US20190111020A1 - Nanosized carotenoid cyclodextrin complexes - Google Patents

Nanosized carotenoid cyclodextrin complexes Download PDF

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Publication number
US20190111020A1
US20190111020A1 US15/954,464 US201815954464A US2019111020A1 US 20190111020 A1 US20190111020 A1 US 20190111020A1 US 201815954464 A US201815954464 A US 201815954464A US 2019111020 A1 US2019111020 A1 US 2019111020A1
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cyclodextrin
carotenoid
composition
carotenoids
fish oil
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US15/954,464
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Mark Bartlett
Angela Mastaloudis
Carsten Smitdt
Stephen J. Poole
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NSE Products Inc
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NSE Products Inc
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Priority to US15/954,464 priority Critical patent/US20190111020A1/en
Publication of US20190111020A1 publication Critical patent/US20190111020A1/en
Priority to US17/216,506 priority patent/US20210322371A1/en
Abandoned legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
    • A61K31/355—Tocopherols, e.g. vitamin E
    • C—CHEMISTRY; METALLURGY
    • C01—INORGANIC CHEMISTRY
    • C01G—COMPOUNDS CONTAINING METALS NOT COVERED BY SUBCLASSES C01D OR C01F
    • C01G23/00—Compounds of titanium
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/115—Fatty acids or derivatives thereof; Fats or oils
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/115—Fatty acids or derivatives thereof; Fats or oils
    • A23L33/12—Fatty acids or derivatives thereof
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
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    • A23L33/15—Vitamins
    • A23L33/155—Vitamins A or D
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/01—Hydrocarbons
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K31/01—Hydrocarbons
    • A61K31/015—Hydrocarbons carbocyclic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A—HUMAN NECESSITIES
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    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/07—Retinol compounds, e.g. vitamin A
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K31/12—Ketones
    • A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/716—Glucans
    • A61K31/724—Cyclodextrins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/40—Cyclodextrins; Derivatives thereof
    • A—HUMAN NECESSITIES
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    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6949—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
    • A61K47/6951—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4866—Organic macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/12—Ophthalmic agents for cataracts
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A61P39/06—Free radical scavengers or antioxidants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82B—NANOSTRUCTURES FORMED BY MANIPULATION OF INDIVIDUAL ATOMS, MOLECULES, OR LIMITED COLLECTIONS OF ATOMS OR MOLECULES AS DISCRETE UNITS; MANUFACTURE OR TREATMENT THEREOF
    • B82B3/00—Manufacture or treatment of nanostructures by manipulation of individual atoms or molecules, or limited collections of atoms or molecules as discrete units
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs

Definitions

  • the present invention relates to compositions and related processes which increase the bioavailability of carotenoids provided by nutritional supplement formulations containing such nutrients. Accordingly, the present invention involves the fields of chemistry, food science, biology and nutrition.
  • Carotenoids are highly colored fat-soluble plant pigments that are well known for their nutritional and health benefits. Benefits associated with carotenoids include antioxidant activity as well as conversion to vitamin A. Studies indicate that higher dietary intake of carotenoids offers protection against developing certain cancers, macular degeneration, cataracts, heart disease, and other health conditions linked with oxidative or free radical damage. Because of the significant and desirable health benefits associate with carotenoids, nutritional companies have been quick to place carotenoid containing products on the market. Unfortunately, carotenoids are not readily soluble in intestinal fluid and therefore their absorption into the body is often quit low.
  • the present invention provides methods and compositions for improving the bioavailability of nutrients, particularly, carotenoids, primarily through specific manufacturing techniques.
  • the invention includes a method for manufacturing a carotenoid containing nutritional supplement.
  • the method includes mixing an amount of cyclodextrin with water to form a water/cyclodextrin slurry at 50° C., admixing an amount of at least one carotenoid to the water/cyclodextrin slurry to form a preblend composition including cyclodextrin carotenoid complexes, pulling a vacuum over the preblend composition and thoroughly mixing the preblend composition for a minimum of 1 hour, forming a final blend by mixing under a vacuum the undried preblend composition with additional nutritional components at a temperature of about 40-45° C. milling the final blend in a vacuum, encapsulating the milled final blend.
  • the cyclodextrin is a gamma-cyclodextrin.
  • the at least one carotenoid is selected from a group consisting of astaxanthin, lycopene, zeaxanthin, beta-carotene, and combinations thereof.
  • additional nutritional components can be incorporated into the composition including fish oil, beeswax, vitamin A, vitamin E, lutein, limonene, hill oil, and combinations thereof.
  • a method for manufacturing a carotenoid containing nutritional supplement includes heating an amount of water to 50° C. in a blending apparatus, mixing an amount of cyclodextrin with water to form a water/cyclodextrin slurry, admixing an amount of at least one carotenoid to the water/cyclodextrin slurry to form a preblend composition including cyclodextrin carotenoid complexes, pulling a vacuum over the preblend composition and thoroughly mixing the preblend composition for a minimum of 1 hour in a separate mixing container, forming a fish oil blend by mixing an amount of fish oil at a temperature of 60° C.
  • subject refers to a mammal that may benefit from the administration of a nutritional supplement or method of this invention.
  • subjects include humans, and may also include other animals such as horses, pigs, cattle, dogs, cats, rabbits, and aquatic mammals.
  • formulation and “composition” are used interchangeably and refer to a mixture of two or more compounds, elements, or molecules.
  • single dose refers to one or multiple capsule delivery units capable of delivering the desired amount of carotenoid to a subject.
  • an “effective amount,” and “sufficient amount” may be used interchangeably and refer to an amount of an ingredient which, when included in a chew composition, is sufficient to achieve an intended compositional or physiological effect.
  • a “sufficient amount” of carotenoid extract would be the minimum amount needed to have a nutritional affect.
  • a “therapeutically effective amount” refers to an amount of a carotenoid which is sufficient to achieve a desired physiological effect. The determination of an effective amount is well within the ordinary skill in the art of pharmaceutical, neutraceutical, herbaceutical, cosmetic, and medical sciences. See, for example, Meiner and Tonascia, “Clinical Trials: Design, Conduct, and Analysis,” Monographs in Epidemiology and Biostatistics, Vol. 8 (1986), incorporated by reference in its entirety.
  • admixed means that the drug and/or enhancer can be dissolved, dispersed, or suspended in the carrier. In some cases, the drug may be uniformly admixed in the carrier.
  • the present invention encompasses a process for preparing a carotenoid containing nutritional supplement including the formation of a carotenoid-cyclodextrin complex.
  • Carotenoids are well known in the nutritional arts for providing a variety of health benefits.
  • the present invention provides for methods of manufacturing a readily absorbable carotenoid containing nutritional supplement that is easy to perform, is time and cost effective, and results in a product in which the carotenoid is both highly stable and readily bioavailable.
  • carotenoids have poor solubility in intestinal fluids. This poor solubility leads to poor absorption or uptake of the carotenoids into systemic circulation. Another factor contributing to poor absorption of carotenoids is that carotenoids tend to aggregate into large particles which are not readily digested or absorbed. Cyclodextrins can encapsulate the poorly soluble compounds increasing their solubility and inhibiting the aggregation which typically occurs. The smaller encapsulated compounds are often referred to as nano-particles because of their extremely small size.
  • the present invention provides a streamlined method for the manufacture of nutritional supplements containing carotenoid-cyclodextrin complexes.
  • the method provides for the production and subsequent direct incorporation of carotenoid-cyclodextrin complexes into a nutritional supplement without the intermediary steps of collection, isolation, and drying. Because the carotenoid-cyclodextrin complexes can be directly incorporated into nutritional supplements without intermediary steps, costs are reduced.
  • the method of the present invention includes creating a cyclodextrin slurry by combining an amount of cyclodextrin with water.
  • the preferred temperature for the manufacture of the slurry is from to 50° C.
  • All types of cyclodextrins and combinations thereof may be used in the present invention including ⁇ -cyclodextrin, ⁇ -cyclodextrin, and ⁇ -cyclodextrin.
  • the cyclodextrin used is ⁇ -cyclodextrin.
  • the cyclodextrin is a mixture of ⁇ -cyclodextrin, and ⁇ -cyclodextrin.
  • the cyclodextrin and water mixture should be mixed for a period of about 20 minutes or until a caramel color is observed.
  • the role of the water is to hydrate the cyclodextrin. Hydrated cyclodextrin can than better complex with the carotenoids. Once the cyclodextrin slurry is formed carotenoids can be admixed therein.
  • the mixing of the carotenoid/cyclodextrin mixture should continue for a minimum of 1 hour at a temperature of from about 40° C. to about 50° C. Mixing the carotenoid/cyclodextrin mixture at high shear can enhance or increase the rate of reaction and thereby the rate of formation of the carotenoid-cyclodextrin complex. However, such lower shear values generated by lower mixing speeds can also be used effectively to form the carotenoid-cyclodextrin complexes.
  • the carotenoids which can be used in the present invention include any carotenoid known in the art to have positive health benefits.
  • the preferred carotenoids for use in the present invention are astazanthin, lycopene, zeaxanthin, beta-carotenes, lutein, and mixtures thereof.
  • a vacuum should be pulled over the carotenoid containing compositions of the present invention so as to slow or inhibit the degradation of the carotenoids.
  • Another acceptable method of maintaining the stability of the carotenoid is to keep the carotenoids containing mixtures under nitrogen.
  • carotenoid-cyclodextrin complexes begin to precipitate out of solution making the solution more viscous. This increase in viscosity can be used as an indicator of successful formation of the carotenoid-cyclodextrin complex.
  • traditional carotenoid-cyclodextrin complex manufacturing methods the precipitated complexes are collected, isolated and dried at this point in the process. By so doing the water originally present in the cyclodextrin slurry is eliminated.
  • the complexes are maintained in the preblend slurry, including the water. The ability of the manufacturing process of the present invention to eliminate the drying process reduces both the time and cost associated with the process.
  • the preblend slurry can then be admixed with additional nutritional components at a temperature of 40° C. to 45° C. to form a final blend.
  • additional nutritional components which can be used in the present invention include but are not limited to vitamin A, vitamin E, lutein, fish oil, limonene, beeswax, and combinations thereof. It is preferred that the final blend be mixed with fish oil. Any type of fish oil known to one skilled in the art can be used with the present invention.
  • krill oil is included as a fish oil.
  • the addition of the fish oil to the preblend slurry helps to stabilize and solubilize any uncomplexed carotenoids found in the preblend slurry and further enhances the bioavailability of both the complexed and uncomplexed carotenoids. It has been determined that when the carotenoid-cyclodextrin complexes of the present invention are co-administered with a minimum amount of fish oil the bioavailability of the carotenoids is increased above that of the carotenoid-cyclodextrin complex alone.
  • the fish oil comprises from about 70 wt % to about 90 wt % of the final blend composition. In another embodiment the fish oil can comprise from about 75 wt % to about 85 wt % of the final blend composition.
  • other nutritional components particularly readily oxidizable components such as Vitamin A and vitamin E, are included in the final blend composition the fish oil also acts to stabilize and protect those components.
  • the final blend composition is milled to assure small particle size of the complexed carotenoids.
  • the final blend can be directly encapsulated or stored in an air tight container under nitrogen.
  • the final blend is encapsulated into soft gelatin capsules.
  • the compositions produced by the methods of the present invention are intended to be delivered to subjects so as to provide therapeutically effective amounts of carotenoids to the subject. Such amounts are readily determinable by one of ordinary skill in the art based on the concentrations of the carotenoids in the invention compositions.
  • the present invention provides a composition and related method for providing enhanced bioavailability of carotenoids.
  • the bioavailability of the carotenoids is unexpectedly increased above the bioavailability of the carotenoid/cyclodextrin complex alone and a fish oil/carotenoid mixture alone.
  • the unexpected increase of bioavailability is due, at least in part, to fish oils stimulation of lipase enzymes in the gut which in turn facilitate the absorption of the carotenoids.
  • a stable carotenoid containing nutritional supplement is preparing according to the following steps.
  • Beta-Carotene (30% Fluid Suspension, B. 500.00 IU 0.273 trispora) Beta-Carotene (Caromin 13%b 6.5%a; oil; 13.000% 0.689 palm fruit) Astaxanthin, 5% OIL BioAstin (H. pluvialis) 5.000% 0.224 Lycopene (20% Oil Susp.) LycoVit synthetic 20.000% 0.560 Zeaxanthin (20% Fluid Susp.) 20.000% 0.056 4. A vacuum is pulled over the mixing container and the composition is mixed on a low speed (9.6 rpm) for at least 1 hour at a temperature of 4-45° C.
  • the mixer container containing the carotenoid-cyclodextrin complex are immediately removed and added to a main mixer containing a fish oil beeswax blend.
  • the fish oil and beeswax blend is made by adding approximately 6.1 kg of beeswax and 73.2 kg of fish oil to the mixer and blending at 60° C. to until thoroughly mixed. The composition is then cooled to 40-45° C.
  • Vitamin A (Palmitate, liquid 1,700 USP) 1600.0 IU 0.043 Vitamin E (d-alpha-tocopherol 1490 oil) 1.430 IU 2.988 Vitamin E, 60% g-t, 6.8% a-t, 20% d-t, 1.4% b-t, 60.000% 2.671 MTS-90G Oil Vitamin E Tocotrienols (50% E&TT, Fr. Palm 38.000% 0.028 Oil) Lutein (Ester, Xangold, oil susp, 15%) 15.000% 0.298 Krill Oil 100.000% 2.035 D-Limonene (liquid) 95.000% 1.071 7.
  • the mixture After the addition of the carotenoid/cyclodextrin complex and the other ingredients the mixture a vacuum is pulled over the mixer container and the mixture is mixed using high shear for 20 minutes at 20-45° C. The mixture is then allowed to cool to 25-28° C. and is removed from the mixer and milled to reduce the particle size. 8. After milling the mixture can be stored in a sealed container under nitrogen or encapsulated immediately. Encapsulation is done in a soft gelatin capsule. Each soft gelatin capsule contains about 1.2 grams of the milled final composition.
  • the study involved the use of Raman Spectroscopy to assess changes in Skin Carotenoid Scores over an eighteen week period of supplementation with the Composition of example 1 in comparison to a placebo.
  • Example 1 Subjects were given their respective capsules, placebo or composition of Example 1, and were instructed to take them twice daily (once with their morning meal and once with their evening meal).

Abstract

Methods for the preparation of nanosized nutrient formulations for enhanced absorption of nutritional agents. The methods include the complexation of cyclodextrin with carotenoids and incorporation of the complexes into the nutritional supplements without intermediate collection, isolation, and drying steps.

Description

    PRIORITY DATA
  • This application is a continuation of U.S. patent application Ser. No. 15/058,046, filed Mar. 1, 2016, which is a continuation of U.S. patent application Ser. No. 12/784,387, filed May 20, 2010, which is a divisional of U.S. patent application Ser. No. 11/538,766 filed on Oct. 4, 2006, which claims the benefit of U.S. Provisional Patent Application Ser. No. 60/724,051 filed on Oct. 5, 2005, each of which is incorporated herein by reference.
    • FIELD OF THE INVENTION
  • The present invention relates to compositions and related processes which increase the bioavailability of carotenoids provided by nutritional supplement formulations containing such nutrients. Accordingly, the present invention involves the fields of chemistry, food science, biology and nutrition.
    • BACKGROUND OF THE INVENTION
  • Carotenoids are highly colored fat-soluble plant pigments that are well known for their nutritional and health benefits. Benefits associated with carotenoids include antioxidant activity as well as conversion to vitamin A. Studies indicate that higher dietary intake of carotenoids offers protection against developing certain cancers, macular degeneration, cataracts, heart disease, and other health conditions linked with oxidative or free radical damage. Because of the significant and desirable health benefits associate with carotenoids, nutritional companies have been quick to place carotenoid containing products on the market. Unfortunately, carotenoids are not readily soluble in intestinal fluid and therefore their absorption into the body is often quit low.
  • Therefore, methods and systems for improving carotenoid absorption and bioavailability, as well as that of other nutrients, continues to be sought.
    • SUMMARY
  • Accordingly, the present invention provides methods and compositions for improving the bioavailability of nutrients, particularly, carotenoids, primarily through specific manufacturing techniques.
  • In one embodiment the invention includes a method for manufacturing a carotenoid containing nutritional supplement. The method includes mixing an amount of cyclodextrin with water to form a water/cyclodextrin slurry at 50° C., admixing an amount of at least one carotenoid to the water/cyclodextrin slurry to form a preblend composition including cyclodextrin carotenoid complexes, pulling a vacuum over the preblend composition and thoroughly mixing the preblend composition for a minimum of 1 hour, forming a final blend by mixing under a vacuum the undried preblend composition with additional nutritional components at a temperature of about 40-45° C. milling the final blend in a vacuum, encapsulating the milled final blend.
  • In one aspect of the invention the cyclodextrin is a gamma-cyclodextrin. In another aspect of the invention the at least one carotenoid is selected from a group consisting of astaxanthin, lycopene, zeaxanthin, beta-carotene, and combinations thereof. In a further aspect of the invention additional nutritional components can be incorporated into the composition including fish oil, beeswax, vitamin A, vitamin E, lutein, limonene, hill oil, and combinations thereof.
  • In another embodiment of the invention a method for manufacturing a carotenoid containing nutritional supplement includes heating an amount of water to 50° C. in a blending apparatus, mixing an amount of cyclodextrin with water to form a water/cyclodextrin slurry, admixing an amount of at least one carotenoid to the water/cyclodextrin slurry to form a preblend composition including cyclodextrin carotenoid complexes, pulling a vacuum over the preblend composition and thoroughly mixing the preblend composition for a minimum of 1 hour in a separate mixing container, forming a fish oil blend by mixing an amount of fish oil at a temperature of 60° C. until thoroughly mixed and then allowing to cool to 40-45° C., forming a final blend by mixing under a vacuum the undried preblend composition with the fish oil/beeswax blend a temperature of about 40-45° C. optionally admixing additional nutritional components to the final blend, cooling final blend mixture to 25-28° C., milling the final blend in a vacuum to reduce particle size, encapsulating the milled final blend.
    • DETAILED DESCRIPTION
  • Definitions
  • In describing and claiming the present invention, the following terminology will be used in accordance with the definitions set forth below.
  • The singular forms “a,” “an,” and, “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to a nutritional supplement containing “a cyclodextrin component” includes one or more cyclodextrin components and reference to “the carotenoid” includes reference to one or more carotenoids.
  • As used herein, “subject” refers to a mammal that may benefit from the administration of a nutritional supplement or method of this invention. Examples of subjects include humans, and may also include other animals such as horses, pigs, cattle, dogs, cats, rabbits, and aquatic mammals.
  • As used herein, the terms “formulation” and “composition” are used interchangeably and refer to a mixture of two or more compounds, elements, or molecules.
  • As used herein, “single dose” refers to one or multiple capsule delivery units capable of delivering the desired amount of carotenoid to a subject.
  • As used herein, an “effective amount,” and “sufficient amount” may be used interchangeably and refer to an amount of an ingredient which, when included in a chew composition, is sufficient to achieve an intended compositional or physiological effect. For example, a “sufficient amount” of carotenoid extract would be the minimum amount needed to have a nutritional affect. Further, a “therapeutically effective amount” refers to an amount of a carotenoid which is sufficient to achieve a desired physiological effect. The determination of an effective amount is well within the ordinary skill in the art of pharmaceutical, neutraceutical, herbaceutical, cosmetic, and medical sciences. See, for example, Meiner and Tonascia, “Clinical Trials: Design, Conduct, and Analysis,” Monographs in Epidemiology and Biostatistics, Vol. 8 (1986), incorporated by reference in its entirety.
  • The term “admixed” means that the drug and/or enhancer can be dissolved, dispersed, or suspended in the carrier. In some cases, the drug may be uniformly admixed in the carrier.
  • As used herein, a plurality of items, structural elements, compositional elements, and/or materials may be presented in a common list for convenience. However, these lists should be construed as though each member of the list is individually identified as a separate and unique member. Thus, no individual member of such list should be construed as a de facto equivalent of any other member of the same list solely based on their presentation in a common group without indications to the contrary.
  • Concentrations, amounts, and other numerical data may be expressed or presented herein in a range format. It is to be understood that such a range format is used merely for convenience and brevity and thus should be interpreted flexibly to include not only the numerical values explicitly recited as the limits of the range, but also to include all the individual numerical values or sub-ranges encompassed within that range as if each numerical value and sub-range is explicitly recited. As an illustration, a numerical range of “about 1 to about 5” should be interpreted to include not only the explicitly recited values of about 1 to about 5, but also include individual values and sub-ranges within the indicated range. Thus, included in this numerical range are individual values such as 2, 3, and 4 and sub-ranges such as from 1-3, from 2-4, and from 3-5, etc.
  • This same principle applies to ranges reciting only one numerical value. Furthermore, such an interpretation should apply regardless of the breadth of the range or the characteristics being described.
  • Invention
  • The present invention encompasses a process for preparing a carotenoid containing nutritional supplement including the formation of a carotenoid-cyclodextrin complex. Carotenoids are well known in the nutritional arts for providing a variety of health benefits. The present invention provides for methods of manufacturing a readily absorbable carotenoid containing nutritional supplement that is easy to perform, is time and cost effective, and results in a product in which the carotenoid is both highly stable and readily bioavailable.
  • It is well known in the nutritional supplement arts that carotenoids have poor solubility in intestinal fluids. This poor solubility leads to poor absorption or uptake of the carotenoids into systemic circulation. Another factor contributing to poor absorption of carotenoids is that carotenoids tend to aggregate into large particles which are not readily digested or absorbed. Cyclodextrins can encapsulate the poorly soluble compounds increasing their solubility and inhibiting the aggregation which typically occurs. The smaller encapsulated compounds are often referred to as nano-particles because of their extremely small size.
  • The present invention provides a streamlined method for the manufacture of nutritional supplements containing carotenoid-cyclodextrin complexes. In particular the method provides for the production and subsequent direct incorporation of carotenoid-cyclodextrin complexes into a nutritional supplement without the intermediary steps of collection, isolation, and drying. Because the carotenoid-cyclodextrin complexes can be directly incorporated into nutritional supplements without intermediary steps, costs are reduced.
  • The method of the present invention includes creating a cyclodextrin slurry by combining an amount of cyclodextrin with water. The preferred temperature for the manufacture of the slurry is from to 50° C. All types of cyclodextrins and combinations thereof may be used in the present invention including α-cyclodextrin, γ-cyclodextrin, and β-cyclodextrin. In one embodiment the cyclodextrin used is γ-cyclodextrin. In another embodiment the cyclodextrin is a mixture of γ-cyclodextrin, and β-cyclodextrin. The cyclodextrin and water mixture should be mixed for a period of about 20 minutes or until a caramel color is observed. The role of the water is to hydrate the cyclodextrin. Hydrated cyclodextrin can than better complex with the carotenoids. Once the cyclodextrin slurry is formed carotenoids can be admixed therein. The mixing of the carotenoid/cyclodextrin mixture should continue for a minimum of 1 hour at a temperature of from about 40° C. to about 50° C. Mixing the carotenoid/cyclodextrin mixture at high shear can enhance or increase the rate of reaction and thereby the rate of formation of the carotenoid-cyclodextrin complex. However, such lower shear values generated by lower mixing speeds can also be used effectively to form the carotenoid-cyclodextrin complexes.
  • The carotenoids which can be used in the present invention include any carotenoid known in the art to have positive health benefits. The preferred carotenoids for use in the present invention are astazanthin, lycopene, zeaxanthin, beta-carotenes, lutein, and mixtures thereof. When possible, it is preferred that a vacuum should be pulled over the carotenoid containing compositions of the present invention so as to slow or inhibit the degradation of the carotenoids. Another acceptable method of maintaining the stability of the carotenoid is to keep the carotenoids containing mixtures under nitrogen.
  • As the carotenoid/cyclodextrin composition is mixed, carotenoid-cyclodextrin complexes begin to precipitate out of solution making the solution more viscous. This increase in viscosity can be used as an indicator of successful formation of the carotenoid-cyclodextrin complex. In traditional carotenoid-cyclodextrin complex manufacturing methods the precipitated complexes are collected, isolated and dried at this point in the process. By so doing the water originally present in the cyclodextrin slurry is eliminated. In the method of the present invention the complexes are maintained in the preblend slurry, including the water. The ability of the manufacturing process of the present invention to eliminate the drying process reduces both the time and cost associated with the process.
  • After formation of the carotenoid-cyclodextrin complexes, the preblend slurry can then be admixed with additional nutritional components at a temperature of 40° C. to 45° C. to form a final blend. The final blend is mixed thoroughly for a minimum of 20 minutes. Examples of additional nutritional components which can be used in the present invention include but are not limited to vitamin A, vitamin E, lutein, fish oil, limonene, beeswax, and combinations thereof. It is preferred that the final blend be mixed with fish oil. Any type of fish oil known to one skilled in the art can be used with the present invention. For the purposes of the present invention krill oil is included as a fish oil.
  • In addition to the health benefits which are inherent in fish oil, the addition of the fish oil to the preblend slurry helps to stabilize and solubilize any uncomplexed carotenoids found in the preblend slurry and further enhances the bioavailability of both the complexed and uncomplexed carotenoids. It has been determined that when the carotenoid-cyclodextrin complexes of the present invention are co-administered with a minimum amount of fish oil the bioavailability of the carotenoids is increased above that of the carotenoid-cyclodextrin complex alone. Without being limited by theory, it is believed that this increase in bioavailability is due, at least in part, to fish oils stimulation of lipase enzymes in the gut which in turn facilitate the absorption of the carotenoids. In a preferred embodiment the fish oil comprises from about 70 wt % to about 90 wt % of the final blend composition. In another embodiment the fish oil can comprise from about 75 wt % to about 85 wt % of the final blend composition. When other nutritional components, particularly readily oxidizable components such as Vitamin A and vitamin E, are included in the final blend composition the fish oil also acts to stabilize and protect those components.
  • Once the final blend composition is complete, it is milled to assure small particle size of the complexed carotenoids. After milling the final blend can be directly encapsulated or stored in an air tight container under nitrogen. In a preferred embodiment of the present invention, the final blend is encapsulated into soft gelatin capsules. The compositions produced by the methods of the present invention are intended to be delivered to subjects so as to provide therapeutically effective amounts of carotenoids to the subject. Such amounts are readily determinable by one of ordinary skill in the art based on the concentrations of the carotenoids in the invention compositions.
  • In addition to the method, the present invention provides a composition and related method for providing enhanced bioavailability of carotenoids. Specifically, it has been found that when fish oil is included in the final blend composition as described above, the bioavailability of the carotenoids is unexpectedly increased above the bioavailability of the carotenoid/cyclodextrin complex alone and a fish oil/carotenoid mixture alone. As discussed above, it is believed that the unexpected increase of bioavailability is due, at least in part, to fish oils stimulation of lipase enzymes in the gut which in turn facilitate the absorption of the carotenoids.
  • The example provided below is illustrative of only one embodiment of making a carotenoid containing nutritional supplement of the present invention. While the processing conditions and ingredients may be preferred, no limitation thereto is to be inferred.
    • EXAMPLE 1
  • A stable carotenoid containing nutritional supplement is preparing according to the following steps.
  • 1. 5.640 kg of water is added to a blender and heated to 50° C. Temperature is confirmed before adding cyclodextrin.
    2. Blades of blender are removed from blender container and 4.070 kg of gamma-cyclodextrin (Cavamax V Wacker Biochem) is added and initially hand mixed, and then mechanically mixed for at least 30 minutes or until a cyclodextrin water slurry is formed. The slurry is caramel in color.
    3. The following carotenoids are added in the amounts shown in the following table:
  • Activity (%
    Carotenoid or IU/mg) kg
    Beta-Carotene (30% Fluid Suspension, B. 500.00 IU 0.273
    trispora)
    Beta-Carotene (Caromin 13%b 6.5%a; oil; 13.000% 0.689
    palm fruit)
    Astaxanthin, 5% OIL BioAstin (H. pluvialis)  5.000% 0.224
    Lycopene (20% Oil Susp.) LycoVit synthetic 20.000% 0.560
    Zeaxanthin (20% Fluid Susp.) 20.000% 0.056

    4. A vacuum is pulled over the mixing container and the composition is mixed on a low speed (9.6 rpm) for at least 1 hour at a temperature of 4-45° C. and carotenoid cyclodextrin complexes form. (Note: as the carotenoids react with the cyclodextrins the compound will precipitate and the mixture increases in viscosity which is an indication of a successful complexation reaction.)
    5. After at least one hour of mixing the mixer container containing the carotenoid-cyclodextrin complex are immediately removed and added to a main mixer containing a fish oil beeswax blend. The fish oil and beeswax blend is made by adding approximately 6.1 kg of beeswax and 73.2 kg of fish oil to the mixer and blending at 60° C. to until thoroughly mixed. The composition is then cooled to 40-45° C. before the carotenoid-cyclodextrin complex is added. A small amount of the fish oil/beeswax composition is used to rinse the carotenoid-cyclodextrin complex into the mixer container.
    6. Additional components can then be added to the mixer. The components and the amounts added are shown in the table below:
  • Activity (%
    Ingredient or IU/mg) kg
    Vitamin A (Palmitate, liquid 1,700 USP) 1600.0 IU 0.043
    Vitamin E (d-alpha-tocopherol 1490 oil)  1.430 IU 2.988
    Vitamin E, 60% g-t, 6.8% a-t, 20% d-t, 1.4% b-t, 60.000% 2.671
    MTS-90G Oil
    Vitamin E Tocotrienols (50% E&TT, Fr. Palm 38.000% 0.028
    Oil)
    Lutein (Ester, Xangold, oil susp, 15%) 15.000% 0.298
    Krill Oil 100.000%  2.035
    D-Limonene (liquid) 95.000% 1.071

    7. After the addition of the carotenoid/cyclodextrin complex and the other ingredients the mixture a vacuum is pulled over the mixer container and the mixture is mixed using high shear for 20 minutes at 20-45° C. The mixture is then allowed to cool to 25-28° C. and is removed from the mixer and milled to reduce the particle size.
    8. After milling the mixture can be stored in a sealed container under nitrogen or encapsulated immediately. Encapsulation is done in a soft gelatin capsule. Each soft gelatin capsule contains about 1.2 grams of the milled final composition.
    • EXAMPLE 2
  • A study was performed to determine the effect of the composition of claim 1 on the Skin Carotenoid Scores (SCS) of subjects. The study involved the use of Raman Spectroscopy to assess changes in Skin Carotenoid Scores over an eighteen week period of supplementation with the Composition of example 1 in comparison to a placebo.
  • Fifty two subjects between 18 and 65 years of age qualified for the study participation. Food frequency and health history questionnaires were used to screen inclusion criteria, and the Pharmanex BioPhotonic Scanner was used to assess skin carotenoid levels. Individuals taking antioxidant supplements, having high exposure to sunlight or tanning bed use, pregnant women, or individuals using sunless tanning products were excluded from the study. All subjects were healthy non-smokers consuming typical U.S. diets containing less than five daily servings of fruit and vegetables, and had baseline Raman Intensity Scores between 13,000 and 35,000 Raman
  • Intensity Counts. Participants were instructed to maintain their dietary and exercise habits throughout the duration of the study. Subjects (n=52) meeting study criteria were randomly assigned in a double blind manner to one of two groups, composition of example 1 (n=27) or placebo (n=25).
  • Subjects were given their respective capsules, placebo or composition of Example 1, and were instructed to take them twice daily (once with their morning meal and once with their evening meal). The dosage amount for the Example 1 participants included two softgel capsules twice daily. The placebo taken twice daily included also included two softgel capsules which contained omega-3 fatty acids but no carotenoids.
  • The results of the study showed an unexpectedly high increase of the Skin Carotenoid Scores. Specifically, the average increase for those taking the composition of Example 1 was 17,757 Raman Intensity counts after the eighteen weeks compared to approximately no change for the placebo participants. Throughout the 18 week study the Carotenoid Scanner Score continually increased with no apparent plateau effect.
  • While the forgoing example is illustrative of the principles of the present invention in one or more particular applications, it will be apparent to those of ordinary skill in the art that numerous modifications in form, usage and details of implementation can be made without the exercise of inventive faculty, and without departing from the principles and concepts of the invention. Accordingly, it is not intended that the invention be limited, except as by the claims set forth below.

Claims (14)

What is claimed is:
1. A carotenoid containing composition comprising:
at least one carotenoid;
a cyclodextrin; and
fish oil, wherein the fish oil comprises from 70 wt % to 90 wt % of the composition.
2. The composition of claim 1, wherein the cyclodextrin is γ-cyclodextrin.
3. The composition of claim 1, wherein the cyclodextrin is a combination of γ-cyclodextrin and β-cyclodextrin.
4. The composition of claim 1, wherein the at least one carotenoid is selected from the group consisting of astaxanthin, lycopene, zeaxanthin, beta-carotene, lutein, and mixtures thereof.
5. The composition of claim 1, further including additional nutritional components selected from the group consisting of beeswax, vitamin A, vitamin E, D-limonene, and mixtures thereof.
6. The composition of claim 1, wherein the fish oil is present comprises from 75 wt % to 85 wt % of the composition.
7. The composition of claim 1, wherein the at least one carotenoid is complexed with the cyclodextrin.
8. A method of enhancing bioavailability of a carotenoid, comprising:
co-administering to a subject in need thereof an a carotenoid and a combination of a cyclodextrin and fish oil.
9. The method of claim 8, wherein the carotenoid and the cyclodextrin are complexed together.
10. The method of claim 8, wherein the cyclodextrin is γ-cyclodextrin.
11. The method of claim 8, wherein the cyclodextrin is a combination of γ-cyclodextrin and β-cyclodextrin.
12. The method of claim 8, wherein the carotenoid is selected from the group consisting of astaxanthin, lycopene, zeaxanthin, beta-carotene, lutein, and mixtures thereof.
13. The method of claim 8, wherein additional nutritional components are co-administered, said additional nutritional components selected from the group consisting of beeswax, vitamin A, vitamin E, D-limonene, and mixtures thereof.
14. The method of claim 8, wherein the carotenoid, cyclodextrin, and the fish oil are administered in a single dosage form.
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