DE212015000031U1 - Composition that uses seed oil extracts and phospholipids to improve the absorption of carotenoids - Google Patents

Abstract

A dietary supplement composition formulated in an effective amount to promote ocular health maintenance comprising 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 , Astaxanthin, and at least one carotenoid selected from the group consisting of lutein, trans-zeaxanthin and meso-zeaxanthin.

Description

Related Application (s)

This application claims the priority of US application Ser. No. 14 / 706,092, filed May 7, 2015, and US Application Ser. 14 / 275,968, filed May 13, 2014.

Field of the invention

This invention relates to phospholipids, seed oil extracts and carotenoids used for ophthalmology or other medical applications.

General state of the art

The jointly transmitted U.S. Patent No. 8,784,904 discloses a perilla seed oil extract which provides a healthy omega-3 source and has a very favorable ratio of ALA to LA (omega-3 to omega-6) of about 6: 1 in one example. This perilla seed oil extract is obtained by pressing the perilla seeds to initiate seed breakage by processing the broken biomass using supercritical CO2 fluid extraction and collecting the extract to provide more of the higher molecular weight compounds.

The jointly transferred and also pending U.S. Patent Publication No. 2013/0011469 and 2013/0295171 disclose compositions and methods that improve eye health, treat eye disorders, delay and ameliorate eye diseases and injuries, improve other medical conditions such as the health of the cardiovascular system. The compositions include a mixture of carotenoids including astaxanthin with phospholipid and triglyceride-bound EPA and DHA derived from krill oil, the krill oil containing at least 30% total of phospholipids. These eye composition is administered in a therapeutically effective amount to prevent, delay or treat ocular diseases and diseases or injuries of the central nervous system, such as age-related macular degeneration, cataract, dry eye syndrome, gland inflammation and other degenerative diseases central nervous system, injury from light, ischemic diseases and inflammatory diseases, including those related to the cardiovascular system.

Brief description of the invention

By way of non-limiting example, phospholipids are added to the seed oil extracts to enhance the absorption of carotenoids such as lutein, astaxanthin, and other components, in one example including coenzyme Q10, as non-limiting examples of both eye health and heart health.

A nutritional supplement composition is formulated in a therapeutically effective amount to treat the eye of an individual with eye impairment, including dry eyes. It contains a mixture of a phospholipid and a seed oil extract in a ratio of ALA to LA between 1: 1 and 6: 1, astaxanthin and at least one carotenoid selected from the group consisting of lutein, trans-zeaxanthin and meso-zeaxanthin. It is formulated into a single dose capsule.

In one example, the phospholipid is formed as a phospholipid-rich egg roe extract comprising at least 50 percent phospholipids. In another example, the phospholipid includes at least one of phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, phosphatidic acid, lysophosphatidylcholine, lysophosphatidylethanolamine, and lysophosphatidylserine. In another example, the phospholipid is derived from at least one of a vegetable source, an algae source, and an animal source or synthetic derivative.

In another example, a mixture of antioxidants is mixed with the phospholipid and the seed oil extract. The astaxanthin may be derived from a natural or synthetic ester or a synthetic diol. In another example, the seed oil extract is formed as a superficial CO2 fluid extracted perilla seed oil derived from a broken biomass of Perilla frutescens, the seed oil containing 60 to 95 percent (w / w) PUFAs in a ratio of 4: 1 to 6: 1 alpha-linolenic acid (ALA) to linoleic acid (LA). The astaxanthin makes in another example about 0.1 to 16 The lutein constitutes about 0.4 to 30% by weight of the mixture of phospholipid and seed oil extract, and the trans-zeaxanthin constitutes about 0.04 to 24% by weight of the mixture of phospholipid and seed oil extract.

A nutritional supplement composition is formulated in a therapeutically effective amount to treat the eye or cardiovascular impairment of an individual and includes a mixture of a phospholipid and a seed oil extract in a ratio of ALA to LA between 1: 1 and 6: 1, and at least one of coenzyme Q10 and lutein. It is formulated into a single dose capsule.

A method of treating the eye of an individual with eye impairment, including dry eye, is by administering in an oral dosage form a therapeutically effective amount of a dietary supplement composition comprising a mixture of a phospholipid and a seed oil extract in a ratio of ALA to LA between 1: 1 and 6: 1, astaxanthin and at least one carotenoid selected from the group consisting of lutein, trans-zeaxanthin and meso-zeaxanthin, said composition being formulated in a single dose capsule.

A method for treating eye impairment or cardiovascular impairment in a human is by administering an oral dosage form of a therapeutically effective amount of a nutritional supplement composition comprising a mixture of a phospholipid and a seed oil extract in a ratio of ALA to LA between 1: 1 and 6: 1 and at least one of coenzyme Q10 and lutein and formulated in a single dose capsule.

Brief description of the drawings

Other objects, features and advantages of the present invention will become apparent from the following detailed description of the invention when considered in light of the accompanying drawings, wherein:

1 Figure 7 is a flow chart illustrating a production diagram as a flow chart for the production of omega-3 chia seed oil, such as sold under the trade name Chia Gold ^™ by Valensa International, Eustis, Florida.

2 Figure 7 is another production diagram, as a flow chart, showing the basic steps for making perilla seed oil extract, by way of non-limiting example.

3 Figure 4 is a graph showing the comparison of the Rancimat performance of various oils, including oils extracted from chia seeds and perilla seeds, by way of non-limiting example.

Detailed Description of the Preferred Embodiments

The present invention will now be described in more detail. 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 seed oil extract and the added phospholipids, such as from rye extract, and the mixed carotenoids, including astaxanthin, such as S, S'-astaxanthin derived from Haematococcus pluvialis and one or more of lutein and / or trans-zeaxanthin or meso-zeaxanthin , in one example, provide an ophthalmic care composition and method which delays and improves eye diseases and injuries and prevents, delays or treats diseases or injuries of the eye and central nervous system, including age-related macular degeneration, cataract, dry eye syndrome is due to glandular inflammation and other degenerative diseases of the central nervous system, light injury, ischemic diseases and inflammatory diseases, including cardiovascular disease. The phospholipids will enhance the absorption of carotenoids and other ingredients, for example, lutein alone and coenzyme Q10.

It should be understood that phospholipids may be used alone or in combination with the seed oil extract, such as a perilla seed extract produced by supercritical COO2 fluid extraction. For example, the phospholipid may be formed as a phospholipid-rich rogen extract comprising at least 50% phospholipids. This extract will often not flow adequately, depending on the end-use application, and the seed oil extract is added to it at a ratio of 1: 1 to 6: 1, which may also include various phospholipids and, in one example, some EPA and DHA. Various phospholipids may be used, including at least one of phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, phosphatidic acid, lysophosphatidylcholine, lysophosphatidylethanolamine and lysophosphatidylserine. This phospholipid may be derived from at least one of a vegetable source, algae source and animal source or a synthetic derivative, and may contain a mixture of antioxidants mixed with the phospholipid alone or with the seed oil extract alone or mixed with the phospholipid and seed oil extract. Phospholipids can be obtained from a marine source such as krill oil or a vegetable source such as soybean, safflower and sunflower, as non-limiting examples. Another example is phospholipids from egg yolks.

The phospholipids may not have phospholipid-linked EPA or DHA in some examples, and in other examples, the phospholipids may contain some EPA or DHA. For example, krill oil in a sample may have 70-190 mg / g EPA and 30-160 mg / g DHA with a total EPA / DHA content of 100-350 mg / g while the fish oil content is about 500-700 mg / g wherein the fish oil triglycerides contain a much higher content of EPA and DHA. Krill oil, algae oil and other similar oils all have omega-3s, while plant-based phospholipids generally have little or no but contain ALA and LA. For this reason, in a non-limiting example, it is preferred to use a phospholipid such as Rogen extract with a seed-based extract or seed oil extract with ALA and LA in a ratio of between 1: 1 and 6: 1.

Phospholipids may contain glycophospholipids and lysophospholipids. The phospholipids are used to deliver small amounts of drug and, in one example, include the plant-based phospholipids and commercially available lecithins and egg yolks and seed-based oils. Phospholipids increase the bioavailability of the added substrate. One example involves phospholipids derived from plant sources that usually do not contain long chain polyunsaturated n-3 fatty acids (PUFAs). While it is explained that the phospholipids aid in the absorption of a carotenoid, such as astaxanthin and lutein, it should be understood that the phospholipids may increase the absorption of other components, such as coenzyme Q10.

The various patents incorporated by reference and the parent applications and original parent applications described below disclose the use of seed oil extracts and of some phospholipids. The description is continued with the description of a seed oil extract, such as one derived from Chia, followed by a description of Perilla seed oil extract and then with examples of other seed oil extracts, followed by examples of phospholipids used alone or in combination with seed oil extracts and carotenoids, such as For example, astaxanthin and lutein, and other components such as coenzyme Q10 may be used. Some of the phospholipids in one example are derived from plants and seed oil extracts because they have ALA and LA, and phospholipids in some instances would be substantially free of EPA and DHA.

Now follows a description directed to the formation of a seed oil extract, such as an oil extracted by solvent extraction using supercritical CO2 fluid from the appropriately pre-milled Salvia hispanica L. seed. This description is followed by a description of the formation of perilla seed oil extract. The perilla seed oil extract can be used in the present composition and method. Chia production is explained because many parts of the manufacturing process are similar to the production of perilla seed oil extract. In another example, other seed oil extracts are disclosed.

The jointly transmitted U.S. Patent No. 8,586,104 discloses a storage stable mixture at room temperature of an approximately 3.1: 1 to about 3.3: 1 mixture of alpha-linolenic acid ("ALA", polyunsaturated omega-3 fatty acid "(" PUFA ")) to linoleic acid ( "LA", "omega-6 PUFA") prepared in the presence of limited amounts of saturated and monounsaturated fatty acids as their mixed triglycerides, using either supercritical fluid CO2 solvent extraction of premilled Salvia hispanica L. " Seeds alone and in particular a supercritical fluid CO2 solvent extraction in the presence of mixtures of hydrophilic and lipophilic antioxidants or below Use of a conventional extraction with an organic solvent, such as hexane, or using Expellerpresstechniken. The supercritical CO2 extraction is preferred.

Omega-3 and omega-6 PUFAs are well known as essential fatty acids in humans and many animals useful in humans and animals, for example, to promote a healthy human heart condition. However, it is also well known that PUFAs are extremely susceptible to rapid, uncontrollable degradation mediated by free radicals.

The chia seed composition includes a supercritical CO2 seed oil derived from Salvia hispanica L. comprising 60-88% PUFAs in a ratio of about 3.1: 1-3.3: 1 alpha-linolenic acid (ALA) to linoleic acid ( LA), 4-10% monounsaturated C-18 fatty acid, 1-5% saturated C-18 fatty acid and 4-8% saturated C-16 fatty acid in a mixed triglyceride form that is stable at room temperature for 12-24 months and a mixture of selected antioxidants.

This composition of matter, as a mixture of a phospholipid and a seed oil extract, may contain nutritional supplement ingredients such as docosahexaenoic acid (DHA) and / or eicosapentaenoic acid (EPA) in pectin or gelatin based confectionery dietary supplement delivery systems. EPA, DHA, docosahexaenoic acid (DPA) or gamma-linolenic acid (GLA), fish oil, krill oil, krill oil concentrate, borage oil, evening primrose oil, olive oil or other seed or fruit oils based on plants, animals or algae may be present either alone or in combination be mixed. Lipophilic antioxidants can be used either alone or in combination with the mixture of phospholipids and seed oil extract and 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) docosenaphenic acid (BHA) and i) tertiary butylhydroquinone (TBHQ) are added. As disclosed, a hydrophilic antioxidant or sequestering agent includes hydrophilic phenolic antioxidants, including at least one of grape seed extract, tea extracts, ascorbic acid, citric acid, tartaric acid and malic acid. These ingredients may be added to the phospholipid and seed oil extract, such as perilla seed oil extract, as used in the eye or cardiovascular system composition of interest.

In this example of chia, a PUFA-rich seed oil extract is prepared from Salvia hispanica L. seed which is one of the most naturally favorable seed-based concentrations and ratios for the essential fatty acids, and in particular the essential fatty acids ALA and LA in a ratio of approximately 3.3: 1 as a mixture of ALA and LA which is stable at room temperature for long periods of time when it is treated as desired and appropriate with antioxidants either before, during or after (or a combination thereof). A shelf life of 12-24 months was found.

Such oils, including chia, and especially the more advantageous perilla or other seed oil extracts, are used either alone or advantageously in combination with other ingredients, for example, phospholipids and alpha-linolenic acid (ALA) or linoleic acid derived from algae, plants or fish oil (LA ) Metabolites, such as eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), gamma-linolenic acid (GLA) or docosahexaenoic acid (DHA), or any combination thereof, incorporated into suitable foods, beverages or nutritional supplements to prevent or alleviate such diseases as cardiovascular Illness, arthritis, pain, blood clotting, dry eyes and brain health.

Alleviation of such diseases has been demonstrated by the competitive control of the LA metabolic cascade and the resulting metabolic cascade products from LA metabolism, commonly known as eicosanoids, such as prostaglandins and thromboxanes of series 2 and 3, the leukotrienes and series 4 lipoxins, and Series 5 leukotrienes, all of which are potent platelet aggregators and / or inhibitors, inflammatory promoters, vasodilators, bronchoconstrictors or anti-asthmatic agents, and the like.

The consumption of ALA has been shown to be a very potent competitive substrate of delta-6-desaturase, which is known as a rate-limiting enzymatic step in both ALA and LA metabolism for the metabolic products discussed above.

An attempt of extraction of unmilled Saliva hispanica L. seeds (and in some cases perilla seeds and other seeds) using supercritical CO2, even at extraordinary results high pressures of 1,000 bar or using hexane solvent at atmospheric pressures little or no seed oil, so that the seed is ground before extraction. The freeness, as measured by particle size distribution, is, in one non-limiting aspect, advantageous for the extraction process, since the efficiency and completeness of the extraction process will be greater, either through organic solvent based or supercritical fluid based processes, the larger the surface area. Moreover, it is often advantageous to grind the seed, such as chia seeds, perilla seeds or other seeds, in a shell of inert gas, such as nitrogen, to prevent peroxidative processes otherwise occurring in the presence of air or oxygen and so on Be initiated light. It should be understood that the modified modification steps used on chia also apply to perilla seeds, but that different pressures, temperatures, cycle times and other parameters would change not only for the different seeds, but also for the extracted desired finished oil.

In one example, whole seed of Salvia Hispanica L. is either minced first in a standard knife mill or hammer mill, or more preferably ground in a roller mill, preferably under a cold nitrogen atmosphere, to produce a broken seed biomass. The seed biomass is preferably treated with one or more hydrophilic and / or lipophilic antioxidants by mixing the antioxidants to the resulting biomass. In another embodiment, the antioxidant may advantageously be added to the seed before or during the milling process or at the time of extraction, without previously blending the antioxidants, due to the nature of the extraction process, evenly with the total resulting biomass. The biomass is then transferred to a supercritical fluid extraction unit to separate the seed oil from the crushed or flaked biomass.

Alternatively, the prepared biomass may be transferred to a conventional hexane solvent extractor or, for example, an expeller press, and the oil extracted from the biomass accordingly. Preferably, each process is carried out in the absence of oxygen or air.

The supercritical fluid extraction of the ground seed mixed with hydrophilic and / or lipophilic antioxidants is achieved by supercritical CO2 or CO2 and propane as co-solvent or supercritical propane at 40-1000 bar in the pre-milled, broken or flaked seeds at 30-100 ° C is exposed. More preferably, the seed oil is extracted from the biomass between 50-800 bar at 50-90 ° C in such amounts of CO2, measured in kg / kg of biomass, and extracted for such times as may be required to produce high levels of seed oil content to extract the biomass. In addition, entrainment solvents can be added to the supercritical fluid to further increase the efficiency of such extractions. For example, the supercritical carbon dioxide extraction of the biomass can be enhanced by the addition of propane to the supercritical extraction fluid.

The resulting seed oil dissolved in supercritical solvent (s) is next fractionated into two separate pressure reduction stages, thereby allowing collection of a light and a heavy fraction of seed oil extract. This light fraction also contains water co-extracted from the seed mass , The resulting seed oil, after degassing, is separated from any water that might have been transferred during the extraction of the water-containing biomass. The light fraction of the seed oil extract is rich in flavor and odor components and can be mixed with the heavy fraction or can be discarded depending on the desired product characteristics.

After separating the water remaining in each fraction, the fractions are then kept under nitrogen or other inert gas and additional amounts of lipophilic and / or hydrophilic antioxidants can then be added. In addition, the resulting fractions may also be treated with bleaching earth, activated charcoal and other processing aids as may be required for the oil to be suitable for its intended use in humans and animals.

The PV (peroxide value) of the resulting seed oil extract is typically below 2.0 meq / km, while the accelerated decomposition using the Rancimat instrument is notably indicative of an extrapolated shelf life at room temperature of about 1-2 years. Surprisingly, if the same procedure is repeated without the use of antioxidants, the resulting PV is below 10.0 meq / kg, most likely due to the use of supercritical CO2, which results in minimal exposure of the oil to oxygen species. However, in the presence of air, the resulting oil begins to rapidly build up a peroxide value even when stored at temperatures of 0 ° C. In addition, such unstabilized oils show very poor stability with accelerated Rancimat testing to heat and oxygen, unlike the Rancimat performance observed with stabilized oils derived from the process described above. Therefore, the antioxidants described above are used.

The resulting ee oil extract extracted with supercritical fluid from chia contains 60-88% PUFAs in a ratio of 3.1: 1-3.3: 1 ALA: LA, 4-10% C18 monounsaturated fatty acid, 1-5 % saturated C-18 fatty acid and 4-8% saturated C-16 fatty acid composition in a mixed triglyceride form, depending on the seed source used.

On the other hand, when the process described above is performed without the use of hydrophilic and / or lipophilic antioxidants, the resulting seed oil extract has an initially low PV, but accelerated stability testing using a Rancimat instrument shows extrapolated room temperature stability of less than two months at.

The stability of the resulting oil at room temperature, which is produced without the use of added antioxidants, is due to the available amounts of strong natural antioxidants found in whole seeds of Salvia hispanica L., whose activity is easily reduced to oxygen radical. Absorbance Capacity Units (ORAC) units, does not explain easily. Salvia hispanica L. has a measured ORAC number of 3,000 micromoles of TE ORAC units / gram of seed and is known to contain anti-oxidants such as myricetin, quercetin, kaempferol, caffeic acid and chlorogenic acid. In addition, it is well known that all the seeds of Salvia hispanica L, unlike many other seeds bearing PUFA-containing oil, have a shelf life of at least 5 years due to their structure and the natural antioxidants present in the seed matrix exhibit.

In addition, cold pressing of whole seeds of Salvia hispanica L. without the gentle addition of suitable antioxidants to the seeds before the expeller pressing process also produces a non-stable seed oil.

All resulting seed oil fractions can be treated with additional antioxidants to achieve the desired stability at room temperature. The amount of oil extraction can be controlled by the particle size distribution of the ground or flaked seeds. Propane can be added as a mixture with supercritical CO2 in the supercritical state as extraction solvent. In another aspect, solvent may be extracted by using hexane extraction at or near atmospheric pressures and the resulting boiling point of hexane in the absence of oxygen, separating the resulting water from the oil / hexane mixture, and removing the hexane solvent by distillation at or below atmospheric pressure Absence of oxygen is removed.

In one aspect, an emulsifier is added. In another aspect, nano- and / or microparticles are dispersed from rice or cane-derived polycosanol to improve a heart health-promoting dietary supplement. A stabilized oil in a fruit juice concentrate, fruit puree or other water based flavor is dispersed in the presence of maltodextrin or other carbohydrates and a suitable emulsifier or emulsion stabilizer which is spray dried under vacuum to form an amorphous or crystalline solid suitable for use as Flavoring ingredient containing stabilized PUFAs in flavored food supplements, foods and beverages. In another aspect, oil-based flavors and fragrances suitable for use as ingredients in foods, beverages and cosmetics are added. ALA and LA are also added as essential fatty acids.

The process, as described with respect to the chia seed oil extract, can be applied to many different seed oil extracts, changing the different CO2 extraction parameters for each seed. It is well known in the pharmaceutical, parapharmaceutical and food industries that the selected processing parameters and production techniques used in CO2 extraction alter the composition of the final product, both the product usually extracted in oil and the solid residue, which could remain in the extractor unit after oil extraction and could be commercially sold as flour with specific restrictions imposed on its characteristics. Although perilla seeds are from the same mint family as chia seeds, the oil extracted from the CO2 extractor and the flour remaining as residue in the extractor are very different. In CO2 extraction, supercritical CO2 has a high solvation capacity, which depends on the density. By changing the density (with pressure), the CO2 extractor is able to select the quality, the quantity and the specific physicochemical characteristics of the oil being extracted and any residue remaining as flour after the oil extraction.

Therefore, the oil extracted from perilla seed or other seed and the yield and residue left after the oil extraction by the supercritical CO2 extraction is largely dependent on the variation in density, pressure parameters and other extraction parameters. The extracted oil and any final residue, such as a flour, may be substantially different from any other type of extracted oil and tailings based on the selected extraction parameters. The final yield from the extractor, such as the oil and any residue remaining after oil extraction, also depends on the type of pre-grinding used to form the broken biomass. The manner of grinding or rolling the seed into flakes to obtain the broken seed biomass can be varied. The extent and nature of seed breakup are relevant to final extraction yield as extracted oil and residual residue during the supercritical fluid extraction process.

As already mentioned, it has also been found that the use of a perilla seed oil extract is more advantageous and, in some instances, has a very favorable ratio of ALA to LA (omega-3 to omega-6) of up to about 6: 1 compared to chia seed oil. where the ratio is usually about 3.3: 1 ALA to LA. Perilla seed oil extract is obtained in a similar manner as described with respect to the production and extraction of the chia seed oil, by way of non-limiting example. However, it has been found in some non-limiting examples that the perilla seed oil extract is an even healthier source of omega-3 than chia seed oil and is well-endowed with astaxanthin and other carotenoids, including phospholipids, for ocular health and cardiovascular health when coenzyme Q10 is used.

1 Figure 3 is a flow chart showing, for a series of steps, a production diagram for the production of omega-3 chia seed oil, such as sold under the tradename Chia Gold ^™ by Valensa International, Eustis, Florida. The Salvia hispanica seed is provided (block 100 ) and the breaking up of the seeds takes place (block 102 ) to form a broken biomass. As described above, various techniques can be used to break up the seeds and to form the biomass. The supercritical CO2 extraction (block 104 ) uses ultra-high pressure carbon dioxide extraction technology and uses CO2 (Block 106 ), Such as DEEP EXTRACT ^® -Herstellungsverfahren, developed by Valensa International, Eustis, Florida. The defatted seed is used, for example, as flour (Block 108 ) produced. The separation of the different proportions takes place, for example, by fractionation of the seed oil extract (block 110 ), Like previously described. The extract is collected (block 112 ). There is a dewatering and decanting (block 114 ) and antioxidants are added (Block 116 ), Such as the OTB ^® peroxidation blocking system of Valensa International. A quality control analysis is performed (block 118 ) and the finished oil is packed (block 120 ).

2 shows a second production diagram as a flow chart for the production of Perillasamenölextrakts according to a non-limiting example. This process can be used with other seeds. The procedure begins with a source of perilla seed, also known as perilla frutescens seed (Block 130 ). According to the process with the omega-3 chia seed oil, the breaking up of the seeds takes place (Block 132 ) to form a broken seed biomass, followed by extraction (Block 134 ) by means of supercritical CO2 extraction and the supply of carbon dioxide (Block 136 ) to the defatted seeds (block 138 ), which are partially or completely defatted perilla seeds as a cake residue with virtually no fat or oil. The other part is the separated oil and the CO2 is recovered (block 140 ). Similar to omega-3 chia seed oil, the extract is collected (block 142 ) and dewatering and decanting takes place (Block 144 ). Antioxidants, such as the ^OTB® components described above, are added (Block 146 ) and the quality control analysis (block 148 ) followed by packaging (block 150 ).

It should be understood that the perilla seed oil extract can be supercritically extracted in a similar process as used with the chia seed, as described above. For example, the resulting seed oil is fractionated with the perilla seed extract after supercritical solvent extraction in two separate pressure reduction stages, thereby allowing the collection of a light and a heavy fraction of the seed oil extract. The process and temperatures may be modified to be suitable for perilla seed oil or other seed oils, such as extraction from the biomass between 50-800 bar at 50-90 ° C, and in such amounts of CO2, measured in kg / kg Biomass, as well described above, but depending on the desired final oil product, different temperatures can be used. It is possible to use propane as co-solvent or only supercritical propane at 40-1000 bar at 30-100 ° C.

As mentioned above, the perilla seed oil extract may have a fatty acid profile range of values depending on the quality and type of seed break parameters and extraction. Total fatty acids, peroxide values and other component values are described below in Table 1, which shows analysis of the perilla seed oil extract and various parameters, specifications and results as a non-limiting example. The results may of course vary for different samples. Ingredients: Perilla (Perilla frutescens (L.) Britton) seed oil, O2B ^™ botanical peroxidation blocker with refined, non-GMO soybean mixed tocopherols and spice extract. parameter specification Result description clear, yellow oil, pourable at room temperature is compliant odor mild is compliant solubility insoluble in water, miscible with oils is compliant Fatty acid profile (%) VQP-050 (GV) palmitic 6.3 stearic acid 1.9 oleic acid 22.3 linoleic acid 9.7 α-linolenic acid > 56 59.8 Total fatty acids (% w / w) 85 ... 95 88.6 Peroxide value {megO2 / kg) <10 VQP-049 2.3 Water content (%) <1.5 VQP-048 <0.2 Heavy metals (ppm) <10 ICP-MS <1 Microbiological data (cfu / g) Total number of aerobic bacteria <10 ³ USP <61> <100 Total number of yeasts and molds <10 ² USP <61> <100 E. coli / total coliforms <10 ² AOAC 991,14 <10 (all values according to current knowledge and technology status)

All ingredients are GMO-free. Therefore, this product complies with EU regulations 1830/2003 and 1829/2003. The product was not treated with gamma rays.

Table 2 shows the accelerated stability study of Perillasamenextrakts with OTB ^® -Peroxidationsblocker and Table 3 shows the accelerated stability study of a Perillasamenextraktprobe, which was produced by Valensa International, Eustis, Florida, compared to Chiasamenextrakten such as Chia GoldTM that through the in 1 shown method is produced. TABLE 2 Accelerated stability study of Valensa Perillasamenextrakt with O2B ^® Rancidity induction time Shelf life at 20 ° C (Hrs.) 1 (Years) 2 Perilla oil (without O2B) 7 0.5 Perilla oil (with O2B) 42 2.8 1. Rancimat induction time, measured in hours, under which air bubbles are passed through heated oil (90 ° C).
2. Ranicmat data is dependent on accelerated exposure to high heat and oxygen. The extrapolated data plots are assumed to be linear in the presence of air and light at 20 ° C, but if the product is stored at 20 ° C in an air- and light-tight package, then the durability doubles at least. TABLE 3 Accelerated stability study of Valensa-Perillasamen- and -Chiasamenextrakten with O2B ^® Rancidity Induction time (hours) 1 Shelf life at 20 ° C (year) 2 Increase in durability (%) Perilla oil (without O2B) 7 0.5 Perilla oil (with O2B) 42 2.8 611% Tresalbio chia oil (without O2B) 12 0.4 Tresalbio chia oil (with O2B) 73 2.2 603% ChiaGold oil (without O2B) 9 0.3 ChiaGold oil (with O2B) 60 1.8 663% 1. Rancimat induction time, measured in hours, under which air bubbles are passed through heated oil (90 ° C).
2. Ranicmat data is dependent on accelerated exposure to high heat and oxygen. The extrapolated data plots are assumed to be linear in the presence of air and light at 20 ° C, but if the product is stored at 20 ° C in an air- and light-tight package, then the durability doubles at least.

Table 1 illustrates various values and shows that the total fatty acids (% w / w) are between 85 and about 95 and that the result in this particular example is 88.6. It should be understood that the seed oil could possibly have only about 60% and up to about 95% w / w PUFAs and a ratio of about 4: 1 to about 6: 1 ALA to LA. The peroxide value of the seed oil is usually below 10.0 meq / km. The PUFAs typically comprise at least over 50% ALA and are in the example shown in Table 1 above 56% and in a particular in 1 example, they are 59.8. The seed oil is, in one particular example, stable at room temperature for up to 32 months. Other data are shown, such as specific components of fatty acids and water content, heavy metals in PPM and microbiological data in CFU / G, such as the total number of aerobic bacteria, the total number of yeasts and molds and E. coli / total coliforms. All values correspond to the current state of knowledge and technology and the ingredients are GMO-free. Therefore, this product complies with EU regulations 1830/2003 and 1829/2003. This product has not been treated with gamma rays. The ingredients include perilla seed oil (Perilla frutescens (L.) Britton), OTB® botanical pro-oxidation ^blocker , including refined tocopherols mixed with non-GMO soybean and spice extracts. GMO corresponds to genetically modified organisms and therefore non-GMO refers to non-genetically modified organisms. The soybean has not been produced by biotechnological or genetic gene splicing techniques.

3 Figure 3 is a graph showing a comparison of the Rancimat performance of various oils, including the chia seed oil extract produced as described above with respect to the perilla seed oil extract, also produced as discussed above. Flaxseed oil and various values including algae oil are also illustrated.

There are marked differences between chia seed-derived compositions and perillasamine compositions. These include not only the ratio of ALA: LA: oleic acid (omega3: omega-6: omega-6), but also the differences between the (partially defatted) post-extraction residues (ChiaMax or PerillaMax). ChiaMax produces a strong thixotropic grease in water. A spoon can stand upright in hydrogenated ChiaMax, while PerillaMax has no thixotropic properties. Chia seed oil has a content of about 32% CO2 extractable oil, while perilla seed has a content of about 45% extractable oil.

A key difference between chia and perilla oils is the amount of omega-9 (oleic acid, a monounsaturated acid) present in perilla seed oil to a much greater extent than in chia seed oil, as shown by the fatty acid profiles shown below. Since perilla seed oil has a very high ALA to LA ratio, it is healthier in a Western diet. Such diets are characterized by ratios of very high levels of proinflammatory LA (omega-6) to low levels of anti-inflammatory ALA (omega-3). Also, because perilla seed oil extract contains three times as much oleic acid as chia seed oil, it is even healthier because it is known that oleic acid lowers LDL levels in humans (Mediterranean diet). When LDLs are oxidized, this triggers the process of atherosclerosis.

The ratio of omega-3 ALA to omega-6 LA is much higher in perilla seed oil than in chia seed oil and one reason is that the LA content in perilla seeds accounts for a large proportion of the LA evident in chia seed oils with oleic acid (omega-9 ), has replaced.

Comparing the Rancimat data between CO2-extracted chia seed oil and CO2-extracted perilla seed oil, the latter is more stable than chia seed oil, both with and without added antioxidants (O2B), despite a high level of unsaturated fatty acids present in extracted perilla seed. Both oils contain the same relative total percentage of unsaturated acids. However, perilla seed oil contains about 10% less polyunsaturated fatty acid than chia seed oil. This explains why CO2-extracted perilla seed oil is intrinsically more stable than CO2-extracted chia seed oil, as shown in the attached Rancimat data in 3 demonstrate. Perilla seed oil (CO2 extracted): component % Average % Fatty acids in profile palmitic 5.8 6.4 stearic acid 1.8 2.0 oleic acid 19.4 21.3 linoleic acid 8.8 9.7 linolenic 55.0 60.6 total fatty acids 90.8 100.0 Chia seed oil (CO2 extracted): test protocol Specifications / limits Result analyst Water content (%) VQP-050 ≤ 1.5 0.1 MS peroxide VQP-050 ≤ 10.0 1.3 MS Palmitic acid (%) VQP-050 n / A 6.4 7.0 GM Stearic acid (%) VQP-050 n / A 3.6 3.9 GM Oleic acid (%) VQP-050 n / A 7.6 8.3 GM Linoleic acid (%) VQP-050 n / A 20.1 21.9 GM Linolenic acid (%) VQP-050 n / A 54.0 58.9 GM Total fatty acids (%) VQP-050 85.0 to 95.0 91.7 100.0 GM

The production diagram in 2 Figure 4 shows the process used to obtain the perilla seed extract according to a non-limiting example. It should be understood that the extraction technology produces materials for human nutrition and nutritional supplementation and offers several advantages, including improved efficiency in the isolation of key components, to allow for higher dosage and targeted performance. The extraction allows for standardization. Natural materials have a rather different composition and through the extraction they become consistent. It is also convenient because smaller dosages of high potency substances allow a consumer to achieve the necessary levels of nutrients in a daily diet. The safety is also higher, because the extraction results in more of the desired products and less of what is undesirable. The extraction allows the removal of compounds that are not optimal for human health from natural substances.

The desired extraction technology utilizes Valensa International's DEEP EXTRACT ^® process as an ultra-high pressure carbon dioxide extraction technology that produces micronutrients and high extraction efficiency to deliver more of the high molecular weight compounds that are more similar to natural source materials. The process is flexible and allows, where appropriate, a possible fractionation of the product and a delivery of specific compounds from the raw material.

This extraction procedure, such as DEEP EXTRACT ^® process provides a more gentle treatment of high quality raw materials at temperatures which are substantially below those used in other Expellerpressverfahren and some chemical solvent extraction processes in the absence of oxygen. This reduces the degradation of susceptible compounds, the chemical change of a component and the oxidation potential. The supercritical CO2 process virtually provides the sterilization of the final product and biomass, which does not come in contact with chemical solvents and remain "natural" prior to extraction. As described above, selective fractionation is advantageous. A major tool used to tailor the resulting fractionated products in terms of product quality and efficient manufacturing is printing. Because CO2 extraction is a purely natural and organic process, the end product has no impurities and residues and, through supercritical CO2 extraction, provides high molecular weight compounds such as sterols, carotenoids and long chain alcohols.

Supercritical CO2 extraction is advantageous over other methods used to extract plant preparations, including tinctures (usually alcohol extraction, steam distillation, expeller pressing, sometimes referred to as "cold pressing", and chemical solvent extraction). The chemical solvent extraction technology using strong solvents and supercritical CO2 technology using high pressures usually provide the most complete extraction of a plant preparation. The supercritical CO2 extraction, which is carried out under very high pressure, is advantageous. When carbon dioxide gas (CO2) is compressed above 73 bar at a temperature above 31 ° C (87.8 ° F), it is converted as supercritical CO2 into a dense gas that has extremely high solvation capacity and the ability to incorporate components of plant preparations to extract. Its solvation capacity is dependent upon its density, and by changing its density under pressure, the manufacturer is able to select the quality, quantity, and specific actives of the target extract. Supercritical CO2 is biocompatible and widely recognized as safe by the FDA (Generally Recognized As Safe = GRAS). It is also not flammable and environmentally friendly.

Any degreased cake resulting from the supercritical CO2 process is generally useful and may be marketed or used for further processing in a wide range of human applications / food applications. Sometimes the defatted cake is the primary product and the oil is the secondary product, as in the co-transferred one U.S. Patent No. 8,652,544 described, which is hereby incorporated by reference in its entirety. The application describes a chia seed composition composition formed from a stable, defatted whole wheat flour derived from ground whole seeds of Salvia hispanica L. using a suitable solvent, such as by using supercritical CO2 fluid extraction. This chia seed extraction shows that after processing supercritical CO2, the extract cake in some examples contains virtually no fat or oil and the resulting powder consists of about 50% protein and 50% carbohydrates, which are essentially fiber. The Perillamehlrückstand, as it remains in the oil extraction, is also useful and in the co-transferred U.S. Patent Publication No. 2013/0280370 disclosed.

The supercritical CO2 process provides a gentle treatment of high quality raw materials at temperatures substantially below those used in expeller pressing in some chemical solvent extraction operations in the absence of oxygen. This reduces the degradation of vulnerable compounds, the chemical change of components and the oxidation potential. The supercritical CO2 process virtually provides the sterilization of the final product and biomass, which do not come in contact with chemical solvents and remain as "natural" as they were before extraction. This also allows for the advantage of selectively fractionating the extracted components under pressure, tailoring the resulting fractionated products for product quality and efficient production. It is focused on pesticide / insecticide residues and addresses concerns about microorganisms present in expellerpress materials.

The Perillasamenextract, by the process 2 and is obtained as described above, drained and decanted, and antioxidants, such as the OTB Valensa ^® peroxidation blocking system are added as a stabilizer to ensure that the botanical extract reaches the consumer in an efficient and safe form ensure. The stabilization with the ^OTB® components enhances durability and continuous product quality and is superior to the use of preservatives to stabilize natural substances, which is often considered negative by consumers. The OTB ^® peroxidation blocking system used by Valensa is 100% natural, GMO-free and protects sensitive oils and in particular the polyunsaturated oils derived from fish and plant preparations, from manufacture to consumption. The ^OTB® peroxidation blocker is a synergistic, proprietary formulation of strong natural compounds, including astaxanthin, phenolic antioxidants and natural tocopherols, as described above. This technology prevents destructive, oxidative, photochemical and rancid reactions. It protects expensive and sensitive compounds, such as carotenoids and polyunsaturated fatty acids, and can greatly enhance the effectiveness of other antioxidants, such as vitamin E, by chemically trapping vitamin E-stable free radicals. The antioxidants exhibit in vivo activity to protect both products and humans.

Perilla has many essential oils. These are extracted from the perilla leaves. About 50% to about 60% perillaldehyde accounts for most of the aroma and taste of perilla. There are other terpenes, such as limonene, caryophyllene and fernese. There are other chemotypes, such as Perilla-Keyton (PK), Escholzia-Keyton (EK), Perillen (PL) and various phenylpropanoids, such as myristicin, dillapiol and elemicin. Citral is a species that is rich in rosefuran. Perilla oil is typically obtained by pressing the perilla seeds, which contain from about 35% to about 45% oil. In some areas of Asia, perilla oil is an edible oil that is valued for its medicinal benefits. As a rule, perilla oil is a rich source of omega-3 fatty acid alpha-linolenic acids. As a drying oil, it is similar to tung oil or linseed oil and is sometimes used in paint, glaze, linoleum, printing ink, varnish and other waterproof protective coatings. In Japan, perillaldehyde oxime (perillartin) is used as an artificial sweetener and is usually about 2,000 times sweeter than sucrose.

Rancimat testing has demonstrated the benefits of perilla seed oil extract, by way of non-limiting example. This process is an accelerated oxidation test, which is a simple, fast and efficient way to screen the effectiveness of the antioxidants used in liquid fats and oils. In general, the Rancimat test is an accelerated oxidation test in which the oil or fat to be tested is run at an elevated temperature, exposing the sample to air, thereby accelerating the oxidation process of the oil. Autooxidation usually occurs within a few hours instead of months or years, and the metabolites are released into a measuring vessel, which in one example measures the change in conductivity. This would indicate the point at which the formation of volatile carboxylic acids and the oxidation took place.

It is also possible to disperse nano- and / or microparticles of policosanol derived from rice or sugarcane to provide a heart health-promoting nutritional supplement. Such additives to dietary supplement compositions are taught in commonly assigned US Pat US Patent No. 7,959,950 discloses, the disclosure of which is incorporated herein by reference in its entirety. This human or animal dietary supplement composition comprises one or more long chain (C24-C36) primary alcohols (polycosanols) dispersed in food grade oils or fats in which the average policosanol particle size in one example is greater than 2 microns and less than 10 microns and in another example is less than 100 microns.

The desired seed oil extract, such as the perilla seed oil extract, is combined with the various carotenoids, and in one example phospholipids, for improved absorption to form a composition and related method for its use, for eye health and / or cardiovascular health to treat or assist. Various carotenoids, including 3,3'S-astaxanthin derived from Haematococcus pluvialis, may be used in combination with other carotenoids, such as lutein, trans-zeaxanthin and meso-zeaxanthin for ocular health. Coenzyme Q10 may be used for cardiac health and cardiovascular health, as discussed in detail below.

It has been found that in terms of people and eye health, carotenoids with their antioxidant properties are important. About ten carotenoids are found in human serum. The major carotenoids in human serum are beta-carotene, alpha-carotene, cryptoxanthin, lycopene and lutein. Low levels of zeaxanthin, phytofluene and phytoene are found in human organs. However, only two, namely trans- and / or meso-zeaxanthin and lutein, of the ten carotenoids found in human serum were found to be found in the human retina. Zeaxanthin is the predominant carotenoid in the central macula or foveal region and comes in concentrated form in the cone cells in the center of the retina, i. H. the fovea, before. Lutein is located mainly in the peripheral retina in the rod cells. Therefore, the eye more preferably absorbs zeaxanthin than lutein in the central macula, which is a more effective scavenger of singlet oxygen than lutein. It has been theorized that zeaxanthin and lutein are concentrated in the retina due to their ability to trap singlet oxygen and eliminate free radicals, thereby limiting or preventing damage to the retina by light.

Therefore, only two of the approximately ten carotenoids present in human serum are found in the retina. Beta carotene and lycopene, the two most common carotenoids in human serum, have either not been detected or have been detected in trace amounts in the retina. Beta-carotene is barely accessible to the retina because beta-carotene is unable to effectively cross the blood-retina-brain barrier of the pigmented retinal epithelium. It is also known that another carotenoid, canthaxanthin, can cross the blood-retina-brain barrier and reach the retina. Canthaxanthin, like all carotenoids, is a pigment and can discolor the skin. Canthaxanthin provides a skin color similar to a tan and is therefore used by humans to create an artificial suntan. However, an undesirable side effect in humans is that intake of canthaxanthin in high doses over an extended period of time resulted in the formation of crystalline canthaxanthin deposits in the inner layers of the retina. Therefore, the blood-retina-brain barrier of the pigmented retinal epithelium allows only certain carotenoids to enter the retina. The carotenoids, which are not zeaxanthin, and lutein, which penetrate into the retina, cause side effects, such as the formation of crystal deposits by canthaxanthin, whose dissolution can take several years. Canthaxanthin in the retina also resulted in less adaptation to the dark.

Researchers have been unsuccessfully searching for additional antioxidants to further counteract the side effects of singlet oxygen and free radical species in the eye. Researchers have investigated the antioxidant capabilities of several compounds, including various carotenoids. Although the carotenoids are powerful antioxidants, researchers have been unable to find specific carotenoids from the 600 naturally occurring carotenoids that effectively quench singlet oxygen and capture free radical species that are able to cross the blood-retina-brain barrier have the side effects of canthaxanthin after crossing the blood-retina-brain barrier, and which improve eye disease or injury and / or delay the progression of a degenerative disease of the eye and are more potent antioxidants than either lutein or zeaxanthin.

It is known that singlet oxygen and free radical species significantly contribute to injuries and diseases of the central nervous system and in particular of the eyes. For example, it has been reported that the consumption of an antioxidant such as ascorbic acid (vitamin C), alpha-tocopherol (vitamin E) or beta-carotene (which is converted to lutein in vivo) may reduce the prevalence of age-related macular degeneration.

Several carotenoids, including astaxanthin, are potent antioxidants compared to beta-carotene, ascorbic acid and other in vitro widely used antioxidants. It is also known that certain carotenoids selectively cross the blood-retina-brain barrier and that certain carotenoids, other than zeaxanthin and lutein, which cross the blood-retin-brain barrier, produce side effects.

Astaxanthin is a more effective antioxidant than carotenoids in vitro, such as zeaxanthin, lutein, tunaxanthin, canthaxanthin, beta-carotene and alpha-tocopherol. For example, some in vitro and in vivo studies regarding astaxanthin showed that the mean effective concentration of astaxanthin, which inhibits lipid peroxidation, was 500-fold lower than that of alpha-tocopherol. In vitro, astaxanthin has a strong quenching effect against singlet oxygen and a strong scavenging effect against free radical species. This free radical theory of retinal damage has been advanced by researchers who have studied the effectiveness of various antioxidants to improve these diseases.

Until now, research efforts have focused on preventing disease and injury because the resulting free radical-induced damage is not effectively treatable. Thus, there is a need for a method that not only prevents or retards degenerative and traumatic diseases and injuries to the central nervous system, and particularly the eye, but also improves it. It has been found that a therapeutically effective amount of an ingredient-rich composition comprises a seed oil extract such as perilla or other seed, and mixed carotenoids comprising at least astaxanthin and preferably S, S'-astaxanthin, which in one example is from Haematococcus pluvialis, and one or more of lutein and / or trans-zeaxanthin or meso-zeaxanthin. Phospholipids may also be added to enhance the bioavailability of the carotenoids and are used in combination with the seed oil extract or alone, without the seed oil extract. The composition comprises 50 to 1,000 mg of oil and in a preferred example 50 to 500 mg of oil, 0.5 to 8 mg of astaxanthin, 2 to 15 mg of lutein and 0.2 to 12 mg of trans-zeaxanthin. The oil may come from perilla seed or another seed. The oil may contain all or part of phospholipids as described below, including those derived from a rye extract. An example of the composition includes 4 mg astaxanthin, about 10 mg lutein and 1.2 mg trans-xeazanthin. This dietary supplement composition is formulated into a single dose capsule in one example. In another example, the 3,3'S astaxanthin derived from Haematococcus pluvialis accounts for 0.1 to 16% by weight of the seed oil extract and / or the phospholipids, including rye extract, the lutein makes up 0.4 to 30% by weight. % of the seed oil extract and / or the phospholipids and the trans-zeaxanthin constitutes from 0.04% to 24% by weight of the seed oil extract and / or the phospholipids. It is possible to add krill oil or an algae based oil as explained below to the seed oil extract and / or the phospholipids. Krill oil will usually give you more phospholipids.

As mentioned above, the phospholipids could be formed from egg yolk or seed oil phospholipids, and include many different plant based phospholipids that remove an omega-3 platform. The composition may contain about 40-60% phospholipids with little phospholipid-bound EPA or DHA. Sunflowers, safflower and soybean can be used as sources of the phospholipids. An example is the phospholipid-rich rye extract and it can be mixed with a seed oil and the composition can contain at least 50% phospholipids. When combined with fish oil containing EPA and DHA, the amount of DHA may be at least 50% greater than the amount of EPA. The composition may comprise about 30% triacylglycerides in one example. The phospholipids can be used alone with the carotenoid without any other type of seed oil extract, for example, phospholipids derived from a marine source or a plant-based source.

The astaxanthin is preferably derived from Haematococcus pluvialis algae, Pfaffia, krill or from synthetic routes in free diol, monoester or diester form, for example at a daily dose of about 0.5 to 8 mg and up to 12 mg, with varying ranges between 2 and 4 mg in one example.

It should be understood that the major cause of vision loss in the elderly is dry or atrophic AMD, which is having an increasing social and economic impact in the United States. As the elderly population in this country increases in numbers, AMD will be a more common cause of blindness than both diabetic retinopathy and glaucoma combined. Although laser treatment has been shown to reduce the risk of excessive macular scarring from the "wet" or neovascular form of the disease, there are currently no effective treatments for the vast majority of patients with wet AMD.

The Eye Diseases Prevalence Research Group (EDPRG) sees AMD as the leading cause of blindness among older people of European descent. White individuals are considered to be responsible for over 50% of blindness.

The EDPRG estimates that approximately 1.2 million US residents live with neovascular AMD and 970,000 live with geographic atrophy, while 3.6 million live with two-sided large drusen. These figures are expected to increase by 50% over the next 20 years, given the predicted demographic shifts.

Age-related developmental changes in retinal morphology and energy metabolism, as well as cumulative effects of environmental exposures, may make the neural and vascular retina and retinal pigment epithelium more susceptible to late-onset injury. Along with these metabolic and structural changes and exposures, the strength of the endogenous and exogenous defense system of the aging eye is also reduced. Pharmacological and surgical treatment options are currently of limited scope and effectiveness. They are expensive and can lead to complications as serious as the disease in the final stage. The likelihood of vision loss in individuals with neovascular AMD can be reduced with anti-VEGF treatment, photodynamic therapy, and laser photocoagulation.

Nutrient-based preventive treatments for AMD development and progression have been investigated in several studies, including, for example, AREDSI, an NEI-sponsored study, the LAST, TOZAL and CARMIS studies. AREDS was a multi-center study of the natural history of AMD and cataract. AREDS included a controlled randomized clinical trial designed to evaluate the effect of zinc medicated doses and / or a formulation containing nutrients with antioxidant properties (vitamin C, vitamin E and beta-carotene) on the progression rate in advanced AMD and evaluated on the visual acuity results. The use of the combination of antioxidants and zinc reduced the risk of developing advanced AMD in participants who had at least a moderate risk of developing AMD by about 25%. The overall risk of moderate vision loss [≥ 15 letters to the Early Treatment Diabetic Retinopathy Study (ETDRS) chart] was reduced by 19% at 5 years.

Out of about 600 carotenoids identified in nature in human nutrition and 20 in human serum, only two forms of nourished xanthophyll, lutein and zeaxanthin, are found in the human macular pigment. Lutein represents about 36% of all retinal carotenoids; Zeaxanthin and meso-zeaxanthin each represent about 18%.

The natural tissue distribution, biochemical and biophysical characteristics of lutein provide a reasonable basis for speculating that this nutrient is present in biological systems as: (1) an important structural molecule in cell membranes; (2) short-wavelength light filter; (3) modulator of intra- and extracellular reduction-oxidation (redox) equilibrium; and (4) modulator acts in signal transduction pathways. It was planned to include lutein and zeaxanthin in the AREDS formulation; however, at the time of the launch of AREDS, no carotenoid was readily available for preparation in a research formulation.

The data suggest that maculaxanthophylls in combination with fish oil omega-3 LCPUFAs may act as modifiable factors capable of modulating processes involved in existing AMD pathogenesis and progression, and form the basis for the ongoing AREDS II study sponsored by the US government. The intake of these compounds can also prove to be a well-tolerated preventative intervention.

The biochemical and biophysical properties of these compounds demonstrate the ability to modulate factors and processes that activate and activate the exposures associated with aging. These exposures involve developmental changes associated with aging, chronic light exposure, changes in energy metabolism, and cellular signaling pathways.

Dry eye syndrome

According to C. Stephen Foster, MD, FACS, FACR, FAAO, Harvard Medical School's Clinical Professor of Ophthalmology; Consultant at the Faculty of Ophthalmology, Massachusetts Eye and Ear Infirmary; Founder and President of the Ocular Immunology and Uveitis Foundation of the Massachusetts Eye Research and Surgery Institution et al., Dry eye is a very common disorder affecting a significant percentage (about 10-30%) of the population, especially those older than 40 years ,

In the United States, an estimated 3.23 million women and 1.68 million men, a total of 4.91 million people, are affected at age 50 or older.

Dry eye is a multifactorial disease of tear secretion and ocular surface, which results in symptoms of discomfort, visual disturbance and tear film instability with potential ocular surface damage. Dry eyes are accompanied by increased osmolarity of the tear film and inflammation of the ocular surface.

• 1) Eine oberflächliche dünne Lipidschicht (0,11 μm) wird durch die Meibom-Drüsen erzeugt und ihre Hauptfunktion besteht darin, die Verdunstung der Tränenflüssigkeit zu verzögern und eine gleichförmige Tränenverteilung zu unterstützen.
• 2) Eine mitteldicke wässrige Schicht {7 μm) wird von den Haupttränendrüsen (reflexhafte Tränenausschüttung) sowie den akzessorischen Krause- und Wolfring-Tränendrüsen (grundlegende Tränenausschüttung) erzeugt.
• 3) Eine innerste hydrophile Mucinschicht (0,02–0,05 μm) wird sowohl durch die Becherzellen der Bindehaut als auch das Oberflächenepithel des Auges erzeugt und verbindet sich mit der Augenoberfläche über ihre losen Verbindungen mit der Glycocalyx der Mikroplicae des Epithels. Es ist die hydrophile Eigenschaft des Mucins, die es der Flüssigkeit erlaubt, sich über das Hornhautepithel zu verteilen.

The tear layer covers the normal ocular surface. It is generally accepted that the tear film consists of 3 interlocking layers as follows:

• 1) A superficial thin lipid layer (0.11 μm) is created by the meibomian glands and its main function is to retard tear fluid evaporation and promote uniform tear distribution.
• 2) A medium-thick aqueous layer {7 μm) is produced by the main lacrimal glands (reflex teardrop) and the accessory Krause and Wolfring lacrimal glands (basic tear release).
• 3) An innermost hydrophilic mucin layer (0.02-0.05 μm) is created by both the goblet cells of the conjunctiva and the surface epithelium of the eye and connects to the ocular surface via its loose connections with the glycocalyx of the microplicae of the epithelium. It is the hydrophilic nature of the mucin that allows the fluid to spread across the corneal epithelium.

The lipid layer produced by the meibomian glands acts as a surfactant as well as an aqueous barrier (retarding the evaporation of the underlying aqueous layer) and provides a smooth optical surface. It can also act as a barrier against foreign substances and may also have some antimicrobial properties. The glands are holocrine, so the secretions contain both polar lipids (liquid-lipid interface) and non-polar lipids (air-tear interface) and proteinaceous material. They are all held together by ionic bonds, hydrogen bonds, and van der Waals forces. The secretions are subject to neuronal (parasympathetic, sympathetic and sensory sources), hormonal (androgenic and estrogenic receptors) and vascular regulation. The loss due to evaporation is mainly due to meibomian gland dysfunction (MGD).

The aqueous component is produced by the lacrimal glands. This component contains about 60 different proteins, electrolytes and water. Lysozyme is the most common (20-40% of all proteins) and also the most alkaline protein present in tears. It is a glycolytic enzyme that is able to break down bacterial cell walls. Lactoferrin has antibacterial and antioxidant functions, and epidermal growth factor (EGF) plays a role in maintaining the normal ocular surface and promoting wound healing in the cornea. Albumin, transferrin, immunoglobulin A (IgA), immunoglobulin M (IgM) and immunoglobulin G (IgG) are also present.

Tear depletion (ATD) is the most common cause of dry eye and is due to inadequate tear production. The lacrimal gland secretion is controlled by a neuronal reflex arc with afferent nerves (sensory trigeminal fibers) in the cornea and conjunctiva leading to the pons (superior salivary nucleus), from the efferent fibers into the nervus intermedius to the pterygopalatine ganglion and the postganglionic sympathetic and Parasympathicus nerves that terminate in the lacrimal glands run.

Keratoconjunctivitis sicca (KCS) is the name given to this ocular surface disorder. A KCS is subdivided into KCS associated with Sjögren syndrome (SS) and KCS not associated with SS. Patients with tear fluid deficiency have SS if they have an associated xerostomia and / or connective tissue disease. In patients with primary SS, there is evidence of a systemic autoimmune disease characterized by the presence of serum autoantibodies and a very serious tear fluid deficiency and ocular surface disease. These patients, mostly women, do not have a separate, identifiable connective tissue disease. There is no evidence of systemic immune dysfunction in some of the patients with primary SS, but they have a similar clinical presentation of the eye. A secondary SS is defined as KCS with a diagnosable Connective tissue disease is associated, usually a rheumatoid arthritis, but also a SLE and systemic sclerosis.

Non-SS KCS is most commonly found in postmenopausal women, in pregnant women, in women taking oral contraceptives, or in women undergoing hormone replacement therapy (especially pure estrogen pills). The common denominator here is a reduction in androgens due to either reduced ovarian function in a postmenopausal woman or increased levels of the sex hormone binding globulin during pregnancy and the use of birth control pills. It is believed that androgens are trophic for the tear and meibomian glands. Through the production of transforming growth factor beta (TGF-beta) they also exert a potent anti-inflammatory effect, which lymphocyte infiltration is suppressed.

Lipocalins (formerly known as tear-specific prealbumin), which are present in the mucus layer, are inducible lipid-binding proteins produced by the lacrimal glands that lower the surface tension of normal tears. This leads to a stability of the tear film and also explains the increase in surface tension seen in dry eye syndrome characterized by lacrimal gland deficiency. Lipocalin deficiency can lead to precipitation in the tear film, forming the characteristic mucus strands found in patients with dry-eye symptoms.

The corneal epithelium glycocalyx contains the transmembrane mucins (glycosylated glycoproteins found in the glycocalyx) MUC1, MUC4 and MUC16. These membrane mucins interact with soluble, secreted, gel-forming mucins produced by the goblet cells (MUC5AC) and also with others such as MUC2. The lacrimal gland also secretes MUC7 into the tear film.

These soluble mucins move freely in the tear film (a process facilitated by blinking and electrostatic repulsion from the negatively charged transmembrane mucins), act as cleansing proteins (collecting debris, debris, and pathogens), hold fluids due to their hydrophilic nature, and host defense molecules. which are produced by the lacrimal gland. Transmembrane mucins prevent the attachment (and entry) of pathogens and provide a smooth sliding surface, allowing the epididymides to glide over the corneal epithelia with minimal friction during blinking and other eye movements. Recently, it has been suggested that the mucins are mixed throughout the aqueous tear layer (due to their hydrophilic nature) and, being soluble, float freely in this layer.

A mucin deficiency (caused by damage to the goblet cells or the epithelial glycocalyx), as found in Stevens-Johnson syndrome or after chemical burns, leads to poor wetting of the corneal surface with subsequent dehydration and epithelial damage, even in the presence of a suitable aqueous tear production.

pathophysiology

Genetic predisposition to SS associated KCS is present, as evidenced by the high prevalence of human leukocyte antigen haplotype B8 (HLA-B8) in these patients. This results in a chronic inflamed condition producing autoantibodies, including an antinuclear antibody (ANA), a rheumatoid factor, fodrin (a cytoskeletal protein), the muscarinic M3 receptor, or SS-specific antibodies (e.g., anti-RO [e.g. SS-A], anti-LA [SS-B]), a release of inflammatory cytokine and focal lymphocyte infiltration (ie mainly CD4 + T cells but also B cells) of the tear and salivary gland in glandular degeneration and cell death induction in the conjunctiva and the tear glands. This results in lacrimal gland dysfunction with reduced tear production and loss of response to nerve stimulation and reduced reflex tear secretion. In the non-SS-associated KCS also an active T-lymphocyte infiltrate in the conjunctiva has been reported.

Both androgen and estrogen receptors are located in the tear and meibomian glands. SS is more common in postmenopausal women. At menopause, there is a reduction in circulating sex hormones (i.e., estrogen, androgen), which may affect the functional and secretory aspect of the lacrimal gland. Forty years ago, interest in this area initially focused on estrogen and / or progesterone deficiency to explain the link between KCS and menopause. However, recent research has focused on androgens, especially on testosterone, and / or metabolized androgens.

It has been found that in a meibomian gland dysfunction an androgen deficiency leads to the loss of the lipid layer, in particular triglycerides, cholesterol, monounsaturated essential fatty acids (eg oleic acid) and polar lipids (eg phosphatidylethanolamine, sphingomyelin) , The loss of polar lipids (present at the liquid-tear interface) exacerbates the tear-loss produced by evaporation and the reduction in unsaturated fatty acids increases the melting point of meibum, resulting in thicker, more viscous secretions that clog the ducts and stagnation of the stool Secretions caused. Patients receiving anti-androgen therapy for prostate disease also show increased viscosity of Meibum, reduced tear tear time and increased tear film algae, all indicative of a deficient or abnormal tear film.

It is known that in various tissues pro-inflammatory cytokines can cause cell breakdown. For example, Interleukin 1 (IL-1), Interleukin 6 (IL-6), Interleukin 8 (IL-8), TGF-beta, TNF-alpha and RANTES are altered in patients with KCS. IL-1-beta and TNF-alpha, which are present in the tears of patients with KCS, cause the release of opioids that bind to opioid receptors on neuronal membranes and inhibit neurotransmitter release by NF-K-B production. IL-2 also binds to the delta-opioid receptor and inhibits cAMP production and neuronal function. This loss of neuronal function reduces normal neuronal tone, leading to sensory isolation of the lacrimal gland and eventually to atrophy.

Inflammatory neurotransmitters, such as substance P and calcitonin gene-related peptide (CGRP), are released, which recruit and activate local lymphocytes. The substance P also acts via the NF-AT and NF-K-β signaling pathways, resulting in ICAM-1 and VCAM-1 expression, with adhesion molecules promoting lymphocyte homing and chemotaxis to the sites of inflammation. Cyclosporin A is an NK-1 and NK-2 receptor inhibitor that can down-regulate these signal molecules, and has been newly added to dry eye therapeutic tools and is used to treat both tears deficiency and meibomian gland dysfunction. There has been an improvement in the number of goblet cells and a reduction in the number of inflammatory cells and cytokines in the conjunctiva.

These pro-inflammatory cytokines, in addition to inhibiting neuronal function, can also convert androgens into estrogens, resulting in meibomian gland dysfunction, as previously discussed. An increased rate of cell death, possibly due to the cytokine cascade, can also be seen in conjunctival and tear acinar cells. Elevated levels of tissue-degrading enzymes, termed matrix metalloproteinases (MMPs), also occur in the epithelial cells.

Mucin-synthesizing genes, termed MUC1-MUC17, which are both transmembrane and goblet-secreted soluble mucins, have been isolated and their role in hydration and stability of the tear film is explored in patients with dry eye syndrome. Of particular importance is MUC5AC, which is expressed by multi-layered squamous epithelial cells of the conjunctiva and whose product is the predominant component of the mucus layer of the tears. A defect in these and other mucin genes may be a factor in the development of a dry eye symptom. In addition to a dry eye, other conditions, such as scar pemphigoid, Stevens-Johnson syndrome and vitamin A deficiency, which lead to dehydration or keratinization of the ocular epithelium, eventually lead to the loss of goblet cells. Both classes of mucins are reduced in these diseases and at the molecular level, mucin gene expression, translation and post-translational processing are altered.

The normal production of tear proteins, such as lysozyme, lactoferrin, lipocalin and phospholipase A2, is reduced in KOS.

It is apparent from the above discussion that the common causes of dry eye syndrome can be improved by treatment with anti-inflammatory agents such as topical corticosteroids, topical cyclosporin A and / or topical / systemic omega-3 fatty acids.

Studies investigating the association between dietary lutein / zeaxanthin intake and advanced AMD have shown inverse ratios that are statistically significant. The magnitude of the probability ratios in these studies ranged from 0.1 to 0.7. Both sets of results are relevant in the leading applied clinical research for the prevention and treatment of retinal disease, as: (1) tissue concentrations of DHA, lutein and zeaxanthin per unit area in the retina are substantially higher than elsewhere in the body; and (2) the retinal tissue status of these compounds is modifiable and depends on the uptake.

The AREDS II study concluded the scientific findings by stating, "It is essential to conduct a clinical study of nutrients that are both concentrated in the retina and involved in the modulation of pathogenic factors and processes of AMD. "

It has been well established that lutein and trans-zeaxanthin are found in human retinal tissue and that their function is to protect the eye from photo-induced injury. The CARMIS study, which included a mixture of lutein, trans-zeaxanthin and astaxanthin, is the only clinical study to report the use of astaxanthin. Unfortunately, there are no reports of the use of astaxanthin alone in a human clinical trial to prevent or ameliorate dry AMD. The CARMIS study has not established whether supplementation with astaxanthin alone is a key determinant of the study's positive results or that astaxanthin is deposited on the retinal epithelial cells. One possible interpretation of the CARMIS study is that lutein and zeaxanthin alone provided the observed benefits of the formulation used, or in another interpretation that astaxanthin in combination with lutein and zeaxanthin provided the benefits observed. However, no possible interpretation concludes that astaxanthin alone prevents or ameliorates dry AMD.

In addition, the work of Tso was based, as in the U.S. Patent No. 5,533,527 , the disclosure of which is hereby incorporated by reference in its entirety, and in the article entitled "Experiments on Visual Cells by Nature and Man: In Search of Treatment for Photoreceptor Degeneration," Investigative Opthalmology and Visual Science, 30 (12), pp. 2421-2454 (December 1989) although promoting the usefulness of astaxanthin to prevent or ameliorate dry AMD in humans, it does not disclose clinical trials conducted on human subjects, but instead on another mammalian species, rat.

Therefore, there is no conclusive evidence that astaxanthin alone can prevent or ameliorate dry AMD in humans, as no human study has been conducted using astaxanthin alone, nor has a human study shown that astaxanthin is actually deposited anywhere in the human retina , the first step that would be required for retinal protection by this powerful carotenoid.

The potential roles of polyunsaturated fatty acids in eye physiology

An inverse relationship of omega-3 LCPUFA dietary intake in advanced AMD has been described in six studies that have investigated this problem. For the prevalent disease, the magnitude of the likelihood ratios for the highest omega-3 LCPUFA uptake compared to the lowest was in the range of 0.4 to 0.9.

Among these studies, those with the highest number of subjects with neovascular or "wet" AMD showed a significantly lower likelihood of disease among the participants reporting the highest omega-3 consumption.

The scientific literature is replete with the particular benefits to humans of triacylglyceride-bound EPA and DHA found in fish oil and fish oil concentrates and, more recently, the potential usefulness of phospholipid-bound EPA and DHA found in krill oil derived from Euphasia superba or Antarctic krill.

The cardiovascular benefits as well as the anti-inflammatory benefits of such fish and krill oils, and in particular triacylglyceride-bound EPA and DHA derived from fish oils, as well as triacylglyceride-bound DHA derived from algae, are well known. Such algal-derived DHA is widely used as a nutritional supplement in infant formulas to ensure a healthy brain in the developing fetus and in infants. Seed oils are also a potent source, as explained above.

LCPUFAs affect factors and processes involved in the pathogenesis of vascular and neuronal retinal disease. Evidence characterizing the structural and functional properties of LCPUFAs indicates that these nutrients can function as both: (1) essential factors in the visual-sensory process and (2) retinal disease protection agents.

Docosahexaenoic acid (DHA) is the major structural lipid of the outer segmental membranes of the retinal photoreceptor. Tissue DHA status affects the retinal cell signaling mechanisms involved in phototransduction. Tissue DHA insufficiency is associated with the conditions characterized by changes in retinal function, and functional deficiencies have in some cases been improved with DHA supplementation. The biophysical and biochemical properties of DHA may affect photoreceptor function through a change in membrane permeability, fluidity, thickness, and lipid phase properties. DHA can work in signaling cascades to enhance the activation of membrane-bound retinal proteins. DHA may also be involved in rhodopsin regeneration.

DHA and eicosapentaenoic acid (EPA) can serve as protective agents because of their effect on gene expression, retinal cell differentiation and survival. DHA activates numerous nuclear hormone receptors that act as transcription factors for molecules that modulate redox-sensitive and pro-inflammatory genes; these include peroxisome proliferator activated receptor α (PPAR-α) and retinoid X receptor (RXR). In the case of PPAR-α, this effect is believed to promote endothelial cell dysfunction and vascular remodeling by inhibition of smooth muscle cell proliferation, inducible nitric oxide synthase production, interleukin (IL) -1-induced cyclooxygenase (COX) -2 production and thrombin generation. prevented endothelin-1 production.

Model system research indicates that omega-3 LCPUFAs also have the ability to influence the production and activation of angiogenic growth factors, arachidonic acid-based proangiogenic eicosanoids, and matrix metalloproteinases involved in vascular remodeling.

EPA suppresses vascular endothelial growth factor (EGF) -specific tyrosine kinase receptor activation and expression. VEGF plays a key role in initiating endothelial cell migration and proliferation, microvascular permeability, endothelial cell release of metalloproteinases and interstitial collagenases, and endothelial cell tube formation. It is believed that the mechanism of down-regulation of the VEGF receptor occurs at the tyrosine kinase nuclear factor kappa B (NFkB) site because EPA treatment causes suppression of NFkB activation. NFkB is a nuclear transcription factor that upregulates COX-2 expression, the intracellular adhesion molecule (ICAM), thrombin, and nitric oxide synthase. All four factors are associated with vascular instability. COX-2 drives the conversion of arachidonic acid into numerous angiogenic and pro-inflammatory eicosanoids.

Although the mechanistic benefits of dietary supplementation with polyunsaturated EPA and DHA fatty acids in triacylglyceride form are well known, it remains speculative that such triacylglyceride bound EPA and DHA can improve vision. Such a hypothesis is now being explored in the 5-year National Eye Institute's AREDS II study.

cataracts

Cataract is an opacity or opacity of the eye lens. The prevalence of cataracts increases dramatically with age. It typically occurs in the following manner. The lens has an elliptical structure that lies behind the pupil and is usually transparent. The function of the lens is to focus light rays into images on the retina (light-sensitive tissues in the fundus).

In young people, the lens is elastic and changes shape slightly, allowing the eyes to focus clearly on both near and distant objects. When people reach the age of mid-40, biochemical changes in the proteins in the lens occur, causing them to harden and lose their elasticity. This causes numerous vision problems. For example, loss of elasticity causes presbyopia or farsightedness, which requires reading glasses for almost everyone as they grow older.

In some individuals, the proteins in the lens, especially those termed alpha-crystalline, may also clump together and form cloudy (opaque) areas called cataracts. They usually develop slowly over several years and are age related. In some cases, vision loss progresses rapidly depending on the cause of cataracts. Depending on their density and location, cataracts can block the passage of light through the lens and interfere with the formation of images on the retina, which obscures vision.

Nuclear cataracts form the nucleus (inner nucleus) of the lens. This is the most common type of cataract associated with the aging process. Cortical cataracts form in the cortex (the outer portion of the lens). Posterior subcapsular cataracts form to the posterior part of a cellophane-like capsule surrounding the lens. They are more common in people with diabetes who are overweight or people who take steroids. Although the causes of cataract formation remain largely unknown, researchers are focusing on particles called free oxygen radicals as a major factor in the development of cataracts. They cause damage in the following way:

Free oxygen radicals (also called oxidants) are molecules that are produced in the body by natural, chemical processes. Toxins, smoking, ultraviolet radiation, infections, and many other factors can produce reactions that produce excessive levels of these free oxygen radicals. If there is an overproduction of oxidants, these chemical reactions can be detrimental to almost any cell type in the body. At times, these reactions may even affect the genetic material in cells.

Cataract formation is one of many destructive changes that can occur with overproduction of oxidants, possibly along with insufficient amounts of an important protective antioxidant called glutathione. Glutathione occurs in high levels in the eye and helps to eliminate these free radicals. One theory is that the aging eye develops barriers that prevent glutathione and other protective antioxidants from reaching the nucleus in the lens, making it susceptible to oxidation. Sunlight consists of ultraviolet radiation (referred to as UVA or UVB) that penetrates the layers of the skin. Both UVA and UVB have destructive properties that can promote cataracts. The eyes are protected from the sun by the eyelids and the facial structure (overhanging eyebrows, protruding cheekbones and nose). However, long-term exposure to sunlight can overcome these defenses.

The UVB radiation produces the shorter wavelength and mainly affects the outer skin layers. It is the main cause of sunburn. The UV radiation is also mainly responsible for cataracts. Long-term exposure, even with low levels of UVB radiation, can eventually lead to changes in the lens, including pigmentation, that contribute to cataract development. (UVB also appears to play a role in macular degeneration, an age-related disorder of the retina.) UVA radiation consists of longer wavelengths. They penetrate deeper and more effectively into the inner skin layers and are responsible for the tanning. The main damaging effect of UVA appears to be the promotion of the release of oxidants. Cataracts are common side effects of whole-body radiation treatments that are administered for certain cancers. This observation shows that ionizing radiation, which generates a large number of free radicals, dramatically accelerates cataract formation.

Glaucoma and its treatments, including certain medications (especially miotics) and a filtering procedure, present a high risk of cataracts. The glaucomatous medicines that pose a particular cataract risk include demecarium (humorsol), isofluorophate (floropryl) and echothiopate (phospholine). Uveitis is a chronic inflammation in the eye that is often caused by an autoimmune disease or reaction. The cause is often unknown. This is a rare condition with a high cataract risk. It is not clear if diet plays an important role in cataract development. Dark (green, red, purple and yellow) fruits and vegetables usually have high levels of important plant chemicals (phytochemicals) and can be associated with a lower risk of cataracts.

In analyzing nutrients, researchers focused on antioxidants and carotenoids. Studies have not shown that antioxidant vitamin supplements (such as vitamins C and E) help prevent cataracts. Lutein and zeaxanthin are the two carotenoids best studied for cataract prevention. These are xanthophyll compounds, which are a certain type of carotinide. Lutein and zeaxanthin are found in the lenses of the eyes. Certain findings indicate that xanthophyll-rich foods (such as dark green leafy vegetables) can help delay the onset of aging and protect against cataracts. However, there is not enough evidence to suggest that taking supplements with these carotenoids reduces the risk of cataract formation. Since little is known about the exact mechanism for the formation of cataracts, it is not surprising that there are no known drugs or nutritional supplements that contain carotenoids that prevent cataract formation, there is still a need to find a suitable preventative treatment to prevent cataracts prevent or prevent further cataract formation improve. Because medications can not reverse or prevent cataract formation, the only treatment currently available for advanced cataract in humans is the lens replacement surgery.

The ability of a carotenoid to penetrate the blood-retina-brain barrier is important because carotenoids are not synthesized by the human body. For humans, the only source of carotenoids is food intake. Furthermore, humans have a very limited ability to modify carotenoids. Therefore, the carotenoids accumulate in various organs in the ingested form. Thus, if a particular carotenoid can not cross the blood-retina-brain barrier, the carotenoid can not accumulate in the retina and serve as an antioxidant.

Furthermore, in some carotenoids, which are not normal components of human plasma but have the ability to cross the blood-retina-brain barrier, adverse effects on the retina have been demonstrated. Canthaxanthin, which is deliberately taken to provide an artificial suntan, has accumulated in the retina in the form of crystals and has at times affected the adaptation of the eye to the dark. In addition, beta-carotene has a very limited ability to cross the blood-retina-brain barrier.

Therefore, although the carotenoids are known to be powerful antioxidants and abundant, the carotenoids have not been used for the treatment of central nervous system damage or eye damage caused by disease or injury. The carotenoids so far explored could not effectively overcome the blood-retinal barrier (i.e., beta-carotene) or have side effects on the eye (i.e., canthaxanthin).

By way of non-limiting example, the composition comprises a therapeutically effective amount of a multi-carotenoid blend composition including at least S, S'-astaxanthin derived from Haematococcus pluvialis and one or more of L and / or trans zeaxanthin or meso-zeaxanthin in admixture with a therapeutically effective amount of seed oil extract, such as perilla and / or optionally a phospholipid from rye extract or other sources, as will be described. In one example, the composition comprises 50 to 500 mg seed oil extract and / or phospholipid, 0.5 to 8 mg astaxanthin, 2 to 15 mg lutein and 0.2 to 12 mg trans-zeaxanthin. Astaxanthin could be 0.5 to 12 mg in one example. By using the phospholipids, the absorption of the carotenoids is improved and a lower range can be used. It is possible to use the phospholipid alone with lutein to increase the absorption of lutein, it is also possible to use the phospholipid alone with coenzyme Q10 to obtain cardiovascular and other benefits. Of course, the phospholipids can be mixed with the seed oil. The composition contains naturally occurring compounds and is a potent antioxidant and anti-inflammatory composition that can be used in a method to improve and delay cell damage in an individual suffering from a degenerative inflammatory disease or injury to the eye prevent. In another non-limiting example, administration of a therapeutically effective amount of the composition to an individual prevents, delays, and / or improves free radical-induced damage resulting from an eye disease or injury. For example, retinal damage may be due to either light injury, neurodegenerative disease, or ischemic insult followed by reperfusion. In terms of damage due to light injury, the composition lowers the loss of photoreceptor cells. In terms of ischemic insult damage, the composition improves the loss of ganglion cells and inner layers of the neuronal retina.

None of the previously tested carotenes and most of the tested xanthophiles have crossed the blood-brain barrier, with a few notable exceptions.

These exceptions include lutein, trans-zeaxanthin, canthaxanthin and astaxanthin.

Human serum typically contains about ten carotenoids. The major carotenoids in human serum include beta-carotene, alpha-carotene, cryptoxanthin, lycopene and lutein. Low levels of zeaxanthin, phytofluene and phytoene are also found in human organs. Of all these carotenoids, however, only zeaxanthin and lutein are found in the human retina. In addition to certain carotenoids, the retina also has the highest concentration of polyunsaturated fatty acids in all tissues in the human body. These polyunsaturated fatty acids are highly susceptible to free radical and singlet oxygen induced degradation. Therefore, there is a need to do this multiple times unsaturated fatty acids, which form part of the cellular membrane bilayer, to protect against photoinduced degradation by free radicals or singlet oxygen.

It has been theorized that zeaxanthin and lutein are concentrated in the retina because of their ability to quench singlet oxygen and trap free radicals as they pass through the blood and eye-brain barrier and into the oxygen-rich environment the retina needed to prevent light-mediated retinal damage from free radicals.

In fact, zeaxanthin is the predominant carotenoid found in the central portion of the retina, and is particularly concentrated in the retinal condyles located in the central area of the retina (i.e., the macula). Lutein, on the other hand, is located in the peripheral region of the retina in the rod cells. Therefore, the eye preferentially accumulates zeaxanthin rather than lutein in the critical central macular retinal area (interestingly, zeaxanthin is a much more potent singlet oxygen scavenger than lutein), which has the greatest amount of light.

Biochemists have determined the exact, though complicated, mechanism for a light sensory reaction in the eye. It comprises a key protein called rhodopsin, the structure of which is a bound, polyunsaturated compound termed retinal (retinal structurally related to vitamin A). When light enters the eye, cis-retinal completely isomerizes into its all-trans isomer, separating it from its protein carrier. The separation triggers a complicated cascade that leads to a nerve-based transfer of electrons to the brain via the optic nerve. All of this "photochemistry" requires only 200 femtoseconds for its occurrence, creating one of the fastest known biochemical-to-electron transformations.

Chemists have learned that the retina is highly susceptible to polymerization by localized free radicals and reactive singlet oxygen. Because the retina absorbs light strongly and because the retina is highly vascularized and therefore rich in dissolved oxygen, nature has provided zeaxanthin, the key retinal carotenoid, to protect the central foveal region of the retina from light-induced damage at the site in the center of the retina Light radiation occurs.

Human clinical studies indicate that light injury due to the cumulative effect of a repeated photochemical insult leading to the gradual loss of photoreceptor cells is a cause of age-related macular degeneration.

Many clinical trials have been designed to support lutein supplementation, but since 2007, there seems to be no clear evidence that lutein supplementation, despite its wide acceptance, is necessary as an adjunct to ophthalmic health care. This may simply mean that supplementation with additional lutein is not necessary as it is available as xanthophyll in many vegetables anyway. However, the use of lutein with a phospholipid to improve absorption was beneficial. Recently, trans-zeaxanthin and meso-zeaxanthin have entered the market as ophthalmic care additives, which really makes sense. However, there is an even better carotinide that meets all the requirements that come with overcoming the ocular / blood / brain barrier, macular accumulation, and long term use. The answer is xanthophyll astaxanthin.

Dr. Mark Tso of the University of Illinois has shown that asthaxanthin is such a naturally occurring antioxidant that fulfills all of these critical criteria in rats. Astaxanthin is the carotenoid xanthophyll, which is responsible for the red color in salmon, lobster, krill, crab, other shellfish and in the microalgae Haematococcus pluvialis. The latter source has made astaxanthin readily available worldwide for such uses. The one issued to the University of Illinois U.S. Patent 5,527,533 describes more fully the use of astaxanthin in eye diseases and is hereby fully incorporated.

In addition, astaxanthin is a much stronger antioxidant than cantohaxanthin, beta-carotene, zeaxanthin, lutein and alpha-tocopherol. Some researchers have discovered that astaxanthin is 550 times more potent than alpha-tocopherol in eliminating singlet oxygen, 27.5 times more potent than lutein and 11 times more potent than beta-carotene. In addition, other researchers have discovered that natural astaxanthin is 14 times more potent than alpha-tocopherol in capturing free oxygen radicals, 54 times more potent than beta-carotene, and 65 times more potent than ascorbic acid (vitamin C). Although there are therefore dramatic differences in the potency of astaxanthin when quenching singlet oxygen and trapping free Oxygen radicals, it is clear that astaxanthin can be compared very well with zeaxanthin and lutein, with the two carotenoids that naturally occur in the retina.

There is another aspect to carotenoids, namely that some carotenoids can act as pro-oxidants. This is important because a carotenoid with pro-oxidative capability actually causes oxidation to occur in the body when high concentrations are present in the tissue. Other researchers have shown that beta-carotene, lycopene and zeaxanthin can become pro-oxidants under certain conditions. Since humans already have a rich source of lutein and trans-zeaxanthin in their diet due to many vegetable sources and these already occur in the human eye, it seems that astaxanthin with its unique qualifying properties, unlike lutein or trans-zeaxanthin, the nutritional supplement of Can be choice for the eye health care. The exceptionally potent antioxidant properties of astaxanthin, its ability to cross the blood-brain / ocular barrier and to concentrate in the retinal macula of other mammalian species, without the side effects seen with canthaxanthin, and in view of the contributions of Tso In a practical dietary supplement presentation, astaxanthin may become the premier additional new ingredient for lutein and / or zeaxanthin supplementation for ophthalmic prevention for the treatment of ocular oxidative stress and therefore for the prevention and alleviation of degenerative diseases of the eye, such as age-related macular degeneration (ARMD ) and cataract formation, when astaxanthin deposition can be experimentally confirmed in human retinal tissue.

In addition, Tso has found that photoinduced injury, photoreceptor cell damage, ganglion cell damage and inner retinal layer neuronal damage can be prevented or ameliorated by the use of astaxanthin, including neuronal damage from ischemic, photochemical, inflammatory and degenerative insult rats. Tso claims the use of astaxanthin over a wide range of ocular conditions, including age-related macular degeneration, diabetic neuropathy, cystoid macular edema, central retinal arterial and venous occlusion, glaucoma and inflammatory ocular diseases such as retinitis, uveitis, iritis, keratitis and scleritis all disease states typical of ocular insult by oxidative species such as free radicals; however, this work has never been confirmed on humans.

Oral administration of astaxanthin confirms that it is transported at least into the human bloodstream; however, its deposition in human retinal tissue has never been confirmed.

Astaxanthin is the essential pigment of certain microalgae and crustaceans. Astaxanthin is a fat-soluble pigment that is mainly used to pigment cultured fish, such as salmon, that needs to absorb astaxanthin to get the consumer-accepted pink salmon muscle. Astaxanthin is also an antioxidant that is about 100 to about 1000 times more potent than alpha-tocopherol.

The main source of commercial S, S'-astaxanthin is microalgae and to a lesser extent it is found in krill oil derived from Euphasia superba (Antarctic krill). Astaxanthin is also synthetically available, however, synthetic astaxanthin may not be safe for human use because it contains 3 known enantiomers, including R, R ', R, S' and S, S ', which are neither easily nor economically separable and of which the safety data are unknown to humans in two. The preferred naturally occurring S, S'-astaxanthin can be used in one example in the composition and method of the present invention.

As indicated previously, the retinal pigment epithelium protects the retina by providing a blood-retinal brain barrier. The barrier excludes plasma components that are potentially harmful to the retina. As previously stated, the blood-retinal brain barrier allows lutein and zeaxanthin to enter the retina and excludes other carotenoids present in human serum, including beta carotene, which is the most abundant carotenoid in human serum. Astaxanthin is not a naturally occurring component of the retina. Thus, the presence of a physiologically significant amount of astaxanthin in the rat retina may illustrate the ability of astaxanthin to readily pass through the blood-retina-brain barrier into the retina of humans. The optimum dose of the composition may be determined by those skilled in the art after considering factors such as the disease or injury to be treated, the severity of central nervous system damage by oral administration. The daily dose of the composition can be administered daily or in accordance with a schedule determined by one skilled in the art, with the length of treatment on the severity and type of injury to the central nervous system, the need to improve accommodation, or to control dry eye syndrome.

The composition can be administered orally to a subject, for example in a single dose capsule. For oral administration, for example, the composition may be in the form of a liquid preparation. Administration of the composition to an individual suffering from an eye injury or disease, such as a free radical induced injury, benefits the individual's vision by preventing further photoreceptor cells from being damaged or destroyed. Free radical-induced injury may be attributed to photo-induced injury or injury resulting from an ischemic insult and subsequent reperfusion or neurodegenerative diseases. In addition to improving light injury, the administration of astaxanthin also helps to prevent and delay light injury.

Administration of the composition improves photoreceptor cell damage induced by light and improves ganglion cell damage induced by an ischemic stroke and subsequent reperfusion. The administration of astaxanthin also delays the progression of degenerative eye diseases and promotes the vision of persons suffering from degenerative eye disease such as age-related macular degeneration.

The administration of the composition also provides a method of treating ischemic retinal diseases, such as diabetic retinopathy, cystoid macular edema, central retinal artery occlusion, central retinal venous occlusion, and glaucoma. In addition, the composition for treating inflammatory diseases of the eye, such as retinitis, uveitis, iris, keratitis and scleritis, wherein excess free radicals are produced, is useful for preventing cataracts and for treating certain causes of dry eye syndrome ,

Therefore, the antioxidant properties of the composition along with the ability of the composition to overcome the blood-retina-brain barrier, as a mixture with anti-inflammatory EPA and DHA sources, and lack of toxicity of the composition and lack of side effects associated with the composition the composition is a useful composition to prevent or ameliorate such ocular disorders, dry eye syndrome and / or dry eye cataracts and syndromes.

The carotenoids that are mixed with the seed oil extract, such as perilla or other seed sources and / or phospholipids in this example, should be able to treat not only the eye diseases known to be ameliorated by carotenoids, but also also the inflammatory diseases of the eye (including, but not limited to dry eye syndrome) associated with the known anti-inflammatory activity of omega-3s.

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 decrease 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. 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 probably all made a major positive contribution to cardiovascular health, as well-known biomarkers for all cardiovascular health risks.

• 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
Serum pharmacokinetics: 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. There are three main sources of astaxanthin, e.g. B. 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 ,

It should be understood that various proportions of ingredients and percentages in compositions can be used, depending on end-uses and other environmental factors and physiological factors, when treating a patient's condition.

The astaxanthin may be 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 and in another example of 0.5 to 12 mg.

When the astaxanthin is combined with the phospholipid, a reduced amount of astaxanthin may be used, such as 0.5 to 4 mg, and 2.0 to 4.0 mg in one example.

Other areas may be available depending on the end applications. The same applies to the use of other carotenoids, such as lutein, when mixed with the phospholipid. The composition may also comprise 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 is alpha-linolenic, stearidonic, eicosapentaenoic or docosapentaenoic acid and in one example, a seed oil extract, with perilla being preferred, and / or other phospholipids. The composition may include naturally occurring and synthetic antioxidants added to delay the degradation of fatty acids and astaxanthin.

Although a perilla seed oil extract is disclosed in combination with the carotenoids, including astaxanthin, it should be understood that other oils may be used, either alone or in combination with the perilla seed oil extract and with the carotenoids as disclosed, for example, additional phospholipids, and Other examples include various marine oils, including a fish oil and / or krill oil, and a fish oil-derived choline phospholipid-linked EPA and DHA. The various oils may include oils derived from shrimp farce and / or peels. An algae-based oil could also be added. The phospholipids are preferred in one example to improve bioavailability.

The oils from seed oil extract, such as Perilla, can be enriched with phospholipids. The composition may contain EPA and DHA functionalized as marine phospholipids and krill derived acyl triglycerides. Some of these components 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)

The phospholipids are added to the perilla seed oil extract and the carotenoid composition and / or the phospholipids and can be produced from seed, egg yolk, plants and Antarctic krill (Euphausia superba), which is a zooplankton (the basis of the food chain). It is one of the most abundant marine biomass with, according to some Estimates, about 500 million tons. 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%.

The krill oil that could be added in one example is described 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.

The seed oil, such as perilla, 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 is alpha-linolenic acid, stearidone, eicosapentaen or docosapentaenoic acid. The composition may include naturally occurring and synthetic antioxidants which are added to delay the breakdown of fatty acids.

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. Pat. Nos. 8,652,544 and 8,586,104 , the disclosures of which are hereby incorporated by reference in their entireties.

It is possible, as an additional oil, to use a fish oil-derived, choline-based, phospholipid-bound omega-3 fatty acid mixture, including phospholipid-linked polyunsaturated EPA and DHA, to improve blood lipid profiles and reduce 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 a phospholipid, omega-3 preparation derived from natural fish oil. An example of such a composition is described below: Ingredients (g / 100 g): 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 / 100 g) (nmt) 2 Physical Properties: consistency viscous liquid

The composition may also be fortified with a fatty acid-rich n-3 oil (omega-3) derived from fish oil, algae oil, linseed oil or chia seed oil, the n-3 fatty acid source alpha-linolenic, stearidone, eicosapentaen or Docosapentaenoic acid. The composition may comprise naturally occurring and synthetic antioxidants added to retard degradation of fatty acids, such as tocopherols, tocotrienols, carnosic acid or carnosol and / or astaxanthin.

It is now known that phospholipids, as briefly described above, will enhance the absorption of certain carotenoids, including astaxanthin and lutein. It can also be used to improve the absorption of coenzyme Q10. For example, a randomized and controlled single-dose trial study showed that plasma levels of plasmalutein, as measured at baseline, gradually increased up to 24 hours after the ingestion of a krill oil, compared with a comparable product having almost no phospholipids. The study showed that the maximum lutein plasma absorption was higher in krill oil and phospholipid intake than in the control subjects who showed little change in lutein absorption. The control product contained equal amounts of lutein esters, such as 6 mg, but contained neither krill nor phospholipids to enhance the absorption of any lutein, as in krill / phospholipids with lutein. Therefore, the phospholipids and the possible antioxidant content may help to increase the bioavailability of the ingredients, including lutein. It has also been determined that the phospholipid molecular structure will allow the body to better absorb krill oil and all DHA and EPA omega-3 fatty acids up to 2.5-fold in certain cases compared to the triglyceride form is most common in fish oils. This can also help absorb other ingredients. Lutein is particularly in the form of luteinic esters, and the present composition may also contain vitamin A and thiamine, such as vitamin B1, so that the improvement with the perilla seed oil and / or the phospholipids will be beneficial.

Lutein is a xanthophyll and is found in green leafy vegetables such as spinach, kale and yellow carrots, and modulates light energy and acts as a non-photochemical extinguishing agent, in some instances it can be from egg yolks and animal fats. It is known that the human retina accumulates lutein and zeaxanthin. Zeaxanthin is predominant in the macula lutea, while lutein elsewhere prevails in the retina and serves as a retinal light stabilizer against the damaging effects of free radicals, especially those produced by blue light. Lutein is isomeric with zeaxanthin, differing in the arrangement of a double bond. It is a lipophilic molecule and, with its long chromophore of conjugated double bonds as the polyene chain, is generally insoluble in water. It has pronounced light-absorbing properties and works well with phospholipids, and therefore, the phospholipids added will function as described below to enhance absorption, cooperating with the perilla seed oil, if used. In plants, it is present as a fatty acid ester with one or two fatty acids attached to two hydroxyl groups and saponified, since the deesterification of lutein esters will yield free lutein in a 1: 1 to 1: 2 molar ratio.

The five-year AREDS2 trial showed that omega-3 fatty acids may not be as beneficial as desired. It has not been determined that phospholipids can increase absorption several times and, according to some studies, up to eightfold. The same could happen with zeaxanthin. It should be understood that lutein and zeaxanthin have identical chemical formulas and are isomers, but are not stereoisomers and a major difference is the location of the double bond in one of the end rings. Lutein has three chiral centers and zeaxanthin has two chiral centers. The 3R, 3'S and 3S, 3'R stereoisomers of zeaxanthin are identical and thus zeaxanthin has only three stereoisomeric forms. The 3R, 3'S stereoisomer is called meso-zeaxanthin. The natural form of zeaxanthin is 3R, 3'R-zeaxanthin and the macula mainly contains the 3R, 3'R and meso-zeaxanthin forms but smaller amounts of the 3S, 3'S form. Some proteins will allow zeaxanthin and lutein to circulate within the macula for better uptake and phospholipids work as indicated above.

It is possible to use natural or synthetic zeaxanthin as prepared by a Wittig reaction yielding 96-98% trans (3R, 3R) zeaxanthin and smaller amounts of cis zeaxanthin. Zeaxanthin is generally insoluble in water and to some extent soluble in ethanol, like other carotenoids, and soluble in chloroform. The hydroxyl groups on two of the outermost carbon atoms would render xanthophylls such as zeaxanthin more water soluble than other very hydrophobic carotenoids.

It is also possible to use the phospholipid with or without the seed oil extract to reduce the absorption of coenzyme Q10, i. H. Ubiquinone, also referred to as COQ10 or Q10, is to be improved. The chemical quinone group refers to 1,4-benzoquinone as part of the chemical quinone group, while 10 are the chemical isoprenyl subunits. As known to those skilled in the art, it is an oil-soluble component of the electron transport chain and is active in aerobic cellular respiration and generates energy in the form of ATP. It has 3-redox states like fully oxidized, semi-quinone and fully reduced. For this reason, it is excellent in the functions for the electron transport chain.

A dosage may range from about 500 to about 1,200 mg / day and 100 to 500 mg / day, depending on phospholipid absorption. Another range is 50 to 500 mg / day or 10 to 100 mg / day. Phospholipids would help to reduce the required amounts. Since COQ10 has the same biosynthetic pathway as cholesterol, those patients taking the statins could benefit from a supplement using the phospholipids and COQ10 found in many membranes of organelles, including the mitochondrion. COQ10 is liposoluble and the phospholipids improve absorption. COQ10 acts from his Energy carrier function as an antioxidant and can absorb the electrons to be reduced. When it gives up electrons, it is oxidized. COQ10 has a similar absorption to that of lipids, with secretion of pancreatic enzymes and bile into the small intestine, which facilitates emulsification and micelle formation, as required for the absorption of lipophilic substances. It is possible to reduce the total particle size to improve bioavailability using nanoparticles. It is possible to use an emulsion system to facilitate absorption from the gastrointestinal tract and improve bioavailability, such as by using lipid microspheres, including emulsions on soybean oil and lecithins for stabilization. It is possible to modify the COQ10 to increase the solubility of water and facilitate absorption. This may involve the use of a tyloxapol polymer and other solubilizers, such as hydrogenated lecithin. It is possible to use other nanoparticles and dendrimers or liposomes to improve the bioavailability of COQ10.

It has now been determined that lower dosages of astaxanthin may be used when added to at least one of a phospholipid, glycolipid and sphingolipid, and preferably larger concentrations of phospholipid. It is believed that the phospholipid greatly increases the bioavailability of the substrate. A pharmaceutical or food grade diluent or other surfactant may be added. The phospholipids may include plant-based phospholipids such as lecithin and lysophospholipids and / or glycophospholipids, including the addition of a seed oil extract such as Perilla. Astaxanthin levels could vary from 0.5-2 mg and 0.5-4 mg and in one embodiment 2-4 mg or 2-6 mg and up to 0.5-8 mg and 0.5-12 mg and 7-12 mg.

In induced uveitis, astaxanthin also showed dose-dependent ocular anti-inflammatory activity through the suppression of NO, PGE-2 and TNF-alpha by direct blockade of NO synthase activity. As mentioned earlier, astaxanthin is also known to reduce blood levels of C-reactive protein (C-RP) in vivo. For example, in human subjects with high-risk C-RP levels, astaxanthin treatment for three months resulted in a 43% decrease in serum C-RP levels in the patient population, thus falling below the risk level. Astaxanthin is absorbed by lens epithelial cells in vitro, where it suppresses UVB-induced lipid peroxidation-mediated cell damage with umol / L concentrations. In human trials, astaxanthin with 4 mg / day joint fatigue prevented after strenuous knee exercise, after exercise, compared to untreated subjects. It has been shown to treat osteoarthritis at 15 mg per day.

Astaxanthin has potent singlet oxygen quenching activity. Astaxanthin, unlike β-carotene, lutein, zeaxanthin and vitamins A and E, generally has no pro-oxidative activity. In some studies, astaxanthin was found to be about 50 times more potent in quenching singlet oxygen than vitamin E, 11 times more potent than beta-carotene and three times more potent than lutein. Astaxanthin is also well known for its ability to quench free radicals. Comparative studies have found that astaxanthin is 65 times more potent in its ability to quench free radicals than vitamin C, 54 times more potent than beta-carotene, 47 times more potent than lutein, and 14 times more potent than vitamin E.

The aforementioned '533 Tso patent discloses the benefits of astaxanthin for delaying and ameliorating central nervous system and ocular damage. Astaxanthin crosses the blood-brain-retinal barrier and this can be measured by direct measurement of retinal astaxanthin concentrations. Thus, Tso detected protection from photon-induced damage to photoreceptors, ganglion and neuronal cell damage.

It is known that oils having oil-based phospholipid-linked EPA and DHA uptake in cell membranes are far more efficient than triacylglyceride-bound EPA and DHA, since the conversion of triacylglycerides in the liver is intrinsically inefficient and because phospholipid-bound EPA and DHA can be transported via the sympathetic system into the bloodstream, thereby preventing liver breakdown.

The present composition, such as for eye health or cardiovascular health, may advantageously be delivered for therapeutic results with 1-4,000 mg of oil, such as a seed-based oil, with or without the addition of phospholipids and in a daily dose. In another example, 500 mg is a preferred amount for a single dose capsule and in another example 1,000 mg. Areas of 500 to 1,000 mg are possible, including 750 mg, including with one added phospholipid. In another example, 0.1-50 mg astaxanthin per daily dose to the oil, but an exemplary amount includes about 2-4 mg and 0.5-12 mg or 0.5-8 mg. The phospholipid-based oils may contain rouge extract with phospholipid and plant-based oils and other phospholipids. Is it also possible to use wax esters and omega-3 salts and ethyl esters.

The composition may also contain a fatty acid-rich n-3 oil (omega-3) derived from various oils including fish oil, algae oil, linseed oil or chia seed oil when the n-3 fatty acid source is alpha-linolenic, stearidone, eicosapentaenoic acid. 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 the peroxidation blocker technology that can be used are being communicated in common U.S. Patent No. 8,652,544 . U.S. Patent No. 8,586,104 ; U.S. Patent No. 8,784,904 ; and U.S. Patent No. 2009/0181114 , the disclosures of which are hereby incorporated by reference in their entireties.

In one example, about 150 mg to about 300 mg perilla or other oil extract and / or other oils and phospholipids are used. In another example, 2 to 4 mg astaxanthin is added to the seed oil extract and / or phospholipids and may range from 0.5 to 4 mg, or 0.5 to 6 mg, 0.5 to 8 mg, 0.5 to 12 mg or 7 to 12 mg and other ranges as described above.

The perilla oil extract and / or other seed oil extract may be prepared using supercritical CO2 extraction and / or solvent extractions to selectively remove triacylglycerides from the phospholipids, such as using the techniques in the incorporated patents. The composition, such as for ocular or cardiovascular treatment, may also include a natural or synthetic cyclooxygenase-1 or -2 inhibitor comprising, for example, aspirin, acetaminophen, steroids, prednisone or NSAIDs. The ophthalmic composition may also contain a gamma-linoleic acid-rich oil comprising borage (Borago officinalis L) or safflower (Carthamus tinctorius L) which provides a metabolic precursor to PGE1 synthesis.

The composition, whether for eye treatment or for cardiovascular treatment or other treatment, may also contain a fatty acid-rich n-3 oil (omega-3) derived from fish oil, algae oil, linseed oil or chia seed oil or perilla seed oil, where the n-3 Fatty acid source comprises alpha-linolenic, stearidonic, eicosapentaenoic or docosapentaenoic acid. The ophthalmic treatment composition may comprise naturally occurring and synthetic antioxidants which are added to retard degradation of fatty acids such as tocopherols, tocotrienols, carnosic acid or carnosol and / or astaxanthin.

It has been found advantageous to use herring gene extract as a source of phospholipids, which may have some EPA and DHA, with the carotenoids, either alone or in combination with the seed oil extract. Other phospholipids without EPA and DHA can be used. Sources include egg yolk extract and seed oil phospholipids. Synergistic results are obtained and enormous improvements observed. One study demonstrated that herbal phospholipids improved phospholipid and glucose tolerance in healthy young adults as published by Bjorndal et al., Lipids in Health Disease, 2014, 13:82. The pure rouge phospholipid can be used using extraction techniques. It is a honey-like product made thinner or thinner with fish oil and / or perilla oil or other seed or vegetable oil and in one example with the perilla oil as described above.

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 perilla seed oil, as described in the '904 patent incorporated by reference, may be added back to the ethanol extract before it is stripped for dilution to form a high phospholipid blend. The rye oil extract may be mixed with fish oil and / or seed oil such as Perilla or any other oil including a marine oil. In one example, the herring gene extract is mixed with seed oil at least 1: 1 and with perilla preferably up to 6: 1 ALA to LA, the concentrate being at least 50% and in another example 60% phospholipids and in another example at least 30% and in another example has 40% triglycerides. This is a non-limiting example.

An exemplary composition for ocular health or cardiovascular health includes a combination of a herring flavor extract or a phospholipid-rich rye extract with phospholipid-bound EPA and DHA mixed 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 optionally contains about 2 to 4 mg or 0.5 to 8 mg or 0.5 to 12 mg astaxanthin or other ranges as mentioned above. The amount of rouge 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 includes the astaxanthin and the lutein and trans-zeaxanthin or meso-zeaxanthin. 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. Phospholipids can be derived from egg yolk and seed oil phospholipids, including sunflower, safflower and soybean. 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 composition is encapsulated in a single dose capsule. In a specific example, the encapsulated composition containing the carotenoids, as explained above, and seed oil extract, such as from Perilla, and / or Heringkaviarphospholipidextrakt (herring roe), seeds extract of Perilla (Perilla frutescens), olive oil, Zanthin ^® astaxanthin (Haematococcus pluvialis alga extract ), Gelatin, spice extract, natural non-GMO tocopherols, cholecalciferol, riboflavin and methylcobalamin. The composition may contain fish such as herring roe and tilapia gelatin. 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 D3 1000 IU; 250% DV Vitamin B2 (riboflavin) 1.7 mg; 100% DV Vitamin B12 6 μg; 100% DV microbiology USP <61> / FDA BAM Total germ number <1000 cfu / g Yeast and mold mushrooms <100 cfu / g 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 HOPE 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 as described above, 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 AM 1044 ALA (C20: 5n-3) mg / g as TG ³ ) 30 AM 1001 DHA (C22: 6n-3) mg / g as TG ³ ) 85 AM 1001 Total omega-3 ¹ ) mg / g as TG ³ ) 370 AM 1001 ALA (C18: 3 n-3) mg / g as FFA ⁴ ) 215 AM 1044 ALA (C20: 5n-3) mg / g as FFA ⁴ ) 28 AM 1001 DHA (C22: 6n-3) mg / g as FFA ⁴ ) 80 AM 1001 Total omega-3 ¹ ) mg / g as FFA ⁴ ) 335 AM 1001 Total PC mg / g 250 AM 1002 Overall PL mg / g 300 AM 1002 Total lipids in total mg / g 700 AM 1003 Water content by Karl Fisher % 3.0 AM 1004 peroxide meq / kg 10.0 AM 1005 Heavy metals (sum of Pb, Hg, Cd & inorganic As) ² ) mg / kg 10 AM 1015
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

As mentioned above, it has surprisingly been found that the bioavailability of astaxanthin can be increased when it is integrated into or used with at least one of phospholipid, glycolipid and sphingolipid and optionally in food grade and / or pharmaceutical grade diluents. The bioavailability of lutein also increases and this can work in conjunction with the seed oil extract, such as Perilla. In one example, the astaxanthin may constitute about 0.1 to 15 weight percent of at least one of phospholipid, glycolipid and sphingolipid and any seed oil extract. The astaxanthin in one example is derived from a natural or synthetic ester or a natural or synthetic diol. A pharmaceutical or food grade diluent may be added instead of astaxanthin. Lutein can be used alone with the phospholipid. COQ10 can be used.

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 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, sunflower and safflower. 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 to improve the phospholipids.

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, safflower, grape seed, egg yolk, krill, fish, fry, cuttlefish 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 can be formed by dispersing the astaxanthin and other carotenoids 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 comprises about 2 to about 10 weight percent of the seed oil extract and / or the phospholipid. It may contain the glycolipid and be derived from a natural or synthetic ester or a synthetic diol. In another example, 50 to 500 mg or 50 to 1000 mg phospholipid and any added glycolipid and sphingolipid may be used together with the carotenoids. The nutritional supplement composition can be formulated in a single dose capsule.

It is also possible to add and use a shrimp oil extracted from shrimp farce and shells containing high levels of phospholipids and omega-3 fatty acids such as EPA and DHA. The oils can be rich in astaxanthin. The parts per million (ppm) of astaxanthin can range from 3,000 to 7,000, ranging from 3,500 to 6,000 ppm in one example. The total phospholipids may be about 25-35% w / w and up to 50% and 60%. The total omega-3 content may be greater than about 6.0 grams per 100 grams with an EPA percentage greater than 17% and about greater than 8 grams per 100 grams of DHA percentage greater than 14. These ranges Of course, they can vary.

It is possible to add to this composition a certain amount of low molecular weight hyaluronic acid, such as one derived from microbial fermentation and other sources, including hydrolyzed animal tissues, and could range from 0.5 to 300 kDa or 0 , 5 to 100 kDa lie. It could be from chicken star cartilage extract. The hyaluronic acid may contain elastin, elastin precursors and collagen. The hyaluronic acid may be contained in a matrix form with chondroitin sulfate and naturally occurring hydrolyzed collagen type II nutraceutical ingredients, forming low molecular weight molecules that the body is more readily able to absorb and deliver to different areas of the body as needed. Fresh chicken stern cartilage can be cut and suspended in an aqueous solution, followed by treating the cartilage with a proteolytic enzyme to form a hydrolyzate. The proteolytic enzyme is able to hydrolyze collagen type II into fragments having a low molecular weight. The hydrolyzate is sterilized and filtered and concentrated and then dried to form powder-enriched collagen type II powder, which is then isolated and contains a percentage of low molecular weight hyaluronic acid. Examples of manufacturing techniques can be found in the U.S. Pat. Nos. 6,780,841 and 6,025,327 , the disclosures of which are hereby incorporated by reference in their entirety. It is possible that the low molecular weight hyaluronic acid may also be derived from the hydrolyzed collagen, such as bovine type I collagen or chicken sternum cartilage type II collagen, or even a natural egg shell membrane containing some hyaluronic acid that can be extracted from the egg shell membrane ,

It is also possible to use a pure diol of S, S'-astaxanthin, including a synthetic diol, with the surfactant, such as the phospholipid and / or the seed oil extract, such as Perilla, with the other carotenoids. It is possible to use this pure diol in combination with an EPA-rich algae-based 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 can be mixed with the CQ10 or Lutein alone. 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 possible algae-based oils and other Hp-derived and other species, there is essentially diester or monoester with very little diol which is 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. Glycolipids may be added to the phospholipids which have EPA and / or DHA together with the added astaxanthin and other carotenoids in their various forms and in particular the S, S 'enantiomeric form in substantially monoester form from Haematococcus pluvialis or in pure diol form from asymmetric synthesis could be more useful for the composition. It is therefore possible to combine them 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 of 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 of 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 of 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. ADAC 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 of Schiedt, K., S. Bischof 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 of 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 article of Coral-Hinostroza, G., T. Ytestoyl, B. Ruyter and B. Bjerkeng, entitled "Plasma Appearance of Unesterified Astaxanthin Geometric 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,' Corp. 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 obtained in one example 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. Thus, the alax-derived astaxanthin can be replaced by the synthetic 5S, 3'S-astaxanthinediol in existing formulations of equal or greater potency.

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 should therefore 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

• US 8784904 [0003, 0188]
• US 2013/0011469 [0004]
• US 2013/0295171 [0004]
• US 8586104 [0023, 0172, 0188]
• US 8652544 [0063, 0172, 0188]
• US 2013/0280370 [0063]
• US 7959950 [0068]
• US 5533527 [0113]
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• US Pat. No. 6,880,841 [0206]
• US 6025327 [0206]

Cited non-patent literature

• in the article entitled "Experiments on Visual Cells by Nature and Man: In Search of Treatment for Photoreceptor Degeneration," Investigative Opthalmology and Visual Science, 30 (12), pp. 2421-2454 (December 1989) [0113]
• Lee et al., Molecules and Cells 16 (1): 97-105, 2003; Ohgami et al., Investigative Ophthalmology and Visual Science 44 (6): 2694-2701, 2003 [0162]
• Spiller et al., J. of the American College of Nutrition 21 (5): October 2002 [0162]
• Fry et al., University of Memphis, Human Performance Laboratories, 2001 and 2004, Reports 1 and 2 [0162]
• 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 [0210]
• Andrewes A. and M. Starr, entitled "(3R, 3'R) -Astaxanthin from the Yeast Pfaffia Rhodozyma," Phytochemistry, 15: 1009-1011, 1976 [0211]
• 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. ADAC Int., 80 (3): 622-632, " 1997 [0212]
• Schiedt, K., S. Bishop and E. Glinz entitled "Metabolism of carotenoid and in vivo racemization of {3S, 3'S) astaxanthin in the crustacean Penaeus," Methods in Enzymology, 214: 148-168, 1993 [0213 ]
• 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 [0215]
• Coral-Hinostroza, G., T. Ytestoyl, B. Ruyter and B. Bjerkeng, entitled "Plasma Appearance of Unesterified Astaxanthin Geometric 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,' Corp. Biochem Phys. C, 139: 99-110, 2004 [0215]
• Coral-Hinostroza et al. (2004) [0216]

Claims (14)

A dietary supplement composition formulated in an effective amount to promote ocular health maintenance comprising 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 , Astaxanthin, and at least one carotenoid selected from the group consisting of lutein, trans-zeaxanthin and meso-zeaxanthin. 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, 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, comprising a mixture of antioxidants mixed with the phospholipid-rich rye extract and the seed oil extract. The dietary supplement composition of claim 1, wherein the astaxanthin is derived from a natural or synthetic ester or a synthetic diol. The dietary supplement composition of claim 1, wherein the seed oil extract comprises a supercritical CO2 fluid-extracted perilla seed oil derived from a broken biomass of Perilla frutescens, the seed oil comprising 60 to 95 percent w / w PUFAs in a ratio of 4: 1 to 6: 1 alpha Linolenic acid (ALA) to linoleic acid (LA). A dietary supplement composition according to claim 1, wherein the astaxanthin constitutes about 0.1 to 16% by weight of the mixture of phospholipid-rich rye extract and seed oil extract, the lutein constitutes about 0.4 to 30% by weight of the mixture of phospholipid-rich rye extract and seed oil extract, and the trans-zeaxanthin is about 0.04 to 24% by weight of the mixture of phospholipid-rich rouge extract and seed oil extract. The dietary supplement composition of claim 1, wherein the dietary supplement composition is formulated in a single dose capsule. A nutritional supplement composition comprising a therapeutically effective amount of a mixture of a phospholipid-rich rye extract and a perilla seed oil extract, comprising a ratio of alpha-linolenic acid (ALA) to linoleic acid (LA) between 1: 1 and 6: 1, astaxanthin, lutein and trans-zeaxanthin, and formulated in a single dose capsule, and wherein the astaxanthin constitutes about 0.1 to 16% by weight of the mixture of phospholipid rich rouge extract and perilla seed oil extract, the lutein constitutes about 0.4 to 30% by weight of the mixture of phospholipid rich rose extract and perilla seed oil extract, and the trans zeaxanthin constitutes about 0.04 to 24 percent by weight of the mixture of phospholipid-rich rouge extract and Perillasamenölextrakt makes .. The dietary supplement composition of claim 10, wherein the phospholipid-rich rye extract comprises at least 50 percent phospholipids. The dietary supplement composition of claim 10 comprising a mixture of antioxidants mixed with the phospholipid-rich rye extract and the perilla seed oil extract. The dietary supplement composition of claim 10, wherein the astaxanthin is derived from a natural or synthetic ester or a synthetic diol. The dietary supplement composition of claim 10, wherein the perilla seed oil extract is a supercritical CO ₂ fluid-extracted perilla seed oil derived from a broken biomass of Perilla frutescens, wherein the perilla seed oil comprises 60 to 95 percent w / w PUFAs in a ratio of 4: 1 to 6: 1 alpha-linolenic acid (ALA) to linoleic acid (LA).

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