WO2024040336A1 - Compositions and methods for the management of blood sugar levels for the prophylaxis of prediabetes and diabetes mellitus - Google Patents
Compositions and methods for the management of blood sugar levels for the prophylaxis of prediabetes and diabetes mellitus Download PDFInfo
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- WO2024040336A1 WO2024040336A1 PCT/CA2023/051104 CA2023051104W WO2024040336A1 WO 2024040336 A1 WO2024040336 A1 WO 2024040336A1 CA 2023051104 W CA2023051104 W CA 2023051104W WO 2024040336 A1 WO2024040336 A1 WO 2024040336A1
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- aronia
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Definitions
- the present invention relates to the field of nutraceuticals and dietary supplement compositions and, in particular, to compositions comprising Aronia juice fortified with Aronia extract, and tart cherry juice fortified with tart cherry extract, and methods for managing blood sugar levels to prevent or manage the onset of prediabetes and diabetes mellitus. BACKGROUND OF THE INVENTION [0002] Managing blood sugar levels is essential to maintaining good health and preventing serious health problems.
- Prediabetes occurs when blood sugar levels are higher than normal (typically between 5.7 to 6.4% (HbA1c)) but the blood sugar levels aren't high enough to be considered diabetes (typically 6.5% or above (HbA1c)). If not managed, prediabetes can lead to diabetes. 1 71740679.2 [0004] More than half a billion people are living with diabetes worldwide, affecting men, women, and children of all ages in every country, and that number is projected to more than double to 1.3 billion people by 2055, with every country seeing an increase. The latest and most comprehensive calculations show the current global prevalence rate is 6.1%, making diabetes one of the top 10 leading causes of death and disability.
- bioavailability is dependent on the absorption of the micronutrients by the epithelial layer of the gut, and the chemical and biochemical transformations into epithelial cells. These processes are endogenous factors that greatly influence the bioavailability of bioactive compounds. Ensuring bioavailability is challenging due to the nature of both the bioactive compounds and the digestive tract of the consumer. As a result, the efficacy of bioactive compounds in nutraceuticals and dietary supplements, is limited at best, and unpredictable. [0008] New compositions and methods that address the shortcomings of existing nutraceuticals are, therefore, needed to realize the prophylactic and/or therapeutic effects of bioactive compounds for managing blood sugar levels to prevent or manage the onset of prediabetes and diabetes mellitus.
- An object of the present invention is to provide compositions and methods for the management of blood sugar levels in a subject, for the prophylaxis of prediabetes and diabetes mellitus.
- a composition comprising Aronia juice fortified with Aronia extract in combination with tart cherry juice fortified with tart cherry extract.
- the composition of the present invention further comprises one or more additional nutraceuticals.
- composition comprising Aronia juice fortified with Aronia extract in combination with tart cherry juice fortified with tart cherry extract, wherein said juices and extracts interact to enhance bioavailability of polyphenols and/or polyphenol gut metabolites from said extracts.
- a formulation for reducing or maintaining blood sugar levels in the prophylaxis of prediabetes or diabetes mellitus comprising Aronia juice fortified with Aronia extract, and tart cherry juice fortified with tart cherry extract.
- a method for reducing or maintaining blood sugar levels in a subject for the prophylaxis of prediabetes or diabetes mellitus comprising administering a therapeutically effective amount of a composition comprising Aronia juice fortified with Aronia extract, and tart cherry juice fortified with tart cherry extract, wherein said composition enhances the bioavailability of 3 71740679.2 polyphenols and/or polyphenol gut metabolites from said extracts.
- the blood sugar level is reduced or maintained within an HbA1c range of 5.6% or less.
- the blood sugar level is reduced or maintained at an HbA1c below a range of 5.7% to 6.4%.
- Figure 1 presents an illustration of the systemic effects resulting from the enhanced bioavailability and absorption of the polyphenol gut metabolites elicited by the composition according to embodiments of the present invention.
- Figure 2 is a graph presenting changes in diastolic blood pressure across three time points (baseline (T0), 3 weeks (T1) and 3 months (T2) of aronia (chokeberry)/tart cherry core formulation consumption). The graph represents results of repeated measures ANOVA of normalized data, presented as relative change from T0.
- Figure 3 presents changes in total body water of right leg (A), left leg (B), Intracellular water of right leg (C), left leg (D), extracellular water of right leg (E) and left leg (F) across three time points (baseline (T0), 3 weeks (T1) and 3 months (T2) of aronia (chokeberry)/tart cherry core formulation consumption).
- the graphs represent repeated measures ANOVA analysis of normalized data, presented as relative change from T0. **p ⁇ 0.01, compared to T0; #, p ⁇ 0.05, compared to T1.
- Figure 4 presents the effect of 3-month long core formulation consumption on markers of endothelial dysfunction.
- Results presented as median with 25-75 percentiles (box) and 10-90 percentile range (whiskers), before and after 3-month long core formulation consumption in subjects of both sexes at increased CVD risk. n 15-17 4 71740679.2 subjects; data analyzed by Wilcoxon signed-rank test for non-normal data distribution. ***, p ⁇ 0.001; ns, p>0.05.
- DETAILED DESCRIPTION OF THE INVENTION Polyphenols are micronutrients found in a wide range of food sources that have gained particular attention for their antioxidant properties and their role in the prevention of various diseases.
- Polyphenols which constitute the active substances found in many medicinal plants, have also been found to modulate the activity of a wide range of enzymes and cell receptors.
- More than 8,000 types of polyphenols have been identified. They can be further categorized into 4 main groups: (i) flavonoids which account for around 60% of all polyphenols and include quercetin, kaempferol, catechins, apigenin, fisetin, proanthocyanidins, and anthocyanins; (ii) phenolic acids which account for around 30% of all polyphenols and include stilbenes and lignans; (iii) polyphenolic amides which include 5 71740679.2 capsaicinoids and avenanthramides; and (iv) other polyphenols which include resveratrol, ellagic acid, ellagitannins, resveratrol, urolithin A, curcumin, and lignans.
- nutraceutical compositions are described that unexpectedly enhance the bioavailability of polyphenols and the polyphenol gut metabolites.
- the nutraceutical compositions of the present invention enhance antioxidant bioavailability in the gut by combining nutrient-rich and polyphenol- high Aronia and tart cherry juice.
- the nutraceutical compositions comprise Aronia and tart cherry juices that are further fortified with Aronia and tart cherry extract which together enhance polyphenol bioavailability.
- the nutraceutical compositions comprise a combination of Aronia juice fortified with Aronia extract in combination with tart cherry juice fortified with tart cherry extract.
- Enhanced bioavailability of polyphenols leads to an increase in the final active metabolites produced by gut bacterial species and subsequent intestinal absorption of the polyphenol gut metabolites.
- the nutraceutical compositions described herein alter the gut’s vascular wall to enhance absorption of micronutrients and bioactive phytochemicals.
- the nutraceutical compositions result in an increase in n3 and a decrease in n6 polyunsaturated fatty acids (PUFAs) in endothelium and vascular wall cell membranes.
- PUFAs polyunsaturated fatty acids
- the components of the nutraceutical compositions interact synergistically to ultimately lead to increased cell membrane fluidity through phospholipid restructuring. According to certain embodiments, this restructuring of the vascular wall cell membrane further enhances the intestinal absorption of micronutrients and bioactive phytochemicals.
- the nutraceutical compositions described herein result in stabilization of the permeability of the gut wall thereby reducing the loss of polyphenol gut metabolites, and thus increasing the amount of bioactive components to be absorbed by the gut epithelium and underlying vasculature.
- the nutraceutical compositions result in the lowering of zonulin production that modulates the permeability of tight junctions between cells of the gut wall to stabilize gut wall permeability.
- the compositions of the present invention are combined with additional nutraceuticals to enhance their absorption.
- the compositions comprise Aronia juice fortified with Aronia extract in combination with tart cherry juice fortified with tart cherry extract, and further in combination with additional nutraceuticals. It is contemplated that the additional nutraceuticals can include any nutraceutical of interest.
- the nutraceutical compositions comprise Aronia juice fortified with Aronia extract, and tart cherry juice fortified with tart cherry extract, in combination with one or more extracts.
- the one or more extracts can include, for example, red beet extract, rosehip extract, chamomile extract, lemon balm extract, lion’s mane mushroom extract, reishi mushroom extract, resveratrol extract, quercetin extract, fisetin extract, berberine extract, urolithin A, NMN, Ca-AKG, spermidine extract, TMG, and/or cannabidiol (CBD).
- the compositions comprise Aronia juice fortified with Aronia extract, and tart cherry juice fortified with tart cherry extract, in combination with, for example, red beet extract, lion’s mane mushroom extract, and/or 7 71740679.2 rosehip extract.
- compositions comprise Aronia juice fortified with Aronia extract, and tart cherry juice fortified with tart cherry extract, in combination with, for example, one or more of rosehip extract, chamomile extract, lemon balm extract, reishi mushroom extract, and/or cannabidiol (CBD).
- Compositions of the present invention comprising Aronia juice fortified with Aronia extract in combination with tart cherry juice fortified with tart cherry extract, are therefore contemplated in certain embodiments for use as an absorption-enhancing carrier for micronutrients and bioactive phytochemicals derived from nutraceutical extracts.
- the present invention provides for the use of the fortified Aronia and tart cherry juice composition prior to consumption of nutraceutical extracts.
- the present invention provides for the use of the fortified Aronia and tart cherry juice composition as a carrier for additional nutraceutical extracts.
- the enhanced bioavailability of the components of the nutraceutical composition, comprising Aronia and tart cherry juices that are fortified with Aronia and tart cherry extract unexpectedly interact to reduce the blood sugar level in a subject.
- the enhanced bioavailability of the components of the nutraceutical composition, comprising Aronia and tart cherry juices that are fortified with Aronia and tart cherry extract unexpectedly interact to maintain the blood sugar level in a subject.
- compositions comprise components that interact to reduce or maintain blood sugar levels in a subject for the prophylaxis of prediabetes or diabetes mellitus.
- Definitions [0032] 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 to which this invention belongs. 8 71740679.2 [0033] As used herein, the term “about” refers to an approximately +/-10% variation from a given value. It is to be understood that such a variation is always included in any given value provided herein, whether or not it is specifically referred to.
- the term “nutraceutical(s)” as used herein refers to a substance that is a food or a part of a food, such as an extract, and contains phytochemicals that are able to induce medical and health benefits.
- polyphenols as used herein refers to the group of plant-derived phytochemicals that can be generally categorized into four main groups: flavonoids, phenolic acids, stilbenes, and lignans.
- polyphenol gut metabolites refers to the polyphenol metabolites of the gut microbiota.
- subject as used herein refers to both human and non-human animals.
- the term “preventing” as used herein refers to reducing the risks associated with developing a disease, including reducing the onset of the disease.
- the term “prevention” or “prophylaxis” may be used herein to refer to an individual known to be at high risk of 9 71740679.2 developing a disease or in a population at large for maintaining good health, for example, maintaining normal blood sugar levels.
- HbA1c hemoglobin A1c
- the term “hemoglobin A1c (HbA1c)” as used herein refers to the percentage of red blood cells that have sugar-coated hemoglobin.
- the HbA1c is measured with a blood test using known methods and indicates an average blood sugar (glucose) level of a subject.
- glucose glucose
- the combination of the extracts with the corresponding juice enhances the bioavailability of the polyphenol gut metabolites.
- the combination of the extracts with the corresponding juice unexpectedly interact to reduce the blood sugar level in a subject.
- the enhanced bioavailability of the components of the nutraceutical composition, comprising Aronia and tart cherry juices that are fortified with Aronia and tart cherry extract unexpectedly interact to maintain the blood sugar level in a subject.
- the compositions comprise components that interact to reduce or maintain blood sugar levels in a subject for the prophylaxis of prediabetes or diabetes mellitus.
- the composition may also comprise additional nutraceutical extracts, wherein said composition enhances the absorption of micronutrients from the additional nutraceutical extracts.
- Fortified Aronia Juice 10 71740679.2 Aronia, also known as chokeberry, is known to contain very high concentrations of polyphenols having antioxidant and radical scavenging properties. Aronia is a deciduous shrub which belongs to the plant family Rosaceae. Within the genus Aronia several species and hybrids are known, such as Aronia melanocarpa (black chokeberry), Aronia arbutifolia (red chokeberry), and Aronia x prunifolia (purple chokeberry).
- the Aronia extract and juice originate from an Aronia species which is pharmaceutically and nutraceutically acceptable or is a mixture of different pharmaceutically or nutraceutically acceptable Aronia species.
- Aronia species that may be used include, but are not limited to A. melanocarpa, A. arbutifolia, and A. x prunifolia.
- the extract and juice are from Aronia melanocarpa.
- the extract and juice are from Aronia melanocarpa rubinia.
- the polyphenol content may vary depending on the maturity of the Aronia berries and the growing conditions of the plant.
- the Aronia plant and fruit may be obtained from various parts of the world, including northern Europe and North America.
- the Aronia extract and juice are derived from the fruit of A. melanocarpa, which may contain between 500 to 2000 mg of polyphenol per 100 mL of juice.
- the polyphenol content is between 400 to 900 mg per 100 mL of juice.
- the polyphenol content is between 600 to 900 mg per 100 mL of juice.
- the Aronia extract may be derived from the whole fruit or from parts of the fruit.
- the extract may be produced from the pomace of the fruit, fresh fruit, dried fruit, or fruit juice.
- the Aronia extract may be obtained according to any suitable extraction method.
- the Aronia extract is prepared by ultrasound, microwave, and pressure assisted extraction. In other embodiments, the Aronia extract is prepared by solvent (ethanol) extraction and the solvent evaporated according to methods known in the art to produce a dry, water-soluble, extract. 11 71740679.2 [0048]
- the Aronia juice may be prepared from the whole fruit or from parts of the fruit. In certain embodiments, the Aronia juice is prepared from the whole fruit in order to retain the full spectrum of fruit sugars, nutrients, vitamins and minerals found in the whole fruit juice.
- the Aronia juice may be obtained according to any suitable juice extraction method.
- the Aronia juice can be prepared by known methods of steam extraction, hot press extraction, cold press extraction, with or without macerating enzyme treatment.
- the Aronia juice is prepared at low temperatures to maintain the integrity of the micronutrients and phytochemicals in the juice.
- the Aronia juice is prepared by cold press extraction.
- the whole Aronia fruit is pressed without heat to allow the release of polyphenols and other berry bioactives from the berry skin.
- the Aronia juice is further pasteurized or sterilized at low temperatures.
- the Aronia juice is fortified with Aronia extract.
- the Aronia extract is a liquid concentrate and is combined with the Aronia juice.
- the Aronia extract is a dry powder that is dissolved in the Aronia juice.
- the fortified Aronia juice comprises from at least about 100 mg to about 4000 mg of Aronia extract per 100 mL of Aronia juice.
- the fortified Aronia juice comprises from at least about 200 mg to about 3500 mg, from at least about 300 mg to about 3000 mg, from at least about 400 mg to about 2500 mg, from at least about 500 mg to about 2000 mg, from at least about 600 mg to about 1500 mg, and from at least about 700 mg to about 1000 mg of Aronia extract per 100 mL of Aronia juice.
- the fortified Aronia juice comprises about 500 mg of Aronia extract per 100 ml of Aronia juice.
- the fortified Aronia juice comprises about 1,000 mg to about 3,000 mg of Aronia extract per 100 ml of Aronia juice.
- the fortified Aronia juice of the present invention comprises Aronia extract in a concentration from at least about 1 mg/mL to about 40 mg/mL, from about 2 mg/mL to about 35 mg/mL, from about 3 mg/mL to about 30 12 71740679.2 mg/mL, from about 4 mg/mL to about 25 mg/mL, and from about 6 mg/mL to about 15 mg/mL.
- Tart cherry, sour cherry, or also referred to as dwarf cherry is a species of Prunus in the subgenus Cerasus of the plant family Rosaceae. Tart cherries have been shown to be a source of several beneficial micronutrients, particularly vitamin C, anthocyanins, and melatonin. According to certain embodiments, the Malawin Oblacinska variety of tart cherry is identified as a suitable variety of tart cherry juice and/or extract. [0052]
- the tart cherry extract may be derived from the whole fruit or from parts of the fruit. For example, according to embodiments, the extract may be produced from the pomace of the fruit, fresh fruit, dried fruit, or fruit juice.
- the tart cherry extract may be obtained according to any suitable extraction method.
- the tart cherry extract is prepared by ultrasound, microwave, and pressure assisted extraction.
- the tart cherry extract is prepared by solvent (ethanol) extraction and the solvent evaporated according to methods known in the art to produce a dry, water- soluble, extract.
- the tart cherry juice may be prepared from the whole fruit or from parts of the fruit.
- the tart cherry juice is prepared from the whole fruit in order to retain the full spectrum of fruit sugars, nutrients, vitamins and minerals found in the whole fruit juice.
- the tart cherry juice may be obtained according to any suitable juice extraction method.
- the tart cherry juice can be prepared by known methods of steam extraction, hot press extraction, cold press extraction, with or without macerating enzyme treatment.
- the tart cherry juice is prepared at low temperatures in order to maintain the integrity of the micronutrients and phytochemicals in the juice.
- the tart cherry juice is prepared by cold press extraction.
- the whole tart cherry fruit is pressed without heat to 13 71740679.2 allow the release of polyphenols and other bioactives from the skin of the fruit.
- the tart cherry juice is further pasteurized or sterilized at low temperatures.
- the tart cherry juice is fortified with tart cherry extract.
- the tart cherry extract is a liquid concentrate and is combined with the tart cherry juice.
- the tart cherry extract is a dry powder that is dissolved in the tart cherry juice.
- the fortified tart cherry juice comprises from at least about 100 mg to about 5000 mg of tart cherry extract per 100 mL of tart cherry juice.
- the fortified tart cherry juice comprises from at least about 50 mg to about 4500 mg, from at least about 150 mg to about 3000 mg, from at least about 375 mg to about 2500 mg, from at least about 500 mg to about 2000 mg, from at least about 600 mg to about 1500 mg, and from at least about 700 mg to about 1000 mg of tart cherry extract per 100 mL of tart cherry juice.
- the fortified tart cherry juice comprises about 1,000 mg to about 3,000 mg of tart cherry extract per 100 mL of tart cherry juice.
- the fortified tart cherry juice of the present invention comprises tart cherry extract in a concentration from at least about 1 mg/mL to about 50 mg/mL, from about 0.5 mg/mL to about 25 mg/mL, from about 5 mg/mL to about 20 mg/mL, from about 6 mg/mL to about 15 mg/mL, and from about 7 mg/mL to about 10 mg/mL.
- Fortified Aronia and Tart Cherry Juice [0056] According to embodiments, the composition of the present invention is prepared by combining the Aronia-extract-fortified Aronia juice and the tart cherry-extract-fortified tart cherry juice.
- the composition comprises a volume ratio of fortified Aronia juice to fortified tart cherry juice in a 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, or 10:1 volume ratio.
- the 14 71740679.2 composition comprises a volume ratio of fortified Aronia juice to fortified tart cherry juice in a 1:1, 2:1, or 4:1 volume ratio.
- the composition comprises a volume ratio of fortified tart cherry juice to fortified Aronia juice in a 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, or 10:1 volume ratio.
- the composition comprises a volume ratio of fortified tart cherry juice to fortified Aronia juice in a 1:1, 2:1, or 4:1 volume ratio.
- the composition of Aronia- extract-fortified Aronia juice and tart cherry-extract-fortified tart cherry juice comprises from at least about 100 mg to about 4000 mg of Aronia extract and from at least about 20 mg to about 5000 mg of tart cherry extract per 100 mL.
- the composition comprises from at least about 200 mg to about 3500 mg, from at least about 300 mg to about 3000 mg, from at least about 400 mg to about 2500 mg, from at least about 500 mg to about 2000 mg, from at least about 600 mg to about 1500 mg, or from at least about 700 mg to about 1000 mg of Aronia extract per 100 mL, and from at least about 50 mg to about 4500 mg, from at least about 150 mg to about 3000 mg, from at least about 375 mg to about 2500 mg, from at least about 500 mg to about 2000 mg, from at least about 600 mg to about 1500 mg, or from at least about 700 mg to about 1000 mg of tart cherry extract per 100 mL.
- the composition comprises about 2000 mg of Aronia extract and about 1500 mg of tart cherry extract per 100 mL.
- ADDITIONAL MICRONUTRIENTS AND BIOACTIVE PHYTOCHEMICALS [0059] According to embodiments of the present invention, it is contemplated that the combination of Aronia and tart cherry extracts with the corresponding juice provides a synergistic effect that enhances the bioavailability of polyphenol and/or polyphenol gut metabolites, and enhances absorption of micronutrients and bioactive phytochemicals.
- the composition of Aronia juice fortified with Aronia extract, and tart cherry juice fortified with tart cherry extract may also comprise additional nutraceutical extracts. In certain embodiments, the additional extracts comprise additional 15 71740679.2 polyphenols.
- the additional micronutrients and bioactive phytochemicals may be provided as one or more active compounds from the group of vitamins, minerals, and trace minerals.
- the additional micronutrient and bioactive phytochemicals may be provided in synthetic or plant-derived form.
- the additional micronutrients and bioactive phytochemicals comprise polyphenols.
- the polyphenols comprise quercetin, resveratrol, fisetin, spermidine, ellagic acid, ellagitannins, and/or anthocyanins apigenin.
- the additional micronutrients are bioactive phytochemicals comprising, for example, alkaloids, and other active compounds.
- the bioactive phytochemicals comprise berberine, urolithin A, NMN (Nicotinamide Mononucleotide), and/or Ca-AKG (Calcium Alpha-Ketoglutarate).
- the additional micronutrients and bioactive phytochemicals are provided as one or more nutraceutical extracts.
- the additional micronutrients and bioactive phytochemicals may be provided as any one or more of the following nutraceutical extracts.
- Beetroot Extract has a high nitrate and antioxidant (betanin) content. Beetroot extract may increase in vivo nitric oxide (NO) bioavailability, enhance endothelial function, improve blood flow and enhance physical performance, as well as combat damaging reactive oxygen species.
- Rosehip Extract 16 71740679.2 [0063] Rosehip extract has a particularly high vitamin C, carotenoid (lycopene), and polyphenol content, which are all beneficial in fighting inflammation and protecting the immune system from viral and bacterial infection.
- Chamomile Extract is traditionally used for its calming effects and is thought to aid in combating depression and anxiety with its unique content of apigenin, an antioxidant that promotes sleepiness, improves sleep quality and reduces insomnia. In addition, chamomile extract is thought to improve gastrointestinal and cardiovascular health, and lower blood pressure.
- Lemon Balm Extract [0065] Lemon balm (Melissa officinalis) is a powerful herb from the mint family that is thought to reduce stress and anxiety, and improve mood and sleep quality. Lemon balm extract is high in flavonoids, phenolic compounds, as well as antioxidants such as rosmarinic and gallic acid, which all help to combat inflammation, promote gastrointestinal health and boost cognitive function.
- Lion’s Mane Mushroom Extract [0066] Lion’s mane mushroom is a medicinal mushroom believed to offer a range of health benefits, including reduced inflammation and improved cognitive and heart health.
- Reishi Mushroom Extract [0067] Reishi mushroom is a polypore fungus belonging to the genus Ganoderma (Ganoderma lucidum) and is considered to be a medicinal mushroom in many Asian cultures for its health-promoting effects. Reishi mushroom is thought to have immunomodulatory, renoprotective, anti-inflammatory, and hepatoprotective properties.
- Natural Wild Species Parsley Extract 17 71740679.2 [0068] The two main groups of parsley are curly leaf (i.e.,P. crispum crispum group; syn. P. crispum var.
- CBD cannabidiol [0069] CBD, particularly from hemp, has a variety of vitamins and minerals such as vitamins A, C, E and B complex, as well as zinc, potassium, iron, calcium, essential amino acids, and omega 3 and 6 fatty acids.
- the composition of Aronia- extract-fortified Aronia juice and tart cherry-extract-fortified tart cherry juice further includes one or more additional nutraceuticals selected from red beet extract, rosehip extract, chamomile extract, Melissa officinalis, lemon balm extract, lion’s mane mushroom extract, reishi mushroom extract, parlsley, cannabidiol (CBD), or any combination of these extracts.
- additional nutraceuticals selected from red beet extract, rosehip extract, chamomile extract, Melissa officinalis, lemon balm extract, lion’s mane mushroom extract, reishi mushroom extract, parlsley, cannabidiol (CBD), or any combination of these extracts.
- the one or more additional nutraceutical extracts are added to the Aronia-extract-fortified Aronia juice and tart cherry-extract-fortified tart cherry juice composition in the following ranges, from at least about 50 mg to 5000 mg of red beet extract, from at least about 20 mg to 5000 mg of rosehip extract, from at least about 10 mg to 2000 mg of chamomile extract, from at least about 10 mg to 3000 mg of Melissa officinalis, from at least about 10 mg to 4000 mg of lemon balm extract, from at least about 100 mg to 1500 mg of lion’s mane mushroom extract, from at least about 100 mg to 1500 mg of reishi mushroom extract, and/or from at least about 1 mg to 300 mg of cannabidiol (CBD) per 100 mL.
- CBD cannabidiol
- the composition includes one or both of the additional nutraceutical extracts selected from red beet extract, lion’s mane mushroom extract, and/or rosehip extract.
- the composition includes from about 50 mg to 5000 mg of red beet extract, and/or from about 20 mg to 5000 mg of rosehip extract, and/or from about 100 mg to 1500 mg of lion’s mane mushroom extract per 100 mL.
- the Aronia-extract-fortified Aronia juice and tart cherry-extract- fortified tart cherry juice composition further includes about 1000 mg of red beet extract, and/or about 1000 mg of rosehip extract, and/or about 1000 mg of lion’s mane mushroom extract, and/or about 300-1000 mg of wild form of parsley extract per 100 mL.
- the Aronia-extract- fortified Aronia juice and tart cherry-extract-fortified tart cherry juice composition further includes one or more additional nutraceutical extracts that comprise one or more of rosehip extract, chamomile extract, reishi mushroom extract, and lemon balm extract.
- the one or more additional nutraceutical extracts are added to the Aronia- extract-fortified Aronia juice and tart cherry-extract-fortified tart cherry juice composition in the following ranges, from at least about 20 mg to 5000 mg of rosehip extract, from at least about 10 mg to 2000 mg of chamomile extract, from at least about 100 mg to 1500 mg of reishi mushroom extract, and/or from at least about 10 mg to 4000 mg of lemon balm extract per 100 mL.
- the Aronia-extract-fortified Aronia juice and tart cherry-extract-fortified tart cherry juice composition further includes about 1000 mg of rosehip extract, 700 mg of chamomile extract, 1000 mg of reishi mushroom extract, and/or 500 mg of lemon balm extract, and/or about 300-1000 mg of wild form of parsley extract per 100 mL.
- the formulation comprises Aronia-extract-fortified Aronia juice, tart cherry-extract-fortified tart cherry juice, with at least about 50 mg to 5000 mg of red beet extract, about 20 mg to 5000 mg of rosehip extract, about 10 mg to 2000 mg of chamomile extract, and 100 mg to 1500 mg of lion’s mane mushroom extract per 100 mL.
- the formulation comprises Aronia-extract-fortified 19 71740679.2 Aronia juice, tart cherry-extract-fortified tart cherry juice, with at least about 10 mg to 2000 mg of chamomile extract, at least about 10 mg to 4000 mg of lemon balm extract, at least about 100 mg to 1500 mg of reishi mushroom extract per 100 mL.
- the additional nutraceuticals added to the Aronia-extract-fortified Aronia juice and tart cherry-extract- fortified tart cherry juice composition further includes cannabidiol (CBD).
- CBD cannabidiol
- the Aronia-extract-fortified Aronia juice and tart cherry- extract-fortified tart cherry juice composition includes one or more of from at least about 20 mg to 5000 mg of rosehip extract, from at least about 10 mg to 2000 mg of chamomile extract, from at least about 10 mg to 4000 mg of lemon balm extract, from at least about 100 to 1500 mg of reishi mushroom extract, from at least about 300 to1000 mg of wild form of parsley, and from at least about 1 mg to 300 mg of cannabidiol (CBD) per 100 mL.
- CBD cannabidiol
- the Aronia-extract-fortified Aronia juice and tart cherry- extract-fortified tart cherry juice composition further includes one or more additional nutraceuticals selected from about 100mg to 2,000mg of resveratrol extract, about 100mg to 1,000mg of quercetin extract, about 100mg to 1,000mg of fisetin extract, 100mg to 3,000mg of berberine extract, about 100mg to 3,000mg of urolithin A, about 100mg to 3,000mg of NMN, about 100mg to 3,000mg of Ca-AKG, about 10mg to 3,000mg of spermidine extract, and/or about 100mg to 3,000mg of TMG.
- additional nutraceuticals selected from about 100mg to 2,000mg of resveratrol extract, about 100mg to 1,000mg of quercetin extract, about 100mg to 1,000mg of fisetin extract, 100mg to 3,000mg of berberine extract, about 100mg
- the Aronia-extract-fortified Aronia juice and tart cherry-extract-fortified tart cherry juice composition can be formulated as a nutritional supplement for oral consumption.
- the formulation comprises the Aronia- extract-fortified Aronia juice and tart cherry-extract-fortified tart cherry juice composition 20 71740679.2 as described herein, formulated as an oral supplement.
- the formulation comprises the Aronia-extract-fortified Aronia juice and tart cherry-extract- fortified tart cherry juice composition in combination with one or more additional nutraceutical extracts as described herein, formulated as an oral supplement.
- the formulation comprises the Aronia-extract-fortified Aronia juice and tart cherry-extract-fortified tart cherry juice composition in combination with one or more additional polyphenol-containing extract.
- the composition according to the present invention may be formulated in a liquid form, i.e., for example in the form of solutions, dispersions, emulsions and gels, or in a solid form.
- the composition is formulated as a capsule, a tablet, a liquid concentrate, a liquid drink, or a powder.
- the composition is formulated as a liquid drink, syrup, tonic, or jelly.
- the composition is formulated as an edible solid or an edible semi-solid.
- the formulation is a powder reconstituted into potable liquid (i.e. water, etc.).
- additional components can be added to the formulation to provide colour, flavour, texture, scent, etc.
- the formulation comprises additional components that act as preservatives or stabilize one or more of the ingredients.
- METHODS AND USE Also within the scope of the invention are methods for treating and/or preventing and/or aiding the treatment and/or prevention of diseases and/or conditions associated with high blood sugar.
- the methods comprise managing, reducing, or maintaining blood sugar levels in a subject for the prophylaxis of prediabetes or diabetes mellitus.
- the methods comprise preventing or reducing side effects associated with high blood sugar, for example, moodiness, fatigue, and headaches.
- the method comprises the maintenance of blood sugar levels below 21 71740679.2 prediabetes levels for the prevention or prophylaxis of prediabetes in an individual known to be at high risk of developing diabetes.
- the methods comprise maintaining normal sugar levels in a subject for the maintenance of general overall good health.
- the methods comprise administering to a subject, an amount of the composition effective to treat, prevent, or aid in the treatment or prevention, or achieve at least the beneficial effect of reducing or maintaining blood sugar levels.
- the methods may further comprise determining the effectiveness of the treatment by, for example, determining blood sugar levels within known targets.
- the method comprises administering an amount of the composition effective to reduce or maintain the blood sugar level of a subject within the normal HbA1c range of 5.6% or less. In other embodiments, the method comprises administering an amount of the composition effective to reduce or maintain the blood sugar level of a subject below the HbA1c range of 5.7% to 6.4% (prediabetes). According to other embodiments, the method comprises administering an amount of the composition effective to prevent the blood sugar level of a subject from exceeding an HbA1c range of 5.7% to 6.4%. [0082]
- the composition may be administered to a healthy subject for prophylactic purposes or to a subject in need of a treatment or being predisposed to high blood sugar levels.
- a method of enhancing absorption of a polyphenol into the blood of a subject comprises administering to the subject an Aronia- extract-fortified Aronia juice and tart cherry-extract-fortified tart cherry juice composition.
- the effective amount may be determined by a person skilled in the art using the guidance provided herein and the general knowledge in the art. It will be appreciated that the amount to be administered depends on the subject to be treated taking into account age, 22 71740679.2 weight and other personal conditions.
- the treatments/preventive administration may be continued as a regimen, e.g., daily, monthly, bimonthly, biannually, annually, or in some other regimen, as determined by the skilled medical practitioner for such time as is necessary.
- the composition is administered daily, most preferably two or three times a day, for example, morning and evening to maintain the levels of the effective compounds in the body of the subject.
- the composition may be administered for at least about 30 to about 60 days. These regimens may be repeated periodically.
- the composition is taken at least once a day for 1 week to 12 months. In other embodiments, the composition is taken at least once a day for 1, 2, 3, or 4 weeks.
- composition is taken at least once a day for 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months.
- EXAMPLE 1 IDENTIFICATION OF THE SYSTEMIC EFFECT OF FORTIFIED ARONIA-TART CHERRY FORMULATION
- core formulation fortified aronia-tart cherry formulation
- the formulation consisted of aronia also known as chokeberry (Aronia melanocarpa) and tart cherry (Prunus cerasus) mother juices combined in a 4:1 ratio 23 71740679.2 (volume/volume) enriched with polyphenol-rich dry extracts from both of these fruits, total of 1000 mg od polyphenols.
- the parameters observed in this preliminary study include: blood count parameters, markers of kidney and liver function, anthropometric parameters, blood pressure, metabolic parameters (blood lipid profiles, blood sugar), markers of cardiovascular risk, intestinal permeability, inflammatory biomarkers, antioxidant defense parameters and erythrocyte fatty acid profiles.
- Study participants were not on special dietary regimens (e.g., vegan and vegetarian) and did not report allergy or intolerance to berries or chokeberry/tart cherry formulation components.
- the study participants were instructed to consume a daily dose of 60 ml of core formulation after breakfast. During the study, participants were asked to maintain their habitual diet and physical activity but abstain from berries and berry-derived products other than the test drink and avoid excess amounts of other polyphenol rich-foods and alcohol.
- trained staff conducted structured interviews with study subjects and collected data using a food frequency questionnaire and repeated 24 71740679.2 24-hour dietary recalls. Adherence to dietary restrictions was monitored by regular contact with members of the research team and unannounced 24-hour dietary recall checks.
- Venous blood was drawn in the morning (8:00-9:00 a.m.) after an overnight fast, at three time points: before the consumption (Baseline, T0), after 3-weeks (short-term, T1), and after 3 months (long-term, T2) of core formulation consumption.
- Blood was collected into the appropriate sample tubes and further processed to obtain serum and plasma samples. Biochemical parameters were determined in fresh serum samples using the clinical biochemistry analyzer. Plasma samples were used to evaluate intestinal permeability and inflammatory parameters by ELISA assays.
- Whole blood was used to assess hematological parameters by the hematology analyzer and the antioxidant defense parameters by commercial kits. Erythrocyte fatty acid profiles in the total lipid pool were determined by gas chromatography.
- Hematological parameters assessed include leukocyte count and differential, erythrocyte count, platelet count, hemoglobin concentration, hematocrit (packed cell volume), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC).
- Kidney function was assessed for ability to perform normal functions like clearing waste products (serum urea (BUN), creatinine, uric acid levels) and maintaining the electrolyte balance (serum sodium, potassium, and chloride levels).
- BUN serum urea
- uric acid levels a parameter that influences the production of core formulation for 3 months.
- Serum concentrations of uric acid are known to directly increase blood sugar level by inducing insulin resistance. As such, the reduction in this parameter indicates a positive influence in controlling blood 27 71740679.2 sugar levels at normal levels.
- the core formulation consumption did not induce significant alterations in other evaluated kidney function parameters.
- liver function was assessed by observing how well the liver is performing its regular function like producing protein (serum albumin, total protein levels) and clearing bilirubin, as well as the measurement of enzymes that liver cells release in response to damage, including serum alanine transaminase (ALT), aspartate transaminase (AST) and lactate dehydrogenase (LDH).
- ALT serum alanine transaminase
- AST aspartate transaminase
- LDH lactate dehydrogenase
- VCAM-1 vascular cell adhesion protein 1
- ICAM-1 intercellular adhesion molecule 1
- ECM-1 endothelin-1
- TNF ⁇ tumor necrosis factor alpha
- IL-6 interleukin 6
- Oxidative stress/antioxidant defense was evaluated as 1) activities of enzymes involved in antioxidant protection: glutathione peroxidase (GPx), superoxide dismutase 32 71740679.2 (SOD), and catalase (CAT); and 2) index of lipid peroxidation determined as thiobarbituric acid-reactive substances (TBARS) expressed as malondialdehyde (MDA) equivalents.
- GPx glutathione peroxidase
- SOD superoxide dismutase 32 71740679.2
- CAT catalase
- index of lipid peroxidation determined as thiobarbituric acid-reactive substances (TBARS) expressed as malondialdehyde (MDA) equivalents.
- ICAM-1 a marker of endothelial dysfunction
- plasma zonulin A significant reduction in junctional protein levels, ICAM-1 (a marker of endothelial dysfunction) and plasma zonulin, suggest that long-term consumption of the aronia/tart cherry core formulation improved intestinal permeability leading to tighter cell junctions and less water and nutrient loss. The resulting systemic effects of this were further shown by a significant effect on the total, intra and extracellular water in both legs and lowered diastolic blood pressure, suggesting potential anticellulite and blood pressure modulating effects of the studied formulation.
- the test drink also showed increased variables associated with anemia and the health of the hemoglobin in the blood (MCH, MCHC) and reduced uric acid levels, a parameter associated with the development of hypertension, metabolic syndrome, and diabetes mellitus.
Abstract
A composition for reducing or maintaining blood sugar levels in a subject for the prophylaxis of prediabetes or diabetes mellitus, comprising a combination of Aronia juice fortified with Aronia extract, and tart cherry juice fortified with tart cherry extract, and methods for reducing or maintaining blood sugar levels in a subject for the prophylaxis of prediabetes or diabetes mellitus, are provided.
Description
COMPOSITIONS AND METHODS FOR THE MANAGEMENT OF BLOOD SUGAR LEVELS FOR THE PROPHYLAXIS OF PREDIABETES AND DIABETES MELLITUS FIELD OF THE INVENTION [0001] The present invention relates to the field of nutraceuticals and dietary supplement compositions and, in particular, to compositions comprising Aronia juice fortified with Aronia extract, and tart cherry juice fortified with tart cherry extract, and methods for managing blood sugar levels to prevent or manage the onset of prediabetes and diabetes mellitus. BACKGROUND OF THE INVENTION [0002] Managing blood sugar levels is essential to maintaining good health and preventing serious health problems. Too much sugar in the blood for a prolong period of time can lead to serious health problems that include heart disease, vision loss, kidney disease, and nerve damage. Moreover, when levels of blood sugar continually become elevated, the excess glucose in the bloodstream stimulates the pancreas to release insulin. Over time, the body stops responding to insulin due to chronic high blood sugar, causing insulin resistance and keeping blood sugar high. Chronically high blood sugar levels have, therefore, been reported to increase the risk of developing prediabetes that can lead to diabetes (type 2). [0003] Prediabetes is a preventable and potentially reversible diabetes condition. Prediabetes occurs when blood sugar levels are higher than normal (typically between 5.7 to 6.4% (HbA1c)) but the blood sugar levels aren't high enough to be considered diabetes (typically 6.5% or above (HbA1c)). If not managed, prediabetes can lead to diabetes. 1 71740679.2
[0004] More than half a billion people are living with diabetes worldwide, affecting men, women, and children of all ages in every country, and that number is projected to more than double to 1.3 billion people by 2055, with every country seeing an increase. The latest and most comprehensive calculations show the current global prevalence rate is 6.1%, making diabetes one of the top 10 leading causes of death and disability. [0005] Modifiable diabetes risk has been associated with poor quality diet, smoking, and physical inactivity. As such, the role of diets rich in bioactive compounds in preventing diabetes has been of interest; in particular, bioactive compounds such as polyphenols. [0006] Despite the potential benefits of such bioactive compounds on the prevention of diabetes, the efficacy in their application has been limited by the limited bioavailability of such compounds when ingested. Polyphenols, specifically, are largely metabolized following ingestion, with polyphenols being metabolized in the stomach, small and large intestine, and liver. As a result, the therapeutic benefits of such compounds are never realized. [0007] The key to the therapeutic efficacy of such bioactive compounds is bioavailability and absorption of the bioactives. Specifically, bioavailability is dependent on the absorption of the micronutrients by the epithelial layer of the gut, and the chemical and biochemical transformations into epithelial cells. These processes are endogenous factors that greatly influence the bioavailability of bioactive compounds. Ensuring bioavailability is challenging due to the nature of both the bioactive compounds and the digestive tract of the consumer. As a result, the efficacy of bioactive compounds in nutraceuticals and dietary supplements, is limited at best, and unpredictable. [0008] New compositions and methods that address the shortcomings of existing nutraceuticals are, therefore, needed to realize the prophylactic and/or therapeutic effects of bioactive compounds for managing blood sugar levels to prevent or manage the onset of prediabetes and diabetes mellitus. 2 71740679.2
[0009] This background information is provided for the purpose of making known information believed by the applicant to be of possible relevance to the present invention. No admission is necessarily intended, nor should be construed, that any of the preceding information constitutes prior art against the present invention. SUMMARY OF THE INVENTION [0010] An object of the present invention is to provide compositions and methods for the management of blood sugar levels in a subject, for the prophylaxis of prediabetes and diabetes mellitus. In accordance with one aspect of the invention, there is provided a composition comprising Aronia juice fortified with Aronia extract in combination with tart cherry juice fortified with tart cherry extract. In accordance with another aspect, the composition of the present invention further comprises one or more additional nutraceuticals. [0011] In accordance with another aspect of the invention, there is provided a composition comprising Aronia juice fortified with Aronia extract in combination with tart cherry juice fortified with tart cherry extract, wherein said juices and extracts interact to enhance bioavailability of polyphenols and/or polyphenol gut metabolites from said extracts. [0012] In accordance with another aspect of the invention, there is provided a formulation for reducing or maintaining blood sugar levels in the prophylaxis of prediabetes or diabetes mellitus, comprising Aronia juice fortified with Aronia extract, and tart cherry juice fortified with tart cherry extract. [0013] In accordance with another aspect of the invention, there is provided a method for reducing or maintaining blood sugar levels in a subject for the prophylaxis of prediabetes or diabetes mellitus, comprising administering a therapeutically effective amount of a composition comprising Aronia juice fortified with Aronia extract, and tart cherry juice fortified with tart cherry extract, wherein said composition enhances the bioavailability of 3 71740679.2
polyphenols and/or polyphenol gut metabolites from said extracts. In certain embodiments, the blood sugar level is reduced or maintained within an HbA1c range of 5.6% or less. In other embodiments, the blood sugar level is reduced or maintained at an HbA1c below a range of 5.7% to 6.4%. BRIEF DESCRIPTION OF THE DRAWINGS [0014] These and other features of the invention will become more apparent in the following detailed description in which reference is made to the appended drawings. [0015] Figure 1 presents an illustration of the systemic effects resulting from the enhanced bioavailability and absorption of the polyphenol gut metabolites elicited by the composition according to embodiments of the present invention. [0016] Figure 2 is a graph presenting changes in diastolic blood pressure across three time points (baseline (T0), 3 weeks (T1) and 3 months (T2) of aronia (chokeberry)/tart cherry core formulation consumption). The graph represents results of repeated measures ANOVA of normalized data, presented as relative change from T0. **p<0.01, compared to T0; #, p<0.05, compared to T1. [0017] Figure 3 presents changes in total body water of right leg (A), left leg (B), Intracellular water of right leg (C), left leg (D), extracellular water of right leg (E) and left leg (F) across three time points (baseline (T0), 3 weeks (T1) and 3 months (T2) of aronia (chokeberry)/tart cherry core formulation consumption). The graphs represent repeated measures ANOVA analysis of normalized data, presented as relative change from T0. **p<0.01, compared to T0; #, p<0.05, compared to T1. [0018] Figure 4 presents the effect of 3-month long core formulation consumption on markers of endothelial dysfunction. Results presented as median with 25-75 percentiles (box) and 10-90 percentile range (whiskers), before and after 3-month long core formulation consumption in subjects of both sexes at increased CVD risk. n=15-17 4 71740679.2
subjects; data analyzed by Wilcoxon signed-rank test for non-normal data distribution. ***, p<0.001; ns, p>0.05. [0019] Figure 5 presents the effect of 3-month long core formulation consumption on intestinal permeability. Results presented as mean ± standard error of the mean, before and after 3-month long core formulation consumption in subjects of both sexes at increased CVD risk. n=17 subjects; data analyzed by paired t-test for normally distributed data. ***, p<0.001. [0020] Figure 6 presents the effect of 3-month core formulation consumption on oxidative stress/antioxidant defense parameters. Results presented as mean ± standard error of the mean for normally distributed data or as median with 25-75 percentiles (box) and 10-90 percentile range (whiskers) for non-normal distribution, before and after 3-month long core formulation consumption in subjects of both sexes at increased CVD risk. n=17 subjects; data analyzed by paired t-test or Wilcoxon signed-rank test. All data are not statistically significant, p>0.05. DETAILED DESCRIPTION OF THE INVENTION [0021] Polyphenols are micronutrients found in a wide range of food sources that have gained particular attention for their antioxidant properties and their role in the prevention of various diseases. Polyphenols, which constitute the active substances found in many medicinal plants, have also been found to modulate the activity of a wide range of enzymes and cell receptors. [0022] More than 8,000 types of polyphenols have been identified. They can be further categorized into 4 main groups: (i) flavonoids which account for around 60% of all polyphenols and include quercetin, kaempferol, catechins, apigenin, fisetin, proanthocyanidins, and anthocyanins; (ii) phenolic acids which account for around 30% of all polyphenols and include stilbenes and lignans; (iii) polyphenolic amides which include 5 71740679.2
capsaicinoids and avenanthramides; and (iv) other polyphenols which include resveratrol, ellagic acid, ellagitannins, resveratrol, urolithin A, curcumin, and lignans. [0023] As with all micronutrients, however, the health effects of polyphenols depend on their bioavailability. There are a number of factors that affect the absorption of polyphenols, in particular, metabolism of the polyphenols by intestinal and hepatic enzymes, catabolism of polyphenols and the production of active metabolites by intestinal microflora, and intestinal absorption, all affect the absorption of polyphenols and the polyphenol metabolites. Accordingly, in various embodiments, nutraceutical compositions are described that unexpectedly enhance the bioavailability of polyphenols and the polyphenol gut metabolites. Without being bound by theory, it is contemplated that polyphenols and the polyphenol gut metabolites are made more bioavailable in compositions that include pure fruit juice that has the full spectrum of fruit sugars, nutrients, vitamins and minerals to aid in nutrient metabolism by intestinal microflora, such as Coriobacteriia (Eggerthellaceae). [0024] In certain embodiments, the nutraceutical compositions of the present invention enhance antioxidant bioavailability in the gut by combining nutrient-rich and polyphenol- high Aronia and tart cherry juice. According to further embodiments, the nutraceutical compositions comprise Aronia and tart cherry juices that are further fortified with Aronia and tart cherry extract which together enhance polyphenol bioavailability. In certain embodiments, the nutraceutical compositions comprise a combination of Aronia juice fortified with Aronia extract in combination with tart cherry juice fortified with tart cherry extract. [0025] Enhanced bioavailability of polyphenols leads to an increase in the final active metabolites produced by gut bacterial species and subsequent intestinal absorption of the polyphenol gut metabolites. In this regard, it is believed that the nutraceutical compositions described herein alter the gut’s vascular wall to enhance absorption of micronutrients and bioactive phytochemicals. 6 71740679.2
[0026] According to certain embodiments, the nutraceutical compositions result in an increase in n3 and a decrease in n6 polyunsaturated fatty acids (PUFAs) in endothelium and vascular wall cell membranes. In further embodiments, the components of the nutraceutical compositions interact synergistically to ultimately lead to increased cell membrane fluidity through phospholipid restructuring. According to certain embodiments, this restructuring of the vascular wall cell membrane further enhances the intestinal absorption of micronutrients and bioactive phytochemicals. [0027] In further embodiments, the nutraceutical compositions described herein result in stabilization of the permeability of the gut wall thereby reducing the loss of polyphenol gut metabolites, and thus increasing the amount of bioactive components to be absorbed by the gut epithelium and underlying vasculature. In certain embodiments, the nutraceutical compositions result in the lowering of zonulin production that modulates the permeability of tight junctions between cells of the gut wall to stabilize gut wall permeability. [0028] In certain embodiments, the compositions of the present invention are combined with additional nutraceuticals to enhance their absorption. According to embodiments of the present invention, the compositions comprise Aronia juice fortified with Aronia extract in combination with tart cherry juice fortified with tart cherry extract, and further in combination with additional nutraceuticals. It is contemplated that the additional nutraceuticals can include any nutraceutical of interest. In certain embodiments, the nutraceutical compositions comprise Aronia juice fortified with Aronia extract, and tart cherry juice fortified with tart cherry extract, in combination with one or more extracts. The one or more extracts can include, for example, red beet extract, rosehip extract, chamomile extract, lemon balm extract, lion’s mane mushroom extract, reishi mushroom extract, resveratrol extract, quercetin extract, fisetin extract, berberine extract, urolithin A, NMN, Ca-AKG, spermidine extract, TMG, and/or cannabidiol (CBD). [0029] According to certain embodiments, the compositions comprise Aronia juice fortified with Aronia extract, and tart cherry juice fortified with tart cherry extract, in combination with, for example, red beet extract, lion’s mane mushroom extract, and/or 7 71740679.2
rosehip extract. In other embodiments, the compositions comprise Aronia juice fortified with Aronia extract, and tart cherry juice fortified with tart cherry extract, in combination with, for example, one or more of rosehip extract, chamomile extract, lemon balm extract, reishi mushroom extract, and/or cannabidiol (CBD). [0030] Compositions of the present invention, comprising Aronia juice fortified with Aronia extract in combination with tart cherry juice fortified with tart cherry extract, are therefore contemplated in certain embodiments for use as an absorption-enhancing carrier for micronutrients and bioactive phytochemicals derived from nutraceutical extracts. In some embodiments, the present invention provides for the use of the fortified Aronia and tart cherry juice composition prior to consumption of nutraceutical extracts. In other embodiments, the present invention provides for the use of the fortified Aronia and tart cherry juice composition as a carrier for additional nutraceutical extracts. [0031] According to further embodiments, the enhanced bioavailability of the components of the nutraceutical composition, comprising Aronia and tart cherry juices that are fortified with Aronia and tart cherry extract, unexpectedly interact to reduce the blood sugar level in a subject. In other embodiments, the enhanced bioavailability of the components of the nutraceutical composition, comprising Aronia and tart cherry juices that are fortified with Aronia and tart cherry extract, unexpectedly interact to maintain the blood sugar level in a subject. In this way, according to embodiments described herein, the compositions comprise components that interact to reduce or maintain blood sugar levels in a subject for the prophylaxis of prediabetes or diabetes mellitus. Definitions [0032] 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 to which this invention belongs. 8 71740679.2
[0033] As used herein, the term “about” refers to an approximately +/-10% variation from a given value. It is to be understood that such a variation is always included in any given value provided herein, whether or not it is specifically referred to. [0034] The use of the word “a” or “an” when used herein in conjunction with the term “comprising” may mean “one,” but it is also consistent with the meaning of “one or more,” “at least one” and “one or more than one.” [0035] As used herein, the words “comprising” (and grammatical variations thereof, such as “comprise” and “comprises”), “having” (and grammatical variations thereof, such as “have” and “has”), “including” (and grammatical variations thereof, such as “includes” and “include”) or “containing” (and grammatical variations thereof, such as “contains” and “contain”) are inclusive or open-ended and do not exclude additional, unrecited elements or method steps. [0036] The term “nutraceutical(s)” as used herein refers to a substance that is a food or a part of a food, such as an extract, and contains phytochemicals that are able to induce medical and health benefits. [0037] The term “polyphenols” as used herein refers to the group of plant-derived phytochemicals that can be generally categorized into four main groups: flavonoids, phenolic acids, stilbenes, and lignans. The term “polyphenol gut metabolites” as used herein refers to the polyphenol metabolites of the gut microbiota. [0038] The term “subject” as used herein refers to both human and non-human animals. [0039] The term “attenuate”, “inhibit”, “treat”, and “reduce” and grammatical variations thereof, as used herein, refer to a measurable decrease in a given parameter or event. [0040] The term “preventing” as used herein refers to reducing the risks associated with developing a disease, including reducing the onset of the disease. The term “prevention” or “prophylaxis” may be used herein to refer to an individual known to be at high risk of 9 71740679.2
developing a disease or in a population at large for maintaining good health, for example, maintaining normal blood sugar levels. [0041] The term “hemoglobin A1c (HbA1c)” as used herein refers to the percentage of red blood cells that have sugar-coated hemoglobin. The HbA1c is measured with a blood test using known methods and indicates an average blood sugar (glucose) level of a subject. [0042] It is contemplated that any embodiment discussed herein can be implemented with respect to any method or composition of the invention, and vice versa. FORTIFIED ARONIA AND TART CHERRY JUICE [0043] The present invention discloses a composition which comprises Aronia juice fortified with Aronia extract in combination with tart cherry juice fortified with tart cherry extract. According to embodiments, the combination of the extracts with the corresponding juice enhances the bioavailability of the polyphenol gut metabolites. In further embodiments, the combination of the extracts with the corresponding juice unexpectedly interact to reduce the blood sugar level in a subject. In other embodiments, the enhanced bioavailability of the components of the nutraceutical composition, comprising Aronia and tart cherry juices that are fortified with Aronia and tart cherry extract, unexpectedly interact to maintain the blood sugar level in a subject. In this way, according to embodiments described herein, the compositions comprise components that interact to reduce or maintain blood sugar levels in a subject for the prophylaxis of prediabetes or diabetes mellitus. [0044] The composition may also comprise additional nutraceutical extracts, wherein said composition enhances the absorption of micronutrients from the additional nutraceutical extracts. Fortified Aronia Juice 10 71740679.2
[0045] Aronia, also known as chokeberry, is known to contain very high concentrations of polyphenols having antioxidant and radical scavenging properties. Aronia is a deciduous shrub which belongs to the plant family Rosaceae. Within the genus Aronia several species and hybrids are known, such as Aronia melanocarpa (black chokeberry), Aronia arbutifolia (red chokeberry), and Aronia x prunifolia (purple chokeberry). In certain embodiments, the Aronia extract and juice originate from an Aronia species which is pharmaceutically and nutraceutically acceptable or is a mixture of different pharmaceutically or nutraceutically acceptable Aronia species. Aronia species that may be used include, but are not limited to A. melanocarpa, A. arbutifolia, and A. x prunifolia. According to other embodiments, the extract and juice are from Aronia melanocarpa. In a preferred embodiment of the present invention, the extract and juice are from Aronia melanocarpa rubinia. [0046] The polyphenol content may vary depending on the maturity of the Aronia berries and the growing conditions of the plant. According to embodiments, the Aronia plant and fruit may be obtained from various parts of the world, including northern Europe and North America. In an exemplary embodiment, the Aronia extract and juice are derived from the fruit of A. melanocarpa, which may contain between 500 to 2000 mg of polyphenol per 100 mL of juice. In certain embodiments, the polyphenol content is between 400 to 900 mg per 100 mL of juice. In further embodiments, the polyphenol content is between 600 to 900 mg per 100 mL of juice. [0047] The Aronia extract may be derived from the whole fruit or from parts of the fruit. For example, according to embodiments, the extract may be produced from the pomace of the fruit, fresh fruit, dried fruit, or fruit juice. The Aronia extract may be obtained according to any suitable extraction method. In certain embodiments, the Aronia extract is prepared by ultrasound, microwave, and pressure assisted extraction. In other embodiments, the Aronia extract is prepared by solvent (ethanol) extraction and the solvent evaporated according to methods known in the art to produce a dry, water-soluble, extract. 11 71740679.2
[0048] The Aronia juice may be prepared from the whole fruit or from parts of the fruit. In certain embodiments, the Aronia juice is prepared from the whole fruit in order to retain the full spectrum of fruit sugars, nutrients, vitamins and minerals found in the whole fruit juice. The Aronia juice may be obtained according to any suitable juice extraction method. For example, the Aronia juice can be prepared by known methods of steam extraction, hot press extraction, cold press extraction, with or without macerating enzyme treatment. In certain embodiments, the Aronia juice is prepared at low temperatures to maintain the integrity of the micronutrients and phytochemicals in the juice. According to embodiments, the Aronia juice is prepared by cold press extraction. In further embodiments, the whole Aronia fruit is pressed without heat to allow the release of polyphenols and other berry bioactives from the berry skin. In further embodiments, the Aronia juice is further pasteurized or sterilized at low temperatures. [0049] According to embodiments of the present invention, the Aronia juice is fortified with Aronia extract. In certain embodiments, the Aronia extract is a liquid concentrate and is combined with the Aronia juice. In other embodiments, the Aronia extract is a dry powder that is dissolved in the Aronia juice. In embodiments of the present invention, the fortified Aronia juice comprises from at least about 100 mg to about 4000 mg of Aronia extract per 100 mL of Aronia juice. In other embodiments, the fortified Aronia juice comprises from at least about 200 mg to about 3500 mg, from at least about 300 mg to about 3000 mg, from at least about 400 mg to about 2500 mg, from at least about 500 mg to about 2000 mg, from at least about 600 mg to about 1500 mg, and from at least about 700 mg to about 1000 mg of Aronia extract per 100 mL of Aronia juice. According to certain embodiments, the fortified Aronia juice comprises about 500 mg of Aronia extract per 100 ml of Aronia juice. In other embodiments, the fortified Aronia juice comprises about 1,000 mg to about 3,000 mg of Aronia extract per 100 ml of Aronia juice. [0050] In certain embodiments, the fortified Aronia juice of the present invention comprises Aronia extract in a concentration from at least about 1 mg/mL to about 40 mg/mL, from about 2 mg/mL to about 35 mg/mL, from about 3 mg/mL to about 30 12 71740679.2
mg/mL, from about 4 mg/mL to about 25 mg/mL, and from about 6 mg/mL to about 15 mg/mL. Fortified Tart Cherry Juice [0051] Tart cherry, sour cherry, or also referred to as dwarf cherry, is a species of Prunus in the subgenus Cerasus of the plant family Rosaceae. Tart cherries have been shown to be a source of several beneficial micronutrients, particularly vitamin C, anthocyanins, and melatonin. According to certain embodiments, the Serbian Oblacinska variety of tart cherry is identified as a suitable variety of tart cherry juice and/or extract. [0052] The tart cherry extract may be derived from the whole fruit or from parts of the fruit. For example, according to embodiments, the extract may be produced from the pomace of the fruit, fresh fruit, dried fruit, or fruit juice. The tart cherry extract may be obtained according to any suitable extraction method. In certain embodiments, the tart cherry extract is prepared by ultrasound, microwave, and pressure assisted extraction. In other embodiments, the tart cherry extract is prepared by solvent (ethanol) extraction and the solvent evaporated according to methods known in the art to produce a dry, water- soluble, extract. [0053] The tart cherry juice may be prepared from the whole fruit or from parts of the fruit. In certain embodiments, the tart cherry juice is prepared from the whole fruit in order to retain the full spectrum of fruit sugars, nutrients, vitamins and minerals found in the whole fruit juice. The tart cherry juice may be obtained according to any suitable juice extraction method. For example, the tart cherry juice can be prepared by known methods of steam extraction, hot press extraction, cold press extraction, with or without macerating enzyme treatment. In certain embodiments, the tart cherry juice is prepared at low temperatures in order to maintain the integrity of the micronutrients and phytochemicals in the juice. According to embodiments, the tart cherry juice is prepared by cold press extraction. In further embodiments, the whole tart cherry fruit is pressed without heat to 13 71740679.2
allow the release of polyphenols and other bioactives from the skin of the fruit. In further embodiments, the tart cherry juice is further pasteurized or sterilized at low temperatures. [0054] According to embodiments of the present invention, the tart cherry juice is fortified with tart cherry extract. In certain embodiments, the tart cherry extract is a liquid concentrate and is combined with the tart cherry juice. In other embodiments, the tart cherry extract is a dry powder that is dissolved in the tart cherry juice. In embodiments of the present invention, the fortified tart cherry juice comprises from at least about 100 mg to about 5000 mg of tart cherry extract per 100 mL of tart cherry juice. In other embodiments, the fortified tart cherry juice comprises from at least about 50 mg to about 4500 mg, from at least about 150 mg to about 3000 mg, from at least about 375 mg to about 2500 mg, from at least about 500 mg to about 2000 mg, from at least about 600 mg to about 1500 mg, and from at least about 700 mg to about 1000 mg of tart cherry extract per 100 mL of tart cherry juice. According to certain embodiments, the fortified tart cherry juice comprises about 1,000 mg to about 3,000 mg of tart cherry extract per 100 mL of tart cherry juice. [0055] In certain embodiments, the fortified tart cherry juice of the present invention comprises tart cherry extract in a concentration from at least about 1 mg/mL to about 50 mg/mL, from about 0.5 mg/mL to about 25 mg/mL, from about 5 mg/mL to about 20 mg/mL, from about 6 mg/mL to about 15 mg/mL, and from about 7 mg/mL to about 10 mg/mL. Fortified Aronia and Tart Cherry Juice [0056] According to embodiments, the composition of the present invention is prepared by combining the Aronia-extract-fortified Aronia juice and the tart cherry-extract-fortified tart cherry juice. In embodiments of the present invention, the composition comprises a volume ratio of fortified Aronia juice to fortified tart cherry juice in a 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, or 10:1 volume ratio. According to certain embodiments, the 14 71740679.2
composition comprises a volume ratio of fortified Aronia juice to fortified tart cherry juice in a 1:1, 2:1, or 4:1 volume ratio. [0057] In other embodiments, the composition comprises a volume ratio of fortified tart cherry juice to fortified Aronia juice in a 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, or 10:1 volume ratio. According to certain embodiments, the composition comprises a volume ratio of fortified tart cherry juice to fortified Aronia juice in a 1:1, 2:1, or 4:1 volume ratio. [0058] According to embodiments of the present invention, the composition of Aronia- extract-fortified Aronia juice and tart cherry-extract-fortified tart cherry juice comprises from at least about 100 mg to about 4000 mg of Aronia extract and from at least about 20 mg to about 5000 mg of tart cherry extract per 100 mL. In other embodiments, the composition comprises from at least about 200 mg to about 3500 mg, from at least about 300 mg to about 3000 mg, from at least about 400 mg to about 2500 mg, from at least about 500 mg to about 2000 mg, from at least about 600 mg to about 1500 mg, or from at least about 700 mg to about 1000 mg of Aronia extract per 100 mL, and from at least about 50 mg to about 4500 mg, from at least about 150 mg to about 3000 mg, from at least about 375 mg to about 2500 mg, from at least about 500 mg to about 2000 mg, from at least about 600 mg to about 1500 mg, or from at least about 700 mg to about 1000 mg of tart cherry extract per 100 mL. In certain embodiments, the composition comprises about 2000 mg of Aronia extract and about 1500 mg of tart cherry extract per 100 mL. ADDITIONAL MICRONUTRIENTS AND BIOACTIVE PHYTOCHEMICALS [0059] According to embodiments of the present invention, it is contemplated that the combination of Aronia and tart cherry extracts with the corresponding juice provides a synergistic effect that enhances the bioavailability of polyphenol and/or polyphenol gut metabolites, and enhances absorption of micronutrients and bioactive phytochemicals. In certain embodiments, the composition of Aronia juice fortified with Aronia extract, and tart cherry juice fortified with tart cherry extract may also comprise additional nutraceutical extracts. In certain embodiments, the additional extracts comprise additional 15 71740679.2
polyphenols. It is contemplated that the increased absorption of the micronutrients and bioactive phytochemicals, when combined with the composition of fortified Aronia and tart cherry juice, results in an enhanced beneficial effect. Additive Micronutrients and Bioactive Phytochemicals [0060] The additional micronutrients and bioactive phytochemicals may be provided as one or more active compounds from the group of vitamins, minerals, and trace minerals. The additional micronutrient and bioactive phytochemicals may be provided in synthetic or plant-derived form. In preferred embodiments, the additional micronutrients and bioactive phytochemicals comprise polyphenols. In certain embodiments, the polyphenols comprise quercetin, resveratrol, fisetin, spermidine, ellagic acid, ellagitannins, and/or anthocyanins apigenin. In further embodiments, the additional micronutrients are bioactive phytochemicals comprising, for example, alkaloids, and other active compounds. In certain embodiments, the bioactive phytochemicals comprise berberine, urolithin A, NMN (Nicotinamide Mononucleotide), and/or Ca-AKG (Calcium Alpha-Ketoglutarate). [0061] In further embodiments, the additional micronutrients and bioactive phytochemicals are provided as one or more nutraceutical extracts. For example, but not limited thereto, the additional micronutrients and bioactive phytochemicals may be provided as any one or more of the following nutraceutical extracts. Beetroot Extract [0062] Beetroot extract has a high nitrate and antioxidant (betanin) content. Beetroot extract may increase in vivo nitric oxide (NO) bioavailability, enhance endothelial function, improve blood flow and enhance physical performance, as well as combat damaging reactive oxygen species. Rosehip Extract 16 71740679.2
[0063] Rosehip extract has a particularly high vitamin C, carotenoid (lycopene), and polyphenol content, which are all beneficial in fighting inflammation and protecting the immune system from viral and bacterial infection. Chamomile Extract [0064] Chamomile extract is traditionally used for its calming effects and is thought to aid in combating depression and anxiety with its unique content of apigenin, an antioxidant that promotes sleepiness, improves sleep quality and reduces insomnia. In addition, chamomile extract is thought to improve gastrointestinal and cardiovascular health, and lower blood pressure. Lemon Balm Extract [0065] Lemon balm (Melissa officinalis) is a powerful herb from the mint family that is thought to reduce stress and anxiety, and improve mood and sleep quality. Lemon balm extract is high in flavonoids, phenolic compounds, as well as antioxidants such as rosmarinic and gallic acid, which all help to combat inflammation, promote gastrointestinal health and boost cognitive function. Lion’s Mane Mushroom Extract [0066] Lion’s mane mushroom is a medicinal mushroom believed to offer a range of health benefits, including reduced inflammation and improved cognitive and heart health. Reishi Mushroom Extract [0067] Reishi mushroom is a polypore fungus belonging to the genus Ganoderma (Ganoderma lucidum) and is considered to be a medicinal mushroom in many Asian cultures for its health-promoting effects. Reishi mushroom is thought to have immunomodulatory, renoprotective, anti-inflammatory, and hepatoprotective properties. Natural Wild Species Parsley Extract 17 71740679.2
[0068] The two main groups of parsley are curly leaf (i.e.,P. crispum crispum group; syn. P. crispum var. crispum) and Italian, or flat leaf (i.e., P. crispum neapolitanum group; syn. P. crispum var. neapolitanum). Of these, the neapolitanum group more closely resembles the natural wild species. It contains a variety of B vitamins including B-5 and B- 2. Parsley may also contain more vitamin K than any other herb since it has more than 1300 percent of the recommended daily intake. Parsley can be used to treat conditions like: water edema, high blood pressure, digestion. Cannabidiol (CBD) [0069] CBD, particularly from hemp, has a variety of vitamins and minerals such as vitamins A, C, E and B complex, as well as zinc, potassium, iron, calcium, essential amino acids, and omega 3 and 6 fatty acids. CBD has been reported to reduce anxiety, stress and depression, as well as improve sleep quality, pain management and overall wellness. [0070] According to embodiments of the present invention, the composition of Aronia- extract-fortified Aronia juice and tart cherry-extract-fortified tart cherry juice, further includes one or more additional nutraceuticals selected from red beet extract, rosehip extract, chamomile extract, Melissa officinalis, lemon balm extract, lion’s mane mushroom extract, reishi mushroom extract, parlsley, cannabidiol (CBD), or any combination of these extracts. In certain embodiments, the one or more additional nutraceutical extracts are added to the Aronia-extract-fortified Aronia juice and tart cherry-extract-fortified tart cherry juice composition in the following ranges, from at least about 50 mg to 5000 mg of red beet extract, from at least about 20 mg to 5000 mg of rosehip extract, from at least about 10 mg to 2000 mg of chamomile extract, from at least about 10 mg to 3000 mg of Melissa officinalis, from at least about 10 mg to 4000 mg of lemon balm extract, from at least about 100 mg to 1500 mg of lion’s mane mushroom extract, from at least about 100 mg to 1500 mg of reishi mushroom extract, and/or from at least about 1 mg to 300 mg of cannabidiol (CBD) per 100 mL. 18 71740679.2
[0071] In further embodiments, the composition includes one or both of the additional nutraceutical extracts selected from red beet extract, lion’s mane mushroom extract, and/or rosehip extract. In certain embodiments, the composition includes from about 50 mg to 5000 mg of red beet extract, and/or from about 20 mg to 5000 mg of rosehip extract, and/or from about 100 mg to 1500 mg of lion’s mane mushroom extract per 100 mL. In other embodiments, the Aronia-extract-fortified Aronia juice and tart cherry-extract- fortified tart cherry juice composition, further includes about 1000 mg of red beet extract, and/or about 1000 mg of rosehip extract, and/or about 1000 mg of lion’s mane mushroom extract, and/or about 300-1000 mg of wild form of parsley extract per 100 mL. [0072] According to other embodiments of the present invention, the Aronia-extract- fortified Aronia juice and tart cherry-extract-fortified tart cherry juice composition further includes one or more additional nutraceutical extracts that comprise one or more of rosehip extract, chamomile extract, reishi mushroom extract, and lemon balm extract. In certain embodiments, the one or more additional nutraceutical extracts are added to the Aronia- extract-fortified Aronia juice and tart cherry-extract-fortified tart cherry juice composition in the following ranges, from at least about 20 mg to 5000 mg of rosehip extract, from at least about 10 mg to 2000 mg of chamomile extract, from at least about 100 mg to 1500 mg of reishi mushroom extract, and/or from at least about 10 mg to 4000 mg of lemon balm extract per 100 mL. In further embodiments, the Aronia-extract-fortified Aronia juice and tart cherry-extract-fortified tart cherry juice composition, further includes about 1000 mg of rosehip extract, 700 mg of chamomile extract, 1000 mg of reishi mushroom extract, and/or 500 mg of lemon balm extract, and/or about 300-1000 mg of wild form of parsley extract per 100 mL. [0073] In certain embodiments, the formulation comprises Aronia-extract-fortified Aronia juice, tart cherry-extract-fortified tart cherry juice, with at least about 50 mg to 5000 mg of red beet extract, about 20 mg to 5000 mg of rosehip extract, about 10 mg to 2000 mg of chamomile extract, and 100 mg to 1500 mg of lion’s mane mushroom extract per 100 mL. In other embodiments, the formulation comprises Aronia-extract-fortified 19 71740679.2
Aronia juice, tart cherry-extract-fortified tart cherry juice, with at least about 10 mg to 2000 mg of chamomile extract, at least about 10 mg to 4000 mg of lemon balm extract, at least about 100 mg to 1500 mg of reishi mushroom extract per 100 mL. [0074] According to certain embodiments of the present invention, the additional nutraceuticals added to the Aronia-extract-fortified Aronia juice and tart cherry-extract- fortified tart cherry juice composition further includes cannabidiol (CBD). The CBD is added to the composition, according to certain embodiments, in an amount that ranges from at least about 1 mg to 300 mg per 100 mL. [0075] In certain embodiments, the Aronia-extract-fortified Aronia juice and tart cherry- extract-fortified tart cherry juice composition includes one or more of from at least about 20 mg to 5000 mg of rosehip extract, from at least about 10 mg to 2000 mg of chamomile extract, from at least about 10 mg to 4000 mg of lemon balm extract, from at least about 100 to 1500 mg of reishi mushroom extract, from at least about 300 to1000 mg of wild form of parsley, and from at least about 1 mg to 300 mg of cannabidiol (CBD) per 100 mL. [0076] In further embodiments, the Aronia-extract-fortified Aronia juice and tart cherry- extract-fortified tart cherry juice composition further includes one or more additional nutraceuticals selected from about 100mg to 2,000mg of resveratrol extract, about 100mg to 1,000mg of quercetin extract, about 100mg to 1,000mg of fisetin extract, 100mg to 3,000mg of berberine extract, about 100mg to 3,000mg of urolithin A, about 100mg to 3,000mg of NMN, about 100mg to 3,000mg of Ca-AKG, about 10mg to 3,000mg of spermidine extract, and/or about 100mg to 3,000mg of TMG. FORMULATIONS [0077] The Aronia-extract-fortified Aronia juice and tart cherry-extract-fortified tart cherry juice composition can be formulated as a nutritional supplement for oral consumption. According to certain embodiments, the formulation comprises the Aronia- extract-fortified Aronia juice and tart cherry-extract-fortified tart cherry juice composition 20 71740679.2
as described herein, formulated as an oral supplement. In other embodiments, the formulation comprises the Aronia-extract-fortified Aronia juice and tart cherry-extract- fortified tart cherry juice composition in combination with one or more additional nutraceutical extracts as described herein, formulated as an oral supplement. In further embodiments, the formulation comprises the Aronia-extract-fortified Aronia juice and tart cherry-extract-fortified tart cherry juice composition in combination with one or more additional polyphenol-containing extract. [0078] The composition according to the present invention may be formulated in a liquid form, i.e., for example in the form of solutions, dispersions, emulsions and gels, or in a solid form. In certain embodiments, the composition is formulated as a capsule, a tablet, a liquid concentrate, a liquid drink, or a powder. According to other embodiments, the composition is formulated as a liquid drink, syrup, tonic, or jelly. In further embodiments, the composition is formulated as an edible solid or an edible semi-solid. In certain embodiments, the formulation is a powder reconstituted into potable liquid (i.e. water, etc.). [0079] In some embodiments, additional components can be added to the formulation to provide colour, flavour, texture, scent, etc. In some embodiments, the formulation comprises additional components that act as preservatives or stabilize one or more of the ingredients. METHODS AND USE [0080] Also within the scope of the invention are methods for treating and/or preventing and/or aiding the treatment and/or prevention of diseases and/or conditions associated with high blood sugar. In certain embodiments, the methods comprise managing, reducing, or maintaining blood sugar levels in a subject for the prophylaxis of prediabetes or diabetes mellitus. In other embodiments, the methods comprise preventing or reducing side effects associated with high blood sugar, for example, moodiness, fatigue, and headaches. In certain embodiments, the method comprises the maintenance of blood sugar levels below 21 71740679.2
prediabetes levels for the prevention or prophylaxis of prediabetes in an individual known to be at high risk of developing diabetes. In other embodiments, the methods comprise maintaining normal sugar levels in a subject for the maintenance of general overall good health. [0081] The methods comprise administering to a subject, an amount of the composition effective to treat, prevent, or aid in the treatment or prevention, or achieve at least the beneficial effect of reducing or maintaining blood sugar levels. The methods may further comprise determining the effectiveness of the treatment by, for example, determining blood sugar levels within known targets. According to certain embodiments, the method comprises administering an amount of the composition effective to reduce or maintain the blood sugar level of a subject within the normal HbA1c range of 5.6% or less. In other embodiments, the method comprises administering an amount of the composition effective to reduce or maintain the blood sugar level of a subject below the HbA1c range of 5.7% to 6.4% (prediabetes). According to other embodiments, the method comprises administering an amount of the composition effective to prevent the blood sugar level of a subject from exceeding an HbA1c range of 5.7% to 6.4%. [0082] The composition may be administered to a healthy subject for prophylactic purposes or to a subject in need of a treatment or being predisposed to high blood sugar levels. Populations of subjects who are susceptible to developing high blood sugar levels will be apparent to one skilled in the art. [0083] A method of enhancing absorption of a polyphenol into the blood of a subject is also provided. The method, which in essence enhances the bioavalability of polyphenols that are beneficial for the subject, comprises administering to the subject an Aronia- extract-fortified Aronia juice and tart cherry-extract-fortified tart cherry juice composition. [0084] The effective amount may be determined by a person skilled in the art using the guidance provided herein and the general knowledge in the art. It will be appreciated that the amount to be administered depends on the subject to be treated taking into account age, 22 71740679.2
weight and other personal conditions. The treatments/preventive administration may be continued as a regimen, e.g., daily, monthly, bimonthly, biannually, annually, or in some other regimen, as determined by the skilled medical practitioner for such time as is necessary. Preferably, the composition is administered daily, most preferably two or three times a day, for example, morning and evening to maintain the levels of the effective compounds in the body of the subject. To obtain the most beneficial results, the composition may be administered for at least about 30 to about 60 days. These regimens may be repeated periodically. [0085] According to some embodiments, the composition is taken at least once a day for 1 week to 12 months. In other embodiments, the composition is taken at least once a day for 1, 2, 3, or 4 weeks. In further embodiments, the composition is taken at least once a day for 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months. [0086] To gain a better understanding of the invention described herein, the following examples are set forth. It will be understood that these examples are intended to describe illustrative embodiments of the invention and are not intended to limit the scope of the invention in any way. EXAMPLES EXAMPLE 1: IDENTIFICATION OF THE SYSTEMIC EFFECT OF FORTIFIED ARONIA-TART CHERRY FORMULATION [0087] The ability of the fortified aronia-tart cherry formulation (“core formulation”) to enhance bioavailability and absorption of polyphenol gut metabolites was assessed by determining the systemic effects resulting from daily consumption of the core formulation over a period of 3 months. [0088] The formulation consisted of aronia also known as chokeberry (Aronia melanocarpa) and tart cherry (Prunus cerasus) mother juices combined in a 4:1 ratio 23 71740679.2
(volume/volume) enriched with polyphenol-rich dry extracts from both of these fruits, total of 1000 mg od polyphenols. [0089] The parameters observed in this preliminary study include: blood count parameters, markers of kidney and liver function, anthropometric parameters, blood pressure, metabolic parameters (blood lipid profiles, blood sugar), markers of cardiovascular risk, intestinal permeability, inflammatory biomarkers, antioxidant defense parameters and erythrocyte fatty acid profiles. These parameters were monitored to identify the systemic effects resulting from prolonged consumption of the core formulation which reflect the bioavailability and absorption of the polyphenols. Methods i) Study participants and treatment [0090] Participants included in this study were subjects of both sexes (11 men and 6 women), mean age 43.8±2.2, with no diagnosed cardiovascular disease (CVD), with an elevated body mass index (BMI≥ 25) or abdominal obesity (waist circumference above ≥94 cm for men, ≥80 cm for women), with or without: blood pressure above optimal values (SBP/DBP ≥ 120/80 mm Hg), elevated triglycerides (≥1.7 mmol/L or ≥150 mg/dL), elevated LDL cholesterol (> 2.6 mmol/L or > 100 mg/dL), elevated total-cholesterol (≥5.0 mmol/L or ≥193 mg/dL) and reduced HDL-cholesterol (men < 1 mmol/L, women < 1.3 mmol/L). Study participants were not on special dietary regimens (e.g., vegan and vegetarian) and did not report allergy or intolerance to berries or chokeberry/tart cherry formulation components. [0091] The study participants were instructed to consume a daily dose of 60 ml of core formulation after breakfast. During the study, participants were asked to maintain their habitual diet and physical activity but abstain from berries and berry-derived products other than the test drink and avoid excess amounts of other polyphenol rich-foods and alcohol. To determine baseline dietary intake, trained staff conducted structured interviews with study subjects and collected data using a food frequency questionnaire and repeated 24 71740679.2
24-hour dietary recalls. Adherence to dietary restrictions was monitored by regular contact with members of the research team and unannounced 24-hour dietary recall checks. ii) Sample collection and processing [0092] Venous blood was drawn in the morning (8:00-9:00 a.m.) after an overnight fast, at three time points: before the consumption (Baseline, T0), after 3-weeks (short-term, T1), and after 3 months (long-term, T2) of core formulation consumption. Blood was collected into the appropriate sample tubes and further processed to obtain serum and plasma samples. Biochemical parameters were determined in fresh serum samples using the clinical biochemistry analyzer. Plasma samples were used to evaluate intestinal permeability and inflammatory parameters by ELISA assays. Whole blood was used to assess hematological parameters by the hematology analyzer and the antioxidant defense parameters by commercial kits. Erythrocyte fatty acid profiles in the total lipid pool were determined by gas chromatography. Results i) Dietary intake assessments. [0093] Dietary data were collected for two non-consecutive days within the baseline evaluation (T0), follow-up assessment, i.e., during the consumption of the provided juice (T1), and at the end of the study period (T2). Dietary assessment was based on the average values derived from repeated reports for each study point to better estimate intra-individual dietary variability over the study continuum. [0094] The results of this dietary intake analysis revealed that there was no statistically significant difference between the estimated energy and macronutrient intake with reference to the baseline assessment (Table 1). These results confirm that the dietary changes were unchanged during supplement intervention and are no reason for any biological effects. 25 71740679.2
Table 1. Changes of the mean dietary intake estimates over the three time-points of the study ii) Hematological parameters [0095] The hematological parameters assessed include leukocyte count and differential, erythrocyte count, platelet count, hemoglobin concentration, hematocrit (packed cell volume), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC). [0096] As shown in Table 2, daily consumption of core formulation induced a significant increase in MCH (the average quantity of hemoglobin in a red blood cell) and MCHC values (the content of hemoglobin per unit volume in red blood cells) over time, with significant changes observed between baseline (T0) and 3 months (T2) as well as 3-week (T1) and 3-month time points. Moreover, the observed changes in MCH remained significant when subjects were stratified according to gender (T0 vs. T2, p=0.023 for men, p=0.045 for women). Thus, these data suggest potential benefits of core formulation consumption on variables associated with anemia and the health of the hemoglobin in the blood. 26 71740679.2
Table 2. The effect of 3-month core formulation consumption on hematological parameters
[0097] Kidney function was assessed for ability to perform normal functions like clearing waste products (serum urea (BUN), creatinine, uric acid levels) and maintaining the electrolyte balance (serum sodium, potassium, and chloride levels). [0098] The consumption of core formulation for 3 months significantly reduced serum uric acid levels by 9% compared to baseline (T0 vs. T2, p=0.004). Serum concentrations of uric acid are known to directly increase blood sugar level by inducing insulin resistance. As such, the reduction in this parameter indicates a positive influence in controlling blood 27 71740679.2
sugar levels at normal levels. As presented in Table 3, the core formulation consumption did not induce significant alterations in other evaluated kidney function parameters. Table 3. The effect of 3-month core formulation consumption on parameters of kidney function
iv) Liver function parameters [0099] Liver function was assessed by observing how well the liver is performing its regular function like producing protein (serum albumin, total protein levels) and clearing bilirubin, as well as the measurement of enzymes that liver cells release in response to damage, including serum alanine transaminase (ALT), aspartate transaminase (AST) and lactate dehydrogenase (LDH). [00100] The consumption of core formulation during 3 months did not significantly affect any of the evaluated parameters of liver function (Table 4). Together with kidney function data, these results support the safety of long-term consumption of core formulation for human health. 28 71740679.2
Table 4. The effect of 3-month core formulation consumption on parameters of liver function
v) Anthropometric parameters and blood pressure [00101] Height was measured to the nearest 0.5 cm using a SECA stadiometer, and waist and hip circumferences were measured to the nearest 0.1 cm using a measuring tape. Body composition was evaluated using bioelectrical impedance analysis (BIA) – InBody 770 (Inbody Co., LTD, Seoul, Korea). During measurements, subjects wore typical athletic clothing and removed all metal jewelry. Subjects stood on the platform of the device barefoot with the soles of their feet on the electrodes and grasped the unit's handles with their thumb and fingers to maintain direct contact with the electrodes. They remained still for ~1 min with elbows fully extended, and their shoulder joint abducted to approximately a 30-degree angle. [00102] As shown in Table 5, daily consumption of chokeberry/tart cherry core formulation induced significant changes in diastolic blood pressure, total body water of right and left leg, and intra and extra-cellular water of right and left leg over time. 29 71740679.2
Table 5. The effects of consumption of chokeberry/tart cherry formulation on body composition and blood pressure
[00103] Consumption of chokeberry/tart cherry core formulation significantly decreased diastolic blood pressure after 3 months (T0 vs. T2, p=0.006; T1 vs. T2, p=0.041), while only three weeks of consumption had an insignificant but clearly noticeable downward trend (Figure 2). [00104] Values of total body water of the right (T0 vs. T2, p=0.002; T1 vs. T2, p=0.012) and left leg (T0 vs. T2, p=0.001; T1 vs. T2, p=0.017) were significantly lower after 3 months consumption compared to both baseline and 3-week time points (Figure 3A, B). Similar lowering effects were observed for intracellular water in right (T0 vs. T2, p=0.003; T1 vs. T2, p=0.010) and left leg (T0 vs. T2, p=0.001; T1 vs. T2, p=0.010) (Figure 3C, D). 30 71740679.2
Additionally, the observed values after 3-month long consumption were also significantly lower for extracellular water in both legs (Figure 3E, F) when compared to both baseline and 3 weeks of consumption (right leg: T0 vs. T2, p=0.002; T1 vs. T2, p=0.015; left leg: T0 vs. T2, p=0.004, T1 vs. T2, p=0.026). vi) Metabolic markers and blood glucose markers [00105] Blood glucose levels and hemoglobin A1C levels (HbA1c) were assessed to determine the efficacy of maintaining or reducing blood glucose levels. [00106] After a 3-month long consumption of core formulation, there was a significant decrease in serum HbA1c levels that reflect an average blood glucose content for the last two to three months (Table 6, T1 vs. T2, p=0.028). By contrast, chronic consumption of core formulation consumption did not induce significant modulations in serum glucose levels, lipid profiles (Table 6), and levels of other evaluated blood markers (Table 7) in studied subjects. Table 6. The effects of 3-week core formulation consumption on metabolic markers
31 71740679.2
Table 7. The effects of long-term core formulation consumption of core formulation on blood markers of CVD risk
vii) Parameters of endothelial dysfunction and inflammation [00107] The markers of endothelial dysfunction that were monitored include: vascular cell adhesion protein 1 (VCAM-1), intercellular adhesion molecule 1 (ICAM-1), endothelin-1 (ET-1) and inflammation: tumor necrosis factor alpha (TNFα) and interleukin 6 (IL-6). [00108] Consumption of core formulation for 3 months significantly reduced plasma ICAM-1 levels by 11.8% compared to baseline (p=0.0005) and lowered plasma VCAM-1 levels by 14.6%, although without statistical significance (p=0.1514) (Figure 4). The levels of another marker of endothelial dysfunction, ET-1, and markers of inflammation TNFα and IL-6 were below the assay detection limit for the majority of evaluated samples (both before and after 3-month long core formulation consumption, data not shown). viii) Intestinal permeability (evaluated as zonulin plasma levels) [00109] The long-term consumption of core formulation for 3 months significantly reduced plasma zonulin levels, a marker of intestinal permeability, by 28.5% compared to baseline (p=0.0002, Figure 5). ix) Parameters of oxidative stress/antioxidant defense [00110] Oxidative stress/antioxidant defense was evaluated as 1) activities of enzymes involved in antioxidant protection: glutathione peroxidase (GPx), superoxide dismutase 32 71740679.2
(SOD), and catalase (CAT); and 2) index of lipid peroxidation determined as thiobarbituric acid-reactive substances (TBARS) expressed as malondialdehyde (MDA) equivalents. [00111] Following the consumption of core formulation for 3 months, there was a slight reduction in catalase and SOD activities in erythrocytes, however, not statistically significant (p=0.086 and p=0.092, respectively) (Figure 6). Furthermore, there were no significant changes in the relative activity of GPx (p=0.7819), and index of lipid peroxidation (MDA equivalent levels) tended to be significantly reduced (p=0.074). Data from the literature show that polyphenols exert high antioxidant action in vitro. Thus, a decrease in antioxidant enzyme activities and lipid peroxidation index observed in this study could be a result of direct antioxidant effects of core formulation’s polyphenols and their metabolites, which could reduce oxidative stress and consequently lower the need for the activity of antioxidant enzymes and lipid peroxidation. Conclusions [00112] Figure 1 illustrates the systemic effects observed with consumption of the core formulation. A significant reduction in junctional protein levels, ICAM-1 (a marker of endothelial dysfunction) and plasma zonulin, suggest that long-term consumption of the aronia/tart cherry core formulation improved intestinal permeability leading to tighter cell junctions and less water and nutrient loss. The resulting systemic effects of this were further shown by a significant effect on the total, intra and extracellular water in both legs and lowered diastolic blood pressure, suggesting potential anticellulite and blood pressure modulating effects of the studied formulation. The test drink also showed increased variables associated with anemia and the health of the hemoglobin in the blood (MCH, MCHC) and reduced uric acid levels, a parameter associated with the development of hypertension, metabolic syndrome, and diabetes mellitus. Furthermore, reduced serum levels of CVD risk biomarker homocysteine, and lowered long-term blood glucose levels, were observed. The polyphenol-rich core formulation also showed a tendency to modulate oxidative stress/antioxidant defense. 33 71740679.2
[00113] The disclosures of all patents, patent applications, publications and database entries referenced in this specification are hereby specifically incorporated by reference in their entirety to the same extent as if each such individual patent, patent application, publication and database entry were specifically and individually indicated to be incorporated by reference. [00114] Although the invention has been described with reference to certain specific embodiments, various modifications thereof will be apparent to those skilled in the art without departing from the spirit and scope of the invention. All such modifications as would be apparent to one skilled in the art are intended to be included within the scope of the following claims. 34 71740679.2
Claims
THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS: 1. A composition comprising Aronia juice fortified with Aronia extract, and tart cherry juice fortified with tart cherry extract.
2. The composition according to claim 1, wherein said fortified Aronia juice and said fortified tart cherry juice are in a volume ratio of 4:1.
3. The composition according to claim 1, wherein said fortified tart cherry juice and said fortified Aronia juice are in a volume ratio of up to 4.1.
4. The composition according to claim 1, wherein said Aronia juice is fortified with 100 mg to 4000 mg of Aronia extract and said tart cherry juice is fortified with 20 mg to 5000 mg of tart cherry extract per 100 mL.
5. The composition according to claim 1, wherein said Aronia juice is fortified with 2000 mg of Aronia extract and said tart cherry juice is fortified with 1500 mg of tart cherry extract per 100 mL.
6. The composition according to claim 1, further comprising one or more additional nutraceuticals selected from the group consisting of red beet extract, rosehip extract, chamomile extract, Melissa officinalis, lemon balm extract, lion’s mane mushroom extract, reishi mushroom extract, cannabidiol (CBD), and a combination thereof.
7. The composition according to claim 6, wherein the one or more additional nutraceuticals comprise red beet extract, lion’s mane mushroom extract, and rosehip extract.
8. The composition according to claim 7, wherein said composition comprises 50 mg to 5000 mg of red beet extract, 100 mg to 1500 mg lion’s mane mushroom extract, and 20 mg to 5000 mg of rosehip extract per 100 mL. 35 71740679.2
9. The composition according to claim 7, wherein said composition comprises 1000 mg of red beet extract, 1000 mg of lion’s mane mushroom extract, and 1000 mg of rosehip extract per 100 mL.
10. The composition according to claim 6, wherein the one or more additional nutraceuticals comprise rosehip extract, chamomile extract, reishi mushroom extract, and lemon balm extract.
11. The composition according to claim 10, wherein the composition further comprises cannabidiol (CBD).
12. The composition according to claim 10, wherein said composition comprises 20 mg to 5000 mg of rosehip extract, 10 mg to 2000 mg of chamomile extract, 100 mg to 1500 mg reishi mushroom extract, and 10 mg to 4000 mg of lemon balm extract per 100 mL.
13. The composition according to claim 10, wherein said composition comprises 1000 mg of rosehip extract, 500 mg of chamomile extract, 1000 mg reishi mushroom extract, and 500 mg of lemon balm extract per 100 mL.
14. The composition according to claim 11, wherein said composition comprises 20 mg to 5000 mg of rosehip extract, 10 mg to 2000 mg of chamomile extract, 10 mg to 4000 mg of lemon balm extract, 100 mg to 1500 mg reishi mushroom extract, and 1 mg to 300 mg of cannabidiol (CBD) per 100 mL.
15. The composition according to claim 1, wherein said juices and extracts interact synergistically to enhance bioavailability of polyphenols and/or polyphenol gut metabolites from said extracts.
16. A formulation for reducing or maintaining blood sugar levels in the prophylaxis of prediabetes or diabetes mellitus, comprising Aronia juice fortified with Aronia extract, and tart cherry juice fortified with tart cherry extract. 36 71740679.2
17. The formulation according to claim 16, wherein said fortified Aronia juice and said fortified tart cherry juice are in a volume ratio of 4:1.
18. The formulation according to claim 16, wherein said fortified tart cherry juice and said fortified Aronia juice are in a volume ratio of up to 4.1.
19. The formulation according to claim 16, wherein said Aronia juice is fortified with 100 mg to 4000 mg of Aronia extract and said tart cherry juice is fortified with 20 mg to 5000 mg of tart cherry extract per 100 mL.
20. The formulation according to claim 16, wherein said Aronia juice is fortified with 2000 mg of Aronia extract and said tart cherry juice is fortified with 1500 mg of tart cherry extract per 100 mL.
21. The formulation according to any one of claims 16 to 20, wherein said formulation is formulated as a capsule, a tablet, a liquid concentrate, a liquid drink, or a powder.
22. The formulation according to any one of claims 16 to 20, wherein said formulation is formulated as a liquid drink, syrup, tonic, or jelly.
23. A method for reducing or maintaining blood sugar levels in a subject for the prophylaxis of prediabetes or diabetes mellitus, comprising administering a therapeutically effective amount of a composition comprising Aronia juice fortified with Aronia extract, and tart cherry juice fortified with tart cherry extract, wherein said composition enhances the bioavailability of polyphenols and/or polyphenol gut metabolites from said extracts.
24. The method according to claim 23, wherein said fortified Aronia juice and said fortified tart cherry juice are in a volume ratio of 4:1.
25. The method according to claim 23, wherein said fortified tart cherry juice and said fortified Aronia juice are in a volume ratio of up to 4.1. 37 71740679.2
26. The method according to claim 23, wherein said Aronia juice is fortified with 100 mg to 4000 mg of Aronia extract and said tart cherry juice is fortified with 20 mg to 5000 mg of tart cherry extract per 100 mL.
27. The method according to claim 23, wherein said Aronia juice is fortified with 2000 mg of Aronia extract and said tart cherry juice is fortified with 1500 mg of tart cherry extract per 100 mL.
28. The method of claim 27, wherein said composition is administered at least once a day.
29. The method of claim 23, wherein said composition is administered orally in a liquid form.
30. The method of claim 23, wherein said blood sugar level is reduced or maintained within an HbA1c range of 5.6% or less.
31. The method of claim 23, wherein said blood sugar level is reduced or maintained at an HbA1c below a range of 5.7% to 6.4%. 38 71740679.2
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PCT/CA2023/051074 WO2024040332A1 (en) | 2022-08-24 | 2023-08-11 | Formulations and methods for treating cellulite |
PCT/CA2023/051084 WO2024040334A1 (en) | 2022-08-24 | 2023-08-15 | Compositions and methods for the maintenance and improvement of vascular health |
PCT/CA2023/051104 WO2024040336A1 (en) | 2022-08-24 | 2023-08-21 | Compositions and methods for the management of blood sugar levels for the prophylaxis of prediabetes and diabetes mellitus |
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PCT/CA2023/051074 WO2024040332A1 (en) | 2022-08-24 | 2023-08-11 | Formulations and methods for treating cellulite |
PCT/CA2023/051084 WO2024040334A1 (en) | 2022-08-24 | 2023-08-15 | Compositions and methods for the maintenance and improvement of vascular health |
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US6818234B1 (en) * | 1999-08-27 | 2004-11-16 | Access Business Group International Llc | Dietary food supplement containing natural cyclooxygenase inhibitors and methods for inhibiting pain and inflammation |
US20090252796A1 (en) * | 2008-04-07 | 2009-10-08 | Mazed Mohammad A | Nutritional supplement for the prevention of cardiovascular disease, alzheimer's disease, diabetes, and regulation and reduction of blood sugar and insulin resistance |
US8449927B2 (en) * | 2007-03-15 | 2013-05-28 | Omnica Gmbh | Stabilized anthocyanin compositions |
US20130171294A1 (en) * | 2010-07-27 | 2013-07-04 | Omniceutica Limited | Nutritional Compositions |
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2023
- 2023-08-11 WO PCT/CA2023/051074 patent/WO2024040332A1/en unknown
- 2023-08-15 WO PCT/CA2023/051084 patent/WO2024040334A1/en unknown
- 2023-08-21 WO PCT/CA2023/051104 patent/WO2024040336A1/en unknown
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US6818234B1 (en) * | 1999-08-27 | 2004-11-16 | Access Business Group International Llc | Dietary food supplement containing natural cyclooxygenase inhibitors and methods for inhibiting pain and inflammation |
US8449927B2 (en) * | 2007-03-15 | 2013-05-28 | Omnica Gmbh | Stabilized anthocyanin compositions |
US20090252796A1 (en) * | 2008-04-07 | 2009-10-08 | Mazed Mohammad A | Nutritional supplement for the prevention of cardiovascular disease, alzheimer's disease, diabetes, and regulation and reduction of blood sugar and insulin resistance |
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ASAL ATAIE‐JAFARI, SAEED HOSSEINI, FARZANEH KARIMI, MOHAMMAD PAJOUHI : "Effects of sour cherry juice on blood glucose and some cardiovascular risk factors improvements in diabetic women", NUTRITION AND FOOD SCIENCE, MCB UNIVERSITY PRESS, YORKS, GB, vol. 38, no. 4, 1 January 2008 (2008-01-01), GB , pages 355 - 360, XP009553324, ISSN: 0034-6659 * |
DESAI TERUN; ROBERTS MICHAEL; BOTTOMS LINDSAY: "Effects of short-term continuous Montmorency tart cherry juice supplementation in participants with metabolic syndrome", EUROPEAN JOURNAL OF NUTRITION, STEINKOPFF VERLAG, DARMSTADT, DE, vol. 60, no. 3, 1 January 1900 (1900-01-01), DE , pages 1587 - 1603, XP037393320, ISSN: 1436-6207, DOI: 10.1007/s00394-020-02355-5 * |
MARTIN KEITH R, COLES KATIE M: "Consumption of 100% Tart Cherry Juice Reduces Serum Urate in Overweight and Obese Adults", CURRENT DEVELOPMENTS IN NUTRITION, OXFORD UNIVERSITY PRESS, US, vol. 3, no. 5, 25 February 2019 (2019-02-25), US, pages nzz011, XP093144778, ISSN: 2475-2991, DOI: 10.1093/cdn/nzz011 * |
MILUTINOVIĆ MILICA, VELIČKOVIĆ RADOVANOVIĆ RADMILA, ŠAVIKIN KATARINA, RADENKOVIĆ SAŠA, ARVANDI MARJAN, PEŠIĆ MILICA, KOSTIĆ MILICA: "Chokeberry juice supplementation in type 2 diabetic patients - impact on health status", JOURNAL OF APPLIED BIOMEDICINE, vol. 17, no. 4, 13 December 2019 (2019-12-13), pages 218 - 224, XP093144774, ISSN: 1214-021X, DOI: 10.32725/jab.2019.020 * |
MU JINGJING, XIN GUANG, ZHANG BO, WANG YUEHUA, NING CHONG, MENG XIANJUN: "Beneficial effects of Aronia melanocarpa berry extract on hepatic insulin resistance in type 2 diabetes mellitus rats", JOURNAL OF FOOD SCIENCE, WILEY-BLACKWELL PUBLISHING, INC, US, vol. 85, no. 4, 1 April 2020 (2020-04-01), US , pages 1307 - 1318, XP093144776, ISSN: 0022-1147, DOI: 10.1111/1750-3841.15109 * |
SIMEONOV, SIMEON B.; BOTUSHANOV, NIKOLAI P.; KARAHANIAN, EKSAPET B.; PAVLOVA, MARIA B.; HUSIANITIS, HARALAMBOS K.; TROEV, DIMITAR : "Effects of Aronia melanocarpa juice as part of the dietary regimen in patients with diabetes mellitus", FOLIA MEDICA., UNIVERSITY OF MEDICINE, PLOVDIV., BG, vol. 44, no. 3, 1 January 2002 (2002-01-01), BG , pages 20 - 23, XP009553322, ISSN: 0204-8043 * |
VALCHEVA-KUZMANOVA S., KUZMANOV K., TANCHEVA S., BELCHEVA A.: "Hypoglycemic and Hypolipidemic Effects of Aronia melanocarpa Fruit Juice in Streptozotocin-Induced Diabetic Rats", METHODS AND FINDINGS IN EXPERIMENTAL AND CLINICAL PHARMACOLOGY., vol. 29, no. 2, 1 January 2007 (2007-01-01), pages 101 - 112, XP009553323, ISSN: 0379-0355, DOI: 10.1358/mf.2007.29.2.1075349 * |
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