Stabilized aqueous compositions containing calcium, vitamin d3, and vitamin k2

Abstract

The disclosure is directed to stabilized aqueous compositions containing calcium (in the form of calcium lactate and calcium gluconate), vitamin D3, and vitamin K2. In addition to calcium, vitamin D3, and vitamin K2, the compositions contain an emulsifier (such as e.g., a polysorbate), an antioxidant (such as e.g., ascorbic acid) and one or more of a sweetener (such as e.g., sucralose and sorbitol), a preservative, a flavoring agent, a pH adjuster, or a combination thereof. The disclosure also includes using the compositions to support bone health.

Description

070589.12881 / 0203W01OPL24002-WO-PCTSTABILIZED AQUEOUS COMPOSITIONS CONTAINING CALCIUM, VITAMIN D3, AND VITAMIN K2FIELD OF THE INVENTION

[0001] This disclosure relates to stabilized aqueous compositions containing calcium (in the form of calcium lactate and calcium gluconate), vitamin D3, and vitamin K2.BACKGROUND OF THE INVENTION

[0002] The combination of calcium, vitamin D3, and vitamin K2 is known to support bone health, and other aspects of health. In the combination, each has a different function.

[0003] There are various commercially available supplements containing the combination of calcium, vitamin D3, and vitamin K2 (as the only active ingredients), typically in tablet form. In certain situations, it may be more desirable to consume calcium, vitamin D3, and vitamin K2 in a liquid supplement. Liquid supplements are known to have faster absorption, provide a more rapid onset of action, and are more convenient to consume.

[0004] However, formulating a liquid supplement containing calcium, vitamin D3, and vitamin K2 has proven to be challenging. Liquid supplements, with very high dose of calcium salt, would need to be clear or almost clear in appearance to be appealing.However, depending on the form of Calcium used, there may be precipitation, which is undesirable. Moreover, adding the oil-soluble vitamins D3 and K2 to aqueous solution is very challenging. They are not soluble and very sensitive in water, leading to phase separation and rapid decrease in vitamin content during storage.

[0005] What is needed is a liquid supplement containing calcium, vitamin D3, and vitamin K2 (as the only active ingredients) that overcomes these challenges; a supplement that does not result in calcium precipitation and does not result in phase separation or decrease in vitamin content.SUMMARY OF THE INVENTION

[0006] This disclosure is directed to stabilized aqueous compositions containing calcium (in the form of calcium lactate and calcium gluconate), vitamin D3, and vitamin K2, method of making these compositions as well as methods of using the compositions.

[0007] One embodiment is a stabilized aqueous composition containing: an active ingredient containing calcium provided as a mixture of calcium lactate and calcium gluconate, vitamin D3, and vitamin K2; an emulsifier; and an antioxidant. In certain embodiments, the active ingredient component of the composition only contains calcium 14873-6574-5118.2070589.12881 / 0203W01OPL24002-WO-PCTprovided as a mixture of calcium lactate and calcium gluconate, vitamin D3, and vitamin K2.

[0008] Another embodiment is a stabilized aqueous composition containing: calcium provided as a mixture of calcium lactate and calcium gluconate; vitamin D3; vitamin K2; an emulsifier; and an antioxidant.

[0009] In certain embodiments, the emulsifier is a polysorbate. In some embodiments, the polysorbate includes polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, or a combination thereof. In other embodiments, the polysorbate is polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, or a combination thereof. In further embodiments, the polysorbate comprises polysorbate 20 and polysorbate 80.

[0010] A variety of different antioxidants can be used in the stabilized aqueous composition. In one embodiment, antioxidant includes disodium ethylenediaminetetraacetic acid (EDTA), butylated hydroxytoluene (BHT), disodium EDTA, tocopherol acetate, tocopheryl polyethylene glycol succinate (TPGS) (with linker of 1000 and 2000), ascorbic acid, sodium metabisulphite, or a combination thereof. In other embodiments, the antioxidant includes or is ascorbic acid. In certain embodiments, the stabilized aqueous composition has an acidic pH, such as e.g., a pH of about 4.

[0011] The stabilized aqueous composition can also include other components. In some embodiments, the stabilized aqueous composition further includes a sweetener, a preservative, a flavoring agent, a pH adjuster, or a combination thereof.

[0012] In certain embodiments, the sweetener includes sucralose, sorbitol, aspartame, acesulfame potassium, saccharin, steviol glycoside, neotame, advantame, saccharin sodium, cyclamate sodium, ammonium glycyrrhizate, or a combination thereof. In some embodiments, the sweetener comprises sucralose and sorbitol.

[0013] In other embodiments, the preservative includes a sorbate, a benzoate, a paraben, a benzyl alcohol, a cresol, a phenol, a quaternary ammonium, or a combination thereof. In one embodiment, the preservative is potassium sorbate.

[0014] In some embodiments, the composition contains: an active ingredient having from about 10 to about 20% (w / v) of the calcium provided as a mixture of calcium lactate and calcium gluconate, from about 0.0001 to about 0.004 % (w / v) of the vitamin D3, and from about 0.01 to about 0.2 % (w / v) of the vitamin K2; from about 0.5 to about 2% (w / v) of the emulsifier; and from about 0.1 to about 0.8% (w / v) of the antioxidant. In other embodiments, the stabilized aqueous composition is formulated to deliver 200 mg calcium, 2.5 mcg of vitamin D3, and 20 mcg of vitamin K2 per 10 ml liquid.24873-6574-5118.2070589.12881 / 0203W01OPL24002-WO-PCT

[0015] Another embodiment of the disclosure is directed to a stabilized aqueous composition containing: calcium provided as a mixture of calcium lactate and calcium gluconate; vitamin D3; vitamin K2; a polysorbate selected from polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, or a combination thereof; and an antioxidant selected from ascorbic acid, sodium metabisulphite, tocopherol, or a combination thereof, whereby the vitamin D3 and the vitamin K2 are encapsulated in micelles.

[0016] In certain embodiments, the stabilized aqueous composition contains: from about 10 to about 20% (w / v) of the calcium provided as a mixture of calcium lactate and calcium gluconate; from about 0.0001 to about 0.004 % (w / v) of the vitamin D3; from about 0.01 to about 0.2 % (w / v) of the vitamin K2; from about 0.5 to about 2% (w / v) of the polysorbate selected from polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, or a combination thereof; and from about 0.1 to about 0.8% (w / v) of the antioxidant selected from ascorbic acid, sodium metabisulphite, tocopherol, or a combination thereof.

[0017] In some embodiments of the stabilized aqueous composition, the polysorbate is polysorbate 20 and polysorbate 80. In other embodiments, the antioxidant is ascorbic acid.

[0018] In some embodiments, the stabilized aqueous composition also contains: a sweetener selected from sucralose, sorbitol, aspartame, saccharin, steviol glycoside, neotame, advantame, or a combination thereof; a preservative selected from potassium sorbate, benzyl alcohol, sodium benzoate, or a combination thereof; an antioxidant selected from disodium ethylenediaminetetraacetic acid (EDTA), butylated hydroxytoluene (BHT), disodium EDTA, tocopherol acetate, tocopheryl polyethylene glycol succinate (TPGS) (with linker of 1000 and 2000), ascorbic acid, sodium metabisulphite, or a combination; a pH adjuster; and / or a flavoring agent.

[0019] In some embodiments, the composition contains: from about 10 to about 34% (w / v) of the sweetener selected from sucralose, sorbitol, aspartame, saccharin, steviol glycoside, neotame, advantame, or a combination thereof; from about 0.01 to about 0.06 % (w / v) of the preservative selected from potassium sorbate, benzyl alcohol, sodium benzoate, or a combination thereof; or from about 0.1 to about 0.8 % (w / v) of the antioxidant selected from disodium ethylenediaminetetraacetic acid (EDTA), butylated hydroxytoluene (BHT), disodium EDTA, tocopherol acetate, tocopheryl polyethylene glycol succinate (TPGS) (with linker of 1000 and 2000), ascorbic acid, sodium metabisulphite, or a combination thereof.

[0020] In other embodiments, the stabilized aqueous composition contains: from about 10 to about 34% (w / v) of the sweetener selected from sucralose, sorbitol, aspartame, saccharin,34873-6574-5118.2070589.12881 / 0203W01OPL24002-WO-PCTsteviol glycoside, neotame, advantame, or a combination thereof; from about 0.01 to about 0.06 % (w / v) of the preservative selected from potassium sorbate, benzyl alcohol, sodium benzoate, or a combination thereof; and from about 0.1 to about 0.8 % (w / v) of the antioxidant selected from disodium ethylenediaminetetraacetic acid (EDTA), butylated hydroxytoluene (BHT), disodium EDTA, tocopherol acetate, tocopheryl polyethylene glycol succinate (TPGS) (with linker of 1000 and 2000), ascorbic acid, sodium metabisulphite, or a combination thereof.

[0021] In additional embodiments, the composition contains sucralose, sorbitol, potassium sorbate, ascorbic acid, a pH adjuster, and a flavoring agent. In certain embodiments, the pH adjuster maintains the pH at about 4.0. In other embodiments, the pH adjuster maintains the pH in the acidic range (i.e. a pH of 7 or less).

[0022] In some embodiments, the pH adjuster is hypophosphorous acid. In other embodiments, the pH adjuster is hypophosphorous acid and / or lactic acid, and / or hydrochloric acid.

[0023] In certain embodiments, the stabilized aqueous compositions are stable for at least 6 months when stored at 40 °C / 75% relative humidity and / or 30 °C / 75% relative humidity.

[0024] The disclosure also includes a bottle containing the stabilized aqueous compositions of the disclosure. Furthermore, the disclosure includes an ampoule (e.g., a glass ampoule) containing the stabilized compositions of the disclosure. The disclosure further includes methods of generating the stabilized aqueous compositions of the disclosure.

[0025] In addition, the disclosure includes use of the stabilized aqueous compositions to support bone health. In one embodiment, the compositions are used to support bone health.

[0026] Other features and advantages of the invention will be apparent from the detailed description and examples that follow.DETAILED DESCRIPTION

[0027] This disclosure provides stabilized aqueous compositions containing calcium (in the form of calcium lactate and calcium gluconate), vitamin D3, and vitamin K2, method of making these compositions as well as methods of using the compositions.

[0028] The compositions of disclosure are formulated for pleasant intake for all ages with no oily sticky aftertaste. Without being bound by theory, the calcium organic salt in liquids allow for better absorption.44873-6574-5118.2070589.12881 / 0203W01OPL24002-WO-PCT

[0029] The compositions of the disclosure also use microglobule technology. The microglobule technologies enables the formulation of oily vitamins in aqueous solution. The resultant liquid formulations are easier to consume (drink) and absorb faster.

[0030] In addition, combining the three nutrients (calcium, vitamin D3, and vitamin K2) into a single product offers absorption of calcium with greater convenience, and facilitates consumers adherence to taking supplements. Furthermore, it contributes to cost savings in purchasing one product rather than several. Lastly, this composition reduces carbon dioxide emissions during manufacturing and transportation, benefiting the environment.

[0031] The high concentration of water-soluble organic calcium in the aqueous composition of the disclosure is maintained and stabilized due to the combination of calcium lactate and calcium gluconate salts, which helps to enhance the solubility, especially when compared to the use of single salts. Sensitive vitamins (vitamin D3 and K2) are dispersed in water via an emulsification system (e.g., Tween 20 & 80) using microglobule technology, which forms small micelles particles to encapsulate the vitamins, preventing direct contact with water while ensuring uniform dispersion within the solution. As evident by Example 1, the composition was very stable after 6 months of storage in under accelerated and long term storage conditions (accelerated: 40 °C / 75% relative humidity; long term: 30 °C / 75% relative humidity).

[0032] The general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention, as defined in the appended claims. Other aspects of the present invention will be apparent to those skilled in the art in view of the detailed description of the invention as provided herein.

[0033] For clarity of disclosure, and not by way of limitation, the detailed description of the invention is divided into subsections that describe or illustrate certain features, embodiments, or applications of the present invention.Definitions

[0034] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present invention, representative illustrative methods, and materials are now described.

[0035] All publications and patents cited in this specification are herein incorporated by reference as if each individual publication or patent were specifically and individually54873-6574-5118.2070589.12881 / 0203W01OPL24002-WO-PCTindicated to be incorporated by reference and are incorporated herein by reference to disclose and describe the methods and / or materials in connection with which the publications are cited. The citation of any publication is for its disclosure prior to the filing date and should not be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. Further, the dates of publication provided may be different from the actual publication dates, which may need to be independently confirmed.

[0036] It is noted that, as used herein and in the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. It is further noted that the claims may be drafted to exclude any optional element. As such, this statement is intended to serve as antecedent basis for use of such exclusive terminology as “solely,” “only” and the like in connection with the recitation of claim elements, or use of a “negative” limitation.

[0037] Each of the individual embodiments described and illustrated herein has discrete components and features which may be readily separated from or combined with the features of any of the other several embodiments without departing from the scope or spirit of the present invention. Any recited method can be carried out in the order of events recited or in any other order which is logically possible.

[0038] As used herein, the term “about” when referring to a measurable value such as an amount, a temporal duration, and the like, is meant to encompass variations of ± 20% or ± 10%, more preferably ± 5%, even more preferably ± 1%, and still more preferably ± 0.1% from the specified value, as such variations are appropriate to perform the disclosed methods.

[0039] It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting.

[0040] As used herein, the terms “comprising,” “including,” “containing” and “characterized by” are exchangeable, inclusive, open-ended and do not exclude additional, unrecited elements or method steps. Any recitation herein of the term “comprising,” particularly in a description of components of a composition or in a description of elements of a device, is understood to encompass those compositions and methods consisting essentially of and consisting of the recited components or elements.

[0041] Throughout this specification, unless the context requires otherwise, the word “comprise” or variations such as “comprises” or “comprising,” will be understood to imply64873-6574-5118.2070589.12881 / 0203W01OPL24002-WO-PCTthe inclusion of a stated integer or group of integers but not the exclusion of any other integer or group of integers.

[0042] As used herein, the term “consisting of’ excludes any element, step, or ingredient not specified in the claim element.

[0043] As used herein, the term “Vitamin K2” includes any menaquinone. Menaquinones have the chemical structure shown below wherein n ranges from 4 to 13.In certain embodiments, vitamin K2 is menaquinone-4 (MK-4), which has the chemical structure shown below. In other embodiments, the vitamin K2 is menaquinone-7 (MK-7), which has the structure shown below:o MK-7

[0044] Before certain embodiments are described in greater detail, it is to be understood that this invention is not limited to certain embodiments described, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing certain embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims.

[0045] Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range, is encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges and are also encompassed within the invention, subject to any specifically excluded limit in the stated74873-6574-5118.2070589.12881 / 0203W01OPL24002-WO-PCTrange. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the invention.

[0046] It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting.

[0047] A “subject” or “consumer,” as used therein, may be a human or non-human mammal. Non-human mammals include, for example, livestock and pets, such as ovine, bovine, porcine, canine, feline and murine mammals. Preferably, the subject is a human.

[0048] Ranges: throughout this disclosure, various aspects of the invention can be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 2.7, 3, 4, 5, 5.3, and 6. This applies regardless of the breadth of the range.

[0049] As used herein, and as well-understood in the art, “treatment” is an approach for obtaining beneficial or desired results, including clinical results. For purposes of this invention, beneficial or desired clinical results include, but are not limited to, alleviation or amelioration of one or more symptoms, diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, preventing spread of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable. “Treatment” can also mean prolonging survival as compared to expected survival if not receiving treatment.Stabilized Aqueous Compositions

[0050] This disclosure relates to stabilized aqueous compositions containing calcium (in the form of calcium lactate and calcium gluconate), vitamin D3 (also known as cholecalciferol), and vitamin K2. In some embodiments, the stabilized aqueous compositions contain calcium lactate, calcium gluconate, vitamin D3, vitamin K2 and one or more an emulsifier, an antioxidant, a preservative, a pH adjuster, a sweetener, a flavoring agent, and a combination thereof.

[0051] In other embodiments, the stabilized aqueous compositions contain: calcium (in84873-6574-5118.2070589.12881 / 0203W01OPL24002-WO-PCTthe form of calcium lactate and calcium gluconate), vitamin D3, and vitamin K2 as the active ingredient; and one or more an emulsifier, an antioxidant, a preservative, a pH adjuster, a sweetener, a flavoring agent, and a combination thereof. In certain embodiments, the compositions contain calcium (in the form of calcium lactate and calcium gluconate), vitamin D3, and vitamin K2 as the active ingredient.

[0052] In yet another embodiment, the stabilized aqueous compositions contain calcium lactate, calcium gluconate, vitamin D3, vitamin K2 and at least an emulsifier and an antioxidant.

[0053] In yet another embodiment, the stabilized aqueous compositions contain calcium lactate, calcium gluconate, vitamin D3, vitamin K2 and at least an emulsifier, an antioxidant, a preservative, and a pH adjuster.

[0054] In certain embodiment, the stabilized aqueous compositions contain calcium (in the form of calcium lactate and calcium gluconate), vitamin D3, and vitamin K2 as the only active ingredients.

[0055] The vitamin D3 and vitamin K2 in the stabilized aqueous compositions are encapsulated in micelles. In certain embodiments, the vitamin D3 and vitamin K2 are dispersed in water via an emulsification system to encapsulate the vitamin D3 and vitamin K2 in micelles. In certain embodiments, the vitamin D3 and vitamin K2 are dispersed in water using a polyethylene glycol sorbitan monolaurate such as Tween 20 and Tween 80. In further embodiments, the vitamin D3 and vitamin K2 are dispersed in water using an emulsifier described below. In one embodiment, the vitamin D3 and vitamin K2 are dispersed in water using a polysorbate such as e.g., polysorbate 20 and polysorbate 80.

[0056] In one embodiment, the stabilized aqueous compositions are formulated to contain up to 250 mg, alternatively about 200 mg, alternatively from about 180 to about 200 mg, alternatively from about 190 to about 210 mg of calcium, about 100 IU (2.5 mcg), alternatively from about 1.5 to about 3.5 mcg, alternatively from about 2.0 to about 3.0 mcg of vitamin D3, and about 20 mcg, alternatively from about 10 to about 30 mcg, alternatively from about 15 to about 25 mcg of vitamin K2 per 10 ml liquid.

[0057] In one embodiment, the stabilized aqueous compositions contain: an active ingredient that has calcium provided as a mixture of calcium lactate and calcium gluconate, Vitamin D3, and Vitamin K2; an emulsifier; and an antioxidant, wherein the K2 and D3 are encapsulated in micelles. In another embodiment, the stabilized aqueous composition contain: an active ingredient of calcium provided as a mixture of calcium lactate and calcium gluconate, Vitamin D3 encapsulated in micelles, and Vitamin K2 encapsulated in 94873-6574-5118.2070589.12881 / 0203W01OPL24002-WO-PCTmicelles; an emulsifier; and an antioxidant. These compositions can also contain a sweetener, a preservative, a flavoring agent, a pH adjuster, or a combination thereof.

[0058] The stabilized aqueous compositions of the disclosure are stable for at least 6 months when stored at 40 °C / 75% relative humidity and / or 30 °C / 75% relative humidity. In certain embodiments, the stabilized aqueous compositions are formulated to contain about 200 mg, alternatively from about 180 to about 200 mg, alternatively from about 190 to about 210 mg of calcium, about 100 IU (2.5 mcg), alternatively from about 1.5 to about 3.5 mcg, alternatively from about 2.0 to about 3.0 mcf of vitamin D3, and about 20 mcg, alternatively from about 10 to about 30 mcg, alternatively from about 15 to about 25 mcg of vitamin K2 after storage for at least 6 months when stored at 40 °C / 75% relative humidity and / or 30 °C / 75% relative humidity.Emulsifier

[0059] A number of emulsifiers may be utilized and include, without limitation, a poloxamer, polysorbate, or polyoxyl hydrogenated castor oil. The term “poloxamer” as used herein refers to nonionic triblock copolymers composed of consisting of a central hydrophobic block of polypropylene glycol flanked by two hydrophilic blocks of polyethylene glycol (PEG). Poloxamers are available in the art by the trade names Pluronic, Kolliphor, Lutrol, and Synperonic. In some embodiments, the emulsifier is a poloxamer such as poloxamer 188, poloxamer 237, poloxamer 338, poloxamer 407, or a combination thereof. The term “polysorbate” as used herein refers to oily liquids derived from ethoxylated sorbitan esterified with fatty acids. Polysorbates are available in the art as Kolliphor, Scattics, Alkest, Canarcel, and Tween products. In other embodiments, the emulsifier is a polysorbate such as polysorbate 20 (polyoxyethylene (20) sorbitan monolaurate), polysorbate 40 (polyoxyethylene (20) sorbitan monopalmitate), polysorbate 60 (polyoxyethylene (20) sorbitan monostearate), polysorbate 80 (polyoxyethylene (20) sorbitan monooleate), or SEPITRAP™ 80 (polysorbate 80 and magnesium aluminometasilicate). In further embodiments, the emulsifier is polysorbate 80 or SEPITRAP™ 80, or such as polysorbate 80, or such as SEPITRAP™ 80. In yet other embodiments, the emulsifier is a polyoxyl hydrogenated castor oil such as SEPITRAP™ 4000 (polyoxyl 40 hydrogenated castor oil and magnesium aluminosilicate). One or more than one emulsifier may be used. In some embodiments, one emulsifier is used. In other embodiments, two emulsifiers are used.

[0060] In one embodiment, emulsifier is a polysorbate. In another embodiment, the emulsifier is polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, or a104873-6574-5118.2070589.12881 / 0203W01OPL24002-WO-PCTcombination thereof. In yet another embodiment, the emulsifier is a combination of polysorbate 20 and polysorbate 80. In further embodiments, the stabilized aqueous compositions only contain polysorbate 20 and polysorbate 80 as emulsifiers.Antioxidant

[0061] Suitable antioxidants to be used in the stabilized aqueous compositions can be selected from, but are not limited to, the group comprising: disodium ethylenediaminetetraacetic acid (EDTA), butylated hydroxytoluene (BHT), disodium EDTA, tocopherol acetate, tocopheryl polyethylene glycol succinate (TPGS) (with linker of 1000 and 2000), ascorbic acid, sodium metabisulphite, and combinations thereof.

[0062] In one embodiment, the antioxidant is ascorbic acid, sodium metabisulphite, tocopherol, or a combination thereof. In another embodiment, the antioxidant is ascorbic acid.Preservative

[0063] A variety of different perseverative may be used in the stabilized aqueous compositions. Some preservatives suitable to be used in the stabilized aqueous compositions can be selected from, but are not limited to, the group comprising: a sorbate (e.g., potassium sorbate), a benzoate, a paraben, a benzyl alcohol, a cresol, a phenol, a quaternary ammonium, or a combination thereof. In some embodiments, the preservative can be potassium sorbate, edetate disodium, domiphen bromide, cetylpyridinium chloride, sodium benzoate, or a combination thereof.

[0064] In one embodiment, the preservative is potassium sorbate, benzyl alcohol, sodium benzoate, or a combination thereof. In yet another embodiment, the preservative is potassium sorbate. In yet another embodiment, potassium sorbate is the only preservative in the stabilized aqueous compositions.pH adjuster

[0065] A variety of different pH adjusters can be used in the stabilized aqueous compositions. In particular, the pH adjuster should be sufficient to maintain the pH of stabilized aqueous composition at a pH of about 4, alternatively from about 3.8 to about 4.2, alternatively from about pH of 3.5 to 4.5, alternatively from about 3 to about 7. In one embodiment, the pH adjuster is hypophosporous acid. In another embodiment, the pH adjuster is hypophosporous acid, lactic acid, and / or hydrochloric acid.Sweetener

[0066] The stabilized aqueous compositions can also contain a sweetener. Examples of sweeteners include sucralose, sorbitol, aspartame, acesulfame potassium, saccharin, steviol 114873-6574-5118.2070589.12881 / 0203W01OPL24002-WO-PCTglycoside, neotame, advantame, saccharin sodium, cyclamate sodium, maltitol, lactose anhydrous, sucrose, ammonium glycyrrhizate, or a combination thereof. In some aspects, the sweetener is sucralose. In other aspects, the sweetener is aspartame. In further aspects, the sweetener is acesulfame potassium. In yet other aspects, the sweetener is sorbitol. In still further aspects, the sweetener is a steviol glycoside. In other aspects, the sweetener is neotame. In further aspects, the sweetener is advantame. In yet other aspects, the sweetener is saccharin sodium. In still further aspects, the sweetener is cyclamate sodium. In other aspects, the sweetener is ammonium glycyrrhizate. One or more sweeteners may be used.

[0067] In one embodiment, the sweetener is a combination of sucralose and sorbitol.Flavoring Agent

[0068] In certain embodiments, the stabilized aqueous compositions can also contain a flavoring agent, such as e.g., a flavoring agent that has been approved for use in humans by the U. S. FDA or an equivalent regional or local agency (e.g., European Medicines Agency (EMA), European Food Safety Authority (EFSA) and the Medicines and Healthcare products Regulatory Agency (MHRA) in the UK). Examples of flavoring agents include agents that have apple, orange, grape, pineapple, lemon, or mint flavor. In one embodiment, the flavoring agent is orange.Examples of Compositions and Other Features

[0069] In certain embodiments, the stabilized aqueous compositions contain from about 10% to about 20% (w / v), alternatively from about 12 to about 17% (w / v), alternatively from about 14 to about 16% (w / v) of a mixture of calcium lactate and calcium gluconate.

[0070] In other embodiments, the stabilized aqueous compositions contain from about 0.0001% to about 0.004% (w / v), alternatively from about 0.0005 to about 0.003% (w / v), alternatively from about 0.0005 to about 0.0025% (w / v) of vitamin D3.

[0071] In further embodiments, the stabilized aqueous compositions contain from about 0.01 to about 0.2% (w / v), alternatively from about 0.01 to about 0.15% (w / v), alternatively from about 0.02 to about 0.1% (w / v) of vitamin K2.

[0072] In other embodiments, the stabilized aqueous compositions contain from about 0.5 to about 2% (w / v), alternatively from about 0.7 to about 1.8% (w / v), alternatively from about 1 to about 1.7% (w / v) of any of the emulsifiers mentioned above (e.g., a polysorbate).

[0073] In further embodiments, the stabilized aqueous compositions contain from about 0.01 to about 0.6 % (w / v), alternatively from about 0.03 to about 0.4 % (w / v), alternatively from about 0.05 to about 0.3% (w / v) of any preservatives mentioned above.124873-6574-5118.2070589.12881 / 0203W01OPL24002-WO-PCT

[0074] In additional embodiments, the stabilized aqueous compositions contain from about 0.1 to about 0.8% (w / v), alternatively from about 0.2 to about 0.7% (w / v), alternatively from about 0.3 to about 0.6% (w / v) of any of the antioxidants mentioned above.

[0075] In further embodiment, the stabilized aqueous compositions contain from about 10% to about 34% (w / v), alternatively from about 15% to about 35% (w / v), alternatively from about 20% to about 30% (w / v) of sweeteners.

[0076] In some embodiments, the stabilized aqueous compositions contain sucralose and sorbitol as a sweetener. In these embodiments, the stabilized aqueous compositions contain: from about 0.01 to 0.1% (w / v), alternatively from about 0.01 to 0.09% (w / v), alternatively from about 0.02 to 0.6% (w / v) of sucralose; and from about 10% to about 34% (w / v), alternatively from about 15% to about 35% (w / v), alternatively from about 20% to about 30% (w / v) of sorbitol.

[0077] In other embodiments, the stabilized aqueous compositions contain polysorbate 20 and polysorbate 80. In these embodiments, the stabilized aqueous compositions contain: from about 0.4 to about 1% (w / v), alternatively from about 0.5 to about 0.9% (w / v), alternatively from about 0.6 to about 0.85% (w / v) of polysorbate 80; and from about 0.1 to 1% (w / v), alternatively from about 0.2 to about 0.9% (w / v), alternatively from about 0.4 to about 0.8% (w / v) of polysorbate 40.

[0078] Further embodiments of the stabilized aqueous compositions of the disclosure are shown in the Tables that follow below. Each of the components for each of the embodiments may be combined with components from other embodiments. For example, the amount of vitamin K2 in Embodiment 1 may be combined with the total amount of sweetener in Embodiment 2.Component Embodiment 1 Embodiment 2 Embodiment 3 Mixture of calcium from about 10% to from about 12 to from about 14 to lactate & calcium about 20% (w / v) about 17% (w / v) about 16% (w / v) gluconateVitamin D3 from about 0.0001% from about 0.0005 from about 0.0005 to about 0.004% to about 0.003% to about 0.0025% (w / v) (w / v) (w / v)Vitamin K2 from about 0.01 to from about 0.01 to from about 0.02 to about 0.2% (w / v) about 0.15% (w / v) about 0.1% (w / v) Total Sweetener from about 10% to from about 15% to from about 20% toabout 34% (w / v) about 35% (w / v) about 30% (w / v)134873-6574-5118.2070589.12881 / 0203W01OPL24002-WO-PCTComponent Embodiment 1 Embodiment 2 Embodiment 3 Total emulsifier from about 0.5 to from about 0.7 to from about 1 to about 2% (w / v) about 1.8% (w / v) about 1.7% (w / v) Preservative from about 0.01 to from about 0.03 to from about 0.05 to about 0.6 % (w / v) about 0.4 % (w / v) about 0.3% (w / v) Antioxidant from about 0.1 to from about 0.2 to from about 0.3 toabout 0.8% (w / v) about 0.7% (w / v) about 0.6% (w / v)Component Embodiment 4 Embodiment 5 Embodiment 6 Mixture of calcium from about 10% to from about 12 to from about 14 to lactate & calcium about 20% (w / v) about 17% (w / v) about 16% (w / v) gluconateVitamin D3 from about 0.0001% from about 0.0005 from about 0.0005 to about 0.004% to about 0.003% to about 0.0025% (w / v) (w / v) (w / v) Vitamin K2 from about 0.01 to from about 0.01 to from about 0.02 to about 0.2% (w / v) about 0.15% (w / v) about 0.1% (w / v) Total emulsifier from about 0.5 to from about 0.7 to from about 1 to (e.g, polysorbate) about 2% (w / v) about 1.8% (w / v) about 1.7% (w / v) Antioxidant (e.g., from about 0.1 to from about 0.2 to from about 0.3 toascorbic acid) about 0.8% (w / v) about 0.7% (w / v) about 0.6% (w / v)Component Embodiment 7 Embodiment 8 Embodiment 9 Mixture of calcium from about 10% to from about 12 to from about 14 to lactate & calcium about 20% (w / v) about 17% (w / v) about 16% (w / v) gluconateVitamin D3 from about 0.0001% from about 0.0005 from about 0.0005 to about 0.004% to about 0.003% to about 0.0025% (w / v) (w / v) (w / v) Vitamin K2 from about 0.01 to from about 0.01 to from about 0.02 to about 0.2% (w / v) about 0.15% (w / v) about 0.1% (w / v) Total emulsifier from about 0.5 to from about 0.7 to from about 1 to (e.g., polysorbate) about 2% (w / v) about 1.8% (w / v) about 1.7% (w / v) Preservative from about 0.01 to from about 0.03 to from about 0.05 to about 0.6 % (w / v) about 0.4 % (w / v) about 0.3% (w / v) Antioxidant (e.g., from about 0.1 to from about 0.2 to from about 0.3 toascorbic acid) about 0.8% (w / v) about 0.7% (w / v) about 0.6% (w / v)144873-6574-5118.2070589.12881 / 0203W01OPL24002-WO-PCTComponent Embodiment 10 Embodiment 11 Embodiment 12 Mixture of calcium from about 10% to from about 12 to from about 14 to lactate & calcium about 20% (w / v) about 17% (w / v) about 16% (w / v) gluconateVitamin D3 from about 0.0001% from about 0.0005 from about 0.0005 to about 0.004% to about 0.003% to about 0.0025% (w / v) (w / v) (w / v) Vitamin K2 from about 0.01 to from about 0.01 to from about 0.02 to about 0.2% (w / v) about 0.15% (w / v) about 0.1% (w / v) Sucralose from about 0.01 to from about 0.01 to from about 0.02 to 0.1% (w / v) 0.09% (w / v) 0.6% (w / v) Sorbitol from about 10% to from about 15% to from about 20% to about 34% (w / v) about 35% (w / v) about 30% (w / v) Polysorbate 80 from about 0.4 to from about 0.5 to from about 0.6 to about 1% (w / v) about 0.9% (w / v) about 0.85% (w / v) Polysorbate 20 from about 0.1 to from about 0.2 to from about 0.4 to 1% (w / v) about 0.9% (w / v) about 0.8% (w / v) Flavor As desired As desired As desired Potassium sorbate from about 0.01 to from about 0.03 to from about 0.05 to about 0.6 % (w / v) about 0.4 % (w / v) about 0.3% (w / v) Ascorbic acid from about 0.1 to from about 0.2 to from about 0.3 toabout 0.8% (w / v) about 0.7% (w / v) about 0.6% (w / v)Component Embodiment 13 Embodiment 14 Embodiment 15 Mixture of calcium lactate from about 10% to from about 12 to from about 14 to & calcium gluconate about 20% (w / v) about 17% (w / v) about 16% (w / v) Vitamin D3 from about from about from about 0.0001% to about 0.0005 to about 0.0005 to about 0.004% (w / v) 0.003% (w / v) 0.0025% (w / v) Vitamin K2 from about 0.01 to from about 0.01 from about 0.02 about 0.2% (w / v) to about 0.15% to about 0.1% (w / v) (w / v) Total Sweetener from about 10% to from about 15% from about 20% about 34% (w / v) to about 35% to about 30% (w / v) (w / v) polysorbate selected from from about 0.5 to from about 0.7 to from about 1 to polysorbate 20, about 2% (w / v) about 1.8% (w / v) about 1.7% (w / v) polysorbate 40,polysorbate 60,polysorbate 80, or acombination thereofantioxidant selected from from about 0.1 to from about 0.2 to from about 0.3 toascorbic acid, sodium about 0.8% (w / v) about 0.7% (w / v) about 0.6% (w / v)154873-6574-5118.2070589.12881 / 0203W01OPL24002-WO-PCTComponent Embodiment 13 Embodiment 14 Embodiment 15 metabisulphite, tocopherol,or a combination thereofComponent Embodiment 16 Embodiment 17 Embodiment 18 Mixture of calcium lactate & from about 10% from about 12 to from about 14 to calcium gluconate to about 20% about 17% (w / v) about 16% (w / v)(w / v)Vitamin D3 from about from about from about 0.0001% to about 0.0005 to about 0.0005 to about 0.004% (w / v) 0.003% (w / v) 0.0025% (w / v) Vitamin K2 (e.g., MK-7) from about 0.01 from about 0.01 from about 0.02 to about 0.2% to about 0.15% to about 0.1% (w / v) (w / v) (w / v) sweetener selected from from about 10% from about 15% from about 20% sucralose, sorbitol, to about 34% to about 35% to about 30% aspartame, saccharin, steviol (w / v) (w / v) (w / v) glycoside, neotame,advantame, or a combinationthereofpolysorbate selected from from about 0.5 to from about 0.7 to from about 1 to polysorbate 20, polysorbate about 2% (w / v) about 1.8% (w / v) about 1.7% (w / v) 40, polysorbate 60,polysorbate 80, or acombination thereofpreservative selected from from about 0.01 from about 0.03 from about 0.05 potassium sorbate, benzyl to about 0.6 % to about 0.4 % to about 0.3% alcohol, sodium benzoate, or (w / v) (w / v) (w / v) a combination thereofantioxidant selected from from about 0.1 to from about 0.2 to from about 0.3 to EDTA, BHT, disodium about 0.8% (w / v) about 0.7% (w / v) about 0.6% (w / v) EDTA, tocopherol acetate,TPGS (with linker of 1000and 2000), ascorbic acid,sodium metabisulphite, or acombination thereof

[0079] In certain embodiments of the stabilized aqueous compositions of the disclosure the vitamin K2 is vitamin K2-7, also known as menaquinone-7 (MK-7). Accordingly in certain embodiments of any of the compositions described above, MK-7 is used as the vitamin K2.

[0080] The disclosure also includes bottles containing the stabilized aqueous compositions. In certain embodiments, the bottles include a label with instructions for consuming (e.g., daily dose) of the stabilized aqueous compositions. In certain164873-6574-5118.2070589.12881 / 0203W01OPL24002-WO-PCTembodiments, the bottle includes dosing cup and / or pipette. In some embodiments, the bottle has a cap, and the dosing cup is integrated into the cap. In other embodiments, the disclosure includes glass ampoules containing the stabilized aqueous compositions.Uses of the stabilized aqueous compositions

[0081] Another aspect of the disclosure is directed to using the stabilized aqueous compositions containing calcium (in the form of calcium lactate and calcium gluconate), vitamin D3, and vitamin K2 to support bone health.

[0082] One embodiment of the disclosure is directed to a method of supporting bone health by consuming a stabilized aqueous composition of the disclosure.

[0083] Another embodiment is directed to a stabilized aqueous composition of the disclosure of use in supporting bone health. Another embodiment is directed to a stabilized aqueous composition of the disclosure in the manufacture of a medicament to support bone health.Methods of generation the stabilized aqueous compositions

[0084] Another aspect of the disclosure is directed to methods of generating the stabilized aqueous compositions of the disclosure.

[0085] One embodiment of the disclosure is a method of manufacturing a stabilized aqueous composition containing calcium (in the form of calcium lactate and calcium gluconate), vitamin D3, and vitamin K2 the method includes dissolving calcium lactate and calcium gluconate in water, generating micelles containing vitamin D3, and vitamin K2, adding the micelles to dissolved calcium lactate and calcium gluconate and then adding the other components of the composition (e.g. an antioxidant, a sweetener, a preservative, a flavoring agent, and / or a pH adjuster).

[0086] In specific embodiments, the method involves adding an antioxidant, a sweetener, a preservative, a flavoring agent, and / or a pH adjuster as described above.

[0087] In another embodiment, the method involves an antioxidant. In a further embodiment, the method involves adding sucralose, sorbitol, a polysorbate (e.g., polysorbate 80 and polysorbate 20), flavoring (Orange), potassium sorbate, ascorbic acid, and a pH adjuster to a pH of about 4 (such as e.g., hypophosphorous acid).

[0088] In certain embodiments, the method involves dissolving calcium lactate and calcium gluconate in water and dispersing vitamin D3 and vitamin K2 in water. In certain174873-6574-5118.2070589.12881 / 0203W01OPL24002-WO-PCTembodiments, vitamin D3 and vitamin K2 are dispersed in water via an emulsification system to encapsulate the vitamin D3 and vitamin K2 in micelles.

[0089] In certain embodiments, the vitamin D3 and vitamin K2 are dispersed in water using a polyethylene glycol sorbitan monolaurate such as Tween 20 and Tween 80. In further embodiments, the vitamin D3 and vitamin K2 are dispersed in water using an emulsifier described below. In one embodiment, the vitamin D3 and vitamin K2 are dispersed in water using a polysorbate, such as e.g., polysorbate 20 and polysorbate 80.

[0090] In certain embodiments, the method includes generating stabilized composition that are formulated to contain about 200 mg, alternatively from about 180 to about 200 mg, alternatively from about 190 to about 210 mg of calcium, about 100 IU (2.5 mcg), alternatively from about 1.5 to about 3.5 mcg, alternatively from about 2.0 to about 3.0 mcf of vitamin D3, and about 20 mcg, alternatively from about 10 to about 30 mcg, alternatively from about 15 to about 25 mcg of vitamin K2 per dose.

[0091] In certain embodiments, the vitamin D3 is provided as 1.0MIU / G (oil). In other embodiments, the vitamin K2 is provided as menaquinone-7 (MK-7) in olive oil (4500 PPm).

[0092] In certain embodiments, the method includes filling the stabilized aqueous composition into a bottle, an ampoule (e.g., a glass ampoule), or container. The bottle can be closed with a cap. The method also includes packaging the bottles filled with the stabilized aqueous composition along with a dosing cup. When an ampoule is used, the method also includes method also includes packaging the ampoules.

[0093] Without further description, it is believed that one of ordinary skill in the art can, using the preceding description and the following illustrative examples, make and utilize the present invention and practice the claimed methods. The following working examples, therefore, specifically point out the preferred embodiments of the present invention and are not to be construed as limiting in any way the remainder of the disclosure.Examples

[0094] While the invention has been described and illustrated herein by references to various specific materials, procedures, and examples, it is understood that the invention is not restricted to the particular combinations of material and procedures selected for that purpose. Numerous variations of such details can be implied as will be appreciated by those skilled in the art. It is intended that the specification and examples be considered as exemplary, only, with the true scope and spirit of the invention being indicated by the184873-6574-5118.2070589.12881 / 0203W01OPL24002-WO-PCTfollowing claims. All references, patents, and patent applications referred to in this application are herein incorporated by reference in their entirety.Example 1 - Stability testing

[0095] An aqueous composition containing calcium (in the form of calcium lactate and calcium gluconate), vitamin D3, and vitamin K2 was subjected to stability testing under accelerated conditions (40 °C / 75% relative humidity) and long term conditions (long term: 30 °C / 75% relative humidity).

[0096] For the testing in this example, an aqueous composition having the features shown in Table 1-1 below was tested:Table 1-1: Formulation tested in stability studiesComponent Quantity of Nutrient Substance Mixture of calcium lactate & calcium gluconate 200 mg (Calcium) Vitamin D3 1.0MIU / G (oil) 100 IU (2.5mcg) (Vitamin D3) Vitamin K2 as MK-7 in olive oil (4500 ppm) 20 mcg (Vitamin K2) Sucralose - Sorbitol - Polysorbate 80 - Polysorbate 20 - Flavoring (Orange) - Potassium sorbate - Ascorbic acid - Hypophosphorous acid (to pH 4) - Purified water -

[0097] The results of the stability testing are shown in Table 1-2 below.194873-6574-5118.2070589.12881 / 0203W01OPL24002-WO-PCTTable 1-2: Results of Stability Testing under Accelerated (40 °C / 75% relative humidity) and Long Term (30 °C / 75% relative humidity) ConditionsNutrient Specification Initial 30°C / 75%RH 40°C / 75%RH 3 months 6 months 3 months 6 months Calcium 180.0 – 200.0 203.2 203.5 202.0 202.0 200.9 (mg / 10 ml)Vitamin D3 2.25 – 6.25 4.65 4.62 4.58 4.70 4.63 (mcg / 10 ml)Vitamin K2 18.0 – 50.0 36.3 43.2 40.7 41.6 39.4 (mcg / 10 ml)

[0098] The stability testing establishes that the composition was very stable after 6 months in both conditions (accelerated: 40 °C / 75% relative humidity & long term: 30 °C / 75% relative humidity).EMBODIMENTS

[0099] The invention provides also the following non-limiting embodiments.

[0100] Embodiment 1 is a stabilized aqueous composition comprising: an active ingredient comprising calcium provided as a mixture of calcium lactate and calcium gluconate, vitamin D3, and vitamin K2; an emulsifier; and an antioxidant.

[0101] Embodiment 2 is the stabilized aqueous composition of embodiment 1, wherein the emulsifier is a polysorbate.

[0102] Embodiment 3 is the stabilized aqueous composition of embodiment 2, wherein the polysorbate comprises polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, or a combination thereof.

[0103] Embodiment 4 is the stabilized aqueous composition of embodiment 3, wherein the polysorbate comprises polysorbate 20 and polysorbate 80.

[0104] Embodiment 5 is the stabilized aqueous composition of any one of embodiments 1 to 5, wherein the antioxidant comprises disodium ethylenediaminetetraacetic acid (EDTA), butylated hydroxytoluene (BHT), disodium EDTA, tocopherol acetate, tocopheryl polyethylene glycol succinate (TPGS) (with linker of 1000 and 2000), ascorbic acid, sodium metabisulphite, or a combination thereof.204873-6574-5118.2070589.12881 / 0203W01OPL24002-WO-PCT

[0105] Embodiment 6 is the stabilized aqueous composition of embodiment 5, wherein the antioxidant comprises ascorbic acid.

[0106] Embodiment 7 is the stabilized aqueous composition of any one of embodiments 1 to 6, wherein the composition has a pH of about 4.

[0107] Embodiment 8 is the stabilized aqueous composition of any one of embodiments 1 to 7, wherein the composition further comprises a sweetener, a preservative, a flavoring agent, a pH adjuster, or a combination thereof.

[0108] Embodiment 9 is the stabilized aqueous composition of embodiment 8, wherein the sweetener comprises sucralose, sorbitol, aspartame, acesulfame potassium, saccharin, steviol glycoside, neotame, advantame, saccharin sodium, cyclamate sodium, ammonium glycyrrhizate, or a combination thereof.

[0109] Embodiment 10 is the stabilized aqueous composition of embodiment 9, wherein the sweetener comprises sucralose and sorbitol.

[0110] Embodiment 11 is the stabilized aqueous composition of embodiment 9, wherein the preservative comprises a sorbate, a benzoate, a paraben, a benzyl alcohol, a cresol, a phenol, a quaternary ammonium, or a combination thereof.

[0111] Embodiment 12 is the stabilized aqueous composition of embodiment 11, wherein the preservative comprises potassium sorbate.

[0112] Embodiment 13 is the stabilized aqueous composition of any one of embodiments 1 to 12, wherein the composition is formulated to deliver 200 mg calcium, 2.5 mcg of vitamin D3, and 20 mcg of vitamin K2 per 10 ml.

[0113] Embodiment 14 is the stabilized aqueous composition of any one of embodiments 1 to 12, wherein the composition, wherein the composition comprises: an active ingredient comprising from about 10 to about 20% (w / v) of the calcium provided as a mixture of calcium lactate and calcium gluconate, from about 0.0001 to about 0.004 % (w / v) of the vitamin D3, and from about 0.01 to about 0.2 % (w / v) of the vitamin K2; from about 0.5 to about 2% (w / v) of the emulsifier; and from about 0.1 to about 0.8% (w / v) of the antioxidant.

[0114] Embodiment 15 is a stabilized aqueous composition comprising: calcium provided as a mixture of calcium lactate and calcium gluconate; vitamin D3; vitamin K2; a polysorbate selected from polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, or a combination thereof; an antioxidant selected from ascorbic acid, sodium metabisulphite, tocopherol, or a combination thereof, wherein the vitamin D3 and the vitamin K2 are encapsulated in micelles.214873-6574-5118.2070589.12881 / 0203W01OPL24002-WO-PCT

[0115] Embodiment 16 is the stabilized aqueous composition of embodiment 15, comprising: from about 10 to about 20% (w / v) of the calcium provided as a mixture of calcium lactate and calcium gluconate; from about 0.0001 to about 0.004 % (w / v) of the vitamin D3; from about 0.01 to about 0.2 % (w / v) of the vitamin K2; from about 0.5 to about 2% (w / v) of the polysorbate selected from polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, or a combination thereof; and from about 0.1 to about 0.8% (w / v) of the antioxidant selected from ascorbic acid, sodium metabisulphite, tocopherol, or a combination thereof.

[0116] Embodiment 17 is the stabilized aqueous composition of embodiments 15 or 16, wherein the polysorbate comprises polysorbate 20 and polysorbate 80.

[0117] Embodiment 18 is the stabilized aqueous composition of any one of embodiments 15 to 17, wherein the antioxidant comprises ascorbic acid.

[0118] Embodiment 19 is the stabilized aqueous composition of any one of embodiments 15 to 17, wherein the composition further comprises: a sweetener selected from sucralose, sorbitol, aspartame, saccharin, steviol glycoside, neotame, advantame, or a combination thereof; a preservative selected from potassium sorbate, benzyl alcohol, sodium benzoate, or a combination thereof; an antioxidant selected from disodium ethylenediaminetetraacetic acid (EDTA), butylated hydroxytoluene (BHT), disodium EDTA, tocopherol acetate, tocopheryl polyethylene glycol succinate (TPGS) (with linker of 1000 and 2000), ascorbic acid, sodium metabisulphite, or a combination; a pH adjuster; and / or a flavoring agent.

[0119] Embodiment 20 is the stabilized aqueous composition of embodiment 19, wherein the composition comprises: from about 10 to about 34% (w / v) of the sweetener selected from sucralose, sorbitol, aspartame, saccharin, steviol glycoside, neotame, advantame, or a combination thereof; from about 0.01 to about 0.06 % (w / v) of the preservative selected from potassium sorbate, benzyl alcohol, sodium benzoate, or a combination thereof; and / or from about 0.1 to about 0.8 % (w / v) of the antioxidant selected from disodium ethylenediaminetetraacetic acid (EDTA), butylated hydroxytoluene (BHT), disodium EDTA, tocopherol acetate, tocopheryl polyethylene glycol succinate (TPGS) (with linker of 1000 and 2000), ascorbic acid, sodium metabisulphite, or a combination thereof.

[0120] Embodiment 21 is the stabilized aqueous composition of embodiments 19 or 20, wherein the composition comprises sucralose, sorbitol, potassium sorbate, ascorbic acid, a pH adjuster, and a flavoring agent.

[0121] Embodiment 22 is the stabilized aqueous composition of any one of embodiments 19 to 21, wherein the pH adjuster maintains a pH at about 4.0.224873-6574-5118.2070589.12881 / 0203W01OPL24002-WO-PCT

[0122] Embodiment 23 is the stabilized aqueous composition of embodiment 22, wherein the pH adjuster comprises hypophosphorous acid.

[0123] Embodiment 24 is the stabilized aqueous composition of any one of embodiments 1 to 23, wherein composition is stable for at least 6 months when stored at 40 °C / 75% relative humidity and / or 30 °C / 75% relative humidity.

[0124] Embodiment 25 is the stabilized aqueous composition of any one of embodiments 1 to 24 for use in supporting bone.

[0125] Embodiment 26 is the stabilized aqueous composition of any one of embodiments 1 to 24 for use in the manufacture of a medicament for supporting bone.

[0126] Embodiment 27 is a method of supporting bone health comprising orally administering the stabilized aqueous composition of any one of embodiments 1 to 24.

[0127] Embodiment 28 is a glass ampoule comprising the stabilized aqueous composition of any one of embodiments 1 to 24.

[0128] Embodiment 29 is a kit comprising the glass ampoule of embodiment 28 and instructions for use.

[0129] Embodiment 30 is the stabilized aqueous composition of any one of embodiments 1 to 24, wherein the vitamin K2 is menaquinone-7.234873-6574-5118.2

Claims

070589.12881 / 0203W01OPL24002-WO-PCTCLAIMSWhat is claimed is:

1. A stabilized aqueous composition comprising:an active ingredient comprising calcium provided as a mixture of calcium lactate and calcium gluconate, vitamin D3, and vitamin K2;an emulsifier; andan antioxidant.

2. The stabilized aqueous composition of claim 1, wherein the emulsifier is a polysorbate.

3. The stabilized aqueous composition of claim 2, wherein the polysorbate comprises polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, or a combination thereof.

4. The stabilized aqueous composition of claim 3, wherein the polysorbate comprises polysorbate 20 and polysorbate 80.

5. The stabilized aqueous composition of any one of claims 1 to 5, wherein the antioxidant comprises disodium ethylenediaminetetraacetic acid (EDTA), butylated hydroxytoluene (BHT), disodium EDTA, tocopherol acetate, tocopheryl polyethylene glycol succinate (TPGS) (with linker of 1000 and 2000), ascorbic acid, sodium metabisulphite, or a combination thereof.

6. The stabilized aqueous composition of claim 5, wherein the antioxidant comprises ascorbic acid.

7. The stabilized aqueous composition of any one of claims 1 to 6, wherein the composition has a pH of about 4.

8. The stabilized aqueous composition of any one of claims 1 to 7, wherein the composition further comprises a sweetener, a preservative, a flavoring agent, a pH adjuster, or a combination thereof.

9. The stabilized aqueous composition of claim 8, wherein the sweetener comprises sucralose, sorbitol, aspartame, acesulfame potassium, saccharin, steviol glycoside, neotame,244873-6574-5118.2070589.12881 / 0203W01OPL24002-WO-PCTadvantame, saccharin sodium, cyclamate sodium, ammonium glycyrrhizate, or a combination thereof.

10. The stabilized aqueous composition of claim 9, wherein the sweetener comprises sucralose and sorbitol.

11. The stabilized aqueous composition of claim 9, wherein the preservative comprises a sorbate, a benzoate, a paraben, a benzyl alcohol, a cresol, a phenol, a quaternary ammonium, or a combination thereof.

12. The stabilized aqueous composition of claim 11, wherein the preservative comprises potassium sorbate.

13. The stabilized aqueous composition of any one of claims 1 to 12, wherein the composition is formulated to deliver 200 mg calcium, 2.5 mcg of vitamin D3, and 20 mcg of vitamin K2 per 10 ml.

14. The stabilized aqueous composition of any one of claims 1 to 12, wherein the composition, wherein the composition comprises:an active ingredient comprising from about 10 to about 20% (w / v) of the calcium provided as a mixture of calcium lactate and calcium gluconate, from about 0.0001 to about 0.004 % (w / v) of the vitamin D3, and from about 0.01 to about 0.2 % (w / v) of the vitamin K2;from about 0.5 to about 2% (w / v) of the emulsifier; andfrom about 0.1 to about 0.8% (w / v) of the antioxidant.

15. A stabilized aqueous composition comprising:calcium provided as a mixture of calcium lactate and calcium gluconate; vitamin D3;vitamin K2;a polysorbate selected from polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, or a combination thereof; andan antioxidant selected from ascorbic acid, sodium metabisulphite, tocopherol, or a combination thereof,254873-6574-5118.2070589.12881 / 0203W01OPL24002-WO-PCTwherein the vitamin D3 and the vitamin K2 are encapsulated in micelles.

16. The stabilized aqueous composition of claim 15, comprising:from about 10 to about 20% (w / v) of the calcium provided as a mixture of calcium lactate and calcium gluconate;from about 0.0001 to about 0.004 % (w / v) of the vitamin D3;from about 0.01 to about 0.2 % (w / v) of the vitamin K2;from about 0.5 to about 2% (w / v) of the polysorbate selected from polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, or a combination thereof; andfrom about 0.1 to about 0.8% (w / v) of the antioxidant selected from ascorbic acid, sodium metabisulphite, tocopherol, or a combination thereof.

17. The stabilized aqueous composition of claims 15 or 16, wherein the polysorbate comprises polysorbate 20 and polysorbate 80.

18. The stabilized aqueous composition of any one of claims 15 to 17, wherein the antioxidant comprises ascorbic acid.

19. The stabilized aqueous composition of any one of claims 15 to 17, wherein the composition further comprises:a sweetener selected from sucralose, sorbitol, aspartame, saccharin, steviol glycoside, neotame, advantame, or a combination thereof;a preservative selected from potassium sorbate, benzyl alcohol, sodium benzoate, or a combination thereof;an antioxidant selected from disodium ethylenediaminetetraacetic acid (EDTA), butylated hydroxytoluene (BHT), disodium EDTA, tocopherol acetate, tocopheryl polyethylene glycol succinate (TPGS) (with linker of 1000 and 2000), ascorbic acid, sodium metabisulphite, or a combination;a pH adjuster; and / ora flavoring agent.

20. The stabilized aqueous composition of claim 19, wherein the composition comprises:264873-6574-5118.2070589.12881 / 0203W01OPL24002-WO-PCTfrom about 10 to about 34% (w / v) of the sweetener selected from sucralose, sorbitol, aspartame, saccharin, steviol glycoside, neotame, advantame, or a combination thereof; from about 0.01 to about 0.06 % (w / v) of the preservative selected from potassium sorbate, benzyl alcohol, sodium benzoate, or a combination thereof; and / orfrom about 0.1 to about 0.8 % (w / v) of the antioxidant selected from disodium ethylenediaminetetraacetic acid (EDTA), butylated hydroxytoluene (BHT), disodium EDTA, tocopherol acetate, tocopheryl polyethylene glycol succinate (TPGS) (with linker of 1000 and 2000), ascorbic acid, sodium metabisulphite, or a combination thereof.

21. The stabilized aqueous composition of claims 19 or 20, wherein the composition comprises sucralose, sorbitol, potassium sorbate, ascorbic acid, a pH adjuster, and a flavoring agent.

22. The stabilized aqueous composition of any one of claims 19 to 21, wherein the pH adjuster maintains a pH at about 4.0.

23. The stabilized aqueous composition of claim 22, wherein the pH adjuster comprises hypophosphorous acid.

24. The stabilized aqueous composition of any one of claims 1 to 23, wherein composition is stable for at least 6 months when stored at 40 °C / 75% relative humidity and / or 30 °C / 75% relative humidity.

25. The stabilized aqueous composition of any one of claims 1 to 24 for use in supporting bone health.

26. The stabilized aqueous composition of any one of claims 1 to 24 for use in the manufacture of a medicament for supporting bone health.

27. A method of supporting bone health comprising orally administering the stabilized aqueous composition of any one of claims 1 to 24.

28. A glass ampoule comprising the stabilized aqueous composition of any one of claims 1 to 24.

29. A kit comprising the glass ampoule of claim 27 and instructions for use.274873-6574-5118.2

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