WO2012023142A2 - Compositions alimentaires fonctionnelles et procédés associés - Google Patents

Compositions alimentaires fonctionnelles et procédés associés Download PDF

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Publication number
WO2012023142A2
WO2012023142A2 PCT/IL2011/000676 IL2011000676W WO2012023142A2 WO 2012023142 A2 WO2012023142 A2 WO 2012023142A2 IL 2011000676 W IL2011000676 W IL 2011000676W WO 2012023142 A2 WO2012023142 A2 WO 2012023142A2
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Prior art keywords
bioactive agent
food
base carrier
functional food
particles
Prior art date
Application number
PCT/IL2011/000676
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English (en)
Other versions
WO2012023142A3 (fr
Inventor
Doron Friedman
Gideon Strassmann
Ascher Shmulewitz
Original Assignee
Clearfarma Industries Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Clearfarma Industries Ltd. filed Critical Clearfarma Industries Ltd.
Priority to MX2013001914A priority Critical patent/MX2013001914A/es
Priority to EP11817865.6A priority patent/EP2605756A4/fr
Priority to KR1020137006551A priority patent/KR20130091761A/ko
Priority to AU2011292760A priority patent/AU2011292760A1/en
Priority to SG2013011952A priority patent/SG187887A1/en
Priority to CN2011800498488A priority patent/CN103167869A/zh
Priority to JP2013524516A priority patent/JP2013537036A/ja
Priority to BR112013003676A priority patent/BR112013003676A2/pt
Priority to RU2013111465/15A priority patent/RU2013111465A/ru
Priority to CA2808710A priority patent/CA2808710A1/fr
Publication of WO2012023142A2 publication Critical patent/WO2012023142A2/fr
Publication of WO2012023142A3 publication Critical patent/WO2012023142A3/fr

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    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/115—Fatty acids or derivatives thereof; Fats or oils
    • A23L33/12—Fatty acids or derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L21/00—Marmalades, jams, jellies or the like; Products from apiculture; Preparation or treatment thereof
    • A23L21/20—Products from apiculture, e.g. royal jelly or pollen; Substitutes therefor
    • A23L21/25—Honey; Honey substitutes
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L29/00—Foods or foodstuffs containing additives; Preparation or treatment thereof
    • A23L29/10—Foods or foodstuffs containing additives; Preparation or treatment thereof containing emulsifiers
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
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    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23P—SHAPING OR WORKING OF FOODSTUFFS, NOT FULLY COVERED BY A SINGLE OTHER SUBCLASS
    • A23P10/00—Shaping or working of foodstuffs characterised by the products
    • A23P10/30—Encapsulation of particles, e.g. foodstuff additives
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
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    • A23P10/00—Shaping or working of foodstuffs characterised by the products
    • A23P10/30—Encapsulation of particles, e.g. foodstuff additives
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Definitions

  • the present invention relates to compositions including bioactive components carried within solid lipid particles dispersed in a food based carrier and to methods of producing such compositions.
  • Nutraceutical a term combining the words "nutrition” and “pharmaceutical”, is a food or food product that provides health and medical benefits, including the prevention and treatment of diseases.
  • Neutraceuticals include, among other categories, functional foods and medical foods [see Chen et al. Trends in Food Science & Technology 17 (2006) 272-283; and Lemes and McClements Trends in Food Science & Technology 20 (2009)].
  • Functional foods are consumed close to their natural state and include components or ingredients that provide a specific medical or physiological benefit beyond (or in addition to) the nutritional effects of the food.
  • Garlic which includes sulfur compounds, and fish, which include omega-3 fatty acids, are examples of functional foods.
  • Functional foods can be enriched or fortified to restore or supplement the nutrient content or physiological effect of food.
  • Medical foods are formulated to be consumed or administered internally under the supervision of a physician and are intended for dietary management of a disease or condition for which there are specific nutritional requirements.
  • Bioactive food components are biomolecules that are present in foods such as fruits and vegetables and which exhibit the capacity to modulate one or more metabolic processes, and thus can be used in the treatment of disease and promotion of better health.
  • Bioactive food components can be ingested as part of the source food or they can be ingested in purified form. In many cases it is unclear whether such components are ingested at effective dosages required for health benefits due to their limited bioavailability, however.
  • Methods of enhancing the bioavailability of bioactive food components are well known in the art and include formulations which are designed to increase the gastrointestinal (GI) absorption of the bioactive food components and/or limit their breakdown in the GI tract or body (see, Davis, DDT, Volume 10, Number 4, Feb. 2005).
  • composition that includes a nutritional base and bioactive components devoid of the above limitations.
  • the present invention successfully addresses the shortcomings of the presently known configurations by providing food-based physiologically-functional compositions that are capable of oral delivery of physiologically effective amounts of a bioactive agent.
  • thermoforming the melted lipid solvent and bioactive agent to a temperature of at least 65 °C; adding a food base carrier to said melted lipid solvent and bioactive agent; and, emulsifying said melted lipid solvent, said bioactive agent, and said food base carrier until an emulsion is formed, said emulsion comprising lipid particles comprising said bioactive agent.
  • step of heating the melted lipid solvent and bioactive agent to a temperature of at least 65 °C comprises a step of heating the melted lipid solvent and bioactive agent to a temperature of between 70 °C and 90 °C.
  • step of cooling further comprises a step of cooling to about 45 °C.
  • step of cooling further comprises a step of cooling to a temperature at least 20 °C below the emulsification temperature.
  • step of adding a food base carrier further comprises adding said first part of said food base carrier, and further comprising a step of adding said second part of said food base carrier during said step of emulsifying, said step of adding said second part taking place only when the temperature of the other components being emulsified is below 60 °C.
  • bioactive agent comprises a bioactive food component.
  • at least one lipid solvent chosen from the group consisting of hydrogenated castor oil; stearin; palm oil; high-omega-3 sage oil; pomegranate oil; avocado oil; olive oil; and any combination thereof.
  • said lipophilic bioactive agent comprises at least one component chosen from the group consisting of curcumin, diindolylmethane, quercetin, diadezin, silymarin, genistein, essential fatty acids, and phytosterols.
  • emulsifier is a PEG ester chosen from the group consisting of PEG6000 esters, PEG 100 stearate, and PEG40 stearate. It is another object of the present invention to provide the functional food as defined above, wherein said food base carrier is mixed with at least one additional bioactive agent.
  • hydrophilic bioactive agent is chosen from the group consisting of cobalamin, folate, and ferrous gluconate.
  • step of administering a functional food further comprises a step of administering a functional food characterized by at least one of the following:
  • said lipophilic bioactive agent is chosen from the group consisting of curcumin, diindolylmethane, quercetin, diadezin, silymarin, genistein, essential fatty acids, and phytosterols; and,
  • said food base carrier is chosen from the group consisting of saccharide and polysaccharide syrups.
  • step of administering a functional food further comprises a step of administering a functional food comprising at least one additional bioactive agent, said at least one additional bioactive agent mixed with said food base carrier.
  • step (b) emulsifying the product of step (a) with a semi-solid food base carrier until the formation of an emulsion comprising solid lipid particles; said solid lipid particles comprising said bioactive agent.
  • bioactive agent is a bioactive food component.
  • bioactive food component is curcumin.
  • bioactive food component is DIM.
  • lipid solvent includes at least one selected from a group consisting of hydrogenated castor oil, stearin, palm oil, AlinaTM oil, High-omega-3 sage oil, pomegranate oil, avocado oil, olive oil, and any combination thereof.
  • step (b) is effected while gradually cooling a mixture of said lipid solvent including said bioactive agent and said food base to a temperature of about 45°C.
  • It is another object of the present invention to provide a composition of matter comprising a food-based carrier comprising solid lipid particles homogenously dispersed therein and at least one bioactive agent, wherein at least 80% of said at least one bioactive agent is associated with said solid lipid particles.
  • bioactive agent is a bioactive food component.
  • bioactive food component is Diindolylmethane (DIM).
  • composition of matter as defined above further comprising an emulsifier.
  • It is another object of the present invention to provide a composition of matter comprising a honey carrier including solid lipid particles homogenously dispersed therein and curcumin and/or DIM entrapped within said solid lipid particles.
  • said lipid solvent is chosen from the group consisting of hydrogenated castor oil; stearin; palm oil; high-omega-3 sage oil; pomegranate oil; avocado oil; olive oil; and any combination thereof.
  • said lipid solvent is chosen from the group consisting of hydrogenated castor oil; stearin; palm oil; high-omega-3 sage oil; pomegranate oil; avocado oil; olive oil; and any combination thereof.
  • NASH Non-Alcoholic Steatohepatitis
  • NASH Non-Alcoholic Steatohepatitis
  • FIG. 1 illustrates the chemical structure of curcumin and its metabolites.
  • FIG. 2 is a flow chart outlining a method of producing a solid lipid fine dispersion of curcumin (and/or DIM) in honey.
  • FIG. 3 is a microscope image of curcumin powder particles (crystals) in honey with particle sizes of 5 - 100 ⁇ .
  • FIG. 4 presents microscope images of curcumin solid lipid particles (SLPs) in honey with a mean particle size of ⁇ 5 um; the curcumin SLPs dispersed in water; and curcumin powder dispersed in water.
  • SLPs curcumin solid lipid particles
  • FIGs. 5a-5c presents graphs of curcumin levels in rats following administration of 400 mg/kg unformulated curcumin or curcumin that had been formulated according to one embodiment of the present invention.
  • Fig. 6a illustrates the delta in the plasma curcumin concentration while using the SLP and Meriva as a function of time (15 minutes, 30 minutes, 60 minutes and 120 minutes).
  • FIG. 6b illustrates the delta in the mucosa curcumin concentration while using the SLP and Meriva as a function of time (15 minutes, 30 minutes, 60 minutes and 120 minutes).
  • the present invention provides a composition which can be used to treat disorders and promote well being.
  • the present invention can be used to treat subjects suffering from e.g., immune disorders cancer, solid cancers, leukemia, lymphoma, gastrointestinal cancers, genitourinary cancers, breast cancer, ovarian cancer, head and neck squamous cell carcinoma, lung cancer, melanoma, neurological cancers, and sarcoma, also gastrointestinal conditions such as: gastric ulcers, colitis, bowel disease, Crohn's disease, colorectal cancer, fatty liver disease and Non-Alcoholic Steatohepatitis (NASH), edema, arthritis, pancreatitis, ocular conditions, inflammatory diseases, comprising incorporating said lipophilic bioactive agent into a pharmaceutical drug or any combination thereof as will be described hereinafer.
  • NASH Non-Alcoholic Steatohepatitis
  • the present inventors While reducing the present invention to practice, the present inventors have devised a novel approach for formulating a composition which includes a food based carrier mixed with solid lipid particles loaded with a bioactive agent.
  • the present composition facilitates delivery of the bioactive agent to the GI tract while providing a nutrient base and eliminating or reducing offensive odors or tastes associated with the bioactive agent.
  • composition which can be used to treat a condition or disorder or promote or maintain well being in a subject such as a human.
  • the present composition can be used alone or as a supplement to other treatment approaches.
  • the present composition includes a food-based carrier mixed with solid lipid particles loaded with at least one bioactive agent.
  • food-based carrier refers to any liquid or semi-solid composition which is defined as food or is derived from food.
  • examples of food-based carriers include saccharide or polysaccharide syrups such as honey, date syrup and maple syrup.
  • Preferred are food based carriers that naturally include a high nutrient content as well as beneficial elements such as minerals.
  • particles when used with reference to solid lipids refers to nano or micro particles.
  • bioactive agent refers to a substantially purified substance that exerts a local or systemic biological (e.g. physiological) effect.
  • a bioactive component can include one or more bioactive agents.
  • a bioactive component can be derived from an extract of a vegetable or fruit or other natural sources.
  • the present inventors have devised a novel approach for producing the present composition.
  • Such an approach enables formation of the solid lipid particles (SLPs) loaded with the bioactive agent within the food based carrier, thus eliminating the need first to manufacture the bioactive agent-loaded SLPs and then to mix them with the carrier. It will be appreciated that such an approach substantially reduces the time and effort, as well as costs needed for production.
  • such an approach obviates the need to use harmful organic solvents such as ethanol, hexanol, ethyl acetate, acetone, ketones or ethyl methyl ketone (see US Pat. 6,086,915).
  • the present composition is produced by co-melting lipophilic bioactive agents and lipids (that are solid at room temperature), heating to a temperature of between 65 and 90 °C and emulsifying the melt in honey (or similar food based carrier) while cooling (in preferred embodiments, to 45 °C) thereby allowing the lipids to solidify into solid or semisolid microspheres within the honey.
  • the present composition is characterized by several unique features.
  • the solid lipid particles are homogenously dispersed within the food-based carrier and constitute 5-40% (w/w) of the composition with.
  • At least 70% (in preferred embodiments, at least 80%; in the most preferred embodiments, at least 90-95%) of the bioactive agent or agents are associated with the solid lipid particles. This enables as much as 30% loading of a carrier such as honey with a bioactive agent thereby enabling delivery of large amounts of the bioactive agent using the present composition.
  • solid lipid particles for entrapping the bioactive agent masks offensive odors or tastes associated therewith as well as protecting the bioactive agent from GI tract degradation.
  • the solid lipid particles within the functional food disclosed herein are small and uniform in size and thus facilitate dissolution and delivery of the active ingredient entrapped therein as well as maintaining the smooth texture of the food carrier.
  • SLP packaging of this active agent reduced the particle size (in water) severalfold (see Figure 4a-c).
  • carriers such as honey (in raw or mostly raw forms), date syrup and maple syrup are presently preferred due to their nutrient and mineral/element content.
  • honey contains about 41% fructose. This makes it the sweetest sugar known to civilization. It also contains about 35% glucose, about 17% water, about 2% sucrose, and small amounts of minerals and amino acids.
  • Honey also contains nearly all of the trace elements that the human body needs.
  • the health benefits of honey depend on its quality which is a function of the pollen collected by honey bees.
  • the quality of honey is also dictated by processing which can remove many of the phytonutrients found in raw honey.
  • Raw honey contains small amounts of the same resins found in propolis which is a complex mixture of resins and other substances that honeybees use to seal the hive and make it safe from bacteria and other micro-organisms.
  • the resins found in propolis only represent a small part of the phytonutrients found in propolis and honey, other phytonutrients found both in honey and propolis have been shown to possess cancer-preventing and anti-tumor properties.
  • These substances include caffeic acid methyl caffeate, phenylethyl caffeate, and phenylethyl dimethylcaffeate.
  • caffeic acid methyl caffeate phenylethyl caffeate
  • phenylethyl dimethylcaffeate phenylethyl dimethylcaffeate.
  • Dates (Phoenix dactylifera L.) are an important crop in the desert regions of Middle Eastern countries.
  • Date fruit is a highly nutritious food product. It is rich in calories and in minerals such as iron and potassium and contains modest amounts of folate, and a small amount of vitamins A and B. Dates are considered beneficial for treatment of anemia, constipation and fatigue.
  • Date syrup has a consistency similar to that of honey while being darker in appearance and having a unique flavor. Date syrup contains about 88% sugars, mainly glucose and fructose, and is a good source of essential elements such as calcium, phosphorus, potassium and magnesium. Date syrup is low in sodium, and as such it is a suitable food for low sodium diets.
  • bioactive agents can be used with the present composition including for example, curcumin, Silymarin, DIM, Genistein, Quercetin and Diadezin.
  • bioactive agents e.g. curcumin + diindolylmethane (DIM) or essential fatty acids (EPA and EHA) and phytosterols such as beta sitosterol, stigmasterol, campesterol, and brassicasterol can also be used with the present invention.
  • DIM diindolylmethane
  • EPA and EHA essential fatty acids
  • phytosterols such as beta sitosterol, stigmasterol, campesterol, and brassicasterol
  • the bioactive agent or agents are preferably associated with the solid lipid particles (e.g. entrapped therein) as described herein, although in some cases, the composition can also include additional bioactive agents (e.g. vitamins or minerals) that are directly mixed with the food based carrier. Since solid lipid particles are designed for entrapping hydrophobic (water insoluble) compounds, hydrophilic bioactive agents would not be suitable for SLP entrapment and as such are preferably added directly to the carrier of the present composition.
  • bioactive agents such as curcumin and DIM as well as quercetin and diadezin which are hydrophobic and thus poorly miscible in a food-based carrier are preferably entrapped in the solid lipid particles of the present composition, while other bioactive agents such as cobalamin, folate and iron (as ferrous gluconate) are preferably mixed directly into the food- based carrier of the present composition.
  • Curcumin a plant polyphenol is an edible component of the plant Curcumina longa, a key ingredient of Indian curry. Curcumin has been shown to be non-toxic, to have antioxidant activity, to inhibit the proliferation of cancer cells, and to inhibit inflammation. Curcumin inhibits the production of pro-inflammatory cytokines, such as TNFa, Interferon gamma, and IL-6 secreted by activated macrophages and T cells during an inflammatory response.
  • the mechanism of action of curcumin involves, among other things, the inhibition of important intracellular signaling pathways that participate in cancer cells and in the inflammatory response mediated by NFkappaB, COX, lipooxygenase (LOX), and inducible nitric oxide synthase (iNOS).
  • Curcumin is capable of reducing aberrant up-regulation of COX and/or iNOS in early stages of carcinogenesis and to also inhibit key intracellular elements involved in cancer cell proliferation.
  • Significant preventive and/or curative effects by curcumin have been observed in experimental animal models of a number of diseases, including cancer. Because of its lack of apparent toxicity, curcumin has been recently added (August, 2009) to FDA's GRAS (Generally Regarded As Safe) list. The recommended maximum safe daily dose was set at up to 1.75 grams, per human, per day.
  • Ingested curcumin exhibits low plasma and tissue levels of mostly due to poor absorption, rapid metabolism (see Figure 1), and rapid systemic elimination (Anand et al. Molecular Pharmaceutics Vol. 4, No. 6; 2007).
  • Numerous approaches have been undertaken to improve the bioavailability of curcumin. These approaches include use of adjuvants such as piperine that interfere with glucuronidation; use of liposomal or particulate delivery approaches; use of curcumin phospholipid complexes; and use of curcumin structural analogues (e.g., EF-24).
  • Figures 4a-c illustrate SLP-curcumin particles mixed in a honey-based carrier (Figure 4a), dispersed in water (Figure 4b) and curcumin crystals resultant from mixing curcumin powder with water (Figure 4c).
  • Diindolylmethane (DIM) Diindolylmethane
  • DIM is a bioactive agent derived from Brassica vegetables such as cabbage, cauliflower, Brussels sprouts and broccoli. Results of several studies indicate that DIM exhibits promising cancer-protective activities, especially against mammary neoplasia (breast cancer). Oral intubation of DIM in a single dose before carcinogen treatment reduced the incidence and multiplicity of dimethylbenzanthracene-induced mammary tumors in rats by 70 to 80% (Wattenberg et al., Cancer Res., 38, (1978) 1410-1413 ).
  • DIM is also widely used as adjunct therapy for recurrent respiratory papillomatosis (Auborn et al., Antivir. Ther. 7 (2002) 1-9.), caused by certain types of human papillomaviruses (HPVs).
  • DIM's anti-tumor activity is possibly through modulation of the immune response. Studies have shown that exposure to DIM could influence major immune responses, including natural killer cell activity, antibody production, and T-cell-mediated immunity. Importantly, DIM upregulates the expression of both interferon (IFN)-y and IF - ⁇ receptor, and potentiates the effects of IFN-y-induced expression of MHC I antigens in human breast cancer cells, making them susceptible to effector T cells.
  • IFN interferon
  • IFN- ⁇ is a central regulator of immune and inflammatory responses that contributes to the inhibition of primary and transplanted tumor development, as well as anti viral response.
  • DIM has generalized immune stimulatory properties, these capacities might indeed contribute to its anti-carcinogenic effects.
  • DIM was shown to induce splenocyte (B and T cell) proliferation, reactive oxygen species (ROS) generation, cytokine production and resistance to viral infection (Xue et al., J. Nutr. Biochem. 19, (2008), 336-344 ).
  • the addition of DIM to cultured cells enhanced both splenocyte proliferation and ROS production by peritoneal macrophages.
  • cytokines are major mediators of host defense they regulate communication between antigen-presenting cells, lymphocytes and other host cells during an immune response.
  • the cytokine repertoire present at a tissue site determines the type of host response directed against a tumor or an infection. Indeed, cytokines promoting the development of T-cell mediated immunity can induce or enhance the anti-tumor and antimicrobial immunity.
  • the hematopoietic growth factor, G-CSF is a cytokine that induces the bone marrow to generate more leukocytes, which are essential for fighting infection and cancer.
  • Quercetin is a plant-derived flavonoid that may have anti-inflammatory and antioxidant properties. Quercetin may have positive effects in combating or helping to prevent cancer, prostatitis, heart disease, cataracts, allergies/inflammations, and respiratory diseases such as bronchitis and asthma.
  • An 8-year study found that the presence of the three flavonols kaempferol, quercetin, and myricetin in a person's normal diet was associated with a reduced risk of pancreatic cancer. Quercetin has demonstrated significant anti-inflammatory activity by inhibiting both manufacture and release of histamine and other allergic/inflammatory mediators. In addition, it exerts potent antioxidant activity and vitamin C-sparing action. In mice, an oral quercetin dose of 12.5 to 25 mg/kg increased gene expression of mitochondrial biomarkers and improved exercise endurance. An in vitro study showed that the combination of quercetin and resveratrol inhibited production of fat cells.
  • Genistein and diadzein are isoflavones found in a number of plants including lupin, fava beans, soybeans, kudzu, and psoralea. Besides functioning as antioxidants and anthelmintics, many isoflavones have been shown to interact with animal and human estrogen receptors, causing effects in the body similar to those caused by the hormone estrogen.
  • Genistein and other isoflavones have been found to have antiangiogenic effects (blocking formation of new blood vessels), and may block the uncontrolled cell growth associated with cancer, most likely by inhibiting the activity of substances in the body that regulate cell division and cell survival. Studies have also found genistein to be useful in combating leukemia and that it can be used in combination with certain other leukemia combating drugs to improve their efficacy.
  • Silymarin (SM) is a lipophilic extract of milk thistle and is composed of several isomer flavonolignans.
  • silibinin major active component of silymarin
  • hepatoprotective antihepatotoxic
  • human prostate adenocarcinoma cells estrogen-dependent and -independent human breast carcinoma cells
  • human ectocervical carcinoma cells human colon cancer cells
  • small and nonsmall human lung carcinoma cells see, for example, http://en.wikipedia.0rg/wiki/Silibinin#cite_note-O.
  • Cobalamin contributes to the formation of red blood cells and bone marrow, the metabolism of carbohydrates, fats and proteins, nerve and cardiovascular functions and plays a role in DNA synthesis. Deficiency of this vitamin may cause anemia, exhaustion, irritation, depression, shortness of breath, difficulty walking, memory loss, mood swings, disorientation, dementia and constipation. Cobalamin doses greater than 3 milligrams daily may cause eye conditions. Cobalamin deficiency occurs primarily in people with malabsorption and myelodysplastic syndrome. The remaining cases of nutrient-deficiency anemia are usually associated with cobalamin, most frequently related to food-cobalamin malabsorption, and/or Folate deficiency. Cobalamin deficiency occurs frequently among patients with malabsorption, but it is often unrecognized or not investigated because the clinical manifestations are subtle.
  • Folate plays an important role in the metabolism of nucleic acids and amino acids. Consequentially, it is essential for cell growth and development and normal functionality of the nervous system. Folate deficiency in the elderly is characterized by anemia which is accompanied by symptoms such as, shortness of breath, fatigue and weakness. Folate deficiency may also cause a sore tongue, depression, nerve damage and infant neural tube defects, heart defects and limb malformations. Folate doses larger than 400 micrograms daily may cause anemia and may mask symptoms of a cobalamin deficiency. Iron
  • Iron is an essential part of many biological molecules such as hemoglobin.
  • the human body absorbs iron from animal sources faster than iron from plant sources. Iron deficiency is a common condition and can lead to disorders such as anemia.
  • the recommended daily dose of iron for humans is about 10 milligrams; a normal diet typically provides that amount but patients with malabsorption or frequent diarrhea require supplementation.
  • the present composition can be used to treat disorders or promote good health.
  • the food based carrier is honey in its minimally processed form, since it contains natural anti-cancer chemicals and provides nutrition and the physiologically active ingredients are DIM and optionally curcumin (both in SLPs).
  • Such a composition is especially suitable for use as adjunct cancer therapy.
  • the effect of chemotherapy is not specific to cancer cells and as such, it leads to severe side effects, such as immunosuppression and myelosuppression.
  • DIM would reduce chemotherapy-induced granulocytopenia, and stimulate immune responses in chemotherapy-treated cancer patients that are immunocompromised.
  • honey, DIM and curcumin have anti-viral and anti-bacterial properties, consumption of the present composition by chemotherapy- treated cancer patients, can help reduce the incidence of viral and bacterial infections associated with chemotherapy.
  • Cancer patients can be treated with three daily doses of the present composition, with each dose including 1 gram of honey, about 200 mg of DIM and about 400 mg of curcumin.
  • the present invention can also be used to treat disorders associated with aging and immunosenescence.
  • the immune system undergoes characteristic and multifaceted changes with aging. These changes occur in all type of leukocytes, including, neutrophils, T-cells, B-cells, monocyte/macrophages, dendritic cells and natural killer cells. Accordingly, aging affects both innate and adaptive immune functions. Collectively, this process is called “immunosenescence” and it refers to the natural gradual deterioration of the immune system with advancing age. It involves both the host's capacity to respond to infections and the development of long-term immune memory, especially by vaccination. This age-associated immune deficiency is ubiquitous and found in both long- and short-lived species as a function of their age relative to life expectancy rather than chronological time.
  • Immunosenescence is not a random deteriorative phenomenon, rather it appears to inversely repeat an evolutionary pattern and most of the parameters affected by immunosenescence appear to be under genetic control. Immunosenescence can also be sometimes envisaged as the result of the continuous challenge of the unavoidable exposure to a variety of antigens such as viruses and bacteria. Immunosenescence is a multifactorial condition leading to many pathologically significant health problems in the aged population. Age-dependent biological changes such as depletion of hematopoietic stem cells, decline in the total number of phagocytes and NK cells and a decline in humoral immunity contribute to the onset of immunosenescence.
  • Anemia is highly prevalent in the elderly population, including those individuals who are in long term care facilities and geriatric wards. Importantly, even mild anemia is associated with adverse health outcomes. Therefore, anemia is of a great healthcare concern.
  • the most frequent etiologies of anemia in the elderly are anemia of chronic disease/inflammation; iron, folate and vitamin Bn (cobalamin).
  • a composition including honey, DIM and vitamins can be used to treat viral and bacterial infections as well as anemia in populations such as the elderly, the malnourished and the like.
  • the honey and DIM would provide antibacterial and antiviral functions while DIM would increase hematopoietic cytokine production.
  • Key vitamins such as cobalamin and folate will enhance blood production.
  • Treatment can include five daily doses of a composition including 1 g of honey, 200 mg of DIM, 50 ⁇ g of cobalamin, 20 g of folate and 3 mg of iron.
  • the present invention can also be used to treat disorders such as Celiac Disease (CD), Non- Celiac Gluten Sensitivity (NCGS) and Irritable Bowel Syndrome (IBS).
  • CD Celiac Disease
  • NCGS Non- Celiac Gluten Sensitivity
  • IBS Irritable Bowel Syndrome
  • Celiac disease is an immunologically-mediated enteropathy, triggered in genetically susceptible subjects, many of whom carry the HLA-DQ (haplotypes 2 or 8).
  • HLA-DQ haplotypes 2 or 8
  • People with CD also have one or more additional food allergies, which may include milk protein, corn and soy. Symptoms include chronic diarrhea, abdominal pain, cramping, weight loss or growth inhibition, musculoskeletal pain, neurological involvement and fatigue.
  • CD can be considered as an archetypal malabsorption syndrome, and is a frequent cause of anemia. In many cases anemia has been reported as the only initial manifestation, or the most frequent extra-intestinal symptom of CD. Folate (vitamin B9) and cobalamin (vitamin B12) deficiencies are known complications of CD. Another common nutritional anemia associated with CD is iron deficiency. Iron deficiency anemia was reported in up to 46% of patients with subclinical CD.
  • Gluten intolerance is a broad term which includes various degrees of gluten sensitivity. It is estimated that about 15% of all people are gluten sensitive, but only about 1% have CD as determined by testing positive in the currently available immunoassays and biopsies.
  • antibody serology is an important tool in the confirmation of CD, it does not always correlate with the typical mucosal appearance of CD, namely, the villus atrophy of the small intestine.
  • NCGS Non Celiac Gluten Sensitivity
  • IBS affects between 5-20% of the population of the western world. The wide range may be linked to the fact that the symptoms of non-specific dyspepsia are sometimes confused with those of IBS. Importantly, IBS is the second leading cause of work absenteeism. Women are four times more likely to suffer from IBS than men. Symptoms of IBS include irregular bowel function, bloating, abdominal pain, cramping, diarrhea, and constipation. Stress and other psychological factors are known to exacerbate the intensity and frequency of the syndrome.
  • IBS The main characteristic of IBS is irregular defecation, and IBS is divided into two types based on the irregularity observed: IBS-D (diarrhea) and IBS-C (constipation). It is estimated that about 50% of all IBS patients use alternative medicine because of the lack of effectiveness of currently prescribed medications.
  • IBS patients have a significantly elevated level of the proinflammatory cytokine IL-6 in their circulation, as well as a very high level of the cyclooxygenase (COX) cycle metabolite prostaglandin E2, which is known to be produced by inflammatory stimuli.
  • COX cyclooxygenase
  • Protaglandin E2 cyclooxygenase
  • compositions including a food based carrier and curcumin in solid lipid particles can be used to treat such disorders.
  • Curcumin inhibits stimulus-dependent activation of immune cells and the production of pro-immune/inflammatory cytokines without causing the severe side-effects frequently associated with the use of anti-inflammatories that inhibit the COX and LOX cycles.
  • curcumin has a chemopreventive effect against the development of cancer. Therefore, its consumption via honey, on a regular basis, may reduce the high risk of adenocarcinoma and lymphoma development in the intestines of people with CD, as well other patients' populations suffering from intestinal malfunction.
  • Treatment can include three daily doses of a composition that includes 1 gram of the honey and about 400 mg of curcumin (in SLPs).
  • the present compositions can be presented in a dispenser device, such as a squeeze bottle or foil sachet or encapsulated in ingestible capsule (e.g. gel capsule) which may be packaged in foil blisters.
  • the dispenser device or pack may include one or more dosage units of the present composition.
  • the dispenser device or capsule pack may be accompanied by instructions for consumption.
  • the dispenser device or pack may also be accompanied by a notice in a form prescribed by a governmental agency regulating the manufacture, use, or sale of neutraceuticals, which notice is reflective of approval by the agency of the form of the compositions for human or veterinary administration. Such notice, for example, may include labeling approved by the U.S. Food and Drug Administration.
  • Solid Lipid Micronized Dispersions of Curcumin in Honey A solid lipid dispersion is a delivery system in which the bioactive agent is solubilized or dissolved in hot melted lipids that do solidify at room temperature.
  • the hot melt is emulsified with an aqueous medium and cooled to room temperature to solidify as particles which include the bioactive agent within their core.
  • curcumin a polyphenolic compound derived from dietary spice turmeric
  • solid Lipid Dispersion technology tested whether curcumin, a polyphenolic compound derived from dietary spice turmeric, can be emulsified within a honey-based carrier using Solid Lipid Dispersion technology.
  • Curcumin is insoluble in water and therefore its solubility was tested in various solvents. Curcumin solubility was measured by vigorously mixing 400 mg of curcumin in 2 g of a test solvent and heating the sample to 90 °C. Samples were cooled to room temperature and inspected visually and solubility recorded. Table 2 below provides the results of the solubility study. Curcumin showed very limited or poor solubility in the oils tested, but was soluble in Polyethylene glycol (PEG).
  • PEG Polyethylene glycol
  • curcumin 10 solubility or partial solubility correlates with the presence of PEG and that PEG therefore contributes to curcumin solubility.
  • Microscopic inspection of curcumin in hydrogenated castor oil (Cutina HR) with PEG 100 stearate produced curcumin as solid lipids. This combination was then selected as the initial lipid phase of the curcumin-honey formulation.
  • Procedure A The lipid phase (curcumin in hydrogenated castor oil with PEG 100 stearate) was heated to 90 °C and the honey was heated to 70 °C. The heated lipid and honey phases were mixed and homogenized using Heidolph DIAX 900 homogenizer at speed 3 until the temperature dropped to at least 20 °C below the emulsification temperature and the formulation appeared semi solid.
  • Procedure B Same as procedure A, but a portion of the honey is not heated above 50 °C in order to preserve unique honey properties that are destroyed above 55C.
  • the lipid phase was heated to 90 °C; half the honey was heated to 70 °C and the rest to 40 °C - 50 °C .
  • the lipid and the hot honey (70 °C) phases were mixed and homogenized with Heidolph homogenizer DIAX 900 at speed 3 until the temperature dropped below 60 °C.
  • the rest of the honey was then heated to 50 °C and added while vigorously mixing and/or homogenizing to the Lipid- honey mix until the formulation reached homogeneity.
  • the formulations produced by the present study were visually inspected for homogeneity, observed under a microscope, tested for smell taste and texture, and for physical and chemical stability.
  • Table 5 summarizes the results of three curcumin in honey formulations, CUR13, 14 and 15.
  • CUR13 and CUR15 were produced using procedure A, while CUR14 was produced using procedure B. Hydrogenated castor oil was the lipid base and PEG100 stearate was used as an emulsifier.
  • CUR15 was a control formulation used for examining the effect of lipid phase concentration and the production procedure on particle size. This formulation was microscopically compared to CUR13 and CUR14.
  • PEG 100 stearate is a good stabilizer and curcumin solvent, but that the mixture solidifies at a relatively high temperature (above 70 °C), making it difficult to carry out the preparation procedure and thus encouraging the present inventors to seek alternative stabilizing emulsifiers.
  • PEG 100 Stearate was replaced with PEG 40 Stearate which has a lower melting point (CUR 17, Table 7).
  • This formulation was produced using procedure A and exhibited satisfactory results. Processing was easier due to lower temperature solidification and the resulting formulation was characterized by good stability and solubility. It had a typical honey smell. The observation of a small number of curcumin crystals indicates that the curcumin was not completely solubilized. The amount of solubilization was not quantified, but it is estimated that the fraction of curcumin that remained unsolubilized was between 1 to 10%.
  • sucrose ester component was tested as the sole stabilizing emulsifier for curcumin using procedure A.
  • the resulting formulation included fine micronized solid lipid particles exhibiting poor water miscibility, probably due to a lack of hydrophilic components such as the PEG moiety of the PEG stearate component.
  • CUR 20 and CUR21 were produced using procedure A.
  • CUR20 contained sucrose ester with PEG40 stearate, while that of CUR21 contained sucrose ester with Tween 80 as stabilizing surfactants. Both were well miscible in water; in the CUR21 formulation the typical smell of honey was lost.
  • CUR22 was produced using procedure A while CUR 22(2) was produced using procedure B (Table 11).
  • the lipid phase was identical for both formulations, and included 0.5% sucrose ester and 1.0% PEG40 stearate. Both were miscible in water, and both exhibited a typical honey smell and a curcumin aftertaste.
  • CUR23 (Table 12) was produced using procedure A or B.
  • the lipid phase was identical to the CUR22 formulation but 4% curcumin was used.
  • the result was a smooth semisolid formulation with typical honey smell and no aftertaste.
  • CUR24 (Table 13) was produced with food grade stearin as the lipid solvent.
  • CUR25 (Table 13) was produced with food grade palm oil as the lipid solvent. Both formulations were produced using procedure A and resulted in a formulation having a smooth texture, a honey smell and no aftertaste. The microscopic observations showed solid lipid spherical particles loaded with curcumin and very few free curcumin crystals. The diameter of the solid lipid spheres was between 0.5 and 5.0 ⁇ .
  • CUR26 is the same formulation as CUR24 but without PEG6000
  • CUR27 is the same formulation as CUR25 but without PEG6000 (Table 14).
  • the purpose of these formulations was to determine whether PEG6000 was necessary as the curcumin solvent. Both formulations were produced using procedure A and in both lipid phases no curcumin solubility was observed. Microscopic observation of these formulations showed spherical lipid particles with no curcumin entrapment and curcumin crystals of various size and unusual shapes. These formulations did not exhibit a homogeneous texture. Both formulations were characterized by a honey smell and a good taste. Table 14: Formulations without PEG 6000
  • the present approach can also be used to generate DIM, Genistein, Diadzin or Quercetin SLP in honey formulations.
  • Table 15 below provides a list of ingredients that can be used in such formulations.
  • CUR64 (Table 16 below) was produced with AlinaTM oil (omega-3 rich sage oil).
  • CUR64 (Table 16 below) was produced using procedure A and resulted in a formulation having a smooth texture, a semisolid product with no smell, a honey sweet taste, and no aftertaste.
  • Table 16 production with AlinaTM oil (sage omega3 rich oil)
  • CUR65, CUR66 and CUR67 were produced with pomegranate oil (CUR65), with avocado oil (CUR66) and with olive oil (CUR67).
  • CUR65, CUR66 and CUR67 were produced using procedure A and resulted in a smooth semisolid product having a smooth texture, no smell, a sweet taste, and no aftertaste.
  • Table 17 production with Pomegranate oil (CUR65), with Avocado oil (CUR66) and with Olive oil (CUR67)
  • CUR66-1 was produced as follows (production of 1 kg):
  • Curcumin was melted with PEG6000 to 90 °C ;
  • Lipid phase was added to the PEG-curcumin solution and heated with stirring to 80
  • the lipid phase was homogenized at 5000 rpm and date syrup was added slowly with homogenization for 3 min;
  • the homogenization speed was reduced to 4000 rpm for 4 min with cooling in a water bath;
  • CUR66-2 was produced as follows (production of 1.5 kg):
  • Curcumin was melted with PEG6000 and lipid phase to 95 °C;
  • Date syrup was heated to 75 °C;
  • the lipid phase and date syrup were further homogenized at 5000 rpm for 3 min; h. The homogenization speed was reduced to 4000 rpm for 4 min with cooling in a water bath to 56 °C;
  • CUR66-3 was produced as follows (production of 1.5 kg):
  • Curcumin was melted with PEG6000 and lipid phase to 90 °C;
  • Date syrup was heated to 70 °C ;
  • the lipid phase was homogenized at 6000 rpm for about 20 s;
  • the homogenization speed was reduced to 4000 rpm for 4 min with cooling in a water bath;
  • Table 18 production with Pomegranate oil (CUR65), with Avocado oil (CUR66) and with
  • Curcumin is known to possess poor systemic availability, in his natural form, i.e. mixed in drinks or food, therefore an in vivo model was used to determine the extent to which the formulations of the present invention increase its oral bioavailability.
  • Mariva® is basically Curcumin (CAS 458-37-7) and curcumin phospholipid complex.
  • the preparation of Meriva® was performed byusing EpiKuronTM 130 P, a de-oiled, powdered soybean lecithin enriched with 30% phosphatidylcholine.
  • Meriva contained 16.89% curcuminoids, of which 93.82% was curcumin, the ratio of curcumin to EpikuronTM 130 P was 1 :4.
  • Meat® is been marketed by a company whom conducted the same protocol of clinical study in purpose to published a new formulation for curcumin, whose added value is to increase the curcumin absorption through the mucosa tissue into the blood stream (See Timothy H. Marczylo et al., Cancer Chemother Pharmacol, 2007, 60:171-177).
  • FIG. 5a shows plasma curcumin levels in rats that had received 400 mg/kg curcumin by oral gavage as a function of time following the administration of the curcumin.
  • the solid line shows results for rats that received SLP formulated curcumin, while the broken line shows results for results that received unformulated curcumin (represented as C3).
  • FIG. 5b shows liver curcumin levels in rats that had received 400 mg/kg curcumin by oral gavage as a function of time following the administration of the curcumin.
  • the solid line shows results for rats that received SLP formulated curcumin, while the broken line shows results for results that received unformulated curcumin (represented as C3).
  • FIG. 5c shows curcumin levels in the gastrointestinal mucosa of rats that had received 400 mg/kg curcumin by oral gavage as a function of time following the administration of the curcumin.
  • the solid line shows results for rats that received SLP formulated curcumin, while the broken line shows results for results that received from unformulated curcumin (i.e., the control, represented as C3).
  • FIG. 6a illustrates the delta in the plasma curcumin concentration while using the SLP and Meriva as a function of time (15 minutes, 30 minutes, 60 minutes and 120 minutes).
  • the SLP concentration was calculated was as follows: SLP formulation concentration minus C3 (i.e., the control) curcumin concentration.
  • the Meriva concentration was calculated was as follows: Meriva formulation concentration minus C3 (i.e., the control) curcumin concentration.
  • the delta was calculated for each time point.
  • the units of the numbers are ng/ml.
  • FIG. 6b illustrates the delta in the mucosa curcumin concentration while using the SLP and Meriva as a function of time (15 minutes, 30 minutes, 60 minutes and 120 minutes).
  • the SLP concentration was calculated was as follows: SLP formulation concentration minus C3 (i.e., the control) curcumin concentration.
  • the Meriva concentration was calculated was as follows: Meriva formulation concentration minus C3 (i.e., the control) curcumin concentration.
  • the delta was calculated for each time point.
  • the units of the numbers are mg/g.
  • the minus mark appears where the C3 curcumin concentration is higher than the SLP/ Meriva curcumin concentration.
  • Hot melt procedures for emulsification of curcumin-filled solid lipid particles in honey were developed and tested. Solid lipid particles produced by hot melt emulsification were the method of choice for curcumin incorporation in honey.
  • the present inventors have shown that curcumin is soluble in mixtures of ethylene oxide polymers and lipids.
  • the present inventors have also shown that free curcumin forms curcumin crystals in honey and water.
  • curcumin solubility is pivotal to product quality and that use of hydrogenated castor oil, stearin, and palm oil as lipid solvent components is preferred since it results in a curcumin-in-honey formulation that does not have an aftertaste, exhibits smooth texture, has a honey smell and includes substantially all of the curcumin in the lipid microparticles suspended in the honey base.

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Abstract

L'invention concerne un aliment fonctionnel et son procédé de production. L'aliment fonctionnel est produit par le mélange d'un solvant lipidique comprenant un agent bioactif avec un support de base alimentaire liquide ou semi-solide jusqu'à la formation d'une émulsion qui comprend des particules lipidiques solides chargées de l'agent bioactif.
PCT/IL2011/000676 2010-08-18 2011-08-18 Compositions alimentaires fonctionnelles et procédés associés WO2012023142A2 (fr)

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KR1020137006551A KR20130091761A (ko) 2010-08-18 2011-08-18 기능성 식품 조성물 및 그 제조방법
AU2011292760A AU2011292760A1 (en) 2010-08-18 2011-08-18 Functional food compositions and methods
SG2013011952A SG187887A1 (en) 2010-08-18 2011-08-18 Functional food compositions and methods
CN2011800498488A CN103167869A (zh) 2010-08-18 2011-08-18 功能性食品组合物及其制备方法
JP2013524516A JP2013537036A (ja) 2010-08-18 2011-08-18 機能的食品組成物とその生産方法
BR112013003676A BR112013003676A2 (pt) 2010-08-18 2011-08-18 composições de alimentos funcionais e métodos
RU2013111465/15A RU2013111465A (ru) 2010-08-18 2011-08-18 Функциональные пищевые композиции и способы
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CN108208838A (zh) * 2018-03-09 2018-06-29 北京素维生物科技有限公司 一种掩味组合物及其用途
CN109883995B (zh) * 2019-03-05 2021-06-29 中国计量大学 基于哈特曼光线追迹的非均匀介质场的测量系统及其方法

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WO2014135967A1 (fr) 2013-03-06 2014-09-12 Capsugel Belgium Nv Particules lipidiques solides de curcumine et procédés de préparation et utilisation
US20160000714A1 (en) * 2013-03-06 2016-01-07 Capsugel Belgium Nv Curcumin solid lipid particles and methods for their preparation and use
US10166187B2 (en) 2013-03-06 2019-01-01 Capsugel Belgium Nv Curcumin solid lipid particles and methods for their preparation and use
US11324699B2 (en) 2014-12-04 2022-05-10 Capsugel Belgium Nv Lipid multiparticulate formulations
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WO2019020663A1 (fr) * 2017-07-26 2019-01-31 Luigi Maiuri Activateur de canal cftr destiné à être utilisé dans le traitement et/ou la prévention d'états de sensibilité au gluten
WO2019175290A1 (fr) 2018-03-13 2019-09-19 Beckley Canopy Therapeutics Limited Cannabis ou compositions dérivées du cannabis pour favoriser l'arrêt de la dépendance chimique
WO2022170181A1 (fr) * 2021-02-08 2022-08-11 Capsugel Belgium Nv Vitamine c à libération prolongée et sa fabrication
WO2022204757A1 (fr) * 2021-03-30 2022-10-06 Noxopharm Limited Formulation d'isoflavone améliorée

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JP2013537036A (ja) 2013-09-30
KR20130091761A (ko) 2013-08-19
RU2013111465A (ru) 2014-09-27
WO2012023142A3 (fr) 2012-05-31
MX2013001914A (es) 2013-05-20
CA2808710A1 (fr) 2012-02-23
SG187887A1 (en) 2013-03-28
CN103167869A (zh) 2013-06-19
BR112013003676A2 (pt) 2016-09-06
AU2011292760A1 (en) 2013-04-04
EP2605756A2 (fr) 2013-06-26

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