DE212015000033U1 - Therapeutic astaxanthin and phospholipid composition - Google Patents

Abstract

A nutritional supplement composition formulated in an amount effective to promote the maintenance of cardiovascular health, comprising astaxanthin and a mixture of a phospholipid-rich rye extract and a seed oil extract, having a ratio of alpha-linolenic acid (ALA) to linoleic acid (LA) between 1: 1 and 6: 1.

Description

Related Application (s)

This application claims the benefit of US patent application Ser. 14 / 658,457, filed March 15, 2015, and U.S. Patent Application Serial No. 14 / 219,484 filed Mar. 19, 2014.

Field of the invention

This invention relates to compositions that use astaxanthin and phospholipids to treat humans.

General state of the art

The use of krill oil and / or marine oil is in the U.S. Patent Publication No. 2004/0234587 ; 2004/0241249 ; and 2007/0098808 , the disclosures of which are hereby incorporated by reference in their entirety, and are described in related U.S. Patent Application Serial Nos. 12 / 840,372 and 13 / 079,238, discussed. The beneficial aspects of using krill oil and / or marine oil are also shown in a research paper published by L German as "Evaluation of the Effect of Neptune Krill Oil on Chronic Inflammatory and Arthritic Symptoms," published in the Journal of the American College of Nutrition, Volume 26, no. 1, 39-49 (2007) , the disclosure of which is hereby incorporated by reference in its entirety.

The published '587 - '249 - and '808 Applications discuss the beneficial aspects of the use of krill oil in conjunction with pharmaceutically acceptable carriers. For example, this krill oil and / or marine oil can be obtained by the combination of individual steps, as in US Pat '808 Application is taught by adding krill and / or marine material in a ketone solvent, whereby the liquid and the solid portion are separated, a first lipid-rich fraction is recovered from the liquid portion by evaporation, the solid content and an organic solvent in an organic solvent Art are arranged, as taught in the description, whereby the liquid portion and the solids content are separated by a second lipid-rich fraction is obtained by evaporation of the solvent from the liquid portion and by the solids content is recovered. The resulting krill oil extract was also used in an attempt to lower lipid profiles in patients with hyperlipidemia. The '808 Publication lists details regarding this krill oil prepared using the general steps identified above.

Brief description of the invention

The jointly assigned previous parent applications and parent applications of U.S. Patent No. 8,663,704 and 8,728,531 , the disclosures of which are fully incorporated herein by reference, are directed to the advantageous use of krill oil and astaxanthin for the treatment of LDL oxidation (low density lipoprotein oxidation (LDL)). The use of krill oil was a focus of '704 - and '531 Patents. Further development has been achieved with various species of algae that produce only EPA or EPA and DHA (docosahexaenoic acid). Further development has been achieved using phospholipid sources and a rogene extract and other surfactants.

 A nutritional supplement composition includes a therapeutic amount of astaxanthin and at least one of a phospholipid, glycolipid and sphingolipid, and is formulated into an oral dosage form. The astaxanthin constitutes from 0.1 to 15% by weight of the at least one phospholipid, glycolipid and sphingolipid. The astaxanthin may in one example be derived from a synthetic or natural ester or a synthetic diol. In another example, the nutritional supplement composition is formulated to treat cardiovascular disease, disorder or impairment in humans. In another example, it is formulated to treat a neurological disorder, disorder or impairment in humans. In another example, it is formulated to treat a cognitive disorder, disorder or impairment in humans or to treat a dermatological disease, disorder or impairment in humans. It can be formulated to treat an inflammatory joint disease, disorder or disability, or joint pain in humans.

The nutritional supplement composition may contain a pharmaceutical grade or food grade diluent. The phospholipid may, in one example, contain at least one of phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, phosphatidic acid, lysophosphatidylcholine, lysophosphatidylethanolamine and lysophosphatidylserine. The phospholipid may be derived from at least one of a vegetable source, an algae source and an animal source or a synthetic derivative. The composition may contain 0.5 to 12 mg of astaxanthin and 50 to 500 mg of at least one of phospholipid, glycolipid and sphingolipid. The nutritional supplement composition can be formulated in a single dose capsule.

 In another example, the nutritional supplement composition contains a therapeutic amount of astaxanthin derived from a synthetic ester or diol and at least one of a phospholipid, glycolipid, and sphingolipid, and is formulated into an oral dosage form. The astaxanthin constitutes from 0.1 to 15% by weight of the at least one phospholipid, glycolipid and sphingolipid. The composition is formulated to treat LDL oxidation in humans.

A method of treating human LDL oxidation involves administering a therapeutic amount of a nutritional supplement composition comprising 0.5 to 12 mg of astaxanthin derived from a synthetic ester or diol and at least one of phospholipid, glycolipid and sphingolipid, and is incorporated herein by reference an oral dosage form wherein the astaxanthin constitutes from 0.1 to 15% by weight of the at least one phospholipid, glycolipid and sphingolipid.

Detailed Description of the Preferred Embodiments

The present invention will now be described in more detail below, in which preferred embodiments of the invention will be described. However, the present invention may be embodied in many different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are given so that the disclosure is exhaustive and complete, and to fully convey the scope of the invention to those skilled in the art.

The following is a description of the dietary supplement composition and associated method used to improve blood lipid profiles and reduce LDL peroxidation in humans, discussed in the respective parent parent applications and parent applications of US Pat '704 - and '531 Patents disclosed in these patents followed by further details of a phospholipid and then a description of the algae-derived oil and its composition with phospholipid and glycolipid-linked EPA or EPA and DHA. The description will be with details of the disclosure in the '704 - and '531 Patents with respect to the use of killer oil contained in the composition, and is then continued with the description and details of the phospholipid-enriched delivery mechanism for astaxanthin and then the oil derived from algae. Some of the components of the composition will change, such as the levels of EPA and / or EPA and DHA and other components when the algae-derived oil is used, as will be shown later in various tables in the following description.

The composition based on the krill oil disclosure in the parent application and the parent application of the '704 - and '531 Contains EPA and DHA functionalized as marine phospholipids and acyl triglycerides derived from krill. However, a krill, algae, rye extract, fish oil and phospholipid composition, by way of non-limiting example, may contain natural or synthetic or synthetic diol esterified astaxanthin. It has been found that a new and potentially quite important cardiovascular risk biomarker is related to the amount of EPA and DHA found in red blood cells divided by the total fatty acid content in red blood cells or the so-called "omega-3 index" , The compositions according to one non-limiting example improve the omega-3 index in humans with prolonged administration and are therefore believed to reduce risks for a cardiovascular event. Some of these components related to krill oil are explained in the following table: components Percentage (%) PHOSPHOLIPIDS PC, PE, PI, PS, S, CL > 40 OMEGA-3 (functionalized on PL) > 30 Eicosapentaenoic Acid (EPA) * > 17 (15% in one example and 10% in another) Docosahexaenoic acid (DHA) + > 11 (9% in one example and 5% in another) ANTIOXIDANTS (Mg / 100g) Astaxanthin, Vitamin A, Vitamin E > 1.25 *> 55% of PL-EPA / total EPA
+> 55% of PL-DHA / total DHA
These quantities may vary depending on the application and the individuals.

The krill oil or algal-derived oil and other phospholipids as disclosed are enriched with astaxanthin to enhance the usefulness of the formulated product. In one study, 4 mg astaxanthin per day for two weeks resulted in a 26% reduction in LDL-cholesterol oxidation. 4 mg of astaxanthin for eight weeks resulted in a 21% reduction in C-reactive protein levels. 3.6 mg astaxanthin per day for two weeks showed that astaxanthin protects LDL cholesterol against in vitro induced oxidation.

Astaxanthin is also known to reduce blood levels of C-reactive protein (C-RP) in vivo. For example, in human subjects with high-risk levels of C-RP, a three-month astaxanthin treatment resulted in a 43% decrease in serum C-RP levels in the patient population, a decline below the risk level for an unacceptable cardiovascular event. Astaxanthin is so potent that it has been shown to reverse in vitro the pro-oxidative activity of Vioxx, a COX-2 inhibitor belonging to the NSAIDS class of drugs, which is known to elicit cell membrane lipid peroxidation leading to heart attacks and strokes leads. For this reason, Vioxx was subsequently removed from the US market by the FDA.

• 1) Lee et al., Molecules and Cells, 16(1): 97–105; 2003 ;
• 2) Ohgami et al., Investigative Ophthalmology and Visual Science 44(6): 2694–2701, 2003 ;
• 3) Spiller et al., J. of the Amer. College of Nutrition, 21 (5): October 2002 ; und
• 4) Harris, Pharmacol. Res. 2007 March; 55(3) 217–223 .

Astaxanthin is also absorbed by lens epithelial cells in vitro, where it suppresses UVB-induced lipid peroxidation-mediated cell damage with umol / L levels. The reduction of C-reactive protein (CRP), the reduction of LDL oxidation, and an increase in the omega-3 index in vivo would probably all provide a major positive contribution to cardiovascular health, as all are well known biomarkers for cardiovascular health risks. These results were shown in:

• 1) Lee et al., Molecules and Cells, 16 (1): 97-105; 2003 ;
• 2) Ohgami et al., Investigative Ophthalmology and Visual Science 44 (6): 2694-2701, 2003 ;
• 3) Spiller et al., J. of the Amer. College of Nutrition, 21 (5): October 2002 ; and
• 4) Harris, Pharmacol. Res. 2007 March; 55 (3) 217-223 ,

The composition contains 300-500 mg of krill oil or an algae-derived oil and 2 mg of astaxanthin. Up to 8 mg and possibly 12 mg may be used in some examples. It may contain 300-500 mg of at least one of phospholipid, glycolipid and sphingolipid.

 Krill oil is usually produced from Antarctic krill (Euphausia superba), which is a zooplankton (feed chain basis). It is one of the most abundant marine biomass with, according to some estimates, about 500 million tonnes. Antarctic krill breeds in the clean, uncontaminated deep-sea waters. It is an unused marine biomass and the catch per year is, according to some estimates, less than or equal to about 0.02%.

 It is believed that krill oil-based phospholipid-linked EPA and DHA uptake in cell membranes is far more efficient than triacylglyceride-bound EPA and DHA because the conversion of triacylglycerides in the liver is inherently inefficient and because phospholipid-linked EPA and DHA can be transported via the sympathetic system into the bloodstream, thereby preventing liver breakdown. In addition, when eating krill oil, no regurgitation observed with fish oil-based products arises. Because of this knock-on feature of fish oils, it has been found that about 50% of all consumers who taste fish oil will never buy it again.

• Oral LD 50: 600 mg/kg (Ratten);
• NOAEL: 465 mg/kg (Ratten); oder
• Serumpharmakokinetik: Stewart et al. 2008
• 1) T_1/2: 16 Stunden;
• 2) T_max: 8 Stunden;
• 3) C_max: 65 μg/l.

The safety standard of Astaxanthin is excellent. An accomplished study yielded the following results:

• Oral LD 50: 600 mg / kg (rats);
• NOAEL: 465 mg / kg (rats); or
• Serumpharmakokinetik: Stewart et al. 2008
• 1) T _1/2 : 16 hours;
• 2) T _max : 8 hours;
• 3) C _max : 65 μg / l.

After eight weeks of supplementation at 6 mg per day, there was no adverse effect on healthy adults. Spiller et al. 2003 ,

By way of non-limiting example, astaxanthin has three important sources. 3 mg astaxanthin per 240 g portion of non-farmed salmon or 1% to 12% astaxanthin oleoresin or 1.5-2.5% microalgae-made beads. References relevant to the above discussion can be found in Lee et al., Molecules and Cells 16 (1): 97-105, 2003 ; Ohgami et al., Investigative Ophthalmology and Visual Science 44 {6): 2694-2701, 2003 ; Spiller et al., J. of the American College of Nutrition 21 (5): October 2002 ; and Fry et al., University of Memphis, Human Performance Laboratories, 2001 and 2004 , Reports 1 and 2.

 Many beneficial and synergistic effects reported herein have been observed when krill oil is used in combination with other active ingredients, and in one example especially when krill oil is used in combination with astaxanthin. It should be understood that various proportions of ingredients and percentages in compositions may be used when treating a patient's condition, depending on the end-uses and other environmental factors and physiological factors.

The krill oil is exemplified by Euphasia spp. including eicosapentaen (EPA) and docosahexaen (DHA) fatty acids in the form of triacylglycerides and phospholipids, although not less than 1% of EPA and 5% of DHA have been found to be beneficial. In another example, the krill oil contains at least 15% EPA and 9% DHA, of which not less than 45% are in the form of phospholipids and in one example more than 50%. The composition may advantageously be delivered as a daily dose for therapeutic results with 1-4,000 mg of krill oil. In another example, 0.1-50 mg astaxanthin per daily dose is added to the krill oil and in one example 0.1-12 mg astaxanthin.

The astaxanthin is derived from Haematococcus pluvialis algae, Pfaffia, krill or synthetic pathways in the known free diol, monoester or diester form and in one example at a daily dose of 0.5-8 mg. When this amount of astaxanthin, especially from Haematococcus pluvialis, is applied to a range of 300-500 mg of krill oil or algae-derived oil, the numerical range is from about 0.1 to 2.7% by weight of the krill oil or Algae obtained oil.

 The composition may also contain a fatty acid-rich n-3 oil (omega-3) derived from fish oil, algae oil, linseed oil or chia seed oil when the n-3 fatty acid source comprises alpha-linolenic, stearidone, eicosapentaenoic or docosapentaenoic acid. The composition may include naturally occurring and synthetic antioxidants added to delay the degradation of fatty acids and astaxanthin.

Details on the nature of CO2 extraction and processing technology (such as supercritical CO2 extraction) and peroxidation blocker technology that can be used are given in the commonly assigned U.S. Patent Publication No. 2009/0181127 ; 2009/0181114 ; and 2009/0258081 , the disclosures of which are hereby incorporated by reference in their entireties.

As mentioned above, there are beneficial aspects of using krill oil or an algae-derived oil in synergistic combination with other ingredients. It has also been determined that a fish oil-derived, choline-based, phospholipid-linked omega-3 fatty acid mixture, including phospholipid-linked polyunsaturated EPA and DHA, is also beneficial for improving blood lipid profiles and reducing LDL, either alone or mixed with other ingredients, for example an LDL peroxidation blocker. A commercially available example of a mixture of a fish oil-derived, choline-based, phospholipid-linked fatty acid mixture, including polyunsaturated EPA and DHA, is Omega Choline 1520F as a phospholipid, omega-3 preparation derived from natural fish oil and from Enzymotec Ltd is sold. An example of such a composition will be described below. Ingredients (g / 100g): pure marine phospholipids not less than (nlt) 15 DHA * (nlt) 12 EPA ** (nlt) 7 * docosahexaenoic acid
** eicosapentaenoic acid Omega 3 (nlt) 22 Omega-6 <3 Analytical data: Peroxide value (meq / kg) not more than (nmt) 5 Drying loss (g / 100g) (nmt) 2 Physical Properties: consistency viscous liquid

 By way of non-limiting example, the method improves blood lipid profiles and either alone or in combination with added astaxanthin, such as a peroxidation blocker, and reduces LDL oxidation in a patient by administering a therapeutic amount of a composition comprising a mixture of fish oil-derived, choline-based, phospholipid-bound omega-3 fatty acid mixture containing phospholipid-linked polyunsaturated EPA and DHA, either alone or in admixture with an LDL peroxidation blocker, such as astaxanthin. In one example, the composition is administered in combination with astaxanthin in an oral dosage form. The mixture of the fish oil-derived, choline-based, phospholipid-linked fatty acid mixture containing polyunsaturated EPA and DHA comprises in one example eicosapentaenoic acid (EPA) and docosahexaenoic (DHA) fatty acids in the form of triacylglycerides and phospholipids. In another example, the omega-choline contains at least 7% EPA and 12% DHA, of which no less than 15% are in the form of phospholipids. The composition may advantageously be delivered for therapeutic results with 1-4,000 mg of a mixture of fish oil and a fish oil-derived, choline-based, phospholipid-linked fatty acid mixture containing polyunsaturated EPA and DHA per daily dose. In another example, 0.1-20 mg astaxanthin is added to the omega-choline per daily dose.

It should be understood that a present formulation for LDL reduction can be used if it employs only a mixture of a fish oil-derived, choline-based, phospholipid-linked fatty acid mixture containing polyunsaturated EPA and DHA. It is also possible to use a mixture of a fish oil-derived, choline-based, phospholipid-bound omega-3 fatty acid mixture (including polyunsaturated EPA and DHA) mixed with astaxanthin. It should also be understood that an enriched version of a mixture of a fish oil-derived, choline-based, phospholipid-linked fatty acid mixture containing polyunsaturated EPA and DHA can be used, with the fraction of added fish oil diluents being reduced and the proportion was increased from fish oil-derived phospholipids. This can be accomplished using supercritical CO2 extraction and / or solvent extraction to selectively remove triacylglycerides from phospholipids. The composition may also include a natural or synthetic cyclooxygenase-1 or -2 inhibitor comprising, for example, aspirin, acetaminophen, steroids, prednisone or NSAIDs. The composition may also include a gamma-linoleic acid rich oil comprising borage (Borago officinalis L) or safflower (Carthamus tinctorius L) which provides a metabolic precursor to PGE ₁ synthesis.

The composition may also contain a fatty acid-rich n-3 oil (omega-3) derived from fish oil, algae oil, linseed oil, chia seed oil or perilla seed oil, the n-3 fatty acid source being alpha-linolenic, stearidonic, eicosapentaenoic or docosapentaenoic acid includes. The composition can from the Naturally derived and synthetic antioxidants which are added to delay the degradation of fatty acids, such as tocopherols, tocotrienols, carnosic acid or carnosol and / or astaxanthin.

It has been found that high dosages of astaxanthin alone are effective in treating osteoarthritis and joint pain. For example, a clinical trial, such as that used in the co-transferred U.S. Patent No. 8,481,072 is described, the disclosure of which is incorporated herein by reference in its entirety, 15 mg astaxanthin. It has now been determined that lower dosages of astaxanthin may be used instead of these much higher dosages, such as 15 mg, as in some clinical trials for osteoarthritis or other applications, including cardiovascular treatment, if it contains at least one of a phospholipid, glycolipid and sphingolipid or other phospholipids is added. A pharmaceutical grade or food grade diluent or other surfactant may be added. Other beneficial and often synergistic results are obtained when astaxanthin is used in the presence of other components, including low molecular weight hyaluronic acid or UC-II. Phospholipids may include plant-derived phospholipids such as lecithin and lysophospholipids and / or glycophospholipids, including perilla oil as described in commonly assigned US Pat U.S. Patent No. 8,784,904 described, the disclosure of which is hereby incorporated by reference in its entirety. Astaxanthin levels could vary from 0.5-2 mg and 0.5-4 mg, and in one embodiment would be 2-4 mg or 2-6 mg and up to 0.5-12 mg and 7-12 mg, respectively.

It has also been found advantageous to use herring gene extract as a source of phospholipids that have some EPA and DHA. Synergistic results are obtained and enormous improvements observed. One study showed that herbal phospholipids improved phospholipid and glucose tolerance in healthy young adults, such as Bjorndal et al., Lipids in Health Disease, 2014, 13:82 released. The pure rouge phospholipid can be used using extraction techniques. It is a honey-like product which, in one example, is thinned or diluted with fish oil and / or perilla oil or other seed or vegetable oil.

The specification before dilution with fish oil and / or perilla oil is as follows: Percentage that is phospholipids 60 Phospholipid mg / g 600 Phosphatidylcholine content mg / g 520 Choline equivalents 83 Total EPA mg / g (TG and PL bound) 75 Total DHA mg / g (TG and PL bound) 195 EPA mg / g bound to phospholipid 67 DHA mg / g bound to phospholipid 175 EPA + DHA mg / g bound to phospholipid 242

The herring gene extract is processed in one example using ethanol extraction. Triacylglycerides are added and stripped with ethanol to have a robust solution. Seed oil, such as the perilla seed oil, as incorporated by reference '904 Pat., May be added back to the ethanol extract before it is stripped for dilution to form a high phospholipid mixture. The rye oil extract may be mixed with fish oil and / or seed oil such as Perilla or any other marine oil. In one example, the herring gene extract is mixed with Perillasamenöl at least 1: 1 and preferably with up to 6: 1 ALA to LA, wherein the concentrate at least 50% and in another example 60% phospholipids and in another example at least 30% and in a another example has 40% triglycerides.

An exemplary composition includes a combination of a herring flavor extract or a phospholipid-rich rye extract with phospholipid-bound EPA and DHA as a mixture with seed / fish oil and / or seed oil, the seed oil having a ratio of ALA to LA between 1: 1 and 1: 6 and in one example contains about 2-4 mg or 0.5 to 12 mg astaxanthin or other ranges as mentioned above. The amount of Rogen extract mixed with the seed oil, such as perilla oil, varies and is about 150 to 500 mg or 300 to 500 mg or up to 1,000 mg daily dose in one example and may contain hyaluronic acid. Other plant-based phospholipids may be used, including commercially available lecithins and an egg yolk derivative, including lysophospholipids and glycophospholipids, which act as surfactants. It is possible to use sunflower based phospholipids and natural plant based oils and natural surfactant extracts. The astaxanthin is enhanced with fats, surfactants or phospholipids and can be delivered more efficiently with phospholipids and sunflower-based and / or the lipophilic perilla oil as described above.

In one example, the perilla oil is a sustained, supercritical CO ₂ fluid-extracted seed oil derived from a broken biomass of Perilla frutescens with 60 to 95 percent (w / w) PUFAs in a ratio of 4: 1 to 6: 1 alpha-linolenic acid (ALA) to form linoleic acid (LA). The seed oil derived from Perilla frutescens is prepared in one example by subjecting the Perilla frutescens seed to supercritical CO2 fluid extraction to produce a seed oil extract; the resulting seed oil extract is fractionated in separate pressure reduction stages to collect light and heavy fractions of the seed oil extract; and separating the heavy fraction from the light fraction to form the finished seed oil from the heavy fraction.

 Selected antioxidants are added in another example and the perilla oil contains a mixture of selected lipophilic and hydrophilic antioxidants. Lipophilic antioxidants may be used either alone or in combination with at least one of: a) phenolic antioxidants, including at least one of sage, oregano and rosemary; b) tocopherol; c) tocotrienol (s); d) carotenoids including at least one of astaxanthin, lutein and zeaxanthin; e) ascorbyl acetate; f) ascorbyl palmitate; g) butylated hydroxytoluene (BHT); h) docosapentaenoic acid (BHA); or i) tertiary butylhydroquinone (TBHQ). A hydrophilic antioxidant or sequestering agent may include hydrophilic phenolic antioxidants, including at least one of grape seed extract, tea extracts, ascorbic acid, citric acid, tartaric acid and malic acid.

 In one example, a peroxide value of this perilla seed oil is below 10.0 meq / km. In another example, this perilla seed oil has 85 to 95 percent (w / w) PUFAs and the PUFAs are at least more than 56 percent alpha-linolenic acid (ALA). The perilla seed oil is stable at room temperature for up to 32 months. In another example, this perilla seed oil is derived from a pre-milled or flocculated fractured biomass of Perilla frutescens. The mixture of selected antioxidants may include astaxanthin, phenolic antioxidants and natural tocopherols. The perilla seed oil may also contain at least one of dispersed nano- and microparticles of polycosanol derived from rice or sugar cane.

In one example, the composition is encapsulated in a single dose capsule and referred to as a deep sea avian capsule. In a specific example, the encapsulated composition Heringkaviarphospholipidextrakt contains (herring roe), perilla seed extract {Perilla frutescens), olive oil, Zanthin ^® astaxanthin (Haematococcus pluvialis alga extract), gelatin, spice extract natural non-GMO-tocopherols, cholecalciferol, riboflavin, and Methylcobalamin. The composition contains fish such as Heringrogen and Tilapia gelatin. It may contain low molecular weight hyaluronic acid as an adjunct to joint care. The following table gives an example. Properties: Appearance clear capsule size 00 with dark red, oily filling fatty acids ALA minute 140 mg EPA minute 18 mg DHA minute 50 mg Total Omega-3 minute 210 mg phospholipids 195 mg astaxanthin 500 μg Vitamin D ₃ 1000 IU; 250% DV Vitamin B ₂ (riboflavin) 1.7 mg; 100% DV Vitamin B ₁₂ 6 μg; 100% DV microbiology USP <61> / FDA BAM Bioburden <1000 cfu / g Yeast and <100 cfu / g molds E. coli not available in 10 g Salmonella not available in 10 g S. aureus not available in 10 g storage conditions tightly closed containers, 15-30 ° C, 30-50% RH durability at least 24 months packaging HDPE or PET bottle (number to be determined) All ingredients are BSE-free and GMO-free

The processing components may contain a mixture of marine omega-3 phospholipids derived from herring caviar and perilla seed oil. They may contain an O2B ^™ botanical peroxidation blocker, including spice extract, non-GMO tocopherols and ascorbyl palmitate. They can be packed in bulk in tightly sealed barrels, 45 and 190 kg net, with inert headspace, which comply with European and American food standards. They are preferably stored below room temperature. The product is protected from light and heat. When the drums are opened for sampling, the headspace may be purged with inert gas during sampling and storage. test unit acceptance criterion method Appearance Amber viscous oil AM2020 solubility Oil-soluble and dispersible in water AM2021 Minimal Maximum ALA (C18: 3 n-3) mg / g as TG ³⁾ 230 AM1044 ALA (C20: 5n-3) mg / g as TG ³⁾ 30 AM1001 DHA (C22: 6n-3) mg / g as TG ³⁾ 85 AM1001 Total omega-3 ¹⁾ mg / g as TG ³⁾ 370 AM1001 ALA (C18: 3 n-3) mg / g as FFA ⁴⁾ 215 AM1044 ALA (C20: 5n-3) mg / g as FFA ⁴⁾ 28 AM1001 DHA (C22: 6n-3) mg / g as FFA ⁴⁾ 80 AM1001 Total omega-3 ¹⁾ mg / g as FFA ⁴⁾ 335 AM1001 Total PC mg / g 250 AM1002 Overall PL mg / g 300 AM1002 Total lipids in total mg / g 700 AM1003 Water content by Karl Fisher % 3.0 AM1004 peroxide meq / kg 10.0 AM1005 Heavy metals (sum of Pb, Hg, Cd & inorganic As) ²⁾ mg / kg 10 AM1015 1) Total n-3: ALA, EPA, DHA, 18: 4, 20: 4, 21: 5, 22: 5
2) Frequency analysis
3) All ALA, EPA, DHA or total omega-3 expressed as triglycerides
4) All ALA, EPA, DHA or total omega-3 expressed as free fatty acids

 Surprisingly, it has been found that the bioavailability of astaxanthin can be increased when it is incorporated into or used with at least one of phospholipid, glycolipid and sphingolipid and optionally in food grade and / or pharmaceutical grade diluents. Lower doses are used compared to the 15 mg used in previous clinical trials for joint pain as the phospholipid improves delivery. The astaxanthin constitutes at least about 0.1 to about 15 weight percent of the at least one phospholipid, glycolipid and sphingolipid. The astaxanthin in one example is derived from a natural or synthetic ester or a synthetic diol. A pharmaceutical or food grade diluent may be added. It can be used to treat various disorders, including cardiovascular, neurological, cognitive, dermatological disorders, disorders or impairments and joint pain problems. When incorporated into microbiologically fermented low molecular weight hyaluronic acid or sodium hyaluronate (hyaluronan), as previously described, a nutritional supplement composition is formed and may be formulated in a therapeutic amount to increase symptoms of joint pain in a person having joint pain treat and improve.

 It should be understood that the triglycerides have two types of molecules, one glycerol and three fatty acids, while the phospholipids contain glycerol and fatty acids, but have one glycerol molecule and two fatty acid molecules. Instead of this third fatty acid, instead, a polar group is attached to the glycerol molecule so that the phospholipids are partially hydrophilic compared to hydrophobic triglycerides. Lysophospholipids can be used as a derivative of a phospholipid in which one or both acyl derivatives have been removed by hydrolysis. Lecithin and its derivatives can be used as emulsifier and surfactant as wetting agents to reduce the surface tension of liquids. Other phospholipids can be used. Various phospholipids include phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, phosphatidic acid, lysophosphatidylcholine, lysophosphatidylethanolamine and lysophosphatidylserine. Some may be derived from egg yolks and extracted chemically using hexane, ethanol, acetone, petroleum ether or benzene, and also extracted mechanically, including from various sources such as soybeans, eggs, milk, marine sources and sunflower. If they come from soy and sunflower, the phospholipids may contain the above products, including phosphatidic acid. Various compositions, such as lecithin, can be enzymatically hydrolyzed and have their fatty acid removed by phospholipase to form the lysophospholipids, which can be added to the rye extract as discussed above. A phospholipase is phospholipase A2 with the fatty acid removed at the C2 position of glycerol. Fractionation can be used.

 The glycolipids are mainly derivatives of ceramides, with one fatty acid linked or linked to the aminoalcohol sphingosine. It should be understood that the phospholipid sphingomyelin is also derived from a ceramide. However, glycolipids contain no phosphates compared to the phospholipids. The fat is linked to a sugar molecule in a glycolipid and the fats are linked to sugar. Because it is composed of a sphingosine, fat and sugar, it is called by some glycosphingolipid. A sphingolipid is a lipid containing a sphingoid-based backbone and a group of aliphatic aminoalcohols containing the sphingosine. As mentioned above, the phospholipid and other components may be derived from at least one of a plant source, algae source and animal source or a synthetic derivative. The phospholipid and other components may be derived from at least one of soybean, sunflower, grape seed, egg yolk, krill, fish, fries, squid and algae. The phospholipid and other components can be formed as compound-rich mono- or diglycerides or fatty acids wherein the fatty acid contains between 2 and 20 carbon atoms. During processing, the composition is formed by dispersing the astaxanthin and phospholipid and optionally a diluent under high shear conditions. The diluent may be a pharmaceutical grade or food grade diluent, as known to those skilled in the art.

In another example, the astaxanthin is about 2 to about 10 weight percent of the phospholipid and the glycolipid and is derived from a natural or synthetic ester or synthetic diol. In another example, 50 to 500 mg of phospholipid, glycolipid and sphingolipid be used. The nutritional supplement composition can be formulated in a single dose capsule.

The astaxanthin may be derived from Haematococcus pluvialis algae, Pfaffia, krill or from synthetic routes in free or synthetic diol, monoester or diester form, both natural and synthetic, at a daily dose of 0.5-8 mg or 0, 5-12 mg, in one example and in another example 1-2 mg, 2-4 mg, 1-6 mg and other ranges, and up to 12 mg, including 7-12 mg.

 The astaxanthin may vary between 2 to 4 mg or 0.5 to 12 mg and other ranges as disclosed above. It should be understood that the astaxanthin and at least one of phospholipid, glycolipid and sphingolipid or other components as described above may be used for many different purposes and results. It can be used to help treat or improve blood lipid profiles and reduce LDL peroxidation in humans. It can be used to counteract or treat depression and other neurological disorders. It can be used against respiratory diseases and skin disorders or diseases.

 The composition may also contain a fatty acid-rich n-3 oil (omega-3) derived from fish oil, algae oil, linseed oil, chia seed oil or perilla seed oil. In one example, the n-3 fatty acid comprises alpha-linolenic, stearidonic, eicosapentaenoic or docosapentaenoic acid. In one example, the composition is as mentioned above. It has been found that an algae-derived oil can be used instead of krill oil. Hydrolyzed or unhydrolyzed collagen and elastin derived from eggshell membranes may also be used to advantage. The composition may also contain anti-inflammatory and / or natural joint health promoting compounds comprising at least one of green lipped mussel (Perna canaliculus), boswellia serrata, turmeric (Curcuma longa), nettle (Urtica dioica), andrographis, cat's claw (Uncaria tomentosa) , Bromelain, methylsulfonylmethane (MSM), chondroitin sulfate, glucosamine sulfate, s-adenosylmethionines, proanthocyanidines, procyanidines or flavonoids. The composition may include naturally occurring and synthetic antioxidants added to delay the degradation of fatty acids and astaxanthin.

 It is also possible to use a pure diol of S, S'-astaxanthin, including a synthetic diol with the surfactant and / or phospholipid. It is possible to use this pure diol in combination with the EPA-rich algae-derived oil or other fish oil, rye extract or plant-based oil and / or phospholipid and / or surfactant as described above, and either with astaxanthin, derived from Haematococcus pluvialis or the free diol form in substantially pure S, S 'enantiomer form. It is possible to add synthetically prepared, mixed enantiomers of the diol. The diol of S, S'-astaxanthin is possible because, in the case of krill oil and oils made from algae and Hp, and phospholipids and other species, essentially diols or monoesters with very little diol, are insoluble. Some research shows that the bioavailability can be many times better than that of the monoester or diester form. It is possible to asymmetrically synthesize the pure S, S'-diol. Despite the poor solubility of pure diol in some examples, there may be an active transport mechanism associated with its bioavailability, or conversely, the monoester or diester forms are only transferred from the intestine to the blood in the diol form. The phospholipid or glycolipid-based product having EPA and / or DHA together with the added astaxanthin in its various forms, and particularly the S, S 'enantiomeric form in substantially monoester form from Haematococcus pluvialis or pure diol form from asymmetric synthesis, could be useful be. It is therefore possible to combine it with algal-derived glycol and phospholipid-based EPA-rich oil.

As mentioned above, astaxanthin (3,3'-dihydroxy-β-β-carotene-4,4'-dione) is a xanthophyll carotenoid found in many marine species, including crustaceans, salmonids and algae. Astaxanthin can not be synthesized by mammals but acts as an antioxidant, anti-inflammatory, when ingested, and has ocular health, heart health and immune system benefits.

Astaxanthin has one hydroxyl group on each β-ionone unit, so it can be found in its free form (diol) as well as mono- or di-esterified. In natural products, astaxanthin is usually present as a mixture: mainly monoesters of C12-C18 fatty acids and minor amounts of diester and free diol. Synthetic astaxanthin is usually provided only in the free diol form.

The astaxanthin molecule has two chiral E / Z centers and three optical R / S isomers. Haematococcus pluvialis algae produce natural astaxanthin only as a (3S, 3'S) isomer. This is in the Article by Renstrøm B., G. Borch, O. Skulberg and S. Liaane Jensen, "Optical Purity of (3S, 3'S) Astaxanthin From Haematococcus Pluvialis," Phytochemistry, 20 (11): 2561-2564, 1981 , the disclosure of which is hereby incorporated by reference in its entirety.

Alternatively, the yeast Phaffia rhodozyma synthesizes only the 3R, 3'R configuration. This is in the Article by Andrewes A. and M. Starr entitled "(3R, 3'R) -Astaxanthin from the Yeast Pfaffia Rhodozyma," Phytochemistry, 15: 1009-1011, 1976 , the disclosure of which is hereby incorporated by reference in its entirety.

Wild salmon contains predominantly the (3S, 3'S) -form with a (3S, 3'S), (3R, 3'S) and (3R, 3'R) -isomer ratio of 22: 1: 5. This is in the Article by Turujman, S, W. Warner, R. Wei and R. Albert entitled "Rapid Liquid Chromatographic Method to Distinguish Wild Salmon From Aquacultured Salmon Fed Synthetic Astaxanthin," J. AOAC Int., 80 (3): 622- 632, 1997 , the disclosure of which is hereby incorporated by reference in its entirety.

However, astaxanthin produced by conventional synthesis will contain a racemic mixture in a (3S, 3'S), (3R, 3'S; meso), {3R, 3'R) ratio of 1: 2: 1. This ratio is also observed in many shrimp species capable of racemizing (3S, 3'S) to the meso form. This is in the Article by Schiedt, K., S. Bishop and E. Glinz entitled "Metabolism of Carotenoids and In Vivo Racemization of {3S, 3'S) -Astaxanthin in the Crustacean Penaeus," Methods in Enzymology, 214: 148-168, 1993 , the disclosure of which is hereby incorporated by reference in its entirety.

 However, most astaxanthin is found in shrimp in the shell so that limited amounts of the meso isomer are absorbed by human food.

Feeding studies have shown that free diol or fatty acid esters of astaxanthin increase the amount of astaxanthin in human plasma. This is in the Article by Østerlie, M., B. Bjerkeng and S. Liaan-Jensen entitled "Plasma Appearance and Distribution of Astaxanthin E / Z and R / S Isomers in Plasma Lipoproteins of Men After Single Dose Administration of Astaxanthin," J. Nutr , Biochem, 11: 482-490, 2000 ; and the Articles by Coral-Hinostroza, G., T. Ytestoyl, B. Ruyter and B. Bjerkeng, entitled "Plasma Appearance of Unesterified Astaxanthin Geometrical E / Z and Optical R / S Isomers" in Men Given Single Doses of a Mixture of Optical 3 and 3'R / S Isomers of Astaxanthin Fatty Acyl Diesters, "Comp. Biochem Phys. C, 139: 99-110, 2004 , the disclosures of which are hereby incorporated by reference in their entirety.

The intake of free astaxanthinediol is about 4-5 times higher than that of esterified astaxanthin, probably due to the limitation of the required enzymatic hydrolysis in the intestine before absorption. These intestinal enzymes may also be R / S selective to astaxanthin esters. Coral-Hinostroza et al. (2004) found a higher relative absorption of astaxanthin (3R, 3'R-astaxanthin dipalmitate compared to the other two isomers, however, the consumption of racemic free diol astaxanthin shows no stereospecific selection.

 Astaxanthin for use in human nutritional supplements is currently derived from the cultured freshwater algae Haematococcus pluvialis. These algae produce 3S, 3'S astaxanthin esters in a fatty acid matrix that can be isolated by solvent or carbon dioxide extraction. The oily extract may be used directly in edible formulations or further processed into solid powder or bead formulations. Many clinical studies have been conducted with H. pluvialis-derived astaxanthin to demonstrate beneficial health effects and safety. Food additive approvals for astaxanthin-rich algae extracts have been approved for many suppliers in the US and the EU.

 The Haematococcus algae culture for use in nutritional supplements may not always meet the demand for the use of astaxanthin in nutritional supplements. The use of synthetic astaxanthinediol may also be advantageous for applications requiring a concentrated, standardized source of astaxanthin. Conventional sources of racemic synthetic astaxanthin are used as a dye in salmonid aquaculture as a feed ingredient. This racemic mixture may be of limited use since only one quarter of the compound is in the 3S, 3'S isomer form commonly found in natural salmon and tested for efficacy and safety in humans.

Astaxanthin can also be synthesized stereospecifically so that the result is exclusively the generally accepted 3S, 3'S isomer in a free diol form. The free diol crystals may be suspended in a vegetable oil or a solid bead to be used in food preparations or in pill, capsule, tablet form. The 3S, 3'S product has the advantage of greater consistency and also less odor than the algae preparation. Therefore, the alax-derived astaxanthin can be replaced by the synthetic 3S, 3'S-astaxanthinediol in existing formulations having the same or higher potency.

 Surprisingly, it has also been found that the use of hyaluronic acid alone and / or in combination with astaxanthin is advantageous and synergistic. For example, low molecular weight hyaluronic acid in its various forms may contain patients in an amount of 1-500 mg per day and preferably about 10-70 mg per day and in another example 20-60 mg, 25-50 mg, 35 mg and 45 be given mg. Astaxanthin may be added at about 2-4 mg in one example but could be in the range of 0.5 to 4 mg daily and in another example in a 7-12 mg range or 0.5 to 12 mg , The hyaluronic acid may be given in the form of low molecular weight pro-inflammatory sodium hyaluronate fragments, which are about 0.5-300 kDa in weight, corresponding to the low molecular weight pro-inflammatory fragments. Although the use of astaxanthin and phospholipids such as krill oil, algae oil, roe, fish oil product or plant derived oils aids in the delivery of hyaluronic acid, the low molecular weight hyaluronic acid and in the form of the fragments is preferably still small enough to pass through the intestine absorbed and used in an oral administration.

 It is also advantageous to use astaxanthin with the low molecular weight hyaluronic acid. Various amounts may be used and in one example 2-4 mg per day and in another example 0.5-12 mg per day with low molecular weight hyaluronic acid such as the amount of 1-500 mg and advantageously about 10 mg. 70 mg and with 0.5-12 mg or 4-12 mg astaxanthin. About 40-120 mg of low molecular weight hyaluronic acid can be used in one example. A dosage of astaxanthin may be about 6-8 mg and low molecular weight hyaluronic acid might be in the range of about 60-80 mg. Although the larger amounts of low molecular weight hyaluronic acid astaxanthin can be used alone, it is possible to use 2 mg astaxanthin and lower levels of low molecular weight hyaluronic acid, such as 20 mg and up to 40 mg, by way of non-limiting example. It should be understood that hyaluronic acid fragments, such as the low molecular weight pro-inflammatory sodium hyaluronate fragments, are potent as innate immune cell receptor signaling molecules associated with the inflammatory cascade, and oral hyaluronic acid in the form of low molecular weight fragments can reach joints as compared to the art Hyaluronic acid of higher molecular weight, which is injected as it is not administered orally.

Many modifications and other embodiments of the invention will occur to those skilled in the art having the benefit of the teachings in the foregoing description and in the accompanying drawings. It is therefore to be understood that the invention is not limited to the specific embodiments disclosed and that the modifications and embodiments are intended to be included within the scope of the dependent claims.

QUOTES INCLUDE IN THE DESCRIPTION

This list of the documents listed by the applicant has been generated automatically and is included solely for the better information of the reader. The list is not part of the German patent or utility model application. The DPMA assumes no liability for any errors or omissions.

Cited patent literature

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• Article by Andrewes A. and M. Starr entitled "(3R, 3'R) -Astaxanthin from the Yeast Pfaffia Rhodozyma," Phytochemistry, 15: 1009-1011, 1976 [0052]
• Article by Turujman, S, W. Warner, R. Wei and R. Albert entitled "Rapid Liquid Chromatographic Method to Distinguish Wild Salmon From Aquacultured Salmon Fed Synthetic Astaxanthin," J. AOAC Int., 80 (3): 622- 632, 1997 [0053]
• Article by Schiedt, K., S. Bishop and E. Glinz entitled "Metabolism of Carotenoids and In Vivo Racemization of {3S, 3'S) -Astaxanthin in the Crustacean Penaeus," Methods in Enzymology, 214: 148-168, 1993 [0054]
• Article by Østerlie, M., B. Bjerkeng and S. Liaan-Jensen entitled "Plasma Appearance and Distribution of Astaxanthin E / Z and R / S Isomers in Plasma Lipoproteins of Men After Single Dose Administration of Astaxanthin," J. Nutr , Biochem, 11: 482-490, 2000 [0056]
• Articles by Coral-Hinostroza, G., T. Ytestoyl, B. Ruyter and B. Bjerkeng, entitled "Plasma Appearance of Unesterified Astaxanthin Geometrical E / Z and Optical R / S Isomers" in Men Given Single Doses of a Mixture of Optical 3 and 3'R / S Isomers of Astaxanthin Fatty Acyl Diesters, "Comp. Biochem Phys. C, 139: 99-110, 2004 [0056]
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Claims (16)

 A nutritional supplement composition formulated in an amount effective to promote the maintenance of cardiovascular health, comprising astaxanthin and a mixture of a phospholipid-rich rye extract and a seed oil extract, having a ratio of alpha-linolenic acid (ALA) to linoleic acid (LA) between 1: 1 and 6: 1.  The dietary supplement composition of claim 1, wherein the phospholipid-rich rye extract comprises at least 50 percent phospholipids.  The dietary supplement composition of claim 1, wherein the composition is formulated to treat low density lipoprotein (LDL) oxidation in humans.  The dietary supplement composition of claim 1 and further comprising a pharmaceutical grade or food grade diluent.  The dietary supplement composition of claim 1, further comprising a phospholipid comprising at least one of phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, phosphatidic acid, lysophosphatidylcholine, lysophosphatidylethanolamine and lysophosphatidylserine. The dietary supplement composition of claim 1, further comprising a phospholipid derived from at least one of a vegetable source, an algae source and an animal source or a synthetic derivative.  The dietary supplement composition of claim 1, wherein the composition contains from 0.5 to 12 mg astaxanthin.  The dietary supplement composition of claim 1, wherein the composition contains from 50 to 500 mg of the phospholipid-rich rogenic extract.  The dietary supplement composition of claim 1, wherein the dietary supplement composition is formulated into a single dose capsule.  The dietary supplement composition of claim 1, wherein the astaxanthin is derived from a synthetic or natural ester or diol. The dietary supplement composition of claim 1, wherein the astaxanthin constitutes about 0.1 to 15 percent by weight of the mixture of phospholipid-rich rye extract and seed oil extract. A nutritional supplement composition formulated in an amount effective to treat low density lipoprotein (LDL) oxidation in humans, comprising astaxanthin derived from a synthetic or natural ester or diol, and a mixture of a phospholipid-rich rye extract and a seed oil extract having a ratio of alpha-linolenic acid (ALA) to linoleic acid (LA) between 1: 1 and 6: 1 and formulated in a single dose capsule, wherein the astaxanthin constitutes about 0.1 to 15% by weight of the mixture of phospholipid-rich rose extract and seed oil extract.  The dietary supplement composition of claim 12, wherein the phospholipid-rich rye extract comprises at least 50 percent phospholipids. The nutritional supplement composition of claim 12 and further comprising a pharmaceutical grade or food grade diluent.  The dietary supplement composition of claim 12, wherein the composition contains from 0.5 to 12 mg astaxanthin.  The dietary supplement composition of claim 12, wherein the composition contains from 50 to 500 mg of the phospholipid-rich rogenic extract.