin-3-gallate (EGCG) 0.1 - i g
Vitamin D 1000 - 5000 IU
18. A composition comprising therapeutically beneficial amount of
one or more Omega-3 fatty acids; and
one or more of a curcuminoid, epigallocatechin-3-gallate (EGCG), and Vitamin D, wherein the composition provides one or more of complementary and synergistic effects, improved bioavailability, improved solubility, and improved stability.
19. The composition of Claim 18, comprising:
one or more Omega-3 fatty acids;
a curcuminoid; and
one of epigallocatechin-3-gallate (EGCG) and Vitamin D,
wherein the composition provides one or more of complementary and synergistic effects, improved bioavailability, improved solubility, and improved stability.
20. The composition of Claim 18, comprising:
one or more Omega-3 fatty acids;
epigallocatechin-3-gallate (EGCG); and
Vitamin D,
wherein the composition provides one or more of complementary and synergistic effects, improved bioavailability, improved solubility, and improved stability.
21. The composition of Claim 19, comprising:
one or more Omega-3 fatty acids;
a curcuminoid;
epigallocatechin-3-gallate (EGCG); and
Vitamin D,
wherein the composition provides one or more of complementary and synergistic effects, improved bioavailability, improved solubility, and improved stability.
22. A method for preventing or alleviating a cancer, metabolic disease, or an inflammatory disease or condition, comprising:
administering to a subject in need thereof a composition comprising therapeutically beneficial amount of
one or more Omega-3 fatty acids, and
one or more of a curcuminoid, epigallocatechin-3-gallate (EGCG) and
Vitamin D; and
monitoring one or more biomarkers to monitor the status of the subject's disease or condition to determine the need for and dose of further administration of the composition.
The method of Claim 22, wherein the composition comprises one or more of Omega-3 fatty acid;
a curcuminoid; and
one of epigallocatechin-3-gallate (EGCG) and Vitamin D. The method of Claim 22, wherein the composition comprises one or more of Omega-3 fatty acid;
epigallocatechin-3-gallate (EGCG); and
Vitamin D.
The method of Claim 23, wherein the composition comprises one or more Omega-3 fatty acids;
a curcuminoid;
epigallocatechin-3-gallate (EGCG); and
Vitamin D.
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Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104489823A (en) * | 2015-01-12 | 2015-04-08 | 中国海洋大学 | Fish oil beverage and production method thereof |
WO2016168021A1 (en) * | 2015-04-14 | 2016-10-20 | Atossa Genetics, Inc. | Compositions and methods of treatment of breast disorders and estrogen-related disorders |
CN106999555A (en) * | 2014-11-13 | 2017-08-01 | J·麦 | New compositions for treating cancer |
EP3076961A4 (en) * | 2013-12-06 | 2017-09-27 | Ambo Innovation LLC | Omega-3 fatty acid articles of manufacture, and methods and apparatus for making same |
CN108740649A (en) * | 2018-05-11 | 2018-11-06 | 李红光 | A kind of deep sea fish oil, lecithin health drink |
Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2000070949A1 (en) * | 1999-05-20 | 2000-11-30 | Heng Madalene C Y | Method for using soluble curcumin to inhibit phosphorylase kinase in inflammatory diseases |
US20030143287A1 (en) * | 2000-08-08 | 2003-07-31 | Advanced Functional Foods International, Inc. | Nutritional supplement for the management of weight |
CN101589808A (en) * | 2008-05-26 | 2009-12-02 | 萨哈春食品供应有限公司 | The beverage preparation that contains curcumin extraction |
WO2010056318A2 (en) * | 2008-11-12 | 2010-05-20 | Andrew Loblaw | Nutritional supplement |
WO2011060307A2 (en) * | 2009-11-13 | 2011-05-19 | Jingxuan Kang | Food products having multiple health benefits |
WO2012122295A2 (en) * | 2011-03-07 | 2012-09-13 | Ned Biosystems, Inc. | Treatment for pancreatic adenocarcinoma and other cancers of epithelial origin |
-
2013
- 2013-12-10 WO PCT/US2013/074071 patent/WO2014093313A1/en active Application Filing
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2000070949A1 (en) * | 1999-05-20 | 2000-11-30 | Heng Madalene C Y | Method for using soluble curcumin to inhibit phosphorylase kinase in inflammatory diseases |
US20030143287A1 (en) * | 2000-08-08 | 2003-07-31 | Advanced Functional Foods International, Inc. | Nutritional supplement for the management of weight |
CN101589808A (en) * | 2008-05-26 | 2009-12-02 | 萨哈春食品供应有限公司 | The beverage preparation that contains curcumin extraction |
WO2010056318A2 (en) * | 2008-11-12 | 2010-05-20 | Andrew Loblaw | Nutritional supplement |
WO2011060307A2 (en) * | 2009-11-13 | 2011-05-19 | Jingxuan Kang | Food products having multiple health benefits |
WO2012122295A2 (en) * | 2011-03-07 | 2012-09-13 | Ned Biosystems, Inc. | Treatment for pancreatic adenocarcinoma and other cancers of epithelial origin |
Non-Patent Citations (5)
Title |
---|
DATABASE PUBMED accession no. 8830563 * |
GROMOVA O.A.: "Vitamin D (ergokaltsiferol, kholekaltsiferol).", ZHURNAL ''PRAKTIKA PEDIATRA, Retrieved from the Internet <URL:http://medi.ru/doc/j01070524.htm> * |
GUINE RAQUEL ET AL.: "Role and health benefits of different functional food components.", INTERNATIONAL JOURNAL OF MEDICAL AND BIOLOGICAL FRONTIERS, vol. 19, no. 9, 2010 * |
KAPAKOS GEORGIA ET AL.: "Cardiovascular Protection by Curcumin: Molecular Aspects.", INDIAN JOURNAL OF BIOCHEMISTRY & BIOPHYSICS, vol. 49, 2012, pages 306 - 315 * |
NAVARRO-PERAN E. ET AL.: "The anti-inflammatory and anti-cancer properties of epigallocatechin-3-gallate are mediated by folate cycle disruption, adenosine release and NF-kappaB suppression.", INFLAMM RES., vol. 57, no. 10, 2008, pages 472 - 478 * |
Cited By (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP3076961A4 (en) * | 2013-12-06 | 2017-09-27 | Ambo Innovation LLC | Omega-3 fatty acid articles of manufacture, and methods and apparatus for making same |
US9827218B2 (en) | 2013-12-06 | 2017-11-28 | Ambo Innovations, Llc | Omega-3 fatty acid articles of manufacture, and methods and apparatus for making same |
US10245247B2 (en) | 2013-12-06 | 2019-04-02 | Ambo Innovations, Llc | Omega-3 fatty acid articles of manufacture, and methods and apparatus for making same |
US10799471B2 (en) | 2013-12-06 | 2020-10-13 | Ambo Innovations, Llc | Omega-3 fatty acid articles of manufacture, and methods and apparatus for making same |
CN106999555A (en) * | 2014-11-13 | 2017-08-01 | J·麦 | New compositions for treating cancer |
CN104489823A (en) * | 2015-01-12 | 2015-04-08 | 中国海洋大学 | Fish oil beverage and production method thereof |
WO2016168021A1 (en) * | 2015-04-14 | 2016-10-20 | Atossa Genetics, Inc. | Compositions and methods of treatment of breast disorders and estrogen-related disorders |
CN108740649A (en) * | 2018-05-11 | 2018-11-06 | 李红光 | A kind of deep sea fish oil, lecithin health drink |
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