MX2008007883A - Composition and methods for inhibiting the progression macular degeneration and promoting healthy vision - Google Patents

Abstract

The present invention provides improved dietary supplements and methods for inhibiting the progression of macular degeneration and promoting healthy vision, while at the same time maintaining general health. The dietary supplements of the invention contain vitamin E and carotenoids in the form of Vitamin A, lutein and/or zeaxanthine. The dietary supplements of the invention further contain Vitamin C, copper and zinc and may also contain such ingredients as rosemary, DHA, and other vitamins and minerals.

Description

COMPOSITION AND METHODS TO INHIBIT THE PROGRESSION OF MACULAR DEGENERATION AND PROMOTE HEALTHY VISION BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates in general to nutritional methods and compositions for alleviating eye ailments and, more specifically, to improved compositions and methods for the treatment of cataracts and macular degeneration. 2. Description of the Related Art Macular degeneration, associated with the aging and appearance of drusen, is a very significant concern, since AMD (age-related macular degeneration) is now a leading cause of blindness in the United States of America for people over 65 years of age. Just in the period of time when the eyes are a more important sense, and when reading and watching television are often the most enjoyable entertainment options, this disease deprives the elderly patient of such possibilities. The lens of the eye has only one condition of suffering that we are aware of, and that is the cataract. The lens loses its clarity as it becomes cloudy, and the vision is altered depending on the degree of opacification. There are different etiologies for cataracts such as trauma or congenital injury, which are well recognized. It is also known that some medicines such as cortisone-like preparations and glaucoma medications can cause cataracts, as early as metabolic errors such as galactosemia or latent genetic errors result in diabetes. These, however, are less common than the more familiar age-related cataract, which is associated with cumulative oxidative stress resulting in the reticulated and precipitated protein. The exact incidence of cataracts in the general population is difficult to determine because it depends in part on one's definition of a cataract. If it is defined as simply an opacity of the lens, then obviously the incidence is much greater than when it is defined as an opacity of the lens that significantly impacts vision. The pathogenesis of age-related cataracts and macular degeneration are not fully understood. The accumulation of drusen and lipofuscma and the loss of retinal pigment, the marks of macular degeneration, seem to be a consequence of the accumulation of biomolecular derivatives of bioactive molecules involved in photoreception and signal processing, and are normally detoxified, processed, and exported from the RPE (retinal pigment epithelium). While recognizing the importance of control the accumulation of lipofuscma and its toxic dominant component A2E, N-retinylidene-N-ret inylethanolamine (Sparro, 2001), which is capable of converting visible wavelength radiation into toxic ROSs (reactive oxygen species), is not has proposed some means to achieve this and in this way one of the best means currently available to limit the damage is by reducing the amount of radiation available for lipofuscin. There is also no effective treatment to date for angiogenesis or the resulting atrophy, except laser photocoagulation attempted in those patients who develop abnormal blood vessels under the retina, ie, sub-retmal neovascularization. The medicated group with advanced AMD is a distinct minority of a much larger group. Individuals so afflicted can anticipate either a progressive deterioration or sometimes a relatively static, but not spontaneous, course improvement, because the basic architecture of the retina is destroyed. Occasionally, there may be variations in vision that seem to show improvement depending on such things as the lighting in the room and the potential resolution of the fluid under the retina. The important point, however, is that when this sensitive neurological tissue is damaged, that damage is permanent.

In 1981, Spector et al. , said that questions still remained concerning the mechanism and the agents involved with the massive oxidation of lens proteins and their relationship to the development of cataract (Spector et al., 1981). They also noted that glutathione (GSH) can act as a reducing agent and trap for free radicals. Glutathione peroxidase (GSHPx) and catalase assist to metabolize H202. While dismutase superoxide (SOD) can detoxify 02, light can photochemically induce oxidation. However, Spector et al. believes that while the complete mechanisms of light and / or metabolically induced oxidation are unclear in terms of causing the observed oxidation products, they appear to be associated with elevated levels of intracellular oxidizing agents, such as peroxide of hydrogen. In 1987, Machlin et al. reported that there was some evidence that free radical damage contributed to the etiology of some conditions, including cataract (Machlin et al., 1987). They noted that defenses against such free radical damage included Vitamin E, Vitamin C, beta carotene, zinc, iron, copper, manganese, and selenium. In 1988, Jacques et al. reported that it is commonly believed that oxidative mechanisms are causally linked to, do not simply associate with, the formation of the cataract. According to Jacques et al. the evidence suggests that GSHPx and SOD decrease with increasing degree of cataract. Jacques et al. They also reported that Vitamin E is believed to be a determinant of cataract formation and that it can act synergistically with GSHPx to prevent oxidative damage. They point to the possibility that Vitamin C may play a role in cataract formation and could influence GSHPx through its ability to regenerate Vitamin E. Dietary supplements are taken for a variety of reasons including improved vision or prophylaxis against loss of vision. An example of a set of dietary supplements useful in promoting healthy eyes are ICAPS® Dietary Supplements (Alcon Laboratories, Inc., Fort Worth, TX). Dietary supplements are generally in the form of powders, tablets, chewable tablets, capsules, gel capsules or soft gels filled with liquid and comprise a variety of vitamins, minerals, and herbs or other organic components. Some dietary supplements are formulated with small beads or beads. Recent data have suggested that the inclusion of xanthophylls and other carotenoids in dietary supplements may provide useful dietary supplements superior to improve the health of the eye. Studies have shown selective admission of carotenoids, zeaxanthin and lutein, by the retina in the ratio of approximately 2: 1 for lutein: zeaxanthin but with the proportion reversing in the macula (Bernstein et al., 1997 & and Landrum et al., 1988 & 2001; Krins et al., 2003; Hammond et al., 1997; and Handelman et al., 1991). This previous work revealed the presence of lutein and its positional isomer, [R, R] -zeaxanthin. More recently, a second isomer of zeaxanthin has been found in the macula, the diastereomer mesozekanxanthin, the [R, S] isomer of zeaxanthin (Bone &Landrum et al., 1988). These and related observations suggest that both are essential for improved eye health and for the protection of the macula. Xanthophylls are effective phytochemical antioxidants and are known to be located in the macula of the retina. It has been suggested that particular xanthophylls, zeaxanthin and its isomer lutein, may be beneficial in maintaining or improving the health of the macula and the clarity of the lens. These molecules can function in a number of ways to protect the eye from high intensity radiation or other insults. It has been suggested that fovea proteins bind xanthophylls, localize and concentrate xanthophylls within the fovea (Bernstein et al., 2004). Because the Xanthophylls are able to absorb photoexcitatory radiation from the short visible wavelength, they can also protect the photosensitive, underlying cells of the neural retina and RPE. Such cells are responsible for high definition vision and have been shown by epidemiological studies to be adversely affected by exposure to high intensity radiation or even by chronic exposure to visible wavelength radiation. It is believed that carotenoids complement the activity of these cells, and also that they protect against photochemical injury. See, for example, Snodderly (1995) and Seddon et al. (1994). Studies have also shown that the portion of the retina associated with the deposition of xanthophyll experiences one of the highest metabolic rates in the body (Berman 1991). The energy to sustain this metabolism is derived from oxidation. While it does not appear that lipophilic xanthophils undergo a rapid change characteristic of surface active or water soluble antioxidants.

(Hammond et al., 1997), the continuous exchange of xanthophylls occurs in response to environmental challenge and tissue environment, and their gradual depletion without nutritional replacement may augur tissue damage (Hammond et al., 1996a, Hammond et al., 1996b). and Seddon et al., 1994). The lack of rapid change also involves the role of other smergistic antioxidants, vitamins C and E, especially but also enzymatic antioxidants that are active in the redox cascade that passes the initial oxidative excitation to less harmful and lower energy species. Carotenes are conjugated C40 compounds that include beta carotene (a provitamma, a precursor of Vitamin A) Carotenes are deeply colored compounds and are found throughout the plant kingdom, for example, in leafy vegetables such as spinach and cabbage, and brightly colored fruits such as melons and pineapple. While carotenes are ubiquitous in the plant kingdom, they are generally not available biosynthetically in mammals. Because carotenes are essential for normal mammalian health, mammals need to ingest several sources of the carotenes, for example, fruits and vegetables. It is known that the absence of carotenoids from the diet, especially the derivative of carotene, vitamin A, is associated with degenerative diseases of the eye. Another important component to maintain the health of elderly or aging patients is to ensure the intake of appropriate amounts of vitamins and minerals. Because of the compromised bioabsorbent capacity, many elderly and aging patients are unable to ingest the recommended amount of vitamins and minerals through diet alone. Further, Aged patients also tend to be on a number of prescription medications. Remembering to take all the prescribed medications at the appropriate time every day can prove to be a challenge for the elderly patient. Adding a multi-vitamma and another dietary supplement for eye health increases the chances of noncompliance with taking the daily medications. A single dietary supplement is needed for a larger, older population that provides the recommended daily allowance of vitamins and minerals while at the same time providing supplementation with additional vitamins, minerals, and essential nutrients at recommended levels to maintain eye health. BRIEF DESCRIPTION OF THE INVENTION The present invention overcomes these and other disadvantages of prior art by providing a multi-vitamin dietary supplement containing recommended dietary amounts, or above, a number of essential minerals / vitamins / necessary for the general health of the body along with a unique combination of vitamins, minerals, and additional essential nutrients needed to maintain or improve eye health. The present invention is directed to improved formulations useful for maintaining and improving ocular and systemic health. In particular, the improved formulations comprise amounts and specific combinations of vitamins and minerals tested in the Age-Related Eye Disease Study (AREDS) to slow the progression of AMD, with components of essential nutrients and minerals, multi-vitamins, to maintain the patient's overall health. Such improved formulations can additionally provide lutein and zeaxanthin in the proportion shown to be present in the retina. Preferred formulations may also contain one or more bioflavonoids and other phytonutrients that provide antioxidant or signaling and control functions to protect ocular tissues from deleterious metabolites generated by photo-oxidative stress. The advantage of specific combinations of ingredients is that they are essentially complete, and are selected to eliminate the ingredient imbalances that can occur when combining multiple products. In addition, different versions are claimed that are specialized for different segments of the population, segments that may have restrictions or specific dietary requirements. DETAILED DESCRIPTION OF THE PREFERRED MODALITIES According to the present invention, the elements of the composition are directed towards searching among the oxidants and free radicals or in other ways slow the progression of the condition of macular degeneration. At the same time, the formulations of the present invention provide components of a multi-vitamin needed by the elderly patient to maintain general health. The free radicals for which the present invention is primarily directed include superoxide and the free radical hydroxide. Oxidants include primarily peroxide. The articles and dosages in the present invention are consistent with those readily available in macrobiotic stores. The dosage form is preferably a mild tablet, capsule or gel form for oral administration, with the patient taking one to four doses taken once or twice a day. The present invention, however, contemplates that the preferred total dose may be administered as a single dose or other doses of multiple parts. The composition may also be of the regular release or delayed release type. In addition, for oral administration, the present composition may be in capsules, lacquered tablets, non-lacquered tablets, soft gels, or mixtures of controlled release powders, prepared according to well-known methods. According to the preferred multiple dosages described above, each tablet, caplet, or soft gel is preferably composed approximately as follows: Vitamin C It has been known that there are high concentrations of Vitamin C in the normal human lens and in the aqueous humor surrounding the lens, and that this is an antioxidant (Harris 1933). It has also been shown in the past that generally increasing Vitamin C in the diet generally increases the concentration of ascorbate in the aqueous humor and in the human lens (Ringvold 1985). It has also been known that Vitamin C concentrations decrease with age and, in particular, in patients with senile cataracts.

(Chatterjee 1956; Purcell 1968). Subsequent work has shown that Vitamin C supplementation is effective in increasing the concentrations of the lens of this water-soluble antioxidant, and epidemiological data support its value in reducing the prevalence of cataract (Taylor, 1999). It has also been shown that Vitamin C is integral to the antioxidant cascade that reduces oxygen to water, capable of regenerating the reduced form of vitamin E, located in biomembranes. There is no known optimal daily dose of vitamin C, although the American RDA is 60 mg. However, doses of 2.0 grams and more have often been taken as a supplement for general health. Although the acid can be used Ascorbic acid, the present composition preferably uses Vitamin C in the form of sodium ascorbate by being easily dissolved in the digestive system and by causing relatively minimal irritation. The concentration is at about 200-250 mg / tablet or caplet, or a preferred total dose of about 0.8-2 grams / day. In such concentrations, Vitamin C represents approximately 20-30% by weight of each tablet or caplet, which includes active as well as inactive ingredients described below. Vitamin E Vitamin E is also a well-known antioxidant, as already mentioned (see also Mansour 1984). Vitamin E can work synergistically with Vitamin C, protecting the vital cell function of endogenous oxidants (Orten 1982). A very common Vitamin E supplement consists of 400 International Units per day. While studies that used more than 800 IU per day have shown possible signs of toxicity, many common dietary supplements available in supermarkets have 1000 units of Vitamin E daily (eg, Chaney 1986). THE North American RDA is 30 IU. The present invention preferably uses Vitamin E in the form of d, l-alpha acetate tocofeplo, for which 1 mg is equivalent to 1 IU. The preferred concentration is about 15 IU-400 IU per tablet or caplet or a total daily dose of 30-800 IU of Vitamin E. This represents from about 1% to preferably less than 20% by weight of each tablet or caplet. Zinc It is known that zinc is important for the health of the retina and the function of vitamin A (Russell 1983, Karcioglu 1982, Leure-duPree 1982). Zinc is a cofactor in an enzyme required to maintain the bioavailability of folate (Chandler et al., 1986), and folate is important for the synthesis of healthy protein and DNA. Zinc is a supplement previously used in a study that showed it to be significantly better than placebo at slowing macular degenerative changes (Newsome 1988). Zinc is also known to be an important cofactor for a whole host of metalloenzymes, not least of which is dismutase superoxide, which looks for the potent superoxide oxidant. There are two types of SOD in mammalian cells. One type contains copper and zinc and is located in the cytosol and the periplasmic space of the mitochondria. The other type contains manganese and is in the matrix of the mitochondria (see generally U.S. Patent No. 4,657,928). The mitochondria is the site of high metabolic activity, and the rapid oxidative process in neural retina cells and retinal pigment epithelium (RPE), which provides the energy needed to convert the stimulus of visible light radiation to a chemical signal. These isoforms of SOD and zinc are also involved in cataract because the activity of dismutase superoxide and zinc are dramatically lower in cataract patients than in non-cataract patients (Ohrloff 1984, Varma 1977, Swanson 1971). Zinc is also involved in enzymes related to the metabolism of vitamin A, regulating the levels of esterification. In doing so, zinc is involved in regulating the hepatic storage, release, and transport of retinol, and therefore its bioavailability for ocular tissues (Russell 1983). Approximately 200 mg of zinc per day, although well tolerated, have been shown to have potential side effects, particularly blocking the absorption of copper, which results in the possibility of copper deficiency anemia (Fischer 1983). High doses have also been shown to have the effect of lowering serum titers of high density lipoprotein, thus potentially exacerbating the risk of atherosclerosis (Hooper 1980). The doses of 100-150 mg of zinc per day have been known in the past for being well tolerated without difficulty (Wagner 1985). The North American RDA is 15 mg. While other forms of salt such as sulfate can be used, picolinate, phosphate, and gluconate, the present invention preferably provides zinc in the form of zinc acetate for its high bioavailability, and zinc oxide for its high zinc density. The preferred daily dose range is from the RDA to a maximum of about 100 mg of a bioavailable form of zinc, such as zinc acetate. This maximum amount of zinc in a less bioavailable form such as zinc oxide could vary as high as 150 mg / day. Any form could be administered in a tablet, caplet, powder or soft gel. Copper Copper is another important cofactor for metalloenzymes, and is a second necessary cofactor for dismutase superoxide (Beem 1974). Copper has been shown to decrease in individuals over 70 years of age and to be basically zero in cataract lenses (Swanson 1971). If copper is significantly decreased, dismutase superoxide has been shown to have decreased function, thereby hampering an important mechanism to protect the lens (Williams 1977). Copper is also protective of the toxicity of zinc, which blocks a part of zinc absorption and, consequently, decreases bioavailability (Van Campen 1970). It has been estimated that two to three mg of copper per day are safe and provide an adequate daily dietary intake (Pennington 1986). A daily dose of two mg is the American RDA. Part of the absorption of copper will be blocked by 100 mg of zinc daily as anticipated previously (Van Campen 1970). Accordingly, the present composition preferably provides about 1-5 mg / day. This amount is considered safe because in the typical American diet, particularly among the elderly, zinc and copper are often significantly below the minimum daily requirements. In this embodiment of the present invention, the copper is preferably provided in the form of copper gluconate, citrate, or an amino acid chelate and the copper in such form typically represents less than about 3% by weight of each tablet or caplet for a typical BID administered supplement such as ICaps® Lutein and Zeaxanthin Formula, and less than 1% for a typical QID administered supplement such as ICaps® AREDS. Cupric oxide has also been used as a source of copper in supplements where the total available space in the dosage form is very limited, because the copper faction is higher in this compound.

Beta-carotene It is well known that Vitamin A is essential for vision. Vitamin A, retinol, is a C2o alkene, which, like the retina, combines with opsin in the retina to form rhodopsin, a visual pigment. The transition from the ci s form to the trans form of the retina results from excitation by light. Thus, Vitamin A clearly is crucial for photoreception. Beta-carotene, a pro-vitamin A carotenoid, is an orange lipid-soluble pigment that can serve as a self-regulating source of the retina. Deficiency and excess retinol can lead to fetal abnormalities because Vitamin A is associated not only with vision but also with growth, reproduction, cell proliferation, cell differentiation, and correct immune function. The amount of ß-carotene converted to retinol is controlled biologically and dictated by the need for retinol. Control is exerted through the central symmetric enzymatic cleavage of the C40 carotenoid to the C2o retinoid. Therefore, none of the toxicity types of Vitamin A have been observed for β-carotene. However, surprisingly, the toxicity of the explicit β-carotene has been discovered. While the treatment of a deficiency of β-carotene reduced the incidence of gastric and esophageal cancers, a compromised management of a xenobiotic was seen in connection to its use in the treatment of lung cancer and cardiovascular disease in smokers given in high daily doses (ie, 30 mg / day) of ß-carotene. As a consequence, smokers (a high-risk category for AMD) are encouraged not to increase their supplemented level of β-carotene above the RDA level. This recommendation directly contradicts the recommendation that comes from the ARED Study of 7 years, in which approximately 17-24 mg / day was consumed (AREDS Research Group 2002). The resolution of these conflicting recommendations, as prescribed below, is to provide versions of a complete formulation, including the vitamins and minerals of a multi-vitamin consumed by two-thirds of those in the ARED study, maintaining total carotenoids at the designated level of 15 mg, or less. In one formulation, lutein and zeaxanthin are replaced by a portion of the β-carotene content, maintaining the daily dose of β-carotene in the RDA, 3 mg per day. In another, lutein and zeaxanthin completely replace ß-carotene. The amount per tablet will be based on the number of tablets recommended for the particular dosage form, usually two to four tablets per day. Xanthophylls While xanthophylls are also C40 compounds, and are carotenoids, this subclass is distinguished by the presence of more polar groups. The isomers of lutein and zeaxanthin have alcoholic hydroxyl groups in both terminal ionone rings, and these play a profound role in the localization and use of these carotenoids. The specific binding proteins for these lipids appear to control their location in the eye, their total absolute amount and their relative amounts. For example, observations in primates and humans (corpse eyes, for example) have indicated that while lutein is the most abundant xanthophyll in the eyes, in the vicinity of the fovea the relative amount of zeaxanthin is greater than lutein. All xanthophylls serve as antioxidants, free radical quenchers, and blue light absorbers, and all of these are protective functions of these molecules for the underlying retina and its supporting tissue, the RPE. All these xanthophylls are isomers of each other; zeaxanthins have one or more of the double bonds in the conjugated sequence, and thus, lutein and zeaxanthin are positional isomers. And the two isomers of zeaxanthin, 3,3 '- [R, R] and 3,3'- [R, S] (the meso form) are diastereomers, differing in only one optical center. It has been observed that all three of these diols are present in the macula. Typically, xanthophylls are considered Very safe compounds, found in vegetables and edible plants, from melons to corn to spinach and cabbage. Epidemiology has shown that the incidence of AMD is lower for those individuals who consume quantities in the upper quartiles and quintiles. The GRAS state has been granted for lutein, in the forms of ester and free alcohol, and for zeaxanthin, in the form of free alcohol. Lutein is shown to be interconvertible to the meso form of zeaxanthin, however the protein (s) responsible for the interconversion has not yet been identified and therefore the precise way and mechanisms to control the interconversion are unknown. As a consequence, some balance of these xanthophylls in the diet and in supplementation is more prudent. Prospective epidemiological and clinical studies indicate that higher macular levels of xanthophylls protect the retina from oxidative stress. Some data support an increased deficit in the average age and in greater age. From the epidemiological data it was perceived that levels above 6 mg / day of xanthophylls were beneficial in delaying the onset of AMD. Studies of the impact of diet on bioavailability suggest that serum levels of xanthophylls increase within a period of approximately four to eight weeks, and levels of Macular pigment respond more slowly but usually within four to six months, probably dependent on the age, sex, and other risk factors and health of the subject. These data also suggest that the rate of increase and levels of the plateau are dependent on daily intake, as well as other individual factors. The levels of the National Health and Nutrition Examination Survey (NHANES), which is the normal domestic North American intake, is approximately 2 mg / day. Thus, in the methods and compositions of the present invention, the total daily supplementation of xanthophylls is preferably in the range of 2 mg / day to 18 mg / day, more preferably less than about 16 mg / day. The ratio of lutein to zeaxanthin in the retina has been shown to be approximately 2: 1. It is believed that providing a similar ratio of lutein to purified zeaxanthin in a dietary supplement is more effective in maintaining eye health than providing a much higher amount of lutein, such as those that can naturally occur in plant sources for the compound. Accordingly, in preferred aspects of the present invention, lutein and zeaxanthin will be present in the formulation in a ratio of 2: 1. For example, if there is 4 mg of lutein in the formulation, there will be 2 mg of zeaxanthin in the formulation. Likewise, 8 mg of lutein corresponds to 4 mg of zeaxanthin, etcetera. The present invention is directed to improved dietary supplement formulations for maintaining the general and ocular health of a patient or consumer. As used herein, "dietary supplement (s)" or the shortened form, "supplement (s)", refers to any dosage form of the finished dietary supplement, which contains dietary substances and which is suitable for the ingestion by a host, for example, a human or other mammal. Thus, the term "dietary supplement" is intended to encompass any form of the dietary supplement, such as the tablet, chewable tablet, capsule, gel capsules, powder, soft gel, etc. As used herein, "xanthophylls" refer to hydroxy- and keto-oxidized carotenes and their derivatives, including esters and free alcohols; the "carotenes" refer to any of the carotenes of 40 carbons and their derivatives; the "retinoids" refer to Vitamin A (retinol) of 20 carbons and their derivatives; and "carotenoids" refer to any of the xanthophylls, carotenes and retinoids or combinations thereof. Carotenoids can be derived synthetically or can be purified from natural sources. The synthetic preparations may contain different isomers of the carotenoids from those contained in the natural preparations. Depending on the use intended, natural, synthetic carotenoids or mixtures of both types can be included as oils, agglomerated solids, mixtures or encapsulated oils, or monolithic co-beads in the present invention. The xanthophyll component can be obtained from various sources such as vegetables and herbal components, such as corn, marigolds and leafy vegetables; marine sources, such as krill; or micro-organic sources, such as algae and genetically engineered bacteria or sources of yeast. Xanthophylls can also be synthesized by methods known in the art and are available from various manufacturers. Examples of xanthophylls include, but are not limited to, lutein, zeaxanthin, astaxanthin, canthaxanthin, cryptoxanthin and related oleoresins (eg, mono and di esters of xanthophyll fatty acids). The purity and concentration of xanthophyll in the various commercial sources will vary. For example, some sources can provide about 1% weight / weight ("weight / weight") or less of the xanthophyll in oil while other sources, for example, Kemin Laboratories, Inc. (Des Moines, Iowa), can provide a source in excess of 20% weight / weight of xanthophyll in oil, or above 50% as provided in the crystalline or semicrystalline 'cake'. The sources of xanthophyll can be individual xanthophyll preparations or combinations thereof, and may vary in concentration depending on the solvent, or in fact its absence due to some powder or cake preparations may provide a more preferable raw material. For example, a xanthophyll preparation may comprise lutein such as exclusive xanthophyll or a combination of lutein and zeaxanthin, including combinations of the diastereomers of zeaxanthin ([R, R '], [R, S], [S, R], and [S, S]), wherein preferred combinations include a mixture of lutein, zeaxanthin [R, R '], and meso zeaxanthin. Other preferred combinations include a mixture of zeaxanthin [R, R '] and meso zeaxanthin and / or a mixture of lutein and any diastereomer of zeaxanthin. The inclusion of a combination of xanthophylls in the formulations, and in particular proportions, may be particularly important when it is intended to deliver such combinations to the host in proportions similar to those found in the retina widely, or in the macula or fovea of the eye, specifically , or in other proportions that, when ingested, support the proportions in the tissues of the host. Xanthophylls can also be included in the formulations as conjugated derivatives, for example, oleoresins of xanthophylls, as exemplified above.

Omega 3 Fatty Acids Omega 3 fatty acids, found naturally and abundantly in cold-water fish tissue, are also abundant in the optical discs of photoreceptors in the human retina. Epidemiologically, it has been found that the predominance of AMD is higher for individuals with diets depleted in omega-3 fatty acids, that is, that the amount of omega-3 in the diet correlates inversely with the predominance of AMD (Seddon). and Willett et al.). The two predominant omega-3 fatty acids, conjugated fatty acids, important in eye health are DHA (docosahexaenoic acid) and EPA (eicosapentaenoic acid). The term "DHA" as used herein refers to either of these two predominant omega-3 fatty acids or to a mixture of the two; that is, when the term "DHA" is used, the skilled artisan would understand that any DHA, EPA, or a mixture of EPA and DHA could be used in that case. The preferred ratio of EPA to DHA when a mixture is used is 0.8: 0.2 to 0.2: 0.8, EPA: DHA. While docosahexaenoic acid has been made available from fermentation and from biotechnology sources, the preferred mixture is usually harvested from the fish and then purified / deodorized. Other Vitamins / Minerals for Systemic Health Vitamins: Vitamin D is a primary regulator of calcium homeostasis and is essential for normal bone, for muscle, and for nerve function and growth. Vitamin D has been shown to protect against osteoporosis, and to have antioxidant and anticarcinogenic activities in the body. It has been established that the RDI for Vitamin D is 400 IU / day. Vitamin K is involved as a cofactor in the regulation of essential hemostatic proteins for the correct coagulation of blood, preventing excessive bleeding. It has been established that the RDI for Vitamin K is 80 μg / day. Thiamine (Vitamin Bi) is essential for the use of carbohydrates and fats to produce energy and support cellular metabolism. Thiamine is important in neuromuscular development and maintenance. Vitamin Bj. It has been shown to have antioxidant effects on neural tissues including the brain. It has been established that the RDI for thiamine is 1.5 mg / day. Riboflavin (Vitamin B2) is important in maintaining energy production and in metabolic processes involving carbohydrates, fats and proteins and for normal cell function and growth. Riboflavin can help preserve healthy eyes, the function of skin and nerves. It has been established that the RDI for riboflavin is 1.7 mg / day. Niacin (Vitamin B3) is involved in a wide array of biochemical reactions that include the production of energy and the synthesis of fats and steroids. It has been found that vitamin B3 lowers total serum cholesterol levels, low density lipoproteins (LDLs), very low density lipoproteins (VLDLs) and triglycerides. Niacin deficiency can result in dermatitis, inflammation of the Gl tract, inadequate tryptophan results. It has been established that the RDI for niacin is 20 mg / day. Pantothenic acid (Vitamin B5) is essential in human nutrition for the correct production of energy, for the synthesis and decomposition of fatty acids, steroids, cholesterol, and amino acids, and works as an antioxidant. The multiple functions of coenzyme A - important in oxidative phosphorylation - and the acyl carrier protein, in which pantothenic acid is incorporated, are well recognized. It has been established that the RDI for pantothenic acid is 10 mg / day. Pyridoxine (Vitamin B6) is important in the metabolism of proteins, fats and carbohydrates in the body. It has been found that vitamin B6 supplementation reduces systolic and diastolic pressure in hypertensive patients, protects vascular endothelial cells against damage induced by platelets and protects against atherosclerosis. It is known that pyridoxine is essential for the formation of hemoglobin and that it is important for the utilization of stored glucose. It has been established that the RDI for pyridoxine is 2 mg / day. Vitamin Bi2, an enzyme co-factor that contains cobalt, is necessary for normal cell growth and development, notably in the development of red blood cells and is protective against neurodegenerative disorders in the body, especially in the elderly. Vegetarians are susceptible to deficiency in Vitamin B12. Insufficient intake of Vitamin B12 may contribute to anemia. Vitamin Bi2 can reduce the risk of atherosclerosis. It has been established that the RDI for Vitamin B? 2 is 6 μg / day. Folic acid (a vitamin B, sometimes referred to as vitamin B9) is essential for proper cell growth and development, and to prevent neural birth defects. Folic acid deficiency can lead to anemia and deficiency of white blood cells, which play an important role in combating conditions infectious Folic acid has been shown to have anticarcinogenic actions and has a role in preventing cardiovascular disease, especially in older individuals. Insufficient intake of folate can contribute to anemia. Low levels of folate is a determinant factor of elevated homocysteine, along with genetic abnormality (a SNP, a single nucleotide mutation), an important risk factor for atherosclerosis. It has been established that the RDI for folate is 400 μg / day. Biotin (a vitamin B, sometimes referred to as Vitamin H) is an enzyme cofactor involved in the biosynthesis of fats and carbohydrates, and amino acid metabolism, in part because of its role in C02 fixation. It has been found that biotin supplementation improves glucose tolerance and decreases insulin resistance. It has been established that the RDI for biotin is 300 μg / day. Botanical Drugs: Lycopene is a carotenoid with potent antioxidant activity that protects cells against oxygen radicals and light damage. Research has shown that Lycopene can be protective against prostate cancer and coronary heart disease. To date, no RDI has been established for Lycopene.

Rosemary is an herb that contains a mixture of bioflavonoids and potent antioxidants, including carnosol and carnosic acid. There is no established RDI for the rosemary bioflavonoids, and there is no mammalian biosynthesis of these antioxidants. Minerals: Calcium is necessary to maintain bone health and cell regulation. Calcium supplementation has been associated with reducing blood pressure in hypertensive patients as well as decreasing serum cholesterol levels in man. It has been established that the RDI for calcium is 1000 mg / day. Chromium is an essential trace element that helps in the regulation of blood glucose by working with insulin to transport glucose to cells. Chromium works with insulin to convert carbohydrates and fat into energy. It has been established that the RDI for chromium is 120 μg / day. Iodine is an essential trace element that is vital to the function of the thyroid gland. Iodine is the essential component of thyroid hormones, which are crucial for normal development and for controlling metabolic rates. It has been established that the RDI for iodine is 150 μg / day.

Magnesium is an essential mineral necessary for the production of ATP, and for the regulation of calcium. Magnesium supplementation may have antihypertensive actions, glucose regulators and cardio-protective actions in the body. Magnesium is essential for the healthy function of muscles and nerves and for the formation of bones, and influences neuromuscular coordination. Magnesium can assist in preventing coronary heart disease. It has been established that the RDI for magnesium is 400 mg / day. Manganese is an essential trace element found in several crucial enzymes that are essential for normal cell metabolism, and helps maintain protection against oxidative damage, to control the levels of and damage reactive oxygen species. Manganese is required for the use of glucose, for the synthesis of cartilage mucopolysaccharides, and for the biosynthesis of steroids. It has been established that the RDI for manganese is 2 mg / day. Molybdenum is an essential trace element necessary for neurological and ocular health, and to process many chemicals in the body that might otherwise be harmful, is known to function as an enzyme cofactor in xanthine oxidase, important in metabolism of the bases purine It has been established that the RDI for molybdenum is 75 μg / day. Phosphorus is an essential mineral that is a central component of DNA, cell membranes and the production of energy and storage within the cell. The match, in parallel with calcium, is essential for the construction and hardening of bones and teeth. It has been established that the RDI for phosphorus is 1000 mg / day. Potassium is an essential mineral that maintains intracellular tonicity and normal blood pressure, and has a primary role in the transmission of neural signals in the body. Studies have shown that supplemental potassium can protect against stroke, cardiovascular disease, and other degenerative conditions. It has been established that the DRV for potassium is 3500 mg / day. Selenium is an essential trace element that acts in concert with Vitamins C and E to protect against oxidative damage in cells, and in particular selenium maintains the health of liver tissue. Selenium promotes the growth and development of the cellular nerve, and cardiac health. As an enzyme cofactor, selenium is essential for the healthy functioning of the heart muscle. It has been established that the RDI for selenium is 70 μg / day. Other considerations Carotene, retinoid or combinations thereof, the component (hereinafter referred to as "carotene (s) / retinoid (s)") can be obtained from various sources such as vegetable and herbal sources, such as corn and leafy vegetables , and sources of fermentation products available from the biotechnology industry. The carotenoids / retinoids can also be synthesized by methods known in the art. Examples of carotenes include, but are not limited to, alpha, beta, gamma, delta, epsilon and psi-carotene, and isomers thereof. Examples or retinoids include, but are not limited to, Vitamin A and analogs of Vitamin A (e.g., retinoic acid). The purity of the carotene / retinoid and the concentration in the various commercial sources will vary. For example, some sources can provide about 1% w / w or less of carotene / retinoid in oil, or as an oil suspension, or in a protected dry form, e.g., a co-pearls. The concentrations of the xanthophylls and carotenes / retinoids in the formulations will vary, but will be in useful amounts in the dietary supplements. In general, the combined concentration of xanthophylls and carotenes / retinoids in the formulations will be in the range of about 0.1 to 10% w / w. The preferred carotenoid concentrations, which are generally depending on the selection of particular carotenoids / retinoids and xanthophylls and their relative proportions, they will be approximately 0.5 to 7% w / w. The individual concentrations of xanthophylls and carotenoids / retinoids will not necessarily be the same. Preferred formulations for a general population of non-smokers will vary from a concentration ratio of about 1:10 to about 10: 1 of xanthophylls: carotenes / retinoids and most preferred formulations will have concentration ratios ranging from about 2: 1 to about 1: 2 of xanthophylls: carotenes / retinoids. Preferred formulations for a population of smokers may vary from 0% of β-carotene to the RDA of β-carotene. More preferred formulations of the present invention include those in Examples 1-4. As indicated above, the formulations will also contain one or more additional antioxidants. The antioxidants can be hydrophobic or hydrophilic. The antioxidants serve to inhibit the oxidative, photochemical and / or thermal degradation of the carotenoid components. Because antioxidants are also considered useful in nutritional health, they can also provide some nutritional benefit to the host. In general, antioxidants will be natural antioxidants or agents derived from same. Examples of natural antioxidants and related derivatives include, but are not limited to, vitamin E and related derivatives, such as tocotrienols, alpha, beta, gamma, delta and epsilon tocopherol, and their derivatives, such as the corresponding acetates, succinates; Vitamin C and related derivatives, for example, ascorbyl palmitate; and natural oils, such as rosemary oil. Preferred formulations will contain one or more hydrophobic antioxidants. The amount of antioxidant (s) contained in the formulation will be an amount effective to inhibit or reduce the oxidative, photochemical and / or thermal degradation of the carotenoid components. Such an amount is referred to herein as "an effective amount of one or more antioxidants". In general, such an amount will vary from about 0.1 to 10 times the amount of the xanthophyll and the carotene / retinoid components and any other chemically sensitive components present, for example, the bioflavonoids. Preferred formulations, which generally will comprise approximately 0.5-25% w / w of carotenoids alone, or including bioflavonoids, will contain approximately 2 to 10% w / w of the antioxidant. Antioxidants may be combined with designated nutrients in isolated co-pearl deposits prior to incorporation into the dosage form. The co-pearls like those described in U.S. Patent Nos. 6,582,721, and 6,716,447, and in U.S. Patent Applications Nos. 2005/0106272, and 2005/0147698, all of which are incorporated herein by reference, would be useful in the formulations of the present invention. The formulations will also comprise one or more solidification, volumetric and agglomeration agents (collectively referred to herein as "solidification agent (s).) The solidification agent (s) is used in the formation of tablets and in the generation of carriers as solids. such as beads or beads, capable of transforming oils into stable agglomerates suitable for the granulation, mixing, and compression required for tabletting Examples of solidifying agents useful in the preparation of the formulations include, but are not limited to , sucrose, glucose, fructose, starches (e.g., corn starch), syrups (e.g., corn syrup), and ionic and nonionic polymers including, but not limited to, PEGs and other polyether-like alkoxy-cellulose compounds (HPMC), gelan, carrageenans, Eucheuma gelatenae, guar, hyaluronates, alginates, chondroitin sulfate, pectins, and proteins, (for example collagen or its hydrolyzed products (for example, gelatins or polypeptides)). Other solidifying agents known per se can also be used.

Those skilled in the art of preparing the dietary supplement in the preparation of the formulations of the present invention. The amount of the solidification agent (s) will vary, depending on the other components contained in the formulation, but will generally comprise the weight and volume of the majority of the dietary supplement. Optionally, the formulations of the present invention may also contain one or more bioflavonoids and / or glycosylated bioflavonoids. The bioflavonoids, or "flavonoids", are structures similar to flavone- and isoflavone- found primarily in fruits and vegetables. Bioflavonoids are commercially available or can be synthesized by methods known in the art. Examples of bioflavonoids include, but are not limited to, quercetin, acacetin, liquiritine, rutin, taxifolin, nobiletin, tangeretin, apigenin, chyrosine, myricetin, genistein, daidzein, luteolin, naringenin, and kaempferol, and their derivatives, such as analogs corresponding methoxy-substituted. Bioflavonoids may be useful in nutritional health as modulators of the rates of reactions mediated by the enzyme in vivo. Bioflavonoids can also provide antioxidant activity and can be included in formulations for this purpose. Other oils may be present in the formulations of the present invention. The formulations will typically comprise an amount of vegetable oils or oleoresins, because the separate carotene / retinoid and / or xanthophyll components to be added to the formulations are generally commercially available as a diluted vegetable oil or oil suspension, or as an extract of oleoresin. Such an amount of oil / oleoresin typically varies from about 1 to 100 times the content of xanthophyll or carotene in the formulation. For example, a xanthophyll extract to be included in a dietary supplement may contain 20% wt / wt. Of lutein, % weight / weight of zeaxanthin and 78% weight / weight of vegetable oil / oleoresin. Other oils may also be included in the formulations. The formulations of the present invention may also comprise additional excipients useful in the preparation and finishing of dietary supplements. Such excipients may include regular release polymer coating agents useful in prolonging the dissolution of the formulation in the digestive tract. Examples of such polymers include, but are not limited to, ionic and nonionic polymers, such as PEGs and other polyether-like alkoxy-cellulosic compounds (HPMC), gelan, carrageenan, Eucheuma gelatenae, starch, hyaluronate, sulfate chondroitin, pectins, and proteins, for example, collagen. Because xanthophyll / carotenes are highly pigmented, coating technology can be applied to the dietary supplement to provide a uniform color dietary supplement. Examples of color coating agents may include, but are not limited to, polymers, dyes, sealants and surface active agents including, but not limited to, fatty acids and esters, di- and triglycerides, phospholipids including mono- glyceryl phosphates. and di-alkyl, nonionic agents (sugars, polysaccharides, for example, HPMC and polysorbate 80) and ionic agents. The above described ingredients contained in the formulations, in some cases, can form microspheres within the dietary supplement. Dietary supplements can be of various shapes and sizes. Dietary supplements can be manufactured using a number of techniques known in the art. The ingredients described herein are preferably present in the dietary supplements of the invention in an amount sufficient to provide the daily dose (the amount consumed per day) when the recommended number of dietary supplements is ingested per day. It is critical, however, that the dietary supplement as described herein contains the described amounts of at least Vitamin C, Vitamin E, lutein, zeaxanthin, copper and zinc. The β-carotene may or may not be present in the preferred dietary supplements of the invention. In some dosage forms, such as mild gels, the use of concentrated oil phases of nutrients is desirable. These can be combined in a flowable core of the compound and can be protected concurrently with the help of common antioxidants and solvents. The following Examples are included to demonstrate the preferred embodiments of the invention. It should be appreciated by those skilled in the art that the techniques described in the examples that follow represent the techniques discovered by the inventor to function adequately in the practice of the invention, and thus may be considered to constitute the preferred modes for their practice. However, those of skill in the art, in view of the present disclosure, should appreciate that many changes can be made in the specific embodiments described and still obtain an analogous or similar result without departing from the spirit and scope of the invention.

Example 1 Example 2 Example 3 The following example, Example 4, indicates that the observations may recommend a combination of different isomers of zeaxanthin, not just all of one or the other. Alternatively in Example 3 the inference would be correctly plotted to interpret "zeaxanthin" to represent a proportion of zeaxanthins, from 0 to infinity, which is all of one or the other. The same inference would be exact for the Examples in the other sets. Example 4 The following example, Example 5, provides higher concentrations of carotenoids for individuals with low serum or pigment levels, or who may be less responsive to supplementation.

Example 5 The compositions in Example 6 describe significant formulations for individuals interested in maintaining ocular health, but who have no difficulty in consuming large tablets (or other dosage form). The composition and dosage regimen of Example 6 would be appropriate and sufficient for the daily supplement requirement of such patients.

Example 6 As the composition in Example 6, the composition in Example 7 describes a significant formulation for individuals interested in maintaining ocular health but who have a need for higher levels of carotenoids because either their serum or pigment levels are low. The composition and dosage regimen of Example 7 would be appropriate and sufficient for the daily supplement requirement of such patients. Example 7 The compositions in Example 8 describe significant formulations for individuals interested in maintaining eye health, but whose diet does not require supplementation with a multi-vitamin. The composition and dosage regimen of Example 6 would be appropriate and sufficient for the daily supplement requirement of such patients. Example 8 The composition in Example 9 describes a significant formulation for individuals interested in maintaining ocular health, but who have a greater need for xanthophylls. This composition and dosage regimen would be appropriate and sufficient for the daily supplement requirement of such patients. Example 9 Example 10 A gentle AREDS gel - Minimum levels assuming normal NHANES intake and mild gels, ie a supplement for a normal diet.

Example 11 All compositions and / or methods described and claimed herein may be made and executed without undue experimentation in light of the present disclosure. While the compositions and methods of this invention have been described in terms of the preferred embodiments, it will be apparent to those skilled in the art that variations may be applied to the compositions and / or methods and in the steps or sequence of the steps of the method described herein without departing from the concept, spirit and scope of the invention. More specifically, it will be apparent that certain agents that are chemically and structurally related can be substituted for the agents described herein to achieve similar results. All such apparent substitutions and modifications for those skilled in the art are deemed to be within the spirit, scope and concept of the invention as defined by the appended claims. References The following references, to the extent that they provide exemplary procedural details or other supplementary details for those set forth herein, are specifically incorporated herein by reference. Patents and US Published Applications 3, 998, 753 4,254,100 4, 657, 928 4, 670, 247 6,582, 721 6,716,447 20030064133 20050106272 20050147698 Books Berman, BIOCHEMISTRY OF THE EYE, (Plenum, 1991). Chaney TEXTBOOK OF BIOCHEMISTRY WITH CLINICAL CORRELATIONS, John Wiley & Sons, pp. 970-1 (1986) Other publications Beem J BIOL CHEM 249: 7298 (1974) Bernstein et al. , Retinal Tubulin Binds Macular Carotenoids, INV OPHTHAL & Vis Sci 38 (1): 167-175 (1997). Bernstein et al. Identification and Characterization of Pi Isofor of Glutathione S-Transf erase (GSTP1) as a Zeaxanthin -binding Protein in the Macula of the Eye, J. BIOL. CHEM 279 (47): 49447-49454 (2004) Bone and Landrum et al. Analyzes of Macular Pigment by HPLC: Retinal Distribution and Age Study INV. OPHTH VIS SCI 29: 843-849 (1988).

Bone and Landrum et al. Macular Pigment in Donor Eyes with and without AMD: a Case-control Study, INV. OPHTH VIS Sci 42: 235-240 (2001). Chandler et al., J. BIOL. CHEM 261: 928-33 (1986) Chatterjee ARCH, OPHTHALMOL 56: 756-60 (1956) Fischer J NUTRITION 113: 462-9 (1983) Hammond et al., Sex differences in macular pigment optical density: relation to plasma carotenoid concentrations and dietary patterns, VISION RESEARCH 36: 2001-2012 (1996a). Hammond et al., Cigarette smoking and retinal carotenoids: implications for age-related macular degeneration, VISION RESEARCH 36: 3003-3009 (1996b). Hammond et al., Dietary modification of human macular pigment density, INV OPHTHAL & VIS SCI 38 (9): 1795-1801 (1997). Handelman et al, Biological control of primate macular pigment: biochemistry and densitometry studies, INV OPHTHAL & VIS Sci 32 (2): 257-267 (1991). Harris, NATURE 132: 27-8 (1993) Hooper, JAMA 244: 1960-1 (1980) Jacques et al., Antioxidant status in persons with and without senile cataract, ARCH. OPHTHALM 106: 337 (1988). Karcioglu SURV OPHTHALMOL 27: 114-22 (1982) Krinsky et al, Biological mechanism of the protective role of lutein and zeaxanthin in the eye, ANNUAL REV NUTR 23: 171- 201 (2003) Leure-duPree, RETINA 2: 294-302 (1982a) Leure-duPree, INVEST OPHTHALMOL Vis Sci 23: 425-34 (1982b) Machlin et al, Free radical tissue da age: protecti ve role of antioxidant nutrients, FASEB J 1: 441-445 (1987). Newsome, D.A., Oral zinc in macular degeneration, ARCH. OPHTHALMOL. 106: 192-198 (1988). Ohrloff GRAEFE'S ARCH CLIN EXP OPHTHALMOL 222: 79-81 (1984) Orten, HUMAN BIOCHEMISTRY 10th Edition, CV Mosby Co. , p. 756 (1982) Pennington J AM DIETETIC ASSOC 86: 876-91 (1986) Purcell ARCH, OPHTHALMOL 51: 1-6 (1968) Ringvold ACTA, OPHTHALMOLOGICA 63: 227-80 (1985) Russell ANN 1NT MED 99: 227-39 (1983) Seddon et al, Dietary carotenoids, vi tamins a, c and e, and advanced age-related macular degeneration, JAMA 272 (8): 1413-1420 (1994). Seddon and Willett et al, Prospective study of dietary fat and the kidney of age-related macular degeneration, AM J CLIN NUTR 73: 209-218 (2001). Snodderly, Evidence for protection agains t age-related macular degeneration by carotenoids and antioxidant vi tamins AM J CLIN NUTR 62 (suppl): 1448S-1461 (1995). Spector et al, EXP. EYE RES. 33: 673 (1981). Swanson BIOCHEM BlPHY RES COMM 45: 1488-96 (1971) Taylor, NUTRITIONAL AND ENVIRONMENTAL INFLUENCES ON THE EYE, (CRC, 1999). Van Campen J NUTRITION 97: 104-8 (1970) Varma OPHTHALMIC RES 9: 421-31 (1977) Wagner GERIATRICS 40: 111-25 (1985) Williams PEDIAT RES 1: 823 (1977)

Claims (13)

1. CLAIMS 1. A dietary supplement characterized in that it comprises, about 0.03 wt% to 0.3 wt% copper, about 0.2 wt% to 4 wt% zinc, and Vitamin C, Vitamin E, and active carotenoid in the form of vitamin A, lutein and / or zeaxantma, wherein the concentration of vitamin C in the dietary supplement is approximately 10% by weight to 30% by weight, the concentration of Vitamin E in the dietary supplement is approximately 0.5% by weight at 25% by weight of Vitamin E, and approximately 0% by weight to 30% by weight by weight of the active carotenoid in the form of vitamin A, lutein and / or zeaxantma, and additionally comprising at least two or more compounds selected from the group consisting of vitamin K, vitamin Bl, vitamin B2, vitamin B3, vitamin B6, folate, vitamin B12, biotin, pantothenic acid, phosphorus, iodine, magnesium, selenium, manganese, chromium, molybdenum, potassium, lycopene, docosahexaenoic acid (DHA) ), and Romero
2. 2. The s Dietetic supplement of claim 1, characterized in that Vitamin A is in the form of β-carotene.
3. 3. The dietary supplement of claim 1, characterized in that it comprises: wherein four supplements per day are ingested to provide the amount of the daily dose
4. 4. The dietary supplement of claim 1, characterized in that it comprises: where four supplements are ingested per day to provide the amount of the daily dose.
5. 5. The dietary supplement of claim 1, characterized in that it comprises: where four supplements are ingested per day to provide the amount of the daily dose.
6. 6. The dietary supplement of claim 1, characterized in that it comprises: where four supplements are ingested per day to provide the amount of the daily dose.
7. 7. The supplement of claim 1, characterized in that it comprises: where four supplements are ingested per day to provide the amount of the daily dose.
8. 8. The dietary supplement of claim 1, characterized in that it comprises: where two supplements are ingested per day to provide the amount of the daily dose.
9. 9. The dietary supplement of claim 1, characterized in that it comprises: where two supplements are ingested per day to provide the amount of the daily dose.
10. 10. The dietary supplement of claim 1, characterized in that it comprises: where two supplements are ingested per day to provide the amount of the daily dose.
11. 11. The dietary supplement of claim 1, characterized in that it comprises: where two supplements are ingested per day to provide the amount of the daily dose.
12. 12. The dietary supplement of claim 1, characterized in that it comprises wherein the supplement is a soft gel and where two supplements are ingested per day to provide the amount of the daily dose.
13. 13. The dietary supplement of claim 1, characterized in that it comprises wherein the supplement is a mild gel and where four supplements are ingested per day to provide the amount of the daily dose.