Claims:We claim
1. A pharmaceutical composition comprising Xanthophil carotenoids and beneficial agent for the treatment of eye diseases.
2. The pharmaceutical composition as claimed in claim 1, wherein the Xanthophil carotenoids comprising Zeaxanthin, Astaxanthin and L-Glutathione.
2. The pharmaceutical composition as claimed in claim 1, wherein the eye diseases includes cataracts and macular degeneration.
3. The pharmaceutical composition as claimed in claim 1, wherein the composition comprises a diluents, disintegrants, bulking agents, surfactants, complexing agent, a pH modifying agent, a solubilizing compound, a stabilizing compound, a permeability enhancing compound, or a combination thereof.
5. The stable pharmaceutical composition as claimed in claim 1, wherein the beneficial agent is Glutathione.
6. The stable pharmaceutical composition as claimed in claim 7, wherein the xanthophyll carotenoids has an average particle size diameter below 25 microns.
7. The stable pharmaceutical composition as claimed in claim 1, wherein said composition retains at least about 90% of the potency of xanthophyll carotenoids in the pharmaceutical composition after storing the composition at 40° C and 75% relative humidity for at least three months.
, Description:Field of the Invention
In one embodiment, the invention provides the method comprising administering to the subject a pharmaceutically effective amount of one or more Xanthophyll carotenoids combination with beneficial agent such as glutathione having antioxidant properties for the treatment of eye diseases, such as cataracts and macular degeneration. Supplementation of Lutein, Zeaxanthin carotenoids and Glutathione has a protective effect against photoinduced damage to the lens and the retina.
Background of the Invention
Carotenoids are a class of hydrocarbon compounds that can be chemically subdivided into xanthophylls (oxygenated molecules) and carotenes (hydrocarbons lacking oxygen). Lutein is a xanthophyll and one of 600 known naturally occurring carotenoids. Lutein is synthesized only by plants, and like other xanthophylls is found in high quantities in green leafy vegetables such as spinach, kale and yellow carrots. Lutein and its close relative, zeaxanthin, are pigments called carotenoids that are related to beta-carotene and lycopene. The name lutein comes from the Latin word, lutea, meaning yellow. At normal concentrations in food, it is a yellow pigment, but can appear orange or red at high concentration.
Lutein and zeaxanthin are made only by plants, so animals normally get them by eating plants. Highest concentrations are found in dark green leafy vegetables such as kale, spinach, swiss chard, and mustard and turnip greens - although these nutrients are also found in a variety of other vegetables. Lutein added to chicken feed intensifies the yellow color of egg yolks. Lutein supplements are typically used in alternative medicine for eye diseases, such as cataracts and macular degeneration. Known to build up in the retina and lens of the eye, lutein is thought to protect the eye from injury induced by free radicals, chemical byproducts shown to damage cells and contribute to the development of certain diseases.
Lutein and zeaxanthin are antioxidants found in the human retina and macula. Recent clinical trials have determined that age- and diet-related loss of lutein and zeaxanthin enhances phototoxic damage to the human eye and that supplementation of these carotenoids has a protective effect against photoinduced damage to the lens and the retina. Two of the major mechanisms of protection offered by lutein and zeaxanthin against age-related blue light damage are the quenching of singlet oxygen and other reactive oxygen species and the absorption of blue light. Determining the specific reactive intermediate(s) produced by a particular phototoxic ocular chromophore not only defines the mechanism of toxicity but can also later be used as a tool to prevent damage.
Carotenoids are nutrients widely distributed in foods, especially in fruit and vegetables, and appear to have antioxidant properties. In recent decades, there has been increasing interest in their effects on health; a high dietary intake of carotenoids has been associated with beneficial effects in several systemic diseases and in eye disorders, with protection of the retina from phototoxic light damage. Most studies have focused on lutein (L), a carotenoid with a strong antioxidant effect in vitro that has been associated with a reduced risk of age-related diseases.
Lutein is a xanthophyll, i.e., an oxygenated carotenoid that all mammalians, humans included, derive from their diet because they are unable to synthesize carotenoids. Several studies have shown that high L intake, either through diet or as nutritional supplement, has beneficial effects on eye diseases, preventing or even improving both age-related macular degeneration (AMD) and cataract. L may indeed have favourable effects via anti-inflammatory activity, improving cognitive functions, and decreasing the risk of cancer, cardiovascular diseases and other systemic conditions.
The structure of L is similar to that of other carotenoids, with a skeleton made up of 40 carbon atoms, organized into eight isoprene units as shown in Figure 1.

Figure 1: Lutein
The supplementation of 10 mg/d of Lutein, as in the AREDS2, might be the most appropriate dosage for chronic L supplementation for the treatment of Age-Related Macular Degeneration. In particular, in over 30,000 participants Brown et al. observed a significant reduction (-19%) in the risk of cataract in the highest quintile of L intake compared with the lowest quintile [A prospective study of carotenoid intake and risk of cataract extraction in US men (Brown L, Rimm EB, Seddon JM, Giovannucci EL, Chasan-Taber L, Spiegelman D, Willett WC, Hankinson SE Am J Clin Nutr. 1999 Oct; 70(4):517-24). Similar results were obtained by both Chasan-Taber et al. [A prospective study of carotenoid and vitamin A intakes and risk of cataract extraction in US women (Chasan-Taber L, Willett WC, Seddon JM, Stampfer MJ, Rosner B, Colditz GA, Speizer FE, Hankinson S, Am J Clin Nutr. 1999 Oct; 70(4):509-16) and Moeller et al. [Associations between age-related nuclear cataract and lutein and zeaxanthin in the diet and serum in the Carotenoids in the Age-Related Eye Disease Study, an Ancillary Study of the Women's Health Initiative (Moeller SM, Voland R, Tinker L, Blodi BA, Klein ML, Gehrs KM, Johnson EJ, Snodderly DM, Wallace RB, Chappell RJ, Parekh N, Ritenbaugh C, Mares JA, CAREDS Study Group., Women's Helath Initiative) Arch Ophthalmol. 2008 Mar; 126(3):354-64]. Along this line, Olmedilla et al. demonstrated that Lutein supplementation for 2 years (15 mg/d) was effective in improving visual function in subjects with age-related nuclear cataract [Olmedilla B., Granado F., Blanco I., Vaquero M. Lutein, but not alpha-tocopherol, supplementation improves visual function in patients with age-related cataracts: A 2-y double-blind, placebo-controlled pilot study. Nutrition. 2003;19:21–24], but these beneficial effects are controversial [Olmedilla B., Granado F., Blanco I., Vaquero M., Cajiga L. Lutein in patients with cataracts and age-related macular degeneration: A long-term supplementation study. J. Sci. Food Agric. 2001;81:904–909]. Lyle et al. showed that neither high L serum levels had an effect on the incidence of cataract [Lyle B.J., Mares-Perlman J.A., Klein B.E., Klein R., Palta M., Bowen P.E., Greger J.L. Serum carotenoids and tocopherols and incidence of age-related nuclear cataract. Am. J. Clin. Nutr. 1999;69:272–277], nor was there a correlation between the disease and L intake [Lyle B.J., Mares-Perlman J.A., Klein B.E., Klein R., Greger J.L. Antioxidant intake and risk of incident age-related nuclear cataracts in the Beaver Dam Eye Study. Am. J. Epidemiol. 1999;149:801–809]. Also, the AREDS2 study showed that L treatment was ineffective both in preventing vision loss and in slowing progression towards cataract surgery [Age-Related Eye Disease Study 2 (AREDS2) Research Group. Chew E.Y., San Giovanni J.P., Ferris F.L., Wong W.T., Agron E., Clemons T.E., Sperduto R., Danis R., Chandra S.R., et al. Lutein/zeaxanthin for the treatment of age-related cataract: AREDS2 randomized trial report no. 4. JAMA Ophthalmol. 2013;131: 843–850].
Glutathione is an antioxidant present in almost every cell in the body, playing a role in the detoxification of drugs and xenobiotics. Furthermore, reduced glutathione (GSH) acts as a hydrogen donor in the detoxification of hydrogen peroxide. As a dietary supplement, GSH possesses various systemic effects such as improvement of liver abnormalities, improvement of diabetic complication, protection from viral infection, and antitumor activity. It is even used to treat autism. In vitro experiments have demonstrated that glutathione is related to melanogenesis. Its antimelanogenic properties result from a variety of mechanisms including stimulation of pheomelanin synthesis rather than darker eumelanin, its antioxidant effects, and interference with intracellular trafficking of melanogenic enzymes. Glutathione also possesses certain antiaging properties. Glutathione is generally a safe ingredient for use as a dietary supplement.
Astaxanthin is a naturally occurring carotenoid found in nature primarily in marine organisms such as microalgae, salmon, trout, krill, shrimp, crayfish, and crustaceans. The green microalga Haematococcus pluvialis is considered the richest source of astaxanthin. Other microalgae, such as Chlorella zofingiensis, Chlorococcum spp., and Botryococcus braunii, also contain astaxanthin. It may also be found in the feathers of birds, such as quail, flamingo, and storks, as well as in propolis, the resinous substance collected by bees. Numerous studies support the use of astaxanthin as a potent antioxidant that may be beneficial in decreasing the risks of certain chronic diseases. It may also reduce oxidative stress in the nervous system, reducing the risk of neurodegenerative diseases. Additionally, astaxanthin has well-documented anti-inflammatory and immune-stimulating effects. Human trials have been conducted in disorders such as carpal tunnel syndrome, rheumatoid arthritis, dyspepsia (with or without Helicobacter pylori infection), hyperlipidemia, male infertility, and skin conditions, and regarding exercise capacity, muscle soreness, and transplants. However, results have been mixed, and more research is needed in these areas before any firm conclusions can be drawn.
The primary function of antioxidants in the human body is to protect our cells against free radicals, such as reactive oxygen species (ROS). Free radicals are unstable molecules that damage or “oxidize” cells and tissues in a process called oxidative stress. ROS are formed as a by-product during normal metabolic processing in our body when food, which serves as fuel, is converted into energy to run cellular processes. ROS are released by immune cells to fight bacterial infections. ROS are also generated by lifestyle factors such as exposure to pollutants, an unhealthy diet, excessive sun bathing, heavy exercise, smoking, etc.
An antioxidant is a molecule stable enough to donate an electron to a free radical and neutralize it, thus reducing its capacity to damage. Antioxidants delay or inhibit cellular damage mainly through their free radical scavenging property. Dietary intake is an important source of antioxidants. Natural astaxanthin is considered a “super antioxidant” and possesses one of the strongest known antioxidant effects. Astaxanthin consists of two terminal rings joined by a polyene chain (Fig. 1 A).

Fig.2. Asaxanthin
While structurally similar to the carotenoid ß-carotene, astaxanthin has thirteen conjugated double bonds whereas ß-carotene has eleven. On cyclohexene structure, it has oxo groups in the 4 and 4 prime positions that increase its antioxidant potential. Additionally, astaxanthin has hydroxyl groups at the 3 and 3 prime position, making the molecule somewhat polar. Because of its unique structure, particularly all the unsaturated bonds and the oxo-groups in both ends, astaxanthin can trap harmful radicals effectively. Comparison studies have shown that natural astaxanthin is six thousand times more capable than vitamin C, one hundred times more powerful than vitamin E, and five times more powerful than ß-carotene in trapping energy from singlet oxygen, a common free radical in biological systems [3] (Fig. 1 B). Astaxanthin can also trap many different types of radicals. In addition, the way astaxanthin neutralizes harmful free radicals is gentle to the body’s cells. Other antioxidant mechanisms can be harmful since they turn the antioxidant itself into highly reactive molecules. Natural astaxanthin from Haematococcus pluvialis supports cardiovascular health, healthy skin, healthy aging, the body’s recovery from heavy exercise and promotes healthy oxidative balance.
Summary of the Invention
In one general aspect, there is provided a pharmaceutical composition comprising xanthophil carotenoids and beneficial agent for the treatment of eye diseases.
In another general aspect there is provided the xanthophil carotenoids comprising Zeaxanthin, Astaxanthin and L-Glutathione.
In another general aspect there is provided the eye diseases includes cataracts and macular degeneration.
In another general aspect there is provided the pharmaceutical composition comprises a diluents, disintegrants, bulking agents, surfactants, complexing agent, a pH modifying agent, a solubilizing compound, a stabilizing compound, a permeability enhancing compound, or a combination thereof.
In another general aspect there is provided the beneficial agent is Glutathione.
Detailed Description of the Invention
The following description is illustrative of embodiments of the invention. The following description is not to be construed as limiting, it being understood that the skilled person may carry out many obvious variations to the process.
Throughout the description, percentages are weight by weight unless specifically noted differently. Carotenoids constitute a large group of pigments with over 700 compounds and comprise of carotenes and their oxygenated derivatives, xanthophylls. Carotenes are polyunsaturated hydrocarbons with 40 carbon atoms, while xanthophylls contain oxygen atoms, most frequently as hydroxyl and epoxide groups, which increase their polarity. Both groups of carotenoids act as accessory light-harvesting pigments or as quenchers of singlet oxygen and chlorophyll triplet states to provide protection against photooxidative damage. The main photoprotective mechanism occurring in photosynthetic organisms is the xanthophyll cycle—a process of enzymatic reactions of epoxidation and de-epoxidation of xanthophylls. Xanthophyll carotenoids include astaxanthin, zeaxanthin, lutein, echinenone, lycophyll, canthaxanthin, and the like. Isomerism around carbon-carbon double bonds yields distinctly different molecular structures that may be isolated as separate compounds (known as Z (“cis”) and E (“trans”), or geometric, isomers). Xanthophyll carotenoids therefore include but are not limited to Lutein, zeaxanthin, ß'-epilutein and 3-hydroxy-ß,e-caroten-3'-one, meso-zeaxanthin, 3'-oxolutein, 3-methoxyzeaxanthin (3-MZ), ß-cryptoxanthin, epsilon-lycopenes, 5-Z-lycopenes, and apo-carotenoid products including 3-OH-ß-ionone, 3-OH-a-ionone, ß-ionone, 3-OH-a-apo-10'-carotenal, 3-OH-ß-apo-10'-carotenal, and ß-apo-10'-carotenal.
Compositions, including pharmaceutical compositions, comprising combinations of an effective amount of at least one Xanthophyll carotenoids according to the present invention, and one or more of the compounds otherwise described herein, all in effective amounts, in combination with a pharmaceutically effective amount of a carrier, additive or excipient, represents a further aspect of the present invention. The compositions used in methods of treatment of the present invention, and pharmaceutical compositions of the invention, may be formulated in a conventional manner using one or more pharmaceutically acceptable carriers.
In one embodiment, the carotenoids which are suitable for use in the present invention are carotenes. Non limiting examples of carotenes include alpha-carotene, beta-carotene, solanorubin and its precursors hexahydrogenosolanorubin and octohydrogenosolanorubin. In another embodiment, the carotenoids which are suitable for us in the present invention are xanthophylls. Non limiting examples of xanthophylls include beta-cryptoxanthin, lutein, and zeaxanthin.
In another embodiment, Xanthophyll Carotenoid is preferably present in the composition in an amount of < 2 weight %, more preferably < 1.5 weight %, even more preferably < 1 weight %, and most preferably < 0.5 weight %.
In another embodiment, Beneficial agent is preferably present in the composition in an amount of < 2 weight %, more preferably < 1.5 weight %, even more preferably < 1 weight %, and most preferably < 0.5 weight %.

The pharmaceutical composition may be constituted into any form suitable for the mode of administration selected. Preferably, the pharmaceutical composition is formulated for oral administration. Other medically acceptable route of administration includes intravenous, subcutaneous, intramuscular, transdermal, rectal or inhalation and the like.
The dosage of the pharmaceutical composition or the carotenoid can be determined by the skilled person in the art according to the embodiments. Unit doses or multiple dose forms are contemplated, each offering advantages in certain clinical settings.
Pharmaceutically acceptable excipients for use in the pharmaceutical 10 composition may comprise one or more diluents, binders, disintegrants, glidants, lubricants, sweeteners/taste masking agents, compression aids, colorants and flavors.
Suitable diluents or bulking agents which include, but are not limited to, Sugars, lactose, mannitol, sorbitol, sucrose Inorganic salts, primarily calcium salts, Polysaccharides, saccharides, including monosaccharides, disaccharides, polysaccharides and 15 sugar alcohols such as arabinose, dextrose, fructose, maltose, erythritol, xylitol, lactitol, and other bulking agents such as powdered cellulose, microcrystalline cellulose, starch, dibasic calcium phosphate, tribasic calcium phosphate, calcium carbonate, dextrose, kaolin, magnesium carbonate, magnesium oxide, purified sugar and derivatives thereof.
Suitable binders, which include, but are not limited to, Sugars, glucose, syrup Polymers, natural gums, starch, gelatin or synthetic celluloses, polyvinylpyrrol-pyrrolidone (PVP), poly-methycrylate (EudragitTM), methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, carbomers, dextrin, ethyl cellulose, methylcellulose, shellac, zein, gelatin, polymethacrylates, polyvinylpyrrolidone, starch, pregelatinized starch, polyvinyl alcohol, tragacanth, sodium alginate, gums, synthetic resins, silicic acid, hydrophilic polymers and the like.
Suitable disintegrants which include, but are not limited to, Starch and derivatives (polyplasdone XL) Microcrystalline cellulose Clays, algins, gums, surfactant, croscarmellose sodium, crospovidone, sodium starch glycolate, corn starch, potato starch, maize starch and modified starches like pregelatinized starch, calcium silicates, lowsubstituted hydroxypropylcellulose and the like.
Suitable lubricants and glidants which include, but are not limited to, Water-insoluble: metal stearates, stearic acid, talc Water-soluble: boric acid, sodium chloride, benzoate and acetate, sodium or magnesium lauryl sulfate Carbowax 4000 or 6000, talc, metallic stearates such as magnesium stearate, calcium stearate, zinc stearate; colloidal silicon dioxide, finely divided silicon dioxide, stearic acid, hydrogenated vegetable oil, glyceryl palmitostearate, glyceryl monostearate, glyceryl behenate, 5 polyethylene glycols, powdered cellulose, starch, sodium stearyl fumarate, sodium benzoate, mineral oil, magnesium trisilicate, kaolin; and the like. It would be appreciated that a person skilled in the art is cognizant of the fact that lubricant, glidant or anti-tacking agent may be used interchangeably. The lubricant, glidant or anti-tacking agent may be present in an amount ranging from 10 0.1 % to 10 % w/w of the composition.
Suitable taste masking agents may include one or more of polymers, sweeteners and flavors. Most preferred polymers include one or more of cellulose acetate, polymethacrylates, hydroxypropylmethylcellulose, hydroxypropyl cellulose, hydroxylethyl cellulose; and the like. Suitable sweeteners that may be 15 used, comprises saccharides such as sucrose, dextrose, glucose, maltose, dextrins, D-tagatose, trehalose, dried invert sugar, fructose, levulose, galactose, corn syrup solids, and the like, alone or in combination. Other examples of sweeteners comprise sodium saccharin; aspartame; sugarless sweeteners including polyhydric alcohols such as sorbitol, mannitol, xylitol, glycerol, hydrogenated 20 starch hydrolysates, maltitol, isomaltitol, erythritol, lactitol and the like, alone or in combination. Suitable flavors that may be used, comprise cinnamon, wintergreen, eucalyptus, spearmint, peppermint, menthol, anise as well as fruit flavors such as apple, pear, peach, strawberry, cherry, apricot, orange, watermelon, banana and the like; bean-derived flavors, such as coffee, cocoa and 25 the like or mixtures thereof. The pharmaceutical composition of xanthophyll carotenoids may be developed in the form of tablets, capsules, powders, pellets, granules, microspheres, minitablets or any suitable solid unit forms known to person skilled in the art; mouth dissolving tablets; dispersible tablets; effervescent tablets; trilayer tablets; inlay tablets. The 15 preferred dosage forms are tablets and capsules filled with pellets, granules or minitablets as these are more convenient and easier to administer.
The pharmaceutical composition of xanthophyll carotenoids may be manufactured by using various granulation techniques known to the person skilled in the art, such as, but not limited to direct compression, wet granulation, dry granulation, hot melt granulation, hot melt extrusion, fluidized bed granulation, extrusion, and solvent evaporation. The components of the pharmaceutical composition defined hereinbefore can be brought together into a suitable composition for oral administration according to standard practice and procedures well known in the art of pharmaceutical science using conventional formulation and manufacturing techniques.
In an embodiment, xanthophyll carotenoids composition may be prepared by granulating the admixture of xanthophyll carotenoids and a beneficial agent optionally with one or more pharmaceutical excipients. The resulting granules may be compressed to form tablets or filled in hard gelatin capsules. Alternatively, the process of manufacturing the xanthophyll carotenoids composition may comprise a step of granulating xanthophyll carotenoids with one or more pharmaceutical excipients followed by complete or partial coating of the resulting granules with a beneficial agent. The coated granules may be compressed to form tablets or filled in hard gelatin capsules. In another embodiment, a stable xanthophyll carotenoids composition may be developed in the form of pellets, which may be prepared by coating one or more layers of xanthophyll carotenoids and a beneficial agent on non-pareil sugar seeds or inert cores. The resulting pellets may be admixed with pharmaceutical excipients and filled into hard gelatin capsules or may be compressed with pharmaceutical excipients to form tablets. Alternatively, the pellets may be prepared by completely or partially coating particles of xanthophyll carotenoids by a beneficial agent. The resulting pellets may be admixed with pharmaceutical excipients and filled into hard gelatin capsules or may be compressed with pharmaceutical excipients to form tablets. The composition may be seal coated. Preferably, the composition is seal coated and finally film coated. The composition can be coated with ready color mix systems (such as opadry color mix systems). In yet another embodiment, the pharmaceutical composition may involve one or more manufacturing process to obtain a single unitary dosage form i.e., wherein the drug is processed by granulation techniques as discussed above and finally compacted to yield a single dosage form.
The invention is further illustrated by the following examples which are provided to be exemplary of the invention and do not limit the scope of the invention. While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
Examples
Example 1: Tablet containing Xanthophyll carotenoids and Beneficial agent or pharmaceutically acceptable salt thereof
Table 1
Each film coated tablet contains
Lutein ( Contains Zeaxanthin 256 mcg ) 3.2mg
Astaxanthin 4% ( Natural source ) 4 mg
L-Glutathione 5mg