Composition and nutritional supplement made therefrom

Abstract

The present disclosure relates to a nutritional supplement composition comprising undenatured or denatured type II collagen in combination with vitamin A and / or one or more carotenoids.Different dietary or nutritional supplements can work synergistically together to improve the health and well-being of humans or animals.This synergistic effect can be manifested as a faster onset of action, an increased number of responders, or a higher level of efficacy, or any combination thereof, compared to the administration of a type II collagen source, vitamin A, or other carotenoids alone.The nutritional supplement can be used to treat arthritis-related joint pain or other joint diseases, improve immune health, improve eye health, and / or improve brain health in humans and animals at risk of and exhibiting these diseases.

Description

[Technical Field]

[0001] Related Applications

[0001] This application is based on and claims priority to U.S. Provisional Patent Application No. 62 / 547,951, filed August 21, 2017, the entire contents of which are incorporated herein by reference. [Background technology]

[0002]

[0002] In recent years, the use of collagen to treat various conditions has become very popular. Collagen is a protein that can be found in muscles, bones, skin, blood vessels, and other parts of the body. There are various different types of collagen depending on their function and form. For example, type I collagen, the most abundant collagen, is made up of fibers found in tendons, ligaments, organs, and skin. On the other hand, type II collagen primarily helps build cartilage, the major structure on the surface of bones that make up articulating joints. Type III collagen is a major component of the extracellular matrix that makes up organs and skin. Type III collagen also forms tissue within blood vessels and the heart.

[0003]

[0003] Collagen can be found in many different products, including cosmetic creams and body lotions. Collagen can also be found in a variety of oral supplements. For example, collagen production in the body tends to slow as people age. Therefore, collagen supplements have been taken in the past to reduce the effects of aging by improving skin and hair health.

[0004] Collagen is also known to effectively treat arthritis and other joint pain. For example, U.S. Patent No. 9,066,926 discloses a method for reducing exercise-induced joint pain in a mammal by administering type II collagen to the mammal. This patent also discloses oral tolerance of the mechanism of action by which this component operates. This putative mechanism involves the stimulation of regulatory T cells (Tregs) located in gastrointestinal-associated lymphoid tissue to specifically recognize antigenic determinants (epitopes) on native collagen proteins. Once induced, Tregs exit the gastrointestinal tract, migrate to the joint cavity, and stimulate chondrocytes to deposit new type II collagen, thereby improving the structural integrity and flexibility of the articulated joint. One example, for which clinical data has been published, is the knee. The '926 patent is incorporated herein by reference.

[0005]

[0005] Various other supplements containing bone material have been proposed. For example, U.S. Patent No. 9,011,930 is directed to a nutritional supplement containing demineralized bone matrix that is believed to act through various bone morphogenetic proteins and other factors that promote bone formation and homeostasis. In this case, the primary mechanism of action is believed to occur through stimulation of bone-forming cells, as indicated in commercial literature for this nutritional ingredient, also known as Cyplexinol®. The supplement may further contain vitamins and is used to maintain or improve bone and cartilage condition.

[0006]

[0006] In addition to treating joint pain, collagen is also known to treat leaky gut syndrome, a condition in which toxins are able to pass through the digestive tract. Collagen intake can also increase metabolism, muscle mass, and energy output, as well as improve liver and cardiovascular health. Summary of the Invention [Problem to be solved by the invention]

[0007]

[0007] While collagen can provide a variety of benefits when administered to humans or animals, there is a need for compositions and methods that can increase the effectiveness of collagen and / or work in combination with collagen to provide synergistic effects such as improved efficacy or faster onset of action. [Means for solving the problem]

[0008]

[0008] In general, the present disclosure is directed to compositions containing a combination of a collagen source and vitamin A, a carotenoid, or a mixture thereof. The compositions of the present disclosure have numerous and diverse applications and uses. In one embodiment, for example, the present disclosure is directed to a nutritional supplement. For example, in one embodiment, the nutritional supplement of the present disclosure contains type II collagen combined with vitamin A, a carotenoid, or a mixture thereof. The collagen source may include, for example, denatured or undenatured collagen. In one embodiment, the collagen source includes undenatured collagen, while another embodiment includes hydrolyzed collagen. Collagen can be obtained from a variety of different sources, such as animal sources, and can be provided as animal parts or as pure protein or active peptide fragments. The resulting compositions can have many different health benefits when administered to humans, animals, or other mammals. For example, the compositions are well suited for treating or managing any of several joint pain, discomfort, or limited performance, improving eye health, improving brain health, and / or improving immune health.

[0009] In addition to nutritional supplements, the compositions of the present disclosure can also be used as pharmaceutical compositions to deliver various health benefits to humans or animals. The pharmaceutical compositions can be administered, for example, orally, subcutaneously, topically, intravenously, or by any other suitable method.

[0010] In yet another embodiment of the present disclosure, a composition containing a collagen source combined with vitamin A, a carotenoid, or a mixture thereof can be included in a topical formulation applied to the skin. For example, the topical composition can be in the form of a gel or cream and can contain numerous and different ingredients depending on the end-use application. For example, the topical composition may contain solvents, surfactants, emulsifiers, consistency factors, conditioners, emollients, skin care ingredients, moisturizers, thickeners, lubricants, etc. The topical composition can be applied to the skin of a user to improve skin health. Alternatively, the composition can be applied to the skin for absorption into the body to provide one or more health benefits.

[0011] As noted above, the compositions of the present disclosure generally comprise a collagen source in combination with vitamin A, a carotenoid, or a mixture thereof.

[0012] Vitamin A can include, for example, retinol, retinal, retinoic acid, or retinyl ester. For example, retinyl ester can include fatty acid retinyl, such as retinyl palmitate. Particularly suitable carotenoids for use in the present disclosure include vitamin A precursors such as beta-carotene, alpha-carotene, beta-cryptoxanthin, or mixtures thereof. Other suitable carotenoids for use in the present disclosure include zeaxanthin, lycopene, crocetin, lutein, or mixtures thereof.

[0012]

[0013] When the composition contains collagen, such as undenatured type II collagen, in combination with vitamin A, the weight ratio between collagen and vitamin A can be about 10:1 to about 1:5 for the lowest amount of type II collagen source added, and about 5000:1 to about 100:1 for the highest amount of type II collagen source added. When the composition contains undenatured collagen and a carotenoid, the weight ratio between collagen material and carotenoid can be about 2:1 to about 1:1,000 for the lowest amount of type II collagen source added, and about 2,000:1 to about 1:1 for the highest amount of type II collagen source added.

[0013]

[0014] When the composition contains collagen, such as hydrolyzed type II collagen, in combination with vitamin A, the weight ratio between collagen and vitamin A can be about 10:1 to about 1:5 for the lowest amount of type II collagen source added, and about 150,000:1 to about 3,000:1 for the highest amount of type II collagen source added. When the composition contains hydrolyzed collagen and carotenoid, the weight ratio between collagen material and carotenoid can be about 2:1 to about 1:1,000 for the lowest amount of type II collagen source added, and about 30,000:1 to about 15:1 for the highest amount of type II collagen source added.

[0014]

[0015] In one embodiment, the composition can be a nutritional supplement in the form of individual dosage units. Each dosage unit can be made from an orally acceptable composition. The dosage units can contain, for example, capsules, tablets, powders, etc. Alternatively, the nutritional supplement can be in the form of a syrup or liquid suspension. Alternatively, the composition of this embodiment can be administered in the form of a food or drink.

[0015]

[0016] When in the form of individual dosage units, each dosage unit can contain type II collagen in an amount of about 1 mg to about 2,000 mg, e.g., about 1 mg to about 1,000 mg, e.g., about 1 mg to about 200 mg, e.g., about 20 mg to about 100 mg. When vitamin A is present, it can generally be present in each dosage unit in an amount of about 100 micrograms to about 5,000 micrograms. On the other hand, when the dosage units contain a carotenoid, each dosage unit can contain the carotenoid in an amount of about 0.5 mg to about 500 mg, e.g., about 1 mg to about 150 mg.

[0016]

[0017] The present disclosure is also directed to methods for treating or managing various ailments. For example, in one embodiment, the present disclosure is directed to a method for treating or managing joint pain, joint discomfort, or limited joint flexibility in an individual ("healthy subject") who is not ill and whose symptoms result from participation in normal daily activities, including, but not limited to, strenuous exercise, walking, running, etc. In another embodiment, the present disclosure is also directed to a method for treating joint ailments caused by diseases (including arthritis) in humans and other mammals, as described above. The method comprises administering to the mammal a therapeutically effective amount of a composition or supplement described above. In one embodiment, the composition contains undenatured type II collagen in combination with vitamin A, a carotenoid, or a mixture thereof. The composition, which may be in the form of an oral dosage device, can be administered to the mammal in an amount sufficient to reduce joint pain.

[0017]

[0018] The present disclosure also relates to a method for improving eye health.This method comprises the step of administering to mammal the composition or supplement described above, which comprises undenatured type II collagen in combination with vitamin A, carotenoid or a mixture thereof.This composition is administered to mammal in a therapeutically effective amount that is sufficient to improve the eye health of mammal.

[0018]

[0019] The present disclosure also relates to a method for improving brain health.This method comprises administering to a mammal the composition or supplement described above, which contains undenatured type II collagen in combination with vitamin A, carotenoids or a mixture thereof.This composition is administered to a mammal in a therapeutically effective amount sufficient to improve the brain health of the mammal.The brain / cognitive health benefits provided by this composition can vary greatly depending on specific application and desired results.For example, this composition can improve memory, verbal fluency and / or various other cognitive functions. definition

[0020] As used herein, the term "therapeutically effective amount" with respect to the compositions described above refers to a dosage or amount of the composition (containing a collagen source combined with vitamin A, carotenoids, or a mixture thereof) administered or delivered to a subject in need of such treatment that provides a specific pharmacological or nutritional response. It is emphasized that a "therapeutically effective amount" administered to a particular subject in certain instances may not always be effective in treating a disease or otherwise improving health as described herein, even if such a dosage is considered "therapeutically effective" by those skilled in the art. Indeed, certain subjects may be "resistant" to a "therapeutically effective amount." For example, a resistant subject may have such low bioavailability that clinical efficacy is not achieved. It should be further understood that in certain instances, the composition or supplement may be measured as an oral dosage or with reference to the level of the component that can be measured in the blood. In other embodiments, the dosage may be measured by the amount applied to the skin when the composition is contained in a topical formulation.

[0019]

[0021] As used herein, the term "delivering" or "administering" refers to any route for providing the composition or nutraceutical to a subject that is recognized as standard by the medical community and regulated by law. For example, the present invention addresses routes of delivery or administration, including oral ingestion as well as any other suitable delivery route, including, but not limited to, transdermal, intravenous, intraperitoneal, intramuscular, topical, or subcutaneous.

[0020]

[0022] The terms "encapsulate," "encapsulated," or "encapsulating" refer to any compound that is completely surrounded by a protective material. For example, a compound may become encapsulated by the formation of a nanoemulsion particle population during microfluidization.

[0021]

[0023] The term "nutraceutical" refers to any compound added to a dietary source (i.e., for example, a fortified food or dietary supplement) that provides a health or medical benefit in addition to its basic nutritional value.

[0022]

[0024] Other features and aspects of the disclosure are described in more detail below. DETAILED DESCRIPTION OF THE INVENTION

[0023]

[0025] It should be understood by those skilled in the art that this description is a description of exemplary embodiments only and is not intended as limiting the broader aspects of the present disclosure.

[0026] Generally, the present disclosure is directed to compositions such as nutritional supplements, medical preparations or topical compositions for administration to humans and animals, which can be used as daily supplements or can be used to treat specific diseases.For particular benefits, the present composition can be formulated to treat or improve the health of many different organ systems in the body.In fact, the compositions of the present disclosure can simultaneously provide multiple health benefits.

[0024]

[0027] In one embodiment, for example, the composition of the present disclosure is specifically formulated to improve joint health.For example, the composition can be used to treat arthritis or non-arthritic joint pain, joint discomfort, or joint inflexibility.The composition of the present disclosure can also be used to improve eye health and treat various eye diseases.In addition, the composition of the present disclosure can improve immune health or brain health.

[0025]

[0028] Generally, the composition of the present disclosure comprises collagen, such as denatured or hydrolyzed or non-denatured type II collagen, in one embodiment, in combination with another dietary agent or nutritional supplement, which can act synergistically with collagen.For example, in one embodiment, dietary agent or nutritional supplement can increase the effectiveness of collagen.In addition, or alternatively, the combination of collagen with dietary agent or nutritional supplement or component can provide a platform for treating two or more diseases, or otherwise improving the health of multiple organ systems in the body.

[0026]

[0029] In one embodiment, for example, type II collagen may be combined with vitamin A or a carotenoid, or may be combined with both vitamin A and a carotenoid. The composition or nutritional supplement formulated according to the present disclosure can be administered orally. Other enteric modes of administration are also possible. In one embodiment, the nutritional supplement is formed into a dosage form, such as a tablet or capsule, that can be taken orally. In addition, the nutritional supplement can be incorporated into beverages, foods, and dietary supplements. The nutritional supplement can be prepared in the form of, for example, a capsule, tablet, chewable gum, edible film, lozenge, powder, liquid suspension, syrup, etc. In one embodiment, the nutritional supplement is encapsulated by a protective material in the form of a capsule or tablet. Alternatively, the composition can be administered subcutaneously, intravenously, or topically applied to the user's skin.

[0027]

[0030] The composition can be taken periodically (i.e., daily or weekly) or for a temporary period to treat or manage a specific condition. As noted above, the composition contains collagen, particularly type II collagen, such as undenatured type II collagen. Type II collagen for use in the present disclosure can be obtained from any suitable source. For example, collagen can be derived from various mammalian sources, avian sources, or from various fish species or combinations thereof. For example, collagen can be obtained from salmon, shark, poultry, pigs, eggshells, turkey cartilage, bovine cartilage, etc. In one embodiment, for example, type II collagen can be obtained as disclosed in U.S. Patent No. 7,083,820 to Schilling, which is incorporated by reference. For example, undenatured type II collagen is commercially available as UC-II® from InterHealth Nutraceuticals. UC-II® is a natural ingredient containing glycosylated undenatured type II collagen. The collagen source can also include hydrolyzed collagen. The collagen source can also contain pure protein or active peptide fragments. In one embodiment, the collagen source can be free of any bone or bone material. In another embodiment, the collagen source can be free of any transforming growth factor (TGF), bone morphogenetic protein (BMP), or both. In yet another embodiment, the collagen source contains type II collagen and is completely free of any type I collagen.

[0028]

[0031] In one embodiment, in preparing animal tissue for oral administration, the type II collagen-containing tissue can be first dissected free of surrounding tissue and then diced or otherwise ground into particles. The particulate or powdered cartilage can be sterilized by any means that does not affect or denature the structure of the majority of the type II collagen in the tissue and can be formed into doses containing therapeutically effective levels of undenatured type II collagen, typically at least about 0.01 grams, preferably about 0.02 to about 0.5 grams of animal tissue per dose. As a natural product, some sample-to-sample variation is expected. These variations can be minimized by blending after grinding. Blending can be assisted by analytical techniques that allow for the determination of the amount of undenatured type II collagen and other constituents.

[0029]

[0032] These measurements allow for blending of batches to obtain uniformity and, in some cases, to modify potency by increasing certain antigenic epitopes through mixing of cartilage from different sources. Optimal dosages may vary.

[0030]

[0033] According to the present disclosure, type II collagen is combined with vitamin A, carotenoids, or a mixture thereof. Vitamin A refers to a group of organic compounds, including various retinoids. For example, vitamin A includes retinol, also known as vitamin A1. Other vitamin A compounds include all different forms of retinoic acid, such as tretinoin, also known as all-trans retinoic acid. Other vitamin A compounds include retinal and retinyl esters. Retinyl esters include retinyl esters of fatty acids. For example, one example is retinyl palmitate. Another vitamin A compound is retinyl acetate. Retinyl acetate and retinyl palmitate are typically referred to as provitamins of vitamin A and are converted to retinol in the small intestine.

[0031]

[0034] Vitamin A ingested by animals and humans can improve immune health, visual health, reproductive health, brain and cognitive health, and cell communication. In improving immune health, retinoic acid is thought to regulate dendritic cell differentiation, migration, and antigen presentation ability, particularly in gastrointestinal-associated lymphoid tissues. Retinoic acid also maintains homeostasis by working with TGF-beta to promote the induction of Treg cells from naive T cells. Retinoic acid may also be important in maintaining mucosal integrity.

[0032]

[0035] Instead of or in addition to vitamin A, the compositions of the present disclosure may contain one or more carotenoids (isolated from the vitamin A species described above). Certain carotenoids are known to be effective antioxidants that can protect organisms from the harmful effects caused by reactive oxygen species, such as free radicals. Carotenoid intake can also reduce the chances of chronic diseases such as heart disease and various cancers. It is believed that including carotenoids in nutritional supplements can improve the immune system of humans or animals. Certain carotenoids, such as lutein and zeaxanthin, can also provide brain and cognitive health benefits. For example, carotenoids can improve memory, improve verbal fluency, or otherwise have beneficial effects on cognitive function. For certain benefits, it is believed that carotenoids can work effectively with type II collagen to increase the overall effectiveness of the composition.

[0033]

[0036] Carotenoid compounds are a type of tetraterpenoid containing long polyene chains. Carotenoids include xanthophylls such as lutein and zeaxanthin, and carotenes such as beta-carotene, alpha-carotene, zeta-carotene, and lycopene and related molecules including 1-HO-3',4'-didehydrolycopene, 3,1'-(HO)2-gamma-carotene, 1,1'-(HO)2-3,4,3',4'-tetradehydrolycopene, and 1,1'-(HO)2-3,4-didehydrolycopene.

[0034]

[0037] Other suitable carotenoid compounds that may be used as described herein include hydrocarbons such as lycopersene (7,8,11,12,15,7',8',11',12',15'-decahydro-γ,γ-carotene), phytofluene, hexahydrolycopene (15-cis-7,8,11,12,7',8'-hexahydro-γ,γ-carotene), tolulene (3',4'-didehydro-β,γ-carotene), and α-zeacarotene (7',8'-dihydro-ε,γ-carotene); alloxanthin, scintillanthin, and cysteine. enthin, pectenoxanthin, cryptomonaxanthin ((3r,3'r)-7,8,7',8'-tetradehydro-β,β-carotene-3,3'-diol), crutaxanthin (β-carotene-3,4,3',4'-tetraol), gazaniaxanthin ((3r)-5'-cis-β,γ-carotene-3-ol), oh-chlorobactene (1',2'-dihydro-f,γ-carotene-1'-ol), loroxanthin (β,ε-carotene-3,19,3'-triol), lycoxanthin (γ,γ- Alcohols such as caroten-16-ol, rhodopin (1,2-dihydro-γ,γ-caroten-1-ol), rhodopinol (also known as warmingol; 13-cis-1,2-dihydro-γ,γ-carotene-1,20-diol), saproxanthin (3',4'-didehydro-1',2'-dihydro-β,γ-carotene-3,1'-diol) and zeaxanthin; osilaxanthin (2,2'-bis(β-l-rhamnopyranosyloxy)-3,4,3',4'-tetradehydro-1,2,1',2'-tetradecanoic acid); glycosides such as 1'-(β- d -glucopyranosyloxy)-3',4'-didehydro-1',2'-dihydro-β,γ-carotene-2'-ol) and freixanthophyll; ethers such as rhodovibrin (1'-methoxy-3',4'-didehydro-1,2,1',2'-tetrahydro-γ,γ-carotene-1-ol) and spheroidene (1-methoxy-3,4-didehydro-1,2,7',8'-tetrahydro-γ,γ-carotene);Diadinoxanthin (5,6-epoxy-7',8'-didehydro-5,6-dihydro-carotene-3,3-diol), luteoxanthin (5,6:5',8'-diepoxy-5,6,5',8'-tetrahydro-β,β-carotene-3,3'-diol), mutatoxanthin, citroxanthin, zeaxanthin (furanoxide 5,8-epoxy-5,8-dihydro-β,β-carotene-3,3'-diol), neochrome (5',8'-epoxy-6,7-didehydro-5,6,5',8'-tetrahydro-β,β Epoxides such as 5',6'-epoxy-6,7-didehydro-5,6,5',6'-tetrahydro-β,β-carotene-3,5,19,3'-triol), foliachrome, trolichrome, and baucheriaxanthin (5',6'-epoxy-6,7-didehydro-5,6,5',6'-tetrahydro-β,β-carotene-3,5,19,3'-tetraol); aldehydes such as rhodopinal, wammingone (13-cis-1-hydroxy-1,2-dihydro-γ,γ-caroten-20-al), and torularhodin aldehyde (3',4'-didehydro-β,γ-caroten-16'-al); Acids and acid esters such as 4'-didehydro-β,γ-carotene-16'-oic acid and torularhodin methyl ester (methyl 3',4'-didehydro-β,γ-carotene-16'-oate); astaxanthin, canthaxanthin (also known as aphanisin), chlorellaxanthin (β,β-carotene-4,4'-dione), capsanthin ((3r,3's,5'r)-3,3'-dihydroxy-β,κ-carotene-6'-one), capsorubin ((3s,5r,3's,5'r)-3,3'-dihydroxy-κ,κ-carotene-6'-one), phenicoxanthin), cryptocapsin ((3'r,5'r)-3'-hydroxy-β,κ-carotene-6'-one), 2,2'-diketospirilloxanthin (1,1'-dimethoxy-3,4,3',4'-tetradehydro-1,2,1',2'-tetrahydro-γ,γ-carotene-2,2'-dione), flexixanthin (3,1'-dihydroxy-3',4'-didehydro-1',2'-dihydro-β,γ-carotene-4-one), 3-oh-canthaxanthin (also known as adonirubin; also known as phoenicoxanthin;3-hydroxy-β,β-carotene-4,4'-dione), hydroxyspheriodenone (1'-hydroxy-1-methoxy-3,4-didehydro-1,2,1',2',7',8'-hexahydro-γ,γ-caroten-2-one), okenone (1'-methoxy-1',2'-dihydro-c,γ-caroten-4'-one), pectenolone (3,3'-dihydroxy-7',8'-didehydro-β,β-caroten-4-one), pheniconone (also known as dehydroadonirubin; 3- Ketones such as hydroxy-2,3-didehydro-β,β-carotene-4,4'-dione, phenicopterone (β,ε-carotene-4-one), rubixanthone (3-hydroxy-β,γ-carotene-4'-one), siphonaxanthin (3,19,3'-trihydroxy-7,8-dihydro-β,ε-carotene-8-one); asteracein (3,3'-bispalmitoyloxy-2,3,2',3'-tetradehydro-β,β-carotene-4,4'-dione or 3,3'-di Hydroxy-2,3,2',3'-tetradehydro-β,β-carotene-4,4'-dione dipalmitate), fucoxanthin (3'-acetoxy-5,6-epoxy-3,5'-dihydroxy-6',7'-didehydro-5,6,7,8,5',6'-hexahydro-β,β-caroten-8-one), isofucoxanthin (3'-acetoxy-3,5,5'-trihydroxy-6',7'-didehydro-5,8,5',6'-tetrahydro-β,β-caroten-8-one) , physaliene, esters of alcohols such as zeaxanthin dipalmitate ((3r,3'r)-3,3'-bispalmitoyloxy-β,β-carotene or (3r,3'r)-β,β-carotene-3,3'-diol dipalmitate) and syphonein (3,3'-dihydroxy-19-lauroyloxy-7,8-dihydro-β,ε-caroten-8-one or 3,19,3'-trihydroxy-7,8-dihydro-β,ε-caroten-8-one 19-laurate);β-Apo-2'-carotenal (3',4'-didehydro-2'-apo-b-carotene-2'-al), apo-2-lycopenal, apo-6'-lycopenal (6'-apo-y-carotene-6'-al), azafurinaldehyde (5,6-dihydroxy-5,6-dihydro-10'-apo-b-carotene-10'-al), bixin (6'-methyl hydrogen 9'-cis-6,6'-diapocarotene-6,6'-dioate), ), citranaxanthin (5',6'-dihydro-5'-apo-β-caroten-6'-one or 5',6'-dihydro-5'-apo-18'-nor-β-caroten-6'-one or 6'-methyl-6'-apo-β-caroten-6'-one), crocetin (8,8'-diapo-8,8'-carotenedioic acid), crocetin semialdehyde (8'-oxo-8,8'-diapo-8-carotenoic acid), crocin (digestive 8, 8'-diapo-8,8'-carotene dioate), hopkinciaxanthin (3-hydroxy-7,8-didehydro-7',8'-dihydro-7'-apo-b-carotene-4,8'-dione or 3-hydroxy-8'-methyl-7,8-didehydro-8'-apo-b-carotene-4,8'-dione), methyl apo-6'-lycopenoate (methyl 6'-apo-y-carotene-6'-oate), paracentrone (3,5-di apocarotenoids such as hydroxy-6,7-didehydro-5,6,7',8'-tetrahydro-7'-apo-b-caroten-8'-one or 3,5-dihydroxy-8'-methyl-6,7-didehydro-5,6-dihydro-8'-apo-b-caroten-8'-one) and syntaxanthin (7',8'-dihydro-7'-apo-b-caroten-8'-one or 8'-methyl-8'-apo-b-caroten-8'-one);Actinioerythrin (3,3'-bisacyloxy-2,2'-dinor-b,b-carotene-4,4'-dione), β-carotenone (5,6:5',6'-diseco-b,b-carotene-5,6,5',6'-tetraone), peridinin (3'-acetoxy-5,6-epoxy-3,5'-dihydroxy-6',7'-didehydro-5,6,5',6'-tetrahydro-12',13',20'-trinor-b,b-carotene-19,11- olide), pyroxanthininol (5,6-epoxy-3,3'-dihydroxy-7',8'-didehydro-5,6-dihydro-12',13',20'-trinor-b,b-carotene-19,11-olide), semi-α-carotenone (5,6-seco-b,e-carotene-5,6-dione), semi-β-carotenone (5,6-seco-b,b-carotene-5,6-dione or 5',6'-seco-b,b-carotene-5',6'-dione) and nor- and seco-carotenoids such as trifasciaxanthin (3-hydroxysemi-b-carotenone 3'-hydroxy-5,6-seco-b,b-carotene-5,6-dione or 3-hydroxy-5',6'-seco-b,b-carotene-5',6'-dione); escholtzuxanthin (4',5'-didehydro-4,5'-retro-b,b-carotene-3,3'-diol), escholtzuxanthon (3'-hydroxy-4',5'- retrocarotenoids and retroapocarotenoids such as didehydro-4,5'-retro-b,b-caroten-3-one), rhodoxanthin (4',5'-didehydro-4,5'-retro-b,b-carotene-3,3'-dione) and tangeraxanthin (3-hydroxy-5'-methyl-4,5'-retro-5'-apo-b-caroten-5'-one or 3-hydroxy-4,5'-retro-5'-apo-b-caroten-5'-one);As well as nonaprenoxanthin (2-(4-hydroxy-3-methyl-2-butenyl)-7',8',11',12'-tetrahydro-e,y-carotene), decaprenoxanthin (2,2'-bis(4-hydroxy-3-methyl-2-butenyl)-e,e-carotene), cp450 (2-[4-hydroxy-3-(hydroxymethyl)-2-butenyl]-2'-(3-methyl-2-butenyl)-b,b-carotene), cp473 Higher carotenoids include 2'-(4-hydroxy-3-methyl-2-butenyl)-2-(3-methyl-2-butenyl)-3',4'-didehydro-1',2'-dihydro-b,y-caroten-1'-ol) and bacterioruberin (2,2'-bis(3-hydroxy-3-methylbutyl)-3,4,3',4'-tetradehydro-1,2,1',2'-tetrahydro-y,y-carotene-1,1'-diol);

[0035]

[0038] The carotenoid compounds for use herein may be natural products, i.e., obtained from natural sources extracted from plants such as tomatoes, melons, or marigolds. A range of methods for extracting, concentrating, and / or purifying carotenoids from plants are known in the art. For example, solvent extraction using ethanol, DMSO, ethyl acetate, hexane, acetone, soybean or other vegetable oils, or non-vegetable oils may be utilized. Carotenoid compounds may be isolated free or substantially free from other molecules found in their natural source or environment. The use of such extraction and purification methods is known to those skilled in the art.

[0036]

[0039] Carotenoid compounds for use as described herein may be synthetic, i.e., produced by artificial means, for example, by chemical synthesis or fermentation. A range of methods for the chemical synthesis of carotenoids are known in the art.

[0037]

[0040] In one embodiment, the carotenoid is included in a composition, such as a nutritional supplement, and includes a carotenoid that is metabolized in the body to vitamin A, such as retinal, retinol, or retinoic acid. Such carotenoids may be considered vitamin A precursors. Examples of such carotenoids include beta-carotene, alpha-carotene, gamma-carotene, and beta-cryptoxanthin.

[0038]

[0041] In an alternative embodiment, the carotenoid contained in the composition may include a carotenoid with antioxidant activity. Such carotenoids include lutein, zeaxanthin, lycopene, crocetin, etc. The above carotenoids, particularly lutein, have been found to be well-matched with type II collagen. For example, type II collagen can influence T-reg cells to produce anti-inflammatory cytokines, which convert the physiological function of chondrocytes from matrix protein destruction to matrix protein creation and adhesion. On the other hand, various carotenoids, such as lutein, are potent antioxidants. Lutein can activate the Nrf2 pathway, which provides cytoprotective activity, and reduce inflammation. In the case of lutein, it has been shown that it can not only reduce oxidative stress induced by monosodium iodoacetate (MIA) in primary chondrocytes, but also alleviate the symptoms of MIA-induced OA in rats. Thus, carotenoids can act synergistically with type II collagen in nutritional supplements to provide better overall efficacy. For example, in one embodiment, it is believed that the combination of type II collagen and a carotenoid with antioxidant activity may provide an overall better composition for treating joint pain resulting from participating in normal daily activities or from arthritis.

[0039]

[0042] As used herein, carotenoids also include carotenoid precursors that release carotenoids in the body through metabolic processes, etc. For example, in one embodiment, carotenoids may include precursors or compounds that result in the synthesis of any of the carotenoids described above, such as carotenoids with antioxidant activity. In one embodiment, for example, carotenoids may include precursors that are converted to lycopene upon ingestion or otherwise incorporation into a patient's body. In yet other embodiments, carotenoids may include precursors that produce downstream metabolic intermediates, such as beta-carotene, alpha-carotene, beta-cryptoxanthin, zeaxanthin, crocetin, lutein, or mixtures thereof.

[0040]

[0043] The amount of type II collagen and vitamin A and / or one or more carotenoids in the dosage taken at any given time varies according to the purpose of intake, the severity of symptoms, and the condition, age, weight, medical history and overall physical characteristics of the subject (human or animal) being treated.Therefore, the dosage, frequency and duration of administration of the dosage can vary widely.The nutritional supplement of the present disclosure can be combined with other digestible ingredients, such as in the form of an aqueous dispersion, such as milk, or in combination with other protein-rich substances, sugars and starches.In one embodiment, the nutritional supplement can be administered directly as a pulverized solid, such as an encapsulated pulverized solid, such as compressed and molded pills, and as a slurry with or without other digestible compositions, such as foodstuffs.

[0041]

[0044] In one embodiment, when the nutritional supplement contains undenatured type II collagen combined with vitamin A, the weight ratio between the type II collagen and vitamin A can generally be about 100:1 to about 20:1. For example, the weight ratio between the collagen and vitamin A can be about 80:1 to about 30:1, e.g., about 60:1 to about 35:1.

[0042]

[0045] On the other hand, when undenatured type II collagen is combined with a carotenoid, the weight ratio between the collagen and the carotenoid can be about 40:1 to about 1:10, for example, about 20:1 to about 1:4. In one embodiment, the weight ratio between the collagen and the carotenoid, such as beta-carotene or lutein, can be about 15:1 to about 1:4.

[0043]

[0046] In one embodiment, when the nutritional supplement contains hydrolyzed type II collagen in combination with vitamin A, the weight ratio between the type II collagen and vitamin A can generally be about 150,000:1 to about 3,000:1. For example, the weight ratio between the collagen and vitamin A can be about 80:1 to about 30:1, e.g., about 60:1 to about 35:1.

[0044]

[0047] On the other hand, when hydrolyzed type II collagen is combined with a carotenoid, the weight ratio between the collagen and the carotenoid can be about 15,000:1 to about 37.5:1, for example, about 20:1 to about 1:4. In one embodiment, the weight ratio between the collagen and the carotenoid, such as beta-carotene or lutein, can be about 15:1 to about 1:4.

[0045]

[0048] In one embodiment, the composition or nutritional supplement of the present disclosure is formed into individual dosage units intended for oral ingestion by humans or animals. The dosage units may contain, for example, tablets, capsules, or other delivery vehicles. In one embodiment, the undenatured type II collagen may generally be present in each dosage unit in an amount of about 1 milligram to about 5,000 milligrams. For example, the type II collagen may be present in each dosage unit in an amount greater than about 5 milligrams, for example, greater than about 10 milligrams, for example, greater than about 15 milligrams, for example, greater than about 20 milligrams, for example, greater than about 25 milligrams, or for example, greater than about 30 milligrams. The amount of type II collagen present in each dosage device may generally be less than about 1000 milligrams, such as less than about 900 milligrams, for example, less than about 800 milligrams, for example, less than about 700 milligrams, for example, less than about 600 milligrams, for example, less than about 500 milligrams, for example, less than about 400 milligrams, for example, less than about 300 milligrams, for example, less than about 200 milligrams, for example, less than about 100 milligrams, for example, less than about 80 milligrams, for example, less than about 70 milligrams, for example, less than about 60 milligrams.

[0046]

[0049] In one embodiment, the composition or nutritional supplement of the present disclosure is formed into individual dosage units intended for oral ingestion by humans or animals. The dosage units may contain, for example, tablets, capsules, or other delivery vehicles. In one embodiment, type II collagen is denatured or hydrolyzed and generally present in each dosage unit in an amount of about 1 milligram to about 15,000 milligrams. For example, type II collagen may be present in each dosage unit in an amount greater than about 5 milligrams, for example, greater than about 10 milligrams, for example, greater than about 15 milligrams, for example, greater than about 20 milligrams, for example, greater than about 25 milligrams, for example, greater than about 30 milligrams. The amount of type II collagen present in each dosage device is generally less than about 15,000 milligrams, such as less than about 14,000 milligrams, for example, less than about 13,000 milligrams, for example, less than about 12,000 milligrams, for example, less than about 11,000 milligrams, for example, less than about 10,000 milligrams, such as less than about 9,000 milligrams, for example, less than about 8,000 milligrams, for example, less than about 7000 milligrams, for example, less than about 6,000 milligrams, for example, less than about 5,000 milligrams, for example, , less than about 4,000 milligrams, for example, less than about 3,000 milligrams, for example, less than about 2,000 milligrams, for example, less than about 1000 milligrams, for example, less than about 900 milligrams, for example, less than about 800 milligrams, for example, less than about 700 milligrams, for example, less than about 600 milligrams, for example, less than about 500 milligrams, for example, less than about 400 milligrams, for example, less than about 300 milligrams, for example, less than about 200 milligrams, for example, less than about 100 milligrams, for example, less than about 50 milligrams.

[0047]

[0050] When type II collagen is combined with vitamin A such as retinol or its esterified form, vitamin A can be present in each dosage unit in an amount greater than about 100 micrograms, for example, greater than about 200 micrograms, for example, greater than about 300 micrograms, for example, greater than about 400 micrograms, for example, greater than about 500 micrograms, for example, greater than about 600 micrograms, for example, greater than about 700 micrograms. Vitamin A can be present in each dosage unit in an amount less than about 5000 micrograms, for example, less than about 3000 micrograms, for example, less than about 2000 micrograms, for example, less than about 1000 micrograms, for example, less than about 900 micrograms.

[0048]

[0051] When type II collagen is combined with a carotenoid, the carotenoid may generally be present in the dosage device in an amount greater than about 0.5 milligrams, such as greater than about 1 milligram, for example, greater than about 2 milligrams, for example, greater than about 2.5 milligrams, for example, greater than about 5 milligrams, for example, greater than about 10 milligrams, for example, greater than about 15 milligrams, for example, greater than about 20 milligrams, for example, greater than about 25 milligrams, for example, greater than about 30 milligrams, for example, greater than about 35 milligrams, for example, greater than about 40 milligrams. The carotenoid is generally present in an amount of less than about 5,000 milligrams, e.g., less than about 3,000 milligrams, e.g., less than about 1,000 milligrams, e.g., less than about 800 milligrams, e.g., less than about 600 milligrams, e.g., less than about 400 milligrams, e.g., less than about 200 milligrams, e.g., less than about 100 milligrams, e.g., less than about 90 milligrams, e.g., less than about 80 milligrams, e.g., less than about 70 milligrams, e.g., less than about 60 milligrams. In one embodiment, for example, the carotenoid may comprise a carotene, such as beta-carotene, and may be present in each individual doser in an amount of about 20 milligrams to about 50 milligrams. In an alternative embodiment, the carotenoid may comprise lutein and may be present in each individual doser in an amount of about 1 milligram to about 140 milligrams, e.g., about 2.5 milligrams to about 60 milligrams.

[0049]

[0052] The dosage device can be taken periodically over a substantial period of time, for example, the dosage device can be taken daily, every 2-5 days, weekly, or every two weeks.

[0050]

[0053] As described above, in one embodiment, the composition of the present disclosure can be formulated as a nutritional supplement to be taken orally.However, it should be understood that the composition of the present disclosure can be administered to humans or animals using any suitable method.In one embodiment, the composition can be incorporated into a topical composition intended to be applied topically to the skin of a user.When formulated as a topical composition, for example, a collagen source combined with vitamin A, carotenoids or a mixture thereof can be mixed with various ingredients and components.For example, when formulated as a topical composition, the composition of the present disclosure can be mixed with solvents, surfactants, emulsifiers, consistency factors, conditioners, emollients, skin care ingredients, moisturizers, thickeners, lubricants, preservatives and various different dermatological ingredients.When applied to the skin of a user, the composition of the present disclosure can be used to improve skin health or can be formulated to be absorbed by the body.

[0051]

[0054] In addition to targeting compositions such as nutritional supplements, the present disclosure also targets the method for administering nutritional supplements to humans or animals.For example, in one embodiment, the present disclosure targets the method for treating joint pain, including arthritis, by administering to mammals a nutritional supplement that comprises undenatured type II collagen in combination with vitamin A and / or at least one carotenoid.The nutritional supplement is administered to mammals in a therapeutically effective amount so as to reduce arthritis or otherwise treat joint pain.In one embodiment, for example, the reduction of joint pain is evidenced by the improvement of the range of motion of joints (for example, knee, elbow, etc.), the increase in the level of activity or any activity that depends on having functional joints.

[0052]

[0055] In other embodiments, the present disclosure is directed to a method of treating a mammal to improve immune health, ocular health, and / or brain health, comprising administering to the mammal a nutritional supplement as described above in a therapeutically effective amount sufficient to improve the mammal's ocular health, immune health, and brain health.

[0053] Aspects of the present invention also include the following. Aspect 1 A composition comprising a type II collagen source in combination with vitamin A, a carotenoid, or a mixture thereof. Aspect 2 10. The composition of embodiment 1, comprising a nutritional supplement for oral consumption. Aspect 3 The composition of embodiment 1, comprising a topical composition for application to the skin. Aspect 4 Aspect 4. The composition of any of aspects 1 to 3, wherein the type II collagen source comprises non-denatured type II collagen. Aspect 5 Aspect 4. The composition of any of aspects 1 to 3, wherein the type II collagen source comprises denatured (hydrolyzed) type II collagen. Aspect 6 Aspect 6. The composition of any of aspects 1 to 5, wherein the nutritional supplement is in the form of an individual dosage unit. Aspect 7 The composition of embodiment 4 or 5, wherein the dosage device comprises a tablet, capsule, powder, or the like. Aspect 8 Aspect 8. The composition of any of aspects 1-7, wherein the type II collagen source is combined with vitamin A, and the vitamin A comprises retinol or a retinyl ester. Aspect 9 Aspect 8. The composition of any of aspects 1-7, wherein the type II collagen is combined with a carotenoid. Aspect 10 10. The composition of embodiment 9, wherein the carotenoid comprises beta-carotene, alpha-carotene, beta-cryptoxanthin, or a mixture thereof, or comprises a precursor that is converted to beta-carotene, alpha-carotene, beta-cryptoxanthin, or a mixture thereof. Aspect 11 10. The composition of embodiment 9, wherein the carotenoid comprises zeaxanthin, lycopene, crocetin, or a mixture thereof, or a precursor that is converted to zeaxanthin, lycopene, crocetin, or a mixture thereof. Aspect 12 10. The composition of embodiment 9, wherein the carotenoid comprises lutein or a precursor that is converted to lutein. Aspect 13 The composition of aspect 6 or 7, wherein the individual dosage device contains between about 1 mg and about 15,000 mg, for example, between about 20 mg and about 100 mg, of type II collagen. Aspect 14 14. The composition of embodiment 6, 7, or 13, wherein the type II collagen source is combined with vitamin A, and the vitamin A is present in each dosage unit in an amount from about 100 micrograms to about 5000 micrograms. Aspect 15 14. The composition of aspect 6, 7, or 13, wherein the type II collagen is combined with a carotenoid, and the carotenoid is present in each dosage unit in an amount of from about 0.5 mg to about 1000 mg, e.g., from about 1 mg to about 150 mg. Aspect 16 16. The composition of any of aspects 1 to 15, wherein the source of undenatured type II collagen is combined with a carotenoid, and the type II collagen source is present in the composition in a weight ratio to carotenoid of about 2:1 to about 1:1,000, with a minimum amount of type II collagen source added being from about 2,000:1 to about 1:1, with a maximum amount of type II collagen source added being from about 2,000:1 to about 1:1. Aspect 17 17. The composition of any of aspects 1 to 16, wherein the hydrolyzed (denatured) type II collagen source is combined with a carotenoid, and the type II collagen source is present in the composition in a weight ratio to carotenoid of about 2:1 to about 1:1,000, with a minimum amount of type II collagen source added being from about 2:1 to about 1:1,000, and a maximum amount of type II collagen source added being from about 30,000:1 to about 15:1. Aspect 18 15. The composition of any of aspects 1 to 14, wherein the source of undenatured type II collagen is combined with vitamin A, and the type II collagen source is present in the composition in a weight ratio to vitamin A of about 10:1 to about 1:5, with a minimum amount of type II collagen source added, and about 5000:1 to about 100:1, with a maximum amount of type II collagen source added. Aspect 19 15. The composition of any of aspects 1 to 14, wherein the hydrolyzed (denatured) type II collagen is combined with vitamin A, and the type II collagen source is present in the composition in a weight ratio to vitamin A of about 10:1 to about 1:5, with a minimum amount of type II collagen source added, and about 150,000:1 to about 3,000:1, with a maximum amount of type II collagen source added. Aspect 20 A method for treating joint pain in a mammal, comprising administering to the mammal a composition comprising undenatured or hydrolyzed type II collagen in combination with vitamin A, a carotenoid, or a mixture thereof, wherein the composition is administered to the mammal in a therapeutically effective amount to reduce joint pain in both healthy individuals and individuals with arthritis of the knee and other joints. Aspect 21 The method of embodiment 20, wherein the composition is taken orally. Aspect 22 22. The method of embodiment 20 or 21, wherein the type II collagen is combined with vitamin A, and the vitamin A comprises retinol, a retinyl ester, or a combination thereof. Aspect 23 22. The method of embodiment 20 or 21, wherein the type II collagen is combined with a carotenoid. Aspect 24 24. The method of embodiment 23, wherein the carotenoid comprises beta-carotene, alpha-carotene, beta-cryptoxanthin, zeaxanthin, lycopene, crocetin, or a mixture thereof. Aspect 25 24. The method of embodiment 23, wherein the carotenoid comprises lutein. Aspect 26 26. The method of any of aspects 20 to 25, wherein the composition is in the form of individual dosage units, each individual dosage unit containing type II collagen in an amount of about 1 mg to about 15,000 mg, e.g., about 20 mg to about 200 mg; if vitamin A is present in the composition, each dosage unit contains vitamin A in an amount of about 100 micrograms to about 5000 micrograms; and if the composition contains a carotenoid, the carotenoid is present in the dosage unit in an amount of about 0.5 mg to about 1000 mg, e.g., about 1 mg to about 150 mg. Aspect 27 A method for treating an eye disease in a mammal, comprising administering to the mammal a composition comprising a source of undenatured or hydrolyzed type II collagen in combination with vitamin A, a carotenoid or a mixture thereof, wherein the composition is administered to the mammal in a therapeutically effective amount that improves eye health. Aspect 28 28. The method of embodiment 27, wherein the composition is taken orally. Aspect 29 29. The method of embodiment 27 or 28, wherein the type II collagen is combined with vitamin A, and the vitamin A comprises retinol, a retinyl ester, or a combination thereof. Aspect 30 29. The method of embodiment 27 or 28, wherein the type II collagen is combined with a carotenoid. Aspect 31 31. The method of embodiment 30, wherein the carotenoid comprises beta-carotene, alpha-carotene, beta-cryptoxanthin, zeaxanthin, lycopene, crocetin, or a mixture thereof. Aspect 32 31. The method of embodiment 30, wherein the carotenoid comprises lutein. Aspect 33 33. The method of any of aspects 27 to 32, wherein the composition is in the form of individual dosage units, each individual dosage unit containing type II collagen in an amount of about 1 mg to about 15,000 mg, e.g., about 20 mg to about 200 mg; if vitamin A is present in the composition, each dosage unit contains vitamin A in an amount of about 100 micrograms to about 5000 micrograms; and if the composition contains a carotenoid, the carotenoid is present in the dosage unit in an amount of about 0.5 mg to about 1000 mg, e.g., about 1 mg to about 150 mg. Aspect 34 1. A method for supporting brain health in a mammal, comprising administering to the mammal a composition comprising a source of undenatured or hydrolyzed (denatured) type II collagen in combination with vitamin A, a carotenoid, or a mixture thereof, wherein the composition is administered to the mammal in a therapeutically effective amount that improves brain health. Aspect 35 The method of embodiment 34, wherein the composition is taken orally. Aspect 36 36. The method of embodiment 34 or 35, wherein the type II collagen is combined with vitamin A, and the vitamin A comprises retinol, a retinyl ester, or a combination thereof. Aspect 37 36. The method of embodiment 34 or 35, wherein the type II collagen is combined with a carotenoid. Aspect 38 38. The method of embodiment 37, wherein the carotenoid comprises beta-carotene, alpha-carotene, beta-cryptoxanthin, zeaxanthin, lycopene, crocetin, or a mixture thereof. Aspect 39 38. The method of embodiment 37, wherein the carotenoid comprises lutein. Aspect 40 40. The method of any of aspects 34 to 39, wherein the composition is in the form of individual dosage units, each individual dosage unit containing type II collagen in an amount of about 1 mg to about 15,000 mg, e.g., about 20 mg to about 200 mg; if vitamin A is present in the composition, each dosage unit contains vitamin A in an amount of about 100 micrograms to about 5000 micrograms; and if the composition contains a carotenoid, the carotenoid is present in the dosage unit in an amount of about 0.5 mg to about 1000 mg, e.g., about 1 mg to about 150 mg.

[0056] These and other modifications and variations to the present invention may be practiced by those of ordinary skill in the art without departing from the spirit and scope of the invention, as more particularly set forth in the appended claims. In addition, it should be understood that aspects of the various embodiments may be interchangeable both in whole or in part. Furthermore, those skilled in the art will appreciate that the foregoing description is by way of example only and is not intended to limit the invention, as further set forth in such appended claims.

Claims

1. 1. A nutritional supplement for oral ingestion comprising undenatured type II collagen in combination with vitamin A and a carotenoid, wherein the undenatured type II collagen is present in the nutritional supplement in an amount of 1 mg to 60 mg, the weight ratio between the type II collagen and vitamin A is 100:1 to 20:1, 10:1 to 1:5, or 5000:1 to 100:1, and the weight ratio between the type II collagen and the carotenoid is 40:1 to 1:10, and the carotenoid comprises beta-carotene or lutein.

2. 10. The nutritional supplement of claim 1, wherein the nutritional supplement is in the form of an individual dosage unit.

3. 3. The nutritional supplement of claim 2, wherein the dosage unit contains a tablet, capsule, or powder.

4. 4. The nutritional supplement of claim 1, wherein the vitamin A comprises retinol or a retinyl ester.

5. 5. The nutritional supplement of claim 4, wherein vitamin A is present in each dosage unit in an amount of from about 100 micrograms to about 5000 micrograms.

6. 10. The nutritional supplement of claim 1, wherein the carotenoid is present in each dosage unit in an amount of from about 0.5 mg to about 1000 mg.

7. 1. A composition for treating joint pain in a mammal, comprising undenatured type II collagen in combination with vitamin A and a carotenoid in a therapeutically effective amount to reduce joint pain in both healthy individuals and individuals with arthritis of the knee and other joints, wherein the undenatured type II collagen is present in the composition in an amount of 1 mg to 60 mg, the weight ratio between the type II collagen and vitamin A is 100:1 to 20:1, 10:1 to 1:5, or 5000:1 to 100:1, and the weight ratio between the type II collagen and the carotenoid is 40:1 to 1:10, and the carotenoid comprises beta-carotene or lutein.

8. The composition of claim 7 , which is taken orally.

9. 9. The composition of claim 7 or 8, wherein the vitamin A comprises retinol, a retinyl ester, or a combination thereof.